WO2011133151A1 - Compositions comprenant des promédicaments opiacés modifiés phénol clivables par enzyme et leurs inhibiteurs - Google Patents

Compositions comprenant des promédicaments opiacés modifiés phénol clivables par enzyme et leurs inhibiteurs Download PDF

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Publication number
WO2011133151A1
WO2011133151A1 PCT/US2010/031955 US2010031955W WO2011133151A1 WO 2011133151 A1 WO2011133151 A1 WO 2011133151A1 US 2010031955 W US2010031955 W US 2010031955W WO 2011133151 A1 WO2011133151 A1 WO 2011133151A1
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Prior art keywords
substituted
alkyl
phenol
prodrug
compound
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PCT/US2010/031955
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English (en)
Inventor
Thomas E. Jenkins
Craig O. Husfeld
Julie D. Seroogy
Jonathan W. Wray
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Pharmacofore, Inc.
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Priority to PCT/US2010/031955 priority Critical patent/WO2011133151A1/fr
Publication of WO2011133151A1 publication Critical patent/WO2011133151A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/66—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
    • A61K47/67—Enzyme prodrug therapy, e.g. gene directed enzyme drug therapy [GDEPT] or VDEPT
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • Phenolic opioids are susceptible to misuse, abuse, or overdose. Use of and access to these drugs therefore needs to be controlled. The control of access to the drugs is expensive to administer and can result in denial of treatment for patients that are not able to present themselves for dosing. For example, patients suffering from acute pain may be denied treatment with an opioid unless they have been admitted to a hospital. Furthermore, control of use is often ineffective, leading to substantial morbidity and deleterious social consequences.
  • compositions and their methods of use, 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 prodrug so as to attenuate enzymatic cleavage of the prodrug.
  • the embodiments include pharmaceutical compositions, which comprise a trypsin- cleavable phenol-modified opioid prodrug and a trypsin inhibitor.
  • a "trypsin-cleavable phenol- modified opioid prodrug” is a phenol-modified opioid prodrug that comprises a promoiety comprising a trypsin-cleavable moiety.
  • a trypsin-cleavable moiety has a site that is susceptible to cleavage by trypsin.
  • compositions comprising a phenol-modified opioid prodrug, 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 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.
  • cleavage can initiate, contribute to or effect phenolic opioid release.
  • the embodiments include dose units comprising compositions comprising a phenol- modified opioid prodrug and a trypsin inhibitor, where 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.
  • 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.
  • the PK parameter value is selected from a phenolic opioid Cmax value, a phenolic opioid exposure value, and a (1/ phenolic opioid Tmax) value.
  • the dose unit provides for a pre-selected PK profile following ingestion of at least two dose units.
  • the pre-selected PK profile of such dose units is modified relative to the PK profile following ingestion of an equivalent dosage of phenol-modified opioid prodrug without inhibitor.
  • such a dose unit provides that ingestion of an increasing number of the dose units provides for a linear PK profile.
  • such a dose unit provides that ingestion of an increasing number of the dose units provides for a nonlinear PK profile.
  • the PK parameter value of the PK profile of such a dose units is selected from a phenolic opioid Cmax value, a (1/ phenolic opioid Tmax) value, and a phenolic opioid exposure value.
  • compositions comprising a container suitable for containing a composition for administration to a patient; and a dose unit as described herein disposed within the container.
  • the embodiments include dose units of a phenol-modified opioid prodrug and a trypsin inhibitor wherein the dose unit has a total weight of from 1 microgram to 2 grams.
  • the embodiments include pharmaceutical compositions of a phenol-modified opioid prodrug and a trypsin inhibitor wherein the combined weight of phenol-modified opioid prodrug and trypsin inhibitor is from 0.1% to 99% per gram of the composition.
  • compositions and dose units wherein the phenol-modified opioid prodrug is a compound of formula PC-(I)
  • 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(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
  • R 1 represents a (l-4C)alkyl group;
  • R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
  • n 2 or 3;
  • 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.
  • compositions and dose units wherein the phenol-modified opioid prodrug is a compound of formula PC-(IIa):
  • 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(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
  • R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • 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 an integer from 2 to 4.
  • 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.
  • the embodiments include compositions and dose units wherein the phenol-modified opioid prodrug is a compound of formula PC-(IIb):
  • 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(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
  • R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • n represents an integer from 2 to 4;
  • 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.
  • compositions and dose units wherein the phenol-modified opioid prodrug is a compound of formula PC-(III):
  • 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(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
  • R 1 represents a (l-4C)alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; n represents 2 or 3;
  • 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.
  • compositions and dose units wherein the phenol-modified opioid prodrug is a compound of formula PC-(IV):
  • R a is hydrogen or hydroxyl
  • the dashed line is a double bond or single bond
  • R 1 represents a (l-4C)alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
  • n 2 or 3;
  • 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.
  • compositions and dose units wherein the phenol-modified opioid prodrug is a compound of formula PC-(Va):
  • R a is hydrogen 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 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • 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 an integer from 2 to 4.
  • 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.
  • compositions and dose units wherein the phenol-modified opioid prodrug is a compound of formula PC-(Vb):
  • R a is hydrogen 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 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • n represents an integer from 2 to 4;
  • 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.
  • compositions and dose units wherein the phenol-modified opioid prodrug is a compound of formula PC-(VI):
  • R a is hydrogen or hydroxyl
  • the dashed line is a double bond or single bond
  • R 1 represents a (l-4C)alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
  • n 2 or 3;
  • 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.
  • compositions and dose units wherein the phenol-modified opioid prodrug is a compound of formula PC-(VII):
  • 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(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-R 6 ;
  • R 1 represents a (l-4C)alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
  • n 2 or 3;
  • R 6 is a trypsin-cleavable moiety.
  • compositions and dose units wherein the phenol-modified opioid prodrug is a compound of formula PC-(VIII): X-C(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-R 6 (PC-(VIII))
  • 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(0)-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 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • 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 an integer from 2 to 4.
  • R 6 is a trypsin-cleavable moiety.
  • compositions and dose units wherein the phenol-modified opioid prodrug is a compound of formula PC-(IX):
  • R a is hydrogen or hydroxyl
  • the dashed line is a double bond or single bond
  • R 1 represents a (l-4C)alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; n represents 2 or 3; and
  • R 6 is a trypsin-cleavable moiety.
  • compositions and dose units wherein the phenol-modified opioid prodrug is a compound of formula PC-(X):
  • R a is hydrogen 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 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • 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 an integer from 2 to 4.
  • R 6 is a trypsin-cleavable moiety.
  • the embodiments include methods for treating a patient comprising administering any of the compositions or dose units described herein to a patient in need thereof.
  • the embodiments include methods to reduce side effects of a therapy comprising administering any of the compositions or dose units described herein to a patient in need thereof.
  • the embodiments include methods of improving patient compliance with a therapy prescribed by a clinician comprising directing administration of any of the compositions or dose units described herein to a patient in need thereof.
  • Such embodiments can provide for improved patient compliance with a prescribed therapy as compared to patient compliance with a prescribed therapy using drug and/or using prodrug without inhibitor as compared to prodrug with inhibitor.
  • the embodiments include methods of reducing risk of unintended overdose of a phenolic opioid comprising directing administration of any of the pharmaceutical compositions or dose units described herein to a patient in need of treatment.
  • the embodiments include methods of making a dose unit comprising combining a phenol-modified opioid prodrug and a trypsin inhibitor in a dose unit, 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.
  • the embodiments include methods of deterring misuse or abuse of multiple dose units of a phenol-modified opioid prodrug comprising combining a phenol-modified opioid prodrug and a trypsin inhibitor in a dose unit, wherein the phenol-modified opioid prodrug and trypsin inhibitor are present in the dose unit in an amount effective to attenutate 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.
  • release of drug is decreased compared to release of drug by an equivalent dosage of prodrug in the absence of inhibitor.
  • One embodiment is a method for identifying a prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit. Such a method can be conducted as, for example, an in vitro assay, an in vivo assay, or an ex vivo assay.
  • the embodiments include methods for identifying a phenol-modified opioid prodrug and a trypsin inhibitor suitable for formulation in a dose unit comprising combining a phenol- modified opioid prodrug, a trypsin inhibitor, and trypsin in a reaction mixture, 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.
  • the embodiments include methods for identifying a phenol-modified opioid prodrug and a trypsin inhibitor suitable for formulation in a dose unit comprising administering to an animal a phenol-modified opioid prodrug and a trypsin inhibitor 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.
  • administering comprises administering to the animal increasing doses of inhibitor co-dosed with a selected fixed dose of phenol-modified opioid prodrug.
  • Detecting prodrug conversion can facilitate identification of a dose of inhibitor and a dose of phenol-modified opioid prodrug that provides for a pre-selected pharmacokinetic (PK) profile.
  • PK pharmacokinetic
  • Such methods can be conducted as, for example, an in vivo assay or an ex vivo assay.
  • the embodiments include methods for identifying a phenol-modified opioid prodrug and a trypsin inhibitor suitable for formulation in a dose unit comprising administering to an animal tissue a phenol-modified opioid prodrug and a trypsin inhibitor 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.
  • Figure 1 is a schematic representing the effect of increasing the level of a GI enzyme inhibitor ("inhibitor", X axis) on a PK parameter (e.g., drug Cmax) (Y axis) for a fixed dose of prodrug.
  • a GI enzyme inhibitor e.g., drug Cmax
  • Y axis e.g., drug Cmax
  • the effect of inhibitor upon a prodrug PK parameter can range from undetectable, to moderate, to complete inhibition (i.e., no detectable drug release).
  • Figure 2 provides schematics of drug concentration in plasma (Y axis) over time (X axis).
  • Panel A is a schematic of a pharmacokinetic (PK) profile following ingestion of prodrug with a GI enzyme inhibitor (dashed line) where the drug Cmax is modified relative to that of prodrug without inhibitor (solid line).
  • Panel B is a schematic of a PK profile following ingestion of prodrug with inhibitor (dashed line) where drug Cmax and drug Tmax are modified relative to that of prodrug without inhibitor (solid line).
  • Panel C is a schematic of a PK profile following ingestion of prodrug with inhibitor (dashed line) where drug Tmax is modified relative to that of prodrug without inhibitor (solid line).
  • Figure 3 provides schematics representing differential concentration-dose PK profiles that can result from the dosing of multiples of a dose unit (X axis) of the present disclosure.
  • Different PK profiles (as exemplified herein for a representative PK parameter, drug Cmax (Y axis)) can be provided by adjusting the relative amount of prodrug and GI enzyme inhibitor contained in a single dose unit or by using a different prodrug or inhibitor in the dose unit.
  • Figure 4 is a graph that compares mean blood concentrations over time of
  • HM hydromorphone
  • Figure 5 is a graph that compares mean plasma concentrations over time of
  • HM hydromorphone
  • Figure 6 is a graph that compares individual blood concentrations over time of hydromorphone (HM) following PO administration to rats of Compound PC-1 alone and Compound PC-1 with Bowman-Birk trypsin-chymotrypsin inhibitor (BBSI).
  • HM hydromorphone
  • BVSI Bowman-Birk trypsin-chymotrypsin inhibitor
  • Figure 7 is a graph that compares mean plasma concentrations over time of
  • hydromorphone (HM) release following PO administration of Compound PC-2 alone and Compound PC-2 with SBTI to rats.
  • Figure 8 is a graph that compares mean plasma concentrations over time of
  • hydromorphone (HM) release following PO administration of Compound PC-3 alone and Compound PC-3 with SBTI to rats.
  • Figure 9 is a graph that compares mean plasma concentrations over time of
  • Figures 10A and 10B are graphs that indicate the in vitro results of exposure of a certain combination of Compound PC-4 and trypsin, in the absence of any trypsin inhibitor or in the presence of SBTI, Compound 107, Compound 108, or Compound 109.
  • Figure 10A depicts the disappearance of Compound PC-4
  • Figure 10B depicts the appearance of hydromorphone, over time under these conditions.
  • Figure 11 is a graph that compares mean plasma concentrations over time of hydromorphone (HM) release following PO administration of Compound PC-3 alone and Compound PC-3 with Compound 101 to rats.
  • HM hydromorphone
  • Figure 12 is a graph that compares mean plasma concentrations over time of
  • hydromorphone (HM) release following PO administration of Compound PC-4 alone and Compound PC-4 with Compound 101 to rats.
  • Figure 13A and Figure 13B compare mean plasma concentrations over time of hydromorphone release following PO administration of increasing doses of prodrug Compound PC-5 to rats.
  • Figure 14 compares mean plasma concentrations over time of hydromorphone release following PO administration of prodrug Compound PC-5 with increasing amounts of co-dosed trypsin inhibitor Compound 109 to rats.
  • Figure 15A and Figure 15B compare mean plasma concentrations over time of hydromorphone release following PO administration of a single dose unit and of multiple dose units of a composition comprising prodrug Compound PC-5 and trypsin inhibitor Compound 109 to rats.
  • Figure 16 compares mean plasma concentrations over time of hydromorphone release following PO administration of increasing doses of prodrug Compound PC-6 to rats.
  • Figure 17 compares mean plasma concentrations over time of hydromorphone release following PO administration of prodrug Compound PC-6 with increasing amounts of co-dosed trypsin inhibitor Compound 109 to rats.
  • Figure 18 compares mean plasma concentrations over time of hydromorphone release following PO administration of a single dose unit and of multiple dose units of a composition comprising prodrug Compound PC-6 and trypsin inhibitor Compound 109 to rats.
  • alkyl by itself or as part of another substituent refers to a saturated branched or straight-chain monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of an alkane.
  • Typical alkyl groups include, but are not limited to, methyl; ethyl, propyls such as propan-l-yl or propan-2-yl; and butyls such as butan-l-yl, butan-2-yl, 2-methyl-propan-l-yl or 2-methyl-propan-2-yl.
  • an alkyl group comprises from 1 to 20 carbon atoms.
  • an alkyl group comprises from 1 to 10 carbon atoms.
  • an alkyl group comprises from 1 to 6 carbon atoms, such as from 1 to 4 carbon atoms.
  • Alkylene refers to a branched or unbranched saturated hydrocarbon chain, usually having from 1 to 40 carbon atoms, more usually 1 to 10 carbon atoms and even more usually 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH 2 -), ethylene
  • Alkenyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of an alkene.
  • the group may be in either the cis or trans conformation about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-l-en-l-yl; cycloprop-2-en-l-yl; butenyls such as but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, but-2-en-2-yl,
  • Alkynyl by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of an alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-l-yn-l-yl, prop-2-yn-l-yl, etc.; butynyls such as but-l-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl, etc. ; and the like.
  • Acyl by itself or as part of another substituent refers to a radical -C(0)R 30 , where R 30 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,
  • heteroarylalkyl as defined herein.
  • Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, piperonyl, and the like.
  • Substituted acyl refers to substituted versions of acyl and include, for example, but not limited to, succinyl and malonyl.
  • aminoacyl and “amide” refers to the group -C(0)NR 21 R 22 , wherein R 21 and
  • R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl,
  • heterocyclic and substituted heterocyclic and where R and R are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • Alkoxy by itself or as part of another substituent refers to a radical -OR where R represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.
  • Alkoxycarbonyl by itself or as part of another substituent refers to a radical -C(0)OR
  • R represents an alkyl or cycloalkyl group as defined herein.
  • Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
  • Aryl by itself or as part of another substituent refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of an aromatic ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,
  • Arylalkyl by itself or as part of another substituent refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with an aryl group.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2- naphthylethen-l-yl, naphthobenzyl, 2-naphthophenyleth-l-yl and the like.
  • an arylalkyl group is (C 7 -C 30 ) arylalkyl, e.g., the alkyl moiety of the arylalkyl group is (C 1 -C 10 ) and the aryl moiety is (C 6 -C 20 ).
  • an arylalkyl group is (C 7 -C 20 ) arylalkyl, e.g., the alkyl moiety of the arylalkyl group is (CrC 8 ) and the aryl moiety is (C 6 -C 12 ).
  • Cycloalkyl by itself or as part of another substituent refers to a saturated cyclic alkyl radical.
  • Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.
  • the cycloalkyl group is (C 3 -C 10 ) cycloalkyl.
  • the cycloalkyl group is (C 3 -C 7 ) cycloalkyl.
  • Cycloheteroalkyl or “heterocyclyl” by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom.
  • Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific level of saturation is intended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.
  • Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine and the like.
  • Heteroalkyl, Heteroalkanyl, Heteroalkenyl and Heteroalkynyl by themselves or as part of another substituent refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatomic groups.
  • Heteroaryl by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a heteroaromatic ring system.
  • Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine,
  • the heteroaryl group is from 5-20 membered heteroaryl. In other embodiments, the heteroaryl group is from 5-10 membered heteroaryl. In still other embodiments, heteroaryl groups are those derived from thiophene, pyrrole,
  • benzothiophene benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • Heteroarylalkyl by itself or as part of another substituent, refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylalkenyl and/or heterorylalkynyl is used.
  • the heteroarylalkyl group is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl moiety is a 5-20-membered heteroaryl.
  • the heteroarylalkyl group is 6-20 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a 5-12-membered heteroaryl.
  • Aromatic Ring System by itself or as part of another substituent, refers to an unsaturated cyclic or polycyclic ring system having a conjugated ⁇ electron system.
  • aromatic ring system fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc.
  • Typical aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.
  • Hetero aromatic Ring System by itself or as part of another substituent, refers to an aromatic ring system in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "heteroaromatic ring systems” are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, arsindole, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc.
  • Typical heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadia
  • Protecting group refers to a grouping of atoms that when attached to a reactive functional group in a molecule masks, reduces or prevents reactivity of the functional group. Examples of protecting groups can be found in Green et ah, "Protective Groups in Organic Chemistry,” (Wiley, 2 nd ed. 1991) and Harrison et ah, “Compendium of Synthetic Organic Methods,” Vols. 1-8 (John Wiley and Sons, 1971-1996).
  • Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ”), te/ -butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
  • Substituted refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituent(s).
  • R 60 , R 61 , R and R are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, or optionally R 60 and R 61 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring.
  • Dose unit refers to a combination of a GI enzyme-cleavable prodrug (e.g., trypsin-cleavable prodrug) and a GI enzyme inhibitor (e.g., a trypsin inhibitor).
  • a GI enzyme-cleavable prodrug e.g., trypsin-cleavable prodrug
  • a GI enzyme inhibitor e.g., a trypsin inhibitor
  • a “single dose unit” is a single unit of a combination of a GI enzyme-cleavable prodrug (e.g., trypsin- cleavable prodrug) and a GI enzyme inhibitor (e.g., trypsin inhibitor), where the single dose unit provide a therapeutically effective amount of drug (i.e., a sufficient amount of drug to effect a therapeutic effect, e.g., a dose within the respective drug's therapeutic window, or therapeutic range).
  • a therapeutically effective amount of drug i.e., a sufficient amount of drug to effect a therapeutic effect, e.g., a dose within the respective drug's therapeutic window, or therapeutic range.
  • PK profile refers to a profile of drug concentration in blood or plasma. Such a profile can be a relationship of drug concentration over time (i.e., a "concentration-time PK profile”) or a relationship of drug concentration versus number of doses ingested (i.e., a "concentration-dose PK profile”).
  • a PK profile is characterized by PK parameters.
  • PK parameter refers to a measure of drug concentration in blood or plasma, such as: 1) “drug Cmax”, the maximum concentration of drug achieved in blood or plasma; 2) “drug Tmax”, the time elapsed following ingestion to achieve Cmax; and 3) “drug exposure”, the total concentration of drug present in blood or plasma over a selected period of time, which can be measured using the area under the curve (AUC) of a time course of drug release over a selected period of time (t). Modification of one or more PK parameters provides for a modified PK profile.
  • PD profile refers to a profile of the efficacy of a drug in a patient
  • PD parameters include “drug Emax” (the maximum drug efficacy), “drug EC50” (the concentration of drug at 50% of the Emax) and side effects.
  • Gastrointestinal enzyme or "GI enzyme” refers to an enzyme located in the central nervous system
  • GI gastrointestinal
  • Trypsin is an example of a GI enzyme.
  • Gastrointestinal enzyme-cleavable moiety or “GI enzyme-cleavable moiety” refers to a group comprising a site susceptible to cleavage by a GI enzyme.
  • a "trypsin- cleavable moiety” refers to a group comprising a site susceptible to cleavage by trypsin.
  • Gastrointestinal enzyme inhibitor or "GI enzyme inhibitor” refers to any agent capable of inhibiting the action of a gastrointestinal enzyme on a substrate.
  • the term also encompasses salts of gastrointestinal enzyme inhibitors.
  • a "trypsin inhibitor” refers to any agent capable of inhibiting the action of trypsin on a substrate.
  • Opioid refers to a chemical substance that exerts its pharmacological action by interaction at an opioid receptor.
  • Phenolic opioid refers to a subset of the opioids that contain a phenol group. Examples of phenolic opioids are provided below.
  • “Pharmaceutical composition” refers to at least one compound and can further comprise a pharmaceutically acceptable carrier, with which the compound is administered to a patient.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound, which possesses the desired pharmacological activity of the compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g. a prodrug or a pharmaceutically-acceptable salt thereof, and one or more molecules of a solvent.
  • solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent.
  • Representative solvents include by way of example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle with, or in which a compound is administered.
  • Patient includes humans, and also other mammals, such as livestock, zoo animals and companion animals, such as a cat, dog or horse.
  • Preventing or “prevention” or “prophylaxis” refers to a reduction in risk of occurrence of a condition, such as pain.
  • Prodrug refers to a derivative of an active agent that requires a transformation within the body to release the active agent. In certain embodiments, the transformation is an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.
  • Promoiety refers to a form of protecting group that, when used to mask a functional group within an active agent, converts the active agent into a prodrug. Typically, the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.
  • Treating” or “treatment” of any condition refers, in certain embodiments, to ameliorating the condition (i.e., arresting or reducing the development of the condition). In certain embodiments “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the patient. In certain embodiments, “treating” or “treatment” refers to inhibiting the condition, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In certain embodiments, “treating” or “treatment” refers to delaying the onset of the condition.
  • “Therapeutically effective amount” means the amount of a compound (e.g., prodrug) that, when administered to a patient for preventing or treating a condition such as pain, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the condition and its severity and the age, weight, etc. , of the patient. Detailed Description
  • a entity or “an” entity refers to one or more of that entity.
  • a compound refers to one or more compounds.
  • the terms “a”, “an”, “one or more” and “at least one” can be used interchangeably.
  • the terms “comprising”, “including” and “having” can be used interchangeably.
  • chromatographic means such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography.
  • HPLC high performance liquid chromatography
  • Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. See, e.g., Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl, Springer- Verlag, New York, 1969.
  • any of the processes for preparation of the compounds of the present disclosure it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Fourth edition, Wiley, New York 2006.
  • the protecting groups can be removed at a convenient subsequent stage using methods known from the art.
  • the compounds described herein can contain one or more chiral centers and/or double bonds and therefore, can exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, all possible enantiomers and stereoisomers of the compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures are included in the description of the compounds herein. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
  • the compounds can also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
  • the compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include, but are not limited to, 2 H, 3 H, n C, 13 C, 14 C, 15 N, 18 0, 17 0, etc.
  • Compounds can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, compounds can be hydrated or solvated. Certain compounds can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure.
  • the present disclosure provides pharmaceutical compositions, and their methods of use, 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 prodrug so as to attenuate enzymatic cleavage of the prodrug.
  • the disclosure provides pharmaceutical compositions which comprise a trypsin inhibitor and a phenol-modified opioid prodrug that contains a trypsin-cleavable moiety that, when cleaved, facilitates release of phenolic opioid.
  • the embodiments include pharmaceutical compositions, which comprise a trypsin-cleavable phenol-modified opioid prodrug and a trypsin inhibitor.
  • pharmaceutical compositions which comprise a trypsin-cleavable phenol-modified opioid prodrug and a trypsin inhibitor. Examples of phenol-modified opioid prodrugs and trypsin inhibitors are described below.
  • opioid refers to a chemical substance that exerts its pharmacological action by interaction at an opioid receptor.
  • An opioid can be an isolated natural product, a synthetic compound or a semi- synthetic compound.
  • Phenolic opioid refers to a subset of the opioids that contain a phenol group.
  • a phenolic opioid is a compound with a pharmacophore that presents to the opioid receptor an aromatic hydroxyl group and an aliphatic amine group in an
  • phenolic opioids include, but are not limited to, buprenorphine,
  • dihydroetorphine diprenorphine, etorphine, hydromorphone, levorphanol, morphine (and metabolites thereof), nalmefene, naloxone, N-methylnaloxone, naltrexone, N-methylnaltrexone, oxymorphone, oripavine, ketobemidone, dezocine, pentazocine, phenazocine, butorphanol, nalbuphine, meptazinol, O-desmethyltramadol, tapentadol, and nalorphine.
  • the structures of the aforementioned phenolic opioids are shown below:
  • the phenolic opioid is oxymorp lone, hydromorphone, morphine, or tapentadol. In certain embodiments, the phenolic opioid is oxymorphone or hydromorphone. In certain embodiments, the phenolic opioid is tapentadol. Further phenolic opioids include, but are not limited to, dihydromorphine, N-methyldiprenorphine, N-methylnalmefene and methyldihydromorphine.
  • opioids bearing at least some of the functionalities described herein will be developed; such opioids are included as part of the scope of this disclosure.
  • the disclosure provides a phenol-modified opioid prodrug which provides enzymatically- controlled release of a phenolic opioid.
  • a promoiety is attached to the phenolic opioid via modification of the phenol moiety.
  • a phenol-modified opioid prodrug can also be referred to as a phenolic opioid prodrug.
  • the hydrogen atom of the phenolic hydroxyl group of the phenolic opioid is replaced by a covalent bond to a promoiety.
  • a trypsin-cleavable phenol-modified opioid prodrug is a phenol- modified opioid prodrug that comprises a promoiety comprising a trypsin-cleavable moiety.
  • a 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 drug. Cleavage can initiate, contribute to or effect drug release.
  • Phenol-modified opioid prodrugs with promoiety comprising cyclizable spacer leaving group and cleavable moiety
  • a phenol-modified opioid prodrug which provides enzymatically-controlled release of a phenolic opioid.
  • the disclosure provides for a phenol-modified opioid prodrug in which the promoiety comprises a cyclizable spacer leaving group and a cleavable moiety.
  • the phenol-modified opioid prodrug is a corresponding compound in which the phenolic hydrogen atom has been substituted with a spacer leaving group bearing a nitrogen nucleophile that is protected with an
  • the configuration of the spacer leaving group and nitrogen nucleophile being such that, upon enzymatic cleavage of the cleavable moiety, the nitrogen nucleophile is capable of forming a cyclic urea, liberating the compound from the spacer leaving group so as to provide a phenolic opioid.
  • the enzyme capable of cleaving the enzymatically-cleavable moiety may be a peptidase, also referred to as a protease - the promoiety comprising the enzymatically-cleavable moiety being linked to the nucleophilic nitrogen through an amide (e.g. a peptide: -NHC(O)-) bond.
  • the enzyme is a digestive enzyme of a protein.
  • the corresponding prodrug provides post administration-activated, controlled release of the phenolic opioid.
  • the prodrug requires enzymatic cleavage to initiate release of the phenolic opioid and thus the rate of release of the phenolic opioid depends upon both the rate of enzymatic cleavage and the rate of cyclization. Accordingly, the prodrug has reduced susceptibility to accidental overdosing or abuse, whether by deliberate overdosing,
  • the prodrug is configured so that it will not provide excessively high plasma levels of the active drug if it is administered inappropriately, and cannot readily be decomposed to afford the active drug other than by enzymatic cleavage followed by controlled cyclization.
  • the enzyme-cleavable moiety linked to the nitrogen nucleophile through an amide bond can be, for example, a residue of an amino acid or a peptide, or an (alpha) N-acyl derivative of an amino acid or peptide (for example an N-acyl derivative of a pharmaceutically acceptable carboxylic acid).
  • the peptide can contain, for example, up to about 100 amino acid residues.
  • Each amino acid can advantageously be a naturally occurring amino acid, such as an L-amino acid.
  • Naturally occurring amino acids are alanine, arginine, asparagine, aspartic acid, cysteine, glycine, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • examples of enzyme-cleavable moieties include residues of the L-amino acids listed hereinabove and N-acyl derivatives thereof, and peptides formed from at least two of the L-amino acids listed hereinabove, and the N-acyl derivatives thereof.
  • the cyclic group formed when the phenolic opioid is released is conveniently
  • cyclic urea is generally very stable and have low toxicity.
  • the embodiments include pharmaceutical compositions, which comprise a compound of general formula PC-(I):
  • R 1 represents a (l-4C)alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
  • n 2 or 3;
  • 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.
  • Examples of values for the phenolic opioid as provided in X are oxymorphone, hydromorphone, and morphine.
  • R 1 examples of values for R 1 are methyl and ethyl groups.
  • Examples of values for each of R 2 and R 3 are hydrogen atoms.
  • n 2
  • N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group;
  • amino acid for an amino acid: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine; and
  • a dipeptide a combination of any two amino acids selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
  • An amino acid can be a naturally occurring amino acid. It will be appreciated that naturally occurring amino acids usually have the L-configuration.
  • R 5 examples of particular values for R 5 are:
  • N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group; and
  • R 5 represents N-acetyl, N-glycinyl or N-acetylglycinyl, such as N- acetyl.
  • An example of the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N-acetylarginyl.
  • the compound of formula PC-(I) is hydromorphone 3-(N- methyl-N-(2-N'-acetylarginylamino)) ethylcarbamate, or a pharmaceutically acceptable salt thereof. This compound is described in Example 3 of WO 2007/140272.
  • compositions which comprises a compound of general formula PC-(IIa):
  • 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(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
  • R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • 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 an integer from 2 to 4.
  • 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.
  • compositions which comprises a compound of general formula PC-(IIb):
  • 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(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
  • R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • n represents an integer from 2 to 4;
  • 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.
  • Reference to formula PC-(II) is meant to include compounds of formula PC-(IIa) and PC-
  • examples of values for the phenolic opioid as provided in X are oxymorphone, hydromorphone, and morphine.
  • R 1 can be selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl. In certain instances, R 1 is (l-6C)alkyl. In other instances, R 1 is (l-4C)alkyl. In other instances, R 1 is methyl or ethyl. In other instances, R 1 is methyl. In some instances, R 1 is ethyl.
  • R 1 is substituted alkyl.
  • R 1 is an alkyl group substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide.
  • R 1 is -(CH 2 ) n -COOH, -(CH 2 ) n -COOCH 3 , or -(CH 2 ) n - COOCH 2 CH 3 , wherein n is a number from one to 10.
  • R 1 is -(CH 2 )5-COOH, -(CH 2 ) 5 -COOCH 3 , or -(CH 2 ) 5 -COOCH 2 CH 3 .
  • R 1 is arylalkyl or substituted arylalkyl. In certain instances, R 1 is arylalkyl. In certain instances, R 1 is substituted arylalkyl. In certain instances, R 1 is an arylalkyl group substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide. In certain instances, R 1 is -(CH 2 ) q (C 6 H 4 )-COOH, -(CH 2 ) q (C 6 H 4 )- COOCH 3 , or -(CH 2 ) q (C 6 H 4 )-COOCH 2 CH 3 , where q is an integer from one to 10. In certain instances, R 1 is -CH 2 (C 6 H 4 )-COOH, -CH 2 (C 6 H 4 )-COOCH 3 , or -CH 2 (C 6 H 4 )-COOCH 2 CH 3 .
  • R 1 is aryl. In certain instances, R 1 is substituted aryl. In certain instances, R 1 is an aryl group with ortho, meta or para-substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide. In certain instances, R 1 is -(C 6 H 4 )-COOH, -(C 6 H 4 )-COOCH 3 , or -(C 6 H 4 )-COOCH 2 CH 3 .
  • each R can be independently selected from hydrogen, alkyl,
  • R is hydrogen
  • R is hydrogen. In certain instances, R is alkyl. In certain instances, R is hydrogen. In certain instances, R is alkyl. In certain
  • R is acyl. In certain instances, R is aminoacyl.
  • each R can be independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl.
  • R is hydrogen or alkyl.
  • R 3 is hydrogen.
  • R 3 is alkyl.
  • R 3 is acyl.
  • R 3 is aminoacyl.
  • R 2 and R 3 are hydrogen. In certain instances, R 2 and R 3 on the same carbon are both alkyl. In certain instances, R 2 and R 3 on the same carbon are methyl. In certain instances, R 2 and R 3 on the same carbon are ethyl.
  • R 2 and R 2 which are vicinal are both alkyl and R 3 and R 3 which are vicinal are both hydrogen. In certain instances, R 2 and R 2 which are vicinal are both ethyl and R 3 and R 3 which are vicinal are both hydrogen. In certain instances, R 2 and R 2 which are vicinal are both methyl and R 3 and R 3 which are vicinal are both hydrogen.
  • R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is alkyl. In certain instances, R 2 and R 2 which are vicinal are both alkyl and R 3 and R 3 which are vicinal are both hydrogen and R 1 is alkyl. In certain instances, R 2 and R 2 which are vicinal are both ethyl and R 3 and R 3 which are vicinal are both hydrogen and R 1 is alkyl. In certain instances, R 2 and R 2 and
  • R 2 which are vicinal are both methyl and R 3 and R 3 which are vicinal are both hydrogen and R 1 is alkyl.
  • one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is substituted alkyl. In certain instances, one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is an alkyl group substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide.
  • one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is -(CH 2 ) q (C 6 H4)-COOH, -(CH 2 ) q (C 6 H4)-COOCH 3 , or -(CH 2 ) q (C 6 H 4 )-COOCH 2 CH 3 , where q is an integer from one to 10.
  • one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is carboxamide.
  • R 2 and R 3 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group.
  • R 2 and R 3 together with the carbon to which they are attached can form a cycloalkyl group.
  • R 2 and R 3 on the same carbon form a spirocycle.
  • R 2 and R 3 together with the carbon to which they are attached can form a substituted cycloalkyl group.
  • two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached can form a cycloalkyl group.
  • two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached can form a substituted cycloalkyl group.
  • R 2 and R 3 together with the carbon to which they are attached can form an 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, can form an aryl or substituted aryl group.
  • two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached form a phenyl ring.
  • two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached form a substituted phenyl ring.
  • two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached form a naphthyl ring.
  • one of R 2 and R 3 is aminoacyl.
  • one of R 2 and R 3 is aminoacyl comprising phenylenediamine.
  • R 2 and R 3 is ; wherein each R 10 is independently selected from hydrogen, alkyl, substituted alkyl, and acyl and R 11 is alkyl or substituted alkyl. In certain instances, at least one of R 10 is acyl. In certain instances, at least one of R 10 is alkyl or substituted alkyl. In certain instances, at least one of R 10 is hydrogen. In certain instances, both of R 10 are hydrogen.
  • one of is hydrogen, alkyl, substituted alkyl, or acyl.
  • R 10 is acyl.
  • R 10 is alkyl or substituted alkyl.
  • R 10 is hydrogen.
  • R 2 and R 3 is R 10 O ; wherein each R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl. In certain instances, one of R and R 3 is ; wherein R 10a is alkyl and each R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl.
  • R 2 and R 3 are . wherein R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl and b is a number from one to 5. In certain instances,
  • R 2 and R 3 are ; wherein R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl.
  • one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein each R 10a and R 10b is independently selected from hydrogen, alkyl, substituted alkyl, and acyl.
  • one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is an alkyl and R 10b is substituted alkyl.
  • one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is an alkyl and R 10b is alkyl substituted with a carboxylic acid or carboxyl ester.
  • one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is methyl and R 10b is alkyl substituted with a carboxylic acid or carboxyl ester.
  • R 2 or R 3 can modulate a rate of intramolecular cyclization.
  • R 2 or R 3 can speed up a rate of intramolecular cyclization, when compared to the corresponding molecule where R 2 and R 3 are both hydrogen.
  • R 2 or R 3 comprise an electron- withdrawing group or an electron-donating group.
  • R 2 or R 3 comprise an electron- withdrawing group.
  • R 2 or R 3 comprise an electron-donating group.
  • Atoms and groups capable of functioning as electron withdrawing substituents are well known in the field of organic chemistry. They include electronegative atoms and groups containing electronegative atoms. Such groups function to lower the basicity or protonation state of a nucleophilic nitrogen in the beta position via inductive withdrawal of electron density. Such groups can also be positioned on other positions along the alkylene chain.
  • halogen atoms for example, a fluorine atom
  • acyl groups for example an alkanoyl group, an aroyl group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group or an aminocarbonyl group (such as a carbamoyl, alkylaminocarbonyl, dialkylaminocarbonyl or arylaminocarbonyl group)
  • ether groups for example an alkoxy group
  • each of the electron withdrawing substituents can be selected independently from these.
  • -[C(R 2 )(R 3 )] n - is selected from -CH(CH 2 F)CH(CH 2 F)-;
  • R 20 , R 21 , R 22 and R 23 each independently represents hydrogen or (l-6C)alkyl, and R 24 and R 25 each independently represents (l-6C)alkyl.
  • n represents an integer from 2 to 4.
  • An example of a value for n is 2.
  • An example of a value for n is 3.
  • An example of a value for n is 4.
  • N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group;
  • amino acid can be a naturally occurring amino acid. It will be appreciated that naturally occurring amino acids usually have the L-configuration.
  • N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group; and
  • R 5 represents N-acetyl, glycinyl or N- acetylglycinyl, such as N-acetyl.
  • an example of the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N- acetylarginyl or N-acetyllysinyl.
  • R 5 represents substituted acyl.
  • R 5 can be malonyl or succinyl.
  • the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N-malonylarginyl, N-malonyllysinyl, N-succinylarginyl and N-succinyllysinyl.
  • compositions which comprises a compound of general formula PC-(III):
  • 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(0)-NR 1 -(C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )- NH(R 5 );
  • R 1 represents a (l-4C)alkyl group
  • R and R each independently represents a hydrogen atom or a (l-4C)alkyl group
  • n 2 or 3;
  • 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.
  • examples of values for the phenolic opioid as provided in X are oxymorphone, hydromorphone, and morphine.
  • N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group;
  • amino acid for an amino acid: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine; and
  • a dipeptide a combination of any two amino acids selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
  • amino acid can be a naturally occurring amino acid. It will be appreciated that naturally occurring amino acids usually have the L-configuration.
  • N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group; and
  • R 5 represents N-acetyl, glycinyl or N- acetylglycinyl, such as N-acetyl.
  • an example of the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N- acetylarginyl or N-acetyllysinyl.
  • R 5 represents substituted acyl.
  • R 5 can be malonyl or succinyl.
  • the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N-malonylarginyl, N-malonyllysinyl, N-succinylarginyl and N-succinyllysinyl.
  • compositions which comprises a compound of general formula PC-(IV):
  • R a is hydrogen or hydroxyl
  • the dashed line is a double bond or single bond
  • R 1 represents a (l-4C)alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
  • n 2 or 3;
  • 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.
  • R a is hydrogen.
  • R a is hydroxyl.
  • R b is hydroxyl.
  • PC-(rV) a certain example of the dashed line is a single bond.
  • examples of values for R 1 are methyl and ethyl groups.
  • N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group;
  • amino acid for an amino acid: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine; and
  • a dipeptide a combination of any two amino acids selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
  • amino acid can be a naturally occurring amino acid. It will be appreciated that naturally occurring amino acids usually have the L-configuration.
  • N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group; and
  • R 5 represents N-acetyl, glycinyl or N- acetylglycinyl, such as N-acetyl.
  • R 5 represents N-acetyl, glycinyl or N- acetylglycinyl, such as N-acetyl.
  • an example of the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N- acetylarginyl.
  • the embodiments provide a pharmaceutical composition, which comprises a compound of general formula PC-(Va):
  • R a is hydrogen 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 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • 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 an integer from 2 to 4.
  • the embodiments provide a pharmaceutical composition, which comprises a compound of general formula PC-(Vb):
  • R a is hydrogen 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 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • n represents an integer from 2 to 4;
  • Reference to formula PC-(V) is meant to include compounds of formula PC-(Va) and
  • R a is hydrogen.
  • R a is hydroxyl.
  • R b is hydroxyl.
  • a certain example of the dashed line is a double bond.
  • a certain example of the dashed line is a single bond.
  • R 1 can be selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl. In certain instances, R 1 is (l-6C)alkyl. In other instances, R 1 is (l-4C)alkyl. In other instances, R 1 is methyl or ethyl. In other instances, R 1 is methyl. In some instances, R 1 is ethyl.
  • R 1 is substituted alkyl.
  • R 1 is an alkyl group substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide.
  • R 1 is -(CH 2 ) n -COOH, -(CH 2 ) n -COOCH 3 , or -(CH 2 ) n - COOCH 2 CH 3 , wherein n is a number from one to 10.
  • R 1 is -(CH 2 )5-COOH, -(CH 2 ) 5 -COOCH 3 , or -(CH 2 ) 5 -COOCH 2 CH 3 .
  • R 1 is arylalkyl or substituted arylalkyl. In certain instances, R 1 is arylalkyl. In certain instances, R 1 is substituted arylalkyl. In certain instances, R 1 is an arylalkyl group substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide. In certain instances, R 1 is -(CH 2 ) q (C 6 H 4 )-COOH, -(CH 2 ) q (C 6 H 4 )- COOCH 3 , or -(CH 2 ) q (C 6 H 4 )-COOCH 2 CH 3 , where q is an integer from one to 10. In certain instances, R 1 is -CH 2 (C 6 H 4 )-COOH, -CH 2 (C 6 H 4 )-COOCH 3 , or -CH 2 (C 6 H 4 )-COOCH 2 CH 3 .
  • R 1 is aryl. In certain instances, R 1 is substituted aryl. In certain instances, R 1 is an aryl group ortho, meta or para-substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide. In certain instances, R 1 is -(C 6 H 4 )-COOH, -(C 6 H 4 )-COOCH 3 , or -(C 6 H 4 )-COOCH 2 CH 3 . 2
  • each R can be independently selected from hydrogen, alkyl,
  • R is hydrogen
  • R is hydrogen. In certain instances, R is alkyl. In certain instances, R is hydrogen. In certain instances, R is alkyl. In certain
  • R is acyl. In certain instances, R is aminoacyl.
  • each R can be independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl.
  • R is hydrogen or alkyl.
  • R 3 is hydrogen.
  • R 3 is alkyl.
  • R 3 is acyl.
  • R 3 is aminoacyl.
  • R 2 and R 3 are hydrogen. In certain instances, R 2 and R 3 on the same carbon are both alkyl. In certain instances, R 2 and R 3 on the same carbon are methyl. In certain instances, R 2 and R 3 on the same carbon are ethyl.
  • R 2 and R 2 which are vicinal are both alkyl and R 3 and R 3 which are vicinal are both hydrogen. In certain instances, R 2 and R 2 which are vicinal are both ethyl and R 3 and R 3 which are vicinal are both hydrogen. In certain instances, R 2 and R 2 which are vicinal are both methyl and R 3 and R 3 which are vicinal are both hydrogen.
  • R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is alkyl. In certain instances, R 2 and R 2 which are vicinal are both alkyl and R 3 and R 3 which are vicinal are both hydrogen and R 1 is alkyl. In certain instances, R 2 and R 2 which are vicinal are both ethyl and R 3 and R 3 which are vicinal are both hydrogen and R 1 is alkyl. In certain instances, R 2 and R 2 and
  • R 2 which are vicinal are both methyl and R 3 and R 3 which are vicinal are both hydrogen and R 1 is alkyl.
  • one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is substituted alkyl. In certain instances, one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is an alkyl group substituted with a carboxylic group such as a carboxylic acid, carboxylic ester or carboxylic amide.
  • one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is -(CH 2 ) q (C 6 H4)-COOH, -(CH 2 ) q (C 6 H4)-COOCH 3 , or -(CH 2 ) q (C 6 H 4 )-COOCH 2 CH 3 , where q is an integer from one to 10.
  • one of R 2 and R 3 is methyl, ethyl or other alkyl and R 1 is carboxamide.
  • R 2 and R 3 together with the carbon to which they are attached can 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, can form a cycloalkyl or substituted cycloalkyl group.
  • R 2 and R 3 together with the carbon to which they are attached can form a cycloalkyl group.
  • R 2 and R 3 on the same carbon form a spirocycle.
  • R 2 and R 3 together with the carbon to which they are attached can form a substituted cycloalkyl group.
  • two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached can form a cycloalkyl group.
  • two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached can form a substituted cycloalkyl group.
  • R 2 and R 3 together with the carbon to which they are attached can form an 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, can form an aryl or substituted aryl group.
  • two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached form a phenyl ring.
  • two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached form a substituted phenyl ring.
  • two R 2 or R 3 groups on adjacent carbon atoms, together with the carbon atoms to which they are attached form a naphthyl ring.
  • one of R 2 and R 3 is aminoacyl.
  • one of R 2 and R 3 is aminoacyl comprising phenylenediamine.
  • R 2 and R 3 is wherein each R 10 is independently selected from hydrogen, alkyl, substituted alkyl, and acyl and R 11 is alkyl or substituted alkyl. In certain instances, at least one of R 10 is acyl. In certain instances, at least one of R 10 is alkyl or substituted alkyl. In certain instances, at least one of R 10 is hydrogen. In certain instances, both of R 10 are hydrogen. In certain instances, one of R 2 and R 3 is ; wherein R 1U is hydrogen, alkyl, substituted alkyl, or acyl. In certain instances, R 10 is acyl. In certain instances, R 10 is alkyl or substituted alkyl. In certain instances, R 10 is hydrogen.
  • one of R 2 and R 3 is O ; wherein each R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl and b is a number from one to 5.
  • R 10 certain instances, one of R 2 and R 3 is R 10 O ; wherein each R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl. In certain instances, one of R 2" and R 3 J is ; wherein R 10a is alkyl and each R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl.
  • R 2 and R 3 are . wherein R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl and b is a number from one to 5. In certain instances,
  • R 2 and R 3 are R 10 O ; wherein R 10 is independently hydrogen, alkyl, substituted alkyl, or acyl.
  • one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein each R 10a and R 10b is independently selected from hydrogen, alkyl, substituted alkyl, and acyl.
  • one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is an alkyl and R 10b is substituted alkyl.
  • one of R 2 and R 3 is an aminoacyl group, such as -C(O)NR 10a R 10b , wherein R 10a is an alkyl and R 10b is alkyl substituted with a carboxylic acid or carboxyl ester.
  • one of R 2 and R 3 is an aminoacyl group, such as -C(0)NR R , wherein R lua is methyl and R lue is alkyl substituted with a carboxylic acid or carboxyl ester.
  • R 2 or R 3 can modulate a rate of intramolecular cyclization.
  • R 2 or R 3 can speed up a rate of intramolecular cyclization, when compared to the corresponding molecule where R 2 and R 3 are both hydrogen.
  • R 2 or R 3 comprise an electron- withdrawing group or an electron-donating group.
  • R 2 or R 3 comprise an electron-withdrawing group.
  • R 2 or R 3 comprise an electron-donating group.
  • Atoms and groups capable of functioning as electron withdrawing substituents are well known in the field of organic chemistry. They include electronegative atoms and groups containing electronegative atoms. Such groups function to lower the basicity or protonation state of a nucleophilic nitrogen in the beta position via inductive withdrawal of electron density. Such groups can also be positioned on other positions along the alkylene chain.
  • halogen atoms for example, a fluorine atom
  • acyl groups for example an alkanoyl group, an aroyl group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group or an aminocarbonyl group (such as a carbamoyl, alkylaminocarbonyl, dialkylaminocarbonyl or arylaminocarbonyl group)
  • ether groups for example an alkoxy group
  • each of the electron withdrawing substituents can be selected independently from these.
  • -[C(R 2 )(R 3 )] n - is selected from -CH(CH 2 F)CH(CH 2 F)-;
  • R 20 , R 21 , R 22 and R 23 each independently represents hydrogen or (l-6C)alkyl, and R 24 and R 25 each independently represents (l-6C)alkyl.
  • n represents an integer from 2 to 4.
  • An example of a value for n is 2.
  • N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group;
  • amino acid for an amino acid: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine; and
  • a dipeptide a combination of any two amino acids selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
  • amino acid can be a naturally occurring amino acid. It will be appreciated that naturally occurring amino acids usually have the L-configuration.
  • N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group; and
  • R 5 represents N-acetyl, glycinyl or N- acetylglycinyl, such as N-acetyl.
  • an example of the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N- acetylarginyl or N-acetyllysinyl.
  • R 5 represents substituted acyl.
  • R 5 can be malonyl or succinyl.
  • the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N-malonylarginyl, N-malonyllysinyl, N-succinylarginyl and N-succinyllysinyl.
  • compositions which comprises a compound of general formula PC-(VI):
  • R a is hydrogen or hydroxyl
  • the dashed line is a double bond or single bond
  • R 1 represents a (l-4C)alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
  • n 2 or 3;
  • 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.
  • a certain example of R a is hydrogen.
  • a certain example of R a is hydroxyl.
  • R b is hydroxyl.
  • a certain example of the dashed line is a double bond.
  • a certain example of the dashed line is a single bond.
  • examples of values for R 1 are methyl and ethyl groups.
  • N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N- benzoyl, or an N-piperonyl group;
  • amino acid for an amino acid: alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine; and
  • a dipeptide a combination of any two amino acids selected independently from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
  • amino acid can be a naturally occurring amino acid. It will be appreciated that naturally occurring amino acids usually have the L-configuration.
  • N-acyl group an N-(l-4C)alkanoyl group, such as acetyl, an N-aroyl group, such as N-benzoyl, or an N-piperonyl group; and
  • R 5 represents N-acetyl, glycinyl or N- acetylglycinyl, such as N-acetyl.
  • an example of the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N- acetylarginyl or N-acetyllysinyl.
  • R 5 represents substituted acyl.
  • R 5 can be malonyl or succinyl.
  • the group represented by -C(0)-CH(R 4 )-NH(R 5 ) is N-malonylarginyl, N-malonyllysinyl, N-succinylarginyl and N-succinyllysinyl.
  • Formula PC-(I) describes compounds of Formula PC-(II), in which R 1 is (l-4C)alkyl group; R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; and R 5 represents a hydrogen atom, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
  • Formula PC-(III) describes compounds of Formula PC-(II), in which R 1 is (l-4C)alkyl group; R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; 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.
  • Formula PC-(IV) describes compounds of Formula PC-(I), wherein "X" is replaced structurally with certain phenolic opioids.
  • Formula PC-(IV) describes compounds of Formula PC-(V), in which R 1 is (l-4C)alkyl group; R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; and R 5 represents a hydrogen atom, an N-acyl group, a residue of an amino acid, a dipeptide, or an N-acyl derivative of an amino acid or dipeptide.
  • Formula PC-(VI) describes compounds of Formula PC-(V), in which R 1 is (l-4C)alkyl group; R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; 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.
  • 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(0)-NR 1 - (C(R 2 )(R 3 )) n -NH-C(0)-CH(R 4 )-NH(R 5 ).
  • compositions which comprise a compound of general formula PC- (VII):
  • 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(0)-NR 1 -(C(R 2 )(R 3 )) n -NHR 6 ;
  • R 1 represents a (l-4C)alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group; n represents 2 or 3; and
  • R 6 is a trypsin-cleavable moiety.
  • the embodiments provide a pharmaceutical composition, which comprises a compound of general formula PC-(VIII):
  • 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(0)-NR 1 -(C(R 2 )(R 3 )) n -NHR 6 ;
  • R 1 is selected from alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, aryl and substituted aryl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • 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 an integer from 2 to 4.
  • R 6 is a trypsin-cleavable moiety.
  • compositions which comprises a compound of general formula PC-(IX):
  • R a is hydrogen or hydroxyl
  • the dashed line is a double bond or single bond
  • R 1 represents a (l-4C)alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or a (l-4C)alkyl group
  • n 2 or 3;
  • R 6 is a trypsin-cleavable moiety.
  • compositions which comprises a compound of general formula PC-(X):
  • R a is hydrogen 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 is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • each R is independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, acyl, and aminoacyl;
  • 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 an integer from 2 to 4.
  • R 6 is a trypsin-cleavable moiety.
  • R 6 is a trypsin-cleavable moiety.
  • a trypsin-cleavable moiety is a structural moiety that is capable of being cleaved by trypsin.
  • a trypsin-cleavable moiety comprises a charged moiety that can fit into an active site of trypsin and is able to orient the prodrug for cleavage at a scissile bond.
  • the charged moiety can be a basic moiety that exists as a charged moiety at physiological pH.
  • R 6 is -C(0)-CH(R 4 )-NH(R 5 ), wherein R 4 represents a side chain of an amino acid or a derivative of a side chain of an amino acid that effects R 6 to be a trypsin-cleavable moiety.
  • a derivative refers to a substance that has been altered from another substance by modification, partial substitution, homologation, truncation, or a change in oxidation state.
  • R 4 can include, but is not limited to, a side chain of lysine (such as L-lysine), arginine (such as L-arginine), homolysine, homoarginine, and ornithine.
  • Other values for R 6 include, but are not limited to, arginine mimics, arginine homologues, arginine truncates, arginine with varying oxidation states (for instance,
  • arginine and lysine mimics include arylguanidines, arylamidines (substituted benzamidines), benzylamines and (bicyclo[2.2.2]octan- l-yl)methanamine and derivatives thereof.
  • R 4 represents
  • R 5 is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl.
  • R 5 is an amino acid or an N-acyl derivative of an amino acid.
  • R 5 is a peptide or N-acyl derivative of such a peptide, where the peptide comprises one to 100 amino acids and where each amino acid can be selected independently. In certain instances, there are one to 50 amino acids in the peptide.
  • promoieties described herein may be prepared and attached to drugs containing phenols by procedures known to those of skill in the art (See e.g., Green et al, "Protective Groups in Organic Chemistry,” (Wiley, 2 nd ed. 1991); Harrison et al., "Compendium of
  • T is NH
  • Y is NR 1
  • W is NH
  • p is one
  • R 1 , R 4 , andR 5 are as previously defined
  • X is a phenolic opioid
  • P is a protecting group
  • M is a leaving group
  • compound PCl-1 may be acylated with an appropriate carboxylic acid or carboxylic acid equivalent to provide compound PCl-2 which then may be deprotected to yield compound PCl-3.
  • Compound PCl-3 is then reacted with an activated carbonic acid equivalent PCl-4 to provide compound PCl-5.
  • the enzyme capable of cleaving the enzymatically-cleavable moiety of a phenol- modified opioid prodrug can be a protease.
  • the enzyme is an enzyme located in the gastrointestinal (GI) tract, i.e., a gastrointestinal enzyme, or a GI enzyme.
  • the enzyme can be a digestive enzyme such as a gastric, intestinal, pancreatic or brush border enzyme or enzyme of GI microbial flora, such as those involved in peptide hydrolysis.
  • Examples include a pepsin, such as pepsin A or pepsin B; a trypsin; a chymotrypsin; a chymosin; an elastase; a carboxypeptidase, such as carboxypeptidase A or carboxypeptidase B; an aminopeptidase, such as aminopeptidase N or aminopeptidase A; an endopeptidase; an exopeptidase; a dipeptidylaminopeptidase such as dipeptidylaminopeptidase IV; a dipeptidase; a tripeptidase; or an enteropeptidase.
  • the enzyme is a cytoplasmic protease located on or in the GI brush border.
  • the enzyme is trypsin.
  • the corresponding composition is administered orally to the patient.
  • composition comprising a GI enzyme inhibitor.
  • a GI enzyme inhibitor can inhibit at least one of any of the GI enzymes disclosed herein.
  • An example of a GI enzyme inhibitor is a protease inhibitor, such as a trypsin inhibitor.
  • trypsin inhibitor refers to any agent capable of inhibiting the action of trypsin on a substrate.
  • trypsin inhibitor also encompasses salts of trypsin inhibitors.
  • the ability of an agent to inhibit trypsin can be measured using assays well known in the art. For example, in a typical assay, one unit corresponds to the amount of inhibitor that reduces the trypsin activity by one benzoyl-L-arginine ethyl ester unit (BAEE-U).
  • BAEE-U benzoyl-L-arginine ethyl ester unit
  • One BAEE-U is the amount of enzyme that increases the absorbance at 253 nm by 0.001 per minute at pH 7.6 and 25°C. See, for example, K. Ozawa, M. Laskowski, 1966, J.
  • a trypsin inhibitor can interact with an active site of trypsin, such as the SI pocket and the S3/4 pocket.
  • the SI pocket has an aspartate residue which has affinity for a positively charged moiety.
  • the S3/4 pocket is a hydrophobic pocket.
  • trypsin inhibitors There are many trypsin inhibitors known in the art, both those specific to trypsin and those that inhibit trypsin and other proteases such as chymotrypsin.
  • the disclosure provides for trypsin inhibitors that are proteins, peptides, and small molecules.
  • the disclosure provides for trypsin inhibitors that are irreversible inhibitors or reversible inhibitors.
  • the disclosure provides for trypsin inhibitors that are competitive inhibitors, non-competitive inhibitors, or uncompetitive inhibitors.
  • the disclosure provides for natural, synthetic or semi- synthetic trypsin inhibitors.
  • Trypsin inhibitors can be derived from a variety of animal or vegetable sources: for example, soybean, corn, lima and other beans, squash, sunflower, bovine and other animal pancreas and lung, chicken and turkey egg white, soy-based infant formula, and mammalian blood. Trypsin inhibitors can also be of microbial origin: for example, antipain; see, for example, H. Umezawa, 1976, Meth. Enzymol. 45, 678.
  • a trypsin inhibitor can also be an arginine or lysine mimic or other synthetic compound: for example arylguanidine, benzamidine, 3,4-dichloroisocoumarin, diisopropylfluorophosphate, gabexate mesylate,
  • trypsin inhibitors comprise a covalently modifiable group, such as a chloroketone moiety, an aldehyde moiety, or an epoxide moiety.
  • Other examples of trypsin inhibitors are aprotinin, camostat and pentamidine.
  • an arginine or lysine mimic is a compound that is capable of binding to the P 1 pocket of trypsin and/or interfering with trypsin active site function.
  • the arginine or lysine mimic can be a cleavable or non-cleavable moiety.
  • the trypsin inhibitor is derived from soybean. Trypsin inhibitors derived from soybean (Glycine max) are readily available and are considered to be safe for human consumption. They include, but are not limited to, SBTI, which inhibits trypsin, and Bowman-Birk inhibitor, which inhibits trypsin and chymotrypsin. Such trypsin inhibitors are available, for example from Sigma- Aldrich, St. Louis, MO, USA.
  • composition according to the embodiments may further comprise one or more other trypsin inhibitors.
  • a trypsin inhibitor can be an arginine or lysine mimic or other synthetic compound.
  • the trypsin inhibitor is an arginine mimic or a lysine mimic, wherein the arginine mimic or lysine mimic is a synthetic compound.
  • Certain trypsin inhibitors include compounds of formula:
  • Q 1 is selected from -O-Q 4 or -Q 4 -COOH, where Q 4 is C C 4 alkyl;
  • Q 2 is N or CH
  • Q is aryl or substituted aryl.
  • Certain trypsin inhibitors include compounds of formula: wherein:
  • Q 5 is -C(0)-COOH or -NH-Q 6 -Q 7 -S0 2 -C 6 H 5 , where Q 6 is -(CH 2 ) p -COOH;
  • Q 7 is -(CH 2 ) r -C 6 H 5 ;
  • n is a number from zero to two
  • o is zero or one
  • p is an integer from one to three;
  • r is an integer from one to three.
  • Certain trypsin inhibitors include compounds of formula:
  • Q 5 is -C(0)-COOH or -NH-Q 6 -Q 7 -S0 2 -C 6 H 5 , where
  • Q 6 is -(CH 2 ) p -COOH
  • Q 7 is -(CH 2 ) r -C 6 H 5 ;
  • p is an integer from one to three;
  • r is an integer from one to three.
  • Certain trypsin inhibitors include the following:
  • the trypsin inhibitor is SBTI, BBSI, Compound 101, Compound 106, Compound 108, Compound 109, or Compound 110. In certain embodiments, the trypsin inhibitor is camostat.
  • the trypsin inhibitor is a compound of formula T-I: (T-I)
  • A represents a group of the following formula:
  • R t9 and R tl0 each represents independently a hydrogen atom or a Ci_ 4 alkyl group
  • R t8 represents a group selected from the following formulae:
  • R tU , R tl2 and R tl3 each represents independently
  • R tl5 represents a single bond or a Ci_8 alkylene group
  • X represents an oxygen atom or an NH-group
  • R tl6 represents a hydrogen atom, a C 1-4 alkyl group, a phenyl group or a C 1-4 alkyl group substituted by a phenyl group, or
  • the structure represents a 4-7 membered monocyclic hetero-ring containing 1 to 2 nitrogen or oxygen atoms
  • R tl4 represents a hydrogen atom, a Ci_ 4 alkyl group substituted by a phenyl group or a tl7 tl7
  • R represents a hydrogen atom, a Ci_ 4 alkyl group or a Ci_ 4 alkyl group substituted by a phenyl group;
  • R tn , R tl2 and R tl3 do not represent simultaneously hydrogen atoms
  • the trypsin inhibitor is a compound selected from the following:
  • the trypsin inhibitor is a compound of formula T-II:
  • X is NH
  • n is zero or one
  • R £l is selected from hydrogen, halogen, nitro, alkyl, substituted alkyl, alkoxy, carboxyl, alkoxycarbonyl, acyl, aminoacyl, guanidine, amidino, carbamide, amino, substituted amino, hydroxyl, cyano and -(CH 2 ) m -C(0)-0-(CH 2 ) m -C(0)-N-R nl R n2 , wherein each m is independe zero to 2; and R nl and R n2 are independently selected from hydrogen and Ci_ 4 alkyl.
  • R u is guanidino or amidino.
  • R u is -(CH 2 ) m -C(0)-0-(CH 2 ) m -C(0)-N-R nl R n2 , wherein m is one and R nl and R n2 are methyl.
  • the trypsin inhibitor is a compound of formula T-III:
  • X is NH; n is zero or one;
  • L u is selected from -C(0)-0- ; -O-C(O)-; -0-(CH 2 ) m -0-;-OCH 2 -Ar t2 -CH 2 0-; -C(O)- NR t3 -; and - NR t3 -C(0)-;
  • R t3 is selected from hydrogen, Ci_ 6 alkyl, and substituted Ci_ 6 alkyl;
  • Ar tl and Ar t2 are independently a substituted or unsubstituted aryl group
  • n is a number from 1 to 3;
  • R t2 is selected from hydrogen, halogen, nitro, alkyl, substituted alkyl, alkoxy, carboxyl, alkoxycarbonyl, acyl, aminoacyl, guanidine, amidino, carbamide, amino, substituted amino, hydroxyl, cyano and -(CH 2 ) m -C(0)-0-(CH 2 ) m -C(0)-N-R nl R n2 , wherein each m is independently zero to 2; and R nl and R n2 are independently selected from hydrogen and C 1-4 alkyl.
  • R t2 is guanidino or amidino.
  • R t2 is -(CH 2 ) m -C(0)-0-(CH 2 ) m -C(0)-N-R nl R n2 , wherein m is one and R nl and R n2 are methyl.
  • the trypsin inhibitor is a compound of formula T-IV:
  • each X is NH
  • each n is independently zero or one
  • L u is selected from -C(0)-0- ; -O-C(O)-; -0-(CH 2 ) m -0-;-OCH 2 -Ar t2 -CH 2 0-; -C(O)- NR t3 -; and - NR t3 -C(0)-;
  • R t3 is selected from hydrogen, Ci- 6 alkyl, and substituted Ci- 6 alkyl;
  • Ar tl and Ar t2 are independently a substituted or unsubstituted aryl group
  • n is a number from 1 to 3.
  • Ar tl or Ar t2 is phenyl.
  • Ar tl or Ar t2 is naphthyl.
  • the trypsin inhibitor is Compound 109.
  • the trypsin inhibitor is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the trypsin inhibitor is Compound 110 or a bis-arylamidine variant thereof; see, for example, J.D. Geratz, M.C.-F. Cheng and R.R. Tidwell (1976) J Med. Chem. 19, 634-639.
  • the invention also includes inhibitors of other enzymes involved in protein assimilation that can be used in combination with a prodrug disclosed herein comprising an amino acid of alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine or amino acid variants thereof.
  • An amino acid variant refers to an amino acid that is modified from a naturally-occurring amino acid but still comprises activity similar to that of the naturally-occurring amino acid.
  • compositions which comprise a trypsin inhibitor and a phenol-modified opioid prodrug that comprises a promoiety comprising a trypsin-cleavable moiety that, when cleaved, facilitates release of phenolic opioid.
  • a phenol-modified opioid prodrug and a trypsin inhibitor are described below.
  • the embodiments provide a pharmaceutical composition, which comprises a trypsin inhibitor and a compound of general Formula PC-(I), or a pharmaceutically acceptable salt thereof.
  • the embodiments provide a pharmaceutical composition, which comprises a trypsin inhibitor and a compound of general Formulae PC-(II) to PC-(VI), or a pharmaceutically acceptable salt thereof.
  • the embodiments provide a pharmaceutical composition, which comprises a compound of Formulae T-I to T-IV and a compound of general Formulae PC-(I) to PC-(VI), or a pharmaceutically acceptable salt thereof.
  • the embodiments provide a pharmaceutical composition, which comprises Compound 109 and a compound of general Formulae PC-(I) to PC-(VI), or a pharmaceutically acceptable salt thereof.
  • the embodiments provide a pharmaceutical composition, which comprises a trypsin inhibitor and a compound disclosed herein other than a compound of general Formula PC-(I), or a pharmaceutically acceptable salt thereof.
  • the embodiments provide a pharmaceutical composition, which comprises a trypsin inhibitor and a compound disclosed herein other than a compound of general Formula PC-(II) to PC-(VI), or a pharmaceutically acceptable salt thereof.
  • Certain embodiments provide for a combination of a compound of Formula PC-(I) and a trypsin inhibitor, in which the phenolic opioid of Formula PC-(I) and the trypsin inhibitor are shown in the following table.
  • Certain embodiments provide for a combination of a compound of formula PC-(II) and trypsin inhibitor, in which the phenolic opioid of formula PC-(II) and the trypsin inhibitor are shown in the following table. Examples of Combinations of:
  • Certain embodiments provide for a combination of a compound of formula PC-(III) and trypsin inhibitor, in which the phenolic opioid of formula PC-(III) and the trypsin inhibitor are shown in the following table.
  • Certain embodiments provide for a combination of Compound PC-1 and a trypsin inhibitor, Compound PC-2 and a trypsin inhibitor, Compound PC-3 and a trypsin inhibitor, Compound PC-4 and trypsin inhibitor, Compound PC-5 and a trypsin inhibitor, and/or Compound PC-6 and a trypsin inhibitor, in which the trypsin inhibitor is shown in the following table.
  • Compound PC-1 is hydromorphone 3-(N-methyl-N-(2-N'-acetylarginylamino)) ethylcarbamate (which can be produced as described in PCT International Publication No. WO 2007/140272, published 6 December 2007, Example 3).
  • Compound PC-2, Compound PC-3, Compound PC-4, Compound PC-5, and Compound PC-6 are each described in the Examples. Examples of combinations of such compounds and a trypsin inhibitor are provided in the following table.
  • the embodiments provide a pharmaceutical composition, which comprises a trypsin inhibitor and a compound of general Formulae PC-(VII) to PC-(X), or a pharmaceutically acceptable salt thereof.
  • the embodiments provide a pharmaceutical composition, which comprises a compound of Formulae T-I to T-IV and a compound of general Formulae PC-(VII) to PC-(X), or a pharmaceutically acceptable salt thereof.
  • the embodiments provide a pharmaceutical composition, which comprises Compound 109 and a compound of general Formulae PC-(VII) to PC-(X), or a pharmaceutically acceptable salt thereof.
  • the embodiments provide a pharmaceutical composition, which comprises a trypsin inhibitor and a compound disclosed herein other than a compound of general Formulae PC-(I) to PC-(VI), or a pharmaceutically acceptable salt thereof.
  • Certain embodiments provide for a combination of a compound of Formula PC-(VII) and a trypsin inhibitor, in which the phenolic opioid of Formula PC-(VII) and the trypsin inhibitor are shown in the following table.
  • Certain embodiments provide for a combination of a compound of Formula PC-(VIII) and a trypsin inhibitor, in which the phenolic opioid of Formula PC-(VIII) and the trypsin inhibitor are shown in the following table.
  • the disclosure provides for a phenol-modified opioid prodrug and a further prodrug or drug included in a pharmaceutical composition.
  • a prodrug or drug would provide additional analgesia or other benefits.
  • examples include opioids, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) and other analgesics.
  • an opioid agonist prodrug or drug would be combined with an opioid antagonist prodrug or drug.
  • Other examples include drugs or prodrugs that have benefits other than, or in addition to, analgesia.
  • the embodiments provide a pharmaceutical composition, which comprises a trypsin inhibitor, a phenol-modified opioid prodrug, and acetaminophen, or a pharmaceutically acceptable salt thereof.
  • the phenol-modified opioid prodrug is a compound of general Formulae PC-(I) to PC-(X).
  • the trypsin inhibitor is selected from SBTI, BBSI, Compound 101, Compound 106, Compound 108, Compound 109, and Compound 110. In certain embodiments, the trypsin inhibitor is Compound 109. In certain embodiments, the trypsin inhibitor is camostat.
  • a pharmaceutical composition can comprise a phenol-modified opioid prodrug, a non-opioid drug and at least one opioid or opioid prodrug.
  • the pharmaceutical composition according to the embodiments can further comprise a pharmaceutically acceptable carrier.
  • the composition is conveniently formulated in a form suitable for oral (including buccal and sublingual) administration, for example as a tablet, capsule, thin film, powder, suspension, solution, syrup, dispersion or emulsion.
  • the composition can contain components conventional in pharmaceutical preparations, e.g. one or more carriers, binders, lubricants, excipients (e.g., to impart controlled release characteristics), pH modifiers, sweeteners, bulking agents, coloring agents or further active agents.
  • Patients can be humans, and also other mammals, such as livestock, zoo animals and companion animals, such as a cat, dog or horse.
  • the embodiments provide a pharmaceutical composition as described hereinabove for use in the treatment of pain.
  • the pharmaceutical composition according to the embodiments is useful, for example, in the treatment of a patient suffering from, or at risk of suffering from, pain.
  • the present disclosure provides methods of treating or preventing pain in a subject, the methods involving administering to the subject a disclosed composition.
  • the present disclosure provides for a disclosed composition for use in therapy or prevention or as a medicament.
  • the present disclosure also provides the use of a disclosed composition for the manufacture of a medicament, especially for the manufacture of a medicament for the treatment or prevention of pain.
  • compositions of the present disclosure can be used in the treatment or prevention of pain including, but not limited to include, acute pain, chronic pain, neuropathic pain, acute traumatic pain, arthritic pain, osteoarthritic pain, rheumatoid arthritic pain, muscular skeletal pain, post-dental surgical pain, dental pain, myofascial pain, cancer pain, visceral pain, diabetic pain, muscular pain, post-herpetic neuralgic pain, chronic pelvic pain, endometriosis pain, pelvic inflammatory pain and child birth related pain.
  • Acute pain includes, but is not limited to, acute traumatic pain or post-surgical pain.
  • Chronic pain includes, but is not limited to, neuropathic pain, arthritic pain, osteoarthritic pain, rheumatoid arthritic pain, muscular skeletal pain, dental pain, myofascial pain, cancer pain, diabetic pain, visceral pain, muscular pain, post-herpetic neuralgic pain, chronic pelvic pain, endometriosis pain, pelvic inflammatory pain and back pain.
  • the present disclosure provides use of a phenol-modified opioid prodrug and a trypsin inhibitor in the treatment of pain.
  • the present disclosure provides use of a phenol-modified opioid prodrug and a trypsin inhibitor in the prevention of pain.
  • the present disclosure provides use of a phenol-modified opioid prodrug and a trypsin inhibitor in the manufacture of a medicament for treatment of pain.
  • the present disclosure provides use of a phenol-modified opioid prodrug and a trypsin inhibitor in the manufacture of a medicament for prevention of pain.
  • the embodiments provide a method of treating pain in a patient requiring treatment, which comprises administering an effective amount of a pharmaceutical composition as described hereinabove. In another aspect, the embodiments provides method of preventing pain in a patient requiring treatment, which comprises administering an effective amount of a pharmaceutical composition as described hereinabove.
  • compositions disclosed herein to be administered to a patient to be effective will depend upon the bioavailability of the particular composition, the susceptibility of the particular composition to enzyme activation in the gut, the amount and potency of trypsin inhibitor present in the composition, as well as other factors, such as the species, age, weight, sex, and condition of the patient, manner of administration and judgment of the prescribing physician.
  • the composition dose can be such that the phenol-modified opioid prodrug is in the range of from 0.01 milligrams prodrug per kilogram to 20 milligrams prodrug per kilogram (mg/kg) body weight.
  • a composition comprising a residue of hydromorphone can be administered at a dose equivalent to administering free hydromorphone in the range of from 0.02 to 0.5 mg/kg body weight or 0.01 mg/kg to 10 mg/kg body weight or 0.01 to 2 mg/kg body weight.
  • the composition comprises a phenol- modified hydromorphone prodrug
  • the composition can be administered at a dose such that the level of hydromorphone achieved in the blood is in the range of from 0.5 ng/ml to 10 ng/ml.
  • the amount of a trypsin inhibitor to be administered to the patient to be effective will depend upon the effective dose of the particular prodrug and the potency of the particular inhibitor, as well as other factors, such as the species, age, weight, sex and condition of the patient, manner of administration and judgment of the prescribing physician.
  • the dose of inhibitor can be in the range of from 0.05 mg to 50 mg per mg of prodrug disclosed herein. In a certain embodiment, the dose of inhibitor can be in the range of from 0.001 mg to 50 mg per mg of prodrug disclosed herein. In one embodiment, the dose of inhibitor can be in the range of from 0.01 nanomoles to 100 micromoles per micromole of prodrug disclosed herein.
  • the present disclosure provides dose units of prodrug and inhibitor that can provide for a desired pharmacokinetic (PK) profile.
  • Dose units can provide a modified PK profile compared to a reference PK profile as disclosed herein. It will be appreciated that a modified PK profile can provide for a modified pharmacodynamic (PD) profile. Ingestion of multiples of such a dose unit can also provide a desired PK profile.
  • PK pharmacokinetic
  • dose unit refers to a combination of a GI enzyme-cleavable prodrug (e.g., trypsin-cleavable prodrug) and a GI enzyme inhibitor (e.g., a trypsin inhibitor).
  • a GI enzyme-cleavable prodrug e.g., trypsin-cleavable prodrug
  • a GI enzyme inhibitor e.g., a trypsin inhibitor
  • a “single dose unit” is a single unit of a combination of a GI enzyme- cleavable prodrug (e.g., trypsin-cleavable prodrug) and a GI enzyme inhibitor (e.g., trypsin inhibitor), where the single dose unit provide a therapeutically effective amount of drug (i.e., a sufficient amount of drug to effect a therapeutic effect, e.g., a dose within the respective drug's therapeutic window, or therapeutic range).
  • a therapeutically effective amount of drug i.e., a sufficient amount of drug to effect a therapeutic effect, e.g., a dose within the respective drug's therapeutic window, or therapeutic range.
  • PK profile refers to a profile of drug concentration in blood or plasma. Such a profile can be a relationship of drug concentration over time (i.e., a
  • concentration-time PK profile or a relationship of drug concentration versus number of doses ingested (i.e., a "concentration-dose PK profile”.)
  • a PK profile is characterized by PK parameters.
  • a "PK parameter” refers to a measure of drug concentration in blood or plasma, such as: 1) “drug Cmax”, the maximum concentration of drug achieved in blood or plasma; 2) “drug Tmax”, the time elapsed following ingestion to achieve Cmax; and 3) “drug exposure”, the total concentration of drug present in blood or plasma over a selected period of time, which can be measured using the area under the curve (AUC) of a time course of drug release over a selected period of time (t). Modification of one or more PK parameters provides for a modified PK profile.
  • PK parameter values that define a PK profile include drug Cmax (e.g., phenolic opioid Cmax), total drug exposure (e.g., area under the curve) (e.g., phenolic opioid exposure) and l/(drug Tmax) (such that a decreased 1/Tmax is indicative of a delay in Tmax relative to a reference Tmax) (e.g., 1/phenolic opioid Tmax).
  • drug Cmax e.g., phenolic opioid Cmax
  • total drug exposure e.g., area under the curve
  • drug Tmax l/(drug Tmax)
  • a decrease in a PK parameter value relative to a reference PK parameter value can indicate, for example, a decrease in drug Cmax, a decrease in drug exposure, and/or a delayed Tmax.
  • Dose units of the present disclosure can be adapted to provide for a modified PK profile, e.g., a PK profile that is different from that achieved from dosing a given dose of prodrug in the absence of inhibitor (i.e., without inhibitor).
  • dose units can provide for at least one of decreased drug Cmax, delayed drug Tmax and/or decreased drug exposure compared to ingestion of a dose of prodrug in the same amount but in the absence of inhibitor.
  • Such a modification is due to the inclusion of an inhibitor in the dose unit.
  • a pharmacodynamic (PD) profile refers to a profile of the efficacy of a drug in a patient (or subject or user), which is characterized by PD parameters.
  • PD parameters include “drug Emax” (the maximum drug efficacy), “drug EC50” (the concentration of drug at 50% of the Emax), and side effects.
  • Figure 1 is a schematic illustrating an example of the effect of increasing inhibitor concentrations upon the PK parameter drug Cmax for a fixed dose of prodrug. At low
  • inhibitor concentrations of inhibitor there may be no detectable effect on drug release, as illustrated by the plateau portion of the plot of drug Cmax (Y axis) versus inhibitor concentration (X axis).
  • concentration increases, a concentration is reached at which drug release from prodrug is attenuated, causing a decrease in, or suppression of, drug Cmax.
  • the effect of inhibitor upon a prodrug PK parameter for a dose unit of the present disclosure can range from
  • a dose unit can be adapted to provide for a desired PK profile (e.g., a concentration-time PK profile) following ingestion of a single dose.
  • a dose unit can be adapted to provide for a desired PK profile (e.g., a concentration-dose PK profile) following ingestion of multiple dose units (e.g., at least 2, at least 3, at least 4 or more dose units).
  • dose units providing modified PK profiles
  • a combination of a prodrug and an inhibitor in a dose unit can provide a desired (or "preselected") PK profile (e.g., a concentration-time PK profile) following ingestion of a single dose.
  • the PK profile of such a dose unit can be characterized by one or more of a pre-selected drug Cmax, a pre-selected drug Tmax or a pre-selected drug exposure.
  • the PK profile of the dose unit can be modified compared to a PK profile achieved from the equivalent dosage of prodrug in the absence of inhibitor (i.e., a dose that is the same as the dose unit except that it lacks inhibitor).
  • a modified PK profile can have a decreased PK parameter value relative to a reference PK parameter value (e.g., a PK parameter value of a PK profile following ingestion of a dosage of prodrug that is equivalent to a dose unit except without inhibitor).
  • a dose unit can provide for a decreased drug Cmax, decreased drug exposure, and/or delayed drug Tmax.
  • Figure 2 presents schematic graphs showing examples of modified concentration-time PK profiles of a single dose unit.
  • Panel A is a schematic of drug concentration in blood or plasma (Y axis) following a period of time (X axis) after ingestion of prodrug in the absence or presence of inhibitor.
  • the solid, top line in Panel A provides an example of drug concentration following ingestion of prodrug without inhibitor.
  • the dashed, lower line in Panel A represents drug concentration following ingestion of the same dose of prodrug with inhibitor.
  • Ingestion of inhibitor with prodrug provides for a decreased drug Cmax relative to the drug Cmax that results from ingestion of the same amount of prodrug in the absence of inhibitor.
  • Panel A also illustrates that the total drug exposure following ingestion of prodrug with inhibitor is also decreased relative to ingestion of the same amount of prodrug without inhibitor.
  • Panel B of Figure 2 provides another example of a dose unit having a modified concentration-time PK profile.
  • the solid top line represents drug concentration over time in blood or plasma following ingestion of prodrug without inhibitor, while the dashed lower line represents drug concentration following ingestion of the same amount of prodrug with inhibitor.
  • the dose unit provides a PK profile having a decreased drug Cmax, decreased drug exposure, and a delayed drug Tmax (i.e., decreased (1/drug Tmax) relative to ingestion of the same dose of prodrug without inhibitor.
  • Panel C of Figure 2 provides another example of a dose unit having a modified concentration-time PK profile.
  • the solid line represents drug concentration over time in blood or plasma following ingestion of prodrug without inhibitor, while the dashed line represents drug concentration following ingestion of the same amount of prodrug with inhibitor.
  • the dose unit provides a PK profile having a delayed drug Tmax (i.e., decreased (1/drug Tmax) relative to ingestion of the same dose of prodrug without inhibitor.
  • Dose units that provide for a modified PK profile find use in tailoring of drug dose according to a patient's needs (e.g., through selection of a particular dose unit and/or selection of a dosage regimen), reduction of side effects, and/or improvement in patient compliance (as compared to side effects or patient compliance associated with drug or with prodrug without inhibitor).
  • patient compliance refers to whether a patient follows the direction of a clinician (e.g., a physician) including ingestion of a dose that is neither significantly above nor significantly below that prescribed.
  • dose units also reduce the risk of misuse, abuse or overdose by a patient as compared to such risk(s) associated with drug or prodrug without inhibitor.
  • dose units with a decreased drug Cmax provide less reward for ingestion than does a dose of the same amount of drug, and/or the same amount of prodrug without inhibitor.
  • a dose unit of the present disclosure can be adapted to provide for a desired PK profile (e.g., a concentration-time PK profile or concentration-dose PK profile) following ingestion of multiples of a dose unit (e.g., at least 2, at least 3, at least 4, or more dose units).
  • a desired PK profile e.g., a concentration-time PK profile or concentration-dose PK profile
  • multiples of a dose unit e.g., at least 2, at least 3, at least 4, or more dose units.
  • concentration-dose PK profile refers to the relationship between a selected PK parameter and a number of single dose units ingested. Such a profile can be dose proportional, linear (a linear PK profile) or nonlinear (a nonlinear PK profile).
  • a modified concentration-dose PK profile can be provided by adjusting the relative amounts of prodrug and inhibitor contained in a single dose unit and/or by using a different prodrug and/or inhibitor.
  • Figure 3 provides schematics of examples of concentration-dose PK profiles (exemplified by drug Cmax, Y axis) that can be provided by ingestion of multiples of a dose unit (X axis) of the present disclosure.
  • Each profile can be compared to a concentration-dose PK profile provided by increasing doses of drug alone, where the amount of drug in the blood or plasma from one dose represents a therapeutically effective amount equivalent to the amount of drug released into the blood or plasma by one dose unit of the disclosure.
  • a "drug alone" PK profile is typically dose proportional, having a forty-five degree angle positive linear slope.
  • a concentration-dose PK profile resulting from ingestion of multiples of a dose unit of the disclosure can also be compared to other references, such as a concentration- dose PK profile provided by ingestion of an increasing number of doses of prodrug without inhibitor wherein the amount of drug released into the blood or plasma by a single dose of prodrug in the absence of inhibitor represents a therapeutically effective amount equivalent to the amount of drug released into the blood or plasma by one dose unit of the disclosure.
  • a dose unit can include inhibitor in an amount that does not detectably affect drug release following ingestion.
  • Ingestion of multiples of such a dose unit can provide a concentration-dose PK profile such that the relationship between number of dose units ingested and PK parameter value is linear with a positive slope, which is similar to, for example, a dose proportional PK profile of increasing amounts of prodrug alone.
  • Panel A of Figure 3 depicts such a profile.
  • Dose units that provide a concentration-dose PK profile having such an undetectable change in drug Cmax in vivo compared to the profile of prodrug alone can find use in thwarting enzyme conversion of prodrug from a dose unit that has sufficient inhibitor to reduce or prevent in vitro cleavage of the enzyme-cleavable prodrug by its respective enzyme.
  • Panel B in Figure 3 represents a concentration-dose PK profile such that the relationship between the number of dose units ingested and a PK parameter value is linear with positive slope, where the profile exhibits a reduced slope relative to panel A.
  • a dose unit provides a profile having a decreased PK parameter value (e.g., drug Cmax) relative to a reference PK parameter value exhibiting dose proportionality.
  • Concentration-dose PK profiles following ingestion of multiples of a dose unit can be non-linear.
  • Panel C in Figure 3 represents an example of a non-linear, biphasic concentration- dose PK profile.
  • the biphasic concentration-dose PK profile contains a first phase over which the concentration-dose PK profile has a positive rise, and then a second phase over which the relationship between number of dose units ingested and a PK parameter value (e.g., drug Cmax) is relatively flat (substantially linear with zero slope).
  • a PK parameter value e.g., drug Cmax
  • drug Cmax can be increased for a selected number of dose units (e.g., 2, 3, or 4 dose units).
  • Panel D in Figure 3 represents another example of a non-linear, biphasic concentration- dose PK profile.
  • the biphasic concentration-dose PK profile is characterized by a first phase over which the concentration-dose PK profile has a positive rise and a second phase over which the relationship between number of dose units ingested and a PK parameter value (e.g., drug Cmax) declines.
  • a PK parameter value e.g., drug Cmax
  • Dose units that provide this concentration-dose PK profile provide for an increase in drug Cmax for a selected number of ingested dose units (e.g., 2, 3, or 4 dose units).
  • ingestion of further additional dose units does not provide for a significant increase in drug Cmax and instead provides for decreased drug Cmax.
  • Panel E in Figure 3 represents a concentration-dose PK profile in which the relationship between the number of dose units ingested and a PK parameter (e.g., drug Cmax) is linear with zero slope.
  • a PK parameter e.g., drug Cmax
  • Such dose units do not provide for a significant increase or decrease in drug Cmax with ingestion of multiples of dose units.
  • Panel F in Figure 3 represents a concentration-dose PK profile in which the relationship between number of dose units ingested and a PK parameter value (e.g., drug Cmax) is linear with a negative slope.
  • drug Cmax decreases as the number of dose units ingested increases.
  • Dose units that provide for concentration-dose PK profiles when multiples of a dose unit are ingested find use in tailoring of a dosage regimen to provide a therapeutic level of released drug while reducing the risk of overdose, misuse, or abuse. Such reduction in risk can be compared to a reference, e.g., to administration of drug alone or prodrug alone. In one embodiment, risk is reduced compared to administration of a drug or prodrug that provides a proportional concentration-dose PK profile.
  • a dose unit that provides for a concentration-dose PK profile can reduce the risk of patient overdose through inadvertent ingestion of dose units above a prescribed dosage. Such a dose unit can reduce the risk of patient misuse (e.g., through self-medication).
  • Such a dose unit can discourage abuse through deliberate ingestion of multiple dose units.
  • a dose unit that provides for a biphasic concentration-dose PK profile can allow for an increase in drug release for a limited number of dose units ingested, after which an increase in drug release with ingestion of more dose units is not realized.
  • a dose unit that provides for a concentration-dose PK profile of zero slope can allow for retention of a similar drug release profile regardless of the number of dose units ingested.
  • Ingestion of multiples of a dose unit can provide for adjustment of a PK parameter value relative to that of ingestion of multiples of the same dose (either as drug alone or as a prodrug) in the absence of inhibitor such that, for example, ingestion of a selected number (e.g., 2, 3, 4 or more) of a single dose unit provides for a decrease in a PK parameter value compared to ingestion of the same number of doses in the absence of inhibitor.
  • a selected number e.g., 2, 3, 4 or more
  • compositions include those having an inhibitor to provide for protection of a therapeutic compound from degradation in the GI tract.
  • Inhibitor can be combined with a drug (i.e., not a prodrug) to provide for protection of the drug from degradation in the GI system.
  • the composition of inhibitor and drug provide for a modified PK profile by increasing a PK parameter.
  • Inhibitor can also be combined with a prodrug that is susceptible to degradation by a GI enzyme and has a site of action outside the GI tract.
  • the inhibitor protects ingested prodrug in the GI tract prior to its distribution outside the GI tract and cleavage at a desired site of action.
  • Dose units that provide for a desired PK profile can be made by combining a prodrug and an inhibitor in a dose unit in relative amounts effective to provide for release of drug that provides for a desired drug PK profile following ingestion by a patient.
  • Prodrugs can be selected as suitable for use in a dose unit by determining the GI enzyme- mediated drug release competency of the prodrug. This can be accomplished in vitro, in vivo or ex vivo.
  • In vitro assays can be conducted by combining a prodrug with a GI enzyme (e.g., trypsin) in a reaction mixture.
  • the GI enzyme can be provided in the reaction mixture in an amount sufficient to catalyze cleavage of the prodrug.
  • Assays are conducted under suitable conditions, and optionally may be under conditions that mimic those found in a GI tract of a subject, e.g., human.
  • Prodrug conversion refers to release of drug from prodrug. Prodrug conversion can be assessed by detecting a level of a product of prodrug conversion (e.g., released drug) and/or by detecting a level of prodrug that is maintained in the presence of the GI enzyme.
  • Prodrug conversion can also be assessed by detecting the rate at which a product of prodrug conversion occurs or the rate at which prodrug disappears. An increase in released drug, or a decrease in prodrug, indicate prodrug conversion has occurred.
  • Prodrugs that exhibit an acceptable level of prodrug conversion in the presence of the GI enzyme within an acceptable period of time are suitable for use in a dose unit in combination with an inhibitor of the GI enzyme that is shown to mediate prodrug conversion.
  • In vivo assays can assess the suitability of a prodrug for use in a dose unit by
  • prodrug conversion can be detected by, for example, detecting a product of prodrug conversion (e.g., released drug or a metabolite of released drug) or detecting prodrug in blood or plasma of the animal at a desired time point(s) following administration.
  • an animal e.g., a human or non-human animal, e.g., rat, dog, pig, etc.
  • Such administration can be enteral (e.g., oral administration).
  • Prodrug conversion can be detected by, for example, detecting a product of prodrug conversion (e.g., released drug or a metabolite of released drug) or detecting prodrug in blood or plasma of the animal at a desired time point(s) following administration.
  • Ex vivo assays can assess the suitability of a prodrug for use in a dose unit by, for example, administration of the prodrug to a ligated section of the intestine of an animal.
  • Prodrug conversion can be detected by, for example, detecting a product of prodrug conversion (e.g., released drug or a metabolite of released drug) or detecting prodrug in the ligated gut loop of the animal at a desired time point(s) following administration.
  • Inhibitors are generally selected based on, for example, activity in interacting with the GI enzyme(s) that mediate release of drug from a prodrug with which the inhibitor is to be co-dosed. Such assays can be conducted in the presence of enzyme either with or without prodrug.
  • Inhibitors can also be selected according to properties such as half-life in the GI system, potency, avidity, affinity, molecular size and/or enzyme inhibition profile (e.g., steepness of inhibition curve in an enzyme activity assay, inhibition initiation rate). Inhibitors for use in prodrug- inhibitor combinations can be selected through use of in vitro, in vivo and/or ex vivo assays.
  • One embodiment is a method for identifying a prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit wherein the method comprises combining a prodrug (e.g., a phenol-modified opioid prodrug), a GI enzyme inhibitor (e.g., a trypsin inhibitor), and a GI enzyme (e.g., trypsin) in a reaction mixture and detecting prodrug conversion.
  • a prodrug e.g., a phenol-modified opioid prodrug
  • a GI enzyme inhibitor e.g., a trypsin inhibitor
  • a GI enzyme e.g., trypsin
  • a decrease in prodrug conversion in the presence of the GI enzyme inhibitor as compared to prodrug conversion in the absence of the GI enzyme inhibitor indicates the prodrug and GI enzyme inhibitor are suitable for formulation in a dose unit.
  • a method can be an in vitro assay.
  • One embodiment is a method for identifying a prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit wherein the method comprises administering to an animal a prodrug (e.g., a phenol-modified opioid prodrug) and a GI enzyme inhibitor (e.g., a trypsin inhibitor) and detecting prodrug conversion.
  • a prodrug e.g., a phenol-modified opioid prodrug
  • a GI enzyme inhibitor e.g., a trypsin inhibitor
  • a decrease in prodrug conversion in the presence of the GI enzyme inhibitor as compared to prodrug conversion in the absence of the GI enzyme inhibitor indicates the prodrug and GI enzyme inhibitor are suitable for formulation in a dose unit.
  • a method can be an in vivo assay; for example, the prodrug and GI enzyme inhibitor can be administered orally.
  • Such a method can also be an ex vivo assay; for example, the prodrug and GI enzyme inhibitor can be administered orally or to a tissue, such as an intestine, that is at least temporarily exposed. Detection can occur in the blood or plasma or respective tissue.
  • tissue refers to the tissue itself and can also refer to contents within the tissue.
  • One embodiment is a method for identifying a prodrug and a GI enzyme inhibitor suitable for formulation in a dose unit wherein the method comprises administering a prodrug and a gastrointestinal (GI) enzyme inhibitor to an animal tissue that has removed from an animal and detecting prodrug conversion.
  • GI gastrointestinal
  • a decrease in prodrug conversion in the presence of the GI enzyme inhibitor as compared to prodrug conversion in the absence of the GI enzyme inhibitor indicates the prodrug and GI enzyme inhibitor are suitable for formulation in a dose unit.
  • In vitro assays can be conducted by combining a prodrug, an inhibitor and a GI enzyme in a reaction mixture.
  • the GI enzyme can be provided in the reaction mixture in an amount sufficient to catalyze cleavage of the prodrug, and assays conducted under suitable conditions, optionally under conditions that mimic those found in a GI tract of a subject, e.g., human.
  • Prodrug conversion can be assessed by detecting a level of a product of prodrug conversion (e.g., released drug) and/or by detecting a level of prodrug maintained in the presence of the GI enzyme. Prodrug conversion can also be assessed by detecting the rate at which a product of prodrug conversion occurs or the rate at which prodrug disappears. Prodrug conversion that is modified in the presence of inhibitor as compared to a level of prodrug conversion in the absence of inhibitor indicates the inhibitor is suitable for attenuation of prodrug conversion and for use in a dose unit. Reaction mixtures having a fixed amount of prodrug and increasing amounts of inhibitor, or a fixed amount of inhibitor and increasing amounts of prodrug, can be used to identify relative amounts of prodrug and inhibitor which provide for a desired modification of prodrug conversion.
  • a product of prodrug conversion e.g., released drug
  • Prodrug conversion can also be assessed by detecting the rate at which a product of prodrug conversion occurs or the rate at which prodrug
  • In vivo assays can assess combinations of prodrugs and inhibitors by co-dosing of prodrug and inhibitor to an animal. Such co-dosing can be enteral. "Co-dosing" refers to administration of prodrug and inhibitor as separate doses or a combined dose (i.e., in the same formulation). Prodrug conversion can be detected by, for example, detecting a product of prodrug conversion (e.g., released drug or drug metabolite) or detecting prodrug in blood or plasma of the animal at a desired time point(s) following administration. Combinations of prodrug and inhibitor can be identified that provide for a prodrug conversion level that yields a desired PK profile as compared to, for example, prodrug without inhibitor.
  • a product of prodrug conversion e.g., released drug or drug metabolite
  • Combinations of prodrug and inhibitor can be identified that provide for a prodrug conversion level that yields a desired PK profile as compared to, for example,
  • Combinations of relative amounts of prodrug and inhibitor that provide for a desired PK profile can be identified by dosing animals with a fixed amount of prodrug and increasing amounts of inhibitor, or with a fixed amount of inhibitor and increasing amounts of prodrug.
  • One or more PK parameters can then be assessed, e.g., drug Cmax, drug Tmax, and drug exposure.
  • Relative amounts of prodrug and inhibitor that provide for a desired PK profile are identified as amounts of prodrug and inhibitor for use in a dose unit.
  • the PK profile of the prodrug and inhibitor combination can be, for example, characterized by a decreased PK parameter value relative to prodrug without inhibitor.
  • a decrease in the PK parameter value of an inhibitor-to- prodrug combination e.g., a decrease in drug Cmax, a decrease in 1/drug Tmax (i.e., a delay in drug Tmax) or a decrease in drug exposure
  • a decrease in the PK parameter value of an inhibitor-to- prodrug combination e.g., a decrease in drug Cmax, a decrease in 1/drug Tmax (i.e., a delay in drug Tmax) or a decrease in drug exposure
  • Assays can be conducted with different relative amounts of inhibitor and prodrug.
  • In vivo assays can be used to identify combinations of prodrug and inhibitor that provide for dose units that provide for a desired concentration-dose PK profile following ingestion of multiples of the dose unit (e.g., at least 2, at least 3, at least 4 or more).
  • Ex vivo assays can be conducted by direct administration of prodrug and inhibitor into a tissue and/or its contents of an animal, such as the intestine, including by introduction by injection into the lumen of a ligated intestine (e.g., a gut loop, or intestinal loop, assay, or an inverted gut assay).
  • An ex vivo assay can also be conducted by excising a tissue and/or its contents from an animal and introducing prodrug and inhibitor into such tissues and/or contents.
  • a dose of prodrug that is desired for a single dose unit is selected (e.g., an amount that provides an efficacious plasma drug level).
  • a multiple of single dose units for which a relationship between that multiple and a PK parameter to be tested is then selected. For example, if a concentration-dose PK profile is to be designed for ingestion of 2, 3, 4, 5, 6, 7, 8, 9 or 10 dose units, then the amount of prodrug equivalent to ingestion of that same number of dose units is determined (referred to as the "high dose").
  • the multiple of dose units can be selected based on the number of ingested pills at which drug Cmax is modified relative to ingestion of the single dose unit.
  • a multiple of 10 can be selected, for example.
  • a variety of different inhibitors e.g., from a panel of inhibitors
  • Assays can be used to identify suitable combination(s) of inhibitor and prodrug to obtain a single dose unit that is therapeutically effective, wherein such a combination, when ingested as a multiple of dose units, provides a modified PK parameter compared to ingestion of the same multiple of drug or prodrug alone (wherein a single dose of either drug or prodrug alone releases into blood or plasma the same amount of drug as is released by a single dose unit).
  • inhibitors are then co-dosed to animals with the high dose of prodrug.
  • the dose level of inhibitor that provides a desired drug Cmax following ingestion of the high dose of prodrug is identified and the resultant inhibitor-to-prodrug ratio determined.
  • Prodrug and inhibitor are then co-dosed in amounts equivalent to the inhibitor-to-prodrug ratio that provided the desired result at the high dose of prodrug.
  • the PK parameter value of interest e.g., drug Cmax
  • a desired PK parameter value results following ingestion of the single dose unit equivalent, then single dose units that provide for a desired concentration-dose PK profile are identified. For example, where a zero dose linear profile is desired, the drug Cmax following ingestion of a single dose unit does not increase significantly following ingestion of a multiple number of the single dose units.
  • Dose units of the present disclosure can be made using manufacturing methods available in the art and can be of a variety of forms suitable for enteral (including oral, buccal and sublingual) administration, for example as a tablet, capsule, thin film, powder, suspension, solution, syrup, dispersion or emulsion.
  • the dose unit can contain components conventional in pharmaceutical preparations, e.g. one or more carriers, binders, lubricants, excipients (e.g., to impart controlled release characteristics), pH modifiers, flavoring agents (e.g., sweeteners), bulking agents, coloring agents or further active agents.
  • Dose units of the present disclosure can include can include an enteric coating or other component(s) to facilitate protection from stomach acid, where desired.
  • Dose units can be of any suitable size or shape.
  • the dose unit can be of any shape suitable for enteral administration, e.g., ellipsoid, lenticular, circular, rectangular, cylindrical, and the like.
  • Dose units provided as dry dose units can have a total weight of from about 1 microgram to about 1 gram, and can be from about 5 micrograms to 1.5 grams, from about 50 micrograms to 1 gram, from about 100 micrograms to 1 gram, from 50 micrograms to 750 milligrams, and may be from about 1 microgram to 2 grams.
  • Dose units can comprise components in any relative amounts.
  • dose units can be from about 0.1% to 99% by weight of active ingredients (i.e., prodrug and inhibitor) per total weight of dose unit (0.1% to 99% total combined weight of prodrug and inhibitor per total weight of single dose unit).
  • dose units can be from 10% to 50%, from 20% to 40%, or about 30% by weight of active ingredients per total weight dose unit.
  • Dose units can be provided in a variety of different forms and optionally provided in a manner suitable for storage.
  • dose units can be disposed within a container suitable for containing a pharmaceutical composition.
  • the container can be, for example, a bottle (e.g., with a closure device, such as a cap), a blister pack (e.g., which can provide for enclosure of one or more dose units per blister), a vial, flexible packaging (e.g., sealed Mylar or plastic bags), an ampule (for single dose units in solution), a dropper, thin film, a tube and the like.
  • Containers can include a cap (e.g., screw cap) that is removably connected to the container over an opening through which the dose units disposed within the container can be accessed.
  • a cap e.g., screw cap
  • Containers can include a seal which can serve as a tamper-evident and/or tamper-resistant element, which seal is disrupted upon access to a dose unit disposed within the container.
  • seal elements can be, for example, a frangible element that is broken or otherwise modified upon access to a dose unit disposed within the container.
  • frangible seal elements include a seal positioned over a container opening such that access to a dose unit within the container requires disruption of the seal (e.g., by peeling and/or piercing the seal).
  • frangible seal elements include a frangible ring disposed around a container opening and in connection with a cap such that the ring is broken upon opening of the cap to access the dose units in the container.
  • Dry and liquid dose units can be placed in a container (e.g., bottle or package, e.g., a flexible bag) of a size and configuration adapted to maintain stability of dose units over a period during which the dose units are dispensed into a prescription.
  • containers can be sized and configured to contain 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more single dry or liquid dose units.
  • the containers can be sealed or resealable.
  • the containers can packaged in a carton (e.g., for shipment from a manufacturer to a pharmacy or other dispensary).
  • Such cartons can be boxes, tubes, or of other configuration, and may be made of any material (e.g., cardboard, plastic, and the like).
  • the packaging system and/or containers disposed therein can have one or more affixed labels (e.g., to provide information such as lot number, dose unit type,
  • the container can include a moisture barrier and/or light barrier, e.g., to facilitate maintenance of stability of the active ingredients in the dose units contained therein.
  • the container can include a desiccant pack which is disposed within the container.
  • the container can be adapted to contain a single dose unit or multiples of a dose unit.
  • the container can include a dispensing control mechanism, such as a lock out mechanism that facilitates maintenance of dosing regimen.
  • the dose units can be provided in solid or semi-solid form, and can be a dry dose unit.
  • “Dry dose unit” refers to a dose unit that is in other than in a completely liquid form.
  • dry dose units include, for example, tablets, capsules (e.g., solid capsules, capsules containing liquid), thin film, microparticles, granules, powder and the like.
  • Dose units can be provided as liquid dose units, where the dose units can be provided as single or multiple doses of a formulation containing prodrug and inhibitor in liquid form.
  • Single doses of a dry or liquid dose unit can be disposed within a sealed container, and sealed containers optionally provided in a packaging system, e.g., to provide for a prescribed number of doses, to provide for shipment of dose units, and the like.
  • Dose units can be formulated such that the prodrug and inhibitor are present in the same carrier, e.g., solubilized or suspended within the same matrix.
  • dose units can be composed of two or more portions, where the prodrug and inhibitor can be provided in the same or different portions, and can be provided in adjacent or non-adjacent portions.
  • Dose units can be provided in a container in which they are disposed, and may be provided as part of a packaging system (optionally with instructions for use).
  • dose units containing different amounts of prodrug can be provided in separate containers, which containers can be disposed with in a larger container (e.g., to facilitate protection of dose units for shipment).
  • one or more dose units as described herein can be provided in separate containers, where dose units of different composition are provided in separate containers, and the separate containers disposed within package for dispensing.
  • dose units can be provided in a double-chambered dispenser where a first chamber contains a prodrug formulation and a second chamber contains an inhibitor formulation.
  • the dispenser can be adapted to provide for mixing of a prodrug formulation and an inhibitor formulation prior to ingestion.
  • the two chambers of the dispenser can be separated by a removable wall (e.g., frangible wall) that is broken or removed prior to administration to allow mixing of the formulations of the two chambers.
  • the first and second chambers can terminate into a dispensing outlet, optionally through a common chamber.
  • the formulations can be provided in dry or liquid form, or a combination thereof.
  • the formulation in the first chamber can be liquid and the formulation in the second chamber can be dry, both can be dry, or both can be liquid.
  • controlled release refers to release of one or both of prodrug and inhibitor from the dose unit over a selected period of time and/or in a pre-selected manner.
  • Dose units are advantageous because they find use in methods to reduce side effects and/or improve tolerability of drugs to patients in need thereof by, for example, limiting a PK parameter as disclosed herein.
  • the present disclosure thus provides methods to reduce side effects by administering a dose unit of the present disclosure to a patient in need so as to provide for a reduction of side effects as compared to those associated with administration of drug and/or as compared to administration of prodrug without inhibitor.
  • the present disclosure also provides methods to improve tolerability of drugs by administering a dose unit of the present disclosure to a patient in need so as to provide for improvement in tolerability as compared to administration of drug and/or as compared to administration of prodrug without inhibitor.
  • Dose units find use in methods for increasing patient compliance of a patient with a therapy prescribed by a clinician, where such methods involve directing administration of a dose unit described herein to a patient in need of therapy so as to provide for increased patient compliance as compared to a therapy involving administration of drug and/or as compared to administrations of prodrug without inhibitor. Such methods can help increase the likelihood that a clinician- specified therapy occurs as prescribed.
  • Dose units can provide for enhanced patient compliance and clinician control. For example, by limiting a PK parameter (e.g., such as drug Cmax or drug exposure) when multiples (e.g., two or more, three or more, or four or more) dose units are ingested, a patient requiring a higher dose of drug must seek the assistance of a clinician.
  • the dose units can provide for control of the degree to which a patient can readily "self-medicate", and further can provide for the patient to adjust dose to a dose within a permissible range.
  • Dose units can provide for reduced side effects, by for example, providing for delivery of drug at an efficacious dose but with a modified PK profile over a period of treatment, e.g., as defined by a decreased PK parameter (e.g., decreased drug Cmax, decreased drug exposure).
  • a decreased PK parameter e.g., decreased drug Cmax, decreased drug exposure
  • Dose units find use in methods to reduce the risk of unintended overdose of drug that can follow ingestion of multiple doses taken at the same time or over a short period of time. Such methods of the present disclosure can provide for reduction of risk of unintended overdose as compared to risk of unintended overdose of drug and/or as compared to risk of unintended overdose of prodrug without inhibitor. Such methods involve directing administration of a dosage described herein to a patient in need of drug released by conversion of the prodrug. Such methods can help avoid unintended overdosing due to intentional or unintentional misuse of the dose unit.
  • the present disclosure provides methods to reduce misuse and abuse of a drug, as well as to reduce risk of overdose, that can accompany ingestion of multiples of doses of a drug, e.g., ingested at the same time.
  • Such methods generally involve combining in a dose unit a prodrug and an inhibitor of a GI enzyme that mediates release of drug from the prodrug, where the inhibitor is present in the dose unit in an amount effective to attenuate release of drug from the prodrug, e.g., following ingestion of multiples of dose units by a patient.
  • Such methods provide for a modified concentration-dose PK profile while providing therapeutically effective levels from a single dose unit, as directed by the prescribing clinician.
  • Such methods can provide for, for example, reduction of risks that can accompany misuse and/or abuse of a prodrug, particularly where conversion of the prodrug provides for release of a narcotic or other drug of abuse (e.g., opioid).
  • a narcotic or other drug of abuse e.g., opioid
  • dose units can provide for reduction of reward that can follow ingestion of multiples of dose units of a drug of abuse.
  • Dose units can provide clinicians with enhanced flexibility in prescribing drug.
  • a clinician can prescribe a dosage regimen involving different dose strengths, which can involve two or more different dose units of prodrug and inhibitor having different relative amounts of prodrug, different amounts of inhibitor, or different amounts of both prodrug and inhibitor.
  • Such different strength dose units can provide for delivery of drug according to different PK parameters (e.g., drug exposure, drug Cmax, and the like as described herein).
  • a first dose unit can provide for delivery of a first dose of drug following ingestion
  • a second dose unit can provide for delivery of a second dose of drug following ingestion.
  • the first and second prodrug doses of the dose units can be different strengths, e.g., the second dose can be greater than the first dose.
  • a clinician can thus prescribe a collection of two or more, or three or more dose units of different strengths, which can be accompanied by instructions to facilitate a degree of self-medication, e.g., to increase delivery of an opioid drug according to a patient's needs to treat pain.
  • the disclosure provides for a composition comprising a compound disclosed herein and a trypsin inhibitor that reduces drug abuse potential.
  • a trypsin inhibitor can thwart the ability of a user to apply trypsin to effect the release of a phenolic opioid from the phenol-modified opioid prodrug in vitro. For example, if an abuser attempts to incubate trypsin with a composition of the embodiments that includes a phenol-modified opioid prodrug and a trypsin inhibitor, the trypsin inhibitor can reduce the action of the added trypsin, thereby thwarting attempts to release phenolic opioid for purposes of abuse. Examples
  • Preparation 7 Synthesis of 4-[(S)-2-Amino-5-((amino-[(E)-2,2,4,6, 7-pentamethyl-2,3-dihydro- benzofuran-5 sulfonylimino] -methyl J -amino )-pentanoyl] -piperazine-1 -carboxylic acid ethyl ester (G).
  • the crude product was purified by preparative reverse phase HPLC [Column: VARIAN, LOAD & LOCK, L&L 4002-2, Packing: Microsorb 100-10 C18, Injection Volume: ⁇ 25 mL, Injection flow rate: 20 mL/ min, 95% A, (water/ 0.1% TFA), Flow rate: 100 mL/ min, Fraction: 30 Sec (50 mL), Method: 5% B (MeCN / 0.1% TFA)/ 5 min/ 25% B/ 20 min/ 25% B/ 15 min/ 50% B/ 25 min/ 100 mL/ min/ 254 nm] . Solvents were removed from pure fractions in vacuo.
  • Compound 107 i.e., 3-(4-carbamimidoylphenyl)-2-oxopropanoic acid can be produced using methods known to those skilled in the art, such as that described by Richter P et al, Pharmazie, 1977, 32, 216-220 and references contained within.
  • the purity of Compound 107 used herein was estimated to be 76%, an estimate due low UV absorbance of this compound via HPLC.
  • Preparation 24 Synthesis of ((S)-4-((amino-[(E)-2,2,4,6, 7-pentamethyl-2,3-dihydro-benzofuran- 5-sulfonylimino]-methylJ-amino)-l-[2-(benzyloxycarbonyl-methyl-amino)-ethyl carbamoyl] - butyl) '-carbamic acid tert-butyl ester (AA).
  • Preparation 25 Synthesis of(S)-2-amino-5-( ⁇ amino-[(E)-2,2,4,6, 7-pentamethyl-2,3-dihydro- benzofuran-5-sulfonylimino ] -methyl ⁇ -amino )-pentanoic acid ( 2-methylamino-ethyl)-amide (BB ).
  • Preparation 26 Synthesis of ⁇ (S)-4-( (amino- [(E)-2,2,4,6, 7-pentamethyl-2,3-dihydro-benzofuran- 5 -sulfonylimino] -methyl ⁇ -amino )-l -[2-( hydromorphylcarbonyl-methyl-amino )-ethyl carbamoyl] - butyl ⁇ -carbamic acid tert-butyl ester ( CC).
  • Preparation 28 Synthesis of ⁇ (S)-5-Amino-5-[2-(benzyloxycarbonyl-methyl-amino)- ethylcarbamoyl] -pentylj-carbamic acid tert-butyl ester (EE).
  • phenylchloroformate 600 mg, 2.97 mmol was added to the reaction mixture and was then sonicated for 100 min.
  • Solvents were then removed in vacuo and the residue was dissolved in a minimum amount of MeOH and precipitated with an excess of Et 2 0. The precipitate was filtered off, washed with Et 2 0 and dried in vacuo to afford compound II.
  • Pbf protected compound PC-4 was dissolved in a mixture of 5% m-cresol/TFA (100 mL). The reaction mixture was maintained at room temperature for 1 h, followed by dilution with ether (2 L). A precipitate was formed and subsequently filtered over sintered glass funnel, washed with ether (200 mL) and dried in vacuo to provide crude compound PC-4 (5.2 g, 97%) as off-white solid. Crude compound PC-4 (5.2g, 5.54 mmol) was dissolved in water (50 mL) and subjected to HPLC purification.

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  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne des compositions pharmaceutiques et leurs méthodes d'utilisation, lesdites compositions pharmaceutiques comprenant un promédicament opiacé modifié phénol permettant la libération sous contrôle enzymatique d'un opiacé phénolique, ainsi qu'un inhibiteur d'enzyme interagissant avec la ou les enzymes intervenant dans la libération sous contrôle enzymatique de l'opiacé phénolique à partir du promédicament opiacé modifié phénol, de sorte à modifier le clivage enzymatique du promédicament opiacé modifié phénol.
PCT/US2010/031955 2010-04-21 2010-04-21 Compositions comprenant des promédicaments opiacés modifiés phénol clivables par enzyme et leurs inhibiteurs WO2011133151A1 (fr)

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PCT/US2010/031955 WO2011133151A1 (fr) 2010-04-21 2010-04-21 Compositions comprenant des promédicaments opiacés modifiés phénol clivables par enzyme et leurs inhibiteurs

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012066347A1 (fr) * 2010-11-18 2012-05-24 Shire, Llc Formulations à base d'huile
WO2023215335A1 (fr) * 2022-05-03 2023-11-09 Lucy Scientific Discovery Composés psychoactifs fonctionnalisés

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7189414B2 (en) * 1994-06-15 2007-03-13 Yissum Research Development Company Of The Hebrew University Of Jerusalem Controlled release oral drug delivery system
WO2007140272A2 (fr) * 2006-05-26 2007-12-06 Pharmacofore, Inc. Libération régulée d'opioïdes phénoliques
WO2010045599A1 (fr) * 2008-10-17 2010-04-22 Pharmacofore, Inc. Compositions pharmaceutiques avec libération atténuée d'opioïdes phénoliques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7189414B2 (en) * 1994-06-15 2007-03-13 Yissum Research Development Company Of The Hebrew University Of Jerusalem Controlled release oral drug delivery system
WO2007140272A2 (fr) * 2006-05-26 2007-12-06 Pharmacofore, Inc. Libération régulée d'opioïdes phénoliques
WO2010045599A1 (fr) * 2008-10-17 2010-04-22 Pharmacofore, Inc. Compositions pharmaceutiques avec libération atténuée d'opioïdes phénoliques

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012066347A1 (fr) * 2010-11-18 2012-05-24 Shire, Llc Formulations à base d'huile
WO2023215335A1 (fr) * 2022-05-03 2023-11-09 Lucy Scientific Discovery Composés psychoactifs fonctionnalisés

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