Opioid compositions resistant to overdose and abuse

Abstract

The invention provides pharmaceutical compositions comprising macromolecular gastrointestinal enzyme-labile opioid prodrugs, co-formulated with small-molecule and/or macromolecular gastrointestinal enzyme inhibitors. The macromolecular constructs are minimally absorbed from the GI tract, and can produce non-linear pharmacokinetic profiles of the delivered opioid agonist following oral ingestion. An optional macromolecular opioid antagonist may also be present in compositions of the invention to discourage tampering by potential abusers.

What is claimed is: 
     
         1 . A composition comprising:
 a gastrointestinal enzyme inhibitor, or a pharmaceutically acceptable salt thereof, and   
       a therapeutically-effective amount of a macromolecule of formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 PD is a gastrointestinal enzyme-labile opioid agonist prodrug; 
 X is a linker group that covalently joins PD to a polymer; 
 P is a polymer; and 
 n is 1 or 2. 
 
     
     
         2 . The composition of  claim 1 , wherein the gastrointestinal enzyme is trypsin or chymotrypsin. 
     
     
         3 . The composition of  claim 1 , wherein the gastrointestinal enzyme inhibitor is a small molecule. 
     
     
         4 . The composition of  claim 1 , wherein the gastrointestinal enzyme inhibitor is formulated in a controlled release matrix. 
     
     
         5 . The composition of  claim 4 , wherein all or portions of the gastrointestinal enzyme inhibitor is formulated in an immediate release or an extended release matrix. 
     
     
         6 . The composition of  claim 4 , wherein all or portions of the gastrointestinal enzyme inhibitor is released from the controlled-release formulation in vivo. 
     
     
         7 . The composition of  claim 6 , wherein all or portions of the gastrointestinal enzyme inhibitor is released from the controlled release formulation in vivo following oral administration of the composition. 
     
     
         8 . The composition of  claim 1 , wherein the gastrointestinal enzyme inhibitor is a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Q 1  is selected from —O-Q 4  or -Q 4 -CO 2 H; 
 Q 4  is C 1 —C4 alkyl; 
 Q 2  is N or CH; and 
 Q 3  is aryl or substituted aryl. 
 
     
     
         9 . The composition of  claim 8 , wherein Q 3  is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The composition of  claim 8 , wherein Q 1  is 
       
         
           
           
               
               
           
         
       
     
     
         11 . The composition of  claim 1 , wherein the gastrointestinal enzyme inhibitor is a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Q 5  is —C(O)—CO 2 H or —NH-Q 6 -Q 7 -SO2-Aryl; 
 Q 6  is —(CH 2 ) p —CO 2 H; 
 Q 7  is —(CH 2 ) r —C6H 5 ; 
 Q 8  is NH; 
 n is 0, 1, or 2; 
 o is 0 or 1; 
 p is 1, 2, or 3; and 
 r is 1, 2, or 3. 
 
     
     
         12 . The composition of  claim 11 , wherein n is 1 and o is 0. 
     
     
         13 . The composition of  claim 1 , wherein the gastrointestinal enzyme inhibitor is a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Q is acetyl, —S(O) 2 -Me, Benzyl, hydrogen, C 1 -C 5  alkyl, or amino acid(s); 
 R is —OH, ═O, or hydrogen; and 
 n is 0, 1, or 2. 
 
     
     
         14 . The composition of  claim 1 , wherein the gastrointestinal enzyme inhibitor is a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
       
       A represents a group of the formula wherein:
 R t9  and R t10  each represent independently a hydrogen atom or C 1-4  alkyl group; 
 R t8  represents a group from the following formulae: 
 
       
         
           
           
               
               
           
         
         
           wherein: 
           each R t11 , R t12 , and R t13  represent independently a hydrogen atom, a phenyl group, a C 1-4  alkyl group substituted by a phenyl group, a C 1-10  alkyl group, a C 1-10  alkoxyl group, a C 1-10  alkenyl group having one to three double bonds, a C 1-10  alkynyl group having one to two triple bonds, a group of formula R t15 —C(O)XR t16 , wherein R t15  represents a single bond or a C 1 -s alkylene group, X represents an oxygen atom or a NH— group, and R t16  represents a hydrogen atom, a C 1-4  alkyl group substituted by a phenyl group, or a C 3-7  cycloalkyl group represented by 
         
       
       
         
           
           
               
               
           
         
       
       with the structure representing a 4-7 membered monocyclic heterocycle containing 1 to 2 nitrogen atoms; R t14  represents a hydrogen atom, a C 1-4  alkyl group substituted by a phenyl group provided that R t11 , R t12 , and R t13  do not simultaneously represent hydrogen atoms, or non-toxic salts, addition acid salts, hydrates, or solvates thereof. 
     
     
         15 . The composition of  claim 1 , wherein the gastrointestinal enzyme inhibitor is a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is NH; 
 n is 0 or 1; and 
 R t1  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(O)—O—(CH 2 ) m —C(O)—N—R n1 R n2 , wherein: 
 each m is independently 0, 1, or 2; and
 R n1  and R n2  are independently selected from hydrogen and C 1-4  alkyl. 
 
 
     
     
         16 . The composition of  claim 15 , wherein R t1  is guanidino or amidino. 
     
     
         17 . The composition of  claim 15 , wherein R t1  is —(CH 2 ) m —C(O)—O—(CH 2 ) m —C(O)—N—R n1 R n2 , wherein m is 1 and R n1  and R n2  are each independently methyl. 
     
     
         18 . The composition of  claim 1 , wherein the gastrointestinal enzyme inhibitor is a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 each X is NH; 
 each n is independently 0 or 1; 
 L′1 is —C(O)—O—, —O—C(O)—, —O—(CH 2 ) m —O—, —OCH 2 —Ar t2 —CH 2 —O—, —C(O)—NR t3 , or —NR t3 —C(O)—; 
 R t3  is hydrogen, C 1-6  alkyl, or substituted C 1-6  alkyl; 
 Ar t1  and Ar t2  are independently a substituted or unsubstituted aryl group; and 
 m is an integer from 1 to 3. 
 
     
     
         19 . The composition of  claim 18 , wherein Ar t1  and Ar t2  are independently phenyl or naphthyl. 
     
     
         20 . The composition of  claim 1 , wherein the gastrointestinal enzyme inhibitor is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The composition of  claim 1 , wherein the gastrointestinal enzyme-labile opioid agonist is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, dihydrocodeine, and tramadol, or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The composition of  claim 1 , wherein X is an ether, an ester, a thioester, an amide, an amine, a carbamate, a carbonate, an ether, a thioether, or a urea,
 wherein the nitrogen atom of the amide, the amine, or the carbamate is substituted, or unsubstituted; and   wherein the nitrogen atoms of the urea are each independently substituted or unsubstituted.   
     
     
         23 . The composition of  claim 1 , wherein the polymer is a polyalkylene glycol. 
     
     
         24 . The composition of  claim 1 , wherein the macromolecule is formulated in an immediate release matrix. 
     
     
         25 . The composition of  claim 1 , wherein the macromolecule is formulated in an extended release matrix. 
     
     
         26 . The composition of  claim 1 , wherein the opioid agonist is released from PD in the presence of the gastrointestinal enzyme. 
     
     
         27 . The composition of  claim 23 , wherein the polyalkylene glycol is polyethylene glycol. 
     
     
         28 . The composition of  claim 1 , wherein the gastrointestinal enzyme-labile opioid agonist prodrug is: 
       
         
           
           
               
               
           
         
         wherein:
 D is opioid agonist, less the oxygen atom to which D is bound and a hydrogen atom; 
 AA is a natural or an unnatural amino acid side chain that is recognized by a digestive enzyme; 
 R is independently hydrogen, methyl, ethyl, substituted alkyl, substituted aryl, a natural or an unnatural amino acid, or a polypeptide consisting of from 2 to 10 natural and/or unnatural amino acids; wherein, adjacent R groups can be joined to form a ring. 
 
       
     
     
         29 . The composition of  claim 1 , wherein the gastrointestinal enzyme-labile opioid agonist prodrug is: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is H or OH; 
 AA is a natural or unnatural amino acid side chain that is recognized by a digestive enzyme; 
 R is independently hydrogen, methyl, ethyl, substituted alkyl, or substituted aryl, or a natural or unnatural amino acid, or a polypeptide comprising up to 10 natural and/or unnatural amino acids; adjacent R groups can be joined to form a ring. 
 
     
     
         30 . The composition of  claim 29 , wherein the gastrointestinal enzyme is trypsin. 
     
     
         31 . The composition of  claim 1 , wherein the molecular weight of the polymer is from about 1,500 to about 50,000 Da. 
     
     
         32 . The composition of  claim 36 , wherein D is 
       
         
           
           
               
               
           
         
         AA is a side chain of lysine or arginine; and 
         R is independently hydrogen, methyl, ethyl, or a natural or unnatural amino acid. 
       
     
     
         33 . The composition of  claim 1 , wherein the macromolecule is 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       wherein D is 
       AA is a side chain of lysine or arginine; and 
       p is an integer from 10 to 200; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 . The composition of  claim 1 , wherein the macromolecule is 
       
         
           
           
               
               
           
         
       
       wherein D is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The composition of  claim 1 , wherein the composition is capable of reducing a systemic exposure of delivered opioid agonist relative to a linear dose-proportional increase of systemic exposure of delivered opioid agonist when a dose of the GI enzyme-labile opioid agonist releasing subunit greater than a prescribed dose is ingested. 
     
     
         36 . A method for treating a condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a macromolecule of formula 
       
         
           
           
               
               
           
         
       
       and a macromolecule of formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 PD is a gastrointestinal enzyme-labile opioid against prodrug; 
 I is a gastrointestinal enzyme inverse substrate; 
 each X 1  and X 2  is independently a linker group that covalently joins I to a polymer; 
 P 1  and P 2  are a polymer, wherein each P 1  and P 2  is independently selected to provide less than 20% absorption of the macromolecule from the gastrointestinal tract of a subject following oral administration; and 
 n is from 1 to 1000.