Abuse-resistant long-acting release opioid prodrugs

Abstract

There are provided, prodrugs of opioid and other controlled substance, having enhanced physical and chemical stability to resist tampering and to make long-acting release formulations, and pharmaceutically accepted salts and solvates thereof. There are also provided methods of using the disclosed compounds as abuse deterrent products.

1 - 11 . (canceled) 
     
     
         12 . A pharmaceutical composition comprising a compound of Formula I-X or a pharmaceutically acceptable salt thereof,
   A-L-D   Formula I-X
   
       wherein
 A is a residue of a lipid or substituted lipid, a natural biodegradable polymer, or a synthetic biodegradable polymer; 
 L is a linker of 
 
       
         
           
           
               
               
           
         
       
       wherein X is O or NR 33 , wherein R 30 , R 31 , R 32  and R 33  are each independently hydrogen, an alkyl, a substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted heteroalkyl, an optionally substituted heterocycloalkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, or R 30  or R 33  can be a bond attached to D when a cyclic —NH— function of the controlled substance forms part of the linker L; and
 D is a residue of a controlled substance; 
 
       wherein the pharmaceutical composition is abuse-deterrent. 
     
     
         13 . The pharmaceutical composition of  claim 12 , which is substantially stable towards acid-catalyzed hydrolysis conditions at a pH of about 1-3, or base-catalyzed hydrolysis conditions at a pH of about 8-9. 
     
     
         14 . The pharmaceutical composition of  claim 12 , which is formulated for intramuscular or subcutaneous injection. 
     
     
         15 . The pharmaceutical composition of  claim 14 , which comprises micelles comprising the compound of Formula I-X or pharmaceutically acceptable salt thereof. 
     
     
         16 . The pharmaceutical composition of  claim 12 , wherein D is a residue of a controlled substance selected from Table 1. 
     
     
         17 . The pharmaceutical composition of  claim 12 , wherein D is a residue of an opioid with a hydroxyl, an —NH— or —NH 2  group, or a carboxylic acid group, or a precursor thereof. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein D is a residue of morphine, oxymorphone, hydromorphone, levorphanol, or oxycodone. 
     
     
         19 . The pharmaceutical composition of  claim 12 , wherein A is a residue of a lipid selected from saturated or unsaturated, straight chain or branched chain fatty acid with eight (8) to twenty four (24) carbons, which is optionally substituted; bile acids; squalene; vitamin E and its derivatives; cholesterols; and retinoic acids. 
     
     
         20 . The pharmaceutical composition of  claim 12 , wherein A is a residue of a straight chain saturated or unsaturated fatty acid with 12-20 carbons. 
     
     
         21 . The pharmaceutical composition of  claim 12 , wherein A is a residue of a biodegradable polymer selected from alginate, chitosan, derived cellulose, starch, hyaluronic acid, dextran, peptides, polyesters, polyethers, polyurethanes, polyphospazines, polycarbonates, and polyesteramide. 
     
     
         22 . The pharmaceutical composition of  claim 12 , wherein A is a residue of a polymer selected from polylactic (PLA), polyglycolic (PGA), polycarprolactone (PCL), copolymers thereof, e.g., polylactic glycolic acid (PLGA); and polyethylene glycol (PEG) and its derivatives. 
     
     
         23 . The pharmaceutical composition of  claim 12 , wherein L is 
       
         
           
           
               
               
           
         
       
       wherein X is O or NR 33 , wherein R 33  is hydrogen or a C 1-4  alkyl optionally substituted with 1-3 substituents each independently oxo, F, hydroxyl, C 1-4  alkyl or C 1-4  alkoxy. 
     
     
         24 . The pharmaceutical composition of  claim 12 , which, after administration, releases the controlled substance, or a metabolite thereof, in a subject user, e.g., over a period of at least 3 days. 
     
     
         25 . The pharmaceutical composition of  claim 12 , wherein the controlled substance is an analgesic. 
     
     
         26 . A method of treating pain in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of pharmaceutical composition of  claim 25 . 
     
     
         27 . The method of  claim 26 , wherein the administration is via the subcutaneous or intramuscular route. 
     
     
         28 . A method of reducing a likelihood of abuse of a controlled substance, the method comprising providing a prodrug of the controlled substance, wherein the prodrug is a compound of Formula I-X as defined in  claim 12 , or a pharmaceutically acceptable salt thereof, wherein D in Formula I-X is a residue of the controlled substance, and formulating the prodrug in a long-acting release abuse-deterrent formulation. 
     
     
         29 . The method of  claim 28 , wherein the abuse-deterrent formulation is a subcutaneous or intramuscular injectable formulation. 
     
     
         30 . The method of  claim 28 , further comprising restricting the administration of the abuse-deterrent formulation to a hospital setting, thereby limiting patient access to the prodrug and reducing the likelihood of abuse of the controlled substance. 
     
     
         31 . The method of  claim 28 , wherein the controlled substance is any one listed in Table 1. 
     
     
         32 . The method of  claim 31 , wherein the prodrug is a compound of Formula 1 or 2, or a pharmaceutically acceptable salt thereof. 
     
     
         33 . The method of  claim 28 , wherein the controlled substance is morphine, oxymorphone, hydromorphone, levorphanol, or oxycodone. 
     
     
         34 . The method of  claim 28 , wherein the abuse deterrent formulation is characterized as being substantially stable towards acid-catalyzed hydrolysis conditions at a pH of about 1-3, or base-catalyzed hydrolysis conditions at a pH of about 8-9. 
     
     
         35 . The method of  claim 28 , wherein the abuse deterrent formulation is characterized as including micelles comprising the compound of Formula I-X or pharmaceutically acceptable salt thereof.