Pharmaceutical compositions for prevention of overdose or abuse

Abstract

The invention relates to pharmaceutical compositions comprised of a chemical moiety attached to an active agent in a manner that substantially decreases the potential of the active agent to cause overdose or to be abused. When delivered at the proper dosage the pharmaceutical composition provides therapeutic activity similar to that of the parent active agent.

1 . A compound of the formula:  
         A-X m -Z n    wherein    A is an active agent;    X is a linker covalently bound to A; and    Z is an amino acid, peptide, or oligopeptide covalently bound to x,    wherein m and n range from 1 to 50.    
     
     
         2 . The compound of  claim 1 , wherein X comprises a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups.  
     
     
         3 . The compound of  claim 2 , wherein the functional groups are selected from amines, amides, alcohols or acids.  
     
     
         4 . The compound of  claim 1 , wherein A is oxycodone or hydrocodone.  
     
     
         5 . The compound of  claim 1 , wherein X an enolate.  
     
     
         6 . The compound of  claim 1 , wherein X is an amino acid.  
     
     
         7 . The compound of  claim 6 , wherein Z is bonded to X through a side chain of the amino acid.  
     
     
         8 . The compound of  claim 6 , wherein Z is bonded to Z through a peptide bond.  
     
     
         9 . The compound of  claim 1 , wherein X is an amino acid or dipeptide and Z is bonded to X through a peptide bond.  
     
     
         10 . The compound of  claim 1 , wherein X comprises Ser, Lys, Glu, Asp, Ala, Leu, Phe, Val, Gly, Tyr, Pro, or Thr.  
     
     
         11 . The compound of  claim 1 , wherein -X-Z comprises Lys-Lys, Lys-Lys-Val, (Lys-Lys-Gly-Gly) 2 , [(l)-Lys-(d)-Lys-Leu] 2 , Glu-Glu, Glu-Glu-Phe-Phe-Phe-Ile, Glu-Glu-Phe-Phe-Phe, Glu-Glu-Phe-Phe-Ile, Glu-Glu-Val, Asp-Asp, Asp-Asp-Asp, Asp-Asp-Glu, Asp-Asp-Ser, Asp-Asp-Lys, Asp-Asp-Cys, Asp-Asp-Val, Ala-Ser, Ala-Cys, Leu-Glu, Leu-Ser, Leu-Asp, Leu-Asn, Leu-Thr, Leu-Arg, Leu-Cys, Leu-Gln, Leu-Tyr, Val-Glu, Val-Ser, Val-Asp, Val-Asn, Val-Thr, Val-Arg, Val-Cys, Val-Gln, Val-Tyr, Val-Val, Gly-Gly-Leu, Gly-Gly-Gly-Gly-Leu, Gly-Gly-Ile, Asp-Asp-Ile, Pro-Pro-Leu, Pro-Pro-Ile, or Thr-Thr-Val.  
     
     
         12 . The compound of  claim 1 , wherein -X-Z comprises Ser-Ser, PolySer, Lys, Glu-Glu, Asp-Asp, Asp-Asp-Asp, Asp-Asp-Glu, Asp-Asp-Ser, Asp-Asp-Lys, Asp-Asp-Cys, Ala-Glu, Ala-Ser, Ala-Asp, Ala-Asn, Ala-Thr, Ala-Arg, Ala-Cys, Ala-Gin, Ala-Tyr, LeuGlu, Leu-Ser, Leu-Asp, Leu-Asn, Leu-Thr, Leu-Arg, Leu-Cys, Leu-Gln, Leu-Tyr, PheGlu, Phe-Ser, Phe-Asp, Phe-Asn, Phe-Thr, Phe-Arg, Phe-Cys, Phe-Gln, Phe-Tyr, Val-Glu, Val-Ser, Val-Asp, Val-Asn, Val-Thr, Val-Arg, Val-Cys, Val-Gln, or Val-Tyr.  
     
     
         13 . The compound of  claim 1 , wherein -X-Z comprises Pro-Pro-Leu, Pro-Pro-Ile, Val-Val, Lys-Lys, Gly-Gly-Ile, Phe-Phe-Ile, Phe-Phe-Leu, Thr-Thr-Val, Tyr-Tyr-Val, Tyr-Tyr-Phe, Glu-Glu-Val, Asp-Asp-Val, Lys-Lys-Val, Glu-Glu-Phe-Phe-Ile, Glu-Glu-Phe-Phe-Phe, Tyr-Tyr-Ile, Asp-Asp-Ile, Tyr-Tyr-Phe-Phe-Ile, Tyr-Tyr-Lys-Tyr-Tyr, Phe-Phe-Lys-Phe-Phe, Glu-Glu-Phe-Phe-Ile, (Lys-Lys-Gly-Gly) 2 , or [(1)-Lys-(d)-Lys-Leu] 2 .  
     
     
         14 . The compound of  claim 1 , wherein -X-Z comprises Ser-Ser, PolySer, Glu-Glu, Asp-Asp, Asp-Asp-Asp, Asp-Asp-Glu, Asp-Asp-Ser, Asp-Asp-Lys, Asp-Asp-Cys, Ala-Glu, Ala-Ser, Ala-Asp, Ala-Asn, Ala-Thr, Ala-Arg, Ala-Cys, Ala-Gln, Ala-Tyr, Leu-Glu, Leu-Ser, Leu-Asp, Leu-Asn, Leu-Thr, Leu-Arg, Leu-Cys, Leu-Gln, Leu-Tyr, Phe-Glu, Phe-Ser, Phe-Asp, Phe-Asn, Phe-Thr, Phe-Arg, Phe-Cys, Phe-Gin, Phe-Tyr, Val-Glu, Val-Ser, Val-Asp, Val-Asn, Val-Thr, Val-Arg, Val-Cys, Val-Gln, Val-Tyr, Ala-Pro, Gly-Gly-Leu, Gly-Gly-Gly-Gly-Leu, Glu-Glu-Phe-Phe-Phe-Ile, Glu-Glu-Phe-Phe-Phe, Tyr-Tyr-Ile, Asp-Asp-Ile, Tyr-Tyr-Phe-Phe-Ile, or Glu-Glu-Phe-Phe-Ile.  
     
     
         15 . The compound of  claim 1 , wherein -X-Z comprises Ser-Ser, PolySer, Lys-Lys, Lys-Lys-Val, (Lys-Lys-Gly-Gly) 2 , [(1)-Lys-(d)-Lys-Leu] 2 , Glu-Glu, Glu-Glu-Phe-Phe-Phe-Ile, Glu-Glu-Phe-Phe-Phe, Glu-Glu-Phe-Phe-Ile, Glu-Glu-Val, Asp-Asp, Asp-Asp-Asp, Asp-Asp-Glu, Asp-Asp-Ser, Asp-Asp-Lys, Asp-Asp-Cys, Asp-Asp-Val, Ala-Glu, Ala-Pro, Ala-Ser, Ala-Asp, Ala-Asn, Ala-Thr, Ala-Arg, Ala-Cys, Ala-Gln, Ala-Tyr, Leu-Glu, Leu-Ser, Leu-Asp, Leu-Asn, Leu-Thr, Leu-Arg, Leu-Cys, Leu-Gln, Leu-Tyr, Phe-Glu, Phe-Ser, Phe-Asp, Phe-Asn, Phe-Thr, Phe-Arg, Phe-Cys, Phe-Gln, Phe-Tyr, Phe-Phe-Ile, Phe-Phe-Leu, Phe-Phe-Lys-Phe-Phe, Val-Glu, Val-Ser, Val-Asp, Val-Asn, Val-Thr, Val-Arg, Val-Cys, Val-Gln, Val-Tyr, Val-Val, Gly-Gly-Leu, Gly-Gly-Gly-Gly-Leu, Gly-Gly-Ile, Tyr-Tyr-Ile, Tyr-Tyr-Phe-Phe-Ile, Tyr-Tyr-Val, Tyr-Tyr-Phe, Tyr-Tyr-Lys-Tyr-Tyr, Asp-Asp-Ile, Pro-Pro-Leu, Pro-Pro-Ile, or Thr-Thr-Val.  
     
     
         16 . The compound of  claim 1 , wherein X is lysine.  
     
     
         17 . The compound of  claim 16 , wherein Z is bonded to lysine through the side chain of the lysine.  
     
     
         18 . The compound of  claim 1 , wherein the active agent is alphacetylmethadol hydrochloride, anileridine, apomorphine, bemidone, betacetylmethadol hydrochloride, buprenorphine hydrochloride, butorphanol tartrate, codeine, dezocine, dihydrocodeine, dihydromorphine, dipanone hydrochloride, eptazocine hydrobromide, ethylmorphine, etorphine hydrochloride, hydromorphone, ketobemidone, levorphanol tartrate, loperamide, meptazinol hydrochloride, methyldihydromorphinone, nalbuphine hydrochloride, nalbuphine hydrochloride, normorphine, oxycodone, oxymorphone, pentazocine, piminodine, tramadol, allobarbitone, alprazolan, amylobarbitone, barbitone sodium, butobarbitone, captodiame hydrochloride, chloral betaine, chloral hydrate, chloralose, chlorhexadol, chlormethiazole edisylate, cinolazepam, potassium clorazepate, cyclobarbitone calcium, delorzepam, difebarbamate, enciprazine hydrochloride, flunitrazepam, hexobarbitone sodium, ibomal, lorazepam, lormetazepam, meprobamate, methylpentynol, midazolam maleate, oxazepam, pentabarbitone calcium, phenprobamate, proxibarbal, quinalbaritone, quinalbarbitone sodium, secbutobarbitone sodium, temazepam, triclofos sodium, zalepan, or zolazepam hydrochloride.  
     
     
         19 . The compound of  claim 1 , wherein A is a radical of a pain relief drug.  
     
     
         20 . The compound of  claim 1 , wherein A is a radical of oxycodone or hydrocodone.  
     
     
         21 . (canceled)  
     
     
         22 . A method of treating pain, comprising administering to a mammal in need thereof a therapeutically effective amount of the compound of  claim 1 .  
     
     
         23 - 24 . (canceled)  
     
     
         25 . A compound of the formula:  
         A-X m -Z n    wherein    A is a drug radical;    X is a small linear or cyclic molecule containing 2-6 atoms with one or more heteroatoms and one or more functional groups, wherein X is bonded to A through a carboxyl group; and    Z is an amino acid, peptide, or oligopeptide covalently bound to X,    wherein m and n range between 1 and 50.    
     
     
         26 - 45 . (canceled)  
     
     
         46 . A compound comprising a drug radical covalently bonded to a first amino acid selected from the group consisting of Ser, Lys, Glu, Asp, Ala, Leu, Phe, Val, Gly, Tyr, Pro, and Thr, and a second amino acid or peptide covalently bonded to the first amino acid, wherein an optional linker attaches the first amino acid to the drug radical.  
     
     
         47 - 61 . (canceled)