Abuse deterrent transdermal formulations of opiate agonists and agonist-antagonists

1. An abuse-resistant patch for transdermally delivering an opioid to a subject, comprising:

(a) a backing layer;

(b) a first layer underlying the backing layer, the first layer comprising: an opioid antagonist or opioid antagonist prodrug which is not transdermally delivered at therapeutic levels when the patch is used for transdermally administering the opioid to the subject; wherein the backing layer is substantially impermeable to the opioid antagonist or opioid antagonist prodrug of the first layer;

(c) a second layer underlying the first layer, the second layer comprising:

(i) an opioid selected from the group consisting of: an opioid agonist, an opioid agonist prodrug, an opioid agonist-antagonist and an opioid agonist-antagonist prodrug;

(ii) a pressure sensitive adhesive; wherein the second layer is adapted to be in diffusional communication with the skin of the subject to transdermally administer a therapeutically effective amount of the opioid to the subject; and

(d) a barrier layer located between the first and second layer, the barrier layer comprising: a water-insoluble polymeric material and a water-soluble polymer;

wherein the release ratio is between about 1:60 and about 60:1 after the patch has been placed in ethanol, water or a phosphate buffer having a pH of about 6.5 for greater than about 30 seconds.

2. The abuse-resistant transdermal patch of claim 1 , wherein the opioid agonist or opioid agonist prodrug is selected from the group consisting of: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levomethadyl, levophenacylmorphan, lofentanil, meperidine, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine and tramadol and prodrugs of any of the foregoing.

3. The abuse-resistant transdermal patch of claim 1 , wherein the opioid agonist-antagonist or opioid agonist-antagonist prodrug is selected from the group consisting of: buprenorphine, butorphanol, dezocine, meptazinol, nalbuphine, nalorphine and pentazocine and prodrugs of any of the foregoing.

4. The abuse-resistant transdermal patch of claim 3 , wherein the opioid agonist-antagonist is buprenorphine.

5. The abuse-resistant transdermal patch of claim 3 , wherein the opioid agonist-antagonist prodrug is a buprenorphine prodrug.

6. The abuse-resistant transdermal patch of claim 5 , wherein the buprenorphine prodrug is selected from the group consisting of:

and salts of the foregoing.

7. The abuse-resistant transdermal patch of claim 1 , wherein the opioid antagonist or the opioid antagonist prodrug is selected from the group consisting of: naltrexone, 6-beta-naltrexol, nalbuphine, nalmefene, naloxone, cyclazocine, levallorphan, cyclorphan and oxilorphan and prodrugs of any of the foregoing.

8. The abuse-resistant transdermal patch of claim 7 , wherein the opioid antagonist is naltrexone or naloxone.

9. The abuse-resistant transdermal patch of claim 7 , wherein the opioid antagonist prodrug is a naltrexone prodrug or a naloxone prodrug.

10. The abuse-resistant transdermal patch of claim 9 , wherein the naltrexone prodrug is:

where R 3 is selected from the group consisting of:

—COC(CH 3 ) 3 ; —COCH(CH 3 ) 2 ; —COCH 2 CH(CH 3 ) 2 ; —COCH(CH 2 CH 3 ) 2 ; —CON(CH 2 CH 3 ) 2 ; —CON(CH(CH 3 ) 2 ) 2 ; —COOCH(CH 3 ) 2 ;

 and

—CO(CH 2 ) 2 OCH 3 .

11. The abuse-resistant transdermal patch of claim 1 , wherein the water-insoluble polymeric material is selected from the group consisting of: ethyl cellulose, cellulose derivatives, cellulose esters, ethylene-vinyl acetate copolymer, polyolefins, polyethylene, low density polyethylene, medium density polyethylene, high density polyethylene, polypropylene, ethylene-propylene copolymers, styrene polymers, polystyrene, vinyl polymers, polyvinyl acetate, acrylic polymers, ethylenemethyl acrylate copolymer, polymethyl acrylate, polyethyl acrylate, ethylene-acrylic acid copolymer, ethylene-ethylacrylate copolymer, homopolymers of acrylic acid, copolymers of acrylic acid, methyl methacrylate, methyl acrylic acid esters with quaternary ammonium groups and combinations of the foregoing.

12. The abuse-resistant transdermal patch of claim 1 , wherein the water insoluble polymeric material is ethylcellulose.

13. The abuse-resistant transdermal patch of claim 1 , wherein the water-soluble polymer is selected from the group consisting of: cellulose derivatives, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methyl cellulose, cellulose gum, sodium carboxymethylhydroxyethylcellulose, methylhydroxyethylcellulose, carboxyalkylcelluloses, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene oxide, polysaccharides, dextran, polysialic acid, corn starch, agar, agarose, alginates, xanthan gums, heparin, chitin, chitosan, polyvinyl alcohol, polyethylene glycol, polyoxazoline, poly acryloylmorpholine and combinations of the foregoing.

14. The abuse-resistant transdermal patch of claim 1 , wherein the water-soluble polymer is hydroxypropylcellulose.

15. The abuse-resistant transdermal patch of claim 1 , wherein the first layer further comprises:

(a) optionally, a water-insoluble polymeric material selected from the group consisting of: ethyl cellulose, cellulose derivatives, cellulose esters, ethylene-vinyl acetate copolymer, polyolefins, polyethylene, low density polyethylene, medium density polyethylene, high density polyethylene, polypropylene, ethylene-propylene copolymers, styrene polymers, polystyrene, vinyl polymers, polyvinyl acetate, acrylic polymers, ethylenemethyl acrylate copolymer, polymethyl acrylate, polyethyl acrylate, ethylene-acrylic acid copolymer, ethylene-ethylacrylate copolymer, homopolymers of acrylic acid, copolymers of acrylic acid, methyl methacrylate, methyl acrylic acid esters with quaternary ammonium groups and combinations of the foregoing, and

(b) optionally, a water-soluble polymer selected from the group consisting of: cellulose derivatives, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methyl cellulose, cellulose gum, sodium carboxymethylhydroxyethylcellulose, methylhydroxyethylcellulose, carboxyalkylcelluloses, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene oxide, polysaccharides, dextran, polysialic acid, corn starch, agar, agarose, alginates, xanthan gums, heparin, chitin, chitosan, polyvinyl alcohol, polyethylene glycol, polyoxazoline, poly acryloylmorpholine and combinations of the foregoing.

16. The abuse-resistant transdermal patch of claim 1 , wherein the solvent is ethanol.

17. The abuse-resistant transdermal patch of claim 1 , wherein the solvent is water.

18. The abuse-resistant transdermal patch of claim 1 , wherein the solvent is a phosphate buffer having a pH of about 6.5.

19. The abuse-resistant transdermal patch of claim 1 , wherein the opioid antagonist is naltrexone and the opioid is buprenorphine or a buprenorphine prodrug and wherein the release ratio is between about 1:1 and about 0.01:1.

20. The abuse-resistant transdermal patch of claim 1 , wherein the opioid antagonist is a naltrexone prodrug and the opioid is buprenorphine or a buprenorphine prodrug and wherein the release ratio is between about 1:1 and about 0.01:1.

21. The abuse-resistant transdermal patch of claim 1 , wherein the opioid antagonist is naloxone and the opioid is buprenorphine or a buprenorphine prodrug and wherein the release ratio is between about 4:1 and about 0.01:1.

22. The abuse-resistant transdermal patch of claim 1 , wherein the opioid antagonist is a prodrug of naloxone and the opioid is buprenorphine or a buprenorphine prodrug and wherein the release ratio is between about 4:1 and about 0.01:1.

23. A method of treating a medical condition comprising affixing to the skin of the subject the transdermal patch of claim 1 ; wherein the medical condition is selected from the group consisting of: opioid dependence, alcohol dependence, polydrug addiction, pain, cocaine addiction, eating disorders and treatment-resistant depression.

24. The method of treating a medical condition of claim 23 , wherein the opioid agonist or opioid agonist prodrug is selected from the group consisting of: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levomethadyl, levophenacylmorphan, lofentanil, meperidine, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine and tramadol and prodrugs of any of the foregoing.

25. The method of treating a medical condition of claim 23 , wherein the opioid agonist-antagonist or opioid agonist-antagonist prodrug selected from the group consisting of: buprenorphine, butorphanol, dezocine, meptazinol, nalbuphine, nalorphine and pentazocine and prodrugs of any of the foregoing.

26. The method of treating a medical condition of claim 23 , wherein the opioid antagonist or opioid antagonist prodrug is selected from the group consisting of: naltrexone, 6-beta-naltrexol, nalbuphine, nalmefene, naloxone, cyclazocine, levallorphan, cyclorphan and oxilorphan and prodrugs of any of the foregoing.

27. A method of making an abuse-resistant transdermal patch for delivering an opioid to a subject comprising the steps of:

(a) applying a first layer to a substrate comprising a backing layer, the layer comprising: an opioid antagonist or opioid antagonist prodrug which is not transdermally delivered at therapeutic levels when the patch is used for transdermally administering the opioid;

(b) applying a barrier layer to the first layer, the barrier layer comprising: a water-insoluble polymeric material and a water-soluble polymer; and

(c) applying a second layer to the barrier layer, the second layer comprising:

(i) an opioid selected from the group consisting of: an opioid agonist, a prodrug of an opioid agonist, an opioid agonist-antagonist and a prodrug of an opioid agonist-antagonist; and

(ii) a pressure sensitive adhesive; wherein the second layer is adapted to be in diffusional communication with the skin of the subject to transdermally administer a therapeutically effective amount of the opioid to the subject;

wherein the release ratio is between about 1:60 and about 60:1 after the patch has been placed in ethanol, water or a phosphate buffer having a pH of about 6.5 for greater than about 30 seconds.

28. The method of claim 27 , wherein the opioid agonist or opioid agonist prodrug is selected from the group consisting of: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levomethadyl, levophenacylmorphan, lofentanil, meperidine, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine and tramadol and prodrugs of any of the foregoing.

29. The method of claim 27 , wherein the opioid agonist-antagonist or opioid agonist-antagonist prodrug is selected from the group consisting of: buprenorphine, butorphanol, dezocine, meptazinol, nalbuphine, nalorphine and pentazocine and prodrugs of any of the foregoing.

30. The method of claim 27 , wherein the opioid antagonist or opioid antagonist prodrug is selected from the group consisting of: naltrexone, 6-beta-naltrexol, nalbuphine, nalmefene, naloxone, cyclazocine, levallorphan, cyclorphan and oxilorphan and prodrugs of any of the foregoing.