Combination analgesic employing opioid and neutral antagonist
A non-addictive analgesic co-formulation comprising an opioid agonist in an amount sufficient to confer analgesia in a mammalian subject and a neutral opioid antagonist in an amount sufficient to inhibit peripheral effects, and insufficient to block substantial central effects, of the opioid agonist in the subject. Such formulations, and methods of using same, may also deter diversion, inhibit peripheral effects, and reduce addiction liability.
1. A unit dosage of an analgesic composition comprising:
an opioid agonist in an amount sufficient to confer analgesia in a mammalian subject; and
a neutral opioid antagonist in an amount sufficient to substantially inhibit peripheral effects, and insufficient to block substantial central effects, of the opioid agonist in the subject, wherein the agonist and antagonist are selected so that a ratio of antinociception ID50 to GI transit ID50 for the agonist and the antagonist is between about 5 and about 50.
2. A unit dosage of analgesic composition according to claim 1 , wherein the opioid agonist is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, noroxycodone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine and tramadol.
3. A unit dosage of an analgesic composition according to claim 2 , wherein the subject is a human.
4. A unit dosage of an analgesic composition according to claim 3 , such composition being suitable for oral, peroral, intragastric, sublingual, suppository, or intravenous administration.
5. A unit dosage according to claim 4 , wherein the neutral opioid antagonist has a blood half-life substantially longer than the blood half-life of the opioid agonist, so that repeated administration of the dosage or administration above a prescribed dosage causes a greater increase in blood concentration of the antagonist than of the agonist, so as to deter diversion, discourage abuse and/or reduce addiction liability to the agonist resulting from such administration.
6. A unit dosage according to claim 4 , wherein the neutral opioid antagonist and/or agonist are suitable for formulation in a slow-release formulation, slow-release co-formulation, or are formulated in a slow-release formulation or co-formulation, either separately or together.
7. A unit dosage of an analgesic composition according to claim 1 wherein the opioid agonist is hydrocodone.
8. A unit dosage according to claim 1 that deters abuse of the opioid agonist, wherein the opioid agonist has a blood half-life; and the neutral opioid antagonist has a blood half-life substantially longer than the blood half-life of the opioid agonist and is also present in an amount effective so that, upon successive administration of the unit dosage, the blood concentration ratio of neutral opioid antagonist to opioid agonist increases with each successive administration until a steady state is reached, as measured in mg per kg of body weight of the subject, and repeated administration of the unit dosage exceeding therapeutically recommended limits results in reduced euphoria and reduced pain relief in the subject so as to deter abuse.
9. A pharmaceutical composition according to claim 8 , wherein the neutral opioid antagonist and/or agonist are suitable for formulation in a slow-release formulation, slow-release co-formulation, or are formulated in a slow-release formulation or co-formulation, either separately or together.
10. A unit dosage according to claim 1 , wherein the opioid antagonist is a naltrexone analog represented by formula Iα or Iβ:
wherein:
R 1 is C 3 -C 6 (cycloalkyl)(alkyl) or C 5 -C 7 (cycloalkenyl)alkyl;
R 2 is H, OH or esters thereof;
R 3 is H, alkyl or C 1 -C 6 alkyl-C═O;
R 4 and R 5 are independently H, halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, nitro, amino, cyano, carboxyl or acyl which may be substituted for one or more hydrogens on the ring;
X 1 and X 2 are the same or different, and may be H, alkyl, —OR 6 , —NR 7 R 8 R 9 , —NCOR 10 , —NO 2 , or —SR 11 ,
wherein,
R 6 and R 11 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, aroyl, polyethyleneglycyl (PEGyl) or a polyether group;
R 7 , R 8 and R 10 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl;
R 9 and R 12 can be present or absent and are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl or pharmaceutically acceptable salts thereof.
11. A unit dosage according to claim 1 , wherein the opioid antagonist is a naloxone analog represented by formula Iα or Iβ:
wherein:
R 1 is C 3 -C 6 alkenyl;
R 2 is H, OH or esters thereof;
R 3 is H, alkyl or C 1 -C 6 alkyl-C═O;
R 4 and R 5 are independently H, halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, nitro, amino, cyano, carboxyl or acyl which may be substituted for one or more hydrogens on the ring;
X 1 and X 2 are the same or different, and may be H, alkyl, —OR 6 , —NR 7 R 8 R 9 , —NCOR 10 , —NO 2 , or —SR 11 ,
wherein,
R 6 and R 11 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, aroyl, polyethyleneglycyl (PEGyl) or a polyether group;
R 7 , R 8 and R 10 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl;
R 9 and R 12 can be present or absent and are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl or pharmaceutically acceptable salts thereof.
12. A unit dosage according to claim 1 , wherein the neutral opioid antagonist is selected from the group consisting of 6β-naltrexamide, a pharmaceutically acceptable isomorph thereof, and a pharmaceutically acceptable salt thereof.
13. A unit dosage according to claim 1 , wherein the neutral opioid antagonist is selected from the group consisting of 6β-naltrexol, a pharmaceutically acceptable isomorph thereof, and a pharmaceutically acceptable salt thereof.
14. A composition according to claim 1 , wherein the neutral opioid antagonist is 6β-naltrexol present in an amount between about 0.008-0.25 mg/kg of body weight of the subject and the opioid agonist is a therapeutically effective amount of hydrocodone.
15. A unit dosage of analgesic composition according to claim 1 , wherein the opioid agonist is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, noroxycodone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine and tramadol.
16. A unit dosage of an analgesic composition according to claim 15 , such composition being suitable for oral, peroral, intragastric, sublingual, suppository, or intravenous administration.
17. A unit dosage according to claim 16 , wherein the neutral opioid antagonist has a blood half-life substantially longer than the blood half-life of the opioid agonist, so that repeated administration of the dosage or administration above a prescribed dosage causes a greater increase in blood concentration of the antagonist than of the agonist, so as to deter diversion, discourage abuse and/or reduce addiction liability to the agonist resulting from such administration.
18. A pharmaceutical composition according to claim 17 , wherein the neutral opioid antagonist and/or agonist are suitable for formulation in a slow-release formulation, slow-release co-formulation, or are formulated in a slow-release formulation or co-formulation, either separately or together.
19. A unit dosage according to claim 16 , wherein the neutral opioid antagonist and/or agonist are suitable for formulation in a slow-release formulation, slow-release co-formulation, or are formulated in a slow-release formulation or co-formulation, either separately or together.
20. A unit dosage of an analgesic composition comprising:
an opioid agonist in an amount sufficient to confer analgesia in a mammalian subject; and
a neutral opioid antagonist in an amount sufficient to produce nearly complete inhibition of peripheral effects, and insufficient to block substantial central effects, of the opioid agonist in the subject.
21. A unit dosage of an analgesic composition according to claim 20 , wherein the subject is a human.
22. A unit dosage of an analgesic composition according to claim 20 , wherein the opioid agonist is hydrocodone.
23. A unit dosage according to claim 20 that deters abuse of the opioid agonist, wherein the opioid agonist has a blood half-life; and the neutral opioid antagonist has a blood half-life substantially longer than the blood half-life of the opioid agonist and is also present in an amount effective so that, upon successive administration of the unit dosage, the blood concentration ratio of neutral opioid antagonist to opioid agonist increases with each successive administration until a steady state is reached, as measured in mg per kg of body weight of the subject, and repeated administration of the unit dosage exceeding therapeutically recommended limits results in reduced euphoria and reduced pain relief in the subject so as to deter abuse.
24. A unit dosage according to claim 20 , wherein the opioid antagonist is a naltrexone analog represented by formula Iα or Iβ:
wherein:
R 1 is C 3 -C 6 (cycloalkyl)(alkyl) or C 5 -C 7 (cycloalkenyl)alkyl;
R 2 is H, OH or esters thereof;
R 3 is H, alkyl or C 1 -C 6 alkyl-C═O;
R 4 and R 5 are independently H, halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, nitro, amino, cyano, carboxyl or acyl which may be substituted for one or more hydrogens on the ring;
X 1 and X 2 are the same or different, and may be H, alkyl, —OR 6 , —NR 7 R 8 R 9 , —NCOR 10 , —NO 2 , or —SR 11 ,
wherein,
R 6 and R 11 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, aroyl, polyethyleneglycyl (PEGyl) or a polyether group;
R 7 , R 8 and R 10 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl;
R 9 and R 12 can be present or absent and are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl or pharmaceutically acceptable salts thereof.
25. A unit dosage according to claim 20 , wherein the opioid antagonist is a naloxone analog represented by formula Iα or Iβ:
wherein:
R 1 is C 3 -C 6 alkenyl;
R 2 is H, OH or esters thereof;
R 3 is H, alkyl or C 1 -C 6 alkyl-C═O;
R 4 and R 5 are independently H, halogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, nitro, amino, cyano, carboxyl or acyl which may be substituted for one or more hydrogens on the ring;
X 1 and X 2 are the same or different, and may be H, alkyl, —OR 6 , —NR 7 R 8 R 9 , —NCOR 10 , —NO 2 , or —SR 11 ,
wherein,
R 6 and R 11 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, acyl, aroyl, polyethyleneglycyl (PEGyl) or a polyether group;
R 7 , R 8 and R 10 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl;
R 9 and R 12 can be present or absent and are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl or pharmaceutically acceptable salts thereof.
26. A unit dosage according to claim 20 , wherein the neutral opioid antagonist is selected from the group consisting of 6β-naltrexamide, a pharmaceutically acceptable isomorph thereof, and a pharmaceutically acceptable salt thereof.
27. A unit dosage according to claim 20 , wherein the neutral opioid antagonist is selected from the group consisting of 6β-naltrexol, a pharmaceutically acceptable isomorph thereof, and a pharmaceutically acceptable salt thereof.
28. A composition according to claim 20 , wherein the neutral opioid antagonist is 6β-naltrexol present in an amount between about 0.008-0.25 mg/kg of body weight of the subject and the opioid agonist is a therapeutically effective amount of hydrocodone.