Novel synergistic opioid-cannabinoid codrug for pain management

• US 20080176885A1
• Filed: 10/10/2007
• Published: 07/24/2008
• Est. Priority Date: 10/10/2006
• Status: Abandoned Application

• Current Assignee: INSYS Therapeutics, Inc.
• Original Assignee: University of Kentucky
• Inventors: Crooks, Peter A., Holtman, Joseph R., Dhooper, Harpreet K.
• Application Number:
  US11/973,818
• Publication Number:
  US 20080176885A1
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds including an opioid, and a cannabinoid covalently bound by a linker; pharmaceutical formulations including codrugs; methods of manufacture as well as methods of treatment are disclosed.

Claims

10. A pharmaceutical composition comprising:

an analgesically effective amount of a compound selected from the group consisting of;

Compound 1;

11. The pharmaceutical composition of claim 10 wherein the compound is Compound 1 or Compound 2;

and X is a C_1-4 alkylene.

12. The pharmaceutical composition of claim 10 wherein the compound is Compound 1 and R is methyl.

13. The pharmaceutical composition of claim 10 wherein the compound is Compound 1 and R is hydrogen.

14. The pharmaceutical composition of claim 10 wherein the compound is Compound 1 or Compound 2;

and X is a bond.

15. The pharmaceutical composition of claim 10 wherein the formulation is suitable for a route of administration selected from the group consisting of:

oral, sublingual, oral inhalation, nasal inhalation, sublingual, rectal, vaginal, urethral, intravenous, intra-arterial, intradermal, intramuscular, subcutaneous, transdermal, mucosal and buccal.

16. The pharmaceutical composition of claim 10 wherein the release of the codrug is substantially controlled over an extended period of time selected from the group consisting of:

about 4 hours, about 8 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours and about 96 hours.

17. The pharmaceutical composition of claim 16 wherein the release of the codrug is substantially controlled for about 6-12 hours.

18. The pharmaceutical composition wherein the release of the codrug is substantially controlled for about 12-24 hours.

19. A method of synthesis of a codrug comprising a linker, an opioid and a cannabinoid, said method comprising:

a) covalently bonding a first attachment point of the linker to the opioid;

b) covalently bonding a second attachment point of the linker to a cannabinoid; and

c) recovering the codrug.

20. The method of claim 19 further comprising:

a) reacting para-nitrophenyl chloroformate with an opiate (opioid) (R1) containing a hydroxy group in the presence of triethyl amine and dry chloroform;

b) cooling the solution;

c) recovering the resulting 6-O-para-nitrophenoxycarbonate ester of an opiate drug;

d) reacting the 6-O-para-nitrophenoxycarbonate ester of an opiate drug with a cannabinoid drug (R₂) with a hydroxyl group;

e) recovering the cannabinoid-opioid codrug.

24. The method of claim 19 wherein step b) is reacted in the presence of dry THF and tri ethyl amine.

25. The method of claim 19 wherein step b) occurs under cooled conditions and in a nitrogen atmosphere.

21-1. The method of claim 26 wherein the codrug substantially remains intact until it reaches the site of action of at least the opioid or the cannabinoid.

26. A method of treatment comprising:

joining an opioid together with a cannabinoid using a linker to form a cleavable codrug; and

administering an analgesically effective amount of the codrug to a human patient.

1. A compound of the following formula:

2. The compound of claim 1, wherein n is 1 and the linker is C_1-4 alkylene.

3. The compound of claim 1 wherein n is 1;

and the linker is an alkylene substituted with a heteroatom selected from the group consisting of O and S.

4. The compound of claim 2, wherein the opioid is Pentazocine, Etorphine, Dihydroetorphine, Phenazocine, Hydrocodone, Methadone, Codeine, Propoxyphene, Meperidine, Morphine, Morphine Sulfate Ester, Tramadol, Hydromorphone, Buprenorphine, Oxymorphone, Levorphanol, L-acetylmethadol, Normethadone, Normorphine, Dihydrocodeine and Ethylmorphine, as well as any pharmaceutically acceptable salts, metabolites, enantiomers, diastereiomers and isomers thereof.

5. The compound of claim 4, wherein the cannabinoid for combination with the opioid is selected from dronabinol (delta-9-tetrahydrocannabinol) and related cannabinoids such as (−

)-delta-9-tetrahydrocannabinol, (+)-delta-9-tetrahydrocannabinoid and delta-8-tetrahydrocannabinol, cannabinol, cannabigerol, cannabicyclol, cannabielsoic acid and their respective pure enantiomers and/or diastereiomers, combinations of the above cannabinoids, plants extracts containing any or all of the above cannabinoids, all naturally occurring cannabinoids, all therapeutically useful and pharmacologically active cannabinoids metabolites, all natural and synthetic nonpsychoactive cannabinoids and their analogs (e.g. dexanabinol), and all psychoactive cannabinoids and their analogs (e.g. nantradol, nabitan) as well as any pharmaceutically acceptable salts, metabolites, enantiomers, diastereiomers and isomers thereof.

6. The compound of claim 1 having the following formula:

7. The compound of claim 1 having the following formula:

8. The compound of claim 1 having the following formula:

9. The compound of claim 1 having the following formula

21. The method of claim 14 comprising:

a) reacting para-nitrophenyl chloroformate with codeine to produce the para-nitrophenoxycarbonate ester of codeine;

b) reacting the para-nitrophenoxycarbonate ester of codeine with Δ

-9 THC to produce 6-O, 1-O carbonate linked codrug of codeine and Δ

-9 THC.

22. The method of claim 21 wherein step a) is reacted in the presence of dry chloroform and triethylamine.

23. The method of claim 21 wherein step a) occurs under cooled conditions and in a nitrogen atmosphere.

27. The method of claim 26, wherein the codrug is more lipophilic than the opioid molecule.

28. The method of claim 26 wherein the codrug provides for a more desirable pharmacokinetic profile as compared to the opioid or cannabinoid when administered as distinct molecules.

29. The method of claim 26 wherein the amount of the opioid present in the codrug would be subtherapeutic if administered without the cannabinoid.

30. The method of claim 26 wherein the amount of the cannabinoid present in the codrug would be subtherapeutic if administered without the opioid.

31. The method of claim 26 wherein the amount of the cannabinoid and the amount of the opioid present in the codrug would each be subtherapeutic if not administered concomitantly.

32. The method of claim 26 wherein the synergistic analgesic effect of morphine and dronabinol is about 1.5-3 times greater than the extrapolated additive effect of administering morphine and dronabinol alone.

33. The method of claim 32 wherein the synergistic analgesic effect of morphine and dronabinol is about 2.5 times greater than the extrapolated additive effect of administering morphine and dronabinol alone.