Pharmaceutical formulations containing an opioid and an alpha-agonist

• US 20020044966A1
• Filed: 07/18/2001
• Published: 04/18/2002
• Est. Priority Date: 01/18/1999
• Status: Abandoned Application

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Betzing, Juergen, Bartholomaeus, Johannes
• Application Number:
  US09/907,447
• Publication Number:
  US 20020044966A1
• Time in Patent Office: Days
• US Class Current: 424/468
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/02 without antiinflammatory effect

Abstract

Pharmaceutical formulations containing an opioid, an α-agonist and/or their physically compatible salts, from which at least one medicinally active ingredient is released in a sustained manner.

Claims

1. A pharmaceutical formulation comprising in combination:

an opioid or physiologically compatible salt thereof, and

an α

-agonist or physiologically compatible salt thereof, wherein at least one of said opioid and α

-agonist is present in delayed release form.

2. A pharmaceutical formulation as claimed in claim 1, wherein the opioid is present in delayed release form.

3. A pharmaceutical formulation as claimed in claim 2, wherein the opioid is released over a period of at least 8 hours.

4. A pharmaceutical formulation as claimed in claim 3, wherein the opioid is released over a period of 12 hours.

5. A pharmaceutical formulation as claimed in claim 3, wherein the opioid is release over a period of 24 hours.

6. A pharmaceutical formulation as claimed in claim 1, wherein both the opioid and the α

-agonist are present in delayed release form.

7. A pharmaceutical formulation as claimed in claim 1, wherein the opioid comprises at least one compound selected from the group consisting of morphine, hydromorphone, codeine, oxycodone, dihydrocodeine, dextropropoxyphene, buprenorphine, levomethadone, fentanyl, sufentanil, etorphine, pentazocine, tilidine, tramadol, levorphanol, methadone, dihydromorphine, pethidine, piritramide, and physiologically compatible salts of any of the foregoing.

8. A pharmaceutical formulation as claimed in claim 7, wherein the opioid is selected from the group consisting of morphine, tramadol and physiologically compatible salts thereof.

9. A pharmaceutical formulation as claimed in claim 1, wherein the α

-agonist comprises at least one compound selected from the group consisting of clonidine, guanfacine, guanabenz, lofexidine, adrenaline, methyldopa, noradrenaline, methoxamine, oxymetazoline, xylometazoline, teryzoline, ST-91, medetomidine, dexmedetomidine, agmatine, UK14, 304, paraaminoclonidine, U-47, 476A, DJ-741, ICI-106270, xylazine, talipexole (BHT-920), naphazoline, tizanidine, and physiologically compatible salts of any of the foregoing.

10. A pharmaceutical formulation as claimed in claim 9, wherein the α

-agonist is selected from the group consisting of clonidine, guanfacine and physiologically compatible salts thereof.

11. A pharmaceutical formulation as claimed in claim 1, wherein the opioid and u-agonist, respectively, are present in a weight ratio of opioid to α

-agonist in the range from 200;

1 to 10;

1.

12. A pharmaceutical formulation as claimed in claim 11, wherein the ratio of opioid to α

-agonist is in the range from 100;

1 to 10;

1.

13. A pharmaceutical formulation as claimed in claim 1, in the form of a tablet or capsule.

14. A pharmaceutical formulation as claimed in claim 13, in the form of a sugar-coated tablet.

15. A pharmaceutical formulation as claimed in claim 13, in the form of a multilayer tablet.

16. A pharmaceutical formulation as claimed claim 1, wherein said formulation is in multi-particulate form.

17. A pharmaceutical formulation as claimed in claim 16, wherein said multi-particulate form is selected from the group consisting of microtablets, microcapsules, ion exchange resinates, granules, active substance crystals, and pellets.

18. A pharmaceutical formulation as claimed in claim 1, wherein said delayed release form comprises a controlled release coating, immobilization on an ion exchange resin, embedding in a controlled release matrix, or a combination at least two of the foregoing.

19. A pharmaceutical formulation as claimed in claim 18, wherein said delayed release form comprises a coating composed of a water-insoluble polymer or wax.

20. A pharmaceutical formulation as claimed in claim 19, wherein said coating comprises a water-insoluble polyacrylic resin or cellulose derivative.

21. A pharmaceutical formulation as claimed in claim 20, wherein said coating comprises a water-insoluble alkylcellulose.

22. A pharmaceutical formulation as claimed in claim 20, wherein said coating comprises a water-insoluble ethylcellulose or poly(meth)acrylate polymer.

23. A pharmaceutical formulation as claimed in claim 18, wherein said delayed release form comprises a controlled release matrix comprising at least one substance selected from the group consisting of polymers, waxes, fats, fatty acids, fatty alcohols, and fatty acid or fatty alcohol esters or ethers.

24. A pharmaceutical formulation as claimed in claim 23, wherein said controlled release matrix comprises at least one polymeric substance selected from the group consisting of cellulose ethers, cellulose esters and acrylic resins.

25. A pharmaceutical formulation as claimed in claim 23, wherein said controlled release matrix comprises at least one substance selected from the group consisting of ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, mono-and diglycerides of C12 to C30 fatty acids, C12-C30 fatty alcohols, and mixtures of two or more of the foregoing.

26. A pharmaceutical formulation as claimed in claim 1, wherein at least one of said opioid and said α

-agonist is present in both controlled release form and non-controlled release form.

27. A pharmaceutical formulation as claimed in claim 1, wherein said formulation is administrable orally, parenterally or transdermally.

28. A pharmaceutical formulation as claimed in claim 1, wherein said formulation is orally administrable.

29. A method of treating a patient suffering from a pain condition, said method comprising administering to said patient an effective pain relieving amount of a pharmaceutical formulation as claimed in claim 1.

30. A method as claimed in claim 29, wherein said pain condition is a moderately severe to severe acute or chronic pain state.