STABILIZATION OF QUINOL COMPOSITION SUCH AS CATECHOLAMINE DRUGS

• US 20120029085A1
• Filed: 07/29/2010
• Published: 02/02/2012
• Est. Priority Date: 07/29/2010
• Status: Abandoned Application

• Current Assignee: Jon Mackay
• Original Assignee: Jon Mackay
• Inventors: MacKay, Jon
• Application Number:
  US12/846,656
• Publication Number:
  US 20120029085A1
• Time in Patent Office: Days
• US Class Current: 514/626
• 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 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 23/00 Anaesthetics

Abstract

Compositions and methods are provided for obtaining stabilized quinol compositions, such as catecholamine drugs (e.g., epinephrine solutions), and also for obtaining stable pharmaceutical formulations that comprise a stabilized quinol composition and a second pharmacologically active component such as a local anesthetic or other active drug ingredient having a reversibly protonated amine group. Stability is achieved through the inclusion of an appropriately selected pH buffer and a thiol agent, based on redox and pH buffering principles including pKa of the buffer and of the reversibly protonated amine group.

Claims

1. A stable pharmaceutical formulation, comprising:

(a) a first composition that comprises at least one quinol compound having a first desired pharmacological activity;

(b) a second composition that comprises at least one local anesthetic compound, said local anesthetic compound comprising at least one amine group that is capable of being reversibly protonated, and being capable of reversibly binding to a voltage-gated Na⁺ channel in a cell membrane to thereby after Na⁺ movement through the voltage-gated Na⁺ channel;

(c) at least one thiol agent; and

(d) at least one pH buffer that maintains a substantially constant pH in the pharmaceutical formulation, wherein the pH is greater than about pH 5.5.

2. A stable pharmaceutical formulation according to claim 1 wherein the quinol compound is present in a reduced form.

3. A stable pharmaceutical formulation according to claim 1 wherein the quinol compound comprises an ortho-quinol moiety or a para-quinol moiety.

4. A stable pharmaceutical formulation according to claim 1 wherein at least one quinol compound comprises a catecholamine.

5. A stable pharmaceutical formulation according to claim 1 wherein at least one quinol compound comprises a compound of Formula (I):

6. A stable pharmaceutical formulation according to claim 1 wherein the quinol compound comprises a compound selected from the group consisting of 1,2-dihydroxybenzene (catechol, pyrocatechol), 1,4-dihydroxybenzene, epinephrine, norepinephrine, dopamine, dobutamine, isoproterenol, racepinephrine, arbutamine, carbidopa, deoxyepinephrine, dioxethedrine, 3-(3,4-dihydroxyphenyl)-alanine (L-, D- or DL-DOPA), dopexamine, droxidopa, ethylnorepinephrine, hexoprenaline, isoetharine, methyldopa, N-methylepinephrine, nordefrin, rimiterol, epinephrine bitartrate, L-epinephrine-D-hydrogentartate, adrenalone (CAS 99-45-6), arbutamine (CAS 128470-16-6), benserazide (CAS 322-35-0), carbidopa (CAS 28860-95-9), deoxyepinephrine (CAS 501-15-5), dioxethdrine (CAS 497-75-6), dobutamine (CAS 34368-04-02), dopa (CAS 63-84-3), dopamine (CAS 51-61-6), dopexamine (CAS 86197-47-9), droxidopa (CAS 23651-95-8), epinephrine (CAS 51-43-4), ethylnorepinephrine (CAS 536-24-3), fluorodopa (CAS 92812-82-3), hexoprenaline (CAS 3215-70-1), isoetharine (CAS 530-08-5), isoproterenol (CAS 7683-59-2), levodopa (CAS 59-92-7), methyldopa (CAS 555-30-6), N-methylepinephrine (CAS 554-99-4), nordefrin (CAS 6539-57-7), norepinephrine (CAS 51-41-2), protokylol (CAS 136-70-9), rimiterol (CAS 32953-89-2), nordihydroguaiaretic acid and tetrahydropapaveroline (CAS 4747-99-3).

7. A stable pharmaceutical formulation according to claim 1 wherein the quinol compound comprises epinephrine.

8. A stable pharmaceutical formulation according to claim 1 wherein the thiol agent is selected from the group consisting of cysteine, N-acetylcysteine, glutathione, monothioglycerol, cysteine ethyl ester, homocysteine, Coenzyme A, dithiothreitol, 2-mercaptoethanol, 2,3-dimercapto-1-propanol, 2,3-butanedithiol, 2-mercaptoethylamine, ethanedithiol, propanedithiol, 3-mercapto-2-butanol, dimercapto-propane-1-sulfonic acid, dimercaptosuccinic acid, trithiocyanuric acid, 2,5-dimercapto-1,3,4-thiadiazole, 3,4-dimercaptotoluene, 1,4-dimercapto-2,3-butanediol, 1,3-propanedithiol, 1,4-butanedithiol, N-acetylpenicillamine, ACV, N-amyl mercaptan, bucillamine, N-butyl mercaptan, sec-butyl bercaptan, tert-butyl mercaptan, captopril, cysteamine, DBHBT, 2,3-dimercapto-1-propanesulfonic acid, dimercaprol, dithiosalicylic acid, 1,2-ethanedithiol, ethanethiol, isobutyl mercaptan, mecysteine, 2-mercaptoethanol, MESNA, methanethiol, pantetheine, penicillamine, 1,3-propanedithiol, succimer, thioacetic acid, thiobenzyl alcohol, thiocyanic acid, thioglycerol, thioglycolic acid, thiolactic acid, thiomalic acid, thionalide, 1-thiosorbitol, tiopronin, tixocortol and trithiocarbonic acid.

9. A stable pharmaceutical formulation according to claim 1 wherein the thiol agent is selected from the group consisting of cysteine, N-acetylcysteine, glutathione, monothioglycerol, and cysteine ethyl ester.

10. A stable pharmaceutical formulation according to claim 1 wherein the thiol agent is selected from the group consisting of glutathione, monothioglycerol, and cysteine ethyl ester.

11. A stable pharmaceutical formulation according to claim 1 wherein the thiol agent is selected from the group consisting of cysteine and N-acetylcysteine.

12. A stable pharmaceutical formulation according to claim 1 wherein the pH buffer is present under conditions and in sufficient quantity to maintain a pH that is from about pH 5.5 to about pH 9.0.

13. A stable pharmaceutical formulation according to claim 1 wherein the pH buffer is present under conditions and in sufficient quantity to maintain a pH that is from about pH 5.5 to about pH 8.5.

14. A stable pharmaceutical formulation according to claim 1 wherein the pH buffer is present under conditions and in sufficient quantity to maintain a pH that is from about pH 5.5 to about pH 8.25.

15. A stable pharmaceutical formulation according to claim 1 wherein the pH buffer is present under conditions and in sufficient quantity to maintain a pH that is from about pH 5.75 to about pH 7.75.

16. A stable pharmaceutical formulation according to claim 1 wherein the pH buffer is present under conditions and in sufficient quantity to maintain a pH that is from about pH 6.0 to about pH 7.5.

17. A stable pharmaceutical formulation according to claim 1 wherein the pH buffer is present under conditions and in sufficient quantity to maintain a pH that is from about pH 6.3 to about pH 7.3.

18. A stable pharmaceutical formulation according to claim 1 wherein the pH buffer is present under conditions and in sufficient quantity to maintain a pH that is from about pH 6.5 to about pH 7.1.

19. A stable pharmaceutical formulation according to claim 1 wherein the pH buffer is present under conditions and in sufficient quantity to maintain a pH that is from about pH 6.3 to about pH 6.9.

20. A stable pharmaceutical formulation according to claim 1 wherein the pH buffer comprises a compound that is selected from the group consisting of Tris (8.3), Tricine (8.15), citrate (pKa₃=5.4), acetate (4.75), phosphate (7.2), borate (9.24), HEPES (7.55), HEPPS (8), MES (6.15), ACES (6.9), imidazole (7), diethylmalonic acid (7.2), MOPS (7.2), PIPES (6.8), TES (7.5), carbonate, bicarbonate, malate, pyridine, piperazine, succinate, histidine, maleate, Bis-Tris, pyrophosphate, histidine, MOPSO, BES, DIPSO, MOBS, TAPSO, triethanolamine, POPSO, cacodylic acid, ADA, Bis-Tris propane and HEPPSO.

21. A stable pharmaceutical formulation according to claim 1 wherein the pH buffer comprises sodium phosphate.

22. A stable pharmaceutical formulation according to claim 1 wherein the quinol compound comprises epinephrine, the thiol agent is N-acetylcysteine and the pH buffer comprises sodium phosphate.

23. A stable pharmaceutical formulation according to claim 1 wherein the quinol compound comprises epinephrine, the thiol agent is cysteine and the pH buffer comprises sodium phosphate.

24. A stable pharmaceutical formulation according to claim 1 wherein the amine group that is capable of being reversibly protonated has a pKa of from about pH 7.5 to about pH 9.3.

25. A stable pharmaceutical formulation according to claim 1 wherein the amine group that is capable of being reversibly protonated has a pKa of from about pH 7.6 to about pH 9.2.

26. A stable pharmaceutical formulation according to claim 1 wherein the amine group that is capable of being reversibly protonated has a pKa of from about pH 7.7 to about pH 9.1.

27. A stable pharmaceutical formulation according to claim 1 wherein the amine group that is capable of being reversibly protonated has a pKa of from about pH 7.8 to about pH 9.0.

28. A stable pharmaceutical formulation according to claim 1 wherein the amine group that is capable of being reversibly protonated has a pKa of from about pH 7.9 to about pH 8.9.

29. A stable pharmaceutical formulation according to claim 1 wherein the amine group that is capable of being reversibly protonated has a pKa of from about pH 8.0 to about pH 8.8.

30. A stable pharmaceutical formulation according to claim 1 wherein the amine group that is capable of being reversibly protonated has a pKa of from about pH 8.1 to about pH 8.7.

31. A stable pharmaceutical formulation according to claim 1 wherein the amine group that is capable of being reversibly protonated has a pKa of from about pH 8.2 to about pH 8.6.

32. A stable pharmaceutical formulation according to claim 1 wherein the amine group that is capable of being reversibly protonated has a pKa of from about pH 8.3 to about pH 8.5.

33. A stable pharmaceutical formulation according to claim 1 wherein the local anesthetic compound is selected from the group consisting of an amino ester anesthetic and an amino amide anesthetic.

34. A stable pharmaceutical formulation according to claim 1 wherein the cell membrane is a plasma membrane of a neuron.

35. The pharmaceutical formulation of claim 1 wherein the cell membrane is selected from the group consisting of a plasma membrane, a mitochondrial membrane, an endoplasmic reticulum membrane, a lysozomal membrane, an exocytic vacuolar membrane and an endocytic vacuolar membrane.

36. A stable pharmaceutical formulation according to claim 1 wherein the second composition comprises a compound that is selected from the group consisting of lidocaine, propoxycaine, procaine, prilocalne, bupivacaine, Articaine, Benzocaine, Chloroprocaine, Cocaine, Dibucaine, Etidocaine, Hexylcaine, Mepivicaine, Piperocaine, Ropivacaine and Tetracaine.

37. A stable pharmaceutical formulation according to claim 1 wherein the second composition comprises a compound that is selected from the group consisting of lidocaine, bupivacaine, ropivacaine, Articaine, mepivicaine, and prilocalne.

38. A stable pharmaceutical formulation according to claim 1 wherein the first composition comprises epinephrine and the second composition comprises lidocaine.

39. A stable pharmaceutical formulation according to claim 1 wherein the first composition comprises epinephrine, the second composition comprises lidocaine, and the thiol agent comprises N-acetylcysteine.

40. A stable pharmaceutical formulation according to claim 1 wherein the first composition comprises epinephrine, the second composition comprises lidocaine, and the thiol agent comprises cysteine.

41. A stable pharmaceutical formulation according to claim 1 wherein the first composition comprises epinephrine, the second composition comprises lidocaine, the thiol agent comprises N-acetylcysteine and the pH buffer comprises sodium phosphate.

45. A stable pharmaceutical formulation according to claim 1 wherein the first composition is present at a mass-to-volume ratio in the formulation that is between 1:

500,000 and 1;

10,000.

46. A stable pharmaceutical formulation according to claim 1 wherein the first composition is present at a mass-to-volume ratio in the formulation that is between 1:

250,000 and 1;

50,000.

47. A stable pharmaceutical formulation according to claim 1 wherein the thiol agent is present at least from about 0.01 percent weight-to-volume to about ten percent weight-to-volume.

48. A stable pharmaceutical formulation according to claim 1 wherein the thiol agent is present at least from about 0.01 percent weight-to-volume to about one percent weight-to-volume.

49. A stable pharmaceutical formulation according to claim 1 wherein the thiol agent is present at least from about 0.05 percent weight-to-volume to about one percent weight-to-volume.

50. A stable pharmaceutical formulation according to claim 1 wherein the thiol agent is present at least from about 0.1 percent weight-to-volume to about five percent weight-to-volume.

42. A stable pharmaceutical formulation, comprising:

(a) a first composition that comprises at least one quinol compound having a first desired pharmacological activity;

(b) a second composition that comprises at least one local anesthetic compound that is capable of reversibly binding to a voltage-gated Na⁺ channel in a cell membrane to thereby after Na⁺ movement through the voltage-gated Na⁺ channel;

(c) at least one thiol agent; and

(d) at least one pH buffer that maintains a substantially constant pH in the pharmaceutical formulation, wherein the pH is greater than about pH 5.5.

43. The stable pharmaceutical formulation of claim 42 wherein the local anesthetic compound is lidocaine.

44. The stable pharmaceutical formulation of claim 42 wherein the local anesthetic compound is selected from the group consisting of lidocaine, bupivacaine, ropivacaine, Articaine, mepivicaine, and prilocalne.

51. A method of stabilizing a pharmaceutical formulation, comprising:

contacting (a) a pharmaceutical formulation,

(b) at least one thiol agent, and

(c) a pH buffer that maintains a substantially constant pH, wherein the pH is greater than about pH 5.5,

wherein;

the pharmaceutical formulation of (a) comprises (i) a first composition that comprises at least one quinol compound having a first desired pharmacological activity, and (ii) a second composition that comprises at least one local anesthetic compound, said local anesthetic compound comprising an amine-containing compound having a second desired pharmacological activity and at least one amine group that is capable of being reversibly protonated, and thereby stabilizing the pharmaceutical formulation.

52. A method of stabilizing a pharmaceutical formulation, comprising:

contacting (a) a pharmaceutical formulation which comprises (i) a first composition that comprises at least one quinol compound having a first desired pharmacological activity, and (ii) a second composition that comprises at least one local anesthetic compound, said local anesthetic compound comprising an amine-containing compound having a second desired pharmacological activity and at least one amine group that is capable of being reversibly protonated,

(b) at least one thiol agent, and

(c) a pH buffer that maintains a substantially constant pH, to produce a stable pharmaceutical formulation.

53. A method of treating a subject, comprising administering to said subject a stable pharmaceutical formulation, comprising:

(a) a first composition that comprises at least one quinol compound having a first desired pharmacological activity;

(b) a second composition that comprises at least one local anesthetic compound, said local anesthetic compound comprising an amine-containing compound having a second desired pharmacological activity and at least one amine group that is capable of being reversibly protonated;

(c) at least one thiol agent; and

(d) at least one pH buffer that maintains a substantially constant pH in the pharmaceutical formulation, wherein the pH is greater than about pH 5.5.

54. A method for the manufacture of a medicament for therapeutic treatment of a subject with a stable pharmaceutical formulation, said method comprising:

contacting (a) a pharmaceutical formulation,

(b) at least one thiol agent, and

(c) a pH buffer that maintains a substantially constant pH, wherein the pH is greater than about pH 5.5,

wherein;

the pharmaceutical formulation of (a) comprises (i) a first composition that comprises at least one quinol compound having a first desired pharmacological activity, and (ii) a second composition that comprises at least one local anesthetic compound, said local anesthetic compound comprising an amine-containing compound having a second desired pharmacological activity and at least one amine group that is capable of being reversibly protonated.