Drug combination pharmaceutical compositions and methods for using them

• US 20080033027A1
• Filed: 07/28/2006
• Published: 02/07/2008
• Est. Priority Date: 03/21/2005
• Status: Abandoned Application

• Current Assignee: Vicus Therapeutics, LLC
• Original Assignee: Vicus Therapeutics Spe 1, LLC
• Inventors: Young, Frederic S., Maki, John, Bascomb, Newell
• Application Number:
  US11/495,191
• Publication Number:
  US 20080033027A1
• Time in Patent Office: Days
• US Class Current: 514/411
• 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 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/472 Non-condensed isoquinolines, e.g. papaverine
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system

Abstract

The invention provides preparations, formulations, kits and other products of manufacture (e.g., blister packs) comprising combinations of beneficial ingredients that are serviceable as therapies for improving states and disease symptoms such as involving inflammation, excessive sympathoneural drive, cachexia, anorexia, and anorexia-cachexia, as well as stress or anxiety related thereto, and methods of making and using them. The invention provides compositions and therapies comprising use of a beta adrenergic antagonist (also called “beta blockers”, e.g., propranolol) in combination with an anti-inflammatory agent, e.g., a nonsteroidal anti-inflammatory drug (NSAID), an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), an anabolic steroid, a natural oil or fatty acid or any combination thereof.

Claims

1. A therapeutic combination of drugs for an individual in need thereof comprising

(a) at least one member of a first drug group and at least one member of a second drug group;

wherein a member of the first drug group comprises a beta adrenergic receptor antagonist (a beta blocker) comprising a propranolol, a 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride, or equivalent; and

a member of the second drug group comprises a non-steroidal anti-inflammatory drug (a NSAID) comprising an etodolac, (+) 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid, or equivalent;

(b) the therapeutic combination of (a), wherein the non-steroidal anti-inflammatory drug (a NSAID) comprises etodolac;

(c) the therapeutic combination of (b), wherein the etodolac is LODINE™

;

(d) the therapeutic combination of any of (a) to (c), wherein the beta adrenergic receptor antagonist (a beta blocker) comprises propranolol;

(e) the therapeutic combination of (d), wherein the propranolol is INDERAL™

;

(f) the therapeutic combination of (a), wherein the beta adrenergic receptor antagonist (a beta blocker) comprises propranolol and the non-steroidal anti-inflammatory drug (a NSAID) comprises etodolac;

(g) the therapeutic combination of (a) or (f), wherein the at least one member of the first drug group and the at least one member of the second drug group are formulated as separate compositions;

(h) the therapeutic combination of (a) or (f), wherein the at least one member of the first drug group and the at least one member of the second drug group are formulated in the same composition;

(i) the therapeutic combination of any of (a) to (h), wherein a first or second group drug is packaged individually in a single package or packette;

an intravenous (IV) package, container or packette;

a plurality of packages or packettes;

a blister packet;

a lidded blister or blister card or packets;

(j) the therapeutic combination of any of (a) to (h), wherein a first and a second group drug are packaged together in a single package or packette;

an intravenous (IV) package, container or packette;

a plurality of packages or packettes;

a blister packet;

a lidded blister or blister card or packets;

or a shrink wrap;

(k) the therapeutic combination of any of (a) to (h), wherein each of the first and second group drugs are packaged together in a single package or packette;

an intravenous (IV) package, container or packette;

a plurality of packages or packettes;

a blister packet;

a lidded blister or blister card or packets;

or a shrink wrap, and with both drugs released upon opening of the single package or packette;

intravenous (IV) package, container or packette;

plurality of packages or packettes;

blister packet;

lidded blister or blister card or packets;

or shrink wrap;

(l) the therapeutic combination of any of (a) to (h), wherein each of the first and second group drugs are packaged together in a single package or packette;

an intravenous (IV) package, container or packette;

a plurality of packages or packettes;

a blister packet;

a lidded blister or blister card or packets;

or a shrink wrap, and with both drugs are formulated as a tablet, a pill, a lozenge, a capsule, a caplet, a patch, a spray, an inhalant, a gel, a geltab, a nanosuspension, a nanoparticle, a microgel and/or a pellet, and the tablet, pill, lozenge, capsule, gel, geltab, nanosuspension, nanoparticle, microgel and/or a pellet are released upon opening of the single package or packette;

intravenous (IV) package, container or packette;

plurality of packages or packettes;

blister packet;

lidded blister or blister card or packets;

or shrink wrap;

(m) the therapeutic combination of any of (a) to (l), wherein the therapeutic combination is formulated or manufactured as a feed, a food, a pellet, a lozenge, a liquid, a liquid suitable for intravenous (IV) administration, an elixir, an aerosol, an inhalant, a spray, a powder, a tablet, a pill, a capsule, a gel, a geltab, a nanosuspension, a nanoparticle, a microgel or a suppository;

(n) the therapeutic combination of any of (a) to (l), wherein the single package or a plurality of packages is a blister pack or plurality of blister packettes, or lidded blister or blister card or packets, or a shrink wrap;

(o) the therapeutic combination of any of (a) to (n), wherein the dosage of etodolac ranges from about 200 mg to 400 mg a day, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more;

(p) the therapeutic combination of any of (a) to (n), wherein the dosage of propranolol ranges from 10 to 320 mg per day based on heart rate and blood pressure of the individual, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more;

(q) the therapeutic combination of any of (a) to (p), wherein the drugs are packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day;

(r) the therapeutic combination of (q), wherein the drugs are packaged in dosages that match a chrono-dosing regimen comprising;

(i) in the AM, 20 mg propranolol, 200 mg etodolac;

in the afternoon, 10 mg propranolol, 200 mg etodolac;

in the PM, 10 mg propranolol, 400 mg etodolac;

(ii) in the AM 40 mg propranolol, 200 mg etodolac;

in the afternoon 20 mg propranolol, 200 mg etodolac;

in the evening, 20 mg propranolol, 400 mg etodolac;

(iii) in the AM 80 mg propranolol, 200 mg etodolac;

in the afternoon 40 mg propranolol, 200 mg etodolac, in the evening 40 mg, etodolac;

or

(iv) a dose escalation comprising a regimen of (i) to (ii) to (iii);

(s) the therapeutic combination of (q), wherein the drugs are packaged in dosages that match a chrono-dosing regimen comprising;

Start;

AM, 20 mg propranolol, 200 mg etodolac;

afternoon, 10 mg propranolol, 200 mg etodolac;

PM 5 mg propranolol, 400 mg etodolac;

Dose Escalation 1;

AM 40 mg propranolol, 200 mg etodolac;

afternoon 20 mg propranolol, 200 mg etodolac;

evening, 10 mg propranolol, 400 mg etodolac;

Dose escalation 2;

AM 80 mg propranolol, 200 mg etodolac;

afternoon 40 mg propranolol, 200 mg etodolac, evening 20 mg, etodolac;

(t) the therapeutic combination of any of (a) to (s), wherein the drugs are formulated for administration once a day, b.i.d. or t.i.d, or weekly, or biweekly, or monthly;

(u) the therapeutic combination of any of (a) to (t), dosaged as set forth in any one of exemplary ingredient combinations 1 to 90;

(v) the therapeutic combination of any of (a) to (u), formulated for administration intravenously, topically, orally, by inhalation, by infusion, by injection, by inhalation, intraperitoneally, intramuscularly, subcutaneously, intra-aurally, for intra-articular administration, for intra-mammary administration, for topical administration or for absorption through epithelial or mucocutaneous linings;

(w) the therapeutic combination of any of (a) to (v), further comprising instructions for use in the treatment of cachexia or anorexia;

(x) the therapeutic combination of (w), wherein the cachexia is defined as at least two of the symptoms selected from the group consisting of;

     1) a hyper-inflammatory state,

     2) altered hormone levels and cytokine levels;

     3) increased heart rate variability;

     4) weight loss, and

     5) increased heart rate, wherein optionally the increased heart rate is having a sustained elevated heart rate of at least about 6 bpm;

(y) the therapeutic combination of (w), wherein the cachexia is defined by an individual having at least a sustained elevated heart rate of at least about 6 bpm and weight loss;

(z) the therapeutic combination of any of (a) to (y), further comprising a nutritional supplement;

or

(aa) any combination of (a) to (z).

27. A pharmaceutical composition comprising:

(a) the therapeutic drug combination of claim 1;

(b) the pharmaceutical composition of (a), further comprising a pharmaceutically acceptable excipient;

or

(c) the pharmaceutical composition of (a) or (b), wherein the pharmaceutical composition is formulated or manufactured as a feed, a food, a food or feed concentrate, a pellet, a lozenge, a liquid, a liquid suitable for intravenous (IV) administration, a lotion, an implant, a nanoparticle, an elixir, an aerosol, a spray, an aerosol, an inhalant, a powder, a tablet, a pill, a capsule, a gel, a geltab, a nanosuspension, a nanoparticle, a patch, a microgel or a suppository.

30. Use of a therapeutic combination in the manufacture of a medicament or pharmaceutical composition for treating, ameliorating or preventing a trauma, condition or disease comprising:

a chronic Systemic Inflammatory Response State (SIRS);

chronic systemic inflammatory stress;

burns, chronic obstructive pulmonary disease;

congestive heart failure;

chronic kidney disease;

surgery;

cancer;

sepsis;

ageing;

acute respiratory distress syndrome;

acute lung injury;

infection;

a CNS disorder or injury;

anemia;

immunosuppression;

insulin resistance;

anorexia;

anxiety;

sleep disturbances;

weakness;

fatigue;

gastrointestinal distress;

sleep disturbances;

wake disturbances;

pain;

listlessness;

shortness of breath;

lethargy;

depression;

malaise;

or, a combination thereof, wherein the therapeutic combination comprises;

(a) the therapeutic combination of claim 1;

(b) the use of (a), wherein the trauma, condition or disease comprises a maladaptive nutritional state secondary to the SIRS;

(c) the use of (b), wherein the maladaptive nutritional state comprises cachexia, and optionally the cachexia comprises cachexia secondary to cancer;

(d) the use of claim (c), wherein the cachexia is defined as at least two of the symptoms selected from the group consisting of;

     1) a hyper-inflammatory state,

     2) altered hormone levels and cytokine levels;

     3) increased heart rate variability;

     4) weight loss, and

     5) increased heart rate, wherein optionally the increased heart rate is having a sustained elevated heart rate of at least about 6 bpm;

(e) the use of (c) or (d), wherein the cachexia is defined by an individual having at least a sustained elevated heart rate of at least about 6 bpm and weight loss;

or

(f) the use of (a), wherein the CNS disorder comprises Parkinson'"'"'s disease or Alzheimer'"'"'s disease;

or

(g) the use of any of (a) to (f), wherein the medicament or pharmaceutical composition further comprises a nutritional supplement.

36. A method for treating or ameliorating a trauma, condition or disease comprising a chronic Systemic Inflammatory Response State (SIRS), chronic systemic inflammatory stress;

burns, chronic obstructive pulmonary disease;

congestive heart failure;

chronic kidney disease;

surgery;

cancer;

sepsis;

ageing;

acute respiratory distress syndrome;

acute lung injury;

infection;

a CNS disorder or injury;

anemia;

immunosuppression;

insulin resistance;

anorexia;

anxiety;

sleep disturbances;

weakness;

fatigue;

gastrointestinal distress;

sleep disturbances;

wake disturbances;

pain;

listlessness;

shortness of breath;

lethargy;

depression;

malaise;

or, a combination thereof, the method comprising;

(i) (a) providing the therapeutic combination of claim 1, or the pharmaceutical composition of claim 30; and

, (b) administering a therapeutically effective amount of the therapeutic combination of step (a) or the pharmaceutical composition of step (a), thereby treating or ameliorating the trauma, condition or disease;

(ii) the method of (i), wherein the condition or disease comprises a maladaptive nutritional state secondary to the SIRS;

(iii) the method of claim (ii), wherein the maladaptive nutritional state comprises cachexia or anorexia;

(iv) the method of (i), wherein the cachexia comprises cachexia secondary to cancer;

(v) the method of (iii) or (iv), wherein the cachexia is defined as at least two of the symptoms selected from the group consisting of;

     1) a hyper-inflammatory state,

     2) altered hormone levels and cytokine levels;

     3) increased heart rate variability;

     4) weight loss, and

     5) increased heart rate, wherein optionally the increased heart rate is having a sustained elevated heart rate of at least about 6 bpm;

(vi) the method of any of (iii) to (v), wherein the cachexia is defined by an individual having at least a sustained elevated heart rate of at least about 6 bpm and weight loss;

or

(v) the method of any of (i) to (vi), wherein the therapeutic combination or the pharmaceutical composition further comprises a nutritional supplement.

42. A kit comprising

(a) the therapeutic combination of claim 1, or the pharmaceutical composition of claim 30;

or

(b) the kit of (a), comprising at least one blister pack, lidded blister or blister card or packets, or an intravenous (IV) package or packette, an intravenous (IV) container, or a shrink wrap, comprising the therapeutic combination or the pharmaceutical composition;

or

(c) the kit of any of (a) or (b), wherein the therapeutic combination or the pharmaceutical composition further comprises a nutritional supplement.

44. A kit for the treatment, amelioration or prevention of a chronic Systemic Inflammatory Response State (SIRS) or a maladaptive nutritional state in a patient population, the kit comprising

(a) the therapeutic combination of claim 1, or the pharmaceutical composition of claim 30, and instructions for use of the therapeutic combination or pharmaceutical composition;

(b) the kit of (a), wherein the maladaptive nutritional state comprises cachexia;

(c) the kit of (a), wherein the cachexia comprises cachexia secondary to cancer;

(d) the kit of any of (a) to (c), wherein the cachexia is defined as at least two of the symptoms selected from the group consisting of;

     1) a hyper-inflammatory state,

     2) altered hormone levels and/or cytokine levels;

     3) increased heart rate variability;

     4) weight loss, and

     5) sustained increased heart rate, wherein optionally the sustained increased heart rate is having a sustained elevated heart rate of at least about 6 bpm;

(e) the kit of any of (a) to (d), wherein the cachexia is defined by an individual having at least a sustained elevated heart rate of at least about 6 bpm and weight loss;

or

(f) the kit of any of (a) to (e), wherein the therapeutic combination or the pharmaceutical composition further comprises a nutritional supplement.

48. A kit for the treatment, amelioration or prevention of a CNS disorder, wherein the kit comprises (a) the therapeutic combination of claim 1, or the pharmaceutical composition of claim 30;

(b) the kit of (a), wherein the CNS disorder comprises Parkinson'"'"'s disease or Alzheimer'"'"'s disease;

or (c) the kit of (a) or (b), further comprising a nutritional supplement.

50. A product of manufacture comprising (a) a blister package;

a lidded blister;

a blister card or packet;

a clamshell;

an intravenous (IV) package, IV packette or IV container;

a tray or a shrink wrap comprising the therapeutic combination of claim 1, or the pharmaceutical composition of claim 30;

or (b) the product of manufacture of (a), further comprising a nutritional supplement.

51. A product of manufacture comprising a blister package, a lidded blister or a blister card or packet, a clamshell, an intravenous (IV) package or packette, an IV container, a tray or a shrink wrap comprising (a) therapeutic combination claim 1, or the pharmaceutical composition of claim 30, wherein the therapeutic combination or pharmaceutical composition are formulated for at least two dosage administrations;

(b) the product of manufacture of (a), wherein the therapeutic combination or pharmaceutical composition are formulated as one dosage administration in the morning and one dosage administration in the evening;

(c) the product of manufacture of (a) or (b), wherein the dosage schedule provides a relatively higher dose of one drug in the morning (the AM) than in the evening, and a relatively higher dose of another medication in the evening than in the morning;

or (d) the product of manufacture of any or (a) to (c), further comprising a nutritional supplement.

55. A method for treating, ameliorating or preventing a chronic Systemic Inflammatory Response State (SIRS), comprising

(a) administering the therapeutic combination of claim 1, or the pharmaceutical composition of claim 30, to an individual in need thereof, and the therapeutic combination or the pharmaceutical composition are formulated for at least two administrations, one in the morning and one in the evening, wherein the dosage schedule provides a relatively higher dose of beta blocker in the morning (the AM) than in the evening, and a relatively higher dose of an anti-inflammatory medication in the evening than in the morning;

(b) the method of (a), wherein the administration regimen comprises at least two dosages of beta adrenergic receptor antagonist (a beta blocker) drug and at least two dosages of non-steroidal anti-inflammatory drug (a NSAID), and further comprising administration of an anti-anxiety drug, and the drugs are organized or labeled in a blister package, a lidded blister or a blister card or packet, a clamshell, an IV package or packette, e.g. IV bag or IV bottle or IV syringe other IV container, a tray or a shrink wrap for usage by an individual for at least two administrations, one in the morning and one in the evening, wherein the dosage schedule provides a relatively higher dose of beta blocker in the morning (the AM) than in the evening, and a relatively higher dose of an anti-anxiety and/or an anti-inflammatory medication in the evening than in the morning;

(c) the method of (a) or (b), wherein the administration regimen comprises doses of propranolol given in 20 or 40 mg tablets immediate release on a bid basis, and in the first dose week the doses for propranolol are 20 mg in the morning and 20 mg at bedtime, and after 1 week the dosage is adjusted to 20 mg of the immediate release product in the morning and 60 mg of the extended release at bedtime, and optionally if after an additional week the subject shows no improvement or has not obtained a 20% reduction in heart rate, without decreasing heart rate below 60 bpm or blood pressure below 90/60, the dose is adjusted to 40 mg of the immediate release propranolol in the morning and 120 mg of the extended release propranolol at bedtime;

or

(d) the method of (a) or (b), wherein the administration regimen comprises doses of etodolac are given in 200 mg capsules or 500 mg tablets on a bid basis, and doses for etodolac are started at 200 mg in the morning and at bedtime, and after 1 week the dosage are adjusted to 200 mg in the morning and 500 mg at bedtime.

59. A blister pack or a plurality of blister packettes, a blister package, a lidded blister or a blister card or packet, a clamshell, an intravenous (IV) package or packette, an IV container, a tray or a shrink wrap, comprising

(i) the therapeutic combination of claim 1, or the pharmaceutical composition of claim 30, wherein the propranolol or equivalent and etodolac or equivalent are arranged or clustered in the blister pack or a plurality of blister packettes:

(a) in a chrono-dosing arrangement or pattern;

or (b) individually;

or

(ii) the blister pack or plurality of blister packettes, blister package, lidded blister, blister card or packet, clamshell, an intravenous (IV) package or packette, an IV container, tray or shrink wrap of (i), further comprising a nutritional or vitamin supplement.

60. A paper, plastic or cellophane package or a plurality of packettes comprising

(i) the therapeutic combination of claim 1, or the pharmaceutical composition of claim 30, wherein the propranolol or equivalent and etodolac or equivalent are arranged or clustered in the package or a plurality of packettes:

(a) in a chrono-dosing arrangement or pattern;

or (b) individually;

or

(ii) the blister pack or plurality of blister packettes, blister package, lidded blister, blister card or packet, clamshell, an intravenous (IV) package or packette, an IV container, tray or shrink wrap of (i), further comprising a nutritional or vitamin supplement.

2-26. -26. (canceled)

28-29. -29. (canceled)

31-35. -35. (canceled)

37-41. -41. (canceled)

43. (canceled)

45-47. -47. (canceled)

49. (canceled)

52-54. -54. (canceled)

56-58. -58. (canceled)