Inhalable formulations for treating pulmonary hypertension and methods of using same

• US 20060104913A1
• Filed: 12/22/2005
• Published: 05/18/2006
• Est. Priority Date: 06/27/2003
• Status: Active Grant

• Current Assignee: Mylan Specialty L.P. (Pfizer Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Chaudry, Imtiaz
• Granted Patent: US 9,498,437 B2
• Time in Patent Office: Days
• US Class Current: 424/45
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/472 Non-condensed isoquinolines, e.g. papaverine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/5575 having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
• CPC Class Codes: A61K 31/5585 having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 38/556 Angiotensin converting enzyme inhibitors
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

The present invention is directed to an inhalable formulation for the treatment of pulmonary hypertension in a mammal (e.g., humans), wherein the formulation comprises at least one hypertension reducing agent, including but not limited to an angiotensin converting enzyme inhibitor, angiotensin receptor blocker, beta-blocker, calcium-channel blocker or vasodilator, or any combination thereof. The formulations of the present invention may be a solution or suspension, and preferably are suitable for administration via nebulization. The present invention is also directed to a method and kit for treating a mammal suffering from pulmonary hypertension.

Claims

1. An inhalable formulation for the treatment of pulmonary hypertension, said formulation comprising a therapeutically effective amount of a hypertension reducing agent, wherein said pulmonary hypertension reducing agent is at least one of an ACEI, ARB, beta-blocker, calcium-channel blocker or vasodilator and wherein said formulation is suitable for administration via inhalation to a mammal in need thereof.

2. The formulation of claim 1, wherein said formulation is suitable for administration via nebulization.

3. The formulation of claim 2 comprising about 0.001 mg/ml to about 20 mg/ml of said pulmonary hypertension reducing agent.

4. The formulation of claim 2 comprising about 0.1 mg/ml to about 15 mg/ml of said pulmonary hypertension reducing agent.

5. The formulation of claim 2 comprising about 1 mg/ml to about 10 mg/ml of said pulmonary hypertension reducing agent.

6. The formulation of claim 2, wherein said formulation is a solution.

7. The formulation of claim 6, wherein said solution is sterile.

8. The formulation of claim 7, wherein said solution is isotonic.

9. The formulation of claim 8, wherein said solution has a pH of about 3 to about 8.

10. The formulation of claim 9, wherein said solution comprises a buffer.

11. The formulation of claim 10, wherein said buffer is at least one selected from the group consisting of sodium hydroxide, sodium citrate and citric acid.

12. The formulation of claim 2, wherein said formulation is an aqueous suspension.

13. The formulation of claim 12, wherein said suspension is sterile.

14. The formulation of claim 13, wherein said suspension comprises an emulsifier.

15. The formulation of claim 14, wherein said suspension is isotonic.

16. The formulation of claim 2, wherein said formulation comprises a preservative.

17. The formulation of claim 2, wherein said formulation is preservative-free.

18. The formulation of claim 2, wherein said ACEI is at least one of the group consisting of benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril.

19. The formulation of claim 2, wherein said ARB is at least one of the group consisting of candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan.

20. The formulation of claim 2, wherein said beta-blocker is at least one of the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol and timolol.

21. The formulation of claim 2, wherein said calcium-channel blocker is at least one of the group consisting of amlodipine, bepridil, diltiazem, felodipine, flunarizine, isradipine, nicardipine, nifedipine, nimodipine and verapamil.

22. The formulation of claim 2, wherein said vasodilator is at least one of the group consisting of adenine, arginine, doxazosin, hydralazine hydrochloride, isosorbide dinitrate, isosorbide mononitrate minoxidil, nicotinates, nitroglycerin, phentolamine, prazosin and terazosin.

23. The formulation of claim 2, wherein said vasodilator comprises one or more prostaglandins.

24. The formulation of claim 23, wherein said prostaglandin is prostacyclin or an analog thereof.

25. The formulation of claim 2, wherein said formulation is suitable for treating primary pulmonary hypertension.

26. The formulation of claim 2, wherein said formulation is suitable for treating secondary pulmonary hypertension.

27. A method of treating pulmonary hypertension in a mammal, said method comprising the step of administering to said mammal a formulation comprising a therapeutically effective amount of a hypertension reducing agent, wherein said hypertension reducing agent is at least one of an ACEI, ARB, beta-blocker, calcium-channel blocker or vasodilator, and wherein said formulation is suitable for administration via inhalation.

28. The method of claim 27, wherein said formulation is administered via nebulization to said mammal.

29. The method of claim 28, wherein said formulation is administered via jet nebulizer, ultrasonic nebulizer or breath-actuated nebulizer to said mammal.

30. The method of claim 27, wherein said formulation is premeasured, premixed and prepackaged.

31. The method of claim 30, wherein said formulation comprises about 0.05 mg/ml to about 15 mg/ml of said hypertension reducing agent.

32. The method of claim 31, wherein said formulation is sterile and stable.

33. The method of claim 27, said method further comprising the step of administering to said mammal an anticoagulant.

34. The method of claim 27, said method further comprising the step of administering to said mammal an inotropic agent.

35. The method of claim 27, said method further comprising the step of administering to said mammal low-flow supplemental oxygen therapy.

36. The method of claim 27, said method further comprising the step of administering to said mammal a diuretic.

37. The method of claim 27, said method further comprising the step of administering to said mammal a low salt diet.

38. A kit for treating pulmonary hypertension in a mammal, said kit comprising an prepackaged formulation comprising a therapeutically effective amount of a hypertension reducing agent, wherein said hypertension reducing agent is at least one of an ACEI, ARB, beta-blocker, calcium-channel blocker or vasodilator, and wherein said formulation is suitable for administration via nebulization to a mammal in need thereof.

39. The kit of claim 38, wherein said formulation is prepackaged.

40. The kit of claim 38, further comprising instructions relating to said formulation.

41. An inhalable formulation for the treatment of pulmonary hypertension, said formulation comprising about 0.2-10.0 mg/ml, Enalaprilat, (s-1-[N-(1-carboxy-3-phenylpropyl)-L-alanyl]-L-praline dehydrate, about 2.0-10.0 mg/ml Sodium Chloride, Sodium Hydroxide and water, wherein said formulation is suitable for administration via nebulization to a mammal in need thereof.

42. An inhalable formulation for the treatment of pulmonary hypertension, said formulation comprising about 1.0-10.0 mg/ml, Atenolol (Benzeneacetamide, 4-[2-hydroxy-3-(1-methylethyl)amino propoxy], about 2.0-10.0 mg/ml Sodium Chloride, Sodium Citrate, Citric Acid and water, wherein said formulation is suitable for administration via nebulization to a mammal in need thereof.

43. An inhalable formulation for the treatment of pulmonary hypertension, said formulation comprising about 0.1-3.0 mg/ml Epoprostenol, about 0.2-2.0 mg/ml, Span 85 and water, wherein said formulation is suitable for administration via nebulization to a mammal in need thereof.

44. An inhalable formulation for the treatment of pulmonary hypertension, said formulation comprising about 0.1-10.0 mg/ml Treprostinil sodium, about 2.0-10.0 mg/ml, Sodium Chloride, Sodium Hydroxide, Citric Acid and water, wherein said formulation is suitable for administration via nebulization to a mammal in need thereof.