Inhalable formulations for treating pulmonary hypertension and methods of using same

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.

What is claimed is:  
     
         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.  
     
     
         45 . The formulation of  claims 41  to  44 , wherein said formulation is an aqueous suspension.  
     
     
         46 . The formulation of  claim 45 , wherein said suspension is sterile.  
     
     
         47 . The formulation of  claim 46 , wherein said suspension has pH of about 3 to about 8.  
     
     
         48 . The formulation of  claim 47 , wherein said suspension is isotonic.  
     
     
         49 . The formulation of  claim 48 , wherein said formulation comprises a preservative.  
     
     
         50 . The formulation of  claim 49 , wherein said formulation is preservative-free.