Highly water-soluble salts of a short acting phenylalkylamine calcium channel blocker and uses thereof

Abstract

The present invention includes surprisingly water-soluble salts of a phenylalkylamine compound that are potent antagonists of L-type calcium channels. Aqueous solutions including salts of the instant invention are formulated for nasal administration and provide a novel therapeutic platform for the treatment of stable angina, migraine, and cardiac arrhythmia, such as paroxysmal supraventricular tachycardia.

What is claimed is: 
     
         1 . An aqueous composition formulated for nasal administration comprising a pharmaceutically acceptable salt or free base of a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         verapamil, gallopamil, and devapamil, or a racemate or enantiomer thereof, wherein the compound is dissolved in the aqueous composition at a concentration of between 150 mg/mL and 600 mg/mL. 
       
     
     
         2 . The aqueous composition of  claim 1 , wherein the compound is compound I. 
     
     
         3 . The aqueous composition of  claim 2 , wherein the compound is the S-enantiomer of compound I. 
     
     
         4 . The aqueous composition of any one of  claims 1 - 3 , wherein the concentration is approximately 350 mg/mL. 
     
     
         5 . The aqueous composition of any one of  claims 1 - 3 , wherein the concentration is approximately 450 mg/mL. 
     
     
         6 . The aqueous composition of any one of  claims 1 - 3 , wherein the aqueous composition comprises from 40% to 85% (w/v) water. 
     
     
         7 . The aqueous composition of any one of  claims 1 - 3 , wherein the aqueous composition has a pH of 4.5±1.5. 
     
     
         8 . The composition of any one of  claims 1 - 7 , wherein the aqueous composition comprises a compound selected from the group consisting of compound I, verapamil, gallopamil, and devapamil and between 0.5 and 1.5 molar equivalents of acetic acid relative to the compound. 
     
     
         9 . The composition of any one of  claims 1 - 7 , wherein the aqueous composition comprises a compound selected from the group consisting of compound I, verapamil, gallopamil, and devapamil and between 0.5 and 1.5 molar equivalents of methanesulfonic acid relative to the compound. 
     
     
         10 . The aqueous composition of any one of  claims 1 - 9 , wherein the composition further comprises a chelating agent. 
     
     
         11 . The composition of  claim 10 , wherein the chelating agent is an aminopolycarboxylic acid. 
     
     
         12 . The composition of claim any one of  claims 1 - 11 , wherein the aqueous composition further comprises EDTA. 
     
     
         13 . The composition of any one of  claims 1 - 12 , wherein the composition further comprises a pH adjusting agent selected from the group consisting of sulfuric acid and methanesulfonic acid. 
     
     
         14 . The composition of  claim 13 , wherein the pH adjusting agent is sulfuric acid. 
     
     
         15 . The composition of any one of  claims 1 - 14 , wherein the composition exhibits a viscosity of between 10 mPa*s and 70 mPa*s. 
     
     
         16 . The composition of any one of  claims 1 - 15 , wherein the composition further comprises a pharmaceutically acceptable excipient. 
     
     
         17 . The composition of  claim 16 , wherein the excipient is polysorbate or propylene glycol. 
     
     
         18 . The composition of any one of  claims 1 - 17 , wherein the aqueous solution comprising the salt of a compound selected from the group consisting of compound I, verapamil, gallopamil, and devapamil remains homogeneous at room temperature. 
     
     
         19 . The composition of any one of  claims 1 - 17 , wherein the aqueous solution comprising the salt of a compound selected from the group consisting of compound L verapamil, gallopamil, and devapamil remains homogeneous at 10° C. for 4 days. 
     
     
         20 . The composition of any one of  claims 1 - 17 , wherein the aqueous solution comprising the salt of a compound selected from the group consisting of compound I, verapamil, gallopamil, and devapamil remains homogeneous at 2-5° C. for 7 days. 
     
     
         21 . A nasal delivery system comprising a composition of any one of  claims 1 - 20  in a unit dosage form comprising no more than four single pump spray dosages. 
     
     
         22 . A nasal delivery system comprising a composition of any one of  claims 1 - 20  in a unit dosage form comprising no more than two single pump spray dosages. 
     
     
         23 . The nasal delivery system of  claim 21  or  22 , wherein the unit dosage form is configured for administration of no more than 200 microliters of the composition to each nostril of a patient. 
     
     
         24 . The nasal delivery system of  claim 21  or  22 , wherein the unit dosage form is configured for administration of no more than 150 microliters of the composition to each nostril of a patient. 
     
     
         25 . A composition comprising the acetate salt of a compound selected from the group consisting of compound I, verapamil, gallopamil, and devapamil. 
     
     
         26 . A composition comprising the methanesulfonate salt of a compound selected from the group consisting of compound I, verapamil, gallopamil, and devapamil. 
     
     
         27 . A method of treating a disease selected from the group consisting of cardiac arrhythmia, stable angina, and migraine, said method comprising nasally administering to a patient in need thereof an aqueous composition comprising a pharmaceutically acceptable salt of a compound selected from the group consisting of compound I, verapamil, gallopamil, and devapamil, wherein the compound is dissolved in the aqueous composition at a concentration of between 150 mg/mL and 600 mg/mL. 
     
     
         28 . The method of  claim 27 , wherein said disease is cardiac arrhythmia. 
     
     
         29 . The method of  claim 27 , wherein said disease is stable angina. 
     
     
         30 . The method of  claim 27 , wherein said disease is migraine. 
     
     
         31 . The method of  claim 28 , wherein said cardiac arrhythmia is PSVT, atrial fibrillation, or ventricular tachycardia. 
     
     
         32 . The method of any one of  claims 27 - 31 , wherein the compound reaches a therapeutically effective concentration in plasma of the patient within 3 to 5 minutes of administration to the patient. 
     
     
         33 . The method of any one of  claims 27 - 32 , the method comprising administering between 150 microliters and 200 microliters of the aqueous composition to the patient. 
     
     
         34 . The method of any one of  claims 27 - 33 , wherein the patient is a human. 
     
     
         35 . Use of the composition of any one of  claims 1 - 20  in the manufacture of a medicament for the treatment of a disease selected from the group consisting of cardiac arrhythmia, stable angina, and migraine. 
     
     
         36 . The use according to  claim 35 , wherein said disease is cardiac arrhythmia. 
     
     
         37 . The use according to  claim 35 , wherein said disease is stable angina. 
     
     
         38 . The use according to  claim 35 , wherein said disease is migraine. 
     
     
         39 . The use according to  claim 36 , wherein said cardiac arrhythmia is PSVT, atrial fibrillation, or ventricular tachycardia. 
     
     
         40 . A method of making a solution formulated for nasal administration to a patient, the method comprising the steps of
 a. adding a solution comprising a first dissolved acid to the free base of a compound of  claim 1  to form a mixture;   b. adding to the mixture a solution comprising ethylenediaminetetracetic acid;   c. heating and mechanically stirring the resulting mixture until the compound has fully dispersed within the mixture;   d. adjusting the pH of the mixture by adding a solution comprising a second dissolved acid to the mixture; and   e. diluting the mixture such that the final concentration of the compound in solution is at least 300 mg per 1 milliliter.   
     
     
         41 . The method of  claim 40 , wherein the first dissolved acid is selected from the group consisting of acetic acid and methanesulfonic acid. 
     
     
         42 . The method of  claim 40 , wherein the second dissolved acid is selected from the group consisting of acetic acid, sulfuric acid, and methanesulfonic acid. 
     
     
         43 . The method of  claim 40 , wherein the final pH of the solution is between about 4.0 and about 5.0. 
     
     
         44 . The method of  claim 43 , wherein the final pH of the solution is about 4.5. 
     
     
         45 . The method of  claim 40 , wherein the solution comprising the salt of the compound remains homogeneous at 10° C. for 4 days. 
     
     
         46 . The method of  claim 40 , wherein the solution comprising the salt of the compound remains homogeneous at 2-5° C. for 7 days.