Epinephrine nanoparticles, methods of fabrication thereof, and methods for use thereof for treatment of conditions responsive to epinephrine

Abstract

The invention provides a composition including epinephrine nanoparticles and methods for therapeutic use of the composition in the treatment of conditions responsive to epinephrine such as a cardiac event or an allergic reaction, particularly anaphylaxis. The epinephrine nanoparticles can be incorporated into orally-disintegrating and fast-disintegrating tablet pharmaceutical formulations and can significantly increase the sublingual bioavailability of epinephrine, and thereby reduce the epinephrine dose required. Additionally, the invention provides methods for fabrication of stabilized epinephrine nanoparticles for use in the described compositions.

1 . A pharmaceutical composition comprising stabilized epinephrine nanoparticles and at least one pharmaceutically-acceptable carrier, the composition formulated for buccal or sublingual administration. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . A method for fabricating stabilized epinephrine nanoparticles, comprising:
 a) combining a pre-determined amount of epinephrine and a solvent in a reaction chamber to form a mixture; and   b) exposing the mixture to at least one pass at a pre-determined pressure and a pre-determined temperature.   
     
     
         5 . The method in accordance with  claim 4 , wherein the epinephrine is an epinephrine base or an epinephrine bitartrate salt. 
     
     
         6 . The method in accordance with  claim 4 , wherein the solvent is selected from the group consisting of water, isopropyl alcohol (ISP), methanol, acetonitrile, acetone, hexan, chloroform, dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, phosphoric acid, acetic acid, and sodium metabisulfite. 
     
     
         7 . The method in accordance with  claim 4 , wherein the pre-determined pressure ranges from about 8,000 psi to 30,000 psi. 
     
     
         8 . The method in accordance with  claim 4 , wherein the pre-determined temperature ranges from about 8.3 to 43.3° C. 
     
     
         9 . The method in accordance with  claim 4 , further including exposing the mixture to a second pass at a different pre-determined pressure and a different pre-determined temperature from that of the first pass. 
     
     
         10 . The method in accordance with  claim 4 , further including lyophilizing nanoparticles obtained by carrying out steps a) and b). 
     
     
         11 . A stabilized epinephrine nanoparticle produced in accordance with the method of  claim 10 . 
     
     
         12 . A pharmaceutical composition comprising the stabilized epinephrine nanoparticle of  claim 11  and at least one of a pharmaceutically-acceptable carrier, a penetration enhancer, and a mucoadhesive, the composition formulated for buccal or sublingual administration. 
     
     
         13 - 14 . (canceled) 
     
     
         15 . A method for treating a condition responsive to epinephrine in a subject in need thereof, comprising:
 providing a composition including epinephrine nanoparticles and a pharmaceutically-acceptable carrier; and   administering the composition to the subject.   
     
     
         16 . The method in accordance with  claim 15 , wherein the condition is a cardiac event or an allergic reaction. 
     
     
         17 . The method in accordance with  claim 16 , wherein the cardiac event is cardiac arrest and the allergic reaction is anaphylaxis, asthma, or bronchial asthma. 
     
     
         18 - 33 . (canceled) 
     
     
         34 . The pharmaceutical composition in accordance with  claim 1 , further comprising at least one of a penetration enhancer and a mucoadhesive. 
     
     
         35 . The method in accordance with  claim 16 , wherein the cardiac event is cardiac arrest. 
     
     
         36 . The method in accordance with  claim 15 , wherein treating includes enhancing sublingual bioavailability of epinephrine. 
     
     
         37 . The method in accordance with  claim 15 , wherein the condition is a breathing difficulty. 
     
     
         38 . The method in accordance with  claim 37 , wherein the breathing difficulty is associated with anaphylaxis, asthma, bronchial asthma, bronchitis, emphysema, or respiratory infections. 
     
     
         39 . The method in accordance with  claim 15 , wherein the condition is an allergic emergency. 
     
     
         40 . The method in accordance with  claim 39 , wherein the allergic emergency is associated with anaphylaxis, asthma, or bronchial asthma.