Intranasal Formulation of Epinephrine for the Treatment of Anaphylaxis

Abstract

This invention relates to pharmaceutical compositions of epinephrine for delivery to the nasal mucosa and methods of treating a subject in acute severe anaphylaxis, bronchospasm or during cardiopulmonary resuscitation (CPR). The composition further comprising agents, that either prevent localized degradation of epinephrine or enhance its absorption in the nasal mucosa to counter anaphylactic effects, symptoms or complications in a subject.

We claim: 
     
         1 . A pharmaceutical composition comprising:
 (a) an anti-anaphylactic agent,   (b) a reversible catechol-O-methyl transferase (COMT) inhibitor, or the pharmaceutically acceptable salts or prodrugs thereof, said composition is suitable for intranasal administration.   
     
     
         2 . A pharmaceutical composition comprising:
 (a) an anti-anaphylactic agent,   (b) a reversible catechol-O-methyl transferase (COMT) inhibitor and/or   (c) a vasodilator,   
       or the pharmaceutically acceptable salts or prodrugs thereof, said composition is suitable for intranasal administration. 
     
     
         3 . The pharmaceutical composition according to  claim 1  or  2 , may additionally contain one or more agents selected from the group comprising of, pharmaceutically acceptable excipients, epinephrine potentiators, mucosal permeation or penetration enhancers, mucosal transit slowing agents, mucosal absorption or transport enhancers, mucoadhesives, non-sulfite stabilizers, preservatives, thickening agents, humectants, antihistamines, solubilizing agents, taste-masking agents, antioxidant enzymes, viscosity enhancing agents, dispersing agents, or any combination thereof. 
     
     
         4 . The composition as in  claim 1  or  2 , wherein the anti-anaphylactic agent is epinephrine, or pharmaceutically acceptable salt or prodrug thereof. 
     
     
         5 . The composition according to  claim 1  or  2 , wherein said reversible COMT inhibitor is entacapone, or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         6 . The composition according to  claim 2 , wherein the vasodilator is phentolamine, or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         7 . The composition according to  claim 4 , wherein epinephrine administered intranasally is present in amounts ranging from 0.05 mg to 10 mg. 
     
     
         8 . The composition according to  claim 7 , wherein the amount of epinephrine administered intranasally is the bioequivalent dose of intramuscularly or subcutaneously injected epinephrine. 
     
     
         9 . The composition according to  claim 5 , wherein the entacapone administered intranasally is present in amounts ranging from 0.001 to 10 mg. 
     
     
         10 . The composition according to  claim 6 , wherein the phentolamine is present in the amount ranging from 0.001 mg to 10 mg. 
     
     
         11 . The composition according to  claim 1  or  2 , when administered intranasally elicits at least a 2-fold increase in epinephrine blood plasma levels within 20 minutes of said administration, preferably within 10, 5, or 3 minutes of said administration. 
     
     
         12 . The composition as in  claim 1  or  2  is in aqueous solution, present in volumes of up to 200 μl, preferably between 50 and 200 μl for intranasal administration. 
     
     
         13 . The composition as in  claim 1  or  2  is a dry powder preparation, present in amount less than 100 mg, preferably from 10 to 20 mg for intranasal administration. 
     
     
         14 . The composition as in  claim 1  or  2  is a nasal spray characterized for single or multiple use. 
     
     
         15 . The composition as in  claim 1  or  2  is used in the treatment of a condition selected from the group comprising, anaphylaxis, bronchospasm and cardiac arrest. 
     
     
         16 . A pharmaceutical product comprising, a device for intranasal administration dispensing a pharmaceutical dose comprising between 0.05 mg to 10 mg of epinephrine, between 0.001 mg to 10 mg of entacapone and/or 0.001 mg to 10 mg of phentolamine, or pharmaceutically acceptable salts or prodrugs thereof. 
     
     
         17 . The pharmaceutical product of  claim 16 , wherein the device comprises a reservoir and means for expelling one or more pharmaceutical dose in the form of a spray, wherein a quantity of the pharmaceutical composition is contained within the reservoir. 
     
     
         18 . A method of treating anaphylaxis or bronchospasm or cardiac arrest in a subject comprising the intranasal administration of a pharmaceutical composition comprising, epinephrine present in the amounts ranging from 0.05 mg to 10 mg, entacopone present in the amounts ranging from 0.001 mg to 10 mg and/or phentolamine present in the amounts ranging from 0.001 mg to 10 mg. 
     
     
         19 . The method of treating anaphylaxis or bronchospasm or cardiopulmonary arrest in a subject comprising the intranasal administration of a pharmaceutical composition according to  claim 18 , wherein the composition may additionally contain agents selected from the group comprising of, pharmaceutically acceptable excipients, epinephrine potentiators, mucosal permeation or penetration enhancers, mucosal transit slowing agents, mucosal absorption and transport enhancers, mucoadhesives, non-sulfite stabilizers, preservatives, thickening agents, humectants, antihistamines, solubilizing agents, taste masking agents, antioxidant enzymes, viscosity enhancing agents, dispersing agents, or any combination thereof. 
     
     
         20 . A method of treating anaphylaxis or bronchospasm or cardiac arrest in a subject the method comprising, administering an intranasal composition of  claim 1  or  2 , wherein the epinephrine dose is adjusted according to the weight of the subject at an increment of at least 0.01 mg/kg or the dose is repeated more than once if the subject is refractory or experiences rebound anaphylaxis.