Patent Publication Number: US-2021177777-A1

Title: Epinephrine spray formulations

Description:
FIELD OF THE INVENTION 
     The present invention is directed to epinephrine spray formulations. The present invention is further directed to methods of treating anaphylaxis by administering epinephrine spray formulations to subjects in need of such treatments. 
     BACKGROUND OF THE INVENTION 
     Epinephrine (i.e. adrenaline) is a catecholamine with the following chemical structure: 
     
       
         
         
             
             
         
       
     
     Epinephrine stimulates the alpha- and beta-adrenergic receptors of the sympathetic nervous system. Epinephrine binds to these adrenergic receptors leading to relief of many life-threatening symptoms of anaphylaxis including: relaxation of the smooth muscle in the bronchi of the lungs opening up the constricted airways; constriction of the blood vessels leading to decreased swelling of the tongue and throat and increased blood pressure; and finally, increased heart rate preventing or reversing cardiovascular collapse. 
     Epinephrine is commercially available as an injection (Adrenalin® a trademark of and available from Par Sterile Products, LLC) and an auto-injector (EpiPen® a trademark of and available from Mylan, Inc. and Auvi-Q® a trademark of and available from Sanofi Corporation). Epinephrine was previously available as a nasal spray (Adrenalin®) and an aerosol spray (Primatene® Mist trademark of Armstrong Pharmaceuticals, Inc.). Racepinephrine is commercially available as a 2.25% oral inhalation solution for use in nebulizers (S2® is available from Nephron Pharmaceuticals, Inc.). Epinephrine differs from racepinephrine in that epinephrine consists of only the L-isomer and racepinephrine is a 50/50 mixture of both the L- and D-isomers. 
     U.S. Pat. No. 8,628,805 is directed to a stable liquid adrenaline/bisulfite composition wherein the molar ratio of adrenaline to bisulfite is 1.31-2.20:1. U.S. Patent Application Publication No. 2012/0322884 A1 is directed to epinephrine nanoparticles, which can be incorporated into sublingual tablets. U.S. Patent Application Publication No. 2007/0202163 A1 is directed to epinephrine tablets for sublingual administration, which contain between 12% and 48% epinephrine. World Intellectual Property Organization (“W.I.P.O.”) Publication No. 2014/127018 A1 is directed to a stable aqueous epinephrine formulation that requires cyclodextrin. W.I.P.O. Publication No. 2014/057365 A1 is directed to an injectable epinephrine formulation. 
     While there are various epinephrine formulations currently available, there remains a need in the art for a quick-onset spray formulation. 
     SUMMARY OF THE INVENTION 
     In one aspect, the present invention is directed to epinephrine spray formulations comprising: 
     from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof, preferably the salt is selected from the group consisting of citrate, hydrochloride, halide, sulfate, phosphate, acetate, maleate, succinate, ascorbate, carbonate, mesylate and lactate;
 
from about 1% w/w to about 80% w/w water, preferably from about 5% to about 77% w/w, more preferably from about 10% to about 65% w/w or from about 15% to about 80% w/w; optionally, from about 1% w/w to about 99% w/w of a solvent selected from the group consisting of ethanol, glycerin, propylene glycol, polyethylene glycol 400 and a combination thereof; and
 
optionally, from about 0.1% w/w to about 60% w/w of at least one acid,
 
wherein the formulation has a pH from about 2 to about 7.0.
 
     In one aspect, the present invention is directed to epinephrine spray formulations comprising:
         from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof, preferably the salt is selected from the group consisting of citrate, hydrochloride, halide, sulfate, phosphate, acetate, maleate, succinate, ascorbate, carbonate, mesylate and lactate;   from about 1% w/w to about 99% w/w of a solvent selected from the group consisting of water, ethanol, glycerin, propylene glycol, polyethylene glycol 400 and a combination thereof, preferably the solvent is a combination of water, ethanol and propylene glycol or water;       

     from about 0.1% w/w to about 60% w/w of at least one acid, preferably the at least one acid is diluted hydrochloric acid, 
     wherein the formulation has a pH from about 2 to about 5.5. 
     In another aspect, the present invention is directed to epinephrine spray formulations, wherein the formulation is free of a propellant. 
     In another aspect, the present invention is directed to epinephrine spray formulations, wherein the formulation does not contain sorbitol. 
     In another aspect, the solvent of the present invention comprises from about 1% w/w to about 30% w/w glycerin. 
     In another aspect, the epinephrine spray formulations of the present invention further comprise a permeation enhancer comprising caprylic acid, preferably the caprylic acid is at a concentration from about 0.1% w/w to about 10% w/w, more preferably from about 0.1% w/w to about 5 w/w. 
     In another aspect, the permeation enhancer of the present invention further comprises a second compound selected from the group consisting of menthol, limonene, carvone, methyl chitosan, polysorbates, sodium lauryl sulfate, glyceryl oleate, caproic acid, enanthic acid, pelargonic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, oleic acid, stearic acid, linolenic acid, arachidonic acid, benzethonium chloride, benzethonium bromide, benzalkonium chloride (BKC), cetylpyridium chloride, edetate disodium dihydrate (EDTA), sodium desoxycholate, sodium deoxyglycolate, sodium glycocholate, sodium caprate, sodium taurocholate, sodium hydroxybenzoyal amino caprylate, dodecyl dimethyl aminopropionate, L-lysine, glycerol oleate, glyceryl monostearate, citric acid, peppermint oil and a combination thereof, preferably menthol, preferably the menthol is at a concentration from about 0.1% to about 5% w/w, more preferably from about 0.1% to about 1% w/w. 
     In another aspect, the epinephrine spray formulations of the present invention contain no permeation enhancer. 
     In another aspect, the epinephrine spray formulations of the present invention further comprise an isotonicity agent comprising sodium chloride. 
     In another aspect, the epinephrine spray formulations of the present invention further comprise a stabilizer selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, methionine, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, ascorbyl palmitate, thioglycerol, alpha tocopherol (vitamin E), cysteine hydrochloride, benzalkonium chloride (“BKC”), citric acid, ethylenediaminetetraacetic acid (EDTA), sodium citrate, propyl gallate, 8-hydroxyquinoline, boric acid, histidine and combinations thereof, preferably the stabilizer comprises EDTA at a concentration from about 0.005% w/w to about 0.5% w/w, preferably the stabilizer comprises sodium bisulfite, sodium metabisulfite or a combination thereof at a concentration from about 0.005% w/w to about 5 w/w and preferably the stabilizer comprises BKC at a concentration from about 0.005% to about 0.5 w/w. 
     In another aspect, the epinephrine spray formulations of the present invention further comprise a preservative selected from the group consisting of butyl paraben, methyl paraben, ethyl paraben, propyl paraben, sodium benzoate, chlorobutanol, benzalkonium chloride (BKC), benzoic acid and combinations thereof, preferably BKC at a concentration from about 0.005% w/w to about 0.5% w/w. 
     In another aspect, the present invention is directed to epinephrine spray formulations comprising:
         from about 0.1% to about 15% w/w epinephrine, or a salt thereof;   from about 1% to about 65% w/w hydrochloric acid with a normality from about 0.1 to 12N;   from about 2% to about 60% w/w ethanol;   from about 2% to about 98% w/w water;   from about 1% to about 20% w/w propylene glycol;   from about 0.001% to about 1% w/w sodium bisulfite;   from about 0.001% to about 1% w/w sodium metabisulfite;   from about 0.005% to about 1 w/w EDTA;   optionally, a permeation enhancer selected from the group consisting of from about 0.5% to about 15% w/w caprylic acid, from about 0.1% to about 10% w/w menthol and a combination thereof; and   optionally, benzalkonium chloride at a concentration from about 0.001% to about 0.1% w/w, wherein the formulation optionally has a pH from about 3 to about 7.0.       

     In another aspect, the present invention is directed to epinephrine spray formulations comprising:
         from about 0.1% to about 15% w/w epinephrine, or a salt thereof;   from about 1% to about 65% w/w hydrochloric acid with a normality from about 0.1 to 12N;   from about 2% to about 98% w/w water;   from about 0.001% to about 7.5% w/w sodium bisulfite;   from about 0.001% to about 7.5% w/w sodium metabisulfite;   from about 0.005% to about 1% w/w EDTA;   from about 0.1% to about 1% sodium chloride;   optionally, benzalkonium chloride at a concentration from about 0.001% to about 0.1% w/w, wherein the formulation optionally has a pH from about 3 to about 5.5.       

     In another aspect, the present invention is directed to epinephrine spray formulations comprising:
         from about 0.1% to about 15% w/w epinephrine, or a salt thereof;   from about 1% to about 65% w/w hydrochloric acid with a normality from about 0.1 to 12N;   from about 2% to about 98% w/w water, preferably from about 10% to about 65% w/w;   from about 0.005% to about 1% w/w sodium bisulfite;   from about 0.005% to about 1% w/w EDTA;   from about 0.005% to about 0.5% w/w BKC;   optionally, from about 2% to about 60% w/w ethanol;   optionally, from about 1% to about 20% w/w propylene glycol;   optionally, from about 0.05% to about 5% w/w sodium chloride;   optionally, benzalkonium chloride at a concentration from about 0.001% to about 0.1% w/w,
 
wherein the formulation optionally has a pH from about 3 to about 7.0.
       

     In another aspect, the present invention is directed to epinephrine spray formulations comprising: 
     from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof; and 
     from about 1% to about 80% w/w water, 
     wherein administration to a human of 7 milligrams of epinephrine or a salt thereof in the formulation provides a pharmacokinetic parameter selected from the group consisting of a C max  of at least about 1000 picograms per milliliter, a T max  of 0.167 hours or less, an AUC last  of at least 750 h*pg/mL, an AUC inf  of at least 950 h*pg/mL and a combination thereof. 
     In another aspect, the present invention is directed to epinephrine spray formulations comprising: 
     from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof; and 
     from about 1% to about 80% w/w water, 
     wherein administration to a human of 8.5 milligrams of epinephrine or a salt thereof in the formulation provides a pharmacokinetic parameter selected from the group consisting of a C max  of at least about 1400 picograms per milliliter, a T max  of 0.267 hours or less, an AUC last  of at least 1200 h*pg/mL, an AUC inf  of at least 1400 h*pg/mL and a combination thereof. 
     In another aspect, the present invention is directed to a method of treating anaphylaxis comprising administering to a subject in need thereof an epinephrine spray formulation of the present invention, preferably administration occurs via the intranasal route or sublingual route and wherein, optionally, the subject is suffering from seasonal allergies. 
     In another aspect, the present invention is directed to a method of treating anaphylaxis comprising administering to a subject in need thereof an epinephrine spray formulation of the present invention via unit dose or a multi-dose device that delivers more than one dose of the formulation, preferably via a bi-dose device that delivers two doses of the formulation. 
     In another aspect the present invention is directed to a method of treating anaphylaxis comprising administering via an assembled device an epinephrine formulation of the present invention. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1 . Epinephrine plasma concentrations over first 6 hours post administration. 
         FIG. 2 . Epinephrine plasma concentrations over first 30 minutes post administration. 
         FIG. 3 . Semi-log plot of epinephrine plasma concentrations over first 6 hours post administration. 
         FIG. 4 . Epinephrine plasma concentrations over first 6 hours post administration. 
         FIG. 5 . Epinephrine plasma concentrations over first 30 minutes post administration. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Definitions 
     Applicants discovered epinephrine spray formulations that have improved bioavailability, a more rapid onset of action, and improved storage stability. 
     As used herein, “epinephrine” refers to the base. 
     As used herein, “free of propellant” refers to a formulation that is not administered using compressed gas. 
     As used herein, all numerical values relating to amounts, weights, and the like, that are defined as “about” each particular value is plus or minus 10%. For example, the phrase “about 10% w/w” is to be understood as “9% w/w to 11% w/w.” Therefore, amounts within 10% of the claimed value are encompassed by the scope of the claims. 
     As used herein “% w/w” and “percent w/w” refer to the percent weight of the total formulation. 
     As used herein the term “effective amount” refers to the amount necessary to treat a patient in need thereof. 
     As used herein the term “treat”, “treating” or “treatment” refers to ameliorating or inhibiting symptoms of type I allergies including anaphylaxis. 
     As used herein the term “subject” refers, but is not limited to, a person that is experiencing type I allergies including anaphylaxis. 
     As used herein the term “anaphylaxis” refers to an allergic reaction involving multiple organ systems in a subject upon contact with an allergen rather or not that allergen is identifiable. 
     As used herein the term “allergen” refers to any chemical capable of causing an immune system response in a subject including, but not limited to, chemicals found in drugs, food, plants, insect bites, and insect stings. 
     As used herein the term “seasonal allergies” refers to an allergic rhinitis. Seasonal allergies symptoms include, but are not limited to, itchy, watery eyes, sneezing, runny or stuffy nose, swollen nasal turbinates, itchy sinuses, throat or ear canals, ear congestion and postnasal drainage. 
     As used herein “nasal congestion” refers to a symptom of swollen nasal turbinates. 
     As used herein the term “pharmaceutically acceptable” refers to ingredients that are not biologically or otherwise undesirable for administration to a living subject. 
     “Sublingual” refers to administration of a substance via the mouth in such a way that the substance is rapidly absorbed via the blood vessels under the tongue. 
     “Intranasal” refers to administration of the composition to any portion of the nasal epithelium. 
     In one embodiment, the present invention is directed to epinephrine spray formulations comprising epinephrine, or a salt thereof. 
     Preferred epinephrine salts include citrate, hydrochloride, halide, sulfate, bitartrate, tartrate, phosphate, acetate, malate, maleate, succinate, ascorbate, carbonate, mesylate and lactate. One of skill in the art could use other pharmaceutically acceptable epinephrine salts in the formulations of the present invention. In a preferred embodiment, the formulations contain epinephrine or the pharmaceutically acceptable salt equivalent to from about 0.1% to about 15% w/w epinephrine. In a more preferred embodiment, the formulation contains epinephrine or the pharmaceutically acceptable salt equivalent to from about 0.1% to about 10% w/w of epinephrine. Other most preferred embodiments include formulations which contain epinephrine or the pharmaceutically acceptable salt equivalent to from about 0.1% w/w to about 10% w/w. In a most preferred embodiment, the epinephrine concentration between 3% and 10% w/w. 
     In another embodiment, the present invention is directed to epinephrine spray formulations comprising epinephrine, or a salt thereof, wherein the formulation is free of a propellant. 
     In another embodiment, the present invention is directed to epinephrine spray formulations comprising epinephrine, or a salt thereof, and one or more excipients selected from acids, solvents, stabilizers, permeation enhancers, viscosity modifiers, sweeteners, sweetness enhancers, pH modifiers, isotonicity agents and flavoring agents. 
     In a preferred embodiment, the formulations of the present invention contain from about 1% to about 65% w/w of an acid, more preferably from about 1% to about 45% w/w. Acids suitable for use in the present invention include, but are not limited to, hydrochloric acid, malic acid, tartaric acid, citric acid, succinic acid and combinations thereof. In a preferred embodiment, the acid is hydrochloric acid or malic acid, even more preferably from about 0.1N to about 12N hydrochloric acid, even more preferably from about 0.5 to about 6 N hydrochloric acid, even more preferably from about 0.5 N to about 3 N hydrochloric acid and most preferably 0.5 N or 3 N hydrochloric acid. 
     In a preferred embodiment, the formulations of the present invention contain from about 1% to 99% w/w of a solvent preferably from about 30% to about 99% w/w of the solvent. 
     Solvents suitable for use in the present invention include, but are not limited to, water, ethanol, glycerin, propylene glycol, polyethylene glycol 400 and combinations thereof, more preferably water. 
     In a preferred embodiment, the formulations of the present invention contain from about 0.001% to about 10% w/w of a stabilizer, preferably from about 0.005% to about 7.5% w/w, and even more preferably from about 0.01% to about 5% w/w. Stabilizers suitable for use in the present invention include, but are not limited to, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, methionine, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, ascorbyl palmitate, thioglycerol, alpha tocopherol (vitamin E), cysteine hydrochloride, citric acid, ethylenediaminetetraacetic acid (“EDTA”), sodium citrate, propyl gallate, 8-hydroxyquinoline, boric acid, histidine and combinations thereof. In a preferred embodiment, the stabilizer is selected from sodium metabisulfite, sodium bisulfite, disodium EDTA, 8-hydroxyquinoline and combinations thereof. In an even more preferred embodiment the stabilizer is a combination of sodium bisulfite, sodium metabisulfite, 8-Hydroxyquinoline and EDTA. In a further preferred embodiment, the formulations of the present invention contain from about 0.005% to 0.5% w/w EDTA as the stabilizer. In a more preferred embodiment, the formulations of the present invention contain from about 0.01% to 0.1% EDTA as the stabilizer. In a most preferred embodiment, the formulations of the present invention contain about 0.05% EDTA as the stabilizer. In a further preferred embodiment, the formulations of the present invention contain sodium bisulfite and sodium metabisulfite as the anti-oxidants at a concentration from about from about 0.005% to 5% w/w. In a more preferred embodiment, the formulations of the present invention contain sodium bisulfite or sodium metabisulfite or a combination thereof as the anti-oxidants at a concentration from about from about 0.05% to 1% w/w. In a more preferred embodiment, the formulations of the present invention contain sodium bisulfite or sodium metabisulfite combination thereof as the anti-oxidants at a concentration from about from about 0.05% to about 1% w/w, more preferably from about 0.1% to about 0.75% w/w. In a most preferred embodiment, the formulations of the present invention contain sodium bisulfite as the anti-oxidant at a concentration at about 0.15% or 0.3% or 0.5% or 0.75% w/w. 
     In some embodiments, the formulations of the present invention contain from about 0.001% w/w to about 15% w/w of a permeation enhancer, preferably from about 0.03% w/w to about 12% w/w, and even more preferably from about 0.05% to 10% w/w. 
     Permeation enhancers suitable for use in the present invention include, but are not limited to, caprylic acid, oleic acid, polysorbate 80, menthol, EDTA, disodium edetate, cetylpyridinium chloride, sodium lauryl sulfate, citric acid, sodium desoxycholate, sodium deoxyglycolate, glyceryl oleate, L-lysine and combinations thereof. Preferred permeation enhancers are caprylic acid, menthol or a combination thereof. 
     Viscosity modifiers suitable for the present invention include, but are not limited to, polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropylmethyl cellulose (“HPMC”), methyl cellulose, hydroxyethyl cellulose, glycerin, polyvinyl alcohol and combinations thereof. In a preferred embodiment, the viscosity modifier is HPMC. 
     Sweeteners suitable for the present invention include, but are not limited to, sucralose, sucrose, aspartame, saccharin, dextrose, mannitol, glycerin, xylitol and combinations thereof. In a preferred embodiment, the sweetener is sucralose. 
     In some embodiments, the formulations of the present invention contain from about 0.001% to about 1% of a sweetness enhancer. Sweetness enhancers suitable for the present invention include, but are not limited to, the ammonium salt forms of crude and refined Glycyrrhizic Acid. Magnasweet® products (available from Mafco Worldwide Corporation, Magnasweet is a registered trademark of Mafco Worldwide Corporation) use the ammonium salt forms of crude and refined Glycyrrhizic Acid. Glycyrrhizic Acid is also available as a pure derivative in the sodium and potassium salt forms. 
     In a preferred embodiment, the formulations of the present invention are at a pH from about 2.0 to about 7.0. In a more preferred embodiment the formulations of the present invention are at a pH from about 3.0 to about 5.0. In a further preferred embodiment, the formulations of the present invention are at a pH from about 4.0 to about 5.0. In a most preferred embodiment the formulations of the present invention are at a pH of 4.5. pH modifiers suitable for the present invention include, but are not limited to, hydrochloric acid, citric acid, fumaric acid, lactic acid, sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate, ammonium carbonate and combinations thereof. 
     Preservatives suitable for the present invention include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, sodium benzoate, chlorobutanol, benzalkonium chloride, benzoic acid and combinations thereof. In a preferred embodiment, the preservative is benzalkonium chloride. In a more preferred embodiment the benzalkonium chloride is at a concentration from about 0.01% to about 0.02% w/w, more preferably 0.01% or 0.02% w/w. 
     Flavoring agents suitable for the present invention include, but are not limited to, peppermint oil, menthol, spearmint oil, citrus oil, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil and a combination thereof. 
     In preferred embodiment, the present invention is directed to epinephrine spray formulations comprising:
         from about 2.8% to about 4% w/w epinephrine, or a salt thereof;   from about 32% to about 38% w/w hydrochloric acid with a normality from 0.5 to 3N;   from about 10% to about 65 w/w ethanol;   from about 2% to about 38% w/w water;   about 5% w/w propylene glycol;   from about 0.1% to about 0.75% w/w sodium bisulfite;   about 0.05% w/w disodium EDTA;   optionally, a permeation enhancer selected from the group consisting of from about 2% to about 10% w/w caprylic acid, from about 0.5% to about 1.0% w/w menthol and a combination thereof; and   optionally, benzalkonium chloride at a concentration from about 0.01% to about 0.02% w/w, wherein the formulation optionally has a pH of about 4.5.       

     In another preferred embodiment, the present invention is directed to epinephrine spray formulations comprising: 
     about 3.24% w/w epinephrine, or a salt thereof; 
     about 36.2% w/w hydrochloric acid with a normality of 0.5; 
     about 40% w/w ethanol; 
     about 14.84% w/w water; 
     about 5% w/w propylene glycol; 
     about 0.01% w/w benzalkonium chloride; and 
     from about 0.15% to about 0.3% w/w sodium bisulfite, 
     wherein the formulation has a pH at about 4.5. 
     In another preferred embodiment, the present invention is directed to intranasal epinephrine spray formulations comprising: 
     about 3.117% w/w epinephrine, or a salt thereof; 
     about 34.8% w/w hydrochloric acid with a normality of 0.5; 
     about 20% w/w ethanol; 
     about 36.87% w/w water; 
     about 5% w/w propylene glycol; 
     about 0.01% w/w benzalkonium chloride; 
     from about 0.15% w/w sodium bisulfite to about 0.3% w/w sodium bisulfite, 
     wherein the formulation has a pH at about 4.5. 
     In another preferred embodiment, the present invention is directed to intranasal epinephrine spray formulations comprising: 
     about 3.04% w/w epinephrine, or a salt thereof; 
     about 33.8% w/w hydrochloric acid with a normality of 0.5; 
     about 62.35% w/w water; 
     about 0.01% w/w benzalkonium chloride; 
     from about 0.15% w/w sodium bisulfite to about 0.3% w/w sodium bisulfite, 
     wherein the formulation has a pH at about 4.5. 
     An epinephrine spray formulation comprising: 
     about 2.96% w/w epinephrine base; 
     about 32.93% w/w hydrochloric acid with a normality of about 0.5N; 
     about 0.05% w/w edetate disodium dihydrate; 
     about 0.15% w/w sodium bisulfite; 
     about 0.01% w/w benzalkonium chloride; 
     about 0.6% w/w sodium chloride; and 
     about 63.30% w/w water, wherein the formulation has a pH at about 4.5. 
     An epinephrine spray formulation comprising: 
     about 3.18% w/w epinephrine base; 
     about 35.47% w/w hydrochloric acid with a normality of about 0.5N; 
     about 0.05% w/w edetate disodium dihydrate; 
     about 0.15% w/w sodium bisulfite; 
     about 0.01% w/w benzalkonium chloride; 
     about 5% w/w propylene glycol; 
     about 40.0% w/w ethanol; and 
     about 16.14% w/w water, wherein the formulation has a pH at about 4.5. 
     An epinephrine spray formulation comprising: 
     about 5.923% w/w epinephrine base; 
     about 16.46% w/w hydrochloric acid with a normality of about 2N; 
     about 0.05% w/w edetate disodium dihydrate; 
     about 0.15% w/w sodium bisulfite; 
     about 0.01% w/w benzalkonium chloride; 
     about 0.6% w/w sodium chloride; and 
     about 76.81% w/w water, wherein the formulation has a pH at about 4.5. 
     An epinephrine spray formulation comprising: 
     about 5.923% w/w epinephrine base; 
     about 16.46% w/w hydrochloric acid with a normality of about 2N; 
     about 0.05% w/w edetate disodium dihydrate; 
     about 0.30% w/w sodium bisulfite; 
     about 0.01% w/w benzalkonium chloride; 
     about 0.6% w/w sodium chloride; and 
     about 76.66% w/w water, wherein the formulation has a pH at about 4.5. 
     An epinephrine spray formulation comprising: 
     about 6.356% w/w epinephrine base; 
     about 17.74% w/w hydrochloric acid with a normality of about 2N; 
     about 0.05% w/w edetate disodium dihydrate; 
     about 0.15% w/w sodium bisulfite; 
     about 0.01% w/w benzalkonium chloride; 
     about 40.0% w/w ethanol; 
     about 5% w/w propylene glycol 
     about 30.70% w/w water, wherein the formulation has a pH at about 4.5. 
     An epinephrine spray formulation comprising: 
     about 6.356% w/w epinephrine base; 
     about 17.74% w/w hydrochloric acid with a normality of about 2N; 
     about 0.05% w/w edetate disodium dihydrate; 
     about 0.30% w/w sodium bisulfite; 
     about 0.01% w/w benzalkonium chloride; 
     about 40.0% w/w ethanol; 
     about 5% w/w propylene glycol 
     about 30.55% w/w water, wherein the formulation has a pH at about 4.5. 
     An epinephrine spray formulation comprising: 
     about 8.885% w/w epinephrine base; 
     about 24.70% w/w hydrochloric acid with a normality of about 2N; 
     about 0.05% w/w edetate disodium dihydrate; 
     about 0.15% w/w sodium bisulfite; 
     about 0.01% w/w benzalkonium chloride; 
     about 0.6% w/w sodium chloride; and 
     about 65.61% w/w water, wherein the formulation has a pH at about 4.5. 
     An epinephrine spray formulation comprising: 
     about 8.885% w/w epinephrine base; 
     about 24.70% w/w hydrochloric acid with a normality of about 2N; 
     about 0.05% w/w edetate disodium dihydrate; 
     about 0.45% w/w sodium bisulfite; 
     about 0.01% w/w benzalkonium chloride; 
     about 0.6% w/w sodium chloride; and 
     about 65.31% w/w water, wherein the formulation has a pH at about 4.5. 
     An epinephrine spray formulation comprising: 
     about 9.534% w/w epinephrine base; 
     about 26.60% w/w hydrochloric acid with a normality of about 2N; 
     about 0.05% w/w edetate disodium dihydrate; 
     about 0.15% w/w sodium bisulfite; 
     about 0.01% w/w benzalkonium chloride; 
     about 40.0% w/w ethanol; 
     about 5% w/w propylene glycol 
     about 18.65% w/w water, wherein the formulation has a pH at about 4.5. 
     An epinephrine spray formulation comprising: 
     about 9.534% w/w epinephrine base; 
     about 26.60% w/w hydrochloric acid with a normality of about 2N; 
     about 0.05% w/w edetate disodium dihydrate; 
     about 0.15% w/w sodium bisulfate; 
     about 0.01% w/w benzalkonium chloride; 
     about 40.0% w/w ethanol; 
     about 5% w/w propylene glycol 
     about 18.35% w/w water, wherein the formulation has a pH at about 4.5. 
     In another embodiment, administration to a human exposed to an allergen of 6 milligrams of epinephrine in the formulation #C1 of Table 62 below produced an epinephrine plasma concentration more than 100 picograms per milliliter at about 1-minute post administration. 
     In another embodiment, administration to a human not exposed to an allergen of 6 milligrams of epinephrine in the formulation #C1 of Table 62 below produced an epinephrine plasma concentration more than 100 picograms per milliliter at about 3-minutes post administration. 
     In another embodiment, administration to a human exposed to an allergen of 6 milligrams of epinephrine in the formulation #C2 of Table 62 below produced an epinephrine plasma concentration more than 100 picograms per milliliter at about 1-minute post administration. 
     In another embodiment, administration to a human exposed to an allergen of 6 milligrams of epinephrine in the formulation #C2 of Table 62 below produced an epinephrine plasma concentration more than 290 picograms per milliliter at about 1-minute post administration. 
     In another embodiment, administration to a human not exposed to an allergen of 6 milligrams of epinephrine in the formulation #C2 of Table 62 below produced an epinephrine plasma concentration more than 100 picograms per milliliter at about 3-minutes post administration. 
     In another aspect, the present invention is directed to epinephrine spray formulations comprising: 
     from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof; 
     from about 2% to about 10% w/w propylene glycol; 
     from about 20% to about 50% w/w ethanol; and 
     from about 1% to about 80% w/w water, 
     wherein administration to a human of 7 milligrams of epinephrine or a salt thereof in the formulation provides:
         a pharmacokinetic parameter selected from the group consisting of a C max  (arithmetic mean) of at least about 1000 picograms per milliliter, a T max  (arithmetic mean) of 0.167 hours or less, an AUC last  (arithmetic mean) of at least 750 h*pg/mL, an AUC inf  (arithmetic mean) of at least 950 h*pg/mL and a combination thereof; or
 
a pharmacokinetic parameter selected from the group consisting of a C max  (geometric mean) of at least about 500 picograms per milliliter, a T max  of 0.167 hours or less, an AUC last  (geometric mean) of at least about 500 h*pg/mL, an AUC inf  (geometric mean) of at least about 800 h*pg/mL and a combination thereof;
   a pharmacokinetic parameter selected from the group consisting of:   a C max  (arithmetic mean) of about 1040 picograms per milliliter, a T max  (arithmetic mean) of about 0.167 hours, an AUC last  (arithmetic mean) of about 785 h*pg/mL, an AUC inf  (arithmetic mean) of about 960 h*pg/mL and a combination thereof; or   a pharmacokinetic parameter selected from the group consisting of a C max  (geometric mean) of about 536 picograms per milliliter, an AUC last  (geometric mean) of about 521 h*pg/mL, an AUC inf  (geometric mean) of about 828 h*pg/mL and a combination thereof; or   a plasma concentration of more than 70 picograms per milliliter in 1 minute or less following administration;   a plasma concentration of more than 750 picograms per milliliter in 3 minutes or less following administration;   provides a plasma concentration of more than 650 picograms per milliliter in 5 minutes or less following administration;   provides a plasma concentration of more than 600 picograms per milliliter in 7 minutes or less following administration; or   provides a plasma concentration of more than 550 picograms per milliliter in 10 minutes or less following administration.       

     In another aspect, the present invention is directed to epinephrine spray formulations comprising: 
     from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof; and 
     from about 1% to about 80% w/w water, 
     wherein administration to a human of 8.5 milligrams of epinephrine or a salt thereof in the formulation provides:
         a pharmacokinetic parameter selected from the group consisting of a C max  (arithmetic mean) of at least about 1400 picograms per milliliter, a T max  of 0.267 hours or less, an AUC last  (arithmetic mean) of at least 1200 h*pg/mL, an AUC inf  (arithmetic mean) of at least 1400 h*pg/mL and a combination thereof;   a pharmacokinetic parameter selected from the group consisting of a C max  (geometric mean) of at least about 650 picograms per milliliter, a T max  of 0.267 hours or less, an AUC last  (geometric mean) of at least about 800 h*pg/mL, an AUC inf  (geometric mean) of at least about 10000 h*pg/mL and a combination thereof;   a pharmacokinetic parameter selected from the group consisting of a C max  (arithmetic mean) of about 1420 picograms per milliliter, a median T max  of about 0.267 hours, an AUC last  (arithmetic mean) of about 1200 h*pg/mL, an AUC inf  (arithmetic mean) of about 1440 h*pg/mL and a combination thereof;   a pharmacokinetic parameter selected from the group consisting of a C max  (geometric mean) of about 686 picograms per milliliter, an AUC last  (geometric mean) of about 813 h*pg/mL, an AUC inf  (geometric mean) of about 10308 h*pg/mL and a combination thereof;   a plasma concentration of more than 200 picograms per milliliter in 1 minute or less following administration;   a plasma concentration of more than 850 picograms per milliliter in 3 minutes or less following administration;   a plasma concentration of more than 1000 picograms per milliliter in 5 minutes or less following administration;   a plasma concentration of more than 975 picograms per milliliter in 7 minutes or less following administration; or   a plasma concentration of more than 950 picograms per milliliter in 10 minutes or less following administration.       

     In another aspect, the present invention is directed to epinephrine spray formulations comprising: 
     from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof; 
     from about 2% to about 10% w/w propylene glycol; 
     from about 20% to about 50% w/w ethanol; and 
     from about 1% to about 80% w/w water, 
     wherein administration to a human of 7 milligrams of epinephrine or a salt thereof in the formulation provides:
 
a geometric mean plasma concentration at 1 minute post-administration of 4.3 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 3 minutes post-administration of 1.7 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 5 minutes post-administration of 1.3 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 7 minutes post-administration of 1.5 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 10 minutes post-administration of 1.6 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 15 minutes post-administration of 1.8 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 20 minutes post-administration of 1.4 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 30 minutes post-administration of 1.4 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 45 minutes post-administration of 1.7 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation; or
 
a geometric mean plasma concentration at 60 minutes post-administration of 2.4 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation,
 
wherein in the second formulation consists of 0.3 milligrams epinephrine, 1.8 milligrams sodium chloride, 0.5 milligrams sodium metabisulfite, hydrochloric acid to adjust pH, and water for injection.
 
     In another aspect, the present invention is directed to epinephrine spray formulations comprising: 
     from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof; 
     from about 2% to about 10% w/w propylene glycol; 
     from about 20% to about 50% w/w ethanol; and 
     from about 1% to about 80% w/w water, 
     wherein administration to a human of 8.5 milligrams of epinephrine or a salt thereof in the formulation provides:
 
a geometric mean plasma concentration at 1 minute post-administration of 5.3 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 3 minutes post-administration of 1.9 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 5 minutes post-administration of 2.0 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 7 minutes post-administration of 2.4 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 10 minutes post-administration of 2.8 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 15 minutes post-administration of 2.8 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 20 minutes post-administration of 2.4 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 30 minutes post-administration of 2.0 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean plasma concentration at 45 minutes post-administration of 2.7 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation; or
 
a geometric mean plasma concentration at 60 minutes post-administration of 3.4 times compared to a geometric mean plasma concentration following administration of 0.3 milligrams of epinephrine in a second formulation,
 
wherein in the second formulation consists of 0.3 milligrams epinephrine, 1.8 milligrams sodium chloride, 0.5 milligrams sodium metabisulfite, hydrochloric acid to adjust pH, and water for injection.
 
     In another aspect, the present invention is directed to epinephrine spray formulations comprising: 
     from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof; 
     from about 2% to about 10% w/w propylene glycol; 
     from about 20% to about 50% w/w ethanol; and 
     from about 1% to about 80% w/w water, 
     wherein administration to a human of 7 milligrams of epinephrine or a salt thereof in the formulation provides:
 
a geometric mean AUC 0-0.017  of 4.2 times compared to a geometric mean AUC 0-0.017  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.05  of 2 times compared to a geometric mean AUC 0-0.5  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.083  of 1.7 times compared to a geometric mean AUC 0-0.083  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.117  of 1.6 times compared to a geometric mean AUC 0-0.117  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.167  of 1.6 times compared to a geometric mean AUC 0-0.167  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.25  of 1.6 times compared to a geometric mean AUC 0-0.25  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.33  of 1.6 times compared to a geometric mean AUC 0-0.33  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0.0.5  of 1.5 times compared to a geometric mean AUC 0.0.5  following administration of 0.3 milligrams of epinephrine in a second formulation; a geometric mean AUC 0-0.75  of 1.5 times compared to a geometric mean AUC 0-0.75  following administration of 0.3 milligrams of epinephrine in a second formulation; or
 
a geometric mean AUC 0-1  of 1.6 times compared to a geometric mean AUC 0-1  following administration of 0.3 milligrams of epinephrine in a second formulation.
 
     In another aspect, the present invention is directed to epinephrine spray formulations comprising: 
     from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof; 
     from about 2% to about 10% w/w propylene glycol; 
     from about 20% to about 50% w/w ethanol; and 
     from about 1% to about 80% w/w water, 
     wherein administration to a human of 8.5 milligrams of epinephrine or a salt thereof in the formulation provides:
 
a geometric mean AUC 0-0.017  of 5 times compared to a geometric mean AUC 0-0.017  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.05  of 2.3 times compared to a geometric mean AUC 0.0.5  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.083  of 2.1 times compared to a geometric mean AUC 0-0.083  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.117  of 2.1 times compared to a geometric mean AUC 0-0.117  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.167  of 2.3 times compared to a geometric mean AUC 0-0.167  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.25  of 2.5 times compared to a geometric mean AUC 0-0.25  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.33  of 2.5 times compared to a geometric mean AUC 0-0.33  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.5  of 2.4 times compared to a geometric mean AUC 0-0.5  following administration of 0.3 milligrams of epinephrine in a second formulation;
 
a geometric mean AUC 0-0.75  of 2.4 times compared to a geometric mean AUC 0-0.75  following administration of 0.3 milligrams of epinephrine in a second formulation; or
 
a geometric mean AUC 0-1  of 2.5 times compared to a geometric mean AUC 0-1  following administration of 0.3 milligrams of epinephrine in a second formulation.
 
     In another aspect, the present invention is directed to epinephrine spray formulations comprising: 
     from about 3% to about 6% w/w epinephrine base; 
     from about 20% to about 30% w/w hydrochloric acid with a normality of about 1.0N; 
     from about 0.025% to about 0.075% w/w edetate disodium dihydrate; 
     from about 0.15% to about 0.30% w/w sodium bisulfate; 
     from about 0.005% to about 0.02% w/w benzalkonium chloride; 
     from about 35% to about 45% w/w ethanol; 
     from about 2.5% to about 7.5% w/w propylene glycol; and 
     from about 20% to about 30% w/w water. 
     In another aspect, the present invention is directed to epinephrine spray formulations comprising: 
     from about 3% to about 5% w/w epinephrine base; 
     from about 20% to about 25% w/w hydrochloric acid with a normality of about 1.0N; 
     from about 0.025% to about 0.075% w/w edetate disodium dihydrate; 
     from about 0.15% to about 0.25% w/w sodium bisulfite; 
     from about 0.005% to about 0.02% w/w benzalkonium chloride; 
     from about 35% to about 45% w/w ethanol; 
     from about 2.5% to about 7.5% w/w propylene glycol; and 
     from about 20% to about 40% w/w water. 
     In another aspect, the present invention is directed to epinephrine spray formulations comprising: 
     from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof; 
     from about 2% to about 10% w/w propylene glycol; 
     from about 20% to about 50% w/w ethanol; and 
     from about 1% to about 80% w/w water, 
     wherein administration to a human of 7 milligrams of epinephrine or a salt thereof in the formulation provides:
         a geometric mean C max  of about 86.2% compared to a geometric mean C max  following intramuscular administration of 0.3 milligrams of epinephrine in a second formulation; AUC last  of about 154% compared to a geometric mean AUC last  following administration of 0.3 milligrams of epinephrine in a second formulation;   AUC inf  of about 217% compared to a geometric mean AUC inf  following administration of 0.3 milligrams of epinephrine in a second formulation;   a geometric mean C max  of about 101% compared to a geometric mean C max  following intramuscular administration of 0.5 milligrams of epinephrine in a third formulation;   AUC last  of about 94.5% compared to a geometric mean AUC last  following administration of 0.5 milligrams of epinephrine in a third formulation; or   AUC inf  of about 120% compared to a geometric mean AUC inf  following administration of 0.5 milligrams of epinephrine in a third formulation,
 
wherein the second formulation consists of 0.3 milligrams epinephrine, 1.8 milligrams sodium chloride, 0.5 milligrams sodium metabisulfite, hydrochloric acid to adjust pH, and water for injection and wherein the third formulation consists of 1.0 milligrams epinephrine, 6.15 milligrams sodium chloride, 0.457 milligrams sodium metabisulfite, 0.920 milligrams sodium hydroxide, 2.25 milligrams tartaric acid, 0.20 milligrams disodium edetate dihydrate, hydrochloric acid to adjust pH, milligrams chlorobutanol and water for injection.
       

     In another aspect, the present invention is directed to epinephrine spray formulations comprising:
         a geometric mean C max  of about 111% compared to a geometric mean C max  following administration of 0.3 milligrams of epinephrine in a second formulation;   AUC last  of about 241% compared to a geometric mean AUC last  following administration of 0.3 milligrams of epinephrine in a second formulation;   AUC inf  of about 282% compared to a geometric mean AUC inf  following administration of 0.3 milligrams of epinephrine in a second formulation;   a geometric mean C max  of about 130% compared to a geometric mean C max  following intramuscular administration of 0.5 milligrams of epinephrine in a third formulation;   AUC last  of about 147% compared to a geometric mean AUC last  following administration of 0.5 milligrams of epinephrine in a third formulation; or   AUC inf  of about 155% compared to a geometric mean AUC inf  following administration of 0.5 milligrams of epinephrine in a third formulation,
 
wherein the second formulation consists of 0.3 milligrams epinephrine, 1.8 milligrams sodium chloride, 0.5 milligrams sodium metabisulfite, hydrochloric acid to adjust pH, and water for injection and wherein the third formulation consists of 1.0 milligrams epinephrine, 6.15 milligrams sodium chloride, 0.457 milligrams sodium metabisulfite, 0.920 milligrams sodium hydroxide, 2.25 milligrams tartaric acid, 0.20 milligrams disodium edetate dihydrate, hydrochloric acid to adjust pH, milligrams chlorobutanol and water for injection.
       

     In another embodiment, the formulations of the present invention are capable of producing a droplet size distribution at 3 cm wherein the mean DV (10) is from about 15 to about 18 microns during administration. 
     In another embodiment, the formulations of the present invention are capable of producing a droplet size distribution at 3 cm wherein the mean DV (50) is from about 30 to about 34 microns during administration. 
     In another embodiment, the formulations of the present invention are capable of producing a droplet size distribution at 3 cm wherein the mean DV (90) is from about 120 to about 230 microns during administration. 
     In another embodiment, the formulations of the present invention are capable of producing a spray span ((Dv90−Dv10)/Dv50) at 3 cm of from about 3 to about 7. 
     In another embodiment, the formulations of the present invention are capable of producing a droplet size distribution at 6 cm wherein the mean DV (10) is from about 22 to about 25 microns during administration. 
     In another embodiment, the formulations of the present invention are capable of producing a droplet size distribution at 6 cm wherein the mean DV (50) is from about 36 to about 41 microns during administration. 
     In another embodiment, the formulations of the present invention are capable of producing a droplet size distribution at 6 cm wherein the mean DV (90) is from about 59 to about 231 microns during administration. 
     In another embodiment, the formulations of the present invention are capable of producing a spray span ((Dv90−Dv10)/Dv50) at 6 cm of from about 1 to about 6. 
     In another embodiment, the formulations of the present invention are capable of producing a spray pattern at 3 cm wherein the Dmin is from about 18 to about 23 millimeters during administration. 
     In another embodiment, the formulations of the present invention are capable of producing a spray pattern at 3 cm wherein the Dmax is from about 29 to about 33 millimeters during administration. 
     In another embodiment, the formulations of the present invention are capable of producing a spray pattern at 3 cm wherein the ovality ratio is from about 1.4 to about 1.7 during administration. 
     In another embodiment, the formulations of the present invention are capable of producing a spray pattern at 6 cm wherein the Dmin is from about 26 to about 33 millimeters during administration. 
     In another embodiment, the formulations of the present invention are capable of producing a spray pattern at 6 cm wherein the Dmax is from about 47 to about 52 millimeters during administration. 
     In another embodiment, the formulations of the present invention are capable of producing a spray pattern at 6 cm wherein the ovality ratio is from about 1.6 to about 1.9 during administration. 
     In another embodiment, the formulations of the present invention are capable of producing a plume geometry at 3 cm wherein the angle is from about 49° to about 64°. 
     In another embodiment, the formulations of the present invention are capable of producing a plume geometry at 3 cm wherein the width is from about 27 to about 38 millimeters. 
     In another embodiment, the formulations of the present invention are capable of producing a plume geometry at 3 cm wherein the angle is from about 37° to about 44°. 
     In another embodiment, the formulations of the present invention are capable of producing a plume geometry at 3 cm wherein the width is from about 37 to about 44 millimeters. 
     In one embodiment, the present invention is directed to a method of treating anaphylaxis comprising administering via an assembled device an epinephrine formulation comprising from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof and from about 1% to about 80% w/w water, wherein the formulation has a pH from about 2 to about 7.0. 
     In a preferred embodiment, the assembled device comprises a reservoir, a plunger, a cannula, a spray pin, a reservoir holder and an actuator or a reservoir, a piston and a swirl chamber. 
     In another preferred embodiment, the assembled device delivers one or more doses of the epinephrine formulation. 
     In another preferred embodiment, the assembled device is a unit-dose device that delivers one dose of the epinephrine formulation upon a single actuation and comprises a single reservoir containing not more than 250 μL of the epinephrine formulation, preferably about 237 μL or not more than 140 μL, preferably about 127 μL. 
     In another preferred embodiment, the assembled device is a unit-dose device that delivers about 200 μL or about 100 μL of the pharmaceutical formulation upon a single actuation. 
     In another preferred embodiment, the assembled device is a bi-dose device that delivers two doses of the epinephrine formulation upon two actuations and delivers about 100 μL of the epinephrine formulation per actuation. 
     In another preferred embodiment, the assembled device is a multi-dose device that delivers multiple doses of the epinephrine formulation upon multiple actuations and delivers about 100 μL of the pharmaceutical solution per actuation. 
     The disclosed embodiments are simply exemplary embodiments of the inventive concepts disclosed herein and should not be considered as limiting, unless the claims expressly state otherwise. 
     The following examples are intended to illustrate the present invention and to teach one of ordinary skill in the art how to use the formulations of the invention. They are not intended to be limiting in any way. 
     EXAMPLES 
     Example 1 
     An epinephrine spray was prepared as follows using the components and amounts listed in Table 1 below. All of the solvents were purged with nitrogen prior to use. Excipients including 0.5 N hydrochloric acid (“HCl”), malic acid, ethanol and propylene glycol, EDTA, sodium chloride, sodium bisulfate, sodium metabisulfite, and 8-hydroxyquinoline were dissolved in water while stirring at room temperature. Epinephrine base was then added to the excipient solution. Finally, sodium hydroxide (“NaOH”)/hydrochloric acid (HCl)) was used to adjust final pH. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Epinephrine Formulations 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 % w/w 
                 #1 
                 #2 
                 #3 
                 #4 
                 #5 
                 #6 
                 #7 
                 #8 
                 #9 
                 #10 
                 #11 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Epinephrine base 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
                 7.5 
                 1 
                 3.0 
                 3.0 
                 3.0 
                 3.0 
               
               
                 HCl (0.5N) 
                 10.66 
                 10.66 
                 10.66 
                 10.66 
                 10.66 
                 — 
                 11.35 
                 — 
                 32.6 
                 32.6  
                 32.6 
               
               
                 EDTA 
                 0.05 
                 0.05 
                 0.05 
                 0.05 
                 0.05 
                 — 
                 — 
                 — 
                 0.05 
                  0.05 
                 0.05 
               
               
                 Sodium metabisulfite 
                 0.01 
                 0.015 
                 0.02 
                 0.025 
                 0.025 
                 0.25 
                 0.025 
                 0.04 
                 — 
                 — 
                 — 
               
               
                 sodium bisulfite 
                 0.01 
                 0.015 
                 0.02 
                 0.025 
                 0.025 
                 — 
                 0.025 
                   
                 0.05 
                 0.2 
                 0.2 
               
               
                 Propylene Glycol 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 5 
               
               
                 Menthol 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 5 
               
               
                 Chlorobutanol 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 0.5 
                 — 
               
               
                 Sucralose 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 0.5 
                 0.5 
               
               
                 8-Hydroxyquinoline 
                 — 
                 — 
                 — 
                 — 
                 0.02 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
               
               
                 Ethanol 
                 — 
                 — 
                 — 
                 — 
                 — 
                 15 
                   
                 — 
                 — 
                 — 
                 50 
               
               
                 Malic Acid 
                 — 
                 — 
                 — 
                 — 
                 — 
                 2.0 
                 — 
                 1.65 
                 — 
                 — 
                 — 
               
               
                 Water 
                 88.27 
                 88.26 
                 88.25 
                 88.24 
                 88.22 
                 79.75 
                 87.6 
                 95.31 
                 64.3 
                 63.15 
                 4.15 
               
               
                   
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100    
                 100 
               
               
                 pH adjusted with NaOH 
                 pH 4.5 
                 pH 4.5 
                 pH 4.5 
                 pH 4.5 
                 pH 4.5 
                 pH 4.5 
                 pH 4.5 
                 pH 4.5 
                 pH 4.5 
                 pH 4.5 
                 pH 4.5 
               
               
                   
               
            
           
         
       
     
     Example 2 
     The formulations listed in Table 1 were subjected to stability at 40° C.±2° C./75%±5% relative humidity and 25° C.±2° C./60%±5% relative humidity. The stability of the formulations was analyzed at specified time points by evaluating their potency (assay value) and impurity levels. Assay and impurities were detected using high-performance liquid chromatography with an ultraviolet detector. The assay was performed at 280 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 210 nm and 280 nm and expressed as a % area. Amounts of particular impurities are listed in Tables 2 to 20 as a percentage of area of each formulation along with amount of total impurities. Relative retention time (“RRT”) is given for each impurity. “ND” indicates that the impurity was not detected. “BQL” indicates purity is below quantification limit. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #1 
               
               
                 stored at 40° C. ± 2° C./75% ± 5% 
               
               
                 Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                 40° C. Formulation #1 
                 RRT 
                 0 Week 
                 2 Weeks 
                 4 Weeks 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of initial conc.) 
                   
                 100.00 
                 97.94 
                 95.80 
               
               
                 % Racemization 
                   
                   0.60 
                  0.93 
                  1.54 
               
               
                 pH 
                   
                   4.50 
                  3.52 
                  3.29 
               
               
                 % Impurity F 
                 0.19 
                   0.13 
                  1.07 
                  1.51 
               
               
                 % Synephrine 
                 1.26 
                  ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                  ND 
                 ND 
                 ND 
               
               
                 % Methoxy 
                 1.88 
                   0.07 
                  0.07 
                  0.07 
               
               
                 % Unknown Impurity 
                 0.21 
                  ND 
                  0.10 
                  0.15 
               
               
                   
                 0.23 
                  ND 
                 ND 
                  0.02 
               
               
                   
                 3.11 
                  ND 
                  BQL 
                  0.03 
               
               
                   
                 3.26 
                  ND 
                  BQL 
                  0.02 
               
               
                 % Total Impurities 
                   
                   0.20 
                  1.24 
                  1.80 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #2 
               
               
                 stored at 40° C. ± 2° C./75% ± 5% 
               
               
                 Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                 40° C. Formulation #2 
                 RRT 
                 0 Week 
                 2 Weeks 
                 4 Weeks 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of initial conc.) 
                   
                 100.00 
                 96.02 
                 97.32 
               
               
                 % Racemization 
                   
                   0.60 
                  0.91 
                  1.77 
               
               
                 pH 
                   
                   4.50 
                  3.39 
                  3.14 
               
               
                 % Impurity F 
                 0.19 
                   0.14 
                  1.27 
                  1.91 
               
               
                 % Synephrine 
                 1.26 
                  ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.38 
                  ND 
                 ND 
                  BQL 
               
               
                 % Methoxy 
                 1.88 
                   0.07 
                  0.07 
                  0.07 
               
               
                 % Unknown Impurity 
                 0.21 
                  ND 
                  0.10 
                  0.11 
               
               
                   
                 0.23 
                  ND 
                 ND 
                  BQL 
               
               
                   
                 3.26 
                  ND 
                 ND 
                 ND 
               
               
                 % Total Impurities 
                   
                   0.21 
                  1.44 
                  2.09 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #3 stored at 40° 
               
               
                 C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 40° C. Formulation #3 
                 RRT 
                 0 Week 
                 2 Weeks 
                 4 Weeks 
                 8 Weeks 
                 3 Months 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of initial conc.) 
                   
                 100.00  
                 98.22  
                 96.87  
                 94.56  
                 93.27  
               
               
                 % Racemization 
                   
                 0.60 
                 1.01 
                 1.48 
                 3.67 
                 4.23 
               
               
                 pH 
                   
                 4.50 
                 3.37 
                 3.14 
                 3.01 
                 — 
               
               
                 % Impurity F 
                 0.19 
                 0.13 
                 1.27 
                 2.19 
                 3.05 
                 3.18 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.88 
                 0.07 
                 0.07 
                 0.07 
                 0.07 
                 0.07 
               
               
                 % Unknown Impurity 
                 0.21 
                 ND 
                 0.08 
                 0.07 
                 0.08 
                 0.24 
               
               
                   
                 3.11 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 3.26 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Total Impurities 
                   
                 0.20 
                 1.42 
                 2.33 
                 3.20 
                 3.49 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #4 stored at  
               
               
                 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
            
               
                 40° C. 
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Formulation 
                   
                 0 
                 1 
                 2 
                 4 
                 6 
                 8 
                 3 
                 4 
               
               
                 #4 
                 RRT 
                 Week 
                 Week 
                 Weeks 
                 Weeks 
                 Weeks 
                 Weeks 
                 Months 
                 Months 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
                 Clear 
                 Clear 
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of 
                   
                 100.0 
                 100.7  
                 98.54 
                 98.35 
                 96.02 
                 94.44 
                 92.60 
                 89.34 
               
               
                 initial conc.) 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 % 
                   
                 0.60 
                 0.68 
                 — 
                 — 
                 3.41 
                 3.46 
                 5.75 
                 9.20 
               
               
                 Racemization 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 % Impurity F 
                 0.19 
                 0.15 
                 0.78 
                 1.29 
                 2.33 
                 3.16 
                 3.83 
                 4.36 
                 4.65 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 % 
                 1.36 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 Epinephrone 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 % Methoxy 
                 1.88 
                 0.08 
                 0.08 
                 0.08 
                 0.08 
                 0.08 
                 0.08 
                 0.08 
                 0.09 
               
               
                 % Unknown 
                 0.21 
                 ND 
                 ND 
                 0.05 
                 0.08 
                 0.07 
                 0.09 
                 0.22 
                 0.23 
               
               
                 Impurity 
                 3.11 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 0.05 
               
               
                   
                 3.26 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Total 
                   
                 0.23 
                 0.86 
                 1.42 
                 2.49 
                 3.31 
                 4.00 
                 4.66 
                 5.02 
               
               
                 Impurities 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #5 stored at  
               
               
                 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 40° C.  
                   
                 0  
                 2  
                 4  
                 8  
                 3  
               
               
                 Formulation #5 
                 RRT 
                 Week 
                 Weeks 
                 Weeks 
                 Weeks 
                 Months 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay  
                   
                 100.00  
                 98.36  
                 96.88  
                 95.35  
                 93.34  
               
               
                 (% of initial conc.) 
                   
                   
                   
                   
                   
                   
               
               
                 % Racemization 
                   
                 0.60 
                 0.85 
                 1.08 
                 2.63 
                 4.23 
               
               
                 pH 
                   
                 4.50 
                 3.64 
                 3.37 
                 3.20 
                 — 
               
               
                 % Impurity F 
                 0.19 
                 0.15 
                 1.48 
                 2.50 
                 3.50 
                 3.75 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.88 
                 0.07 
                 0.07 
                 0.07 
                 0.07 
                 0.07 
               
               
                 % Unknown  
                 0.21 
                 ND 
                 0.10 
                 0.11 
                 0.15 
                 0.35 
               
               
                 Impurity 
                 0.88 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 3.11 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 3.26 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Total Impurities 
                   
                 0.22 
                 1.65 
                 2.68 
                 3.72 
                 4.17 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #6  
               
               
                 stored at 40° C. ± 2° C./75% ± 5% 
               
               
                 Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                 40° C. Formulation #6 
                 RRT 
                 0 Week 
                 2 Weeks 
                 1 Month 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of initial conc.) 
                   
                 100.00 
                 97.75 
                 95.95 
               
               
                 % Impurity F 
                 0.19 
                   0.15 
                  2.38 
                  4.04 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                  BQL 
                  BQL 
               
               
                 % Methoxy 
                 1.88 
                  BQL 
                  BQL 
                  BQL 
               
               
                 % Unknown Impurity 
                 0.21 
                 ND 
                  0.05 
                  0.08 
               
               
                 % Total Impurities 
                   
                   0.15 
                  2.43 
                  4.08 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #7  
               
               
                 stored at 40° C. ± 2° C./75% ± 5% 
               
               
                 Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                 40° C. Formulation #7  
                 RRT 
                 0 Week 
                 2 Weeks 
                 4 Weeks 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
               
               
                 % Impurity F 
                 0.19 
                 0.32 
                 1.85 
                 2.75 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
                 ND 
               
               
                 % Methoxy 
                 1.88 
                 0.07 
                 0.07 
                 0.07 
               
               
                 % Unknown Impurity 
                 0.21 
                 0.17 
                 0.36 
                 0.44 
               
               
                 % Total Impurities 
                   
                 0.56 
                 2.28 
                 3.26 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #8  
               
               
                 stored at 40° C. ± 2° C./75% ± 5% 
               
               
                 Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                   
                 40° C. Formulation #8 
                 RRT 
                 0 Week 
                 2 Weeks 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Appearance 
                   
                 Clear 
                 Light Brown 
               
               
                   
                 Assay (% of initial conc.) 
                   
                 100.00 
                 95.55 
               
               
                   
                 % Racemization 
                   
                   0.63 
                  0.62 
               
               
                   
                 % Impurity F 
                 0.19 
                   0.22 
                  1.56 
               
               
                   
                 % Synephrine 
                 1.26 
                  ND 
                 ND 
               
               
                   
                 % Epinephrone 
                 1.36 
                  ND 
                 ND 
               
               
                   
                 % Methoxy 
                 1.88 
                   0.07 
                  0.07 
               
               
                   
                   
                 0.21 
                  ND 
                  0.12 
               
               
                   
                   
                 0.26 
                  ND 
                  BQL 
               
               
                   
                 % Unknown Impurity 
                 0.88 
                  ND 
                  BQL 
               
               
                   
                   
                 3.11 
                  ND 
                  BQL 
               
               
                   
                   
                 3.26 
                  ND 
                  BQL 
               
               
                   
                 % Total Impurities 
                   
                   0.29 
                  1.75 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #9  
               
               
                 stored at 40° C. ± 2° C./75% ± 5% 
               
               
                 Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                 40° C. Formulation #9 
                 RRT 
                 0 Week 
                 1 Week 
                 4 Weeks 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of initial conc.) 
                   
                 100.00 
                 100.76 
                 99.73 
               
               
                 % Racemization 
                   
                   0.60 
                   0.68 
                 — 
               
               
                 % Impurity F 
                 0.19 
                   0.15 
                   0.84 
                 1.86 
               
               
                 % Synephrine 
                 1.26 
                  ND 
                  ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                  ND 
                  ND 
                 ND 
               
               
                 % Methoxy 
                 1.88 
                   0.07 
                   0.07 
                 0.07 
               
               
                   
                 0.21 
                  ND 
                  ND 
                 0.06 
               
               
                 % Unknown Impurity 
                 3.11 
                  ND 
                  BQL 
                 0.09 
               
               
                   
                 3.26 
                  ND 
                  BQL 
                 0.08 
               
               
                 % Total Impurities 
                   
                   0.22 
                   0.91 
                 2.16 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 11 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #10 stored at  
               
               
                 40°C. ± 2°C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
            
               
                 40°C. Formulation #10 
                 RRT 
                 0 Week 
                 1 Week 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
               
               
                 Assay (% of initial conc.) 
                   
                 100.00 
                 100.76 
               
               
                 % Racemization 
                   
                 0.60 
                 0.68 
               
               
                 % Impurity F 
                 0.19 
                 0.12 
                 2.89 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
               
               
                 % Methoxy 
                 1.88 
                 0.07 
                 0.07 
               
               
                 % Unknown Impurity 
                 0.21 
                 ND 
                 BQL 
               
               
                   
                 3.11 
                 ND 
                 BQL 
               
               
                   
                 3.26 
                 ND 
                 BQL 
               
               
                 % Total Impurities 
                   
                 0.19 
                 2.96 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 12 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #11 stored at  
               
               
                 40°C. ± 2°C./ 75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
            
               
                 40°C. Formulation #11 
                 RRT 
                 0 Week 
                 1 Week 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
               
               
                 Assay (% of initial conc.) 
                   
                 100.00 
                 100.76 
               
               
                 % Racemization 
                   
                  0.60 
                  0.68 
               
               
                 % Impurity F 
                 0.19 
                  0.12 
                  0.90 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
               
               
                 % Methoxy 
                 1.88 
                  0.07 
                  0.07 
               
               
                 % Unknown Impurity 
                 0.21 
                 ND 
                 BQL 
               
               
                   
                 3.11 
                 ND 
                 BQL 
               
               
                   
                 3.26 
                 ND 
                 BQL 
               
               
                 % Total Impurities 
                   
                  0.19 
                  0.97 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 13 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #1 stored at  
               
               
                 25°C. ± 2°C./60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                 25°C. Formulation #1 
                 RRT 
                 0 Week 
                 1 Month 
                 3 Months 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of initial 
                   
                 100.00 
                 97.91 
                 97.32 
               
               
                 conc.) 
                   
                   
                   
                   
               
               
                 % Racemization 
                   
                  0.60 
                  0.76 
                  0.93 
               
               
                 % Impurity F 
                 0.19 
                  0.13 
                  0.53 
                  1.04 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
                 ND 
               
               
                 % Methoxy 
                 1.88 
                  0.07 
                  0.07 
                  0.07 
               
               
                 % Unknown Impurity 
                 0.21 
                 ND 
                  0.05 
                  0.19 
               
               
                   
                 3.11 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 3.26 
                 ND 
                 ND 
                 BQL 
               
               
                 % Total Impurities 
                   
                  0.20 
                  0.65 
                  1.30 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 14 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #2 stored at  
               
               
                 25°C. ± 2°C./60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                 25°C. Formulation #2 
                 RRT 
                 0 Week 
                 1 Month 
                 3 Months 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of initial 
                   
                 100.00 
                 97.56 
                 96.88 
               
               
                 conc.) 
                   
                   
                   
                   
               
               
                 % Racemization 
                   
                  0.60 
                  0.78 
                  1.01 
               
               
                 % Impurity F 
                 0.19 
                  0.14 
                  0.55 
                  1.25 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
                 ND 
               
               
                 % Methoxy 
                 1.88 
                  0.07 
                  0.07 
                  0.07 
               
               
                 % Unknown Impurity 
                 0.21 
                 ND 
                  0.08 
                  0.18 
               
               
                   
                 3.11 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 3.26 
                 ND 
                 ND 
                 BQL 
               
               
                 % Total Impurities 
                   
                  0.21 
                  0.70 
                  1.50 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 15 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #3 stored at  
               
               
                 25°C. ± 2°C./60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                 25°C. Formulation #3 
                 RRT 
                 0 Week 
                 1 Month 
                 3 Months 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of initial 
                   
                 100.00 
                 99.32 
                 98.16 
               
               
                 conc.) 
                   
                   
                   
                   
               
               
                 % Racemization 
                   
                  0.60 
                  0.75 
                  0.84 
               
               
                 % Impurity F 
                 0.19 
                  0.13 
                  0.52 
                  1.29 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
                 ND 
               
               
                 % Methoxy 
                 1.88 
                  0.07 
                  0.07 
                  0.07 
               
               
                 % Unknown Impurity 
                 0.21 
                 ND 
                 BQL 
                  0.09 
               
               
                   
                 3.11 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 3.26 
                 ND 
                 ND 
                 BQL 
               
               
                 % Total Impurities 
                   
                  0.20 
                  0.59 
                  1.45 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 16 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #4 stored at  
               
               
                 25° C. ± 2° C./60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 25° C.  
                   
                 0  
                 3 
                 4 
                 8 
                 3 
                 6 
               
               
                 Formulation #4 
                 RRT 
                 Week 
                 Weeks 
                 Weeks 
                 Weeks 
                 Months 
                 Months 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of initial 
                   
                 100.00  
                 100.76  
                 99.79  
                 99.31  
                 99.09  
                 98.69  
               
               
                 conc.) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 % Racemization 
                   
                 0.60 
                 0.68 
                 — 
                 0.91 
                 0.97 
                 — 
               
               
                 % Impurity F 
                 0.19 
                 0.15 
                 0.41 
                 0.50 
                 1.01 
                 1.46 
                 2.39 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.88 
                 0.08 
                 0.08 
                 0.08 
                 0.08 
                 0.08 
                 0.08 
               
               
                 % Unknown Impurity 
                 0.21 
                 ND 
                 0.05 
                 0.06 
                 0.06 
                 0.11 
                 0.10 
               
               
                   
                 3.02 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.12 
               
               
                   
                 3.11 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.12 
               
               
                   
                 3.26 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.10 
               
               
                 % Total Impurities 
                   
                 0.23 
                 0.54 
                 0.64 
                 1.15 
                 1.65 
                 2.91 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 17 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #5 stored at  
               
               
                 25°C. ± 2°C./ 60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                 25°C. Formulation #5 
                 RRT 
                 0 Week 
                 1 Month 
                 3 Months 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of initial 
                   
                 100.00 
                 98.40 
                 97.29 
               
               
                 conc.) 
                   
                   
                   
                   
               
               
                 % Racemization 
                   
                  0.60 
                  0.77 
                  0.84 
               
               
                 % Impurity F 
                 0.19 
                  0.15 
                  0.67 
                  1.41 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
                 ND 
               
               
                 % Methoxy 
                 1.88 
                  0.07 
                  0.07 
                  0.07 
               
               
                 % Unknown Impurity 
                 0.21 
                 ND 
                  0.05 
                  0.18 
               
               
                   
                 3.11 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 3.26 
                 ND 
                 ND 
                 BQL 
               
               
                 % Total Impurities 
                   
                  0.22 
                  0.79 
                  1.66 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 18 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #6 stored at  
               
               
                 25°C. ± 2°C./ 60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
            
               
                 25°C. Formulation #6 
                 RRT 
                 0 Week 
                 2 Weeks 
                 1 Month 
                 6 Months 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of initial 
                   
                 100.00 
                 100.25 
                 99.75 
                 94.80 
               
               
                 conc.) 
                   
                   
                   
                   
                   
               
               
                 % Impurity F 
                 0.19 
                  0.15 
                  0.45 
                  0.76 
                  2.93 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.88 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Unknown Impurity 
                 0.21 
                 ND 
                 ND 
                 BQL 
                  0.30 
               
               
                   
                 0.26 
                 ND 
                 ND 
                 ND 
                  0.13 
               
               
                   
                 0.88 
                 ND 
                 ND 
                 ND 
                  0.15 
               
               
                   
                 2.58 
                 ND 
                 ND 
                 ND 
                  0.10 
               
               
                   
                 3.11 
                 ND 
                 ND 
                 ND 
                  0.24 
               
               
                   
                 3.26 
                 ND 
                 ND 
                 ND 
                  0.17 
               
               
                 % Total Impurities 
                   
                  0.15 
                  0.45 
                  0.76 
                  4.02 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 19 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #8 stored at  
               
               
                 25°C. ± 2°C./60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
            
               
                 25°C. Formulation #8 
                 RRT 
                 0 Week 
                 1 Month 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
               
               
                 Assay (% of initial 
                   
                 100.00 
                 99.21 
               
               
                 conc.) 
                   
                   
                   
               
               
                 % Racemization 
                   
                 0.63 
                 0.66 
               
               
                 % Impurity F 
                 0.19 
                 0.22 
                 0.64 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
               
               
                 % Methoxy 
                 1.88 
                 0.07 
                 0.07 
               
               
                 % Unknown Impurity 
                 0.21 
                 ND 
                 0.06 
               
               
                   
                 3.11 
                 ND 
                 BQL 
               
               
                   
                 3.26 
                 ND 
                 BQL 
               
               
                 % Total Impurities 
                   
                 0.29 
                 0.77 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 20 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #9 stored at  
               
               
                 25°C. ± 2°C./60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                 25°C. Formulation #9 
                 RRT 
                 0 Week 
                 1 Month 
                 6 Months 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
               
               
                 Assay (% of initial 
                   
                 100.00 
                 99.64 
                 98.88 
               
               
                 conc.) 
                   
                   
                   
                   
               
               
                 % Impurity F 
                 0.19 
                 0.15 
                 0.52 
                 1.71 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
                 ND 
               
               
                 % Methoxy 
                 1.88 
                 0.08 
                 0.07 
                 0.07 
               
               
                 % Unknown Impurity 
                 0.21 
                 ND 
                 0.05 
                 0.07 
               
               
                   
                 3.11 
                 ND 
                 BQL 
                 0.09 
               
               
                   
                 3.26 
                 ND 
                 BQL 
                 0.08 
               
               
                 % Total Impurities 
                   
                 0.23 
                 0.64 
                 2.02 
               
               
                   
               
            
           
         
       
     
     Formulations #1-#5 had less than 3% total impurities after 4 Weeks (1 Month) at 40° C.±2° C./75%±5% Relative Humidity and less than 1% total impurities after 4 Weeks (1 Month) at 25° C.±2° C./60%±5% relative humidity. Of Formulations #6-#8, only Formulation #8 was analyzed at 4 Weeks or later at 40° C. where 4.68% total impurities were found. Formulation #9 exhibited total impurities of 2.17% at 4 weeks 40° C. Formulation #11 exhibited total impurities of 1% at one week 40° C. The superior and surprising stability characteristics of the formulations of the present invention will allow the formulations to be effective when used by patients. 
     When compared with formulation 4, formulation 7 showed a faster generation of impurities and was not stable for more than a month at 40° C. Formulation 4 was stable for 4 months when stored at 40° C. which indicates that EDTA increases the stability of epinephrine formulations. 
     Example 3 
     Formulation #4 was further tested for stability during freeze-thaw cycling. Specifically, Formulation #4 was run through 3 cycles of −20° C. for 48 hours and then 25° C. for 48 hours, where the physical appearance of the formulation was recorded. The formulation remained clear and colorless throughout the entire freeze-thaw cycling indicating a stable formulation throughout. 
     Example 4 
     In order to determine the spray profile of Formulation #4, it was subjected to standardized droplet testing. A challenge of creating an epinephrine spray formulation is that it must be capable of producing spray droplets that are over 10 microns in diameter. Spray droplets of 10 microns or smaller could be inhaled into the lungs. 
     Droplet analysis was conducted using standard laser analysis procedures known by those of skill in the art. Droplet size distribution (Dv 10 , Dv 50 , Dv 90 , and Span) was tested at two distances, 3 cm and 6 cm. Dv 10  refers to the droplet size at which 10% of the volume is smaller; Dv 50  refers to the median droplet size; Dv 90  refers to droplet size for which 90% of the total volume is smaller; Span refers to distribution span (Dv90−Dv10)/Dv50. %&lt;10 μm refers to the percentage of the total volume that is made up of droplets less than 10 μm in diameter. 
     Spray pattern, specifically Dmin, Dmax, and ovality ratio were tested at two distances, 3 cm and 6 cm. Dmin refers to the shortest diameter of the spray pattern in mm, Dmax refers to the widest diameter of the spray pattern in mm, and ovality ratio refers to the ratio of Dmax to Dmin. The spay pattern is measured by shining a laser sheet perpendicular to the spray at a specific distance from the orifice. The ovality ratio is useful as it provides information regarding the shape and density of the spray pump plume. 
     The results of these tests can be seen below in Tables 17 to 22. 
     
       
         
           
               
             
               
                 TABLE 21 
               
             
            
               
                   
               
               
                 Droplet size distribution of Epinephrine Spray Formulation at 3 cm 
               
            
           
           
               
               
               
               
               
               
            
               
                 Droplet Size 
                   
                   
                   
                   
                   
               
               
                 Distribution 
                   
                   
                   
                   
                   
               
               
                 3 cm 
                 DV 10  (μm) 
                 DV 50  (μm) 
                 DV 90  (μm) 
                 % &lt;10 μm 
                 Span 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Min 
                 15.8 
                 30.84 
                 124 
                 0.05 
                 3.145 
               
               
                 Max 
                 17.23 
                 33.96 
                 228.7 
                 0.89 
                 6.283 
               
               
                 Mean 
                 16.34 
                 32.88 
                 177.9 
                 0.473 
                 4.93 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 22 
               
             
            
               
                   
               
               
                 Droplet size distribution of Epinephrine Spray Formulation at 6 cm 
               
            
           
           
               
               
               
               
               
               
            
               
                 Droplet Size 
                   
                   
                   
                   
                   
               
               
                 Distribution 
                   
                   
                   
                   
                   
               
               
                 6 cm 
                 DV 10  (μm) 
                 DV 50  (μm) 
                 DV 90  (μm) 
                 % &lt;10 μm 
                 Span 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Min 
                 22.72 
                 36.07 
                 59.52 
                 0 
                 1.017 
               
               
                 Max 
                 24.05 
                 40.35 
                 230.9 
                 0 
                 5.127 
               
               
                 Mean 
                 23.2 
                 38.48 
                 121.5 
                 0 
                 2.49 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 23 
               
             
            
               
                   
               
               
                 Spray pattern of Epinephrine Spray Formulation at 3 cm 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Dmin 
                 Dmax 
                 Ovality 
               
               
                   
                 Spray Pattern 3 cm 
                 (mm) 
                 (mm) 
                 ratio 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Min 
                 18.9 
                 29.8 
                 1.415 
               
               
                   
                 Max 
                 22.2 
                 32.1 
                 1.696 
               
               
                   
                 Mean 
                 20.4 
                 31.1 
                 1.53 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 24 
               
             
            
               
                   
               
               
                 Spray pattern of Epinephrine Spray Formulation at 6 cm 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                 Dmin 
                 Dmax 
                 Ovality 
               
               
                   
                 Spray Pattern 6 cm 
                 (mm) 
                 (mm) 
                 ratio 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Min 
                 26.5 
                 47 
                 1.68 
               
               
                   
                 Max 
                 32.2 
                 54.2 
                 1.852 
               
               
                   
                 Mean 
                 29.1 
                 51.4 
                 1.768 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 25 
               
             
            
               
                   
               
               
                 Plume geometry of Epinephrine Spray Formulation at 3 cm 
               
            
           
           
               
               
               
            
               
                   
                   
                 Width 
               
               
                 Plume Geometry 3 cm 
                 Angle (°) 
                 (mm) 
               
               
                   
               
               
                 Min 
                 49.2 
                 27.6 
               
               
                 Max 
                 63.4 
                 37.8 
               
               
                 Mean 
                 55.4 
                 32.2 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 26 
               
             
            
               
                   
               
               
                 Plume geometry of Epinephrine Spray Formulation at 6 cm 
               
            
           
           
               
               
               
            
               
                   
                   
                 Width 
               
               
                 Plume Geometry 6 cm 
                 Angle (°) 
                 (mm) 
               
               
                   
               
               
                 Min 
                 37.7 
                 37.7 
               
               
                 Max 
                 43.5 
                 43.5 
               
               
                 Mean 
                 40.7 
                 40.7 
               
               
                   
               
            
           
         
       
     
     Applicant found during testing that formulations of the present invention yielded desirable droplet sizes for spray administration. The testing also revealed that the formulation dose remains consistent when administered with a spray pump. 
     Example 5. Preparation of Additional Hydro-Alcoholic Epinephrine Spray Formulations 
     Additional epinephrine spray formulations were prepared using the components and amounts listed in Table 27 below. All solvents were purged with nitrogen prior to use. Excipients including 0.5 N or 1.0 N hydrochloric acid (“HCl”), ethanol, propylene glycol, EDTA, sodium bisulfite and/or caprylic acid were dissolved in water while stirring at room temperature. Epinephrine base was then added to the excipient solution. Finally, sodium hydroxide (“NaOH”)/hydrochloric acid (“HCl”) was used to adjust final pH. 
     
       
         
           
               
             
               
                 TABLE 27 
               
             
            
               
                   
               
               
                 Additional Hydro-alcoholic Epinephrine Spray Formulations 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 % w/w 
                 #12 
                 #13 
                 #14 
                 #15 
                 #16 
                 #17 
                 #18 
                 #19 
                 #20 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Epinephrine base 
                 3.2 
                 3.2 
                 3.2 
                 3.2 
                 3.2 
                 3.38 
                 3.38 
                 3.24 
                 3.12 
               
               
                 Hydrochloric acid (0.5N) 
                 34.6 
                 34.6 
                 34.6 
                 34.6 
                 34.6 
                 37.7 
                 37.7 
                 36.2 
                 34.8 
               
               
                 EDTA 
                 0.05 
                 0.05 
                 0.05 
                 0.05 
                 0.05 
                 0.05 
                 0.05 
                 0.05 
                 0.05 
               
               
                 Sodium bisulfite 
                 0.1 
                 0.15 
                 0.20 
                 0.25 
                 0.30 
                 0.15 
                 0.15 
                 0.15 
                 0.15 
               
               
                 Propylene Glycol 
                 5.0 
                 5.0 
                 5.0 
                 5.0 
                 5.0 
                 5.0 
                 5.0 
                 5.0 
                 5.0 
               
               
                 Caprylic acid 
                 — 
                 — 
                 — 
                 — 
                 — 
                 2.0 
                 10.0 
                 — 
                 — 
               
               
                 Benzalkonium chloride 
                 — 
                 — 
                 — 
                 — 
                 — 
                 0.02 
                 0.02 
                 0.01 
                 0.01 
               
               
                 Menthol 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
                 1.0 
                 0.5 
                 0.5 
                 — 
                 — 
               
               
                 Sucralose 
                 0.5 
                 0.5 
                 0.5 
                 0.5 
                 0.5 
                 0.5 
                 0.5 
                 — 
                 — 
               
               
                 Ethanol 
                 40.0 
                 40.0 
                 40.0 
                 40.0 
                 40.0 
                 40.0 
                 40.0 
                 40.0 
                 20.0 
               
               
                 Water 
                 15.55 
                 15.50 
                 15.45 
                 15.40 
                 15.35 
                 10.7 
                 2.7 
                 15.35 
                 36.87 
               
               
                 pH adjusted with 
                 4.5 
                 4.5 
                 4.5 
                 4.5 
                 4.5 
                 4.5 
                 4.5 
                 4.5 
                 4.5 
               
               
                 2 NaOH/0.5N HCl 
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 28 
               
             
            
               
                   
               
               
                 Additional Aqueous based Epinephrine Spray Formulation 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 % w/w 
                 #21 
                 #22 
                 #23 
                 #24 
                 #25 
                 #26 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Epinephrine base 
                 3.040 
                 3.040 
                 3.040 
                 3.040 
                 3.040 
                 3.040 
               
               
                 Hydrochloric  
                 33.80 
                 33.80 
                 33.80 
                 33.80 
                 33.80 
                 33.80 
               
               
                 acid (0.5N) 
                   
                   
                   
                   
                   
                   
               
               
                 EDTA 
                 0.05 
                 0.05 
                 0.05 
                 0.05 
                 0.05 
                 0.05 
               
               
                 Sodium bisulfite 
                 0.150 
                 0.250 
                 0.5 
                 1.00 
                 2.00 
                 5.00 
               
               
                 Benzalkonium 
                 0.01 
                 0.01 
                 0.01 
                 0.01 
                 0.01 
                 0.01 
               
               
                 chloride 
                   
                   
                   
                   
                   
                   
               
               
                 Sodium Chloride 
                 0.6 
                 0.6 
                 0.6 
                 0.6 
                 0.6 
                 0.6 
               
               
                 Water 
                 62.35 
                 62.25 
                 62.00 
                 61.5 
                 60.5 
                 57.5 
               
               
                 pH adjusted  
                 4.5 
                 4.5 
                 4.5 
                 4.5 
                 4.5 
                 4.5 
               
               
                 with 2  
                   
                   
                   
                   
                   
                   
               
               
                 NaOH/0.5N HCl 
                   
                   
                   
                   
                   
                   
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 29 
               
             
            
               
                   
               
               
                 Additional Epinephrine (6 mg/spray) Formulations 
               
            
           
           
               
               
               
               
               
               
            
               
                 % w/w 
                 Function 
                 #27 
                 #28 
                 #29 
                 #30 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Epinephrine base 
                 Active 
                 5.923 
                 6.356 
                 5.923 
                 6.356 
               
               
                   
                 Ingredient 
                   
                   
                   
                   
               
               
                 Benzalkonium chloride 
                 Preservative 
                 0.010 
                 0.010 
                 0.010 
                 0.010 
               
               
                 Sodium Chloride 
                 Tonicity 
                 0.600 
                 — 
                 0.600 
                 — 
               
               
                   
                 Agent 
                   
                   
                   
                   
               
               
                 Sodium bisulfite 
                 Anti-Oxidant 
                 0.150 
                 0.150 
                 0.300 
                 0.300 
               
               
                 Edetate Disodium 
                 Chelating 
                 0.050 
                 0.050 
                 0.050 
                 0.050 
               
               
                 Dihydrate (EDTA) 
                 agent 
                   
                   
                   
                   
               
               
                 Hydrochloric acid 
                 pH modifier 
                 16.462 
                 17.736 
                 16.462 
                 17.736 
               
               
                 (2N) 
                   
                   
                   
                   
                   
               
               
                 Purified Water 
                 Vehicle 
                 76.805 
                 30.698 
                 76.655 
                 30.548 
               
               
                 Dehydrated Alcohol 
                 Co-Solvent 
                 — 
                 40.000 
                 — 
                 40.000 
               
               
                 (Ethanol) 
                   
                   
                   
                   
                   
               
               
                 Propylene Glycol 
                 Co-Solvent 
                 — 
                 5.000 
                 — 
                 5.000 
               
               
                 Solution containing 
                 pH 
                 Adjust to 
                 Adjust to  
                 Adjust to 
                 Adjust to 
               
               
                 2.0N NaOH and  
                 adjustment 
                 pH 4.5 ± 0.1 
                 pH 4.5 ± 0.1 
                 pH 4.5 ± 0.1 
                 pH 4.5 ± 0.1 
               
               
                 0.5N HCl 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 30 
               
             
            
               
                   
               
               
                 Additional Epinephrine (9 mg/spray) Formulations 
               
            
           
           
               
               
               
               
               
               
            
               
                 % w/w 
                 Function 
                 #31 
                 #32 
                 #33 
                 #34 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Epinephrine base 
                 Active 
                 8.885 
                 9.534 
                 8.885 
                 9.534 
               
               
                   
                 Ingredient 
                   
                   
                   
                   
               
               
                 Benzalkonium chloride 
                 Preservative 
                 0.010 
                 0.010 
                 0.010 
                 0.010 
               
               
                 Sodium Chloride 
                 Tonicity 
                 0.600 
                 — 
                 0.600 
                 — 
               
               
                   
                 Agent 
                   
                   
                   
                   
               
               
                 Sodium bisulfite 
                 Anti-Oxidant 
                 0.150 
                 0.150 
                 0.45 
                 0.45 
               
               
                 Edetate Disodium 
                 Chelating 
                 0.050 
                 0.050 
                 0.050 
                 0.050 
               
               
                 Dihydrate (EDTA) 
                 agent 
                   
                   
                   
                   
               
               
                 Hydrochloric acid 
                 pH modifier 
                 24.695 
                 26.603 
                 24.695 
                 26.603 
               
               
                 (2N) 
                   
                   
                   
                   
                   
               
               
                 Purified Water 
                 Vehicle 
                 65.610 
                 18.653 
                 65.310 
                 18.353 
               
               
                 Dehydrated Alcohol 
                 Co-Solvent 
                 — 
                 40.000 
                 — 
                 40.000 
               
               
                 (Ethanol) 
                   
                   
                   
                   
                   
               
               
                 Propylene Glycol 
                 Co-Solvent 
                 — 
                 5.000 
                 — 
                 5.000 
               
               
                 Solution containing 
                 pH 
                 Adjust to 
                 Adjust to  
                 Adjust to 
                 Adjust to 
               
               
                 2.0N NaOH and  
                 adjustment 
                 pH 4.5 ± 0.1 
                 pH 4.5 ± 0.1 
                 pH 4.5 ± 0.1 
                 pH 4.5 ± 0.1 
               
               
                 0.5N HCl 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 31 
               
             
            
               
                   
               
               
                 Epinephrine (3-5 mg/spray) Formulations 
               
            
           
           
               
               
               
               
               
               
            
               
                 % w/w 
                 Function 
                 #35 
                 #36 
                 #37 
                 #38 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Epinephrine base 
                 Active 
                 3.178 
                 2.962 
                 3.885 
                 4.702 
               
               
                   
                 Ingredient 
                   
                   
                   
                   
               
               
                 Benzalkonium chloride 
                 Preservative 
                 0.010 
                 0.010 
                 0.010 
                 0.010 
               
               
                 Sodium Chloride 
                 Tonicity 
                 — 
                 0.6 
                 — 
                 — 
               
               
                   
                 Agent 
                   
                   
                   
                   
               
               
                 Sodium bisulfite 
                 Anti-Oxidant 
                 0.150 
                 0.150 
                 0.184 
                 0.223 
               
               
                 Edetate Disodium 
                 Chelating 
                 0.050 
                 0.050 
                 0.050 
                 0.050 
               
               
                 Dihydrate (EDTA) 
                 agent 
                   
                   
                   
                   
               
               
                 Hydrochloric acid 
                 pH modifier 
                 35.471 
                 32.936 
                 21.681 
                 26.241 
               
               
                   
                   
                 (0.5N) 
                 (0.5N) 
                 (1.0N) 
                 (1.0N) 
               
               
                 Purified Water 
                 Vehicle 
                 16.141 
                 63.298 
                 29.190 
                 23.774 
               
               
                 Dehydrated Alcohol 
                 Co-Solvent 
                 40.000 
                 — 
                 40.000 
                 40.000 
               
               
                 (Ethanol) 
                   
                   
                   
                   
                   
               
               
                 Propylene Glycol 
                 Co-Solvent 
                 5.000 
                 — 
                 5.000 
                 5.000 
               
               
                 Solution containing 
                 pH 
                 Adjust to 
                 Adjust to  
                   
                   
               
               
                 2.0N NaOH and  
                 adjustment 
                 pH 4.5 ± 0.1 
                 pH 4.5 ± 0.1 
                   
                   
               
               
                 0.5N HCl 
               
               
                   
               
            
           
         
       
     
     The formulations listed in Table 27 and Table 28 were filled in unit dose devices, packed into an oxygen impermeable pouches with oxygen scavengers, and then subjected to stability at 40° C.±2° C./75%±5% relative humidity and 25° C.±2° C./60%±5% relative humidity. The stability of the formulations was analyzed at specified time points by evaluating their potency (assay value) and impurity levels. Assay and impurities were detected using high-performance liquid chromatography with an ultraviolet detector. The assay was performed at 280 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 210 nm and 280 nm and expressed as a % area. Amounts of particular impurities are listed in Tables 32 to 55 as a percentage of area of each formulation along with amount of total impurities. Relative retention time (“RRT”) is given for each impurity. “ND” indicates that the impurity was not detected. Any impurity which is less than 0.05% is indicated as BQL. NP refers to Not Performed. 
     
       
         
           
               
             
               
                 TABLE 32 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulations # 12 to # 16 stored at 
               
               
                 25° C. ± 2° C./60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
            
               
                   
                   
                 Stability @18 M 25° C./60% RH 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 F # 12 
                 F # 13 
                 F # 14 
                 F # 15 
                 F # 16 
               
               
                   
                 RRT 
                 0 Week 
                 18 months 
                 18 Months 
                 18 Months 
                 18 months 
                 18 months 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
                 Clear 
                 Clear  
                 Clear 
               
               
                 % Impurity F 
                 0.19 
                 0.11  
                 1.91 
                 2.53 
                 3.27 
                 3.57 
                  4.79* 
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.90 
                 0.07  
                 0.08 
                 0.08 
                 0.07 
                 0.07 
                 0.08 
               
               
                 % Unknown Impurities 
                 0.22 
                 0.01  
                 0.12 
                 0.12 
                 0.13 
                 0.12 
                 0.12 
               
               
                   
                 0.25 
                 ND 
                 0.09 
                 BQL 
                 BQL 
                 ND 
                 0.07 
               
               
                   
                 0.26 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 0.64 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 0.88 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 1.21 
                 ND 
                 0.09 
                 0.09 
                 0.08 
                 BQL 
                 0.06 
               
               
                   
                 1.34 
                 ND 
                 BQL 
                 0.05 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 1.50 
                 ND 
                 ND 
                 ND 
                 0.07 
                 BQL 
                 BQL 
               
               
                   
                 1.51 
                 ND 
                 0.1  
                 0.07 
                 ND 
                 ND 
                 ND 
               
               
                   
                 2.43 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.06 
                 ND 
               
               
                   
                 2.44 
                 ND 
                 ND 
                 0.07 
                 0.08 
                 ND 
                 ND 
               
               
                   
                 2.45 
                 ND 
                 0.11 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 2.57 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.06 
               
               
                   
                 2.71 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 2.90 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
               
               
                   
                 2.91 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
               
               
                   
                 2.93 
                 ND 
                 0.07 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 2.96  
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 3.11 
                 ND 
                 0.05 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 3.26 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
               
               
                 Total Impurities 
                   
                 0.19 
                 2.62 
                 3.01 
                 3.70 
                 3.82 
                 5.18 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 33 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 17 stored at  
               
               
                 25° C. ± 2° C./60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
            
               
                   
                 RRT 
                 1 Month 
                 2 Month 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
               
               
                 % Impurity F 
                 0.19 
                 0.50 
                 0.72 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
               
               
                 % Methoxy 
                 1.90 
                 0.07 
                 0.07 
               
               
                 % Unknown 
                 1.08 
                 0.14 
                 0.08 
               
               
                 Impurities 
                   
                   
                   
               
               
                 % Total Impurities 
                   
                 0.71 
                 0.87 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 34 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 18 stored at  
               
               
                 25° C. ± 2° C./60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
            
               
                   
                 RRT 
                 1 Month 
                 2 Months 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
               
               
                 % Impurity F 
                 0.19 
                 0.57 
                 0.75 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
               
               
                 % Methoxy 
                 1.90 
                 0.07 
                 0.07 
               
               
                   
                 1.08 
                 0.08 
                 0.14 
               
               
                   
                 1.12 
                 BQL 
                 0.07 
               
               
                 % Total Impurities 
                   
                 0.72 
                 1.03 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 35 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulations # 19 stored at 
               
               
                 25° C. ± 2° C./60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Epinephrine 
                 RRT 
                 T = 0 
                 1 M 
                 3 M 
                 6 M 
                 12 M 
                 18 M 
               
               
                   
               
               
                 Assay (%) 
                   
                 101.32  
                 99.22  
                 100.49  
                 98.92  
                 100.41  
                 98.60  
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 Colorless 
                 Colorless 
                 Colorless 
                 Colorless 
                 Colorless 
                 Colorless 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 0.47 
                 1.03 
                 2.37 
                 5.38 
                 7.44 
               
               
                 % Epinephrone 
                 1.34 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.77 
                 0.07 
                 0.06 
                 0.06 
                 0.06 
                 0.05 
                 0.06 
               
               
                   
                 0.20 
                 ND 
                 ND 
                 0.06 
                 0.15 
                 0.08 
                 0.09 
               
               
                   
                 0.21 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.07 
                 0.05 
               
               
                 Unknown Impurities  
                 0.26 
                 ND 
                 ND 
                 ND 
                 0.08 
                 0.16 
                 0.20 
               
               
                 (%) 
                 1.06 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.13 
               
               
                   
                 1.20 
                 ND 
                 ND 
                 ND 
                 0.09 
                 0.05 
                 0.05 
               
               
                   
                 2.50 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 0.06 
               
               
                 Total impurities (%) 
                   
                 0.23 
                 0.53 
                 1.15 
                 2.75 
                 5.79 
                 8.08 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 36 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 20 stored at 
               
               
                 25° C. ± 2° C./60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
            
               
                 Epinephrine 
                 RRT 
                 T = 0 
                 1 M 
                 3 M 
                 6 M 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Assay (% LC) 
                   
                 103.9307 
                 102.23 
                 99.07 
                 97.70 
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 Colorless 
                 Colorless 
                 Colorless 
                 Colorless 
               
               
                 Imp-F 
                 0.19 
                 0.16 
                 0.53 
                 1.25 
                 2.86 
               
               
                 epinephrone 
                 1.35 
                 ND 
                 BQL 
                 BQL 
                 BQL 
               
               
                 Methoxy 
                 1.78 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
               
               
                 Unknown  
                 0.21 
                 ND 
                 ND 
                 0.05 
                 0.05 
               
               
                 Impurities 
                 0.26 
                 ND 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 0.70 
                 ND 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 0.83 
                 ND 
                 BQL 
                 BQL 
                 ND 
               
               
                   
                 0.88 
                 BQL 
                 BQL 
                 BQL 
                 ND 
               
               
                   
                 1.22 
                 ND 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 1.41 
                 ND 
                 ND 
                 BQL 
                 BQL 
               
               
                   
                 1.49 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 1.51 
                 BQL 
                 ND 
                 ND 
                 ND 
               
               
                   
                 1.55 
                 ND 
                 BQL 
                 BQL 
                 ND 
               
               
                   
                 2.55 
                 ND 
                 BQL 
                 BQL 
                 ND 
               
               
                   
                 2.56 
                 ND 
                 BQL 
                 BQL 
                 ND 
               
               
                   
                 2.61 
                 ND 
                 BQL 
                 BQL 
                 ND 
               
               
                   
                 2.72 
                 ND 
                 ND 
                 BQL 
                 BQL 
               
               
                   
                 2.80 
                 ND 
                 ND 
                 BQL 
                 ND 
               
               
                   
                 2.87 
                 ND 
                 BQL 
                 ND 
                 ND 
               
               
                   
                 2.96 
                 ND 
                 BQL 
                 ND 
                 ND 
               
               
                   
                 3.09 
                 BQL 
                 BQL 
                 ND 
                 ND 
               
               
                   
                 3.22 
                 ND 
                 ND 
                 BQL 
                 ND 
               
               
                   
                 3.45 
                 ND 
                 ND 
                 BQL 
                 ND 
               
               
                   
                 3.73 
                 ND 
                 ND 
                 ND 
                 BQL 
               
               
                 Total  
                   
                 0.22 
                 0.59 
                 1.36 
                 2.97 
               
               
                 impurities (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 37 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 21 stored at 
               
               
                 25° C. ± 2° C./60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 RRT 
                 T = 0 
                 1 M 
                 2 M 
                 3 M 
                 4 M 
                 6 M 
                 8 M 
                 12 M 
               
               
                   
               
               
                 Assay 
                   
                 98.20  
                 101.02  
                 99.07  
                 100.13  
                 98.45  
                 98.45  
                 98.45  
                 95.12  
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 Colorless 
                 Colorless 
                 Colorless 
                 Colorless  
                 Colorless 
                 Colorless 
                 Colorless 
                 Colorless 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 0.72 
                 1.38 
                 1.99 
                 2.54 
                 4.30 
                 5.40 
                 7.05 
               
               
                 % Epinephrone 
                 1.34 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.77 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
                 0.05 
                 0.05 
                 0.05 
               
               
                 Unknown 
                 0.20 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
               
               
                 Impurities 
                 0.66 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.05 
               
               
                 Total impurities 
                   
                 0.22 
                 0.78 
                 1.44 
                 2.05 
                 2.60 
                 4.35 
                 5.45 
                 7.15 
               
               
                 (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 38 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulations # 12 to 16 stored at  
               
               
                 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 F# 12 
                 F# 13 
                 F# 14 
                 F# 15 
                 F# 16 
               
               
                 Epinephrine 
                 RRT 
                 0 Week 
                 2 Months 
                 2 Months 
                 2 Months 
                 2 Months 
                 2 Months 
               
               
                   
               
               
                 Assay 
                   
                 100.00  
                 98.13  
                 94.51  
                 93.02  
                 93.26  
                 92.02  
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
                 Clear 
                 Clear 
                 Clear 
               
               
                 % Impurity F 
                 0.19 
                 0.11 
                 3.22 
                 5.64 
                 7.42 
                 9.7  
                 11.3  
               
               
                 % Synephrine 
                 1.26 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.90 
                 0.07 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
               
               
                   
                 0.22 
                 BQL 
                 0.16 
                 0.16 
                 0.15 
                 0.14 
                 0.12 
               
               
                   
                 0.25 
                 ND 
                 0.06 
                 0.06 
                 0.05 
                 0.05 
                 0.05 
               
               
                 % Unknown 
                 0.26 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 Impurities 
                 0.88 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 1.21 
                 ND 
                 0.06 
                 0.06 
                 0.05 
                 BQL 
                 BQL 
               
               
                   
                 1.34 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 1.55 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 2.57 
                 ND 
                 0.18 
                 0.11 
                 0.1  
                 0.08 
                 0.07 
               
               
                   
                 3.11 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 3.26 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 ND 
               
               
                 % Total 
                   
                 0.18 
                 3.74 
                 6.09 
                 7.83 
                 10.03  
                 11.60  
               
               
                 Impurities 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 39 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulations # 17 stored  
               
               
                 at 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 RRT 
                 2 Weeks 
                 4 Weeks 
                 6 Weeks 
                 3 Months 
               
               
                   
               
               
                 Physical 
                   
                 Clear 
                 Clear 
                 Clear 
                 Clear 
               
               
                 appearance 
                   
                   
                   
                   
                   
               
               
                 % Impurity F 
                 0.19 
                 1.02 
                 2.03 
                 3.01 
                 5.11 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 ND 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.90 
                 0.07 
                 0.07 
                 0.07 
                 0.06 
               
               
                   
                 1.08 
                 0.08 
                 0.15 
                 0.15 
                 0.09 
               
               
                   
                 1.12 
                 ND 
                 ND 
                 0.15 
                 0.15 
               
               
                   
                 1.21 
                 ND 
                 BQL 
                 0.06 
                 0.13 
               
               
                   
                 2.53 
                 BQL 
                 BQL 
                 0.05 
                 0.15 
               
               
                   
                 2.58 
                 ND 
                 ND 
                 BQL 
                 0.06 
               
               
                   
                 3.04 
                 ND 
                 ND 
                 BQL 
                 0.06 
               
               
                 % Total 
                   
                 1.17 
                 2.25 
                 3.49 
                 5.81 
               
               
                 Impurities 
                   
                   
                   
                   
                   
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 40 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulations #18 stored 
               
               
                 at 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                   
                 RRT 
                 2 Weeks 
                 1 Month 
                 2 Months 
               
               
                   
               
               
                 Appearance 
                   
                 Clear 
                 Clear 
                 Clear 
               
               
                 % Impurity F 
                 0.19 
                 0.93 
                 2.16 
                 3.71 
               
               
                 % Epinephrone 
                 1.36 
                 ND 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.90 
                 0.07 
                 0.07 
                 0.07 
               
               
                   
                 1.08 
                 0.09 
                 0.09 
                 0.10 
               
               
                   
                 1.12 
                 BQL 
                 0.06 
                 0.14 
               
               
                   
                 1.21 
                 ND 
                 BQL 
                 0.18 
               
               
                   
                 2.53 
                 0.09 
                 0.23 
                 0.17 
               
               
                   
                 2.58 
                 BQL 
                 0.08 
                 0.07 
               
               
                   
                 3.04 
                 BQL 
                 BQL 
                 0.05 
               
               
                 % Total Impurities 
                   
                 1.18 
                 2.69 
                 4.49 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 41 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 19 stored at 
               
               
                 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Epinephrine 
                 RRT 
                 0 Month 
                 1 M 
                 2 M 
                 3 M 
                 4 M 
                 5 M 
                 6 M 
                 10 M 
               
               
                   
               
               
                 Assay 
                   
                 101.32  
                 101.11  
                 97.06  
                 95.85  
                 96.08  
                 96.52  
                 95.58  
                 NP 
               
               
                 Appearance 
                   
                 Clear, 
                 Clear,  
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear,  
                 Clear, 
                 Clear, 
               
               
                   
                   
                 colorless 
                 colorless 
                 colorless 
                 Light 
                 Light 
                 Light 
                 Light 
                 Light 
               
               
                   
                   
                   
                   
                   
                 Yellow 
                 Yellow 
                 Yellow 
                 Yellow 
                 Yellow 
               
               
                 Imp-F 
                 0.19 
                 0.16 
                 1.92 
                 4.25 
                 6.42 
                 7.20 
                 7.28 
                 7.22 
                 7.61 
               
               
                 epinephrone 
                 1.34 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 Methoxy 
                 1.77 
                 0.07 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
               
               
                 Unknown Impurities 
                 0.21 
                 ND 
                 0.09 
                 0.19 
                 0.11 
                 0.3  
                 0.07 
                 0.14 
                 0.18 
               
               
                 (%) 
                 0.26 
                 ND 
                 ND 
                 0.14 
                 0.21 
                 0.31 
                 0.32 
                 0.31 
                 0.52 
               
               
                   
                 0.52 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 0.64 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
               
               
                   
                 0.79 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
                 BQL 
                 BQL 
               
               
                   
                 0.88 
                 ND 
                 BQL 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 1.17 
                 ND 
                 0.06 
                 0.07 
                 0.05 
                 0.09 
                 0.08 
                 ND 
                 ND 
               
               
                   
                 1.25 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 0.07 
                 0.07 
                 0.07 
               
               
                   
                 1.38 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 1.55 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 1.68 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 ND 
                 BQL 
                 BQL 
               
               
                   
                 1.73 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 1.99 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 2.07 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 2.38 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
               
               
                   
                 2.22 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
               
               
                   
                 2.44 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
               
               
                   
                 2.60 
                 ND 
                 BQL 
                 0.05 
                 0.1  
                 0.19 
                 0.33 
                 0.76 
                 0.99 
               
               
                   
                 2.80 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 2.86 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 2.98 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
               
               
                   
                 3.13 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 3.22 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 2.82 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.07 
                 0.12 
                 0.13 
                 0.21 
               
               
                   
                 3.38 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
               
               
                   
                 3.41 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
               
               
                   
                 3.44 
                 ND 
                 ND 
                 ND 
                 BQL 
                 0.14 
                 0.06 
                 ND 
                 ND 
               
               
                   
                 3.51 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.13 
                 0.12 
               
               
                   
                 3.68 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 0.07 
                 0.06 
               
               
                 Total impurities (%) 
                   
                 0.23 
                 2.13 
                 4.76 
                 6.95 
                 8.36 
                 8.39 
                 8.89 
                 9.82 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 42 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 20 stored at 
               
               
                 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Epinephrine 
                 RRT 
                 T = 0 
                 1 M 
                 2 M 
                 3 M 
                 4 M 
                 5 M 
                 6 M 
               
               
                   
               
               
                 Assay (%) 
                   
                 103.93  
                 99.44  
                 96.16  
                 96.35  
                 96.38  
                 96.05  
                 93.96  
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 colorless 
                 colorless 
                 colorless 
                 Light 
                 Light 
                 Light 
                 Light 
               
               
                   
                   
                   
                   
                   
                 Yellow  
                 Yellow 
                 Yellow 
                 Yellow 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 2.61 
                 5.66 
                 7.69  
                 6.30 
                 7.42 
                 7.67 
               
               
                 % Epinephrone 
                 1.35 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.78 
                 0.06 
                 0.07 
                 0.06 
                 0.06  
                 0.06 
                 0.07 
                 0.07 
               
               
                 Unknown 
                 0.21 
                 ND 
                 0.08 
                 0.10 
                 0.09  
                 0.29 
                 0.10 
                 0.13 
               
               
                 Impurities (%) 
                 0.26 
                 ND 
                 ND 
                 0.06 
                 0.12  
                 0.17 
                 0.18 
                 0.19 
               
               
                   
                 0.70 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 ND 
                 BQL 
               
               
                   
                 0.88 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 1.13 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.08 
                 ND 
               
               
                   
                 1.18 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 0.11 
                 ND 
                 ND 
               
               
                   
                 1.21 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.06 
               
               
                   
                 1.34 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 ND 
               
               
                   
                 1.36 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 ND 
                 BQL 
               
               
                   
                 1.49 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 1.42 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
               
               
                   
                 1.51 
                 BQL 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 1.55 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 ND 
                 ND 
                 ND 
               
               
                   
                 1.58 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.09 
                 ND 
                 ND 
               
               
                   
                 1.64 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
               
               
                   
                 1.73 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 0.05 
               
               
                   
                 1.89 
                 ND 
                 ND 
                 ND 
                 BQL 
                 ND 
                 BQL 
                 ND 
               
               
                   
                 2.00 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 0.05 
                 0.08 
               
               
                   
                 2.09 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.08 
               
               
                   
                 2.21 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.08 
               
               
                   
                 2.39 
                 ND 
                 BQL 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 ND 
               
               
                   
                 2.44 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.05 
               
               
                   
                 2.56 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
               
               
                   
                 2.61 
                 ND 
                 BQL 
                 BQL 
                 0.07 
                 ND 
                 ND 
                 ND 
               
               
                   
                 2.71 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.39 
                 0.54 
                 1.10 
               
               
                   
                 2.87 
                 ND 
                 BQL 
                 ND 
                 BQL 
                 BQL 
                 ND 
                 ND 
               
               
                   
                 2.96 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 3.09 
                 BQL 
                 BQL 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 3.14 
                 ND 
                 BQL 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 3.36 
                 ND 
                 ND 
                 ND 
                 0.14 
                 0.16 
                 0.16 
                 0.17 
               
               
                   
                 3.48 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.22 
                 0.04 
                 0.19 
               
               
                   
                 3.55 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 ND 
                 BQL 
               
               
                   
                 3.71 
                 ND 
                 ND 
                 0.05 
                 ND 
                 ND 
                 0.05 
                 0.08 
               
               
                   
                 3.83 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 4.34 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
               
               
                 Total impurities 
                   
                 0.22 
                 2.76 
                 5.93 
                 8.17 
                 7.79 
                 8.69 
                 10.00  
               
               
                 (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 43 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 21 stored at 
               
               
                 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                 Epinephrine 
                 RRT 
                 T = 0 
                 1 M 
                 2 M 
                 3 M 
                 4 M 
                 5 M 
                 8 M 
                 12 M 
               
               
                   
               
               
                 Assay (%) 
                   
                 98.20  
                 94.84  
                 94.14  
                 95.37  
                 95.07  
                 95.87  
                 95.18  
                 96.1  
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 colorless 
                 colorless 
                 Light 
                 Light 
                 Light 
                 Light 
                 Light 
                 Light 
               
               
                   
                   
                   
                   
                 Yellow 
                 Yellow 
                 Yellow 
                 Yellow 
                 Yellow 
                 Yellow 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 4.43 
                 7.96 
                 8.20 
                 8.31 
                 7.93 
                 8.47 
                 8.36 
               
               
                 % Epinephrone 
                 1.34 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.77 
                 0.06 
                 0.06 
                 0.06 
                 0.06 
                 0.05 
                 0.09 
                 0.05 
                 0.05 
               
               
                 Unknown 
                 0.20 
                 ND 
                 0.06 
                 ND 
                 ND 
                 0.11 
                 0.11 
                 BQL 
                 BQL 
               
               
                 Impurities (%) 
                 0.66 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
               
               
                   
                 0.83 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.05 
                 ND 
               
               
                   
                 1.67 
                 ND 
                 ND 
                 ND 
                 0.15 
                 0.14 
                 0.14 
                 0.11 
                 0.12 
               
               
                   
                 1.70 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.08 
               
               
                   
                 1.73 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.07 
                 0.06 
                 0.13 
               
               
                   
                 1.81 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.08 
                 0.05 
               
               
                   
                 1.82 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.06 
                 BQL 
               
               
                   
                 1.92 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.08 
                 0.31 
               
               
                   
                 1.95 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.08 
                 0.09 
               
               
                   
                 2.00 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.06 
                 0.1  
               
               
                   
                 2.09 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.09 
                 0.27 
               
               
                   
                 2.27 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.06 
               
               
                   
                 2.40 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.24 
                 0.29 
               
               
                   
                 2.72 
                 ND 
                 ND 
                 ND 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
                 0.08 
               
               
                   
                 2.79 
                 ND 
                 ND 
                 ND 
                 0.17 
                 0.18 
                 0.26 
                 BQL 
                 0.57 
               
               
                   
                 2.84 
                 BQL 
                 BQL 
                 ND 
                 0.05 
                 ND 
                 0.12 
                 0.12 
                 0.2  
               
               
                   
                 2.87 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.2 
                 0.13 
                 0.12 
                 0.62 
               
               
                   
                 2.96 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.08 
               
               
                   
                 2.98 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.11 
               
               
                   
                 3.06 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.14 
               
               
                   
                 3.15 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.08 
               
               
                   
                 3.18 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 ND 
                 0.06 
               
               
                 Total impurities 
                   
                 0.22 
                 4.55 
                 8.02 
                 8.63 
                 8.99 
                 8.85 
                 9.67 
                 11.85  
               
               
                 (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 44 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 27 stored 
               
               
                 at 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 RRT 
                 T = 0 
                 1 M 
                 3 M 
                 4 M 
               
               
                   
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 colorless 
                 colorless 
                 Light 
                 Light 
               
               
                   
                   
                   
                   
                 Yellow 
                 Yellow 
               
               
                 Assay 
                   
                 101.98  
                 101.74  
                 NP 
                 NP 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 3.36 
                 3.26 
                 3.49 
               
               
                 % Epinephrone 
                 1.34 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.77 
                 0.06 
                 0.06 
                 0.08 
                 0.08 
               
               
                   
                 0.20 
                 ND 
                 0.05 
                 0.05 
                 0.06 
               
               
                   
                 1.12 
                 ND 
                 ND 
                 0.09 
                 0.05 
               
               
                   
                 2.14 
                 ND 
                 ND 
                 ND 
                 0.05 
               
               
                 Unknown 
                 2.34 
                 ND 
                 ND 
                 ND 
                 0.06 
               
               
                 (%)Impurities 
                 2.89 
                 ND 
                 ND 
                 ND 
                 0.16 
               
               
                   
                 2.96 
                 ND 
                 ND 
                 0.50 
                 0.48 
               
               
                   
                 2.99 
                 ND 
                 ND 
                 0.10 
                 0.19 
               
               
                   
                 3.05 
                 ND 
                 0.38 
                 0.46 
                 0.43 
               
               
                 Total impurities 
                   
                 0.22 
                 3.85 
                 4.54 
                 5.05 
               
               
                 (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 45 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 28 stored 
               
               
                 at 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 RRT 
                 T = 0 
                 1 M 
                 3 M 
                 4 M 
               
               
                   
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 colorless 
                 colorless 
                 Light 
                 Light 
               
               
                   
                   
                   
                   
                 Yellow 
                 Yellow 
               
               
                 Assay 
                   
                 108.90  
                 107.20  
                 NP 
                 NP 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 1.75 
                 3.15 
                 3.61 
               
               
                 % Epinephrone 
                 1.34 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.77 
                 0.06 
                 0.06 
                 0.08 
                 0.08 
               
               
                 Unknown 
                 0.20 
                 ND 
                 0.24 
                 0.24 
                 0.33 
               
               
                 Impurities (%) 
                 0.25 
                 ND 
                 ND 
                 0.09 
                 0.09 
               
               
                   
                 2.50 
                 ND 
                 0.10 
                 0.25 
                 0.83 
               
               
                   
                 2.96 
                 ND 
                 ND 
                 0.21 
                 0.37 
               
               
                   
                 2.99 
                 ND 
                 ND 
                 ND 
                 0.05 
               
               
                   
                 3.05 
                 ND 
                 0.07 
                 0.15 
                 0.28 
               
               
                   
                 3.21 
                 ND 
                 ND 
                 ND 
                 0.27 
               
               
                 Total impurities 
                   
                 0.22 
                 2.22 
                 4.17 
                 5.91 
               
               
                 (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 46 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 29 stored 
               
               
                 at 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 RRT 
                 T = 0 
                 1 M 
                 3 M 
                 4 M 
               
               
                   
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 colorless 
                 colorless 
                 Light 
                 Light 
               
               
                   
                   
                   
                   
                 Yellow 
                 Yellow 
               
               
                 Assay 
                   
                 101.08  
                 102.42  
                 NP 
                 NP 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 6.12 
                 8.87 
                 8.86 
               
               
                 % Epinephrone 
                 1.34 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.77 
                 0.06 
                 0.06 
                 0.06 
                 0.08 
               
               
                 Unknown 
                 0.20 
                 ND 
                 BQL 
                 BQL 
                 BQL 
               
               
                 Impurities  
                 0.25 
                 ND 
                 ND 
                 ND 
                 ND 
               
               
                   
                 1.06 
                 ND 
                 ND 
                 ND 
                 0.14 
               
               
                   
                 1.12 
                 ND 
                 ND 
                 0.09 
                 0.09 
               
               
                   
                 1.99 
                 ND 
                 ND 
                 0.06 
                 0.12 
               
               
                   
                 2.05 
                 ND 
                 ND 
                 ND 
                 0.14 
               
               
                   
                 2.15 
                 ND 
                 ND 
                 ND 
                 0.08 
               
               
                   
                 2.34 
                 ND 
                 ND 
                 ND 
                 0.08 
               
               
                   
                 2.89 
                 ND 
                 ND 
                 0.11 
                 0.23 
               
               
                   
                 2.96 
                 ND 
                 ND 
                 0.45 
                 0.47 
               
               
                   
                 2.99 
                 ND 
                 ND 
                 0.13 
                 0.27 
               
               
                   
                 3.05 
                 BQL 
                 BQL 
                 0.40 
                 0.43 
               
               
                   
                 3.20 
                 ND 
                 ND 
                 0.15 
                 0.23 
               
               
                 Total impurities 
                   
                 0.22 
                 6.18 
                 10.32  
                 11.22  
               
               
                 (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 47 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 30 stored 
               
               
                 at 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 RRT 
                 T = 0 
                 1 M 
                 3 M 
                 4 M 
               
               
                   
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 colorless 
                 colorless 
                 Light 
                 Light 
               
               
                   
                   
                   
                   
                 Yellow 
                 Yellow 
               
               
                 Assay 
                   
                 106.62  
                 107.37  
                 NP 
                 NP 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 5.00 
                 8.76 
                 8.41 
               
               
                 % Epinephrone 
                 1.34 
                 BQL 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.77 
                 0.06 
                 0.06 
                 0.09 
                 0.08 
               
               
                 Unknown 
                 0.20 
                 ND 
                 BQL 
                 0.07 
                 0.07 
               
               
                 Impurities  
                 0.25 
                 ND 
                 ND 
                 0.14 
                 0.16 
               
               
                   
                 1.06 
                 ND 
                 ND 
                 ND 
                 0.14 
               
               
                   
                 1.12 
                 ND 
                 ND 
                 0.05 
                 BQL 
               
               
                   
                 2.50 
                 ND 
                 0.05 
                 0.12 
                 0.43 
               
               
                   
                 2.96 
                 ND 
                 ND 
                 0.06 
                 0.29 
               
               
                   
                 2.99 
                 ND 
                 ND 
                 ND 
                 0.07 
               
               
                   
                 3.05 
                 ND 
                 BQL 
                 0.05 
                 0.23 
               
               
                   
                 3.20 
                 ND 
                 BQL 
                 0.05 
                 0.16 
               
               
                 Total impurities 
                   
                 0.22 
                 5.11 
                 9.39 
                 10.04  
               
               
                 (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 48 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 31 stored 
               
               
                 at 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                   
                 RRT 
                 T = 0 
                 1 M 
                 3 M 
               
               
                   
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 colorless 
                 colorless 
                 Light 
               
               
                   
                   
                   
                   
                 Yellow 
               
               
                 Assay 
                   
                 101.23  
                 115.59  
                 NP 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 2.75 
                 2.35 
               
               
                 % Epinephrone 
                 1.34 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.77 
                 0.06 
                 0.06 
                 0.09 
               
               
                 Unknown 
                 0.18 
                 ND 
                 BQL 
                 BQL 
               
               
                 Impurities (%) 
                 1.12 
                 ND 
                 ND 
                 0.05 
               
               
                   
                 2.03 
                 ND 
                 ND 
                 0.05 
               
               
                   
                 2.79 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 2.86 
                 ND 
                 ND 
                 0.12 
               
               
                   
                 2.92 
                 ND 
                 ND 
                 0.82 
               
               
                   
                 2.99 
                 ND 
                 0.05 
                 0.14 
               
               
                   
                 3.05 
                 ND 
                 0.92 
                 0.72 
               
               
                   
                 3.16 
                 ND 
                 ND 
                 0.08 
               
               
                 Total impurities 
                   
                 0.22 
                 3.78 
                 4.42 
               
               
                 (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 49 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 32 stored 
               
               
                 at 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                   
                 RRT 
                 T0 
                 1 M 
                 3 M 
               
               
                   
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 colorless 
                 colorless 
                 Light 
               
               
                   
                   
                   
                   
                 Yellow 
               
               
                 Assay 
                   
                 108.96  
                 103.80  
                 NP 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 1.89 
                 2.50 
               
               
                 % Epinephrone 
                 1.34 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.77 
                 0.06 
                 0.06 
                 0.09 
               
               
                 Unknown 
                 0.18 
                 ND 
                 0.11 
                 0.08 
               
               
                 Impurities  
                 0.25 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 1.12 
                 ND 
                 ND 
                 0.07 
               
               
                   
                 1.19 
                 ND 
                 ND 
                 0.05 
               
               
                   
                 2.48 
                 ND 
                 0.16 
                 0.50 
               
               
                   
                 2.92 
                 ND 
                 ND 
                 0.49 
               
               
                   
                 3.00 
                 ND 
                 0.16 
                 0.37 
               
               
                   
                 3.16 
                 ND 
                 ND 
                 0.16 
               
               
                 Total impurities 
                   
                 0.22 
                 2.38 
                 4.31 
               
               
                 (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 50 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 33 stored 
               
               
                 at 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                   
                 RRT 
                 T = 0 
                 1 M 
                 3 M 
               
               
                   
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 colorless 
                 colorless 
                 Light 
               
               
                   
                   
                   
                   
                 Yellow 
               
               
                 Assay 
                   
                 100.05  
                 99.36  
                 NP 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 9.14 
                 9.82 
               
               
                 % Epinephrone 
                 1.34 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.77 
                 0.06 
                 0.06 
                 0.09 
               
               
                 Unknown 
                 0.18 
                 ND 
                 BQL 
                 BQL 
               
               
                 Impurities (%) 
                 1.74 
                 ND 
                 ND 
                 0.60 
               
               
                   
                 1.98 
                 ND 
                 ND 
                 0.07 
               
               
                   
                 2.04 
                 ND 
                 ND 
                 0.07 
               
               
                   
                 2.32 
                 ND 
                 ND 
                 0.07 
               
               
                   
                 2.86 
                 ND 
                 ND 
                 0.18 
               
               
                   
                 2.92 
                 ND 
                 ND 
                 0.70 
               
               
                   
                 2.95 
                 ND 
                 ND 
                 0.23 
               
               
                   
                 3.01 
                 ND 
                 ND 
                 0.62 
               
               
                   
                 3.16 
                 ND 
                 ND 
                 0.15 
               
               
                   
                 3.29 
                 ND 
                 ND 
                 0.05 
               
               
                 Total impurities 
                   
                 0.22 
                 9.20 
                 12.65  
               
               
                 (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 51 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation # 34 stored 
               
               
                 at 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
            
               
                   
                 RRT 
                 T = 0 
                 1 M 
                 3 M 
               
               
                   
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 colorless 
                 colorless 
                 Light 
               
               
                   
                   
                   
                   
                 Yellow 
               
               
                 Assay 
                   
                 113.33  
                 112.55  
                 NP 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 6.30 
                 9.61 
               
               
                 % Epinephrone 
                 1.34 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.77 
                 0.06 
                 0.06 
                 0.08 
               
               
                 Unknown 
                 0.18 
                 ND 
                 BQL 
                 0.06 
               
               
                 Impurities (%) 
                 0.25 
                 ND 
                 ND 
                 0.09 
               
               
                   
                 1.06 
                 ND 
                 ND 
                 0.16 
               
               
                   
                 1.12 
                 ND 
                 ND 
                 0.07 
               
               
                   
                 1.32 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 2.32 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 2.55 
                 ND 
                 0.07 
                 0.23 
               
               
                   
                 2.93 
                 ND 
                 ND 
                 0.34 
               
               
                   
                 2.96 
                 ND 
                 ND 
                 0.07 
               
               
                   
                 2.98 
                 ND 
                 ND 
                 0.08 
               
               
                   
                 3.02 
                 ND 
                 0.08 
                 0.28 
               
               
                   
                 3.17 
                 ND 
                 ND 
                 0.08 
               
               
                 Total impurities 
                   
                 0.22 
                 6.51 
                 11.15  
               
               
                 (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 52 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #35 stored  
               
               
                 at 40° C. ± 2° C./75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 RRT 
                 T = 0 
                 2M 
                 3M 
                 6M 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Assay 
                   
                 101.32 
                 83.12 
                 91.78 
                 100.20 
               
               
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                 colorless 
                 colorless 
                 colorless 
                 colorless 
               
               
                 % Impurity F 
                 0.19 
                 0.16 
                 4.56 
                 6.40 
                 7.56 
               
               
                 % Epinephrone 
                 1.34 
                 ND 
                 BQL 
                 BQL 
                 BQL 
               
               
                 % Methoxy 
                 1.77 
                 0.07 
                 0.06 
                 0.05 
                 0.05 
               
               
                 Unknown 
                 0.20 
                 ND 
                 ND 
                 ND 
                 0.13 
               
               
                 Impurities  
                 0.21 
                 ND 
                 0.26 
                 0.05 
                 0.08 
               
               
                 (%) 
                 0.26 
                 ND 
                 0.13 
                 0.12 
                 0.30 
               
               
                   
                 1.19 
                 ND 
                 0.06 
                 BQL 
                 BQL 
               
               
                   
                 1.71 
                 ND 
                 BQL 
                 BQL 
                 0.05 
               
               
                   
                 1.95 
                 ND 
                 ND 
                 ND 
                 0.07 
               
               
                   
                 2.45 
                 ND 
                 0.06 
                 0.05 
                 0.73 
               
               
                   
                 2.92 
                 ND 
                 ND 
                 ND 
                 0.19 
               
               
                   
                 2.95 
                 ND 
                 ND 
                 ND 
                 0.13 
               
               
                   
                 2.97 
                 ND 
                 ND 
                 ND 
                 0.16 
               
               
                 Total  
                   
                 0.23 
                 5.13 
                 6.67 
                 9.45 
               
               
                 Impurities 
                   
                   
                   
                   
                   
               
               
                 (%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 53 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #36  
               
               
                 stored at 40° C. ± 2° C./ 75% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 RRT 
                 T = 0 
                 2M 
                 6M 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Assay 
                   
                 101.32 
                 91.40 
                 103.10 
               
               
                   
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                   
                 colorless 
                 colorless 
                 colorless 
               
               
                   
                 % Impurity F 
                 0.19 
                 0.16 
                 6.81 
                 6.90 
               
               
                   
                 % Epinephrone 
                 1.34 
                 ND 
                 BQL 
                 BQL 
               
               
                   
                 % Methoxy 
                 1.77 
                 0.07 
                 0.06 
                 0.05 
               
               
                   
                 Unknown 
                 0.21 
                 ND 
                 0.09 
                 0.07 
               
               
                   
                 Impurities  
                 0.70 
                 ND 
                 BQL 
                 ND 
               
               
                   
                 (%) 
                 1.71 
                 ND 
                 ND 
                 0.07 
               
               
                   
                   
                 1.92 
                 ND 
                 ND 
                 0.07 
               
               
                   
                   
                 1.95 
                 ND 
                 ND 
                 0.05 
               
               
                   
                   
                 2.00 
                 ND 
                 ND 
                 0.05 
               
               
                   
                   
                 2.09 
                 ND 
                 ND 
                 0.06 
               
               
                   
                   
                 2.27 
                 ND 
                 ND 
                 0.05 
               
               
                   
                   
                 2.41 
                 ND 
                 ND 
                 0.08 
               
               
                   
                   
                 2.84 
                 ND 
                 ND 
                 0.19 
               
               
                   
                   
                 2.90 
                 ND 
                 ND 
                 0.29 
               
               
                   
                   
                 2.93 
                 ND 
                 ND 
                 0.31 
               
               
                   
                   
                 2.98 
                 ND 
                 ND 
                 0.25 
               
               
                   
                 Total  
                   
                 0.23 
                 6.96 
                 8.49 
               
               
                   
                 Impurities 
                   
                   
                   
                   
               
               
                   
                 (%) 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 54 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #35  
               
               
                 stored at 25° C. ± 2° C./ 60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 RRT 
                 T = 0 
                 3M 
                 6M 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Assay 
                   
                 101.32 
                 92.83 
                 101.79 
               
               
                   
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                   
                 colorless 
                 colorless 
                 colorless 
               
               
                   
                 % Impurity F 
                 0.19 
                 0.16 
                 1.08 
                 2.32 
               
               
                   
                 % Epinephrone 
                 1.34 
                 ND 
                 BQL 
                 BQL 
               
               
                   
                 % Methoxy 
                 1.77 
                 0.07 
                 0.05 
                 0.06 
               
               
                   
                 Unknown 
                 0.21 
                 ND 
                 BQL 
                 0.07 
               
               
                   
                 Impurities (%) 
                 0.26 
                 ND 
                 ND 
                 ND 
               
               
                   
                   
                 0.23 
                 ND 
                 ND 
                 BQL 
               
               
                   
                   
                 1.20 
                 ND 
                 ND 
                 BQL 
               
               
                   
                   
                 2.45 
                 ND 
                 ND 
                 BQL 
               
               
                   
                 Total  
                   
                 0.23 
                 1.13 
                 2.45 
               
               
                   
                 Impurities 
                   
                   
                   
                   
               
               
                   
                 (%) 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 55 
               
             
            
               
                   
               
               
                 Stability Data for Epinephrine Spray Formulation #36  
               
               
                 stored at 25° C. ± 2° C./ 60% ± 5% Relative Humidity 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 RRT 
                 T = 0 
                 3M 
                 6M 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Assay 
                   
                 101.32 
                 103.80 
                 104.79 
               
               
                   
                 Appearance 
                   
                 Clear, 
                 Clear, 
                 Clear, 
               
               
                   
                   
                   
                 colorless 
                 colorless 
                 colorless 
               
               
                   
                 % Impurity F 
                 0.19 
                 0.16 
                 1.54 
                 4.00 
               
               
                   
                 % Epinephrone 
                 1.34 
                 ND 
                 BQL 
                 BQL 
               
               
                   
                 % Methoxy 
                 1.77 
                 0.07 
                 0.06 
                 0.05 
               
               
                   
                 Unknown 
                 0.21 
                 ND 
                 BQL 
                 BQL 
               
               
                   
                 Impurities (%) 
                 0.72 
                 ND 
                 BQL 
                 BQL 
               
               
                   
                   
                 0.83 
                 ND 
                 BQL 
                 ND 
               
               
                   
                   
                 3.09 
                 ND 
                 BQL 
                 0.05 
               
               
                   
                 Total  
                   
                 0.23 
                 1.60 
                 4.10 
               
               
                   
                 impurities 
                   
                   
                   
                   
               
               
                   
                 (%) 
               
               
                   
                   
               
            
           
         
       
     
     All formulas exemplified in Tables 27 to 31 above, remained clear throughout stability testing. Formulations were filled in to unit dose spray devices under nitrogen blanket, and then subjected to accelerated stability testing at 25° C.±2° C./60%±5% and 40° C.±2° C./75%±5% without pouching (Formulations 12 to 18), while formulations (F #19 to 36) were subjected to accelerated stability testing under similar conditions with pouching containing oxygen scavenges. Formulation 13, un-pouched showed impurity F levels at 5.64% at  2 M/40° C. However similar formulation 19, pouched, exhibited impurity F levels at 4.25% at  2 M/40° C. Stability data suggest that epinephrine spray formulations which are pouched with oxygen scavenges are more stable compare to un-pouched formulations. Both hydro-alcoholic and aqueous formulations of present invention are stable at room temperature as well as 40° C.±2° C./75%±5. 
     For the Epinephrine 6 mg aqueous formulation in pouches, 3.49% and 8.86% of impurity F was observed after a period of 4 months at 40° C.±2° C./75% RH±5% RH for Formulations #27 and 29 respectively. Total impurities for Formulations #27 and 29 were found to be 5.05% and 11.22% after a period of 4 months at 40° C.±2° C./75% RH±5% RH, respectively. In the case of hydro-alcoholic formulations of the same strength in pouches, 3.61% and 8.41% of impurity F was observed after the same period for formulations #28 and 30, respectively. Total impurities for Formulations #28 and 30 were found to be 5.91% and 10.04% after a period of 4 months at 40° C.±2° C./75% RH±5% RH, respectively. 
     For the Epinephrine 9 mg aqueous formulation in pouches, 2.35% and 9.82% of impurity F was observed after a period of 4 months at 40° C.±2° C./75% RH±5% RH for Formulations #31 and 33 respectively. Total impurities for formulations #31 and 33 were found to be 4.42% and 12.65% after a period of 4 months at 40° C.±2° C./75% RH±5% RH, respectively. In the case of hydro-alcoholic formulations of the same strength in pouches, 2.50% and 9.61% of impurity F was observed after the same period for Formulations #32 and 34. Total impurities for Formulations #32 and 34 were found to be 4.31% and 11.15% after a period of 4 months at 40° C.±2° C./75% RH±5% RH, respectively. 
     Example 6. Mini-Pig Pharmacokinetic Data for Epinephrine Formulations 
     Protocol design was a single-dose crossover study. Five healthy male Yucatan mini-pigs weighing approximately eighty to ninety-five kilograms each were administered epinephrine formulations. The minipigs were fasted overnight till four hours&#39; post administration. Each dosing was followed by a washout period of at least one-week. Blood samples were taken prior to administration and 2, 5, 10, 15, 20, 30, 45 min, 1, 1.5, 2, 4, and 24 hours&#39; post dose. Minipig plasma samples were measured for epinephrine concentrations via liquid chromatography-tandem mass spectrometry. 
     The following pharmacokinetic parameters were calculated: peak concentration in plasma (C max ), time to reach C max  (T max ), and area under the concentration-time curve from time-zero to 24 hours postdose (AUC 0-24h ). 
     The pharmacokinetic behavior of epinephrine formulations was evaluated. At 5 minutes after a single-dose intramuscular (IM) administration of epinephrine in minipigs, the geometric mean plasma concentration of epinephrine was 0.046 ng/mL. When epinephrine was formulated in #M1 and administered intranasally, a more rapid absorption of epinephrine was observed. Specifically, #M1 showed a geometric mean epinephrine plasma concentration of 0.26 ng/mL at 5 minutes postdose. It was also noted that a plasma concentration of 0.41 ng/mL was achieved as early as 2 minutes after an intranasal administration of #M1. In addition, #M1 showed a geometric mean Cmax of 1.01 ng/mL and a geometric mean AUC 0-24h  of 161.0 ng*min/L. 
     
       
         
           
               
             
               
                 TABLE 56 
               
             
            
               
                   
               
               
                 Epinephrine Formulations for Minipig Dosing 
               
            
           
           
               
               
               
            
               
                   
                 Formulation 
                 #M1 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 Epinephrine base 
                 3.25 
               
               
                   
                 Dilute Hydrochloric acid 0.5 N 
                 36.2 
               
               
                   
                 Benzalkonium Chloride 
                 0.01 
               
               
                   
                 Ethanol 
                 40 
               
               
                   
                 Propylene Glycol 
                 5 
               
               
                   
                 Sodium Bisulfite 
                 0.15 
               
               
                   
                 EDTA 
                 0.05 
               
               
                   
                 Water 
                 15.34 
               
               
                   
                 Total 
                 100 
               
               
                   
                   
               
               
                   
                 Components: % w/w 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 57 
               
             
            
               
                   
               
               
                 Plasma concentrations for epinephrine after  
               
               
                 administration to Yucatan minipigs under fasted conditions. 
               
            
           
           
               
               
               
               
            
               
                   
                 Formulation 
                 IM solution 
                 #M1 
               
               
                   
                   
               
               
                   
                 Route of administration 
                 IM 
                 Intranasal 
               
               
                   
                 Dose per animal (mg) 
                 0.3 
                 6 
               
               
                   
                 Concentration @ 2 min (ng/mL) 
                 0.036 
                 0.41 
               
               
                   
                 Concentration @ 5 min (ng/mL) 
                 0.046 
                 0.26 
               
               
                   
                 Concentration @ 10 min (ng/mL) 
                 0.073 
                 0.31 
               
               
                   
                 Concentration @ 15 min (ng/mL) 
                 0.103 
                 0.17 
               
               
                   
                 Concentration @ 30 min (ng/mL) 
                 0.100 
                 0.19 
               
               
                   
                 T max  (min) 
                 90 
                 5 
               
               
                   
                 C max  (ng/mL) 
                 0.25 
                 1.01 
               
               
                   
                 AUC 0-24h  (ng * min/mL) 
                 173.7 
                 161.0 
               
               
                   
                   
               
               
                   
                 Plasma concentration: geometric mean 
               
               
                   
                 T max : median value 
               
               
                   
                 C max  and AUC 0-24h : geometric mean 
               
            
           
         
       
     
     Example 7. Rabbit Pharmacokinetic Data for Epinephrine Formulations 
     Protocol design was a single-dose non-crossover study. Pharmacokinetics of a number of epinephrine formulations were evaluated in healthy male New Zealand white rabbits weighing approximately two to three kilograms. For dosing of each formulation, five or six rabbits were used. The rabbits were fasted overnight till four hours&#39; post administration. Blood samples were taken prior to administration and 5, 10, 15, 20, 30, 40 min, 1, 1.5, 2, 4, and 5 hours&#39; post dose. Rabbit plasma samples were measured for epinephrine concentrations via liquid chromatography-tandem mass spectrometry. 
     Formulation #R1-#R8 were provided in Table 43 and 44. Formulation #R9 existed as a spray-dried powder of epinephrine bitartrate salt. For the evaluation of #R9, approximately 21.83 mg of powder was dosed to each animal, as an equivalent dose of 12 mg epinephrine. 
     The following pharmacokinetic parameters were calculated: peak concentration in plasma (C max ), time to reach C max  (T max ), and area under the concentration-time curve from time-zero to 24 hours postdose (AUC 0-24h ). 
     The pharmacokinetic behavior of epinephrine formulations was evaluated. At 5 minutes after a single-dose IM administration of epinephrine in rabbits, the mean plasma concentration of epinephrine was 0.988 ng/mL. In comparison, a sublingual administration of #R9 enabled a similar absorption of epinephrine in the early phase. Specifically, #R9 showed a mean epinephrine plasma concentration of 0.0.814 ng/mL at 5 minutes postdose. It was also noted that a plasma concentration of 0.713 ng/mL was achieved at 5 minutes after a sublingual administration of #R6. In addition, #R9 showed a geometric mean Cmax of 7.0 ng/mL and a geometric mean AUC0-24 h of 1050.1 ng*min/L. 
     
       
         
           
               
             
               
                 TABLE 58 
               
             
            
               
                   
               
               
                 Epinephrine Formulations for Rabbit Dosing 
               
            
           
           
               
               
               
               
               
               
            
               
                 Formulation 
                 #R1 
                 #R2 
                 #R3 
                 #R4 
                 #R5 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Epinephrine base 
                 0 
                 0.006 
                 3.025 
                 3.243 
                 3.243 
               
               
                 Dilute Hydrochloric  
                 0.3 
                 0.5 
                 33.27 
                 36.2 
                 36.2 
               
               
                 Acid 0.5 N 
                   
                   
                   
                   
                   
               
               
                 Dehydrated Alcohol 
                   
                   
                   
                 40 
                 40 
               
               
                 Menthol 
                   
                   
                   
                 1 
                 1 
               
               
                 Sucralose 
                 0.5 
                   
                 0.5 
                 0.5 
                 0.5 
               
               
                 Propylene Glycol 
                   
                   
                   
                 5 
                 5 
               
               
                 Sodium Bisulfite 
                 0.2 
                 0.01 
                 0.2 
                 0.3 
                 0.3 
               
               
                 Edetate Disodium  
                 0.05 
                   
                 0.05 
                 0.05 
                 0.05 
               
               
                 (EDTA) 
                   
                   
                   
                   
                   
               
               
                 Water USP 
                 98.45 
                 98.584 
                 62.455 
                 13.707 
                 13.707 
               
               
                 Total 
                 100 
                 100 
                 100 
                 100 
                 100 
               
               
                   
               
               
                 Components: % w/w 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 59 
               
             
            
               
                   
               
               
                 Additional Epinephrine Formulations for Rabbit Dosing 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Formulation 
                 #R6 
                 #R7 
                 #R8 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Epinephrine base 
                 6.648 
                 12.88 
                 12.88 
               
               
                   
                 Dilute Hydrochloric Acid 1.5 N 
                 24.6 
                   
                   
               
               
                   
                 Dilute Hydrochloric Acid 3 N 
                   
                 24.2 
                 24.2 
               
               
                   
                 Dehydrated Alcohol 
                 40 
                 40 
                 40 
               
               
                   
                 Menthol 
                 0.5 
                 0.5 
                 0.5 
               
               
                   
                 Sucralose 
                 0.5 
                 0.5 
                 0.5 
               
               
                   
                 Propylene Glycol 
                 5 
                 5 
                 5 
               
               
                   
                 Sodium Bisulfite 
                 0.6 
                 0.6 
                 0.6 
               
               
                   
                 Edetate Disodium (EDTA) 
                 0.1 
                 0.1 
                 0.1 
               
               
                   
                 Water USP 
                 21.552 
                 15.72 
                 15.72 
               
               
                   
                 Caprylic acid 
                 0.5 
                   
                   
               
               
                   
                 Capric acid 
                   
                   
                 0.5 
               
               
                   
                 Total 
                 100 
                 100 
                 100 
               
               
                   
                   
               
               
                   
                 Components: % w/w 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 60 
               
             
            
               
                   
               
               
                 Plasma concentrations for epinephrine after  
               
               
                 administration to rabbits under fasted conditions. 
               
            
           
           
               
               
               
               
               
               
            
               
                 Formulation 
                 #R1 
                 #R2 
                 #R3 
                 #R4 
                 #R5 
               
               
                   
               
               
                 Route of administration 
                 SL 
                 IM 
                 SL 
                 SL 
                 SL 
               
               
                 Dose per animal (mg) 
                 0 
                 0.03 
                 3 
                 3 
                 6 
               
               
                 Concentration @  
                 0.020 
                 0.99 
                 0.28 
                 0.19 
                 0.11 
               
               
                 5 min (ng/mL) 
                   
                   
                   
                   
                   
               
               
                 Concentration @  
                 0.011 
                 0.83 
                 0.24 
                 0.32 
                 0.35 
               
               
                 10 min (ng/mL) 
                   
                   
                   
                   
                   
               
               
                 Concentration @  
                 0.014 
                 0.79 
                 0.49 
                 0.55 
                 0.86 
               
               
                 15 min (ng/mL) 
                   
                   
                   
                   
                   
               
               
                 Concentration @  
                 0.012 
                 0.73 
                 0.44 
                 1.24 
                 1.94 
               
               
                 30 min (ng/mL) 
                   
                   
                   
                   
                   
               
               
                 T max  (min) 
                 300 
                 15 
                 240 
                 90 
                 90 
               
               
                 C max  (ng/mL) 
                 0.05 
                 1.1 
                 1.3 
                 2.9 
                 6.3 
               
               
                 AUC 0-24h  (ng * min/mL) 
                 6.7 
                 96.7 
                 217.0 
                 537.1 
                 956.8 
               
               
                   
               
               
                 Plasma concentration: mean 
               
               
                 T max : median value 
               
               
                 C max  and AUC 0-24h : geometric mean 
               
               
                 IM denotes intramuscular, SL denotes sublingual 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 61 
               
             
            
               
                   
               
               
                 Plasma concentrations for epinephrine after administration  
               
               
                 to rabbits under fasted conditions. 
               
            
           
           
               
               
               
               
               
            
               
                 Formulation 
                 #R6 
                 #R7 
                 #R8 
                 #R9 
               
               
                   
               
               
                 Route of administration 
                 SL 
                 SL 
                 SL 
                 SL 
               
               
                 Dose per animal (mg) 
                 6 
                 12 
                 12 
                 12 
               
               
                 Concentration @ 5 min (ng/mL) 
                 0.71 
                 0.28 
                 0.12 
                 0.81 
               
               
                 Concentration @ 10 min (ng/mL) 
                 0.37 
                 0.46 
                 0.17 
                 1.10 
               
               
                 Concentration @ 15 min (ng/mL) 
                 0.51 
                 0.83 
                 0.53 
                 1.40 
               
               
                 Concentration @ 30 min (ng/mL) 
                 0.93 
                 2.75 
                 3.34 
                 3.57 
               
               
                 T max  (min) 
                 120 
                 120 
                 180 
                 65 
               
               
                 C max  (ng/mL) 
                 3.1 
                 6.0 
                 14.3 
                 7.0 
               
               
                 AUC 0-24h  (ng * min/mL) 
                 482.2 
                 867.0 
                 2145.1 
                 1050.1 
               
               
                   
               
               
                 Plasma concentration: mean 
               
               
                 T max : median value 
               
               
                 C max  and AUC 0-24h : geometric mean 
               
            
           
         
       
     
     Example 8. Intranasal Administration of Epinephrine Spray Formulations 
     Methods 
       
     
       
         
           
               
             
               
                 TABLE 62 
               
             
            
               
                   
               
               
                 Clinical Formulations 
               
            
           
           
               
               
               
            
               
                 Formulation 
                 #C1 
                 #C2 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Epinephrine Base 
                 2.962 
                 3.178 
               
               
                 Hydrochloric Acid 0.5N 
                 32.93 
                 35.471 
               
               
                 Edetate Disodium Dihydrate 
                 0.05 
                 0.05 
               
               
                 Sodium Bisulfite 
                 0.15 
                 0.15 
               
               
                 Benzalkonium Chloride 
                 0.01 
                 0.01 
               
               
                 Dehydrated alcohol 
                 — 
                 40 
               
               
                 Sodium Chloride 
                 0.6 
                 — 
               
               
                 Water 
                 63.298 
                 16.141 
               
               
                   
               
               
                 Components: % w/w 
               
            
           
         
       
     
     Protocol design was a Phase I, proof-of-concept, single-dose open-label, 5-treatment, crossover study to assess the bioavailability of intranasal formulations in adults with seasonal allergies. The study assessed the bioavailability of a single dose 3 milligrams and 6 milligrams dose of epinephrine in a formulation of the present invention to a single 0.3 milligram intramuscular dose of epinephrine via an EpiPen® (0.3 milligrams epinephrine, 1.8 milligrams sodium chloride, 0.5 milligrams sodium metabisulfite, hydrochloric acid to adjust pH, and water for injection). 50 subjects were randomly assigned to one of five groups including 3 milligram intranasal dose of an aqueous formulation of the present invention, 3 milligram intranasal dose of a hydro-alcoholic formulation of the present invention, 6 milligram intranasal dose of an aqueous formulation of the present invention, 6 milligram intranasal dose of a hydro-alcoholic formulation of the present invention and a 0.3 milligram intramuscular dose administered over 4 periods with periods 1 and 2 administered in the absence of allergen and periods 3 and 4 in the presence of an allergen that caused seasonal allergies in the subject. Plasma concentrations were taken at −60, −30, 0, 1, 3, 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 180, 240 and 360 minutes post-dose. 
     Results 
       
     
       
         
           
               
             
               
                 TABLE 63 
               
             
            
               
                   
               
               
                 Pharmacokinetic profile prior to allergen exposure 
               
            
           
           
               
               
               
               
               
            
               
                 Formulation 
                 T max  (Mean) 
                 C max  (pg/mL) 
                 AUC last  (h * pg/mL) 
                 AUC inf  (h * pg/mL) 
               
               
                   
               
               
                 Aqueous 
                 0.376 (0.05-1.25) 
                 Mean 256 (23.4-1260) 
                 Mean 231 (31.4-958) 
                 Mean 377 (37.9-1860) 
               
               
                   
                   
                 GeoMean 149 
                 GeoMean 153 
                 GeoMean 206 
               
               
                 Hydro- 
                 0.41 (0.05-2.0) 
                 Mean 419 (77.6-1110) 
                 Mean 596 (30.7-3520)  
                 Mean 727 (31.2-4150) 
               
               
                 alcoholic 
                   
                 GeoMean 314 
                 GeoMean 317 
                 GeoMean 385 
               
               
                 Epipen ® 
                 0.281 (0.05-0.833) 
                 Mean 511 (148-1160) 
                 Mean 307 (89.1-698) 
                 Mean 329 (91.4-749) 
               
               
                   
                   
                 GeoMean 429 
                 GeoMean 255 
                 GeoMean 273 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 64 
               
             
            
               
                   
               
               
                 Pharmacokinetic profile after allergen exposure 
               
            
           
           
               
               
               
               
               
            
               
                 Formulation 
                 T max  (Mean) 
                 C max  (pg/mL) 
                 AUC last  (h * pg/mL) 
                 AUC inf  (h * pg/mL) 
               
               
                   
               
               
                 Aqueous 
                 0.13 (0.017-0.667) 
                 Mean 418 (78.5-1900). 
                 Mean 231 (76.1-573).  
                 Mean 273 (94.9-620). 
               
               
                   
                   
                 GeoMean 268 
                 GeoMean 197 
                 GeoMean 237 
               
               
                 Hydro- 
                 0.12 (0.017-0.667) 
                 Mean 639 (60.6-3150). 
                 Mean 429 (51.8-963).  
                 Mean 497 (52-1100). 
               
               
                 alcoholic 
                   
                 GeoMean 447 
                 GeoMean- 
                 GeoMean 376 
               
               
                 Epipen ® 
                 0.225 (0.05-0.667) 
                 Mean 649 (201-1750). 
                 Mean 317 (125-557). 
                 Mean 362 (166-706). 
               
               
                   
                   
                 GeoMean 517 
                 GeoMean 286 
                 GeoMean 326 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 65 
               
               
                   
               
               
                 Early Epinephrine plasma concentrations 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 Before Allergen  
                 Time  
                 Mean  
               
               
                 Exposure 
                 (Minutes) 
                 (Min-Max) pg/ml 
               
               
                   
               
               
                 Aqueous 
                 1 
                 47.8 ( 0-264) 
               
               
                   
                 3 
                 154 (0-749) 
               
               
                   
                 5 
                 171 (9.17-844) 
               
               
                   
                 10 
                 198 (9.37-1260) 
               
               
                 Hydro-alcoholic 
                 1 
                 84 (0-353) 
               
               
                   
                 3 
                 244 (6.73-933) 
               
               
                   
                 5 
                 250 (2.13-1030) 
               
               
                   
                 10 
                 200 (34.5-718) 
               
               
                   
               
               
                 After Allergen  
                 Time  
                 Mean  
               
               
                 Exposure 
                 (Minutes) 
                 (Min-Max) pg/ml 
               
               
                   
               
               
                 Aqueous 
                 1 
                 174 (1.77-1390) 
               
               
                   
                 3 
                 353 (28.2-1900) 
               
               
                   
                 5 
                 288 (31.3-1040) 
               
               
                   
                 10 
                 183 (36.2-461) 
               
               
                 Hydro-alcoholic 
                 1 
                 290 (10.5-1300) 
               
               
                   
                 3 
                 581 (42.3-3150) 
               
               
                   
                 5 
                 398 (43.5-1340) 
               
               
                   
                 10 
                 257 (20.6-692) 
               
               
                   
               
            
           
         
       
     
     As seen in Tables 63-65 and  FIGS. 1-3 , subjects administered 6 milligrams of epinephrine in a hydroalcoholic formulation of the present invention in the presence of an allergen had a higher C max  than all other cohorts. Further, as seen in  FIGS. 1-3 , subjects administered 0.3 milligrams of epinephrine as an intramuscular injection in absence of an allergen had a higher C max  than all other cohorts in the absence of an allergen. Among subjects receiving either the aqueous or the hydroalcoholic formulations the subjects receiving the hydroalcoholic formulations had a higher C max  across the entire sampling time than those receiving the aqueous formulation both in the absence and presence of an allergen. Epinephrine plasma concentrations were greater than 100 pg/mL up to 30 min post dose for all formulations. Further, epinephrine plasma concentration were greater than 100 pg/mL in less than 5 minutes post dose for all formulations of the present invention regardless of exposure to an allergen. Subjects administered the hydroalcoholic formulation had higher exposure in the entire sampling times for up to 6 hours compared to the aqueous formulation. 
     In conclusion, the bioavailability of intranasal formulations of the present invention is as good or better than that of the intramuscular injection both in subject that are and are not experiencing seasonal allergies. 
     Example 9. Comparison of Intranasal Formulations of the Invention with Epipen® and IM Adrenalin 
     Methods 
     This was a single-dose, open-label, randomized, four-treatment, four-way crossover study to assess the pharmacokinetics of two test formulations of hydro-alcoholic Epinephrine Nasal Spray containing 7 mg (2 sprays of Composition #37) and 8.5 mg (2 sprays of Composition #38) epinephrine in comparison with reference formulations of Epinephrine IM Injection, EpiPen® (0.30 mg administered intra muscularly), and Epinephrine IM Injection, Adrenalin® (0.50 mg administered intramuscularly; Adrenalin® contains 1.0 milligrams epinephrine, 6.15 milligrams sodium chloride, 0.457 milligrams sodium metabisulfite, 0.920 milligrams sodium hydroxide, 2.25 milligrams tartaric acid, 0.20 milligrams disodium edetate dihydrate, hydrochloric acid to adjust pH, milligrams chlorobutanol and water for injection). Each dose of study treatment was separated by a washout period of 24 hours. Healthy volunteer subjects received hydro-alcoholic Epinephrine Nasal Spray (7 mg and 8.5 mg) and Epinephrine IM Injection (EpiPen® [0.30 mg] and Adrenalin® [0.50 mg]), following an overnight fast of at least 10 hours. 
     This study consisted of five periods: a Screening Period and four Treatment Periods. During screening (Day −28 to Day −1), subjects signed the informed consent and then underwent determination of eligibility. Based on successful completion of the screening process, approximately 48 subjects were enrolled. Subjects received a single dose of each test formulation and a single dose of each reference formulation administered on Day 1 Period 1, Day 2 Period 2, Day 3 Period 3, and Day 4 Period 4, depending upon treatment sequence assignment. Subjects were confined before dosing to ensure adherence to the 10 hour fast and remained confined until all study procedures are completed on Day 5. No food was allowed until at least 4 hours after each dose administration. No water was consumed from 1 hour prior until 1 hour after each dose administration. Meals were provided at scheduled times. Blood samples for pharmacokinetic (PK) analyses was collected prior to and at multiple times following each dose of study drug. Safety and tolerability was assessed throughout the study. 
     Pharmacokinetics: 
     Sampling times: A total of 288 mL (72×4 mL samples) of blood was collected for pharmacokinetic analysis from each subject. Blood samples (1×4 mL) for epinephrine analysis was collected in Vacutainer tubes containing K 2 -EDTA as a preservative at −60 and −30 minutes, 0 hour (pre-dose), 1, 3, 5, 7, 10, 15, 20, 30, and 45 minutes; and at 1, 1.5, 2, 3, 4, and 6 hours post dose (18 time points) in each study period. The pre-dose blood sample was collected within 60 minutes prior to each dose of study drug. 
     Bioanalytical method: Plasma concentrations of epinephrine was analyzed using a validated liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) assay with a lower limit of quantification (LLOQ) of 10.0 pg/mL. 
     PK parameters: Plasma concentrations of epinephrine (with and without baseline-correction) were used to determine the following PK parameters using noncompartmental PK analysis (NCA):
         1. Maximum plasma concentration observed (C max ),   2. Time to reach maximum plasma concentration (t max ),   3. Area under the curve from time 0 to the last measured concentration (AUC last ),   4. Area under the curve extrapolated to infinity (AUC 0-inf ),   5. The time prior to the first measurable (non-zero) concentration (t lag ),   6. Terminal elimination half-life (t 1/2 ),   7. The last quantifiable concentration (Clast), and time corresponding this concentration (t last ),   8. Apparent total body clearance after extravascular administration (CL/F),   9. Apparent volume of distribution in the terminal phase (Vz/F), and   10. Relative bioavailability of epinephrine for test formulation compared to reference formulation (Frel).       

     Baseline-correction was performed by subtracting the mean of epinephrine concentrations at −1, −0.5, and 0 h from each post-dose concentration. Baseline-corrected concentrations that are less than 0 will be set to 0 pg/mL. 
     Results 
       
     
       
         
           
               
             
               
                 TABLE 66 
               
             
            
               
                   
               
               
                 Mean plasma concentration after administration of nasal compositions #37 and #38, 
               
               
                 Epipen ® and intramuscular adrenalin 
               
            
           
           
               
               
               
               
               
            
               
                 BC-Mean 
                   
                   
                   
                   
               
               
                 Plasma 
                 Composition #37 
                 Composition #38 
                 Epipen ® IM 
                 Adrenalin IM 
               
               
                 Conc 
                 (7.0 mg) 
                 (8.5 mg) 
                 (0.3 mg) 
                 (0.5 mg) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 h 
                 Mean 
                 CV (%) 
                 Mean 
                 CV (%) 
                 Mean 
                 CV (%) 
                 Mean 
                 CV (%) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 0.0000 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 0.0167 
                 176 
                 147 
                 217 
                 188 
                 41.2 
                 131 
                 39.6 
                 177 
               
               
                 0.0500 
                 768 
                 178 
                 860 
                 187 
                 444 
                 143 
                 222 
                 158 
               
               
                 0.0833 
                 663 
                 167 
                 1020 
                 189 
                 502 
                 86.6 
                 288 
                 110 
               
               
                 0.1167 
                 623 
                 158 
                 1000 
                 188 
                 416 
                 78.7 
                 246 
                 87.8 
               
               
                 0.1667 
                 566 
                 157 
                 965 
                 193 
                 346 
                 98.6 
                 196 
                 70.8 
               
               
                 0.2500 
                 535 
                 142 
                 863 
                 156 
                 303 
                 63.5 
                 197 
                 75.4 
               
               
                 0.3333 
                 455 
                 129 
                 749 
                 131 
                 314 
                 50.1 
                 251 
                 73.3 
               
               
                 0.5000 
                 389 
                 105 
                 580 
                 104 
                 288 
                 45.6 
                 391 
                 65.9 
               
               
                 0.7500 
                 283 
                 95.8 
                 440 
                 99.0 
                 164 
                 56.7 
                 438 
                 59.9 
               
               
                 1.0 
                 251 
                 108 
                 356 
                 98.0 
                 104 
                 57.9 
                 310 
                 48.1 
               
               
                 1.5 
                 175 
                 109 
                 249 
                 81.8 
                 44.1 
                 76.2 
                 130 
                 58.9 
               
               
                 2.0 
                 123 
                 97.0 
                 199 
                 85.7 
                 30.7 
                 79.8 
                 65.8 
                 54.0 
               
               
                 3.0 
                 73.8 
                 90.2 
                 117 
                 79.2 
                 17.7 
                 103 
                 34.4 
                 66.6 
               
               
                 4.0 
                 54.6 
                 140 
                 72.0 
                 94.5 
                 18.1 
                 93.8 
                 37.3 
                 68.7 
               
               
                 6.0 
                 14.5 
                 176 
                 33.3 
                 113 
                 6.10 
                 156 
                 18.3 
                 87.6 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 67 
               
             
            
               
                   
               
               
                 Pharmacokinetic parameters after administration of nasal compositions #37 and #38, 
               
               
                 Epipen ® and intramuscular adrenalin 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Composition #37 
                 Composition #38 
                 Epipen ® IM 
                 Adrenalin IM 
               
               
                   
                 (7.0 mg) 
                 (8.5mg) 
                 (0.3mg) 
                 (0.5mg) 
               
               
                   
               
               
                 N 
                 48 
                 49 
                 49 
                 49 
               
               
                 C max  (pg/mL) 
                 1040 ± 1380 
                 1420 ± 2080 
                 768 ± 585 
                 602 ±326 
               
               
                   
                 (133) [536] 
                 (146) [686] 
                 (76.2) [617] 
                 (54.1) [531] 
               
               
                 t max   b  (h) 
                 0.167 (0.0167-4.0)  
                 0.267 (0.0167-3.0) 
                 0.0833 (0.05-1.0) 
                 0.550 (0.05-1.0) 
               
               
                 AUC last   
                 785 ± 795 
                 1200 ± 1040 
                 357 ± 119 
                 598 ± 229 
               
               
                 (pg · h/mL) 
                 (101) [521] 
                 (86.7) [813] 
                 (33.4) [338] 
                 (38.3) [555] 
               
               
                 AUC 0-inf   
                 960 ± 594 
                 1440 ± 1160 
                 365 ± 118 
                 685 ± 281 
               
               
                 (pg · h/mL) 
                 (61.9) [828] 
                 (80.6) [1030] 
                 (32.3) [346] 
                 (41.0) [627] 
               
               
                 t 1/2  (h) 
                 1.20 ± 0.542 
                 1.51 ± 0.914 
                 0.979 ± 0.586 
                 1.99 ± 1.76 
               
               
                   
                 (45.3) [1.09] 
                 (60.7) [1.31] 
                 (59.9) [0.833] 
                 (88.3) [1.37] 
               
               
                   
               
               
                 Note: 
               
               
                 C max , AUC and t 1/2  values represent Mean ± SD (CV) [GeoMean]  
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 68 
               
             
            
               
                   
               
               
                 Baseline-adjusted Epinephrine Plasma Concentrations and Their Ratios to 
               
               
                 EpiPen ® 0.3 mg IM Injection at Early Times Through 60 Minutes Post-dose 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Compositions #37 
                 Composition #38 
                   
                 Adrenalin ® 0.5 mg 
               
               
                   
                 (7.0 mg) [N = 48]  
                 (8.5 mg) [N = 49] 
                 EpiPen ® 0.3 mg 
                 IM Injection (N = 49) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Time in 
                   
                 Ratio to 
                   
                 Ratio to 
                 IM Injection [N = 49] 
                   
                 Ratio to 
               
               
                 Minutes 
                 Conc* 
                 EpiPen 
                 Conc* 
                 EpiPen 
                 Conc* 
                 Conc* 
                 EpiPen 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 1 
                 176 
                 4.3 
                 217 
                 5.3 
                 41.2 
                 39.6 
                 1.0 
               
               
                   
                 (147) 
                   
                 (188) 
                   
                 (131) 
                 (177) 
                   
               
               
                 3 
                 768 
                 1.7 
                 860 
                 1.9 
                 444 
                 222 
                 0.5 
               
               
                   
                 (178) 
                   
                 (187) 
                   
                 (143) 
                 (158) 
                   
               
               
                 5 
                 663 
                 1.3 
                 1020 
                 2    
                 502 
                 288 
                 0.6 
               
               
                   
                 (167) 
                   
                 (189) 
                   
                 (86.6) 
                 (110) 
                   
               
               
                 7 
                 623 
                 1.5 
                 1000 
                 2.4 
                 416 
                 246 
                 0.6 
               
               
                   
                 (158) 
                   
                 (188) 
                   
                 (78.7) 
                 (87.8) 
                   
               
               
                 10 
                 566 
                 1.6 
                 965 
                 2.8 
                 346 
                 196 
                 0.6 
               
               
                   
                 (157) 
                   
                 (193) 
                   
                 (98.6) 
                 (70.8) 
                   
               
               
                 15 
                 535 
                 1.8 
                 863 
                 2.8 
                 303 
                 197 
                 0.7 
               
               
                   
                 (142) 
                   
                 (156) 
                   
                 (63.5) 
                 (75.4) 
                   
               
               
                 20 
                 455 
                 1.4 
                 749 
                 2.4 
                 314 
                 251 
                 0.8 
               
               
                   
                 (129) 
                   
                 (131) 
                   
                 (50.1) 
                 (73.3) 
                   
               
               
                 30 
                 389 
                 1.4 
                 580 
                 2   
                 288 
                 391 
                 1.4 
               
               
                   
                 (105) 
                   
                 (104) 
                   
                   
                 (65.9) 
                   
               
               
                 45 
                 283 
                 1.7 
                 440 
                 2.7 
                 164 
                 438 
                 2.7 
               
               
                   
                 (95.8) 
                   
                 (99.0) 
                   
                 (56.7) 
                 (59.9) 
                   
               
               
                 60 
                 251 
                 2.4 
                 356 
                 3.4 
                 104 
                 310 
                 3   
               
               
                   
                 (108) 
                   
                 (98.0) 
                   
                 (57.9) 
                 (48.13) 
               
               
                   
               
               
                 *Mean (CV %) plasma concentration in pg/Ml 
               
               
                 Conc = Concentration 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 69 
               
             
            
               
                   
               
               
                 Epinephrine Baseline-Adjusted Partial Areas Under the Plasma Epinephrine 
               
               
                 Concentration Versus Time Curve and Their Ratios to EpiPen 0.3 mg IM Injection at Early 
               
               
                 Times Through 60 Minutes Post-dose 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Compositions #37 
                 Composition #38 
                 EpiPen ® 0.3 mg 
                 Adrenalin ® 0.5 mg 
               
               
                   
                 (7.0 mg) [N = 48] 
                 (8.5 mg) [N = 49] 
                 IM Injection  
                 IM Injection (N = 49) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                 Ratio to 
                   
                 Ratio to 
                 [N = 49] 
                   
                 Ratio to 
               
               
                   
                 AUC* 
                 EpiPen 
                 AUC* 
                 EpiPen 
                 AUC* 
                 AUC* 
                 EpiPen 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 AUC 0-0017   
                 1.50 
                 4.2 
                 1.80 
                 5   
                 0.358 
                 0.324 
                 0.9 
               
               
                   
                 (150) 
                   
                 (195) 
                   
                 (130) 
                 (180) 
                   
               
               
                 AUC 0-0.05   
                 16.8 
                 2   
                 19.1 
                 2.3 
                 8.44 
                 4.54 
                 0.5 
               
               
                   
                 (153) 
                   
                 (182) 
                   
                 (131) 
                 (141) 
                   
               
               
                 AUC 0-0.083   
                 39.8 
                 1.7 
                 49.8 
                 2.1 
                 23.9 
                 12.8 
                 0.5 
               
               
                   
                 (163) 
                   
                 (180) 
                   
                 (112) 
                 (129) 
                   
               
               
                 AUC 0-0.117   
                 61.1 
                 1.6 
                 83.9 
                 2.1 
                 39.3 
                 21.8 
                 0.6 
               
               
                   
                 (161.0) 
                   
                 (179) 
                   
                 (94.1) 
                 (113) 
                   
               
               
                 AUC 0-0.167   
                 90.4 
                 1.6 
                 133 
                 2.3 
                 58.1 
                 32.7 
                 0.6 
               
               
                   
                 (156) 
                   
                 (180) 
                   
                 (82) 
                 (98.6) 
                   
               
               
                 AUC 0-0.25   
                 136 
                 1.6 
                 208 
                 2.5 
                 84.7 
                 48.8 
                 0.6 
               
               
                   
                 (148) 
                   
                 (176.0) 
                   
                 (72.3) 
                 (85.6) 
                   
               
               
                 AUC 0-0.33   
                 175 
                 1.6 
                 272 
                 2.5 
                 109 
                 66.4 
                 0.6 
               
               
                   
                 (143) 
                   
                 (167) 
                   
                 (64) 
                 (77.4) 
                   
               
               
                 AUC 0-0.5   
                 246 
                 1.5 
                 386 
                 2.4 
                 160 
                 120 
                 0.8 
               
               
                   
                 (132.0) 
                   
                 (147) 
                   
                 (51.0) 
                 (65.6) 
                   
               
               
                 AUC 0-0.75   
                 329 
                 1.5 
                 513 
                 2.4 
                 214 
                 223 
                 1   
               
               
                   
                 (120) 
                   
                 (129) 
                   
                 (42.2) 
                 (57.6) 
                   
               
               
                 AUC 0-1   
                 395 
                 1.6 
                 611 
                 2.5 
                 247 
                 315 
                 1.3 
               
               
                   
                 (112) 
                   
                 (120) 
                   
                 (38.7) 
                 (50.5) 
               
               
                   
               
               
                 *Mean (CV %) area under the curve (AUC) between time 0 and t, h*pg/mL 
               
            
           
         
       
     
     As can be seen in Table 66, intranasal administration of compositions #37 and #38 resulted in higher plasma concentrations 5 minutes (0.0833 hours) after administration than either Epipen® or intramuscular adrenalin. In fact, the 8.5 mg dose of composition #38 resulted in more than twice the plasma concentration of either Epipen® or intramuscular adrenalin. Plasma concentrations of epinephrine remained higher in subjects administered compositions #37 or #38 than Epipen® or intramuscular adrenalin for 6 hours following administration. 
     As can be seen in Table 67, intranasal administration of compositions #37 and #38 resulted in higher C max , AUC last  and AUC 0-inf  than either Epipen® or intramuscular adrenalin. In fact, administration of compositions #37 and #38 resulted in 1.4 and 1.8 times greater C max  than Epipen®. 
     As seen in Table 68, intranasal administration of compositions #37 and #38 resulted in much higher ratios of epinephrine plasma concentrations compared to EpiPen® than did Adrenalin® IM injections. In fact, administration of compositions #37 and #38 resulted in 4.3- and 5.3-times higher epinephrine plasma concentration after 1 minute compared to EpiPen®. 
     As seen in Table 69, intranasal administration of compositions #37 and #38 resulted in much higher ratios of epinephrine AUC compared to EpiPen® than did Adrenalin® IM injections. In fact, administration of compositions #37 and #38 resulted in 4.2- and 5-times higher epinephrine AUC after 1 minute compared to EpiPen®.