CA3060078C - Epinephrine spray formulations - Google Patents

Abstract

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.

Description

EPINEPHRINE SPRAY FORMULATIONS FIELD OF THE INVENTION

[0001] 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

[0002] Epinephrine (i.e. adrenaline) is a catecholamine with the following chemical structure:

[0003] Epinephrine stimulates the alpha- and beta- adrenergic receptors of the sympathetic nervous system. Epinephrine binds to these adrenergic receptors leading to relief of many lifethreatening 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.

[0004] 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 Land D-isomers.

[0005] U.S. Patent 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 Al is directed to epinephrine nanoparticles, which can be incorporated into sublingual tablets. U.S. Patent Application Publication No. 2007/0202163 Al 1CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 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 Al is directed to a stable aqueous epinephrine formulation that requires cyclodextrin. W.I.P.O. Publication No. 2014/057365 Al is directed to an injectable epinephrine formulation.

[0006] 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

[0007] 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 and ethanol or water, preferably the water is at a concentration from about 15% to about 65% w/w; 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.

[0008] In another aspect, the present invention is directed to epinephrine spray formulations, wherein the formulation is free of a propellant.

[0009] In another aspect, the solvent of the present invention comprises from about 1 % w/w to about 30% w/w glycerin.

[0010] In another aspect, the epinephrine spray formulations of the present invention further comprise a permeation enhancer selected from the group consisting of caprylic acid, 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, sodium desoxycholate, sodium deoxyglycolate, sodium glycocholate, sodium caprate, 2CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 sodium taurocholate, sodium hydroxybenzoyal amino caprylate, dodecyl dimethyl aminopropionate, L-lysine, glycerol oleate, glyceryl monostearate, citric acid, peppermint oil and a combination thereof, preferably a combination of edetate disodium dihydrate and BKC, preferably the edetate disodium dihydrate is from about 0.005% to about 0.05% w/w and the benzalkonium chloride is at a concentration from about 0.005% to about 0.5% w/w.

[0011] In another aspect, permeation enhancer comprises 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.

[0012] In another aspect, the epinephrine spray formulations of the present invention contain no permeation enhancer

[0013] In another aspect, the epinephrine spray formulations of the present invention further comprise an isotonicity agent comprising sodium chloride.

[0014] 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, 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.

[0015] 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.

[0016] 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; 3CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 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 0.001 % to about 0.5 % w/w sodium bisulfite; from about 0.005 % to about 1 % w/w edetate disodium dihydrate; and from about 0.001% to about 0.5% w/w benzalkonium chloride.

[0017] 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 0.5 % w/w sodium bisulfite; from about 0.005 % to about 1 % w/w edetate disodium dihydrate; from about 0.001% to about 0.5% w/w benzalkonium chloride; and from about 0.1% to about 1% w/w sodium chloride.

[0018] In another aspect, the present invention is directed to an epinephrine spray formulation comprising: about 3.2 % w/w epinephrine, or a salt thereof; about 35.5 % w/w hydrochloric acid with a normality of 0.5; about 40 % w/w ethanol; about 16.1% w/w water; about 0.05 % w/w edetate disodium dihydrate; about 0.15% w/w sodium bisulfite; about 0.01 % w/w benzalkonium chloride; wherein % w/w denotes weight by total weight of the formulation.

[0019] In another aspect, the present invention is directed to an epinephrine spray formulation comprising: about 3.0 % w/w epinephrine, or a salt thereof; about 32.9 % w/w hydrochloric acid with a normality of 0.5; 4CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 about 63.3 % w/w water; about 0.05 % w/w edetate disodium dihydrate; about 0.15 % w/w sodium bisulfite; about 0.01 % w/w benzalkonium chloride; and about 0.6% w/w sodium chloride.

[0020] 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. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0021] Applicants discovered epinephrine spray formulations that have improved bioavailability, a more rapid onset of action, and improved storage stability.

[0022] As used herein, “epinephrine” refers to the base.

[0023] As used herein, “free of propellant” refers to a formulation that is not administered using compressed gas.

[0024] 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.

[0025] As used herein “% w/w” and “percent w/w” refer to the percent weight of the total formulation.

[0026] As used herein the term “effective amount” refers to the amount necessary to treat a patient in need thereof.

[0027] As used herein the term “treat”, “treating” or “treatment” refers to ameliorating or inhibiting symptoms of type I allergies including anaphylaxis.

[0028] As used herein the term “subject” refers, but is not limited to, a person that is experiencing type I allergies including anaphylaxis.

[0029] 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. 5CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889

[0030] 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.

[0031] As used herein the term “pharmaceutically acceptable” refers to ingredients that are not biologically or otherwise undesirable for administration to a living subject. [0032] “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. [0033] ‘‘Intranasal” refers to administration of the composition to any portion of the nasal epithelium.

[0034] In one embodiment, the present invention is directed to epinephrine spray formulations comprising epinephrine, or a salt thereof.

[0035] Preferred epinephrine salts include citrate, hydrochloride, halide, sulfate, 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 8 % w/w, from about 0.1 % to about 6.5 % w/w. In a most preferred embodiment, the epinephrine concentration is 3% and 6% w/w.

[0036] 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.

[0037] 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.

[0038] 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 6CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 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 0. IN to 12N hydrochloric acid and most preferably 0.5N-3N hydrochloric acid, even most preferably 0.5 N or 1 N.

[0039] 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.

[0040] 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.

[0041] 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, 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 7CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 bisulfite or sodium metabisulfite combination thereof as the anti-oxidants at a concentration from about from about 0.1% to 0.5% 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 % w/w.

[0042] 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.

[0043] Permeation enhancers suitable for use in the present invention include, but are not limited to, caprylic acid, oleic acid, polysorbate 80, menthol, edetate disodium dihydrate, benzalkonium chloride, EDTA, sodium 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] In a preferred embodiment, the formulations of the present invention are at a pH from about 2.0 to about 5.0. 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 8CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 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.

[0048] 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.

[0049] 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.

[0050] 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 0.001 % to about 0.5 % w/w sodium bisulfite; from about 0.005 % to about 1 % w/w edetate disodium dihydrate; and from about 0.001% to about 0.5% w/w benzalkonium chloride.

[0051] 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 0.5 % w/w sodium bisulfite; from about 0.005 % to about 1 % w/w edetate disodium dihydrate; from about 0.001% to about 0.5% w/w benzalkonium chloride; and 9CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 from about 0.1% to about 1% w/w sodium chloride.

[0052] 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 of 0.5; 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 0.3 % w/w sodium bisulfite; about 0.05% w/w 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.

[0053] 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.

[0054] 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; 10CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 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.

[0055] 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

[0056] In another preferred embodiment, the present invention is directed to epinephrine spray formulations comprising: about 2.962 % w/w epinephrine, or a salt thereof; about 32.93 % w/w hydrochloric acid with a normality of 0.5; about 63.298 % w/w water; about 0.05% w/w edetate disodium dihydrate; about 0.15 % w/w sodium bisulfite; about 0.01% w/w benzalkonium chloride; and about 0.6% sodium chloride.

[0057] In another preferred embodiment, the present invention is directed to epinephrine spray formulations comprising: about 3.178 % w/w epinephrine, or a salt thereof; about 35.471 % w/w hydrochloric acid with a normality of 0.5; about 16.141 % w/w water; about 40 % ethanol; about 0.05% w/w edetate disodium dihydrate; about 0.15 % w/w sodium bisulfite; and about 0.01% w/w benzalkonium chloride. 11CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889

[0058] 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.

[0059] 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.

[0060] 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.

[0061] In another embodiment, the formulations of the present invention are capable of producing a spray span ((Dv90-Dvl0)/Dv50) at 3 cm of from about 3 to about 7.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] In another embodiment, the formulations of the present invention are capable of producing a spray span ((Dv90-Dvl0)/Dv50) at 6 cm of from about 1 to about 6.

[0066] 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.

[0067] 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.

[0068] 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. 12CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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°.

[0073] 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.

[0074] 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°.

[0075] 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.

[0076] 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.

[0077] 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

[0078] 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 (“HC1”), malic acid, ethanol and propylene glycol, EDTA, sodium chloride, sodium bisulfite, sodium metabisulfite, and 8-hydroxyquinoline were dissolved in water while stirring at room temperature. Epinephrine base was then added to the excipient 13CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 solution. Finally, sodium hydroxide (“NaOH”)/ hydrochloric acid (HC1)) 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 HC1 (0.5 N) 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

[0079] 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 280nm 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. 14CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 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 cone.) 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 0.01 0.03 3.26 ND 0.01 0.02 % Total Impurities 0.20 1.26 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 cone.) 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 0.01 % Methoxy 1.88 0.07 0.07 0.07 % Unknown Impurity 0.21 ND 0.10 0.11 0.23 ND ND 0.01 3.26 ND ND ND % Total Impurities 0.21 1.44 2.11 Table 4. Stability Data for Epinephrine Spray Formulation #3 stored at 40°C ± 2°C/ 75 % ± 5 % Relative Humidity 15CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 40 °C Formulation #3 RRT 0 Week 2 Weeks 4 Weeks 8 Weeks 3 Months Appearance Clear Clear Clear Clear Clear Assay (% of initial cone.) 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 0.01 0.01 0.03 % 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 0.02 0.02 0.04 3.26 ND ND 0.02 0.02 0.04 % Total Impurities 0.20 1.42 2.38 3.25 3.60 Table 5. Stability Data for Epinephrine Spray Formulation #4 stored at 40°C ± 2°C/ 75 % ± 5 % Relative Humidity Table 6. Stability Data for Epinephrine Spray Formulation #5 stored at 40°C ± 2°C/ 75 % ± 5 % Relative Humidity 40 °C Formulation #4 RRT 0 Week 1 Week 2 Weeks 4 Weeks 6 Weeks 8 Weeks 3 Months 4 Months Appearance Clear Clear Clear Clear Clear Clear Clear Clear Assay (% of initial cone.) 100.0 100.7 98.54 98.35 96.02 94.44 92.60 89.34 % Racemization 0.60 0.68 - - 3.41 3.46 5.75 9.20 % 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 % Epinephrone 1.36 ND ND ND 0.01 0.01 0.02 0.01 0.02 % Methoxy 1.88 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.09 % Unknown Impurity 0.21 ND ND 0.05 0.08 0.07 0.09 0.22 0.23 3.11 ND ND ND 0.02 0.02 0.02 0.02 0.05 3.26 ND ND ND 0.02 0.02 0.02 0.02 0.03 % Total Impurities 0.23 0.86 1.42 2.54 3.36 4.06 4.71 5.07 40 °C Formulation #5 RRT 0 Week 2 Weeks 4 Weeks 8 Weeks 3 Months Appearance Clear Clear Clear Clear Clear Assay (% of initial cone.) 100.00 98.36 96.88 95.35 93.34 16CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 Table 7. Stability Data for Epinephrine Spray Formulation #6 stored at 40°C ± 2°C/ 75 % ± 5 % Relative Humidity % 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 0.01 0.01 0.03 % Methoxy 1.88 0.07 0.07 0.07 0.07 0.07 % Unknown Impurity 0.21 ND 0.10 0.11 0.15 0.35 0.88 ND ND ND ND 0.02 3.11 ND ND 0.02 0.02 0.01 3.26 ND ND 0.01 0.02 0.01 % Total Impurities 0.22 1.65 2.72 3.77 4.24 40 °C Formulation #6 RRT OWeek 2 Weeks 1 Month Appearance Clear Clear Clear Assay (% of initial cone.) 0.19 100.00 97.75 95.95 % Impurity F 0.15 2.38 4.04 % Synephrine 1.26 ND ND ND % Epinephrone 1.36 ND 0.01 0.01 % Methoxy 1.88 0.04 0.04 0.04 % Unknown Impurity 0.21 ND 0.05 0.08 % Total Impurities 0.23 2.55 4.25 Table 8. Stability Data for Epinephrine Spray Formulation #7 stored at 40°C ± 2°C/ 75 % ± 5 % Relative Humidity 40 °C Formulation #7 RRT OWeek 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 17CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 40 °C Formulation #8 RRT OWeek 2 Weeks Appearance Clear Light Brown Assay (% of initial cone.) 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 % Unknown Impurity 0.21 ND 0.12 0.26 ND 0.03 0.88 ND 0.03 3.11 ND 0.02 3.26 ND 0.02 % Total Impurities 0.27 4.68 Table 10. Stability Data for Epinephrine Spray Formulation #9 stored at 40°C ± 2°C/ 75 % ± 5 % Relative Humidity 40 °C Formulation #9 RRT OWeek 1 Week 4 Weeks Appearance Clear Clear Clear Assay (% of initial cone.) 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 % Unknown Impurity 0.21 ND ND 0.06 3.11 ND 0.04 0.09 3.26 ND 0.04 0.08 % Total Impurities 0.22 1.00 2.17 Table 11. Stability Data for Epinephrine Spray Formulation #10 stored at 40°C ± 2°C/ 75 % ± 5 % Relative Humidity 40 °C Formulation #10 RRT OWeek 1 Week Appearance Clear Clear Assay (% of initial cone.) 100.00 100.76 % Racemization 0.60 0.68 % Impurity F 0.19 0.12 2.89 18CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 % Synephrine 1.26 ND ND % Epinephrone 1.36 ND ND % Methoxy 1.88 0.07 0.07 % Unknown Impurity 0.21 ND 0.02 3.11 ND 0.04 3.26 ND 0.04 % Total Impurities 0.22 3.74 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 cone.) 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 0.03 3.11 ND 0.04 3.26 ND 0.04 % Total Impurities 0.22 1.00 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 cone.) 100.00 97.91 97.32 % 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 0.04 3.26 ND ND 0.03 % Total Impurities 0.20 0.65 1.37 19CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 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 cone.) 100.00 97.56 96.88 % 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 0.02 3.26 ND ND 0.03 % Total Impurities 0.21 0.70 1.55 Table 15. Stability Data for Epinephrine Spray Formulation #3 stored at 25°C ± 2°C/ 60 % ± 5 % Relative Humidity 25 °C Formulation #3 RRT OWeek 1 Month 3 Months Appearance Clear Clear Clear Assay (% of initial cone.) 100.00 99.32 98.16 % 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 0.03 0.09 3.11 ND ND 0.02 3.26 ND ND 0.03 % Total Impurities 0.20 0.62 1.50 Table 16. Stability Data for Epinephrine Spray Formulation #4 stored at 25°C ± 2°C/ 60 % ± 5 % Relative Humidity 25 °C Formulation #4 RRT OWeek 3 Weeks 4 Weeks 8 Weeks 3 Months 6 Months Appearance Clear Clear Clear Clear Clear Clear 20CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 Assay (% of initial cone.) 100.00 100.76 99.79 99.31 99.09 98.69 % 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 0.01 0.01 % 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 1.66 2.92 Table 17. Stability Data for Epinephrine Spray Formulation #5 stored at 25°C ± 2°C/ 60 % ± 5 % Relative Humidity 25 °C Formulation #5 RRT OWeek 1 Month 3 Months Appearance Clear Clear Clear Assay (% of initial cone.) 100.00 98.40 97.29 % 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 0.01 3.26 ND ND 0.01 % Total Impurities 0.22 0.79 1.68 Table 18. Stability Data for Epinephrine Spray Formulation #6 stored at 25°C ± 2°C/ 60 % ± 5 % Relative Humidity 25 °C Formulation #6 RRT OWeek 2 Weeks 1 Month 6 Months Appearance Clear Clear Clear Clear Assay (% of initial cone.) 100.00 100.25 99.75 94.80 % Impurity F 0.19 0.15 0.45 0.76 2.93 % Synephrine 1.26 ND ND ND ND % Epinephrone 1.36 ND 0.01 0.02 0.04 21CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 % Methoxy 1.88 0.04 0.04 0.04 0.04 % Unknown Impurity 0.21 ND ND 0.04 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 0.18 0.53 0.89 4.10 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 cone.) 100.00 99.21 % 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 0.02 3.26 ND 0.02 % Total Impurities 0.29 0.81 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 cone.) 100.00 99.64 98.88 % 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 0.03 0.09 3.26 ND 0.02 0.08 22CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 | % Total Impurities | | 0-23 | 0,70 | 2,02 |

[0080] Formulations #l-#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.

[0081] 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

[0082] 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

[0083] 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.

[0084] Droplet analysis was conducted using standard laser analysis procedures known by those of skill in the art. Droplet size distribution (Dvio, Dvso, Dvgo, and Span) was tested at two distances, 3 cm and 6 cm. Dvio refers to the droplet size at which 10% of the volume is smaller; Dv5o refers to the median droplet size; Dvgo refers to droplet size for which 90 % of the total volume is smaller; Span refers to distribution span (Dv90-Dvl0)/Dv50. % < 10pm refers to the percentage of the total volume that is made up of droplets less than 10 pm in diameter. 23CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889

[0085] 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.

[0086] 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 DVio (pm) DVso(pm) DV90 (pm) % < 10pm 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 DV10 (pm) DV5o(pm) DV90 (pm) % < 10pm 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 Spray Pattern 3 cm Dmin (mm) Dmax (mm) Ovality 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 Spray Pattern 6 cm Dmin (mm) Dmax (mm) Ovality ratio Min 26.5 47 1.68 24CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 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 Plume Geometry 3 cm Angle (°) Width (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 Plume Geometry 6 cm Angle (°) Width (mm) Min 37.7 37.7 Max 43.5 43.5 Mean 40.7 40.7

[0087] 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.

[0088] 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 hydrochloric acid (“HC1”), ethanol, propylene glycol, EDTA, sodium bisulfite, 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 (“HO”) 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 (0.5 N) 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 25CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 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 2NaOH/0.5N HC1 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 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 acid (0.5 N) 33.80 33.80 33.80 33.80 33.80 33.80 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 chloride 0.01 0.01 0.01 0.01 0.01 0.01 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 with 2 NaOH/0.5N HC1 4.5 4.5 4.5 4.5 4.5 4.5

[0089] 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 280nm and expressed as a % area. Amounts of particular impurities are listed in Tables 29 to 40 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. 26CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 Table 29. Stability Data for Epinephrine Spray Formulations # 12 to # 16 stored at 25°C ± 2°C/ 60 % ± 5 % Relative Humidity Sta nlity @18M 25°C/ 60%RH RRT 0 Week F# 12 18 months F# 13 18 Months F# 14 18 Months F# 15 18 months F# 16 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 0.01 0.02 0.01 0.01 0.01 %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 0.03 0.03 ND 0.07 0.26 ND ND ND ND ND ND 0.64 ND ND ND ND ND 0.04 0.88 ND 0.03 0.03 0.04 0.02 0.01 1.21 ND 0.09 0.09 0.08 0.04 0.06 1.34 ND 0.02 0.05 0.03 0.04 0.03 1.50 ND ND ND 0.07 0.04 0.03 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 0.03 ND ND 2.91 ND ND 0.04 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 0.03 0.03 0.03 0.02 3.26 ND ND 0.04 ND ND ND Total Impurities 0.19 2.68 3.20 3.87 4.00 5.32 Table 30. 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 27CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 % Impurity F 0.19 0.50 0.72 % Epinephrone 1.36 ND ND % Methoxy 1.90 0.07 0.07 % Unknown Impurities 1.08 0.14 0.08 % Total Impurities 0.71 0.87 Table 31. 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 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 32. Stability Data for Epinephrine Spray Formulations #19 stored at 25°C ± 2°C/ 60 % ± 5 % Relative Humidity RRT 0 Week 1 Month 3 Months Assay - 101.32 99.22 100.49 Appearance - Clear Clear Clear % Impurity F 0.19 0.16 0.47 1.03 % Epinephrone 1.34 ND 0.01 0.01 % Methoxy 1.77 0.07 0.06 0.06 % Unknown Impurities 0.21 ND ND 0.06 0.71 ND 0.02 0.01 0.88 ND 0.01 0.01 1.23 ND ND 0.02 1.42 ND ND 0.01 1.53 ND 0.01 ND 1.60 ND ND 0.01 28CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 1.64 ND ND 0.01 1.86 ND 0.01 ND 2.55 ND 0.02 0.02 2.56 ND 0.02 ND 2.86 ND 0.02 0.01 2.93 ND 0.01 0.02 3.05 0.01 0.03 ND 3.22 0.01 0.03 0.03 3.44 0.01 0.03 0.02 Total impurities (%) 0.26 0.75 1.33 Table 33. Stability Data for Epinephrine Spray Formulations # 20 stored at 25°C ± 2°C/ 60 % ± 5 % Relative Humidity RRT OWeek 1 Month 3 Months Assay (% LC) - 103.9307 102.23 99.07 Appearance Clear Clear Clear % Impurity F 0.19 0.16 0.53 1.25 % Epinephrone 1.35 ND 0.01 0.01 % Methoxy 1.78 0.06 0.06 0.06 % Unknown Impurities 0.21 ND ND 0.05 0.70 ND 0.03 0.02 0.83 ND 0.01 0.01 0.88 0.01 0.01 0.01 1.38 ND ND 0.01 1.51 0.04 ND ND 1.55 ND 0.01 0.01 2.55 ND 0.01 ND 2.56 ND 0.01 0.01 2.61 ND 0.02 ND 2.75 ND ND 0.01 2.80 ND ND 0.02 2.87 ND 0.02 ND 2.96 ND 0.01 ND 3.09 0.02 0.02 ND 3.22 ND ND 0.01 3.45 ND ND 0.02 Total impurities (%) 0.22 0.75 1.50 29CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 Table 34. Stability Data for Epinephrine Spray Formulations # 12 to 16 stored at 40 °C ± 2°C/ 75 % ± 5 % Relative Humidity Epinephrine F# 12 F# 13 F# 14 F# 15 F# 16 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 0.01 0.01 0.01 0.02 0.02 % Methoxy 1.90 0.07 0.06 0.06 0.06 0.06 0.06 % Unknown Impurities 0.22 0.01 0.16 0.16 0.15 0.14 0.12 0.25 ND 0.06 0.06 0.05 0.05 0.05 0.26 ND ND 0.01 0.01 0.01 0.01 0.88 ND ND 0.01 0.01 0.02 0.01 1.21 ND 0.06 0.06 0.05 0.04 0.03 1.34 ND 0.02 0.02 0.02 0.02 0.01 1.55 ND 0.03 0.03 0.02 0.02 0.02 2.57 ND 0.18 0.11 0.1 0.08 0.07 3.11 ND 0.03 0.02 0.01 0.01 0.01 3.26 ND 0.02 0.01 0.01 0.02 ND % Total Impurities 0.19 3.85 6.20 7.92 10.19 11.71 Table 35. 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 appearance Clear Clear Clear Clear % 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 30CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 2.53 BQL BQL 0.05 0.15 2.58 ND ND BQL 0.06 3.04 ND ND BQL 0.06 % Total Impurities 1.17 2.25 3.49 5.81 Table 36. 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 0.01 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 2.7 4.49 Table 37. Stability Data for Epinephrine Spray Formulations #19 stored at 40 °C ± 2°C/ 75 % ± 5 % Relative Humidity RRT 0 Week 1 Months 2 Months 3 Months 4 Months Assay 101.32 101.11 97.06 95.85 96.08 Appearance Clear Clear Clear Clear, Light Yellow Clear, Light Yellow % Impurity F 0.19 0.16 1.92 4.25 6.42 7.20 % Epinephrone 1.34 ND 0.01 0.01 0.01 0.01 % Methoxy 1.77 0.07 0.06 0.06 0.06 0.06 % Unknown Impurities 0.21 ND 0.09 0.19 0.11 0.3 0.26 ND ND 0.14 0.21 0.31 0.52 ND ND ND ND 0.03 0.64 ND ND ND ND 0.02 0.71 ND ND ND 0.01 ND 0.84 ND ND ND ND 0.01 0.88 ND 0.01 ND ND 0.01 31CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 1.17 ND 0.06 0.07 0.05 0.09 1.28 ND 0.02 0.04 0.02 0.02 1.38 ND 0.02 0.04 0.02 0.02 1.55 ND ND ND 0.02 ND 1.68 ND ND ND 0.01 0.02 1.83 ND ND ND 0.01 ND 1.99 ND ND ND ND 0.01 2.07 ND ND ND ND 0.01 2.38 ND 0.04 ND ND ND 2.57 ND 0.01 ND ND ND 2.60 ND 0.02 0.05 0.1 0.19 2.80 ND ND ND 0.02 ND 2.86 ND 0.02 ND ND ND 2.98 ND 0.01 ND ND ND 3.05 0.01 ND ND ND ND 3.13 ND 0.03 ND ND ND 3.22 ND ND ND 0.03 ND 3.26 ND 0.03 ND 0.03 ND 3.33 ND ND ND ND 0.07 3.38 ND ND ND ND 0.02 3.44 ND ND ND 0.02 0.14 3.68 ND ND ND 0.02 0.03 Total impurities (%) 0.24 2.33 4.85 7.15 8.57 Table 38 Stability Data for Epinephrine Spray Formulations # 20 stored at 40 °C ± 2°C/ 75 % ± 5 % Relative Humidity RRT 0 Week 1 Month 2 Months 3 Months 4 Months Assay - 103.93 99.44 96.16 96.35 96.38 Appearance Clear Clear Clear Clear Clear % Impurity F 0.19 0.16 2.61 5.66 7.69 6.30 % Epinephrone 1.35 ND 0.01 0.01 0.01 0.01 % Methoxy 1.78 0.06 0.07 0.06 0.06 0.06 Unknown Impurities 0.21 ND 0.08 0.10 0.09 0.29 0.26 ND ND 0.06 0.12 0.17 0.70 ND 0.02 0.02 0.02 0.02 0.88 0.01 0.01 ND 0.01 0.01 1.18 ND 0.03 0.04 0.03 0.11 1.34 ND ND ND ND 0.04 1.36 ND ND ND 0.02 0.03 1.49 ND 0.01 ND ND ND 1.42 ND ND ND 0.02 ND 1.51 0.04 ND ND ND ND 1.55 ND 0.01 0.02 0.02 ND 32CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 1.58 ND ND ND ND 0.09 1.64 ND ND ND 0.01 ND 1.89 ND ND ND 0.01 ND 2.07 ND ND ND ND 0.02 2.39 ND 0.02 ND ND 0.01 2.56 ND 0.01 ND ND ND 2.61 ND 0.02 0.04 0.07 ND 2.71 ND ND ND ND 0.39 2.78 ND ND ND ND 0.20 2.87 ND 0.01 ND 0.02 0.01 2.96 ND 0.02 ND ND ND 3.09 0.02 0.01 ND ND ND 3.14 ND 0.02 ND ND ND 3.22 ND ND ND 0.14 0.16 3.36 ND ND ND 0.03 ND 3.48 ND ND ND ND 0.22 3.55 ND ND ND 0.02 0.02 3.60 ND ND 0.05 ND ND Total impurities (%) 0.22 2.96 6.06 8.39 8.16 Table 39. Stability Data for Epinephrine Spray Formulations # 21 stored at 40 °C ± 2°C/ 75 % ± 5 % Relative Humidity OWeek 1Month 2Month Assay 98.20 94.84 94.14 Appearance Clear Clear Clear % Impurity F 0.19 0.16 4.43 7.96 % Epinephrone 1.34 ND 0.01 0.01 % Methoxy 1.77 0.06 0.06 0.06 % Unknown Impurities 0.21 ND 0.06 ND 0.71 ND 0.03 ND 0.81 ND 0.01 ND 1.08 ND ND 0.09 1.17 ND ND ND 1.38 ND 0.01 ND 1.60 ND 0.01 ND 2.15 ND 0.01 ND 2.76 ND 0.01 ND 2.81 ND 0.01 ND 2.91 0.02 ND ND 3.13 ND ND 0.03 3.22 ND 0.04 ND 3.44 0.02 0.02 ND 33CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 | Total impurities (%) | | 0.26 | 4,71 | 8,15 | Table 40. Stability Data for Epinephrine Spray Formulations # 21 stored at 25°C ± 2°C/ 60 % ± 5 % Relative Humidity RRT 0 Week 1 Month 2 Months Assay 98.20 101.02 99.07 Appearance Clear Clear Clear % Impurity F 0.19 0.16 0.72 1.38 % Epinephrone 1.34 ND 0.01 0.01 % Methoxy 1.77 0.06 0.06 0.06 % Unknown Impurities 0.21 ND 0.03 0.04 0.71 ND 0.04 0.03 0.81 ND 0.03 0.02 1.38 ND ND 0.01 1.60 ND 0.01 ND 1.68 ND ND ND 1.83 ND ND ND 2.15 ND 0.02 ND 2.38 ND ND ND 2.76 ND 0.01 ND 2.81 ND 0.02 ND 2.86 ND ND ND 2.91 0.02 ND ND 3.22 3.44 ND 0.01 ND 0.02 0.02 ND Total impurities (%) 0.26 0.98 1.55 All formulas exemplified in Tables 27 and 28 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 26) 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 2M/40°C. However similar formulation 19, pouched, exhibited impurity F levels at 4.25% at 2M/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. 34CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 Example 6, Mini-pig pharmacokinetic data for epinephrine formulations

[0090] 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’ 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’ post dose. Minipig plasma samples were measured for epinephrine concentrations via liquid chromatography¬ tandem mass spectrometry.

[0091] The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmax), time to reach Cmax (Tmax), and area under the concentration-time curve from time¬ zero to 24 hours postdose (AUCo-24h).

[0092] 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 AUCo-24h of 161.0 ng*min/L. Table 41. 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 35CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 Total 100 Components: %w/w Table 42. 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 Tmax (min) 90 5 Cmax (ng/mL) 0.25 1.01 AUCo-24h (ng*min/mL) 173.7 161.0 Plasma concentration: geometric mean Tmax: median value Cmax and AUCo-24h: geometric mean Example 7, Rabbit pharmacokinetic data for epinephrine formulations

[0093] 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’ 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’ post dose. Rabbit plasma samples were measured for epinephrine concentrations via liquid chromatography-tandem mass spectrometry.

[0094] 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. 36CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889

[0095] The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmax), time to reach Cmax (Tmax), and area under the concentration-time curve from time¬ zero to 24 hours postdose (AUCo-24h).

[0096] 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 AUCo-24h of 1050.1 ng*min/L. Table 43. Epinephrine Formulations for Rabbit Dosing Formulation #R1 #R2 #R3 #R4 #R5 Epinephrine base 0 0.006 3.025 3.243 3.243 Dilute Hydrochloric Acid 0.5 N 0.3 0.5 33.27 36.2 36.2 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 (EDTA) 0.05 0.05 0.05 0.05 Water USP 98.45 98.584 62.455 13.707 13.707 Total 100 100 100 100 100 Components: %w/w Table 44. 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 37CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 Components: %w/w Table 45. Plasma concentrations for epinephrine after administration to rabbits under fasted conditions. 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 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 @ 5 min (ng/mL) 0.020 0.99 0.28 0.19 0.11 Concentration @10 min (ng/mL) 0.011 0.83 0.24 0.32 0.35 Concentration @15 min (ng/mL) 0.014 0.79 0.49 0.55 0.86 Concentration @30 min (ng/mL) 0.012 0.73 0.44 1.24 1.94 Tmax (min) 300 15 240 90 90 Cmax (ng/mL) 0.05 1.1 1.3 2.9 6.3 AUCo-24h (ng*min/mL) 6.7 96.7 217.0 537.1 956.8 Plasma concentration: mean Tmax: median value Cmax and AUCo-24h: geometric mean 38CA 03060078 2019-10-15 WO 2018/195029 PCT/US2018/027889 IM denotes intramuscular, SL denotes sublingual Table 46. 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 Tmax (min) 120 120 180 65 Cmax (ng/mL) 3.1 6.0 14.3 7.0 AUCo-24h (ng*min/mL) 482.2 867.0 2145.1 1050.1 Plasma concentration: mean Tmax: median value Cmax and AUCo-24h: geometric mean

Claims (5)

1. 40 Claims 1. An epinephrine spray formulation for intranasal administration comprising: from about 0.1% w/w to about 15% w/w epinephrine or a salt thereof; 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; from about 0.1% w/w to about 60% w/w of at least one acid, wherein w/w denotes weight by weight of the formulation.
2. 2. The formulation of claim 1 wherein the epinephrine is a salt selected from the group consisting of citrate, hydrochloride, halide, sulfate, phosphate, acetate, maleate, succinate, ascorbate, carbonate, mesylate and lactate.
3. 3. The formulation of claim 1, wherein the solvent is a combination of water and ethanol.
4. 4. The formulation of claim 1, wherein the solvent is water. 5. The formulation of claim 1, wherein the at least one acid is diluted hydrochloric acid. 6. The formulation of claim 1, wherein the formulation does not contain a permeation enhancer. 7. The formulation of claim 1, further comprising a permeation enhancer selected from the group consisting of caprylic acid, 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, 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. 8. The formulation of claim 7, wherein the permeation enhancer is a combination of edetate disodium dihydrate and benzalkonium chloride. 9. The formulation of claim 1, further comprising an isotonicity agent comprising sodium chloride. 10. The formulation of claim 1, further comprising a stabilizer selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, CA 3060078 Date reçue / Received date 2025-06-0341 methionine, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, ascorbyl palmitate, thioglycerol, alpha tocopherol (vitamin E), cysteine hydrochloride, benzalkonium chloride, citric acid, ethylenediaminetetraacetic acid (EDTA), sodium citrate, propyl gallate, 8-hydroxyquinoline, boric acid, histidine and combinations thereof. 11. An epinephrine spray formulation for intranasal administration 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 about 12N; from about 2 % to about 60 % w/w ethanol; from about 2% to about 65 % w/w water; from about 0.001 % to about 0.5 % w/w sodium bisulfite; from about 0.005 % to about 1 % w/w edetate disodium dihydrate; from about 0.001% to about 0.5% w/w benzalkonium chloride; and optionally from about 0.1% to about 1% w/w sodium chloride, wherein w/w denotes weight by weight of the formulation. 12. An epinephrine spray formulation for intranasal administration comprising: about 3.2 % w/w epinephrine, or a salt thereof; about 35.5 % w/w hydrochloric acid with a normality of 0.5; about 40 % w/w ethanol; about 16.1 % w/w water; about 0.05% w/w edetate disodium dihydrate; about 0.15% w/w sodium bisulfite; and about 0.01% w/w benzalkonium chloride, wherein % w/w denotes weight by total weight of the formulation. 13. An epinephrine spray formulation for intranasal administration comprising: about 3.0 % w/w epinephrine, or a salt thereof; about 32.9 % w/w hydrochloric acid with a normality of 0.5; about 63.3 % w/w water; about 0.05 % w/w edetate disodium dihydrate; about 0.15% w/w sodium bisulfite; about 0.01% w/w benzalkonium chloride; and CA 3060078 Date reçue / Received date 2025-06-0342 about 0.6 % w/w sodium chloride, wherein % w/w denotes weight by total weight of the formulation. 14. The formulation of claim 1 for use in treating anaphylaxis comprising administration of the formulation of claim 1 to a subject in need thereof. 15. The formulation of claim 11, further comprising from about 1% to about 20% w/w propylene glycol. 16. The formulation of claim 12, further comprising about 5% w/w propylene glycol. 17. The formulation of claim 15, 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 of 0.
5. 5 N; from about 10 % to about 60 % w/w ethanol; from about 2 % to about 38 % w/w water; about 5 % w/w propylene glycol; from about 0.1 % to about 0.3 % w/w sodium bisulfite; about 0.05% w/w edetate disodium dihydrate; and from about 0.01 % to about 0.02 % w/w benzalkonium chloride. 18. Use of the formulation of claim 1 in the manufacture of a medicament for the treatment of anaphylaxis.