JP7443258B2 - epinephrine spray formulation - Google Patents

Description

FIELD OF THE INVENTION The present invention is directed to epinephrine spray formulations. The present invention is further directed to a method of treating anaphylaxis by administering an epinephrine spray formulation to a subject in need of treatment.

BACKGROUND OF THE INVENTION Epinephrine (i.e., adrenaline) is a catecholamine with the following chemical structure.

Epinephrine stimulates alpha- and beta-adrenergic receptors of the sympathetic nervous system. Epinephrine binds to these adrenergic receptors and provides relief from many of the life-threatening symptoms of anaphylaxis, including: relaxation of smooth muscles in the bronchi of the lungs that widen narrowed trajectories; swelling of the tongue and throat. Constriction of blood vessels leading to relief and increase in blood pressure; and increase in heart rate, ultimately preventing or reversing cardiovascular collapse.

Epinephrine is available for injection (Adrenalin®, a trademark of Par Sterile Products, LLC, available for purchase here) and for autoinjectors (EpiPen, a trademark of Mylan, Inc., available for purchase here). Auvi-Q®), a trademark of Sanofi Corporation and available for purchase from here. Epinephrine has been available for some time as a nasal spray (Adrenaline®) and an aerosol spray (Primatene® Mist, a trademark of Armstrong Pharmaceuticals, Inc.). Racepinephrine is commercially available as a 2.25% oral inhalation solution for personal use in a nebulizer (S2® is available from Nephron Pharmaceuticals, Inc.). Epinephrine differs from racepinephrine in that epinephrine consists only of the L-isomer and racepinephrine is a 50/50 mixture of the L- and D-isomers.

US Patent No. 8,628,805 is directed to stable liquid adrenaline/bisulfite compositions having a molar ratio of adrenaline to bisulfite of 1.31 to 2.20:1. US Patent Application Publication No. 2012/0322884A1 is directed to epinephrine nanoparticles that can be incorporated into sublingual tablets. US Patent Application Publication No. 2007/0202163A1 is directed to epinephrine tablets for sublingual administration containing between 12% and 48% epinephrine. World Intellectual Property Organization (“W.I.P.O.”) Publication No. 2014/127018A1 is directed to stable aqueous epinephrine formulations that require cyclodextrins. W. I. P. O. Publication number 2014/057365A1 is directed to a directedtoan parkable epinephrine formulation.

US Patent No. 8,628,805 US Patent Application Publication No. 2012/0322884 US Patent Application Publication No. 2007/0202163 International Publication No. 2014/127018 International Publication No. 2014/057365

Although there are various epinephrine formulations currently available, there remains a need for rapid onset spray formulations.

SUMMARY OF THE INVENTION In one aspect, the present invention is directed to an epinephrine spray formulation, which includes:
From about 0.1% w/w to about 15% w/w epinephrine or a salt thereof, preferably the salt is citrate, hydrochloride, halide, sulfate, phosphate, acetate, selected from the group consisting of maleate, succinate, ascorbate, carbonate, mesylate and lactate;
about 1% w/w to about 80% w/w, preferably about 5% to about 77% w/w, more preferably about 10% to about 65% w/w or about 15% to about 80% w/w w water;
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 combinations thereof; and optionally about 0.1% w/w to about 60% w/w of at least one acid;
wherein the formulation has a pH of about 2 to about 7.0.

In one aspect, the invention is directed to an epinephrine spray formulation, comprising:
From about 0.1% w/w to about 15% w/w epinephrine or a salt thereof, preferably the salt is citrate, hydrochloride, halide, sulfate, phosphate, acetate, selected from the group consisting of maleate, succinate, ascorbate, carbonate, mesylate and lactate;
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 combinations thereof, preferably the solvent is water , a combination of 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 dilute hydrochloric acid;
wherein the formulation has a pH of about 2 to about 5.5.

In another aspect, the invention is directed to an epinephrine spray formulation, which does not include a propellant.

In another aspect, the invention is directed to an epinephrine spray formulation, which formulation does not include sorbitol.

In another aspect, the solvents of the invention contain from about 1% w/w to about 30% w/w glycerin.

In another aspect, the epinephrine spray formulation of the invention further comprises a penetration enhancer comprising caprylic acid, preferably from about 0.1% w/w to about 10% w/w, more preferably from about 0.1% w/w to about 10% w/w. is at a concentration of about 0.1% w/w to about 5% w/w.

In another aspect, the penetration enhancers of the invention include 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), cetylpyridinium 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 combinations thereof, preferably menthol, preferably the menthol is about 0.1% to about 5%. The concentration is w/w, more preferably about 0.1% to about 1% w/w.

In another aspect, the epinephrine spray formulation of the invention does not include a penetration enhancer.

In another aspect, the epinephrine spray formulation of the invention further comprises an isotonic agent comprising sodium chloride.

In another aspect, the epinephrine spray formulation of the invention comprises butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, methionine, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium bisulfite, 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 of about 0.005% w/w to about 0.5% w/w. and preferably the stabilizer comprises sodium bisulfite, sodium bisulfite or a combination thereof at a concentration of about 0.005% w/w to about 5% w/w, and preferably the stabilizer comprises: BKC is included at a concentration of about 0.005% to about 0.5% w/w.

In another aspect, the epinephrine spray formulation of the invention is selected from the group consisting of butylparaben, methylparaben, ethylparaben, propylparaben, sodium benzoate, chlorobutanol, benzalkonium chloride (BKC), benzoic acid, and combinations thereof. The composition further includes a preservative, preferably BKC at a concentration of about 0.005% w/w to about 0.5% w/w.

In one aspect, the present invention includes:
about 0.1% w/w to about 15% w/w epinephrine or its salt;
about 2% to about 10% w/w propylene glycol;
An epinephrine spray formulation is provided comprising about 20% to about 50% w/w ethanol; and about 1% to about 80% w/w water.

In another aspect, the present invention includes:
about 0.1% w/w to about 15% w/w epinephrine or its salt;
An epinephrine spray formulation is provided comprising about 0.1% to about 1% sodium chloride; and about 1% to about 80% w/w water.

In another aspect, the present invention includes:
about 3% to about 6% w/w epinephrine;
about 20% to about 30% w/w of about 1.0N normal hydrochloric acid;
about 0.100% to about 0.600 w/w sodium bisulfite;
about 35% to about 45% w/w ethanol;
An epinephrine spray formulation is provided comprising about 2.5% to about 7.5% w/w propylene glycol; and about 10% to about 30% w/w water.

In another aspect, the present invention includes:
about 3% to about 10% w/w epinephrine;
about 20% to about 30% w/w of about 1.0N normal hydrochloric acid;
about 0.3% to about 0.8% sodium chloride;
An epinephrine spray formulation is provided comprising about 0.100% to about 0.600 w/w sodium bisulfite; and about 60% to about 80% w/w water.

In another aspect, the present invention includes:
about 0.1% to about 15% w/w epinephrine, or a salt thereof;
about 1% to about 65% w/w of about 0.1 to 12N normal hydrochloric acid;
about 2% to about 60% w/w ethanol;
about 2% to about 98% w/w water;
about 1% to about 20% w/w propylene glycol;
about 0.001% to about 1% w/w sodium bisulfite;
about 0.001% to about 1% w/w sodium bisulfite;
about 0.005% to about 1% w/w EDTA;
Optionally, a penetration enhancer selected from the group consisting of about 0.5% to about 15% w/w caprylic acid, about 0.1% to about 10% w/w menthol, and combinations thereof; and optionally directed to an epinephrine spray formulation comprising benzalkonium chloride at a concentration of about 0.001% to about 0.1% w/w, wherein the formulation optionally comprises a concentration of about 0.001% to about 0.1% w/w. It has a pH of 3 to about 7.0.

In another aspect, the present invention includes:
about 0.1% to about 15% w/w epinephrine, or a salt thereof;
about 1% to about 65% w/w of about 0.1 to 12N normal hydrochloric acid;
about 2% to about 98% w/w water;
about 0.001% to about 7.5% w/w sodium bisulfite;
about 0.001% to about 7.5% w/w sodium bisulfite;
about 0.005% to about 1% w/w EDTA;
about 0.1% to about 1% sodium chloride;
Optionally, directed to an epinephrine spray formulation comprising benzalkonium chloride at a concentration of about 0.001% to about 0.1% w/w, where the formulation optionally comprises a concentration of about 3 to about It has a pH of 5.5.

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

In another aspect, the present invention includes:
Directed to an epinephrine spray formulation comprising about 0.1% w/w to about 15% w/w epinephrine or a salt thereof; and about 1% to about 80% w/w water;
wherein administration of 7 milligrams of epinephrine or its salt in the formulation to a human has a C _max of at least about 1000 picograms/ml, a T _max of 0.167 hours or less, an AUC _last of at least 750 h*pg/mL, Provides a pharmacokinetic parameter selected from the group consisting of AUC _inf of at least 950 h*pg/mL and combinations thereof.

In another aspect, the present invention includes:
Directed to an epinephrine spray formulation comprising about 0.1% w/w to about 15% w/w epinephrine or a salt thereof; and about 1% to about 80% w/w water;
wherein administration of 8.5 milligrams of epinephrine or its salt in the formulation to a human has a C _max of at least about 1400 picograms/ml, a T _max of 0.267 hours or less, and an AUC of at least 1200 h*pg/mL. AUC _{inf of} at least 1400 h*pg/mL, and combinations thereof.

In another aspect, the invention is directed to a method of treating anaphylaxis, the method comprising administering to a subject in need of treatment for anaphylaxis an epinephrine spray formulation of the invention, preferably the administration , via intranasal or sublingual administration, and wherein the subject optionally suffers from seasonal allergies.

In another aspect, the invention is directed to a method of treating anaphylaxis, which method comprises administering an epinephrine spray formulation of the invention to a subject in need of treatment for anaphylaxis via a unit dosage or a single dose. including administering via a multi-dose device that delivers more doses of the formulation, preferably via a dual-dose device that delivers two doses of the formulation.

In another aspect, the invention is directed to a method of treating anaphylaxis comprising administering an epinephrine formulation of the invention via a prefabricated device.

Figure 1. Epinephrine plasma concentrations over the first 6 hours after administration. Figure 2. Epinephrine plasma concentrations over the first 30 minutes after administration. Figure 3. Semi-log plot of epinephrine plasma concentrations over the first 6 hours post-dose. Figure 4. Epinephrine plasma concentrations over the first 6 hours after administration. Figure 5. Epinephrine plasma concentrations over the first 30 minutes after administration.

DETAILED DESCRIPTION OF THE INVENTION Definitions Applicants have discovered epinephrine spray formulations that have improved bioavailability, faster onset of action, and improved storage stability.

As used herein, "epinephrine" refers to a base.

As used herein, "propellant-free" refers to formulations that are administered without compressed gas.

As used herein, all numerical values relating to amounts, weights, etc. defined by "about" are ±10% of each particular numerical value. For example, the phrase "about 10% w/w" is understood to be "9% w/w to 11% w/w". Accordingly, amounts within 10% of the claimed numerical values are included within the scope of the claims.

As used herein, "% w/w" and "percentage w/w" refer to a percentage of the total weight of the formulation.

As used herein, the term "effective amount" refers to the amount necessary to treat a patient in need of treatment.

As used herein, the terms "treat," "treating," or "treatment" refer to alleviating or inhibiting symptoms of type I allergy, including anaphylaxis.

As used herein, the term "subject" refers to a human experiencing type I allergy, including, but not limited to, anaphylaxis.

As used herein, the term "anaphylaxis" refers to an allergic reaction involving multiple organs in a subject upon contact with an identifiable or non-identifiable allergen.

As used herein, the term "allergen" refers to any chemical substance that can provoke an immune system response in a subject, including drugs, foods, plants, insect bites, and insect stings.

As used herein, the term "seasonal allergy" refers to allergic rhinitis. Seasonal allergy symptoms include, but are not limited to, itching, watery eyes, sneezing, runny or stuffy nose, swelling of the nasal turbinates, itching of the nasal cavity, throat or ear canal, ear congestion and nasal drainage.

As used herein, "nasal congestion" refers to the symptoms of swelling of the nasal turbinates.

As used herein, the term "pharmaceutically acceptable" refers to a component that is not biologically or otherwise undesirable for administration to a biological subject.

"Sublingual" refers to the administration of a substance through the mouth such that the substance is rapidly absorbed through the blood vessels on the underside of the tongue.

"Intranasal" refers to administration of the composition to any part of the nasal mucosal epithelium.

In one embodiment, the invention is directed to an epinephrine spray formulation 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 skilled in the art may use other pharmaceutically acceptable epinephrine salts in the formulations of the present invention. In a preferred embodiment, the formulation comprises an epinephrine equivalent of about 0.1% to about 15% w/w of epinephrine or a pharmaceutically acceptable salt. In a more preferred embodiment, the formulation comprises an epinephrine equivalent of about 0.1% to about 10% w/w of epinephrine or a pharmaceutically acceptable salt. Other most preferred embodiments include formulations containing epinephrine or a pharmaceutically acceptable salt in an epinephrine equivalent of about 0.1% to about 10% w/w. In the most preferred embodiment, the epinephrine concentration is between 3% and 10% w/w.

In another embodiment, the invention is directed to an epinephrine spray formulation comprising epinephrine or a salt thereof, wherein the formulation is propellant-free.

In another embodiment, the invention provides epinephrine or a salt thereof selected from acids, solvents, stabilizers, penetration enhancers, viscosity modifiers, sweeteners, sweetness enhancers, pH modifiers, isotonic agents and flavorants. The present invention is directed to epinephrine spray formulations containing one or more excipients.

In preferred embodiments, the formulations of the invention contain about 1% to about 65% w/w, more preferably about 1% to about 45% w/w acid. 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 about 0.1N to about 12N hydrochloric acid, even more preferably about 0.5 to about 6N hydrochloric acid, even more preferably about 0.1N to about 6N hydrochloric acid. 5N to about 3N hydrochloric acid, and most preferably 0.5N or 3N hydrochloric acid.

In preferred embodiments, formulations of the invention contain about 1% to 99% w/w solvent, preferably about 30% to about 99% w/w solvent.

Suitable solvents for use in the present invention include, but are not limited to, water, ethanol, glycerin, propylene glycol, polyethylene glycol 400, and combinations thereof, with water being more preferred.

In preferred embodiments, the formulations of the invention contain about 0.001% to about 10% w/w, preferably about 0.005% to about 7.5% w/w, and even more preferably about 0.01% w/w. % to about 5% w/w stabilizer. 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 Bisulfite, 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 bisulfite, sodium bisulfite, disodium EDTA, 8-hydroxyquinoline, and combinations thereof. In an even more preferred embodiment, the stabilizer is a combination of sodium bisulfite, sodium bisulfite, 8-hydroxyquinoline, and EDTA. In a further preferred embodiment, the formulations of the invention contain about 0.005% to 0.5% w/w EDTA as a stabilizer. In more preferred embodiments, the formulations of the invention contain about 0.01% to 0.1% EDTA as a stabilizer. In the most preferred embodiment, the formulations of the invention contain about 0.05% EDTA as a stabilizer. In a further preferred embodiment, the formulation of the invention comprises sodium bisulfite and sodium bisulfite as antioxidants at a concentration of about 0.005% to 5% w/w. In a more preferred embodiment, the formulation of the invention comprises sodium bisulfite or sodium bisulfite or a combination thereof as an antioxidant at a concentration of about 0.05% to 1% w/w. In more preferred embodiments, the formulations of the invention contain sodium bisulfite or a combination of sodium bisulfites as an antioxidant from about 0.05% to about 1% w/w, more preferably from about 0.1% to about 1% w/w. Contains at a concentration of approximately 0.75% w/w. In the most preferred embodiments, the formulations of the invention contain sodium bisulfite as an antioxidant at a concentration of about 0.15% or 0.3% or 0.5% or 0.75% w/w.

In some embodiments, formulations of the invention contain from about 0.001% w/w to about 15% w/w, preferably from about 0.03% w/w to about 12% w/w, and even more. Preferably contains about 0.05% to 10% w/w penetration enhancer.

Suitable penetration enhancers for use in the present invention include, but are not limited to, caprylic acid, oleic acid, polysorbate 80, menthol, EDTA, edetate disodium, cetylpyridinium chloride, sodium lauryl sulfate, citric acid, desoxy Included are sodium cholate, sodium deoxyglycolate, glyceryl oleate, L-lysine, and combinations thereof. Preferred penetration enhancers are caprylic acid, menthol or combinations thereof.

Suitable viscosity modifiers for the present invention include, but are not limited to, polyvinylpyrrolidone, carboxymethylcellulose, hydroxypropylmethylcellulose ("HPMC"), methylcellulose, hydroxyethylcellulose, 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 invention include about 0.001% to about 1% sweetness enhancer. Sweetness enhancers suitable for the present invention include, but are not limited to, ammonium salt forms of crude and purified glycyrrhizic acid. The Magnasweet® product (available from Mafco Worldwide Corporation, Magnasweet is a trademark of Mafco Worldwide Corporation) uses ammonium salt forms of crude and purified glycyrrhizic acid. Glycyrrhizic acid is also available as a pure derivative in the form of sodium and potassium salts.

In preferred embodiments, the formulations of the invention have a pH of about 2.0 to about 7.0. In more preferred embodiments, the formulations of the invention have a pH of about 3.0 to about 5.0. In more preferred embodiments, the formulations of the invention have a pH of about 4.0 to about 5.0. In the most preferred embodiment the formulation of the invention has a pH of 4.5. Suitable pH adjusting agents 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. It will be done.

Preservatives suitable for the present invention include, but are not limited to, butylparaben, methylparaben, ethylparaben, propylparaben, sodium benzoate, chlorobutanol, benzalkonium chloride, benzoic acid, and combinations thereof. In a preferred embodiment, the preservative is benzalkonium chloride. In a more preferred embodiment, benzalkonium chloride is at a concentration of about 0.01% to about 0.02% w/w, more preferably 0.01% or 0.02% w/w.

Flavors 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 combinations thereof.

In a preferred embodiment, the invention comprises:
about 2.8% to about 4% w/w epinephrine or a salt thereof;
about 32% to about 38% w/w 0.5 to 3N normal hydrochloric acid;
about 10% to about 65% w/w ethanol;
about 2% to about 38% w/w water;
Approximately 5% w/w propylene glycol;
about 0.1% to about 0.75% w/w sodium bisulfite;
Approximately 0.05% w/w disodium EDTA;
Optionally, a penetration enhancer selected from the group consisting of about 2% to about 10% w/w caprylic acid, about 0.5% to about 1.0% w/w menthol, and combinations thereof; and optionally directed to an epinephrine spray formulation comprising benzalkonium chloride at a concentration of about 0.01% to about 0.02% w/w, wherein the formulation optionally comprises about 4% w/w of benzalkonium chloride. It has a pH of .5.

In another preferred embodiment, the invention provides:
about 3.24% w/w epinephrine or its salt;
Approximately 36.2% w/w 0.5N hydrochloric acid;
Approximately 40% w/w ethanol;
Approximately 14.84% w/w water;
Approximately 5% w/w propylene glycol;
Directed to an epinephrine spray formulation comprising about 0.01% w/w benzalkonium chloride; and about 0.15% to about 0.3% w/w sodium bisulfite, wherein the formulation comprises about It has a pH of 4.5.

In another preferred embodiment, the invention provides:
about 3.117% w/w epinephrine, or a salt thereof;
Approximately 34.8% w/w 0.5N hydrochloric acid;
Approximately 20% w/w ethanol;
Approximately 36.87% w/w water;
Approximately 5% w/w propylene glycol;
about 0.01% w/w benzalkonium chloride;
Directed to intranasal epinephrine spray formulations containing from about 0.15% w/w sodium bisulfite to about 0.3% w/w sodium bisulfite, wherein the formulation has a pH of about 4.5. have

In another preferred embodiment, the invention provides:
about 3.04% w/w epinephrine, or a salt thereof;
Approximately 33.8% w/w 0.5N hydrochloric acid;
Approximately 62.35% w/w water;
about 0.01% w/w benzalkonium chloride;
Directed to intranasal epinephrine spray formulations containing from about 0.15% w/w sodium bisulfite to about 0.3% w/w sodium bisulfite, wherein the formulation has a pH of about 4.5. have

below:
Approximately 2.96% w/w epinephrine base;
about 32.93% w/w of about 0.5N normal hydrochloric acid;
Approximately 0.05% w/w edetate disodium dihydrate;
approximately 0.15% w/w sodium bisulfite;
about 0.01% w/w benzalkonium chloride;
An epinephrine spray formulation comprising about 0.6% w/w sodium chloride; and about 63.30% w/w water, wherein the formulation has a pH of about 4.5.

below:
Approximately 3.18% w/w epinephrine base;
about 35.47% w/w of about 0.5N normal hydrochloric acid;
Approximately 0.05% w/w edetate disodium dihydrate;
approximately 0.15% w/w sodium bisulfite;
about 0.01% w/w benzalkonium chloride;
Approximately 5% w/w propylene glycol;
An epinephrine spray formulation comprising about 40.0% w/w ethanol; and about 16.14% w/w water, wherein the formulation has a pH of about 4.5.

below:
Approximately 5.923% w/w epinephrine base;
about 2N normal hydrochloric acid at about 16.46% w/w;
Approximately 0.05% w/w edetate disodium dihydrate;
approximately 0.15% w/w sodium bisulfite;
about 0.01% w/w benzalkonium chloride;
An epinephrine spray formulation comprising about 0.6% w/w sodium chloride; and about 76.81% w/w water, wherein the formulation has a pH of about 4.5.

below:
Approximately 5.923% w/w epinephrine base;
about 2N normal hydrochloric acid at about 16.46% w/w;
Approximately 0.05% w/w edetate disodium dihydrate;
Approximately 0.30% w/w sodium bisulfite;
about 0.01% w/w benzalkonium chloride;
An epinephrine spray formulation comprising about 0.6% w/w sodium chloride; and about 76.66% w/w water, wherein the formulation has a pH of about 4.5.

below:
Approximately 6.356% w/w epinephrine base;
about 2N normal hydrochloric acid at about 17.74% w/w;
Approximately 0.05% w/w edetate disodium dihydrate;
approximately 0.15% w/w sodium bisulfite;
about 0.01% w/w benzalkonium chloride;
Approximately 40.0% w/w ethanol;
An epinephrine spray formulation comprising about 5% w/w propylene glycol and about 30.70% w/w water, wherein the formulation has a pH of about 4.5.

below:
Approximately 6.356% w/w epinephrine base;
Approximately 17.74% w/w 2N normal hydrochloric acid;
Approximately 0.05% w/w edetate disodium dihydrate;
Approximately 0.30% w/w sodium bisulfite;
about 0.01% w/w benzalkonium chloride;
Approximately 40.0% w/w ethanol;
An epinephrine spray formulation comprising about 5% w/w propylene glycol and about 30.55% w/w water, wherein the formulation has a pH of about 4.5.

below:
Approximately 8.885% w/w epinephrine base;
about 2N normal hydrochloric acid at about 24.70% w/w;
Approximately 0.05% w/w edetate disodium dihydrate;
approximately 0.15% w/w sodium bisulfite;
about 0.01% w/w benzalkonium chloride;
An epinephrine spray formulation comprising about 0.6% w/w sodium chloride; and about 65.61% w/w water, wherein the formulation has a pH of about 4.5.

below:
Approximately 8.885% w/w epinephrine base;
about 2N normal hydrochloric acid at about 24.70% w/w;
Approximately 0.05% w/w edetate disodium dihydrate;
Approximately 0.45% w/w sodium bisulfite;
about 0.01% w/w benzalkonium chloride;
An epinephrine spray formulation comprising about 0.6% w/w sodium chloride; and about 65.31% w/w water, wherein the formulation has a pH of about 4.5.

below:
Approximately 9.534% w/w epinephrine base;
about 2N normal hydrochloric acid at about 26.60% w/w;
Approximately 0.05% w/w edetate disodium dihydrate;
approximately 0.15% w/w sodium bisulfite;
about 0.01% w/w benzalkonium chloride;
Approximately 40.0% w/w ethanol;
An epinephrine spray formulation comprising about 5% w/w propylene glycol and about 18.65% w/w water, wherein the formulation has a pH of about 4.5.

below:
Approximately 9.534% w/w epinephrine base;
about 2N normal hydrochloric acid at about 26.60% w/w;
Approximately 0.05% w/w edetate disodium dihydrate;
approximately 0.15% w/w sodium bisulfite;
about 0.01% w/w benzalkonium chloride;
Approximately 40.0% w/w ethanol;
An epinephrine spray formulation comprising about 5% w/w propylene glycol and about 18.35% w/w water, wherein the formulation has a pH of about 4.5.

In another embodiment, administration of 6 milligrams of epinephrine in Formulation #C1 of Table 62 below to a human exposed to an allergen results in an epinephrine plasma concentration of greater than 100 picograms/ml at about 1 minute after administration.

In another embodiment, administration of 6 milligrams of epinephrine in Formulation #C1 of Table 62 below to a human not exposed to the allergen results in an epinephrine plasma concentration of greater than 100 picograms/milliliter at about 3 minutes after administration. .

In another embodiment, administration of 6 milligrams of epinephrine in Formulation #C2 of Table 62 below to a human exposed to an allergen results in an epinephrine plasma concentration of greater than 100 picograms/milliliter at about 1 minute after administration.

In another embodiment, administration of 6 milligrams of epinephrine in Formulation #C2 of Table 62 below to a human exposed to an allergen results in an epinephrine plasma concentration of greater than 290 picograms/ml at about 1 minute after administration.

In another embodiment, administration of 6 milligrams of epinephrine in Formulation #C2 of Table 62 below to a human not exposed to the allergen results in an epinephrine plasma concentration of greater than 100 picograms/milliliter at about 3 minutes after administration. .

In another aspect, the present invention includes:
about 0.1% w/w to about 15% w/w epinephrine or its salt;
about 2% to about 10% w/w propylene glycol;
about 20% to about 50% w/w ethanol; and about 1% to about 80% w/w water;
, wherein administration to humans of 7 milligrams of epinephrine or a salt thereof in the formulation comprises:
C _max (arithmetic mean) of at least about 1000 picograms/ml, T _max (arithmetic mean) of at least 0.167 hours, AUC _last (arithmetic mean) of at least 750 h*pg/mL, AUC _inf of at least 950 h*pg/mL. (arithmetic mean) and combinations thereof; or C _max (geometric mean) of at least about 500 picograms/milliliter, T _max of at least about 0.167 h, at least about 500 h*pg/mL _{AUC inf} (geometric mean) of at least about 800 h*pg/mL, and combinations thereof; or a C _max (arithmetic mean) of about 1040 picograms/ml; , T _max (arithmetic mean) of about 0.167 hours, AUC _last (arithmetic mean) of about 785 h*pg/mL, AUC _inf (arithmetic mean) of about 960 h*pg/mL, and combinations thereof. or C _max (geometric mean) of about 536 picograms/ml, AUC _last (geometric mean) of about 521 h*pg/mL, AUC _inf (geometric mean) of about 828 h*pg/mL; a pharmacokinetic parameter selected from the group consisting of a combination; or a plasma concentration greater than 70 picograms per milliliter within 1 minute of administration;
Plasma concentration greater than 750 picograms/ml within 3 minutes after administration;
Plasma concentration greater than 650 picograms/ml within 5 minutes of administration;
A plasma concentration of greater than 600 picograms/milliliter within 7 minutes after administration; or a plasma concentration greater than 550 picograms/mL within 10 minutes of administration.

In another aspect, the present invention includes:
about 0.1% w/w to about 15% w/w epinephrine or its salt; and about 1% to about 80% w/w water;
, wherein administration to humans of 8.5 milligrams of epinephrine or a salt thereof in the formulation comprises:
C _max (arithmetic mean) of at least about 1400 picograms/ml, T _max less than or equal to 0.267 hours, AUC _last (arithmetic mean) of at least 1200 h*pg/mL, AUC _inf (arithmetic mean) of at least 1400 h*pg/mL and a combination thereof;
C _max (geometric mean) of at least about 650 picograms/ml, T _max of at least about 0.267 hours, AUC _last (geometric mean) of at least about 800 h*pg/mL, AUC of at least about 10000 h*pg/mL a pharmacokinetic parameter selected from the group consisting of _inf (geometric mean) and combinations thereof;
C _max (arithmetic mean) of approximately 1420 picograms/ml, median T _max of approximately 0.267 hours, AUC _last (arithmetic mean) of approximately 1200 h*pg/mL, AUC _inf (arithmetic mean) of approximately 1440 h*pg/mL ) and combinations thereof;
selected from the group consisting of C _max (geometric mean) of about 686 picograms/ml, AUC _last (geometric mean) of about 813 h*pg/mL, AUC _inf (geometric mean) of about 10308 h*pg/mL, and combinations thereof. pharmacokinetic parameters;
plasma concentration greater than 200 picograms per milliliter within 1 minute after administration;
plasma concentration greater than 850 picograms per milliliter within 3 minutes after administration;
plasma concentration greater than 1000 picograms/ml within 5 minutes after administration;
Provides a plasma concentration greater than 975 picograms/milliliter within 7 minutes after administration, or a plasma concentration greater than 950 picograms/milliliter within 10 minutes after administration.

In another aspect, the present invention includes:
about 0.1% w/w to about 15% w/w epinephrine or its salt;
about 2% to about 10% w/w propylene glycol;
directed to an epinephrine spray formulation comprising about 20% to about 50% w/w ethanol; and about 1% to about 80% w/w water, wherein 7 milligrams of epinephrine or a salt thereof in the formulation The administration to
a geometric mean plasma concentration at 1 minute post-dose that is 4.3 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 3 minutes post-dose that is 1.7 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 5 minutes post-dose that is 1.3 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 7 minutes post-dose that is 1.5 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 10 minutes post-dose that is 1.6 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 15 minutes post-dose that is 1.8 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 20 minutes post-dose that is 1.4 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 30 minutes post-dose that is 1.4 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
the geometric mean plasma concentration at 45 minutes post-dose that is 1.7 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation; or providing a geometric mean plasma concentration at 60 minutes post-dose that is 2.4 times greater than the geometric mean plasma concentration after administration of epinephrine;
Here, the second formulation consists of 0.3 milligrams of epinephrine, 1.8 milligrams of sodium chloride, 0.5 milligrams of sodium bisulfite, hydrochloric acid to adjust pH, and water for parking.

In another aspect, the present invention includes:
about 0.1% w/w to about 15% w/w epinephrine or its salt;
about 2% to about 10% w/w propylene glycol;
about 20% to about 50% w/w ethanol; and about 1% to about 80% w/w water;
, wherein administration to humans of 8.5 milligrams of epinephrine or a salt thereof in the formulation comprises:
a geometric mean plasma concentration at 1 minute post-dose that is 5.3 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 3 minutes post-dose that is 1.9 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 5 minutes post-dose that is 2.0 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 7 minutes post-dose that is 2.4 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 10 minutes post-dose that is 2.8 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 15 minutes post-dose that is 2.8 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 20 minutes post-dose that is 2.4 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
a geometric mean plasma concentration at 30 minutes post-dose that is 2.0 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation;
the geometric mean plasma concentration at 45 minutes post-dose that is 2.7 times greater than the geometric mean plasma concentration after administration of 0.3 milligrams of epinephrine in the second formulation; or providing a geometric mean plasma concentration at 60 minutes post-dose that is 3.4 times greater than the geometric mean plasma concentration after administration of epinephrine;
Here, the second formulation for injection consists of 0.3 milligrams of epinephrine, 1.8 milligrams of sodium chloride, 0.5 milligrams of sodium bisulfite, hydrochloric acid to adjust the pH, and water.

In another aspect, the present invention includes:
about 0.1% w/w to about 15% w/w epinephrine or its salt;
about 2% to about 10% w/w propylene glycol;
directed to an epinephrine spray formulation comprising about 20% to about 50% w/w ethanol; and about 1% to about 80% w/w water, wherein 7 milligrams of epinephrine or a salt thereof in the formulation The administration to
Geometric mean AUC _0-0.017 of 4.2 times compared to geometric mean AUC _0-0.017 after administration of 0.3 milligrams of epinephrine in the second formulation;
twice the geometric mean AUC _0-0.5 compared to the geometric mean AUC _0-0.05 after administration of 0.3 milligrams of epinephrine in the second formulation;
1.7 times the geometric mean AUC _0-0.083 compared to the geometric mean AUC _0-0.083 after administration of 0.3 milligrams of epinephrine in the second formulation;
1.6 times the geometric mean AUC _0-0.117 compared to the geometric mean AUC _0-0.117 after administration of 0.3 milligrams of epinephrine in the second formulation;
Geometric mean AUC _0-0.167 of 1.6 times compared to geometric mean AUC _0-0.167 after administration of 0.3 milligrams of epinephrine in the second formulation;
Geometric mean AUC _0-0.25 of 1.6 times compared to geometric mean AUC _0-0.25 after administration of 0.3 milligrams of epinephrine in the second formulation;
1.6 times the geometric mean AUC _0-0.33 compared to the geometric mean AUC _0-0.33 after administration of 0.3 milligrams of epinephrine in the second formulation;
1.5 times the geometric mean AUC _0-0.5 compared to the geometric mean AUC _0-0.5 after administration of 0.3 milligrams of epinephrine in the second formulation;
1.5 times the geometric mean AUC _0-0.75 compared to the geometric mean AUC _0-0.75 after administration of 0.3 milligrams of epinephrine in the second formulation; or 0.3 in the second formulation Provides 1.6 times the geometric mean AUC _0-1 compared to the geometric mean AUC _0-1 after administration of milligrams of epinephrine.

In another aspect, the present invention includes:
about 0.1% w/w to about 15% w/w epinephrine or its salt;
about 2% to about 10% w/w propylene glycol;
directed to an epinephrine spray formulation comprising about 20% to about 50% w/w ethanol; and about 1% to about 80% w/w water, wherein 8.5 milligrams of epinephrine or a salt thereof in the formulation; Human administration of
5 times the geometric mean AUC _0-0.017 compared to the geometric mean AUC _0-0.017 after administration of 0.3 milligrams of epinephrine in the second formulation;
2.3 times the geometric mean AUC _0-0.5 compared to the geometric mean AUC _0-0.05 after administration of 0.3 milligrams of epinephrine in the second formulation;
2.1 times the geometric mean AUC _0-0.083 compared to the geometric mean AUC _0-0.083 after administration of 0.3 milligrams of epinephrine in the second formulation;
2.1 times the geometric mean AUC _0-0.117 compared to the geometric mean AUC _0-0.117 after administration of 0.3 milligrams of epinephrine in the second formulation;
2.3 times the geometric mean AUC _0-0.167 compared to the geometric mean AUC _0-0.167 after administration of 0.3 milligrams of epinephrine in the second formulation;
2.5 times the geometric mean AUC _0-0.25 compared to the geometric mean AUC _0-0.25 after administration of 0.3 milligrams of epinephrine in the second formulation;
2.5 times the geometric mean AUC _0-0.33 compared to the geometric mean AUC _0-0.33 after administration of 0.3 milligrams of epinephrine in the second formulation;
2.4 times the geometric mean AUC _0-0.5 compared to the geometric mean AUC _0-0.5 after administration of 0.3 milligrams of epinephrine in the second formulation;
2.4 times the geometric mean AUC _0-0.75 compared to the geometric mean AUC _0-0.75 after administration of 0.3 milligrams of epinephrine in the second formulation; or 0.3 in the second formulation Provides 2.5 times the geometric mean AUC _0-1 compared to the geometric mean AUC _0-1 after administration of milligrams of epinephrine.

In another aspect, the present invention includes:
about 3% to about 6% w/w epinephrine base;
about 20% to about 30% w/w of about 1.0N normal hydrochloric acid;
about 0.025% to about 0.075% w/w edetate disodium dihydrate;
about 0.15% to about 0.30% w/w sodium bisulfite;
about 0.005% to about 0.02% w/w benzalkonium chloride;
about 35% to about 45% w/w ethanol;
Epinephrine spray formulations are directed that include about 2.5% to about 7.5% w/w propylene glycol; and about 20% to about 30% w/w water.

In another aspect, the present invention includes:
about 3% to about 5% w/w epinephrine base;
about 20% to about 25% w/w of about 1.0N normal hydrochloric acid;
about 0.025% to about 0.075% w/w edetate disodium dihydrate;
about 0.15% to about 0.25% w/w sodium bisulfite;
about 0.005% to about 0.02% w/w benzalkonium chloride;
about 35% to about 45% w/w ethanol;
Epinephrine spray formulations are directed that include about 2.5% to about 7.5% w/w propylene glycol; and about 20% to about 40% w/w water.

In another aspect, the present invention includes:
about 0.1% w/w to about 15% w/w epinephrine or its salt;
about 2% to about 10% w/w propylene glycol;
about 20% to about 50% w/w ethanol; and about 1% to about 80% w/w water;
, wherein administration to humans of 7 milligrams of epinephrine or a salt thereof in the formulation comprises:
A geometric mean _Cmax that is about 86.2% compared to the geometric mean _Cmax after intramuscular administration of 0.3 milligrams of epinephrine in the second formulation;
A geometric mean AUC _last that is about 154% compared to the AUC _last after administration of 0.3 milligrams of epinephrine in the second formulation;
Geometric mean AUC _inf that is approximately 217% compared to AUC _inf after administration of 0.3 milligrams of epinephrine in the second formulation;
A geometric mean C _max that is about 101% compared to the geometric mean C _max after intramuscular administration of 0.5 milligrams of epinephrine in the third formulation;
a geometric mean AUC _last that is about 94.5% compared to the AUC _last after administration of 0.5 milligrams of epinephrine in the third formulation; or the AUC after administration of 0.5 milligrams of epinephrine in the third formulation; provides a geometric mean AUC _inf that is approximately 120% compared to _inf ;
wherein the second formulation for injection consists of 0.3 milligrams of epinephrine, 1.8 milligrams of sodium chloride, 0.5 milligrams of sodium bisulfite, hydrochloric acid to adjust pH, and water; The third formulation for injection contained 1.0 milligrams of epinephrine, 6.15 milligrams of sodium chloride, 0.457 milligrams of sodium bisulfite, 0.920 milligrams of sodium hydroxide, 2.25 milligrams of tartaric acid, It consists of 0.20 milligrams of edetate disodium dihydrate, hydrochloric acid to adjust the pH, milligrams of chlorobutanol and water.

In another aspect, the present invention includes:
A geometric mean C _max that is about 111% compared to the geometric mean C _max after administration of 0.3 milligrams of epinephrine in the second formulation;
Geometric mean AUC _last that is about 241% compared to AUC _last after administration of 0.3 milligrams of epinephrine in the second formulation;
Geometric mean AUC _inf that is approximately 282% compared to AUC _inf after administration of 0.3 milligrams of epinephrine in the second formulation;
A geometric mean C _max that is about 130% compared to the geometric mean C _max after intramuscular administration of 0.5 milligrams of epinephrine in the third formulation;
A geometric mean AUC _last that is about 147% compared to AUC _last after administration of 0.5 milligrams of epinephrine in the third formulation; or AUC _inf after administration of 0.5 milligrams of epinephrine in the third formulation. The geometric mean AUC _inf , which is about 155% compared to
A second formulation for injection is directed to an epinephrine spray formulation comprising: 0.3 milligrams epinephrine, 1.8 milligrams sodium chloride, 0.5 milligrams sodium bisulfite, hydrochloric acid to adjust pH. , and water, and wherein the third formulation for injection comprises 1.0 milligrams of epinephrine, 6.15 milligrams of sodium chloride, 0.457 milligrams of sodium bisulfite, and 0.920 milligrams of sodium hydroxide. , 2.25 milligrams of tartaric acid, 0.20 milligrams of edetate disodium dihydrate, hydrochloric acid to adjust the pH, milligrams of chlorobutanol, and water.

In another embodiment, the formulations of the invention are capable of providing a droplet size distribution at 3 cm, where the average DV(10) is about 15 to about 18 microns during administration.

In another embodiment, the formulations of the invention are capable of providing a droplet size distribution at 3 cm, where the average DV(50) is about 30 to about 34 microns during administration.

In another embodiment, the formulations of the invention are capable of providing a droplet size distribution at 3 cm, where the average DV(90) is about 120 to about 230 microns during administration.

In another embodiment, the formulations of the invention are capable of providing a spray range of about 3 to about 7 at 3 cm ((Dv90-Dv10)/Dv50).

In another embodiment, the formulations of the invention are capable of providing a droplet size distribution at 6 cm, where the average DV(10) is about 22 to about 25 microns during administration.

In another embodiment, the formulations of the invention are capable of providing a droplet size distribution at 6 cm, where the average DV(50) is about 36 to about 41 microns during administration.

In another embodiment, the formulations of the invention are capable of providing a droplet size distribution at 6 cm, where the average DV(90) is about 59 to about 231 microns during administration.

In another embodiment, the formulations of the invention are capable of providing a spray range of about 1 to about 6 at 6 cm ((Dv90-Dv10)/Dv50).

In another embodiment, the formulations of the invention are capable of providing a spray pattern at 3 cm, where Dmin is about 18 to about 23 millimeters during administration.

In another embodiment, the formulations of the invention are capable of providing a spray pattern at 3 cm, where Dmax is about 29 to about 33 millimeters during administration.

In another embodiment, the formulations of the invention are capable of providing a spray pattern at 3 cm, where the ellipse ratio is about 1.4 to about 1.7 during administration.

In another embodiment, the formulations of the invention are capable of providing a spray pattern at 6 cm, where Dmin is about 26 to about 33 millimeters during administration.

In another embodiment, the formulations of the invention are capable of providing a spray pattern at 6 cm, where Dmax is about 47 to about 52 millimeters during administration.

In another embodiment, the formulations of the invention are capable of providing a spray pattern at 6 cm, where the ellipse ratio is about 1.6 to about 1.9 during administration.

In another embodiment, the formulations of the invention are capable of providing a plume geometry at 3 cm, where the angle is from about 49° to about 64°.

In another embodiment, the formulations of the invention are capable of providing a plume geometry of 3 cm, where the width is about 27 to about 38 millimeters.

In another embodiment, the formulations of the invention are capable of providing a plume geometry at 3 cm, where the angle is about 37° to about 44°.

In another embodiment, the formulations of the invention are capable of providing a plume geometry of 3 cm, where the width is about 37 to about 44 millimeters.

In one embodiment, the present invention is directed to a method of treating anaphylaxis, the method 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. administering an epinephrine formulation containing % w/w water via a prefabricated device, wherein the formulation has a pH of about 2 to about 7.0.

In a preferred embodiment, the assembled device comprises a container, a plunger, a cannula, a spray pin, a container holder and a drive or a container, a piston and a vortex chamber.

In another preferred embodiment, the prefabricated device delivers one or more doses of the epinephrine formulation.

In another preferred embodiment, the prefabricated device is a unit dosage device that delivers a single dose of epinephrine formulation upon a single actuation, and is less than or equal to 250 μL, preferably about 237 μL, or 140 μL, preferably about One container containing 127 μL of epinephrine formulation is provided.

In another preferred embodiment, the assembled device is a unit dosage device that delivers about 200 μL or about 100 μL of pharmaceutical formulation during a single actuation.

In another preferred embodiment, the assembled device is a two-dose device that delivers two doses of epinephrine formulation upon two actuations, delivering about 100 μL of pharmaceutical formulation per actuation. .

In another preferred embodiment, the assembled device is a multi-dose device that delivers multiple doses of epinephrine formulation during multiple actuations, delivering about 100 μL of pharmaceutical solution per actuation.

The embodiments of this disclosure are merely exemplary embodiments of the inventive concepts disclosed herein and are not to be construed as limiting unless the claims express otherwise.

The following examples are intended to illustrate the invention and to teach those skilled in the art how to use the formulations of the invention. They are not intended to be limiting in any way.

Example 1
An epinephrine spray was prepared as follows using the ingredients and amounts listed in Table 1 below. All solvents were purged under nitrogen before use. Excipients containing 0.5N hydrochloric acid ("HCl"), malic acid, ethanol and propylene glycol, EDTA, sodium chloride, sodium bisulfite, sodium bisulfite, and 8-hydroxyquinoline are added to the water with stirring at room temperature. Dissolved. Epinephrine base was then added to the excipient solution. Finally, the final pH was adjusted using sodium hydroxide ('NaOH')/hydrochloric acid (HCl).

Example 2
The formulations listed in Table 1 were stabilized at 40°C±2°C/75%±5% relative humidity and 25°C±2°C/60%±5% relative humidity. The stability of this formulation was analyzed by evaluating its potency (assay values) and impurity levels at specific time points. Assays and impurities were detected using high performance liquid chromatography with an ultraviolet detector. Assays were performed at 280 nm and expressed as % of initial concentration. For all impurities, analysis was performed at 210 nm and 280 nm and expressed as % area. The amounts of specific impurities are listed in Tables 2-20, along with total impurities as a percentage of each formulation. Relative retention times ('RRT') are shown for each impurity. "ND" indicates that no impurities were detected. "BQL" indicates that the impurity is below the limit of quantification.

Formulation #1 to #5 contained less than 3% total impurities and 25% ± 2°C/75% ± 5% relative humidity after 4 weeks (1 month) at 40°C ± 2°C/75% ± 5% relative humidity. It had less than 1% total impurities after 4 weeks (1 month) at 60%±5% relative humidity. For formulations #6-#8, only formulation #8 was analyzed after 4 weeks or more at 40°C and a total of 4.68% impurities were determined. Formulation #9 showed a total of 2.17% impurities after 4 weeks at 40°C. Formulation #11 showed a total of 1% impurities after 1 week at 40°C. The excellent and surprising stability properties of the formulations of the present invention will make them effective when used by patients.

When compared to Formulation 4, Formulation 7 showed faster formation of impurities and was not stable for more than 1 month at 40°C. Formulation 4 is stable for 4 months when stored at 40°C, indicating 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 subjected to three cycles of -20°C for 48 hours, then 25°C for 48 hours, at which time the physical appearance of the formulation was recorded. The formulation remained clear and colorless throughout the entire freeze-thaw cycle, indicating a stable formulation throughout.

Example 4
To determine the spray profile of Formulation #4, it was subjected to a standardized drop test. The challenge of manufacturing epinephrine spray formulations is that it must be possible to create spray droplets greater than 10 microns in diameter. Spray droplets smaller than 10 microns can be inhaled into the lungs.

Droplet analysis was performed using standardized laser analysis procedures known to those skilled in the art. Droplet size distribution (Dv ₁₀ , Dv ₅₀ , Dv ₉₀ , and range) was tested at two distances, 3 cm and 6 cm. Dv ₁₀ represents the droplet size below which 10% of the volume is smaller; Dv ₅₀ represents the median droplet size; Dv ₉₀ represents the droplet size below which 90% of the total volume is smaller; range represents the distribution range (Dv90-Dv10)/Dv50. %<10 μm represents the percentage of the total volume of droplets with a diameter of less than 10 μm.

Spray patterns, specifically Dmin, Dmax, and ellipse ratio, were tested at two distances, 3 cm and 6 cm. Dmin represents the smallest diameter of the spray pattern in mm, Dmax represents the largest diameter of the spray pattern in mm, and ellipse ratio represents the ratio of Dmax to Dmin. The spray pattern is measured by the shine of the laser sheet perpendicular to the spray at a specified distance from the aperture. The ellipticity ratio is useful because it provides information regarding the shape and density of the spray pump plume.

The results of these tests are shown in sections 21 to 26 below.

Applicants found during testing that the formulations of the present invention produced desirable droplet sizes for spray administration. This study also revealed that the formulation dosage remained constant when administered by spray pump.

Example 5. Preparation of additional water-alcoholic epinephrine spray formulations Additional epinephrine spray formulations were prepared using the ingredients and amounts listed in Table 27 below. All solvents were purged under nitrogen before use. Excipients including 0.5N or 1.0N hydrochloric acid ("HCl"), ethanol, propylene glycol, EDTA, sodium bisulfite, and/or caprylic acid were dissolved in water with stirring at room temperature. Epinephrine base was then added to the excipient solution. Finally, the final pH was adjusted using sodium hydroxide ('NaOH')/hydrochloric acid ('HCl').

The formulations listed in Tables 27 and 28 were filled into unit dosage devices, packaged in oxygen impermeable pouches with oxygen scavengers and then heated at 40°C ± 2°C/75% ± 5% relative humidity and 25% Stabilized at °C ± 2 °C/60% ± 5% relative humidity. The stability of this formulation was analyzed by evaluating its potency (assay values) and impurity levels at specific time points. Assays and impurities were detected using high performance liquid chromatography with an ultraviolet detector. Assays were performed at 280 nm and expressed as % of initial concentration. For all impurities, analysis was performed at 210 nm and 280 nm and expressed as % area. The amounts of specific impurities are listed in Tables 32-55, along with total impurities as a percentage of each formulation. Relative retention times ('RRT') are shown for each impurity. "ND" indicates that no impurities were detected. Any impurity that is less than 0.05% is indicated by BQL. NP indicates that it was not performed.

All formulations exemplified in Tables 27-31 above remained transparent throughout stability testing. The formulations were filled into unit dose spray devices under a nitrogen blanket and then not packaged in pouches (Formulations 12-18) at 25°C ± 2°C/60% ± 5% and 40°C ± 2°C/75%. On the other hand, formulations (F#19-36) were packaged in pouches (Formulations 12-18) with oxygen scavengers at 25°C ± 2°C/60% ± 5%. % and 40°C±2°C/75%±5%. Formulation 13, which was not packaged in a pouch, showed an impurity F level of 5.64% at 2M/40°C. However, a similar formulation 19 packaged in a pouch showed an impurity F level of 4.25% at 2M/40°C. Stability data suggest that epinephrine spray formulations packaged in pouches with oxygen scavengers are more stable than formulations not packaged in pouches. The hydro-alcoholic and aqueous formulations of the invention are stable at room temperature and at 40°C±2°C/75%±5.

For epinephrine 6 mg aqueous formulation in pouch, 3.49% and 8.86% Impurity F for 4 months at 40°C ± 2°C/75% RH ± 5% RH for formulations #27 and 29, respectively. Observed later. After 4 months at 40°C ± 2°C/75% RH ± 5% RH for formulations #27 and 29, the total impurities were found to be 5.05% and 11.22%, respectively. Ta. For hydro-alcoholic formulations in pouches of the same strength, 3.61% and 8.41% 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%, respectively, after 4 months at 40°C ± 2°C/75% RH ± 5% RH. Ta.

2.35% and 9.82% impurities for formulations #31 and 33, respectively, after 4 months at 40°C ± 2°C/75% RH ± 5% RH for epinephrine 9 mg aqueous formulation in pouch. F was observed. Total impurities for formulations #31 and 33 were found to be 4.42% and 12.65%, respectively, after 4 months at 40°C ± 2°C/75% RH ± 5% RH. . For hydro-alcoholic formulations in pouches of the same strength, 2.50% and 9.61% impurity F was observed after the same period for formulations #32 and 34, respectively. Total impurities for formulations #32 and 34 were found to be 4.31% and 11.15%, respectively, after 4 months at 40°C ± 2°C/75% RH ± 5% RH. Ta.

Example 6. Minipig Pharmacokinetic Data for Epinephrine Formulations The protocol design was a single dose crossover study. Five healthy male Yucatan minipigs each weighing approximately 80-95 kg were administered the epinephrine formulation. Minipigs were fasted overnight and up to 4 hours after dosing. Each dose was followed by a washout period of at least one week. Blood samples were taken pre-dose and 2, 5, 10, 15, 20, 30, 45 minutes, 1, 1.5, 2, 4, and 24 hours after dosing. Minipig plasma samples were measured for epinephrine concentration via liquid chromatography tandem mass spectrometry.

The following pharmacokinetic parameters were calculated: peak plasma concentration (C _max ), time to C _max (T _max ), and area under the concentration-time curve from time 0 to 24 hours postdose (AUC _0-24h ).

The pharmacokinetic behavior for epinephrine formulations was evaluated. Five minutes after single-dose intramuscular (IM) administration of epinephrine in minipigs, the geometric mean plasma concentration of epinephrine was 0.046 ng/mL. A more rapid absorption of epinephrine was observed when epinephrine was prescribed in #M1 and administered intranasally. Specifically, #M1 exhibited a geometric mean epinephrine plasma concentration of 0.26 ng/mL 5 minutes after dosing. It was also noted that a plasma concentration of 0.41 ng/mL was achieved as quickly as 2 minutes after intranasal administration of #M1. Furthermore, #M1 exhibited a geometric mean Cmax of 1.01 ng/mL and a geometric mean AUC _0-24h of 161.0 ng*min/L.

Example 7. Rabbit Pharmacokinetic Data for Epinephrine Formulations The protocol design was a single dose crossover study. The pharmacokinetics of a number of epinephrine formulations were evaluated in healthy male New Zealand white rabbits weighing approximately 2-3 kilograms. Six rabbits were used for each dose. Rabbits were fasted overnight and up to 4 hours post-dose. Blood samples were taken pre-dose and 5, 10, 15, 20, 30, 40 minutes, 1, 1.5, 2, 4, and 5 hours after dosing. Rabbit plasma samples were measured for epinephrine concentration via liquid chromatography tandem mass spectrometry.

Formulations #R1 to #R8 are shown in Tables 58 and 59. Formulation #R9 was present as a spray-dried powder of epinephrine bitartrate. For evaluation of #R9, each animal was dosed with approximately 21.83 mg of powder, an equivalent dose of 12 mg of epinephrine.

The following pharmacokinetic parameters were calculated: peak plasma concentration (C _max ), time to C _max (T _max ), and area under the concentration-time curve from time 0 to 24 hours postdose (AUC _{0 ). -24h} ).

The pharmacokinetic behavior for epinephrine formulations was evaluated. Five minutes after single-dose IM administration of epinephrine in minipigs, the mean plasma concentration of epinephrine was 0.988 ng/mL. As a comparison, sublingual administration of epinephrine allowed similar absorption of epinephrine in an earlier phase. Specifically, #R9 exhibited a mean epinephrine plasma concentration of 0.0.814 ng/mL 5 minutes after dosing. It was also noted that a plasma concentration of 0.713 ng/mL was achieved 5 minutes after sublingual administration of #R6. Furthermore, #R9 exhibited a geometric mean Cmax of 7.0 ng/mL and a geometric mean AUC _0-24h of 1050.1 ng*min/L.

Example 8. Method for intranasal administration of epinephrine spray formulations

The protocol design was a Phase I, proof-of-concept, single-dose, open-label, five-treatment, cross-over study to evaluate the bioavailability of an intranasal formulation in adults with seasonal allergies. This study was conducted using EpiPen® (0.3 milligrams of epinephrine, 1.8 milligrams of sodium chloride, 0.5 milligrams of sodium bisulfite, hydrochloric acid to adjust pH, and water for injection). The bioavailability of single 3-milligram and 6-milligram doses of epinephrine versus a single 0.3-milligram intramuscular dose of epinephrine in the formulations of the invention was evaluated. Fifty subjects were randomly placed into one of five groups and administered a 3 milligram intranasal dosage of an aqueous formulation of the invention, a 3 milligram intranasal dosage of a hydro-alcoholic formulation of the invention, an aqueous formulation of the invention. An intranasal dosage of 6 milligrams of the formulation, an intranasal dosage of 6 milligrams and an intramuscular dosage of 0.3 milligrams of the hydro-alcoholic formulation of the invention, during periods 1 and 2 of the allergen that causes seasonal allergies to develop in the subject. was administered over four periods in the absence of and periods 3 and 4 were administered in the presence of allergen. Plasma concentrations were collected at -60, -30, 0, 1, 3, 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 180, 240 and 360 minutes post-dose.

result

As shown in Tables 63-65 and Figures 1-3, subjects who received 6 milligrams of epinephrine in the hydroalcoholic formulation of the invention in the presence of allergen had a higher C _max than all other cohorts. Furthermore, as shown in Figures 1-3, subjects who received 0.3 milligrams of epinephrine intramuscularly in the absence of allergen had a higher C _max than all other cohorts in the absence of allergen. It had Among subjects who received either the aqueous or hydroalcoholic formulation, those who received the hydroalcoholic formulation had higher C than those who received the aqueous formulation across all samples, both in the absence and presence of allergen. It had _max . Epinephrine plasma concentrations were greater than 100 pg/mL until 30 minutes post-dose for all formulations. Furthermore, for all formulations of the invention, epinephrine plasma concentrations were greater than 100 pg/mL within 5 minutes after dosing, regardless of allergen exposure. Subjects administered the hydroalcoholic formulation had higher exposure throughout the entire sampling period up to 6 hours compared to the aqueous formulation.

In conclusion, the bioavailability of intranasal formulations of the invention is good or better than intramuscular formulations in subjects both experiencing and not experiencing seasonal allergies.

Example 9. How does the intranasal formulation of the invention compare with IM Adrenaline by Epipen®? - Two test formulations of alcoholic epinephrine nasal spray: epinephrine IM injection, EpiPen® (0.30 mg administered intramuscularly), and epinephrine IM injection, Adrenaline® (administered intramuscularly). 0.50 mg; Adrenaline®, 1.0 mg epinephrine, 6.15 mg sodium chloride, 0.457 mg sodium bisulfite, 0.920 mg sodium hydroxide, 2.25 mg tartaric acid, To evaluate pharmacokinetics, a simple formulation was used to evaluate pharmacokinetics compared to a reference formulation of 0.20 milligrams of edetate disodium dihydrate, hydrochloric acid to adjust pH, milligrams of chlorobutanol and water, for injection). It was a single-dose, open-label, randomized, four-treatment, four-way crossover study. Each dose for the study treatment was separated by a 24 hour washout period. Water-alcoholic epinephrine nasal sprays (7 mg and 8.5 mg) and epinephrine IM injections (EpiPen® [0.30 mg] and Adrenalin®) were administered to healthy volunteer subjects after an overnight fast of at least 10 hours. ) [0.50 mg]) was given.

This study consisted of five periods: a screening period and four treatment periods. During screening (days -28 to -1), subjects sign informed consent and then undergo eligibility determination. Approximately 48 subjects were included based on successful completion of the screening process. Subjects received a single dose of each test formulation and a single dose of each reference formulation on day 1, period 1, day 2, period 2, day 3, period 3, and day 4, period 4, according to the assigned treatment order. given the amount. Subjects were confined to ensure observance of a 10 hour fast and remained until all procedures were completed on day 5. No food was allowed until at least 4 hours after each dose administration. No water was allowed from 1 hour before to 1 hour after each dose administration. Meals were served at the appointed time. Blood samples for pharmacokinetic (PK) analysis were taken before and multiple times after each dose of study drug. Safety and tolerability were evaluated throughout the study.

Pharmacokinetics:
Sample collection time: A total of 288 mL (72 x 4 mL samples) of blood was collected from each subject for pharmacokinetic analysis. Blood samples (1 x 4 mL) for epinephrine analysis were placed in vacutainer tubes containing K ₂ -EDTA as preservative at −60 and −30 min, 0 h (pre-dose), 1 and 3 post-dose for each study period. , 5, 7, 10, 15, 20, 30, and 45 minutes; and 1, 1.5, 2, 3, 4, and 6 hours (18 time points). Pre-dose blood samples were collected within 60 minutes before each dose of study drug.

Bioanalytical Method: Plasma concentrations of epinephrine were analyzed using a validated liquid chromatography with tandem mass spectrometry (LC/MS/MS) assay using a lower limit of quantitation (LLOQ) of 10.0 pg/mL. did.

PK parameters: Plasma concentrations of epinephrine (with or without baseline calibration) were used to determine the following PK parameters using noncompartmental PK analysis (NCA):
1. maximum observed plasma concentration (C _max ),
2. time to maximum plasma concentration (t _max );
3. Area under the curve from time 0 to the time of the last concentration measurement (AUC _last ),
4. Area under the curve sheathed to infinity (AUC _0-inf ),
5. time to first measurable (non-zero) concentration (t _lag ),
6. half-life (t _1/2 ),
7. the last quantifiable concentration (C _last ) and the time corresponding to this concentration (t _last ),
8. apparent systemic clearance (CL/F) after extravascular administration;
9. Apparent distribution volume in the final phase (Vz/F), and 10. Relative epinephrine bioavailability (Frel) for test formulation compared to reference formulation.

Baseline calibration was performed by subtracting the mean epinephrine concentrations at -1, -0.5, and 0 hours from each post-dose concentration. Baseline calibrated concentrations less than 0 were set as 0 pg/mL.

result

As shown in Table 66, intranasal administration of compositions #37 and #38 results in higher plasma concentrations 5 minutes after administration than either Epipen® or intramuscular epinephrine. In fact, the 8.5 mg dosage of Composition #38 produced more than twice as high plasma concentrations of either Epipen® or intramuscular adrenaline. Plasma concentrations of epinephrine remained higher than Epipen® or intramuscular epinephrine for 6 hours post-dose in subjects receiving Compositions #37 or #38.

As shown in Table 67, intranasal administration of compositions #37 and #38 results in higher C _max , AUC _last and AUC _0-inf than either Epipen® or intramuscular epinephrine. In fact, administration of compositions #37 and #38 resulted in 1.4 and 1.8 times higher C _max than Epipen®.

As shown in Table 68, intranasal administration of Compositions #37 and #38 resulted in higher epinephrine plasma concentrations than Adrenaline® IM injection compared to EpiPen®. In fact, administration of compositions #37 and #38 resulted in 4.3-fold and 5.3-fold higher epinephrine plasma concentrations at 1 minute compared to EpiPen®.

As shown in Table 69, intranasal administration of Compositions #37 and #38 resulted in a much higher ratio of epinephrine AUC than Adrenaline® IM injection compared to EpiPen®. In fact, administration of compositions #37 and #38 resulted in 4.2-fold and 5-fold higher epinephrine AUC at 1 minute compared to EpiPen®.

Claims (3)

from about 3.885% w/w to about 6.356% w/w epinephrine or a salt thereof;
Approximately 5% w/w propylene glycol;
Approximately 40% w/w ethanol;
about 0.01% w/w benzalkonium chloride;
about 0.05% w/w edetate disodium dihydrate; and
An epinephrine spray formulation comprising from about 0.184% w/w to about 0.3% w/w sodium bisulfite , where w/w indicates weight/weight of the formulation. Epinephrine approximately 4.702% w/w;
Contains approximately 0.223% w/w sodium bisulfite, and
about 26.241% w/w of about 1.0N normal hydrochloric acid; and
Approximately 23.774% w/w water
The formulation according to claim 1, comprising: Epinephrine approximately 3.885% w/w;
Contains approximately 0.184% w/w of sodium bisulfite, and
2. The formulation of claim 1, comprising: about 21.681% w/w of about 1.0N normal hydrochloric acid; and about 29.190% w/w of water.

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