EA045992B1 - COMPOSITIONS OF Epinephrine IN THE FORM OF SPRAY - Google Patents

Description

Link to related applications

The invention claims benefit from U.S. Provisional Patent Application No. 62/644,834 filed Mar. 19, 2018, U.S. Provisional Patent Application No. 62/663,100 filed April 26, 2018, U.S. Provisional Patent Application No. 62/712678, filed in July. August 31, 2018, US Provisional Patent Application No. 62/747,048, filed October 17, 2018, and US Provisional Patent Application No. 62/810,261, filed February 25, 2019, which are incorporated herein in their entirety by links.

BACKGROUND OF THE INVENTION Epinephrine (adrenaline) is a catecholamine that stimulates the α- and β-adrenergic receptors of the sympathetic nervous system. Epinephrine binds to these adrenergic receptors, resulting in relief of many of the life-threatening symptoms of anaphylaxis (eg, relaxation of smooth muscle in the bronchi of the lungs, opening up narrowed airways, constriction of blood vessels, resulting in decreased swelling of the tongue and throat, and increased blood pressure, and also increasing heart rate, thereby preventing or causing regression of cardiovascular collapse).

Brief Disclosure of the Present Invention

In an aspect, a pharmaceutical composition is provided herein in the form of a spray. In some embodiments, the pharmaceutical spray composition includes from about 0.5% to about 25% w/w. epinephrine or a pharmaceutically acceptable salt of epinephrine in water, the pH of the composition being between about 4.0 and about 6.5. In some embodiments, the pharmaceutical spray composition includes from about 0.5% to about 25% w/w. epinephrine or a pharmaceutically acceptable salt of epinephrine in water, ethanol, propylene glycol, or a combination thereof. In some embodiments, the pharmaceutical spray composition includes from about 0.5% to about 25% w/w. epinephrine or a pharmaceutically acceptable salt of epinephrine in water, ethanol, propylene glycol, or a combination thereof. In some embodiments, the pharmaceutical spray composition includes about 0.5% to about 10% wt./wt. epinephrine or a pharmaceutically acceptable salt of epinephrine in water, ethanol, propylene glycol, or a combination thereof. In some embodiments, the pH of the pharmaceutical spray formulation is between about 4.0 and about 6.5.

In one aspect, the present document discloses a pharmaceutical composition in the form of a spray containing from about 0.5% to about 25% wt./wt. epinephrine or a pharmaceutically acceptable salt of epinephrine in water, the pH of the composition being between about 4.0 and about 6.5. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 0.5% to about 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof. According to some embodiments, the pharmaceutical composition in the form of a spray contains about 2% to about 5% wt./wt. epinephrine. In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray formulation further comprises one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffer agent. In some embodiments, the pharmaceutical spray composition contains an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, and a buffer agent. In some embodiments, the pharmaceutical spray composition contains an antioxidant. In some embodiments, the pharmaceutical spray composition comprises an antioxidant containing sodium bisulfite or sodium metabisulfite. In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of about 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of about 0.001% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of about 0.01% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of about 0.05% (w/w). In some embodiments, the pharmaceutical spray composition contains an antimicrobial preservative. In some embodiments, the pharmaceutical spray composition comprises an antimicrobial preservative comprising chlorobutanol. In some embodiments, the pharmaceutical spray formulation contains an antimicrobial preservative at a concentration of about 0.005% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray composition contains an antimicrobial preservative at a concentration of about 0.01% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation contains an antimicrobial preservative at a concentration of about 0.1% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray composition contains

- 1 045992 live antimicrobial preservative in a concentration of approximately 0.21% (w/v). In some embodiments, the pharmaceutical spray composition contains an isotonic agent. In some embodiments, the pharmaceutical spray composition comprises an isotonic agent comprising sodium chloride. In some embodiments, the pharmaceutical spray composition contains an isotonic agent at a concentration of about 0.1% to about 5%. In some embodiments, the pharmaceutical spray formulation contains an isotonic agent at a concentration of about 0.1% to about 1%. In some embodiments, the pharmaceutical spray formulation contains an isotonic agent at a concentration of about 0.4%. In some embodiments, the pharmaceutical spray composition contains an absorption enhancer. In some embodiments, the pharmaceutical spray composition comprises an absorption enhancer comprising diethylene glycol monoethyl ether. In some embodiments, the pharmaceutical spray formulation contains an absorption enhancer at a concentration of about 0.05% to about 15%. In some embodiments, the pharmaceutical spray formulation contains an absorption enhancer at a concentration of about 0.1% to about 5%. In some embodiments, the pharmaceutical spray formulation contains an absorption enhancer at a concentration of about 1%. In some embodiments, the pharmaceutical spray composition contains a viscosity modifier. In some embodiments, the pharmaceutical spray composition comprises a viscosity modifier comprising hypromellose. In some embodiments, the pharmaceutical spray formulation contains a viscosity modifier at a concentration of about 0.001% to about 0.5%. In some embodiments, the pharmaceutical spray formulation contains a viscosity modifier at a concentration of about 0.01% to about 0.2%. In some embodiments, the pharmaceutical spray formulation contains a viscosity modifier at a concentration of about 0.1%. In some embodiments, the pharmaceutical spray composition contains a buffering agent. In some embodiments, the pharmaceutical spray composition comprises a buffer agent comprising citric acid or citric acid monohydrate. In some embodiments, the pharmaceutical spray composition contains a buffering agent at a concentration of about 0.01% to about 2%. In some embodiments, the pharmaceutical spray formulation contains a buffering agent at a concentration of about 0.1% to about 1%. In some embodiments, the pharmaceutical spray formulation contains a buffering agent at a concentration of about 0.42%. In some embodiments, the pharmaceutical spray composition contains sodium metabisulfite, sodium chloride, hypromellose, citric acid monohydrate, and diethylene glycol monoethyl ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2% citric acid monohydrate and about 0.05% - about 15% diethylene glycol monoethyl ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1% sodium chloride, about 0. 01% is about 0.2% hypromellose, about 0.1% is about 1% citric acid monohydrate and about 0.1% is about 5% diethylene glycol monoethyl ether. In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2% citric acid monohydrate and about 0.05% - about 15% diethylene glycol monoethyl ether. In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% about 1% sodium chloride, about 0.01 % - about 0.2% hypromellose, about 0.1% - about 1% citric acid monohydrate and about 0.1% - about 5% diethylene glycol monoethyl ether. In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2% citric acid monohydrate and about 0.05% - about 15% diethylene glycol monoethyl ether. According to

- 2 045992 In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1% sodium chloride, about 0. 01% is about 0.2% hypromellose, about 0.1% is about 1% citric acid monohydrate and about 0.1% is about 5% diethylene glycol monoethyl ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2% citric acid monohydrate and about 0.05% - about 15% diethylene glycol monoethyl ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1% sodium chloride, about 0. 01% - about 0.2% hypromellose, about 0.1% - about 1% citric acid monohydrate and about 0.1% - about 5% diethylene glycol monoethyl ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2% citric acid monohydrate and about 0.05% - about 15% diethylene glycol monoethyl ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1% sodium chloride, about 0. 01% is about 0.2% hypromellose, about 0.1% is about 1% citric acid monohydrate and about 0.1% is about 5% diethylene glycol monoethyl ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether. In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.005% (w/v) to about 10% (w/v). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.01% (w/v) to about 10% (w/v). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.1% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.21% (w/v). In another aspect, a spray containing drops is disclosed herein, the drops containing a pharmaceutical spray composition described herein. In another aspect, disclosed herein is a method of treating anaphylaxis, anaphylactic shock, severe allergic reaction, and/or bronchoconstriction, comprising delivering an injection of a pharmaceutical solution from a pre-filled device into the nostril of a subject in need thereof, wherein: the device is configured for nasal delivery; a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and the pharmaceutical solution contains a pharmaceutical spray composition described herein. In another aspect, disclosed herein is a method of treating respiratory depression or distress caused by anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a pre-filled device into the nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution in the form of a circular spray stream with an ovality ratio, less than about 2.0 when measured at a distance of about 1 to about 10 cm from the prefilled device, wherein: the device is configured for nasal delivery; a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and the pharmaceutical solution contains a pharmaceutical spray composition described herein. In another aspect, disclosed herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein: orally

- 3 045992 the swarm is designed for nasal delivery; a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and the pharmaceutical solution contains a pharmaceutical spray composition described herein. In some embodiments, a therapeutic plasma concentration of epinephrine in a subject is achieved less than 20 minutes after administration to the subject. In some embodiments, the therapeutic plasma concentration of epinephrine in a subject is approximately 0.5 ng/mL epinephrine. In some embodiments, the subject has a maximum plasma concentration ( _Cmax ) of about 0.1 ng/mL to about 1 ng/mL of epinephrine. In some embodiments, the area under the plasma concentration-time curve for epinephrine in a subject is from about 0.1 ng-hour/mL to about 5 ng-hour/mL. In some embodiments, the plasma concentration-time curve for epinephrine in a subject has a tmax of less than about 10 minutes to about 120 minutes. In some embodiments, the device is a single-dose device. In some embodiments, the device is a two-dose device. In some embodiments, the device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, the device comprises a first reservoir containing about 50 μL to about 250 μL of a pharmaceutical solution and a second reservoir containing about 50 μL to about 250 μL of a pharmaceutical solution. In some embodiments, less than about 20% of the composition leaves the nasal cavity via nasopharyngeal or external drainage. In some embodiments, a single spray into a subject's nostril provides a plasma concentration of at least 0.2 ng/mL within 2 minutes in the subject. According to another aspect, the present document discloses a stable pharmaceutical composition in the form of a spray containing: about 1% - about 25% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof in water; and one or more of the following: excipients, carrier vehicles, emulsifiers, stabilizers, preservatives, mucosal adhesion agents, antibacterial agents, buffers and/or other excipients, the composition being stable at a temperature of at least about 20 °C and at a relative humidity of at least about 30%, and wherein the formulation is stable for a period of at least about two months, wherein the stable pharmaceutical formulation is a spray pharmaceutical formulation disclosed herein.

In an aspect, provided herein is a method of treating anaphylaxis, anaphylactic shock, severe allergic reaction, and/or bronchoconstriction comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical spray composition described herein. In some embodiments, the subject is an adult. In some embodiments, the subject is a child. In some embodiments, the child weighs between about 10 pounds and about 80 pounds.

In an aspect, provided herein is a spray including drops. The spray drops include a total of about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent, and benzalkonium chloride or chlorobutanol. In some embodiments, the spray contains about 0.005% to about 10% (w/v) benzalkonium chloride or about 0.005% to about 10% (w/v) chlorobutanol. In some embodiments, provided herein is a spray containing drops, wherein the drops contain a total of about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent, and about 0.005% (w/v) to about 10 % (w/v) benzalkonium chloride or about 0.005% (w/v) - about 10% (w/v) chlorobutanol. In some embodiments, the spray is delivered from the device. In some embodiments, the device is a single-dose device. In some embodiments, the device is a two-dose device. In some embodiments, the device comprises a single reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the spray is delivered from a device and the device is pre-filled. In some embodiments, the isotonic agent is present at a concentration of about 0.1% (w/v) to about 5% (w/v). In some embodiments, the isotonic agent is sodium chloride. In some embodiments, the spray takes the form of a circular jet with an ovality ratio of less than about 2.0. In some embodiments, the spray takes the form of a circular spray with an ovality ratio of less than about 1.5. In some embodiments, the spray takes the form of a circular stream with a coefficient

- 4,045,992 ovality of less than about 1.3. In some embodiments, the spray takes the form of a circular spray with an ovality ratio of less than about 1.2. In some embodiments, the spray takes the form of a circular jet with an ovality ratio of less than about 1.1. In some embodiments, the ovality factor is measured at a distance of about 1 cm to about 10 cm from the device. In some embodiments, the ovality factor is measured at a distance of about 1 cm to about 5 cm from the device. In some embodiments, the ovality factor is measured at a distance of approximately 3 cm from the device. In some embodiments, epinephrine is at least 10% bioavailable. In some embodiments, epinephrine is at least 40% bioavailable. In some embodiments, epinephrine is at least 50% bioavailable. In some embodiments, epinephrine is at least 60% bioavailable. In some embodiments, the average droplet size is between about 10 microns and about 120 microns. In some embodiments, no more than about 10% of the droplets have a diameter less than about 10 microns. In some embodiments, no more than about 5% of the droplets have a diameter less than about 10 microns. In some embodiments, no more than about 2% of the droplets have a diameter less than about 10 microns. In some embodiments, about 50% of the droplets have a diameter of about 10 μm to about 120 μm. In some embodiments, about 50% of the droplets have a diameter of about 10 μm to about 60 μm. In some embodiments, about 90% of the droplets have a diameter less than about 120 microns. In some embodiments, the spray further contains a stabilizer and an acid. In some embodiments, the spray further comprises a stabilizer and an acid, wherein the stabilizer is disodium edetate. In some embodiments, the spray further contains a stabilizer and an acid. In some embodiments, the spray further comprises a stabilizer and an acid, wherein the acid is hydrochloric acid or citric acid or a combination thereof. In some embodiments, epinephrine or a pharmaceutically acceptable salt thereof is dissolved in water, ethanol, or propylene glycol, or a combination thereof. In some embodiments, the spray further comprises sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w), or sodium metabisulfite at a concentration of about 0.0001 % (w/w) - approximately 0.1% (w/w). In some embodiments, the spray further comprises sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.05% (w/w), or sodium metabisulfite at a concentration of about 0.0001 % (w/w) - approximately 0.05% (w/w). In some embodiments, the spray further comprises sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w), or sodium metabisulfite at a concentration of about 0.0001 % (w/w) - approximately 0.1% (w/w). In some embodiments, the spray further comprises sodium bisulfite at a concentration of about 0.01% (w/w) to about 0.1% (w/w), or sodium metabisulfite at a concentration of about 0.01 % (w/w) - approximately 0.1% (w/w). In some embodiments, the spray further contains chlorobutanol at a concentration of about 0.005% (w/w) to about 1% (w/w). In some embodiments, the spray further comprises a vasodilator. In some embodiments, the spray further comprises a vasodilator, wherein the vasodilator is nitroprusside, phentolamine, or nifedipine. In some embodiments, the spray further comprises a penetration enhancer. In some embodiments, the spray further comprises a penetration enhancer, wherein the penetration enhancer is diethylene glycol monoethyl ether. In some embodiments, the spray further comprises a viscosity modifier. In some embodiments, the spray further comprises a penetration enhancer, wherein the viscosity modifier is polyethylene glycol, methylcellulose, or hypromellose. In some embodiments, the spray further contains trisodium citrate or citric acid monohydrate. In some embodiments, the spray is delivered from a device, the device comprising at least one oxygen absorbent or scavenger. In some embodiments, the spray is delivered from a device, wherein the device contains at least one oxygen absorbent or scavenger, and wherein the at least one oxygen absorbent or scavenger is iron, ferric carbonate, ascorbate or sodium bicarbonate, or a combination thereof. In some embodiments, the spray contains per 100 μl of solution: about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof; about 0.1 mg - about 2 mg sodium chloride; approximately 0.01 mg - approximately 1 mg benzalco chloride

- 5 045992 nia; about 0.1 mg - about 2 mg disodium edetate; and hydrochloric acid or citric acid or a combination thereof in an amount sufficient to achieve a pH value of about 3.5 to about 6.5. In some embodiments, the spray is delivered from a spray nozzle of a prefilled device, with no more than about 10% of the droplets having a diameter less than 10 microns. In some embodiments, atomization is measured using laser diffraction with beams measured at both 3 cm and 6 cm from the spray nozzle.

In another aspect, a stable pharmaceutical spray formulation is provided herein, wherein the pharmaceutical spray formulation is stable for a period of at least about two months at a temperature of at least about 20° C. and relative humidity, of at least about 30%. The stable pharmaceutical composition in the form of a spray includes the following:

(i) about 1% - about 25% w/w. epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol or a combination thereof; and (ii) one or more of the following: excipients, carrier vehicles, emulsifiers, stabilizers, preservatives, mucosal adhesion agents, antibacterial agents, buffers and/or other excipients, the composition being stable at a temperature of at least at least about 20°C, and at a relative humidity of at least about 30%, and wherein the composition is stable over a period of at least about two months. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical spray formulation is stable at a temperature of at least about 25°C. In some embodiments, the pharmaceutical spray formulation is stable at a temperature of at least about 30°C. In some embodiments, the pharmaceutical spray formulation is stable at a temperature of at least about 35°C. In some embodiments, the pharmaceutical spray formulation is stable at a temperature of at least about 40°C. In some embodiments, the pharmaceutical spray formulation is stable at a temperature of at least about 45°C. In some embodiments, the pharmaceutical spray formulation is stable at a relative humidity of at least about 40%. In some embodiments, the pharmaceutical spray formulation is stable at a relative humidity of at least about 50%. In some embodiments, the pharmaceutical spray formulation is stable at a relative humidity of at least about 60%. In some embodiments, the pharmaceutical spray formulation is stable at a relative humidity of at least about 70%. In some embodiments, the pharmaceutical spray formulation is stable at a relative humidity of at least about 80%. In some embodiments, the pharmaceutical spray formulation is stable for a period of at least about six months. In some embodiments, the pharmaceutical spray formulation is stable over a period of at least about 12 months. In some embodiments, the pharmaceutical spray formulation is stable for a period of at least about 18 months. In some embodiments, the pharmaceutical spray formulation is stable for a period of at least about 24 months. In some embodiments, the pharmaceutical spray formulation is stable for a period of at least about 36 months. In some embodiments, the pharmaceutical spray formulation has a viscosity of about 100 to about 2500 cP. In some embodiments, the pharmaceutical spray formulation is capable of parenteral dosing. In some embodiments, the pharmaceutical spray formulation is capable of dosing by inhalation. In some embodiments, the pharmaceutical spray formulation is configured for intranasal dosing. In some embodiments, the pharmaceutical spray formulation further comprises an isotonic agent present at a concentration of about 0.1% (w/w) to about 5% (w/w). In some embodiments, the pharmaceutical spray composition further comprises an isotonic agent present at a concentration of about 0.1% (w/w) to about 5% (w/w), wherein the isotonic agent is sodium chloride. In some embodiments, the pharmaceutical spray composition contains a stabilizer. In some embodiments, the pharmaceutical spray composition contains a stabilizer, wherein the stabilizer is disodium edetate. In some embodiments, the pharmaceutical

- 6 045992 the spray composition further contains an acid sufficient to achieve a pH value of about 3.5 to about 6.5. In some embodiments, the pharmaceutical spray composition further comprises an acid sufficient to achieve a pH value of about 3.5 to about 6.5, wherein the acid is hydrochloric acid or citric acid, or a combination thereof. In some embodiments, the spray further comprises sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w), or sodium metabisulfite at a concentration of about 0.0001 % (w/w) - approximately 0.1% (w/w). In some embodiments, the pharmaceutical spray composition further comprises sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.05% (w/w), or sodium metabisulfite at a concentration of about 0.0001% (w/w) - about 0.05% (w/w). In some embodiments, the spray further comprises sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w), or sodium metabisulfite at a concentration of about 0.0001 % (w/w) - approximately 0.1% (w/w). In some embodiments, the spray further comprises sodium bisulfite at a concentration of about 0.01% (w/w) to about 0.1% (w/w), or sodium metabisulfite at a concentration of about 0.01 % (w/w) - approximately 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation further comprises chlorobutanol at a concentration of about 0.005% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray composition further comprises a vasodilator. In some embodiments, the pharmaceutical spray composition further comprises a vasodilator, wherein the vasodilator is nitroprusside, phentolamine, or nifedipine. In some embodiments, the pharmaceutical spray composition further comprises a penetration enhancer. In some embodiments, the pharmaceutical spray composition further comprises a penetration enhancer, wherein the penetration enhancer is diethylene glycol monoethyl ether. In some embodiments, the pharmaceutical spray composition further comprises a viscosity modifier. In some embodiments, the pharmaceutical spray composition further comprises a viscosity modifier, wherein the viscosity modifier is polyethylene glycol, methylcellulose, or hypromellose. In some embodiments, the pharmaceutical spray formulation further comprises trisodium citrate or citric acid monohydrate. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.05% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2.0% trisodium citrate and about 0.05% - about 15% diethylene glycol monoethyl ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.05% (w/w) sodium metabisulfite, about 0.1% - about 1.0% sodium chloride, about 0.01% is about 0.2% hypromellose, about 0.1% is about 1.0% trisodium citrate, and about 0.1% is about 2.0% diethylene glycol monoethyl ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 5% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.05% (w/w) sodium metabisulfite, about 0.1% about 1.0% sodium chloride, about 0 .05% - about 0.5% hypromellose, about 0.1% - about 1.0% trisodium citrate, and about 0.5% - about 5% diethylene glycol monoethyl ether. In some embodiments, the pharmaceutical spray composition contains about 2.4 % w/w epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . In some embodiments, the pharmaceutical spray composition contains about

- 7 045992

1% - approximately 20% w/w epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2.0% citric acid monohydrate and about 0.05% - about 15% diethylene glycol monoethyl ether. In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether. In some embodiments, the pharmaceutical spray formulation further comprises chlorobutanol at a concentration of about 0.05% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical composition is delivered as a spray from the device. In some embodiments, the device is a single-dose device. In some embodiments, the device is a two-dose device. In some embodiments, the device comprises a single reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device delivers one injection of a pharmaceutical solution from a first reservoir, and one injection of a pharmaceutical solution from a second reservoir. In some embodiments, the pharmaceutical composition is delivered as a spray from the device, and the device is pre-filled. In some embodiments, the pharmaceutical composition is delivered as a spray from the device, the device being suitable for delivering the composition to the nostril of a subject. In some embodiments, the pharmaceutical composition is delivered as a spray from the device, the device comprising at least one oxygen absorbent or scavenger. In some embodiments, the pharmaceutical composition is delivered as a spray from a device, wherein the device contains at least one oxygen absorbent or scavenger, and wherein the at least one oxygen absorbent or scavenger is iron, ferric carbonate, ascorbate or sodium bicarbonate, or a combination thereof . In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection. In some embodiments, the spray takes the form of a circular jet with an ovality ratio of less than about 2.0. In some embodiments, the spray takes the form of a circular spray with an ovality ratio of less than about 1.5. In some embodiments, the spray takes the form of a circular spray with an ovality ratio of less than about 1.3. In some embodiments, the spray takes the form of a circular spray with an ovality ratio of less than about 1.2. In some embodiments, the spray takes the form of a circular jet with an ovality ratio of less than about 1.1. In some embodiments, the ovality factor is measured at a distance of about 1 cm to about 10 cm from the device. In some embodiments, the ovality factor is measured at a distance of about 1 cm to about 5 cm from the device. In some embodiments, the ovality factor is measured at a distance of approximately 3 cm from the device. In some embodiments, epinephrine is at least 10% bioavailable. In some embodiments, epinephrine is at least 40% bioavailable. In some embodiments, epinephrine is at least 50% bioavailable. In some embodiments, epinephrine is at least 60% bioavailable. In some embodiments, the average droplet size is between about 10 microns and about 120 microns. In some embodiments, no more than about 10% of the droplets have a diameter less than about 10 microns. In some embodiments, no more than about 5% of the droplets have a diameter less than about 10 microns. In some embodiments, no more than about 2% of the droplets have a diameter less than about 10 microns. In some embodiments, about 50% of the droplets have a diameter of about 10 μm to about 120 μm. In some embodiments, about 50% of the droplets have a diameter of about 10 μm to about 60 μm. In some embodiments, about 90% of the droplets have a diameter less than about 120 microns.

- 8 045992

Provided herein is a method of treating anaphylaxis, anaphylactic shock, severe allergic reaction and/or bronchoconstriction. The method involves delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need, wherein:

(i) the device is configured for nasal delivery;

(ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains about 0.5 mg to about 100 mg epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent, and about 0.005% (w/v) to about 1% (w/v) benzalkonium chloride . In some embodiments, the device is a single-dose device. In some embodiments, the device is a two-dose device. In some embodiments, the device comprises a single reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device delivers one injection of a pharmaceutical solution from a first reservoir, and one injection of a pharmaceutical solution from a second reservoir. In some embodiments, epinephrine or a pharmaceutically acceptable salt thereof is dissolved in water, ethanol, propylene glycol, or a combination thereof. In some embodiments, the isotonic agent is present at a concentration of about 0.2% (w/v) to about 1.2% (w/v). In some embodiments, the pharmaceutical solution further contains about 0.1% (w/v) to about 0.5% (w/v) stabilizer. In some embodiments, the pharmaceutical solution further contains an amount of acid sufficient to achieve a pH value of about 3.5 to about 6.5.

In some embodiments, the pharmaceutical solution further comprises an amount of acid sufficient to achieve a pH value of about 3.5 to about 6.5, wherein the acid is hydrochloric acid or citric acid, or a combination thereof. In some embodiments, the isotonic agent is sodium chloride, the stabilizer is disodium edetate, and the acid is hydrochloric acid or citric acid, or a combination thereof. In some embodiments, the plasma concentration-time curve for epinephrine in a subject has a t _max of less than about 10 minutes to about 120 minutes. In some embodiments, a therapeutic plasma concentration of epinephrine in a subject is achieved less than 20 minutes after administration to the subject. In some embodiments, a therapeutic plasma concentration of epinephrine in a subject is achieved less than 15 minutes after administration to the subject. In some embodiments, a therapeutic plasma concentration of epinephrine in a subject is achieved less than 10 minutes after administration to the subject. In some embodiments, a therapeutic plasma concentration of epinephrine in a subject is achieved less than 5 minutes after administration to the subject. In some embodiments, the therapeutic plasma concentration of epinephrine in a subject is approximately 500 pg/mL epinephrine. In some embodiments, the therapeutic plasma epinephrine concentration in the subject is approximately 450 pg/mL epinephrine. In some embodiments, the therapeutic plasma concentration of epinephrine in a subject is approximately 400 pg/mL epinephrine. In some embodiments, the therapeutic plasma concentration of epinephrine in a subject is approximately 350 pg/mL epinephrine. In some embodiments, the therapeutic plasma concentration of epinephrine in a subject is approximately 300 pg/mL epinephrine. In some embodiments, the subject has a maximum plasma concentration ( _Cmax ) of about 50 pg/mL to about 500 pg/mL of epinephrine. In some embodiments, the area under the plasma concentration-time curve for epinephrine in a subject is about 5 ng/min/mL to about 50 ng/min/mL. In some embodiments, the device includes a piston that receives a container lid containing:

(i) a bottle containing an opening;

(ii) cannula; and (iii) rubber stopper;

wherein the stopper is configured to plug the opening of the vial, and wherein the cannula is configured to pierce the stopper when the piston applies sufficient force to the cannula. In some embodiments, the spray delivers about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the prefilled device is operated with one hand. In some embodiments, the prefilled device contains one

- 9 045992 reservoir containing approximately 125 µl of pharmaceutical solution. In some embodiments, approximately 100 μL of the pharmaceutical solution is delivered with a single actuation of the device. In some embodiments, the reservoir volume is no more than about 140 μL. In some embodiments, the delivery time of the pharmaceutical solution is less than about 25 seconds. In some embodiments, the delivery time of the pharmaceutical solution is less than about 20 seconds. In some embodiments, less than about 20% of the pharmaceutical solution leaves the nasal cavity via nasopharyngeal or external drainage. In some embodiments, less than about 10% of the pharmaceutical solution leaves the nasal cavity via nasopharyngeal or external drainage. In some embodiments, less than about 5% of the pharmaceutical solution leaves the nasal cavity via nasopharyngeal or external drainage. In some embodiments, the subject suffers a severe allergic reaction from exposure or suspected exposure to an allergen. In some embodiments, the allergen is a food, drug, or insect bite or sting. In some embodiments, the subject exhibits one or more symptoms selected from the following: respiratory depression or distress, airway constriction, wheezing, tingling in the arms, legs, mouth, or scalp, shortness of breath, swelling or inflammation of the face, eyes, lips, tongue or throat, urticaria, central nervous system depression, cardiovascular depression, impaired level of consciousness, dilated pupils, hypoxemia, hypotension, unresponsiveness to stimuli, loss of consciousness, respiratory arrest, erratic or stopped pulse, and vomiting. In some embodiments, the subject exhibits respiratory depression or distress, or cardiovascular depression. In some embodiments, the subject does not experience respiratory depression or distress for at least about 1 hour following treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience respiratory depression or distress for at least about 2 hours after treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience respiratory depression or distress for at least about 4 hours following treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience respiratory depression or distress for at least about 6 hours following treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is in a supine, supine, or rescue position. In some embodiments, a single nostril spray provides a plasma concentration of =0.2 ng/mL within 2.5 minutes in a subject. In some embodiments, a single nostril spray provides a plasma concentration of = 1 ng/mL within 5 minutes in a subject. In some embodiments, a single nostril spray provides a plasma concentration of =3 ng/mL within 10 minutes in a subject.

In an aspect, provided herein is a method of treating anaphylaxis or anaphylactic shock-induced respiratory depression or disorder comprising delivering an injection of a pharmaceutical solution from a pre-filled device into the nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution in the form of a circular spray stream with an ovality ratio of less than about 2.0 when measured at a distance of about 1 to about 10 cm from the prefilled device, wherein:

(i) the device is configured for nasal delivery;

(ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains about 0.5 mg to about 100 mg epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent, and about 0.005% (w/v) to about 1% (w/v) benzalkonium chloride . In some embodiments, the device is a single-dose device. In some embodiments, the device is a two-dose device. In some embodiments, the device comprises a single reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device delivers one injection of a pharmaceutical solution from a first reservoir, and one injection of a pharmaceutical solution from a second reservoir. In some embodiments, the ovality ratio is

- 10 045992 is less than about 1.5. In some embodiments, the ovality ratio is less than about 1.3. In some embodiments, the ovality ratio is less than about 1.2. In some embodiments, the ovality ratio is less than about 1.1. In some embodiments, the jet ovality coefficient is measured at a distance of about 1 cm to about 5 cm from the device.

In another aspect, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock comprising delivering an injection of a pharmaceutical solution into the nostril of a subject in need thereof, wherein:

(i) the device is configured for nasal delivery;

(ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and the pharmaceutical solution contains about 0.5 mg to about 100 mg epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent, and about 0.005% (w/v) to about 1% (w/v) benzalkonium chloride. In some embodiments, the device is a single-dose device. In some embodiments, the device is a two-dose device. In some embodiments, the device comprises a single reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device delivers one injection of a pharmaceutical solution from a first reservoir, and one injection of a pharmaceutical solution from a second reservoir. In some embodiments, the subject is an adult. In some embodiments, the subject is a child. In some embodiments, the child weighs between about 10 pounds and about 80 pounds.

In another aspect, provided herein is a method of treating anaphylaxis, anaphylactic shock, severe allergic reaction, and/or bronchoconstriction comprising administering or delivering to a subject in need thereof a pharmaceutical spray composition described herein. In some embodiments, the pharmaceutical composition is administered as a spray or delivered into the nostril of a subject from a prefilled device configured for nasal delivery. In some embodiments, a volume of about 20 μL to about 250 μL of spray is delivered. In some embodiments, the plasma concentration-time curve for epinephrine in a subject has a tmax of less than about 10 minutes to about 120 minutes. In some embodiments, the subject has a maximum plasma concentration ( _Cmax ) of about 50 pg/mL to about 500 pg/mL of epinephrine. In some embodiments, the area under the plasma concentration-time curve for epinephrine in a subject is about 5 ng/min/mL to about 50 ng/min/mL. In some embodiments, the prefilled device is operated with one hand. In some embodiments, the prefilled device comprises a single reservoir containing about 125 μL to about 250 μL of pharmaceutical solution. In some embodiments, approximately 100 μL of the pharmaceutical solution is delivered with a single actuation of the device. In some embodiments, the reservoir volume is no more than about 140 μL. In some embodiments, the delivery time of the pharmaceutical solution is less than about 25 seconds. In some embodiments, the delivery time of the pharmaceutical solution is less than about 20 seconds. In some embodiments, less than about 20% of the pharmaceutical solution leaves the nasal cavity via nasopharyngeal or external drainage. In some embodiments, less than about 10% of the pharmaceutical solution leaves the nasal cavity via nasopharyngeal or external drainage. In some embodiments, less than about 5% of the pharmaceutical solution leaves the nasal cavity via nasopharyngeal or external drainage. In some embodiments, the subject suffers a severe allergic reaction from exposure or suspected exposure to an allergen. In some embodiments, the allergen is a food, drug, or insect bite or sting. In some embodiments, the subject exhibits one or more symptoms selected from the following: respiratory depression or distress, airway constriction, wheezing, tingling in the arms, legs, mouth, or scalp, shortness of breath, swelling or inflammation of the face, eyes, lips, tongue or throat, urticaria, central nervous system depression, cardiovascular depression, impaired level of consciousness, dilated pupils, hypoxemia, hypotension, unresponsiveness to stimuli, loss of consciousness, respiratory arrest, erratic or stopped pulse, and vomiting. In some embodiments, the subject exhibits respiratory depression or distress, or cardiovascular depression. In some embodiments, the subject

- 11 045992 no respiratory depression or impairment is observed for at least about 1 hour after treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience respiratory depression or distress for at least about 2 hours following treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience respiratory depression or distress for at least about 4 hours after treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience respiratory depression or distress for at least about 6 hours after treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is in a supine, supine, or rescue position. In some embodiments, a single nostril spray provides a plasma concentration of =0.2 ng/mL within 2.5 minutes in a subject.

In some embodiments, a single nostril spray provides a plasma concentration of =1 ng/mL within 5 minutes in a subject. In some embodiments, a single nostril spray provides a plasma concentration of =3 ng/mL within 10 minutes in a subject.

In another aspect, provided herein is a method of treating depression or respiratory distress caused by anaphylaxis or anaphylactic shock, comprising administering or delivering to a subject in need thereof a spray composition described herein from a pre-filled device into the nostril of the subject in a manner that delivers the composition to in the form of a circular spray stream with an ovality coefficient of less than about 2.0 when measured at a distance of about 1 to about 10 cm from the prefilled device, wherein:

(i) the device is configured for nasal delivery; and (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered.

In some embodiments, the ovality ratio is less than about 1.5. In some embodiments, the ovality ratio is less than about 1.3. In some embodiments, the ovality ratio is less than about 1.2. In some embodiments, the ovality ratio is less than about 1.1. In some embodiments, the ovality factor of the jet is measured at a distance of about 1 cm to about 5 cm from the device.

In another aspect, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising administering or delivering to a subject in need thereof a pharmaceutical spray composition described herein from a device into the nostril of the subject, wherein:

(iii) the device is configured for nasal delivery; and (iv) a volume of approximately 20 μl to approximately 250 μl of spray is delivered.

In some embodiments, the subject is an adult. In some embodiments, the subject is a child. In some embodiments, the child weighs between about 10 pounds and about 80 pounds.

In another aspect, provided herein is an apparatus as described herein, the apparatus comprising the following: at least one processor, an operating system configured to execute executable instructions, a storage device, and a computer program including instructions executable by the digital apparatus. processing to create an application containing the following:

a) a software module sending a first notification to the user's portable device when the device has been launched to administer the formulation;

b) a software module sending a second notification to the second device of the designated third party when the device has been started to administer the formulation;

c) a software module sending a third notification to the user's portable device when the device is outside a predetermined range from the portable device;

d) a software module sending a fourth notification to the second device of the designated third party when the device is outside a predetermined range from the portable device;

e) a software module that collects geographic data about a device when the device is in the control of a user or a secondary user;

f) a software module that saves the device’s geographic data to a remote or cloud database; And

- 12 045992

g) a software module that allows a user or a second user to order a new device using the user's device or portable device.

In some embodiments, the device or second device comprises one or more of the following: a computer, a laptop, a laptop, mobile smartphones, a tablet computer, and a personal digital assistant. In some embodiments, the device further comprises a communication element configured to provide two-way communication with the user's portable device and the digital processing device using a wireless data transfer protocol. In some embodiments, the first, second, third, or fourth notification is sent within the application. In some embodiments, the first, second, third, or fourth notification is automatic. In some embodiments, the first, second, third, or fourth notification comprises one or more of the following: text, graphics, sound, and vibration.

According to another aspect of the methods described herein, the method includes the following:

a) sending the first notification to the user's portable device when the device has been launched to administer the formulation;

b) sending a second notification to the second designated third party device when the device has been started to administer the formulation;

c) sending a third notification to the user's portable device when the device is outside a predetermined range from the portable device;

d) sending a fourth notification to the second device of the designated third party when the device is outside a predetermined range from the portable device;

e) collecting geographic data about a device when the device is in the control of a user or a secondary user;

f) storing the device's geographic data in a remote or cloud database; And

g) allowing the user or co-user to order a new device using the user's device or handheld device.

In another aspect, provided herein is a method of treating anaphylaxis, anaphylactic shock, severe allergic reaction, and/or bronchoconstriction, comprising delivering an injection of a pharmaceutical solution from a pre-filled device into the nostril of a subject in need thereof, wherein: the device is configured for nasal delivery, a volume is delivered, comprising about 20 μl to about 250 μl of spray, and the pharmaceutical solution contains the pharmaceutical spray composition described herein.

In another aspect, provided herein is a method of treating anaphylaxis, anaphylactic shock, severe allergic reaction, and/or bronchoconstriction, comprising delivering an injection of a pharmaceutical solution from a pre-filled device into the nostril of a subject in need thereof, wherein: the device is configured for nasal delivery, a volume is delivered, comprising about 20 μl to about 250 μl of spray, and the pharmaceutical solution contains the pharmaceutical spray composition described herein.

In an aspect, provided herein is a method of treating depression or respiratory distress caused by anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a pre-filled device into the nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution in the form of a circular spray stream with an ovality ratio of less than about 2.0 when measured at a distance of about 1 to about 10 cm from a prefilled device, wherein: the device is configured for nasal delivery, a volume of about 20 μL to about 250 μL of spray is delivered, and the pharmaceutical solution contains a pharmaceutical the spray formulation described herein.

In another aspect, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein: the device is configured for nasal delivery, a volume of approximately 20 μl is delivered - approximately 250 μl of spray, and the pharmaceutical solution contains the pharmaceutical spray composition described herein.

In an aspect, provided herein is a stable pharmaceutical formulation in the form of a spray containing: about 1% to about 25% w/w. epinephrine or a pharmaceutically acceptable salt thereof in water; and one or more of the following: excipients, carrier vehicles, emulsifiers, stabilizers, preservatives, mucosal adhesion agents, antibacterial agents, buffers and/or other excipients, the composition being stable at a temperature of at least about 20 °C, and at a relative humidity of at least about 30%, and wherein the composition is stable in those

- 13 045992 over a period of at least about two months, wherein the stable pharmaceutical formulation is a spray pharmaceutical formulation as described herein.

In another aspect, disclosed herein is a pharmaceutical spray composition comprising: (i) about 1% to about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (ii) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the composition is formulated to be administered into the nostril of a subject as a nasal spray that provides a plasma concentration of at least 0.5 ng/ml within 1 minute of administration. In some embodiments, the pH of the composition is between about 4.0 and about 6.5. In some embodiments, the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration of about 0.01% to about 0.1% (w/w). In some embodiments, the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration of about 0.1% to about 1% (w/w). In some embodiments, the isotonic agent contains sodium chloride at a concentration of about 0.1% to about 1% (w/w). In some embodiments, the viscosity modifier contains hypromellose at a concentration of about 0.01% to about 0.2% (w/w). In some embodiments, the buffer agent contains citric acid or citric acid monohydrate at a concentration of about 0.1% to about 1% (w/w). In some embodiments, the pharmaceutical spray composition contains about 2% or about 5% (w/w) epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical spray composition comprises sodium metabisulfite, sodium chloride, hypromellose, citric acid monohydrate, diethylene glycol monoethyl ether, and chlorobutanol hemihydrate. In some embodiments, the pharmaceutical spray composition contains about 1% to about 10% (w/w) epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% to about 0.1% (w/w) metabisulfite sodium, about 0.1% - about 1% (w/w) sodium chloride, about 0.01% - about 0.2% (w/w) hypromellose, about 0.1% - about 1% (w/w) citric acid monohydrate, about 0.1% to about 5% (w/w) diethylene glycol monoethyl ether, and about 0.1% to about 1% (w/w) chlorobutanol hemihydrate . In another aspect, disclosed herein is a stable pharmaceutical spray composition containing: (a) about 1% to about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (b) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the composition is stable for a period of at least about one month at a temperature of at least about 20°C. In some embodiments, the formulation is stable for a period of at least one month at a temperature of at least about 40°C. In some embodiments, the composition contains no more than about 2% total impurities after storage for a period of at least about one month at a temperature of at least about 40°C. In some embodiments, the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration of about 0.01% to about 0.1% (w/w). In some embodiments, the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration of about 0.1% to about 1% (w/w). In some embodiments, the isotonic agent contains sodium chloride at a concentration of about 0.1% to about 1% (w/w). In some embodiments, the buffer agent contains citric acid or citric acid monohydrate at a concentration of about 0.1% to about 1% (w/w). In another aspect, disclosed herein is a pharmaceutical spray composition comprising: (i) about 1% to about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (ii) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the absorption enhancer is diethylene glycol monoethyl ether. In some embodiments, the composition contains diethylene glycol monoethyl ether at a concentration of about 0.1% to about 5% (w/w). In some embodiments, the absorption enhancer comprises diethylene glycol monoethyl ether at a concentration of about 1% (w/w).

In another aspect, disclosed herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical composition in the form of a spray from a nasal spray device into the nostril of a subject in need thereof, the pharmaceutical composition in the form of a spray comprising: (a) about 1% to about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (b) one or more of the following: antioxidant, antimicrobial preservative

- 14 045992 vant, isotonic agent, absorption enhancer, viscosity modifier or buffer agent; wherein the composition is adapted for administration to the nostril of a subject in the form of a nasal spray that provides a plasma concentration of at least 0.5 ng/ml within 1 minute after administration. In some embodiments, the subject suffers a severe allergic reaction from exposure or suspected exposure to an allergen. In some embodiments, the allergen is a food, drug, or insect bite or sting. In some embodiments, the subject exhibits one or more symptoms selected from the following: respiratory depression or distress, airway constriction, wheezing, tingling in the arms, legs, mouth, or scalp, shortness of breath, swelling or inflammation of the face, eyes, lips, tongue or throat, urticaria, central nervous system depression, cardiovascular depression, impaired level of consciousness, dilated pupils, hypoxemia, hypotension, unresponsiveness to stimuli, loss of consciousness, respiratory arrest, erratic or stopped pulse, and vomiting. In some embodiments, the subject exhibits respiratory depression or distress, or cardiovascular depression. In some embodiments, the subject does not experience respiratory depression or distress for at least about 1 hour after delivery of the pharmaceutical composition as a spray. In some embodiments, the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration of about 0.01% to about 0.1% (w/w). In some embodiments, the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration of about 0.1% to about 1% (w/w). In some embodiments, the isotonic agent contains sodium chloride at a concentration of about 0.1% to about 1% (w/w). In some embodiments, the viscosity modifier contains hypromellose at a concentration of about 0.01% to about 0.2% (w/w). In some embodiments, the buffer agent contains citric acid or citric acid monohydrate at a concentration of about 0.1% to about 1% (w/w). In some embodiments, the pharmaceutical spray composition contains about 2% or about 5% (w/w) epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical spray composition comprises sodium metabisulfite, sodium chloride, hypromellose, citric acid monohydrate, diethylene glycol monoethyl ether, and chlorobutanol hemihydrate. In another aspect, disclosed herein is a method of treating at least one of anaphylaxis, anaphylactic shock, severe allergic reaction, or bronchoconstriction, comprising administering or delivering to a subject in need thereof a stable pharmaceutical spray formulation, wherein the stable pharmaceutical spray formulation comprises : (a) about 1% to about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (b) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the composition is stable for a period of at least about one month at a temperature of at least about 20°C. In some embodiments, the formulation is stable for a period of at least one month at a temperature of at least about 40°C. In some embodiments, the composition contains no more than 2% total impurities after storage for a period of at least about one month at a temperature of at least about 40°C. In another aspect, disclosed herein is a method of treating at least one of anaphylaxis, anaphylactic shock, severe allergic reaction, or bronchoconstriction, comprising administering or delivering to a subject in need thereof a pharmaceutical spray formulation, wherein the pharmaceutical spray formulation comprises: ( c) about 1% to about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (d) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the therapeutic plasma concentration of epinephrine in the subject is achieved less than 15 minutes after administration to the subject. In some embodiments, the absorption enhancer is diethylene glycol monoethyl ether. In some embodiments, the composition contains diethylene glycol monoethyl ether at a concentration of about 0.1% to about 5% (w/w). In some embodiments, the composition contains diethylene glycol monoethyl ether at a concentration of about 1% (w/w).

In another aspect, disclosed herein is a two-dose nasal delivery device configured to deliver a pharmaceutical solution to the nostril of a subject, comprising: (a) a pharmaceutical solution in the form of a pharmaceutical spray composition containing about 1% to about 25% (wt/wt). wt.) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol or a combination thereof; (b) a reservoir containing about 125 μl to about 250 μl of pharmaceutical solution; and wherein the two-dose device is configured to administer the pharmaceutical solution into the nostril of the subject in two nasal sprays. According to

- 15 045992 In some embodiments, the device is a pre-filled device that is designed to be operated with one hand. In some embodiments, the device is configured to deliver approximately 100 μL of pharmaceutical solution from the reservoir each time the device is activated. In some embodiments, the pH of the pharmaceutical solution is between about 4.0 and about 6.5. In some embodiments, the one or more injections take the form of a circular jet with an ovality ratio of less than about 2.0. In some embodiments, the pharmaceutical solution contains an antioxidant. In some embodiments, the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration of about 0.01% to about 0.1% (w/w). In some embodiments, the pharmaceutical solution contains an antimicrobial preservative. In some embodiments, the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration of about 0.1% to about 1% (w/w). In some embodiments, the pharmaceutical solution contains an isotonic agent. In some embodiments, the isotonic agent contains sodium chloride at a concentration of about 0.1% to about 1% (w/w). In some embodiments, the pharmaceutical solution contains a viscosity modifier. In some embodiments, the viscosity modifier contains hypromellose at a concentration of about 0.01% to about 0.2% (w/w). In some embodiments, the pharmaceutical solution contains a buffering agent. In some embodiments, the buffer agent comprises citric acid or citric acid monohydrate at a concentration of about 0.1% to about 1% (w/w). In some embodiments, the pharmaceutical solution contains about 2% or about 5% (wt/wt) epinephrine or a pharmaceutically acceptable salt thereof. In another aspect, disclosed herein is a pre-filled device configured to deliver a pharmaceutical solution to one or both nostrils of a subject, comprising a reservoir containing about 125 μL to about 250 μL of a pharmaceutical solution, wherein the pharmaceutical solution contains: (a) about 1% - about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (b) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the prefilled device is configured to administer the pharmaceutical solution in one or more sprays into one or both nostrils of the subject. In some embodiments, the composition contains diethylene glycol monoethyl ether at a concentration of about 0.1% to about 5% (w/w). In another aspect, disclosed herein is a two-dose device configured to deliver a pharmaceutical solution to one or both nostrils of a subject, comprising a reservoir containing about 125 μL to about 250 μL of a pharmaceutical solution, wherein the pharmaceutical solution contains: (a) about 1% to about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (b) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the pharmaceutical solution is stable for a period of at least about one month at a temperature of at least about 20°C. In some embodiments, the pharmaceutical solution is stable for a period of at least about three months at a temperature of at least about 20°C.

In another aspect, disclosed herein is a method of administering a pharmaceutical solution comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution as a circular spray stream with an ovality coefficient of less than about 1.4 as measured at a distance of about 1 to about 10 cm from the device, wherein: (i) the device is configured for nasal delivery; (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains from about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray stream has a particle size distribution of no more than about 2.2 when measured at a distance of about 1 to about 10 cm from the device. In some embodiments, the spray stream has a D _max of less than about 28 mm when measured at a distance of about 1 to about 10 cm from the device. In some embodiments, the device is a two-dose device configured to deliver two injections of a pharmaceutical solution. In some embodiments, the device comprises a single reservoir containing about 125 μL to about 250 μL of pharmaceutical solution. In some embodiments, the device includes a piston that receives a container cap containing the following: (i) a bottle containing an opening; (ii) cannula; and (iii) rubber stopper; and the traffic jam

- 16 045992 is configured to plug the opening of the vial, and wherein the cannula is configured that the cannula can pierce the stopper when the piston applies sufficient force to the cannula. In some embodiments, the device is a pre-filled device that is designed to be operated with one hand. In some embodiments, the delivery time of the pharmaceutical solution is less than about 25 seconds. In some embodiments, the subject suffers a severe allergic reaction from exposure or suspected exposure to an allergen. In some embodiments, the allergen is a food, drug, or insect bite or sting. In some embodiments, the subject exhibits one or more symptoms selected from the following: respiratory depression or distress, airway constriction, wheezing, tingling in the arms, legs, mouth, or scalp, shortness of breath, swelling or inflammation of the face, eyes, lips, tongue or throat, urticaria, central nervous system depression, cardiovascular depression, impaired level of consciousness, dilated pupils, hypoxemia, hypotension, unresponsiveness to stimuli, loss of consciousness, respiratory arrest, erratic or stopped pulse, or vomiting. In some embodiments, the subject exhibits respiratory depression or distress, or cardiovascular depression. In some embodiments, the subject does not experience respiratory depression or distress for at least about 1 hour following treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In another aspect, disclosed herein is a method of administering a pharmaceutical solution comprising delivering an injection of the pharmaceutical solution from a device into the nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution in a spray stream with a particle size distribution having a spread of no more than about 2 ,2 when measured at a distance of about 1 to about 10 cm from the device, wherein: (i) the device is configured for nasal delivery; (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains about 0.5 mg of about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the particle size distribution has a spread of no more than about 2.0 when measured at a distance of about 1 to about 10 cm from the device. In some embodiments, the device comprises a single reservoir containing about 125 μL to about 250 μL of pharmaceutical solution. In some embodiments, the device is a two-dose device configured to deliver two injections of a pharmaceutical solution from a single reservoir. In another aspect, disclosed herein is a method of administering a pharmaceutical solution comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution in a spray stream with a D _max of less than about 28 mm as measured at a distance, approximately 1 to 10 cm from the device, wherein: (i) the device is configured for nasal delivery; (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains from about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the device is a two-dose device configured to deliver two injections of a pharmaceutical solution. In some embodiments, D _max is less than about 26 mm when measured at a distance of about 1 to about 10 cm from the device.

Incorporation by reference

All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application were specifically and individually incorporated by reference.

Brief description of graphic materials

A better understanding of the features and advantages of the present subject matter will be obtained by reference to the following detailed description, in which illustrative embodiments and accompanying drawings are set forth.

In fig. 1 shows plasma epinephrine concentrations in dogs administered a single nostril dose of 5 mg of the formulation described in Example 3 (Formulation 2) compared to plasma epinephrine concentrations in dogs administered an adult dose of EpiPen (0.3 mg/ ml).

In fig. 2 shows plasma epinephrine concentrations in dogs administered a single nostril dose of 10 mg of the formulation described in Example 3 (Formulation 2) compared with plasma epinephrine concentrations in dogs administered an adult dose of EpiPen (0.3 mg/ ml).

In fig. Figure 3 shows a diagram of the congestion test system.

In fig. Figure 4 shows the results of epinephrine inhibition of histamine-induced nasal congestion.

- 17 045992

In fig. Figure 5 shows a chart of individual heart rates for beagle dogs exposed to histamine and treated with epinephrine.

In fig. Figure 6 shows a graph of individual heart rates for Beagle dogs exposed to saline (control) and treated with epinephrine.

In fig. Figure 7 shows a graph of average heart rate comparing the effects of histamine and saline.

In fig. Figure 8 shows plasma epinephrine concentration profiles over time for individual animals in group 1.

In fig. Figure 9 shows plasma epinephrine concentration profiles over time for individual animals in group 2.

In fig. Figure 10 shows group mean epinephrine concentration profiles over time for the two study groups.

In fig. Figure 11 shows a Student's t test comparison of A) AUC, B) Cmax, and C) Tmax between the two study groups.

In fig. 12 shows plasma epinephrine levels before and after dosing in the CSF.

In fig. 13 shows the mean heart rate over time before and after the 4 mg epinephrine dose compared to baseline for SD29-30 for the overall study (intranasal administration).

In fig. 14 shows the mean heart rate over time before and after the 5 mg dose of epinephrine compared to baseline for SD29-30 for the overall study (intranasal administration).

In fig. Figure 15 shows the mean heart rate over time before and after the 0.3 mg dose of epinephrine compared to baseline for SD29-30 for the general study (IM).

In fig. 16 shows individual plasma concentration-time profiles comparing animals receiving epinephrine via intranasal administration and animals receiving epinephrine via intramuscular injection.

In fig. 17 is an exemplary diagram of a nasal spray delivery device.

Detailed Disclosure of the Present Invention

Provided herein are, for example, pharmaceutical formulations of epinephrine spray for the treatment of anaphylaxis. Further provided herein are, for example, methods of treating anaphylaxis, anaphylactic shock and/or severe allergic reaction or at least one symptom thereof.

I. Definitions.

Abbreviations used herein have the meanings generally accepted in the fields of chemistry and biology. The chemical structures and formulas given herein are constructed in accordance with standard rules of chemical valence known in the chemical field.

As used herein, the terms about or approximately, when referring to a numerical value or range, allow for a degree of variability in the value or range, for example, within 10% or 5% of a stated value or specified range limit.

As used herein, the term actuation refers to operating the device such that the pharmaceutical composition is delivered therefrom.

As used herein, the term AUC refers to the area under the plasma concentration of a drug (eg, epinephrine) versus time curve. As used herein, the term AUC _0-t refers to the area under the plasma drug concentration versus time curve from t=0 to the last measured concentration. As used herein, the term AUC _0-/ refers to the area under the plasma drug concentration versus time curve extrapolated to yes.

As used herein, the term bioavailability (F) refers to that portion of a dose of a drug (eg, epinephrine) that is absorbed from the site of administration and reaches the systemic circulation in an unchanged form. The term absolute bioavailability is used when the proportion of a drug absorbed refers to its IV bioavailability. It can be calculated using the following formula:

A UС extravascular Intravenous dose

intravenous D° ^for extravessel.

The term relative bioavailability (F _oth .) is used to compare two different extravascular routes of drug administration and can be calculated using the following formula:

- 18 045992

AU C extravascular.1 Extravascular dose.2

FomH. — ----------- X ---------------extravessel.2 Dose _introduced0C y _D d

As used herein, the term clearance (CL) refers to the rate at which a drug is cleared divided by its plasma concentration, resulting in the volume of plasma from which the drug is completely removed per unit time. CL is equal to the elimination rate constant (λ) multiplied by the volume of distribution (Vd), where Vd is the volume of fluid that would be required to contain the amount of drug present in the body at the same concentration as that found in plasma. As used herein, the term apparent clearance (CL/F) refers to clearance that does not take into account the bioavailability of the drug. This is the dose to AUC ratio.

As used herein, the term Cmax refers to the maximum observed plasma concentration.

As used herein, the term coefficient of variation (CV) refers to the ratio of the sample standard deviation to the sample mean. Often expressed as a percentage.

As used herein, the term confidence interval refers to the range of values that would include the true mean value of a parameter given a specified percentage of cases.

As used herein, the term device refers to a device capable of delivering a drug to a patient in need.

As used herein, the term delivery time refers to the amount of time that elapses between the determination by a healthcare professional or untrained person that a person requires nasal delivery of epinephrine and completion of delivery.

As used herein, the term elimination rate constant (λ) refers to the partial rate of removal of a drug from the body. This rate is constant in first order kinetics and does not depend on the concentration of the drug in the body. λ represents the slope of the plasma concentration versus time curve (on a logarithmic y scale). As used herein, the term λ/ refers to the terminal phase elimination rate constant, where the terminal phase of the plasma drug concentration versus time curve is a straight line when plotted on a semi-logarithmic graph. The terminal phase is often referred to as the elimination phase because the primary mechanism by which drug concentrations decrease during the terminal phase is the elimination of the drug from the body. A distinctive feature of the terminal elimination phase is that the relative proportion of drug in plasma and peripheral volumes of distribution remains constant. During this terminal phase, the drug is returned from the rapid and slow distribution volumes to the plasma and is finally eliminated from the plasma by metabolism or renal excretion.

As used herein, the term epinephrine refers to a compound with the following structure:

OH or a pharmaceutically acceptable salt, hydrate or solvate thereof. The CAS registration number for epinephrine is 51-43-4. Other names for epinephrine include, but are not limited to, ^)-4-(1-hydroxy-2-(methylamino)ethyl)benzene-1,2-diol and epinephrine.

As used herein, the term nostril is synonymous with the term nasal opening.

The terms penetration enhancer, permeation enhancer, and absorption enhancer as disclosed herein are intended to be equivalent, all four referring to an agent that helps deliver and/or increase the bioavailability and _Cmax of a compound through a mucosal surface, such as the nasal mucosa. Permeation or absorption enhancers suitable for use in the present invention include, but are not limited to, the following: caprylic acid, oleic acid, polysorbate 80, menthol, EDTA, sodium edetate, cetylpyridinium chloride, sodium lauryl sulfate, citric acid, sodium deoxycholate, sodium deoxyglycolate, glyceryl oleate, L-lysine, diethylene glycol monoethyl ether, α-β- or γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, phosphatidylcholine and combinations thereof. In some cases, the absorption enhancer contains diethylene glycol monoethyl ether. In some cases, the use of absorption enhancers may reduce _Tmax . In some cases, the use of absorption enhancers reduces the time during which the target plasma concentration of the active ingredient is reached after administration. Absorption enhancers can be used to increase the AUC of the active ingredient.

The terms stabilizer and stabilizing agent are intended to be equivalent

- 19 045992 tape and refer to a chemical substance that is used to prevent decomposition. Examples of stabilizers or stabilizing agents 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, thioglycerin, alpha-tocopherol (vitamin E) , cysteine hydrochloride, citric acid, ethylenediaminetetraacetic acid (EDTA), sodium citrate, propyl gallate, 8-hydroxyquinoline, boric acid, histidine, vitamin A and combinations thereof.

The term viscosity modifier refers to a product or combination of products designed to change the thickness or texture of pharmaceutical ingredients or formulations. Viscosity modifiers may include products such as thickeners, texture improvers, gelling agents and stiffening agents. Examples of viscosity modifiers include, but are not limited to, the following: polyethylene glycol, methylcellulose, hypromellose, polyvinylpyrrolidone, carboxymethylcellulose, hydroxypropylmethylcellulose (HPMC), methylcellulose, hydroxyethylcellulose, glycerin, polyvinyl alcohol, xanthan gum, chitosan, alginate, and combinations thereof.

Solvents suitable for use in accordance with the present invention include, but are not limited to, water, ethanol, glycerin, propylene glycol, polyethylene glycol 400, and combinations thereof.

As used herein, the term prefilled refers to a device, such as a nasal spray, that is capable of delivering a pharmaceutical composition to a patient in need thereof upon first actuation of the nebulization pump, i.e. without having to prime the pump before administering the dose, for example by operating the pump one or more times until the spray appears.

As used herein, the term rescue position means a position of the human body in which the patient lies on his side with a leg or knee extended forward (eg, to prevent rolling onto his stomach) and at least one hand supporting the head (eg, to elevate the face to facilitate breathing and prevent inhalation of vomit).

As used herein, the term shelf stable refers to a pharmaceutical composition in which at least about 95% - such as at least about 99.5% - of the active ingredient remains in an undegraded state after storing the pharmaceutical composition at a specified temperature and humidity for a period of time. specified time, for example 12 months at 25°C and 60% relative humidity.

As used herein, the term supine refers to the patient lying face up.

As used herein, the term t _1/2 or half-life refers to the amount of time required for half the drug to be eliminated from the body, or the time required for the concentration of the drug to be reduced by half.

As used herein, the terms tonicity regulator and isotonic agent are used interchangeably and refer to a compound that modifies the osmolality of a formulation, for example, to make it isotonic. Tonicity regulators include, but are not limited to, dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine, and the like.

As used herein, the term tmax refers to the time from administration of the pharmaceutical compositions described herein to maximum plasma drug concentration.

Liquid nasal formulations are primarily aqueous solutions, but suspensions and emulsions can also be delivered. In traditional spray pump systems, antimicrobial preservatives are typically required to maintain microbiological stability of liquid formulations.

The size distribution of nasal spray droplets influences drug deposition in the nasal cavity in vivo. The droplet size is influenced by the device's actuation parameters and composition. In some embodiments, the average droplet size is about 30 to about 100 microns. If the droplets are too large (eg, greater than about 120 μm), deposition occurs primarily in the anterior portions of the nose, and if the droplets are too small (eg, less than about 10 μm), they can be inhaled and reach the lungs.

The spray characteristics (e.g., jet geometry, spray pattern, pump flow, droplet size distribution, DSD) of the delivered spray after atomization can be measured under specified experimental and instrumental conditions using appropriate and validated and/or calibrated analytical procedures known in the art . These include photography, laser diffraction and impactor systems (cascade impactor method, Next Generation Impactor (NGI) method, etc.). The droplet size distribution can be controlled in ranges for D10, D50, D90, spread [(D90-D10)/D50] and percentage of droplets less than 10 mm. In some embodiments, the formulation will have a narrow DSD.

- 20 045992

In some embodiments, the composition will have a Dv(50) of 30-70 μm and a Dv(90) < 120 μm. Particle diameter (D) designations refer to a representative diameter where 10% (D10), 50% (D50) and 90% (D90) of the total volume of liquid sprayed consist of droplets with a diameter less than or equal to the stated value. Spray characteristics may refer to the average or median value obtained from multiple sprays. The plurality of sprays may be at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more sprays.

All percentage compositions are given as percentages by weight unless otherwise noted.

All average molecular weights of polymers are weight average molecular weights unless otherwise noted.

As used herein, the terms subject or patient (as in the subject of treatment) refers to both mammals and non-mammalian animals. Mammals include, for example, humans; non-human primates, such as apes and lesser primates; and non-primate mammals such as dogs, cats, cattle, horses, sheep and goats. Non-mammalian animals include, for example, fish and birds. The terms subject and patient are synonymous and refer, without limitation, to a person suffering from type I allergies, including anaphylaxis. A patient or subject in need thereof refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition as provided herein. In some embodiments, the patient is a human.

The terms disease, disorder or condition are used interchangeably and refer to a condition or condition of health of a patient or subject that can be treated with the compounds or methods presented herein. The illness may be anaphylaxis. The disease may be a severe allergic reaction and the like. The disease may be cancer. The disease may be an autoimmune disease. The disease may be an inflammatory disease. The disease may be an infectious disease.

As used herein, the terms type I reactions, type I allergies, and severe allergic reactions are used interchangeably (ie, immediate hypersensitivity reactions) and refer to the involvement of immunoglobulin E (IgE)-mediated release of histamine and other mediators from mast cells and basophils. Examples include, but are not limited to, anaphylaxis, anaphylactic reaction, anaphylactic shock, and allergic rhinoconjunctivitis. Severe allergic reactions are caused by allergens. Non-limiting examples of allergens include an insect sting (eg, a bee sting), a drug (eg, an antibiotic such as penicillin), a food (eg, eggs, nuts, or shellfish), and a chemical (eg, latex).

As used herein, the term propellant-free refers to a formulation that is not introduced using compressed gas.

The terms spray and aerosol are used interchangeably herein and refer to a liquid (eg, an intranasal formulation) that is airborne or travels through the air in the form of droplets.

As used herein, all numerical values relating to quantity, weight, etc., which are defined as approximately or approximately, each specific value being plus or minus 10%. For example, the phrase about 10 wt.% should be understood as from 9% wt./wt. up to 11% w/w. Thus, amounts within 10% of the claimed value are within the scope of the present claims.

As used herein, the terms %wt./wt. and w/w in % refer to the mass in % of the total composition.

As used herein, the term effective amount refers to the amount needed to treat a patient in need thereof.

The terms treatment or treatment refer to any evidence of success in therapy or reduction in the intensity of an injury, disease, pathology or condition, including any objective or subjective parameter such as attenuation; remission; reducing symptoms or increasing tolerance to the injury, pathology or condition for the patient; slowing the rate of degeneration or decline in health; the ability to make the end point of degeneration less debilitating; improving the patient's physical or mental well-being. Treatment or reduction of symptoms may be based on objective or subjective parameters; including the results of a medical examination, neuropsychiatric examination and/or psychiatric examination. The term treatment and combinations thereof may include the prevention of injury, pathology, condition or disease. In some embodiments, the treatment is prophylaxis. In some embodiments, treatment does not include prophylaxis. In some embodiments, treat, administer a treatment, or treat

- 21 045992 relate to the reduction of intensity or suppression of symptoms of type I allergy, including anaphylaxis.

As used herein (and as well understood in the art), the terms treatment or treatment also broadly include any approach for producing beneficial or desirable results in a subject's condition, including clinical results. Beneficial or desirable clinical outcomes may include, but are not limited to, alleviation or reduction in the intensity of one or more symptoms or conditions, reduction in the severity of a disease, stabilization (i.e., not worsening) of a disease state, prevention of transmission or spread of a disease, delay or slowing of disease progression, a decrease in the severity of or alleviation of the disease state, reduction in recurrence of the disease, and remission, partial or complete, detectable or undetectable. In other words, as used herein, the term treatment includes any of the treatment, amelioration, or prevention of a disease. Treatment can prevent the disease from occurring; contain the spread of the disease; relieve symptoms of a disease (eg, swelling of the throat or tongue, itchy rash, shortness of breath, low blood pressure, inflammation, bronchospasm, etc.), eliminate all or part of the underlying cause of the disease, shorten the duration of the disease, or a combination of these aspects.

As used herein, the terms treatment and treatment include prophylactic treatment. Methods of treatment include administering to a subject a therapeutically effective amount of a compound described herein. The administration step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on many factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the potency of the compositions used in the treatment, or combinations thereof. It will also be understood that the effective dosage of an agent used for treatment or prophylaxis may be increased or decreased over the course of a particular treatment or prophylactic regimen. Changes in dosage may become apparent using standard diagnostic tests known in the art. In some cases, continuous administration may be required. For example, the compositions are administered to a subject in an amount and for a period of time sufficient to treat the patient.

The term prevent refers to reducing the occurrence of symptoms of a disease in a patient. As stated above, prevention can be complete (no symptoms are detected) or partial, so that fewer symptoms are observed than would otherwise occur without treatment. In some embodiments, prevent refers to slowing the progression of a disease, disorder or condition or inhibiting its progression to a harmful or other undesirable state.

An effective amount is an amount sufficient to cause the compound to achieve its stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an effective amount is an amount sufficient to help treat, prevent, or reduce a symptom or symptoms of a disease, which may also be referred to as a therapeutically effective amount. Reducing a symptom or symptoms (and the grammatical equivalents of this phrase) means reducing the severity or frequency of the symptom(s) or eliminating the symptom(s). A prophylactically effective amount of a drug is an amount of drug that, when administered to a subject, will produce the intended prophylactic effect, such as preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury , disease, pathology or condition or its symptoms. The full prophylactic effect does not necessarily occur with a single dose and may only occur after a series of doses. Thus, a prophylactically effective amount can be administered in one or more administrations. The exact amounts will depend on the purpose of treatment and can be determined by one skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). The therapeutically effective amount can be determined by measuring the corresponding physiological effects, and can be adjusted in connection with the dosage schedule, diagnostic analysis of the subject's condition, and the like.

For any compound described herein, a therapeutically effective amount may be initially determined using cell culture assays. Target concentrations will be those concentrations of active compound(s) that allow the methods described herein to be carried out, as measured using the methods described in

- 22 045992 herein or known in the present technical field.

As is well known in the art, therapeutically effective amounts for use in humans can also be determined in animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. Dosage adjustments in humans can be made by monitoring the effectiveness of the compounds and adjusting the dosage up or down as described above. Adjusting the dose to achieve maximum effectiveness in humans based on the methods described above and other methods is within the capabilities of one of ordinary skill in the art. Adjusting the dose to achieve the maximum therapeutic window of efficacy or toxicity in humans based on the methods described above and other methods is within the capabilities of one of ordinary skill in the art.

As used herein, the term therapeutically effective amount refers to an amount of therapeutic agent sufficient to reduce the severity of the disorder as described above. For example, for a given parameter, a therapeutically effective amount will show an increase or decrease of at least 5, 10, 15, 20, 25, 40, 50, 60, 75, 80, 90, or at least 100%. Therapeutic efficacy can also be expressed as fold increase or decrease. For example, a therapeutically effective amount may have an effect of at least 1.2-fold, 1.5-fold, 2-fold, 5-fold, or greater than a control.

Dosages may vary depending on the requirements of the patient and the compound used. The dose administered to the patient, in the context of the present invention, should be sufficient to ensure a favorable therapeutic response in the patient over time. The dose size will also depend on the presence, nature and severity of any unwanted side effects. Determining the correct dosage for a particular situation is within the purview of the practitioner. Typically, treatment is started with smaller doses that are less than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect is achieved under certain circumstances. Dose numbers and intervals can be adjusted individually to provide levels of compound administered that are effective for the particular clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

As used herein, the term administration means administration by inhalation or intranasal administration. The term intranasal refers to the administration of the composition to any part of the nasal epithelium.

Administration may also mean oral administration, administration by suppository, local contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial or subcutaneous administration, or implantation of a slow release device, such as an osmotic minipump, into a subject. Administration may be by any route, including parenteral and transmucosal (eg, buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial administration. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By co-administration is meant that the composition described herein is administered simultaneously, immediately before or immediately after the administration of one or more additional therapies (eg, an anti-inflammatory agent). The compound of the present invention may be administered alone or may be co-administered to a patient. By co-administration is meant the simultaneous or sequential administration of a compound alone or in combination (more than one compound or agent). Thus, if desired, the drugs can be combined with other active substances (for example, to reduce metabolic degradation). Preparations in liquid form include solutions, suspensions and emulsions. In some embodiments, the compositions are water or water/propylene glycol solutions. The compositions of the present invention may further include components to provide sustained release and/or convenience.

By co-administration is meant that the composition described herein is administered simultaneously, immediately before or immediately after the administration of one or more additional treatments. The compounds according to the present description can be administered separately or can be administered together to a patient. By co-administration is meant the simultaneous or sequential administration of compounds individually or in combination (more than one compound).

In some embodiments, coadministration includes administering one active agent for 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week, or 1 months from the introduction of the second active agent. Coadministration involves administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20

- 23 045992 or 30 minutes from each other) or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e. obtaining a single pharmaceutical composition including both active agents. In other embodiments, the active agents may be formulated separately. In another embodiment, the active and/or additional agents may be linked or conjugated to each other.

The term anti-inflammatory agent is used in accordance with its simple ordinary meaning and refers to a composition (eg, compound, drug, antagonist, inhibitor, modulator) used in any way to reduce inflammation or swelling. In some embodiments, the anti-inflammatory agent is an agent identified herein for use in methods of treating an inflammatory disease or disorder. In some embodiments, the anti-inflammatory agent is an agent approved by the FDA or similar regulatory authority in a country other than the United States to reduce swelling and inflammation.

For any compound described herein, a therapeutically effective amount can be initially determined using cell culture assays. Target concentrations will be those concentrations of active compound(s) that allow the methods described herein to be carried out, as measured using the methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for use in humans can also be determined in animal models. For example, a human dose may be formulated to achieve a concentration that has been found to be effective in animals. Dosage adjustments in humans can be made by monitoring the effectiveness of the compounds and adjusting the dosage up or down as described above. Adjusting the dose to achieve maximum effectiveness in humans based on the methods described above and other methods is within the capabilities of one of ordinary skill in the art.

Dosages may vary depending on the requirements of the patient and the compound used. The dose administered to the patient, in the context of the present invention, should be sufficient to ensure a favorable therapeutic response in the patient over time. The dose size will also depend on the presence, nature and severity of any unwanted side effects. Determining the correct dosage for a particular situation is within the purview of the practitioner. Typically, treatment is started with smaller doses that are less than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect is achieved under certain circumstances.

Dosages and intervals can be adjusted individually to provide levels of compound administered that are effective for the particular clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual's disease state.

Using the ideas provided herein, it is possible to plan an effective prophylactic or therapeutic treatment regimen that does not cause significant toxicity and is still effective in treating the clinical symptoms demonstrated by a particular patient. This planning should include careful selection of the active compound, taking into account factors such as compound potency, relative bioavailability, patient body weight, the presence and severity of unwanted side effects, the preferred route of administration, and the toxicity profile of the selected agent.

As used herein, the term anaphylaxis refers to an allergic reaction affecting multiple organ systems in a subject upon exposure to an allergen, whether the allergen is identifiable or not.

As used herein, the term allergen refers to any chemical that is capable of eliciting an immune system response in a subject, including, but not limited to, chemicals found in drugs, foods, plants, insect bites and stings.

As used herein, the term pharmaceutically acceptable refers to ingredients that are not biologically or otherwise undesirable for administration to a living subject.

The term pharmaceutically acceptable salts includes salts of the active compounds that are prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be prepared by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include

- 24 045992 sodium, potassium, calcium, ammonium, organic amino or magnesium salt or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be prepared by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarboxylic, phosphoric, monohydrophosphoric, dihydrophosphoric, sulfuric, monohydrosulfuric, hydroiodic or phosphoric acids and the like, as well as salts derived from relatively non-toxic organic acids, such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, etc. .P. Also included are salts of amino acids such as arginate and the like, and salts of organic acids such as glucuronic or galactunic acids and the like. (See, for example, Berge et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66, 1-19). Some specific compounds of the present invention contain both basic and acidic functional groups, which allow the compounds to be converted into either base or acid addition salts.

Thus, the compounds of the present invention may exist as salts, for example with pharmaceutically acceptable acids. The present invention provides such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including themselves racemic mixtures), succinates, benzoates and salts with amino acids such as glutamic acid, and quaternary ammonium salts (for example, methyl iodide, ethyl iodide and the like). These salts can be prepared by methods known to those skilled in the art.

Neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of a compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In some embodiments, the compounds of the present invention contain both basic and acidic functional groups, which allow the compounds to be converted into either base or acid addition salts. Neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compounds differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but unless specifically stated, the salts disclosed herein are equivalent to the parent form of the compound for purposes of the present invention.

In some embodiments, epinephrine salts may include citrate, hydrochloride, sulfate, tartrate, phosphate, acetate, malate, maleate, succinate, ascorbate, carbonate, mesylate, and lactate salts. One skilled in the art may use other pharmaceutically acceptable salts of epinephrine in the formulations disclosed herein.

In addition to salt forms, the present invention provides compounds that are in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Prodrugs of the compounds described herein may undergo in vivo transformations following administration. In addition, prodrugs can be converted into the compounds of the present invention by chemical or biochemical means in an ex vivo environment, for example, by contact with a suitable enzyme or chemical reagent.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to non-solvated forms and are within the scope of the present invention. Certain compounds of the present invention may exist in a variety of crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

A pharmaceutically acceptable excipient and a pharmaceutically acceptable carrier refer to a substance that facilitates administration of the compound and absorption by a subject, and can be included in the compositions of the present invention without causing significant adverse toxicological effects in the patient. Such preparations can be sterilized and, if desired, mixed with auxiliaries such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to influence osmotic pressure, buffers, dyes and/or flavorings and the like, which do not react adversely with the compounds of the present invention. A person skilled in the art

- 25 045992 it is clear that other pharmaceutical excipients can be used in the present disclosure. Examples of preservatives include, but are not limited to, butylparaben, methylparaben, ethylparaben, propylparaben, sodium benzoate, chlorobutanol, benzalkonium chloride, benzoic acid, and combinations thereof.

It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to those skilled in the art and are intended to be included within the spirit and scope of the present invention and the scope of the appended claims. inventions.

II. Compositions.

In an aspect, a pharmaceutical composition is provided herein in the form of a spray. In some embodiments, the pharmaceutical spray composition comprises epinephrine or a pharmaceutically acceptable salt of epinephrine in water, ethanol, propylene glycol, or a combination thereof. In some embodiments, the pH of the pharmaceutical spray formulation is between about 3.5 and about 6.5.

In some aspects, the pharmaceutical spray composition contains an active ingredient. In some embodiments, the active ingredient is epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 0.5% to about 25% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 0.5% to about 20% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 0.5% to about 10% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1.0% to about 25% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1.0% to about 20% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1.0% to about 10% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains about 2.0% to about 25% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 2.0% to about 20% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 2.0% to about 10% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 3.0% to about 25% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 3.0% to about 20% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 3.0% to about 10% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 4.0% to about 25% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 4.0% to about 20% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 4.0% to about 25% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 4.0% to about 20% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 4.0% to about 10% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 5.0% to about 25% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 5.0% to about 20% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains about 5.0% - about 10% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains about 0.5% to about 5% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1.0% to about 5% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 2.0% to about 5% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 0.5% w/w. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 0.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 1% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 1.5% w/w. epinephrine. In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 2.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 3% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 3.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 4% wt./wt. epinephrine.

- 26 045992

In some embodiments, the pharmaceutical spray composition contains approximately 4.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 6.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 7% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 7.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 8% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 8.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 9% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 9.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 10% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 10.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 11% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 11.5% w/w. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 12% w/w. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 12.5% w/w. epinephrine. In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 13% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 13.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 14% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 14.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 15% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 15.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 16% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 16.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 17% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 17.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 18% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 18.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 19% wt./wt. epinephrine. In some embodiments, the pharmaceutical spray composition contains approximately 19.5% w/w. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 20% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 21% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 22% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 23% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 24% wt./wt. epinephrine. According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 25% wt./wt. epinephrine.

In an aspect, provided herein is a stable pharmaceutical formulation in spray form comprising:

(i) about 1% - about 25% w/w. epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (ii) one or more of the following: excipients, carrier vehicles, emulsifiers, stabilizers, preservatives, mucoadhesive agents, antibacterial agents, buffers and/or other excipients, the composition being stable at a temperature of at least at least about 20°C, and at a relative humidity of at least about 30%, and wherein the composition is stable over a period of at least about two months.

In an aspect, provided herein is a stable pharmaceutical formulation in spray form comprising:

(iii) about 1% - about 10% w/w. epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (iv) one or more of the following: excipients, carrier vehicles, emulsifiers,

- 27 045992 stabilizers, preservatives, mucosal adhesion agents, antibacterial agents, buffers and/or other auxiliary agents, the composition being stable at a temperature of at least about 20°C and a relative humidity of at least about 30%, and wherein the composition is stable over a period of at least about two months.

In some embodiments, the pharmaceutical spray formulation is stable at a temperature of at least about 25°C. In some embodiments, the pharmaceutical spray formulation is stable at a temperature of at least about 30°C. In some embodiments, the pharmaceutical spray formulation is stable at a temperature of at least about 35°C. In some embodiments, the pharmaceutical spray formulation is stable at a temperature of at least about 40°C. In some embodiments, the pharmaceutical spray formulation is stable at a temperature of at least about 45°C.

In some embodiments, the pharmaceutical spray formulation is stable at a relative humidity of at least about 40%. In some embodiments, the pharmaceutical spray formulation is stable at a relative humidity of at least about 50%. In some embodiments, the pharmaceutical spray formulation is stable at a relative humidity of at least about 60%. In some embodiments, the pharmaceutical spray formulation is stable at a relative humidity of at least about 70%. In some embodiments, the pharmaceutical spray formulation is stable at a relative humidity of at least about 80%.

In some embodiments, the pharmaceutical spray formulation is stable for a period of at least about six months. In some embodiments, the pharmaceutical spray formulation is stable over a period of at least about 12 months. In some embodiments, the pharmaceutical spray formulation is stable for a period of at least about 18 months. In some embodiments, the pharmaceutical spray formulation is stable for a period of at least about 24 months. In some embodiments, the pharmaceutical spray formulation is stable for a period of at least about 30 months. In some embodiments, the pharmaceutical spray formulation is stable for a period of at least about 36 months.

Viscosity modifiers.

In some embodiments, the pharmaceutical spray composition contains a viscosity modifier. Viscosity modifiers may include products such as thickeners, texture improvers, gelling agents and stiffening agents. In some embodiments, the viscosity modifier is the following: polyethylene glycol, methylcellulose, hypromellose, polyvinylpyrrolidone, carboxymethylcellulose, hydroxypropylmethylcellulose (HPMC), methylcellulose, hydroxyethylcellulose, glycerin, polyvinyl alcohol, xanthan gum, chitosan, alginate, or any combination thereof. In some embodiments, the viscosity modifier is polyethylene glycol. In some embodiments, the viscosity modifier is methylcellulose. In some embodiments, the viscosity modifier is hypromellose. In some embodiments, the viscosity modifier is polyvinylpyrrolidone. In some embodiments, the viscosity modifier is carboxymethylcellulose. In some embodiments, the viscosity modifier is hydroxypropyl methylcellulose. In some embodiments, the viscosity modifier is methylcellulose. In some embodiments, the viscosity modifier is hydroxyethylcellulose. In some embodiments, the viscosity modifier is glycerol. In some embodiments, the viscosity modifier is polyvinyl alcohol. In some embodiments, the viscosity modifier is xanthan gum. In some embodiments, the viscosity modifier is chitosan. In some embodiments, the viscosity modifier is an alginate.

In some embodiments, the pharmaceutical spray composition contains from about 0.001% (w/w) to about 1% (w/w) viscosity modifier. In some embodiments, the pharmaceutical spray formulation contains from about 0.001% (w/w) to about 0.5% (w/w) viscosity modifier. In some embodiments, the pharmaceutical spray composition contains from about 0.001% (w/w) to about 1% (w/w)

- 28 045992 viscosity modifier. In some embodiments, the pharmaceutical spray formulation contains about 0.01% (w/w) to about 1% (w/w) viscosity modifier. In some embodiments, the pharmaceutical spray formulation contains about 0.01% (w/w) to about 0.5% (w/w) viscosity modifier. In some embodiments, the pharmaceutical spray formulation contains about 0.1% (w/w) viscosity modifier. In some embodiments, the pharmaceutical spray composition contains at least about 0.001% (wt/wt), at least about 0.01% (wt/wt), or at least about 0.1% (wt/wt). ./wt.), and/or not more than about 5% (wt./wt.), not more than about 1% (wt./wt.), not more than about 0.5% (wt./wt. .), not more than about 0.4% (w/w), not more than about 0.3% (w/w), not more than about 0.2% (w/w) or no more than about 0.1% (w/w) viscosity modifier.

In some embodiments, the pharmaceutical spray formulation contains a viscosity modifier at a concentration of about 0.001% (w/w) to about 2% (w/w). In some embodiments, the pharmaceutical spray composition contains a viscosity modifier at a concentration of at least about 0.001% (w/w). In some embodiments, the pharmaceutical spray composition contains a viscosity modifier at a concentration of no more than about 2% (w/w). In some embodiments, the pharmaceutical spray composition contains a viscosity modifier at a concentration of about 0.001% (w/w) - about 0.01% (w/w), about 0.001% (w/w) - approximately 0.05% (w/w), approximately 0.001% (w/w), approximately 0.06% (w/w), approximately 0.001% (w/w) - approximately 0 .07% (w/w), about 0.001% (w/w) - about 0.08% (w/w), about 0.001% (w/w) - about 0.09 % (w/w), about 0.001% (w/w) - about 0.1% (w/w), about 0.001% (w/w) - about 0.5% ( w/w), about 0.001% (w/w) - about 1% (w/w), about 0.001% (w/w) - about 1.5% (w/w) .), about 0.001% (w/w) - about 2% (w/w), about 0.01% (w/w) - about 0.05% (w/w) , about 0.01% (w/w) - about 0.06% (w/w), about 0.01% (w/w) - about 0.07% (w/w) .), about 0.01% (wt./wt.) - about 0.08% (wt./wt.), about 0.01% (wt./wt.) - about 0.09% (wt. /wt.), about 0.01% (wt./wt.) - about 0.1% (wt./wt.), about 0.01% (wt./wt.) - about 0.5% ( w/w), about 0.01% (w/w) - about 1% (w/w), about 0.01% (w/w) - about 1.5% ( w/w), about 0.01% (w/w) - about 2% (w/w), about 0.05% (w/w) - about 0.06% ( w/w), about 0.05% (w/w) - about 0.07% (w/w), about 0.05% (w/w) - about 0.08 % (w/w), about 0.05% (w/w) - about 0.09% (w/w), about 0.05% (w/w) - about 0 .1% (w/w), approximately 0.05% (w/w) - approximately 0.5% (w/w), approximately 0.05% (w/w) - about 1% (w/w), about 0.05% (w/w) - about 1.5% (w/w), about 0.05% (w/w) - about 2% (w/w), about 0.06% (w/w) - about 0.07% (w/w), about 0.06% (w/w) - about 0.08% (w/w), about 0.06% (w/w) - about 0.09% (w/w), about 0.06% (w/w) ) - about 0.1% (wt./wt.), about 0.06% (wt./wt.) - about 0.5% (wt./wt.), about 0.06% (wt./wt.) wt.) - about 1% (wt./wt.), about 0.06% (wt./wt.) - about 1.5% (wt./wt.), about 0.06% (wt./wt.) wt.) - about 2% (wt./wt.), about 0.07% (wt./wt.) - about 0.08% (wt./wt.), about 0.07% (wt./wt.) wt.) - about 0.09% (wt./wt.), about 0.07% (wt./wt.) - about 0.1% (wt./wt.), about 0.07% (wt. ./wt.) - about 0.5% (wt./wt.), about 0.07% (wt./wt.) - about 1% (wt./wt.), about 0.07% (wt. ./wt.) - about 1.5% (wt./wt.), about 0.07% (wt./wt.) - about 2% (wt./wt.), about 0.08% (wt. ./wt.) about 0.09% (wt./wt.), about 0.08% (wt./wt.) - about 0.1% (wt./wt.), about 0.08% ( w/w) - about 0.5% (w/w), about 0.08% (w/w) - about 1% (w/w), about 0.08% ( w/w) - about 1.5% (w/w), about 0.08% (w/w) - about 2% (w/w), about 0.09% ( w/w) - about 0.1% (w/w), about 0.09% (w/w) - about 0.5% (w/w), about 0.09 % (w/w) - approximately 1% (w/w), approximately 0.09% (w/w) - approximately 1.5% (w/w), approximately 0.09 % (w/w) - approximately 2% (w/w), approximately 0.1% (w/w) - approximately 0.5% (w/w), approximately 0.1 % (w/w) - approximately 1% (w/w), approximately 0.1% (w/w) approximately 1.5% (w/w), approximately 0.1% (w/w) - approximately 2% (w/w), approximately 0.5% (w/w) - approximately 1% (w/w), approximately 0.5% (w/w) ./wt.) - approximately 1.5% (wt./wt.), approximately 0.5% (wt./wt.) - approximately 2% (wt./wt.), approximately 1% (wt./wt.) wt.) - about 1.5% (wt./wt.), about 1% (wt./wt.) - about 2% (wt./wt.) or about 1.5% (wt./wt.) ) - approximately 2% (w/w). In some embodiments, the pharmaceutical spray composition contains a viscosity modifier at a concentration of about 0.001% (w/w), about 0.01% (w/w), about 0.05% (w/w) .), about 0.06% (wt./wt.), about 0.07% (wt./wt.), about 0.08% (wt./wt.), about 0.09% (wt. /wt.), about 0.1% (wt./wt.), about 0.5% (wt./wt.), about 1% (wt./wt.), about 1.5% (wt. /wt.) or about 2% (wt./wt.). In some embodiments, the viscosity modifier is hypromellose.

In some embodiments, the pharmaceutical spray composition is characterized

- 29 045992 is characterized by a viscosity of at least about 100 cP, at least about 250 cP, at least about 500 cP, at least about 750 cP, at least about 1000 cP, at least about 1250 cP, according to at least about 1500 cP, at least about 1750 cP, at least about 2000 cP, at least about 2250 cP or at least about 2500 cP, and/or not more than about 100 cP, not more than about 250 cP , not more than about 500 cP, not more than about 750 cP, not more than about 1000 cP, not more than about 1250 cP, not more than about 1500 cP, not more than about 1750 cP, not more than about 2000 cP, no more than about 2250 cP or no more than about 2500 cP.

In some embodiments, the pharmaceutical spray formulation has a viscosity of about 100 cP to about 2500 cP. In some embodiments, the pharmaceutical spray formulation has a viscosity of at least about 100 cP. In some embodiments, the pharmaceutical spray formulation has a viscosity of no more than about 2500 cP. In some embodiments, the pharmaceutical spray formulation has a viscosity of about 100 cP - about 250 cP, about 100 cP - about 500 cP, about 100 cP - about 750 cP, about 100 cP - about 1000 cP, about 100 cP - about 1250 cP, approximately 100 cP - approximately 1500 cP, approximately 100 cP - approximately 1750 cP, approximately 100 cP - approximately 2000 cP, approximately 100 cP - approximately 2250 cP, approximately 100 cP - approximately 2500 cP, approximately 250 cP approximately 500 cP, approximately 250 cP - approximately 750 cP, approximately 250 cP - approximately 1000 cP, approximately 250 cP - approximately 1250 cP, approximately 250 cP - approximately 1500 cP, approximately 250 cP - approximately 1750 cP, approximately 250 cP - approximately 2000 cP, approximately 250 cP - approximately 2250 cP, approximately 250 cP - approximately 2500 cP, approximately 500 cP - approximately 750 cP, approximately 500 cP - approximately 1000 cP, approximately 500 cP - approximately 1250 cP, approximately 500 cP - approximately 1500 cP, approximately 500 cP - approximately 1750 cP, approximately 500 cP - approximately 2000 cP, approximately 500 cP - approximately 2250 cP, approximately 500 cP - approximately 2500 cP, approximately 750 cP - approximately 1000 cP, approximately 750 cP - approximately 1250 cP, approximately 750 cP approximately 1500 cP , approximately 750 cP - approximately 1750 cP, approximately 750 cP - approximately 2000 cP, approximately 750 cP - approximately 2250 cP, approximately 750 cP - approximately 2500 cP, approximately 1000 cP - approximately 1250 cP, approximately 1000 cP - approximately 1500 cP, approximately 1000 cP - approximately 1750 cP, approximately 1000 cP approximately 2000 cP, approximately 1000 cP - approximately 2250 cP, approximately 1000 cP - approximately 2500 cP, approximately 1250 cP - approximately 1500 cP, approximately 1250 cP - approximately 1750 cP, approximately 1250 cP - approximately 2000 cP, approximately 1250 cP - approximately 2250 cP, approximately 1250 cP - approximately 2500 cP, approximately 1500 cP - approximately 1750 cP, approximately 1500 cP - approximately 2000 cP, approximately 1500 cP - approximately 2250 cP, approximately 1500 cP - approximately 2500 cP, approximately 1750 cP - approximately 2000 cP, approximately 1750 cP - approximately 2250 cP, approximately 1750 cP - approximately 2500 cP, approximately 2000 cP - approximately 2250 cP, approximately 2000 cP - approximately 2500 cP or approximately 2250 cP - approximately 2500 cP. In some embodiments, the pharmaceutical spray formulation has a viscosity of about 100 cP, about 250 cP, about 500 cP, about 750 cP, about 1000 cP, about 1250 cP, about 1500 cP, about 1750 cP, about 2000 cP, about 2250 cP or approximately 2500 cP.

According to an aspect provided herein, the pharmaceutical spray composition further comprises a viscosity modifier. In some embodiments, the viscosity modifier is polyethylene glycol, methylcellulose, or hypromellose.

In some embodiments, the pharmaceutical spray composition further comprises polyethylene glycol. In some embodiments, the pharmaceutical spray formulation further contains from about 0.5% to about 50% polyethylene glycol.

In some embodiments, the pharmaceutical spray formulation further comprises methylcellulose. In some embodiments, the pharmaceutical spray formulation further contains from about 0.001% to about 5% methylcellulose.

In some embodiments, the pharmaceutical spray composition further comprises hypromellose. In some embodiments, the pharmaceutical spray formulation further contains about 0.001% to about 0.5% hypromellose. In some embodiments, the pharmaceutical spray formulation further comprises about 0.05% to about 0.5% hypromellose. In some embodiments, the pharmaceutical spray formulation further comprises about 0.05% to about 0.4% hypromellose. In some embodiments, the pharmaceutical spray formulation further contains about 0.05% to about 0.3% hypromellose. In some embodiments, the pharmaceutical spray formulation further contains about 0.05% to about 0.3% hypromellose. In some embodiments, the pharmaceutical spray formulation further contains about 0.1% hypromellose.

Buffer means.

In some embodiments, the pharmaceutical spray composition contains a buffering agent. In some embodiments, the buffering agent is

- 30 045992 fight citric acid, citrate, citric acid monohydrate or any combination thereof. In some embodiments, the buffering agent is sodium phosphate or sodium citrate.

In some embodiments, the pH of the pharmaceutical spray formulation is between about 3.5 and about 6.5. In some embodiments, the pH of the pharmaceutical spray formulation is between about 3.5 and about 5.5. In some embodiments, the pH of the pharmaceutical spray formulation is between about 3.5 and about 4.5. In some embodiments, the pH of the pharmaceutical spray formulation is between about 4.0 and about 5.0. In some embodiments, the pH of the pharmaceutical spray formulation is between about 4.5 and about 5.5. In some embodiments, the pH of the pharmaceutical spray formulation is between about 4.5 and about 6.5. In some embodiments, the pH of the pharmaceutical spray formulation is between about 5.5 and about 6.5. In some embodiments, the pH of the pharmaceutical spray formulation is about 3.5. In some embodiments, the pH of the pharmaceutical spray formulation is about 4. In some embodiments, the pH of the pharmaceutical spray formulation is about 4.5. In some embodiments, the pH of the pharmaceutical spray formulation is about 4.7. In some embodiments, the pH of the pharmaceutical spray formulation is about 5. In some embodiments, the pH of the pharmaceutical spray formulation is about 5.5. In some embodiments, the pH of the pharmaceutical spray formulation is about 6. In some embodiments, the pH of the pharmaceutical spray formulation is about 6.5. In some embodiments, the pH of the pharmaceutical spray formulation is at least about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8 , 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 or about 6.0 and /or not more than about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 or about 6.0. In some embodiments, the pH of the pharmaceutical spray formulation is about 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4. 9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 or about 6.0.

In some embodiments, the pharmaceutical spray formulation has a pH value of about 3.5 to about 7.5. In some embodiments, the pharmaceutical spray formulation has a pH value of at least about 3.5. In some embodiments, the pharmaceutical spray formulation has a pH value of no more than about 7.5. In some embodiments, the pharmaceutical spray formulation has a pH value of about 3.5 - about 4, about 3.5 - about 4.5, about 3.5 - about 5, about 3.5 - about 5.5, approximately 3.5 - approximately 6, approximately 3.5 - approximately 6.5, approximately 3.5 approximately 7, approximately 3.5 - approximately 7.5, approximately 4 - approximately 4.5, approximately 4 - approximately 5, approximately 4 - approximately 5.5, approximately 4 - approximately 6, approximately 4 - approximately 6.5, approximately 4 - approximately 7, approximately 4 - approximately 7.5, approximately 4.5 - approximately 5, approximately 4.5 - approximately 5 ,5, approximately 4.5 - approximately 6, approximately 4.5 - approximately 6.5, approximately 4.5 - approximately 7, approximately 4.5 - approximately 7.5, approximately 5 approximately 5.5, approximately 5 - approximately 6, about 5 - about 6.5, about 5 - about 7, about 5 - about 7.5, about 5.5 - about 6, about 5.5 - about 6.5, about 5.5 - about 7, about 5.5 - about 7.5, about 6 - about 6.5, about 6 - about 7, about 6 - about 7.5, about 6.5 - about 7, about 6.5 - about 7.5 or approximately 7 - approximately 7.5. In some embodiments, the pharmaceutical spray composition has a pH value of about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, or about 7.5 .

In some embodiments, the pH is controlled by adding hydrochloric acid, citric acid, citrate, citric acid monohydrate, or a combination thereof. In some embodiments, the pH is controlled by adding hydrochloric acid. In some embodiments, the pH is controlled by adding citric acid. In some embodiments, the pH is controlled by adding citrate. In some embodiments, the pH is controlled by adding citric acid monohydrate. In some embodiments, the pH is controlled by adding a combination of hydrochloric acid and any of citric acid, citrate, or citric acid monohydrate.

In some embodiments, the pharmaceutical spray composition contains a buffering agent at a concentration of about 0.01% (w/w) to about 2% (w/w). In some embodiments, the pharmaceutical spray composition contains a buffering agent at a concentration of at least about 0.01% (w/w). In some embodiments, the pharmaceutical spray composition contains a buffering agent at a concentration of no more than about 2% (w/w). In some embodiments, the pharmaceutical spray composition contains a buffering agent at a concentration of about 0.01% (w/w) - about 0.1% (w/w), about 0.01%

- 31 045992 (w/w) - approximately 0.2% (w/w), approximately 0.01% (w/w) - approximately 0.3% (w/w), about 0.01% (w/w) - about 0.4% (w/w), about 0.01% (w/w) - about 0.5% (w/w) ), about 0.01% (wt./wt.) - about 0.6% (wt./wt.), about 0.01% (wt./wt.) - about 0.7% (wt./wt.) wt.), about 0.01% (wt./wt.) - about 0.8% (wt./wt.), about 0.01% (wt./wt.) - about 0.9% (wt. ./wt.), about 0.01% (wt./wt.) - about 1% (wt./wt.), about 0.01% (wt./wt.) - about 2% (wt./wt.) wt.), about 0.1% (wt./wt.) - about 0.2% (wt./wt.), about 0.1% (wt./wt.) - about 0.3% (wt. ./wt.), about 0.1% (wt./wt.) - about 0.4% (wt./wt.), about 0.1% (wt./wt.) - about 0.5% (w/w), about 0.1% (w/w) - about 0.6% (w/w), about 0.1% (w/w) - about 0, 7% (w/w), about 0.1% (w/w) - about 0.8% (w/w), about 0.1% (w/w) - about 0.9% (w/w), approximately 0.1% (w/w), approximately 1% (w/w), approximately 0.1% (w/w) - approximately 2 % (w/w), approximately 0.2% (w/w) - approximately 0.3% (w/w), approximately 0.2% (w/w) - approximately 0 .4% (w/w), approximately 0.2% (w/w) - approximately 0.5% (w/w), approximately 0.2% (w/w) - about 0.6% (w/w), about 0.2% (w/w) - about 0.7% (w/w), about 0.2% (w/w) ) - about 0.8% (wt./wt.), about 0.2% (wt./wt.) - about 0.9% (wt./wt.), about 0.2% (wt./wt.) wt.) - about 1% (wt./wt.), about 0.2% (wt./wt.) - about 2% (wt./wt.), about 0.3% (wt./wt.) ) - about 0.4% (wt./wt.), about 0.3% (wt./wt.) - about 0.5% (wt./wt.), about 0.3% (wt./wt.) wt.) about 0.6% (wt./wt.), about 0.3% (wt./wt.) - about 0.7% (wt./wt.), about 0.3% (wt. /wt.) - about 0.8% (wt./wt.), about 0.3% (wt./wt.) - about 0.9% (wt./wt.), about 0.3% ( wt./wt.) - about 1% (wt./wt.), about 0.3% (wt./wt.) - about 2% (wt./wt.), about 0.4% (wt./wt.) /wt.) - about 0.5% (wt./wt.), about 0.4% (wt./wt.) - about 0.6% (wt./wt.), about 0.4% ( w/w) - about 0.7% (w/w), about 0.4% (w/w) - about 0.8% (w/w), about 0.4 % (w/w) - approximately 0.9% (w/w), approximately 0.4% (w/w) approximately 1% (w/w), approximately 0.4% (w/w) - approximately 2% (w/w), approximately 0.5% (w/w) - approximately 0.6% (w/w), approximately 0.5% (w/w) - approximately 0.7% (w/w), approximately 0.5% (w/w) - approximately 0.8% (w/w), approximately 0. 5% (w/w) - approximately 0.9% (w/w), approximately 0.5% (w/w) - approximately 1% (w/w), approximately 0. 5% (w/w) - approximately 2% (w/w), approximately 0.6% (w/w) - approximately 0.7% (w/w), approximately 0. 6% (w/w) - approximately 0.8% (w/w), approximately 0.6% (w/w) - approximately 0.9% (w/w), approximately 0.6% (w/w) - approximately 1% (w/w), approximately 0.6% (w/w) - approximately 2% (w/w), approximately 0. 7% (w/w) - approximately 0.8% (w/w), approximately 0.7% (w/w) - approximately 0.9% (w/w), approximately 0.7% (w/w) - approximately 1% (w/w), approximately 0.7% (w/w) - approximately 2% (w/w), approximately 0. 8% (w/w) - approximately 0.9% (w/w), approximately 0.8% (w/w) - approximately 1% (w/w), approximately 0. 8% (w/w) - approximately 2% (w/w), approximately 0.9% (w/w) - approximately 1% (w/w), approximately 0.9% (w/w) - about 2% (w/w) or about 1% (w/w) - about 2% (w/w). In some embodiments, the pharmaceutical spray composition contains a buffering agent at a concentration of about 0.01% (wt/wt), about 0.1% (wt/wt), about 0.2% (wt/wt). /wt.), about 0.3% (wt./wt.), about 0.4% (wt./wt.), about 0.5% (wt./wt.), about 0.6% ( w/w), about 0.7% (w/w), about 0.8% (w/w), about 0.9% (w/w), about 1% ( w/w) or about 2% (w/w). In some embodiments, the buffering agent is citric acid, such as citric acid monohydrate. In some embodiments, the pharmaceutical spray formulation further comprises trisodium citrate or citric acid monohydrate. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.01% to about 2.0% trisodium citrate or citric acid monohydrate. In some embodiments, the pharmaceutical spray formulation further comprises about 0.1% to about 2.0% trisodium citrate or citric acid monohydrate. In some embodiments, the pharmaceutical spray formulation further comprises about 0.1% to about 1.0% trisodium citrate or citric acid monohydrate. In some embodiments, the pharmaceutical spray formulation further comprises about 0.42% trisodium citrate or citric acid monohydrate.

Antioxidants.

According to an aspect provided herein, the pharmaceutical spray composition contains an antioxidant. Antioxidants may reduce or reduce the oxidation of an active ingredient such as epinephrine. Examples of antioxidants include sodium bisulfite, sodium metabisulfite, butylated hydroxytoluene and tocopherol. In some embodiments, the antioxidant comprises sodium bisulfite or sodium metabisulfite. In some embodiments, the antioxidant comprises sodium bisulfite. In some embodiments, the antioxidant comprises sodium metabisulfite. In some embodiments, the antioxidant acts as a preservative. In some embodiments, the antioxidant is a preservative. In some embodiments, the preservative is sodium bisulfite or sodium metabisulfite. According to some embodiments

- 32 045992 leniya pharmaceutical composition in the form of a spray contains an antioxidant that reduces the oxidation of the active ingredient so that the pharmaceutical composition in the form of a spray contains no more than 1%, no more than 2%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, no more than 10%, no more than 11%, no more than 12%, no more less than 13%, not more than 14%, not more than 15% impurities after storage at room temperature for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months , at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, according to at least 22 months, at least 23 months or at least 24 months. Room temperature can be approximately 20 degrees Celsius - approximately 25 degrees Celsius. In some embodiments, the room temperature is about 20, 21, 22, 23, 24, or 25 degrees Celsius.

In some embodiments, the pharmaceutical spray formulation is a stable and/or pure formulation that minimizes oxidation of the active ingredient and/or the presence of impurities (w/w). In some embodiments, the pharmaceutical spray composition contains no more than 0.1%, no more than 0.2%, no more than 0.3%, no more than 0.4%, no more than 0.5%, no more than 0.6%, no more than 0.7%, no more than 0.8%, no more than 0.9%, no more than 1%, no more than 2%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, no more than 10%, no more than 11%, no more more than 12%, no more than 13%, no more than 14%, no more than 15% impurities after storage for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months or at least 24 months. In some embodiments, the pharmaceutical spray formulation is stored at a temperature of at least about 5 degrees Celsius, at least about 10 degrees Celsius, at least about 20 degrees Celsius, at least about 25 degrees Celsius, at least about 35 degrees Celsius, or at least about 40 degrees Celsius and/or a temperature of no more than about 5 degrees Celsius, no more than about 10 degrees Celsius, no more than about 20 degrees Celsius, no more than about 25 degrees Celsius, no more than about 35 degrees Celsius, no more than about 40 degrees Celsius, or no more than about 45 degrees Celsius. In some embodiments, the pharmaceutical spray formulation is stored at a temperature of about 5 degrees Celsius, about 10 degrees Celsius, about 20 degrees Celsius, about 25 degrees Celsius, about 35 degrees Celsius, or about 40 degrees Celsius. In some embodiments, the impurity content of the composition is determined relative to the initial impurity content measured at time 0 months (t=0). In some embodiments, the impurity content of the composition is determined as an absolute percentage.

In some embodiments, the impurities include one or more of the following: epinephrine sulfonic acid, adrenochrome, norepinephrine, or epinephrine. In some embodiments, the pharmaceutical spray composition has an epinephrine sulfonic acid content of no more than 0.1%, no more than 0.2%, no more than 0.3%, no more than 0.4%, no more no more than 0.5%, no more than 0.6%, no more than 0.7%, no more than 0.8%, no more than 0.9%, no more than 1%, no more than 2%, not more than 3%, not more than 4%, not more than 5%, not more than 6%, not more than 7%, not more than 8% or not more than 9%, after storage at approximately 5 degrees Celsius, about 25 degrees Celsius or about 40 degrees Celsius for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months , at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, or at least 24 months.

In some embodiments, the pharmaceutical spray composition has an adrenochrome content of no more than 0.1%, no more than 0.2%, no more than 0.3%, no more than 0.4%, or no more than 0. .5% after storage at approximately 5 degrees Celsius, at

- 33 045992 approximately 25 degrees Celsius or approximately 40 degrees Celsius for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months or at least 24 months.

In some embodiments, the pharmaceutical spray composition has a norepinephrine content of no more than 0.05%, no more than 0.1%, no more than 0.2%, no more than 0.3%, no more than 0 ,4%, no more than 0.5%, no more than 0.6%, no more than 0.7%, no more than 0.8%, no more than 0.9%, no more than 1%, no more than 2%, no more than 3% or no more than 4% after storage at about 5 degrees Celsius, about 25 degrees Celsius or about 40 degrees Celsius for at least 1 month, at least 2 months, at least at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months or at least 24 months.

In some embodiments, the pharmaceutical spray composition has an epinephrine content of no more than 0.05%, no more than 0.1%, no more than 0.2%, no more than 0.3%, no more than 0 ,4%, no more than 0.5%, no more than 0.6%, no more than 0.7%, no more than 0.8%, no more than 0.9%, no more than 1%, not more than 2% or not more than 3% after storage at about 5 degrees Celsius, about 25 degrees Celsius or about 40 degrees Celsius for at least 1 month, at least 2 months, at least 3 months, at least at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months or at least 24 months.

In some embodiments, the pharmaceutical spray composition contains the L isomer of epinephrine at an enantiomeric purity of at least 95, 96, 97, 98, 99, or 99.5%. In some embodiments, the pharmaceutical spray composition comprises the L-isomer of epinephrine at an enantiomeric purity of at least 95, 96, 97, 98, 99, or 99.5% after storage at about 5 degrees Celsius, about 25 degrees Celsius, or about 40 degrees Celsius for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months , at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months or at least 24 months.

In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of about 0.0001% (w/w) to about 0.5% (w/w). In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of at least about 0.0001% (w/w). In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of no more than about 0.5% (w/w). In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of about 0.0001% (w/w) - about 0.001% (w/w), about 0.0001% (w/w) ) - about 0.01% (wt./wt.), about 0.0001% (wt./wt.) - about 0.02% (wt./wt.), about 0.0001% (wt./wt.) wt.) - about 0.03% (wt./wt.), about 0.0001% (wt./wt.) - about 0.04% (wt./wt.), about 0.0001% (wt. ./wt.) - about 0.05% (wt./wt.), about 0.0001% (wt./wt.) - about 0.1% (wt./wt.), about 0.0001% (w/w) - approximately 0.2% (w/w), approximately 0.0001% (w/w) - approximately 0.3% (w/w), approximately 0. 0001% (w/w) - about 0.4% (w/w), about 0.0001% (w/w) - about 0.5% (w/w), about 0.001% (w/w) - about 0.01% (w/w), about 0.001% (w/w) - about 0.02% (w/w), about 0.001% (w/w) about 0.03% (w/w), about 0.001% (w/w) - about 0.04% (w/w), about 0.001%

- 34 045992 (w/w) - approximately 0.05% (w/w), approximately 0.001% (w/w) - approximately 0.1% (w/w), approximately 0.001 % (w/w) - about 0.2% (w/w), about 0.001% (w/w) - about 0.3% (w/w), about 0.001% ( w/w) - about 0.4% (w/w), about 0.001% (w/w) - about 0.5% (w/w), about 0.01% ( w/w) - about 0.02% (w/w), about 0.01% (w/w) - about 0.03% (w/w), about 0.01 % (w/w) - approximately 0.04% (w/w), approximately 0.01% (w/w) - approximately 0.05% (w/w), approximately 0 .01% (w/w) - approximately 0.1% (w/w), approximately 0.01% (w/w) - approximately 0.2% (w/w), about 0.01% (w/w) - about 0.3% (w/w), about 0.01% (w/w) - about 0.4% (w/w) ), about 0.01% (w/w) - about 0.5% (w/w), about 0.02% (w/w) - about 0.03% (w/w) wt.), about 0.02% (wt./wt.) - about 0.04% (wt./wt.), about 0.02% (wt./wt.) - about 0.05% (wt. ./wt.), about 0.02% (wt./wt.) - about 0.1% (wt./wt.), about 0.02% (wt./wt.) - about 0.2% (w/w), about 0.02% (w/w) - about 0.3% (w/w), about 0.02% (w/w) - about 0, 4% (w/w), about 0.02% (w/w) - about 0.5% (w/w), about 0.03% (w/w) - about 0.04% (w/w), about 0.03% (w/w) - about 0.05% (w/w), about 0.03% (w/w) - about 0.1% (w/w), about 0.03% (w/w) - about 0.2% (w/w), about 0.03% (w/w) .) - about 0.3% (wt./wt.), about 0.03% (wt./wt.) - about 0.4% (wt./wt.), about 0.03% (wt./wt.) /wt.) - about 0.5% (wt./wt.), about 0.04% (wt./wt.) - about 0.05% (wt./wt.), about 0.04% ( w/w) - about 0.1% (w/w), about 0.04% (w/w) - about 0.2% (w/w), about 0.04 % (w/w) - approximately 0.3% (w/w), approximately 0.04% (w/w) - approximately 0.4% (w/w), approximately 0 .04% (w/w) - approximately 0.5% (w/w), approximately 0.05% (w/w) - approximately 0.1% (w/w), about 0.05% (w/w) - about 0.2% (w/w), about 0.05% (w/w) - about 0.3% (w/w) ), about 0.05% (w/w) - about 0.4% (w/w), about 0.05% (w/w) - about 0.5% (w/w) wt.), about 0.1% (wt./wt.) - about 0.2% (wt./wt.), about 0.1% (wt./wt.) - about 0.3% (wt. ./wt.), about 0.1% (wt./wt.) - about 0.4% (wt./wt.), about 0.1% (wt./wt.) about 0.5% ( w/w), about 0.2% (w/w) - about 0.3% (w/w), about 0.2% (w/w) - about 0.4 % (w/w), approximately 0.2% (w/w) - approximately 0.5% (w/w), approximately 0.3% (w/w) - approximately 0 .4% (w/w), about 0.3% (w/w) - about 0.5% (w/w) or about 0.4% (w/w) - approximately 0.5% (w/w). In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of about 0.0001% (w/w), about 0.001% (w/w), about 0.01% (w/w). ), about 0.02% (w/w), about 0.03% (w/w), about 0.04% (w/w), about 0.05% (w/w) wt.), about 0.1% (wt./wt.), about 0.2% (wt./wt.), about 0.3% (wt./wt.), about 0.4% (wt. ./wt.) or about 0.5% (wt./wt.).

In some embodiments, the pharmaceutical spray composition comprises sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.05% (w/w), or sodium metabisulfite at a concentration of about 0.0001% (w/w) about 0.1% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w), or sodium metabisulfite at a concentration of about 0 .0001% (w/w) - approximately 0.1% (w/w). In some embodiments, the pharmaceutical spray composition comprises sodium bisulfite at a concentration of about 0.001% (w/w) to about 0.05% (w/w), or sodium metabisulfite at a concentration of about 0.001% (w/w) - approximately 0.1% (w/w). In some embodiments, the pharmaceutical spray composition comprises sodium bisulfite at a concentration of about 0.01% (w/w) to about 0.05% (w/w), or sodium metabisulfite at a concentration of about 0.01% (w/w) - approximately 0.1% (w/w).

In some embodiments, the pharmaceutical spray composition contains sodium bisulfite. In some embodiments, the pharmaceutical spray composition contains sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation contains sodium bisulfite at a concentration of about 0.001% (w/w) to about 0.05% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium bisulfite at a concentration of about 0.005% (w/w) to about 0.05% (w/w). In some embodiments, the pharmaceutical spray formulation contains sodium bisulfite at a concentration of about 0.001% (w/w) to about 0.05% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium bisulfite at a concentration of about 0.01% (w/w) to about 0.05% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium bisulfite at a concentration of about 0.005% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium bisulfite at a concentration of about 0.01% (w/w). According to some variants

- 35 045992 The pharmaceutical composition in the form of a spray contains sodium bisulfite in a concentration of approximately 0.02% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium bisulfite at a concentration of about 0.03% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium bisulfite at a concentration of about 0.04% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium bisulfite at a concentration of about 0.05% (w/w).

In some embodiments, the pharmaceutical spray composition contains sodium metabisulfite. In some embodiments, the pharmaceutical spray composition contains sodium metabisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation contains sodium metabisulfite at a concentration of about 0.001% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium metabisulfite at a concentration of about 0.005% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium metabisulfite at a concentration of about 0.01% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation contains sodium metabisulfite at a concentration of about 0.005% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium metabisulfite at a concentration of about 0.01% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium metabisulfite at a concentration of about 0.02% (w/w). In some embodiments, the pharmaceutical spray formulation contains sodium metabisulfite at a concentration of about 0.03% (w/w). In some embodiments, the pharmaceutical spray formulation contains sodium metabisulfite at a concentration of about 0.04% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium metabisulfite at a concentration of about 0.05% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium metabisulfite at a concentration of about 0.06% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium metabisulfite at a concentration of about 0.07% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium metabisulfite at a concentration of about 0.08% (w/w). In some embodiments, the pharmaceutical spray formulation contains sodium metabisulfite at a concentration of about 0.09% (w/w). In some embodiments, the pharmaceutical spray composition contains sodium metabisulfite at a concentration of about 0.1% (w/w).

In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of 0.01% (w/w) - 0.3% (w/w). In some embodiments, the antioxidant is sodium metabisulfite. In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of 0.01 - 0.02% (w/w), 0.01 - 0.03% (w/w), 0.01 - 0.04% (w/w), 0.01 - 0.05% (w/w), 0.01 - 0.06% (w/w), 0.01 - 0 .07% (w/w), 0.01 - 0.08% (w/w), 0.01 - 0.09% (w/w), 0.01 - 0.1 % (w/w), 0.01 - 0.2% (w/w), 0.01 - 0.3% (w/w), 0.02 - 0.03% ( w/w), 0.02% (w/w) - 0.04% (w/w), 0.02% (w/w) - 0.05% (w/w) /wt.), 0.02% (wt./wt.) - 0.06% (wt./wt.), 0.02 - 0.07% (wt./wt.), 0.02 - 0 .08% (w/w), 0.02 - 0.09% (w/w), 0.02 - 0.1% (w/w), 0.02 - 0.2 % (w/w), 0.02 - 0.3% (w/w), 0.03 - 0.04% (w/w), 0.03 - 0.05% ( w/w), 0.03 - 0.06% (w/w), 0.03 - 0.07% (w/w), 0.03 - 0.08% (w/w) /wt.), 0.03 - 0.09% (wt./wt.), 0.03 0.1% (wt./wt.), 0.03 - 0.2% (wt./wt.) ), 0.03 - 0.3% (w/w), 0.04 - 0.05% (w/w), 0.04 - 0.06% (w/w), 0.04 - 0.07% (w/w), 0.04 - 0.08% (w/w), 0.04 - 0.09% (w/w), 0, 04 - 0.1% (w/w), 0.04 - 0.2% (w/w), 0.04 - 0.3% (w/w), 0.05 - 0.06% (w/w), 0.05 - 0.07% (w/w), 0.05 - 0.08% (w/w), 0.05 - 0, 09% (w/w), 0.05 - 0.1% (w/w), 0.05 - 0.2% (w/w), 0.05 - 0.3% (w/w), 0.06 - 0.07% (w/w), 0.06 - 0.08% (w/w), 0.06 - 0.09% (w/w) ./wt.), 0.06 - 0.1% (wt./wt.), 0.06 - 0.2% (wt./wt.), 0.06 - 0.3% (wt./wt.) wt.), 0.07 - 0.08% (wt./wt.), 0.07 - 0.09% (wt./wt.), 0.07 - 0.1% (wt./wt.) ), 0.07 - 0.2% (w/w), 0.07 - 0.3% (w/w), 0.08 - 0.09% (w/w), 0.08 - 0.1% (w/w), 0.08 - 0.2% (w/w), 0.08 - 0.3% (w/w), 0, 09 - 0.1% (w/w), 0.09 - 0.2% (w/w), 0.09 - 0.3% (w/w), 0.1 - 0.2% (w/w), 0.1 - 0.3% (w/w) or 0.2 - 0.3% (w/w). In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 , 0.1, 0.2 or 0.3% (w/w). In some embodiments, the pharmaceutical spray composition contains an antioxidant at a concentration of at least 0.01% (w/w), 0.02% (w/w), 0.03% (w/w). wt.), 0.04% (wt./wt.), 0.05% (wt./wt.), 0.06% (wt./wt.), 0.07% (wt./wt.) ), 0.08% (w/w), 0.09% (w/w), 0.1% (w/w), or 0.2% (w/w). According to some options

- 36 045992 where the pharmaceutical composition in the form of a spray contains an antioxidant in a concentration of no more than 0.02% (wt./wt.), 0.03% (wt./wt.), 0.04% (wt./wt.). /wt.), 0.05% (wt./wt.), 0.06% (wt./wt.), 0.07% (wt./wt.), 0.08% (wt./wt.) .), 0.09% (w/w), 0.1% (w/w), 0.2% (w/w) or 0.3% (w/w) .

Preservatives.

According to an aspect provided herein, the pharmaceutical spray composition contains a preservative. In some embodiments, the preservative contains a chelating agent. In some embodiments, the chelating agent is disodium edetate (EDTA). In some embodiments, the pharmaceutical spray composition contains disodium edetate. In some embodiments, the pharmaceutical spray composition contains disodium edetate at a concentration of about 0.0001% to about 0.01%. In some embodiments, the pharmaceutical spray composition contains disodium edetate at a concentration of about 0.0005% to about 0.01%. In some embodiments, the pharmaceutical spray composition contains disodium edetate at a concentration of about 0.001% to about 0.01%.

In some embodiments, the pharmaceutical spray formulation contains a chelating agent at a concentration of about 0.0001% to about 0.05%. In some embodiments, the pharmaceutical spray formulation contains a chelating agent at a concentration of at least about 0.0001%. In some embodiments, the pharmaceutical spray formulation contains a chelating agent at a concentration of no more than about 0.05%. In some embodiments, the pharmaceutical spray formulation comprises a chelating agent at a concentration of about 0.0001% to about 0.0002%, about 0.0001% to about 0.0003%, about 0.0001% to about 0.0004% , about 0.0001% - about 0.0005%, about 0.0001% - about 0.001%, about 0.0001% - about 0.005%, about 0.0001% - about 0.01%, about 0.0001% - approximately 0.02%, approximately 0.0001% - approximately 0.03%, approximately 0.0001% - approximately 0.04%, approximately 0.0001% approximately 0.05%, approximately 0.0002% - approximately 0 .0003%, approximately 0.0002% - approximately 0.0004%, approximately 0.0002% - approximately 0.0005%, approximately 0.0002% - approximately 0.001%, approximately 0.0002% - approximately 0.005%, approximately 0 .0002% - approximately 0.01%, approximately 0.0002% - approximately 0.02%, approximately 0.0002% - approximately 0.03%, approximately 0.0002% - approximately 0.04%, approximately 0.0002 % - approximately 0.05%, approximately 0.0003% - approximately 0.0004%, approximately 0.0003% - approximately 0.0005%, approximately 0.0003% approximately 0.001%, approximately 0.0003% - approximately 0.005% , approximately 0.0003% - approximately 0.01%, approximately 0.0003% - approximately 0.02%, approximately 0.0003% - approximately 0.03%, approximately 0.0003% - approximately 0.04%, approximately 0.0003% - approximately 0.05%, approximately 0.0004% - approximately 0.0005%, approximately 0.0004% - approximately 0.001%, approximately 0.0004% - approximately 0.005%, approximately 0.0004% - approximately 0.01%, approximately 0.0004% - approximately 0.02%, approximately 0.0004% - approximately 0.03%, approximately 0.0004% - approximately 0.04%, approximately 0.0004% - approximately 0. 05%, approximately 0.0005% - approximately 0.001%, approximately 0.0005% approximately 0.005%, approximately 0.0005% - approximately 0.01%, approximately 0.0005% - approximately 0.02%, approximately 0.0005 % - approximately 0.03%, approximately 0.0005% - approximately 0.04%, approximately 0.0005% - approximately 0.05%, approximately 0.001% - approximately 0.005%, approximately 0.001% - approximately 0.01%, approximately 0.001% - approximately 0.02%, approximately 0.001% - approximately 0.03%, approximately 0.001% - approximately 0.04%, approximately 0.001% approximately 0.05%, approximately 0.005% - approximately 0.01%, approximately 0.005% - approximately 0.02%, approximately 0.005% - approximately 0.03%, approximately 0.005% - approximately 0.04%, approximately 0.005% - approximately 0.05%, approximately 0.01% - approximately 0.02% , approximately 0.01% - approximately 0.03%, approximately 0.01% - approximately 0.04%, approximately 0.01% - approximately 0.05%, approximately 0.02% - approximately 0.03%, approximately 0.02% - approximately 0.04%, approximately 0.02% - approximately 0.05%, approximately 0.03% - approximately 0.04%, approximately 0.03% - approximately 0.05% or approximately 0. 04% - approximately 0.05%. In some embodiments, the pharmaceutical spray composition contains a chelating agent at a concentration of about 0.0001%, about 0.0002%, about 0.0003%, about 0.0004%, about 0.0005%, about 0.001%, about 0.005%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, or about 0.05%.

According to an aspect provided herein, the pharmaceutical spray composition contains a preservative. Examples of preservatives include parabens, phenylethyl alcohol, benzalkonium chloride, EDTA and benzyl alcohol. In some embodiments, the preservative comprises an antimicrobial preservative. In some embodiments, the antimicrobial preservative is sodium benzalkonium or chlorobutanol. In some embodiments, the antimicrobial preservative is chlorobutanol. In some embodiments, the pharmaceutical spray composition contains sodium benzalkonium at a concentration of about 0.005% (w/v) to about 1% (w/v) or chlorobutanol at a concentration of about 0.005% (w/v). vol.) - approximately 1% (wt./vol.).

In some embodiments, the pharmaceutical spray composition contains an antimicrobial preservative at a concentration of about 0.01% (w/w) to about 1%

- 37 045992 (w/w). In some embodiments, the antimicrobial preservative is a chlorobutanol, such as chlorobutanol hemihydrate. In some embodiments, the pharmaceutical spray composition contains an antimicrobial preservative at a concentration of at least about 0.01% (w/w). In some embodiments, the pharmaceutical spray composition contains an antimicrobial preservative at a concentration of no more than about 1% (w/w). In some embodiments, the pharmaceutical spray composition contains an antimicrobial preservative at a concentration of about 0.01% (wt./wt.) - about 0.05% (wt./wt.), about 0.01% (wt./wt.) /wt.) - about 0.1% (wt./wt.), about 0.01% (wt./wt.) - about 0.2% (wt./wt.), about 0.01% ( w/w) - about 0.3% (w/w), about 0.01% (w/w) - about 0.4% (w/w), about 0.01 % (w/w) - approximately 0.5% (w/w), approximately 0.01% (w/w) - approximately 0.6% (w/w), approximately 0 .01% (w/w) - approximately 0.7% (w/w), approximately 0.01% (w/w) - approximately 0.8% (w/w), about 0.01% (w/w) - about 0.9% (w/w), about 0.01% (w/w) - about 1% (w/w), about 0.05% (w/w) - about 0.1% (w/w), about 0.05% (w/w) - about 0.2% (w/w) ), about 0.05% (w/w) - about 0.3% (w/w), about 0.05% (w/w) - about 0.4% (w/w) wt.), about 0.05% (wt./wt.) - about 0.5% (wt./wt.), about 0.05% (wt./wt.) - about 0.6% (wt. ./wt.), about 0.05% (wt./wt.) - about 0.7% (wt./wt.), about 0.05% (wt./wt.) - about 0.8% (w/w), about 0.05% (w/w) - about 0.9% (w/w), about 0.05% (w/w) - about 1% (w/w), about 0.1% (w/w) - about 0.2% (w/w), about 0.1% (w/w) - about 0, 3% (w/w), approximately 0.1% (w/w), approximately 0.4% (w/w), approximately 0.1% (w/w) - approximately 0 .5% (w/w), approximately 0.1% (w/w) - approximately 0.6% (w/w), approximately 0.1% (w/w) - about 0.7% (w/w), about 0.1% (w/w) - about 0.8% (w/w), about 0.1% (w/w) ) - about 0.9% (w/w), about 0.1% (w/w) - about 1% (w/w), about 0.2% (w/w) ) - about 0.3% (wt./wt.), about 0.2% (wt./wt.) - about 0.4% (wt./wt.), about 0.2% (wt./wt.) wt.) - about 0.5% (wt./wt.), about 0.2% (wt./wt.) - about 0.6% (wt./wt.), about 0.2% (wt. ./wt.) about 0.7% (wt./wt.), about 0.2% (wt./wt.) - about 0.8% (wt./wt.), about 0.2% ( w/w) - about 0.9% (w/w), about 0.2% (w/w) - about 1% (w/w), about 0.3% ( w/w) - about 0.4% (w/w), about 0.3% (w/w) - about 0.5% (w/w), about 0.3 % (w/w) - approximately 0.6% (w/w), approximately 0.3% (w/w) - approximately 0.7% (w/w), approximately 0 .3% (w/w) - approximately 0.8% (w/w), approximately 0.3% (w/w) - approximately 0.9% (w/w), about 0.3% (w/w) - about 1% (w/w), about 0.4% (w/w) - about 0.5% (w/w), about 0.4% (w/w) - about 0.6% (w/w), about 0.4% (w/w) - about 0.7% (w/w) ), about 0.4% (wt./wt.) - about 0.8% (wt./wt.), about 0.4% (wt./wt.) - about 0.9% (wt./wt.) wt.), about 0.4% (wt./wt.) - about 1% (wt./wt.), about 0.5% (wt./wt.) - about 0.6% (wt./wt.) wt.), about 0.5% (wt./wt.) - about 0.7% (wt./wt.), about 0.5% (wt./wt.) - about 0.8% (wt. ./wt.), about 0.5% (wt./wt.) - about 0.9% (wt./wt.), about 0.5% (wt./wt.) - about 1% (wt. ./wt.), about 0.6% (wt./wt.) - about 0.7% (wt./wt.), about 0.6% (wt./wt.) - about 0.8% (w/w), about 0.6% (w/w) about 0.9% (w/w), about 0.6% (w/w) - about 1% ( w/w), about 0.7% (w/w) - about 0.8% (w/w), about 0.7% (w/w) - about 0.9 % (w/w), about 0.7% (w/w) - about 1% (w/w), about 0.8% (w/w) - about 0.9 % (w/w), about 0.8% (w/w) - about 1% (w/w) or about 0.9% (w/w) - about 1% ( w/w). In some embodiments, the pharmaceutical spray composition contains an antimicrobial preservative at a concentration of about 0.01% (wt/wt), about 0.05% (wt/wt), about 0.1% (wt/wt). /wt.), about 0.2% (wt./wt.), about 0.3% (wt./wt.), about 0.4% (wt./wt.), about 0.5% ( w/w), about 0.6% (w/w), about 0.7% (w/w), about 0.8% (w/w), about 0.9 % (w/w) or about 1% (w/w).

In some embodiments, the pharmaceutical spray composition contains sodium benzalkonium. In some embodiments, the pharmaceutical spray composition contains sodium benzalkonium at a concentration of about 0.005% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray composition contains sodium benzalkonium at a concentration of about 0.01% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray composition contains sodium benzalkonium at a concentration of about 0.05% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray composition contains sodium benzalkonium at a concentration of about 0.1% (w/v) to about 1% (w/v).

In some embodiments, the pharmaceutical spray composition contains chlorobutanol. In some embodiments, the chlorobutanol is chlorobutanol hemihydrate. In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.005% (w/v) to about 1%

- 38 045992 (w/v) (or alternatively w/w). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.01% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.05% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.1% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.1% (w/v) to about 0.5% (w/v). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.21% (w/v). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.2% (w/v). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.5% (w/v).

Isotonic drugs.

Disclosed herein are various ingredients of a pharmaceutical spray formulation. In some embodiments, the pharmaceutical spray composition contains an isotonic agent. In some embodiments, the isotonic agent is sodium chloride. An isotonic agent can be used to regulate the tonicity of the composition. In some embodiments, the pharmaceutical spray formulation is hypotonic. In some embodiments, the pharmaceutical spray formulation is hypertonic. In some embodiments, the pharmaceutical spray formulation is isotonic.

In some embodiments, the pharmaceutical spray formulation has an osmolality of about 550 mOsm/kg to about 800 mOsm/kg. In some embodiments, the pharmaceutical spray composition has an osmolality of about 550 mOsm/kg - about 575 mOsm/kg, about 550 mOsm/kg - about

600 mOsm/kg, approximately 550 mOsm/kg - approximately 625 mOsm/kg, approximately 550 mOsm/kg - approximately 650 mOsm/kg, approximately 550 mOsm/kg - approximately 675 mOsm/kg, approximately 550 mOsm/kg - approximately 700 mOsm/ kg, approximately 550 mOsm/kg - approximately 725 mOsm/kg, approximately 550 mOsm/kg - approximately 750 mOsm/kg, approximately 550 mOsm/kg - approximately 775 mOsm/kg, approximately 550 mOsm/kg - approximately 800 mOsm/kg, approximately 575 mOsm/kg - approximately 600 mOsm/kg, approximately 575 mOsm/kg - approximately 625 mOsm/kg, approximately 575 mOsm/kg - approximately 650 mOsm/kg, approximately 575 mOsm/kg - approximately 675 mOsm/kg, approximately 575 mOsm/kg - approximately 700 mOsm/kg, approximately 575 mOsm/kg - approximately 725 mOsm/kg, approximately 575 mOsm/kg - approximately 750 mOsm/kg, approximately 575 mOsm/kg - approximately 775 mOsm/kg, approximately 575 mOsm/kg - approximately 800 mOsm/ kg, approximately 600 mOsm/kg - approximately 625 mOsm/kg, approximately 600 mOsm/kg - approximately 650 mOsm/kg, approximately 600 mOsm/kg - approximately 675 mOsm/kg, approximately 600 mOsm/kg - approximately 700 mOsm/kg, approximately 600 mOsm/kg - approximately 725 mOsm/kg, approximately 600 mOsm/kg - approximately 750 mOsm/kg, approximately 600 mOsm/kg - approximately 775 mOsm/kg, approximately 600 mOsm/kg - approximately 800 mOsm/kg, approximately 625 mOsm/kg - approximately 650 mOsm/kg, approximately 625 mOsm/kg - approximately 675 mOsm/kg, approximately 625 mOsm/kg - approximately 700 mOsm/kg, approximately 625 mOsm/kg - approximately 725 mOsm/kg, approximately 625 mOsm/kg - approximately 750 mOsm/kg , approximately 625 mOsm/kg - approximately 775 mOsm/kg, approximately 625 mOsm/kg - approximately 800 mOsm/kg, approximately 650 mOsm/kg - approximately 675 mOsm/kg, approximately 650 mOsm/kg - approximately 700 mOsm/kg, approximately 650 mOsm /kg - approximately 725 mOsm/kg, approximately 650 mOsm/kg - approximately 750 mOsm/kg, approximately 650 mOsm/kg - approximately 775 mOsm/kg, approximately 650 mOsm/kg - approximately 800 mOsm/kg, approximately 675 mOsm/kg - approximately 700 mOsm/kg, approximately 675 mOsm/kg - approximately 725 mOsm/kg, approximately 675 mOsm/kg - approximately 750 mOsm/kg, approximately 675 mOsm/kg - approximately 775 mOsm/kg, approximately 675 mOsm/kg - approximately 800 mOsm/kg , approximately 700 mOsm/kg - approximately 725 mOsm/kg, approximately 700 mOsm/kg - approximately 750 mOsm/kg, approximately 700 mOsm/kg - approximately 775 mOsm/kg, approximately 700 mOsm/kg - approximately 800 mOsm/kg, approximately 725 mOsm /kg - approximately 750 mOsm/kg, approximately 725 mOsm/kg - approximately 775 mOsm/kg, approximately 725 mOsm/kg - approximately 800 mOsm/kg, approximately 750 mOsm/kg - approximately 775 mOsm/kg, approximately 750 mOsm/kg - approximately 800 mOsm/kg or approximately 775 mOsm/kg - approximately 800 mOsm/kg. In some embodiments, the pharmaceutical spray formulation has an osmolality of about 550 mOsm/kg, about 575 mOsm/kg, about 600 mOsm/kg, about 625 mOsm/kg, about 650 mOsm/kg, about 675 mOsm/kg, about 700 mOsm/kg, about 725 mOsm/kg, about 750 mOsm/kg, about 775 mOsm/kg, or about 800 mOsm/kg. In some embodiments, the pharmaceutical spray formulation has an osmolality of at least about 550 mOsm/kg, about 575 mOsm/kg, about 600 mOsm/kg, about 625 mOsm/kg, about 650 mOsm/kg, about 675 mOsm /kg, about 700 mOsm/kg, about 725 mOsm/kg, about 750 mOsm/kg, or about 775 mOsm/kg. In some embodiments, the pharmaceutical spray composition has an osmolality of no more than about 575

- 39 045992 mOsm/kg, approximately 600 mOsm/kg, approximately 625 mOsm/kg, approximately 650 mOsm/kg, approximately 675 mOsm/kg, approximately 700 mOsm/kg, approximately 725 mOsm/kg, approximately 750 mOsm/kg, approximately 775 mOsm/kg or approximately 800 mOsm/kg.

In some embodiments, the pharmaceutical spray formulation contains an isotonic agent at a concentration of about 0.1% to about 4%. In some embodiments, the pharmaceutical spray composition contains an isotonic agent at a concentration of at least about 0.1%. In some embodiments, the pharmaceutical spray composition contains an isotonic agent at a concentration of no more than about 4%. In some embodiments, the pharmaceutical spray composition contains an isotonic agent at a concentration of about 0.1% to about 0.2%, about 0.1% to about 0.4%, about 0.1% to about 0.5 %, approximately 0.1% - approximately 0.6%, approximately 0.1% - approximately 0.8%, approximately 0.1% - approximately 1%, approximately 0.1% - approximately 1.5%, approximately 0 .1% - approximately 2%, approximately 0.1% - approximately 2.5%, approximately 0.1% approximately 3%, approximately 0.1% - approximately 4%, approximately 0.2% - approximately 0.4% , approximately 0.2% - approximately 0.5%, approximately 0.2% - approximately 0.6%, approximately 0.2% - approximately 0.8%, approximately 0.2% - approximately 1%, approximately 0. 2% - approximately 1.5%, approximately 0.2% - approximately 2%, approximately 0.2% - approximately 2.5%, approximately 0.2% - approximately 3%, approximately 0.2% - approximately 4% , approximately 0.4% - approximately 0.5%, approximately 0.4% - approximately 0.6%, approximately 0.4% - approximately 0.8%, approximately 0.4% - approximately 1%, approximately 0. 4% - approximately 1.5%, approximately 0.4% - approximately 2%, approximately 0.4% - approximately 2.5%, approximately 0.4% approximately 3%, approximately 0.4% - approximately 4%, approximately 0.5% - approximately 0.6%, approximately 0.5% - approximately 0.8%, approximately 0.5% - approximately 1%, approximately 0.5% - approximately 1.5%, approximately 0.5 % - approximately 2%, approximately 0.5% - approximately 2.5%, approximately 0.5% - approximately 3%, approximately 0.5% - approximately 4%, approximately 0.6% - approximately 0.8%, approximately 0.6% - approximately 1%, approximately 0.6% - approximately 1.5%, approximately 0.6% - approximately 2%, approximately 0.6% - approximately 2.5%, approximately 0.6% - approximately 3%, approximately 0.6% approximately 4%, approximately 0.8% - approximately 1%, approximately 0.8% - approximately 1.5%, approximately 0.8% - approximately 2%, approximately 0.8% - approximately 2.5%, approximately 0.8% - approximately 3%, approximately 0.8% - approximately 4%, approximately 1% - approximately 1.5%, approximately 1% - approximately 2%, approximately 1% - approximately 2.5%, approximately 1% - approximately 3%, approximately 1% - approximately 4%, approximately 1.5% - approximately 2%, approximately 1.5% - approximately 2.5%, approximately 1.5% - approximately 3%, approximately 1.5% - approximately 4%, approximately 2% - approximately 2.5%, approximately 2% - approximately 3%, approximately 2% - approximately 4%, approximately 2.5% - approximately 3%, approximately 2.5% - approximately 4% or approximately 3% - approximately 4%. In some embodiments, the pharmaceutical spray composition contains an isotonic agent at a concentration of about 0.1%, about 0.2%, about 0.4%, about 0.5%, about 0.6%, about 0.8 %, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, or about 4%.

According to an aspect provided herein, the pharmaceutical spray composition contains sodium chloride. In some embodiments, the pharmaceutical spray formulation contains sodium chloride at a concentration of about 0.1% to about 5%. In some embodiments, the pharmaceutical spray formulation contains sodium chloride at a concentration of about 0.1% to about 1%. In some embodiments, the pharmaceutical spray formulation contains sodium chloride at a concentration of about 0.5% to about 5%. In some embodiments, the pharmaceutical spray formulation contains sodium chloride at a concentration of about 1% to about 5%. In some embodiments, the pharmaceutical spray formulation contains sodium chloride at a concentration of about 2% to about 5%. In some embodiments, the pharmaceutical spray formulation contains sodium chloride at a concentration of about 3% to about 5%. In some embodiments, the pharmaceutical spray composition contains sodium chloride at a concentration of about 4% to about 5%. In some embodiments, the pharmaceutical spray formulation contains sodium chloride at a concentration of about 0.1% to about 3%. In some embodiments, the pharmaceutical spray formulation contains sodium chloride at a concentration of about 0.1% to about 2%. In some embodiments, the pharmaceutical spray formulation contains sodium chloride at a concentration of about 0.1% to about 1%. In some embodiments, the pharmaceutical spray formulation contains sodium chloride at a concentration of about 0.4%.

In some embodiments, the pharmaceutical spray formulation is a stable pharmaceutical spray formulation that contains no more than 1%, no more than 2%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, no more than 10%, no more than 11%, no more than 12%, no more than 13%, no more less than 14%, not more than 15% impurities after storage at room temperature for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11

- 40 045992 months or at least 12 months. In some embodiments, the pharmaceutical spray formulation contains one or more buffering agents and/or preservatives to improve the stability of the active ingredient (eg, reducing oxidation or degradation of epinephrine) during storage.

Vasodilators.

According to an aspect provided herein, the pharmaceutical spray composition further comprises a vasodilator. In some embodiments, the vasodilator is nitroprusside, phentolamine, or nifedipine.

In some embodiments, the pharmaceutical spray composition further comprises nitroprusside. In some embodiments, the pharmaceutical spray formulation further contains from about 0.05 mg to about 5 mg of nitroprusside. In some embodiments, the pharmaceutical spray formulation further contains from about 0.1 mg to about 5 mg of nitroprusside. In some embodiments, the pharmaceutical spray formulation further contains from about 0.5 mg to about 5 mg of nitroprusside. In some embodiments, the pharmaceutical spray formulation further contains from about 1 mg to about 5 mg of nitroprusside. In some embodiments, the pharmaceutical spray formulation further contains from about 1 mg to about 4 mg of nitroprusside. In some embodiments, the pharmaceutical spray composition further comprises nitroprusside. In some embodiments, the pharmaceutical spray formulation further contains from about 0.05 mg to about 3 mg of nitroprusside. In some embodiments, the pharmaceutical spray composition further comprises nitroprusside. In some embodiments, the pharmaceutical spray formulation further contains from about 0.5 mg to about 3 mg of nitroprusside. In some embodiments, the pharmaceutical spray composition further comprises nitroprusside. In some embodiments, the pharmaceutical spray formulation further contains from about 0.5 mg to about 2 mg nitroprusside.

In some embodiments, the pharmaceutical spray composition further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further contains from about 1 mg to about 50 mg of phentolamine. In some embodiments, the pharmaceutical spray composition further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further contains from about 1 mg to about 40 mg of phentolamine. In some embodiments, the pharmaceutical spray composition further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further contains from about 1 mg to about 30 mg of phentolamine. In some embodiments, the pharmaceutical spray composition further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further contains from about 1 mg to about 20 mg of phentolamine. In some embodiments, the pharmaceutical spray composition further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further contains from about 1 mg to about 10 mg of phentolamine. In some embodiments, the pharmaceutical spray composition further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further contains from about 5 mg to about 50 mg of phentolamine. In some embodiments, the pharmaceutical spray composition further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further contains from about 10 mg to about 50 mg of phentolamine. In some embodiments, the pharmaceutical spray composition further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further contains from about 20 mg to about 50 mg of phentolamine. In some embodiments, the pharmaceutical spray composition further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further contains from about 20 mg to about 40 mg of phentolamine.

In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 500 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further contains from about 10 mg to about 450 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 400 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. According to some options,

- 41 045992 The pharmaceutical composition in the form of a spray additionally contains approximately 10 mg - approximately 350 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 300 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further contains from about 10 mg to about 250 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further contains from about 10 mg to about 200 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises about 10 mg to about 150 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises about 10 mg to about 100 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further contains from about 10 mg to about 75 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 50 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises about 10 mg of about 40 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises about 10 mg to about 30 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises about 50 mg to about 500 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises about 100 mg to about 500 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 100 mg to about 400 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises about 100 mg to about 350 mg of nifedipine. In some embodiments, the pharmaceutical spray composition further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises about 100 mg to about 300 mg of nifedipine.

Absorption enhancers.

According to an aspect provided herein, the pharmaceutical spray composition contains an absorption enhancer. In some embodiments, the absorption enhancer contains the following: caprylic acid, oleic acid, polysorbate 80, menthol, EDTA, sodium edetate, cetylpyridinium chloride, sodium lauryl sulfate, citric acid, sodium deoxycholate, sodium deoxyglycolate, glyceryl oleate, L-lysine, diethylene glycol monoethyl ether, α-β- or γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, phosphatidylcholine or combinations thereof. Absorption enhancers can improve the pharmacokinetics of the active ingredient(s) of a pharmaceutical spray formulation. In some embodiments, improved pharmacokinetics includes one or more of _Cmax , _Tmax , and AUC. In some cases, the absorption enhancer contains diethylene glycol monoethyl ether. In some cases, the use of absorption enhancers may reduce _Tmax . Absorption enhancers can be used to increase the AUC of the active ingredient.

In some embodiments, the pharmaceutical spray formulation contains an absorption enhancer at a concentration of about 0.1% to about 2%. In some embodiments, the pharmaceutical spray composition contains an absorption enhancer at a concentration of at least about 0.1%. In some embodiments, the pharmaceutical spray composition contains an absorption enhancer at a concentration of no more than about 2%. In some embodiments, the pharmaceutical spray composition contains an absorption enhancer at a concentration of about 0.1% to about 0.2%, about 0.1% to about 0.3%, about 0.1% to about 0.4% , approximately 0.1% - approximately 0.5%, approximately 0.1% - approximately 0.6%, approximately 0.1% - approximately 0.7%, approximately 0.1% - example

- 42 045992 but 0.8%, approximately 0.1% - approximately 0.9%, approximately 0.1% - approximately 1%, approximately 0.1% - approximately 1.5%, approximately 0.1% - approximately 2%, approximately 0.2% - approximately 0.3%, approximately 0.2% - approximately 0.4%, approximately 0.2% - approximately 0.5%, approximately 0.2% - approximately 0.6% , approximately 0.2% - approximately 0.7%, approximately 0.2% - approximately 0.8%, approximately 0.2% - approximately 0.9%, approximately 0.2% - approximately 1%, approximately 0. 2% - approximately 1.5%, approximately 0.2% - approximately 2%, approximately 0.3% - approximately 0.4%, approximately 0.3% approximately 0.5%, approximately 0.3% - approximately 0 .6%, approximately 0.3% - approximately 0.7%, approximately 0.3% - approximately 0.8%, approximately 0.3% - approximately 0.9%, approximately 0.3% - approximately 1%, approximately 0.3% - approximately 1.5%, approximately 0.3% - approximately 2%, approximately 0.4% - approximately 0.5%, approximately 0.4% - approximately 0.6%, approximately 0.4 % - approximately 0.7%, approximately 0.4% - approximately 0.8%, approximately 0.4% - approximately 0.9%, approximately 0.4% - approximately 1%, approximately 0.4% - approximately 1 .5%, approximately 0.4% - approximately 2%, approximately 0.5% - approximately 0.6%, approximately 0.5% - approximately 0.7%, approximately 0.5% - approximately 0.8%, approximately 0.5% - approximately 0.9%, approximately 0.5% - approximately 1%, approximately 0.5% - approximately 1.5%, approximately 0.5% - approximately 2%, approximately 0.6% - approximately 0.7%, approximately 0.6% - approximately 0.8%, approximately 0.6% - approximately 0.9%, approximately 0.6% - approximately 1%, approximately 0.6% - approximately 1.5 %, approximately 0.6% - approximately 2%, approximately 0.7% - approximately 0.8%, approximately 0.7% - approximately 0.9%, approximately 0.7% - approximately 1%, approximately 0.7 % - approximately 1.5%, approximately 0.7% - approximately 2%, approximately 0.8% - approximately 0.9%, approximately 0.8% - approximately 1%, approximately 0.8% - approximately 1.5 %, approximately 0.8% - approximately 2%, approximately 0.9% approximately 1%, approximately 0.9% - approximately 1.5%, approximately 0.9% - approximately 2%, approximately 1% - approximately 1, 5%, approximately 1% - approximately 2% or approximately 1.5% - approximately 2%. In some embodiments, the pharmaceutical spray composition contains an absorption enhancer at a concentration of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6 %, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, or about 2%.

In some embodiments, the pharmaceutical spray composition contains an absorption enhancer at a concentration of at least about 0.1%, at least about 0.2%, about 0.5%, about 0.8%, about 1.1%, about 1.4% each, about 1.7% each, about 2.0% each, at least about at least about at least about at least about at least about at least about at least about at least about at least about at least about

0.3%, at least

0.6%, at least

0.9%, at least

1.2%, at least

1.5%, at least

1.8%, at least

2.5%, at least about 0.4%, at least about 0.7%, at least about 1.0%, at least about 1.3%, at least about 1.6%, at least about 1.9%, at least about 3.0%, about 4.0%, at least about 5.0%, and/or not more than about 0.1%, at least at least at least at least at least at least not more than about 0.2%, not more than about 0.3%, not more than about 0.4%, not more than about 0.5%, not more than about 0.6%, not more than about 0.7%, no more than about 0.8%, no more than about 0.9%, no more than about 1.0%, no more than about 1.1%, no more than about 1, 2%, not more than about 1.3%, not more than about 1.4%, not more than about 1.5%, not more than about 1.6%, not more than about 1.7%, not more no more than about 1.8%, no more than about 1.9%, no more than about 2.0%, no more than about 2.5%, no more than about 3.0%, no more than about 4.0 % or not more than about 5.0%. In some embodiments, the absorption enhancer is diethylene glycol monoethyl ether. In some embodiments, the pharmaceutical spray formulation contains 1% diethylene glycol ether.

According to an aspect provided herein, the pharmaceutical spray composition further comprises a permeation enhancer or absorption enhancer.

According to an aspect provided herein, the pharmaceutical spray composition further comprises diethylene glycol monoethyl ether. In some embodiments, the pharmaceutical spray formulation further comprises diethylene glycol monoethyl ether at a concentration of about 0.05% to about 15%. In some embodiments, the pharmaceutical spray formulation further comprises diethylene glycol monoethyl ether at a concentration of about 0.5% to about 10%. In some embodiments, the pharmaceutical spray formulation further comprises diethylene glycol monoethyl ether at a concentration of about 0.5% to about 5%. In some embodiments, the pharmaceutical spray formulation further comprises diethylene glycol monoethyl ether at a concentration of about 0.5% to about 4%. In some embodiments, the pharmaceutical spray formulation further comprises diethylene glycol monoethyl ether at a concentration of about 0.5% to about 3%. In some embodiments, the pharmaceutical spray formulation further comprises diethylene glycol monoethyl ether at a concentration of about 0.5% to about 2%. In some embodiments, the pharmaceutical spray formulation further comprises diethylene glycol monoethyl ether at a concentration of about 1%.

- 43 045992

Compositions.

In some aspects, disclosed herein are pharmaceutical spray formulations containing an active ingredient or a pharmaceutically acceptable salt thereof, and one or more of the following: excipients, carrier vehicles, emulsifiers, stabilizers, preservatives, mucosal adhesion agents, antibacterial agents , buffers and/or other auxiliary means. In some embodiments, the pharmaceutical spray composition comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight of the following: excipient, carrier medium, emulsifier, stabilizer, preservative, mucosal adhesive agent, antibacterial agent, buffer and/or other adjuvant. In some embodiments, the pharmaceutical spray composition contains at least one, at least two, at least three, at least four, at least five, at least six of the following: an antioxidant, a chelating agent, an antimicrobial preservative, viscosity modifier, buffering agent or absorption enhancer. In some embodiments, the pharmaceutical spray composition contains at least one preservative that is an antioxidant, a chelating agent, an antimicrobial preservative, or any combination thereof. In some embodiments, the pharmaceutical spray composition comprises an active ingredient (e.g., epinephrine) or a pharmaceutically acceptable salt thereof and at least one, at least two, at least three, at least four, at least five, at least at least six of the following: antioxidant, isotonic agent, viscosity modifier, buffer agent, absorption enhancer, or antimicrobial preservative. In some embodiments, the pharmaceutical spray composition contains an active ingredient (eg, epinephrine) or a pharmaceutically acceptable salt thereof, an antioxidant, an isotonic agent, a viscosity modifier, a buffering agent, an absorption enhancer, and an antimicrobial preservative.

According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) antioxidant, about 0.1% - about 5% isotonic agent, about 0.001% - about 0.5% viscosity modifier, about 0.01% about 2.0% buffering agent, and about 0.05% about 15% absorption enhancer.

In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) antioxidant, about 0.1% - about 5% isotonic agent, about 0.001% - about 0.5% viscosity modifier, about 0.01% - about 2% buffering agent and about 0.05% - about 15% absorption enhancer.

In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) antioxidant, about 0.1% - about 1% isotonic agent, about 0.01 % is about 0.2% viscosity modifier, about 0.1% is about 1% buffering agent and about 0.1% is about 5% absorption enhancer.

In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.42% buffering agent and about 1% absorption enhancer .

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) antioxidant, about 0.1% - about 5% isotonic agent, about 0.001% - about 0.5% viscosity modifier, about 0.01% - about 2% buffering agent and about 0.05% - about 15% absorption enhancer.

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) antioxidant, about 0.1% - about 1% isotonic agent, about 0.01 % is about 0.2% viscosity modifier, about 0.1% is about 1% buffering agent and about 0.1% is about 5% absorption enhancer.

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.42% buffering agent and about 1% absorption enhancer .

According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) antioxidant, about 0.1% - about 1.0% isotonic agent, about 0 .01% - approximately 0.2% viscosity modifier, approximately 0.1% - example

- 44 045992 but 1.0% buffer agent and approximately 0.1% - approximately 2.0% absorption enhancer.

According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 5% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) antioxidant, about 0.1% - about 1.0% isotonic agent, about 0 .05% is about 0.5% viscosity modifier, about 0.1% is about 1.0% buffering agent, and about 0.5% is about 5% absorption enhancer.

In some embodiments, the pharmaceutical spray composition contains approximately 2.4% w/w. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.7% buffering agent and about 1% absorption enhancer .

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.7% buffering agent and about 1% absorption enhancer . According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.7% buffering agent and about 1% absorption enhancer .

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.7% buffering agent and about 1% absorption enhancer .

According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) antioxidant, about 0.1% - about 5% isotonic agent, about 0.001% - about 0.5% viscosity modifier, about 0.01% about 2% buffering agent, and about 0.05% about 15% absorption enhancer.

According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) antioxidant, about 0.1% - about 1% isotonic agent, about 0.01 % is about 0.2% viscosity modifier, about 0.1% is about 1% citrate buffer, and about 0.1% is about 5% absorption enhancer.

According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 5% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) antioxidant, about 0.1% - about 1% isotonic agent, about 0.01 % is about 0.2% viscosity modifier, about 0.1% is about 1% buffering agent and about 0.1% is about 5% absorption enhancer.

In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.42% buffering agent and about 1% absorption enhancer .

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.42% buffering agent and about 1% absorption enhancer .

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.42% buffering agent and about 1% absorption enhancer .

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.42% buffering agent and about 1% absorption enhancer .

In some embodiments, the pharmaceutical spray formulation further comprises an antimicrobial preservative at a concentration of about 0.05% (w/v) to about 1% (w/v).

In some embodiments, the pharmaceutical spray composition contains approximately 2.4% w/w. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.7% buffering agent, about 1% absorption enhancer and approximately 0.2% antimicrobial preservative.

In some embodiments, the pharmaceutical spray composition comprises

- 45 045992 approximately 4.6% w/w. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.7% buffering agent, about 1% absorption enhancer and approximately 0.2% antimicrobial preservative.

In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.42% buffering agent, about 1% absorption enhancer and approximately 0.21% antimicrobial preservative.

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) antioxidant, about 0.4% isotonic agent, about 0.1% viscosity modifier, about 0.42% buffering agent, about 1% absorption enhancer and approximately 0.21% antimicrobial preservative.

According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2.0% trisodium citrate and about 0.05% - about 15% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2% citric acid monohydrate and about 0.05% - about 15% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1% sodium chloride, about 0. 01% is about 0.2% hypromellose, about 0.1% is about 1% citric acid monohydrate and about 0.1% is about 5% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether.

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2% citric acid monohydrate and about 0.05% - about 15% diethylene glycol monoethyl ether.

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1% sodium chloride, about 0. 01% is about 0.2% hypromellose, about 0.1% is about 1% citric acid monohydrate and about 0.1% is about 5% diethylene glycol monoethyl ether.

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether.

According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1.0% sodium chloride, about 0.01% is about 0.2% hypromellose, about 0.1% is about 1.0% trisodium citrate, and about 0.1% is about 2.0% diethylene glycol monoethyl ether.

According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 5% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1.0% sodium chloride, about 0.05% is about 0.5% hypromellose, about 0.1% is about 1.0% trisodium citrate, and about 0.5% is about 5% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical spray composition contains approximately 2.4% w/w. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether .

In some embodiments, the pharmaceutical spray composition comprises

- 46 045992 approximately 5% w/w. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether .

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether .

According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2% citric acid monohydrate and about 0.05% - about 15% diethylene glycol monoethyl ether.

According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 1% to about 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1% sodium chloride, about 0. 01% is about 0.2% hypromellose, about 0.1% is about 1% citric acid citrate monohydrate, and about 0.1% is about 5% diethylene glycol monoethyl ether.

According to some embodiments, the pharmaceutical composition in the form of a spray contains from about 5% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1% sodium chloride, about 0. 01% is about 0.2% hypromellose, about 0.1% is about 1% citric acid monohydrate and about 0.1% is about 5% diethylene glycol monoethyl ether.

In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether.

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether.

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether.

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether.

In some embodiments, the pharmaceutical spray formulation further comprises chlorobutanol at a concentration of about 0.05% (w/v) to about 1% (w/v).

In some embodiments, the pharmaceutical spray composition contains approximately 2.4% w/w. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether and approximately 0.2% chlorobutanol.

In some embodiments, the pharmaceutical spray composition contains approximately 4.6% w/w. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether and approximately 0.2% chlorobutanol.

In some embodiments, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% monoethyl diethylene glycol ether and approximately 0.21% chlorobutanol.

- 47 045992

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% monoethyl diethylene glycol ether and about 0.21% chlorobutanol.

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether and approximately 0.2% chlorobutanol.

According to some embodiments, the pharmaceutical composition in the form of a spray contains approximately 4% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether and approximately 0.2% chlorobutanol.

Intranasal delivery.

According to an aspect provided herein, the pharmaceutical spray formulation has a droplet size D50 of about 10 μm to about 100 μm. In some embodiments, the pharmaceutical spray formulation has a D50 droplet size of about 10 μm to about 80 μm. In some embodiments, the pharmaceutical spray formulation has a droplet size D50 of about 10 μm to about 60 μm. In some embodiments, the pharmaceutical spray formulation has a droplet size D50 of about 10 μm to about 40 μm. In some embodiments, the pharmaceutical spray formulation has a droplet size D50 of about 10 μm to about 20 μm. In some embodiments, the pharmaceutical spray formulation has a droplet size D50 of about 10 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size D50 of approximately 20 microns. In some embodiments, the pharmaceutical spray formulation has a D50 droplet size of approximately 30 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size D50 of approximately 40 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size D50 of approximately 50 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size D50 of approximately 60 microns. In some embodiments, the pharmaceutical spray formulation has a D50 droplet size of approximately 70 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size D50 of approximately 80 microns. In some embodiments, the pharmaceutical spray formulation has a D50 droplet size of approximately 90 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size D50 of approximately 100 microns.

In some embodiments, the pharmaceutical spray formulation is delivered in one or more sprays with a droplet size distribution characterized by certain D10, D50, or D90 values. In some embodiments, the pharmaceutical spray formulation is delivered as an injection with a D10 droplet size value of about 15 μm to about 30 μm. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection with a D10 droplet size value of about 15 μm - about 16 μm, about 15 μm - about 17 μm, about 15 μm - about 18 μm, about 15 μm - about 19 µm, approximately 15 µm - approximately 20 µm, approximately 15 µm - approximately 21 µm, approximately 15 µm - approximately 22 µm, approximately 15 µm - approximately 25 µm, approximately 15 µm - approximately 30 µm, approximately 16 µm - approximately 17 µm, approximately 16 μm approximately 18 μm, approximately 16 μm - approximately 19 μm, approximately 16 μm - approximately 20 μm, approximately 16 μm - approximately 21 μm, approximately 16 μm - approximately 22 μm, approximately 16 μm - approximately 25 μm, approximately 16 μm - approximately 30 µm, approximately 17 µm - approximately 18 µm, approximately 17 µm - approximately 19 µm, approximately 17 µm - approximately 20 µm, approximately 17 µm - approximately 21 µm, approximately 17 µm - approximately 22 µm, approximately 17 µm - approximately 25 µm, approximately 17 µm - approximately 30 µm, approximately 18 µm - approximately 19 µm, approximately 18 µm - approximately 20 µm, approximately 18 µm - approximately 21 µm, approximately 18 µm - approximately 22 µm, approximately 18 µm - approximately 25 µm, approximately 18 µm - approximately 30 µm, approximately 19 µm - approximately 20 µm, approximately 19 µm - approximately 21 µm, approximately 19 µm - approximately 22 µm, approximately 19 µm - approximately 25 µm, approximately 19 µm - approximately 30 µm, approximately 20 µm - approximately 21 μm, approximately 20 μm - approximately 22 μm, approximately 20 μm - approximately 25 μm, approximately 20 μm - approximately 30 μm, approximately 21 μm - approximately 22 μm, approximately 21 μm - approximately

- 48 045992 µm, approximately 21 µm - approximately 30 µm, approximately 22 µm - approximately 25 µm, approximately 22 µm - approximately 30 µm or approximately 25 µm - approximately 30 µm. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection with a droplet size D10 value of about 15 μm, about 16 μm, about 17 μm, about 18 μm, about 19 μm, about 20 μm, about 21 μm, about 22 µm, about 25 µm or about 30 µm. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection with a droplet size D10 value of at least about 15 μm, about 16 μm, about 17 μm, about 18 μm, about 19 μm, about 20 μm, about 21 μm , about 22 µm or about 25 µm. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection with a droplet size D10 value of no more than about 16 μm, about 17 μm, about 18 μm, about 19 μm, about 20 μm, about 21 μm, about 22 μm , about 25 µm or about 30 µm.

In some embodiments, the pharmaceutical spray formulation is delivered as an injection with a D50 droplet size value of about 35 μm to about 80 μm. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection with a droplet size D50 value of about 35 μm - about 40 μm, about 35 μm - about 42 μm, about 35 μm - about 44 μm, about 35 μm - about 46 µm, approximately 35 µm - approximately 48 µm, approximately 35 µm - approximately 50 µm, approximately 35 µm - approximately 52 µm, approximately 35 µm - approximately 55 µm, approximately 35 µm - approximately 60 µm, approximately 35 µm - approximately 70 µm, about 35 µm - about 80 µm, about 40 µm - about 42 µm, about 40 µm - about 44 µm, about 40 µm - about 46 µm, about 40 µm - about 48 µm, about 40 µm - about 50 µm, about 40 µm - approximately 52 µm, approximately 40 µm - approximately 55 µm, approximately 40 µm - approximately 60 µm, approximately 40 µm - approximately 70 µm, approximately 40 µm - approximately 80 µm, approximately 42 µm - approximately 44 µm, approximately 42 µm - approximately 46 μm, approximately 42 μm - approximately 48 μm, approximately 42 μm - approximately 50 μm, approximately 42 μm - approximately 52 μm, approximately 42 μm - approximately 55 μm, approximately 42 μm - approximately 60 μm, approximately 42 μm - approximately 70 µm, approximately 42 µm - approximately 80 µm, approximately 44 µm - approximately 46 µm, approximately 44 µm - approximately 48 µm, approximately 44 µm - approximately 50 µm, approximately 44 µm - approximately 52 µm, approximately 44 µm - approximately 55 µm, approximately 44 µm - approximately 60 µm, approximately 44 µm - approximately 70 µm, approximately 44 µm - approximately 80 µm, approximately 46 µm - approximately 48 µm, approximately 46 µm - approximately 50 µm, approximately 46 µm - approximately 52 µm, approximately 46 µm - approximately 55 µm, approximately 46 µm - approximately 60 µm, approximately 46 µm - approximately 70 µm, approximately 46 µm - approximately 80 µm, approximately 48 µm - approximately 50 µm, approximately 48 µm - approximately 52 µm, approximately 48 µm - about 55 µm, about 48 µm - about 60 µm, about 48 µm - about 70 µm, about 48 µm - about 80 µm, about 50 µm - about 52 µm, about 50 µm - about 55 µm, about 50 µm - about 60 µm, approximately 50 µm - approximately 70 µm, approximately 50 µm - approximately 80 µm, approximately 52 µm - approximately 55 µm, approximately 52 µm - approximately 60 µm, approximately 52 µm - approximately 70 µm, approximately 52 µm - approximately 80 µm, about 55 µm - about 60 µm, about 55 µm - about 70 µm, about 55 µm - about 80 µm, about 60 µm - about 70 µm, about 60 µm - about 80 µm or about 70 µm - about 80 µm. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection with a droplet size D50 value of about 35 μm, about 40 μm, about 42 μm, about 44 μm, about 46 μm, about 48 μm, about 50 μm, about 52 μm, about 55 μm, about 60 μm, about 70 μm, or about 80 μm. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection with a droplet size D50 value of at least about 35 μm, about 40 μm, about 42 μm, about 44 μm, about 46 μm, about 48 μm, about 50 μm , about 52 μm, about 55 μm, about 60 μm, or about 70 μm. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection with a droplet size D50 value of no more than about 40 μm, about 42 μm, about 44 μm, about 46 μm, about 48 μm, about 50 μm, about 52 μm , about 55 μm, about 60 μm, about 70 μm, or about 80 μm.

In some embodiments, the pharmaceutical spray formulation is delivered as an injection with a D90 droplet size value of about 80 μm to about 180 μm. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection with a droplet size D90 value of about 80 μm - about 90 μm, about 80 μm - about 100 μm, about 80 μm - about 110 μm, about 80 μm - about 115 μm , approximately 80 μm - approximately 120 μm, approximately 80 μm - approximately 130 μm, approximately 80 μm - approximately 140 μm, approximately 80 μm - approximately 150 μm, approximately 80 μm - approximately 160 μm, approximately 80 μm - approximately 170 μm, approximately 80 µm - approximately 180 µm, approximately 90 µm - approximately 100 µm, approximately 90 µm - approximately 110 µm, approximately 90 µm - approximately 115 µm, approximately 90 µm - approximately 120 µm, approximately 90 µm - approximately 130 µm, approximately 90 µm - approximately

- 49 045992

140 µm, approximately 90 µm - approximately 150 µm, approximately 90 µm - approximately 160 µm, approximately 90 µm - approximately 170 µm, approximately 90 µm - approximately 180 µm, approximately 100 µm - approximately 110 µm, approximately 100 µm - approximately 115 µm , approximately 100 μm - approximately 120 μm, approximately 100 μm - approximately 130 μm, approximately 100 μm - approximately 140 μm, approximately 100 μm - approximately 150 μm, approximately 100 μm - approximately 160 μm, approximately 100 μm - approximately 170 μm, approximately 100 microns - approximately 180 microns, approximately 110 microns - approximately 115 microns, approximately 110 microns - approximately 120 microns, approximately 110 microns - approximately 130 microns, approximately 110 microns - approximately 140 microns, approximately 110 microns - approximately 150 microns, approximately 110 microns - approximately 160 μm, approximately 110 μm - approximately 170 μm, approximately 110 μm - approximately 180 μm, approximately 115 μm - approximately 120 μm, approximately 115 μm - approximately 130 μm, approximately 115 μm - approximately 140 μm, approximately 115 μm - approximately 150 µm, approximately 115 µm - approximately 160 µm, approximately 115 µm - approximately 170 µm, approximately 115 µm - approximately 180 µm, approximately 120 µm - approximately 130 µm, approximately 120 µm - approximately 140 µm, approximately 120 µm - approximately 150 µm, approximately 120 µm - approximately 160 µm, approximately 120 µm - approximately 170 µm, approximately 120 µm - approximately 180 µm, approximately 130 µm - approximately 140 µm, approximately 130 µm - approximately 150 µm, approximately 130 µm - approximately 160 µm, approximately 130 µm - approximately 170 μm, approximately 130 μm - approximately 180 μm, approximately 140 μm - approximately 150 μm, approximately 140 μm - approximately 160 μm, approximately 140 μm approximately 170 μm, approximately 140 μm - approximately 180 μm, approximately 150 μm - approximately 160 µm, about 150 µm - about 170 µm, about 150 µm - about 180 µm, about 160 µm - about 170 µm, about 160 µm - about 180 µm or about 170 µm - about 180 µm. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection with a D90 droplet size value of about 80 μm, about 90 μm, about 100 μm, about 110 μm, about 115 μm, about 120 μm, about 130 μm, about 140 μm, about 150 μm, about 160 μm, about 170 μm, or about 180 μm. In some embodiments, the pharmaceutical spray formulation is delivered as an injection with a D90 droplet size value of at least about 80 μm, about 90 μm, about 100 μm, about 110 μm, about 115 μm, about 120 μm, about 130 μm , about 140 μm, about 150 μm, about 160 μm, or about 170 μm. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection with a droplet size D90 value of no more than about 90 μm, about 100 μm, about 110 μm, about 115 μm, about 120 μm, about 130 μm, about 140 μm , about 150 μm, about 160 μm, about 170 μm, or about 180 μm.

In some embodiments, the pharmaceutical composition in the form of a spray is delivered in the form of an injection, which is characterized by % volume < 10 μm, being about 0.2% to about 5%. In some embodiments, the pharmaceutical composition in the form of a spray is delivered in the form of an injection, which is characterized by a % volume < 10 microns, being about 0.2% - about 0.4%, about 0.2% - about 0.6%, about 0. 2% - approximately 0.8%, approximately 0.2% - approximately 1%, approximately 0.2% - approximately 1.5%, approximately 0.2% - approximately 2%, approximately 0.2% - approximately 3% , approximately 0.2% - approximately 4%, approximately 0.2% - approximately 5%, approximately 0.4% - approximately 0.6%, approximately 0.4% - approximately 0.8%, approximately 0.4% - approximately 1%, approximately 0.4% - approximately 1.5%, approximately 0.4% - approximately 2%, approximately 0.4% - approximately 3%, approximately 0.4% - approximately 4%, approximately 0, 4% - approximately 5%, approximately 0.6% - approximately 0.8%, approximately 0.6% - approximately 1%, approximately 0.6% approximately 1.5%, approximately 0.6% - approximately 2%, approximately 0.6% - approximately 3%, approximately 0.6% - approximately 4%, approximately 0.6% - approximately 5%, approximately 0.8% - approximately 1%, approximately 0.8% - approximately 1.5 %, approximately 0.8% - approximately 2%, approximately 0.8% - approximately 3%, approximately 0.8% - approximately 4%, approximately 0.8% - approximately 5%, approximately 1% - approximately 1.5 %, approximately 1% - approximately 2%, approximately 1% - approximately 3%, approximately 1% - approximately 4%, approximately 1% - approximately 5%, approximately 1.5% - approximately 2%, approximately 1.5% - approximately 3%, approximately 1.5% - approximately 4%, approximately 1.5% - approximately 5%, approximately 2% - approximately 3%, approximately 2% - approximately 4%, approximately 2% - approximately 5%, approximately 3 % - approximately 4%, approximately 3% - approximately 5% or approximately 4% - approximately 5%. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection, which is characterized by a % volume <10 μm of about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1% , about 1.5%, about 2%, about 3%, about 4%, or about 5%. In some embodiments, the pharmaceutical composition in the form of a spray is delivered as an injection that is characterized by a % volume <10 μm of at least about 0.2%, about 0.4%, about 0.6%, about 0.8%, about 1%, about 1.5%, about 2%, about 3%, or about 4%. In some embodiments, the pharmaceutical composition in the form of a spray is delivered in the form of an injection, which is characterized by a % volume <10 μm, being no more than about 0.4%, about 0.6%, about 0.8%, about 1%, about 1 .5%, about 2%, about 3%, about 4% or about 5%.

In some embodiments, the pharmaceutical composition in the form of a spray is delivered in the form of an injection, which has a spread of about 1.5 to about 2.5. In some embodiments, the pharmaceutical composition is delivered as a spray to

- 50 045992 form of injection, which is characterized by a spread of about 1.5 - about 1.6, about 1.5 - about 1.7, about 1.5 - about 1.8, about 1.5 - about 1.9 , approximately 1.5 approximately 2, approximately 1.5 - approximately 2.1, approximately 1.5 - approximately 2.2, approximately 1.5 - approximately 2.3, approximately 1.5 - approximately 2.4, approximately 1 .5 - approximately 2.5, approximately 1.6 - approximately 1.7, approximately 1.6 approximately 1.8, approximately 1.6 - approximately 1.9, approximately 1.6 - approximately 2, approximately 1.6 - approximately 2.1, approximately 1.6 - approximately 2.2, approximately 1.6 - approximately 2.3, approximately 1.6 - approximately 2.4, approximately 1.6 approximately 2.5, approximately 1.7 - approximately 1.8, about 1.7 - about 1.9, about 1.7 - about 2, about 1.7 - about 2.1, about 1.7 - about 2.2, about 1.7 - about 2, 3, approximately 1.7 approximately 2.4, approximately 1.7 - approximately 2.5, approximately 1.8 - approximately 1.9, approximately 1.8 - approximately 2, approximately 1.8 - approximately 2.1, approximately 1.8 - approximately 2.2, approximately 1.8 - approximately 2.3, approximately 1.8 approximately 2.4, approximately 1.8 - approximately 2.5, approximately 1.9 - approximately 2, approximately 1.9 - approximately 2.1, approximately 1.9 - approximately 2.2, approximately 1.9 - approximately 2.3, approximately 1.9 - approximately 2.4, approximately 1.9 approximately 2.5, approximately 2 - approximately 2 ,1, approximately 2 - approximately 2.2, approximately 2 - approximately 2.3, approximately 2 - approximately 2.4, approximately 2 - approximately 2.5, approximately 2.1 - approximately 2.2, approximately 2.1 - approximately 2.3, approximately 2.1 - approximately 2.4, approximately 2.1 - approximately 2.5, approximately 2.2 - approximately 2.3, approximately 2.2 - approximately 2.4, approximately 2.2 - about 2.5, about 2.3 - about 2.4, about 2.3 - about 2.5, or about 2.4 - about 2.5. In some embodiments, the pharmaceutical composition in the form of a spray is delivered in the form of an injection that has a spread of about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2, 1, about 2.2, about 2.3, about 2.4, or about 2.5. In some embodiments, the pharmaceutical spray composition is delivered as an injection that has a spread of at least about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2. about 2.1, about 2.2, about 2.3, or about 2.4. In some embodiments, the pharmaceutical composition in the form of a spray is delivered in the form of an injection that has a spread of no more than about 1.6, about 1.7, about 1.8, about 1.9, about 2, about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5.

According to an aspect provided herein, the pharmaceutical composition in the form of a spray is present in the device and/or is delivered from the device. In some embodiments, a pharmaceutical spray formulation is present in and/or delivered from a prefilled device. In some embodiments, a pharmaceutical composition in the form of a spray is present in the device and/or is delivered from a device suitable for delivering the composition to the nostril of a subject. In some embodiments, the device is a single-dose device. In some embodiments, the device is a two-dose device. In some embodiments, the device comprises a single reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device contains a single reservoir containing about 75 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device comprises a single reservoir containing about 100 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device comprises a single reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device comprises a single reservoir containing about 150 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, a single-dose device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, a two-dose device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL of about 250 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 75 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 75 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 100 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 100 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 225 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 225 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 200 μL of pharmaceutical co

- 51 045992 stav, and a second reservoir containing approximately 50 μl - approximately 175 μl of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 175 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 175 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 150 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 150 μL of the pharmaceutical composition. In some embodiments, a two-dose device delivers one injection of a pharmaceutical solution from a first reservoir, and one injection of a pharmaceutical solution from a second reservoir. In some embodiments, the pharmaceutical composition is present in the form of a spray in the device and/or is delivered from the device with an oxygen absorbent or scavenger. In some embodiments, the oxygen absorbent or scavenger is iron, ferric carbonate, sodium ascorbate, or sodium bicarbonate. In some embodiments, a pharmaceutical composition in the form of a spray is present in and/or delivered from the device, wherein the device includes an enlarged reservoir. In some embodiments, the device comprises at least one oxygen absorbent or scavenger. In some embodiments, the oxygen absorbent or scavenger is iron, ferric carbonate, sodium ascorbate or bicarbonate, or a combination thereof.

According to an aspect provided herein, the pharmaceutical composition in the form of a spray is configured to be administered by dosage by inhalation.

According to an aspect provided herein, the pharmaceutical composition in the form of a spray is configured for intranasal dosing.

In an aspect provided herein, a spray containing drops is provided. In an aspect, provided herein is a spray delivered from a device comprising droplets. In an aspect, provided herein is a spray containing drops, the drops containing epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent, and benzalkonium chloride or chlorobutanol.

In some embodiments, the drops contain a total of about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 0.5 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 1 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 2 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 3 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 4 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 5 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 6 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 7 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 8 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 9 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 10 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 15 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 20 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 25 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 30 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 35 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 40 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 45 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 50 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 55 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 60 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 65 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 70 mg of epinephrine or a pharmaceutically acceptable salt thereof. According to some embodiments

- 52 045992 drops contain a total of approximately 75 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 80 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 85 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 90 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 95 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the drops contain a total of about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof.

In some embodiments, epinephrine is at least about 10% bioavailable. In some embodiments, epinephrine is at least about 20% bioavailable. In some embodiments, epinephrine is at least about 30% bioavailable. In some embodiments, epinephrine is at least about 40% bioavailable. In some embodiments, epinephrine is at least about 50% bioavailable. In some embodiments, epinephrine is at least about 60% bioavailable. In some embodiments, epinephrine is at least about 70% bioavailable. In some embodiments, epinephrine is at least about 80% bioavailable.

In some embodiments, epinephrine or a pharmaceutically acceptable salt thereof is dissolved in water, ethanol, or propylene glycol, or a combination thereof. In some embodiments, epinephrine or a pharmaceutically acceptable salt thereof is dissolved in water. In some embodiments, epinephrine or a pharmaceutically acceptable salt thereof is dissolved in ethanol. In some embodiments, epinephrine or a pharmaceutically acceptable salt thereof is dissolved in propylene glycol. In some embodiments, epinephrine or a pharmaceutically acceptable salt thereof is dissolved in a combination of water and ethanol. In some embodiments, epinephrine or a pharmaceutically acceptable salt thereof is dissolved in a combination of water and propylene glycol. In some embodiments, epinephrine or a pharmaceutically acceptable salt thereof is dissolved in a combination of ethanol and propylene glycol.

In some embodiments, the droplets contain a total of about 0.005% to about 10% (w/v) benzalkonium chloride or chlorobutanol.

In some embodiments, the droplets contain a total of about 0.005% to about 10% (w/v) benzalkonium chloride. In some embodiments, the pharmaceutical spray formulation contains benzalkonium chloride at a concentration of about 0.005% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation contains benzalkonium chloride at a concentration of about 0.01% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray composition contains benzalkonium chloride at a concentration of about 0.05% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation contains benzalkonium chloride at a concentration of about 0.1% (w/v) to about 1% (w/v). In some embodiments, the droplets contain a total of about 0.01% to about 10% (w/v) benzalkonium chloride. In some embodiments, the droplets contain a total of about 0.05% to about 10% (w/v) benzalkonium chloride. In some embodiments, the droplets contain a total of about 0.5% to about 10% (w/v) benzalkonium chloride. In some embodiments, the droplets contain a total of about 1% to about 10% (w/v) benzalkonium chloride. In some embodiments, the droplets contain a total of about 0.005% to about 5% (w/v) benzalkonium chloride. In some embodiments, the droplets contain a total of about 0.01% to about 2% (w/v) benzalkonium chloride.

In some embodiments, the droplets contain a total of about 0.005% to about 10% (w/v) chlorobutanol. In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.005% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.01% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.05% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation contains chlorobutanol at a concentration of about 0.1% (w/v) to about 1% (w/v). In some embodiments, the droplets contain a total of about 0.01% to about 10% (w/v) chlorobutanol. In some embodiments, the droplets contain a total of about 0.05% to about 10% (w/v) chlorobutanol. In some embodiments, the droplets contain a total of about 0.5% to about 10% (w/v) chlorobutanol. According to some

- 53 045992 Antam implementation drops contain a total of about 1% - about 10% (w/v) chlorobutanol. In some embodiments, the droplets contain a total of about 0.005% to about 5% (w/v) chlorobutanol. In some embodiments, the droplets contain a total of about 0.01% to about 2% (w/v) chlorobutanol. In some embodiments, the droplets contain a total of about 2.1% (w/v) chlorobutanol.

In some embodiments, the isotonic agent is present at a concentration of about 0.1% to about 5% (w/v). In some embodiments, the isotonic agent is sodium chloride.

According to an aspect provided herein, the spray is delivered from the device. In some embodiments, the device is pre-filled.

According to an aspect provided herein, the spray takes the form of a circular stream. In some embodiments, the spray takes the form of a circular jet with an ovality ratio of less than about 2.0. In some embodiments, the spray takes the form of a circular spray with an ovality ratio of less than about 1.9. In some embodiments, the spray takes the form of a circular spray with an ovality ratio of less than about 1.8. In some embodiments, the spray takes the form of a circular jet with an ovality ratio of less than about 1.7. In some embodiments, the spray takes the form of a circular spray with an ovality ratio of less than about 1.6. In some embodiments, the spray takes the form of a circular spray with an ovality ratio of less than about 1.5. In some embodiments, the spray takes the form of a circular spray with an ovality ratio of less than about 1.4. In some embodiments, the spray takes the form of a circular spray with an ovality ratio of less than about 1.3. In some embodiments, the spray takes the form of a circular spray with an ovality ratio of less than about 1.2. In some embodiments, the spray takes the form of a circular jet with an ovality ratio of less than about 1.1. In some embodiments, the spray takes the form of a circular jet with an ovality ratio of less than about 1.0. In some embodiments, the spray takes the form of a circular stream with an ovality ratio of at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, and/or no more than about 2.0, no more than about 1.9, no more than about 1.8, no more than about 1.7, no more than about 1.6, not more than about 1.5, not more than about 1.4, not more than about 1.4, not more than about 1.3, not more than about 1.2, or not more than about 1 ,1.

According to an aspect provided herein, the spray ovality coefficient is measured at a distance of about 1 cm to about 10 cm from the device from which the spray is delivered. According to an aspect provided herein, the spray ovality coefficient is measured at a distance of about 1 cm to about 5 cm from the device from which the spray is delivered. According to an aspect provided herein, the spray ovality coefficient is measured at a distance of about 3 cm to about 6 cm from the device from which the spray is delivered. According to an aspect provided herein, the spray ovality coefficient is measured at a distance of approximately 3 cm from the device from which the spray is delivered. According to an aspect provided herein, the spray ovality coefficient is measured at a distance of approximately 5 cm from the device from which the spray is delivered. In an embodiment, the injection is measured from a nozzle, such as a spray nozzle, on the device from which the spray is delivered.

According to an aspect provided herein, spray droplets have an average droplet size of about 10 μm to about 120 μm. In some embodiments, no more than about 10% of the droplets have a diameter less than about 10 microns. In some embodiments, no more than about 5% of the droplets have a diameter less than about 10 microns. In some embodiments, no more than about 2% of the droplets have a diameter less than about 10 microns. In some embodiments, about 50% of the droplets have a diameter of about 10 μm to about 120 μm. In some embodiments, about 50% of the droplets have a diameter of about 10 μm to about 60 μm. In some embodiments, about 90% of the droplets have a diameter less than about 120 microns.

According to an aspect provided herein, the spray further contains a stabilizer and an acid. In some embodiments, the stabilizer is disodium edetate. In some embodiments, the acid is hydrochloric acid or citric acid, or a combination thereof. According to some embodiments,

- 54 045992 slot represents hydrochloric acid. In some embodiments, the acid is citric acid. In some embodiments, the acid is a combination of hydrochloric acid and citric acid.

According to an aspect provided herein, the spray further contains sodium bisulfite or sodium metabisulfite.

According to an aspect provided herein, the spray further contains sodium bisulfite or sodium metabisulfite. In some embodiments, the spray further comprises sodium bisulfite at a concentration of about 0.0001% w/w, about 0.1% w/w, or sodium metabisulfite at a concentration of about 0.0001% (w/w) - approximately 0.1% (w/w). In some embodiments, the spray contains sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.05% (w/w), or sodium metabisulfite at a concentration of about 0.0001% (w/w) about 0.05%(w/w). In some embodiments, the spray contains sodium bisulfite at a concentration of about 0.001% (w/w) to about 0.05% (w/w), or sodium metabisulfite at a concentration of about 0.001% (w/w). wt.) - approximately 0.05% (wt./wt.). In some embodiments, the spray contains sodium bisulfite at a concentration of about 0.01% (w/w) to about 0.05% (w/w), or sodium metabisulfite at a concentration of about 0.01% (w/w) - approximately 0.05% (w/w). In some embodiments, the spray further comprises sodium bisulfite at a concentration of about 0.001% w/w to about 0.1% w/w, or sodium metabisulfite at a concentration of about 0.001% w/w. /wt.) - approximately 0.1% (wt./wt.). In some embodiments, the spray further comprises sodium bisulfite at a concentration of about 0.01% (w/w) to about 0.1% (w/w), or sodium metabisulfite at a concentration of about 0.01 % (w/w) - approximately 0.1% (w/w).

In some embodiments, the spray contains sodium bisulfite. In some embodiments, the spray further contains sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the spray contains sodium bisulfite at a concentration of about 0.001% to about 0.05%. In some embodiments, the spray contains sodium bisulfite at a concentration of about 0.01% to about 0.05%. In some embodiments, the spray contains sodium bisulfite at a concentration of about 0.01%. In some embodiments, the spray contains sodium bisulfite at a concentration of about 0.02%. In some embodiments, the spray contains sodium bisulfite at a concentration of about 0.03%. In some embodiments, the spray contains sodium bisulfite at a concentration of about 0.04%. In some embodiments, the spray contains sodium bisulfite at a concentration of about 0.05%.

In some embodiments, the spray contains sodium metabisulfite. In some embodiments, the spray further contains sodium metabisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the spray contains sodium metabisulfite at a concentration of about 0.001% to about 0.1%. In some embodiments, the spray contains sodium metabisulfite at a concentration of about 0.01% to about 0.1%. In some embodiments, the spray further contains sodium metabisulfite at a concentration of about 0.001% (w/w) to about 0.1% (w/w). In some embodiments, the spray further contains sodium metabisulfite at a concentration of about 0.01% (w/w) to about 0.1% (w/w). In some embodiments, the spray contains sodium metabisulfite at a concentration of about 0.01%. In some embodiments, the spray contains sodium metabisulfite at a concentration of about 0.02%. In some embodiments, the spray contains sodium metabisulfite at a concentration of about 0.03%. In some embodiments, the spray contains sodium metabisulfite at a concentration of about 0.04%. In some embodiments, the spray contains sodium metabisulfite at a concentration of about 0.05%. In some embodiments, the spray contains sodium metabisulfite at a concentration of about 0.06%. In some embodiments, the spray contains sodium metabisulfite at a concentration of about 0.07%. In some embodiments, the spray contains sodium metabisulfite at a concentration of about 0.08%. In some embodiments, the spray contains sodium metabisulfite at a concentration of about 0.09%. In some embodiments, the spray contains sodium metabisulfite at a concentration of about 0.1%.

According to an aspect provided herein, the spray further contains disodium edetate. In some embodiments, the spray contains disodium edetate at the end

- 55,045,992 tration amounting to approximately 0.0001% - approximately 0.01%. In some embodiments, the spray contains disodium edetate at a concentration of about 0.001% to about 0.01%.

According to an aspect provided herein, the spray further contains an antimicrobial preservative. In some embodiments, the antimicrobial preservative is sodium benzalkonium or chlorobutanol. In some embodiments, the spray contains sodium benzalkonium at a concentration of about 0.005% (w/v) to about 1% (w/v) or chlorobutanol at a concentration of about 0.005% to about 1%.

In some embodiments, the spray contains sodium benzalkonium. In some embodiments, the spray contains sodium benzalkonium at a concentration of about 0.005% to about 1%.

In some embodiments, the spray contains chlorobutanol. In some embodiments, the spray contains chlorobutanol at a concentration of about 0.005% to about 1%.

According to an aspect provided herein, the spray further contains sodium chloride. In some embodiments, the spray contains sodium chloride at a concentration of about 0.1% to about 5%. In some embodiments, the spray contains sodium chloride at a concentration of about 0.1% to about 1%. In some embodiments, the spray contains sodium chloride at a concentration of about 0.5% to about 5%. In some embodiments, the spray contains sodium chloride at a concentration of about 1% to about 5%. In some embodiments, the spray contains sodium chloride at a concentration of about 2% to about 5%. In some embodiments, the spray contains sodium chloride at a concentration of about 3% to about 5%. In some embodiments, the spray contains sodium chloride at a concentration of about 4% to about 5%.

According to an aspect provided herein, the spray further comprises a vasodilator. In some embodiments, the vasodilator is nitroprusside, phentolamine, or nifedipine.

In some embodiments, the spray further comprises nitroprusside. In some embodiments, the spray further contains from about 0.05 mg to about 5 mg nitroprusside. In some embodiments, the spray further contains from about 0.1 mg to about 5 mg of nitroprusside. In some embodiments, the spray further contains from about 0.5 mg to about 5 mg of nitroprusside. In some embodiments, the spray further contains from about 1 mg to about 5 mg of nitroprusside. In some embodiments, the spray further contains from about 1 mg to about 4 mg of nitroprusside. In some embodiments, the spray further comprises nitroprusside. In some embodiments, the spray further contains from about 0.05 mg to about 3 mg of nitroprusside. In some embodiments, the spray further comprises nitroprusside. In some embodiments, the spray further contains from about 0.5 mg to about 3 mg of nitroprusside. In some embodiments, the spray further comprises nitroprusside. In some embodiments, the spray further contains from about 0.5 mg to about 2 mg nitroprusside.

In some embodiments, the spray further contains phentolamine. In some embodiments, the spray further contains from about 1 mg to about 50 mg of phentolamine. In some embodiments, the spray further contains phentolamine. In some embodiments, the spray further contains about 1 mg of about 40 mg of phentolamine. In some embodiments, the spray further contains phentolamine. In some embodiments, the spray further contains from about 1 mg to about 30 mg of phentolamine. In some embodiments, the spray further contains phentolamine. In some embodiments, the spray further contains from about 1 mg to about 20 mg of phentolamine. In some embodiments, the spray further contains phentolamine. In some embodiments, the spray further contains from about 1 mg to about 10 mg of phentolamine. In some embodiments, the spray further contains phentolamine. In some embodiments, the spray further contains from about 5 mg to about 50 mg of phentolamine. In some embodiments, the spray further contains phentolamine. In some embodiments, the spray further contains from about 10 mg to about 50 mg of phentolamine. In some embodiments, the spray further contains phentolamine. In some embodiments, the spray further contains from about 20 mg to about 50 mg of phentolamine. In some embodiments, the spray further contains phentolamine. In some embodiments, the spray further contains about 20 mg

- 56 045992 approximately 40 mg of phentolamine.

In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 10 mg to about 500 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 10 mg to about 450 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 10 mg to about 400 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 10 mg to about 350 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 10 mg to about 300 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 10 mg to about 250 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 10 mg to about 200 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 10 mg to about 150 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains about 10 mg to about 100 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 10 mg to about 75 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 10 mg to about 50 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 10 mg to about 40 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 10 mg to about 30 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 50 mg to about 500 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 100 mg to about 500 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 100 mg to about 400 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 100 mg to about 350 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further contains from about 100 mg to about 300 mg of nifedipine.

According to an aspect provided herein, the spray further comprises a penetration enhancer.

According to an aspect provided herein, the spray further comprises diethylene glycol monoethyl ether. In some embodiments, the spray further comprises diethylene glycol monoethyl ether at a concentration of about 0.05% to about 15%.

According to an aspect provided herein, the spray further contains a viscosity modifier. In some embodiments, the viscosity modifier is polyethylene glycol, methylcellulose, or hypromellose.

In some embodiments, the spray further comprises polyethylene glycol. In some embodiments, the spray further contains from about 0.5% to about 50% polyethylene glycol.

In some embodiments, the spray further contains methylcellulose. In some embodiments, the spray further contains from about 0.001% to about 5% methylcellulose.

In some embodiments, the spray further contains hypromellose. In some embodiments, the spray further contains about 0.001% to about 0.5% hypromellose. In some embodiments, the spray further contains about 0.05% to about 0.5% hypromellose.

According to an aspect provided herein, the spray contains per 100 μl of solution: about 0.5 mg to about 100 mg epinephrine or a pharmaceutically acceptable salt thereof;

about 0.1 mg - about 2 mg sodium chloride;

- 57 045992 approximately 0.01 mg - approximately 1 mg benzalkonium chloride;

about 0.1 mg - about 2 mg disodium edetate; and hydrochloric acid or citric acid or a combination thereof in an amount sufficient to achieve a pH value of about 3.5 to about 6.5.

In some embodiments, the pH of the spray is about 4. In some embodiments, the pH of the spray is about 4.5. In some embodiments, the pH of the spray is about 5. In some embodiments, the pH of the spray is about 5.5. In some embodiments, the pH of the spray is about 6. In some embodiments, the pH of the spray is about 6.5.

According to an aspect provided herein, the spray is delivered from a spray nozzle of a prefilled device, and wherein no more than about 10% of the droplets have a diameter of less than 10 microns. In some embodiments, atomization is measured using laser diffraction with beams measured at both 3 cm and 6 cm from the spray nozzle.

According to an aspect provided herein, the pharmaceutical composition in the form of a spray or spray is administered from a single-dose device or delivery system. According to an aspect provided herein, the pharmaceutical composition in the form of a spray or spray is administered from a two-dose device or delivery system. According to an aspect provided herein, the pharmaceutical composition in the form of a spray or spray is administered from a multi-dose device or delivery system.

Pharmacokinetics.

In some aspects, a pharmaceutical spray formulation disclosed herein provides desired pharmacokinetic profiles upon administration to an individual. In some embodiments, the pharmacokinetic profile comprises _Cmax , _Tmax , area under the curve (AUC), or any combination thereof. In some embodiments, administration involves a single injection. In some embodiments, administration involves two injections. In some embodiments, the pharmaceutical spray formulation is administered into each nostril. In some embodiments, administration involves one or more injections from a single-dose device or delivery system. In some embodiments, administration involves one or more injections from a multi-dose or two-dose device or delivery system.

In some embodiments, the pharmaceutical spray formulation is formulated to achieve a desired pharmacokinetic profile. In some embodiments, administration of the pharmaceutical composition as a spray achieves the desired pharmacokinetic profile. In some embodiments, administration of the pharmaceutical composition as a spray involves one spray or two or more sprays. For example, two-dose delivery involves one spray into each nostril of an individual. In some embodiments, the desired pharmacokinetic profile is achieved through a pharmaceutical formulation as a spray, delivery of a pharmaceutical formulation as a spray, or both. In some embodiments, the combination of a delivery device and a pharmaceutical spray composition provides one or more injections that are characterized by a desired ovality ratio as described herein. The ovality factor may influence the pharmacokinetic profile, for example, by increasing the rate of absorption of the spray(s), thereby improving pharmacokinetic parameters such as plasma concentration, Cmax, _Tmax and/or AUC of the active ingredient. The pharmaceutical spray formulation may also be formulated to enhance absorption, for example by including one or more absorption enhancers. In some embodiments, the pharmaceutical spray formulation contains one or more preservatives, which may include antioxidants, chelating agents, antimicrobial preservatives, and other types of preservatives that help maintain the stability and/or durability of the formulation.

In some embodiments, the pharmaceutical spray formulation contains one or more buffering agents to maintain an appropriate pH to enhance the stability of the formulation. In some embodiments, the pharmaceutical spray formulation is formulated to provide pharmacokinetics that are substantially equivalent to those administered by intramuscular injection.

In some embodiments, the pharmaceutical composition is formulated to be stable. In some embodiments, at least a minimum percentage of the active ingredient (eg, epinephrine) remains in the pharmaceutical composition in an undegraded state after storage. In some embodiments, the stable pharmaceutical composition contains at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least

- 58 045992

95%, at least 96%, at least 97%, at least 98%, or at least 99% or more of the active ingredient in an undegraded state after a period of storage at a specified temperature and/or humidity. In some embodiments, the storage period is at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, etc. at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months or more. In some embodiments, the humidity is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least at least 80% or at least 90% or more. In some embodiments, the stable pharmaceutical composition contains no more than 1%, no more than 2%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, no more than 10%, no more than 15% or no more than 20% or more impurities after a period of storage at a specified temperature and/or humidity. In some embodiments, the impurities comprise degradation products of the active ingredient.

In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration of at least 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0 ,8, 0.9, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 ng/ml, and/or not more than 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 15, 20, 25 or 30 ng/ml within a range of not more than 0.1, 0 ,2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4 , 4.5, 5, 6, 7, 8, 9, 10 or 15 min. In some embodiments, the desired pharmacokinetic profile is achieved after administration of a single injection of the pharmaceutical composition in the form of a spray. In some embodiments, the desired pharmacokinetic profile is achieved after administration of two spray injections of the pharmaceutical formulation. In some embodiments, the desired pharmacokinetic profile is achieved after administration of two or more sprays of the pharmaceutical formulation, such as three sprays, four sprays, five sprays, or six sprays. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a target plasma concentration within a minimum period of time after administration.

In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration within a minimum period of time after administration of about 0.1 ng/mL to about 1 ng/mL. In some embodiments, the minimum time period is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5 , 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 or 10 min. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration within a minimum period of time after administration of at least about 0.1 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration within a minimum period of time after administration of no more than about 1 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration within a minimum period of time after administration of about 0.1 ng/mL, about 0.2 ng/mL, about 0.1 ng/mL, about 0.3 ng/ml, approximately 0.1 ng/ml - approximately 0.4 ng/ml, approximately 0.1 ng/ml - approximately 0.5 ng/ml, approximately 0.1 ng/ml - approximately 0.6 ng/ ml, approximately 0.1 ng/ml approximately 0.7 ng/ml, approximately 0.1 ng/ml - approximately 0.8 ng/ml, approximately 0.1 ng/ml - approximately 0.9 ng/ml, approximately 0.1 ng/ml - approximately 1 ng/ml, approximately 0.2 ng/ml - approximately 0.3 ng/ml, approximately 0.2 ng/ml approximately 0.4 ng/ml, approximately 0.2 ng/ ml - approximately 0.5 ng/ml, approximately 0.2 ng/ml - approximately 0.6 ng/ml, approximately 0.2 ng/ml - approximately 0.7 ng/ml, approximately 0.2 ng/ml - approximately 0.8 ng/ml, approximately 0.2 ng/ml approximately 0.9 ng/ml, approximately 0.2 ng/ml - approximately 1 ng/ml, approximately 0.3 ng/ml - approximately 0.4 ng /ml, approximately 0.3 ng/ml - approximately 0.5 ng/ml, approximately 0.3 ng/ml - approximately 0.6 ng/ml, approximately 0.3 ng/ml approximately 0.7 ng/ml, approximately 0.3 ng/ml - approximately 0.8 ng/ml, approximately 0.3 ng/ml - approximately 0.9 ng/ml, approximately 0.3 ng/ml - approximately 1 ng/ml, approximately 0.4 ng/ml - approximately 0.5 ng/ml, approximately 0.4 ng/ml approximately 0.6 ng/ml, approximately 0.4 ng/ml - approximately 0.7 ng/ml, approximately 0.4 ng/ml - approximately 0.8 ng/ml, approximately 0.4 ng/ml - approximately 0.9 ng/ml, approximately 0.4 ng/ml - approximately 1 ng/ml, approximately 0.5 ng/ml approximately 0.6 ng/ml, approximately 0.5 ng/ml - approximately 0.7 ng/ml, approximately 0.5 ng/ml - approximately 0.8 ng/ml, approximately 0.5 ng/ml - approximately 0.9 ng/ ml, approximately 0.5 ng/ml - approximately 1 ng/ml, approximately 0.6 ng/ml approximately 0.7 ng/ml, approximately 0.6 ng/ml - approximately 0.8 ng/ml, approximately 0. 6 ng/ml - approximately 0.9 ng/ml, approximately 0.6 ng/ml - approximately 1 ng/ml, approximately 0.7 ng/ml - approximately 0.8 ng/ml, approximately 0.7 ng/ml approximately 0.9 ng/ml, approximately 0.7 ng/ml - approximately 1 ng/ml, approximately 0.8 ng/ml - approximately 0.9 ng/ml, approximately 0.8 ng/ml - approximately 1 ng/ ml or approximately 0.9 ng/ml - approximately 1 ng/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration within a minimum period of time after administration of about 0.1 ng/mL, about 0.2 ng/mL, about 0.3 ng/mL, about 0. 4 ng/ml, about 0.5 ng/ml, about 0.6 ng/ml, about 0.7 ng/ml, about 0.8 ng/ml, about 0.9 ng/ml, or about 1 ng/ml .

In some embodiments, the pharmaceutical spray composition is formulated

- 59 045992 to achieve a plasma concentration within a minimum period of time after administration of approximately 1 ng/ml - approximately 40 ng/ml. In some embodiments, the minimum time period is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5 , 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 or 10 minutes. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration within a minimum period of time after administration of at least about 1 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration within a minimum period of time after administration of no more than about 40 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration within a minimum period of time after administration of about 1 ng/mL, about 2 ng/mL, about 1 ng/mL, about 3 ng/mL, about 1 ng/mL. ml - approximately 4 ng/ml, approximately 1 ng/ml - approximately 5 ng/ml, approximately 1 ng/ml - approximately 6 ng/ml, approximately 1 ng/ml - approximately 7 ng/ml, approximately 1 ng/ml - approximately 8 ng/ml, approximately 1 ng/ml - approximately 9 ng/ml, approximately 1 ng/ml - approximately 10 ng/ml, approximately 1 ng/ml - approximately 20 ng/ml, approximately 1 ng/ml - approximately 40 ng/ml, approximately 2 ng/ml - approximately 3 ng/ml, approximately 2 ng/ml - approximately 4 ng/ml, approximately 2 ng/ml - approximately 5 ng/ml, approximately 2 ng/ml - approximately 6 ng/ml ml, approximately 2 ng/ml - approximately 7 ng/ml, approximately 2 ng/ml - approximately 8 ng/ml, approximately 2 ng/ml - approximately 9 ng/ml, approximately 2 ng/ml - approximately 10 ng/ml, approximately 2 ng/ml - approximately 20 ng/ml, approximately 2 ng/ml - approximately 40 ng/ml, approximately 3 ng/ml - approximately 4 ng/ml, approximately 3 ng/ml - approximately 5 ng/ml, approximately 3 ng/ml - approximately 6 ng/ml, approximately 3 ng/ml - approximately 7 ng/ml, approximately 3 ng/ml - approximately 8 ng/ml, approximately 3 ng/ml - approximately 9 ng/ml, approximately 3 ng/ml ml - approximately 10 ng/ml, approximately 3 ng/ml - approximately 20 ng/ml, approximately 3 ng/ml - approximately 40 ng/ml, approximately 4 ng/ml - approximately 5 ng/ml, approximately 4 ng/ml - approximately 6 ng/ml, approximately 4 ng/ml - approximately 7 ng/ml, approximately 4 ng/ml - approximately 8 ng/ml, approximately 4 ng/ml - approximately 9 ng/ml, approximately 4 ng/ml approximately 10 ng /ml, approximately 4 ng/ml - approximately 20 ng/ml, approximately 4 ng/ml - approximately 40 ng/ml, approximately 5 ng/ml - approximately 6 ng/ml, approximately 5 ng/ml - approximately 7 ng/ml , approximately 5 ng/ml - approximately 8 ng/ml, approximately 5 ng/ml - approximately 9 ng/ml, approximately 5 ng/ml - approximately 10 ng/ml, approximately 5 ng/ml approximately 20 ng/ml, approximately 5 ng/ml - approximately 40 ng/ml, approximately 6 ng/ml - approximately 7 ng/ml, approximately 6 ng/ml - approximately 8 ng/ml, approximately 6 ng/ml - approximately 9 ng/ml, approximately 6 ng/ml ml - approximately 10 ng/ml, approximately 6 ng/ml - approximately 20 ng/ml, approximately 6 ng/ml - approximately 40 ng/ml, approximately 7 ng/ml approximately 8 ng/ml, approximately 7 ng/ml - approximately 9 ng/ml, approximately 7 ng/ml - approximately 10 ng/ml, approximately 7 ng/ml - approximately 20 ng/ml, approximately 7 ng/ml - approximately 40 ng/ml, approximately 8 ng/ml - approximately 9 ng /ml, approximately 8 ng/ml - approximately 10 ng/ml, approximately 8 ng/ml - approximately 20 ng/ml, approximately 8 ng/ml approximately 40 ng/ml, approximately 9 ng/ml - approximately 10 ng/ml, about 9 ng/ml - about 20 ng/ml, about 9 ng/ml - about 40 ng/ml, about 10 ng/ml - about 20 ng/ml, about 10 ng/ml - about 40 ng/ml or about 20 ng/ml - approximately 40 ng/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration within a minimum period of time after administration of about 1 ng/mL, about 2 ng/mL, about 3 ng/mL, about 4 ng/mL, about 5 ng /ml, about 6 ng/ml, about 7 ng/ml, about 8 ng/ml, about 9 ng/ml, about 10 ng/ml, about 20 ng/ml, or about 40 ng/ml.

In some embodiments, the pharmaceutical spray formulation is formulated to achieve plasma concentrations within a minimum period of time after administration. In some embodiments, the minimum time period is at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least at least 9, at least 10, at least 15, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least at least 90, at least 100, at least 110, at least 120, at least 130, at least 140 or at least 150 minutes.

In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration after a minimum period of time after administration of about 1 ng/mL to about 10 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration, after a minimum period of time after administration, of at least about 1 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration, after a minimum period of time after administration, of no more than about 10 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration after a minimum period of time after administration of about 1 ng/mL - about 1.5 ng/mL, about 1 ng/mL - about 2 ng/mL, about 1 ng/ml - approximately 2.5 ng/ml, approximately 1 ng/ml - approximately 3 ng/ml, approximately 1 ng/ml - approximately 3.5 ng/ml, approximately 1 ng/ml - approximately 4 ng/ml, approximately 1 ng/ml - approximately 4.5 ng/ml, approximately 1 ng/ml - approximately 5 ng/ml, approximately 1 ng/ml - approximately 6 ng/ml, approximately 1 ng/ml - approximately 8 ng/ml, approximately 1 ng/ml - approximately 10 ng/ml, approximately 1.5 ng/ml - approximately 2 ng/ml, approximately 1.5 ng/ml - approximately 2.5 ng/ml, approximately 1.5 ng/ml - approximately 3 ng/ml, approximately 1.5 ng/ml - approximately 3.5 ng/ml, approximately 1.5 ng/ml - approximately 4 ng/ml, approximately 1.5

- 60 045992 ng/ml - approximately 4.5 ng/ml, approximately 1.5 ng/ml - approximately 5 ng/ml, approximately 1.5 ng/ml - approximately 6 ng/ml, approximately 1.5 ng/ml - approximately 8 ng/ml, approximately 1.5 ng/ml - approximately 10 ng/ml, approximately 2 ng/ml - approximately 2.5 ng/ml, approximately 2 ng/ml - approximately 3 ng/ml, approximately 2 ng /ml - approximately 3.5 ng/ml, approximately 2 ng/ml - approximately 4 ng/ml, approximately 2 ng/ml - approximately 4.5 ng/ml, approximately 2 ng/ml - approximately 5 ng/ml, approximately 2 ng/ml - approximately 6 ng/ml, approximately 2 ng/ml - approximately 8 ng/ml, approximately 2 ng/ml approximately 10 ng/ml, approximately 2.5 ng/ml - approximately 3 ng/ml, approximately 2 .5 ng/ml - approximately 3.5 ng/ml, approximately 2.5 ng/ml - approximately 4 ng/ml, approximately 2.5 ng/ml - approximately 4.5 ng/ml, approximately 2.5 ng/ ml approximately 5 ng/ml, approximately 2.5 ng/ml - approximately 6 ng/ml, approximately 2.5 ng/ml - approximately 8 ng/ml, approximately 2.5 ng/ml - approximately 10 ng/ml, approximately 3 ng/ml - approximately 3.5 ng/ml, approximately 3 ng/ml - approximately 4 ng/ml, approximately 3 ng/ml - approximately 4.5 ng/ml, approximately 3 ng/ml - approximately 5 ng/ml , approximately 3 ng/ml - approximately 6 ng/ml, approximately 3 ng/ml - approximately 8 ng/ml, approximately 3 ng/ml - approximately 10 ng/ml, approximately 3.5 ng/ml - approximately 4 ng/ml , approximately 3.5 ng/ml - approximately 4.5 ng/ml, approximately 3.5 ng/ml approximately 5 ng/ml, approximately 3.5 ng/ml - approximately 6 ng/ml, approximately 3.5 ng/ ml - approximately 8 ng/ml, approximately 3.5 ng/ml - approximately 10 ng/ml, approximately 4 ng/ml - approximately 4.5 ng/ml, approximately 4 ng/ml - approximately 5 ng/ml, approximately 4 ng/ml - approximately 6 ng/ml, approximately 4 ng/ml - approximately 8 ng/ml, approximately 4 ng/ml - approximately 10 ng/ml, approximately 4.5 ng/ml - approximately 5 ng/ml, approximately 4 .5 ng/ml - approximately 6 ng/ml, approximately 4.5 ng/ml - approximately 8 ng/ml, approximately 4.5 ng/ml - approximately 10 ng/ml, approximately 5 ng/ml approximately 6 ng/ml , about 5 ng/ml - about 8 ng/ml, about 5 ng/ml - about 10 ng/ml, about 6 ng/ml - about 8 ng/ml, about 6 ng/ml - about 10 ng/ml or about 8 ng/ml - approximately 10 ng/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a plasma concentration after a minimum period of time after administration of about 1 ng/mL, about 1.5 ng/mL, about 2 ng/mL, about 2.5 ng/mL, about 3 ng/ml, about 3.5 ng/ml, about 4 ng/ml, about 4.5 ng/ml, about 5 ng/ml, about 6 ng/ml, about 8 ng/ml or about 10 ng/ml ml.

In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C _max of about 0.1 ng/mL to about 1 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C _max of at least about 0.1 ng/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a _Cmax of no more than about 1 ng/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a _Cmax of about 0.1 ng/ml - about 0.2 ng/ml, about 0.1 ng/ml - about 0.3 ng/ml, about 0 .1 ng/ml - approximately 0.4 ng/ml, approximately 0.1 ng/ml - approximately 0.5 ng/ml, approximately 0.1 ng/ml - approximately 0.6 ng/ml, approximately 0.1 ng/ml - approximately 0.7 ng/ml, approximately 0.1 ng/ml approximately 0.8 ng/ml, approximately 0.1 ng/ml - approximately 0.9 ng/ml, approximately 0.1 ng/ml - approximately 1 ng/ml, approximately 0.2 ng/ml - approximately 0.3 ng/ml, approximately 0.2 ng/ml - approximately 0.4 ng/ml, approximately 0.2 ng/ml approximately 0.5 ng/ml, approximately 0.2 ng/ml - approximately 0.6 ng/ml, approximately 0.2 ng/ml - approximately 0.7 ng/ml, approximately 0.2 ng/ml - approximately 0.8 ng/ ml, approximately 0.2 ng/ml - approximately 0.9 ng/ml, approximately 0.2 ng/ml approximately 1 ng/ml, approximately 0.3 ng/ml - approximately 0.4 ng/ml, approximately 0. 3 ng/ml - approximately 0.5 ng/ml, approximately 0.3 ng/ml - approximately 0.6 ng/ml, approximately 0.3 ng/ml - approximately 0.7 ng/ml, approximately 0.3 ng /ml approximately 0.8 ng/ml, approximately 0.3 ng/ml - approximately 0.9 ng/ml, approximately 0.3 ng/ml - approximately 1 ng/ml, approximately 0.4 ng/ml - approximately 0 .5 ng/ml, approximately 0.4 ng/ml - approximately 0.6 ng/ml, approximately 0.4 ng/ml approximately 0.7 ng/ml, approximately 0.4 ng/ml - approximately 0.8 ng /ml, approximately 0.4 ng/ml - approximately 0.9 ng/ml, approximately 0.4 ng/ml - approximately 1 ng/ml, approximately 0.5 ng/ml - approximately 0.6 ng/ml, approximately 0.5 ng/ml approximately 0.7 ng/ml, approximately 0.5 ng/ml - approximately 0.8 ng/ml, approximately 0.5 ng/ml - approximately 0.9 ng/ml, approximately 0.5 ng/ml - approximately 1 ng/ml, approximately 0.6 ng/ml - approximately 0.7 ng/ml, approximately 0.6 ng/ml approximately 0.8 ng/ml, approximately 0.6 ng/ml - approximately 0.9 ng/ml, approximately 0.6 ng/ml - approximately 1 ng/ml, approximately 0.7 ng/ml - approximately 0.8 ng/ml, approximately 0.7 ng/ml - approximately 0.9 ng /ml, approximately 0.7 ng/ml approximately 1 ng/ml, approximately 0.8 ng/ml - approximately 0.9 ng/ml, approximately 0.8 ng/ml - approximately 1 ng/ml or approximately 0.9 ng/ml - approximately 1 ng/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C^ of about 0.1 ng/mL, about 0.2 ng/mL, about 0.3 ng/mL, about 0.4 ng/mL, about 0 .5 ng/ml, about 0.6 ng/ml, about 0.7 ng/ml, about 0.8 ng/ml, about 0.9 ng/ml, or about 1 ng/ml.

In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C _max of about 1 ng/mL to about 40 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a Cmax of at least about 1 ng/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a Cm _ax of no more than about 40 ng/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a _Cmax of about 1 ng/mL to about 2 ng/mL, about 1 ng/mL to about 3 ng/mL, about 1 ng/mL to about 4 ng/mL ml, approximately 1 ng/ml - approximately 5 ng/ml, approximately 1 ng/ml approximately 6 ng/ml, approximately 1 ng/ml - approximately 7 ng/ml, approximately 1 ng/ml - approximately 8 ng/ml, approximately 1 ng/ml - approximately 9 ng/ml, approximately 1 ng/ml - approximately 10 ng/ml, approximately 1 ng/ml - approximately 20

- 61 045992 ng/ml, approximately 1 ng/ml - approximately 40 ng/ml, approximately 2 ng/ml - approximately 3 ng/ml, approximately 2 ng/ml approximately 4 ng/ml, approximately 2 ng/ml - approximately 5 ng/ml, approximately 2 ng/ml - approximately 6 ng/ml, approximately 2 ng/ml - approximately 7 ng/ml, approximately 2 ng/ml - approximately 8 ng/ml, approximately 2 ng/ml - approximately 9 ng/ml ml, approximately 2 ng/ml - approximately 10 ng/ml, approximately 2 ng/ml - approximately 20 ng/ml, approximately 2 ng/ml - approximately 40 ng/ml, approximately 3 ng/ml - approximately 4 ng/ml, approximately 3 ng/ml - approximately 5 ng/ml, approximately 3 ng/ml - approximately 6 ng/ml, approximately 3 ng/ml - approximately 7 ng/ml, approximately 3 ng/ml - approximately 8 ng/ml, approximately 3 ng/ml - approximately 9 ng/ml, approximately 3 ng/ml - approximately 10 ng/ml, approximately 3 ng/ml - approximately 20 ng/ml, approximately 3 ng/ml - approximately 40 ng/ml, approximately 4 ng/ml ml - approximately 5 ng/ml, approximately 4 ng/ml - approximately 6 ng/ml, approximately 4 ng/ml - approximately 7 ng/ml, approximately 4 ng/ml - approximately 8 ng/ml, approximately 4 ng/ml - approximately 9 ng/ml, approximately 4 ng/ml - approximately 10 ng/ml, approximately 4 ng/ml - approximately 20 ng/ml, approximately 4 ng/ml - approximately 40 ng/ml, approximately 5 ng/ml - approximately 6 ng/ml, approximately 5 ng/ml - approximately 7 ng/ml, approximately 5 ng/ml - approximately 8 ng/ml, approximately 5 ng/ml - approximately 9 ng/ml, approximately 5 ng/ml - approximately 10 ng/ml ml, approximately 5 ng/ml - approximately 20 ng/ml, approximately 5 ng/ml - approximately 40 ng/ml, approximately 6 ng/ml - approximately 7 ng/ml, approximately 6 ng/ml - approximately 8 ng/ml, approximately 6 ng/ml - approximately 9 ng/ml, approximately 6 ng/ml - approximately 10 ng/ml, approximately 6 ng/ml - approximately 20 ng/ml, approximately 6 ng/ml - approximately 40 ng/ml, approximately 7 ng/ml - approximately 8 ng/ml, approximately 7 ng/ml - approximately 9 ng/ml, approximately 7 ng/ml - approximately 10 ng/ml, approximately 7 ng/ml - approximately 20 ng/ml, approximately 7 ng/ml ml - approximately 40 ng/ml, approximately 8 ng/ml - approximately 9 ng/ml, approximately 8 ng/ml - approximately 10 ng/ml, approximately 8 ng/ml - approximately 20 ng/ml, approximately 8 ng/ml - approximately 40 ng/ml, approximately 9 ng/ml - approximately 10 ng/ml, approximately 9 ng/ml - approximately 20 ng/ml, approximately 9 ng/ml - approximately 40 ng/ml, approximately 10 ng/ml - approximately 20 ng/ml, about 10 ng/ml - about 40 ng/ml or about 20 ng/ml - about 40 ng/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a Cmax of about 1 ng/mL, about 2 ng/mL, about 3 ng/mL, about 4 ng/mL, about 5 ng/mL, about 6 ng/mL , about 7 ng/ml, about 8 ng/ml, about 9 ng/ml, about 10 ng/ml, about 20 ng/ml, or about 40 ng/ml.

In some embodiments, the pharmaceutical spray formulation is formulated to achieve a _Tmax of no more than 10 s, 20 s, 30 s, 40 s, 50 s, 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 15 min or 20 min. In some embodiments, administration of the pharmaceutical composition as a spray achieves a T _max of at least 10 s, 20 s, 30 s, 40 s, 50 s, 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 15 min or 20 min.

In some embodiments, the pharmaceutical spray formulation is formulated to achieve a _Tmax of about 0.1 min to about 10 min. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a T _max of at least about 0.1 min. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a _Tmax of no more than about 10 minutes. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a T _max of about 0.1 min - about 0.2 min, about 0.1 min - about 0.4 min, about 0.1 min - about 0. 6 min, approximately 0.1 min - approximately 0.8 min, approximately 0.1 min approximately 1 min, approximately 0.1 min - approximately 2 min, approximately 0.1 min - approximately 4 min, approximately 0.1 min - approximately 5 minutes, approximately 0.1 minutes - approximately 6 minutes, approximately 0.1 minutes - approximately 8 minutes, approximately 0.1 minutes - approximately 10 minutes, approximately 0.2 minutes - approximately 0.4 minutes, approximately 0.2 min - approximately 0.6 min, approximately 0.2 min - approximately 0.8 min, approximately 0.2 min - approximately 1 min, approximately 0.2 min - approximately 2 min, approximately 0.2 min - approximately 4 min, approximately 0.2 minutes - approximately 5 minutes, approximately 0.2 minutes - approximately 6 minutes, approximately 0.2 minutes - approximately 8 minutes, approximately 0.2 minutes - approximately 10 minutes, approximately 0.4 minutes - approximately 0.6 min, approximately 0.4 min - approximately 0.8 min, approximately 0.4 min - approximately 1 min, approximately 0.4 min - approximately 2 min, approximately 0.4 min - approximately 4 min, approximately 0.4 min - approximately 5 minutes, approximately 0.4 minutes - approximately 6 minutes, approximately 0.4 minutes - approximately 8 minutes, approximately 0.4 minutes - approximately 10 minutes, approximately 0.6 minutes - approximately 0.8 minutes, approximately 0.6 min - approximately 1 minute, approximately 0.6 minutes - approximately 2 minutes, approximately 0.6 minutes - approximately 4 minutes, approximately 0.6 minutes - approximately 5 minutes, approximately 0.6 minutes - approximately 6 minutes, approximately 0.6 min - approximately 8 minutes, approximately 0.6 minutes - approximately 10 minutes, approximately 0.8 minutes - approximately 1 minute, approximately 0.8 minutes - approximately 2 minutes, approximately 0.8 minutes - approximately 4 minutes, approximately 0.8 min - approximately 5 min, approximately 0.8 min - approximately 6 min, approximately 0.8 min - approximately 8 min, approximately 0.8 min - approximately 10 min, approximately 1 min - approximately 2 min, approximately 1 min - approximately 4 min , approximately 1 minute - approximately 5 minutes, approximately 1 minute - approximately 6 minutes, approximately 1 minute approximately 8 minutes, approximately 1 minute - approximately 10 minutes, approximately 2 minutes - approximately 4 minutes, approximately 2 minutes - approximately 5 minutes, approximately 2 min - approximately 6 minutes, approximately 2 minutes - approximately 8 minutes, approximately 2 minutes - approximately 10 minutes, approximately 4 minutes - approximately 5 minutes, approximately 4 minutes - approximately 6 minutes, approximately 4 minutes - approximately 8 minutes, approximately 4 minutes - approximately 10 minutes, approximately 5 minutes - approximately 6 minutes, approximately 5 minutes - approximately 8 minutes, approximately 5 minutes - approximately 10 minutes, approximately 6 minutes - approximately 8 minutes, approximately 6 minutes - approximately 10 minutes or approximately 8 minutes - approximately 10 min. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a T _max of about 0.1 minutes, about 0.2 minutes, about 0.4 minutes, about 0.6 minutes, about 0.8 minutes, about

- 62 045992 min, approximately 2 min, approximately 4 min, approximately 5 min, approximately 6 min, approximately 8 min or approximately 10 min.

In some embodiments, the pharmaceutical spray formulation is formulated to achieve an AUC value of about 0.1 ng-hr/ml to about 50 ng-hr/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve an AUC value of at least about 0.1 ng-hr/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve an AUC value of no more than about 50 ng-hr/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve an AUC value of about 0.1 ng-hr/mL - about 0.5 ng-hr/mL, about 0.1 ng-hr/mL - about 1 ng- h/ml, approximately 0.1 ng-h/ml - approximately 2 ng-h/ml, approximately 0.1 ng-h/ml - approximately 4 ng-h/ml, approximately 0.1 ng-h/ml - approximately 6 ng-h/ml, approximately 0.1 ng-h/ml - approximately 8 ng-h/ml, approximately 0.1 ng-h/ml - approximately 10 ng-h/ml, approximately 0.1 ng- h/ml - approximately 20 ng-h/ml, approximately 0.1 ng-h/ml - approximately 30 ng-h/ml, approximately 0.1 ng-h/ml - approximately 40 ng-h/ml, approximately 0 .1 ng-h/ml - approximately 50 ng-h/ml, approximately 0.5 ng-h/ml - approximately 1 ng-h/ml, approximately 0.5 ng-h/ml - approximately 2 ng-h/ ml, approximately 0.5 ng-h/ml - approximately 4 ng-h/ml, approximately 0.5 ng-h/ml - approximately 6 ng-h/ml, approximately 0.5 ng-h/ml - approximately 8 ng-h/ml, approximately 0.5 ng-h/ml - approximately 10 ng-h/ml, approximately 0.5 ng-h/ml - approximately 20 ng-h/ml, approximately 0.5 ng-h/ ml - approximately 30 ng-h/ml, approximately 0.5 ng-h/ml - approximately 40 ng-h/ml, approximately 0.5 ng-h/ml - approximately 50 ng-h/ml, approximately 1 ng- h/ml - approximately 2 ng-h/ml, approximately 1 ng-h/ml - approximately 4 ng-h/ml, approximately 1 ng-h/ml - approximately 6 ng-h/ml, approximately 1 ng-h/ ml - approximately 8 ng-h/ml, approximately 1 ng-h/ml - approximately 10 ng-h/ml, approximately 1 ng-h/ml - approximately 20 ng-h/ml, approximately 1 ng-h/ml - approximately 30 ng-h/ml, approximately 1 ng-h/ml - approximately 40 ng-h/ml, approximately 1 ng-h/ml - approximately 50 ng-h/ml, approximately 2 ng-h/ml - approximately 4 ng-h/ml, approximately 2 ng-h/ml - approximately 6 ng-h/ml, approximately 2 ng-h/ml - approximately 8 ng-h/ml, approximately 2 ng-h/ml - approximately 10 ng- h/ml, approximately 2 ng-h/ml - approximately 20 ng-h/ml, approximately 2 ng-h/ml - approximately 30 ng-h/ml, approximately 2 ng-h/ml - approximately 40 ng-h/ ml, approximately 2 ng-h/ml - approximately 50 ng-h/ml, approximately 4 ng-h/ml - approximately 6 ng-h/ml, approximately 4 ng-h/ml - approximately 8 ng-h/ml, approximately 4 ng-h/ml - approximately 10 ng-h/ml, approximately 4 ng-h/ml - approximately 20 ng-h/ml, approximately 4 ng-h/ml - approximately 30 ng-h/ml, approximately 4 ng-h/ml - approximately 40 ng-h/ml, approximately 4 ng-h/ml - approximately 50 ng-h/ml, approximately 6 ng-h/ml - approximately 8 ng-h/ml, approximately 6 ng- h/ml - approximately 10 ng-h/ml, approximately 6 ng-h/ml - approximately 20 ng-h/ml, approximately 6 ng-h/ml - approximately 30 ng-h/ml, approximately 6 ng-h/ ml - approximately 40 ng-h/ml, approximately 6 ng-h/ml approximately 50 ng-h/ml, approximately 8 ng-h/ml - approximately 10 ng-h/ml, approximately 8 ng-h/ml - approximately 20 ng-h/ml, approximately 8 ng-h/ml - approximately 30 ng-h/ml, approximately 8 ng-h/ml - approximately 40 ng-h/ml, approximately 8 ng-h/ml - approximately 50 ng -h/ml, approximately 10 ng-h/ml - approximately 20 ng-h/ml, approximately 10 ng-h/ml - approximately 30 ng-h/ml, approximately 10 ng-h/ml - approximately 40 ng-h /ml, approximately 10 ng-h/ml - approximately 50 ng-h/ml, approximately 20 ng-h/ml - approximately 30 ng-h/ml, approximately 20 ng-h/ml - approximately 40 ng-h/ml , about 20 ng-h/ml - about 50 ng-h/ml, about 30 ng-h/ml - about 40 ng-h/ml, about 30 ng-h/ml - about 50 ng-h/ml or about 40 ng-h/ml - approximately 50 ng-h/ml. In some embodiments, the pharmaceutical spray formulation is formulated to achieve an AUC value of about 0.1 ng-hr/mL, about 0.5 ng-hr/mL, about 1 ng-hr/mL, about 2 ng-hr/mL. ml, approximately 4 ng-h/ml, approximately 6 ng-h/ml, approximately 8 ng-h/ml, approximately 10 ng-h/ml, approximately 20 ng-h/ml, approximately 30 ng-h/ml, about 40 ng-h/ml or about 50 ng-h/ml.

In some embodiments, intranasal administration of a pharmaceutical formulation as a spray produces a plasma concentration of epinephrine that is at least 5% higher, at least 10% higher, at least 15% higher, at least 20% higher, at least 25% higher, at least 30% higher, at least 35% higher, at least 40% higher, at least 45% higher, at least 50% higher, at least at least 60% higher, at least 70% higher, at least 80% higher, at least 90% higher, at least 100% higher, at least 150% higher, at least 200 % higher, at least 250% higher, at least 300% higher, at least 350% higher, at least 400% higher, at least 450% higher, at least 500% higher, at least 600% higher, at least 700% higher, at least 800% higher, at least 900% higher, or at least 1000% higher than injection using a commercially available device for delivery (e.g., EpiPen) in about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0, 9, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, or about 15 minutes after administration. In some embodiments, intranasal administration of a pharmaceutical formulation as a spray results in plasma epinephrine concentrations having a relative standard deviation of no more than about 10%, about 20%, about

- 63 045992

30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or not more than about 100% based on plasma concentrations measured within 15 minutes (inclusive) after administration. In some embodiments, intranasal administration of a pharmaceutical formulation as a spray results in plasma epinephrine concentrations having a relative standard deviation that is lower than injection using a commercially available delivery device based on plasma concentrations measured within 15 minutes (inclusive) after introduction. In some embodiments, plasma concentrations are measured at 1 minute and at two or more later time points within 15 minutes (inclusive).

III. Methods of application.

In another aspect, there is provided a method of treating anaphylaxis, anaphylactic shock, severe allergic reaction, and/or bronchoconstriction comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition in the form of a spray or spray as described herein, including embodiments.

In an aspect, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical formulation in the form of a spray or spray as described herein, including embodiments.

In an aspect, provided herein is a method of treating respiratory depression or disorder caused by anaphylaxis or anaphylactic shock, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition in the form of a spray or spray as described herein, including embodiments.

In another aspect, there is provided a method of treating anaphylaxis, anaphylactic shock, severe allergic reaction and/or bronchoconstriction comprising delivering an injection of a pharmaceutical solution from a pre-filled device into the nostril of a subject in need thereof, wherein:

(i) the device is configured for nasal delivery;

(ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent and about 0.005% to about 1% (w/v) benzalkonium chloride.

In some embodiments, the pharmaceutical solution contains from about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 0.5 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 1 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 2 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 3 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 4 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 5 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 6 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 7 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 8 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 9 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 10 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 15 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 20 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 25 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 30 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 35 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 40 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 45 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 50 mg of epinephrine or a pharmaceutically acceptable salt thereof. According to

- 64 045992 In some embodiments, the pharmaceutical solution contains about 55 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 60 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 65 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 70 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 75 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 80 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 85 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 90 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 95 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof.

In some embodiments, the spray delivers about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution contains from about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 0.5 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 1 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 2 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 3 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 4 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 5 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 6 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 7 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 8 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 9 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 10 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 15 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 20 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 25 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 30 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 35 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 40 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 45 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 50 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 55 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 60 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 65 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 70 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 75 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 80 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 85 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 90 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 95 mg of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof.

In some embodiments, the plasma concentration-time curve for epinephrine in a subject has a t _max of less than about 10 minutes to about 120 minutes. In some embodiments, the concentration curve in

- 65 045992 plasma versus time for epinephrine in a subject is characterized by a _tmax of approximately 5 minutes to approximately 50 minutes. In some embodiments, the plasma concentration-time curve for epinephrine in a subject has a t _max of about 5 minutes - about 10 minutes, about 5 minutes - about 15 minutes, about 5 minutes - about 20 minutes, about 5 minutes - about 25 minutes , approximately 5 minutes - approximately 30 minutes, approximately 5 minutes - approximately 40 minutes, approximately 5 minutes - approximately 50 minutes, approximately 10 minutes - approximately 15 minutes, approximately 10 minutes - approximately 20 minutes, approximately 10 minutes - approximately 25 minutes, approximately 10 minutes - approximately 30 minutes, approximately 10 minutes - approximately 40 minutes, approximately 10 minutes - approximately 50 minutes, approximately 15 minutes - approximately 20 minutes, approximately 15 minutes approximately 25 minutes, approximately 15 minutes - approximately 30 minutes, approximately 15 minutes - approximately 40 minutes, approximately 15 minutes - approximately 50 minutes, approximately 20 minutes - approximately 25 minutes, approximately 20 minutes - approximately 30 minutes, approximately 20 minutes - approximately 40 minutes, approximately 20 minutes - approximately 50 minutes, approximately 25 minutes - approximately 30 min, approximately 25 min - approximately 40 min, approximately 25 min - approximately 50 min, approximately 30 min - approximately 40 min, approximately 30 min - approximately 50 min or approximately 40 min - approximately 50 min. In some embodiments, the plasma concentration-time curve for epinephrine in a subject has a t _max of about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, or about 50 minutes. min. In some embodiments, the plasma concentration-time curve for epinephrine in a subject has a t _max of at least about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, or about 40 minutes. . In some embodiments, the plasma concentration-time curve for epinephrine in a subject has a t _max of no more than about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, or about 50 minutes. .

In some embodiments, the therapeutic plasma concentration of epinephrine in the subject is achieved within 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 min after administration to the subject. In some embodiments, a therapeutic plasma concentration of epinephrine in a subject is achieved less than 20 minutes after administration to the subject. In some embodiments, a therapeutic plasma concentration of epinephrine in a subject is achieved less than 15 minutes after administration to the subject. In some embodiments, a therapeutic plasma concentration of epinephrine in a subject is achieved less than 10 minutes after administration to the subject. In some embodiments, a therapeutic plasma concentration of epinephrine in a subject is achieved less than 5 minutes after administration to the subject.

In some embodiments, the therapeutic plasma concentration of epinephrine in a subject is approximately 500 pg/mL epinephrine. In some embodiments, the therapeutic plasma epinephrine concentration in the subject is approximately 450 pg/mL epinephrine. In some embodiments, the therapeutic plasma concentration of epinephrine in a subject is approximately 400 pg/mL epinephrine. In some embodiments, the therapeutic plasma concentration of epinephrine in a subject is approximately 350 pg/mL epinephrine. In embodiments, the therapeutic plasma concentration of epinephrine in a subject is approximately 300 pg/mL epinephrine. In some embodiments, the subject has a maximum plasma concentration ( _Cmax ) of about 50 pg/mL to about 500 pg/mL of epinephrine. In some embodiments, the area under the plasma concentration-time curve for epinephrine in a subject is about 5 ng/min/mL to about 50 ng/min/mL.

In some embodiments, the device includes a piston that receives a container lid containing the following:

(i) a bottle containing an opening;

(ii) cannula; and (iii) rubber stopper; wherein the stopper is configured to plug the opening of the vial, and wherein the cannula is configured to pierce the stopper when the piston applies sufficient force to the cannula.

In some embodiments, the prefilled device is operated with one hand. In some embodiments, the device is a single-dose device. In some embodiments, the device is a two-dose device. In some embodiments, the reservoir volume is no more than about 140 μL. In some embodiments, the device comprises a single reservoir containing approximately 125 μL of pharmaceutical solution. In some embodiments, approximately 100 μL of the pharmaceutical solution is delivered with a single actuation of the device. In some embodiments, the device comprises a single reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device contains a single reservoir containing about 75 μL to about 250 μL of the pharmaceutical composition. According to some embodiments

- 66 045992 The device contains one reservoir containing approximately 100 μl - approximately 250 μl of the pharmaceutical composition. In some embodiments, the device comprises a single reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device comprises a single reservoir containing about 150 μL of about 250 μL of the pharmaceutical composition. In some embodiments, the device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, a single-dose device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, a two-dose device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 75 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 75 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 100 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 100 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 225 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 225 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 200 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 175 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 175 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 175 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 150 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 150 μL of the pharmaceutical composition. In some embodiments, a two-dose device delivers one injection of a pharmaceutical solution from a first reservoir, and one injection of a pharmaceutical solution from a second reservoir.

In some embodiments, the delivery time of the pharmaceutical solution is less than about 25 seconds. In some embodiments, the delivery time of the pharmaceutical solution is less than about 20 seconds.

In some embodiments, less than about 20% of the pharmaceutical solution leaves the nasal cavity via nasopharyngeal or external drainage. In some embodiments, less than about 10% of the pharmaceutical solution leaves the nasal cavity via nasopharyngeal or external drainage. In some embodiments, less than about 5% of the pharmaceutical solution leaves the nasal cavity via nasopharyngeal or external drainage.

In some embodiments, the subject suffers a severe allergic reaction from exposure or suspected exposure to an allergen. In some embodiments, the allergen is a food, drug, or insect bite or sting. In some embodiments, the allergen is an inhalant allergen.

In some embodiments, the subject exhibits one or more symptoms selected from the following: respiratory depression or distress, airway constriction, wheezing, tingling in the arms, legs, mouth, or scalp, shortness of breath, swelling or inflammation of the face, eyes, lips, tongue or throat, urticaria, central nervous system depression, cardiovascular depression, impaired level of consciousness, dilated pupils, hypoxemia, hypotension, unresponsiveness to stimuli, loss of consciousness, respiratory arrest, erratic or stopped pulse, and vomiting. In some embodiments, the subject exhibits respiratory depression or distress, or cardiovascular depression. In some embodiments, the subject exhibits respiratory depression. In some embodiments, the subject exhibits respiratory distress. In some embodiments, the subject exhibits cardiovascular depression.

In some embodiments, the subject does not experience respiratory depression or distress for at least about 1 hour following treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience respiratory depression or distress for at least about 2 hours after treatment comprising delivery of the therapeutic

- 67 045992 a commercially effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience respiratory depression or distress for at least about 4 hours following treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject does not experience respiratory depression or distress for at least about 6 hours following treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is in a supine, supine, or rescue position.

In some embodiments, a single nostril spray provides a plasma concentration of =0.2 ng/mL within 2.5 minutes in a subject. In some embodiments, a single nostril spray provides a plasma concentration of = 1 ng/mL within 5 minutes in a subject. In some embodiments, a single nostril spray provides a plasma concentration of =3 ng/mL within 10 minutes in a subject. In some embodiments, a single nostril spray provides a plasma concentration of =0.2 ng/mL within 2.5 minutes in a subject. In some embodiments, a single nostril spray provides a plasma concentration of =1 ng/mL within 5 minutes in a subject. In some embodiments, a single nostril spray provides a plasma concentration of = 1 ng/mL within 5 minutes in a subject.

In some embodiments, administration of a nasal spray as described herein provides rapid absorption of epinephrine. In some embodiments, administration of a nasal spray described herein provides absorption of epinephrine that is substantially equivalent to that of intramuscular or subcutaneous injection. In some embodiments, administration of a nasal spray described herein provides pharmacokinetics that are substantially equivalent to those of intramuscular or subcutaneous injection. In some embodiments, described herein are methods of administering a nasal spray to a subject with blocked and/or inflamed nasal passages, thereby providing rapid absorption of epinephrine. For example, experimental data provided herein indicate that congestion enhances absorption, providing an unexpected beneficial effect. In some embodiments, a single spray into the nostril within about 1, 2, 3, 4, or 5 minutes after administration provides a plasma concentration of at least about 0.2 ng/mL to about 3 ng/mL. In some embodiments, a single spray into the nostril within about 1, 2, 3, 4, or 5 minutes after administration provides a plasma concentration of at least about 0.2 ng/mL to about 0.3 ng/mL, about 0.2 ng/ml - approximately 0.4 ng/ml, approximately 0.2 ng/ml - approximately 0.5 ng/ml, approximately 0.2 ng/ml - approximately 0.6 ng/ml, approximately 0. 2 ng/ml - approximately 0.7 ng/ml, approximately 0.2 ng/ml - approximately 0.8 ng/ml, approximately 0.2 ng/ml - approximately 0.9 ng/ml, approximately 0.2 ng /ml - approximately 1 ng/ml, approximately 0.2 ng/ml - approximately 1.5 ng/ml, approximately 0.2 ng/ml - approximately 2 ng/ml, approximately 0.2 ng/ml - approximately 3 ng /ml, approximately 0.3 ng/ml - approximately 0.4 ng/ml, approximately 0.3 ng/ml - approximately 0.5 ng/ml, approximately 0.3 ng/ml - approximately 0.6 ng/ml , approximately 0.3 ng/ml - approximately 0.7 ng/ml, approximately 0.3 ng/ml - approximately 0.8 ng/ml, approximately 0.3 ng/ml - approximately 0.9 ng/ml, approximately 0.3 ng/ml - approximately 1 ng/ml, approximately 0.3 ng/ml - approximately 1.5 ng/ml, approximately 0.3 ng/ml - approximately 2 ng/ml, approximately 0.3 ng/ml - approximately 3 ng/ml, approximately 0.4 ng/ml - approximately 0.5 ng/ml, approximately 0.4 ng/ml - approximately 0.6 ng/ml, approximately 0.4 ng/ml - approximately 0, 7 ng/ml, approximately 0.4 ng/ml - approximately 0.8 ng/ml, approximately 0.4 ng/ml - approximately 0.9 ng/ml, approximately 0.4 ng/ml - approximately 1 ng/ml , approximately 0.4 ng/ml - approximately 1.5 ng/ml, approximately 0.4 ng/ml - approximately 2 ng/ml, approximately 0.4 ng/ml - approximately 3 ng/ml, approximately 0.5 ng /ml - approximately 0.6 ng/ml, approximately 0.5 ng/ml - approximately 0.7 ng/ml, approximately 0.5 ng/ml - approximately 0.8 ng/ml, approximately 0.5 ng/ml - approximately 0.9 ng/ml, approximately 0.5 ng/ml - approximately 1 ng/ml, approximately 0.5 ng/ml - approximately 1.5 ng/ml, approximately 0.5 ng/ml - approximately 2 ng /ml, approximately 0.5 ng/ml - approximately 3 ng/ml, approximately 0.6 ng/ml - approximately 0.7 ng/ml, approximately 0.6 ng/ml - approximately 0.8 ng/ml, approximately 0.6 ng/ml - approximately 0.9 ng/ml, approximately 0.6 ng/ml - approximately 1 ng/ml, approximately 0.6 ng/ml - approximately 1.5 ng/ml, approximately 0.6 ng /ml - approximately 2 ng/ml, approximately 0.6 ng/ml - approximately 3 ng/ml, approximately 0.7 ng/ml - approximately 0.8 ng/ml, approximately 0.7 ng/ml - approximately 0. 9 ng/ml, approximately 0.7 ng/ml - approximately 1 ng/ml, approximately 0.7 ng/ml - approximately 1.5 ng/ml, approximately 0.7 ng/ml - approximately 2 ng/ml, approximately 0.7 ng/ml - approximately 3 ng/ml, approximately 0.8 ng/ml - approximately 0.9 ng/ml, approximately 0.8 ng/ml - approximately 1 ng/ml, approximately 0.8 ng/ml - approximately 1.5 ng/ml, approximately 0.8 ng/ml - approximately 2 ng/ml, approximately 0.8 ng/ml - approximately 3 ng/ml, approximately 0.9 ng/ml - approximately 1 ng/ml , approximately 0.9 ng/ml - approximately 1.5 ng/ml, approximately 0.9 ng/ml - approximately 2 ng/ml, approximately 0.9 ng/ml - approximately 3 ng/ml, approximately 1 ng/ml - approximately 1.5 ng/ml, approximately 1 ng/ml - approximately 2 ng/ml, approximately 1 ng/ml approximately 3 ng/ml, approximately 1.5 ng/ml - approximately 2 ng/ml, approximately 1.5 ng/ml - approximately 3 ng/ml or approximately 2 ng/ml - approximately 3 ng/ml. In some embodiments, a single spray into the nostril within about 1, 2, 3, 4, or 5 minutes after administration provides a concentration of

- 68 045992 plasma of at least about 0.2 ng/ml, about 0.3 ng/ml, about 0.4 ng/ml, about 0.5 ng/ml, about 0.6 ng/ml, about 0.7 ng/ml, about 0.8 ng/ml, about 0.9 ng/ml, about 1 ng/ml, about 1.5 ng/ml, about 2 ng/ml, or about 3 ng/ml. In some embodiments, a single spray into the nostril within about 1, 2, 3, 4, or 5 minutes after administration provides a plasma concentration of at least about 0.2 ng/mL, about 0.3 ng/mL ml, about 0.4 ng/ml, about 0.5 ng/ml, about 0.6 ng/ml, about 0.7 ng/ml, about 0.8 ng/ml, about 0.9 ng/ml, about 1 ng/ml, about 1.5 ng/ml, or about 2 ng/ml. In some embodiments, a single spray into the nostril within about 1, 2, 3, 4, or 5 minutes after administration provides a plasma concentration of at least no more than about 0.3 ng/mL, about 0.4 ng/mL ml, about 0.5 ng/ml, about 0.6 ng/ml, about 0.7 ng/ml, about 0.8 ng/ml, about 0.9 ng/ml, about 1 ng/ml, about 1 .5 ng/ml, about 2 ng/ml or about 3 ng/ml. In some embodiments, the plasma concentration described herein refers to the average plasma concentration (eg, the mean or median concentration determined over a plurality of sprays into one or both nostrils in a subject, or sprays in a plurality of subjects).

In an aspect, provided herein is a method of treating anaphylaxis or anaphylactic shock-induced respiratory depression or disorder comprising delivering an injection of a pharmaceutical solution from a pre-filled device into the nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution in the form of a circular spray stream with an ovality ratio of less than about 2.0 when measured at a distance of about 1 to about 10 cm from the prefilled device, wherein:

(i) the device is configured for nasal delivery;

(ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and the pharmaceutical solution contains about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent and about 0.005% to about 1% (w/v) benzalkonium chloride.

In some embodiments, the circular spray jet has an ovality coefficient of less than about 2.0. In some embodiments, the circular spray jet has an ovality coefficient of less than about 1.9. In some embodiments, the circular spray stream has an ovality coefficient of less than about 1.8. In some embodiments, the circular spray stream has an ovality coefficient of less than about 1.7. In some embodiments, the circular spray jet has an ovality coefficient of less than about 1.6. In some embodiments, the circular spray stream has an ovality coefficient of less than about 1.5. In some embodiments, the circular spray jet has an ovality coefficient of less than about 1.4. In some embodiments, the circular spray jet has an ovality coefficient of less than about 1.3. In some embodiments, the circular spray jet has an ovality coefficient of less than about 1.2. In some embodiments, the circular spray jet has an ovality coefficient of less than about 1.1. In some embodiments, the circular spray jet has an ovality coefficient of less than about 1.0.

In some embodiments, the spray ovality factor is measured at a distance of about 1 cm to about 5 cm from the device from which the spray is delivered.

In an aspect, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein:

(i) the device is configured for nasal delivery;

(ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent and about 0.005% to about 1% (w/v) benzalkonium chloride.

In some embodiments, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein the pharmaceutical spray composition contains about 1% to about 20% by weight. /wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2.0% trisodium citrate and about 0.05% - about 15% diethylene glycol monoethyl ether.

- 69 045992

In some embodiments, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein the pharmaceutical spray composition contains about 5% to about 20% by weight. /wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1.0% sodium chloride, about 0.05% is about 0.5% hypromellose, about 0.1% is about 1.0% trisodium citrate, and about 0.5% is about 5% diethylene glycol monoethyl ether.

In some embodiments, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein the pharmaceutical spray composition contains about 5% w/w. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether .

In some embodiments, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein the pharmaceutical spray composition contains about 1% to about 20% by weight. /wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1% sodium chloride, about 0. 05% is about 0.5% hypromellose, about 0.1% is about 1.0% citric acid monohydrate and about 0.1% is about 5% diethylene glycol monoethyl ether.

In some embodiments, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein the pharmaceutical spray composition contains about 2% w/w. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether.

In some embodiments, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein the pharmaceutical spray composition contains about 5% w/w. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether.

In some embodiments, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein the pharmaceutical spray composition contains about 10% w/w. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether .

In some embodiments, provided herein is a method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein the pharmaceutical spray composition contains about 20% w/w. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether .

In some embodiments, the subject in need is an adult. In some embodiments, the subject in need is a child. In some embodiments, the subject in need weighs about 10 pounds - about 80 pounds.

IV. Device.

In an aspect provided herein, the pharmaceutical solution is administered from a single-dose device or delivery system. In an aspect provided herein, the pharmaceutical solution is administered from a two-dose device or delivery system. In an aspect provided herein, the pharmaceutical solution is administered from a multi-dose device or delivery system.

In some embodiments, the device comprises the following: a reservoir containing

- 70 045992 pressing at least two doses of liquid; a dispensing element, such as a plunger, which is mounted to slide in said reservoir for dispensing liquid; a dispenser head which is provided with a dispenser opening, said head being movable relative to said reservoir to move said actuator in said reservoir and thereby dispense liquid through said dispenser opening; said dispenser head includes at least two viewing windows, said device includes an indicator that can move with said reservoir, said indicator interacts with a corresponding viewing window after each activation of the device. In some embodiments, said indicator comprises at least one colored display zone, said display zone appearing in said first viewing window after a first dose of liquid is dispensed and in a second viewing window after a second dose of liquid is dispensed. According to some embodiments, said indicator is configured to mask colored indication zones that are provided in said dispenser head, said indicator masks a colored indication zone in said first viewing window after a first dose of liquid has been dispensed, and masks a colored indication zone in said second viewing window after the second dose of liquid has been dispensed. According to some embodiments, said indicator is configured to indicate through at least one viewing window that an incomplete dose has been dispensed. In some embodiments, the device is held between the second and third fingers while the thumb is on the mouthpiece. In some embodiments, a point pressure mechanism is included in the device to provide repeatable actuation force and jet characteristics. In some embodiments, a lid is incorporated into the device. In some embodiments, the device includes a trigger guard on the mouthpiece. In some embodiments, the device includes a window for viewing the liquid in the reservoir. In some embodiments, a dosimeter is integrated into the device. In some embodiments, a mechanism is built into the device to lock the device and prevent the device from reactivating. In some embodiments, a timer is built into the device to lock the device and prevent the device from firing a second time after a predetermined period of time.

An exemplary circuit diagram of the device is shown in FIG. 17. The device shown includes a tip 1701 for dispensing a pharmaceutical formulation as a spray, a cannula 1702 that is connected to the tip and transports the formulation or solution from a reservoir 1705. When the device is actuated, the needle 1703 pierces a seal (e.g., a polymer or elastomeric seal) 1704, to enter the reservoir 1705 to access the pharmaceutical spray formulation stored as a solution inside.

In some embodiments, the device is a single-dose device. In some embodiments, the device is a two-dose device. In some embodiments, the reservoir volume is no more than about 140 μL. In some embodiments, the device comprises a single reservoir containing approximately 125 μL of pharmaceutical solution. In some embodiments, approximately 100 μL of the pharmaceutical solution is delivered with a single actuation of the device. In some embodiments, the device comprises a single reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device contains a single reservoir containing about 75 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device comprises a single reservoir containing about 100 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device comprises a single reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device comprises a single reservoir containing about 150 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, a single-dose device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, a two-dose device delivers two injections of a pharmaceutical solution from a single reservoir. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 75 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 75 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 100 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 100 μL to about 250 μL of the pharmaceutical composition. In some embodiments, the two-dose device includes a first reservoir containing about 125

- 71 045992 μl - approximately 250 μl of the pharmaceutical composition, and a second reservoir containing approximately 125 μl - approximately 250 μl of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 225 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 225 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 200 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 175 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 175 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 175 μL of the pharmaceutical composition. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 150 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 150 μL of the pharmaceutical composition. In some embodiments, a two-dose device delivers one injection of a pharmaceutical solution from a first reservoir, and one injection of a pharmaceutical solution from a second reservoir.

According to some embodiments described herein, a two-dose device configured to nasally deliver a pharmaceutical composition to a patient comprises a first volume of said pharmaceutical composition in a first reservoir and a second volume of said pharmaceutical composition in a second reservoir, and wherein said therapeutically effective amount of said pharmaceutical composition is delivered by substantially first actuating said device to deliver a medicament from said first reservoir to a patient's nostril and a second actuating said device to deliver a medicament from said second reservoir to a patient's nostril. In some embodiments, the two-dose device comprises a first reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. In some embodiments, each reservoir of a prefilled, two-dose device configured to nasally deliver a pharmaceutical composition to a patient contains from about 0.5 mg to about 100 mg of epinephrine.

According to some embodiments of the device described herein, the pharmaceutical composition in the form of a spray contains from about 1% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2.0% trisodium citrate and about 0.05% - about 15% diethylene glycol monoethyl ether.

According to some embodiments of the device described herein, the pharmaceutical composition in the form of a spray contains from about 1% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2.0% citric acid monohydrate and about 0.05% about 15% diethylene glycol monoethyl ether.

According to some embodiments of the device described herein, the pharmaceutical composition in the form of a spray contains about 5% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1.0% sodium chloride, about 0.05% is about 0.5% hypromellose, about 0.1% is about 1.0% trisodium citrate, and about 0.5% is about 5% diethylene glycol monoethyl ether.

According to some embodiments of the device described herein, the pharmaceutical composition in the form of a spray contains about 5% to about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1.0% sodium chloride, about 0.01% is about 0.2% hypromellose, about 0.1% is about 1.0% citric acid monohydrate, and about 0.1% is about 5% diethylene glycol monoethyl ether.

According to some embodiments of the device described herein, the pharmaceutical composition in the form of a spray contains approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether.

According to some embodiments of the device described herein, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% monoethyl

- 72 045992 diethylene glycol ether.

According to some embodiments of the device described herein, the pharmaceutical composition in the form of a spray contains approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether.

According to some embodiments of the device described herein, the pharmaceutical composition in the form of a spray contains approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether .

According to some embodiments of the device described herein, the pharmaceutical composition in the form of a spray contains approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether.

According to some embodiments of the device described herein, the pharmaceutical composition in the form of a spray contains approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether .

According to some embodiments of the device described herein, the pharmaceutical composition in the form of a spray contains approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether.

In some embodiments, the composition devices and methods described herein include or use a digital processing device. In further embodiments, a digital processing device includes one or more hardware central processing units (CPUs) or general purpose graphics processing units (GPGPUs) that perform the functions of the device. In other embodiments, the digital processing device further comprises an operating system configured to execute executable instructions. In some embodiments, the digital processing device is optionally connected to a computer network. According to further embodiments, the digital processing device is optionally connected to the Internet, such that it has access to the Internet. In other embodiments, the digital processing device is optionally connected to a cloud computing infrastructure. In other embodiments, the digital processing device is not necessarily connected to an intranet. In other embodiments, the digital processing device is optionally connected to the data storage device.

As described herein, suitable digital processing devices include, but are not limited to, server computers, desktop computers, laptops, notebooks, subnotebooks, netbooks, tablets, set-top boxes, media streaming devices, handheld computers, devices for accessing the Internet, mobile smartphones, tablet computers, personal digital assistants, game consoles and media. Those skilled in the art will appreciate that many smart phones are suitable for use in the system described herein. Those skilled in the art will also appreciate that certain televisions, video players, and digital music players with optional network connectivity are suitable for use in the system described herein. Suitable tablet computers include booklet, thin screen, and convertible configuration computers known to those skilled in the art.

In some embodiments, the digital processing device includes an operating system configured to execute executable instructions. An operating system is, for example, software, including programs and data, that manages the device's hardware and provides services for running applications.

In some embodiments, the device includes a storage device and/or storage device. A storage and/or storage device is one or more physical devices used to store data or programs on a temporary or permanent basis. In some embodiments, the device is a volatile storage device and requires power to maintain stored memory.

- 73 045992 information. In some embodiments, the device is a non-volatile storage device and retains stored information when power is not supplied to the digital processing device. In further embodiments, the nonvolatile storage device includes flash memory. In some embodiments, the nonvolatile storage device includes dynamic random access memory (DRAM). In some embodiments, the nonvolatile memory device includes ferroelectric random access memory (FRAM). In some embodiments, the non-volatile memory device includes phase change random access memory (PRAM). In other embodiments, the device is a storage device, including, but not limited to, CD-ROM, DVD, flash memory devices, magnetic disk drives, magnetic tape drives, optical disk drives, and cloud-based storage . In further embodiments, the memory and/or storage device is a combination of devices such as those disclosed herein.

In some embodiments, the digital processing device includes a display for sending visual information to the user.

In some embodiments, the digital processing apparatus includes an input device for receiving information from a user. In some embodiments, the input device is a keyboard. In some embodiments, the input device is a pointing device, including, but not limited to, a mouse, trackball, trackpad, joystick, game controller, or stylus. In some embodiments, the input device is a touch screen or multi-touch screen. In other embodiments, the input device is a microphone for inputting voice or other audio. In other embodiments, the input device is a video camera or other sensor for capturing motion or visual input. In further embodiments, the input device is a Kinect, Leap Motion, or the like. In other embodiments, the input device is a combination of devices such as those disclosed herein.

Computer program.

In some embodiments, the platforms, systems, media, and methods disclosed herein include at least one computer program or use thereof. A computer program includes a sequence of instructions, executed in the CPU of a digital processing device, written to perform a specific task. Machine-readable instructions can be implemented as software modules, such as functions, objects, application programming interfaces (APIs), data structures, and the like, that perform specific tasks or implement specific abstract data types. In light of the disclosure provided herein, those skilled in the art will appreciate that a computer program may be written in various versions of various languages.

The functionality of machine-readable instructions can be combined or distributed as desired across different environments. In some embodiments, a computer program comprises a single sequence of instructions. In some embodiments, a computer program comprises a plurality of instruction sequences. In some embodiments, the computer program is provided from a single location. In other embodiments, the computer program is provided from multiple locations. According to various embodiments, a computer program includes one or more program modules. In various embodiments, a computer program includes, in whole or in part, one or more web applications, one or more mobile applications, one or more standalone applications, one or more web browser plug-ins, extensions, add-ons or add-ons, or combinations thereof. .

Mobile app.

In some embodiments, the computer program includes a mobile application installed on a digital processing device or portable device. In some embodiments, the mobile application is installed on the mobile digital processing device at the time of manufacture. In other embodiments, the mobile application is installed on a mobile digital processing device via a computer network described herein.

Software modules.

In some embodiments, the platforms, systems, media, and methods disclosed herein include or use software, server modules, and/or database modules. In view of the disclosure herein, program modules are created by methods known to those skilled in the art, using machines, software, and languages known in the art.

- 74 045992

The software modules disclosed herein are implemented in a variety of ways. In various embodiments, a software module comprises a file, a section of code, a program object, a programming structure, or combinations thereof. In further various embodiments, a software module comprises a plurality of files, a plurality of code sections, a plurality of programming objects, a plurality of programming structures, or combinations thereof. In various embodiments, the one or more software modules include, but are not limited to, a web application, a mobile application, and an offline application. In some embodiments, the program modules are located in a single computer program or application. In other embodiments, the program modules are located in more than one computer program or application. In some embodiments, the software modules reside on a single machine. In other embodiments, software modules are located on more than one machine. In further embodiments, software modules are hosted on cloud computing platforms. In some embodiments, software modules are located on one or more machines in a single location. In other embodiments, software modules are located on one or more machines in more than one location.

Database.

In some embodiments, the platforms, systems, media, and methods disclosed herein include one or more databases or the use thereof. Taking into account the disclosure presented herein, those skilled in the art will understand that many databases are suitable for storing and retrieving information such as geological information and introduction information. In various embodiments, suitable databases include, but are not limited to, relational databases, non-relational databases, object-oriented databases, object databases, entity-relationship model databases, association databases, and XML databases. Other non-limiting examples include SQL, PostgreSQL, MySQL, Oracle, DB2 and Sybase. In some embodiments, the database is located on the Internet. In further embodiments, the database is network-based. In other embodiments, the database is based on cloud computing. In other embodiments, the database is based on one or more local computer storage devices.

Numbered Embodiments.

The following embodiments list non-limiting permutations of combinations of features disclosed herein. In addition, other permutations of feature combinations are provided. 1. Pharmaceutical composition in the form of a spray containing about 0.5% - about 25% wt./wt. epinephrine or a pharmaceutically acceptable salt of epinephrine in water, ethanol, propylene glycol, or a combination thereof; the pH of the composition being between about 4.0 and about 6.5. 2. Pharmaceutical composition in the form of a spray according to embodiment 1, containing about 0.5% - about 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof. 3. The pharmaceutical composition in the form of a spray according to embodiment 1 or 2, the pH being controlled by adding hydrochloric acid, citric acid or a combination thereof. 4. The pharmaceutical composition in the form of a spray according to embodiment 3, the pH being controlled by adding hydrochloric acid. 5. The pharmaceutical composition in the form of a spray according to embodiment 3, the pH being controlled by adding citric acid. 6. The pharmaceutical composition in the form of a spray according to embodiment 3, the pH being controlled by adding a combination of hydrochloric acid and citric acid. 7. The pharmaceutical spray composition according to any one of embodiments 1-6, further comprising sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w) , or sodium metabisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w). 8. The pharmaceutical spray composition according to any one of embodiments 1-7, further comprising sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.05% (w/w) , or sodium metabisulfite at a concentration of about 0.0001% (w/w) to about 0.05% (w/w). 9. The pharmaceutical spray composition according to any one of embodiments 1-8, further comprising sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.05% (w/w) . 10. The pharmaceutical spray composition according to any one of embodiments 1-8, further comprising sodium metabisulfite at a concentration of about 0.0001% (w/w) to about 0.05% (w/w) . 11. The pharmaceutical spray composition according to any one of embodiments 1-10, further comprising disodium edetate in a concentration of about 0.0001% to about 0.01%. 12. The pharmaceutical composition in the form of a spray according to any of embodiments 1-11, further comprising an antimicrobial preservative. 13. The pharmaceutical composition in the form of a spray according to any of embodiments 1-12, further comprising an antimicrobial preservative selected from sodium benzalkonium in a concentration of about 0.005% (w/v) - about 1% (w/v). ), and chlorobutanol in concentration,

- 75 045992 comprising approximately 0.005% (w/v) - approximately 1% (w/v). 14. The pharmaceutical spray composition according to any one of embodiments 1-13, further comprising sodium benzalkonium at a concentration of about 0.005% (w/v) to about 1% (w/v). 15. The pharmaceutical spray composition according to any one of embodiments 1-13, further comprising chlorobutanol at a concentration of about 0.005% (w/v) to about 1% (w/v). 16. The pharmaceutical spray composition according to any one of embodiments 1-15, further comprising sodium chloride in a concentration of about 0.1% to about 5%. 17. The pharmaceutical composition in the form of a spray according to any of embodiments 1-16, further comprising a vasodilator. 18. The pharmaceutical spray composition of any one of embodiments 1-17, further comprising a vasodilator selected from about 0.05 mg to about 5 mg nitroprusside, about 1 mg to about 50 mg phentolamine, and about 10 mg to about 500 mg nifedipine. 19. The pharmaceutical composition in the form of a spray according to any of embodiments 1-18, additionally containing about 0.05 mg to about 5 mg of nitroprusside. 20. The pharmaceutical spray composition of any one of embodiments 1-18, further comprising about 1 mg to about 50 mg of phentolamine. 21. The pharmaceutical composition in the form of a spray according to any of embodiments 1-18, additionally containing about 10 mg to about 500 mg of nifedipine. 22. The pharmaceutical composition in the form of a spray according to any of embodiments 1-21, further comprising a penetration enhancer. 23. The pharmaceutical spray composition according to any one of embodiments 1-22, further comprising diethylene glycol monoethyl ether at a concentration of about 0.05% to about 15%. 24. The pharmaceutical composition in the form of a spray according to any of embodiments 1-23, further comprising a viscosity modifier. 25. The pharmaceutical spray formulation of Embodiment 24, wherein the viscosity modifier is about 0.5% to about 50% polyethylene glycol, about 0.001% to about 5% methylcellulose, or about 0.001% to about 0.5% hypromellose. 26. The pharmaceutical spray composition of any one of embodiments 1-25, further comprising about 0.5% to about 50% polyethylene glycol. 27. The pharmaceutical spray composition of any one of embodiments 1-25, further comprising about 0.001% to about 5% methylcellulose. 28. The pharmaceutical spray composition of any one of embodiments 1-25, further comprising about 0.001% to about 0.5% hypromellose. 29. The pharmaceutical spray composition according to any one of embodiments 1-28, further comprising about 0.01% to about 2.0% trisodium citrate 30. The pharmaceutical spray composition according to embodiment 1, containing about 1% to about 20 % w/w epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2.0% trisodium citrate and about 0.05% - about 15% diethylene glycol monoethyl ether. 31. The pharmaceutical composition in the form of a spray according to embodiment 30, containing about 1% - about 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% about 1.0% sodium chloride, about 0 01% is about 0.2% hypromellose, about 0.1% is about 1.0% trisodium citrate, and about 0.1% is about 2.0% diethylene glycol monoethyl ether. 32. The pharmaceutical composition in the form of a spray according to embodiment 30, containing about 5% - about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1.0% sodium chloride, about 0.05% is about 0.5% hypromellose, about 0.1% is about 1.0% trisodium citrate, and about 0.5% is about 5% diethylene glycol monoethyl ether. 33. The pharmaceutical composition in the form of a spray according to embodiment 30, containing approximately 2.4% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . 34. The pharmaceutical composition in the form of a spray according to embodiment 30, containing approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . 35. The pharmaceutical composition in the form of a spray according to embodiment 30, containing approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . 36. The pharmaceutical composition in the form of a spray according to embodiment 30, containing approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . 37. The pharmaceutical composition in the form of a spray according to any of embodiments 30-36, additionally containing chlorobutanol at the end

- 76 045992 tration comprising approximately 0.05% (w/v) - approximately 1% (w/v). 38. The pharmaceutical composition in the form of a spray according to any of embodiments 1-37, wherein the droplet size D50 is about 10 μm to about 100 μm. 39. The pharmaceutical composition in the form of a spray according to any of embodiments 1-38, wherein the composition is present in the device and/or is delivered from the device. 40. The pharmaceutical composition in the form of a spray according to embodiment 39, wherein the device contains an absorbent or oxygen scavenger. 41. The pharmaceutical spray composition of Embodiment 40, wherein the absorbent or oxygen scavenger is iron, ferric carbonate, ascorbate or sodium bicarbonate. 42. The pharmaceutical composition in the form of a spray according to any one of embodiments 39-41, the device comprising an enlarged reservoir. 43. The pharmaceutical composition in the form of a spray according to any one of embodiments 39-41, wherein the device is a single-dose device. 44. The pharmaceutical composition in the form of a spray according to any one of embodiments 39-41, wherein the device is a two-dose device. 45. The pharmaceutical composition in the form of a spray according to any one of embodiments 39-44, wherein the device contains a single reservoir containing about 125 μl to about 250 μl of the pharmaceutical composition. 46. The pharmaceutical spray formulation of embodiment 44, wherein the device comprises a first reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. 47. The pharmaceutical composition in the form of a spray according to any of embodiments 1-46, wherein the composition is configured to be dosed by inhalation. 48. The pharmaceutical composition in the form of a spray according to any of embodiments 1-47, the composition being configured for intranasal dosing. 49. A pharmaceutical composition in the form of a spray according to any of embodiments 1-37, the composition being configured for parenteral dosing. 50. A method of treating anaphylaxis, anaphylactic shock, severe allergic reaction, and/or bronchoconstriction, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition in the form of a spray according to any of embodiments 1-49. 51. A spray containing drops, wherein the drops contain a total of about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent and about 0.005% (wt./vol.) to about 10% (wt./vol.) ) benzalkonium chloride or about 0.005% (w/v) - about 10% (w/v) chlorobutanol. 52. The spray according to embodiment 51, wherein the spray is delivered from the device. 53. The spray according to embodiment 52, wherein the device is a single-dose device. 54. The spray according to embodiment 52, wherein the device is a two-dose device. 55. The spray according to any one of embodiments 52-54, wherein the device comprises a single reservoir containing about 125 μl to about 250 μl of the pharmaceutical composition. 56. The spray of embodiment 54, wherein the device comprises a first reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition and a second reservoir containing about 50 μL to about 250 μL of the pharmaceutical composition. 57. The spray according to any one of embodiments 52-56, wherein the device is pre-filled. 58. The spray according to any one of embodiments 51-57, wherein the isotonic agent is present at a concentration of about 0.1% (w/w) to about 5% (w/w). 59. The spray according to any one of embodiments 51-58, wherein the isotonic agent is sodium chloride. 60. The spray according to any one of embodiments 51-59, wherein the spray takes the form of a circular stream with an ovality coefficient of less than about 2.0. 61. The spray according to any one of embodiments 51-59, wherein the spray takes the form of a circular stream with an ovality coefficient of less than about 1.5. 62. The spray according to any one of embodiments 51-59, wherein the spray takes the form of a circular stream with an ovality coefficient of less than about 1.3. 63. The spray according to any one of embodiments 51-59, wherein the spray takes the form of a circular stream with an ovality coefficient of less than about 1.2. 64. The spray according to any one of embodiments 51-59, wherein the spray takes the form of a circular stream with an ovality ratio of less than about 1.1. 65. The spray according to any one of embodiments 60-64, wherein the ovality coefficient of the spray is measured at a distance of about 1 cm to about 10 cm from the device. 66. The spray according to any one of embodiments 60-64, wherein the ovality coefficient of the spray is measured at a distance of about 1 cm to about 5 cm from the device. 67. The spray according to any one of embodiments 60-64, wherein the ovality coefficient of the spray is measured at a distance of approximately 3 cm from the device. 68. The spray according to any one of embodiments 51-67, wherein the epinephrine is at least 10% bioavailable. 69. The spray according to any one of embodiments 51-68, wherein the epinephrine is at least 40% bioavailable. 70. The spray according to any one of embodiments 51-69, wherein the epinephrine is at least 50% bioavailable. 71. The spray of any one of embodiments 5170, wherein the epinephrine is at least 60% bioavailable. 72. The spray according to any one of embodiments 51-71, wherein the average droplet size is about 10 microns to about 120 microns. 73. Spray according to any of embodiments 50-71, with no more than about 10%

- 77 045992 droplets have a diameter of less than about 10 μm. 74. The spray according to any one of embodiments 51-72, wherein no more than about 5% of the droplets have a diameter of less than about 10 microns. 75. The spray according to any one of embodiments 51-72, wherein no more than about 2% of the droplets have a diameter of less than about 10 microns. 76. The spray according to any one of embodiments 51-72, wherein about 50% of the droplets have a diameter of about 10 microns to about 120 microns. 77. The spray according to any one of embodiments 51-72, wherein about 50% of the droplets have a diameter of about 10 microns to about 60 microns. 78. The spray according to any one of embodiments 51-72, wherein about 90% of the droplets have a diameter of less than about 120 microns. 79. The spray according to any one of embodiments 51-78, further comprising a stabilizer and an acid. 80. The spray according to embodiment 79, wherein the stabilizer is disodium edetate. 81. The spray of embodiment 79 or 80, wherein the acid is hydrochloric acid or citric acid or a combination thereof. 82. The spray according to any one of embodiments 51-81, wherein epinephrine or a pharmaceutically acceptable salt thereof is dissolved in water, ethanol or propylene glycol, or a combination thereof. 83. The spray of any one of embodiments 51-82, further comprising sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.05% (w/w), or sodium metabisulfite at a concentration of about 0.0001% (w/w) to about 0.05% (w/w). 84. The spray of any one of embodiments 51-83, further comprising chlorobutanol at a concentration of about 0.005% (w/v) to about 1% (w/v). 85. The spray according to any one of embodiments 51-84, further comprising a vasodilator. 86. The spray of embodiment 85, wherein the vasodilator is nitroprusside, phentolamine, or nifedipine. 87. The spray according to any one of embodiments 51-86, further comprising a penetration enhancer. 88. The spray according to embodiment 87, wherein the penetration enhancer is diethylene glycol monoethyl ether. 89. The spray according to any one of embodiments 51-88, further comprising a viscosity modifier. 90. The spray of embodiment 89, wherein the viscosity modifier is polyethylene glycol, methylcellulose, or hypromellose. 91. The spray according to any one of embodiments 51-90, wherein the device contains at least one oxygen absorbent or scavenger. 92. The spray of embodiment 91, wherein the at least one oxygen absorbent or scavenger is iron, ferric carbonate, ascorbate or sodium bicarbonate, or a combination thereof. 93. The spray according to any of embodiments 51-92, wherein the spray contains per 100 μl of solution: about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof; about 0.1 mg - about 2 mg sodium chloride; about 0.01 mg - about 1 mg benzalkonium chloride; about 0.1 mg - about 2 mg disodium edetate; and hydrochloric acid or citric acid or a combination thereof in an amount sufficient to achieve a pH value of about 3.5 to about 6.5. 94. The spray according to any one of embodiments 51-93, wherein the spray is delivered from a spray nozzle of a prefilled device, and wherein no more than about 10% of the droplets have a diameter of less than 10 microns. 95. The spray according to embodiment 94, wherein the spray is measured using laser diffraction with beams measured at both 3 cm and 6 cm from the spray nozzle. 96. A method of treating anaphylaxis, anaphylactic shock, severe allergic reaction and/or bronchoconstriction, comprising delivering an injection of a pharmaceutical solution from a pre-filled device into the nostril of a subject in need thereof, wherein: (i) the device is configured for nasal delivery; (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent and about 0.005% (w/v) to about 1% (w/v) benzalkonium chloride. 97. The method of embodiment 96, wherein the device is a single-dose device. 98. The method of embodiment 96, wherein the device is a two-dose device. 99. The method of any one of embodiments 96-98, wherein the device comprises a single reservoir containing about 125 μL to about 250 μL of a pharmaceutical solution. 100. The method of embodiment 99, wherein the device delivers two squirts of a pharmaceutical solution from a single reservoir. 101. The method of Embodiment 98, wherein the device comprises a first reservoir containing about 50 μL to about 250 μL of a pharmaceutical solution and a second reservoir containing about 50 μL to about 250 μL of a pharmaceutical solution. 102. The method of embodiment 101, wherein the device delivers one spray of the pharmaceutical solution from the first reservoir, and one spray of the pharmaceutical solution from the second reservoir. 103. The method of any one of embodiments 96102, wherein epinephrine or a pharmaceutically acceptable salt thereof is dissolved in water, ethanol, propylene glycol, or a combination thereof. 104. The method of any one of embodiments 96-103, wherein the isotonic agent is present at a concentration of about 0.2%

- 78 045992 (w/w) - approximately 1.2% (w/v). 105. The method of any one of embodiments 96-104, wherein the pharmaceutical solution further contains about 0.1% (w/v) to about 0.5% (w/v) stabilizer. 106. The method of any one of embodiments 96-105, wherein the pharmaceutical solution further contains an amount of acid sufficient to achieve a pH value of about 3.5 to about 6.5. 107. The method of embodiment 106, wherein the acid is hydrochloric acid or citric acid or a combination thereof. 108. The method according to any one of embodiments 96-107, wherein: the isotonic agent is sodium chloride; the stabilizer is disodium edetate; and the acid is hydrochloric acid or citric acid or a combination thereof. 109. The method of any one of embodiments 96-108, wherein the plasma concentration-time curve for epinephrine in a subject has a _tmax of less than about 10 minutes to about 120 minutes. 110. The method of any one of embodiments 96-109, wherein the subject has a maximum plasma concentration ( _Cmax ) of about 50 pg/mL to about 500 pg/mL of epinephrine. 111. The method of any one of embodiments 96-110, wherein the area under the plasma concentration-time curve for epinephrine in the subject is about 5 ng/min/mL to about 50 ng/min/mL. 112. The method according to any one of embodiments 96-111, wherein the device comprises a piston in which is located a container cap containing the following: (i) a bottle containing an opening; (ii) cannula; and (iii) rubber stopper; wherein the stopper is configured to plug the opening of the vial, and wherein the cannula is configured to pierce the stopper when the piston applies sufficient force to the cannula. 113. The method of any one of embodiments 96-112, wherein the spray delivers about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof. 114. The method of any one of embodiments 96-113, wherein the prefilled device is operated with one hand. 115. The method of any one of embodiments 96-114, wherein the prefilled device comprises a single reservoir containing approximately 125 μL of the pharmaceutical solution. 116. The method of any one of embodiments 96-115, wherein approximately 100 μl of the pharmaceutical solution is delivered by a single actuation of the device. 117. The method of any one of embodiments 96-116, wherein the volume of the reservoir is no more than about 140 μL. 118. The method of any one of embodiments 96-117, wherein the delivery time of the pharmaceutical solution is less than about 25 seconds. 119. The method of any one of embodiments 96-117, wherein the delivery time of the pharmaceutical solution is less than about 20 seconds. 120. The method of any one of embodiments 96-119, wherein less than about 20% of the pharmaceutical solution leaves the nasal cavity through nasopharyngeal or external drainage. 121. The method of any one of embodiments 96-120, wherein less than about 10% of the pharmaceutical solution leaves the nasal cavity through nasopharyngeal or external drainage. 122. The method of any one of embodiments 96-121, wherein less than about 5% of the pharmaceutical solution leaves the nasal cavity through nasopharyngeal or external drainage. 123. The method of any one of embodiments 96-122, wherein the subject suffers a severe allergic reaction from exposure or suspected exposure to an allergen. 124. The method of embodiment 123, wherein the allergen is a food, drug, or insect bite or sting. 125. The method of any one of embodiments 96-124, wherein the subject exhibits one or more symptoms selected from the following: respiratory depression or distress, airway narrowing, wheezing, tingling in the arms, legs, mouth or scalp, shortness of breath, swelling or inflammation of the face, eyes, lips, tongue or throat, urticaria, central nervous system depression, cardiovascular depression, impaired level of consciousness, dilated pupils, hypoxemia, hypotension, unresponsiveness to stimuli, loss of consciousness, respiratory arrest, unstable or stopped pulse and vomiting. 126. The method of any one of embodiments 96-125, wherein the subject exhibits respiratory depression or distress, or cardiovascular depression. 127. The method of any one of embodiments 96-126, wherein the subject does not experience respiratory depression or distress for at least about 1 hour after treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. 128. The method of any one of embodiments 96-127, wherein the subject does not experience respiratory depression or distress for at least about 2 hours after treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. 129. The method of any one of embodiments 96-128, wherein the subject does not experience respiratory depression or distress for at least about 4 hours after treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. 130. The method of any one of embodiments 96-129, wherein the subject does not experience respiratory depression or distress for at least about 6 hours after treatment providing delivery of a therapeutically effective co

- 79 045992 quantity of epinephrine or its pharmaceutically acceptable salt. 131. The method of any one of embodiments 96-130, wherein the subject is in a supine, supine, or rescue position. 132. The method of any one of embodiments 96-131, wherein a single nostril spray provides a plasma concentration of =0.2 ng/mL within 2.5 minutes in a subject. 133. The method of any one of embodiments 96-131, wherein a single nostril spray provides a plasma concentration of = 1 ng/mL within 5 minutes in a subject. 134. The method of any one of embodiments 96-131, wherein a single nostril spray provides a plasma concentration of =3 ng/mL within 10 minutes in a subject. 135. A method of treating depression or respiratory distress caused by anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a pre-filled device into the nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution as a circular spray stream with an ovality factor of less than about 2 ,0 when measured at a distance of about 1 to about 10 cm from the prefilled device, wherein: (i) the device is configured for nasal delivery; (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent and about 0.005% (w/v) to about 1% (w/v) benzalkonium chloride. 136. The method of embodiment 135, wherein the device is a single-dose device. 137. The method of embodiment 135, wherein the device is a two-dose device. 138. The method of any one of embodiments 135-137, wherein the device comprises a single reservoir containing about 125 μL to about 250 μL of a pharmaceutical solution. 139. The method of embodiment 138, wherein the device delivers two squirts of a pharmaceutical solution from a single reservoir. 140. The method of embodiment 138, wherein the device comprises a first reservoir containing about 50 μL to about 250 μL of a pharmaceutical solution and a second reservoir containing about 50 μL to about 250 μL of a pharmaceutical solution. 141. The method of embodiment 140, wherein the device delivers one spray of the pharmaceutical solution from the first reservoir, and one spray of the pharmaceutical solution from the second reservoir. 142. The method of any one of embodiments 135-141, wherein the ovality factor is less than about 1.5. 143. The method of any one of embodiments 135-141, wherein the ovality ratio is less than about 1.3. 144. The method of any one of embodiments 135-141, wherein the ovality ratio is less than about 1.2. 145. The method of any one of embodiments 135-141, wherein the ovality ratio is less than about 1.1. 146. The method according to any one of embodiments 135-145, wherein the ovality coefficient of the jet is measured at a distance of about 1 cm to about 5 cm from the device. 147. A method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein: (i) the device is configured for nasal delivery; (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains about 0.5 mg of about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof, an isotonic agent and about 0.005% (w/v) to about 1% (w/v) benzalkonium chloride. 148. The method of embodiment 147, wherein the device is a single-dose device. 149. The method of any embodiment 147, wherein the device is a two-dose device. 150. The method of any one of embodiments 147-149, wherein the device comprises a single reservoir containing about 125 μL to about 250 μL of a pharmaceutical solution. 151. The method of embodiment 150, wherein the device delivers two squirts of a pharmaceutical solution from a single reservoir. 152. The method of embodiment 149, wherein the device comprises a first reservoir containing about 50 μL to about 250 μL of a pharmaceutical solution and a second reservoir containing about 50 μL to about 250 μL of a pharmaceutical solution. 153. The method of embodiment 152, wherein the device delivers one spray of the pharmaceutical solution from the first reservoir, and one spray of the pharmaceutical solution from the second reservoir. 154. A stable pharmaceutical composition in the form of a spray containing: (i) about 1% - about 25% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol or a combination thereof; and (ii) one or more of the following: excipients, carrier vehicles, emulsifiers, stabilizers, preservatives, mucosal adhesion agents, antibacterial agents, buffers and/or other excipients, the composition being stable at a temperature of at least at least about 20°C, and at a relative humidity of at least about 30%, and wherein the composition is stable over a period of at least about two months. 155. The pharmaceutical composition in the form of a spray according to embodiment 154, containing about 1% - about 10% wt./wt. epinephrine or its pharmaceuticals

- 80 045992 commercially acceptable salt. 156. The pharmaceutical spray formulation of embodiment 154 or 155, wherein the formulation is stable at a temperature of at least about 25°C. 157. The pharmaceutical spray formulation of embodiment 154 or 155, wherein the formulation is stable at a temperature of at least about 30°C. 158. The pharmaceutical spray formulation of any one of embodiments 154-157, wherein the formulation is stable at a temperature of at least about 35°C. 159. The pharmaceutical spray formulation of any one of embodiments 154-158, wherein the formulation is stable at a temperature of at least about 40°C. 160. The pharmaceutical spray formulation of any one of embodiments 154-159, wherein the formulation is stable at a temperature of at least about 45°C. 161. The pharmaceutical spray formulation of any one of embodiments 154-160, wherein the formulation is stable at a relative humidity of at least about 40%. 162. The pharmaceutical spray formulation of any one of embodiments 154-161, wherein the formulation is stable at a relative humidity of at least about 50%. 163. The pharmaceutical spray formulation of any one of embodiments 154-162, wherein the formulation is stable at a relative humidity of at least about 60%. 164. The pharmaceutical spray formulation of any one of embodiments 154-163, wherein the formulation is stable at a relative humidity of at least about 70%. 165. The pharmaceutical spray formulation of any one of embodiments 154-164, wherein the formulation is stable at a relative humidity of at least about 80%. 166. The pharmaceutical spray formulation of any one of embodiments 154-165, wherein the formulation is stable over a period of at least about six months. 167. The pharmaceutical spray formulation of any one of embodiments 154-166, wherein the formulation is stable over a period of at least about 12 months. 168. The pharmaceutical spray formulation of any one of embodiments 154-167, wherein the formulation is stable over a period of at least about 18 months. 169. The pharmaceutical spray formulation of any one of embodiments 154-168, wherein the formulation is stable over a period of at least about 24 months. 170. The pharmaceutical spray formulation of any one of embodiments 154-169, wherein the formulation is stable over a period of at least about 36 months. 171. The pharmaceutical composition in the form of a spray according to any of embodiments 154-170, wherein the composition has a viscosity of about 100 to about 2500 cps. 172. The pharmaceutical composition in the form of a spray according to any of embodiments 154-171, wherein the composition is configured to administer dosages by inhalation. 173. The pharmaceutical composition in the form of a spray according to any of embodiments 154-172, the composition being configured for intranasal dosing. 174. The pharmaceutical composition in the form of a spray according to any of embodiments 154-171, the composition being configured for parenteral dosing. 175. The pharmaceutical spray composition of any one of embodiments 154-174, further comprising an isotonic agent present at a concentration of about 0.1% (w/w) to about 5% (w/w). 176. The pharmaceutical composition in the form of a spray according to embodiment 175, wherein the isotonic agent is sodium chloride. 177.

The pharmaceutical composition in the form of a spray according to any of embodiments 154-176, containing a stabilizer. 178. The pharmaceutical composition in the form of a spray according to embodiment 177, wherein the stabilizer is disodium edetate. 179. The pharmaceutical spray composition of any one of embodiments 154-178, further comprising an acid sufficient to achieve a pH value of about 3.5 to about 6.5. 180. The pharmaceutical spray composition of embodiment 179, wherein the acid is hydrochloric acid or citric acid or a combination thereof. 181. The pharmaceutical spray composition of any one of embodiments 154-180, further comprising sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w) , or sodium metabisulfite at a concentration of about 0.0001% (w/w) to about 0.1% (w/w). 182. The pharmaceutical spray composition of any one of embodiments 154-181, further comprising sodium bisulfite at a concentration of about 0.0001% (w/w) to about 0.05% (w/w) , or sodium metabisulfite at a concentration of about 0.0001% (w/w) to about 0.05% (w/w). 183. The pharmaceutical spray composition of any one of embodiments 154-182, further comprising chlorobutanol at a concentration of about 0.005% (w/v) to about 1% (w/v). 184. The pharmaceutical composition in the form of a spray according to any one of embodiments 154-183, further comprising further comprising a vasodilator. 185. The pharmaceutical composition in the form of a spray according to embodiment 184, wherein the vasodilator is nitroprusside, phentolamine or nifedipine. 186. Pharmaceutical composition in the form of a spray according to

- 81 045992 to any of embodiments 154-185, additionally containing a permeation enhancer. 187. The pharmaceutical spray formulation of embodiment 186, wherein the penetration enhancer is diethylene glycol monoethyl ether. 188. The pharmaceutical composition in the form of a spray according to any of embodiments 154-187, further comprising a viscosity modifier. 189. The pharmaceutical spray formulation of Embodiment 188, wherein the viscosity modifier is polyethylene glycol, methylcellulose, or hypromellose. 190. The pharmaceutical spray composition according to any one of embodiments 154-189, further comprising trisodium citrate. 191. The pharmaceutical composition in the form of a spray according to embodiment 154, containing about 1% - about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2.0% trisodium citrate and about 0.05% - about 15% diethylene glycol monoethyl ether. 192. The pharmaceutical composition in the form of a spray according to embodiment 191, containing about 1% - about 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1.0% sodium chloride, about 0.01% is about 0.2% hypromellose, about 0.1% is about 1.0% trisodium citrate, and about 0.1% is about 2.0% diethylene glycol monoethyl ether. 193. The pharmaceutical composition in the form of a spray according to embodiment 191, containing about 5% - about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1.0% sodium chloride, about 0.05% - about 0.5% hypromellose, about 0.1% - about 1.0% trisodium citrate and about 0.5% - about 5% diethylene glycol monoethyl ether. 194. The pharmaceutical composition in the form of a spray according to embodiment 191, containing approximately 2.4% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . 195. The pharmaceutical composition in the form of a spray according to embodiment 191, containing approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . 196. The pharmaceutical composition in the form of a spray according to embodiment 191, containing approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . 197. The pharmaceutical composition in the form of a spray according to embodiment 191, containing approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate and about 1% diethylene glycol monoethyl ether . 198. The pharmaceutical spray composition of any one of embodiments 154-197, further comprising chlorobutanol at a concentration of about 0.05% (w/v) to about 1% (w/v). 199. The pharmaceutical composition in the form of a spray according to any one of embodiments 154-198, wherein the composition is delivered from the device. 200. The pharmaceutical composition in the form of a spray according to embodiment 199, wherein the device is a single-dose device. 201. The pharmaceutical composition in the form of a spray according to embodiment 199, wherein the device is a two-dose device. 202. The pharmaceutical spray formulation of any one of embodiments 199-201, wherein the device comprises a single reservoir containing about 125 μL to about 250 μL of the pharmaceutical solution. 203. The pharmaceutical spray formulation of embodiment 202, wherein the device delivers two sprays of the pharmaceutical solution from a single reservoir. 204. The pharmaceutical spray formulation of embodiment 201, wherein the device comprises a first reservoir containing about 50 μL of about 250 μL of the pharmaceutical solution and a second reservoir containing about 50 μL to about 250 μL of the pharmaceutical solution. 205. The pharmaceutical spray formulation of embodiment 204, wherein the device delivers one spray of the pharmaceutical solution from the first reservoir, and one spray of the pharmaceutical solution from the second reservoir. 206. The pharmaceutical spray formulation of any one of embodiments 196-205, wherein the device is pre-filled. 207. The pharmaceutical composition in the form of a spray according to any one of embodiments 199-206, wherein the device is suitable for delivering the composition to the nostril of a subject. 208. The pharmaceutical composition in the form of a spray according to any of embodiments 199-207, wherein the device contains at least one oxygen absorbent or scavenger. 209. The pharmaceutical spray composition of embodiment 208, wherein the at least one oxygen absorbent or scavenger is iron, ferric carbonate, ascorbate or sodium bicarbonate, or a combination thereof. 210. The pharmaceutical composition in the form of a spray according to any of embodiments 154-209, wherein the composition is delivered in the form of an injection.

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211. The pharmaceutical composition in the form of a spray according to embodiment 210, wherein the spray takes the form of a circular stream with an ovality coefficient of less than about 2.0. 212. The pharmaceutical composition in the form of a spray according to embodiment 210 or 211, wherein the spray takes the form of a circular stream with an ovality coefficient of less than about 1.5. 213. The pharmaceutical composition in the form of a spray according to any of embodiments 210-212, wherein the spray takes the form of a circular stream with an ovality coefficient of less than about 1.3. 214. The pharmaceutical composition in the form of a spray according to any of embodiments 210-213, wherein the spray takes the form of a circular stream with an ovality coefficient of less than about 1.2. 215. The pharmaceutical composition in the form of a spray according to any of embodiments 210-214, wherein the spray takes the form of a circular stream with an ovality coefficient of less than about 1.1. 216. The pharmaceutical composition in the form of a spray according to any of embodiments 210-215, wherein the ovality coefficient of the spray is measured at a distance of about 1 cm to about 10 cm from the device from which the composition is administered or delivered.

217. The pharmaceutical composition in the form of a spray according to any of embodiments 210-216, wherein the ovality coefficient of the spray is measured at a distance of about 1 cm to about 5 cm from the device from which the composition is administered or delivered.

218. The pharmaceutical spray formulation of any one of embodiments 210-217, wherein the spray ovality coefficient is measured at a distance of approximately 3 cm from the device from which the formulation is administered or delivered. 219. The pharmaceutical composition in the form of a spray according to any one of embodiments 154-218, wherein the epinephrine is at least 10% bioavailable. 220. The pharmaceutical composition in the form of a spray according to any of embodiments 154-219, wherein the epinephrine is at least 40% bioavailable. 221. The pharmaceutical composition in the form of a spray according to any one of embodiments 154-220, wherein the epinephrine is at least 50% bioavailable. 222. The pharmaceutical composition in the form of a spray according to any of embodiments 154-221, wherein the epinephrine is at least 60% bioavailable. 223. The pharmaceutical spray formulation of any one of embodiments 154-222, wherein the formulation comprises droplets with an average droplet size of about 10 microns to about 120 microns. 224. The pharmaceutical spray composition of embodiment 223, wherein no more than about 10% of the droplets have a diameter of less than about 10 microns. 225. The pharmaceutical spray composition of embodiment 223 or 224, wherein no more than about 5% of the droplets have a diameter of less than about 10 microns. 226. The pharmaceutical spray composition of any one of embodiments 223-225, wherein no more than about 2% of the droplets have a diameter of less than about 10 microns. 227. The pharmaceutical composition in the form of a spray according to any of embodiments 223-226, with about 50% of the droplets having a diameter of about 10 μm to about 120 μm. 228. The pharmaceutical composition in the form of a spray according to any of embodiments 223-227, with about 50% of the droplets having a diameter of about 10 μm to about 60 μm. 229. The pharmaceutical spray composition of any one of embodiments 223-228, wherein about 90% of the droplets have a diameter of less than about 120 microns. 230. A method of treating anaphylaxis, anaphylactic shock, severe allergic reaction and/or bronchoconstriction comprising administering or delivering to a subject in need thereof a pharmaceutical composition in the form of a spray according to any of embodiments 154-229. 231. The method of embodiment 230, wherein the pharmaceutical composition is administered as a spray or delivered into the nostril of a subject from a prefilled device configured for nasal delivery. 232. The method of embodiment 231, wherein a volume of about 20 μL to about 250 μL of spray is delivered. 233. The method of any one of embodiments 230-232, wherein the plasma concentration-time curve for epinephrine in a subject has a t _max of less than about 10 minutes to about 120 minutes. 234. The method of any one of embodiments 230-233, wherein a therapeutic plasma concentration of epinephrine in the subject is achieved less than 20 minutes after administration to the subject. 235. The method of any one of embodiments 230-234, wherein a therapeutic plasma concentration of epinephrine in the subject is achieved less than 15 minutes after administration to the subject. 236. The method of any one of embodiments 230-235, wherein a therapeutic plasma concentration of epinephrine in the subject is achieved less than 10 minutes after administration to the subject. 237. The method of any one of embodiments 230-236, wherein a therapeutic plasma concentration of epinephrine in the subject is achieved less than 5 minutes after administration to the subject. 238. The method of any one of embodiments 234-237, wherein the therapeutic plasma concentration of epinephrine in the subject is approximately 500 pg/mL epinephrine. 239. The method of any one of embodiments 234-238, wherein the therapeutic plasma concentration of epinephrine in the subject is approximately 450 pg/mL epinephrine. 240. The method of any one of embodiments 234-239, wherein a therapeutic concentration of epinephrine in

- 83 045992 the subject's plasma is approximately 400 pg/ml epinephrine. 241. The method of any one of embodiments 234-240, wherein the therapeutic plasma concentration of epinephrine in the subject is approximately 350 pg/mL epinephrine. 242. The method of any one of embodiments 234-241, wherein the therapeutic plasma concentration of epinephrine in the subject is approximately 300 pg/mL epinephrine. 243. The method of any one of embodiments 230-242, wherein the subject has a maximum plasma concentration ( _Cmax ) of about 50 pg/mL to about 500 pg/mL of epinephrine. 244. The method of any one of embodiments 230-243, wherein the area under the plasma concentration-time curve for epinephrine in the subject is about 5 ng/min/mL to about 50 ng/min/mL. 245. The method of any one of embodiments 231-244, wherein the prefilled device is operated with one hand. 246. The method of any one of embodiments 231-245, wherein the prefilled device is a single-dose device. 247. The method of any one of embodiments 231-245, wherein the prefilled device is a two-dose device. 248. The method of any one of embodiments 231-247, wherein the prefilled device comprises a single reservoir containing about 125 μL to about 250 μL of the pharmaceutical composition. 249. The method of embodiment 248, wherein the device delivers two squirts of a pharmaceutical solution from a single reservoir. 250. The method of embodiment 247, wherein the device comprises a first reservoir containing about 50 μL to about 250 μL of a pharmaceutical solution and a second reservoir containing about 50 μL to about 250 μL of a pharmaceutical solution. 251. The method of embodiment 250, wherein the device delivers one squirt of pharmaceutical solution from a first reservoir, and one squirt of pharmaceutical solution from a second reservoir. 252. The method of any one of embodiments 230251, wherein approximately 100 μl of the pharmaceutical composition is delivered by a single actuation of the device. 253. The method of embodiment 248, wherein the volume of the reservoir is no more than about 140 μL. 254. The method of embodiment 250, wherein the volume of each reservoir is no more than about 140 μl. 255. The method of any one of embodiments 230-254, wherein the delivery time is less than about 25 seconds. 256. The method of any one of embodiments 230-255, wherein the delivery time is less than about 20 seconds. 257. The method of any one of embodiments 230-256, wherein less than about 20% of the composition leaves the nasal cavity via nasopharyngeal or external drainage. 258. The method of any one of embodiments 230-257, wherein less than about 10% of the composition leaves the nasal cavity via nasopharyngeal or external drainage. 259. The method of any one of embodiments 230-258, wherein less than about 5% of the composition leaves the nasal cavity via nasopharyngeal or external drainage. 260. The method of any one of embodiments 230-259, wherein the subject suffers a severe allergic reaction from exposure or suspected exposure to an allergen. 261. The method of embodiment 260, wherein the allergen is a food, drug, or insect bite or sting. 262. The method of any one of embodiments 230-261, wherein the subject exhibits one or more symptoms selected from the following: respiratory depression or distress, airway narrowing, wheezing, tingling in the arms, legs, mouth or scalp, shortness of breath, swelling or inflammation of the face, eyes, lips, tongue or throat, urticaria, central nervous system depression, cardiovascular depression, impaired level of consciousness, dilated pupils, hypoxemia, hypotension, unresponsiveness to stimuli, loss of consciousness, respiratory arrest, unstable or stopped pulse and vomiting. 263. The method of any one of embodiments 230-262, wherein the subject exhibits respiratory depression or distress, or cardiovascular depression. 264. The method of any one of embodiments 230-263, wherein the subject does not experience respiratory depression or distress for at least about 1 hour after treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. 265. The method of any one of embodiments 230-264, wherein the subject does not experience respiratory depression or distress for at least about 2 hours after treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. 266. The method of any one of embodiments 230-265, wherein the subject does not experience respiratory depression or distress for at least about 4 hours after treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. 267. The method of any one of embodiments 230-266, wherein the subject does not experience respiratory depression or distress for at least about 6 hours after treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. 268. The method of any one of embodiments 230267 wherein the subject is in a supine, supine, or rescue position. 269. The method according to any one of embodiments 230-268, wherein one injection into

- 84 045992 nostril provides a plasma concentration of =0.2 ng/ml within 2.5 minutes in a subject. 270. The method of any one of embodiments 230-268, wherein a single nostril spray provides a plasma concentration of =1 ng/mL within 5 minutes in a subject. 271. The method of any one of embodiments 230-268, wherein a single nostril spray provides a plasma concentration of =3 ng/mL within 10 minutes in a subject. 272. A method of treating depression or respiratory distress caused by anaphylaxis or anaphylactic shock, comprising administering or delivering to a subject in need thereof a spray formulation according to any one of embodiments 154-229 from a pre-filled device into the subject's nostril in a manner that delivers the formulation in the form of a round a spray jet having an ovality coefficient of less than about 2.0 when measured at a distance of about 1 to about 10 cm from the prefilled device, wherein: (i) the device is configured for nasal delivery; and (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered. 273. The method of embodiment 272, wherein the ovality factor is less than about 1.5. 274. The method of embodiment 272, wherein the ovality factor is less than about 1.3. 275. The method of embodiment 272, wherein the ovality factor is less than about 1.2. 276. The method of embodiment 272, wherein the ovality factor is less than about 1.1. 277. The method of any one of embodiments 272276, wherein the ovality coefficient of the jet is measured at a distance of about 1 cm to about 5 cm from the device. 278. A method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising administering or delivering to a subject in need thereof a pharmaceutical composition in the form of a spray according to any one of embodiments 154-229 from the device into the nostril of the subject, wherein: (i) the device is configured with possibility of nasal delivery; and (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered. 279. An apparatus according to any of the preceding embodiments, wherein the apparatus comprises the following: at least one processor, an operating system configured to execute executable instructions, a storage device, and a computer program including instructions executable by a digital processing device to create an application, comprising the following: a) a software module that sends a first notification to the user's portable device when the device has been launched to administer the formulation; b) a software module sending a second notification to the second device of the designated third party when the device has been started to administer the formulation; c) a software module sending a third notification to the user's portable device when the device is outside a predetermined range from the portable device; d) a software module sending a fourth notification to the second device of the designated third party when the device is outside a predetermined range from the portable device; f) a software module that collects geographic data about the device when the device is in the control of a user or a second user; f) a software module that saves the device’s geographic data to a remote or cloud database; and g) a software module allowing the user or a second user to order a new device using the user's device or portable device. 280. The method according to any of the previous embodiments, the method comprising: a) sending a first notification to the user's portable device when the device has been started to administer the formulation; b) sending a second notification to the second designated third party device when the device has been started to administer the formulation; c) sending a third notification to the user's portable device when the device is outside a predetermined range from the portable device; d) sending a fourth notification to the second device of the designated third party when the device is outside a predetermined range from the portable device; f) collecting geographic data about a device when the device is in the control of a user or a secondary user; f) storing the device's geographic data in a remote or cloud database; and g) allowing the user or a second user to order a new device using the user's device or handheld device. 281. The device of embodiment 279, wherein the portable device or second device comprises one or more of the following: a computer, a laptop, a laptop, mobile smartphones, a tablet computer, and a personal digital assistant. 282. The apparatus of embodiment 279, further comprising a communication element configured to provide two-way communication with a user's portable device and a digital processing device using a wireless data transfer protocol. 283. The apparatus of embodiment 279, wherein the first, second, third, or fourth notification is sent within the application. 284. The apparatus of embodiment 279, wherein the first, second, third, or fourth notification is automatic. 285. The apparatus of embodiment 279, wherein the first, second, third, or fourth notification comprises one or more of the following: text, graphics, sound, and vibration. 286. Far

- 85 045992 maceutical composition in the form of a spray containing approximately 0.5% - approximately 25% w/w. epinephrine or a pharmaceutically acceptable salt of epinephrine in water, the pH of the composition being about 4.0 to about 6.5. 287. The pharmaceutical composition in the form of a spray according to embodiment 286, containing about 0.5% to about 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof. 288. The pharmaceutical composition in the form of a spray according to embodiment 286, containing about 2% - about 5% wt./wt. epinephrine. 289. The pharmaceutical composition in the form of a spray according to embodiment 286, containing approximately 2% wt./wt. epinephrine. 290. The pharmaceutical composition in the form of a spray according to embodiment 286, containing approximately 5% wt./wt. epinephrine. 291. The pharmaceutical spray composition of any one of embodiments 286-290, further comprising one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffer agent. 292. The pharmaceutical composition in the form of a spray according to embodiment 291, wherein the pharmaceutical composition contains an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, and a buffer agent. 293. The pharmaceutical spray composition according to any one of embodiments 286-293, further comprising an antioxidant. 294. The pharmaceutical composition in the form of a spray according to embodiment 293, wherein the antioxidant contains sodium bisulfite or sodium metabisulfite. 295. The pharmaceutical spray formulation of embodiment 293 comprising an antioxidant at a concentration of about 0.0001% (w/w) to about 0.1% (w/w). 296. The pharmaceutical spray formulation of embodiment 293 comprising an antioxidant at a concentration of about 0.001% (w/w) to about 0.1% (w/w). 297. The pharmaceutical spray formulation of embodiment 293 comprising an antioxidant at a concentration of about 0.01% (w/w) to about 0.1% (w/w). 298. The pharmaceutical spray formulation of embodiment 293 comprising an antioxidant at a concentration of about 0.05% (w/w). 299. The pharmaceutical spray composition according to any one of embodiments 286-298, further comprising an antimicrobial preservative. 300. The pharmaceutical composition in the form of a spray according to embodiment 299, wherein the antimicrobial preservative contains chlorobutanol. 301. The pharmaceutical spray formulation of Embodiment 299 comprising an antimicrobial preservative at a concentration of about 0.005% (w/v) to about 1% (w/v). 302. The pharmaceutical spray formulation of embodiment 299 comprising an antimicrobial preservative at a concentration of about 0.01% (w/v) to about 1% (w/v). 303. The pharmaceutical spray formulation of Embodiment 299, comprising an antimicrobial preservative at a concentration of about 0.1% (w/v) to about 1% (w/v). 304. The pharmaceutical spray formulation of embodiment 299 comprising an antimicrobial preservative at a concentration of about 0.21% (w/v). 305. The pharmaceutical spray composition of embodiment 286, further comprising an isotonic agent. 306. The pharmaceutical composition in the form of a spray according to embodiment 305, wherein the isotonic agent contains sodium chloride. 307. The pharmaceutical composition in the form of a spray according to embodiment 305, containing an isotonic agent at a concentration of about 0.1% to about 5%. 308. The pharmaceutical spray formulation of embodiment 305, comprising an isotonic agent at a concentration of about 0.1% to about 1%. 309. The pharmaceutical spray formulation of embodiment 305, comprising an isotonic agent at a concentration of about 0.4%. 310. The pharmaceutical spray composition according to any one of embodiments 286-309, further comprising an absorption enhancer. 311. The pharmaceutical spray composition of embodiment 310, wherein the absorption enhancer comprises diethylene glycol monoethyl ether. 312. The pharmaceutical spray formulation of embodiment 310 comprising an absorption enhancer at a concentration of about 0.05% to about 15%. 313. The pharmaceutical spray formulation of embodiment 310, comprising an absorption enhancer at a concentration of about 0.1% to about 5%. 314. The pharmaceutical spray formulation of embodiment 310 comprising an absorption enhancer at a concentration of about 1%. 315. The pharmaceutical spray composition of any one of embodiments 286-314, further comprising a viscosity modifier. 316. The pharmaceutical spray composition of embodiment 315, wherein the viscosity modifier contains hypromellose. 317. The pharmaceutical spray formulation of embodiment 315, comprising a viscosity modifier at a concentration of about 0.001% to about 0.5%. 318. The pharmaceutical spray formulation of embodiment 315 comprising a viscosity modifier at a concentration of about 0.01% to about 0.2%. 319. The pharmaceutical spray formulation of embodiment 315 comprising a viscosity modifier at a concentration of about 0.1%. 320. The pharmaceutical spray composition according to any one of embodiments 286-319, further comprising a buffering agent. 321. The pharmaceutical composition in the form of a spray according to embodiment 320, wherein the buffer agent contains citric acid or citric acid monohydrate. 322. The pharmaceutical spray formulation of embodiment 320 comprising a buffering agent at a concentration of about 0.01% to about 2%. 323.

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The pharmaceutical spray formulation of Embodiment 320 comprising a buffering agent at a concentration of about 0.1% to about 1%. 324. The pharmaceutical spray formulation of embodiment 320 comprising a buffering agent at a concentration of about 0.42%. 325. The pharmaceutical spray composition of embodiment 286, further comprising sodium metabisulfite, sodium chloride, hypromellose, citric acid monohydrate, and diethylene glycol monoethyl ether. 326. The pharmaceutical composition in the form of a spray according to embodiment 325, containing about 1% - about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2% citric acid monohydrate and about 0.05% - about 15% diethylene glycol monoethyl ether. 327. The pharmaceutical composition in the form of a spray according to embodiment 325, containing about 1% - about 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1% sodium chloride, about 0. 01% is about 0.2% hypromellose, about 0.1% is about 1% citric acid monohydrate and about 0.1% is about 5% diethylene glycol monoethyl ether. 328. The pharmaceutical composition in the form of a spray according to embodiment 325, containing approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2% citric acid monohydrate and about 0.05% - about 15% diethylene glycol monoethyl ether. 329. The pharmaceutical composition in the form of a spray according to embodiment 325, containing approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% about 1% sodium chloride, about 0.01 % - about 0.2% hypromellose, about 0.1% - about 1% citric acid monohydrate and about 0.1% - about 5% diethylene glycol monoethyl ether. 330. The pharmaceutical composition in the form of a spray according to embodiment 325, containing approximately 2% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether. 331. The pharmaceutical composition in the form of a spray according to embodiment 325, containing approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% to about 2% citric acid monohydrate, and about 0.05% to about 15% diethylene glycol monoethyl ether. 332. The pharmaceutical composition in the form of a spray according to embodiment 325, containing approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1% sodium chloride, about 0. 01% to about 0.2% hypromellose, about 0.1% to about 1% citric acid monohydrate, and about 0.1% to about 5% diethylene glycol monoethyl ether. 333. The pharmaceutical composition in the form of a spray according to embodiment 325, containing approximately 5% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether. 334. The pharmaceutical composition in the form of a spray according to embodiment 325, containing approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% - about 2% citric acid monohydrate and about 0.05% - about 15% diethylene glycol monoethyl ether. 335. The pharmaceutical composition in the form of a spray according to embodiment 325, containing approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% about 1% sodium chloride, about 0.01 % - about 0.2% hypromellose, about 0.1% - about 1% citric acid monohydrate and about 0.1% - about 5% diethylene glycol monoethyl ether. 336. The pharmaceutical composition in the form of a spray according to embodiment 325, containing approximately 10% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether. 337. The pharmaceutical composition in the form of a spray according to embodiment 325, containing approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.0001% (w/w) about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 5% sodium chloride, about 0.001% - about 0.5% hypromellose, about 0.01% to about 2% citric acid monohydrate, and about 0.05% to about 15% diethylene glycol monoethyl ether. 338. The pharmaceutical composition in the form of a spray according to embodiment 325, containing approximately 20% wt./wt.

- 87 045992 epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% (w/w) - about 0.1% (w/w) sodium metabisulfite, about 0.1% - about 1% sodium chloride, about 0.01% to about 0.2% hypromellose, about 0.1% to about 1% citric acid monohydrate, and about 0.1% to about 5% diethylene glycol monoethyl ether. 339. The pharmaceutical composition in the form of a spray according to embodiment 325, containing approximately 20% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) sodium metabisulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate and about 1% monoethyl diethylene glycol ether. 340. The pharmaceutical spray formulation of any one of embodiments 286-339, further comprising chlorobutanol at a concentration of about 0.005% (w/v) to about 10% (w/v). 341. The pharmaceutical spray formulation of any one of embodiments 286-339, further comprising chlorobutanol at a concentration of about 0.01% (w/v) to about 10% (w/v). 342. The pharmaceutical spray formulation of any one of embodiments 286-339, further comprising chlorobutanol at a concentration of about 0.1% (w/v) to about 1% (w/v). 343. The pharmaceutical spray composition of any one of embodiments 286-339, further comprising chlorobutanol at a concentration of about 0.21% (w/v). 344. A spray containing drops, wherein the drops contain a pharmaceutical composition in the form of a spray according to any of embodiments 286-343. 345. A method of treating anaphylaxis, anaphylactic shock, severe allergic reaction and/or bronchoconstriction, comprising delivering an injection of a pharmaceutical solution from a pre-filled device into the nostril of a subject in need thereof, wherein: (i) the device is configured for nasal delivery; (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains a pharmaceutical composition in the form of a spray according to any of embodiments 286-343. 346. A method of treating depression or respiratory distress caused by anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a pre-filled device into the nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution in the form of a circular spray stream with an ovality factor of less than about 2 ,0 when measured at a distance of about 1 to about 10 cm from the prefilled device, wherein: (i) the device is configured for nasal delivery; (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains a pharmaceutical composition in the form of a spray according to any of embodiments 286-343. 347. A method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof, wherein: (i) the device is configured for nasal delivery; (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and the pharmaceutical solution contains a pharmaceutical composition in the form of a spray according to any of embodiments 286-343. 348. The method of any one of embodiments 345-347, wherein a therapeutic plasma concentration of epinephrine in the subject is achieved less than 20 minutes after administration to the subject. 349. The method of any one of embodiments 345-347, wherein the therapeutic plasma concentration of epinephrine in the subject is approximately 0.5 ng/mL epinephrine. 350. The method of any one of embodiments 345-347, wherein the subject has a maximum plasma concentration ( _Cmax ) of about 0.1 ng/mL to about 1 ng/mL of epinephrine. 351. The method of any one of embodiments 345-347, wherein the area under the plasma concentration-time curve for epinephrine in the subject is from about 0.1 ng-hr/mL to about 5 ng-hr/mL. 352. The method of any one of embodiments 345-347, wherein the plasma concentration-time curve for epinephrine in a subject has a tmax of less than about 10 minutes to about 120 minutes. 353. The method of any one of embodiments 345-352, wherein the device is a single-dose device. 354. The method of any one of embodiments 345-352, wherein the device is a two-dose device. 355. The method of any one of embodiments 345-354, wherein the device delivers two squirts of a pharmaceutical solution from a single reservoir. 356. The method of any one of embodiments 345-354, wherein the device comprises a first reservoir containing about 50 μL of about 250 μL of a pharmaceutical solution and a second reservoir containing about 50 μL of about 250 μL of a pharmaceutical solution. 357. The method of any one of embodiments 345-356, wherein less than about 20% of the composition leaves the nasal cavity via nasopharyngeal or external drainage. 358. The method of any one of embodiments 345-357, wherein a single spray into a subject's nostril provides a plasma concentration of at least 0.2 ng/mL within 2 minutes in the subject. 359. A stable pharmaceutical composition in the form of a spray containing: (i) about 1% - about 25% wt./wt. epinephrine or a pharmaceutically acceptable salt thereof in water; and (ii) one or more of the following: excipients, carrier vehicles, emulsifiers, stabilizers, preservatives, mucosal adhesion agents,

- 88 045992 antibacterial agents, buffers and/or other auxiliaries, wherein the composition is stable at a temperature of at least about 20°C and at a relative humidity of at least about 30%, and wherein the composition is stable for a period of at least about two months, wherein the stable pharmaceutical composition is a spray pharmaceutical composition according to one of embodiments 286-343. 360. A pharmaceutical composition in the form of a spray containing: (i) about 1% about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (ii) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the composition is adapted for administration to the nostril of a subject in the form of a nasal spray that provides a plasma concentration of at least 0.5 ng/ml within 1 minute after administration. 361. The pharmaceutical formulation in the form of a spray according to embodiment 360, wherein the pH of the formulation is from about 4.0 to about 6.5. 362. The pharmaceutical spray formulation of embodiment 360 or 361, wherein the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration of about 0.01% to about 0.1% (w/w). 363. The pharmaceutical spray formulation of any one of embodiments 360-362, wherein the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration of about 0.1% to about 1% (w/w). 364. The pharmaceutical spray formulation of any one of embodiments 360-363, wherein the isotonic agent comprises sodium chloride at a concentration of about 0.1% to about 1% (w/w). 365. The pharmaceutical spray formulation of any one of embodiments 360-364, wherein the viscosity modifier comprises hypromellose at a concentration of about 0.01% to about 0.2% (w/w). 366. The pharmaceutical spray formulation of any one of embodiments 360-365, wherein the buffer agent comprises citric acid or citric acid monohydrate at a concentration of about 0.1% to about 1% (w/w). 367. The pharmaceutical spray composition of any one of embodiments 360-366, comprising about 2% or about 5% (w/w) epinephrine or a pharmaceutically acceptable salt thereof. 368. The pharmaceutical spray composition of any one of embodiments 360-367, wherein the pharmaceutical spray composition comprises sodium metabisulfite, sodium chloride, hypromellose, citric acid monohydrate, diethylene glycol monoethyl ether, and chlorobutanol hemihydrate. 369. The pharmaceutical spray composition of any one of embodiments 360-367, comprising about 1% to about 10% (w/w) epinephrine or a pharmaceutically acceptable salt thereof, about 0.01% to about 0.1% ( w/w) sodium metabisulfite, about 0.1% - about 1% (w/w) sodium chloride, about 0.01% - about 0.2% (w/w) hypromellose, about 0 .1% about 1% (w/w) citric acid monohydrate, about 0.1% to about 5% (w/w) diethylene glycol monoethyl ether, and about 0.1% to about 1% (w/w) /wt.) chlorobutanol hemihydrate. 370. A stable pharmaceutical composition in the form of a spray containing: (a) about 1% to about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (b) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the composition is stable for a period of at least about one month at a temperature of at least about 20°C. 371. The pharmaceutical spray formulation of embodiment 370, wherein the formulation is stable for a period of at least one month at a temperature of at least about 40°C. 372. The pharmaceutical spray formulation of Embodiment 370 or 371, wherein the formulation contains no more than about 2% total impurities after storage for a period of at least about one month at a temperature of at least about 40° C. . 373. The pharmaceutical spray formulation of any one of embodiments 370-372, wherein the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration of about 0.01% to about 0.1% (w/w). 374. The pharmaceutical spray formulation of any one of embodiments 370-373, wherein the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration of about 0.1% to about 1% (w/w). 375. The pharmaceutical spray formulation of any one of embodiments 370-374, wherein the isotonic agent comprises sodium chloride at a concentration of about 0.1% to about 1% (w/w). 376. The pharmaceutical spray formulation of any one of embodiments 370-375, wherein the buffer agent comprises citric acid or citric acid monohydrate at a concentration of about 0.1% to about 1% (w/w). 377. A pharmaceutical composition in the form of a spray containing: (i) about 1% to about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (ii) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the absorption enhancer is diethylene glycol monoethyl ether. 378. The pharmaceutical spray formulation of Embodiment 377, wherein the formulation comprises diethylene glycol monoethyl ether at a concentration of about

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0.1% - approximately 5% (w/w). 379. The pharmaceutical spray formulation of embodiment 377 or 378, wherein the absorption enhancer comprises diethylene glycol monoethyl ether at a concentration of about 1% (w/w). 380. A method of treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering an injection of a pharmaceutical composition in the form of a spray from a nasal spray device into the nostril of a subject in need thereof, wherein the pharmaceutical composition in the form of a spray contains: (a) about 1% - about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (b) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the composition is adapted for administration to the nostril of a subject in the form of a nasal spray that provides a plasma concentration of at least 0.5 ng/ml within 1 minute after administration. 381. The method of embodiment 380, wherein the subject suffers a severe allergic reaction from exposure or suspected exposure to an allergen. 382. The method of embodiment 381, wherein the allergen is a food, drug, or insect bite or sting. 383. The method of any one of embodiments 380-382, wherein the subject exhibits one or more symptoms selected from the following: respiratory depression or distress, airway narrowing, wheezing, tingling in the arms, legs, mouth or scalp, shortness of breath, swelling or inflammation of the face, eyes, lips, tongue or throat, urticaria, central nervous system depression, cardiovascular depression, impaired level of consciousness, dilated pupils, hypoxemia, hypotension, unresponsiveness to stimuli, loss of consciousness, respiratory arrest, unstable or stopped pulse and vomiting. 384. The method of any one of embodiments 380-383, wherein the subject exhibits respiratory depression or distress, or cardiovascular depression. 385. The method of any one of embodiments 380-384, wherein the subject does not experience respiratory depression or distress for at least about 1 hour after delivery of the pharmaceutical composition as a spray. 386. The method of any one of embodiments 380-385, wherein the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration of about 0.01% to about 0.1% (w/w). 387. The method of any one of embodiments 380-386, wherein the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration of about 0.1% to about 1% (w/w). 388. The method of any one of embodiments 380-387, wherein the isotonic agent contains sodium chloride at a concentration of about 0.1% to about 1% (w/w). 389. The method of any one of embodiments 380-388, wherein the viscosity modifier contains hypromellose at a concentration of about 0.01% to about 0.2% (w/w). 390. The method of any one of embodiments 380-389, wherein the buffering agent contains citric acid or citric acid monohydrate at a concentration of about 0.1% to about 1% (w/w). 391. The method of any one of embodiments 380-390, comprising about 2% or about 5% (w/w) epinephrine or a pharmaceutically acceptable salt thereof. 392. The method according to any one of embodiments 380-391, wherein the pharmaceutical spray composition contains sodium metabisulfite, sodium chloride, hypromellose, citric acid monohydrate, diethylene glycol monoethyl ether and chlorobutanol hemihydrate. 393. A method of treating at least one of the following: anaphylaxis, anaphylactic shock, severe allergic reaction, or bronchoconstriction, comprising administering or delivering to a subject in need thereof a stable pharmaceutical formulation in the form of a spray, wherein the stable pharmaceutical formulation in the form of a spray contains: (a) about 1% - about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (b) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the composition is stable for a period of at least about one month at a temperature of at least about 20°C. 394. The method of embodiment 393, wherein the composition is stable for a period of at least one month at a temperature of at least about 40°C. 395. The method of embodiment 393 or 394, wherein the composition contains no more than 2% total impurities after storage for a period of at least about one month at a temperature of at least about 40°C. 396. A method of treating at least one of the following: anaphylaxis, anaphylactic shock, severe allergic reaction, or bronchoconstriction, comprising administering or delivering to a subject in need thereof a pharmaceutical composition in the form of a spray, wherein the pharmaceutical composition in the form of a spray contains: (c) about 1% - about 25% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol, or a combination thereof; and (d) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the therapeutic plasma concentration of epinephrine in the subject is achieved less than 15 minutes after administration to the subject. 397. The method according to embodiment 396, wherein the absorption enhancer is

- 90 045992 diethylene glycol monoethyl ether. 398. The method of embodiment 396 or 397, wherein the formulation comprises diethylene glycol monoethyl ether at a concentration of about 0.1% to about 5% (w/w). 399. The method of any one of embodiments 396-398, wherein the formulation comprises diethylene glycol monoethyl ether at a concentration of about 1% (w/w). 400. A two-dose nasal delivery device configured to deliver a pharmaceutical solution to the nostril of a subject, comprising: (a) a pharmaceutical solution in the form of a pharmaceutical spray composition containing about 1% to about 25% (w/w) epinephrine or its a pharmaceutically acceptable salt in water, ethanol, propylene glycol, or a combination thereof; (b) a reservoir containing about 125 μl to about 250 μl of pharmaceutical solution; and wherein the two-dose device is configured to administer the pharmaceutical solution into the nostril of the subject in two nasal sprays. 401. The device of embodiment 400, wherein the device is a pre-filled device that is operable with one hand. 402. The device of embodiment 400 or 401, wherein the device is configured to deliver approximately 100 μL of the pharmaceutical solution from the reservoir each time the device is activated. 403. The apparatus of any one of embodiments 400-402, wherein the pH of the pharmaceutical solution is between about 4.0 and about 6.5. 404. The apparatus of any one of embodiments 400-403, wherein the one or more injections take the form of a circular jet with an ovality ratio of less than about 2.0. 405. The device according to any one of embodiments 400404, wherein the pharmaceutical solution contains an antioxidant. 406. The apparatus of embodiment 405, wherein the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration of about 0.01% to about 0.1% (w/w). 407. The device according to any one of embodiments 400-406, wherein the pharmaceutical solution contains an antimicrobial preservative. 408. The apparatus of embodiment 407, wherein the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration of about 0.1% to about 1% (w/w). 409. The device according to any one of embodiments 400-408, wherein the pharmaceutical solution contains an isotonic agent. 410. The device of embodiment 409, wherein the isotonic agent contains sodium chloride at a concentration of about 0.1% to about 1% (w/w). 411. The device according to any one of embodiments 400-410, wherein the pharmaceutical solution contains a viscosity modifier. 412. The apparatus of embodiment 411, wherein the viscosity modifier comprises hypromellose at a concentration of about 0.01% to about 0.2% (w/w). 413. The apparatus of any one of embodiments 400-412, wherein the pharmaceutical solution contains a buffering agent. 414. The apparatus of embodiment 413, wherein the buffer agent comprises citric acid or citric acid monohydrate at a concentration of about 0.1% to about 1% (w/w). 415. The device of any one of embodiments 400-414, wherein the pharmaceutical solution contains about 2% or about 5% (w/w) epinephrine or a pharmaceutically acceptable salt thereof. 416. A pre-filled device configured to deliver a pharmaceutical solution to one or both nostrils of a subject, comprising a reservoir containing about 125 μl to about 250 μl of a pharmaceutical solution, wherein the pharmaceutical solution contains: (a) about 1% to about 25% (wt. ./wt.) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol or a combination thereof; and (b) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the prefilled device is configured to administer the pharmaceutical solution in one or more sprays into one or both nostrils of the subject. 417. The apparatus of embodiment 416, wherein the composition comprises diethylene glycol monoethyl ether at a concentration of about 0.1% to about 5% (w/w). 418. A two-dose device configured to deliver a pharmaceutical solution to one or both nostrils of a subject, comprising a reservoir containing about 125 μl to about 250 μl of a pharmaceutical solution, wherein the pharmaceutical solution contains: (a) about 1% to about 25% (wt. /wt.) epinephrine or a pharmaceutically acceptable salt thereof in water, ethanol, propylene glycol or a combination thereof; and (b) one or more of the following: an antioxidant, an antimicrobial preservative, an isotonic agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the pharmaceutical solution is stable for a period of at least about one month at a temperature of at least about 20°C. 419. The apparatus of embodiment 418, wherein the pharmaceutical solution is stable for a period of at least about three months at a temperature of at least about 20°C. 420. A method of administering a pharmaceutical solution comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution in the form of a circular spray stream with an ovality coefficient of less than about 1.4 when measured over a distance of about 1 - approximately 10 cm from the device, and: (i) the device is configured for nasal delivery; (ii) delivered volume, composition

- 91 045992 dispensing approx. 20 µl - approx. 250 µl spray; and (iii) the pharmaceutical solution contains from about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof. 421. The method of embodiment 420, wherein the spray stream has a particle size distribution of no more than about 2.2 when measured at a distance of about 1 to about 10 cm from the device. 422. The method of embodiment 420 or 421, wherein the spray stream has a D _max of less than about 28 mm when measured at a distance of about 1 to about 10 cm from the device. 423. The method of any one of embodiments 420-422, wherein the device is a two-dose device configured to deliver two injections of a pharmaceutical solution. 424. The method of any one of embodiments 420-423, wherein the device comprises a single reservoir containing about 125 μL to about 250 μL of a pharmaceutical solution. 425. The method of any one of embodiments 420-424, wherein the device comprises a piston that receives a container cap containing the following: (i) a bottle containing an opening; (ii) cannula; and (iii) rubber stopper; wherein the stopper is configured to plug the opening of the vial, and wherein the cannula is configured to pierce the stopper when the piston applies sufficient force to the cannula. 426. The method of any one of embodiments 420-426, wherein the device is a pre-filled device that is operable with one hand. 427. The method of any one of embodiments 420-427, wherein the delivery time of the pharmaceutical solution is less than about 25 seconds. 428. The method of any one of embodiments 420-427, wherein the subject suffers a severe allergic reaction from exposure or suspected exposure to an allergen. 429. The method of embodiment 428, wherein the allergen is a food, drug, or insect bite or sting. 430. The method of any one of embodiments 420-429, wherein the subject exhibits one or more symptoms selected from the following: respiratory depression or distress, airway constriction, wheezing, tingling in the arms, legs, mouth or scalp, shortness of breath, swelling or inflammation of the face, eyes, lips, tongue or throat, urticaria, central nervous system depression, cardiovascular depression, impaired level of consciousness, dilated pupils, hypoxemia, hypotension, unresponsiveness to stimuli, loss of consciousness, respiratory arrest, unstable or stopped pulse or vomiting. 431. The method of any one of embodiments 420-430, wherein the subject exhibits respiratory depression or distress, or cardiovascular depression. 432. The method of embodiment 431, wherein the subject does not experience respiratory depression or distress for at least about 1 hour following treatment providing a therapeutically effective amount of epinephrine or a pharmaceutically acceptable salt thereof. 433. A method of administering a pharmaceutical solution comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution in a spray stream with a particle size distribution having a spread of no more than about 2.2 when measured at a distance of about 1 to about 10 cm from the device, wherein: (i) the device is configured for nasal delivery; (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains about 0.5 mg of about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof. 434. The method of embodiment 433, wherein the particle size distribution has a spread of no more than about 2.0 when measured at a distance of about 1 to about 10 cm from the device. 435. The method of embodiment 433 or 434, wherein the device comprises a single reservoir containing about 125 μl to about 250 μl of a pharmaceutical solution. 436. The method of any one of embodiments 433-435, wherein the device is a two-dose device configured to deliver two injections of a pharmaceutical solution from a single reservoir. 437. A method of administering a pharmaceutical solution comprising delivering an injection of a pharmaceutical solution from a device into the nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution in a spray stream with a D _max of less than about 28 mm when measured at a distance of about 1 - about 10 cm from the device, wherein: (i) the device is configured for nasal delivery; (ii) a volume of approximately 20 μl to approximately 250 μl of spray is delivered; and (iii) the pharmaceutical solution contains from about 0.5 mg to about 100 mg of epinephrine or a pharmaceutically acceptable salt thereof. 438. The method of embodiment 437, wherein the device is a two-dose device configured to deliver two injections of a pharmaceutical solution. 439. The method of embodiment 437 or 438, wherein D _max is less than about 26 mm when measured at a distance of about 1 cm from the device.

Examples

Example 1: Composition of epinephrine spray and related studies.

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Table 1

Composition of epinephrine spray

Raw material Directory CAS# Quantity, g (-) -Epinephrine U.S.P 51-43-4 0.05 g Sodium metabisulfite European Pharmacopoeia, British Pharmacopoeia or 7681-57-4 0.001 g National formulary NS1* European Pharmacopoeia, British Pharmacopoeia or USP/National Formulary 7647-01-0 as needed until pH 4.7 +/0.2 NaCl European Pharmacopoeia. British Pharmacopoeia or US Pharmacopoeia 7647-14-5 0.008 g Water for injections U.S.P how much is needed up to 1000 g +/0.002 g

*Dilute HCl solutions can be prepared from concentrated or fuming HCl or purchased directly from the supplier.

Viscosity.

Viscosity will be modified using a viscosity modifier such as methylcellulose. Viscosity will be adjusted within a range of spray characteristics that will be analyzed at 10, 50 and 100 centipoise.

Preservative.

Composition in table. 1 will be modified using 0.05% benzalkonium chloride. The effect of surfactant on spray performance will be analyzed.

Vasodilator.

Composition in table. 1 will be modified by adding a vasodilator such as phentolamine at a concentration of 20 mg/ml. The effect on spray performance will be analyzed.

Permeability enhancer

Composition in table. 1 will be modified using a penetration enhancer such as 1% diethylene glycol monoethyl ether. The effect on spray performance will be analyzed.

Vitamin A.

Formulation development will be carried out to support the addition of lecithin, Tween or other suitable surfactant to solubilize vitamin A and epinephrine, including pH modification. Initial examinations may reveal a visual color change after 5-7 days.

The compositions will be formulated and filled in a low O ₂ environment. Supplying a layer of nitrogen and purging the solution.

NaCl will be added until 300 mOsmol is reached.

Compatibility with the main container components (glass and piston) will be investigated. In parallel, component options will be explored (for example: different rubbers for the piston, piston coating and/or glass surface treatment).

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Changes in pH during formulation preparation and the effect on stability will be investigated. Solutions with pH 4.0, 4.5 and 5.0 will be studied.

Stability studies will be carried out at 25, 30, 40 and 50°C.

Formulations will be tested for potency, impurities, pH and osmolality.

Research will be carried out to determine the characteristics of the spray.

Stability.

table 2

Stability at 25, 30 and 40°C

0 1 weeks 3 weeks 6 weeks 10 weeks 16 weeks 26 weeks Primary composition 50 mg/ml A IN A IN A IN A Secondary composition 36 mg/ml A IN A IN A IN A Low pH value A IN A IN A IN A high pH value A V A V A V A Configuration 2 A V A V A V A Configuration 3 A V A V A V A

A=Analysis, purity, pH, osmolality and spray characteristics.

B=Analysis and purity.

Table 3

Stability at 50°C

0 1 week 2 weeks 3 weeks 6 weeks 10 weeks Primary composition N/A IN IN IN IN AB Low pH value N/A IN IN IN IN A High pH value N/A IN V V V A Configuration 2 N/A V V V V A Configuration 3 N/A V V V V A

Example 2. Preparation of epinephrine composition 1.

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Table 4

Composition of epinephrine 1

Component Directory Composition (mg/ml) Quantity per injection (mg/injection) (-) - Epinephrine U.S.P 50.0 or 25.0 5.0 or 2.5 Sodium metabisulfite EP, British Pharmacopoeia or National Formulary 0.5 0.05 NS1* EP, British Pharmacopoeia or USP/National Formulary as needed until pH 4.7 +/- 0.3 NaCl** U.S.P 4.0 0.4 Purified water U.S.P how much is needed

* bring pH to 4.7 ± 0.3 ** reach 300 mOsm.

Epinephrine Formulation 1 was prepared by dissolving sodium metabisulfite in Water for Injection, USP, followed by the addition of sodium chloride, USP. Epinephrine, USP, was added as a dry powder and the dissolution of epinephrine was promoted by the addition of HCl until a pH of 4.7 was achieved.

Example 3. Preparation of epinephrine composition 2.

Table 5

Composition of epine Rina 2 Component Directory Composition (mg/ml) Quantity per injection (mg/injection) (-) - Epinephrine U.S.P 50.0 or 25.0 5.0 or 2.5 Sodium metabisulfite EP, British Pharmacopoeia or National Formulary 0.5 0.05 NS1* EP, British Pharmacopoeia or USP/National Formulary as needed until pH 4.7 +/- 0.3 NaCl** U.S.P 4.0 0.4 Monoethyl ether diethylene glycol National formulary 10.0 1.0 C,sodium itrate National formulary 7.0 0.7 Hypromellose U.S.P 1.0 0.1 Purified water U.S.P how much is needed

* bring pH to 4.7 ± 0.3 ** reach 300 mOsm.

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Water for injection (~20% of the final volume of the composition) was added to a clean, dry glass. A sufficient volume of 10 mg/ml sodium metabisulfite solution and 80 mg/ml sodium chloride solution was added and mixed well. Sufficient volumes of 10% solutions of each of trisodium citrate, hypromellose and diethylene glycol monoethyl ether were added separately and mixed between additions. Epinephrine was added as a slightly soluble powder. 1.5 M HCl was added slowly until almost all of the epinephrine had dissolved. 0.3 M HCl was added slowly until the pH reached 4.7 +/- 0.3. Water was added to bring the mixture to final volume.

Example 4. Preparation of epinephrine composition 3.

Table 6

Composition of epinephrine 3

Component Directory Composition (mg/ml) Quantity per injection (mg/injection) (-) - Epinephrine U.S.P 50.0 or 25.0 5.0 or 2.5 Sodium metabisulfite EP, British Pharmacopoeia or National Formulary 0.5 0.05 NS1* EP, British Pharmacopoeia or USP/National Formulary how much is needed until pH 4.7 +/o.s. AR NaCl** U.S.P 4.0 0.4 Monoethyl ether diethylene glycol National formulary 10.0 1.0 Chlorobutanol National formulary 2.0 0.2 Sodium citrate National formulary 7.0 0.7 Hypromellose U.S.P 1.0 0.1 Purified water U.S.P AR AR

* bring pH to 4.7 ± 0.3 ** reach 300 mOsm.

Water for injection (~20% of the final volume of the composition) was added to a clean, dry glass. A sufficient volume of 10 mg/ml sodium metabisulfite solution and 80 mg/ml sodium chloride solution was added and mixed well. Sufficient volumes of 10% solutions of each of trisodium citrate and hypromellose were added separately and mixed between additions. Separately, a solution of 10% diethylene glycol monoethyl ether and 2% chlorobutanol in water was prepared. The diethylene glycol monoethyl ether/chlorobutanol solution was then added to the main mixing vessel and then mixed well. Epinephrine was added to the main mixing vessel as a poorly soluble powder. 1.5 M HCl was added slowly until almost all of the epinephrine had dissolved. 0.3M HCl was added slowly until the pH reached 4.7 +/- 0.3. Water was added to bring the mixture to final volume.

Example 5. Preparation of epinephrine composition 4.

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Table 7

Composition of epineph )rina 4 Component Directory Composition (mg/ml) Quantity per injection (mg/injection) (-) - Epinephrine U.S.P 50.0 or 20.0 5.0 or 2.0 Sodium metabisulfite EP, British Pharmacopoeia or National Formulary 0.5 0.05 NS1* EP, British Pharmacopoeia or USP/National Formulary as needed until pH 4.7 +/- 0.3 AR NaCl** U.S.P 4.0 0.4 Monoethyl ether diethylene glycol National formulary 10.0 1.0 Chlorobutanol hemihydrate National formulary 2.1 0.21 Lemon monohydrate acids National formulary 4.2 0.42 Hypromellose U.S.P 1.0 0.1 Purified water U.S.P AR AR

* bring pH to 4.7 ± 0.3 ** reach 300 mOsm.

Water for injection (~20% of the final volume of the composition) was added to a clean, dry glass. A sufficient volume of 10 mg/ml sodium metabisulfite solution and 80 mg/ml sodium chloride solution was added and mixed well. Sufficient volumes of 10% solutions of each of citrate acid monohydrate and hypromellose were added separately and mixed between additions. Separately, a solution of 10% diethylene glycol monoethyl ether and 2.1% chlorobutanol hemihydrate in water was prepared. Next, the diethylene glycol monoethyl ether/chlorobutanol hemihydrate solution was added to the main mixing vessel and then mixed well. Epinephrine was added to the main mixing vessel as a poorly soluble powder. 1.5 M HCl was added slowly until almost all of the epinephrine had dissolved. 0.3 M HCl was added slowly until the pH reached 4.7 +/- 0.3. Water was added to bring the mixture to final volume.

Example 6: In vivo study.

The study used conscious animals that did not receive any sedative or anesthetic medication. Before dosing, three electrode leads were placed on the animal to continuously monitor heart rate and a standard electrocardiogram using telemetry, in which the signal from the electrode leads was transmitted to a receiving device using Bluetooth. Cardiovascular parameters were continuously recorded throughout the experiment. In addition, three blood samples were collected from veins in the forepaws between 60 and 1 min predose to measure baseline plasma epinephrine levels. A specific dose of epinephrine (epinephrine formulation 2) was injected into the right nostril of each of the six animals. The doses of epinephrine used in these studies ranged from 2 to 20 milligrams (mg). The delivered volume was 100 microliters (μL), delivered into a 200 μL cannula attached to a calibrated 100 μL pipette. There _{was no dead space in the cannula and the entire amount was injected approximately 3/4} ^inch deep into the nostril. Following intranasal administration of epinephrine, blood samples were obtained at 1, 5, 10, 15, 20, 30, 60, and 90 min postdose. Blood samples were immediately stored on ice and the tubes were centrifuged to separate the plasma from heavier elements such as red blood cells. Sodium metabisulfite was added to plasma samples to prevent epinephrine oxidation. Samples were stored at -70 degrees until they were analyzed by HPLC.

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The average of the three epinephrine samples before drug administration was considered the baseline level. It was subtracted from epinephrine levels obtained at specific time points ranging from 1 to 90 minutes after dosing. The resulting epinephrine concentrations, expressed in nanograms/milliliter, were considered to represent intranasal absorption over time.

In a separate experiment, six animals were given 0.3 mg of epinephrine intramuscularly in the upper quadrant of the left paw. Plasma samples were obtained at the same time points as during intranasal experiments. The resulting time course of action of epinephrine in plasma was compared with curves obtained with intranasal administration.

The results of two experiments comparing the plasma concentrations observed following either 5 mg or 10 mg administered intranasally versus the standard dose of 0.3 mg in an adult EpiPen administered intramuscularly are shown in FIG. 1 and 2. In all cases the number of animals was six per group. As shown in FIG. 1, intranasal administration of 5 mg epinephrine produced significantly higher plasma levels than those achieved with the EpiPen at the earliest time points of 1 and 5 min after drug delivery. In addition, plasma epinephrine concentrations were maintained at essentially the same level during the 30, 60, and 90 min time periods. At these later time points, epinephrine levels as a result of EpiPen administration had already decreased significantly from the peak observed at 15 min. In fig. Figure 2 shows a comparison of plasma epinephrine levels after intranasal administration of 10 mg compared with EpiPen. As shown in FIG. 2, plasma epinephrine levels are much higher during the initial periods of 1 and 5 minutes after intranasal administration. Indeed, the plasma levels achieved by the intranasal route are higher than those observed with the EpiPen for the full 90 min after administration.

Epinephrine is considered an essential therapeutic treatment for acute anaphylaxis following unintentional exposure to a triggering agent such as nuts. This is a life-threatening situation in which rapid absorption of epinephrine after administration is essential. As can be seen in FIG. 1 and 2, intranasal delivery of epinephrine produces higher plasma levels during the first few critical minutes after exposure to the triggering agent than EpiPen. Moreover, plasma epinephrine levels remained elevated at higher levels throughout the 90-minute action-time curve at the higher dose of 10 mg intranasal epinephrine compared with EpiPen. These data suggest that the intranasal route will provide both faster and longer-lasting treatment for anaphylaxis. Finally, plasma levels after 10 mg are higher than levels after 5 mg, suggesting a dose-dependent effect.

Example 7 Absorption Study of Intranasal Epinephrine Compared to Conventional Intramuscular Epinephrine Administration.

The purpose of this study is to obtain pharmacokinetic data for epinephrine administered by the intranasal (IN) route and compare them with the intramuscular (IM) route in healthy adult volunteers.

Patients are reluctant to use EpiPen® in emergencies, possibly due to poor training, hesitancy, and fear of the needle. Another route of epinephrine administration (EPI) may be more effective, such as the intranasal route.

Main criteria for effectiveness: a set of pharmacokinetic parameters of epinephrine [time frame: before dose, 5, 10, 15, 20, 30, 45, 60, 90, 120, 180 minutes after dose] C _max , area under the curve, T _max of epinephrine are compared between 0.3 mg intramuscular and 5 mg intranasal.

Secondary efficacy endpoints: number of participants with adverse events as an indicator of safety and tolerability [time frame: 1 year].

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Study design

Distribution: non-randomized (12 participants)

Intervention model: single group assignment

Camouflage: no (open)

Primary purpose: treatment

Condition Anaphylaxis Medicine: Epinephrine 1. Intranasal epinephrine 5 mg/spray Intervention 2. Intramuscular epinephrine 0.3 mg 3. Intranasal saline spray Other name: adrenaline Experimental: epinephrine IN, epinephrine IM, saline IN Groups 1. Intranasal saline solution research 2. Intramuscular epinephrine 3. Intranasal epinephrine Intervention: Drug: Epinephrine

Example 8. Evaluation of efficacy and safety in patients with anaphylactic reaction.

This study has three main objectives:

(1) compare the bioavailability of aqueous formulations with the bioavailability of hydroalcoholic formulations of branded epinephrine nasal spray at two doses (3 mg and 6 mg);

(2) compare the bioavailability of both formulations (aqueous and hydroalcoholic) with the bioavailability of a standard intramuscular injection, specifically EpiPen® (0.30 mg); and (3) evaluate the effect of intranasal allergen administration on the bioavailability of both formulations of intranasal epinephrine spray at both doses.

Second, the study will evaluate the safety and tolerability of both formulations at both doses.

The study will include a total of 60 adult patients aged 18-45 years in five cohorts of 12 patients at a single clinical site. To be included in the study, all patients must be healthy and have a history of seasonal allergies; Once enrolled in the trial, they will be exposed to the intranasal allergen at specific time points as part of the protocol. Subjects who are taking current medications that affect plasma epinephrine levels (eg, pseudoephedrine) will be excluded from the study.

Patients were required to have no exposure to epinephrine before enrollment in the study. Patients should not receive treatment for allergy/anaphylaxis within 2 weeks of study entry. Treatment includes intravenous (I.V.) or intramuscular (I.M.) epinephrine injections and/or immunotherapy.

All subjects are assessed for safety, and all blood samples for pharmacokinetic analysis are collected as scheduled. All studies were performed with institutional ethics committee approval and patient consent.

Example 9: Evaluation of the effect of pre-existing nasal congestion on the systemic absorption of intranasal epinephrine in Beagle dogs.

This study assessed the absorption of epinephrine during congestion and noncongestion and the effect of epinephrine on congestion following exposure to aerosolized histamine.

This study consisted of two dosing groups (group 1 histamine and group 2 saline) with three male and three female beagle dogs in each group (n 6/group). This study was conducted over four days (study days 0-3), with three dogs studied per day. On study day (SD) 0 and SD 2, three dogs from group 1 were anesthetized and administered a single dose of 5% histamine (dissolved in saline) via inhaler over 5 min. Epinephrine (4 mg/100 ml) was injected into the same nostril 15 min after histamine administration. At SD 1 and SD 3, three dogs from group 2 were anesthetized and given saline via an inhaler over 5 min. Epinephrine (4 mg/100 ml) was injected into the same nostril 15 min after saline administration. The complete study design is presented in Table. 8.

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Table 8

Study design

Group Histamine Physiol. solution (ml) Administration of epinephrine Floor Males Females 1 5% 0 4 mg IN into a blocked nostril 3 3 2 0% 0.4-0.7 ^a 4 mg IN into saline-irrigated nostril 3 3

a See table. 11 for individual values.

Composition of epinephrine.

The vehicle for the study drug (epinephrine) consisted of sterile water for injection containing 5 mg/10 ml sodium metabisulfite, 40 mg/10 ml sodium chloride, 0.7% trisodium citrate, 0.1% hypromellose, 0.05% chlorobutanol and 1 % diethylene glycol monoethyl ether with a final pH of 5.0 ± 0.5. For information on the final concentration of each chemical in the formulated test product, see Table 1. 9.

Table 9

Composition of the study drug

Compound Final concentration Final pH value Epinephrine 4 mg/100 µl 5.18 Sodium chloride 0.4 mg/100 µl Sodium metabisulfite 0.05 mg/100 µl Trisodium citrate 0.7% Chlorobutanol 0.2% Hypromellose 0.1% Monoethyl ether diethylene glycol 1%

Intranasal aerosol delivery and pressure measurement system.

The test system was designed and constructed to deliver intranasal histamine and saline aerosols and to measure nasal congestion limitation in real time. The system and methods used are similar to those performed by Tiniakov et al., 2003. The system delivered aerosolized histamine in concentrations sufficient to induce congestion in a canine model through a conventional nebulizer to deliver the drug to the patient. A diagram of the congestion test system is shown in Fig. 3.

Exposure to histamine through the nose.

Before each test, the initial ambient pressure of the test system was recorded at a flow condition of 3 L/min. The histamine generation inhaler was filled with approximately 5 ml of 5% histamine solution or 0.9% saline. The inhaler was weighed before and after each exposure to determine the histamine/saline formed (see Table 11). The dogs were anesthetized and a cannula was lubricated with saline and inserted into the left nostril. The air flow was slowly increased to provide fresh air into the dog's nostril at a rate of 3 L/min, and pressure measurements were taken every five minutes while the cannula was in place (see Table 10). Approximately 10 min after insertion of the cannula, 5% histamine (5 mg/ml) or 0.9% saline was aerosolized over 5 min.

The nasal cannula was removed 5 min after cessation of histamine/saline administration (T=20 min) to facilitate intranasal administration of epinephrine. Approximately 10 min after removal of the nasal cannula, epinephrine (4 mg/100 μl) was administered intranasally (T = 30 min). The nasal cannula was reinserted into the nose 60 minutes after epinephrine administration (T=90 minutes). The cannula remained in the nose for 40 min, during which time the nasal constriction pressure was monitored. Blood was drawn several times during each test to analyze plasma epinephrine levels in the groups of dogs.

- 100 045992 exposed to histamine and saline. In table 10 shows the time course of the test plan in minutes with measurements/samples taken at each time point.

Table 10

Aerosol Exposure Test Plan

Plan for conducting an epinephrine study in minutes and tasks T-5 ^1st blood draw T = 0 Insert the nasal cannula and measure the initial ΔΡ values T = 5 ^2nd blood draw and measure ΔΡ nasal restriction T= 10 Start administration of histamine aerosol or saline and measure ΔΡ nasal restrictions T= 15 Stop administration of histamine aerosol or saline and measure ΔΡ nasal restrictions T = 20 Measure ΔΡ nasal restriction and nasal removal cannulas T = 25 ^3rd blood draw T = 30 Nasal administration of epinephrine T = 31, 35, 40, 45, 50, 55, 60, 90 Blood draws T = 91, 100, 105, 110, 115 Re-insert the nasal cannula and measure nasal ΔΡ T= 120 Collect blood and measure ΔΡ nasal cannula T= 122, 124, 126, 128, 130 Measure ΔΡ of the nasal cannula

Bioanalytical analysis.

Heart rate data were collected and recorded every 5 min throughout the experiment. Plasma samples were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) using a d8-PFP column. LC-MS/MS analysis was performed in positive electrospray ionization (ESI+) mode using multiple reaction monitoring (MRM) ionization.

Pharmacokinetic analysis.

Plasma epinephrine concentrations were adjusted to baseline plasma epinephrine concentrations by using the average concentrations of the three predose samples and subtracting this value from the postdose values for each dog. If subtraction of the original value resulted in negative values, these samples were assigned a value of zero. In addition, epinephrine concentrations were considered outliers and were excluded from analysis if they were greater than twice the standard deviation of the mean of baseline-subtracted post-dose epinephrine plasma concentrations for each animal during blood sampling (i.e., 1- 90 minutes after dosing).

Histamine-induced nasal congestion.

Histamine administration caused congestion in all animals to varying degrees. Data were plotted to show the effect of histamine- and saline-induced nasal congestion effects following aerosol administration, as well as the effect of epinephrine administration on reducing nasal congestion. A graph including the results of the pilot study with the baseline results of the histamine-induced congestion assay (far left bar at each time point), results of the histamine infusion test with epinephrine (center bar), and results of the saline infusion test with epinephrine (far right bar) is shown in fig. 4.

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Table 11

Histamine-induced congestion

Test number Nostril size ¹¹ (cm) Dog ID/gender Cannula pressure (in NGO) Exposure to aerosol Net inhaler use (g) Before exposure ⁰ After exposure' ¹ 1 (pilots.) ¹¹ 7.5 SRK/M 0.530 0.714 G istamine N.A. 2 (pilot) ³ 6.5 CGV/F 0.730 1.626 G istamine 0.63 3 (pilot) ³ 8 CXV/M 0.336 0.414 G istamine 0.56 1 8 CVL/M 0.692 1.232 G istamine 0.43 2 8 CWZ/M 0.399 0.653 G istamine 0.43 3 9 CWT/M 0.406 0.752 G istamine 0.43 4 7 CWP/F 0.460 0.433 Saline solution 0.63 5 7 CFI/F 0.522 0.535 Saline solution 0.44 6 7 CSW/F 0.580 0.701 Saline solution 0.48 7 8 BCHG/F 0.420 0.531 G istamine 0.44 8 7 CBC/F 0.735 3,411 G istamine 0.49 9 7.5 CIH/F 0.606 2,372 G istamine 0.46 10 8 CXU/M 0.530 0.688 Saline solution 0.47 eleven 7.5 CUU/M 0.543 0.636 Saline solution 0.52 12 7.5 CYA/M 0.657 0.636 Saline solution 0.57

a - intranasal epinephrine was not administered, b - nostril measurement as the average of the vertical and horizontal diameters of the nostril, c - nasal pressure before exposure, measured 5 minutes after insertion of the cannula into the left nostril, d - nasal pressure measured 5 minutes after the end of administration aerosol.

The mean nasal constriction pressure levels in groups 1 and 2 and in the pilot study are shown in FIG. 4. Restriction levels are shown at key time points: baseline, after histamine/saline aerosol administration, and after epinephrine administration. Data indicate a progressive increase in nasal congestion and flow restriction pressure 5 and 10 min after histamine exposure (group 1). In contrast, no increase in flow restriction pressure was observed following administration of saline aerosol at the same time points. Epinephrine was administered by micropipette into the left nostril 15 minutes after the administration of histamine aerosol or saline was stopped. Data show that epinephrine administration had a significant effect on reducing histamine-induced nasal congestion at the 60-, 80-, and 100-minute time points while reducing nasal constriction pressure to baseline levels. These data indicate that epinephrine has a significant anticongestion effect. Data from a pilot study show that without epinephrine administration, histamine-induced congestion remains elevated at significant levels up to the 60, 80, and 100 minute time points.

Telemetry.

Group 1 (5% histamine + 4 mg/100 μl epinephrine).

Study drug-related increases in heart rate were observed following intranasal (IN) administration of epinephrine and generally remained above baseline levels following epinephrine administration. Baseline heart rate (red line, Figure 5) was set at 104 beats per minute based on the average of predose measurements. Summary information on individual and average heart rate values in animals of group 1 is presented in table. 12.

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Table 12

Individual and average heart rate in dogs in the 1-5% histamine + 4 mg/100 µl epinephrine group

Individual and average heart rate (bpm) in the histamine group (group 1) Event/time (min) CVL CWZ C.W.T. BCHG svs CIH Average Average STDEV BD/-5 114 105 124 80 118 85 104 18.1 Insert cannula/ 0 112 111 FROM 85 120 83 104 15.8 AP,BD/5 112 FROM 115 85 122 87 106 15.6 ΔΡ, start administering saline/10 112 122 108 84 129 88 107 18.0 ΔΡ, finish administration of saline solution/15 N.A. 143 126 84 143 99 119 26.6 ΔΡ, remove cannula/20 119 135 124 83 143 95 117 23.2 BD/25 105 134 123 84 148 104 116 23.2 Epinephrine 30 115 126 112 84 145 121 117 20.0 BD/1 115 126 116 75 134 123 115 20.7 BD/5 146 139 120 75 195 119 132 39.4 BD/10 153 143 114 79 201 96 131 44.1 BD/15 137 146 118 81 197 94 129 41.5 BD/20 127 141 117 86 203 99 129 41.3 BD/25 117 132 119 90 207 93 126 42.7 BD/30 116 139 119 89 205 127 133 39.2 BD/60 116 134 117 90 168 154 130 28.3 Re-enter cannula 61 116 133 114 93 155 147 126 23.1 ΔΡ, 70 123 140 117 107 154 147 131 18.4 ΔΡ, 75 124 143 FROM 111 142 151 131 17.0 ΔΡ, 80 121 142 116 107 144 150 130 17.6 DP, 85 117 146 116 102 144 149 129 19.8 ΔΡ, BD, 90 120 143 114 103 137 146 127 17.4 ΔΡ, 92 121 146 117 100 129 146 127 17.8 ΔΡ, 94 120 147 117 99 141 139 127 18.3 ΔΡ, 96 123 147 115 99 133 145 127 18.5 ΔΡ, 98 132 147 117 99 137 142 129 17.9 ΔΡ, 100 153 148 112 99 136 140 131 21.3

Group 2 (saline + 4 mg/100 μl epinephrine).

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An increase in heart rate associated with study drug was noted in group 2 (Fig. 6), but the pattern was significantly different from group 1. Baseline heart rate (red line, Fig. 6) was set at 97 beats per minute based on the mean value of measurements before dosing. While initial changes in heart rate (related to stabilization of the level of anesthesia) were present in group 2, no obvious increase in heart rate was observed until 30-60 minutes after epinephrine administration. This reflects an increase in plasma epinephrine levels in group 1, but with a delayed effect in group 2 at the 30-60 minute mark (this is discussed further below). Once heart rate increased in group 2 animals, it usually remained elevated until the end of the experiment. Summary data on individual and average heart rate in animals of group 2 are presented in table. 13.

Table 13 Individual and average heart rate in dogs in group 2 - saline + 4 mg/100 μl epinephrine

Individual and average heart rate (bpm) in the saline group (group 2) Event/time (min) CWP CFI C.S.W. CXU CVU C.Y.A. Average Average STDEV

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BD/-5 94 80 102 106 95 107 97 YD Insert cannula/ 0 95 89 101 120 95 108 101 AND 2 ΔΡ, BD/5 96 92 99 123 88 101 100 12.3 ΔΡ, start administering saline/10 95 98 109 126 80 100 101 15.3 ΔΡ, finish administration of saline solution/15 95 99 108 125 83 99 102 14.1 ΔΡ, remove cannula/20 86 102 109 128 85 95 101 16.2 BD/25 93 103 116 121 85 94 102 14.1 Epinephrine 30 94 105 118 114 88 95 102 12.0 BD/1 100 108 109 96 91 96 100 7.2 BD/5 97 107 FROM 93 93 90 99 9.1 BD/10 94 107 108 94 96 97 99 6.4 BD/15 91 109 107 99 100 96 100 6.7 BD/20 91 111 106 103 102 91 101 8.1 BD/25 90 FROM 107 104 103 93 102 8.7 BD/30 99 115 107 109 104 98 105 6.4 BD/60 92 137 127 137 103 104 117 19.4 Re-enter cannula 61 91 133 127 131 114 108 117 16.2 ΔΡ, 70 88 136 127 138 134 115 123 19.1 ΔΡ, 75 91 132 120 140 136 115 122 18.1 ΔΡ, 80 88 132 115 138 138 114 121 19.4 ΔΡ, 85 96 133 108 138 136 116 121 17.2 ΔΡ. B.D. 90 95 132 102 138 137 116 120 18.6 ΔΡ, 92 96 132 99 136 134 FROM 118 18.1 ΔΡ, 94 96 129 105 136 133 116 119 16.2 ΔΡ, 96 96 133 109 139 136 118 122 17.1 ΔΡ, 98 118 139 FROM 135 137 125 128 10.8 ΔΡ, 100 135 158 118 145 142 135 139 13.3

Pharmacokinetic results.

Plasma samples were collected at the indicated time points and analyzed. Plasma epinephrine concentration profiles over time are plotted for individual animals in the group (Fig. 8, Fig. 9). AUC, Tmax, and Cmax were calculated using postdose baseline-subtracted epinephrine concentrations for each individual animal and the trapezoidal rule (Table 1415).

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Table 14

AUC and Cmax of epinephrine in dogs from group 1

Parameter ^a Group 1 Average SD BCHG svs US CVL C.W.T. CWZ Dose, mg 4 4 4 4 4 4 — — Ttah, MIN 1 25 5 1 5 1 6 9 Stach^ MG/ML 1.4 3.4 4.0 7.2 2.2 2.9 3.5 2.1 AUC1-90 min, ng/ml'min 42 194 182 109 106 68 117 61

^a Abbreviations: Cmax, maximum plasma concentration before subtraction of baseline value; Tmax, time to reach Cmax; AUC _{1-90 min} , the area under the plasma concentration-time curve from 1 min to 90 min after subtracting the baseline value.

Table 15

AUC and Cmax of epinephrine in dogs from group 2

Parameter ^a Group 2 Average SD CFI C.S.W. these CWP schema C.Y.A. Dose, mg 4 4 4 4 4 4 — — Ttah, MIN 90 60 90 90 1 90 70 36 Stach^ MG/ML 0.8 1.1 1.4 0.9 4.8 1.4 1.7 1.5 AUC1-90 min, ng/ml'min 33 83 71 478 67 56 59 18

^a Abbreviations: Cmax, maximum plasma concentration before subtraction of baseline value; Tmax, time to reach Cmax; AUC _{1-90 min} , area under the plasma concentration-time curve from 1 min to 90 min after subtracting the baseline value

In table 14 and 15, plasma concentration-time data were first analyzed for an individual animal, and then PK measurements (AUC, Cmax, Tmax) for individual animals were averaged within a group.

In addition, group mean epinephrine concentration profiles were plotted over time for the two study groups (Fig. 10). AUC, T _max and C _max calculated using the trapezoidal rule are shown in table. 16.

Table 16

AUC, Tmax and Cmax of epinephrine after administration in dogs (mean plasma concentrations for all dogs in the same group)

Parameter ^ ^b , units Study - congestion compared to saline Group 1 - congestion (4 mg x 1 nostril) Group 2 - saline (4 mg x 1 nostril) Dose, mg 4 4 Tmax, min 1 90 Stach, Ng/mL 2.9 1.2 AUCl-seq., ng/ml'min 117 60 tl/2 NC NC

^a Abbreviations: Cmax, maximum plasma concentration before subtraction of baseline value; Tmax, time to reach Cmax; AUC _{1-90 min} , area under the plasma concentration-time curve from 1 min to 90 min after subtracting the baseline value; NC, not calculated due to pre-dose concentration being higher than post-dose concentration, elimination phase could not be established.

^b Values were obtained from NCA using WinNonlin (build 8.1.0.3530).

In table 16 plasma concentration-time data were first averaged for all animals in the same group, and then PK measurements were obtained from the averaged data. Compared to the values indicated in table. 14 and 15, where individual _Tmax varied from one

- 106 045992 animal to another, this resulted in different Tmax and Cmax values between the two types of analyzes (Table 14/15 compared to Table 16). On the other hand, the AUC remained essentially the same for both of these assays.

In the congestion model (Table 16), Tmax was 1 min versus 90 min for congestion dogs versus saline-treated dogs, respectively. Cmax was 2.9 ng/ml versus 1.2 ng/ml for dogs with congestion versus saline-treated dogs, respectively. Finally, the AUC was 117 ng/ml-min versus 60 ng/ml-min for dogs with congestion versus saline-treated dogs, respectively. For all of these above IN values, a dose of 4 mg/100 μl of epinephrine was injected into the same nostril into which histamine (congestion dogs) or saline (control) had previously been injected. It is clear that epinephrine, when administered intranasally to congested dogs, was absorbed more quickly, resulting in higher plasma levels compared to non-congested dogs that received saline only. This was an unexpected and surprising result, as it was thought that in dogs with congestion, the nasal passages become narrower, reducing the efficiency of absorption. Upon further investigation, it was noted that Bleske et al. demonstrated in dogs that plasma epinephrine levels after intranasal administration were increased by concomitant intranasal administration of the alpha-blocker phentolamine. The explanation was that phentolamine prevented epinephrine-induced vasoconstriction, thereby increasing mucosal absorption of epinephrine. Allergy-related nasal congestion occurs due to the release of histamine from mast cells, which causes deep vasodilation in the nasal tissue. Therefore, it is likely that histamine-induced vasodilation compensates for the vasoconstrictor properties of intranasal epinephrine, resulting in increased absorption. Finally, there was a difference in heart rate levels in congested dogs administered epinephrine compared with epinephrine in saline-treated dogs, with heart rates clearly elevated due to increased plasma epinephrine levels in congested dogs. compared to dogs injected with saline.

To determine whether nasal congestion affected the systemic absorption of IN administered epinephrine, a Student's t test was first used to compare AUC, Tmax, and Cmax between the two study groups (Figure 11). The AUC and _Cmax of group 1 and group 2 were not significantly different, while the _Tmax of animals in group 1 was significantly lower than that of animals in group 2.

In addition, bioequivalence was assessed using Ln-transformed AUC, Cmax and Tmax of individual animals (Table 17). Bioequivalence is defined as when the 90% confidence interval [CI] of the human geometric relationship between the test (group 1 - congestion) and the reference (group 2 - saline) is between 80-125%. The results indicate that epinephrine administered intranasally (IN) does not demonstrate bioequivalence between group 1 and group 2 animals, as ratios deviate from 100% and CI values (90%) fall well outside the 80-125% range. In addition, bioequivalence analysis shows that the study is underpowered (statistical power of the study <80%), likely due to large interindividual variability and the small number of animals in each group.

Table 17

Analysis of the bioequivalence of epinephrine after a single IN dose in dogs administered saline (reference) and dogs with congestion (test)

Parameter^ ^b , units NCA RK Attitude geometric mean (% of standard) 90% CI Study power at 20% (80/20 rule) ^b Dose, mg per animal 4 Ttah, MIN 7.4 1.4-3.9 0.107 Stakh^ NG/ML 217 115-408 0.151 AUCl-seq., ng/ml'min 180 109-296 0.182

a Abbreviations: Cmax, maximum plasma concentration before subtraction of baseline value; Tmax, time to reach Cmax; AUC _0- /, area under the plasma concentration-time curve from 0 min to infinity; CI, confidence interval.

^b Capable of detecting a difference in rms equal to 20% of the reference rms and the desired result being that the power was greater than 0.8 or 80%.

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Blood samples were collected 35 minutes before and up to 90 minutes after drug administration to determine plasma epinephrine concentrations (see Table 18). The results show that a surge in plasma epinephrine concentrations is often achieved within 1 or 5 minutes after intranasal administration.

Table18

Plasma epinephrine concentration. ID Quantity Collection time Certain Floor dose (mg) (min) matrix animal conc. (ng/ml)

CVL m 4 for 35 0.148 CVL m 4 for 25 0.192 CVL m 4 for 5 0.347 CVL m 4 1 7,469 CVL m 4 5 5,314 CVL m 4 10 1,595 CVL m 4 15 1,192 CVL m 4 20 0.883 CVL m 4 25 0.786 CVL m 4 thirty 1.139 CVL m 4 60 1.076 CVL m 4 90 0.96 CWZ m 4 for 35 ND CWZ m 4 for 25 0.139 CWZ m 4 for 5 0.161 CWZ m 4 1 3,002 CWZ m 4 5 1.137 CWZ m 4 10 0.843 CWZ m 4 15 0.773 CWZ m 4 20 1,092 CWZ m 4 25 1.213 CWZ m 4 thirty 0.852 CWZ m 4 60 0.74 CWZ m 4 90 0.83 C.W.T. m 4 for 35 ND C.W.T. m 4 for 25 0.125 C.W.T. m 4 for 5 0.493 C.W.T. m 4 1 1.153 C.W.T. m 4 5 2.465 C.W.T. m 4 10 0.976 C.W.T. m 4 15 1,091 C.W.T. m 4 20 1.211 C.W.T. m 4 25 1.378 C.W.T. m 4 thirty 1,387 C.W.T. m 4 60 1.605

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C.W.T. M 4 90 1.663 BCHG F 4 for 35 0.147 BCHG F 4 for 25 0.147 BCHG F 4 for 5 0.144 BCHG F 4 1 1,507 BCHG F 4 5 0.736 BCHG F 4 10 0.405 BCHG F 4 15 0.697 BCHG F 4 20 0.718 BCHG F 4 25 0.503 BCHG F 4 thirty 0.445 BCHG F 4 60 0.527 BCHG F 4 90 0.846 CBC F 4 for 35 ND CBC F 4 for 25 ND CBC F 4 for 5 ND CBC F 4 1 2,171 CBC F 4 5 1.459 CBC F 4 10 1.81 CBC F 4 15 1.833 CBC F 4 20 1,731 CBC F 4 25 3.385 CBC F 4 thirty 1.926 CBC F 4 60 1.839 CBC F 4 90 3.313 CIH F 4 for 35 ND CIH F 4 for 25 ND CIH F 4 for 5 ND CIH F 4 1 2,801 CIH F 4 5 3,969 CIH F 4 10 1.014 CIH F 4 15 1,099 CIH F 4 20 1,144

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CIH F 4 25 1.04 CIH F 4 thirty 1,694 CIH F 4 60 2,356 CIH F 4 90 2,439 CWP F 4 for 35 ND CWP F 4 for 25 ND CWP F 4 for 5 0.125 CWP F 4 1 0.575 CWP F 4 5 0.512 CWP F 4 10 0.385 CWP F 4 15 0.686 CWP F 4 20 0.721 CWP F 4 25 0.463 CWP F 4 thirty 0.415 CWP F 4 60 0.682 CWP F 4 90 1.067 CFI F 4 for 35 0.263 CFI F 4 for 25 0.418 CFI F 4 for 5 0.327 CFI F 4 1 0.407 CFI F 4 5 0.545 CFI F 4 10 0.427 CFI F 4 15 0.44 CFI F 4 20 0.453 CFI F 4 25 0.5 CFI F 4 thirty 0.799 CFI F 4 60 0.642 CFI F 4 90 1.141 C.S.W. F 4 for 35 0.147 C.S.W. F 4 for 25 0.127 C.S.W. F 4 for 5 0.166 C.S.W. F 4 1 0.577 C.S.W. F 4 5 0.82

- 110 045992

csw F 4 10 0.927 csw F 4 15 0.761 csw F 4 20 0.922 csw F 4 25 0.867 csw F 4 thirty 1.133 csw F 4 60 1,202 csw F 4 90 1.166 cxu M 4 for 35 0.461 cxu M 4 for 25 ND cxu M 4 for 5 ND cxu M 4 1 5.229 cxu M 4 5 3.036 cxu M 4 10 1.009 cxu M 4 15 0.787 cxu M 4 20 0.856 cxu M 4 25 0.906 cxu M 4 thirty 0.703 cxu M 4 60 0.801 cxu M 4 90 1,969 cuu M 4 for 35 ND cuu M 4 for 25 0.263 cuu M 4 for 5 0.317 cuu M 4 1 0.32 cuu M 4 5 0.434 cuu M 4 10 0.662 cuu M 4 15 0.749 cuu M 4 20 0.789 cuu M 4 25 0.881 cuu M 4 thirty 0.9 cuu M 4 60 1.222 cuu M 4 90 1,729 C.Y.A. M 4 for 35 ND C.Y.A. M 4 for 25 0.234

- 111 045992

C.Y.A. m 4 for 5 0.732 C.Y.A. m 4 1 0.433 C.Y.A. m 4 5 0.903 C.Y.A. m 4 10 0.422 C.Y.A. m 4 15 0.872 C.Y.A. m 4 20 0.917 C.Y.A. m 4 25 0.781 C.Y.A. m 4 thirty 0.9 C.Y.A. m 4 60 1.125 C.Y.A. m 4 90 1.92

Example 10: Assessing whether epinephrine crosses the blood-brain barrier.

Plasma and cerebrospinal fluid samples before and after IN administration of epinephrine (4 mg/0.1 ml IN) were collected immediately before dosing (0 min) and 15 min after dosing for the study in Example 9. Blood samples were processed before plasma; plasma and cerebrospinal fluid samples were stabilized. Samples were analyzed for epinephrine content.

As shown in FIG. 12, plasma epinephrine levels before and after dosing averaged 0.214 ng/ml before dosing, and 15 minutes after dosing, epinephrine levels averaged 1.123 ng/ml. Neither before nor after dosing, epinephrine was not detected in the cerebrospinal fluid.

was (see Table 19). Epinephrine concentration in blood plasma Table 19 Matrix ID Quantity Time and type Floor collection concentration animal dose (mg) (ng/ml)

CVX m 4 before dose, CSF ND CVX m 4 after 15 min, CSF ND CVX m 4 before dose, plasma 0.360 DRY m 4 after 15 min, plasma 1,060

- 112 045992

CWD m 4 before dose, CSF ND CWD m 4 after 15 min, CSF ND CWD m 4 before dose, plasma 0.276 CWD m 4 after 15 min, plasma 0.369 CWP F 4 before dose, CSF ND CWP F 4 after 15 min, CSF ND CWP F 4 before dose, plasma 0.218 CWP F 4 after 15 min, plasma 2,151 BCHG F 4 before dose, CSF ND BCHG F 4 after 15 min, CSF ND BCHG F 4 before dose, plasma ND BCHG F 4 after 15 min, plasma 0.910

IN administration of epinephrine to dogs did not result in detection of epinephrine in cerebrospinal fluid samples 15 min after dosing, whereas plasma levels did increase at this same time point. Thus, IN administration of epinephrine to dogs does not result in epinephrine crossing the blood-brain barrier.

Example 11: Pharmacokinetic comparison of intranasal GLP with existing therapeutic approaches in Beagle dogs.

In this GLP study, which was based on previous studies that optimized the pharmacokinetics (PK) of intranasal epinephrine in terms of delivery and dose selection, a dose-selected dose was tested to evaluate PK as the primary endpoint in dogs, and heart rate was also assessed. to demonstrate the effects of epinephrine on the cardiovascular system.

The epinephrine formulation consisted of sterile water for injection containing 5 mg/10 ml sodium metabisulfite, 40 mg/10 ml sodium chloride, 0.7% sodium citrate, 0.1% hypromellose, 0.2% chlorobutanol and 1% diethylene glycol monoethyl ether with a final pH value of 5.0 ± 0.5. Epinephrine was administered in the concentrations indicated in Table. 20. For information about the supplier, lot number, and final concentration of each chemical in the test formulation, see Table. 20.

- 113 045992

Table 20

Chemicals used in the test formulation

Compound Provider Batch number Final concentration (-) Epinephrine Spectram 2HD0281 4 mg/100 µl (group 1) 5 mg/100 µl (group 2) Sodium chloride Spectram 1FIO675 0.4 mg/100 µl Sodium metabisulfite Spectram 1GC1002 0.05 mg/100 µl T sodium citrate Sigma BCBV1682 0.7% Hypromellose Sigma SLBR5196V 0.1% Ethylene glycol monoethyl ether Sigma O4508HEV 1% Chlorobutanol Spectram 1FF0469 0.2% Hydrochloric acid Spectram 2GJ0228 N.A. Sterile water for injection Spectram A1705131 N.A.

Two dosage concentrations (4 mg/100 μl and 5 mg/100 μl) were administered twice during this study. Complete information regarding the date of formulation, the lot identifier associated with each compounded study drug, the amount of epinephrine (in grams) used in each formulation, and the final pH value of each compounded study drug used for dosing is included in Table 1. 21.

Table 21

Batches of investigational drug formulations

Date of preparation Dose concentration (pre-dose) Amount of epinephrine used Final pH value Research day Dose concentration (post-dose) 8/21/2018 4.4 mg/100 µl 0.8008 g 5.207 16-17 4.4 mg/100 µl 8/21/2018 5.4 mg/100 µl 1.0033 g 5,202 16-17 5.4 mg/100 µl 08/31/2018 4.1 mg/100 µl 0.8004 g 4,729 29-30 4.0 mg/100 µl 08/31/2018 5.3 mg/100 µl 1.0010 g 4,814 29-30 5.1 mg/100 µl

EpiPen® 0.3 mg auto-injector (Mylan Specialty, L.P., USP pharmaceutical grade reagent) was used as the control product in this study. Individual EpiPens® were purchased from local pharmacies and stored at room temperature (20-25°C) in protected from light place.

A total of 48 dogs were enrolled in this study with 16 dogs (8/sex) per treatment group. In table 22 presents the study design.

Table 22

Study design

Group Epinephrine (mg), total Route of administration Floor Male Female 1 4 mg in 100 µl volume of carrier medium IN through the pipette tip into the right nostril 8 8 2 5 mg in 100 µl volume of carrier medium IN through the pipette tip into the right nostril 8 8 3 0.3 mg in 0.3 ml (EpiPen® for adults) Single intramuscular injection into the thigh muscle 8 8

- 114 045992

Two dogs/sex/group received a single dose of either IN epinephrine 4 mg or 5 mg (Groups 1 and 2) or a single intramuscular injection of EpiPen® (Group 3) on study days 0, 1, 16 and 17. Please note: that individual dogs in each group were dosed only once during this study.

Telemetry measurements were collected from all animals during the treatment phase of this study. Before dosing, animals were fitted with vests to collect telemetry data. Data collection points occurred from 60 min before dosing (baseline) to the 120-min endpoint for a total collection time of 180 min. The following parameters were assessed: ECG (PR, QRS, QT and RR; continuous data collection). Heart rate values were collected predose 60, 12, and 2–3 min before epinephrine administration and at the following intervals after epinephrine administration: 1, 5, 10, 15, 20, 25, 30, 60, 90, and 120 min. A six-second ECG was recorded at C _max for epinephrine for each dog to evaluate the ECG parameters listed above.

Approximately 2 ml of whole blood was collected at the following time points: pre-dose (60 min, 15 min, 2-3 min before dosing) and 1, 5, 10, 15, 20, 25, 30, 60, 90 and 120 min after dosing (±10% of target time point).

Prior to analysis of PK data, plasma epinephrine values were averaged at three predose time points (60 min, 15 min, 2–3 min predose) for each dog, and this average was then subtracted from postdose epinephrine values at time points. times 1, 5, 10, 15, 20, 25, 30, 60, 90 and 120 min after dosing for all animals in the study. If one or more pre-dose samples were below the limit of quantitation (BLQ), the average of the remaining quantifiable values was used to adjust the baseline. If all three pre-dose samples were below the detection limit (ie, values not determined), no baseline adjustment was performed for the post-dose samples. If post-dose values were negative (i.e., >0) after baseline adjustment, these values were changed to 0 for subsequent PK analysis.

Pharmacokinetic (PK) data were analyzed and plasma concentration-time curves were assessed. Individual time profiles of plasma epinephrine concentrations in epinephrine-treated animals were analyzed using model-independent methods. Pharmacokinetic parameters were obtained for each animal after a single intranasal administration of epinephrine to animals in groups 1 and 2 or after a single intramuscular injection of epinephrine to animals in group 3. Concentrations below the lower limit of quantitation (LLOQ < 0.4 ng/ml) were set to 0 for pharmacokinetic analysis.

The following pharmacokinetic parameters were determined for each animal: maximum observed plasma concentration ( _Cmax ), time to reach maximum observed plasma concentration ( _Tmax ), and area under the plasma concentration-time curve (AUC). AUC from 0 to 120 min (AUC ₀ to _{20 min} ) and AUC from 0 to infinity (AUCINF) were calculated by the linear trapezoidal method for all animals with at least 3 consecutive quantifiable concentrations. For day 1, 0 was used as an estimate of the concentration at 0 hours. Half-life (T _1/2 ) values were reported for each time plasma concentration profile that had sufficient plasma concentrations in the final elimination phase (at least 3 samples, not including T _max ), adjusted R ² of >0.9, and were determined from data from at least 3 half-lives. Additional pharmacokinetic parameters calculated were clearance divided by fraction of dose absorbed (Cl/F), volume of distribution divided by fraction of dose absorbed (Vz/F), and mean retention time (MRTlast). The exposure ratio for males and females (F:M) was calculated for each dose group using the following formula: F:M = mean

AUC

0-120 min for females t average AUC

0-120 min for males.

Extrapolated % AUC (% AUCExtrap) was calculated as: % AUCExtrap = [(AUCINFAUCtU/AUCmf] x 100.

Group 1 - 4 mg IN epinephrine.

Study formulation-related increases in heart rate were observed following intranasal (IN) administration of epinephrine (4 mg) on study days (SD) 0-1 and SD 16-17. All animals received epinephrine IN (4 mg, 100 μl) via cannula. The average heart rate of all animals treated with 4 mg epinephrine is shown in FIG. 13.

At SD 16-17, heart rate increased post-dose, with the maximum heart rate measurement (181 bpm) occurring 25 min post-dose. 120 minutes after dosing, the heart rate of 2 animals returned to the normal baseline range, while the heart rate of the remaining 6 animals remained elevated (Table 23).

At SD 29-30, heart rate increased post-dose, with the maximum heart rate measurement (226 bpm) occurring 15 min post-dose. 120 minutes after dosing, heart rates of seven dogs

- 115 045992 returned to the normal baseline range, while one animal's heart rate remained slightly above baseline (Table 23).

Table 23

Individual and average heart rates of dogs in group 1 - 4 mg IN epinephrine

Individual and average heart rate (bpm) - 4 mg IN epinephrine Study days 16-17 Time CVR CLB C.W.B. CNB CWD xxx CWZ CYN Average -60 137 155 111 146 90 154 134 109 130 -12 117 135 117 154 160 139 129 106 132 -2 102 152 81 151 108 170 119 92 122 1 106 144 166 156 85 135 125 115 129 5 157 137 105 156 125 144 136 119 135 10 116 158 123 164 116 151 122 126 135 15 124 163 117 143 129 131 130 99 130 20 137 146 98 130 76 142 128 114 121 25 120 174 87 145 126 181 118 132 135 thirty 122 157 83 158 115 138 137 153 133 60 171 159 119 122 153 127 153 117 140 90 97 157 112 155 105 135 124 127 127 120 74 129 140 139 108 121 150 141 125 Study days 29-30 Time CGR ACHG IBS svs CUD CFU CUE C.J.E. Average -60 181 92 106 131 106 132 111 135 124 -12 139 141 130 141 109 95 83 138 122 -2 117 99 98 123 135 95 57 103 103 1 132 125 120 126 142 114 119 128 126 5 122 126 FROM 135 158 105 154 118 129 10 182 156 FROM 146 97 95 119 130 130 15 226 100 101 138 134 103 65 135 125 20 116 122 118 129 168 72 77 126 116 25 119 120 112 139 144 76 73 121 FROM thirty 150 134 112 140 162 112 86 114 126 60 114 122 94 137 98 125 93 128 114 90 222 99 91 131 86 85 67 99 110 120 89 100 88 125 76 71 70 97 90

Group 2 - 5 mg IN epinephrine.

Study drug-related increases in heart rate were observed following intranasal (IN) administration of epinephrine (5 mg) on study days (SD) 0-1 and SD 16-17. All animals received epinephrine IN (5 mg, 100 μl) via cannula. The average heart rate of all animals treated with 5 mg epinephrine is shown in FIG. 14.

At SD 16–17, heart rate increased postdose, with the maximum heart rate measurement (174 bpm) occurring 60 min postdose. 90 minutes after dosing, the heart rates of all 8 animals had returned to the normal baseline range (Table 24).

At SD 29-30, heart rate increased after dosing, with the maximum heart rate measurement (220 beats per minute) occurring 1 minute after dosing. At 120 minutes post-dose, the heart rates of five animals had returned to the normal baseline range, while the heart rates of three animals remained elevated above the normal baseline range (Table 24).

Table 24

Individual and average heart rates of dogs in group 2 - 5 mg IN epinephrine

Individual and average heart rate (bpm) - 5 mg IN epinephrine Study days 16-17 Min CVL C.S.W. CVX CTZ C.W.T. CWF CXV CGF Average -60 93 128 138 158 103 112 119 149 125 -12 163 118 129 152 104 145 116 124 131 -2 65 128 73 145 86 133 104 124 107 1 121 126 120 151 129 FROM 100 137 125 5 146 141 88 132 111 131 129 146 128 10 145 130 128 144 105 130 123 128 129 15 135 132 140 147 95 140 122 FROM 128 20 147 145 122 129 137 124 130 137 134 25 115 139 121 139 124 109 138 135 128 thirty 168 128 125 123 128 101 118 136 128 60 174 133 149 134 139 102 124 128 135 90 120 109 105 118 FROM 120 90 117 112 120 92 108 125 FROM 84 105 116 109 107 Study days 29-30 Time CNE BCHG CRA CTZ CUF CIH these CRF Average -60 146 108 127 142 85 133 122 116 122 -12 126 132 135 137 96 116 115 151 126 -2 126 72 127 110 84 133 99 122 109 1 181 140 220 119 91 122 102 142 140 5 172 109 153 123 103 173 FROM 119 133 10 144 109 143 125 FROM 156 106 118 127 15 125 FROM 160 114 111 130 109 124 123 20 125 100 149 127 101 114 106 149 121 25 129 84 142 117 98 130 104 119 115 thirty FROM 133 155 120 116 133 103 112 123 60 130 92 122 97 108 127 86 96 107 90 106 92 124 128 73 140 133 127 115 120 105 90 125 129 63 116 88 142 107

Group - 0.3 mg IM EpiPen® injection.

Intramuscular (IM) injection of 0.3 mg EpiPen® resulted in a general increase in heart rate in all animals. All animals received an intramuscular injection of 0.3 mg EpiPen® into the right hind paw. The average heart rate over time for all animals administered EpiPen® Adult is presented in FIG. 15.

At SD 16-17, heart rate increased after dosing, with the maximum heart rate measurement (222 beats per minute) occurring at 20 min.

- 117 045992 after dose administration. Consistent with the SD 0-1 results, heart rates in all eight dogs remained elevated above the normal baseline range 120 minutes post-dose (Table 25).

At SD 29-30, heart rate increased post-dose, with the maximum heart rate measurement (222 bpm) occurring 20 min post-dose. Consistent with the SD 0-1 results, heart rates in all eight dogs remained elevated above the normal baseline range 120 minutes post-dose (Table 25).

Table 25

Individual and average heart rate of dogs in group 3 - 0.3 mg injection EpiPen® Individual and average heart rate (bpm) - EpiPen® 0.3 mg injection Study days 16-17 Min C.W.U. SNT schema CLZ C.Y.A. CPL C.Y.R. CPN Average -60 112 122 121 117 152 106 106 110 118 -12 124 87 100 87 107 109 153 149 115 -2 105 145 123 111 135 83 85 107 112 1 123 194 143 147 157 133 174 108 147 5 142 144 144 103 172 137 148 112 138 10 182 137 157 127 124 153 112 147 142 15 169 148 127 121 101 153 119 124 133 20 222 145 158 107 157 153 179 151 159 25 212 167 142 120 144 156 157 134 154 thirty 205 144 190 154 131 191 147 176 167 60 160 186 211 144 148 180 188 162 172 90 151 173 199 204 159 178 165 151 173 120 163 151 193 123 153 167 151 145 156 Study days 29-30 Time C.P.J. SVE CTE CEU sit CFI CUZ CGV Average -60 61 FROM 124 103 66 73 80 84 88 -12 71 130 127 from 70 120 112 82 103 -2 121 108 108 98 74 73 96 91 96 1 104 156 127 125 94 151 107 89 119 5 115 132 107 FROM 86 162 110 109 117 10 103 131 138 116 178 107 161 103 130 15 142 131 136 137 134 184 93 103 133 20 166 136 138 139 163 124 108 118 137 25 165 139 140 146 155 FROM 98 111 133 thirty 179 175 122 142 192 130 110 125 147 60 154 173 130 179 201 148 129 146 158 90 155 182 151 173 189 179 144 125 162 120 155 182 114 151 162 132 154 133 148

Pharmacokinetic analysis.

All plasma epinephrine concentrations were adjusted at baseline to endogenous epinephrine levels.

- 118 045992 rin using average pre-dose concentrations; therefore, the following discussion of systemic effects of epinephrine is based on data above endogenous levels.

Systemic exposure to epinephrine was independent of gender. There were no consistent differences in individual plasma concentration profiles over time, Cmax and AUC values between males and females (F:M _AUC0-24h ratios after intranasal administration were 0.711 and 1.20 for groups 1 and 2, respectively, and F ratio :M AUC0-24 _hours after intramuscular administration was 1.27 for group 3); therefore, the following discussion is based on data for males and females combined.

The variability in mean plasma epinephrine concentrations, as measured by CV values, ranged from 53.4 to 170% after a single dose of epinephrine in dogs in groups 1 and 2 and from 48.7 to 174% after a single dose of 0.3 mg intramuscular epinephrine in dogs in group 3. Epinephrine was quantified up to 120 minutes post-dose for Group 1 (4 mg), up to 30 or 120 minutes post-dose for Group 2 (5 mg), and up to 120 minutes post-dose for Group 3 (0.3 mg). . Individual peak plasma epinephrine concentrations were observed between 1 and 30 min postdose for group 1 (4 mg), between 1 and 90 min postdose for group 2 (5 mg), and between 5 and 60 min postdose for group 3 (0.3 mg).

Following a single IN administration of epinephrine to dogs, the mean _{0-120 min} Cmax and AUC values for epinephrine increased slightly as the dose was increased from 4 to 5 mg. Increasing the epinephrine dose by 1.25 times resulted in an approximately 1.22-fold increase in mean epinephrine Cmax values (2.48 and 3.01 ng/mL at 4 and 5 mg, respectively) and an approximately 1.09-fold increase in mean values. AUC _{0-120 min} of epinephrine. (75.0 and 81.8 min*ng/ml at 4 and 5 mg, respectively). Following a single intramuscular injection of 0.3 mg epinephrine in dogs, the mean Cmax and AUC _0-120muh for epinephrine were 2.76 ng/ml and 110 min*ng/ml, respectively.

The mean MRTlast values for epinephrine after IN administration were 51.1 and 53.9 min at 4 and 5 mg, respectively. The mean MRT _last for epinephrine after intramuscular injection was 50.4 minutes. A complete overview of the pharmacokinetic parameters mentioned above is presented in Table. 26.

Overall, individual plasma concentration-time profiles were generally similar in animals receiving epinephrine via IN compared to animals receiving epinephrine via intramuscular injection (FIG. 16).

Table 26

Pharmacokinetic parameters of epinephrine after a single IN injection of 4 or 5 mg of epinephrine or a single intramuscular injection of 0.3 mg of epinephrine in dogs (male and female combined)

Group Path Dose (mg) Statistics (ng/ml) USA/DOZYA (ng/ml/mg) (min) Tlast ^a (min) AUCo- 120min (min*ng/ml) AUCopmin/dose (min*ng/ml/mg) MRTlast (min) 1 IN 4 N 16 16 16 16 16 16 16 Average 2.48 0.619 20 120 75.0 18.7 51.1 SD 2.27 0.568 (1-30) (120-120) 53.8 13.5 11.3 CV% 91.7 91.7 N.A. N.A. 71.8 71.8 22.2 2 IN 5 N 16 16 16 16 15 15 15 Average 3.01 0.602 15 120 81.8 16.4 53.9 SD 2.96 0.592 (1-90) (30-120) 46.3 9.26 12.9 CV% 98.3 98.3 N.A. N.A. 56.6 56.6 23.8 3 IM 0.3 N 16 16 16 16 16 16 16 Average 2.76 9.22 25 120 BUT 365 50.4 SD 2.78 9.25 (5-60) (120-120) 42.1 140 9.39 CV% 100 100 N.A. N.A. 38.4 38.4 18.6

NA - not applicable.

a: median (minimum - maximum), median value is presented only if there is an actual collection interval.

Three groups of 8 male and 8 female Beagle dogs received 4 mg/100 μl IN epinephrine in the right nostril (group 1), 5 mg/100 μl epinephrine in the right nostril (group 2), or 0.3 mg in 0.3 ml EpiPen® (adults) intramuscularly into the thigh muscle (Group 3) followed by blood sampling for this PK study. In addition, the dogs underwent telemetry to monitor their heart rates before and after dosing.

Heart rate data were comparable between dogs in Groups 1 and 2 (respectively) 4 and 5 mg IN, with an increase in mean heart rate occurring approximately 5-10 min post-dose in Group 1 dogs and approximately 1 min post-dose dose for dogs in Group 2. The maximum increase in mean heart rate was 132 beats per

- 119 045992 minute after 10 minutes and 132 beats per minute after 1 minute after administration of IN for dogs of groups 1 and 2, respectively. The heart rate of Group 3 dogs administered EpiPen® began to increase 1 minute after dosing, with the maximum increase in mean heart rate (167 beats per minute) occurring approximately 90 minutes after dosing.

Systemic exposure to epinephrine was independent of gender. Individual peak plasma epinephrine concentrations were observed between 1 and 30 min postdose for group 1 (4 mg), between 1 and 90 min postdose for group 2 (5 mg), and between 5 and 60 min postdose for group 3 (0.3 mg). Following a single IN administration of epinephrine to dogs, the mean _{0-120 min} Cmax and AUC values for epinephrine increased slightly as the dose was increased from 4 to 5 mg. Increasing the epinephrine dose by 1.25 times resulted in an approximately 1.22-fold increase in mean epinephrine Cmax values (2.48 and 3.01 ng/mL at 4 and 5 mg, respectively) and an approximately 1.09-fold increase in mean values. AUC _{0-120 min} of epinephrine. (75.0 and 81.8 min*ng/ml at 4 and 5 mg, respectively). Following a single intramuscular injection of 0.3 mg epinephrine in dogs, the mean _{0-120 min} Cmax and AUC values for epinephrine were 2.76 ng/mL and 110 min*ng/mL, respectively.

The mean MRTlast values for epinephrine after IN administration were 51.1 and 53.9 min at 4 and 5 mg, respectively. The mean MRTlast for epinephrine after intramuscular injection was 50.4 minutes.

Overall, individual plasma concentration-time profiles were generally similar in animals receiving epinephrine via IN compared with animals receiving epinephrine via intramuscular injection.

Example 12: Administering a dose of epinephrine through one or both nostrils.

This study examined intranasal administration of epinephrine in Beagle dogs to evaluate whether administration of epinephrine into one or both nostrils produced optimal plasma levels.

The composition of epinephrine used is defined in table. 27. Three male and three female hounds per group participated in the study (Table 28). Groups 1–4 received epinephrine through a 100-μL intranasal device. After dosing, serial blood samples were collected from all animals for pharmacokinetic analysis.

Table 27

Composition of the study drug

Compound Final concentration Final pH value Epinephrine 5 mg/100 µl 5.35 Sodium chloride 0.4 mg/100 µl Sodium metabisulfite 0.05 mg/100 µl Trisodium citrate 0.7% Hypromellose 0.1% Monoethyl ether diethylene glycol 1% Epinephrine 10 mg/100 µl 4.90 Sodium chloride 0.4 mg/100 µl Sodium metabisulfite 0.05 mg/100 µl Trisodium citrate 0.7% Hypromellose 0.1% Monoethyl ether diethylene glycol 1%

- 120 045992

Table 28

Study design

Groups Total dose level (mg) of epinephrine Dose volume (µl) Nostril insertion Males Females 1 5 100 One ^{Behind Behind} 2 10 (two nostrils, 5 mg/nostril) 100 Both Z ^{b h} 3 10 100 One ^{behind behind 4th} 20 (two nostrils each 10 mg/nostril) 100 Both ^{h h}

A total of 264 PK samples from groups 1, 2, 3 and 4 were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using a C18-PFP column. LC-MS/MS analysis was performed in positive electrospray ionization (ESI+) mode using multiple reaction monitoring (MRM) ionization.

Plasma epinephrine concentrations were subtracted from baseline using the mean concentrations of the three predose samples. If subtraction of the original value resulted in negative values, these samples were assigned a value of zero. In some cases (eg, low-dose groups 1 and 3), all post-dose epinephrine concentrations in several animals were below baseline pre-dose concentrations. In addition, epinephrine concentrations were considered to be outliers if they were greater than twice the standard deviation of the mean of baseline-subtracted postdose plasma epinephrine concentrations in each animal at the time of blood sampling (i.e., 1–90 min postdose dose).

AUC, Tmax, and Cmax were calculated using the trapezoidal rule (GraphPad Prism 7.0c) and epinephrine concentrations with statistical outliers removed after entering the baseline value for each individual animal (Tables 29–32).

Table 29

AUC and _Cmax of epinephrine in dogs from group 1 (5 mg x 1 nostril)_________

Parameter, units Group 1 (5 mg x 1 nostril) 1 2 3 4 5 6 Average SD Dose, mg 5 5 5 5 5 5 Stach, ng/ml NC NC OD 0.7 0.1 NC o, s 0.3 Tmax, min NC NC 90 90 7 NC 62 48 AUC1-90 min, ng/ml*min NC NC 2 13 6 NC 7 6

Table 30

AUC and _Cmax of epinephrine in dogs from group 2 (5 mg x 2 nostrils)________

Parameter, units Group 2 (5 mg x 2 nostrils) 1 2 3 4 5 6 Average SD Dose, mg 10 10 10 10 10 10 Stach, ng/ml 1.4 1.7 4.2 2 4.7 0.3 2.4 1.7 Tmax, min 15 10 90 22 5 thirty 29 31 AUC1-90 min, ng/ml* min 23 38 117 76 166 5 71 62

- 121 045992

Table 31

AUC and Cmax of epinephrine in dogs from group 3 (10 mg x 1 nostril)

Parameter, units Group 3 (10 mg x 1 nostril) 1 2 3 4 5 6 Average SD Dose, mg 10 10 10 10 10 10 Stach, ng/ml NC NC 8.7 0.8 NC NC 4.8 5.6 Tmax, min NC NC 12 85 NC NC 51 54 AUC1-90 min, ng/ml* min NC NC 378 20 NC NC 199 253

Table 32

AUC and Cmx of epinephrine in dogs from the group! 4 (10 mg x 2 nostrils)________

Parameter, units Group 4 (10 mg x 2 nostrils) 1 2 3 4 5 6 Average SD Dose, mg 20 20 20 20 20 20 Stach, ng/ml 2.8 3.1 2.5 2 6.7 3.4 3.4 1.7 Tmax, min 60 15 10 90 63 90 55 35 AUC1-90 min, ng/ml* min 178 96 80 62 241 151 135 68

Example 13: Intranasal and intramuscular administration of epinephrine in search of a dose range in Beagle dogs.

This study examined the intranasal administration of epinephrine at various doses to Beagle dogs. In addition, Adult Epi-Pen and JR Epi-Pen were administered intramuscularly to obtain pharmacokinetic profiles for comparison.

The composition of epinephrine used is defined in table. 33. Three males and three females of the Beagle breed per group participated in the study (Table 34). Groups 1-4 were administered 100 μl of epinephrine at various concentrations. The dose was administered intranasally using a cannula. Groups 5 and 6 were administered epinephrine by intramuscular injection using an Adult or Jr. EpiPen. EpiPen, respectively. After dosing, serial blood samples were taken from all animals.

- 122 045992

Table 33

Composition of the study drug

Compound Final concentration Final pH value Epinephrine 5 mg/100 µl Sodium chloride 0.4 mg/100 µl Sodium metabisulfite 0.05 mg/100 µl Trisodium citrate 0.7% 4.94 Hypromellose 0.1% Monoethyl ether diethylene glycol 1% Epinephrine 10 mg/100 µl Sodium chloride 0.4 mg/100 µl Sodium metabisulfite 0.05 mg/100 µl Trisodium citrate 0.7% 4.85 Hypromellose 0.1% Monoethyl ether diethylene glycol 1% Epinephrine 20 mg/100 µl Sodium chloride 0.4 mg/100 µl 4.50 Sodium metabisulfite 0.05 mg/100 µl Trisodium citrate 0.7% Hypromellose 0.1% Monoethyl ether diethylene glycol 1%

Table 34

Study design

Groups Total dose level (mg) of epinephrine Dose volume (µl) Route of administration Males Females 1 10 100 Nostril, both ^{Behind Behind} 2 20 100 Nostril, one ^{h h} 3 5 100 Nostril, one ^{behind behind} 4 10 100 Nostril, one ^{h h} 5 EpiPen for adults (0.3) 300 I.M. ^{behind behind} 6 Jr EpiPen (0.15) 300 TM ^{h h}

PK samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using a C18-PFP column. LC-MS/MS analysis was performed in positive electrospray ionization (ESI+) mode using multiple reaction monitoring (MRM) ionization AUC, Tmax and Cmax were calculated using the trapezoidal rule (GraphPad Prism 7.0c) and epinephrine concentrations with outliers removed, subtracted from baseline after dosing, for each individual animal (Table 35-40). For groups 5 and 6 (groups

- 123 045992

EpiPen) AUC, Tmax, and Cmax were also calculated using epinephrine concentrations subtracted from baseline after dosing (without removing statistical outliers) for comparison (number in parentheses in Tables 39 and 40).

Table 35

AUC and Cmax of epinephrine in dogs from group 1 (10 mg x 2 nostrils)_________

Parameter, units Group 1 (10 mg x 2 nostrils) 1 2 3 4 5 6 Average SD Dose, mg 20 20 20 20 20 20 Stach, ng/ml 1.8 7.2 2.2 3.2 6.8 7.4 4.8 2.7 Tmax, min 1 5 60 60 90 90 51 40 AUC1-90 min, ng/ml* min 59 249 72 134 284 485 214 161

Table 36

AUC and Cmax of epinephrine in dogs from group 2 (10 mg x 1 nostril)________

Parameter, units Group 2 (10 mg x 1 nostril) 1 2 3 4 5 N/A Average SD Dose, mg 20 20 20 20 20 Stach, ng/ml 15.7 53 4.7 32.3 10.8 23.3 19.5 Tmax, min 5 5 1 60 5 15 25 AUC1-90 min, ng/ml* min 769 1875 201 1700 495 1008 742

Table 37

AUC and Cmax of epinephrine in dogs from group 3 (5 mg x 1 nostril)_________

Parameter, units Group 3 (5 mg x 1 nostril) 1 2 3 4 5 6 Average SD Dose, mg 5 5 5 5 5 5 Stach, ng/ml 1.3 3.5 2.7 6 3 4.1 3.4 1.6 Tmax, min 90 5 thirty thirty 5 90 42 39 AUC1-90 min, ng/ml* min 67 185 117 177 131 205 147 51

Table 38

AUC and Cmax of epinephrine in dogs from group 4 (10 mg x 1 nostril)________

Parameter, units Group 4 (10 mg x 1 nostril) 1 2 3 4 5 6 Average SD Dose, mg 10 10 10 10 10 10 Stach, ng/ml 4.1 13.9 5.7 10.6 17.8 2.4 9.1 6 Tmax, min 28 5 15 15 4 10 13 9 AUC1-90 min, ng/ml* min 228 339 94 259 491 85 249 154

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Table 39

Epinephrine AUC and Cmax in Group 5 Dogs (EpiPen Adult 0.3 mg IM)

Parameter, units Group 5 (EpiPen Adult 0.3 mg IM) 1 2 3 4 5 6 Average SD Dose, mg 0.3 o, s 0.3 0.3 o, s 0.3 Stach, ng/ml 1.4 3 1.6 1.3 2.1(4.1) 7.5 2.8(3.1) 2.4 (2.4) Tmax, min 60 60 thirty 15 10(14) 15 32 (32) 23 (22) AUC1-90 min, ng/ml* min 94 158 101 62 111 (123) 193 120(122) 47 (47)

Table 40

AUC and Cmax of epinephrine in dogs from group 6 (EpiPen for children 0.15 mg IM)

Parameter, units Group 6 (EpiPen for children 0.15 mg IM) 1 2 3 4 5 6 Average SD Dose, mg 0.15 0.15 0.15 0.15 0.15 0.15 Stach, ng/ml 0.9 1.1 (2.5) 1.2 (3.8) 2.2 (4.6) 1.1 1.1 (3.0) 1.3 (2.7) 0.5 (1.4) Tmax, min 1 5(Yu) 60 (20) Yu(5) 20 30 (20) 21(13) 22 (9) AUC1-90 min, ng/ml* min 33 56 (65) 77(101) 50 (63) 74 66 (80) 59 (69) 16 (22)

Example 14: Intranasal administration of low doses of epinephrine in search of a dose range in Beagle dogs.

This is a study examining intranasal administration of epinephrine at different doses and dosing intervals in Beagle dogs. In this non-GLP PK study, an Adult EpiPen® administered intramuscularly was used to obtain a pharmacokinetic profile for comparison.

Plasma levels and changes in heart rate induced by intranasal administration of increasing concentrations of epinephrine (2 mg/100 μL, 3 mg/100 μL, and 4 mg/100 μL) were assessed (groups 1–3). In addition, plasma epinephrine concentrations and changes in heart rate were assessed after intranasal administration of 2 doses of epinephrine (4 mg/100 μl) into the same or opposite nostril (group 4 and group 8B) with a 20-minute interval between doses. For pharmacokinetic comparison, a double intramuscular injection of 0.3 mg EpiPen® for adults was used with a 20-minute interval between doses (group 5/8A).

Serial blood samples were collected for bioanalytical and pharmacokinetic (PK) analysis and multiple pre- and post-dose time points.

Part I. Estimation of plasma epinephrine concentrations after intranasal administration of 2 mg, 3 mg, and 4 mg epinephrine.

Each group in Part I of Study 4 consisted of three males and three females ( n = six per group). Each dog was given a single dose of epinephrine via cannula into the right nostril. An overview of the study design of Part I is presented in Table. 41 Plasma samples were obtained at the following time points after epinephrine administration: 1, 5, 10, 15, 20, 30, 60, and 90 minutes.

Table 41 ___________________________Research Design___________________________

Group Epinephrine (mg) per dose Volume dose (µl) Nostril insertion Introduction Males Females 1 2 100 one IN BEHIND BEHIND 2 3 100 one IN ZV ZV 3 4 100 one IN zs ZS

The vehicle vehicle for the test device consisted of sterile water for injection containing 5 mg/10 mL sodium metabisulfite, 40 mg/10 mL sodium chloride, 0.7% trisodium citrate, 0.1% hypromellose, 0.2% chlorobutanol, and 1% monoethyl diethylene glycol ether with a final pH value of 5.0 ± 0.5 (see Table 42).

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Table 42

Composition of the study drug

Compound Final concentration Final pH value Epinephrine 2 mg/100 µl 5.30 Sodium chloride 0.4 mg/100 µl Sodium metabisulfite 0.05 mg/100 µl Trisodium citrate 0.7% Chlorobutanol 0.2% Hypromellose 0.1% Monoethyl ether diethylene glycol 1% Epinephrine 3 mg/100 µl 5.08 Sodium chloride 0.4 mg/100 µl Sodium metabisulfite 0.05 mg/100 µl Trisodium citrate 0.7% Chlorobutanol 0.2% Hypromellose 0.1% Monoethyl ether diethylene glycol 1% Epinephrine 4 mg/100 µl 5.32 Sodium chloride 0.4 mg/100 µl Sodium metabisulfite 0.05 mg/100 µl Trisodium citrate 0.7% Chlorobutanol 0.2% Hypromellose 0.1% Monoethyl ether diethylene glycol 1%

Plasma epinephrine concentrations were adjusted to account for baseline plasma epinephrine levels by using the average predose concentrations of the three samples and subtracting this value from the postdose values for each dog. If baseline subtraction resulted in negative values, these samples were assigned a value of zero. In addition, in accordance with the sponsor's instructions, epinephrine concentrations were considered statistical outliers and were excluded from analysis if they were greater than twice the standard deviation of the mean of baseline-subtracted post-dose plasma epinephrine concentrations for each animal during blood sampling (t i.e. 1-90 minutes after dose administration).

Table 43

AUC and Cmax of epinephrine in dogs from group 1

Parameter, units Group 1 (2 mg x 1 nostril) Average SD 1 2 3 4 5 6 Dose, g 2 2 2 2 2 2 — — Ttah, MIN 1 60 90 1 60 1 36 39 Stakh, NG/ML 1.0 0.7 6.2 0.6 5.1 2.8 2.7 2.4 AUC1-90 min, ng/ml'MIN 47 43 237 13 209 25 96 100

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Table 44

AUC and Cmax of epinephrine in dogs from group 2

Parameter, units Group 2 (3 mg x 1 nostril) Average SD 1 2 3 4 5 6 Dose, g 3 3 3 3 3 3 — — Ttah, MIN 90 5 1 15 5 5 20 35 Stakh, NG/ML 0.7 1.5 8.2 0.2 3.4 o, s 2.4 3.1 AUC1-90 min, ng/ml'MII 25 64 227 14 167 18 86 90

Table 45

AUC and Cmax of epinephrine in dogs from group 3

Parameter^ units Group 3 (4 mg x 1 nostril) Average SD 1 2 3 4 5 6 Dose, g 4 4 4 4 4 4 — — Ttah, MII 60 60 1 20 60 90 49 32 Stakh, NG/ML 2.9 1.7 2.1 2.2 12.2 1.4 3.7 4.2 AUC1-90 min, ng/ml'MII 84 112 98 88 688 59 188 246

Three doses of epinephrine, 2, 3, and 4 mg IN (100 μL volume each), were evaluated and the lowest dose was evaluated compared with PK and HR results for the Pediatric EpiPen. The Cmax of 2, 3, and 4 mg was 2.7, 2.4, and 3.7 ng/mL, respectively, while the AUC was 96, 86, and 188 ng/mL-min, respectively. It appears that the two lower doses of IN epinephrine showed similar pharmacokinetics, whereas the pharmacokinetics of the higher dose of 4 mg IN increased in a dose-dependent manner.

The 2 mg/100 μL dose produced plasma epinephrine levels comparable to the pediatric EpiPen®. Finally, the PK results of 4 mg IN epinephrine were comparable to the PK results of the adult EpiPen® (EpiPen® results presented in study 3 compared with the PK values of 4 mg IN from arm 3 of this report; Cmax values of 3.7 and 2.8 ng/mL and AUC 188 and 120 ng/mL-min for 4 mg IN compared with EpiPen®, respectively). Most importantly, epinephrine 4 mg IN resulted in an increase in plasma concentrations much more rapidly (within 1 min after dosing) compared to

EpiPen IM when plasma epinephrine concentrations do not begin to increase until 5 to 10 minutes after administration.

Part II. Evaluation of plasma epinephrine concentration after repeated intranasal administration of 4 mg epinephrine.

This study compared plasma levels and changes in heart rate observed after a second dose of epinephrine administered either intranasally or intramuscularly 20 minutes after the first dose. One potential pitfall of repeated intranasal administration is that the first intranasal administration may result in severe vasoconstriction of the nasal epithelium, which will significantly and negatively affect the absorption of the second dose. Therefore, this study also assessed this possibility by administering a second intranasal dose of epinephrine into the contralateral nostril. Similar to the first intranasal paradigm (2 doses, same nostril), repeated intramuscular injection of EpiPen® was used for pharmacokinetic comparison.

Groups 4 and 5 consisted of three dogs/sex (n=six/group), while Group 8A consisted of one dog/sex (n=2 dogs), and Group 8B consisted of two dogs of each sex (n=4 dogs). Each dog in groups 4 and 8B was given two doses of epinephrine (4 mg/100 μl) with an interval of 21 min between doses. All intranasal doses were administered via cannula. Dose 1 was administered into the right nostril, followed by a second intranasal dose into the right (Group 4, same nostril) or left (Group 8B, opposite nostril) nostril. Dogs in groups 5 and 8A were given two intramuscular injections of Adult EpiPen® (0.3 mg) with an interval of 21 minutes between injections. Injections were given into opposite thighs, with the first dose being given in the right thigh and the second dose being given in the left thigh. A complete overview of the study design is presented in Table 1. 46.

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Table 46

D research design Group Epinephrine (mg) per dose Dose volume (µl) Nostril Introduction Introduction Males Females 4 4+4 100+ 100 Twice (same nostril) IN 3 3 5 1 EpiPen® FOR ADULTS 300+ 300 IM, once every 3 3 (0.3) + 1 EpiPen® for adults (0.3) thigh muscle 8A 1 EpiPen® Adult (0.3) + 1 Adult EpiPen® (0.3) 300+ 300 IM, once into each thigh muscle 1 1 8V 4+4 100+ 100 Twice (opposite nostril) IN 2 2

The study drug used was formulated as described in Part I of this study (see Table 47). EpiPen® Adult Auto-Injector (0.3 mg) was used as the control product for the pharmacokinetic comparison in this part.

Table 47

Composition of the study drug

Compound Final concentration Final pH value Epinephrine 4 mg/100 µl 5.04 ² 5.18 ³ Sodium chloride 0.4 mg/100 µl Sodium metabisulfite 0.05 mg/100 µl Trisodium citrate 0.7% Hypromellose 0.1% Monoethyl ether diethylene glycol 1%

² Composition for groups 4, 6 and 7.

³ Composition for group 8B.

Plasma epinephrine concentrations were adjusted to each dog's baseline plasma epinephrine level by using the mean concentrations of the three predose samples and subtracting this mean from subsequent postdose plasma epinephrine values. If this adjustment resulted in negative values, these samples were assigned a value of zero. In addition, epinephrine concentrations were considered outliers and were excluded from analysis if they exceeded

- 128 045992 twice the standard deviation of the mean baseline subtracted epinephrine plasma concentrations of each animal after dosing at the time of blood sampling (i.e., 1120 min post-dose).

AUC, Tmax, and Cmax were calculated using the trapezoidal rule (GraphPad Prism 7.0c) and epinephrine concentrations after subtracting baseline values and removed outliers for each individual animal (Tables 48-50).

For the 5/8A group, the elimination phase can be determined, so AUC, _Tmax , _Cmax and half-life (t1 _/2 ) were also calculated using NCA for comparison (AUC=740 ng/ml-min; _Tmax =30 min; C _max =15 ng/ml; t _1/2 =38 min).

Table 48

AUC and _Cmax of epinephrine in dogs from group 5 and group 8A

Parameter, units Group 5 (EpiPen® for adults 0.3 mg x 2 injections) Average SD 1 2 3 4 5 6 STR ¹ схх ¹ Dose, g 0.3 + 0.3 0.3 + 0.3 0.3 + 0.3 0.3 + 0.3 0.3 + o, z 0.3 + 0.3 0.3 + 0.3 0.3 + 0.3 — — Tmax, MIN 10 thirty 10 thirty 25 thirty thirty 60 28 16 Stakh, NG/ML 17.0 22.7 9.9 27.3 54.9 24.5 3.2 5.0 20.6 16.6 AUC1-90 min, ng/ml'MIN 713 737 785 1067 1218 1014 208 375 765 343

¹ Animals fall into group 8A.

Table 49

AUC and _Cmax of epinephrine in dogs from group 4

Parameter, units Group 4 (4 mg x 2 doses x 1 nostril) Average SD 1 2 3 4 5 6 Dose, g 4+4 4+4 4+4 4+4 4+4 4+4 — — Tmax, MIN 60 10 60 5 25 25 31 24 Stakh, NG/ML 2.3 2.6 38.1 18.6 1.5 1.2 10.7 15.0 AUC1-90 min, ng/mL ⁴ min 107 88 1324 811 50 62 407 537

Table 50

AUC and _Cmax of epinephrine in dogs from group 8B

Parameter, units Group 8B (4 mg x 2 doses x 2 nostrils) Average SD 1 2 3 4 — — Dose, g 4+4 4+4 4+4 4+4 — — — — Tmax, MIN 90 1 25 60 — — 44 39 Stakh, NG/ML 2.6 2.7 3.1 6.5 — — 3.7 1.9 AUC1-90 min, ng/ml ⁴ MIN 161 135 151 372 — — 205 112

Plasma levels and changes in heart rate were assessed after a second dose of epinephrine was administered either intranasally (same nostril), intranasally (opposite nostrils), or intramuscularly 21 minutes after the first dose. Compared to a single 4 mg IN dose of epinephrine (see Part 1, Group 3), _Cmax and AUC in Group 4 dogs (two IN doses of epinephrine in the same nostril) were 10.7 ng/mL and 407 ng/mL. ml-min respectively. Two doses of EpiPen® administered 21 minutes apart also resulted in higher Cmax and AUC of 20.6 ng/mL and 765 ng/mL-min compared with a single dose.

Example 15: Testing the stability of pharmaceutical formulations in the form of a spray.

The pharmaceutical formulation in spray form was quantified and monitored using high pressure liquid chromatography (HPLC). Detected impurities include epinephrine sulfonic acid, adrenochrome, norepinephrine and epinephrine. In the following tables. 51-58 show the results of testing compositions of epinephrine in the form of a spray at various dosages, storage temperatures

- 129 045992 information and storage duration.

Table 51 mg/ml or 2 mg/dose pH 4.7, 0.5% chlorobutanol at 5, 25 and 40°C

Trial Specification (stability) Time points (months) THAT 5°С 25°C 40°C T = 2.27 T = 1 T = 1 rn 4.2 - 5.2 4,614 4,593 4.615 4,607 Osmolality 300 - 500 mOsm/kg 394 403 405 Mass loss Max. < 2.2%, avg. < 1.1% 0.00% Analysis 95.0% - 110.0% 95.85% 97.47% 96.44% 96.35% Epinephrine sulfonic acid NMT 9.0% 0.46% 0.20% 1.09% 3.69% Adrenochrome NMT 0.5% 0.08% 0.05% 0.11% 0.23% Norepinephrine NMT 4.0% ND ND ND ND Adrenalone NMT 3.0% ND ND ND ND Total amount of impurities < 12.0% 0.60% 0.44% 1.44% 4.17% Enantiomeric purity 99.14% 99.19% 99.01% Chlorobutanol analysis 3.94 mg/ml Sodium metabisulfite analysis 0.345 mg/ml 0.206 mg/ml 0.014 mg/ml

Table 52 mg/ml or 6 mg/dose pH 4.7, 0.5% chlorobutanol at 5, 25 and 40°C

Trial Specification (stability) Time points (months) THAT 5°С 25°C 40°C T= 1.6 T= 1 T = 1 rn 4.2 - 5.2 4,644 4,649 4.622 4.585 Osmolality 600 - 1000 mOsm/kg 797 790 793 Mass loss Max. < 2.2%, avg. < 1.1% Analysis 95.0% - 110.0% 100.60% 100.80% 100.60% 98.60% Epinephrine sulfonic acid NMT 3.0% 0.42% 0.20% 0.81% 1.74% Adrenochrome NMT 0.2% 0.06% ND ND 0.05% Norepinephrine NMT 4.0% ND ND ND ND

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Adrenalone NMT 1.2% ND ND ND ND Total amount of impurities < 12.0% 0.54% 0.30% 0.95% 2.38% Enantiomeric purity 99.01% 99.77% 98.42% Chlorobutanol analysis 4.41 mg/ml Sodium metabisulfite analysis .019 mg/ml .013 mg/ml ND

Table 53 mg/ml or 2 mg/dose pH 4.7, 0.2% chlorobutanol at 25°C

Trial Specification (stability) Time points (days), 25°C THAT 28 56 84 rn 4,662 4,587 4,591 4.545 Osmolality 428 Analysis 95.0% - 110.0% 101.55% 97.58% 99.05% 98.51% Epinephrine sulfonic acid NMT 3.0% 0.00% 1.05% 1.74% 2.08% Adrenochrome NMT 0.5% 0.09% 0.22% 0.36% 0.53% Norepinephrine NMT 4.0% ND ND ND ND Adrenalone NMT 3.0% ND ND ND ND Total amount of impurities < 12.0% 0.34% 1.70% 2.29% 3.30% Chlorobutanol analysis 1.56 mg/ml 1.46 mg/ml 1.36 mg/ml 1.37 mg/ml

Table 54 mg/ml or 2 mg/dose pH 4.7, 0.2% chlorobutanol at 40°C

Trial Specification (stability) Time points (days), 40°C THAT 28 56 84 rn 4,662 4.556 4.537 4,474 Osmolality 428

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Analysis 95.0% - 110.0% 101.55% 97.90% 97.31% 96.96% Epinephrine sulfonic acid NMT 3.0% 0.00% 2.52% 2.65% 2.57% Adrenochrome NMT 0.5% 0.09% 0.45% 0.41% 0.43% Norepinephrine NMT 4.0% ND ND ND ND Adrenalone NMT 3.0% ND ND ND 0.47% Total amount of impurities < 12.0% 1.27% 3.76% 3.86% 4.41% Chlorobutanol analysis 1.56 mg/ml 1.25 mg/ml 1.16 mg/ml 1.07 mg/ml

Table 55 mg/ml or 5 mg/dose pH 4.7, 0.2% chlorobutanol at 25°C

Trial Specification (stability) Time points (days), 25°C THAT 28 56 84 rn 4,667 4.63 4,598 4.525 Osmolality 689 Analysis 95.0% - 110.0% 101.69% 98.46% 98.73% 99.61% Epinephrine sulfonic acid NMT 3.0% 0.29% 0.85% 1.08% 1.07% Adrenochrome NMT 0.5% 0.04% 0.13% 0.17% 0.18% Norepinephrine NMT 4.0% ND ND ND ND Adrenalone NMT 3.0% ND ND ND ND Total amount of impurities < 12.0% 0.47% 1.09% 1.73% 2.01% Chlorobutanol analysis 1.55 mg/ml 1.47 mg/ml 1.36 mg/ml 1.35 mg/ml

Table 56 mg/ml or 5 mg/dose pH 4.7, 0.2% chlorobutanol at 40°C

Trial Specification (stability) Time points (days), 40°C THAT 28 56 84 rn 4,667 4,586 4,524 4.47 Osmolality 689

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Analysis 95.0% - 110.0% 101.69% 100.14% 97.42% 98.92% Epinephrine sulfonic acid NMT 3.0% 0.29% 1.19% 1.34% 1.19% Adrenochrome NMT 0.5% 0.04% 0.17% 0.10% 0.15% Norepinephrine NMT 4.0% ND ND ND ND Adrenalone NMT 3.0% ND ND ND 0.05% Total amount of impurities < 12.0% 0.47% 2.45% 2.54% 3.53% Chlorobutanol analysis 1.55 mg/ml 1.25 mg/ml 1.08 mg/ml 1.07 mg/ml

Table 57 mg/ml or 6 mg/dose pH 4.7, 0.2% chlorobutanol at 25°C

Trial Specification (stability) Time points (days), 25°C THAT 28 56 84 rn 4,684 4,643 4,592 4,598 Osmolality 777 Analysis 95.0% - 110.0% 101.96% 99.59% 98.91% 100.95% Epinephrine sulfonic acid NMT 3.0% 0.30% 0.59% 0.59% 0.60% Adrenochrome NMT 0.5% 0.06% 0.13% 0.14% 0.15% Norepinephrine NMT 4.0% ND ND ND ND Adrenalone NMT 3.0% ND ND ND ND Total amount of impurities < 12.0% 0.47% 1.03% 1.48% 1.75% Chlorobutanol analysis 1.42 mg/ml 1.36 mg/ml 1.25 mg/ml 1.26 mg/ml

Table 58 mg/ml or 6 mg/dose pH 4.7, 0.2% chlorobutanol at 40°C

Trial Specification (stability) Time points (days), 40°C THAT 28 56 84 rn 4,684 4,581 4.526 4,448 Osmolality 777

- 133 045992

Analysis 95.0% - 110.0% 101.96% 99.11% 98.43% 98.67% Epinephrine sulfonic acid NMT 3.0% 0.30% 0.70% 0.70% 0.67% Adrenochrome NMT 0.5% 0.06% 0.10% 0.10% 0.11% Norepinephrine NMT 4.0% ND ND ND ND Adrenalone NMT 3.0% ND ND ND 0.06% Total amount of impurities < 12.0% 0.47% 1.97% 2.23% 3.14% Chlorobutanol analysis 1.42 mg/ml 1.21 mg/ml 1.02 mg/ml 1.01 mg/ml

Example 16. Spray characteristics.

Administration of the epinephrine spray formulation using a nasal delivery device was tested for spray characteristics including Dmax, ovality, D10, D50, D90, volume % <10 microns, and dispersion. The test results are presented in table. 59.

Table 59

Spray characteristics

Trial results results Spray pattern (n = 5 at 30 mm) Epinephrine 2 mg double dose Epinephrine 5 mg double dose First spray Form Ellipsoidal Ellipsoidal Density Relatively uniform density Relatively uniform density Dmax 26.9 mm 24.0 mm Ovality 1.454 1.327 Second spray Form Ellipsoidal Ellipsoidal Density Relatively uniform density Relatively uniform density

- 134 -

Claims (16)

Dmax 26.2 mm 24.6 Ovality 1.378 1.377 Droplet size distribution (n = 5 at 30 mm) First spray D10 21.80 µm 19.79 µm D50 53.69 µm 47.73 µm D90 126.3 µm 112.0 µm % volume < 10 µm 0.52% 0.75% Scatter 1.945 1.928 Second spray D10 20.58 µm 19.92 µm D50 50.51 µm 47.82 µm D90 119.0 µm 112.0 µm % volume < 10 µm 0.57% 0.45% Scatter 1,941 1.925 Particulate matter >10 µm: 98 particles/container >25 µm: 1 particle/container >10 µm: 28 particles/container >25 µm: 1 particle/container pH 4.6 4.7 Osmolality (mOsm/kg) 425 693 Although preferred embodiments of the present invention have been shown and described herein, those skilled in the art will recognize that such embodiments are provided by way of example only. Numerous variations, changes and substitutions will now be apparent to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in the practice of the present invention. It is intended that the following claims define the scope of the present invention and that the methods and structures within the scope of these claims and their equivalents are covered therein. CLAIM 1. Pharmaceutical composition in the form of a nasal spray containing: (a) from 1% to 10% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water; (b) 0.1% to 1.0% (w/w) chlorobutanol or chlorobutanol hemihydrate; (c) from 0.01% to 0.1% (w/w) sodium bisulfite or sodium metabisulfite, and (d) from 0.1% to 5% (w/w) diethylene glycol monoethyl ether, wherein The pharmaceutical nasal spray formulation is an aqueous solution suitable for administration into the nostril of a human subject in the form of a spray. 2. The pharmaceutical composition in the form of a nasal spray according to claim 1, wherein the pharmaceutical composition in the form of a nasal spray contains no more than 4% of the total amount of impurities after storage for a period of one month at a temperature of 40°C. 3. Pharmaceutical composition in the form of a nasal spray according to claim 1 or 2, in which the mass ratio of epinephrine to chlorobutanol or chlorobutanol hemihydrate is from 12:1 to 30:1. 4. Pharmaceutical composition in the form of a nasal spray according to claim 2, in which sodium bisulfite or meta - 135 045992 sodium bisulfite is sodium metabisulfite. 5. Pharmaceutical composition in the form of a nasal spray according to any one of claims 1 to 4, containing from 0.01% to 0.2% (w/w) hypromellose. 6. Pharmaceutical composition in the form of a nasal spray according to any one of claims 1 to 5, containing from 0.1% to 1% (w/w) citric acid or citric acid monohydrate. 7. Pharmaceutical composition in the form of a nasal spray according to any one of claims 1 to 6, containing from 0.1% to 1.0% (w/w) sodium chloride. 8. Pharmaceutical composition in the form of a nasal spray according to any one of claims 1 to 7, containing from 4% to 10% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water. 9. Pharmaceutical composition in the form of a nasal spray according to any one of claims 1 to 8, containing: (a) from 1% to 10% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water; (b) 0.1% to 5% (w/w) diethylene glycol monoethyl ether; (c) 0.01% to 0.2% (w/w) hypromellose; (d) 0.01% to 0.1% (w/w) sodium metabisulfite; (e) 0.1% to 1.0% (w/w) chlorobutanol or chlorobutanol hemihydrate; (f) 0.1% to 1.0% (w/w) citric acid or citric acid monohydrate; and (g) 0.1% to 1.0% (w/w) sodium chloride. 10. Pharmaceutical composition in the form of a nasal spray according to any one of claims 1 to 9, containing: (a) 4% to 10% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water; (b) 0.1% to 5% (w/w) diethylene glycol monoethyl ether; (c) 0.01% to 0.2% (w/w) hypromellose; (d) 0.01% to 0.1% (w/w) sodium metabisulfite; (e) 0.1% to 1.0% (w/w) chlorobutanol or chlorobutanol hemihydrate; (f) 0.1% to 1.0% (w/w) citric acid or citric acid monohydrate; and (g) 0.1% to 1.0% (w/w) sodium chloride. 11. Pharmaceutical composition in the form of a nasal spray according to any one of claims 1 to 10, containing: (a) 4% to 10% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water; (b) 1% (w/w) diethylene glycol monoethyl ether; (c) 0.1% (w/w) hypromellose; (d) 0.05% (w/w) sodium metabisulfite; (e) 0.21% (w/w) chlorobutanol or chlorobutanol hemihydrate; (f) 0.42% (w/w) citric acid or citric acid monohydrate; and (g) 0.4% (w/w) sodium chloride. 12. Pharmaceutical composition in the form of a nasal spray according to claim 1, containing: (a) 6% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water; (b) 1% (w/w) diethylene glycol monoethyl ether; (c) 0.1% (w/w) hypromellose; (d) 0.05% (w/w) sodium metabisulfite; (e) 0.21% (w/w) chlorobutanol or chlorobutanol hemihydrate; (f) 0.42% (w/w) citric acid or citric acid monohydrate; and (g) 0.4% (w/w) sodium chloride. 13. Pharmaceutical composition in the form of a nasal spray according to claim 1, containing: (a) 6.5% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water; (b) 1% (w/w) diethylene glycol monoethyl ether; (c) 0.1% (w/w) hypromellose; (d) 0.05% (w/w) sodium metabisulfite; (e) 0.21% (w/w) chlorobutanol or chlorobutanol hemihydrate; (f) 0.42% (w/w) citric acid or citric acid monohydrate; and (g) 0.4% (w/w) sodium chloride. 14. Pharmaceutical composition in the form of a nasal spray according to claim 1, containing: (h) 2% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water; (i) 1% (w/w) diethylene glycol monoethyl ether; (j) 0.1% (w/w) hypromellose; (k) 0.05% (w/w) sodium metabisulfite; (l) 0.21% (w/w) chlorobutanol or chlorobutanol hemihydrate; (m) 0.42% (w/w) citric acid or citric acid monohydrate; and (n) 0.4% (w/w) sodium chloride. 15. Pharmaceutical composition in the form of a nasal spray according to claim 1 or 3, containing 2%, 5% or 6.5% (w/w) epinephrine or a pharmaceutically acceptable salt thereof in water. 16. The pharmaceutical composition in the form of a nasal spray according to any one of claims 1 to 15, containing not more than 3% of the total amount of impurities after storage for a period of at least one month at a temperature of at least 40°C. - 136 -