WO2021026330A1

WO2021026330A1 - Methods, devices, and systems for administered epinephrine

Info

Publication number: WO2021026330A1
Application number: PCT/US2020/045165
Authority: WO
Inventors: Steven Hartman; Michelle LOBEL; Matthew P. Robben; Kenneth L. Dretchen; Michael Mesa
Original assignee: Bryn Pharma, LLC
Priority date: 2019-08-06
Filing date: 2020-08-06
Publication date: 2021-02-11

Abstract

Provided herein are epinephrine spray formulations. Also provided herein are methods of treating anaphylaxis by administering epinephrine spray formulations to subjects in need of such treatment.

Description

METHODS, DEVICES, AND SYSTEMS FOR ADMINISTERED EPINEPHRINE

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This international PCT application claims the benefit of U.S. Provisional Application No. 62/883,394, filed on August 6, 2019. This document is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Epinephrine is a catecholamine that stimulates the a- and b-adrenergic receptors of the sympathetic nervous system. Epinephrine binds to these adrenergic receptors leading to relief of many life-threatening symptoms of anaphylaxis (e.g., relaxation of the smooth muscle in the bronchi of the lungs thereby opening up constricted airways, constriction of the blood vessels leading to decreased swelling of the tongue and throat and increasing blood pressure, and increased heart rate thereby preventing or reversing cardiovascular collapse).

BRIEF SUMMARY OF THE INVENTION

[0003] Disclosed herein are pharmaceutical spray formulations. The formulations can include epinephrine formulations configured to be delivered as one or more nasal sprays. Certain advantages of the formulations disclosed herein human pharmacokinetic profiles that are substantially similar or commensurate with non-nasal modes of epinephrine administration such as, for example, intramuscular injection.

[0004] In an aspect, provided herein is a pharmaceutical spray formulation, comprising:

(i) from about 1% to about 15% (w/w) of epinephrine, or a pharmaceutically acceptable salt thereof, in water, ethanol, propylene glycol, or a combination thereof; and

(ii) at least one of an antioxidant, an antimicrobial preservative, an isotonicity agent, an absorption enhancer, a viscosity modifier, a buffering agent, or combinations thereof; wherein the formulation is configured to be administered into a nostril of a subject as a nasal spray that yields a plasma concentration of at least 0.25 pg/mL within 1 minute of administration.

[0005] In certain embodiments, the pH of the formulation is from about 4.0 to about 6.5. [0006] In certain embodiments, the pH of the formulation is from about 4.0 to about 5.0. [0007] In certain embodiments, the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration from about 0.01% to about 0.1% (w/w).

[0008] In certain embodiments, the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration from about 0.1% to about 1% (w/w). [0009] In certain embodiments, the isotonicity agent comprises sodium chloride at a concentration from about 0.1% to about 1% (w/w).

[0010] In certain embodiments, the viscosity modifier comprises hypromellose at a concentration from about 0.01% to about 0.2% (w/w).

[0011] In certain embodiments, the buffering agent comprises citric acid or citric acid monohydrate at a concentration from about 0.1% to about 1% (w/w).

[0012] In certain embodiments, the formulation comprises about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), or about 10% (w/w) of epinephrine, or a pharmaceutically acceptable salt thereof.

[0013] In certain embodiments, the formulation comprises sodium metabi sulfite, sodium chloride, hypromellose, citric acid monohydrate, diethylene glycol monoethyl ether, and chlorobutanol hemihydrate.

[0014] In certain embodiments, the formulation comprises from about 1% to about 10% (w/w) of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% (w/w) sodium chloride, from about 0.01% to about 0.2% (w/w) hypromellose, from about 0.1% to about 1% (w/w) citric acid monohydrate, from about 0.1% to about 5% (w/w) di ethylene glycol monoethyl ether, and from about 0.1% to about 1% (w/w) chlorobutanol hemihydrate.

[0015] In certain embodiments, the formulation comprises from about 0.05% (w/w) of sodium metabi sulfite, from about 0.4% sodium chloride, from about 0.1% hypromellose, about 0.42% citric acid monohydrate, and from about 1% diethylene glycol monoethyl ether. [0016] In certain embodiments, the formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof.

[0017] In another aspect, provided herein is a stable pharmaceutical spray formulation, comprising:

(ii) at least one of an antioxidant, an antimicrobial preservative, an isotonicity agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the formulation is stable for a period of at least about one month at a temperature of at least about 20 °C.

[0018] In certain embodiments, the formulation is stable for a period of at least about one month at a temperature of at least about 40 °C.

[0019] In certain embodiments, the formulation has 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. [0020] In certain embodiments, the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration from about 0.01% to about 0.1% (w/w).

[0021] In certain embodiments, the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration from about 0.1% to about 1% (w/w).

[0022] In certain embodiments, the isotonicity agent comprises sodium chloride at a concentration from about 0.1% to about 1% (w/w).

[0023] In certain embodiments, the buffering agent comprises citric acid or citric acid monohydrate at a concentration from about 0.1% to about 1% (w/w). [0024] In an aspect, provided herein is a stable pharmaceutical spray formulation, comprising:

(ii) at least one of an antioxidant, an antimicrobial preservative, an isotonicity agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the absorption enhancer is di ethylene glycol monoethyl ether.

[0025] In certain embodiments, the formulation comprises diethylene glycol monoethyl ether at a concentration from about 0.1% to about 5% (w/w).

[0026] In certain embodiments, the absorption enhancer comprises diethylene glycol monoethyl ether at a concentration of about 1% (w/w).

[0027] In an aspect, provided herein is a method of treating anaphylaxis, anaphylactic shock, a severe allergic reaction, and/or bronchial constriction, comprising delivering at least one spray of a pharmaceutical solution from a pre-primed device into a nostril of a subject in need thereof, wherein:

(i) the device is adapted for nasal delivery;

(ii) a volume of from about 20 pL to about 250 pL of spray is delivered; and

(iii) the pharmaceutical solution comprises a pharmaceutical spray formulation as disclosed herein.

[0028] In an aspect, provided herein is a method of treating anaphylaxis, anaphylactic shock, a severe allergic reaction, and/or bronchial constriction, comprising delivering at least one spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein:

(i) the device is adapted for nasal delivery; and

(ii) a volume of from about 20 pL to about 250 pL of spray is delivered; wherein the pharmaceutical solution comprises a pharmaceutical spray formulation as disclosed herein.

[0029] In certain embodiments, a therapeutic plasma concentration of epinephrine in the subject is achieved in less than 20 minutes following administration to the subject.

[0030] In certain embodiments, the therapeutic plasma concentration of epinephrine in the subject is about 0.5 ng/mL of epinephrine.

[0031] In certain embodiments, the subject has a maximum plasma concentration (C_max) of from about 50 pg/mL to about 250 pg/mL of epinephrine. [0032] In certain embodiments, the area under a plasma concentration-time curve from 0 to 180 minutes (AU o-iso₎) of epinephrine in the subject is from about 4,000 min_*pg/mL to about 20,000 mimpg /mL.

[0033] In certain embodiments, the plasma concentration versus time curve of epinephrine in the subject has a T_maxof less than from about 10 minutes to about 120 minutes.

[0034] In certain embodiments, the device is a single-dose device. In certain embodiments, the device is a bi-dose device.

[0035] In certain embodiments, the device delivers two sprays of the pharmaceutical solution from a single reservoir. In certain embodiments, the device has a first reservoir containing from about 50 pL to about 250 pL of the pharmaceutical solution and a second reservoir containing from about 50 pL to about 250 pL of the pharmaceutical solution.

[0036] In certain embodiments, less than about 20% of the formulation leaves the nasal cavity via drainage into the nasopharynx or externally.

[0037] In certain embodiments, a single spray in the nostril yields a plasma concentration of at least 25 pg/mL within 2 minutes in the subject.

[0038] In certain embodiments, a therapeutic plasma concentration of epinephrine in the subject is achieved in less than 15 minutes following administration to the subject.

[0039] In certain embodiments, a single spray in the nostril yields a plasma concentration of > 25 pg/mL within 1 minute in the subject. In certain embodiments, a single spray in the nostril yields a plasma concentration of > 45 pg/mL within 5 minutes in the subject.

INCORPORATION BY REFERENCE

[0040] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS [0041] A better understanding of the features and advantages of the present subject matter will be obtained by reference to the following detailed description that sets forth illustrative embodiments and the accompanying drawings.

[0042] FIG. 1 shows an illustrative diagram of a nasal spray delivery device.

[0043] FIG. 2 is a line graph of mean baseline adjusted blood plasma concentrations of epinephrine in humans dosed intranasally with epinephrine formulations disclosed herein and in humans dosed with an intramuscular injection administered from an autoinjector as provided in Example 2.

DETAILED DESCRIPTION

[0044] Provided herein are, for example, pharmaceutical spray formulations of epinephrine for treating anaphylaxis. Also provided herein are, for example, methods of treating anaphylaxis, anaphylactic shock, and/or a severe allergic reaction, or at least one symptom thereof.

[0045] I. DEFINITIONS

[0046] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0047] The terms "about" or "approximately", as used herein, when referring to a numerical value or range, allow for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated limit of a range.

[0048] The term "actuation", as used herein, refers to operation of the device such that the pharmaceutical composition is delivered therefrom.

[0049] The term "AUC", as used herein, refers to the area under the drug (e.g., epinephrine) plasma concentration-time curve. The term "AUCo-_t," as used herein, refers to the area under the drug plasma concentration-time curve from t=0 to the last measurable concentration. The term "AUCo-_¥," as used herein, refers to the area under the drug plasma concentration-time curve extrapolated to ¥.

[0050] The term "bioavailability" or "F", as used herein, refers to the fraction of a dose of drug (e.g., epinephrine) that is absorbed from its site of administration and reaches, in an unchanged form, the systemic circulation. The term "absolute bioavailability" is used when the fraction of absorbed drug is related to its I.V. bioavailability. It may be calculated using the following formula: p AU C extr avascular _c Dose intravenous

AUCintravenous Dose ex ravascular

[0051] The term "relative bioavailability" or "F_rei", is used to compare two different extravascular routes of drug administration and it may be calculated using the following formula:

[0052] The term "clearance" or "CL", as used herein, refers to the rate at which a drug is eliminated divided by its plasma concentration, giving a volume of plasma from which drug is completely removed per unit of time. CL is equal to the elimination rate constant (l) multiplied by the volume of distribution (Vd), wherein "Vd" is the fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma. The term "apparent clearance (CL/F)," as used herein, refers to clearance that does not take into account the bioavailability of the drug. It is the ratio of the dose over the AUC. [0053] The term "C_max", as used herein, refers to the maximum observed plasma concentration.

[0054] The term "coefficient of variation" or "CV", as used herein, refers to the ratio of the sample standard deviation to the sample mean. It is often expressed as a percentage.

[0055] The term "confidence interval", as used herein, refers to a range of values which will include the true average value of a parameter a specified percentage of the time.

[0056] The term "device", as used herein, refers to an apparatus capable of delivering a drug to patient in need thereof.

[0057] The term "delivery time", as used herein, refers to the amount of time that elapses between a determination made by a healthcare professional, or an untrained individual that an individual is in need of nasal delivery of epinephrine and completion of the delivery.

[0058] The term "elimination rate constant" or "l", as used herein, refers to the fractional rate of drug removal from the body. This rate is constant in first-order kinetics and is independent of drug concentration in the body l is the slope of the plasma concentration-time line (on a logarithmic y scale). The term "l_z," as used herein, refers to the terminal phase elimination rate constant, wherein the "terminal phase" of the drug plasma concentration-time curve is a straight line when plotted on a semi -logarithmic graph. The terminal phase is often called the "elimination phase" because the primary mechanism for decreasing drug concentration during the terminal phase is drug elimination from the body. The distinguishing characteristic of the terminal elimination phase is that the relative proportion of drug in the plasma and peripheral volumes of distribution remains constant. During this "terminal phase" drug returns from the rapid and slow distribution volumes to the plasma, and is permanently removed from the plasma by metabolism or renal excretion.

[0059] The term "epinephrine", as used herein, refers to a compound of the following structure:

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

[0060] The term "nostril", as used herein, is synonymous with "naris."

[0061] The terms "permeation enhancer", "permeability enhancer", "absorption enhancer", and "penetration enhancer", as used herein, are intended to be equivalent, all four terms referring to an agent which aids in delivering and/or increasing bioavailability and Cmax of a compound through a mucosal barrier, such as through the nasal mucosa. Permeation or absorption enhancers suitable for use in the present invention include, but are not limited to, caprylic acid, oleic acid, polysorbate 80, menthol, EDTA, sodium edetate, cetylpyridinium chloride, sodium lauryl sulfate, citric acid, sodium desoxycholate, sodium deoxyglycolate, glyceryl oleate, L-lysine, diethylene glycol monoethyl ether, a- b- or g-cyclodextrin, hydroxypropyl b-cyclodextrin, phosphatidylcholine, and combinations thereof. In some cases, the absorption enhancer comprises diethylene glycol monoethyl ether. In some cases, use of absorption enhancers can reduce T_max. In some cases, use of absorption enhancers decreases the time within which a given plasma concentration of the active ingredient is achieved following administration. Absorption enhancers may be used to increase the AUC of the active ingredient.

[0062] The term "stabilizer" and "stabilizing agent" are intended to be equivalent and refer to a chemical that is used to prevent degradation. 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 metabi sulfite, ascorbyl palmitate, thioglycerol, 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.

[0063] 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 can include such products as thickeners, texturizers, gelation agents and stiffening agents. Examples of viscosity modifiers include, but are not limited to, polyethylene glycol, methylcellulose, hypromellose, polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropylmethyl cellulose ("HPMC"), methyl cellulose, hydroxy ethyl cellulose, glycerin, polyvinyl alcohol, xanthan gum, chitosan, alginate, and combinations thereof.

[0064] Solvents suitable for use in the present invention include, but are not limited to, water, ethanol, glycerin, propylene glycol, polyethylene glycol 400 and combinations thereof.

[0065] The term "pre-primed", as used herein, refers to a device, such as a nasal spray which is capable of delivering a pharmaceutical composition to a patient in need thereof with the first actuation of the spray pump, i.e., without the need to prime a pump prior to dosing, such as by actuating the pump one or more times until a spray appears.

[0066] The term "recovery position", as used herein, means a position of the human body in which a patient lies on his/her side, with a leg or knee out in front (e.g., to prevent rolling onto his/her stomach) and at least one hand supporting the head (e.g., to elevate the face to facilitate breathing and prevent inhalation of vomit).

[0067] The term "storage-stable", as used herein, refers to a pharmaceutical composition in which at least about 95% — for example at least about 99.5% — of the active ingredient remains in an undegraded state after storage of the pharmaceutical composition at specified temperature and/or humidity for a specified time, for example, for 12 months at 25° C and 60% relative humidity.

[0068] The term "supine", as used herein, refers to a patient who is lying face up.

[0069] The term "ti_/2" or "half-life", as used herein, refers to the amount of time required for half of a drug to be eliminated from the body or the time required for a drug concentration to decline by half.

[0070] The terms "tonicity agent" and "isotonicity agent", as used herein, are interchangeable and refer to a compound which modifies the osmolality of a formulation, for example, to render it isotonic. Tonicity agents include, but are not limited to, dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffmose, polyethylene glycol, hydroxyethyl starch, glycine and the like.

[0071] The term "T_max" or "tmax", as used herein, refers to the time from administration of the pharmaceutical compositions described herein to maximum drug plasma concentration.

[0072] Liquid nasal formulations are mainly aqueous solutions, but suspensions and emulsions can also be delivered. In traditional spray pump systems, antimicrobial preservatives are typically required to maintain microbiological stability in liquid formulations. [0073] The droplet size distribution of a nasal spray influences the in vivo deposition of the drug in the nasal cavity. The droplet size is influenced by the actuation parameters of the device and the formulation. In some embodiments, the median droplet size is from about 30 pm to about 100 pm. If the droplets are too large (e.g., greater than about 120 pm), deposition takes place mainly in the anterior parts of the nose, and if the droplets are too small (e.g., less than about 10 pm), they can possibly be inhaled and reach the lungs.

[0074] Spray characterization (e.g., plume geometry, spray pattern, pump delivery, droplet size distribution, DSD) of the delivered plume subsequent to spraying may be measured under specified experimental and instrumental conditions by appropriate and validated and/or calibrated analytical procedures known in the art. These include photography, laser diffraction, and impaction systems (cascade impaction, next generation impaction (NGI), etc.). Droplet size distribution can be controlled in terms of ranges for the D10, D50, D90, span [(D90-D10)/D50], and percentage of droplets less than 10 mm. In some embodiments, the formulation will have a narrow DSD. In some embodiments, the formulation will have a Dv(50) of 30-70 pm and a Dv(90)<120 pm. The particle diameter "(D)" designations refer to the representative diameter where 10% (D10), 50% (D50) and 90% (D90) of the total volume of the liquid sprayed is made up of droplets with diameters smaller than or equal to the stated value. The spray characteristics can refer to a mean (average) or median value collected for a plurality of sprays. The plurality of sprays can be at least 2, 3, 4, 5, 6, 7, 8, 9, 10, or more sprays.

[0075] All percent compositions are given as weight-percentages, unless otherwise stated. [0076] All average molecular weights of polymers are weight-average molecular weights, unless otherwise specified.

[0077] As used herein, "subject" or "patient" (as in the subject of the treatment) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates (e.g., apes and monkeys) and non-primates (e.g., dogs, cats, cattle, horses, sheep, and goats). Non-mammals include, for example, fish and birds. Terms "subject" and "patient" are synonymous and refer, but are not limited to, a person that is experiencing type I allergies including anaphylaxis. "Patient" or "subject in need thereof refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. In some embodiments, a patient is human. [0078] The terms "disease," "disorder," or "condition" are used interchangeably and refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. The disease may be anaphylaxis. The disease may be a severe allergic reaction, and the like. The disease may be a cancer. The disease may be an autoimmune disease. The disease may be an inflammatory disease. The disease may be an infectious disease.

[0079] As used herein, the terms "type I reactions", "type I allergies", and "severe allergic reactions" are used interchangeably (i.e., 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, an anaphylactic reaction, anaphylactic shock and allergic rhinoconjunctivitis. Severe allergic reactions are caused by allergens. Non-limiting examples of allergens include an insect bite (for example a bee sting), medication (for example an antibiotic such as a penicillin), food (such as eggs, nuts, or shellfish), a chemical (for example latex), and/or any combination thereof.

[0080] As used herein, "free of propellant" refers to a formulation that is not administered using compressed gas.

[0081] The terms "spray" and "mist" are used interchangeably herein and refer to liquid (e.g., a formulation for intranasal administration) that is blown or driven through the air in the form of drops or droplets.

[0082] As used herein, all numerical values relating to amounts, weights, and the like, that are defined as "about" or "approximately" each particular value is plus or minus 10%. For example, the phrase "about 10% w/w" is to be understood as "9% w/w to 11% w/w." Therefore, amounts within 10% of the claimed value are encompassed by the scope of the claims.

[0083] As used herein, the terms "weight percent", "wt %", "% w/w", and "percent w/w" refer to the percentage concentration calculated as the fraction of the weight of the solute in a solution or formulation relative to the total weight of the solution or formulation.

[0084] As used herein, the terms "% w/v" and "percent w/v" refer to the percentage concentration calculated as the fraction of the weight of the solute in a solution or formulation relative to the total volume of the solution or formulation.

[0085] As used herein, the terms "% v/v" and "percent v/v" refer to the percentage concentration calculated as the fraction of the volume of the solute in a solution or formulation relative to the total volume of the solution or formulation. As used herein, whenever % w/w, % w/v, or % v/v is used individually, the other units of concentration are also contemplated. For example, a reference to 1% w/w of component A in a formulation also contemplates 1% w/v and/or 1% v/v of component A.

[0086] As used herein, the term "effective amount" refers to the amount necessary to treat a patient in need thereof.

[0087] The terms "treating" or "treatment" refer to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In some embodiments, treating is preventing. In some embodiments, treating does not include preventing. In some embodiments, "treat", "treating", or "treatment" refer to ameliorating or inhibiting symptoms of type I allergies including anaphylaxis.

[0088] "Treating" or "treatment", as used herein (and as well-understood in the art), also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (z.e., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms (e.g., throat or tongue swelling, itchy rash, shortness of breath, low blood pressure, inflammation, bronchoconstriction, etc.), fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things.

[0089] "Treating" and "treatment", as used herein, include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of a compound described herein. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of the compound, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.

[0090] The term "prevent" refers to a decrease in the occurrence of disease symptoms in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment. In some embodiments, prevent refers to slowing the progression of the disease, disorder or condition or inhibiting progression thereof to a harmful or otherwise undesired state.

[0091] An "effective amount" is an amount sufficient for a compound to accomplish a 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 contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a "therapeutically effective amount." A "reduction" of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., 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 their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., 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 and Wilkins). The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it can be adjusted in connection with the dosing regimen and diagnostic analysis of the subject’s condition, and the like.

[0092] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan. Adjusting the dose to achieve maximal therapeutic window efficacy or toxicity in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0093] The term "therapeutically effective amount", as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above. For example, for the 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 can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.

[0094] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state. [0095] As used herein, the term "administering" means administration by inhalation or intranasal administration. The term "intranasal" refers to administration of the composition to any portion of the nasal epithelium.

[0096] Administering may also mean oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, or subcutaneous administration, or the implantation of a slow-release device (e.g., a mini-osmotic pump) to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anti-inflammatory agent). The compound of the invention can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). Liquid form preparations include solutions, suspensions, and emulsions. In some embodiments, the compositions are water or water/propylene glycol solutions. The compositions of the present invention may additionally include components to provide sustained release and/or comfort.

[0097] By "co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds of the disclosure can be administered alone or can be co administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). [0098] In some embodiments, co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours, 2 days, 4 days, 1 week or 1 month of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another.

[0099] The term "anti-inflammatory agent" is used in accordance with its plain ordinary meaning and refers to a composition (e.g., compound, drug, antagonist, inhibitor, modulator) used in any way to reduce inflammation or swelling. In some embodiments, an anti inflammatory agent is an agent identified herein having utility in methods of treating an inflammatory disease or disorder. In some embodiments, an anti-inflammatory agent is an agent approved by the FDA or similar regulatory agency of a country other than the USA, for reducing swelling and inflammation.

[0100] For any compound, pharmaceutical composition, and/or anti-inflammatory agent described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.

[0101] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0102] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.

[0103] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

[0104] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.

[0105] As used herein, the term "anaphylaxis" refers to an allergic reaction involving multiple organ systems in a subject upon contact with an allergen whether or not that allergen is identifiable.

[0106] As used herein, the term "allergen" refers to any chemical capable of causing an immune system response in a subject including, but not limited to, chemicals found in drugs, food, plants, insect bites, and insect stings.

[0107] As used herein, the term "pharmaceutically acceptable" refers to ingredients that are not biologically or otherwise undesirable for administration to a living subject.

[0108] The term "pharmaceutically acceptable salts" is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained 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 sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained 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 like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolyl sulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge etal. , "Pharmaceutical Salts,"

Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0109] Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.

[0110] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents. In some embodiments, compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may 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 indicated, the salts disclosed herein are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0111] In some embodiments, epinephrine salts may include citrate, hydrochloride, sulfate, tartrate, phosphate, acetate, malate, maleate, succinate, ascorbate, carbonate, mesylate, and lactate salts. One of skill in the art could use other pharmaceutically acceptable epinephrine salts in the formulations disclosed herein.

[0112] In addition to salt forms, the present disclosure provides compounds, which are in a 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 disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.

[0113] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0114] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids the administration of a compound to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure. Examples of preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, sodium benzoate, chlorobutanol, benzalkonium chloride, benzoic acid and combinations thereof.

[0115] It is 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 persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

[0116] II. COMPOSITIONS/FORMULATIONS

[0117] In an aspect, provided herein is a pharmaceutical spray formulation, comprising:

(ii) at least one (e.g., at least 2 of, at least 3 of, or at least 4 of) of an antioxidant, an antimicrobial preservative, an isotonicity agent, an absorption enhancer, a viscosity modifier, a buffering agent, or combinations thereof; wherein the formulation is configured to be administered into a nostril of a subject as a nasal spray that yields a plasma concentration of at least about 0.25 pg/mL (e.g., at least about 0.35 pg/mL, at least about 0.45 pg/mL, or at least about 0.55 pg/mL) within about 1 minute (e.g., within about 1.5 min, within about 3 min, or within about 5 min) of administration.

[0118] In certain embodiments, the pH of the formulation is from about 4.0 to about 6.5. In certain embodiments, the pH of the formulation is from about 4.0 to about 5.0 (e.g., from about 4.1 to about 4.8, from about 4.2 to about 4.7, from about 4.5 to about 4.7, about 4.5, about 4.6, or about 4.7).

[0119] In certain embodiments, the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration from about 0.01% to about 0.1% (w/w). For example, in certain embodiments, the antioxidant comprises (or consists essentially of) sodium metabisulfite at a concentration from about 0.01% to about 0.08% (w/w) (e.g., from about 0.03% to about 0.07% (w/w), from about 0.04% to about 0.06% (w/w), about 0.04% (w/w), about 0.05% (w/w), about 0.07% (w/w), or about 0.08% (w/w)).

[0120] In certain embodiments, the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration from about 0.1% to about 1% (w/w). For example, in certain embodiments, the antimicrobial preservative comprises (or consists essentially of) chlorobutanol hemihydrate at a concentration from about 0.1% to about 1% (w/w) (e.g., from about 0.1% to about 0.5% (w/w), from about 0.15% to about 0.35% (w/w), from about 0.2% to about 0.3% (w/w), from about 0.3% to about 0.5% (w/w), from about 0.2% to about 0.25% (w/w), about 0.1% (w/w), about 0.2% (w/w), about 0.3% (w/w), about 0.4% (w/w), or about 0.5% (w/w)).

[0121] In certain embodiments, the isotonicity agent comprises sodium chloride (NaCl) at a concentration from about 0.1% to about 1% (w/w). For example, in certain embodiments, the isotonicity agent comprises (or consists essentially of) sodium chloride at a concentration from about 0.1% to about 1% (w/w) (e.g., from about 0.3% to about 0.8% (w/w), from about 0.4% to about 0.7% (w/w), from about 0.5% to about 0.7% (w/w), from about 0.3% to about 0.5% (w/w), from about 0.35% to about 0.45% (w/w), about 0.2% (w/w), about 0.3% (w/w), about 0.4% (w/w), about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), or about 0.8% (w/w)).

[0122] In certain embodiments, the viscosity modifier comprises (or consists essentially of) hypromellose at a concentration from about 0.01% to about 0.2% (w/w). For example, in certain embodiments, the viscosity modifier comprises (or consists essentially of) hypromellose at a concentration from about 0.05% to about 0.15% (w/w) (e.g., from about 0.06% to about 0.12% (w/w), from about 0.07% to about 0.125% (w/w), or from about 0.08% to about 0.12% (w/w)).

[0123] In certain embodiments, the buffering agent comprises citric acid or citric acid monohydrate at a concentration from about 0.1% to about 1% (w/w). For example, in certain embodiments, the buffering agent comprises (or consists essentially of) citric acid monohydrate at a concentration from about 0.1% to about 1% (w/w) (e.g., from about 0.1% to about 0.75% (w/w), from about 0.2% to about 0.65% (w/w), from about 0.3% to about 0.5% (w/w), about 0.3% (w/w), about 0.4% (w/w), about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), or about 0.8% (w/w)).

[0124] In certain embodiments, the formulation comprises about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), or about 10% (w/w) of epinephrine, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In certain embodiments, the formulation comprises from about 2.5% to about 15% (w/w) (e.g., from about 2.6% to about 12% (w/w), from about 2.85% to about 10% (w/w), from about 3% to about 10% (w/w), from about 2.75% to about 7.5% (w/w), from about 3.00% to about 7.5% (w/w), from about 3.5% to about 6.5% (w/w), from about 2.75% to about 8% (w/w), from about 3% to about 8% (w/w), about 3.0% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w), about 5% (w/w), about 5.5% (w/w), about 6% (w/w), about 6.5% (w/w), about 7% (w/w), about 7.5% (w/w), about 8% (w/w), about 8.5% (w/w), or about 9% (w/w)) of epinephrine, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0125] In certain embodiments, the formulation comprises (or consists essentially of) sodium metabi sulfite, sodium chloride, hypromellose, citric acid monohydrate, diethylene glycol monoethyl ether, and chlorobutanol hemihydrate.

[0126] In certain embodiments, the formulation comprises (or consists essentially of) from about 1% to about 15% (w/w) (e.g., from about 2.75% to about 12% (w/w), from about 2.85% to about 10% (w/w), from about 3% to about 10% (w/w), from about 2.75% to about 7.5% (w/w), from about 3.00% to about 7.5% (w/w), from about 3.5% to about 6.5% (w/w), from about 2.75% to about 8% (w/w), from about 3% to about 8% (w/w), about 3.0% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w), about 5% (w/w), about 5.5% (w/w), about 6% (w/w), about 6.5% (w/w), about 7% (w/w), about 7.5% (w/w), about 8% (w/w), about 8.5% (w/w), or about 9% (w/w)) of epinephrine, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; from about 0.01% to about 0.1% (w/w) (e.g., from about 0.03% to about 0.07% (w/w), from about 0.04% to about 0.06% (w/w), about 0.04% (w/w), about 0.05% (w/w), about 0.07% (w/w), or about 0.08% (w/w)) of sodium metabi sulfite; from about 0.1% to about 1% (w/w) (e.g., from about 0.3% to about 0.8% (w/w), from about 0.4% to about 0.7% (w/w), from about 0.5% to about 0.7% (w/w), from about 0.3% to about 0.5% (w/w), from about 0.35% to about 0.45% (w/w), about 0.2% (w/w), about 0.3% (w/w), about 0.4% (w/w), about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), or about 0.8% (w/w)) sodium chloride; from about 0.01% to about 0.2% (w/w) (e.g., from about 0.06% to about 0.12% (w/w), from about 0.07% to about 0.125% (w/w), or from about 0.08% to about 0.12% (w/w)) hypromellose; from about 0.1% to about 1% (w/w) (e.g., from about 0.1% to about 0.75% (w/w), from about 0.2% to about 0.65% (w/w), from about 0.3% to about 0.5% (w/w), about 0.3% (w/w), about 0.4% (w/w), about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), or about 0.8% (w/w)) citric acid monohydrate; from about 0.1% to about 5% (w/w) (e.g., from about 0.25% to about 4.5% (w/w), from about 2% to about 4.5% (w/w), from about 0.5% to about 2.5% (w/w), from about 0.75% to about 1.25% (w/w), from about 3.25% to about 3.75% (w/w), from about 0.5% to about 1.5%

(w/w), about 3.25% (w/w), about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), or about 4.5% (w/w)) diethylene glycol monoethyl ether; and from about 0.1% to about 1% (w/w) (e.g., from about 0.1% to about 0.5% (w/w), from about 0.15% to about 0.35% (w/w), from about 0.2% to about 0.3% (w/w), from about 0.3% to about 0.5% (w/w), from about 0.2% to about 0.25% (w/w), about 0.1% (w/w), about 0.2% (w/w), about 0.3% (w/w), about 0.4% (w/w), or about 0.5% (w/w)) chlorobutanol hemihydrate.

[0127] In certain embodiments, the formulation comprises from about 0.05% (w/w) of sodium metabi sulfite, from about 0.4% sodium chloride, from about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0128] In certain embodiments, the formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof. In certain embodiments, the formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof.

[0129] In another aspect, provided herein is a stable pharmaceutical spray formulation, comprising:

(ii) at least one (e.g., at least 2, at least 3, or at least 4) of an antioxidant, an antimicrobial preservative, an isotonicity agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the formulation is stable for a period of at least about one month at a temperature of at least about 20 °C.

[0130] In certain embodiments, the formulation is stable for a period of at least about one month at a temperature of at least about 40 °C.

[0131] In certain embodiments, the formulation has 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. [0132] In certain embodiments, the pH of the formulation is from about 4.0 to about 6.5. In certain embodiments, the pH of the formulation is from about 4.0 to about 5.0 (e.g., from about 4.1 to about 4.8, from about 4.2 to about 4.7, from about 4.5 to about 4.7, about 4.5, about 4.6, or about 4.7).

[0133] In certain embodiments, the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration from about 0.01% to about 0.1% (w/w). For example, in certain embodiments, the antioxidant comprises (or consists essentially of) sodium metabisulfite at a concentration from about 0.01% to about 0.08% (w/w) (e.g., from about 0.03% to about 0.07% (w/w), from about 0.04% to about 0.06% (w/w), about 0.04% (w/w), about 0.05% (w/w), about 0.07% (w/w), or about 0.08% (w/w)).

[0134] In certain embodiments, the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration from about 0.1% to about 1% (w/w). For example, in certain embodiments, the antimicrobial preservative comprises (or consists essentially of) chlorobutanol hemihydrate at a concentration from about 0.1% to about 1% (w/w) (e.g., from about 0.1% to about 0.5% (w/w), from about 0.15% to about 0.35% (w/w), from about 0.2% to about 0.3% (w/w), from about 0.3% to about 0.5% (w/w), from about 0.2% to about 0.25% (w/w), about 0.1% (w/w), about 0.2% (w/w), about 0.3% (w/w), about 0.4% (w/w), or about 0.5% (w/w)).

[0135] In certain embodiments, the isotonicity agent comprises sodium chloride (NaCl) at a concentration from about 0.1% to about 1% (w/w). For example, in certain embodiments, the isotonicity agent comprises (or consists essentially of) sodium chloride at a concentration from about 0.1% to about 1% (w/w) (e.g., from about 0.3% to about 0.8% (w/w), from about 0.4% to about 0.7% (w/w), from about 0.5% to about 0.7% (w/w), from about 0.3% to about 0.5% (w/w), from about 0.35% to about 0.45% (w/w), about 0.2% (w/w), about 0.3% (w/w), about 0.4% (w/w), about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), or about 0.8% (w/w)).

[0136] In certain embodiments, the viscosity modifier comprises (or consists essentially of) hypromellose at a concentration from about 0.01% to about 0.2% (w/w). For example, in certain embodiments, the viscosity modifier comprises (or consists essentially of) hypromellose at a concentration from about 0.05% to about 0.15% (w/w) (e.g., from about 0.06% to about 0.12% (w/w), from about 0.07% to about 0.125% (w/w), or from about 0.08% to about 0.12% (w/w)).

[0137] In certain embodiments, the buffering agent comprises citric acid or citric acid monohydrate at a concentration from about 0.1% to about 1% (w/w). For example, in certain embodiments, the buffering agent comprises (or consists essentially of) citric acid monohydrate at a concentration from about 0.1% to about 1% (w/w) (e.g., from about 0.1% to about 0.75% (w/w), from about 0.2% to about 0.65% (w/w), from about 0.3% to about 0.5% (w/w), about 0.3% (w/w), about 0.4% (w/w), about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), or about 0.8% (w/w)). [0138] In certain embodiments, the formulation comprises about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), or about 10% (w/w) of epinephrine, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. In certain embodiments, the formulation comprises from about 2.5% to about 15% (w/w) (e.g., from about 2.6% to about 12% (w/w), from about 2.85% to about 10% (w/w), from about 3% to about 10% (w/w), from about 2.75% to about 7.5% (w/w), from about 3.00% to about 7.5% (w/w), from about 3.5% to about 6.5% (w/w), from about 2.75% to about 8% (w/w), from about 3% to about 8% (w/w), about 3.0% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w), about 5% (w/w), about 5.5% (w/w), about 6% (w/w), about 6.5% (w/w), about 7% (w/w), about 7.5% (w/w), about 8% (w/w), about 8.5% (w/w), or about 9% (w/w)) of epinephrine, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0139] In certain embodiments, the formulation comprises (or consists essentially of) sodium metabi sulfite, sodium chloride, hypromellose, citric acid monohydrate, diethylene glycol monoethyl ether, and chlorobutanol hemihydrate.

[0140] In certain embodiments, the formulation comprises (or consists essentially of) from about 1% to about 15% (w/w) (e.g., from about 2.75% to about 12% (w/w), from about 2.85% to about 10% (w/w), from about 3% to about 10% (w/w), from about 2.75% to about 7.5% (w/w), from about 3.00% to about 7.5% (w/w), from about 3.5% to about 6.5% (w/w), from about 2.75% to about 8% (w/w), from about 3% to about 8% (w/w), about 3.0% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w), about 5% (w/w), about 5.5% (w/w), about 6% (w/w), about 6.5% (w/w), about 7% (w/w), about 7.5% (w/w), about 8% (w/w), about 8.5% (w/w), or about 9% (w/w)) of epinephrine, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; from about 0.01% to about 0.1% (w/w) (e.g., from about 0.03% to about 0.07% (w/w), from about 0.04% to about 0.06% (w/w), about 0.04% (w/w), about 0.05% (w/w), about 0.07% (w/w), or about 0.08% (w/w)) of sodium metabi sulfite; from about 0.1% to about 1% (w/w) (e.g., from about 0.3% to about 0.8% (w/w), from about 0.4% to about 0.7% (w/w), from about 0.5% to about 0.7% (w/w), from about 0.3% to about 0.5% (w/w), from about 0.35% to about 0.45% (w/w), about 0.2% (w/w), about 0.3% (w/w), about 0.4% (w/w), about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), or about 0.8% (w/w)) sodium chloride; from about 0.01% to about 0.2% (w/w) (e.g., from about 0.06% to about 0.12% (w/w), from about 0.07% to about 0.125% (w/w), or from about 0.08% to about 0.12% (w/w)) hypromellose; from about 0.1% to about 1% (w/w) (e.g., from about 0.1% to about 0.75% (w/w), from about 0.2% to about 0.65% (w/w), from about 0.3% to about 0.5% (w/w), about 0.3% (w/w), about 0.4% (w/w), about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), or about 0.8% (w/w)) citric acid monohydrate; from about 0.1% to about 5% (w/w) (e.g., from about 0.25% to about 4.5% (w/w), from about 2% to about 4.5% (w/w), from about 0.5% to about 2.5% (w/w), from about 0.75% to about 1.25% (w/w), from about 3.25% to about 3.75% (w/w), from about 0.5% to about 1.5% (w/w), about 3.25% (w/w), about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), or about 4.5% (w/w)) diethylene glycol monoethyl ether; and from about 0.1% to about 1% (w/w) (e.g., from about 0.1% to about 0.5% (w/w), from about 0.15% to about 0.35% (w/w), from about 0.2% to about 0.3% (w/w), from about 0.3% to about 0.5% (w/w), from about 0.2% to about 0.25% (w/w), about 0.1% (w/w), about 0.2% (w/w), about 0.3% (w/w), about 0.4% (w/w), or about 0.5% (w/w)) chlorobutanol hemihydrate.

[0141] In certain embodiments, the formulation comprises (or consists essentially of) from about 1% to about 15% (w/w) (e.g., from about 2.75% to about 12% (w/w), from about 2.85% to about 10% (w/w), from about 3% to about 10% (w/w), from about 2.75% to about 7.5% (w/w), from about 3.00% to about 7.5% (w/w), from about 3.5% to about 6.5% (w/w), from about 2.75% to about 8% (w/w), from about 3% to about 8% (w/w), about 3.0% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w), about 5% (w/w), about 5.5% (w/w), about 6% (w/w), about 6.5% (w/w), about 7% (w/w), about 7.5% (w/w), about 8% (w/w), about 8.5% (w/w), or about 9% (w/w)) of epinephrine, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; from about 0.01% to about 0.1% (w/w) (e.g., from about 0.03% to about 0.07% (w/w), from about 0.04% to about 0.06% (w/w), about 0.04% (w/w), about 0.05% (w/w), about 0.07% (w/w), or about 0.08% (w/w)) of sodium metabi sulfite; from about 0.1% to about 1% (w/w) (e.g., from about 0.3% to about 0.8% (w/w), from about 0.4% to about 0.7% (w/w), from about 0.5% to about 0.7% (w/w), from about 0.3% to about 0.5% (w/w), from about 0.35% to about 0.45% (w/w), about 0.2% (w/w), about 0.3% (w/w), about 0.4% (w/w), about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), or about 0.8% (w/w)) sodium chloride; from about 0.01% to about 0.2% (w/w) (e.g., from about 0.06% to about 0.12% (w/w), from about 0.07% to about 0.125% (w/w), or from about 0.08% to about 0.12% (w/w)) hypromellose; from about 0.1% to about 1% (w/w) (e.g., from about 0.1% to about 0.75% (w/w), from about 0.2% to about 0.65% (w/w), from about 0.3% to about 0.5% (w/w), about 0.3% (w/w), about 0.4% (w/w), about 0.5% (w/w), about 0.6% (w/w), about 0.7% (w/w), or about 0.8% (w/w)) citric acid monohydrate; from about 0.1% to about 5% (w/w) (e.g., from about 0.25% to about 4.5% (w/w), from about 2% to about 4.5% (w/w), from about 0.5% to about 2.5% (w/w), from about 0.75% to about 1.25% (w/w), from about 3.25% to about 3.75% (w/w), from about 0.5% to about 1.5% (w/w), about 3.25% (w/w), about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), or about 4.5% (w/w)) diethylene glycol monoethyl ether; from about 0.1% to about 1% (w/w) (e.g., from about 0.1% to about 0.5% (w/w), from about 0.15% to about 0.35% (w/w), from about 0.2% to about 0.3% (w/w), from about 0.3% to about 0.5% (w/w), from about 0.2% to about 0.25% (w/w), about 0.1% (w/w), about 0.2% (w/w), about 0.3% (w/w), about 0.4% (w/w), or about 0.5% (w/w)) chlorobutanol hemihydrate; and from about 0.05% to about 0.15% (w/w) (e.g., from about 0.06% to about 0.12% (w/w), from about 0.07% to about 0.125% (w/w), or from about 0.08% to about 0.12% (w/w)) hypromellose.

[0142] In certain embodiments, the formulation comprises from about 0.05% (w/w) of sodium metabi sulfite, from about 0.4% sodium chloride, from about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0143] In an aspect, provided herein is a stable pharmaceutical spray formulation, comprising:

[0144] In certain embodiments, the formulation comprises diethylene glycol monoethyl ether at a concentration from about 0.1% to about 5% (w/w) (e.g., from about 0.25% to about 4.5% (w/w), from about 2% to about 4.5% (w/w), from about 0.5% to about 2.5% (w/w), from about 0.75% to about 1.25% (w/w), from about 3.25% to about 3.75% (w/w), from about 0.5% to about 1.5% (w/w), about 3.25% (w/w), about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), or about 4.5% (w/w)).

[0145] 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 any of the temperatures provided herein for a period of at least 3 months, at least 4 months, at least 5 months, at least 6 months, or at least 12 months.

[0146] 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%.

[0147] 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 for 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.

[0148] 1 Viscosity Modifiers

[0149] In some embodiments, the pharmaceutical spray formulation comprises a viscosity modifier. Viscosity modifiers can include such products as thickeners, texturizers, gelation agents and stiffening agents. In some embodiments, the viscosity modifier is polyethylene glycol, methylcellulose, hypromellose, polyvinylpyrrolidone, carboxymethyl cellulose, hydroxypropylmethyl cellulose ("HPMC"), methyl cellulose, hydroxy ethyl cellulose, glycerin, polyvinyl alcohol, xanthan gum, chitosan, alginate, or any combinations 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 carboxymethyl cellulose. In some embodiments, the viscosity modifier is hydroxypropylmethyl cellulose. In some embodiments, the viscosity modifier is methyl cellulose. In some embodiments, the viscosity modifier is hydroxyethyl cellulose. In some embodiments, the viscosity modifier is glycerin. 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 alginate.

[0150] In some embodiments, the pharmaceutical spray formulation comprises about 0.001% (w/w) to about 1% (w/w) of a viscosity modifier. In some embodiments, the pharmaceutical spray formulation comprises about 0.001% (w/w) to about 0.5% (w/w) of a viscosity modifier. In some embodiments, the pharmaceutical spray formulation comprises about 0.001% (w/w) to about 1% (w/w) of a viscosity modifier. In some embodiments, the pharmaceutical spray formulation comprises about 0.01% (w/w) to about 1% (w/w) of a viscosity modifier. In some embodiments, the pharmaceutical spray formulation comprises about 0.01% (w/w) to about 0.5% (w/w) of a viscosity modifier. In some embodiments, the pharmaceutical spray formulation comprises about 0.1% (w/w) of a viscosity modifier. In some embodiments, the pharmaceutical spray formulation comprises at least about 0.001% (w/w), at least about 0.01% (w/w), or at least about 0.1% (w/w), and/or no more than about 5% (w/w), no more than about 1% (w/w), no more than about 0.5% (w/w), no more than about 0.4% (w/w), no more than about 0.3% (w/w), no more than about 0.2% (w/w), or no more than about 0.1% (w/w) of a viscosity modifier.

[0151] In some embodiments, the pharmaceutical spray formulation comprises a viscosity modifier at a concentration of about 0.001 % (w/w) to about 2 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises a viscosity modifier at a concentration of at least about 0.001 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises a viscosity modifier at a concentration of at most about 2 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises a viscosity modifier at a concentration of about 0.001 % (w/w) to about 0.01 % (w/w), about 0.001 % (w/w) to about 0.05 % (w/w), about 0.001 % (w/w) to about 0.06 % (w/w), about

0.001 % (w/w) to about 0.07 % (w/w), about 0.001 % (w/w) to about 0.08 % (w/w), about

0.001 % (w/w) to about 0.09 % (w/w), about 0.001 % (w/w) to about 0.1 % (w/w), about

0.001 % (w/w) to about 0.5 % (w/w), about 0.001 % (w/w) to about 1 % (w/w), about 0.001 % (w/w) to about 1.5 % (w/w), about 0.001 % (w/w) to about 2 % (w/w), about 0.01 % (w/w) to about 0.05 % (w/w), about 0.01 % (w/w) to about 0.06 % (w/w), about 0.01 % (w/w) to about 0.07 % (w/w), about 0.01 % (w/w) to about 0.08 % (w/w), about 0.01 % (w/w) to about 0.09 % (w/w), about 0.01 % (w/w) to about 0.1 % (w/w), about 0.01 % (w/w) to about 0.5 % (w/w), about 0.01 % (w/w) to about 1 % (w/w), about 0.01 % (w/w) to about 1.5 % (w/w), about 0.01 % (w/w) to about 2 % (w/w), about

0.05 % (w/w) to about 0.06 % (w/w), about 0.05 % (w/w) to about 0.07 % (w/w), about

0.05 % (w/w) to about 0.08 % (w/w), about 0.05 % (w/w) to about 0.09 % (w/w), about

0.05 % (w/w) to about 0.1 % (w/w), about 0.05 % (w/w) to about 0.5 % (w/w), about

0.05 % (w/w) to about 1 % (w/w), about 0.05 % (w/w) to about 1.5 % (w/w), about

0.05 % (w/w) to about 2 % (w/w), about 0.06 % (w/w) to about 0.07 % (w/w), about

0.06 % (w/w) to about 0.08 % (w/w), about 0.06 % (w/w) to about 0.09 % (w/w), about

0.06 % (w/w) to about 0.1 % (w/w), about 0.06 % (w/w) to about 0.5 % (w/w), about

0.06 % (w/w) to about 1 % (w/w), about 0.06 % (w/w) to about 1.5 % (w/w), about

0.06 % (w/w) to about 2 % (w/w), about 0.07 % (w/w) to about 0.08 % (w/w), about

0.07 % (w/w) to about 0.09 % (w/w), about 0.07 % (w/w) to about 0.1 % (w/w), about

0.07 % (w/w) to about 0.5 % (w/w), about 0.07 % (w/w) to about 1 % (w/w), about

0.07 % (w/w) to about 1.5 % (w/w), about 0.07 % (w/w) to about 2 % (w/w), about

0.08 % (w/w) to about 0.09 % (w/w), about 0.08 % (w/w) to about 0.1 % (w/w), about

0.08 % (w/w) to about 0.5 % (w/w), about 0.08 % (w/w) to about 1 % (w/w), about

0.08 % (w/w) to about 1.5 % (w/w), about 0.08 % (w/w) to about 2 % (w/w), about

0.09 % (w/w) to about 0.1 % (w/w), about 0.09 % (w/w) to about 0.5 % (w/w), about

0.09 % (w/w) to about 1 % (w/w), about 0.09 % (w/w) to about 1.5 % (w/w), about

0.09 % (w/w) to about 2 % (w/w), about 0.1 % (w/w) to about 0.5 % (w/w), about

0.1 % (w/w) to about 1 % (w/w), about 0.1 % (w/w) to about 1.5 % (w/w), about 0.1 % (w/w) to about 2 % (w/w), about 0.5 % (w/w) to about 1 % (w/w), about 0.5 % (w/w) to about

1.5 % (w/w), about 0.5 % (w/w) to about 2 % (w/w), about 1 % (w/w) to about 1.5 % (w/w), about 1 % (w/w) to about 2 % (w/w), or about 1.5 % (w/w) to about 2 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises 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 % (w/w), about 0.07 % (w/w), about 0.08 % (w/w), about 0.09 % (w/w), about

0.1 % (w/w), about 0.5 % (w/w), about 1 % (w/w), about 1.5 % (w/w), or about 2 % (w/w).

In some embodiments, the viscosity modifier is hypromellose.

[0152] In some embodiments, the pharmaceutical spray formulation has 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, 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 no more than about 100 cP, no more than about 250 cP, no more than about 500 cP, no more than about 750 cP, no more than about 1000 cP, no more than about 1250 cP, no more than about 1500 cP, no more than about 1750 cP, no more than about 2000 cP, no more than about 2250 cP, or no more than about 2500 cP.

[0153] In some embodiments, the pharmaceutical spray formulation has a viscosity of about 100 cP to about 2,500 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 at most about 2,500 cP. In some embodiments, the pharmaceutical spray formulation has a viscosity of about 100 cP to about 250 cP, about 100 cP to about 500 cP, about 100 cP to about 750 cP, about 100 cP to about 1,000 cP, about 100 cP to about 1,250 cP, about 100 cP to about 1,500 cP, about 100 cP to about 1,750 cP, about 100 cP to about 2,000 cP, about 100 cP to about 2,250 cP, about 100 cP to about

2.500 cP, about 250 cP to about 500 cP, about 250 cP to about 750 cP, about 250 cP to about 1,000 cP, about 250 cP to about 1,250 cP, about 250 cP to about 1,500 cP, about 250 cP to about 1,750 cP, about 250 cP to about 2,000 cP, about 250 cP to about 2,250 cP, about

250 cP to about 2,500 cP, about 500 cP to about 750 cP, about 500 cP to about 1,000 cP, about 500 cP to about 1,250 cP, about 500 cP to about 1,500 cP, about 500 cP to about 1,750 cP, about 500 cP to about 2,000 cP, about 500 cP to about 2,250 cP, about 500 cP to about 2,500 cP, about 750 cP to about 1,000 cP, about 750 cP to about 1,250 cP, about 750 cP to about 1,500 cP, about 750 cP to about 1,750 cP, about 750 cP to about 2,000 cP, about 750 cP to about 2,250 cP, about 750 cP to about 2,500 cP, about 1,000 cP to about

1,250 cP, about 1,000 cP to about 1,500 cP, about 1,000 cP to about 1,750 cP, about 1,000 cP to about 2,000 cP, about 1,000 cP to about 2,250 cP, about 1,000 cP to about 2,500 cP, about

1.250 cP to about 1,500 cP, about 1,250 cP to about 1,750 cP, about 1,250 cP to about 2,000 cP, about 1,250 cP to about 2,250 cP, about 1,250 cP to about 2,500 cP, about 1,500 cP to about 1,750 cP, about 1,500 cP to about 2,000 cP, about 1,500 cP to about 2,250 cP, about

1.500 cP to about 2,500 cP, about 1,750 cP to about 2,000 cP, about 1,750 cP to about

2.250 cP, about 1,750 cP to about 2,500 cP, about 2,000 cP to about 2,250 cP, about 2,000 cP to about 2,500 cP, or about 2,250 cP to about 2,500 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 1,000 cP, about 1,250 cP, about 1,500 cP, about 1,750 cP, about 2,000 cP, about 2,250 cP, or about 2,500 cP. [0154] In an aspect provided herein, the pharmaceutical spray formulation further comprises a viscosity modifier. In some embodiments, the viscosity modifier is polyethylene glycol, methylcellulose, or hypromellose.

[0155] In some embodiments, the pharmaceutical spray formulation further comprises polyethylene glycol. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.5% to about 50% polyethylene glycol.

[0156] In some embodiments, the pharmaceutical spray formulation further comprises methylcellulose. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.001% to about 5% methylcellulose.

[0157] In some embodiments, the pharmaceutical spray formulation further comprises hypromellose. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.001% to about 0.5% hypromellose. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.05% to about 0.5% hypromellose. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.05% to about 0.4% hypromellose. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.05% to about 0.3% hypromellose. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.05% to about 0.3% hypromellose. In some embodiments, the pharmaceutical spray formulation further comprises about 0.1% hypromellose.

[0158] 2. _ Buffering Agents

[0159] In some embodiments, the pharmaceutical spray formulation comprises a buffering agent. In some embodiments, the buffering agent is citric acid, citrate, citric acid monohydrate, or any combination thereof. In some embodiments, the buffering agent is sodium phosphate or sodium citrate.

[0160] In some embodiments, the pH of the pharmaceutical spray formulation is from about 3.5 to about 6.5. In some embodiments, the pH of the pharmaceutical spray formulation is from about 3.5 to about 6.0. In some embodiments, the pH of the pharmaceutical spray formulation is from about 3.5 to about 5.5. In some embodiments, the pH of the pharmaceutical spray formulation is from about 3.5 to about 5.0. In some embodiments, the pH of the pharmaceutical spray formulation is from about 3.5 to about 4.5. In some embodiments, the pH of the pharmaceutical spray formulation is from about 3.5 to about 4.0. [0161] In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.0 to about 6.5. In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.0 to about 6 0 In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.0 to about 5 5 In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.0 to about 5 0 In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.0 to about 4 5

[0162] In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.0 to about 4 5 In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.0 to about 5 0 In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.0 to about 5 5 In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.0 to about 6 0 In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.0 to about 6 5

[0163] In some embodiments, the pH of the pharmaceutical spray formulation is from about

4.5 to about 5 0 In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.5 to about 5 5 In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.5 to about 6 0 In some embodiments, the pH of the pharmaceutical spray formulation is from about 4.5 to about 6 5

[0164] In some embodiments, the pH of the pharmaceutical spray formulation is from about 5.0 to about 5 5 In some embodiments, the pH of the pharmaceutical spray formulation is from about 5.0 to about 6 0 In some embodiments, the pH of the pharmaceutical spray formulation is from about 5.0 to about 6 5

[0165] In some embodiments, the pH of the pharmaceutical spray formulation is from about

5.5 to about 6 0 In some embodiments, the pH of the pharmaceutical spray formulation is from about 5.5 to about 6 5 In some embodiments, the pH of the pharmaceutical spray formulation is from about 6.0 to about 6 5

[0166] 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 1 In some embodiments, the pH of the pharmaceutical spray formulation is about 4 2 In some embodiments, the pH of the pharmaceutical spray formulation is about 4 3 In some embodiments, the pH of the pharmaceutical spray formulation is about 4 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 6 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 4 8 In some embodiments, the pH of the pharmaceutical spray formulation is about 4.9. 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 no 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.

[0167] In some embodiments, the pharmaceutical spray formulation has a pH of about 3.5 to about 7.5. In some embodiments, the pharmaceutical spray formulation has a pH of at least about 3.5. In some embodiments, the pharmaceutical spray formulation has a pH of at most about 7.5. In some embodiments, the pharmaceutical spray formulation has a pH of about 3.5 to about 4, about 3.5 to about 4.5, about 3.5 to about 5, about 3.5 to about 5.5, about 3.5 to about 6, about 3.5 to about 6.5, about 3.5 to about 7, about 3.5 to about 7.5, about 4 to about

4.5, about 4 to about 5, about 4 to about 5.5, about 4 to about 6, about 4 to about 6.5, about 4 to about 7, about 4 to about 7.5, about 4.5 to about 5, about 4.5 to about 5.5, about 4.5 to about 6, about 4.5 to about 6.5, about 4.5 to about 7, about 4.5 to about 7.5, about 5 to about

5.5, about 5 to about 6, about 5 to about 6.5, about 5 to about 7, about 5 to about 7.5, about 5.5 to about 6, about 5.5 to about 6.5, about 5.5 to about 7, about 5.5 to about 7.5, about 6 to about 6.5, about 6 to about 7, about 6 to about 7.5, about 6.5 to about 7, about 6.5 to about

7.5, or about 7 to about 7.5. In some embodiments, the pharmaceutical spray formulation has a pH 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

[0168] In some embodiments, the pH is controlled (or adjusted) by the addition of hydrochloric acid, citric acid, citrate, citric acid monohydrate, or a combination thereof. In some embodiments, the pH is controlled by the addition of hydrochloric acid. In some embodiments, the pH is controlled by the addition of citric acid. In some embodiments, the pH is controlled by the addition of citrate. In some embodiments, the pH is controlled by the addition of citric acid monohydrate. In some embodiments, the pH is controlled by the addition of a combination of hydrochloric acid and any of citric acid, citrate, of citric acid monohydrate

[0169] In some embodiments, the pharmaceutical spray formulation comprises a buffering agent at a concentration of about 0.01 % (w/w) to about 2 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises a buffering agent at a concentration of at least about 0.01 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises a buffering agent at a concentration of at most about 2 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises a buffering agent at a concentration of about 0.01 % (w/w) to about 0.1 % (w/w), about 0.01 % (w/w) to about

0.2 % (w/w), about 0.01 % (w/w) to about 0.3 % (w/w), about 0.01 % (w/w) to about

0.4 % (w/w), about 0.01 % (w/w) to about 0.5 % (w/w), about 0.01 % (w/w) to about

0.6 % (w/w), about 0.01 % (w/w) to about 0.7 % (w/w), about 0.01 % (w/w) to about

0.8 % (w/w), about 0.01 % (w/w) to about 0.9 % (w/w), about 0.01 % (w/w) to about

1 % (w/w), about 0.01 % (w/w) to about 2 % (w/w), about 0.1 % (w/w) to about 0.2 % (w/w), about 0.1 % (w/w) to about 0.3 % (w/w), about 0.1 % (w/w) to about 0.4 % (w/w), about

0.1 % (w/w) to about 0.5 % (w/w), about 0.1 % (w/w) to about 0.6 % (w/w), about

0.1 % (w/w) to about 0.7 % (w/w), about 0.1 % (w/w) to about 0.8 % (w/w), about

0.1 % (w/w) to about 0.9 % (w/w), about 0.1 % (w/w) to about 1 % (w/w), about 0.1 % (w/w) to about 2 % (w/w), about 0.2 % (w/w) to about 0.3 % (w/w), about 0.2 % (w/w) to about

0.4 % (w/w), about 0.2 % (w/w) to about 0.5 % (w/w), about 0.2 % (w/w) to about

0.6 % (w/w), about 0.2 % (w/w) to about 0.7 % (w/w), about 0.2 % (w/w) to about

0.8 % (w/w), about 0.2 % (w/w) to about 0.9 % (w/w), about 0.2 % (w/w) to about

1 % (w/w), about 0.2 % (w/w) to about 2 % (w/w), about 0.3 % (w/w) to about 0.4 % (w/w), about 0.3 % (w/w) to about 0.5 % (w/w), about 0.3 % (w/w) to about 0.6 % (w/w), about

0.3 % (w/w) to about 0.7 % (w/w), about 0.3 % (w/w) to about 0.8 % (w/w), about

0.3 % (w/w) to about 0.9 % (w/w), about 0.3 % (w/w) to about 1 % (w/w), about 0.3 % (w/w) to about 2 % (w/w), about 0.4 % (w/w) to about 0.5 % (w/w), about 0.4 % (w/w) to about

0.6 % (w/w), about 0.4 % (w/w) to about 0.7 % (w/w), about 0.4 % (w/w) to about

0.8 % (w/w), about 0.4 % (w/w) to about 0.9 % (w/w), about 0.4 % (w/w) to about

1 % (w/w), about 0.4 % (w/w) to about 2 % (w/w), about 0.5 % (w/w) to about 0.6 % (w/w), about 0.5 % (w/w) to about 0.7 % (w/w), about 0.5 % (w/w) to about 0.8 % (w/w), about

0.5 % (w/w) to about 0.9 % (w/w), about 0.5 % (w/w) to about 1 % (w/w), about 0.5 % (w/w) to about 2 % (w/w), about 0.6 % (w/w) to about 0.7 % (w/w), about 0.6 % (w/w) to about 0.8 % (w/w), about 0.6 % (w/w) to about 0.9 % (w/w), about 0.6 % (w/w) to about 1 % (w/w), about 0.6 % (w/w) to about 2 % (w/w), about 0.7 % (w/w) to about 0.8 % (w/w), about 0.7 % (w/w) to about 0.9 % (w/w), about 0.7 % (w/w) to about 1 % (w/w), about 0.7 % (w/w) to about 2 % (w/w), about 0.8 % (w/w) to about 0.9 % (w/w), about 0.8 % (w/w) to about 1 % (w/w), about 0.8 % (w/w) to about 2 % (w/w), about 0.9 % (w/w) to about 1 % (w/w), about 0.9 % (w/w) to about 2 % (w/w), or about 1 % (w/w) to about 2 % (w/w).

In some embodiments, the pharmaceutical spray formulation comprises a buffering agent at a concentration of about 0.01 % (w/w), about 0.1 % (w/w), about 0.2 % (w/w), about 0.3 % (w/w), about 0.4 % (w/w), 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), about 1 % (w/w), or about 2 % (w/w). In some embodiments, the buffering agent is citric acid, for example, citric acid monohydrate.

[0170] 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 from about 0.1% to about 2.0% trisodium citrate or citric acid monohydrate. In some embodiments, the pharmaceutical spray formulation further comprises from 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.

[0171] 3, _ Antioxidants

[0172] In an aspect provided herein, the pharmaceutical spray formulation comprises an antioxidant. Antioxidants can reduce or mitigate oxidation of the active ingredient such as epinephrine. Examples of antioxidants include sodium bisulfite, sodium metabi sulfite, 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. In some embodiments, the pharmaceutical spray formulation comprises an antioxidant that reduces oxidation of the active ingredient such that the pharmaceutical spray formulation that has 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 than 14%, no 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, at least 22 months, at least 23 months, or at least 24 months. Room temperature can be from about 20 degrees Celsius to about 25 degrees Celsius. In some embodiments, room temperature is about 20, 21, 22, 23, 24, or 25 degrees Celsius.

[0173] 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 formulation has 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 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 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 impurities content of the formulation is determined relative to an initial impurities content measured at 0 months (t = 0). In some embodiments, the impurities content of the formulation is determined as an absolute percentage.

[0174] In some embodiments, the impurities include one or more of epinephrine sulfonic acid, adrenochrome, norepinephrine, or adrenalone. In some embodiments, the pharmaceutical spray formulation 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 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%, or no more than 9%, 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.

[0175] In some embodiments, the pharmaceutical spray formulation 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 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.

[0176] In some embodiments, the pharmaceutical spray formulation 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 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.

[0177] In some embodiments, the pharmaceutical spray formulation has an adrenalone 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%, or no 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 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. [0178] In some embodiments, the pharmaceutical spray formulation comprises 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 formulation 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. [0179] In some embodiments, the pharmaceutical spray formulation comprises an antioxidant at a concentration of about 0.0001 % (w/w) to about 0.5 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises an antioxidant at a concentration of at least about 0.0001 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises an antioxidant at a concentration of at most about 0.5 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises an antioxidant at a concentration of about 0.0001 % (w/w) to about 0.001 % (w/w), about 0.0001 % (w/w) to about 0.01 % (w/w), about 0.0001 % (w/w) to about 0.02 % (w/w), about 0.0001 % (w/w) to about 0.03 % (w/w), about 0.0001 % (w/w) to about 0.04 % (w/w), about 0.0001 % (w/w) to about 0.05 % (w/w), about 0.0001 % (w/w) to about 0.1 % (w/w), about 0.0001 % (w/w) to about 0.2 % (w/w), about 0.0001 % (w/w) to about 0.3 % (w/w), about 0.0001 % (w/w) to about 0.4 % (w/w), about 0.0001 % (w/w) to about 0.5 % (w/w), about 0.001 % (w/w) to about 0.01 % (w/w), about 0.001 % (w/w) to about 0.02 % (w/w), about 0.001 % (w/w) to about 0.03 % (w/w), about 0.001 % (w/w) to about 0.04 % (w/w), about 0.001 % (w/w) to about 0.05 % (w/w), about 0.001 % (w/w) to about 0.1 % (w/w), about 0.001 % (w/w) to about 0.2 % (w/w), about 0.001 % (w/w) to about 0.3 % (w/w), about 0.001 % (w/w) to about 0.4 % (w/w), about 0.001 % (w/w) to about 0.5 % (w/w), about 0.01 % (w/w) to about 0.02 % (w/w), about 0.01 % (w/w) to about 0.03 % (w/w), about 0.01 % (w/w) to about 0.04 % (w/w), about 0.01 % (w/w) to about 0.05 % (w/w), about 0.01 % (w/w) to about 0.1 % (w/w), about 0.01 % (w/w) to about 0.2 % (w/w), about 0.01 % (w/w) to about

0.3 % (w/w), about 0.01 % (w/w) to about 0.4 % (w/w), about 0.01 % (w/w) to about

0.5 % (w/w), about 0.02 % (w/w) to about 0.03 % (w/w), about 0.02 % (w/w) to about 0.04 % (w/w), about 0.02 % (w/w) to about 0.05 % (w/w), about 0.02 % (w/w) to about 0.1 % (w/w), about 0.02 % (w/w) to about 0.2 % (w/w), about 0.02 % (w/w) to about

0.3 % (w/w), about 0.02 % (w/w) to about 0.4 % (w/w), about 0.02 % (w/w) to about

0.5 % (w/w), about 0.03 % (w/w) to about 0.04 % (w/w), about 0.03 % (w/w) to about 0.05 % (w/w), about 0.03 % (w/w) to about 0.1 % (w/w), about 0.03 % (w/w) to about 0.2 % (w/w), about 0.03 % (w/w) to about 0.3 % (w/w), about 0.03 % (w/w) to about

0.4 % (w/w), about 0.03 % (w/w) to about 0.5 % (w/w), about 0.04 % (w/w) to about

0.05 % (w/w), about 0.04 % (w/w) to about 0.1 % (w/w), about 0.04 % (w/w) to about 0.2 % (w/w), about 0.04 % (w/w) to about 0.3 % (w/w), about 0.04 % (w/w) to about

0.4 % (w/w), about 0.04 % (w/w) to about 0.5 % (w/w), about 0.05 % (w/w) to about

0.1 % (w/w), about 0.05 % (w/w) to about 0.2 % (w/w), about 0.05 % (w/w) to about

0.3 % (w/w), about 0.05 % (w/w) to about 0.4 % (w/w), about 0.05 % (w/w) to about

0.5 % (w/w), about 0.1 % (w/w) to about 0.2 % (w/w), about 0.1 % (w/w) to about

0.3 % (w/w), about 0.1 % (w/w) to about 0.4 % (w/w), about 0.1 % (w/w) to about

0.5 % (w/w), about 0.2 % (w/w) to about 0.3 % (w/w), about 0.2 % (w/w) to about

0.4 % (w/w), about 0.2 % (w/w) to about 0.5 % (w/w), about 0.3 % (w/w) to about

0.4 % (w/w), about 0.3 % (w/w) to about 0.5 % (w/w), or about 0.4 % (w/w) to about 0.5 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises 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), about 0.1 % (w/w), about 0.2 % (w/w), about 0.3 % (w/w), about 0.4 % (w/w), or about 0.5 % (w/w). [0180] In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of from about 0.0001% (w/w) to about 0.05% (w/w) or sodium metabisulfite at a concentration of from about 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of from about 0.0001% (w/w) to about 0.1% (w/w) or sodium metabisulfite at a concentration of from about 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of from about 0.001% (w/w) to about 0.05% (w/w) or sodium metabisulfite at a concentration of from about 0.001% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of from about 0.01% (w/w) to about 0.05% (w/w) or sodium metabisulfite at a concentration of from about 0.01% (w/w) to about 0.1% (w/w).

[0181] In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite. In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of from about 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of from about 0.001% (w/w) to about 0.05% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of from about 0.005% (w/w) to about 0.05% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of from about 0.001% (w/w) to about 0.05% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of from about 0.01% (w/w) to about 0.05% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of about 0.005% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of about 0.01% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of about 0.02% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of about 0.03% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of about 0.04% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium bisulfite at a concentration of about 0.05% (w/w).

[0182] In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite. In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of from about 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of from about 0.001% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of from about 0.005% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of from about 0.01% (w/w) to about 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of about 0.005% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of about 0.01% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of about 0.02% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of about 0.03% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of about 0.04% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of about 0.05% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of about 0.06% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of about 0.07% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of about 0.08% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of about 0.09% (w/w). In some embodiments, the pharmaceutical spray formulation comprises sodium metabisulfite at a concentration of about 0.1% (w/w). In some embodiments, the pharmaceutical spray formulation comprises an antioxidant at a concentration of 0.01 % (w/w) to 0.3 % (w/w). In some embodiments, the antioxidant is sodium metabisulfite. In some embodiments, the pharmaceutical spray formulation comprises an antioxidant at a concentration of 0.01 % (w/w) to 0.02 % (w/w), 0.01 % (w/w) to 0.03 % (w/w), 0.01 %

(w/w) to 0.04 % (w/w), 0.01 % (w/w) to 0.05 % (w/w), 0.01 % (w/w) to 0.06 % (w/w),

0.01 % (w/w) to 0.07 % (w/w), 0.01 % (w/w) to 0.08 % (w/w), 0.01 % (w/w) to 0.09 % (w/w), 0.01 % (w/w) to 0.1 % (w/w), 0.01 % (w/w) to 0.2 % (w/w), 0.01 % (w/w) to 0.3 % (w/w), 0.02 % (w/w) to 0.03 % (w/w), 0.02 % (w/w) to 0.04 % (w/w), 0.02 % (w/w) to 0.05 % (w/w), 0.02 % (w/w) to 0.06 % (w/w), 0.02 % (w/w) to 0.07 % (w/w), 0.02 % (w/w) to 0.08 % (w/w), 0.02 % (w/w) to 0.09 % (w/w), 0.02 % (w/w) to 0.1 % (w/w), 0.02 % (w/w) to 0.2 % (w/w), 0.02 % (w/w) to 0.3 % (w/w), 0.03 % (w/w) to 0.04 % (w/w), 0.03 % (w/w) to 0.05 % (w/w), 0.03 % (w/w) to 0.06 % (w/w), 0.03 % (w/w) to 0.07 % (w/w),

0.03 % (w/w) to 0.08 % (w/w), 0.03 % (w/w) to 0.09 % (w/w), 0.03 % (w/w) to 0.1 % (w/w), 0.03 % (w/w) to 0.2 % (w/w), 0.03 % (w/w) to 0.3 % (w/w), 0.04 % (w/w) to 0.05 % (w/w), 0.04 % (w/w) to 0.06 % (w/w), 0.04 % (w/w) to 0.07 % (w/w), 0.04 % (w/w) to 0.08 % (w/w), 0.04 % (w/w) to 0.09 % (w/w), 0.04 % (w/w) to 0.1 % (w/w), 0.04 % (w/w) to 0.2 % (w/w), 0.04 % (w/w) to 0.3 % (w/w), 0.05 % (w/w) to 0.06 % (w/w), 0.05 % (w/w) to 0.07 % (w/w), 0.05 % (w/w) to 0.08 % (w/w), 0.05 % (w/w) to 0.09 % (w/w), 0.05 % (w/w) to 0.1 % (w/w), 0.05 % (w/w) to 0.2 % (w/w), 0.05 % (w/w) to 0.3 % (w/w), 0.06 % (w/w) to 0.07 % (w/w), 0.06 % (w/w) to 0.08 % (w/w), 0.06 % (w/w) to 0.09 % (w/w), 0.06 % (w/w) to 0.1 % (w/w), 0.06 % (w/w) to 0.2 % (w/w), 0.06 % (w/w) to 0.3 % (w/w), 0.07 % (w/w) to 0.08 % (w/w), 0.07 % (w/w) to 0.09 % (w/w), 0.07 % (w/w) to 0.1 % (w/w), 0.07 % (w/w) to 0.2 % (w/w), 0.07 % (w/w) to 0.3 % (w/w), 0.08 % (w/w) to 0.09 % (w/w), 0.08 % (w/w) to 0.1 % (w/w), 0.08 % (w/w) to 0.2 % (w/w), 0.08 % (w/w) to 0.3 % (w/w), 0.09 % (w/w) to 0.1 % (w/w), 0.09 % (w/w) to 0.2 % (w/w), 0.09 % (w/w) to 0.3 % (w/w), 0.1 % (w/w) to 0.2 % (w/w), 0.1 % (w/w) to 0.3 % (w/w), or 0.2 % (w/w) to 0.3 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises an antioxidant at a concentration of 0.01 % (w/w), 0.02 % (w/w), 0.03 % (w/w), 0.04 % (w/w), 0.05 % (w/w), 0.06 % (w/w), 0.07 % (w/w), 0.08 % (w/w), 0.09 % (w/w), 0.1 % (w/w), 0.2 % (w/w), or 0.3 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises an antioxidant at a concentration of at least 0.01 % (w/w), 0.02 % (w/w), 0.03 % (w/w),

0.04 % (w/w), 0.05 % (w/w), 0.06 % (w/w), 0.07 % (w/w), 0.08 % (w/w), 0.09 % (w/w),

0.1 % (w/w), or 0.2 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises an antioxidant at a concentration of at most 0.02 % (w/w), 0.03 % (w/w),

0.1 % (w/w), 0.2 % (w/w), or 0.3 % (w/w).

[0183] 4 Preservatives

[0184] In an aspect provided herein, the pharmaceutical spray formulation comprises a preservative. In some embodiments, the preservative comprises a chelating agent. In some embodiments, the chelating agent is disodium edetate (EDTA). In some embodiments, the pharmaceutical spray formulation comprises disodium edetate. In some embodiments, the pharmaceutical spray formulation comprises disodium edetate at a concentration of from about 0.0001% to about 0.01%. In some embodiments, the pharmaceutical spray formulation comprises disodium edetate at a concentration of from about 0.0005% to about 0.01%. In some embodiments, the pharmaceutical spray formulation comprises disodium edetate at a concentration of from about 0.001% to about 0.01%.

[0185] In some embodiments, the pharmaceutical spray formulation comprises a chelating agent at a concentration of about 0.0001 % to about 0.05 %. In some embodiments, the pharmaceutical spray formulation comprises a chelating agent at a concentration of at least about 0.0001 %. In some embodiments, the pharmaceutical spray formulation comprises a chelating agent at a concentration of at most 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 % to about 0.0005 %, about 0.0001 % to about 0.001 %, about 0.0001 % to about 0.005 %, about 0.0001 % to about 0.01 %, about 0.0001 % to about 0.02 %, about 0.0001 % to about 0.03 %, about 0.0001 % to about 0.04 %, about 0.0001 % to about 0.05 %, about 0.0002 % to about 0.0003 %, about 0.0002 % to about 0.0004 %, about 0.0002 % to about 0.0005 %, about 0.0002 % to about 0.001 %, about 0.0002 % to about 0.005 %, about 0.0002 % to about 0.01 %, about 0.0002 % to about 0.02 %, about 0.0002 % to about 0.03 %, about 0.0002 % to about 0.04 %, about 0.0002 % to about 0.05 %, about 0.0003 % to about 0.0004 %, about 0.0003 % to about 0.0005 %, about 0.0003 % to about 0.001 %, about 0.0003 % to about 0.005 %, about 0.0003 % to about 0.01 %, about 0.0003 % to about 0.02 %, about 0.0003 % to about 0.03 %, about 0.0003 % to about 0.04 %, about 0.0003 % to about 0.05 %, about 0.0004 % to about 0.0005 %, about 0.0004 % to about 0.001 %, about 0.0004 % to about 0.005 %, about 0.0004 % to about 0.01 %, about 0.0004 % to about 0.02 %, about 0.0004 % to about 0.03 %, about 0.0004 % to about 0.04 %, about 0.0004 % to about 0.05 %, about 0.0005 % to about 0.001 %, about 0.0005 % to about 0.005 %, about 0.0005 % to about 0.01 %, about 0.0005 % to about 0.02 %, about 0.0005 % to about 0.03 %, about 0.0005 % to about 0.04 %, about 0.0005 % to about 0.05 %, about 0.001 % to about 0.005 %, about 0.001 % to about 0.01 %, about 0.001 % to about 0.02 %, about 0.001 % to about 0.03 %, about 0.001 % to about 0.04 %, about 0.001 % to about 0.05 %, about 0.005 % to about 0.01 %, about 0.005 % to about 0.02 %, about 0.005 % to about 0.03 %, about 0.005 % to about 0.04 %, about 0.005 % to about 0.05 %, about 0.01 % to about 0.02 %, about 0.01 % to about 0.03 %, about 0.01 % to about 0.04 %, about 0.01 % to about 0.05 %, about 0.02 % to about 0.03 %, about 0.02 % to about 0.04 %, about 0.02 % to about 0.05 %, about 0.03 % to about 0.04 %, about 0.03 % to about 0.05 %, or about 0.04 % to about 0.05 %. In some embodiments, the pharmaceutical spray formulation comprises 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 %.

[0186] In an aspect provided herein, the pharmaceutical spray formulation comprises a preservative. Examples of preservatives include parabens, phenyl ethyl alcohol, benzalkonium chloride, EDTA, and benzoyl alcohol. In some embodiments, the preservative comprises an antimicrobial preservative. In some embodiments, the antimicrobial preservative is benzalkonium sodium or chlorobutanol. In some embodiments, the antimicrobial preservative is chlorobutanol. In some embodiments, the pharmaceutical spray formulation comprises benzalkonium sodium at a concentration of from about 0.005% (w/v) to about 1% (w/v) or chlorobutanol at a concentration of from about 0.005% (w/v) to about 1% (w/v).

[0187] In some embodiments, the pharmaceutical spray formulation comprises an antimicrobial preservative at a concentration of about 0.01 % (w/w) to about 1 % (w/w). In some embodiments, the antimicrobial preservative is chlorobutanol, for example, chlorobutanol hemihydrate. In some embodiments, the pharmaceutical spray formulation comprises an antimicrobial preservative at a concentration of at least about 0.01 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises an antimicrobial preservative at a concentration of at most about 1 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises an antimicrobial preservative at a concentration of about 0.01 % (w/w) to about 0.05 % (w/w), about 0.01 % (w/w) to about 0.1 % (w/w), about 0.01 % (w/w) to about 0.2 % (w/w), about 0.01 % (w/w) to about 0.3 % (w/w), about 0.01 % (w/w) to about 0.4 % (w/w), about 0.01 % (w/w) to about 0.5 % (w/w), about

0.01 % (w/w) to about 0.6 % (w/w), about 0.01 % (w/w) to about 0.7 % (w/w), about

0.01 % (w/w) to about 0.8 % (w/w), about 0.01 % (w/w) to about 0.9 % (w/w), about

0.01 % (w/w) to about 1 % (w/w), about 0.05 % (w/w) to about 0.1 % (w/w), about 0.05 % (w/w) to about 0.2 % (w/w), about 0.05 % (w/w) to about 0.3 % (w/w), about

0.05 % (w/w) to about 0.4 % (w/w), about 0.05 % (w/w) to about 0.5 % (w/w), about

0.05 % (w/w) to about 0.6 % (w/w), about 0.05 % (w/w) to about 0.7 % (w/w), about

0.05 % (w/w) to about 0.8 % (w/w), about 0.05 % (w/w) to about 0.9 % (w/w), about

0.05 % (w/w) to about 1 % (w/w), about 0.1 % (w/w) to about 0.2 % (w/w), about 0.1 % (w/w) to about 0.3 % (w/w), about 0.1 % (w/w) to about 0.4 % (w/w), about 0.1 % (w/w) to about 0.5 % (w/w), about 0.1 % (w/w) to about 0.6 % (w/w), about

0.1 % (w/w) to about 0.7 % (w/w), about 0.1 % (w/w) to about 0.8 % (w/w), about

0.1 % (w/w) to about 0.9 % (w/w), about 0.1 % (w/w) to about 1 % (w/w), about 0.2 % (w/w) to about 0.3 % (w/w), about 0.2 % (w/w) to about 0.4 % (w/w), about 0.2 % (w/w) to about

0.5 % (w/w), about 0.2 % (w/w) to about 0.6 % (w/w), about 0.2 % (w/w) to about

0.7 % (w/w), about 0.2 % (w/w) to about 0.8 % (w/w), about 0.2 % (w/w) to about

0.9 % (w/w), about 0.2 % (w/w) to about 1 % (w/w), about 0.3 % (w/w) to about 0.4 % (w/w), about 0.3 % (w/w) to about 0.5 % (w/w), about 0.3 % (w/w) to about 0.6 % (w/w), about 0.3 % (w/w) to about 0.7 % (w/w), about 0.3 % (w/w) to about

0.8 % (w/w), about 0.3 % (w/w) to about 0.9 % (w/w), about 0.3 % (w/w) to about

1 % (w/w), about 0.4 % (w/w) to about 0.5 % (w/w), about 0.4 % (w/w) to about 0.6 % (w/w), about 0.4 % (w/w) to about 0.7 % (w/w), about 0.4 % (w/w) to about

0.8 % (w/w), about 0.4 % (w/w) to about 0.9 % (w/w), about 0.4 % (w/w) to about

1 % (w/w), about 0.5 % (w/w) to about 0.6 % (w/w), about 0.5 % (w/w) to about 0.7 % (w/w), about 0.5 % (w/w) to about 0.8 % (w/w), about 0.5 % (w/w) to about 0.9 % (w/w), about 0.5 % (w/w) to about 1 % (w/w), about 0.6 % (w/w) to about 0.7 % (w/w), about 0.6 % (w/w) to about 0.8 % (w/w), about 0.6 % (w/w) to about 0.9 % (w/w), about 0.6 % (w/w) to about 1 % (w/w), about 0.7 % (w/w) to about 0.8 % (w/w), about 0.7 % (w/w) to about 0.9 % (w/w), about 0.7 % (w/w) to about 1 % (w/w), about 0.8 % (w/w) to about 0.9 % (w/w), about 0.8 % (w/w) to about 1 % (w/w), or about 0.9 % (w/w) to about 1 % (w/w). In some embodiments, the pharmaceutical spray formulation comprises an antimicrobial preservative at a concentration of about 0.01 % (w/w), about 0.05 % (w/w), about 0.1 % (w/w), about 0.2 % (w/w), about 0.3 % (w/w), about 0.4 % (w/w), 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).

[0188] In some embodiments, the pharmaceutical spray formulation comprises benzalkonium sodium. In some embodiments, the pharmaceutical spray formulation comprises benzalkonium sodium at a concentration of from about 0.005% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation comprises benzalkonium sodium at a concentration of from about 0.01% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation comprises benzalkonium sodium at a concentration of from about 0.05% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation comprises benzalkonium sodium at a concentration of from about 0.1% (w/v) to about 1% (w/v).

[0189] In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol. In some embodiments, the chlorobutanol is chlorobutanol hemihydrate. In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of from about 0.005% (w/v) to about 1% (w/v) (or alternatively 0.005% (w/w) to about 1% (w/w). In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of from about 0.01% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of from about 0.05% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of from about 0.1% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of from about 0.1% (w/v) to about 0.5% (w/v). In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of about 0.21% (w/v). In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of about 0.2% (w/v). In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of about 0.5% (w/v). In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of about 0.525% (w/v).

[0190] 5 Isotoni city Agents

[0191] Disclosed herein are various ingredients of the pharmaceutical spray formulation. In some embodiments, the pharmaceutical spray formulation comprises an isotonicity agent. In some embodiments, an isotonicity agent is sodium chloride, dextrose, glycerin, mannitol, potassium chloride, or any combination thereof. An isotonicity agent can be used to adjust the tonicity of the formulation. 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.

[0192] 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 formulation has an osmolality of about 550 mOsm/kg to about 575 mOsm/kg, about 550 mOsm/kg to about 600 mOsm/kg, about 550 mOsm/kg to about 625 mOsm/kg, about 550 mOsm/kg to about 650 mOsm/kg, about 550 mOsm/kg to about 675 mOsm/kg, about 550 mOsm/kg to about 700 mOsm/kg, about 550 mOsm/kg to about 725 mOsm/kg, about 550 mOsm/kg to about 750 mOsm/kg, about 550 mOsm/kg to about 775 mOsm/kg, about 550 mOsm/kg to about 800 mOsm/kg, about 575 mOsm/kg to about 600 mOsm/kg, about 575 mOsm/kg to about 625 mOsm/kg, about 575 mOsm/kg to about 650 mOsm/kg, about 575 mOsm/kg to about 675 mOsm/kg, about 575 mOsm/kg to about 700 mOsm/kg, about 575 mOsm/kg to about 725 mOsm/kg, about 575 mOsm/kg to about 750 mOsm/kg, about 575 mOsm/kg to about 775 mOsm/kg, about 575 mOsm/kg to about 800 mOsm/kg, about 600 mOsm/kg to about 625 mOsm/kg, about 600 mOsm/kg to about 650 mOsm/kg, about 600 mOsm/kg to about 675 mOsm/kg, about 600 mOsm/kg to about 700 mOsm/kg, about 600 mOsm/kg to about 725 mOsm/kg, about 600 mOsm/kg to about 750 mOsm/kg, about 600 mOsm/kg to about 775 mOsm/kg, about 600 mOsm/kg to about 800 mOsm/kg, about 625 mOsm/kg to about 650 mOsm/kg, about 625 mOsm/kg to about 675 mOsm/kg, about 625 mOsm/kg to about 700 mOsm/kg, about 625 mOsm/kg to about 725 mOsm/kg, about 625 mOsm/kg to about 750 mOsm/kg, about 625 mOsm/kg to about 775 mOsm/kg, about 625 mOsm/kg to about 800 mOsm/kg, about 650 mOsm/kg to about 675 mOsm/kg, about 650 mOsm/kg to about 700 mOsm/kg, about 650 mOsm/kg to about 725 mOsm/kg, about 650 mOsm/kg to about 750 mOsm/kg, about 650 mOsm/kg to about 775 mOsm/kg, about 650 mOsm/kg to about 800 mOsm/kg, about 675 mOsm/kg to about 700 mOsm/kg, about 675 mOsm/kg to about 725 mOsm/kg, about 675 mOsm/kg to about 750 mOsm/kg, about 675 mOsm/kg to about 775 mOsm/kg, about 675 mOsm/kg to about 800 mOsm/kg, about 700 mOsm/kg to about 725 mOsm/kg, about 700 mOsm/kg to about 750 mOsm/kg, about 700 mOsm/kg to about 775 mOsm/kg, about 700 mOsm/kg to about 800 mOsm/kg, about 725 mOsm/kg to about 750 mOsm/kg, about 725 mOsm/kg to about 775 mOsm/kg, about 725 mOsm/kg to about 800 mOsm/kg, about 750 mOsm/kg to about 775 mOsm/kg, about 750 mOsm/kg to about 800 mOsm/kg, or about 775 mOsm/kg to about 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 formulation has an osmolality of at most 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.

[0193] In some embodiments, the pharmaceutical spray formulation comprises an isotonicity agent at a concentration of about 0.1 % to about 4 %. In some embodiments, the pharmaceutical spray formulation comprises an isotonicity agent at a concentration of at least about 0.1 %. In some embodiments, the pharmaceutical spray formulation comprises an isotonicity agent at a concentration of at most about 4 %. In some embodiments, the pharmaceutical spray formulation comprises an isotonicity 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 %, about 0.1 % to about 0.6 %, about 0.1 % to about 0.8 %, about 0.1 % to about 1 %, about 0.1 % to about

1.5 %, about 0.1 % to about 2 %, about 0.1 % to about 2.5 %, about 0.1 % to about 3 %, about 0.1 % to about 4 %, about 0.2 % to about 0.4 %, about 0.2 % to about 0.5 %, about 0.2 % to about 0.6 %, about 0.2 % to about 0.8 %, about 0.2 % to about 1 %, about 0.2 % to about 1.5 %, about 0.2 % to about 2 %, about 0.2 % to about 2.5 %, about 0.2 % to about

3 %, about 0.2 % to about 4 %, about 0.4 % to about 0.5 %, about 0.4 % to about 0.6 %, about 0.4 % to about 0.8 %, about 0.4 % to about 1 %, about 0.4 % to about 1.5 %, about 0.4 % to about 2 %, about 0.4 % to about 2.5 %, about 0.4 % to about 3 %, about 0.4 % to about 4 %, about 0.5 % to about 0.6 %, about 0.5 % to about 0.8 %, about 0.5 % to about 1 %, about 0.5 % to about 1.5 %, about 0.5 % to about 2 %, about 0.5 % to about 2.5 %, about 0.5 % to about 3 %, about 0.5 % to about 4 %, about 0.6 % to about 0.8 %, about 0.6 % to about 1 %, about 0.6 % to about 1.5 %, about 0.6 % to about 2 %, about 0.6 % to about

2.5 %, about 0.6 % to about 3 %, about 0.6 % to about 4 %, about 0.8 % to about 1 %, about 0.8 % to about 1.5 %, about 0.8 % to about 2 %, about 0.8 % to about 2.5 %, about 0.8 % to about 3 %, about 0.8 % to about 4 %, about 1 % to about 1.5 %, about 1 % to about 2 %, about 1 % to about 2.5 %, about 1 % to about 3 %, about 1 % to about 4 %, about 1.5 % to about 2 %, about 1.5 % to about 2.5 %, about 1.5 % to about 3 %, about 1.5 % to about 4 %, about 2 % to about 2.5 %, about 2 % to about 3 %, about 2 % to about 4 %, about 2.5 % to about 3 %, about 2.5 % to about 4 %, or about 3 % to about 4 %. In some embodiments, the pharmaceutical spray formulation comprises an isotonicity 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 %.

[0194] In an aspect provided herein, the pharmaceutical spray formulation comprises sodium chloride. In some embodiments, the pharmaceutical spray formulation comprises sodium chloride at a concentration of from about 0.1% to about 5%. In some embodiments, the pharmaceutical spray formulation comprises sodium chloride at a concentration of from about 0.1% to about 1%. In some embodiments, the pharmaceutical spray formulation comprises sodium chloride at a concentration of from about 0.5% to about 5%. In some embodiments, the pharmaceutical spray formulation comprises sodium chloride at a concentration of from about 1% to about 5%. In some embodiments, the pharmaceutical spray formulation comprises sodium chloride at a concentration of from about 2% to about 5%. In some embodiments, the pharmaceutical spray formulation comprises sodium chloride at a concentration of from about 3% to about 5%. In some embodiments, the pharmaceutical spray formulation comprises sodium chloride at a concentration of from about 4% to about 5%. In some embodiments, the pharmaceutical spray formulation comprises sodium chloride at a concentration of from about 0.1% to about 3%. In some embodiments, the pharmaceutical spray formulation comprises sodium chloride at a concentration of from about 0.1% to about 2%. In some embodiments, the pharmaceutical spray formulation comprises sodium chloride at a concentration of from about 0.1% to about 1%. In some embodiments, the pharmaceutical spray formulation comprises sodium chloride at a concentration of about 0.4%.

[0195] In some embodiments, the pharmaceutical spray formulation is a stable pharmaceutical spray formulation that has 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 than 14%, no 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, or at least 12 months. In some embodiments, the pharmaceutical spray formulation comprises one or more buffering agents and/or preservatives to improve stability of the active ingredient (e.g., reduce oxidation or degradation of epinephrine) during storage. [0196] 6 Vasodilators

[0197] In an aspect provided herein, the pharmaceutical spray formulation further comprises a vasodilator. In some embodiments, the vasodilator is nitroprusside, phentolamine, or nifedipine.

[0198] In some embodiments, the pharmaceutical spray formulation further comprises nitroprusside. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.05 mg to about 5 mg of nitroprusside. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.1 mg to about 5 mg of nitroprusside. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.5 mg to about 5 mg of nitroprusside. In some embodiments, the pharmaceutical spray formulation further comprises from about 1 mg to about 5 mg of nitroprusside. In some embodiments, the pharmaceutical spray formulation further comprises from about 1 mg to about 4 mg of nitroprusside. In some embodiments, the pharmaceutical spray formulation further comprises nitroprusside. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.05 mg to about 3 mg of nitroprusside. In some embodiments, the pharmaceutical spray formulation further comprises nitroprusside. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.5 mg to about 3 mg of nitroprusside. In some embodiments, the pharmaceutical spray formulation further comprises nitroprusside. In some embodiments, the pharmaceutical spray formulation further comprises from about 0.5 mg to about 2 mg of nitroprusside.

[0199] In some embodiments, the pharmaceutical spray formulation further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises from about 1 mg to about 50 mg of phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises from about 1 mg to about 40 mg of phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises from about 1 mg to about 30 mg of phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises from about 1 mg to about 20 mg of phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises from about 1 mg to about 10 mg of phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises from about 5 mg to about 50 mg of phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 50 mg of phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises from about 20 mg to about 50 mg of phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises phentolamine. In some embodiments, the pharmaceutical spray formulation further comprises from about 20 mg to about 40 mg of phentolamine.

[0200] In some embodiments, the pharmaceutical spray formulation 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 formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 450 mg of nifedipine. In some embodiments, the pharmaceutical spray formulation 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 formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 350 mg of nifedipine. In some embodiments, the pharmaceutical spray formulation 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 formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 250 mg of nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 200 mg of nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 150 mg of nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 100 mg of nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 75 mg of nifedipine. In some embodiments, the pharmaceutical spray formulation 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 formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 40 mg of nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 10 mg to about 30 mg of nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 50 mg to about 500 mg of nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 100 mg to about 500 mg of nifedipine. In some embodiments, the pharmaceutical spray formulation 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 formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 100 mg to about 350 mg of nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises nifedipine. In some embodiments, the pharmaceutical spray formulation further comprises from about 100 mg to about 300 mg of nifedipine.

[0201] 7. _ Absorption Enhancers

[0202] In an aspect provided herein, the pharmaceutical spray formulation comprises an absorption enhancer. In some embodiments, the absorption enhancer comprises caprylic acid, oleic acid, polysorbate 80, menthol, EDTA, sodium edetate, cetylpyridinium chloride, sodium lauryl sulfate, citric acid, sodium desoxycholate, sodium deoxyglycolate, glyceryl oleate, L-lysine, diethylene glycol monoethyl ether, a- b- or g-cyclodextrin, hydroxypropyl b-cyclodextrin, phosphatidylcholine, or combinations thereof. Absorption enhancers can improve the pharmacokinetics of the active ingredient(s) of the pharmaceutical spray formulation. In some embodiments, the improved pharmacokinetics includes one or more of Cmax, Tmax, and AUC. In some cases, the absorption enhancer comprises di ethylene glycol monoethyl ether. In some cases, use of absorption enhancers can reduce Tmax. Absorption enhancers may be used to increase the AUC of the active ingredient.

[0203] In some embodiments, the pharmaceutical spray formulation comprises an absorption enhancer at a concentration of about 0.1 % to about 2 %. In some embodiments, the pharmaceutical spray formulation comprises an absorption enhancer at a concentration of at least about 0.1 %. In some embodiments, the pharmaceutical spray formulation comprises an absorption enhancer at a concentration of at most about 2 %. In some embodiments, the pharmaceutical spray formulation comprises 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 %, about 0.1 % to about 0.5 %, about 0.1 % to about 0.6 %, about 0.1 % to about 0.7 %, about 0.1 % to about 0.8 %, about 0.1 % to about 0.9 %, about 0.1 % to about 1 %, about 0.1 % to about

1.5 %, about 0.1 % to about 2 %, about 0.2 % to about 0.3 %, about 0.2 % to about 0.4 %, about 0.2 % to about 0.5 %, about 0.2 % to about 0.6 %, about 0.2 % to about 0.7 %, about 0.2 % to about 0.8 %, about 0.2 % to about 0.9 %, about 0.2 % to about 1 %, about 0.2 % to about 1.5 %, about 0.2 % to about 2 %, about 0.3 % to about 0.4 %, about 0.3 % to about 0.5 %, about 0.3 % to about 0.6 %, about 0.3 % to about 0.7 %, about 0.3 % to about 0.8 %, about 0.3 % to about 0.9 %, about 0.3 % to about 1 %, about 0.3 % to about 1.5 %, about 0.3 % to about 2 %, about 0.4 % to about 0.5 %, about 0.4 % to about 0.6 %, about 0.4 % to about 0.7 %, about 0.4 % to about 0.8 %, about 0.4 % to about 0.9 %, about 0.4 % to about 1 %, about 0.4 % to about 1.5 %, about 0.4 % to about 2 %, about 0.5 % to about 0.6 %, about 0.5 % to about 0.7 %, about 0.5 % to about 0.8 %, about 0.5 % to about 0.9 %, about 0.5 % to about 1 %, about 0.5 % to about 1.5 %, about 0.5 % to about 2 %, about 0.6 % to about 0.7 %, about 0.6 % to about 0.8 %, about 0.6 % to about 0.9 %, about 0.6 % to about 1 %, about 0.6 % to about 1.5 %, about 0.6 % to about 2 %, about 0.7 % to about 0.8 %, about 0.7 % to about 0.9 %, about 0.7 % to about 1 %, about 0.7 % to about 1.5 %, about 0.7 % to about 2 %, about 0.8 % to about 0.9 %, about 0.8 % to about 1 %, about 0.8 % to about 1.5 %, about 0.8 % to about 2 %, about 0.9 % to about 1 %, about 0.9 % to about

1.5 %, about 0.9 % to about 2 %, about 1 % to about 1.5 %, about 1 % to about 2 %, or about

1.5 % to about 2 %. In some embodiments, the pharmaceutical spray formulation comprises 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 %.

[0204] In some embodiments, the pharmaceutical spray formulation comprises an absorption enhancer at a concentration of at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9%, 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%, at least about 1.6%, at least about 1.7%, at least about 1.8%, at least about 1.9%, at least about 2.0% , at least about 2.5%, at least about 3.0%, at least about 4.0%, at least about 5.0%, and/or no more than about 0.1%, no more than about 0.2%, no more than about 0.3%, no more than about 0.4%, no more than about 0.5%, no more than about 0.6%, no 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%, no more than about 1.3%, no more than about 1.4%, no more than about 1.5%, no more than about 1.6%, no more than about 1.7%, 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 no more than about 5.0%. In some embodiments, the absorption enhancer is di ethylene glycol monoethyl ether. In some embodiments, the pharmaceutical spray formulation comprises 1% diethylene glycol monoethyl ether.

[0205] In an aspect provided herein, the pharmaceutical spray formulation further comprises a permeability enhancer or absorption enhancer.

[0206] In an aspect provided herein, the pharmaceutical spray formulation further comprises diethylene glycol monoethyl ether. In some embodiments, the pharmaceutical spray formulation further comprises diethylene glycol monoethyl ether at a concentration of from about 0.05% to about 15%. In some embodiments, the pharmaceutical spray formulation further comprises di ethylene glycol monoethyl ether at a concentration of from about 0.5% to about 10%. In some embodiments, the pharmaceutical spray formulation further comprises di ethylene glycol monoethyl ether at a concentration of from about 0.5% to about 5%. In some embodiments, the pharmaceutical spray formulation further comprises diethylene glycol monoethyl ether at a concentration of from about 0.5% to about 4%. In some embodiments, the pharmaceutical spray formulation further comprises diethylene glycol monoethyl ether at a concentration of from about 0.5% to about 3%. In some embodiments, the pharmaceutical spray formulation further comprises diethylene glycol monoethyl ether at a concentration of from 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%.

[0207] 8, _ Formulations

[0208] In some aspects, disclosed herein are pharmaceutical spray formulations comprising an active ingredient or pharmaceutically acceptable salt thereof, and one or more excipients, vehicles, emulsifiers, stabilizing agents, preservatives, mucosal adhesives, antibacterial agents, buffers, and/or other additives. In some embodiments, the pharmaceutical spray formulation 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 an excipient, vehicle, emulsifier, stabilizing agent, preservative, mucosal adhesive, antibacterial agent, buffer, and/or other additive. In some embodiments, the pharmaceutical spray formulation comprises at least one, at least two, at least three, at least four, at least five, or at least six of an antioxidant, a chelating agent, an antimicrobial preservative, a viscosity modifier, a buffering agent, or an absorption enhancer. In some embodiments, the pharmaceutical spray formulation comprises at least one preservative that is an antioxidant, a chelating agent, an antimicrobial preservative, or any combination thereof. In some embodiments, the pharmaceutical spray formulation 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, or at least six of an antioxidant, an isotonicity agent, a viscosity modifier, a buffering agent, an absorption enhancer, or an antimicrobial preservative. In some embodiments, the pharmaceutical spray formulation comprises an active ingredient (e.g., epinephrine), or a pharmaceutically acceptable salt thereof, an antioxidant, an isotonicity agent, a viscosity modifier, a buffering agent, an absorption enhancer, and an antimicrobial preservative.

[0209] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2.0% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0210] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2.0% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0211] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2.0% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0212] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0213] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0214] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0215] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0216] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0217] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0218] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0219] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0220] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0221] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0222] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0223] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0224] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0225] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0226] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0227] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0228] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0229] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0230] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0231] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0232] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0233] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0234] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0235] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0236] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0237] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0238] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0239] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0240] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0241] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0242] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0243] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0244] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0245] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0246] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0247] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0248] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0249] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0250] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0251] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0252] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0253] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0254] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0255] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0256] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0257] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1.0% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1.0% of a buffering agent, and from about 0.1% to about 2.0% of an absorption enhancer.

[0258] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1.0% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1.0% of a buffering agent, and from about 0.1% to about 2.0% of an absorption enhancer.

[0259] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1.0% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1.0% of a buffering agent, and from about 0.1% to about 2.0% of an absorption enhancer.

[0260] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1.0% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1.0% of a buffering agent, and from about 0.1% to about 2.0% of an absorption enhancer.

[0261] In some embodiments, the pharmaceutical spray formulation comprises from about 5% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1.0% of an isotonicity agent, from about 0.05% to about 0.5% of a viscosity modifier, from about 0.1% to about 1.0% of a buffering agent, and from about 0.5% to about 5% of an absorption enhancer.

[0262] In some embodiments, the pharmaceutical spray formulation comprises from about 5% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1.0% of an isotonicity agent, from about 0.05% to about 0.5% of a viscosity modifier, from about 0.1% to about 1.0% of a buffering agent, and from about 0.5% to about 5% of an absorption enhancer.

[0263] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0264] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0265] In some embodiments, the pharmaceutical spray formulation comprises about 2.4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0266] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0267] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0268] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer. In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0269] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0270] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0271] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0272] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0273] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0274] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0275] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0276] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0277] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0278] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0279] In some embodiments, the pharmaceutical spray formulation comprises about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, and about 1% of an absorption enhancer.

[0280] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0281] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0282] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 5% of an isotonicity agent, from about 0.001% to about 0.5% of a viscosity modifier, from about 0.01% to about 2% of a buffering agent, and from about 0.05% to about 15% of an absorption enhancer.

[0283] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent citrate, and from about 0.1% to about 5% of an absorption enhancer.

[0284] In some embodiments, the pharmaceutical spray formulation comprises from about 5% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0285] In some embodiments, the pharmaceutical spray formulation comprises from about 5% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of an antioxidant, from about 0.1% to about 1% of an isotonicity agent, from about 0.01% to about 0.2% of a viscosity modifier, from about 0.1% to about 1% of a buffering agent, and from about 0.1% to about 5% of an absorption enhancer.

[0286] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0287] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0288] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0289] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0290] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0291] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0292] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0293] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0294] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0295] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0296] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0297] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0298] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0299] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0300] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0301] In some embodiments, the pharmaceutical spray formulation comprises about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, and about 1% of an absorption enhancer.

[0302] In some embodiments, the pharmaceutical spray formulation further comprises an antimicrobial preservative at a concentration of from about 0.05% (w/v) to about 1% (w/v). [0303] In some embodiments, the pharmaceutical spray formulation comprises about 2.4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, about 1% of an absorption enhancer, and about 0.2% an antimicrobial preservative. [0304] In some embodiments, the pharmaceutical spray formulation comprises about 4.6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.7% of a buffering agent, about 1% of an absorption enhancer, and about 0.2% an antimicrobial preservative.

[0305] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0306] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0307] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0308] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0309] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0310] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0311] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0312] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0313] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0314] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0315] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0316] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative. [0317] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0318] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0319] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of an antioxidant, about 0.4% of an isotonicity agent, about 0.1% of a viscosity modifier, about 0.42% of a buffering agent, about 1% of an absorption enhancer, and about 0.21% an antimicrobial preservative.

[0320] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0% trisodium citrate, and from about 0.05% to about 15% diethylene glycol monoethyl ether.

[0321] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0% trisodium citrate, and from about 0.05% to about 15% diethylene glycol monoethyl ether.

[0322] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0% trisodium citrate, and from about 0.05% to about 15% diethylene glycol monoethyl ether. [0323] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0324] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0325] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0326] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0327] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0328] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether. [0329] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0330] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0331] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0332] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0333] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0334] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether. [0335] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0336] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0337] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0338] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0339] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0340] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether. [0341] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0342] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0343] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0344] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0345] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0346] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether. [0347] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0348] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0349] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0350] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0351] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0352] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether. [0353] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0354] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0355] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0356] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0357] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0358] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether. [0359] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0360] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0361] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0362] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0363] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0364] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether. [0365] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0366] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0367] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0368] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1.0% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1.0% trisodium citrate, and from about 0.1% to about 2.0% diethylene glycol monoethyl ether.

[0369] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1.0% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1.0% trisodium citrate, and from about 0.1% to about 2.0% diethylene glycol monoethyl ether.

[0370] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1.0% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1.0% trisodium citrate, and from about 0.1% to about 2.0% diethylene glycol monoethyl ether.

[0371] In some embodiments, the pharmaceutical spray formulation comprises from about 5% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1.0% sodium chloride, from about 0.05% to about 0.5% hypromellose, from about 0.1% to about 1.0% trisodium citrate, and from about 0.5% to about 5% diethylene glycol monoethyl ether.

[0372] In some embodiments, the pharmaceutical spray formulation comprises from about 5% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1.0% sodium chloride, from about 0.05% to about 0.5% hypromellose, from about 0.1% to about 1.0% trisodium citrate, and from about 0.5% to about 5% diethylene glycol monoethyl ether.

[0373] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0374] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0375] In some embodiments, the pharmaceutical spray formulation comprises about 2.4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0376] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0377] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0378] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0379] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0380] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0381] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0382] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0383] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0384] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0385] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0386] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0387] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0388] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0389] In some embodiments, the pharmaceutical spray formulation comprises about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0390] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2% citric acid monohydrate, and from about 0.05% to about 15% diethylene glycol monoethyl ether.

[0391] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate citrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0392] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 10% (w/w) of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate citrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0393] In some embodiments, the pharmaceutical spray formulation comprises from about 1% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate citrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0394] In some embodiments, the pharmaceutical spray formulation comprises from about 5% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0395] In some embodiments, the pharmaceutical spray formulation comprises from about 5% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0396] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0397] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0398] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether. [0399] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0400] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0401] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0402] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0403] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0404] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0405] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0406] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether. [0407] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0408] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0409] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0410] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0411] In some embodiments, the pharmaceutical spray formulation comprises about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% di ethylene glycol monoethyl ether.

[0412] In some embodiments, the pharmaceutical spray formulation further comprises chlorobutanol at a concentration of from about 0.05% (w/v) to about 1% (w/v).

[0413] In some embodiments, the pharmaceutical spray formulation comprises about 2.4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% chlorobutanol.

[0414] In some embodiments, the pharmaceutical spray formulation comprises about 4.6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% chlorobutanol. [0415] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0416] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0417] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0418] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0419] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0420] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0421] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0422] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0423] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0424] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0425] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0426] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0427] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol. [0428] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0429] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, about 1% diethylene glycol monoethyl ether, and about 0.21% chlorobutanol.

[0430] In some embodiments, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0431] In some embodiments, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0432] In some embodiments, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0433] In some embodiments, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0434] In some embodiments, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0435] In some embodiments, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0436] In some embodiments, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0437] In some embodiments, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0438] In some embodiments, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0439] In some embodiments, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0440] In some embodiments, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol. [0441] In some embodiments, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0442] In some embodiments, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0443] In some embodiments, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0444] In some embodiments, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, about 1% diethylene glycol monoethyl ether, and about 0.2% of chlorobutanol.

[0445] 9. _ Intranasal Delivery

[0446] In an aspect provided herein, the pharmaceutical spray formulation has a droplet size of D50 of from about 10 microns to about 100 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of from about 10 microns to about 80 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of from about 10 microns to about 60 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of from about 10 microns to about 40 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of from about 10 microns to about 20 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of about 10 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of about 20 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of about 30 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of about 40 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of about 50 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of about 60 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of about 70 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of about 80 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of about 90 microns. In some embodiments, the pharmaceutical spray formulation has a droplet size of D50 of about 100 microns.

[0447] In some embodiments, the pharmaceutical spray formulation is delivered as one or more sprays having a droplet size distribution characterized by certain D10, D50, or D90 values. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D10 droplet size of about 15 microns to about 30 microns. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D10 droplet size of about

15 microns to about 16 microns, about 15 microns to about 17 microns, about 15 microns to about 18 microns, about 15 microns to about 19 microns, about 15 microns to about

20 microns, about 15 microns to about 21 microns, about 15 microns to about 22 microns, about 15 microns to about 25 microns, about 15 microns to about 30 microns, about

16 microns to about 17 microns, about 16 microns to about 18 microns, about 16 microns to about 19 microns, about 16 microns to about 20 microns, about 16 microns to about

21 microns, about 16 microns to about 22 microns, about 16 microns to about 25 microns, about 16 microns to about 30 microns, about 17 microns to about 18 microns, about

17 microns to about 19 microns, about 17 microns to about 20 microns, about 17 microns to about 21 microns, about 17 microns to about 22 microns, about 17 microns to about

25 microns, about 17 microns to about 30 microns, about 18 microns to about 19 microns, about 18 microns to about 20 microns, about 18 microns to about 21 microns, about

18 microns to about 22 microns, about 18 microns to about 25 microns, about 18 microns to about 30 microns, about 19 microns to about 20 microns, about 19 microns to about

21 microns, about 19 microns to about 22 microns, about 19 microns to about 25 microns, about 19 microns to about 30 microns, about 20 microns to about 21 microns, about 20 microns to about 22 microns, about 20 microns to about 25 microns, about 20 microns to about 30 microns, about 21 microns to about 22 microns, about 21 microns to about 25 microns, about 21 microns to about 30 microns, about 22 microns to about 25 microns, about 22 microns to about 30 microns, or about 25 microns to about 30 microns. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a DIO droplet size of about 15 microns, about 16 microns, about 17 microns, about 18 microns, about 19 microns, about 20 microns, about 21 microns, about 22 microns, about 25 microns, or about 30 microns. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D10 droplet size of at least about 15 microns, about 16 microns, about 17 microns, about 18 microns, about 19 microns, about 20 microns, about 21 microns, about 22 microns, or about 25 microns. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D10 droplet size of at most about 16 microns, about 17 microns, about 18 microns, about 19 microns, about 20 microns, about 21 microns, about 22 microns, about 25 microns, or about 30 microns.

[0448] In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D50 droplet size of about 35 microns to about 80 microns. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D50 droplet size of about 35 microns to about 40 microns, about 35 microns to about 42 microns, about 35 microns to about 44 microns, about 35 microns to about 46 microns, about 35 microns to about 48 microns, about 35 microns to about 50 microns, about 35 microns to about 52 microns, about 35 microns to about 55 microns, about 35 microns to about 60 microns, about 35 microns to about 70 microns, about 35 microns to about 80 microns, about 40 microns to about 42 microns, about 40 microns to about 44 microns, about 40 microns to about 46 microns, about 40 microns to about 48 microns, about 40 microns to about 50 microns, about 40 microns to about 52 microns, about 40 microns to about 55 microns, about 40 microns to about 60 microns, about 40 microns to about 70 microns, about 40 microns to about 80 microns, about 42 microns to about 44 microns, about 42 microns to about 46 microns, about 42 microns to about 48 microns, about 42 microns to about 50 microns, about 42 microns to about 52 microns, about 42 microns to about 55 microns, about 42 microns to about 60 microns, about 42 microns to about 70 microns, about 42 microns to about 80 microns, about 44 microns to about 46 microns, about 44 microns to about 48 microns, about 44 microns to about 50 microns, about 44 microns to about 52 microns, about 44 microns to about 55 microns, about 44 microns to about 60 microns, about 44 microns to about 70 microns, about 44 microns to about 80 microns, about 46 microns to about 48 microns, about 46 microns to about 50 microns, about 46 microns to about 52 microns, about 46 microns to about 55 microns, about 46 microns to about 60 microns, about 46 microns to about 70 microns, about 46 microns to about 80 microns, about 48 microns to about 50 microns, about 48 microns to about 52 microns, about 48 microns to about 55 microns, about 48 microns to about 60 microns, about 48 microns to about 70 microns, about 48 microns to about 80 microns, about 50 microns to about 52 microns, about 50 microns to about 55 microns, about 50 microns to about 60 microns, about 50 microns to about 70 microns, about 50 microns to about 80 microns, about 52 microns to about 5 5 microns, about 52 microns to about 60 microns, about 52 microns to about 70 microns, about 52 microns to about 80 microns, about 55 microns to about 60 microns, about 55 microns to about 70 microns, about 55 microns to about 80 microns, about 60 microns to about 70 microns, about 60 microns to about 80 microns, or about 70 microns to about 80 microns. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D50 droplet size of about 35 microns, about 40 microns, about 42 microns, about 44 microns, about 46 microns, about 48 microns, about 50 microns, about 52 microns, about 55 microns, about 60 microns, about 70 microns, or about 80 microns. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D50 droplet size of at least about 35 microns, about 40 microns, about 42 microns, about 44 microns, about 46 microns, about 48 microns, about 50 microns, about 52 microns, about 55 microns, about 60 microns, or about 70 microns. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D50 droplet size of at most about 40 microns, about 42 microns, about 44 microns, about 46 microns, about 48 microns, about 50 microns, about 52 microns, about 55 microns, about 60 microns, about 70 microns, or about 80 microns.

[0449] In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D90 droplet size of about 80 microns to about 180 microns. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D90 droplet size of about 80 microns to about 90 microns, about 80 microns to about 100 microns, about 80 microns to about 110 microns, about 80 microns to about 115 microns, about 80 microns to about 120 microns, about 80 microns to about 130 microns, about 80 microns to about 140 microns, about 80 microns to about 150 microns, about 80 microns to about 160 microns, about 80 microns to about 170 microns, about 80 microns to about 180 microns, about 90 microns to about 100 microns, about 90 microns to about 110 microns, about 90 microns to about 115 microns, about 90 microns to about 120 microns, about 90 microns to about 130 microns, about 90 microns to about 140 microns, about 90 microns to about 150 microns, about 90 microns to about 160 microns, about 90 microns to about 170 microns, about 90 microns to about 180 microns, about 100 microns to about 110 microns, about 100 microns to about 115 microns, about 100 microns to about 120 microns, about 100 microns to about

130 microns, about 100 microns to about 140 microns, about 100 microns to about

150 microns, about 100 microns to about 160 microns, about 100 microns to about

170 microns, about 100 microns to about 180 microns, about 110 microns to about

115 microns, about 110 microns to about 120 microns, about 110 microns to about

130 microns, about 110 microns to about 140 microns, about 110 microns to about

150 microns, about 110 microns to about 160 microns, about 110 microns to about

170 microns, about 110 microns to about 180 microns, about 115 microns to about

120 microns, about 115 microns to about 130 microns, about 115 microns to about

140 microns, about 115 microns to about 150 microns, about 115 microns to about

160 microns, about 115 microns to about 170 microns, about 115 microns to about

180 microns, about 120 microns to about 130 microns, about 120 microns to about

140 microns, about 120 microns to about 150 microns, about 120 microns to about

160 microns, about 120 microns to about 170 microns, about 120 microns to about

180 microns, about 130 microns to about 140 microns, about 130 microns to about

150 microns, about 130 microns to about 160 microns, about 130 microns to about

170 microns, about 130 microns to about 180 microns, about 140 microns to about

150 microns, about 140 microns to about 160 microns, about 140 microns to about

170 microns, about 140 microns to about 180 microns, about 150 microns to about

160 microns, about 150 microns to about 170 microns, about 150 microns to about

180 microns, about 160 microns to about 170 microns, about 160 microns to about

180 microns, or about 170 microns to about 180 microns. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D90 droplet size of about 80 microns, about 90 microns, about 100 microns, about 110 microns, about 115 microns, about 120 microns, about 130 microns, about 140 microns, about 150 microns, about 160 microns, about 170 microns, or about 180 microns. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D90 droplet size of at least about 80 microns, about 90 microns, about 100 microns, about 110 microns, about 115 microns, about 120 microns, about 130 microns, about 140 microns, about 150 microns, about 160 microns, or about 170 microns. In some embodiments, the pharmaceutical spray formulation is delivered as a spray with a D90 droplet size of at most about 90 microns, about 100 microns, about 110 microns, about 115 microns, about 120 microns, about 130 microns, about 140 microns, about 150 microns, about 160 microns, about 170 microns, or about 180 microns.

[0450] In some embodiments, the pharmaceutical spray formulation is delivered as a spray that has a % volume < 10 microns of about 0.2 % to about 5 %. In some embodiments, the pharmaceutical spray formulation is delivered as a spray that has a % volume < 10 microns of about 0.2 % to about 0.4 %, about 0.2 % to about 0.6 %, about 0.2 % to about 0.8 %, about 0.2 % to about 1 %, about 0.2 % to about 1.5 %, about 0.2 % to about 2 %, about 0.2 % to about 3 %, about 0.2 % to about 4 %, about 0.2 % to about 5 %, about 0.4 % to about 0.6 %, about 0.4 % to about 0.8 %, about 0.4 % to about 1 %, about 0.4 % to about 1.5 %, about 0.4 % to about 2 %, about 0.4 % to about 3 %, about 0.4 % to about 4 %, about 0.4 % to about 5 %, about 0.6 % to about 0.8 %, about 0.6 % to about 1 %, about 0.6 % to about 1.5 %, about 0.6 % to about 2 %, about 0.6 % to about 3 %, about 0.6 % to about 4 %, about 0.6 % to about 5 %, about 0.8 % to about 1 %, about 0.8 % to about 1.5 %, about 0.8 % to about 2 %, about 0.8 % to about 3 %, about 0.8 % to about 4 %, about 0.8 % to about 5 %, about 1 % to about 1.5 %, about 1 % to about 2 %, about 1 % to about 3 %, about 1 % to about 4 %, about 1 % to about 5 %, about 1.5 % to about 2 %, about 1.5 % to about 3 %, about 1.5 % to about 4 %, about 1.5 % to about 5 %, about 2 % to about 3 %, about 2 % to about 4 %, about 2 % to about 5 %, about 3 % to about 4 %, about 3 % to about 5 %, or about 4 % to about 5 %. In some embodiments, the pharmaceutical spray formulation is delivered as a spray that has a % volume < 10 microns 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 spray formulation is delivered as a spray that has a % volume < 10 microns 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 spray formulation is delivered as a spray that has a % volume < 10 microns of at most about 0.4 %, about 0.6 %, about 0.8 %, about 1 %, about 1.5 %, about 2 %, about 3 %, about 4 %, or about 5 %.

[0451] In some embodiments, the pharmaceutical spray formulation is delivered as a spray that has a span of about 1.5 to about 2.5. In some embodiments, the pharmaceutical spray formulation is delivered as a spray that has a span of about 1.5 to about 1.6, about 1.5 to about 1.7, about 1.5 to about 1.8, about 1.5 to about 1.9, about 1.5 to about 2, about 1.5 to about 2.1, about 1.5 to about 2.2, about 1.5 to about 2.3, about 1.5 to about 2.4, about 1.5 to about 2.5, about 1.6 to about 1.7, about 1.6 to about 1.8, about 1.6 to about 1.9, about 1.6 to about 2, about 1.6 to about 2.1, about 1.6 to about 2.2, about 1.6 to about 2.3, about 1.6 to about 2.4, about 1.6 to about 2.5, about 1.7 to about 1.8, about 1.7 to about 1.9, about 1.7 to about 2, about 1.7 to about 2.1, about 1.7 to about 2.2, about 1.7 to about 2.3, about 1.7 to about 2.4, about 1.7 to about 2.5, about 1.8 to about 1.9, about 1.8 to about 2, about 1.8 to about 2.1, about 1.8 to about 2.2, about 1.8 to about 2.3, about 1.8 to about 2.4, about 1.8 to about 2.5, about 1.9 to about 2, about 1.9 to about 2.1, about 1.9 to about 2.2, about 1.9 to about 2.3, about 1.9 to about 2.4, about 1.9 to about 2.5, about 2 to about 2.1, about 2 to about 2.2, about 2 to about 2.3, about 2 to about 2.4, about 2 to about 2.5, about 2.1 to about 2.2, about 2.1 to about 2.3, about 2.1 to about 2.4, about 2.1 to about 2.5, about 2.2 to about 2.3, about 2.2 to about 2.4, about 2.2 to about 2.5, about 2.3 to about 2.4, about 2.3 to about 2.5, or about 2.4 to about 2.5. In some embodiments, the pharmaceutical spray formulation is delivered as a spray that has a span 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 formulation is delivered as a spray that has a span 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 spray formulation is delivered as a spray that has a span of at most 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.

[0452] In an aspect provided herein, the pharmaceutical spray formulation is present in and/or delivered from a device. In some embodiments, the pharmaceutical spray formulation is present in and/or delivered from a pre-primed device. In some embodiments, the pharmaceutical spray formulation is present in and/or delivered from a device suitable for delivering the formulation into the nostril of a subject. In some embodiments, the device is a single-dose device. In some embodiments, the device is a bi-dose device. In some embodiments, the device has a single reservoir containing from about 50 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device has a single reservoir containing from about 75 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device has a single reservoir containing from about 100 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device has a single reservoir containing from about 125 pL to about 250 pL of the pharmaceutical formulation.

In some embodiments, the device has a single reservoir containing from about 150 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device delivers two sprays of the pharmaceutical solution from a single reservoir. In some embodiments, the single-dose device delivers two sprays of the pharmaceutical solution from a single reservoir. In some embodiments, the bi-dose device delivers two sprays of the pharmaceutical solution from a single reservoir. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 75 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 75 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 100 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 100 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 125 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 125 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 225 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 225 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 200 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 175 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 175 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 175 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 150 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 150 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device delivers one spray of the pharmaceutical solution from the first reservoir and one spray of the pharmaceutical solution from the second reservoir. In some embodiments, the pharmaceutical spray formulation is present in and/or delivered from a device with an oxygen absorber or scavenger. In some embodiments, the oxygen absorber or scavenger is iron, ferrous carbonate, ascorbate, or sodium bicarbonate. In some embodiments, the pharmaceutical spray formulation is present in and/or delivered from a device wherein the device has an increased reservoir. In some embodiments, the device comprises at least one oxygen absorber or scavenger. In some embodiments, the oxygen absorber or scavenger is iron, ferrous carbonate, ascorbate, or sodium bicarbonate, or a combination thereof.

[0453] In an aspect provided herein, the pharmaceutical spray formulation is adapted for dosing by inhalation.

[0454] In an aspect provided herein, the pharmaceutical spray formulation is adapted for intranasal dosing.

[0455] In an aspect provided herein, is a spray, comprising droplets. In an aspect provided herein, is a spray delivered from a device, comprising droplets. In an aspect provided herein, is a spray, comprising droplets, wherein the droplets comprise epinephrine or a pharmaceutically acceptable salt thereof, an isotonicity agent, and benzalkonium chloride or chlorobutanol.

[0456] In some embodiments, the droplets comprise in aggregate from about 0.5 mg to about 100 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 0.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 1 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 2 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 3 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 4 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 6 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 7 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 8 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 9 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 10 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 11 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 12 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 13 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 14 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 15 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 20 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 25 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 30 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 35 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 40 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 45 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 50 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 55 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 60 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 65 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 70 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 75 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 80 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 85 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 90 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 95 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the droplets comprise in aggregate about 100 mg of epinephrine, or a pharmaceutically acceptable salt thereof.

[0457] In some embodiments, the epinephrine is at least about 10% bioavailable. In some embodiments, the epinephrine is at least about 20% bioavailable. In some embodiments, the epinephrine is at least about 30% bioavailable. In some embodiments, the epinephrine is at least about 40% bioavailable. In some embodiments, the epinephrine is at least about 50% bioavailable. In some embodiments, the epinephrine is at least about 60% bioavailable. In some embodiments, the epinephrine is at least about 70% bioavailable. In some embodiments, the epinephrine is at least about 80% bioavailable. In some embodiments, the epinephrine is at least about 90% bioavailable.

[0458] In some embodiments, the epinephrine, or a pharmaceutically acceptable salt thereof, is dissolved in water, ethanol, or propylene glycol, or a combination thereof. In some embodiments, the epinephrine, or a pharmaceutically acceptable salt thereof, is dissolved in water. In some embodiments, the epinephrine, or a pharmaceutically acceptable salt thereof, is dissolved in ethanol. In some embodiments, the epinephrine, or a pharmaceutically acceptable salt thereof, is dissolved in propylene glycol. In some embodiments, the epinephrine, or a pharmaceutically acceptable salt thereof, is dissolved in a combination of water and ethanol. In some embodiments, the epinephrine, or a pharmaceutically acceptable salt thereof, is dissolved in a combination of water and propylene glycol. In some embodiments, the epinephrine, or a pharmaceutically acceptable salt thereof, is dissolved in a combination of ethanol and propylene glycol.

[0459] In some embodiments, the droplets comprise in aggregate from about 0.005% to about 10% (w/v) of benzalkonium chloride or chlorobutanol.

[0460] In some embodiments, the droplets comprise in aggregate from about 0.005% to about 10% (w/v) of benzalkonium chloride. In some embodiments, the pharmaceutical spray formulation comprises benzalkonium chloride at a concentration of from about 0.005% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation comprises benzalkonium chloride at a concentration of from about 0.01% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation comprises benzalkonium chloride at a concentration of from about 0.05% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation comprises benzalkonium chloride at a concentration of from about 0.1% (w/v) to about 1% (w/v). In some embodiments, the droplets comprise in aggregate from about 0.01% to about 10% (w/v) of benzalkonium chloride. In some embodiments, the droplets comprise in aggregate from about 0.05% to about 10% (w/v) of benzalkonium chloride. In some embodiments, the droplets comprise in aggregate from about 0.5% to about 10% (w/v) of benzalkonium chloride. In some embodiments, the droplets comprise in aggregate from about 1% to about 10% (w/v) of benzalkonium chloride. In some embodiments, the droplets comprise in aggregate from about 0.005% to about 5% (w/v) of benzalkonium chloride. In some embodiments, the droplets comprise in aggregate from about 0.01% to about 2% (w/v) of benzalkonium chloride.

[0461] In some embodiments, the droplets comprise in aggregate from about 0.005% to about 10% (w/v) of chlorobutanol. In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of from about 0.005% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of from about 0.01% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of from about 0.05% (w/v) to about 1% (w/v). In some embodiments, the pharmaceutical spray formulation comprises chlorobutanol at a concentration of from about 0.1% (w/v) to about 1% (w/v). In some embodiments, the droplets comprise in aggregate from about 0.01% to about 10% (w/v) of chlorobutanol. In some embodiments, the droplets comprise in aggregate from about 0.05% to about 10% (w/v) of chlorobutanol. In some embodiments, the droplets comprise in aggregate from about 0.5% to about 10% (w/v) of chlorobutanol. In some embodiments, the droplets comprise in aggregate from about 1% to about 10% (w/v) of chlorobutanol. In some embodiments, the droplets comprise in aggregate from about 0.005% to about 5% (w/v) of chlorobutanol. In some embodiments, the droplets comprise in aggregate from about 0.01% to about 2% (w/v) of chlorobutanol. In some embodiments, the droplets comprise in aggregate about 2.1% (w/v) of chlorobutanol.

[0462] In some embodiments, the isotonicity agent is present at a concentration of from about 0.1% to about 5% (w/v). In some embodiments, the isotonicity agent is sodium chloride. [0463] In an aspect provided herein, the spray is delivered from a device. In some embodiments, the device is pre-primed. In some embodiments, the device is configured to deliver the spray. In some embodiments, the device is configured to deliver the spray having the shape of a round plume.

[0464] In an aspect provided herein, the spray takes the shape of a round plume. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 2.0. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.9. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.8. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.7. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.6. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.5. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.4. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.35. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.3. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.25. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.2. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.15. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.1. In some embodiments, the spray takes the shape of a round plume with an ovality ratio less than about 1.0. In some embodiments, the spray takes the shape of a round plume with an ovality ratio of at least about 1.0, at least about 1.1, at least about 1.15, at least about 1.2, at least about 1.25, at least about 1.3, at least about 1.35, 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, no more than about 1.5, no more than about 1.4, no more than about 1.35, no more than about 1.3, no more than about 1.25, no more than about 1.2, no more than about 1.15, or no more than about 1.1.

[0465] In an aspect provided herein, the ovality ratio of the spray is measured at a distance of from about 1 cm to about 10 cm from the device from which the spray is delivered. In an aspect provided herein, the ovality ratio of the spray is measured at a distance of from about 1 cm to about 5 cm from the device from which the spray is delivered. In an aspect provided herein, the ovality ratio of the spray is measured at a distance of from about 3 cm to about 6 cm from the device from which the spray is delivered. In an aspect provided herein, the ovality ratio of the spray is measured at a distance of about 3 cm from the device from which the spray is delivered. In an aspect provided herein, the ovality ratio of the spray is measured at a distance of about 5 cm from the device from which the spray is delivered. In an embodiment, the spray is measured from a nozzle, such as a spray nozzle, on the device from which the spray is delivered.

[0466] In an aspect provided herein, the droplets of the spray have a median droplet size of from about 10 pm to about 120 pm. In some embodiments, no more than about 10% of the droplets have a diameter less than about 10 pm. In some embodiments, no more than approximately 5% of the droplets have a diameter less than about 10 pm. In some embodiments, no more than approximately 2% of the droplets have a diameter less than about 10 pm. In some embodiments, approximately 50% of the droplets have a diameter of from about 10 mih to about 120 mih. In some embodiments, approximately 50% of the droplets have a diameter of from about 10 pm to about 60 pm. In some embodiments, approximately 90% of the droplets have a diameter less than about 120 pm.

[0467] In an aspect provided herein, the spray further comprises a stabilizing agent and an acid. In some embodiments, the stabilizing agent is disodium edetate. In some embodiments, the acid is hydrochloric acid or citric acid, or a combination thereof. In some embodiments, the acid is hydrochloric acid. In some embodiments, the acid is citric acid. In some embodiments, the acid is a combination of hydrochloric acid and citric acid.

[0468] In an aspect provided herein, the spray further comprises sodium bisulfite or sodium metabisulfite.

[0469] In an aspect provided herein, the spray further comprises sodium bisulfite or sodium metabisulfite. In some embodiments, the spray further comprises sodium bisulfite at a concentration of from about 0.0001% (w/w) to about 0.1% (w/w) or sodium metabisulfite at a concentration of from about 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the spray comprises sodium bisulfite at a concentration of from about 0.0001% (w/w) to about 0.05% (w/w) or sodium metabisulfite at a concentration of from about 0.0001% (w/w) to about 0.05% (w/w). In some embodiments, the spray comprises sodium bisulfite at a concentration of from about 0.001% (w/w) to about 0.05% (w/w) or sodium metabisulfite at a concentration of from about 0.001% (w/w) to about 0.05% (w/w). In some embodiments, the spray comprises sodium bisulfite at a concentration of from about 0.01% (w/w) to about 0.05% (w/w) or sodium metabisulfite at a concentration of from about 0.01% (w/w) to about 0.05% (w/w). In some embodiments, the spray further comprises sodium bisulfite at a concentration of from about 0.001% (w/w) to about 0.1% (w/w) or sodium metabisulfite at a concentration of from about 0.001% (w/w) to about 0.1% (w/w). In some embodiments, the spray further comprises sodium bisulfite at a concentration of from about 0.01% (w/w) to about 0.1% (w/w) or sodium metabisulfite at a concentration of from about 0.01% (w/w) to about 0.1% (w/w).

[0470] In some embodiments, the spray comprises sodium bisulfite. In some embodiments, the spray further comprises sodium bisulfite at a concentration of from about 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the spray comprises sodium bisulfite at a concentration of from about 0.001% to about 0.05%. In some embodiments, the spray comprises sodium bisulfite at a concentration of from about 0.01% to about 0.05%. In some embodiments, the spray comprises sodium bisulfite at a concentration of about 0.01%. In some embodiments, the spray comprises sodium bisulfite at a concentration of about 0.02%. In some embodiments, the spray comprises sodium bisulfite at a concentration of about 0.03%. In some embodiments, the spray comprises sodium bisulfite at a concentration of about 0.04%. In some embodiments, the spray comprises sodium bisulfite at a concentration of about 0.05%.

[0471] In some embodiments, the spray comprises sodium metabisulfite. In some embodiments, the spray further comprises sodium metabisulfite at a concentration of from about 0.0001% (w/w) to about 0.1% (w/w). In some embodiments, the spray comprises sodium metabisulfite at a concentration of from about 0.001% to about 0.1%. In some embodiments, the spray comprises sodium metabisulfite at a concentration of from about 0.01% to about 0.1%. In some embodiments, the spray further comprises sodium metabisulfite at a concentration of from about 0.001% (w/w) to about 0.1% (w/w). In some embodiments, the spray further comprises sodium metabisulfite at a concentration of from about 0.01% (w/w) to about 0.1% (w/w). In some embodiments, the spray comprises sodium metabisulfite at a concentration of about 0.01%. In some embodiments, the spray comprises sodium metabisulfite at a concentration of about 0.02%. In some embodiments, the spray comprises sodium metabisulfite at a concentration of about 0.03%. In some embodiments, the spray comprises sodium metabisulfite at a concentration of about 0.04%. In some embodiments, the spray comprises sodium metabisulfite at a concentration of about 0.05%. In some embodiments, the spray comprises sodium metabisulfite at a concentration of about 0.06%. In some embodiments, the spray comprises sodium metabisulfite at a concentration of about 0.07%. In some embodiments, the spray comprises sodium metabisulfite at a concentration of about 0.08%. In some embodiments, the spray comprises sodium metabisulfite at a concentration of about 0.09%. In some embodiments, the spray comprises sodium metabisulfite at a concentration of about 0.1%.

[0472] In an aspect provided herein, the spray further comprises disodium edetate. In some embodiments, the spray comprises disodium edetate at a concentration of from about 0.0001% to about 0.01%. In some embodiments, the spray comprises disodium edetate at a concentration of from about 0.001% to about 0.01%.

[0473] In an aspect provided herein, the spray further comprises an antimicrobial preservative. In some embodiments, the antimicrobial preservative is benzalkonium sodium or chlorobutanol. In some embodiments, the spray comprises benzalkonium sodium at a concentration of from about 0.005% (w/v) to about 1% (w/v) or chlorobutanol at a concentration of from about 0.005% to about 1%.

[0474] In some embodiments, the spray comprises benzalkonium sodium. In some embodiments, the spray comprises benzalkonium sodium at a concentration of from about 0.005% to about 1%.

[0475] In some embodiments, the spray comprises chlorobutanol. In some embodiments, the spray comprises chlorobutanol at a concentration of from about 0.005% to about 1%.

[0476] In an aspect provided herein, the spray further comprises sodium chloride. In some embodiments, the spray comprises sodium chloride at a concentration of from about 0.1% to about 5%. In some embodiments, the spray comprises sodium chloride at a concentration of from about 0.1% to about 1%. In some embodiments, the spray comprises sodium chloride at a concentration of from about 0.5% to about 5%. In some embodiments, the spray comprises sodium chloride at a concentration of from about 1% to about 5%. In some embodiments, the spray comprises sodium chloride at a concentration of from about 2% to about 5%. In some embodiments, the spray comprises sodium chloride at a concentration of from about 3% to about 5%. In some embodiments, the spray comprises sodium chloride at a concentration of from about 4% to about 5%.

[0477] In an aspect provided herein, the spray further comprises a vasodilator. In some embodiments, the vasodilator is nitroprusside, phentolamine, or nifedipine.

[0478] In some embodiments, the spray further comprises nitroprusside. In some embodiments, the spray further comprises from about 0.05 mg to about 5 mg of nitroprusside. In some embodiments, the spray further comprises from about 0.1 mg to about 5 mg of nitroprusside. In some embodiments, the spray further comprises from about 0.5 mg to about 5 mg of nitroprusside. In some embodiments, the spray further comprises from about 1 mg to about 5 mg of nitroprusside. In some embodiments, the spray further comprises from about 1 mg to about 4 mg of nitroprusside. In some embodiments, the spray further comprises nitroprusside. In some embodiments, the spray further comprises 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 comprises 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 comprises from about 0.5 mg to about 2 mg of nitroprusside. [0479] In some embodiments, the spray further comprises phentolamine. In some embodiments, the spray further comprises from about 1 mg to about 50 mg of phentolamine. In some embodiments, the spray further comprises phentolamine. In some embodiments, the spray further comprises from about 1 mg to about 40 mg of phentolamine. In some embodiments, the spray further comprises phentolamine. In some embodiments, the spray further comprises from about 1 mg to about 30 mg of phentolamine. In some embodiments, the spray further comprises phentolamine. In some embodiments, the spray further comprises from about 1 mg to about 20 mg of phentolamine. In some embodiments, the spray further comprises phentolamine. In some embodiments, the spray further comprises from about 1 mg to about 10 mg of phentolamine. In some embodiments, the spray further comprises phentolamine. In some embodiments, the spray further comprises from about 5 mg to about 50 mg of phentolamine. In some embodiments, the spray further comprises phentolamine. In some embodiments, the spray further comprises from about 10 mg to about 50 mg of phentolamine. In some embodiments, the spray further comprises phentolamine. In some embodiments, the spray further comprises from about 20 mg to about 50 mg of phentolamine. In some embodiments, the spray further comprises phentolamine. In some embodiments, the spray further comprises from about 20 mg to about 40 mg of phentolamine.

[0480] In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further comprises from about 10 mg to about 500 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further comprises from about 10 mg to about 450 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further comprises from about 10 mg to about 400 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further comprises from about 10 mg to about 350 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further comprises from about 10 mg to about 300 mg of nifedipine.

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

In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further comprises from about 100 mg to about 500 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further comprises from about 100 mg to about 400 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further comprises from about 100 mg to about 350 mg of nifedipine. In some embodiments, the spray further comprises nifedipine. In some embodiments, the spray further comprises from about 100 mg to about 300 mg of nifedipine.

[0481] In an aspect provided herein, the spray further comprises a permeability enhancer. [0482] In 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 from about 0.05% to about 15%.

[0483] In an aspect provided herein, the spray further comprises a viscosity modifier. In some embodiments, the viscosity modifier is polyethylene glycol, methylcellulose, or hypromellose.

[0484] In some embodiments, the spray further comprises polyethylene glycol. In some embodiments, the spray further comprises from about 0.5% to about 50% polyethylene glycol.

[0485] In some embodiments, the spray further comprises methylcellulose. In some embodiments, the spray further comprises from about 0.001% to about 5% methylcellulose. [0486] In some embodiments, the spray further comprises hypromellose. In some embodiments, the spray further comprises from about 0.001% to about 0.5% hypromellose.

In some embodiments, the spray further comprises from about 0.05% to about 0.5% hypromellose.

[0487] In an aspect provided herein, the spray comprises per 100 pL of solution (or per spray): from about 0.5 mg to about 100 mg of epinephrine, or a pharmaceutically acceptable salt thereof; from about 0.1 mg to about 2 mg sodium chloride; from about 0.01 mg to about 1 mg benzalkonium chloride; from about 0.1 mg to about 2 mg disodium edetate; and hydrochloric acid or citric acid, or a combination thereof sufficient to achieve a pH of from about 3.5 to about 6.5.

[0488] In some embodiments, the pH of the spray is about 4. In some embodiments, the pH of the spray is about 4.1. In some embodiments, the pH of the spray is about 4.2. In some embodiments, the pH of the spray is about 4.3. In some embodiments, the pH of the spray is about 4.4. In some embodiments, the pH of the spray is about 4.5. In some embodiments, the pH of the spray is about 4.6. In some embodiments, the pH of the spray is about 4.7. In some embodiments, the pH of the spray is about 4.8. In some embodiments, the pH of the spray is about 4.9. 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.

[0489] In an aspect provided herein, the spray is delivered from a spray nozzle of a pre primed device, and wherein no more than about 10% of the droplets have a diameter less than 10 pm. In some embodiments, the spray is measured by laser diffraction with beams measuring at both 3 cm and 6 cm from the spray nozzle.

[0490] In an aspect provided herein, the pharmaceutical spray formulation or spray is administered from a unit-dose device or delivery system. In an aspect provided herein, the pharmaceutical spray formulation or spray is administered from a bi-dose device or delivery system. In an aspect provided herein, the pharmaceutical spray formulation or spray is administered from a multi-dose device or delivery system.

[0491] In an aspect provided herein, the spray comprises (or consists essentially of) per 100 pL of solution (or per spray): from about 2.5 mg to about 15 mg (e.g., from about 2.6 mg to about 12 mg, from about 2.6 mg to about 7.5 mg, from about 2.6 mg to about 6 mg, from about 2.6 mg to about 5.75 mg, from about 2.6 mg to about 5.5 mg, from about 2.6 mg to about 5 mg, from about 2.6 mg to about 4.5 mg, from about 2.6 mg to about 4.25 mg, from about 2.6 mg to about 4.0 mg, from about 2.6 mg to about 3.75 mg, from about 2.6 mg to about 3.5 mg, from about 2.6 mg to about 3.25 mg, or from about 2.6 mg to about 3 mg) of epinephrine, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; from about 0.01 mg to about 0.1 mg (e.g., from about 0.03 mg to about 0.07 mg, from about 0.04 mg to about 0.06 mg, about 0.04 mg, about 0.05 mg, about 0.07 mg, or about 0.08 mg) of sodium metabi sulfite; from about 0.1 mg to about 1 mg (e.g., from about 0.3 mg to about 0.8 mg, from about 0.4 mg to about 0.7 mg, from about 0.5 mg to about 0.7 mg, from about 0.3 mg to about 0.5 mg, from about 0.35 mg to about 0.45 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, or about 0.8 mg) sodium chloride; from about 0.01 mg to about 0.2 mg (e.g., from about 0.06 mg to about 0.12 mg, from about 0.07 mg to about 0.125 mg, or from about 0.08 mg to about 0.12 mg) hypromellose; from about 0.1 mg to about 1 mg (e.g., from about 0.1 mg to about 0.75 mg, from about 0.2 mg to about 0.65 mg, from about 0.3 mg to about 0.5 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, or about 0.8 mg) citric acid monohydrate; from about 0.1 mg to about 5 mg (e.g., from about 0.25 mg to about 4.5 mg, from about 2 mg to about 4.5 mg, from about 0.5 mg to about 2.5 mg, from about 0.75 mg to about

1.25 mg, from about 3.25 mg to about 3.75 mg, from about 0.5 mg to about 1.5 mg, about

3.25 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 4.5 mg) di ethylene glycol monoethyl ether; and from about 0.1 mg to about 1 mg (e.g., from about 0.1 mg to about 0.5 mg, from about 0.15 mg to about 0.35 mg, from about 0.2 mg to about 0.3 mg, from about 0.3 mg to about 0.5 mg, from about 0.2 mg to about 0.25 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, or about 0.5 mg) chlorobutanol hemihydrate.

[0492] 10 Pharmacokinetics

[0493] In some aspects disclosed herein, the pharmaceutical spray formulation provides desirable pharmacokinetic profiles following administration to an individual. In some embodiments, the pharmacokinetic profile comprises a C_max, a T_max, an area under curve (AUC), or any combination thereof. In some embodiments, the administration comprises a single spray. In some embodiments, the administration comprises two sprays. In some embodiments, the pharmaceutical spray formulation comprises a spray in each nostril. In some embodiments, the administration comprises one or more sprays from a unit-dose device or delivery system. In some embodiments, the administration comprises one or more sprays from a multi-dose or bi-dose device or delivery system.

Ill [0494] In some embodiments, the pharmaceutical spray formulation is formulated to achieve a desired pharmacokinetic profile. In some embodiments, administration of the pharmaceutical spray formulation achieves a desired pharmacokinetic profile. In some embodiments, administration of the pharmaceutical spray formulation comprises a single spray, or two or more sprays. For example, a bi-dose delivery includes a single spray in each nostrils of an individual. In some embodiments, the desired pharmacokinetic profile is achieved based on the pharmaceutical spray formulation, the delivery of the pharmaceutical spray formulation, or both. In some embodiments, the combination of the delivery device and the pharmaceutical spray formulation achieves one or more sprays that have a desired ovality ratio as described herein. The ovality ratio can affect the pharmacokinetic profile, for example, by increasing the rate of absorption of the spray(s), thereby improving pharmacokinetic parameters such as blood plasma concentration, C_max, T_max, and/or AUC of the active ingredient. The pharmaceutical spray formulation may also be formulated to improve absorption such as by including one or more absorption enhancers. In some embodiments, the pharmaceutical spray formulation comprises one or more preservatives, which can include antioxidants, chelating agents, antimicrobial preservatives, and other types of preservatives that help maintain stability and/or longevity of the formulation. In some embodiments, the pharmaceutical spray formulation comprises one or more buffering agents to maintain an appropriate pH for enhancing stability of the formulation. In some embodiments, the pharmaceutical spray formulation is formulated to provide pharmacokinetics that is substantially equivalent to that of administration through intramuscular injection.

[0495] In some embodiments, the pharmaceutical formulation is formulated to be stable. In some embodiments, at least a minimum percentage of the active ingredient (e.g., epinephrine) remains in the pharmaceutical formulation in an un-degraded state after storage. In some embodiments, a stable pharmaceutical formulation has at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or more of the active ingredient in an un-degraded state after a period of storage at a given temperature and/or humidity. In some embodiments, the period of storage 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, 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 80%, or at least 90% or more. In some embodiments, a stable pharmaceutical formulation has 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 given temperature and/or humidity. In some embodiments, the impurities comprise degradation products of the active ingredient.

[0496] In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood 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 no 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 no 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 minutes. In some embodiments, the desired pharmacokinetic profile is achieved following administration of a single spray of the pharmaceutical spray formulation. In some embodiments, the desired pharmacokinetic profile is achieved following administration of two sprays of the pharmaceutical spray formulation. In some embodiments, the desired pharmacokinetic profile is achieved following administration of two or more sprays of the pharmaceutical spray 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 blood plasma concentration within a minimum time period following administration.

[0497] In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration within a minimum time period following 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 minutes. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration within a minimum time period following administration of at least about 0.1 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration within a minimum time period following administration of at most about 1 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration within a minimum time period following administration of about 0.1 ng/mL to about 0.2 ng/mL, about 0.1 ng/mL to about 0.3 ng/mL, about 0.1 ng/mL to about 0.4 ng/mL, about 0.1 ng/mL to about 0.5 ng/mL, about 0.1 ng/mL to about 0.6 ng/mL, about 0.1 ng/mL to about 0.7 ng/mL, about 0.1 ng/mL to about 0.8 ng/mL, about 0.1 ng/mL to about 0.9 ng/mL, about 0.1 ng/mL to about 1 ng/mL, about 0.2 ng/mL to about 0.3 ng/mL, about 0.2 ng/mL to about 0.4 ng/mL, about 0.2 ng/mL to about 0.5 ng/mL, about 0.2 ng/mL to about 0.6 ng/mL, about 0.2 ng/mL to about 0.7 ng/mL, about 0.2 ng/mL to about 0.8 ng/mL, about 0.2 ng/mL to about 0.9 ng/mL, about 0.2 ng/mL to about 1 ng/mL, about 0.3 ng/mL to about 0.4 ng/mL, about 0.3 ng/mL to about 0.5 ng/mL, about 0.3 ng/mL to about 0.6 ng/mL, about 0.3 ng/mL to about 0.7 ng/mL, about 0.3 ng/mL to about 0.8 ng/mL, about 0.3 ng/mL to about 0.9 ng/mL, about 0.3 ng/mL to about 1 ng/mL, about 0.4 ng/mL to about 0.5 ng/mL, about 0.4 ng/mL to about 0.6 ng/mL, about 0.4 ng/mL to about 0.7 ng/mL, about 0.4 ng/mL to about 0.8 ng/mL, about 0.4 ng/mL to about 0.9 ng/mL, about 0.4 ng/mL to about 1 ng/mL, about 0.5 ng/mL to about 0.6 ng/mL, about 0.5 ng/mL to about 0.7 ng/mL, about 0.5 ng/mL to about 0.8 ng/mL, about 0.5 ng/mL to about 0.9 ng/mL, about 0.5 ng/mL to about 1 ng/mL, about 0.6 ng/mL to about 0.7 ng/mL, about 0.6 ng/mL to about 0.8 ng/mL, about 0.6 ng/mL to about 0.9 ng/mL, about 0.6 ng/mL to about 1 ng/mL, about 0.7 ng/mL to about 0.8 ng/mL, about 0.7 ng/mL to about 0.9 ng/mL, about 0.7 ng/mL to about 1 ng/mL, about 0.8 ng/mL to about 0.9 ng/mL, about 0.8 ng/mL to about 1 ng/mL, or about 0.9 ng/mL to about 1 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration within a minimum time period following 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.

[0498] In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration after a minimum time period following 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 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 90, at least 100, at least 110, at least 120, at least 130, at least 140, or at least 150 minutes.

[0499] In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration after a minimum time period following administration of about 10 pg/mL to about 100 pg/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration after a minimum time period following administration of about 10 pg/mL to about 20 pg/mL, about 10 pg/mL to about 30 pg/mL, about 10 pg/mL to about 40 pg/mL, about 10 pg/mL to about 50 pg/mL, about 10 pg/mL to about 60 pg/mL, about 10 pg/mL to about 70 pg/mL, about 10 pg/mL to about 80 pg/mL, about 10 pg/mL to about 90 pg/mL, about 10 pg/mL to about 100 pg/mL, about 20 pg/mL to about 30 pg/mL, about 20 pg/mL to about 40 pg/mL, about 20 pg/mL to about 50 pg/mL, about 20 pg/mL to about 60 pg/mL, about 20 pg/mL to about 70 pg/mL, about 20 pg/mL to about 80 pg/mL, about 20 pg/mL to about 90 pg/mL, about 20 pg/mL to about 100 pg/mL, about 30 pg/mL to about 40 pg/mL, about 30 pg/mL to about 50 pg/mL, about 30 pg/mL to about 60 pg/mL, about 30 pg/mL to about 70 pg/mL, about 30 pg/mL to about 80 pg/mL, about 30 pg/mL to about 90 pg/mL, about 30 pg/mL to about 100 pg/mL, about 40 pg/mL to about 50 pg/mL, about 40 pg/mL to about 60 pg/mL, about 40 pg/mL to about 70 pg/mL, about 40 pg/mL to about 80 pg/mL, about 40 pg/mL to about 90 pg/mL, about 40 pg/mL to about 100 pg/mL, about 50 pg/mL to about 60 pg/mL, about 50 pg/mL to about 70 pg/mL, about 50 pg/mL to about 80 pg/mL, about 50 pg/mL to about 90 pg/mL, about 50 pg/mL to about 100 pg/mL, about 60 pg/mL to about 70 pg/mL, about 60 pg/mL to about 80 pg/mL, about 60 pg/mL to about 90 pg/mL, about 60 pg/mL to about 100 pg/mL, about 70 pg/mL to about 80 pg/mL, about 70 pg/mL to about 90 pg/mL, about 70 pg/mL to about 100 pg/mL, about 80 pg/mL to about 90 pg/mL, about 80 pg/mL to about 100 pg/mL, or about 90 pg/mL to about 100 pg/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration after a minimum time period following administration of about 10 pg/mL, about 20 pg/mL, about 30 pg/mL, about 40 pg/mL, about 50 pg/mL, about 60 pg/mL, about 70 pg/mL, about 80 pg/mL, about 90 pg/mL, or about 100 pg/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration after a minimum time period following administration of at least about 10 pg/mL, about 20 pg/mL, about 30 pg/mL, about 40 pg/mL, about 50 pg/mL, about 60 pg/mL, about 70 pg/mL, about 80 pg/mL, or about 90 pg/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration after a minimum time period following administration of at most about 20 pg/mL, about 30 pg/mL, about 40 pg/mL, about 50 pg/mL, about 60 pg/mL, about 70 pg/mL, about 80 pg/mL, about 90 pg/mL, or about 100 pg/mL.

[0500] In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration after a minimum time period following administration of about 1 ng/mL to about 5 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration after a minimum time period following administration of about 1 ng/mL to about 1.5 ng/mL, about 1 ng/mL to about 2 ng/mL, about 1 ng/mL to about 2.5 ng/mL, about 1 ng/mL to about 3 ng/mL, about 1 ng/mL to about 3.5 ng/mL, about 1 ng/mL to about 4 ng/mL, about 1 ng/mL to about 4.5 ng/mL, about 1 ng/mL to about 5 ng/mL, about 1.5 ng/mL to about 2 ng/mL, about 1.5 ng/mL to about

2.5 ng/mL, about 1.5 ng/mL to about 3 ng/mL, about 1.5 ng/mL to about 3.5 ng/mL, about

1.5 ng/mL to about 4 ng/mL, about 1.5 ng/mL to about 4.5 ng/mL, about 1.5 ng/mL to about 5 ng/mL, about 2 ng/mL to about 2.5 ng/mL, about 2 ng/mL to about 3 ng/mL, about

2 ng/mL to about 3.5 ng/mL, about 2 ng/mL to about 4 ng/mL, about 2 ng/mL to about

4.5 ng/mL, about 2 ng/mL to about 5 ng/mL, about 2.5 ng/mL to about 3 ng/mL, about

2.5 ng/mL to about 3.5 ng/mL, about 2.5 ng/mL to about 4 ng/mL, about 2.5 ng/mL to about

4.5 ng/mL, about 2.5 ng/mL to about 5 ng/mL, about 3 ng/mL to about 3.5 ng/mL, about

3 ng/mL to about 4 ng/mL, about 3 ng/mL to about 4.5 ng/mL, about 3 ng/mL to about

5 ng/mL, about 3.5 ng/mL to about 4 ng/mL, about 3.5 ng/mL to about 4.5 ng/mL, about

3.5 ng/mL to about 5 ng/mL, about 4 ng/mL to about 4.5 ng/mL, about 4 ng/mL to about

5 ng/mL, or about 4.5 ng/mL to about 5 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration after a minimum time period following 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, or about 5 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration after a minimum time period following administration of at least 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, or about 4.5 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a blood plasma concentration after a minimum time period following administration of at most 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, or about 5 ng/mL.

[0501] In some embodiments, the pharmaceutical spray formulation is formulated to achieve a Cmax of about 0.1 ng/mL to about 1 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C_maxof at least about 0.1 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C_maxof at most about 1 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C_max of about 0.1 ng/mL to about 0.2 ng/mL, about 0.1 ng/mL to about 0.3 ng/mL, about 0.1 ng/mL to about 0.4 ng/mL, about 0.1 ng/mL to about 0.5 ng/mL, about 0.1 ng/mL to about 0.6 ng/mL, about 0.1 ng/mL to about 0.7 ng/mL, about 0.1 ng/mL to about 0.8 ng/mL, about 0.1 ng/mL to about 0.9 ng/mL, about 0.1 ng/mL to about 1 ng/mL, about 0.2 ng/mL to about 0.3 ng/mL, about 0.2 ng/mL to about 0.4 ng/mL, about 0.2 ng/mL to about 0.5 ng/mL, about 0.2 ng/mL to about 0.6 ng/mL, about 0.2 ng/mL to about 0.7 ng/mL, about 0.2 ng/mL to about 0.8 ng/mL, about 0.2 ng/mL to about 0.9 ng/mL, about 0.2 ng/mL to about 1 ng/mL, about 0.3 ng/mL to about 0.4 ng/mL, about 0.3 ng/mL to about 0.5 ng/mL, about 0.3 ng/mL to about 0.6 ng/mL, about 0.3 ng/mL to about 0.7 ng/mL, about 0.3 ng/mL to about 0.8 ng/mL, about 0.3 ng/mL to about 0.9 ng/mL, about 0.3 ng/mL to about 1 ng/mL, about 0.4 ng/mL to about 0.5 ng/mL, about 0.4 ng/mL to about 0.6 ng/mL, about 0.4 ng/mL to about 0.7 ng/mL, about 0.4 ng/mL to about 0.8 ng/mL, about 0.4 ng/mL to about 0.9 ng/mL, about 0.4 ng/mL to about 1 ng/mL, about 0.5 ng/mL to about 0.6 ng/mL, about 0.5 ng/mL to about 0.7 ng/mL, about 0.5 ng/mL to about 0.8 ng/mL, about 0.5 ng/mL to about 0.9 ng/mL, about 0.5 ng/mL to about 1 ng/mL, about 0.6 ng/mL to about 0.7 ng/mL, about 0.6 ng/mL to about 0.8 ng/mL, about 0.6 ng/mL to about 0.9 ng/mL, about 0.6 ng/mL to about 1 ng/mL, about 0.7 ng/mL to about 0.8 ng/mL, about 0.7 ng/mL to about 0.9 ng/mL, about 0.7 ng/mL to about 1 ng/mL, about 0.8 ng/mL to about 0.9 ng/mL, about 0.8 ng/mL to about 1 ng/mL, or about 0.9 ng/mL to about 1 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C_maxof 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.

[0502] In some embodiments, the pharmaceutical spray formulation is formulated to achieve a Cmax of about 1 ng/mL to about 5 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C_max of about 1 ng/mL to about 1.5 ng/mL, about 1 ng/mL to about 2 ng/mL, about 1 ng/mL to about 2.5 ng/mL, about 1 ng/mL to about

3 ng/mL, about 1 ng/mL to about 3.5 ng/mL, about 1 ng/mL to about 4 ng/mL, about

1 ng/mL to about 4.5 ng/mL, about 1 ng/mL to about 5 ng/mL, about 1.5 ng/mL to about

2 ng/mL, about 1.5 ng/mL to about 2.5 ng/mL, about 1.5 ng/mL to about 3 ng/mL, about

1.5 ng/mL to about 3.5 ng/mL, about 1.5 ng/mL to about 4 ng/mL, about 1.5 ng/mL to about

4.5 ng/mL, about 1.5 ng/mL to about 5 ng/mL, about 2 ng/mL to about 2.5 ng/mL, about

2 ng/mL to about 3 ng/mL, about 2 ng/mL to about 3.5 ng/mL, about 2 ng/mL to about

4 ng/mL, about 2 ng/mL to about 4.5 ng/mL, about 2 ng/mL to about 5 ng/mL, about

2.5 ng/mL to about 3 ng/mL, about 2.5 ng/mL to about 3.5 ng/mL, about 2.5 ng/mL to about 4 ng/mL, about 2.5 ng/mL to about 4.5 ng/mL, about 2.5 ng/mL to about 5 ng/mL, about

3 ng/mL to about 3.5 ng/mL, about 3 ng/mL to about 4 ng/mL, about 3 ng/mL to about

4.5 ng/mL, about 3 ng/mL to about 5 ng/mL, about 3.5 ng/mL to about 4 ng/mL, about

3.5 ng/mL to about 4.5 ng/mL, about 3.5 ng/mL to about 5 ng/mL, about 4 ng/mL to about 4.5 ng/mL, about 4 ng/mL to about 5 ng/mL, or about 4.5 ng/mL to about 5 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C_max 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, or about 5 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C_max of at least 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, or about 4.5 ng/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a C_max of at most 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, or about 5 ng/mL.

[0503] In some embodiments, the pharmaceutical spray formulation is formulated to achieve a T_maxof no more than 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, 1 minute,

2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, or 20 minutes. In some embodiments, administration of the pharmaceutical spray formulation achieves a T_maxof at least 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, or 20 minutes.

[0504] 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_maxof at least about 0.1 min. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a T_max of at most about 10 min. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a T_max of about 0.1 min to about 0.2 min, about 0.1 min to about 0.4 min, about 0.1 min to about 0.6 min, about 0.1 min to about 0.8 min, about 0.1 min to about 1 min, about 0.1 min to about 2 min, about 0.1 min to about 4 min, about 0.1 min to about 5 min, about 0.1 min to about 6 min, about 0.1 min to about 8 min, about 0.1 min to about 10 min, about 0.2 min to about 0.4 min, about 0.2 min to about 0.6 min, about 0.2 min to about 0.8 min, about 0.2 min to about 1 min, about 0.2 min to about 2 min, about 0.2 min to about 4 min, about 0.2 min to about 5 min, about 0.2 min to about 6 min, about 0.2 min to about 8 min, about 0.2 min to about 10 min, about 0.4 min to about 0.6 min, about 0.4 min to about 0.8 min, about 0.4 min to about 1 min, about 0.4 min to about 2 min, about 0.4 min to about 4 min, about 0.4 min to about 5 min, about 0.4 min to about 6 min, about 0.4 min to about 8 min, about 0.4 min to about 10 min, about 0.6 min to about 0.8 min, about 0.6 min to about 1 min, about 0.6 min to about 2 min, about 0.6 min to about 4 min, about 0.6 min to about 5 min, about 0.6 min to about 6 min, about 0.6 min to about 8 min, about 0.6 min to about 10 min, about 0.8 min to about 1 min, about 0.8 min to about 2 min, about 0.8 min to about 4 min, about 0.8 min to about 5 min, about 0.8 min to about 6 min, about 0.8 min to about 8 min, about 0.8 min to about 10 min, about 1 min to about 2 min, about 1 min to about 4 min, about 1 min to about 5 min, about 1 min to about 6 min, about 1 min to about 8 min, about 1 min to about 10 min, about 2 min to about 4 min, about 2 min to about 5 min, about 2 min to about 6 min, about 2 min to about 8 min, about 2 min to about 10 min, about 4 min to about 5 min, about 4 min to about 6 min, about 4 min to about 8 min, about 4 min to about 10 min, about 5 min to about 6 min, about 5 min to about 8 min, about 5 min to about 10 min, about 6 min to about 8 min, about 6 min to about 10 min, or about 8 min to about 10 min. In some embodiments, the pharmaceutical spray formulation is formulated to achieve a T_maxof about 0.1 min, about 0.2 min, about 0.4 min, about 0.6 min, about 0.8 min, about 1 min, about 2 min, about 4 min, about 5 min, about 6 min, about 8 min, or about 10 min.

[0505] In some embodiments, the pharmaceutical spray formulation is formulated to achieve an AUC of about 0.1 ng h/mL to about 10 ng h/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve an AUC of about 0.1 ng h/mL to about 0.5 ng h/mL, about 0.1 ng h/mL to about 1 ng h/mL, about 0.1 ng h/mL to about 2 ng h/mL, about 0.1 ng h/mL to about 3 ng h/mL, about 0.1 ng h/mL to about 4 ng h/mL, about 0.1 ng h/mL to about 5 ng h/mL, about 0.1 ng h/mL to about 6 ng h/mL, about 0.1 ng h/mL to about 7 ng h/mL, about 0.1 ng h/mL to about 8 ng h/mL, about 0.1 ng h/mL to about 9 ng h/mL, about 0.1 ng h/mL to about 10 ng h/mL, about 0.5 ng h/mL to about

1 ng h/mL, about 0.5 ng h/mL to about 2 ng h/mL, about 0.5 ng h/mL to about 3 ng h/mL, about 0.5 ng h/mL to about 4 ng h/mL, about 0.5 ng h/mL to about 5 ng h/mL, about

0.5 ng h/mL to about 6 ng h/mL, about 0.5 ng h/mL to about 7 ng h/mL, about 0.5 ng h/mL to about 8 ng h/mL, about 0.5 ng h/mL to about 9 ng h/mL, about 0.5 ng h/mL to about 10 ng h/mL, about 1 ng h/mL to about 2 ng h/mL, about 1 ng h/mL to about 3 ng h/mL, about 1 ng h/mL to about 4 ng h/mL, about 1 ng h/mL to about 5 ng h/mL, about 1 ng h/mL to about 6 ng h/mL, about 1 ng h/mL to about 7 ng h/mL, about 1 ng h/mL to about 8 ng h/mL, about 1 ng h/mL to about 9 ng h/mL, about 1 ng h/mL to about 10 ng h/mL, about 2 ng h/mL to about 3 ng h/mL, about 2 ng h/mL to about 4 ng h/mL, about 2 ng h/mL to about 5 ng h/mL, about 2 ng h/mL to about 6 ng h/mL, about 2 ng h/mL to about 7 ng h/mL, about 2 ng h/mL to about 8 ng h/mL, about 2 ng h/mL to about 9 ng h/mL, about

2 ng h/mL to about 10 ng h/mL, about 3 ng h/mL to about 4 ng h/mL, about 3 ng h/mL to about 5 ng h/mL, about 3 ng h/mL to about 6 ng h/mL, about 3 ng h/mL to about 7 ng h/mL, about 3 ng h/mL to about 8 ng h/mL, about 3 ng h/mL to about 9 ng h/mL, about 3 ng h/mL to about 10 ng h/mL, about 4 ng h/mL to about 5 ng h/mL, about 4 ng h/mL to about 6 ng h/mL, about 4 ng h/mL to about 7 ng h/mL, about 4 ng h/mL to about 8 ng h/mL, about 4 ng h/mL to about 9 ng h/mL, about 4 ng h/mL to about 10 ng h/mL, about 5 ng h/mL to about 6 ng h/mL, about 5 ng h/mL to about 7 ng h/mL, about 5 ng h/mL to about 8 ng h/mL, about 5 ng h/mL to about 9 ng h/mL, about 5 ng h/mL to about 10 ng h/mL, about

6 ng h/mL to about 7 ng h/mL, about 6 ng h/mL to about 8 ng h/mL, about 6 ng h/mL to about 9 ng h/mL, about 6 ng h/mL to about 10 ng h/mL, about 7 ng h/mL to about

8 ng h/mL, about 7 ng h/mL to about 9 ng h/mL, about 7 ng h/mL to about 10 ng h/mL, about 8 ng h/mL to about 9 ng h/mL, about 8 ng h/mL to about 10 ng h/mL, or about

9 ng h/mL to about 10 ng h/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve an AUC of about 0.1 ng h/mL, about 0.5 ng h/mL, about 1 ng h/mL, about 2 ng h/mL, about 3 ng h/mL, about 4 ng h/mL, about 5 ng h/mL, about 6 ng h/mL, about 7 ng h/mL, about 8 ng h/mL, about 9 ng h/mL, or about 10 ng h/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve an AUC of at least about 0.1 ng h/mL, about 0.5 ng h/mL, about 1 ng h/mL, about 2 ng h/mL, about

3 ng h/mL, about 4 ng h/mL, about 5 ng h/mL, about 6 ng h/mL, about 7 ng h/mL, about 8 ng h/mL, or about 9 ng h/mL. In some embodiments, the pharmaceutical spray formulation is formulated to achieve an AUC of at most about 0.5 ng h/mL, about 1 ng h/mL, about 2 ng h/mL, about 3 ng h/mL, about 4 ng h/mL, about 5 ng h/mL, about 6 ng h/mL, about

7 ng h/mL, about 8 ng h/mL, about 9 ng h/mL, or about 10 ng h/mL.

[0506] In some embodiments, intranasal administration of the pharmaceutical spray formulation produces an epinephrine plasma concentration that is within 5%, within 10%, within 20%, within 30%, within 40%, within 50%, within 60%, within 70%, within 80%, within 90%, within 100%, within 110%, within 120%, within 130%, within 140%, within 150%, within 160%, within 170%, within 180%, within 190%, or within 200% of the epinephrine plasma concentration achieved using a commercially available delivery device (e.g., an intramuscular epinephrine injection device such as EpiPen) after 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 following administration. In some embodiments, intranasal administration of the pharmaceutical spray formulation results in epinephrine plasma concentrations having a relative standard deviation of no more than about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or no more than about 100% based on plasma concentrations measured within 15 minutes (inclusive) following administration. In some embodiments, intranasal administration of the pharmaceutical spray formulation results in epinephrine plasma concentrations having a relative standard deviation that is lower than by injection using a commercially available delivery device based on plasma concentration measured within 15 minutes (inclusive) following administration. In some embodiments, the plasma concentrations are measured at 1 minute and two or more later time points within 15 minutes (inclusive).

[0507] In some embodiments, intranasal administration of the pharmaceutical spray formulation produces an epinephrine plasma concentration 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 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 by injection using a commercially available delivery device (e.g., an EpiPen) after 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 following administration. In some embodiments, intranasal administration of the pharmaceutical spray formulation results in epinephrine plasma concentrations having a relative standard deviation of no more than about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or no more than about 100% based on plasma concentrations measured within 15 minutes (inclusive) following administration. In some embodiments, intranasal administration of the pharmaceutical spray formulation results in epinephrine plasma concentrations having a relative standard deviation that is lower than by injection using a commercially available delivery device based on plasma concentration measured within 15 minutes (inclusive) following administration. In some embodiments, the plasma concentrations are measured at 1 minute and two or more later time points within 15 minutes (inclusive). [0508] III. METHODS OF USE

[0509] In an aspect, provided herein is a method of treating anaphylaxis, anaphylactic shock, a severe allergic reaction, and/or bronchial constriction, comprising delivering at least one spray of a pharmaceutical solution from a pre-primed device into a nostril of a subject in need thereof, wherein:

(i) the device is adapted for nasal delivery;

(ii) a volume of from about 20 pL to about 250 pL of spray is delivered; and

[0510] In certain embodiments, the volume of each spray delivers from about 2.5 mg to about 15 mg (e.g., from about 2.6 mg to about 12 mg, from about 2.6 mg to about 7.5 mg, from about 2.6 mg to about 6 mg, from about 2.6 mg to about 5.75 mg, from about 2.6 mg to about

5.5 mg, from about 2.6 mg to about 5 mg, from about 2.6 mg to about 4.5 mg, from about

2.6 mg to about 4.25 mg, from about 2.6 mg to about 4.0 mg, from about 2.6 mg to about 3.75 mg, from about 2.6 mg to about 3.5 mg, from about 2.6 mg to about 3.25 mg, or from about 2.6 mg to about 3 mg) of epinephrine, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0511] In certain embodiments, the volume of each spray is from about 90 pL to about 200 pL (e.g., from about 90 pL to about 175 pL, from about 90 pL to about 150 pL, from about 90 pL to about 120 pL, or from about 90 pL to about 110 pL) and delivers from about

2.5 mg to about 15 mg (e.g., from about 2.6 mg to about 12 mg, from about 2.6 mg to about

7.5 mg, from about 2.6 mg to about 6 mg, from about 2.6 mg to about 5.75 mg, from about

2.6 mg to about 5.5 mg, from about 2.6 mg to about 5 mg, from about 2.6 mg to about

4.5 mg, from about 2.6 mg to about 4.25 mg, from about 2.6 mg to about 4.0 mg, from about

2.6 mg to about 3.75 mg, from about 2.6 mg to about 3.5 mg, from about 2.6 mg to about 3.25 mg, or from about 2.6 mg to about 3 mg) of epinephrine, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0512] In certain embodiments, the volume of spray is from about 90 pL to about 200 pL (e.g., from about 90 pL to about 175 pL, from about 90 pL to about 150 pL, from about 90 pL to about 120 pL, or from about 90 pL to about 110 pL) and delivers from about 2.5 mg to about 15 mg (e.g., from about 2.6 mg to about 12 mg, from about 2.6 mg to about 7.5 mg, from about 2.6 mg to about 6 mg, from about 2.6 mg to about 5.75 mg, from about 2.6 mg to about 5.5 mg, from about 2.6 mg to about 5 mg, from about 2.6 mg to about 4.5 mg, from about 2.6 mg to about 4.25 mg, from about 2.6 mg to about 4.0 mg, from about 2.6 mg to about 3.75 mg, from about 2.6 mg to about 3.5 mg, from about 2.6 mg to about 3.25 mg, or from about 2.6 mg to about 3 mg) of epinephrine, or a pharmaceutically acceptable salt, hydrate, or solvate thereof; from about 0.01 mg to about 0.1 mg (e.g., from about 0.03 mg to about 0.07 mg, from about 0.04 mg to about 0.06 mg, about 0.04 mg, about 0.05 mg, about 0.07 mg, or about 0.08 mg) of sodium metabi sulfite; from about 0.1 mg to about 1 mg (e.g., from about 0.3 mg to about 0.8 mg, from about 0.4 mg to about 0.7 mg, from about 0.5 mg to about 0.7 mg, from about 0.3 mg to about 0.5 mg, from about 0.35 mg to about 0.45 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, or about 0.8 mg) sodium chloride; from about 0.01 mg to about 0.2 mg (e.g., from about 0.06 mg to about 0.12 mg, from about 0.07 mg to about 0.125 mg, or from about 0.08 mg to about 0.12 mg) hypromellose; from about 0.1 mg to about 1 mg (e.g., from about 0.1 mg to about 0.75 mg, from about 0.2 mg to about 0.65 mg, from about 0.3 mg to about 0.5 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, or about 0.8 mg) citric acid monohydrate; from about 0.1 mg to about 5 mg (e.g., from about 0.25 mg to about 4.5 mg, from about 2 mg to about 4.5 mg, from about 0.5 mg to about 2.5 mg, from about 0.75 mg to about

[0513] In an aspect, provided herein is a method of treating anaphylaxis, anaphylactic shock, a severe allergic reaction, and/or bronchial constriction, comprising delivering at least one spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein:

(i) the device is adapted for nasal delivery; and

(ii) a volume of from about 20 pL to about 250 pL (e.g., from about 90 pL to about 175 pL, from about 90 pL to about 150 pL, from about 90 pL to about 120 pL, or from about 90 pL to about 110 pL) of spray is delivered; wherein the pharmaceutical solution comprises a pharmaceutical spray formulation as disclosed herein.

[0514] In certain embodiments, a therapeutic plasma concentration of epinephrine in the subject is achieved in less than 20 minutes following administration to the subject.

[0515] In certain embodiments, the therapeutic plasma concentration of epinephrine in the subject is about 0.5 ng/mL of epinephrine.

[0516] In certain embodiments, the subject has a maximum plasma concentration (Cmax) of from about 50 pg/mL to about 250 pg/mL of epinephrine.

[0517] In certain embodiments, the area under a plasma concentration-time curve from 0 to 180 minutes (AU o-iso₎) of epinephrine in the subject is from about 4,000 min_*pg/mL to about 20,000 mimpg /mL.

[0518] In certain embodiments, the plasma concentration versus time curve of epinephrine in the subject has a tmax of less than from about 10 minutes to about 120 minutes.

[0519] In certain embodiments, the device is a single-dose device. In certain embodiments, the device is a bi-dose device.

[0520] In certain embodiments, the device delivers two sprays of the pharmaceutical solution from a single reservoir. In certain embodiments, the device has a first reservoir containing from about 50 pL to about 250 pL of the pharmaceutical solution and a second reservoir containing from about 50 pL to about 250 pL of the pharmaceutical solution.

[0521] In certain embodiments, less than about 20% of the formulation leaves the nasal cavity via drainage into the nasopharynx or externally.

[0522] In certain embodiments, a single spray in the nostril yields a plasma concentration of at least 25 pg/mL within 2 minutes in the subject.

[0523] In certain embodiments, a therapeutic plasma concentration of epinephrine in the subject is achieved in less than 15 minutes following administration to the subject.

[0524] In certain embodiments, a single spray in the nostril yields a plasma concentration of > 25 pg/mL within 1 minute in the subject. In certain embodiments, a single spray in the nostril yields a plasma concentration of > 45 pg/mL within 5 minutes in the subject.

[0525] In another aspect is provided a method of treating anaphylaxis, anaphylactic shock, a severe allergic reaction, and/or bronchial constriction, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical spray formulation or a spray as described herein, including embodiments. [0526] In an aspect provided herein is a method for 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 spray formulation or a spray as described herein, including embodiments.

[0527] In an aspect provided herein is a method of treating anaphylaxis- or anaphylactic shock-induced respiratory depression or distress, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical spray formulation or a spray as described herein, including embodiments.

[0528] In another aspect is provided a method of treating anaphylaxis, anaphylactic shock, a severe allergic reaction, and/or bronchial constriction, comprising delivering a spray of a pharmaceutical solution from a pre-primed device into a nostril of a subject in need thereof, wherein:

(i) the device is adapted for nasal delivery;

(ii) a volume of from about 20 pL to about 250 pL (e.g., from about 90 pL to about 175 pL, from about 90 pL to about 150 pL, from about 90 pL to about 120 pL, or from about 90 pL to about 110 pL) of spray is delivered; and

(iii) the pharmaceutical solution comprises from about 0.5 mg to about 100 mg of epinephrine, or a pharmaceutically acceptable salt thereof, an isotonicity agent, and from about 0.005% to about 1% (w/v) of benzalkonium chloride.

[0529] In some embodiments, the pharmaceutical solution comprises from about 0.5 mg to about 100 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 0.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 1 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 1.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 2 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 2.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 3 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 3.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 4 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 4.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 5.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 6 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 6.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 7 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 7.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 8 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 8.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 9 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 9.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 10 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 10.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 11 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 11.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 12 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 12.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 13 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 13.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 14 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 14.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 15 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 20 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 25 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 30 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 35 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 40 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 45 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 50 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 55 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 60 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 65 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 70 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 75 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 80 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 85 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 90 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 95 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises about 100 mg of epinephrine, or a pharmaceutically acceptable salt thereof.

[0530] In some embodiments, the spray delivers from about 0.5 mg to about 100 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical solution comprises 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 1.5 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

2.5 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 3.5 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

4.5 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 5.5 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

6.5 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 7.5 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

8.5 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 9.5 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

10.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 11 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 11.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 12 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about

12.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 13 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 13.5 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about 14 mg of epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the spray delivers about

14.5 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.

[0531] In some embodiments, the plasma concentration versus time curve of epinephrine in the subject has a T_maxof less than from about 10 minutes to about 120 minutes. In some embodiments, the plasma concentration versus time curve of epinephrine in the subject has a T_max of about 5 minutes to about 50 minutes. In some embodiments, the plasma concentration versus time curve of epinephrine in the subject has a T_max of about 5 minutes to about 10 minutes, about 5 minutes to about 15 minutes, about 5 minutes to about 20 minutes, about 5 minutes to about 25 minutes, about 5 minutes to about 30 minutes, about 5 minutes to about 40 minutes, about 5 minutes to about 50 minutes, about 10 minutes to about 15 minutes, about 10 minutes to about 20 minutes, about 10 minutes to about 25 minutes, about 10 minutes to about 30 minutes, about 10 minutes to about 40 minutes, about 10 minutes to about 50 minutes, about 15 minutes to about 20 minutes, about 15 minutes to about 25 minutes, about 15 minutes to about 30 minutes, about 15 minutes to about 40 minutes, about 15 minutes to about 50 minutes, about 20 minutes to about 25 minutes, about 20 minutes to about 30 minutes, about 20 minutes to about 40 minutes, about 20 minutes to about 50 minutes, about 25 minutes to about 30 minutes, about 25 minutes to about 40 minutes, about 25 minutes to about 50 minutes, about 30 minutes to about 40 minutes, about 30 minutes to about 50 minutes, or about 40 minutes to about 50 minutes. In some embodiments, the plasma concentration versus time curve of epinephrine in the 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. In some embodiments, the plasma concentration versus time curve of epinephrine in the 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 versus time curve of epinephrine in the subject has a T_max of at most about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 40 minutes, or about 50 minutes.

[0532] In some embodiments, a therapeutic plasma concentration of epinephrine in the subject is achieved within 15 minutes, 14 minutes, 13 minutes, 12 minutes, 11 minutes, 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, or 1 minute following administration to the subject. In some embodiments, a therapeutic plasma concentration of epinephrine in the subject is achieved in less than 20 minutes following administration to the subject. In some embodiments, a therapeutic plasma concentration of epinephrine in the subject is achieved in less than 15 minutes following administration to the subject. In some embodiments, a therapeutic plasma concentration of epinephrine in the subject is achieved in less than 10 minutes following administration to the subject. In some embodiments, a therapeutic plasma concentration of epinephrine in the subject is achieved in less than 5 minutes following administration to the subject. In some embodiments, the therapeutic plasma concentration of epinephrine in the subject is about 500 pg/mL of epinephrine. In some embodiments, the therapeutic plasma concentration of epinephrine in the subject is about 450 pg/mL of epinephrine. In some embodiments, the therapeutic plasma concentration of epinephrine in the subject is about 400 pg/mL of epinephrine. In some embodiments, the therapeutic plasma concentration of epinephrine in the subject is about 350 pg/mL of epinephrine. In embodiments, the therapeutic plasma concentration of epinephrine in the subject is about 300 pg/mL of epinephrine. In some embodiments, the subject has a maximum plasma concentration (C_max) of from about 50 pg/mL to about 500 pg/mL of epinephrine. In some embodiments, the area under a plasma concentration-time curve of epinephrine in the subject is from about 5 ng/minute/mL to about 50 ng/minute/mL.

[0533] In some embodiments, the device comprises a plunger that houses a container closure comprising:

(i) a vial comprising an opening;

(ii) a cannula; and

(iii) a rubber stopper; wherein the stopper is configured to occlude the opening of the vial, and wherein the cannula is configured such that the cannula can pierce the stopper when the plunger applies sufficient force to the cannula.

[0534] In some embodiments, the pre-primed device is actuatable with one hand. In some embodiments, the device is a single-dose device. In some embodiments, the device is a bi dose device. In some embodiments, the volume of the reservoir is not more than about 140 pL. In some embodiments, the device has a single reservoir containing approximately 125 pL of the pharmaceutical solution. In some embodiments, approximately 100 pL of the pharmaceutical solution is delivered by one actuation of the device. In some embodiments, the device has a single reservoir containing from about 50 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device has a single reservoir containing from about 75 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device has a single reservoir containing from about 100 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device has a single reservoir containing from about 125 pL to about 250 pL of the pharmaceutical formulation.

In some embodiments, the device has a single reservoir containing from about 150 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device delivers two sprays of the pharmaceutical solution from a single reservoir. In some embodiments, the single-dose device delivers two sprays of the pharmaceutical solution from a single reservoir. In some embodiments, the bi-dose device delivers two sprays of the pharmaceutical solution from a single reservoir. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 75 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 75 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 100 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 100 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 125 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 125 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 225 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 225 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 200 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 175 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 175 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 175 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 150 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 150 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device delivers one spray of the pharmaceutical solution from the first reservoir and one spray of the pharmaceutical solution from the second reservoir.

[0535] In some embodiments, 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.

[0536] In some embodiments, less than about 20% of the pharmaceutical solution leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, less than about 10% of the pharmaceutical solution leaves the nasal cavity via drainage into the nasopharynx or externally. In some embodiments, less than about 5% of the pharmaceutical solution leaves the nasal cavity via drainage into the nasopharynx or externally.

[0537] In some embodiments, the subject is suffering from a severe allergic reaction from exposure or suspected exposure to an allergen. In some embodiments, the allergen is food, medication, or an insect bite or sting. In some embodiments, the allergen is an airborne allergen. [0538] In some embodiments, the subject exhibits one or more symptoms chosen from: respiratory depression or distress, airway constriction, wheezing, tingling hands, feet, mouth, or scalp, shortness of breath, swelling or inflammation of the face, eyes, lips, tongue, or throat, hives, central nervous system depression, cardiovascular depression, altered level consciousness, mydriatic pupils, hypoxemia, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing, 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.

[0539] In some embodiments, the subject is free from respiratory depression or distress for at least about 1 hour following treatment comprising delivery of the therapeutically effective amount of the epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is free from respiratory depression or distress for at least about 2 hours following treatment comprising delivery of the therapeutically effective amount of the epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is free from respiratory depression or distress for at least about 4 hours following treatment comprising delivery of the therapeutically effective amount of the epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is free from respiratory depression or distress for at least about 6 hours following treatment comprising delivery of the therapeutically effective amount of the epinephrine, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is in a lying, supine, or recovery position.

[0540] In some embodiments, a single spray in the nostril yields a plasma concentration of

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

> 1 ng/mL within 5 minutes in the subject. [0541] In some embodiments, the nasal spray administration described herein provides rapid absorption of epinephrine. In some embodiments, the nasal spray administration described herein provides absorption of epinephrine that is substantially equivalent to that of intramuscular or subcutaneous injection. In some embodiments, the nasal spray administration described herein provides pharmacokinetics that is substantially equivalent to that of intramuscular or subcutaneous injection. In some embodiments, described herein are methods of administration of a nasal spray to a subject having congested and/or inflamed nasal passageways, thereby providing rapid absorption of epinephrine. For example, experimental data provided herein indicate congestion enhances absorption, providing a surprising benefit. In some embodiments, a single spray in the nostril within about 1, 2, 3, 4, or 5 minutes of administration yields a plasma concentration of at least about 0.2 ng/mL to about 3 ng/mL. In some embodiments, a single spray in the nostril within about 1, 2, 3, 4, or 5 minutes of administration yields a plasma concentration of at least about 0.2 ng/mL to about 0.3 ng/mL, about 0.2 ng/mL to about 0.4 ng/mL, about 0.2 ng/mL to about 0.5 ng/mL, about 0.2 ng/mL to about 0.6 ng/mL, about 0.2 ng/mL to about 0.7 ng/mL, about 0.2 ng/mL to about 0.8 ng/mL, about 0.2 ng/mL to about 0.9 ng/mL, about 0.2 ng/mL to about 1 ng/mL, about 0.2 ng/mL to about 1.5 ng/mL, about 0.2 ng/mL to about 2 ng/mL, about 0.2 ng/mL to about 3 ng/mL, about 0.3 ng/mL to about 0.4 ng/mL, about 0.3 ng/mL to about 0.5 ng/mL, about 0.3 ng/mL to about 0.6 ng/mL, about 0.3 ng/mL to about 0.7 ng/mL, about 0.3 ng/mL to about 0.8 ng/mL, about 0.3 ng/mL to about 0.9 ng/mL, about 0.3 ng/mL to about 1 ng/mL, about 0.3 ng/mL to about 1.5 ng/mL, about 0.3 ng/mL to about 2 ng/mL, about 0.3 ng/mL to about 3 ng/mL, about 0.4 ng/mL to about 0.5 ng/mL, about 0.4 ng/mL to about 0.6 ng/mL, about 0.4 ng/mL to about 0.7 ng/mL, about 0.4 ng/mL to about 0.8 ng/mL, about 0.4 ng/mL to about 0.9 ng/mL, about 0.4 ng/mL to about 1 ng/mL, about 0.4 ng/mL to about 1.5 ng/mL, about 0.4 ng/mL to about 2 ng/mL, about 0.4 ng/mL to about 3 ng/mL, about 0.5 ng/mL to about 0.6 ng/mL, about 0.5 ng/mL to about 0.7 ng/mL, about 0.5 ng/mL to about 0.8 ng/mL, about 0.5 ng/mL to about 0.9 ng/mL, about 0.5 ng/mL to about 1 ng/mL, about 0.5 ng/mL to about 1.5 ng/mL, about 0.5 ng/mL to about 2 ng/mL, about 0.5 ng/mL to about 3 ng/mL, about 0.6 ng/mL to about 0.7 ng/mL, about 0.6 ng/mL to about 0.8 ng/mL, about 0.6 ng/mL to about 0.9 ng/mL, about 0.6 ng/mL to about 1 ng/mL, about 0.6 ng/mL to about 1.5 ng/mL, about 0.6 ng/mL to about 2 ng/mL, about 0.6 ng/mL to about 3 ng/mL, about 0.7 ng/mL to about 0.8 ng/mL, about 0.7 ng/mL to about 0.9 ng/mL, about 0.7 ng/mL to about 1 ng/mL, about 0.7 ng/mL to about 1.5 ng/mL, about 0.7 ng/mL to about 2 ng/mL, about 0.7 ng/mL to about 3 ng/mL, about 0.8 ng/mL to about 0.9 ng/mL, about 0.8 ng/mL to about 1 ng/mL, about 0.8 ng/mL to about 1.5 ng/mL, about 0.8 ng/mL to about 2 ng/mL, about 0.8 ng/mL to about 3 ng/mL, about 0.9 ng/mL to about 1 ng/mL, about 0.9 ng/mL to about 1.5 ng/mL, about 0.9 ng/mL to about 2 ng/mL, about 0.9 ng/mL to about 3 ng/mL, about 1 ng/mL to about 1.5 ng/mL, about 1 ng/mL to about 2 ng/mL, about 1 ng/mL to about 3 ng/mL, about 1.5 ng/mL to about 2 ng/mL, about 1.5 ng/mL to about 3 ng/mL, or about 2 ng/mL to about 3 ng/mL. In some embodiments, a single spray in the nostril within about 1, 2, 3, 4, or 5 minutes of administration yields a plasma concentration 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 in the nostril within about 1, 2, 3, 4, or 5 minutes of administration yields a plasma concentration of at least 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, or about 2 ng/mL. In some embodiments, a single spray in the nostril within about 1, 2, 3, 4, or 5 minutes of administration yields a plasma concentration of at least at most 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, the plasma concentration described herein refers to average plasma concentration (e.g., a mean or median concentration determined for multiple sprays in one or both nostrils in a subject, or sprays in multiple subjects).

[0542] In an aspect provided herein is a method of treating anaphylaxis- or anaphylactic shock-induced respiratory depression or distress, comprising delivering a spray of a pharmaceutical solution from a pre-primed device into a nostril of a subject in need thereof in a manner that delivers the pharmaceutical solution in a round spray plume with an ovality ratio less than about 2.0 when measured at a distance of from about 1 to about 10 cm from the pre-primed device, wherein:

(i) the device is adapted for nasal delivery;

(ii) a volume of from about 20 pL to about 250 pL of spray is delivered; and the pharmaceutical solution comprises from about 0.5 mg to about 100 mg of epinephrine, or a pharmaceutically acceptable salt thereof, an isotonicity agent, and from about 0.005% to about 1% (w/v) of benzalkonium chloride. [0543] In some embodiments, the round spray plume has an ovality ratio less than about 2.0. In some embodiments, the round spray plume has an ovality ratio less than about 1.9. In some embodiments, the round spray plume has an ovality ratio less than about 1.8. In some embodiments, the round spray plume has an ovality ratio less than about 1.7. In some embodiments, the round spray plume has an ovality ratio less than about 1.6. In some embodiments, the round spray plume has an ovality ratio less than about 1.5. In some embodiments, the round spray plume has an ovality ratio less than about 1.4. In some embodiments, the round spray plume has an ovality ratio less than about 1.3. In some embodiments, the round spray plume has an ovality ratio less than about 1.2. In some embodiments, the round spray plume has an ovality ratio less than about 1.1. In some embodiments, the round spray plume has an ovality ratio less than about 1.0.

[0544] In some embodiments, the ovality ratio of the spray is measured at a distance of from about 1 cm to about 5 cm from the device from which the spray is delivered.

[0545] In an aspect provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein:

(i) the device is adapted for nasal delivery;

(ii) a volume of from about 20 pL to about 250 pL of spray is delivered; and

[0546] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises from about 1% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0% trisodium citrate, and from about 0.05% to about 15% diethylene glycol monoethyl ether.

[0547] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises from about 5% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1.0% sodium chloride, from about 0.05% to about 0.5% hypromellose, from about 0.1% to about 1.0% trisodium citrate, and from about 0.5% to about 5% di ethylene glycol monoethyl ether.

[0548] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0549] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises from about 1% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.05% to about 0.5% hypromellose, from about 0.1% to about 1.0% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0550] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises from about 1% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.05% to about 0.5% hypromellose, from about 0.1% to about 1.0% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0551] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises from about 1% to about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% sodium chloride, from about 0.05% to about 0.5% hypromellose, from about 0.1% to about 1.0% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0552] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0553] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0554] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0555] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0556] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0557] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0558] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0559] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0560] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether. [0561] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0562] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0563] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0564] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0565] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0566] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0567] In some embodiments provided herein is a method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering a spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein the pharmaceutical spray formulation comprises about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether.

[0568] In some embodiments, the subject in need thereof is an adult. In some embodiments, the subject in need thereof is a child. In some embodiments, the subject in need thereof weighs from about 10 lbs to about 80 lbs.

[0569] IV. DEVICE

[0570] In an aspect provided herein, the pharmaceutical solution is administered from a unit- dose device or delivery system. In an aspect provided herein, the pharmaceutical solution is administered from a bi-dose device or delivery system. In an aspect provided herein, the pharmaceutical solution is administered from a multi-dose device or delivery system.

[0571] In some embodiments, the device comprises: a reservoir containing at least two doses of fluid; a dispenser member, such as a piston, that is mounted to slide in said reservoir so as to dispense the fluid; a dispenser head that is provided with a dispenser orifice, said head being movable relative to said reservoir so as to move said actuator member in said reservoir and thus dispense the fluid through said dispenser orifice; said dispenser head including at least two viewing windows, said device including an indicator that is movable together with said reservoir, said indicator co-operating with a respective viewing window after each actuation of the device. In some embodiments, said indicator comprises at least one colored indication zone, said indication zone appearing in said first viewing window after the first dose of fluid has been dispensed, and in the second viewing window after the second dose of fluid has been dispensed. In some embodiments, said indicator is adapted to mask colored indication zones that are provided in said dispenser head, said indicator masking a colored indication zone in said first viewing window after the first dose of fluid has been dispensed, and masking a colored indication zone in said second viewing window after the second dose of fluid has been dispensed. In some embodiments, said indicator is adapted 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 the third fingers with the thumb on the actuator. In some embodiments, a pressure point mechanism is incorporated in the device to secure reproducibility of the actuation force and emitted plume characteristics. In some embodiments, a cap is incorporated in the device. In some embodiments, a trigger guard on the actuator is incorporated in the device. In some embodiments, a window is incorporated in the device to view the fluid in the reservoir. In some embodiments, a dose meter is incorporated in the device. In some embodiments, a mechanism is incorporated in the device to lock the device and prevent a second actuation of the device. In some embodiments, a timing mechanism is incorporated in the device to lock the device and prevent a second actuation of the device after a specified period of time.

[0572] An illustrative diagram of a device is shown in FIG. 1 The device as shown has a tip 1701 for dispensing the pharmaceutical spray formulation, a cannula 1702 that is coupled to die tip and transports the formulation or solution from the reservoir 1705 Upon actuation of the device, a needle 1703 pierces a seal (e.g., polymeric or elastomeric seal) 1704 to enter the reservoir 1705 to access the pharmaceutical spray formulation stored as a solution within. [0573] In some embodiments, the device is a single-dose device. In some embodiments, the device is a bi-dose device. In some embodiments, the volume of the reservoir is not more than about 140 pL. In some embodiments, the device has a single reservoir containing approximately 125 pL of the pharmaceutical solution. In some embodiments, approximately 100 pL of the pharmaceutical solution is delivered by one actuation of the device. In some embodiments, the device has a single reservoir containing from about 50 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device has a single reservoir containing from about 75 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device has a single reservoir containing from about 100 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device has a single reservoir containing from about 125 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device has a single reservoir containing from about 150 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the device delivers two sprays of the pharmaceutical solution from a single reservoir. In some embodiments, the single-dose device delivers two sprays of the pharmaceutical solution from a single reservoir. In some embodiments, the bi-dose device delivers two sprays of the pharmaceutical solution from a single reservoir. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 75 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 75 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 100 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 100 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 125 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 125 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 225 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 225 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 200 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 175 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 175 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 175 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 150 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 150 pL of the pharmaceutical formulation. In some embodiments, the bi-dose device delivers one spray of the pharmaceutical solution from the first reservoir and one spray of the pharmaceutical solution from the second reservoir.

[0574] In some embodiments described herein, a bi-dose device adapted for nasal delivery of a pharmaceutical composition to a patient comprises a first volume of a pharmaceutical formulation in a first reservoir, and a second volume of said pharmaceutical formulation in a second reservoir, and wherein said therapeutically effective amount of said pharmaceutical formulation is delivered essentially by a first actuation of said drug delivery device from said first reservoir into a nostril of a patient and a second actuation of said drug delivery device from said second reservoir into a nostril of said patient. In some embodiments, the bi-dose device has a first reservoir containing from about 50 pL to about 250 pL of the pharmaceutical formulation and a second reservoir containing from about 50 pL to about 250 pL of the pharmaceutical formulation. In some embodiments, each reservoir of the pre primed, bi-dose device adapted for nasal delivery of a pharmaceutical composition to a patient comprises between about 0.5 mg to about 100 mg of epinephrine.

[0575] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises from about 1% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0% trisodium citrate, and from about 0.05% to about 15% diethylene glycol monoethyl ether.

[0576] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises from about 1% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0% trisodium citrate, and from about 0.05% to about 15% diethylene glycol monoethyl ether.

[0577] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises from about 1% to about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0% trisodium citrate, and from about 0.05% to about 15% diethylene glycol monoethyl ether.

[0578] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises from about 1% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether. [0579] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises from about 1% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0580] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises from about 1% to about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.0001% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 5% sodium chloride, from about 0.001% to about 0.5% hypromellose, from about 0.01% to about 2.0% citric acid monohydrate, and from about 0.05% to about 15% di ethylene glycol monoethyl ether.

[0581] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises from about 5% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1.0% sodium chloride, from about 0.05% to about 0.5% hypromellose, from about 0.1% to about 1.0% trisodium citrate, and from about 0.5% to about 5% di ethylene glycol monoethyl ether.

[0582] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises from about 5% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1.0% sodium chloride, from about 0.05% to about 0.5% hypromellose, from about 0.1% to about 1.0% trisodium citrate, and from about 0.5% to about 5% di ethylene glycol monoethyl ether.

[0583] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises from about 5% to about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1.0% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1.0% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0584] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises from about 5% to about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% (w/w) to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1.0% sodium chloride, from about 0.01% to about 0.2% hypromellose, from about 0.1% to about 1.0% citric acid monohydrate, and from about 0.1% to about 5% diethylene glycol monoethyl ether.

[0585] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0586] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0587] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0588] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0589] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0590] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether. [0591] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0592] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0593] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0594] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0595] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0596] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0597] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0598] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0599] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0600] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.42% citric acid monohydrate, and about 1% diethylene glycol monoethyl ether.

[0601] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 1% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0602] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 2% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0603] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0604] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0605] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0606] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0607] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0608] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0609] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0610] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0611] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 11% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0612] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 12% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0613] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 13% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0614] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 14% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0615] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 15% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0616] In some embodiments of the device described herein, the pharmaceutical spray formulation comprises about 20% w/w of epinephrine, or a pharmaceutically acceptable salt thereof, about 0.05% (w/w) of sodium metabi sulfite, about 0.4% sodium chloride, about 0.1% hypromellose, about 0.7% trisodium citrate, and about 1% diethylene glycol monoethyl ether. [0617] In some embodiments, the formulation devices and methods described herein include a digital processing device or use of the same. In further embodiments, the digital processing device includes one or more hardware central processing units (CPUs) or general purpose graphics processing units (GPGPUs) that carry out the device’s functions. In still further embodiments, the digital processing device further comprises an operating system configured to perform executable instructions. In some embodiments, the digital processing device is optionally connected to a computer network. In further embodiments, the digital processing device is optionally connected to the Internet such that it accesses the World Wide Web. In still further embodiments, the digital processing device is optionally connected to a cloud computing infrastructure. In other embodiments, the digital processing device is optionally connected to an intranet. In other embodiments, the digital processing device is optionally connected to a data storage device.

[0618] In accordance with the description herein, suitable digital processing devices include, by way of non-limiting examples, server computers, desktop computers, laptop computers, notebook computers, sub-notebook computers, netbook computers, netpad computers, set-top computers, media streaming devices, handheld computers, Internet appliances, mobile smartphones, tablet computers, personal digital assistants, video game consoles, and vehicles. Those of skill in the art will recognize that many smartphones are suitable for use in the system described herein. Those of skill in the art will also recognize that select televisions, video players, and digital music players with optional computer network connectivity are suitable for use in the system described herein. Suitable tablet computers include those with booklet, slate, and convertible configurations, known to those of skill in the art.

[0619] In some embodiments, the digital processing device includes an operating system configured to perform executable instructions. The operating system is, for example, software, including programs and data, which manages the device’s hardware and provides services for execution of applications.

[0620] In some embodiments, the device includes a storage and/or memory device. The storage and/or memory device is one or more physical apparatuses used to store data or programs on a temporary or permanent basis. In some embodiments, the device is volatile memory and requires power to maintain stored information. In some embodiments, the device is non-volatile memory and retains stored information when the digital processing device is not powered. In further embodiments, the non-volatile memory comprises flash memory. In some embodiments, the non-volatile memory comprises dynamic random-access memory (DRAM). In some embodiments, the non-volatile memory comprises ferroelectric random access memory (FRAM). In some embodiments, the non-volatile memory comprises phase- change random access memory (PRAM). In other embodiments, the device is a storage device including, by way of non-limiting examples, CD-ROMs, DVDs, flash memory devices, magnetic disk drives, magnetic tapes drives, optical disk drives, and cloud computing based storage. In further embodiments, the storage and/or memory device is a combination of devices such as those disclosed herein.

[0621] In some embodiments, the digital processing device includes a display to send visual information to a user.

[0622] In some embodiments, the digital processing device includes an input device to receive information from a user. In some embodiments, the input device is a keyboard. In some embodiments, the input device is a pointing device including, by way of non-limiting examples, a mouse, trackball, track pad, joystick, game controller, or stylus. In some embodiments, the input device is a touch screen or a multi-touch screen. In other embodiments, the input device is a microphone to capture voice or other sound input. In other embodiments, the input device is a video camera or other sensor to capture motion or visual input. In further embodiments, the input device is a Kinect, Leap Motion, or the like. In still further embodiments, the input device is a combination of devices such as those disclosed herein.

[0623] 1 Computer Program

[0624] In some embodiments, the platforms, systems, media, and methods disclosed herein include at least one computer program, or use of the same. A computer program includes a sequence of instructions, executable in the digital processing device’s CPU, written to perform a specified task. Computer readable instructions may be implemented as program modules, such as functions, objects, Application Programming Interfaces (APIs), data structures, and the like, that perform particular tasks or implement particular abstract data types. In light of the disclosure provided herein, those of skill in the art will recognize that a computer program may be written in various versions of various languages.

[0625] The functionality of the computer readable instructions may be combined or distributed as desired in various environments. In some embodiments, a computer program comprises one sequence of instructions. In some embodiments, a computer program comprises a plurality of sequences of instructions. In some embodiments, a computer program is provided from one location. In other embodiments, a computer program is provided from a plurality of locations. In various embodiments, a computer program includes one or more software modules. In various embodiments, a computer program includes, in part or in whole, one or more web applications, one or more mobile applications, one or more standalone applications, one or more web browser plug-ins, extensions, add-ins, or add-ons, or combinations thereof.

[0626] 2. _ Mobile Application

[0627] In some embodiments, a computer program includes a mobile application provided to a digital processing device or a portable device. In some embodiments, the mobile application is provided to a mobile digital processing device at the time it is manufactured. In other embodiments, the mobile application is provided to a mobile digital processing device via the computer network described herein.

[0628] 3, _ Software modules

[0629] In some embodiments, the platforms, systems, media, and methods disclosed herein include software, server, and/or database modules, or use of the same. In view of the disclosure provided herein, software modules are created by techniques known to those of skill in the art using machines, software, and languages known to the art. The software modules disclosed herein are implemented in a multitude of ways. In various embodiments, a software module comprises a file, a section of code, a programming object, a programming structure, or combinations thereof. In further various embodiments, a software module comprises a plurality of files, a plurality of sections of code, a plurality of programming objects, a plurality of programming structures, or combinations thereof. In various embodiments, the one or more software modules comprise, by way of non-limiting examples, a web application, a mobile application, and a standalone application. In some embodiments, software modules are in one computer program or application. In other embodiments, software modules are in more than one computer program or application. In some embodiments, software modules are hosted on one machine. In other embodiments, software modules are hosted on more than one machine. In further embodiments, software modules are hosted on cloud computing platforms. In some embodiments, software modules are hosted on one or more machines in one location. In other embodiments, software modules are hosted on one or more machines in more than one location.

[0630] 4 Databases

[0631] In some embodiments, the platforms, systems, media, and methods disclosed herein include one or more databases, or use of the same. In view of the disclosure provided herein, those of skill in the art will recognize that many databases are suitable for storage and retrieval of information such as geological information and administration information. In various embodiments, suitable databases include, by way of non-limiting examples, relational databases, non-relational databases, object oriented databases, object databases, entity- relationship model databases, associative databases, and XML databases. Further non limiting examples include SQL, PostgreSQL, MySQL, Oracle, DB2, and Sybase. In some embodiments, a database is internet-based. In further embodiments, a database is web-based. In still further embodiments, a database is cloud computing-based. In other embodiments, a database is based on one or more local computer storage devices.

[0632] V. EXAMPLES

[0633] Example 1: Exemplary Pharmaceutical Spray Formulations [0634] Table 1 A: 2 mg, 3 mg, 4 mg, and 5 mg Epinephrine Spray Formulations.

* qs = quantity sufficient to meet the required total

[0635] Table IB: 6 mg, 7 mg, and 8 mg Epinephrine Spray Formulations.

* qs = quantity sufficient to meet the required total

[0636] Example 2: A Pilot Study for Absorption of Intranasal Epinephrine Compared to Conventional Intramuscular Epinephrine.

[0637] The purpose of this study was to obtain pharmacokinetic data of epinephrine spray formulations administered via intranasal ("IN") route for comparison with epinephrine administered via intramuscular (IM) route (using autoinjectors commercially available from Mylan and Impax) in healthy adult volunteers.

[0638] The pilot study was designed as a 15-subject, 5-way cross-over design, testing:

• 5.0 mg nasal (IN)

• 2.0 mg nasal (IN)

• 0.15 mg Impax autoinj ector (IM)

• 0.3 mg Impax autoinjector (IM)

• 0.3 mg Mylan autoinjector (IM)

[0639] Objectives:

1. To verify that epinephrine could be administered via IN administration using the device disclosed herein (e.g., FIG. 1);

2. To assess plasma concentration variability of IN vs. IM administration of epinephrine to determine the sample size for the pivotal study;

3. To determine the optimal IN dose to take into a pivotal study; and

4. Safety and tolerance of IN dosing.

[0640] Study Results:

[0641] All Pre-Defmed Objectives Achieved

1. No untoward events in any subject dosed with IN;

2. No correlation of plasma concentration to HR;

3. Confirmed device could deliver therapeutic levels of epinephrine via the nasal mucosa; and

4. Confirmed sample size and study design for pivotal study.

5. Although the pilot study was not designed or powered to determine statistical comparability between the IN and IM products, the data suggested that the plasma epinephrine levels for the 2.0 and 5.0 mg IN doses were slightly lower than those seen in the IM doses.

[0642] Based on the study findings, 6.0 mg IN doses will be used in the pivotal study design, in addition to the 5.0 mg IN dose, to ensure relative comparability to the Mylan generic IM product and a point of comparison to the pilot study are achieved. The results indicate comparability to the IM product (FIG. 2).

[0643] The IN and IM pilot study data confirms the relative dose linearity for these formulations. [0644] Pharmacokinetic Analytics

[0645] Table 2A: Pharmacokinetic Parameters 5.0 mg and 2.0 mg IN.

[0646] Table 2B: Pharmacokinetic Parameters 0.3 mg and 0.15 mg IM Impax; 0.3 mg IM My lan.

[0647] Table 3: Pharmacokinetic Parameter (AUC) 5.0 mg IN vs. 0.3 mg IM Mylan.

[0648] Table 4A: (A) - 5.0 mg IN, Plasma Levels Baseline corrected (pg/mL) (Subjects 01- 09).

[0649] Table 4B: (A) - 5.0 mg IN, Plasma Levels Baseline corrected (pg/mL) (Subjects 10- 103).

[0650] NOTE: Subject 03 was replaced with Subject 103. Subject 03 received 0.15mg IM Impax during dosing period 1 with no untoward event. During dosing period 2, Subject 03 experienced a short episode of ventricular tachycardia (several seconds) a few minutes after being dosed with 0.3 mg IM Mylan, which spontaneously resolved. Subject 03 was withdrawn from the study.

[0651] Table 5A: (B) - 2.0 mg IN Plasma Levels Baseline corrected (pg/mL) (Subjects 01- 09).

[0652] Table 5B: (B) - 2.0 mg IN Plasma Levels Baseline corrected (pg/mL) (Subjects 10- 103).

[0653] NOTE: Subject 03 was replaced with Subject 103. Subject 03 received 0.15mg IM Impax during dosing period 1 with no untoward event. During dosing period 2, Subject 03 experienced a short episode of ventricular tachycardia (several seconds) a few minutes after being dosed with 0.3 mg IM Mylan, which spontaneously resolved. Subject 03 was withdrawn from the study.

[0654] Table 6A: (C) - 0.3 mg IM Impax Plasma Levels Baseline corrected (pg/mL) (Subjects 01-09).

[0655] Table 6B: (C) - 0.3 mg IM Impax Plasma Levels Baseline corrected (pg/mL) (Subjects 10-103).

[0656] NOTE: Subject 03 was replaced with Subject 103. Subject 03 received 0.15mg IM Impax during dosing period 1 with no untoward event. During dosing period 2, Subject 03 experienced a short episode of ventricular tachycardia (several seconds) a few minutes after being dosed with 0.3 mg IM Mylan, which spontaneously resolved. Subject 03 was withdrawn from the study.

[0657] Table 7A: (D) - 0.15 mg IM Impax Plasma Levels Baseline corrected (pg/mL) (Subjects 01-09).

[0658] Table 7B: (D) - 0.15 mg IM Impax Plasma Levels Baseline corrected (pg/mL) (Subjects 10-103).

[0659] NOTE: Subject 03 was replaced with Subject 103. Subject 03 received 0.15 mg IM Impax during dosing period 1 with no untoward event. During dosing period 2, Subject 03 experienced a short episode of ventricular tachycardia (several seconds) a few minutes after being dosed with 0.3 mg IM Mylan, which spontaneously resolved. Subject 03 was withdrawn from the study.

[0660] Table 8A: (E) - 0.3 mg IM Mylan Plasma Level Baseline corrected (pg/mL) (Subjects 01-09).

[0661] Table 8B: (E) - 0.3 mg IM Mylan Plasma Level Baseline corrected (pg/mL) (Subjects 10-103).

[0662] NOTE: Subject 03 was replaced with Subject 103. Subject 03 received 0.15 mg IM Impax during dosing period 1 with no untoward event. During dosing period 2, Subject 03 experienced a short episode of ventricular tachycardia (several seconds) a few minutes after being dosed with 0.3 mg IM Mylan, which spontaneously resolved. Subject 03 was withdrawn from the study.

[0663] Table 9A: Mean Baseline Adjusted Plasma Concentration (n=15) (pg/mL) (Nominal Time 0-25 min).

[0664] Table 9B: Mean Baseline Adjusted Plasma Concentration (n=15) (pg/mL) (Nominal Time 30-180 min).

[0665] Table 10 A: 5.0 mg Epinephrine IN.

[0666] Table 10B: 5.0 mg Epinephrine IN.

[0667] Table 11 A: 2.0 mg Epinephrine IN.

[0668] Table 1 IB: 2.0 mg Epinephrine IN.

[0669] Table 12A: 0.3 mg Epinephrine IM (Impax).

[0670] Table 12B: 0.3 mg Epinephrine IM (Impax).

[0671] Table 13A: 0.15 mg Epinephrine IM (Impax).

[0672] Table 13B: 0.15 mg Epinephrine IM (Impax).

[0673] Table 14A: 0.3 mg Epinephrine IM (Mylan).

[0674] Table 14B: 0.3 mg Epinephrine IM (Mylan).

[0675] Based on pilot study, pivotal study design has been determined to be a modified repeat dose (scaling) design testing:

• 5.0 mg nasal (IN) vs. 0.3 mg IM Mylan Generic (anchor comparator to pilot study)

• 6.0 mg nasal (IN) vs. 0.3 mg IM Mylan Generic

• 6.0 mg nasal (IN) repeat dosing (5-min apart in the same nostril)

• 6.0 mg nasal (IN) repeat dosing (5-min apart dosing in opposite nostrils)

• 6.0 mg IN vs. 0.5 mg SC dose

[0676] Example 3: Stability Studies.

[0677] Description of the Stability Studies

[0678] Each of the following aqueous epinephrine nasal spray formulations was prepared in a single batch:

[0679] Table 15: 20 mg/mL or 2 mg/dose pH 4.7, 0.5% Chlorobutanol.

[0680] Table 16: 20 mg/mL or 2 mg/dose pH 4.7, 0.2% Chlorobutanol.

[0681] Table 17: 50 mg/mL or 5 mg/dose pH 4.7, 0.2% Chlorobutanol.

[0682] Table 18: 60 mg/mL or 6 mg/dose pH 4.7, 0.5% Chlorobutanol.

[0683] Table 19: 60 mg/mL or 6 mg/dose pH 4.7, 0.2% Chlorobutanol.

[0684] Aliquots from each of the batches of the formulations above were bottled under low humidity, low oxygen conditions and stored in a specialty pharmaceutical containers consisting of Type I serum glass with an approximate inner diameter of 5 mm, an approximate length of 28 mm giving a surface area to volume ratio of approximately 3 : 1 containing approximately 250 pL of solution containing active ingredient, sealed with an elastomeric halobutyl stopper at a temperature of 5 °C, 25 °C, or 40 °C for the periods of time set forth in the Results of Stability Studies below.

[0685] The spray formulations were quantified and monitored by high pressure liquid chromatography (HPLC). The impurities detected include epinephrine sulfonic acid, adrenochrome, norepinephrine, and adrenalone (also referred to as epinephrone). The following tables show the test results for epinephrine spray formulations at varying dosages, storage temperatures, and storage lengths.

[0686] Table 20: Results of Stability Studies - 20 mg/mL or 2 mg/dose pH 4.7, 0.5% Chlorobutanol at 5 °C, 25 °C, and 40 °C.

[0687] Table 21 : Results of Stability Studies - 20 mg/mL or 2 mg/dose pH 4.7, 0.2% Chlorobutanol at 25 °C.

[0688] Table 22: Results of Stability Studies - 20 mg/mL or 2 mg/dose pH 4.7, 0.2% Chlorobutanol at 40 °C.

[0689] Table 23: Results of Stability Studies - 50 mg/mL or 5 mg/dose pH 4.7, 0.2% Chlorobutanol at 25 °C.

[0690] Table 24: Results of Stability Studies - 50 mg/mL or 5 mg/dose pH 4.7, 0.2% Chlorobutanol at 40 °C.

[0691] Table 25: Results of Stability Studies - 60 mg/mL or 6 mg/dose pH 4.7, 0.5% Chlorobutanol at 5 °C, 25 °C, and 40 °C.

[0692] Table 26: Results of Stability Studies - 60 mg/mL or 6 mg/dose pH 4.7, 0.2%

Chlorobutanol at 25 °C.

[0693] Table 27: Results of Stability Studies - 60 mg/mL or 6 mg/dose pH 4.7, 0.2%

Chlorobutanol at 40 °C.

[0694] In Tables 20 - 27 above, NMT = not more than, and ND = nothing detected.

[0695] The tested epinephrine nasal spray formulations present sustained stability over extended periods of time at temperatures of 5 °C, 25 °C, and 40 °.

OTHER EMBODIMENTS

[0696] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical spray formulation, comprising:

(ii) at least one of an antioxidant, an antimicrobial preservative, an isotonicity agent, an absorption enhancer, a viscosity modifier, a buffering agent, or combinations thereof; wherein the formulation is configured to be administered into a nostril of a subject as a nasal spray that yields a plasma concentration of at least about 0.25 pg/mL within about 1 minute of administration.

2. The formulation of claim 1, wherein the pH of the formulation is from about 4.0 to about 6.5.

3. The formulation of claim 1 or 2, wherein the pH of the formulation is from about 4.0 to about 5.0.

4. The formulation of any one of claims 1-3, wherein the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration from about 0.01% to about 0.1% (w/w).

5. The formulation of any one of claims 1-4, wherein the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration from about 0.1% to about 1% (w/w).

6. The formulation of any one of claims 1-5, wherein the isotonicity agent comprises sodium chloride at a concentration from about 0.1% to about 1% (w/w).

7. The formulation of any one of claims 1-6, wherein the viscosity modifier comprises hypromellose at a concentration from about 0.01% to about 0.2% (w/w).

8. The formulation of any one of claims 1-7, wherein the buffering agent comprises citric acid or citric acid monohydrate at a concentration from about 0.1% to about 1% (w/w).

9. The formulation of any one of claims 1-8, comprising about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), or about 10% (w/w) of epinephrine, or a pharmaceutically acceptable salt thereof.

10. The formulation of any one of claims 1-9, wherein the formulation comprises sodium metabi sulfite, sodium chloride, hypromellose, citric acid monohydrate, diethylene glycol monoethyl ether, and chlorobutanol hemihydrate.

11. The formulation of any one of claims 1-8, wherein the formulation comprises from about 1% to about 10% (w/w) of epinephrine, or a pharmaceutically acceptable salt thereof, from about 0.01% to about 0.1% (w/w) of sodium metabi sulfite, from about 0.1% to about 1% (w/w) sodium chloride, from about 0.01% to about 0.2% (w/w) hypromellose, from about 0.1% to about 1% (w/w) citric acid monohydrate, from about 0.1% to about 5% (w/w) diethylene glycol monoethyl ether, and from about 0.1% to about 1% (w/w) chlorobutanol hemihydrate.

12. The formulation of claim 11, wherein the formulation comprises from about 0.05% (w/w) of sodium metabi sulfite, from about 0.4% sodium chloride, from about 0.1% hypromellose, about 0.42% citric acid monohydrate, and from about 1% diethylene glycol monoethyl ether.

13. The formulation of claim 11 or 12, wherein the formulation comprises about 3% w/w of epinephrine, or a pharmaceutically acceptable salt thereof.

14. The formulation of claim 11 or 12, wherein the formulation comprises about 4% w/w of epinephrine, or a pharmaceutically acceptable salt thereof.

15. The formulation of claim 11 or 12, wherein the formulation comprises about 5% w/w of epinephrine, or a pharmaceutically acceptable salt thereof.

16. The formulation of claim 11 or 12, wherein the formulation comprises about 6% w/w of epinephrine, or a pharmaceutically acceptable salt thereof.

17. The formulation of claim 11 or 12, wherein the formulation comprises about 7% w/w of epinephrine, or a pharmaceutically acceptable salt thereof.

18. The formulation of claim 11 or 12, wherein the formulation comprises about 8% w/w of epinephrine, or a pharmaceutically acceptable salt thereof.

19. The formulation of claim 11 or 12, wherein the formulation comprises about 9% w/w of epinephrine, or a pharmaceutically acceptable salt thereof.

20. The formulation of claim 11 or 12, wherein the formulation comprises about 10% w/w of epinephrine, or a pharmaceutically acceptable salt thereof.

21. A stable pharmaceutical spray formulation, comprising:

22. The formulation of claim 21, wherein the formulation is stable for a period of at least about one month at a temperature of at least about 40 °C.

23. The formulation of claim 21 or 22, wherein the formulation has 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.

24. The formulation of any one of claims 21-23, wherein the antioxidant comprises sodium bisulfite or sodium metabisulfite at a concentration from about 0.01% to about 0.1% (w/w).

25. The formulation of any one of claims 21-24, wherein the antimicrobial preservative comprises chlorobutanol or chlorobutanol hemihydrate at a concentration from about 0.1% to about 1% (w/w).

26. The formulation of any one of claims 21-25, wherein the isotonicity agent comprises sodium chloride at a concentration from about 0.1% to about 1% (w/w).

27. The formulation of any one of claims 21-26, wherein the buffering agent comprises citric acid or citric acid monohydrate at a concentration from about 0.1% to about 1% (w/w).

28. A pharmaceutical spray formulation, comprising:

(ii) at least one of an antioxidant, an antimicrobial preservative, an isotonicity agent, an absorption enhancer, a viscosity modifier, or a buffering agent; wherein the absorption enhancer is diethylene glycol monoethyl ether.

29. The formulation of claim 28, wherein the formulation comprises diethylene glycol monoethyl ether at a concentration from about 0.1% to about 5% (w/w).

30. The formulation of claim 28 or 29, wherein the absorption enhancer comprises di ethylene glycol monoethyl ether at a concentration of about 1% (w/w).

31. A method of treating anaphylaxis, anaphylactic shock, a severe allergic reaction, and/or bronchial constriction, comprising delivering at least one spray of a pharmaceutical solution from a pre-primed device into a nostril of a subject in need thereof, wherein:

(i) the device is adapted for nasal delivery;

(ii) a volume of from about 20 pL to about 250 pL of spray is delivered; and

(iii) the pharmaceutical solution comprises the formulation of any one of claims 1-

30

32. A method for treating at least one symptom of anaphylaxis or anaphylactic shock, comprising delivering at least one spray of a pharmaceutical solution from a device into a nostril of a subject in need thereof, wherein:

(i) the device is adapted for nasal delivery; and

(ii) a volume of from about 20 pL to about 250 pL of spray is delivered; wherein the pharmaceutical solution comprises the formulation of any one of claims 1-30.

33. The method of claim 31 or 32, wherein a therapeutic plasma concentration of epinephrine in the subject is achieved in less than 20 minutes following administration to the subject.

34. The method of any one of claims 31-33, wherein the therapeutic plasma concentration of epinephrine in the subject is about 0.5 ng/mL of epinephrine.

35. The method of any one of claims 31-34, wherein the subject has a maximum plasma concentration (Cma_x) of from about 50 pg/mL to about 250 pg/mL of epinephrine.

36. The method of any one of claims 31-35, wherein the area under a plasma concentration-time curve from 0 to 180 minutes (AU o-iso₎) of epinephrine in the subject is from about 4,000 min»pg/mL to about 20,000 mimpg /mL.

37. The method of any one of claims 31-36, wherein the plasma concentration versus time curve of epinephrine in the subject has a T_maxof less than from about 10 minutes to about 120 minutes.

38. The method of any one of claims 31-37, wherein the device is a single-dose device.

39. The method of any one of claims 31-38, wherein the device is a bi-dose device.

40. The method of claim 39, wherein the device delivers two sprays of the pharmaceutical solution from a single reservoir.

41. The method of any one of claims 31 -40, wherein less than about 20% of the formulation leaves the nasal cavity via drainage into the nasopharynx or externally.

42. The method of any one of claims 31-41, wherein a single spray in the nostril yields a plasma concentration of at least 25 pg/mL within 2 minutes in the subject.

43. The method of any one of claims 31-42, wherein a therapeutic plasma concentration of epinephrine in the subject is achieved in less than 15 minutes following administration to the subject.

44. The method of any one of claims 31-43, wherein a single spray in the nostril yields a plasma concentration of > 25 pg/mL within 1 minute in the subject.

45. The method of any one of claims 31-44, wherein a single spray in the nostril yields a plasma concentration of > 45 pg/mL within 5 minutes in the subject.