Intranasal epinephrine formulations and methods for treatment of disease

Abstract

To provide needle-free and non-invasive methods of dosing epinephrine for anaphylaxis.SOLUTION: The present invention provides a nasal spray pharmaceutical formulation, wherein a single dose of the nasal spray pharmaceutical formulation comprises between about 0.40 mg and about 2.4 mg of epinephrine, or a salt thereof.SELECTED DRAWING: Figure 4

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Patent Application No. 15 / 890,131, filed February 6, 2018; and U.S. Provisional Patent Application No. 62 / 784,057, filed December 21, 2018; each of which is incorporated by reference in its entirety.

[0002] Described herein are intranasal (IN) epinephrine formulations and methods of using such formulations in the treatment of diseases or disorders. [Background technology]

[0003] Anaphylaxis is a medical emergency that may require resuscitation measures, such as airway management, supplemental oxygen, large amounts of intravenous fluids, and close monitoring. Administration of epinephrine is the treatment of choice. There remains a need for needle-free and non-invasive methods of administering epinephrine. Provided herein are methods, formulations, and devices for the treatment of anaphylaxis and other diseases. Summary of the Invention

[0004] Provided herein are formulations of epinephrine and methods of using the same in the treatment of diseases such as type 1 hypersensitivity reactions (systemic allergic reactions), asthma, and cardiac arrest.

[0005] Anaphylaxis is a severe, potentially life-threatening, type 1 hypersensitivity reaction (systemic allergic reaction) that affects many body systems and typically has a rapid onset, on average, about 5-30 minutes after intravenous exposure to an antigen and about 2 hours after oral exposure. Anaphylaxis results from the release of inflammatory mediators and cytokines from mast cells and basophils, typically due to an immune response, but occasionally due to non-immune mechanisms. The most common areas of the body affected include the skin (80-90%), respiratory tract (70%), gastrointestinal tract (30-45%), heart and vasculature (10-45%), and central nervous system (10-15%), with two or more usually involved in a single episode.

[0006] Anaphylaxis is a medical emergency that may require resuscitation measures, such as airway management, supplemental oxygen, large amounts of intravenous fluids, and close monitoring. Administration of epinephrine is generally the treatment of choice, with antihistamines and steroids (e.g., dexamethasone) often used as adjuncts. Due to concerns about biphasic anaphylaxis, a period of 2-24 hours of in-hospital observation is often required once people have returned to normal.

[0007] Epinephrine (adrenaline, (R)-4-(1-hydroxy-2-(methylamino)ethyl)benzene-1,2-diol) is the primary treatment for anaphylaxis, and there are no absolute contraindications to its use. Currently, epinephrine is administered as a solution and is given by injection, preferably into the mid-anterolateral thigh, as soon as anaphylaxis is suspected. Injections may be repeated every 5-15 minutes if the response is insufficient. A second dose is required in 16-35% of episodes, but more than two doses are rarely required. The intramuscular route is preferred over subcutaneous administration, because the latter delays epinephrine absorption. However, while only minor side effects have been reported from epinephrine (tremors, anxiety, headache, and palpitations), there have been numerous reports of highly variable exposure from injectable products depending on the location of the injection (intramuscular or subcutaneous), and other factors such as body mass index (BMI).

[0008] There is a significant need in the medical community to develop products that will help improve the clinical management of anaphylaxis in the out-of-hospital setting. Epinephrine is effective when delivered by intramuscular injection, but there is published evidence that pharmacokinetics vary widely depending on the site of injection, whether intramuscular or subcutaneous. There are also significant product quality issues with approved autoinjection devices that utilize complex technology, resulting in numerous recalls of these products by the FDA in the United States. Epinephrine autoinjection devices, such as the EpiPen®, are also cumbersome, requiring training and time to administer properly in potentially life-threatening situations.

[0009] The need for alternative, needle-free, and non-invasive methods for epinephrine administration is well documented because many patients have a fear of injections and, as a result, are resistant to any kind of auto-injection device. Furthermore, because auto-injection devices are bulky and cumbersome, many patients in need do not always have an epinephrine syringe on hand. Resistance to self-medication in public settings is also well documented.

[0010] Thus, there is a need for improved or alternative methods of administering epinephrine in emergency situations, as well as improved or alternative formulations and devices. Desirable improvements, individually or in combination, are convenience (intranasal vs. intramuscular), faster administration, more reliable and more consistent dosing, no needles, more discrete to allow for public dosing, and the ability to be administered by untrained individuals or non-professionals.

[0011] Thus, provided herein are methods, formulations, and devices for the treatment of anaphylaxis and other diseases, the methods comprising administering an intranasal formulation of epinephrine using a small, compact, unit-dose spray device.

[0012] In one embodiment, the present specification describes a nasal spray pharmaceutical formulation comprising about 0.40 mg to about 2.4 mg of epinephrine or a salt thereof. In another embodiment, the present specification describes a nasal spray pharmaceutical formulation comprising about 0.40 mg to about 2.4 mg of epinephrine or a salt thereof in a single dose of the nasal spray pharmaceutical formulation. In another embodiment, the present specification describes a nasal spray pharmaceutical formulation comprising about 0.40 mg to about 2.4 mg of epinephrine or a salt thereof in a single dose of the nasal spray pharmaceutical formulation. In some embodiments, the nasal spray pharmaceutical formulation comprises about 0.40 mg to about 2.0 mg of epinephrine or a salt thereof. In some embodiments, the nasal spray pharmaceutical formulation comprises about 0.40 mg to about 1.8 mg of epinephrine or a salt thereof. In some embodiments, a single dose of the nasal spray pharmaceutical formulation comprises about 0.5 mg to about 2.0 mg of epinephrine or a salt thereof. In some embodiments, a single dose of the nasal spray pharmaceutical formulation contains about 0.5 mg to about 1.5 mg of epinephrine or a salt thereof. In some embodiments, a single dose of the nasal spray pharmaceutical formulation contains about 0.5 mg to about 0.7 mg of epinephrine or a salt thereof. In some embodiments, a single dose of the nasal spray pharmaceutical formulation contains about 1.0 mg of epinephrine or a salt thereof. In some embodiments, a single dose of the nasal spray pharmaceutical formulation contains about 1.3 mg to about 1.5 mg of epinephrine or a salt thereof. In some embodiments, intranasal administration of a single dose of the nasal spray pharmaceutical formulation to a subject results in a plasma epinephrine concentration effective for treating acute hypersensitivity reactions. In some embodiments, the nasal spray pharmaceutical formulation is an aqueous solution, an aqueous suspension, an aqueous emulsion, a non-aqueous solution, a non-aqueous suspension, a non-aqueous emulsion, or a dry powder.

[0013] In one aspect, the present specification describes a nasal spray formulation comprising about 0.40 mg to about 2.4 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the present specification describes a nasal spray formulation comprising about 0.5 mg to about 2.0 mg of epinephrine or a salt thereof per dose dispensed from the device; about 0.5 mg to about 1.5 mg of epinephrine or a salt thereof per dose dispensed from the device; about 0.5 mg to about 0.7 mg of epinephrine or a salt thereof per dose dispensed from the device; about 1.0 mg of epinephrine or a salt thereof per dose dispensed from the device; or about 1.3 mg to about 1.5 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, a single intranasal dose of the nasal spray pharmaceutical formulation, upon intranasal administration, provides a plasma epinephrine concentration effective for treating acute hypersensitivity reactions. In some embodiments, epinephrine or a salt thereof is present in the pharmaceutical formulation in an amount effective to treat acute hypersensitivity reactions, hi some embodiments, the nasal spray formulation is an aqueous solution, an aqueous suspension, an aqueous emulsion, a non-aqueous solution, a non-aqueous suspension, or a non-aqueous emulsion.

[0014] In some embodiments, the nasal spray formulation contains about 1 mg / mL to about 40 mg / mL of epinephrine or a salt thereof per dose. In some embodiments, the nasal spray formulation contains about 5 mg / mL to about 40 mg / mL of epinephrine or a salt thereof per dose. In some embodiments, the nasal spray formulation contains about 1 mg / mL to about 20 mg / mL of epinephrine or a salt thereof per dose. In some embodiments, the nasal spray formulation contains about 3 mg / mL to about 20 mg / mL of epinephrine or a salt thereof per dose. In some embodiments, the nasal spray formulation contains about 3 mg / mL to about 15 mg / mL of epinephrine or a salt thereof per dose. In some embodiments, the nasal spray formulation comprises about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, or about 20 mg / mL of epinephrine or a salt thereof per dose. In some embodiments, the dose of the nasal spray formulation comprises about 100 μL of the nasal spray epinephrine formulation described herein.

[0015] In some embodiments, the nasal spray formulations described herein contain from about 1 mg / mL to about 40 mg / mL of epinephrine or a salt thereof. In some embodiments, the nasal spray formulations described herein contain from about 1 mg / mL to about 20 mg / mL of epinephrine or a salt thereof. In some embodiments, the nasal spray formulations described herein contain from about 1 mg / mL to about 18 mg / mL of epinephrine or a salt thereof. In some embodiments, the nasal spray formulations described herein contain about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 11 mg / mL, about 12 mg / mL, about 13 mg / mL, about 14 mg / mL, about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 19 mg / mL, or about 20 mg / mL of epinephrine or a salt thereof. In some embodiments, the nasal spray formulations described herein contain about 3 mg / mL, about 5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, about 10.5 mg / mL, about 11 mg / mL, about 11.5 mg / mL, about 12 mg / mL, about 12.5 mg / mL, about 13 mg / mL, about 13.5 mg / mL, about 14 mg / mL, about 14.5 mg / mL, or about 15 mg / mL of epinephrine or a salt thereof. In some embodiments, the nasal spray formulations described herein contain about 10 mg / mL of epinephrine or a salt thereof. In some embodiments, the nasal spray formulations described herein contain about 6 mg / mL to about 8 mg / mL of epinephrine or a salt thereof. In some embodiments, the nasal spray formulations described herein contain about 13 mg / mL to about 15 mg / mL of epinephrine or a salt thereof. In some embodiments, a dose of the nasal spray formulation contains about 100 μL of the nasal spray epinephrine formulations described herein.

[0016] In some embodiments, a dose of about 100 μL of a nasal spray formulation described herein contains from 1 mg / mL to about 40 mg / mL of epinephrine or a salt thereof. In some embodiments, a dose of about 100 μL of a nasal spray formulation described herein contains from 1 mg / mL to 20 mg / mL of epinephrine or a salt thereof. In some embodiments, a dosage of about 100 μL of a nasal spray formulation described herein contains 3 mg / mL, 3.5 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.5 mg / mL, 8 mg / mL, 8.5 mg / mL, 9 mg / mL, 9.5 mg / mL, 10 mg / mL, 10.5 mg / mL, 11 mg / mL, 11.5 mg / mL, 12 mg / mL, 12.5 mg / mL, 13 mg / mL, 13.5 mg / mL, 14 mg / mL, 14.5 mg / mL, or 15 mg / mL of epinephrine or a salt thereof.

[0017] In some embodiments, the nasal spray formulation includes one or more absorption enhancers.

[0018] In some embodiments, the nasal spray formulation provides intramuscular (IM) injection-like pharmacokinetics when IM injection is given in the outer thigh, or subcutaneous (SC)-like absorption, or something in between.

[0019] In some embodiments, the nasal spray formulation provides intramuscular (IM)-like absorption.

[0020] In some embodiments, the nasal spray formulation provides subcutaneous (SC)-like absorption and has a SC pharmacokinetic profile with a C of at least 100 pg / mL. max and 150h * AUC in pg / mL 0-240min There is.

[0021] In some embodiments, intranasal administration of a single dose of a nasal spray pharmaceutical formulation to a subject results in absorption similar to that of an intramuscular (IM) injection.

[0022] In some embodiments, the nasal spray formulation, upon administration to a subject, has the following pharmacokinetic characteristics: mean AUC 0-20min and AUC 0-t Both were AUC 0.3 mg intramuscularly. 0-20min and AUC 0-t at least 80% of the C produced by intramuscular injection of 0.3 mg max At least 80% of C max Average C is 150% or less of max ;Average t under 45 minutes max or IM injection-like absorption under optimal dosing conditions in the thigh. In some embodiments, the nasal spray formulation, upon administration to a subject, provides one or more of the following pharmacokinetic characteristics: mean AUC 0-20min and AUC 0-t Both were AUC 0.3 mg intramuscularly. 0-20min and AUC 0-t at least 80% of the C produced by intramuscular injection of 0.3 mg max At least 80% of C max Average C is 150% or less of max ;Average t under 45 minutes max and IM injection-like absorption under optimal dosing conditions in the thigh.

[0023] In some embodiments, the nasal spray formulation, upon administration to a subject, has the following pharmacokinetic characteristics: mean AUC 0-20min and AUC 0-t Both were AUC 0.15 mg intramuscularly. 0-20min and AUC 0-t at least 80% of the C produced by intramuscular injection of 0.15 mg max At least 80% of C max Average C is 150% or less of max ;Average t under 45 minutes max or IM injection-like absorption under optimal dosing conditions in the thigh. In some embodiments, the nasal spray formulation, upon administration to a subject, provides one or more of the following pharmacokinetic characteristics: mean AUC 0-20min and AUC 0-tBoth were AUC 0.15 mg intramuscularly. 0-20min and AUC 0-t at least 80% of the C produced by intramuscular injection of 0.15 mg max At least 80% of C max Average C is 150% or less of max ;Average t under 45 minutes max and IM injection-like absorption under optimal dosing conditions in the thigh.

[0024] In some embodiments, the nasal spray formulation, upon administration to a subject, has the following pharmacokinetic characteristics: mean AUC 0-20min and AUC 0-t Both were AUC 0.5 mg intramuscularly. 0-20min and AUC 0-t at least 80% of the C produced by intramuscular injection of 0.5 mg max At least 80% of C max Average C is 150% or less of max ;Average t under 45 minutes max or IM injection-like absorption under optimal dosing conditions in the thigh. In some embodiments, the nasal spray formulation, upon administration to a subject, provides one or more of the following pharmacokinetic characteristics: mean AUC 0-20min and AUC 0-t Both were AUC 0.5 mg intramuscularly. 0-20min and AUC 0-t at least 80% of the C produced by intramuscular injection of 0.5 mg max At least 80% of C max Average C is 150% or less of max ;Average t under 45 minutes max and IM injection-like absorption under optimal dosing conditions in the thigh.

[0025] In some embodiments, for each mole of epinephrine, the nasal spray formulation contains about 0.5 to about 1.1 molar equivalents of acid. In some embodiments, the acid is adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, or tartaric acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, no base is added to the nasal spray formulation during its preparation. In some embodiments, the nasal spray formulation has a pH of about 2.0 to about 6.0. In some embodiments, the nasal spray formulation has a pH of about 4.0.

[0026] In some embodiments, the nasal spray formulation contains about 5 mg / mL to about 40 mg / mL of epinephrine or a salt thereof per dose. In some embodiments, the nasal spray formulation contains about 0.9 mg to about 2.40 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 0.5 mg to about 2.0 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 0.9 mg to about 1.5 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 0.75 mg to about 1.5 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 0.45 mg to about 1.15 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 1.0 mg to about 2.0 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 0.5 mg to about 2.0 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 0.5 mg to about 1.5 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 0.5 mg to about 0.7 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 1.0 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 1.3 mg to about 1.5 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0027] In some embodiments, the nasal spray pharmaceutical formulation comprises one or more absorption enhancers; and optionally one or more agents selected from isotonicity agents; stabilizers; preservatives; flavoring agents; viscosity modifiers; antioxidants; buffers, and pH adjusters; wherein the pH of the nasal spray pharmaceutical formulation is from about 2.0 to about 6.0.

[0028] In some embodiments, the nasal spray pharmaceutical formulation has a pH of about 3.0 to about 5.0. In some embodiments, the nasal spray pharmaceutical formulation has a pH of about 4.0. In some embodiments, the nasal spray pharmaceutical formulation includes a pH adjusting agent. In some embodiments, the pH adjusting agent is an acid, a base, a buffer, or a combination thereof. In some embodiments, the acid is adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, or tartaric acid; the base is sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate; and the buffer is a phosphate buffer, an acetate buffer, or a citrate buffer. In some embodiments, the nasal spray pharmaceutical formulation includes about 0.5 to about 1.1 molar equivalents of acid for each mole of epinephrine. In some embodiments, the acid is hydrochloric acid.

[0029] In some embodiments, the nasal spray formulation comprises one or more absorption enhancers selected from dodecyl maltoside, benzalkonium chloride, oleic acid or its salts, polysorbate 20, polysorbate 80, and sodium lauryl sulfate.

[0030] In some embodiments, the formulation may contain at least one selected from the group consisting of alcohol, aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetylpyridinium chloride, chitosan, cyclodextrin, deoxycholic acid, decanoyl, dimethylsulfoxide, glyceryl monooleate, glycofurol, glycosylated sphingosine, glycyrrhetinic acid, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroylcarnitine, lysophosphatidylcholine, and one or more absorption enhancers selected from menthol, poloxamer 407 or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, isopropyl myristate, isopropyl palmitate, lanolin, light mineral oil, linoleic acid, menthol, myristic acid, myristic alcohol, oleic acid or a salt thereof, oleyl alcohol, palmitic acid, polysorbate 20, polysorbate 80, propylene glycol, polyoxyethylene alkyl ethers, polyoxylglycerides, pyrrolidone, quillaia saponin, salicylic acid, sodium salt, β-sitosterol, β-D-glucoside, sodium lauryl sulfate, sucrose cocoate, taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid, thymol, tricaprin, triolein, and alkyl saccharides.

[0031] In some embodiments, the formulation comprises one or more absorption enhancers selected from dodecyl maltoside, benzalkonium chloride, oleic acid or its salts, polysorbate 20, polysorbate 80, and sodium lauryl sulfate.

[0032] In some embodiments, the one or more absorption enhancers are from about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside; or from about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride; or from about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof; or from about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and from about 0.001 (w / v) to about a combination of about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof; or a combination of about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof.

[0033] In some embodiments, the one or more absorption enhancers are from about 0.005% (w / v) to about 0.08% (w / v) benzalkonium chloride; or from about 0.01% (w / v) to about 0.06% (w / v) benzalkonium chloride; or from about 0.01% (w / v) to about 0.04% (w / v) benzalkonium chloride; wherein the benzalkonium chloride is the only absorption enhancer in the formulation or is present in a formulation that includes one or more additional absorption enhancers.

[0034] In some embodiments, the formulation comprises a preservative, hi some embodiments, the preservative is benzalkonium chloride.

[0035] In some embodiments, the nasal spray pharmaceutical formulation comprises an isotonicity agent. In some embodiments, the isotonicity agent is dextrose, glycerin, mannitol, potassium chloride, or sodium chloride. In some embodiments, the isotonicity agent is sodium chloride.

[0036] In some embodiments, the nasal spray formulation further comprises a stabilizer. In some embodiments, the stabilizer is ethylenediaminetetraacetic acid (EDTA) or a salt thereof. In some embodiments, the EDTA is disodium EDTA. In some embodiments, the nasal spray formulation comprises about 0.001% (w / v) to about 1% (w / v) disodium EDTA.

[0037] In some embodiments, the nasal spray formulation further comprises a preservative, hi some embodiments, the preservative is benzalkonium chloride.

[0038] In some embodiments, the nasal spray formulation comprises one or more absorption enhancers selected from alkyl glycosides, benzalkonium chloride, oleic acid or its salts, polysorbate 20, polysorbate 80, sodium lauryl sulfate, cyclodextrin, medium and long chain fatty acids or their salts, saturated and unsaturated fatty acids or their salts, alcohol, glycerin, propylene glycol, PEG 300 / 400, and benzyl alcohol.

[0039] In some embodiments, the nasal spray formulation further comprises an antioxidant. In some embodiments, the nasal spray formulation further comprises an antioxidant. In some embodiments, the nasal spray formulation further comprises an antioxidant. In some embodiments, the nasal spray formulation further comprises an antioxidant. In some embodiments, the nasal spray formulation further comprises an antioxidant. In some embodiments, the nasal spray formulation further comprises an antioxidant. In some embodiments, the nasal spray formulation further comprises an antioxidant. and an antioxidant selected from phosphorus, lauric acid, limonene, linolenic acid, lysine, malic acid, menthol, methionine, monothioglycerol, myristic acid, oleic acid, palmitic acid, pelargonic acid, peppermint oil, phosphoric acid, polysorbates, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium sulfite, sodium caprate, sodium desoxycholate, sodium deoxyglycolate, sodium formaldehyde sulfoxylate, sodium glycocholate, sodium hydroxybenzoyal amino caprylate, sodium lauryl sulfate, sodium metabisulfite, sodium sulfite, sodium taurocholate, sodium thiosulfate, stearic acid, sulfur dioxide, and combinations thereof.

[0040] In some embodiments, the nasal spray formulation further comprises a synergist comprising an antioxidant selected from citric acid monohydrate, tartaric acid, thymol, tocopherol (alpha tocopherol), tocopherasol, vitamin E, and vitamin E polyethylene glycol succinate, and combinations thereof.

[0041] In some embodiments, the nasal spray formulation may further comprise any of the following: alcohol, arachidonic acid, benzethonium chloride, benzethonium bromide, benzalkonium chloride, capric acid, caproic acid, carvone, cetylpyridinium chloride, chitosan, citric acid, 6-cyclohexyl-1-hexyl-β-D-maltopyranoside, n-decyl-β-D-maltopyranoside, dimethylsulfoxide, dodecyl dimethylaminopropionate, 1-On-dodecyl-β-D-maltopyranoside, dodecyl polyethylene glycol ether, edetate disodium dihydrate, enanthic acid, glyceryl monooleate, glyceryl monostearate, glycofurol, isopropyl myristate, isopropyl palmitate, isopropyl palmitate, isopropyl myristate ... The penetration enhancers include those selected from isopropyl, pelargonic acid, lanolin, lauric acid, light mineral oil, limonene, linoleic acid, lysine, menthol, myristic acid, myristic alcohol, oleic acid, oleyl alcohol, palmitic acid, peppermint oil, polyoxyethylene alkyl ethers, polyoxylglycerides, polysorbates, pyrrolidone, sodium caprate, sodium desoxycholate, sodium deoxyglycolate, sodium glycocholate, sodium hydroxybenzoylaminocaprylate, sodium lauryl sulfate, sodium taurocholate, stearic acid, thymol, tricapric acid, triolein, undecylenic acid, and combinations thereof.

[0042] In some embodiments, the nasal spray formulation comprises from about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside; from about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride; from about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof; from about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and from about 0.001 (w / v) to about 1% (w / v) a combination of about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof; or a combination of about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof; or about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof and about 0.001% to 1% sodium metabisulfite; or about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof and about 0.001% to 10% polysorbate. or a combination of about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof and about 0.001% to 10% polysorbate 80 and about 0.001% to 1% sodium metabisulfite and about 0.001% to 1% citric acid.

[0043] In some embodiments, the nasal spray formulation is about 0.005% (w / v) to about 0.08% (w / v) benzalkonium chloride; about 0.01% (w / v) to about 0.06% (w / v) benzalkonium chloride; or about 0.01% (w / v) to about 0.04% (w / v) benzalkonium chloride; wherein the benzalkonium chloride is the only absorption enhancer in the nasal spray formulation or is present in a formulation that includes one or more additional absorption enhancers.

[0044] In some embodiments, the nasal spray formulation contains about 0.001% to 1% of any one of the antioxidants described herein, or a combination of any one of the antioxidants described herein.

[0045] In some embodiments, the nasal spray formulation comprises a buffering agent, including but not limited to adipic acid, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, tribasic citric acid monohydrate, sodium hydrogen phosphate, diethanolamine, glycine, maleic acid, malic acid, methionine, monobasic sodium phosphate, monoethanolamine, sodium glutamate, phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate dihydrate, sodium hydroxide, sodium lactate, and triethanolamine.

[0046] In one aspect, provided herein is a method for treating an adrenergic receptor-mediated disease, the method comprising intranasal administration of any one of the formulations as described herein. In some embodiments, the disease is selected from type 1 hypersensitivity reaction (systemic allergic reaction), acute asthma attack, cardiac arrest, and Stokes-Adams syndrome. In some embodiments, the disease is type 1 hypersensitivity reaction (systemic allergic reaction). In some embodiments, the type 1 hypersensitivity reaction is selected from allergic asthma, allergic conjunctivitis, allergic rhinitis, anaphylaxis, angioedema, urticaria, eosinophilia, drug allergy, and food allergy. In some embodiments, the drug allergy medication is an antibiotic allergy.

[0047] In one aspect, described herein is a nasal spray formulation comprising epinephrine or a salt thereof, which upon administration to a subject has the following pharmacokinetic characteristics: mean AUC 0-20min and AUC 0-t Both were AUC 0.3 mg intramuscularly. 0-20min and AUC 0-t at least 80% of the C produced by intramuscular injection of 0.3 mg maxAt least 80% of C max Average C is 150% or less of max ;Average t under 45 minutes max or IM injection-like absorption under optimal dosing conditions in the thigh. In another aspect, described herein is a nasal spray formulation comprising epinephrine or a salt thereof, which upon administration to a subject, has the following pharmacokinetic characteristics: mean AUC 0-20min and AUC 0-t Both were AUC 0.3 mg intramuscularly. 0-20min and AUC 0-t at least 80% of the C produced by intramuscular injection of 0.3 mg max At least 80% of C max Average C is 150% or less of max ;Average t under 45 minutes max and IM injection-like absorption under optimal dosing conditions in the thigh.

[0048] In another aspect, described herein is a nasal spray formulation comprising epinephrine or a salt thereof, which upon administration to a subject has the following pharmacokinetic characteristics: mean AUC 0-20min and AUC 0-t Both were AUC 0.15 mg intramuscularly. 0-20min and AUC 0-t at least 80% of the C produced by intramuscular injection of 0.15 mg max At least 80% of C max Average C is 150% or less of max ;Average t under 45 minutes max or IM injection-like absorption under optimal dosing conditions in the thigh. In another aspect, described herein is a nasal spray formulation comprising epinephrine or a salt thereof, which upon administration to a subject, has the following pharmacokinetic characteristics: mean AUC 0-20min and AUC 0-t Both were AUC 0.15 mg intramuscularly. 0-20min and AUC 0-t at least 80% of the C produced by intramuscular injection of 0.15 mg maxAt least 80% of C max Average C is 150% or less of max ;Average t under 45 minutes max and IM injection-like absorption under optimal dosing conditions in the thigh.

[0049] In yet another aspect, described herein is a nasal spray formulation comprising epinephrine or a salt thereof, which upon administration to a subject has the following pharmacokinetic characteristics: mean AUC 0-20min and AUC 0-t Both were AUC 0.5 mg intramuscularly. 0-20min and AUC 0-t at least 80% of the C produced by intramuscular injection of 0.5 mg max At least 80% of C max Average C is 150% or less of max ;Average t under 45 minutes max or IM injection-like absorption under optimal dosing conditions in the thigh.

[0050] In some embodiments, the nasal spray formulation is a pharmaceutical formulation.

[0051] In some embodiments, epinephrine or a salt thereof is present in the nasal spray formulation in an amount effective to treat an acute hypersensitivity reaction.

[0052] In some embodiments, intranasal administration of a single dose of the nasal spray pharmaceutical formulation to a subject results in a plasma epinephrine concentration effective for treating acute hypersensitivity reactions. In some embodiments, a single dose of the nasal spray pharmaceutical formulation contains about 0.5 mg to about 2.0 mg of epinephrine or a salt thereof. In some embodiments, a single dose of the nasal spray pharmaceutical formulation contains about 0.5 mg to about 1.5 mg of epinephrine or a salt thereof. In some embodiments, a single dose of the nasal spray pharmaceutical formulation contains about 0.5 mg to about 0.7 mg of epinephrine or a salt thereof. In some embodiments, a single dose of the nasal spray pharmaceutical formulation contains about 1.0 mg of epinephrine or a salt thereof. In some embodiments, a single dose of the nasal spray pharmaceutical formulation contains about 1.3 mg to about 1.5 mg of epinephrine or a salt thereof. In some embodiments, the nasal pharmaceutical formulation is an aqueous solution, an aqueous suspension, an aqueous emulsion, a non-aqueous solution, a non-aqueous suspension, a non-aqueous emulsion, a pressurized metered dose inhaler, or a dry powder.

[0053] In some embodiments, the nasal spray formulation is an aqueous solution, an aqueous suspension, an aqueous emulsion, a non-aqueous solution, a non-aqueous suspension, or a non-aqueous emulsion.

[0054] In some embodiments, the nasal spray formulation has pharmacokinetics like an intramuscular (IM) injection when the IM injection is given in the outer thigh, or subcutaneous (SC) like absorption, or something in between.

[0055] In some embodiments, the nasal spray formulation has subcutaneous (SC)-like absorption and an SC pharmacokinetic profile with a C of at least 100 pg / mL. max and 150h * AUC in pg / mL 0-240min There is.

[0056] In some embodiments, the nasal spray formulation has intramuscular (IM)-like absorption.

[0057] In some embodiments, the nasal spray formulation includes an absorption enhancer.

[0058] In some embodiments, the nasal spray pharmaceutical formulation comprises one or more absorption enhancers; and optionally one or more agents selected from isotonicity agents; stabilizers; preservatives; flavoring agents; viscosity modifiers; antioxidants; buffers and pH adjusters; wherein the pH of the nasal spray pharmaceutical formulation is about 2.0 to about 6.0. In some embodiments, the nasal spray pharmaceutical formulation has a pH of about 3.0 to about 5.0. In some embodiments, the nasal spray pharmaceutical formulation has a pH of about 4.0.

[0059] In some embodiments, the nasal spray pharmaceutical formulation comprises a pH adjusting agent. In some embodiments, the pH adjusting agent is an acid, a base, a buffer, or a combination thereof. In some embodiments, the acid is adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, or tartaric acid; the base is sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate; and the buffer is a phosphate buffer, an acetate buffer, or a citrate buffer.

[0060] In some embodiments, for each mole of epinephrine, the nasal spray formulation contains about 0.5 to about 1.1 molar equivalents of acid. In some embodiments, the acid is adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, or tartaric acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, no base is added to the nasal formulation during its preparation. In some embodiments, the nasal spray formulation has a pH of about 2.0 to about 6.0. In some embodiments, the nasal spray formulation has a pH of about 4.0.

[0061] In some embodiments, the nasal spray formulation contains about 5 mg / mL to about 40 mg / mL of epinephrine or a salt thereof per dose. In some embodiments, the nasal spray formulation contains about 0.40 mg to about 2.40 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 0.9 mg to about 2.40 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 0.5 mg to about 2.0 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 0.9 mg to about 1.5 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 0.75 mg to about 1.5 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 0.45 mg to about 1.15 mg of epinephrine or a salt thereof per dose dispensed from the device. In some embodiments, the nasal spray formulation contains about 1.0 mg to about 2.0 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0062] In some embodiments, the nasal spray formulation comprises an active ingredient selected from the group consisting of alcohol, aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetylpyridinium chloride, chitosan, cyclodextrin, deoxycholic acid, decanoyl, dimethylsulfoxide, glyceryl monooleate, glycofurol, glycosylated sphingosine, glycyrrhetinic acid, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroylcarnitine, lysophosphatidylcholine, menthol, poloxamer 407 or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, isoprenaline, glyceryl stearate, glyceryl oleate ... The composition further comprises one or more absorption enhancers selected from the group consisting of propyl, isopropyl palmitate, lanolin, light mineral oil, linoleic acid, menthol, myristic acid, myristic alcohol, oleic acid, oleyl alcohol, palmitic acid, polysorbate 20, polysorbate 80, propylene glycol, polyoxyethylene alkyl ethers, polyoxylglycerides, pyrrolidone, quillaja saponin, salicylic acid, sodium salt, β-sitosterol, β-D-glucoside, sodium lauryl sulfate, sucrose cocoate, taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid, thymol, tricaprylic acid, triolein, and alkyl saccharides.

[0063] In some embodiments, the nasal spray formulation comprises one or more absorption enhancers selected from dodecyl maltoside, benzalkonium chloride, oleic acid or its salts, polysorbate 20, polysorbate 80, and sodium lauryl sulfate.

[0064] In some embodiments, the nasal spray formulation comprises about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside; about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride; about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof; about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride. combination; a combination of about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof; or a combination of about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof, and about 0.001 to 1% of an antioxidant (e.g., sodium metabisulfite). In some embodiments, the nasal spray formulation comprises about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside; about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride; about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof; about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride. a combination of about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof; or a combination of about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof. In some embodiments, the nasal spray formulation is about 0.005% (w / v) to about 0.08% (w / v) benzalkonium chloride; about 0.01% (w / v) to about 0.06% (w / v) benzalkonium chloride; or about 0.01% (w / v) to about 0.04% (w / v) benzalkonium chloride; wherein the benzalkonium chloride is the only absorption enhancer in the nasal spray formulation or is present in a formulation that includes one or more additional absorption enhancers.

[0065] In some embodiments, the nasal spray formulation further comprises a stabilizer. In some embodiments, the stabilizer is ethylenediaminetetraacetic acid (EDTA) or a salt thereof. In some embodiments, the EDTA is disodium EDTA. In some embodiments, the EDTA is present in an amount of about 0.001% to about 1%.

[0066] In some embodiments, the nasal spray formulation further comprises a preservative, hi some embodiments, the preservative is benzalkonium chloride.

[0067] In one aspect, described herein is a method for treating an adrenergic receptor-mediated disease, the method comprising intranasal administration of any one of the formulations described herein. In some embodiments, the disease is selected from type 1 hypersensitivity reaction (systemic allergic reaction), acute asthma attack, cardiac arrest, and Stokes-Adams syndrome. In some embodiments, the disease is type 1 hypersensitivity reaction (systemic allergic reaction). In some embodiments, the type 1 hypersensitivity reaction is selected from allergic asthma, allergic conjunctivitis, allergic rhinitis, anaphylaxis, angioedema, urticaria, eosinophilia, drug allergy, and food allergy. In some embodiments, the drug allergy medication is an antibiotic allergy.

[0068] In another aspect, described herein is a method for treating anaphylaxis, the method comprising intranasal administration of an intranasal formulation of epinephrine in an amount less than about 2.0 mg. In some embodiments, the nasal pharmaceutical formulation comprises about 0.5 mg to about 1.5 mg of epinephrine or a salt thereof. In some embodiments, the nasal pharmaceutical formulation comprises about 0.5 mg to about 0.7 mg of epinephrine or a salt thereof. In some embodiments, the nasal pharmaceutical formulation comprises about 1.0 mg of epinephrine or a salt thereof. In some embodiments, the nasal pharmaceutical formulation comprises about 1.3 mg to about 1.5 mg of epinephrine or a salt thereof.

[0069] In some embodiments of the method of treatment, the intranasal formulation comprises one or more absorption enhancers; isotonicity agents; stabilizers; preservatives; optional antioxidants; and optional pH adjusters. In some embodiments of the method of treatment, the one or more absorption enhancers are selected from dodecyl maltoside; benzalkonium chloride; oleic acid or a salt thereof; sodium lauryl sulfate; a combination of dodecyl maltoside and benzalkonium chloride; a combination of dodecyl maltoside and oleic acid or a salt thereof; and a combination of benzalkonium chloride and oleic acid or a salt thereof. In some embodiments of the method of treatment, the one or more absorption enhancers are from about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside; from about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride; from about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof; from about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and from about 0.001 (w / v) to about a combination of about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof; or a combination of about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof. In some embodiments of the method of treatment, the intranasal formulation comprises about 0.005% (w / v) to about 0.08% (w / v) benzalkonium chloride; about 0.01% (w / v) to about 0.06% (w / v) benzalkonium chloride; or about 0.01% (w / v) to about 0.04% (w / v) benzalkonium chloride; where benzalkonium chloride is the only absorption enhancer in the formulation or is present in a formulation that includes one or more absorption enhancers. In some embodiments of the method of treatment, the isotonicity agent is sodium chloride. In some embodiments of the method of treatment, the stabilizing agent is EDTA. In some embodiments of the method of treatment, the stabilizing agent is EDTA in an amount of about 0.001% (w / v) to about 1% (w / v). In some embodiments of the method of treatment, the preservative is benzalkonium chloride. In some embodiments of the methods of treatment, the preservative is benzalkonium chloride in an amount of about 0.001% (w / v) to about 1% (w / v).

[0070] An article of manufacture is provided that includes packaging material, a nasal spray formulation described herein within the packaging material, and a label indicating that the nasal spray formulation is used for treating any of the conditions described herein (e.g., anaphylaxis).

[0071] Other objects, features and advantages of the compositions and methods described herein will become apparent from the following detailed description. It will be understood, however, that the detailed description and specific examples, while indicating particular embodiments, are given by way of example only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from the detailed description. [Brief description of the drawings]

[0072] [Figure 1] 1 shows the area under the plasma concentration versus time curve at 0-120 minutes (AUC0-120min) of epinephrine absorption at different doses and routes of administration as disclosed in Srisawat et al., “A preliminary study of intranasal epinephrine administration as a potential route for anaphylaxis treatment,” Asian Pac J Allergy Immunol, 2016 Mar;34(1):38-43, discussed below. [Diagram 2] FIG. 1 shows plasma epinephrine concentration versus time plots following administration of IN saline, 5 mg IN epinephrine, and 0.3 mg IM epinephrine, as disclosed in Srisawat et al. [Diagram 3] FIG. 1 shows mean plasma epinephrine concentrations above baseline (pg / mL) versus time (min) curves from the first clinical study described in Example 2A comparing 0.3 mg epinephrine IM and IN; the curve with squares represents IM and the curve with circles represents IN. [Figure 4]1 shows mean plasma epinephrine concentrations above baseline (pg / mL) versus time (min) curves from the second clinical study described in Example 2B comparing 0.5, 1.0, and 2.0 mg of epinephrine IN; the curve with circles represents 0.5 mg; the curve with triangles represents 1.0 mg, and the curve with squares represents 2.0 mg. [Diagram 5] 1 shows the first 30 minutes of mean plasma epinephrine concentration above baseline (pg / mL) versus time (minutes) curves from the second clinical study described in Example 2B comparing 0.5, 1.0, and 2.0 mg IN epinephrine; the curve with circles represents 0.5 mg; the curve with triangles represents 1.0 mg, and the curve with squares represents 2.0 mg. [Figure 6] The data from Figure 4 is repeated and overlaid on the mean plasma concentration versus time curve for IM epinephrine from the first clinical study described in Example 2A. [Figure 7] The data from FIG. 5 is repeated and overlaid onto the first 30 minutes of the mean plasma concentration versus time curve for IM epinephrine from the first clinical study described in Example 2A. [Figure 8] 1 shows mean plasma epinephrine concentrations above baseline (pg / mL) versus time (min) curves from the comparative bioavailability portion of the second clinical study described in Example 2B comparing 1.0 mg epinephrine IN (curve w / circles) with 0.3 mg epinephrine IM (epinephrine autoinjector, curve w / triangles). [Figure 9] FIG. 1 shows the first 30 minutes of mean plasma epinephrine concentrations above baseline (pg / mL) versus time (minutes) curves from the comparative bioavailability portion of the second clinical study described in Example 2B comparing 1.0 mg epinephrine IN (curve w / circles) with 0.3 mg epinephrine IM (EpiPen®, curve w / triangles). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0073] Disclosed herein are methods and formulations useful for treating anaphylaxis and other diseases, the methods comprising administering an intranasal formulation of epinephrine. Also provided are devices adapted for the nasal delivery of pharmaceutical formulations to a patient, including the delivery of single, double, and multiple doses comprising a therapeutically effective amount of epinephrine and pharma- ceutical acceptable salts thereof.

[0074] Intranasal epinephrine has a long history of use in low doses as a decongestant and vasoconstrictor in sinus and nasal surgery, often formulated in combination with anesthetics. Historically, epinephrine has been difficult to formulate as an intranasal solution for systemic delivery. See, for example, Srisawat C et al., “A preliminary study of intranasal epinephrine administration as a potential route for anaphylaxis treatment,” Asian Pac J Allergy Immunol, 2016 Mar; 34(1):38-43. Srisawat showed that significant systemic absorption of epinephrine via the IN route was observed only at 5 mg (see Figure 1), and the pharmacokinetic parameters of IN epinephrine at 5 mg were not significantly different from those of the IM epinephrine group (see Table 1 below).

[0075] [Table 1]

[0076] Figure 1 is reproduced from Srisawat C et al. and demonstrates that Srisawat et al. did not observe plasma concentrations of epinephrine at intranasal dose levels below 2.5 mg.

[0077] Furthermore, FIG. 2 shows that even at a 5 mg dose, Srisawat was unable to produce an intranasal formulation capable of achieving higher plasma concentrations than intramuscular epinephrine delivered by an autoinjector at any time prior to about 60 minutes, and thus absorption during the critical early time points was delayed when rapid absorption was required to stop a systemic allergic reaction (anaphylaxis). This can be potentially detrimental in severe conditions such as anaphylaxis, where emergency treatment, and therefore injection-like pharmacokinetics, are desirable. The PK profile of IM injection into the thigh is considered the optimal dosing method by the literature, considering that the higher vascularity of the leg muscle allows for more rapid absorption and distribution of epinephrine than other routes of administration, resulting in a more rapid increase in plasma levels to stop anaphylactic reactions more quickly. FIG. 2 also shows that the 5 mg formulation of Srisawat was almost totally cleared from plasma in about 2 hours, in contrast to intramuscular epinephrine delivered by an autoinjector. Finally, epinephrine is known to be associated with dose-related cardiac side effects, including myocardial infarction, at doses as low as 0.3-0.5 mg intramuscularly; therefore, doses as high as 5 mg would likely be dangerous in the general population if intranasal disease is present that could allow excessive absorption. Thus, lower dose preparations that avoid such risks would be preferred as would safer intranasal preparations.

[0078] Disclosed herein are intranasal formulations of epinephrine, and nasal spray devices containing the formulations, that overcome the problems of past attempts. Various aspects can be attributed to the success of the formulations, devices, and methods of use disclosed herein.

[0079] For example, in certain embodiments, formulation of epinephrine in aqueous solution by appropriate addition of a molar equivalent of acid for each mole of epinephrine serves to solubilize and stabilize epinephrine. This allows the formulation to avoid the use of buffers commonly used in aqueous pharmaceutical compositions for injection, including phosphate, acetate, and citrate buffers, which are sometimes avoided in the intranasal formulations disclosed herein. Other salts of epinephrine, such as epinephrine acetate, epinephrine hydrochloride, epinephrine tartrate, epinephrine tartrate, epinephrine hydrogen tartrate, and epinephrine borate, can also be used to formulate aqueous solutions of epinephrine.

[0080] Certain embodiments of the formulations, devices, and methods of use disclosed herein provide advantages over epinephrine formulated in other ways. Epinephrine is considered a narrow therapeutic index drug. As a sympathomimetic catecholamine, epinephrine has a narrow therapeutic index and serious adverse reactions, including cardiovascular and cerebrovascular reactions, may be associated with its use. Nevertheless, the use of epinephrine for this indication is life-saving, and the benefits of using it outweigh the potential safety risks. Intranasal delivery and formulations are suitable for safe and painless delivery of drugs such as epinephrine, with consistent content uniformity, delivered dose, and absorption, thereby minimizing serious adverse reactions, including cardiovascular and cerebrovascular reactions, that may be associated with use via injection mechanisms. There is low variability in shot weight, delivering the labeled dose consistently.

[0081] In one aspect, described herein is a pharmaceutical composition comprising: a) epinephrine; and b) an alkyl glycoside; wherein the pharmaceutical composition is formulated for administration to the circulatory system of a subject via an administration route such as intranasal, inhalation, or pulmonary. In some embodiments, described herein is a pharmaceutical composition comprising: a) ibrutinib; and b) an alkyl glycoside; wherein the pharmaceutical composition is a liquid formulated for intranasal delivery.

[0082] In some embodiments, the alkyl glycoside has an alkyl chain having 8-20 carbons. In some embodiments, the alkyl glycoside is selected from the group consisting of undecyl maltoside, dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, and sucrose mono-tetradecanoate. In some embodiments, the alkyl glycoside is dodecyl-β-D-maltoside. In some embodiments, the alkyl glycoside concentration is about 0.001%-10.0% (w / v). In some embodiments, the alkyl glycoside concentration is about 0.05%-0.5% (w / v).

[0083] In some embodiments, the composition further comprises a membrane permeation enhancer. In some embodiments, the membrane permeation enhancer is a surfactant, a bile salt, a phospholipid, an alcohol, an enamine, a long chain amphiphilic molecule, a hydrophobic small molecule, a derivative of sodium or salicylic acid, a glycerol ester of acetoacetic acid, a cyclodextrin, a medium or long chain fatty acid, a chelating agent, an amino acid or a salt thereof, an enzyme, or a combination thereof. In some embodiments, the membrane permeation enhancer is selected from the group consisting of citric acid, sodium citrate, propylene glycol, glycerin, ascorbic acid, sodium metabisulfite, disodium ethylenediaminetetraacetic acid (EDTA), benzalkonium chloride, hydroxyquinolones, sodium hydroxide, and combinations thereof. In some embodiments, the membrane permeation enhancer is selected from the group consisting of citric acid, sodium citrate, propylene glycol, glycerin, ascorbic acid, sodium metabisulfite, disodium ethylenediaminetetraacetic acid (EDTA), benzalkonium chloride, sodium hydroxide, and combinations thereof. In some embodiments, the membrane permeation enhancer is benzalkonium chloride, EDTA, or a combination thereof.

[0084] In some embodiments, the composition has a C for epinephrine that is about 2-fold or greater compared to administration without the alkyl glycoside. max is provided to the subject.

[0085] In some embodiments, the composition has a t agonist effect on epinephrine that is about 2-fold or less compared to administration without the alkyl glycoside. max is provided to the subject.

[0086] In some embodiments, the composition has a t response to epinephrine of about 0.3 hours or less. max is provided to the subject.

[0087] In some embodiments, the composition has a pH of about 2.0 to 6.0, In some embodiments, the composition has a pH of about 2.0 to 5.0.

[0088] In another aspect, described herein is a method of increasing the bioavailability of epinephrine in a subject, comprising administering to the subject a pharmaceutical composition comprising epinephrine and an alkyl glycoside, thereby increasing the bioavailability of epinephrine in the subject; wherein the pharmaceutical composition is formulated for administration to the subject's circulatory system via an administration route such as intranasal, inhalation, or pulmonary. In some embodiments, described herein is a method of increasing the bioavailability of epinephrine in a subject, comprising administering to the subject a pharmaceutical composition comprising epinephrine and an alkyl glycoside, thereby increasing the bioavailability of epinephrine in the subject; wherein the pharmaceutical composition is a liquid formulated for intranasal delivery.

[0089] In some embodiments, increased epinephrine bioavailability allows smaller doses of epinephrine to be delivered intrasally and be effective in treating anaphylaxis. In some embodiments, exposure to larger doses of epinephrine can result in overdosing of epinephrine. There is an increasing interest and need to develop alternative non-invasive epinephrine dosage forms that provide epinephrine plasma concentrations equivalent to those achieved by epinephrine auto-injection devices, are available in a range of dosages, have long shelf life, and eliminate needle anxiety, potential administration errors, unintentional injection and injury. The epinephrine nasal dosage forms described herein offer a potential user-friendly non-invasive alternative for emergency treatment of anaphylaxis in community settings.

[0090] In some embodiments, the alkyl glycoside has an alkyl chain having 8-20 carbons. In some embodiments, the alkyl glycoside is selected from the group consisting of undecyl maltoside, dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, and sucrose mono-tetradecanoate. In some embodiments, the alkyl glycoside is dodecyl-β-D-maltoside. In some embodiments, the alkyl glycoside concentration is about 0.001%-10.0% (w / v). In some embodiments, the alkyl glycoside concentration is about 0.05%-0.5% (w / v).

[0091] In some embodiments, the composition further comprises a membrane permeation enhancer. In some embodiments, the membrane permeation enhancer is a surfactant, a bile salt, a phospholipid, an alcohol, an enamine, a medium and / or long chain amphiphilic molecule, a hydrophobic small molecule, a derivative of sodium or salicylic acid, a glycerol ester of acetoacetic acid, a cyclodextrin, a medium or long chain fatty acid, a chelating agent, an amino acid or a salt thereof, an enzyme, or a combination thereof. In some embodiments, the membrane permeation enhancer is selected from the group consisting of citric acid, sodium citrate, propylene glycol, glycerin, ascorbic acid, sodium metabisulfite, disodium ethylenediaminetetraacetic acid (EDTA), benzalkonium chloride, sodium hydroxide, and combinations thereof. In some embodiments, the membrane permeation enhancer is benzalkonium chloride, EDTA, or a combination thereof.

[0092] In some embodiments, the composition has a C for epinephrine that is about 2-fold or greater compared to administration without the alkyl glycoside. max is provided to the subject.

[0093] In some embodiments, the composition has a t agonist effect on epinephrine that is about 2-fold or less compared to administration without the alkyl glycoside. max is provided to the subject.

[0094] In some embodiments, the composition has a t response to epinephrine of about 0.3 hours or less. max is provided to the subject.

[0095] In some embodiments, the composition has a pH of about 2.0 to 6.0, In some embodiments, the composition has a pH of about 2.0 to 5.0.

[0096] In some embodiments, the compositions described herein are liquid compositions suitable for intranasal administration.

[0097] In one aspect, the invention provides a method for increasing the absorption of epinephrine into the circulatory system of a subject by administering via a delivery route, such as nasal, inhalation, or pulmonary, a composition comprising: (a) epinephrine; (b) a suitable non-toxic, non-ionic alkyl glycoside having a hydrophobic alkyl group attached by linkage to a hydrophilic saccharide, providing enhanced absorption; and (c) a mucosal delivery enhancer.

[0098] The term "mucosal delivery enhancer" includes agents that enhance the release or solubility (e.g., from a pharmaceutical delivery vehicle), rate of dissemination, permeation capacity and timing, uptake, residence time, stability, effective half-life, peak or sustained concentration levels, clearance of a compound (e.g., a biologically active compound), and other desired mucosal delivery characteristics (e.g., as measured at the site of delivery or at a selected target site of activity such as the bloodstream or central nervous system). Enhancement of mucosal delivery may occur by any of a variety of mechanisms, including, for example, increasing nucleic acid, transport, persistence, or stability of the compound, increasing membrane fluidity, modulating the availability or activity of calcium and other ions that regulate intracellular or paracellular permeation, stabilizing mucosal membrane components (e.g., lipids), altering non-protein and protein sulfhydryl levels in mucosal tissues, increasing water flux across mucosal surfaces, modulating epithelial junctional physiology, decreasing the viscosity of the mucus overlying the mucosal epithelium, decreasing the rate of mucociliary clearance, and other mechanisms.

[0099] Exemplary mucosal delivery enhancing agents include the following agents and any combination thereof: (a) aggregation inhibitors; (b) a charge control agent; (c) pH control agent; (d) degradative enzyme inhibitors; (e) mucus-dissolving or mucus-clearing agents; (f) fimbrial inhibitors; (g) Below: (i) a surfactant; (ii) bile acids; (ii) phospholipid-loaded mixed micelles, liposomes, or carriers; (iii) alcohol; (iv) enamines; (v) NO donor compounds; (vi) long-chain amphiphilic molecules; (vii) small hydrophobic permeation enhancers; (viii) sodium or salicylic acid derivatives; (ix) glycerol ester of acetoacetic acid; (x) cyclodextrin or a beta-cyclodextrin derivative; (xi) medium chain fatty acids; (xii) a chelating agent; (xiii) an amino acid or a salt thereof; (xiv) N-acetylamino acid or a salt thereof; (xv) enzymes that degrade selected membrane components; (ix) inhibitors of fatty acid synthesis; (x) inhibitors of cholesterol synthesis; and (xi) any combination of the membrane permeation enhancers listed in (i)-(x). A membrane permeation enhancer selected from: (h) regulators of epithelial junction physiology; (i) Vasodilators; (j) a selective transport enhancer; and (k) A stabilizing delivery vehicle, carrier, mucoadhesive, support, or complexing species with which a compound is effectively combined, associated, encapsulated, encapsulated, or bound to provide stabilization of the compound for enhanced nasal mucosal delivery, and formulation of the compound with an intranasal delivery-enhancing agent increases the bioavailability of the compound in the plasma of a subject.

[0100] Additional mucosal delivery enhancers include, for example, citric acid, sodium citrate, propylene glycol, glycerin, ascorbic acid (e.g., L-ascorbic acid), sodium metabisulfite, disodium ethylenediaminetetraacetic acid (EDTA), benzalkonium chloride, sodium hydroxide, and mixtures thereof. For example, EDTA or a salt thereof (e.g., sodium or potassium) is utilized in an amount ranging from about 0.01% to 2% by weight of the composition containing the alkyl saccharide preservative.

[0101] In yet another aspect, described herein is a pharmaceutical composition having a suitable non-toxic, non-ionic alkyl glycoside having a hydrophobic alkyl group attached by a bond to a hydrophilic saccharide in combination with a mucosal delivery enhancing agent selected from the following: (a) aggregation inhibitors; (b) a charge control agent; (c) pH control agent; (d) degradative enzyme inhibitors; (e) mucus-dissolving or mucus-clearing agents; (f) fimbrial inhibitors; (g) Below: (i) a surfactant; (ii) bile acids; (ii) phospholipid-loaded mixed micelles, liposomes, or carriers; (iii) alcohol; (iv) enamines; (v) NO donor compounds; (vi) long-chain amphiphilic molecules; (vii) small hydrophobic permeation enhancers; (viii) sodium or salicylic acid derivatives; (ix) glycerol ester of acetoacetic acid; (x) cyclodextrin or a beta-cyclodextrin derivative; (xi) medium- or long-chain fatty acids; (xii) a chelating agent; (xiii) an amino acid or a salt thereof; (xiv) N-acetylamino acid or a salt thereof; (xv) enzymes that degrade selected membrane components; (ix) inhibitors of fatty acid synthesis; (x) inhibitors of cholesterol synthesis; and (xi) any combination of the membrane permeation enhancers listed in (i)-(x). A membrane permeation enhancer selected from: (h) regulators of epithelial junction physiology; (i) Vasodilators; (j) a selective transport enhancer; and (k) A stabilizing delivery vehicle, carrier, mucoadhesive, support, or complexing species with which a compound is effectively combined, associated, encapsulated, encapsulated, or bound to provide stabilization of the compound for enhanced nasal mucosal delivery, and formulation of the compound with an intranasal delivery-enhancing agent increases the bioavailability of the compound in the plasma of a subject.

[0102] In another embodiment, described herein are methods of administering alkyl glycoside compositions by administering a therapeutically effective amount of at least one alkyl glycoside having an alkyl chain length of about 12 to about 14 carbon atoms, at least one saccharide having antibacterial activity, and epinephrine.

[0103] In one aspect, provided herein is an antibacterial alkyl saccharide composition comprising n-dodecyl-4-O-α-D-glucopyranosyl-β-D-glucopyranoside or n-tetradecyl-4-O-α-D-glucopyranosyl-β-D-glucopyranoside.

[0104] Thus, herein provided is a nasal spray formulation comprising about 0.40 mg to about 2.40 mg of epinephrine or a salt thereof per dose dispensed from the device as embodiment 1. Alternative embodiment 1. Provided is a nasal spray formulation comprising about 0.40 mg to about 2.0 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0105] Embodiment 2. The nasal spray formulation of embodiment 1, wherein the formulation is a pharmaceutical formulation.

[0106] Embodiment 3. The nasal spray formulation of embodiment 2, wherein epinephrine or a salt thereof is present in the pharmaceutical formulation in an amount effective to treat an acute hypersensitivity reaction.

[0107] Embodiment 4. The nasal spray formulation of any one of embodiments 1 to 3, wherein the formulation is aqueous.

[0108] Embodiment 5. The nasal spray formulation of any one of embodiments 1 to 4, wherein the formulation comprises an absorption enhancer. In alternative embodiment 5, the nasal spray formulation of any one of embodiments 1 to 4, wherein the formulation comprises one or more absorption enhancers.

[0109] Embodiment 6. The nasal spray formulation of any one of embodiments 1 to 5, wherein the formulation has an absorption such as an intramuscular (IM) injection or such as a subcutaneous (SQ) injection, or therebetween.

[0110] Embodiment 7. A nasal spray formulation according to embodiment 6, having intramuscular (IM) injection-like absorption.

[0111] Embodiment 8. The nasal spray formulation of embodiment 6, wherein the formulation has subcutaneous (SC)-like absorption.

[0112] Embodiment 9. The SC pharmacokinetic profile has a C of at least 100 pg / mL. max and 150h * AUC in pg / mL 0-240min The nasal spray formulation of embodiment 8,

[0113] Embodiment 10. The formulation, upon administration to a subject, has the following pharmacokinetic characteristics: ·Average AUC 0-20min and AUC 0-t Both were AUC 0.3 mg intramuscularly. 0-20min and AUC 0-t is at least 80%; Intramuscular injection of 0.3 mg results in max At least 80% of C max Average C is 150% or less of max ; -Average t under 45 minutes max and IM injection-like absorption in the thigh under optimal dosing conditions 10. The nasal spray formulation of any one of embodiments 1 to 9, which provides one or more of the following:

[0114] Embodiment 11. The formulation, upon administration to a subject, has the following pharmacokinetic characteristics: ·Average AUC 0-20min and AUC 0-t Both were AUC 0.15 mg intramuscularly. 0-20min and AUC 0-t is at least 80%; Intramuscular injection of 0.15 mg results in max At least 80% of C max Average C is 150% or less of max ; -Average t under 45 minutes max and IM injection-like absorption in the thigh under optimal dosing conditions 10. The nasal spray formulation of any one of embodiments 1 to 9, which provides one or more of the following:

[0115] Embodiment 12. The formulation, upon administration to a subject, has the following pharmacokinetic characteristics: ·Average AUC 0-20min and AUC 0-t Both were AUC 0.5 mg intramuscularly. 0-20min and AUC 0-t is at least 80%; Intramuscular injection of 0.5 mg results in max At least 80% of C max Average C is 150% or less of max ; -Average t under 45 minutes max and IM injection-like absorption in the thigh under optimal dosing conditions 10. The nasal spray formulation of any one of embodiments 1 to 9, which provides one or more of the following:

[0116] Embodiment 13. The formulation, upon administration to a subject, has a t of less than 40 minutes. max , t less than 35 minutes max , 30~45 minutes t max , 30~40 minutes t max , or 30 to 35 minutes maxThe nasal spray formulation of any one of embodiments 1 to 12, wherein the formulation, upon administration to a subject, provides a t of less than 40 minutes. max , t less than 35 minutes max , 15~45 minutes t max , 20~45 minutes t max , 25~45 minutes t max , 30~45 minutes t max , 30~40 minutes t max , 30~35 minutes t max , 15~20 minutes t max , 15~25 minutes t max , or 15 to 30 minutes max 13. The nasal spray formulation of any one of embodiments 1 to 12,

[0117] Embodiment 14. The nasal spray formulation of any one of embodiments 1 to 13, wherein the formulation contains less than 1 molar equivalent of acid for each mole of epinephrine.

[0118] Embodiment 15. The method of any one of embodiments 1 to 13, wherein the formulation comprises about 0.5 to about 1.1 molar equivalents of acid for each mole of epinephrine.

[0119] Embodiment 16. The nasal spray formulation of any one of embodiments 14 to 15, wherein the acid is hydrochloric acid. Alternative embodiment 16. The nasal spray formulation of any one of embodiments 14 to 15, wherein the acid is acetic acid, adipic acid, ammonium chloride, boric acid, citric acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, or tartaric acid.

[0120] Embodiment 17. The nasal spray formulation of any one of embodiments 1 to 16, wherein the formulation has a pH of about 3.0 to about 6.0. Alternative embodiment 17. The nasal spray formulation of any one of embodiments 1 to 16, wherein the formulation has a pH of about 2.0 to about 6.0.

[0121] Embodiment 18. The nasal spray formulation of embodiment 17, wherein the formulation has a pH of about 3.5 to about 5.0.

[0122] Embodiment 19. The nasal spray formulation of embodiment 17, wherein the formulation has a pH of about 4.0 to about 4.5.

[0123] Embodiment 20. The nasal spray formulation of embodiment 17, wherein the formulation has a pH of about 4.5.

[0124] Embodiment 21. The nasal spray formulation of embodiment 17, wherein the formulation has a pH of about 4.0.

[0125] Embodiment 22. The nasal spray formulation of any one of embodiments 1 to 21, wherein the formulation comprises from about 5 mg / mL to about 40 mg / mL of epinephrine or a salt thereof. Alternative embodiment 22. The nasal spray formulation of any one of embodiments 1 to 21, wherein the formulation comprises from about 3 mg / mL to about 40 mg / mL of epinephrine or a salt thereof.

[0126] Embodiment 23. A nasal spray formulation described in any one of embodiments 1 to 22, wherein the formulation contains from about 0.9 mg to about 2.4 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0127] Embodiment 24. A nasal spray formulation described in any one of embodiments 1 to 22, wherein the formulation comprises from about 0.5 mg to about 2.0 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0128] Embodiment 25. A nasal spray formulation described in any one of embodiments 1 to 22, wherein the formulation comprises from about 0.75 mg to about 1.5 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0129] Embodiment 26. A nasal spray formulation described in any one of embodiments 1 to 22, wherein the formulation comprises from about 0.9 mg to about 1.15 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0130] Embodiment 27. A nasal spray formulation according to any one of embodiments 1 to 22, wherein the formulation comprises about 1.0 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0131] Embodiment 28. A nasal spray formulation described in any one of embodiments 1 to 22, wherein the formulation comprises from about 0.45 mg to about 1.15 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0132] Embodiment 29. A nasal spray formulation described in any one of embodiments 1 to 22, wherein the formulation comprises about 1.0 mg to about 2.0 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0133] Embodiment 30. The nasal spray formulation of any one of embodiments 1 to 29, wherein the formulation further comprises a stabilizer.

[0134] Embodiment 31. The nasal spray formulation of embodiment 30, wherein the stabilizer is ethylenediaminetetraacetic acid (EDTA) or a salt thereof.

[0135] Embodiment 32. A nasal spray formulation according to embodiment 31, wherein the EDTA is disodium EDTA.

[0136] Embodiment 33. A nasal spray formulation according to embodiment 31 or 32, wherein EDTA is present in an amount that is 5% to 15% of the amount of epinephrine, both measured in mmol. Alternative embodiment 33. A nasal spray formulation according to embodiment 31 or 32, wherein EDTA is present in an amount that is 0.001% (w / v) to 1% (w / v).

[0137] Embodiment 34. A nasal spray formulation according to embodiment 31 or 32, wherein the mmol of EDTA is about 10% of the mmol of epinephrine.

[0138] Embodiment 35. The nasal spray formulation of any one of embodiments 1 to 34, wherein the formulation further comprises a preservative.

[0139] Embodiment 36. The nasal spray formulation of embodiment 35, wherein the preservative is benzalkonium chloride.

[0140] Embodiment 37. The nasal spray formulation of any one of embodiments 1 to 34, wherein the formulation further comprises an absorption enhancer.

[0141] Embodiment 38. The nasal spray formulation of embodiment 37, wherein the absorption enhancer is an alkyl saccharide.

[0142] Embodiment 39. The nasal spray formulation of embodiment 38, wherein the absorption enhancer is dodecyl maltoside.

[0143] Embodiment 40. The nasal spray formulation of embodiment 39, wherein the formulation comprises about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside.

[0144] Embodiment 41. The nasal spray formulation of embodiment 40, wherein the formulation comprises about 0.1% (w / v) to about 0.5% (w / v) dodecyl maltoside.

[0145] Embodiment 42. The nasal spray formulation of embodiment 41, wherein the formulation comprises about 0.25% (w / v) dodecyl maltoside. Alternative embodiment 42. The nasal spray formulation of embodiment 41, wherein the formulation comprises about 0.25% (w / v) dodecyl maltoside, and about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride. Alternative embodiment 42. The nasal spray formulation of embodiment 41, wherein the formulation comprises about 0.25% (w / v) dodecyl maltoside, and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof. Alternative embodiment 42. The nasal spray formulation of embodiment 41, wherein the formulation comprises about 0.25% (w / v) dodecyl maltoside, and about 0.001% (w / v) to about 1% (w / v) benzalkonium chloride, and about 0.001 to about 1% (w / v) oleic acid or a salt thereof.

[0146] Embodiment 43a. In certain embodiments, the formulation comprises about 0.75 mg to about 1.5 mg of epinephrine or a salt thereof per dose dispensed from the device and, when administered to a subject as a nasal spray, has the following pharmacokinetic characteristics: ·Average AUC 0-20min and AUC 0-t Both were AUC 0.3 mg intramuscularly. 0-20min and AUC 0-t is at least 80%; Intramuscular injection of 0.3 mg results in max At least 80% of C max Average C is 150% or less of max ; -Average t under 45 minutes max and IM injection-like absorption in the thigh under optimal dosing conditions results in one or more of the following:

[0147] Embodiment 43b. In certain embodiments, the formulation comprises about 0.5 mg to about 1.15 mg of epinephrine or a salt thereof per dose dispensed from the device and, when administered to a subject as a nasal spray, has the following pharmacokinetic characteristics: ·Average AUC 0-20min and AUC 0-t Both were AUC 0.15 mg intramuscularly. 0-20min and AUC 0-t is at least 80%; Intramuscular injection of 0.15 mg results in max At least 80% of C max Average C is 150% or less of max ; -Average t under 45 minutes max and IM injection-like absorption in the thigh under optimal dosing conditions results in one or more of the following:

[0148] Embodiment 43c. In certain embodiments, the formulation comprises about 1.0 mg to about 2.0 mg of epinephrine or a salt thereof per dose dispensed from the device and, when administered to a subject as a nasal spray, has the following pharmacokinetic characteristics: ·Average AUC 0-20min and AUC 0-t Both were AUC 0.5 mg intramuscularly. 0-20min and AUC 0-t is at least 80%; Intramuscular injection of 0.5 mg results in max At least 80% of C max Average C is 150% or less of max ; -Average t under 45 minutes max and IM injection-like absorption in the thigh under optimal dosing conditions results in one or more of the following:

[0149] Also provided are embodiments in which any of embodiments 43a, 43b, and 43c include one or more of the limitations set forth above in embodiments 2-22 and 30-42.

[0150] Also provided herein is embodiment 44, a nasal spray formulation comprising epinephrine or a salt thereof, which upon administration to a subject has the following pharmacokinetic characteristics: ·Average AUC 0-20min and AUC 0-t Both were AUC 0.3 mg intramuscularly. 0-20min and AUC 0-t is at least 80%; Intramuscular injection of 0.3 mg results in max At least 80% of C max Average C is 150% or less of max ; -Average t under 45 minutes max and IM injection-like absorption in the thigh under optimal dosing conditions results in one or more of the following:

[0151] Also provided herein is embodiment 45, a nasal spray formulation comprising epinephrine or a salt thereof, which upon administration to a subject has the following pharmacokinetic characteristics: ·Average AUC 0-20min and AUC 0-t Both were AUC 0.15 mg intramuscularly. 0-20min and AUC 0-t is at least 80%; Intramuscular injection of 0.15 mg results in max At least 80% of C max Average C is 150% or less of max ; -Average t under 45 minutes max and IM injection-like absorption in the thigh under optimal dosing conditions results in one or more of the following:

[0152] Also provided herein is embodiment 46, a nasal spray formulation comprising epinephrine or a salt thereof, the formulation having, upon administration to a subject, the following pharmacokinetic characteristics: ·Average AUC 0-20min and AUC 0-t Both were AUC 0.5 mg intramuscularly. 0-20min and AUC 0-t is at least 80%; Intramuscular injection of 0.5 mg results in max At least 80% of C max Average C is 150% or less of max ; -Average t under 45 minutes max and IM injection-like absorption in the thigh under optimal dosing conditions results in one or more of the following:

[0153] Embodiment 47. A nasal spray described in any one of embodiments 45 to 46, comprising from about 0.4 mg to about 2.40 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0154] Embodiment 48. The nasal spray formulation of embodiment 47, wherein the formulation is a pharmaceutical formulation.

[0155] Embodiment 49. The nasal spray formulation of embodiment 48, wherein epinephrine or a salt thereof is present in the pharmaceutical formulation in an amount effective to treat acute hypersensitivity reactions.

[0156] Embodiment 50. The nasal spray formulation of any one of embodiments 44 to 49, wherein the formulation is aqueous.

[0157] Embodiment 51. A nasal spray formulation according to any one of embodiments 44 to 50, wherein the formulation has an intramuscular (IM) injection-like or subcutaneous (SQ)-like absorption.

[0158] Embodiment 52. The nasal spray formulation of embodiment 51, wherein the formulation has intramuscular (IM) injection-like absorption.

[0159] Embodiment 53. A nasal spray formulation according to embodiment 51, wherein the formulation has subcutaneous (SQ)-like absorption.

[0160] Embodiment 54. The SC pharmacokinetic profile has a C of at least 100 pg / mL. max and 150h * AUC in pg / mL 0-240min The nasal spray formulation of any one of embodiments 1 to 51,

[0161] Embodiment 55. The nasal spray formulation of any one of embodiments 44 to 54, wherein the formulation contains from about 5 mg / mL to about 40 mg / mL of epinephrine or a salt thereof.

[0162] Embodiment 56. A nasal spray formulation described in any one of embodiments 44 to 55, wherein the formulation contains from about 0.9 mg to about 2.4 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0163] Embodiment 57. A nasal spray formulation described in any one of embodiments 44 to 55, wherein the formulation contains from about 0.5 mg to about 2.0 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0164] Embodiment 58. A nasal spray formulation described in any one of embodiments 44 to 55, wherein the formulation contains from about 0.75 mg to about 1.5 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0165] Embodiment 59. A nasal spray formulation described in any one of embodiments 44 to 55, wherein the formulation comprises from about 0.9 mg to about 1.15 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0166] Embodiment 60. A nasal spray formulation according to any one of embodiments 44 to 55, wherein the formulation comprises about 1.0 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0167] Embodiment 61. A nasal spray formulation described in any one of embodiments 44 to 55, wherein the formulation contains from about 0.45 mg to about 1.15 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0168] Embodiment 62. A nasal spray formulation described in any one of embodiments 44 to 55, wherein the formulation contains from about 0.5 mg to about 2.0 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0169] Embodiment 63. A nasal spray formulation according to any one of embodiments 44 to 55, wherein the formulation comprises about 0.5 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0170] Embodiment 64. A nasal spray formulation according to any one of embodiments 44 to 55, wherein the formulation comprises about 0.75 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0171] Embodiment 65. A nasal spray formulation according to any one of embodiments 44 to 55, wherein the formulation comprises about 1.0 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0172] Embodiment 66. A nasal spray formulation according to any one of embodiments 44 to 55, wherein the formulation comprises about 1.5 mg of epinephrine or a salt thereof per dose dispensed from the device.

[0173] Embodiment 67. The nasal spray formulation of any one of embodiments 44 to 66, wherein the formulation contains less than 1 molar equivalent of acid for each mole of epinephrine.

[0174] Embodiment 68. The method of any one of embodiments 44 to 46, wherein the formulation comprises about 0.5 to about 1.1 molar equivalents of acid for each mole of epinephrine.

[0175] Embodiment 69 The nasal spray formulation of any one of embodiments 66 to 67, wherein the acid is a strong acid. Strong acids include hydrochloric acid, phosphoric acid, and sulfuric acid.

[0176] Embodiment 70. The nasal spray formulation of embodiment 69, wherein the acid is hydrochloric acid.

[0177] Embodiment 71. A nasal spray formulation according to any one of embodiments 44 to 70, wherein no base is added to the formulation during preparation.

[0178] Embodiment 72. The nasal spray formulation of any one of embodiments 44 to 71, wherein the formulation has a pH of about 3.0 to about 6.0. Alternative Embodiment 72. The nasal spray formulation of any one of embodiments 44 to 71, wherein the formulation has a pH of about 2.0 to about 6.0.

[0179] Embodiment 73. The nasal spray formulation of embodiment 72, wherein the formulation has a pH of about 3.5 to about 5.0.

[0180] Embodiment 74. The nasal spray formulation of embodiment 72, wherein the formulation has a pH of about 4.0 to about 4.5.

[0181] Embodiment 75. The nasal spray formulation of embodiment 72, wherein the formulation has a pH of about 4.5.

[0182] Embodiment 76. The nasal spray formulation of embodiment 72, wherein the formulation has a pH of about 4.0.

[0183] Embodiment 77. The nasal spray formulation of any one of embodiments 44 to 76, wherein the formulation further comprises a stabilizer.

[0184] Embodiment 78. The nasal spray formulation of embodiment 77, wherein the stabilizer is ethylenediaminetetraacetic acid (EDTA) or a salt thereof.

[0185] Embodiment 79. A nasal spray formulation according to embodiment 78, wherein the EDTA is disodium EDTA.

[0186] Embodiment 80. The nasal spray formulation of embodiment 78, wherein EDTA is present in an amount that is 5% to 15% of the amount of epinephrine, both measured in mmol. Alternative Embodiment 80. The nasal spray formulation of embodiment 78, wherein EDTA is present in an amount that is about 0.001% (w / v) to about 1% (w / v).

[0187] Embodiment 81. A nasal spray formulation according to embodiment 79, wherein the mmol of EDTA is about 10% of the mmol of epinephrine.

[0188] Embodiment 82. The nasal spray formulation of any one of embodiments 44 to 81, wherein the formulation further comprises a preservative.

[0189] Embodiment 83. The nasal spray formulation of embodiment 82, wherein the preservative is benzalkonium chloride.

[0190] Embodiment 84. The nasal spray formulation of any one of embodiments 44 to 83, wherein the formulation further comprises an absorption enhancer. Alternative Embodiment 84. The nasal spray formulation of any one of embodiments 44 to 83, wherein the formulation further comprises one or more absorption enhancers.

[0191] Embodiment 85. The nasal spray formulation of embodiment 84, wherein the absorption enhancer is an alkyl saccharide. Alternative Embodiment 85. The nasal spray formulation of embodiment 84, wherein the absorption enhancer is an alkyl saccharide and / or benzalkonium chloride.

[0192] Embodiment 86. The nasal spray formulation of embodiment 85, wherein the absorption enhancer is dodecyl maltoside. Alternative Embodiment 86. The nasal spray formulation of embodiment 85, wherein the absorption enhancer is dodecyl maltoside, benzalkonium chloride, or a combination of dodecyl maltoside and benzalkonium chloride.

[0193] Embodiment 87. The nasal spray formulation of embodiment 86, wherein the formulation comprises about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside.

[0194] Embodiment 88. The nasal spray formulation of embodiment 87, wherein the formulation comprises about 0.1% (w / v) to about 0.5% (w / v) dodecyl maltoside.

[0195] Embodiment 89. The nasal spray formulation of embodiment 88, wherein the formulation comprises about 0.25% (w / v) dodecyl maltoside. Also provided is embodiment 90, a method for treating an adrenergic receptor mediated disease, comprising intranasal administration of a formulation as detailed in any one of embodiments 1 to 89 above.

[0196] Embodiment 91. The method of embodiment 90, wherein the disease is selected from type 1 hypersensitivity reactions (systemic allergic reactions), acute asthma attacks, cardiac arrest, and Stokes-Adams syndrome.

[0197] Embodiment 92. The method of embodiment 91, wherein the disease is a type 1 hypersensitivity reaction (a systemic allergic reaction).

[0198] Embodiment 93. The method of embodiment 92, wherein the type 1 hypersensitivity reaction (systemic allergic reaction) is selected from allergic asthma, allergic conjunctivitis, allergic rhinitis, anaphylaxis, angioedema, urticaria, eosinophilia, drug allergy, and food allergy.

[0199] Embodiment 94. The method of embodiment 93, wherein the drug allergy is an antibiotic allergy.

[0200] Embodiment 95. Also provided herein is a method for treating systemic allergic reactions and anaphylaxis comprising intranasal administration of a non-buffered intranasal formulation of epinephrine in an amount of less than about 2.0 mg.

[0201] Also provided are embodiments, where embodiment 95 includes one or more of the limitations set forth above in embodiments 2-22, 25-28, 30-55, 58-61, and 63-89.

[0202] Embodiment 96. A pharmaceutical composition comprising: a) ibrutinib; and b) an alkyl glycoside; wherein the pharmaceutical composition is formulated for administration to the circulatory system of a subject via an administration route such as intranasal, inhalation, or pulmonary. Alternative embodiment 96. A pharmaceutical composition comprising: a) ibrutinib; and b) an alkyl glycoside; wherein the pharmaceutical composition is a liquid formulated for intranasal delivery.

[0203] Embodiment 97. The pharmaceutical composition of embodiment 96, wherein the alkyl glycoside has an alkyl chain having 8 to 20 carbons.

[0204] Embodiment 98. The pharmaceutical composition of embodiment 97, wherein the alkyl glycoside is selected from the group consisting of undecyl maltoside, dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, and sucrose mono-tetradecanoate.

[0205] Embodiment 99. The pharmaceutical composition of embodiment 98, wherein the alkyl glycoside is dodecyl-β-D-maltoside.

[0206] Embodiment 100. The pharmaceutical composition of embodiment 96, wherein the alkyl glycoside concentration is about 0.001% to 10.0% (w / v).

[0207] Embodiment 101. The pharmaceutical composition of embodiment 100, wherein the alkyl glycoside concentration is about 0.05% to 0.5% (w / v).

[0208] Embodiment 102. The pharmaceutical composition of embodiment 96, wherein the composition further comprises a membrane permeation enhancer. The pharmaceutical composition of embodiment 96, wherein the composition further comprises a membrane permeation enhancer, a pH modifier, a buffering agent, an isotonicity agent, an antioxidant, a chelating agent, a preservative, or a combination thereof.

[0209] Embodiment 103. The pharmaceutical composition of embodiment 102, wherein the membrane permeation enhancer is a surfactant, bile salt, phospholipid, alcohol, enamine, medium and / or long chain amphiphilic molecule, hydrophobic small molecule, sodium or derivative of salicylic acid, glycerol ester of acetoacetic acid, cyclodextrin, medium or long chain fatty acid, chelating agent, amino acid or its salt, enzyme, or combination thereof.

[0210] Embodiment 104. The pharmaceutical composition of embodiment 102, wherein the membrane permeation enhancer is selected from the group consisting of citric acid, sodium citrate, propylene glycol, glycerin, ascorbic acid, sodium metabisulfite, disodium ethylenediaminetetraacetic acid (EDTA), benzalkonium chloride, sodium hydroxide, and combinations thereof.

[0211] Embodiment 105. The pharmaceutical composition of embodiment 102, wherein the membrane permeation enhancer is benzalkonium chloride, EDTA, or a combination thereof.

[0212] Embodiment 106. The composition has a C β -glycerol-binding protein (C β -glycerol) of about 2-fold or more relative to administration without the alkyl glycoside. max The pharmaceutical composition of embodiment 96, wherein the pharmaceutical composition is provided to a subject.

[0213] Embodiment 107. The composition has a t-to-epinephrine effect that is about 2-fold or less than that of administration without the alkyl glycoside. max The pharmaceutical composition of embodiment 96, wherein the pharmaceutical composition is provided to a subject.

[0214] Embodiment 108. The composition has a t response to epinephrine of about 0.3 hours or less. max The pharmaceutical composition of embodiment 96, wherein the pharmaceutical composition is provided to a subject.

[0215] Embodiment 109. The pharmaceutical composition of embodiment 96, wherein the composition has a pH of about 2.0 to 5.0.

[0216] Embodiment 110. A method of increasing the bioavailability of epinephrine in a subject, comprising administering to the subject a composition comprising epinephrine and an alkyl glycoside, thereby increasing the bioavailability of epinephrine in the subject, wherein the composition is administered to the subject's circulatory system via an administration route such as intranasally, inhalation, or pulmonary. Alternative embodiment 110. A method of increasing the bioavailability of epinephrine in a subject, comprising administering to the subject a composition comprising epinephrine and an alkyl glycoside, thereby increasing the bioavailability of epinephrine in the subject, wherein the composition is a liquid composition administered intranasally.

[0217] Embodiment 111. The method of embodiment 110, wherein the alkyl glycoside has an alkyl chain having 8 to 20 carbons.

[0218] Embodiment 112. The method of embodiment 111, wherein the alkyl glycoside is selected from the group consisting of undecyl maltoside, dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, and sucrose mono-tetradecanoate.

[0219] Embodiment 113. The method of embodiment 112, wherein the alkyl glycoside is dodecyl-β-D-maltoside.

[0220] Embodiment 114. The method of embodiment 110, wherein the alkyl glycoside concentration is about 0.001% to 10.0% (w / v).

[0221] Embodiment 115. The method of embodiment 114, wherein the alkyl glycoside concentration is about 0.05% to 0.5% (w / v).

[0222] Embodiment 116. The method of embodiment 110, wherein the composition further comprises a membrane permeation enhancer.

[0223] Embodiment 117. The method of embodiment 116, wherein the membrane permeation enhancer is a surfactant, a bile salt, a phospholipid, an alcohol, an enamine, a long-chain amphipathic molecule, a hydrophobic small molecule, a derivative of sodium or salicylic acid, a glycerol ester of acetoacetic acid, a cyclodextrin, a medium-chain fatty acid, a chelating agent, an amino acid or its salt, an enzyme, or a combination thereof.

[0224] Embodiment 118. The method of embodiment 117, wherein the membrane permeation enhancer is selected from the group consisting of citric acid, sodium citrate, propylene glycol, glycerin, ascorbic acid, sodium metabisulfite, disodium ethylenediaminetetraacetic acid (EDTA), benzalkonium chloride, sodium hydroxide, and combinations thereof.

[0225] Embodiment 119. The method of embodiment 116, wherein the membrane permeation enhancer is benzalkonium chloride, EDTA, or a combination thereof.

[0226] Embodiment 120. The composition has a C β -reactive protein (C β -reactive protein) for epinephrine that is about 2-fold or greater compared to administration without the alkyl glycoside. max 111. The method of embodiment 110, wherein the subject is provided with

[0227] Embodiment 121. The composition has a t-to-epinephrine effect that is about 2-fold or less than that of administration without the alkyl glycoside. max 111. The method of embodiment 110, wherein the subject is provided with

[0228] Embodiment 122. The composition has a t response to epinephrine of about 0.3 hours or less. max 111. The method of embodiment 110, wherein the subject is provided with

[0229] Embodiment 123 The method of embodiment 110, wherein the composition has a pH of about 2.0 to 6.0. Alternative Embodiment 123 The method of embodiment 110, wherein the composition has a pH of about 2.0 to 5.0.

[0230] definition As used herein, the following terms have the following meanings:

[0231] When a range of values ​​is disclosed and the notation "from n1 to ... n2" or "between n1 ... and n2" is used, n1 and n2 are numbers and, unless otherwise specified, this notation is intended to include the numbers themselves and the range of numbers therebetween. The range may be integers between and including the end values ​​or may be continuous. As an example, the range "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons since carbons occur in whole number units. As an example, take the range "1 to 3 μM (micromolar)", this is intended to include 1 μM, 3 μM, and all numbers in between to any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0232] The term "about," as used herein, is intended to modify the numerical value that it modifies, and refers to such value as a variable within a margin of error. When no range is listed, such as an error range or standard deviation for an average value provided in a chart or table of data, the term "about" should be understood to mean a range that includes the listed value and the larger of the ranges that are included by rounding up or down the number as well as a range that includes plus or minus 20% of the listed value.

[0233] "Weight per volume" or "w / v" refers to the mass in grams of a solute divided by the volume in milliliters of the total solution. Typically, weight by volume is expressed as a percentage.

[0234] The term "absorption enhancer", as used herein, refers to a functional excipient included in a formulation to improve the absorption of an active agent, such as a pharmacologically active drug. This term generally refers to an agent whose function is to increase absorption by enhancing nasal mucosal penetration rather than increasing solubility. Therefore, such agents are sometimes referred to as penetration enhancers or permeation enhancers. In particular, the absorption enhancers described herein may improve paracellular transport (i.e., passing through intercellular spaces and tight junctions), transcellular transport (i.e., passive diffusion or active transport across cell membranes), or transcytosis (i.e., cellular vesicular uptake). Ozsoy et al., Molecules 14:3754-79, 2009.

[0235] Examples of absorption enhancers include alcohol, aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetylpyridinium chloride, chitosan, cyclodextrin, deoxycholic acid, decanoyl, dimethyl sulfoxide, glyceryl monooleate, glycofurol, glycosylated sphingosine, glycyrrhetinic acid, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroyl carnitine, sodium lauryl sulfate, lysophosphatidylcholine, menthol, poloxamer 407 or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, isopropyl myristate, isopropyl palmitate, lanolin, light mineral oil, and linoleic acid. , menthol, myristic acid, myristic alcohol, oleic acid or its salts, oleyl alcohol, palmitic acid, polysorbate 80, propylene glycol, polyoxyethylene alkyl ethers, polyoxylglycerides, pyrrolidone, quillaja saponin, salicylic acid, sodium salt, β-sitosterol, β-D-glucoside, sucrose cocoate, taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid, thymol, tricaprylin, triolein, and alkyl saccharides, and combinations thereof, including, but not limited to, dodecyl maltoside, dodecyl-β-D-maltoside, tetradecyl maltoside, tetradecyl-β-D-maltoside, and sucrose dodecanoate. Alkyl saccharides (e.g., nonionic alkyl saccharide surfactants such as alkyl glycosides and sucrose esters of fatty acids, which consist of an aliphatic hydrocarbon chain attached to a sugar moiety by a glycosidic or ester bond, respectively), cyclodextrins (cyclic oligosaccharides composed of six or more monosaccharide units with a central cavity, which form inclusion complexes with hydrophobic molecules and are used primarily to increase drug solubility and dissolution and improve absorption of low molecular weight drugs), chitosan (a linear cationic polysaccharide produced from the deacetylation of chitin), and bile salts and their derivatives (such as sodium glycocholate, sodium taurocholate, and sodium taurodihydrofusidate) tend to be among the best tolerated absorption enhancers.See, e.g., Aungst BJ, AAPS Journal 14(1):10-8, 2011; and Maggio, ET, Excipients and Food Chem. 5(2):100-12, 2014. Due to their chemical properties, certain absorption enhancers can function as preservatives and / or cationic surfactants in certain circumstances, depending on their concentration in the formulation and other factors.

[0236] Described herein are compositions comprising at least one absorption enhancer and / or preservative and / or surfactant, wherein the at least one absorption enhancer and / or preservative and / or surfactant comprises at least one alkyl glycoside and / or at least one saccharide alkyl ester.

[0237] As used herein, the term "alkyl saccharide" (also referred to herein as "alkyl glycoside") refers to a type of absorption enhancer. As used herein, alkyl saccharide refers to any sugar linked by a bond to any hydrophobic alkyl, as known in the art. Alkyl saccharides include, but are not limited to: alkyl saccharides, such as octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl-α- or β-D-maltoside, -glucoside, or -sucroside; alkyl thiomaltosides, such as heptyl-, octyl-, dodecyl-, tridecyl-, and tetradecyl-β-D-thiomaltoside; alkyl thioglucosides, such as heptyl-, octyl-, dodecyl-, tridecyl-, and tetradecyl-β-D-thiomaltoside; alkyl thioglucosides, such as heptyl-, octyl-, dodecyl-, tridecyl-, and tetradecyl-β-D-thiomaltoside; Such as butyl- or octyl 1-thio α- or β-D-glucopyranosides; alkylthiosucrose; alkylmaltotriosides; long chain aliphatic carbonate amides of sucrose β-amino-alkyl ethers; derivatives of palatinose and isomaltamine attached by an amide bond to the alkyl chain; derivatives of isomaltamine attached by a urea to the alkyl chain; long chain aliphatic ureido carbonates of sucrose β-amino-alkyl ethers; and long chain aliphatic carbonate amides of sucrose β-amino-alkyl ethers. The hydrophobic alkyls can be selected from any desired size depending on the desired hydrophobicity and hydrophilicity of the saccharide moiety. For example, one preferred range for the alkyl chain is from about 9 to about 24 carbon atoms. A more preferred range is from about 9 to about 16 or about 14 carbon atoms. Similarly, some preferred saccharides include maltose, sucrose, and glucose attached by a glycosidic bond to an alkyl chain of 9, 10, 12, 13, 14, 16, 18, 20, 22, or 24 carbon atoms, such as nonyl-, decyl-, dodecyl-, and tetradecyl sucrosides, glucosides, and maltosides. The alkyl chain of the alkyl saccharide is often attached to the saccharide via a glycosidic bond, and thus alkyl saccharides are often referred to interchangeably as alkyl glycosides.

[0238] Any "suitable" alkyl glycoside is meant to meet the characteristics considered herein, i.e., an alkyl glycoside that is non-toxic and non-ionic, and that increases the absorption of a compound when administered together with a compound (e.g., epinephrine) via the nasal spray route.

[0239] As used herein, "saccharide" includes monosaccharides, oligosaccharides, or polysaccharides, or combinations thereof, in linear or cyclic form to form a saccharide chain. An oligosaccharide is a saccharide having two or more monosaccharide residues. Saccharides can be selected, for example, from any currently commercially available saccharide species, or can be synthesized. Some examples of the many possible saccharides for use include glucose, maltose, maltotriose, maltotetraose, sucrose, and trehalose. Preferred saccharides include maltose, sucrose, and glucose.

[0240] In some embodiments, described herein are compositions comprising at least one alkyl glycoside and / or saccharide alkyl ester and epinephrine, methods of administering and using the compounds via an intranasal delivery route, and methods of ameliorating a disease condition in a subject by administering the compositions.

[0241] In some embodiments, described herein are methods of administering a composition containing at least one alkyl glycoside and / or saccharide alkyl ester that is mixed, admixed, or fused with epinephrine and administered or delivered to a subject, where the alkyl has about 10-24, 10-20, 10-16, or 10-14 carbon atoms, and the at least one alkyl glycoside and / or saccharide alkyl ester increases the stability and bioavailability of the therapeutic agent.

[0242] In some embodiments, contemplated alkyl saccharides contain a hydrophobic alkyl group attached to a hydrophilic saccharide. The linkage between the hydrophobic alkyl group and the hydrophilic saccharide may involve, among other possibilities, a glycosidic, thioglycosidic (Horton), amide (Carbohydrates as Organic Raw Materials, FW Lichtenthaler ed., VCH Publishers, New York, 1991), VCH Publishers, New York, 1991), ureido (see Australian Patent No. 386,414 (1988); Chem. Abstr. 110:137536p (1989); Gruber, H. and Greber, G., "Reactive Sucrose Derivatives" in Carbohydrates as Organic Raw Materials, pp. 95-116) or ester bond (Sugar Esters: Preparation and Application, JC Colbert ed., (Noyes Data Corp., New Jersey), (1974)). Further preferred glycosides may include maltose, sucrose, and glucose linked by glycosidic bonds to alkyl chains of about 9-16 carbon atoms, such as nonyl-, decyl-, dodecyl-, and tetradecyl sucrosides, glucosides, and maltosides. These compositions are amphiphilic and non-toxic because they break down into alcohols and oligosaccharides.

[0243] The above examples are illustrative of the types of glycosides contemplated, but the list is not exhaustive. Derivatives of the above compounds that meet the criteria described herein are also contemplated when selecting an alkyl saccharide.

[0244] In some embodiments, it is contemplated that the membrane permeation enhancer functions as an antibacterial agent. An agent is an "antibacterial" agent or substance if the agent or its equivalent destroys bacteria or inhibits bacterial growth or reproduction.

[0245] The term "active ingredient" or "pharmaceutical active compound" is defined in terms of a "formulation" and is intended to mean the component of a pharmaceutical formulation that provides the primary pharmacological effect, in contrast to "inactive ingredients," which are generally recognized as not providing medicinal benefit.

[0246] The term "operation", as used herein, refers to the manipulation of the device such that the pharmaceutical formulation is delivered.

[0247] The term "antimicrobial preservative" as used herein refers to a pharma- ceutically acceptable excipient with antimicrobial properties that is added to a pharmaceutical formulation to maintain microbiological stability. Antimicrobial preservatives include, but are not limited to, antibacterial agents, antifungal agents, antioxidants, and preservatives.

[0248] The term "AUC" as used herein refers to the area under the drug plasma concentration time curve. 0-t " as used herein refers to the area under the drug plasma concentration time curve from t=0 to the last measured or measurable concentration. 0-∞ ", or equivalently "AUC 0-inf " as used herein refers to the area under the drug plasma concentration time curve extrapolated to infinity (∞).

[0249] As used herein, the term “benzalkonium chloride” (“BZK”) refers to a member of a class of quaternary ammonium compounds having the following structure:

[0250] [ka] where n is an integer. Benzalkonium chloride is a mixture of alkylbenzyldimethylammonium chlorides, where a mixture of n greater than 1 is used. In certain embodiments, n is 8, 10, 12, 14, 16, or 18. In other embodiments, n is 10, 12, or 14. In some embodiments, the mixture of n is predominantly 10, 12, and / or 14. In some embodiments, the mixture of n is predominantly 10, 12, 14, and / or 16. In some embodiments, benzalkonium chloride functions as a preservative (even in low amounts), a preservative, a disinfectant, a solubilizer and wetting agent, and / or a cationic surfactant. In some cases, benzalkonium chloride refers to a type of absorption enhancer.

[0251] The term "bioavailability (F)" as used herein refers to the fraction of a dose of a drug that is absorbed from the site of administration and reaches the systemic circulation in an unchanged form. The term "absolute bioavailability" is used when the fraction of a drug absorbed is related to its IV bioavailability. This can be calculated using the following formula:

[0252]

number

[0253] The term “relative bioavailability (F rel ) is used to compare two different extravascular routes of drug administration and can be calculated using the following formula:

[0254]

number

[0255] The term "clearance (CL)" as used herein refers to the rate at which a drug is partitioned and eliminated from its plasma concentration and takes into account the volume of plasma from which the drug is completely removed per unit time. CL is calculated using the volume of distribution (V d ) multiplied by the elimination rate constant (λ), where V d" is the fluid volume required to contain the amount of drug present in the body at the same concentration, such as in plasma. The term "apparent clearance (CL / F)" as used herein refers to the clearance without considering the bioavailability of the drug. It is the ratio of the administered dose to the AUC.

[0256] The term “C max " as used herein refers to the maximum observed plasma concentration.

[0257] The term "coefficient of variation (CV)" as used herein refers to the ratio of the sample standard deviation to the sample mean, which is often expressed as a percentage.

[0258] The term "confidence interval," as used herein, refers to a range of values ​​that includes the true mean value of a parameter for a particular percentage of the time.

[0259] The term "device," as used herein, refers to an apparatus capable of delivering a drug to a patient in need thereof.

[0260] The term "delivery time," as used herein, refers to the amount of time that elapses between the decision made by a medical professional or untrained individual that intranasal delivery of epinephrine is required and the completion of delivery.

[0261] The term "disease", as used herein, is intended to be generally synonymous with, and is used interchangeably with, the terms "disorder", "syndrome", and "disease" (as in medical disorder), all of which refer to an abnormal condition of the human or animal body, or parts thereof, that impairs normal functioning, is typically manifested by discernable signs and symptoms, and causes a shortened or impaired quality of life in a human or animal.

[0262] As used herein, the "dose dispensed from the device" is typically measured in a nasal spray setting by the difference in weight of the device before and after actuation to release a dose of the formulation encompassed herein. The volume of the liquid formulation and the weight in milligrams of the active moiety encompassed herein can be determined by standard calculations.

[0263] The term "elimination rate constant (λ)" as used herein refers to the distribution rate of drug elimination from the body. This rate is constant in first order kinetics and is independent of drug concentration in the body. λ is the slope of the plasma concentration time line (on a logarithmic y-scale). The term "λ" refers to the distribution rate of drug elimination from the body. This rate is constant in first order kinetics and is independent of drug concentration in the body. λ is the slope of the plasma concentration time line (on a logarithmic y-scale). z " as used herein refers to the terminal elimination rate constant, where the "terminal" phase of a drug plasma concentration time curve is a straight line when plotted on a semi-logarithmic graph. The terminal phase is often referred to as the "elimination phase" because the primary mechanism for decreasing drug concentration during the terminal phase is drug elimination from the body. The distinguishing feature of the terminal elimination phase is that the relative proportions of the drug in the plasma and peripheral volumes of distribution remain constant. During this "terminal phase", the drug rapidly and slowly returns to the plasma from the distribution volume and is permanently removed from the plasma by metabolism or renal excretion.

[0264] The term "equivalent," as used herein, means essentially the same mass, amount, value, degree, or size (i.e., minor differences). The term "equivalent" can include "bioequivalent" in certain embodiments, although this term is not within the same scope.

[0265] The term "bioequivalent," as used herein, describes the relationship of a reference to a putative equivalent or substitute drug, and means, in accordance with 21 CFR § 320.1, that there is no significant difference in the rate and extent to which the active ingredient or moiety in a pharmaceutical equivalent or substitute becomes available at the site of drug action when administered at the same molar dose under similar conditions in properly designed studies. The rate and extent of absorption are, respectively, measured by the C maxand AUC. In certain embodiments, the statistical criterion may be used, for example, 80%-125% of the reference value, or a 90% CI.

[0266] The term "molar equivalent," as used herein, refers to an amount of epinephrine that is equimolar to a particular amount of acid.

[0267] The term "excipient," as used herein, refers to a natural or synthetic substance formulated with an active pharmaceutical ingredient. Excipients are included in the formulation for a variety of reasons, including but not limited to, long-term stabilization, bulking the solid formulation, or imparting a therapeutic enhancement to the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or enhancing solubility.

[0268] The term "loaded," as used herein, refers to the association of a pharmaceutical formulation described herein with a device, for example, when a pharmaceutical formulation containing a therapeutically effective amount of epinephrine is present in a reservoir forming part of a device described herein.

[0269] The term "formulation," with or without the modifier "pharmaceutical product," as used herein, refers to a composition containing at least one biologically active ingredient (e.g., a drug); including but not limited to, salts, solvates, and hydrates of epinephrine and related compounds described herein, whereby the formulation is suitable for use for a particular efficacious result in a mammal (e.g., but not limited to, a human).

[0270] The term "pharmaceutical formulation," as used herein, refers to a formulation that is suitable for use, alone or in combination, for the treatment (or in certain embodiments, prevention) of a disease in a subject.

[0271] The term "hydrate," as used herein, refers to epinephrine or a salt thereof as described herein, which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0272] The terms "in need of treatment" and "in need of" are used interchangeably when referring to treatment and refer to a judgment made by a caregiver (e.g., a doctor, nurse, nurse practitioner, or other person that the patient will benefit from the treatment).

[0273] As used herein, an "intramuscular (IM) injection" of epinephrine is typically administered via IM epinephrine delivered by an autoinjection device in the thigh, e.g., the vastus lateralis muscle (referred to herein as the "optimal thigh dosing condition"). Therefore, when comparing the pharmacokinetic parameters produced by IM epinephrine injection to those produced by IN epinephrine administration, the comparison must be assumed as if the IM injection were in the thigh, which is the optimal method of dosing epinephrine. In one embodiment, the IM epinephrine injection is accomplished with an EpiPen® autoinjection device (0.3 mg / 0.3 mL epinephrine injection, USP, prefilled autoinjection device; Mylan Specialty LP).

[0274] As used herein, a "subcutaneous (SQ) injection" of epinephrine is typically administered by injection into the subcutaneous layer of the deltoid muscle in the upper arm. Simons et al. Epinephrine absorption in adults: Intramuscular versus subcutaneous injection. J Allergy. Clin. Immunol. 2001;108:871-3.

[0275] As used herein, two embodiments are "mutually exclusive" when one is defined as being distinct from the other. For example, an embodiment that specifies a concentration of epinephrine of 5 mg / mL is mutually exclusive from an embodiment that specifies an amount of epinephrine of 10 mg / mL. However, an embodiment that specifies an amount of epinephrine of 5 mg / mL is not mutually exclusive from an embodiment in which less than about 10% of the pharmaceutical formulation exits the nasal cavity via the nasopharynx or external drainage.

[0276] The term "pharmaceutically acceptable" as used herein refers to a component of a formulation, which is often referred to as a carrier or excipient, that is compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof.

[0277] The term "pre-primed," as used herein, refers to a device, such as a nasal spray, that can deliver a formulation to a patient in need thereof upon a first actuation of the spray pump, such as by operating the pump one or more times until a spray occurs, i.e., without the need to prime the pump prior to dosing.

[0278] The term "prone position," as used herein, refers to a patient lying face down.

[0279] As used herein, the term "protective packaging" refers to an overwrap.

[0280] The term "solvate" as used herein refers to epinephrine or a salt thereof as described herein, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and / or acceptable for administration to humans in trace amounts.

[0281] The term "storage stable," as used herein, refers to a formulation in which at least about 90%-115% of the active ingredient remains within acceptable regulatory specifications after storage of the formulation at a particular temperature and humidity for a particular period of time, e.g., at least 12 months at 25° C. and 60% relative humidity, and about 6 months at about 40° C. and about 75% relative humidity.

[0282] The term "subject," as used herein, is intended to be synonymous with "patient" and refers to any mammal, preferably a human, suffering from a disease that may benefit from treatment with a therapeutically effective amount of epinephrine, e.g., a subject experiencing a type 1 hypersensitivity reaction (a systemic allergic reaction), such as anaphylaxis.

[0283] The term "supine position," as used herein, refers to a patient lying on his back.

[0284] The term "nostril," as used herein, is synonymous with "naris."

[0285] The term "therapeutically effective amount" or "therapeutically effective dosage," as used herein, refers to an amount or dosage of an active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, or individual that is desired by a researcher, health care provider, or individual. A therapeutically effective amount may, but does not necessarily, eliminate one, more than one, or all symptoms of the disease, disorder, or condition being treated. A therapeutically effective amount may also prevent disease progression or the appearance of further symptoms.

[0286] The term "t" 1 / 2 " or "half-life," as used herein, refers to the amount of time required for half of a drug or other analyte of interest to be eliminated from the body, or the time required for the drug concentration to decrease by half.

[0287] The term "tonicity agent" as used herein refers to a compound that modifies the osmolality of a formulation, for example, to make the formulation isotonic. Tonicity agents include dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine, and the like. In some embodiments, the formulations contemplated herein include one or more tonicity agents selected from dextrose, glycerin, mannitol, potassium chloride, and sodium chloride. In some embodiments, the formulations contemplated herein include sodium chloride as an isotonicity agent.

[0288] The term "tomography," as used herein, refers to the process of imaging in sections. The images can be viewed individually, as a series of two-dimensional slices, or together as a computer-generated three-dimensional representation.

[0289] The term "t" max " as used herein refers to the maximum drug plasma concentration (C) from administration of a drug or other analyte. max ) is reached.

[0290] Epinephrine The term "epinephrine," as used herein, refers to the compound (R)-4-(1-hydroxy-2-(methylamino)ethyl)benzene-1,2-diol, which is also known as adrenaline, and is shown below and has the following structure, elemental structure, molecular weight, and CAS Registry Number:

[0291] [ka] The term includes any metabolites, salts, esters, hydrates, anhydrides, solvates, isomers, isotopes, enantiomers, free acid forms, free base forms, crystalline forms, co-crystalline forms, complexes, amorphous forms, prodrug (including ester prodrug) forms, racemates, polymorphs, chelates, isomers, tautomers, or optically active forms thereof, or mixtures of any two or more of the foregoing.

[0292] Drug products suitable for nasal epinephrine delivery, including formulations and devices, are provided. Epinephrine acts by binding to various adrenergic receptors. Epinephrine is a non-selective agonist of all adrenergic receptors, including the major subtypes α1, α2, β1, β2, and β3. Its action varies depending on the tissue type and tissue expression of the adrenergic receptor. For example, high levels of epinephrine cause smooth muscle relaxation in the airways, but cause contraction of the smooth muscle lining most small arteries.

[0293] Formulations, provided devices suitable for nasal delivery of the formulations to a patient, kits including the devices, and methods of using the devices in treatment are provided, each comprising a therapeutically effective amount of epinephrine.

[0294] Epinephrine may be present in the formulations administered herein at a concentration of from 1 mg / mL to 40 mg / mL, for example, about 5 mg / mL, about 10 mg / mL, or about 20 mg / mL.

[0295] Epinephrine may be present in the formulations administered herein in dosage amounts of 0.1 mg to 0.4 mg, e.g., about 0.5 mg, about 1.0 mg, or about 2.0 mg, which dosage amounts may be scaled based on the molecular weight of the counterion if a salt is used to prepare the formulation.

[0296] Epinephrine may optionally be present as a pharma- ceutically acceptable salt, including pharma- ceutically acceptable acid addition salts prepared from pharma- ceutically acceptable non-toxic acids, including inorganic and organic acids. Representative acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethenesulfonic acid, dichloroacetic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, and the pharma- ceutically acceptable salts listed in Berge et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977). Acid addition salts may be obtained as the direct product of compound synthesis. Alternatively, the free base can be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and the solvent. Due to the recognized insolubility of epinephrine base, finished dosage forms (solutions, aerosols, etc.) of epinephrine used in health care are typically salts, such as hydrochloride, bitartrate, borate. In certain embodiments, the formulations contemplated herein include a salt form of epinephrine that is epinephrine acetate, epinephrine hydrochloride, epinephrine tartrate, epinephrine bitartrate, epinephrine hydrogen tartrate, or epinephrine borate.

[0297] Thus, provided herein is a pharmaceutical formulation for intranasal administration comprising epinephrine. In certain embodiments, the formulation is an aqueous solution. In certain embodiments, the formulation comprises about 25-250 μL of aqueous solution per dose. In certain embodiments, the formulation comprises about 50-250 μL of aqueous solution per dose. In certain embodiments, the formulation comprises about 50-200 μL of aqueous solution per dose. In certain embodiments, the formulation comprises about 140 μL or less per dose. In certain embodiments, the formulation comprises about 100 μL or less per dose. In certain embodiments, the formulation comprises about 100 μL per dose. The formulation may comprise about 25 μL, about 50 μL, about 75 μL, about 100 μL, about 125 μL, about 150 μL, about 175 μL, about 200 μL, or about 250 μL of aqueous solution per dose.

[0298] The pharmaceutical formulations for intranasal administration containing epinephrine described herein bypass potential metabolic transformations in the first-pass metabolism of the gastrointestinal tract and liver and reach the systemic circulation in a pharmacologically active form. Epinephrine is extensively metabolized after oral administration by catechol-O-methyltransferase in the gastrointestinal tract and by monoamine oxidase in the gastrointestinal tract and liver. Avoidance of first-pass clearance ensures that more of the administered epinephrine is available for the treatment of anaphylaxis. Avoidance of first-pass hepatic clearance increases the bioavailability of epinephrine.

[0299] <Preparation> Further provided is a pharmaceutical formulation comprising epinephrine.Particular embodiments of the present disclosure include a method for producing the formulation, comprising mixing epinephrine with a pharma- ceutical acceptable carrier.The pharmaceutical formulation is administered directly to the nasal cavity using the device described herein.In the case of spraying, this can be achieved, for example, by a metered dose spray pump, for example, a single dose, double dose, or multiple dose spray device, with or without a propellant.

[0300] Liquid formulations include solutions, suspensions and emulsions, such as water, or water-ethanol, or water-propylene glycol aqueous solutions. Typically, the formulations are aqueous solutions. Additional components in liquid formulations may include preservatives, stabilizers, isotonicity agents, absorption enhancers, pH adjusters, antioxidants, buffers, sweeteners / flavors / taste masking agents, and optionally other components. Components in liquid formulations may also perform different functions. The function of a particular component will depend on a number of factors, including, but not limited to, the presence or absence of other components, concentration, and other factors.

[0301] Preservatives include benzalkonium chloride, methylparaben, sodium benzoate, benzoic acid, phenylethyl alcohol, and the like, and mixtures thereof. Due to their chemical nature, certain preservatives can function as surfactants and / or absorption enhancers in some circumstances, depending on the concentration in the formulation and other factors.

[0302] Other preservatives include: alcohol, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylated hydroxyanisole (BHA), butylene glycol, butylparaben, calcium acetate, calcium chloride, calcium lactate, carbon dioxide, bentonite, cetrimide, cetylpyridium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric acid monohydrate, cresol, dimethyl ether, ethylparaben, glycerin, hexetidine, imidurea, magnesium trisilicate, isopropyl alcohol, lactic acid, methylparaben, monothioglycerol, para Ben (methyl, ethyl, and propyl), pentetic acid, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium sorbate, propionic acid, propyl gallate, propylene glycol, propylparaben, propylparaben sodium, sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodium metabisulfite, sodium propionate, sodium sulfite, sorbic acid, sulfobutyletherb-cyclodextrin, sulfur dioxide, edetic acid, xylitol.

[0303] In some embodiments, preservatives include, but are not limited to, antibacterial agents, antifungal agents, and antioxidants.

[0304] Antimicrobial agents include, but are not limited to, chlorocresol, diazolidinyl urea, dimethyl sulfoxide, glacial acetic acid, imidurea, iodine / edetic acid, phenylmercuric acetate, phenylmercuric borate, phenylmercuric hydroxide, potassium sorbate, sodium hydroxide, sorbic acid, thymol, preservatives, and disinfectants.

[0305] Antifungal agents include, but are not limited to, benzoic acid, butylene glycol, butylparaben, chlorocresol, coconut oil, dimethylsulfoxide, ethylparaben, glacial acetic acid, imidurea, methylparaben, phenylmercuric acetate, phenylmercuric borate, phenylmercuric hydroxide, potassium sorbate, propylparaben, sodium propionate, sodium thiosulfate, thymol, and vanillin.

[0306] Surfactants include, but are not limited to, polysorbate 80 NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 monoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate, and the like, and mixtures thereof. Due to their chemical nature, certain surfactants can function as preservatives and / or absorption enhancers in some circumstances, depending on the concentration in the formulation and other factors.

[0307] Surfactants include, but are not limited to, cationic, anionic, nonionic, and zwitterionic surfactants.

[0308] Surfactants further include: anionic surfactants (e.g., carboxylate sulfonates, petroleum sulfonates, alkylbenzene sulfonates, naphthalene sulfonates, olefin sulfonates, alkyl sulfates, sulfates, sulfated natural oils and fats, sulfated esters, sulphated alkanolamides, alkylphenols, ethoxylated and sulfated), nonionic surfactants (e.g., ethoxylated fatty alcohols, polyoxyethylene surfactants, carboxyl esters, polyethylene glycol esters, anhydrosorbitol esters and their ethoxylated derivatives, glycol esters of fatty acids, carboxylic acid amides, monoalkanolamine condensates polyoxyethylene fatty acid amides), cationic surfactants (e.g., quaternary ammonium salts, amines with amide bonds, polyoxyethylene alkyl and alicyclic amines, 4.n, n, n', n, tetrakis substituted ethylenediamines, 2-alkyl 1-hydroxyethyl 2-imidazoline), amphoteric surfactants (amphoteric surfactants containing both acidic and basic hydrophilic moieties on their surface, e.g., n-coco 3-aminopropionic acid / sodium salt, n-tallow 3-iminodipropionate, disodium salt, n-carboxymethyl n dimethyl n-9 octadecenyl ammonium hydroxide, n-cocoamidoethyl n hydroxyethylglycine, sodium salt, etc.).

[0309] Antioxidants include, but are not limited to, tocopherol, arachidonic acid, ascorbic acid, ascorbyl palmitate, benzethonium chloride, benzethonium bromide, benzalkonium chloride, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), capric acid, caproic acid, carbon dioxide, cetylpyridinium chloride, chelating agents, chitosan derivatives, citric acid monohydrate, dodecyl dimethylaminopropionate, enanthic acid, erythorbic acid, ethyl oleate, fumaric acid, glyceryl oleate, glyceryl monostearate, lauryl oleate ... acid, limonene, linoleic acid, lysine, malic acid, menthol, methionine, monothioglycerol, myristic acid, oleic acid or its salts, palmitic acid, pelargonic acid, peppermint oil, phosphoric acid, polysorbate, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium sulfite, sodium caprate, sodium desoxycholate, sodium deoxyglycolate, sodium formaldehyde sulfoxylate, sodium glycocholate, sodium hydroxybenzoyal amino caprylate, sodium lauryl sulfate, sodium metabisulfite, sodium sulfite, sodium taurocholate, sodium thiosulfate, stearic acid, sulfur dioxide, and combinations thereof.

[0310] Buffers include, but are not limited to, phosphate buffers, acetate buffer, and citrate buffer.

[0311] In some embodiments, the nasal spray formulation comprises a buffering agent, including but not limited to adipic acid, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, tribasic citric acid monohydrate, sodium hydrogen phosphate, diethanolamine, glycine, maleic acid, malic acid, methionine, monobasic sodium phosphate, monoethanolamine, sodium glutamate, phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate dihydrate, sodium hydroxide, sodium lactate, and triethanolamine.

[0312] Isotonicity agents include sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, dextrose, lactose, mannitol, trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycerin, glycine, and the like, and mixtures thereof. In certain embodiments, the isotonicity agent is selected from dextrose, glycerin, mannitol, potassium chloride, and sodium chloride. In certain embodiments, the isotonicity agent is sodium chloride. In certain embodiments, the formulations disclosed herein contain a sufficient amount of sodium chloride such that the final composition has a nasally acceptable osmolality, preferably 240-350 mOsm / kg. In certain embodiments, the formulations contain 0.3-1.9% sodium chloride.

[0313] Sweeteners / flavoring / taste masking agents include, but are not limited to, refined white sugar, dextrose, lactose, sucralose, acesulfame-K, aspartame, saccharin, sodium saccharin, citric acid, aspartic acid, eucalyptol, mannitol, glycerin, xylitol, menthol, glycyrrhizic acid, citrus oils such as cinnamon oil, oil of wintergreen, peppermint oil, clover oil, bay oil, anise oil, eucalyptus oil, vanilla oil, lemon oil, orange oil, grape oil, and grapefruit oil, fruit extracts including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, apricot, and the like, and combinations thereof. In some embodiments, the formulations contain from about 0.0001 percent to about 1 percent sweetener / flavoring / taste-masking agent, which may be present in lesser or greater amounts depending on one or more of the potency of the effect on flavor, the solubility of the flavoring material, the effect of the flavoring material on solubility, or other physicochemical or pharmacokinetic properties of other formulation ingredients, or other factors.

[0314] In certain embodiments, the pharmaceutical formulation further comprises an isotonicity agent. The intranasal formulation comprises between about 0.2% (w / v) and about 0.2% (w / v), e.g., about 1.2% (w / v), about 0.3% (w / v), about 0.4% (w / v), about 0.5% (w / v), about 0.6% (w / v), about 0.7% (w / v), about 0.8% (w / v), about 0.9% (w / v), about 1.0% (w / v), about 1.1% (w / v), or about 1.2% (w / v). The intranasal formulation may comprise more than about 0.1% (w / v) of the isotonicity agent. The intranasal formulation may comprise less than about 1.2% (w / v) of the isotonicity agent. In other embodiments, the intranasal formulation may comprise between about 0.2% (w / v) and about 0.2% (w / v), e.g., about 1.2% (w / v), about 0.3% (w / v), about 0.4% (w / v), about 0.5% (w / v), about 0.6% (w / v), about 0.7% (w / v), about 0.8% (w / v), about 0.9% (w / v), about 1.0% (w / v), about 1.1% (w / v), or about 1.2% (w / v). The isotonicity agent may comprise between about 1.9% (w / v), for example, about 0.2% (w / v), about 0.3% (w / v), about 0.4% (w / v), about 0.5% (w / v), about 0.6% (w / v), about 0.7% (w / v), about 0.8% (w / v), about 0.9% (w / v), about 1.0% (w / v), about 1.1% (w / v), about 1.2% (w / v), about 1.3% (w / v), about 1.4% (w / v), about 1.5% (w / v), about 1.6% (w / v), about 1.7% (w / v), about 1.8% (w / v), or about 1.9% (w / v). Intranasal formulations may comprise less than about 1.9% (w / v) of the isotonicity agent.

[0315] In certain embodiments, the formulation further comprises an absorption enhancer. In certain embodiments, the pharmaceutical formulation comprises from about 0.005% (w / v) to about 2.5% (w / v) of the absorption enhancer. In certain embodiments, the pharmaceutical formulation comprises from about 0.05% (w / v) to about 2.5% (w / v) of the absorption enhancer. In certain embodiments, the pharmaceutical formulation comprises from about 0.1% (w / v) to about 0.5% (w / v) of the absorption enhancer. In certain embodiments, the pharmaceutical formulation comprises from about 0.25% (w / v) of the absorption enhancer. In certain embodiments, the pharmaceutical formulation comprises from about 0.18% (w / v) of the absorption enhancer.

[0316] In certain embodiments, the absorption enhancer is selected from benzalkonium chloride, cyclodextrin, chitosan, deoxycholic acid, alkylsaccharides (e.g., non-ionic alkylsaccharide surfactants, such as alkylglycosides and sucrose esters of fatty acids, consisting of an aliphatic hydrocarbon chain linked to a sugar moiety by a glycosidic or ester bond), fusidic acid derivatives, glycocholic acid, laureth-9, phosphatidylcholine, taurocholic acid, taurodihydrofusidic acid, microspheres and liposomes, and bile salts. In certain embodiments, the absorption enhancer is benzalkonium chloride. The formulation comprises about 0.01% (w / v) to about 1% (w / v) benzalkonium chloride. In certain embodiments, the pharmaceutical formulation comprises about 0.005% (w / v) to about 0.015% (w / v) benzalkonium chloride. In certain embodiments, the pharmaceutical formulation comprises about 0.01% (w / v), about 0.02% (w / v), about 0.03% (w / v), or about 0.04% (w / v) benzalkonium chloride. In certain embodiments, the pharmaceutical formulation comprises about 0.01% (w / v) benzalkonium chloride. In certain embodiments, the pharmaceutical formulation comprises about 0.02% (w / v) benzalkonium chloride. In certain embodiments, the pharmaceutical formulation comprises about 0.04% benzalkonium chloride.

[0317] In certain embodiments, the pharmaceutical formulation comprises benzalkonium chloride in an amount of about 0.001% (w / v) to about 1% (w / v). In certain other embodiments, the pharmaceutical formulation comprises benzalkonium chloride in an amount of about 0.001% (w / v) to about 0.5% (w / v). In certain other embodiments, the pharmaceutical formulation comprises benzalkonium chloride in an amount of about 0.001% (w / v) to about 0.2% (w / v). In some embodiments, the pharmaceutical formulation comprises 0.001% (w / v), 0.003% (w / v), 0.005% (w / v), 0.007% (w / v), 0.009% (w / v), 0.01% (w / v), 0.02% (w / v), 0.03% (w / v), 0.04% (w / v), 0.05% (w / v), 0.06% (w / v), 0.08% (w / v), 0.09% (w / v), 0.10% (w / v), 0.12% (w / v), 0.16% (w / v), 0.18% (w / v), 0.19% (w / v), 0.20% (w / v), 0.21% (w / v), 0.22% (w / v), 0.23% (w / v), 0.24% (w / v), 0.25% (w / v), 0.26% (w / v), 0.27% (w / v), 0.28% (w / v), 0.29% (w / v), 0.30% (w / v), 0.31% (w / v), 0.32% (w / v), 0.33% (w / v), 0.34% (w / v), 0.35% (w / v), 0.36% (w / v), 0.37% (w / v), 0.38% (w / v), 0.39% (w / v), 0.40 ... .07%(w / v), 0.08%(w / v), 0.09%(w / v), 0.1%(w / v), 0.11%(w / v), 0.12%(w / v), 0.13%(w / v ), 0.14%(w / v), 0.15%(w / v), 0.16%(w / v), 0.17%(w / v), 0.18%(w / v), 0.19%(w / v), 0.2%(w / v), 0.31%(w / v), 0.22%(w / v), 0.23%(w / v), 0.24%(w / v), 0.25%(w / v), 0.26%(w / v), 0.27%(w / v), 0.28%(w / v), 0.29%(w / v), 0.3%(w / v), 0.31%(w / v), 0.32%(w / v), 0.33%(w / v), 0.34%(w / v), 0.35%(w / v), 0.36%(w / v), 0.37%(w / v), 0.38%(w / v), 0.39%(w / v), 0.4%(w / v), 0.41%(w / v), 0.42%(w / v), 0.43%(w / v), 0.44%(w / v), 0.45%(w / v), 0.46%(w / v), 0.47% w / v), 0.48%(w / v), 0.49%(w / v), 0.5%(w / v), 0.51%(w / v), 0.52%(w / v), 0.53%(w / v), 0.54%(w / v), 0.55%(w / v), 0.56%(w / v), 0.57%(w / v), 0.58 %(w / v), 0.59%(w / v), 0.6%(w / v), 0.61%(w / v), 0.62%(w / v), 0.63%(w / v ), 0.64%(w / v), 0.65%(w / v), 0.66%(w / v), 0.67%(w / v), 0.68%(w / v), 0.69%(w / v), 0.7%(w / v), 0.71%(w / v), 0.72%(w / v), 0.73%(w / v), 0.74%(w / v), 0.75%(w / v), 0.76%(w / v), 0.77% (w / v), 0.78%(w / v), 0.79%(w / v), 0.8%(w / v), 0.81%(w / v), 0.82%(w / v), 0.83%(w / v), 0.84%(w / v), 0.85%(w / 0.86% (w / v), 0.87% (w / v), 0.88% (w / v), 0.89% (w / v), 0.9% (w / v), 0.91% (w / v), 0.92% (w / v), 0.93% (w / v), 0.94% (w / v), 0.95% (w / v), 0.96% (w / v), 0.97% (w / v), 0.98% (w / v), 0.99% (w / v), or 1% (w / v) of benzalkonium chloride.

[0318] In some embodiments, the absorption enhancer is an alkyl saccharide, hi some embodiments, the alkyl saccharide is selected from dodecyl maltoside, tetradecyl maltoside (TDM), and sucrose dodecanoate.

[0319] In one embodiment, the alkyl saccharide is dodecyl maltoside (alkyl glycoside 1-On-dodecyl-β-D-maltopyranoside, alternatively lauryl-β-D-maltopyranoside, dodecyl maltopyranoside, and DDM; 24 H 46 Q 11 Alkyl saccharides are also known as sucrose phosphate esters, and are often referred to by the trade name Intravail®. Alkyl saccharides are used in commercial food and personal care products and are designated as generally recognized as safe (GRAS) for food applications. They are non-irritant enhancers of transmucosal absorption that are odorless, tasteless, non-toxic, non-mutagenic, and non-sensitizing in the Draize method at concentrations up to 25%. Alkyl saccharides increase absorption by increasing paracellular permeability, as indicated by a decrease in transepithelial electrical resistance, and may also increase transcytosis. The effect is temporary. Other alkyl saccharides include tetradecyl maltoside (TDM) and sucrose dodecanoate.

[0320] In certain embodiments, the intranasal formulation comprises about 0.05% (w / v) to about 2.5% (w / v) Intravail®. In certain embodiments, the intranasal formulation comprises about 0.1% (w / v) to about 0.5% (w / v) Intravail®. In certain embodiments, the intranasal formulation comprises about 0.15% (w / v) to about 0.35% (w / v) Intravail®. In certain embodiments, the intranasal formulation comprises about 0.15% (w / v) to about 0.2% (w / v) Intravail®. In certain embodiments, the intranasal formulation comprises about 0.18% (w / v) Intravail®. In certain embodiments, the intranasal formulation comprises about 0.2% (w / v) to about 0.3% (w / v) Intravail®. In certain embodiments, the intranasal formulation comprises about 0.25% (w / v) Intravail®.

[0321] In one embodiment, the absorption enhancer is Intravail® (dodecyl maltoside).

[0322] In some embodiments, the absorption enhancer of the intranasal formulation is a combination of dodecylmaltoside and benzalkonium chloride. While the use of dodecylmaltoside or benzalkonium chloride as an absorption enhancer in the intranasal formulations described herein provides intranasal epinephrine bioavailability, the combination of dodecylmaltoside and benzalkonium chloride as an absorption enhancer in the intranasal formulations described herein provides pharmacokinetics that closely match those obtained by intramuscular injection of epinephrine.

[0323] In certain embodiments, each dose dispensed from the device of the pharmaceutical formulation contains from about 0.4 mg to about 2.40 mg of epinephrine or a salt thereof, and from 0.1 to 0.50 mg of Intravail® (dodecyl maltoside) per dose.

[0324] In certain embodiments, each dose dispensed from the device of the formulation contains from about 0.5 mg to about 2.0 mg of epinephrine or a salt thereof, and from about 0.1 to about 0.50 mg of Intravail® (dodecyl maltoside) per dose.

[0325] In certain embodiments, each dose dispensed from the device of the formulation contains from about 0.4 mg to about 2.40 mg of epinephrine or a salt thereof, and from 0.1 to 0.50 mg of Intravail® (dodecyl maltoside) per dose.

[0326] In one embodiment, each dose dispensed from the device of the formulation contains from about 0.9 mg to about 1.15 mg of epinephrine or a salt thereof, and about 0.25 mg of Intravail® (dodecyl maltoside) per dose.

[0327] In certain embodiments, each dose dispensed from the device of the formulation contains about 1.0 mg of epinephrine or a salt thereof and about 0.25 mg of Intravail® (dodecyl maltoside) per dose.

[0328] In certain embodiments, the pharmaceutical formulation further comprises a chelating agent or antioxidant (stabilizing agent) to improve stability. In certain embodiments, the chelating agent / stabilizing agent is EDTA.

[0329] Examples of additional stabilizers include: carboxymethylcellulose acacia, agar, albumin, alginic acid, aluminum stearate, ammonium alginate, ascorbic acid, ascorbyl palmitate, bentonite, butylated hydroxytoluene (BHT), calcium alginate, calcium stearate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carrageenan, cellulose, microcrystalline, sodium carboxymethylcellulose, ceratonia, colloidal silicon dioxide, cyclodextrin, diethanolamine, edetate, ethylcellulose, ethylene glycol palmitostearate, glyceryl monostearate, guar gum, hectorite, hydroxypropyl betadex, methylcellulose, ethyl ... betadex), hydroxypropyl cellulose, hypromellose, inulin, invert sugar, lauric acid, lecithin, magnesium aluminum silicate, mineral oil and lanolin alcohol, monoethanolamine, pectin, pentetic acid, phospholipids, polacrilin potassium, poloxamer, polyvinyl alcohol, potassium alginate, potassium chloride, povidone, propyl gallate, propylene glycol, propylene glycol alginate, raffinose, sodium acetate, sodium alginate, sodium borate, sodium stearyl fumarate, sorbitol, stearyl alcohol, sulfobutyl ether b-cyclodextrin, tagatose, trehalose, triethanolamine, white wax, xanthan gum, xylitol, yellow wax, and zinc acetate.

[0330] Examples of additional chelating agents include: citric acid monohydrate, edetate disodium, edetate calcium disodium, edetate, fumaric acid, malic acid, maltol, pentetic acid, edetate sodium, and edetate trisodium.

[0331] In certain embodiments, the pharmaceutical formulation comprises benzalkonium chloride. In certain embodiments, the pharmaceutical formulation comprises about 0.005% (w / v) to about 1% (w / v) benzalkonium chloride.

[0332] In its capacity as a surfactant, benzalkonium chloride can affect the surface tension of droplets from the delivered nasal spray plume, as well as the viscosity of the liquid formulation, producing spherical, or substantially spherical particles with a narrow droplet size distribution (DSD).

[0333] In some embodiments, the absorption enhancer is an alkyl saccharide, e.g., a non-ionic alkyl saccharide surfactant, such as an alkyl glycoside of a fatty acid and a sucrose ester, each consisting of an aliphatic hydrocarbon chain linked to a sugar moiety by a glycosidic or ester bond. In some embodiments, the absorption enhancer is an alkyl maltoside, e.g., tetradecyl maltoside (TDM), dodecyl maltoside (DDM), etc. In some embodiments, the absorption enhancer is sucrose dodecanoate. Alkyl saccharides are used in commercial food and personal care products and are generally recognized as safe (GRAS) for food use. They are non-irritating enhancers of transmucosal absorption that are odorless, tasteless, non-toxic, non-mutagenic, and non-sensitizing in the Draize method at concentrations up to 25%. Without being bound by any theory, alkyl saccharides are believed to increase absorption by increasing paracellular permeability, as indicated by a decrease in transepithelial electrical resistance; they may also increase transcytosis. The effect may be temporary. In their performance as absorption enhancers, alkyl maltosides (e.g., tetradecyl maltoside (TDM), dodecyl maltoside (DDM), etc.) may affect the surface tension of droplets from the delivered nasal spray plume, as well as the viscosity of the liquid formulation, producing spherical or substantially spherical particles with a narrow droplet size distribution (DSD).

[0334] In one embodiment, the absorption enhancer is the alkyl saccharide 1-On-dodecyl-β-D-maltopyranoside (alternatively, lauryl-β-D-maltopyranoside, dodecylmaltopyranoside, dodecylmaltoside, and DDM; 24 H 46 Q11 ; and is often referred to by the trade name Intravail®). In certain embodiments, the intranasal formulation comprises about 0.01% (w / v) to about 2.5% (w / v) DDM. In certain embodiments, the intranasal formulation comprises about 0.1% (w / v) to about 0.5% (w / v) DDM. In certain embodiments, the intranasal formulation comprises about 0.15% (w / v) to about 0.35% (w / v) DDM. In certain embodiments, the intranasal formulation comprises about 0.15% (w / v) to about 0.2% (w / v) DDM. In certain embodiments, the intranasal formulation comprises about 0.18% (w / v) DDM. In certain embodiments, the intranasal formulation comprises about 0.2% (w / v) to about 0.3% (w / v) DDM. In certain embodiments, the intranasal formulation comprises about 0.25% (w / v) DDM.

[0335] In sugar chemistry, an anomer is either a pair of cyclic stereoisomers (designated α or β) of a sugar or glycoside, also called the anomeric or reduced carbon, that differ only in the configuration of the hemiacetal (or hemiketal) carbon. If the structure resembles that of glucose with a hydroxyl group on the anomeric carbon at the axial position, the sugar is an α anomer. However, if the hydroxyl is equatorial, the sugar is a β anomer. For example, α-D-glucopyranose, β-D-glucopyranose, the two cyclic forms of glucose, are anomers. Similarly, alkyl glycosides occur as anomers. For example, dodecyl β-D-maltoside and dodecyl α-D-maltoside are two cyclic forms of dodecyl maltoside. The two different anomers are two separate chemical structures and therefore have different physical and chemical properties. In one aspect of the invention, the alkyl glycosides of the invention are β anomers. In an exemplary embodiment, the alkyl glycoside is the β anomer of an alkyl maltoside, such as tetradecyl-β-D-maltoside (TDM).

[0336] In some embodiments, the alkyl glycoside used is a substantially pure alkyl glycoside. As used herein, a "substantially pure" alkyl glycoside refers to one anomeric form of an alkyl glycoside (either the α or β anomeric form) having less than about 2% of the other anomeric form, preferably less than about 1.5% of the other anomeric form, more preferably less than about 1% of the other anomeric form. In one aspect, a substantially pure alkyl glycoside contains 98% or more of either the α or β anomer. In another aspect, a substantially pure alkyl glycoside contains 99% or more of either the α or β anomer. In another aspect, a substantially pure alkyl glycoside contains 99.5% or more of either the α or β anomer. In another aspect, a substantially pure alkyl glycoside contains 99.9% or more of either the α or β anomer.

[0337] In certain embodiments, described herein are aqueous formulations suitable for intranasal administration, the aqueous formulations comprising: epinephrine; water; and one or more ingredients selected from absorption enhancers, chelating agents, antioxidants, stabilizers, surfactants, isotonicity agents, and pH adjusters.

[0338] In certain embodiments, described herein are aqueous formulations suitable for intranasal administration, the aqueous formulations comprising: epinephrine; water; and one or more ingredients selected from alkyl glycosides, chitosan, alkyl cyclodextrins, benzalkonium chloride, sodium chloride, and EDTA.

[0339] In certain embodiments, an aqueous formulation suitable for intranasal administration is described herein, the aqueous formulation comprising: epinephrine; water; and one or more ingredients selected from dodecyl maltoside (DDM), tetradecyl maltoside (TDM), benzalkonium chloride, sodium chloride, hydrochloric acid, and EDTA. In certain other embodiments, an aqueous formulation suitable for intranasal administration is described herein, the aqueous formulation comprising: epinephrine; water; and one or more ingredients selected from dodecyl maltoside (DDM), benzalkonium chloride, sodium chloride, and EDTA.

[0340] In certain embodiments, described herein are aqueous formulations suitable for intranasal administration, the aqueous formulations comprising: epinephrine; water; dodecyl maltoside (DDM); and one or more ingredients selected from benzalkonium chloride, sodium chloride, a pH adjuster, and EDTA.

[0341] In certain embodiments, described herein are aqueous formulations suitable for intranasal administration, the aqueous formulations comprising: epinephrine; water; benzalkonium chloride; and one or more ingredients selected from dodecyl maltoside (DDM), sodium chloride, a pH adjuster, and EDTA.

[0342] In certain embodiments, described herein are aqueous formulations suitable for intranasal administration, the aqueous formulations comprising: epinephrine; water; dodecyl maltoside (DDM) or benzalkonium chloride, or a combination of dodecyl maltoside (DDM) and benzalkonium chloride; and one or more additional ingredients selected from sodium chloride, a pH adjuster, and EDTA.

[0343] pH adjusters include acids (e.g., hydrochloric acid, citric acid), buffers (e.g., phosphate, acetate, and citrate buffers), and bases (e.g., sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate) as described herein.

[0344] In certain embodiments, described herein are aqueous formulations suitable for intranasal administration, the aqueous formulations comprising: from about 0.5% (w / v) to about 2.5% (w / v) epinephrine; water; and one or more components selected from the following: from about 0.05% (w / v) to about 2.5% (w / v) dodecyl maltoside (DDM); from about 0.005% (w / v) to about 1% (w / v) benzalkonium chloride; from about 0.2% (w / v) to about 1.2% (w / v) sodium chloride, optionally hydrochloric acid or sodium hydroxide, in an amount sufficient to adjust the pH to a final pH of from about 4.0 to about 5.0; and from about 0.05% (w / v) to about 2.0% (w / v) EDTA.

[0345] In certain embodiments, an aqueous formulation suitable for intranasal administration is described herein, the aqueous formulation comprising: i) about 0.5% (w / v) to about 2.5% (w / v) epinephrine; ii) water; iii) about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside (DDM), or about 0.05% (w / v) to about 1% (w / v) benzalkonium chloride, or about 0.05% (w / v) to about 2.5% (w / v) dodecyl maltoside (DDM). a) about 0.2% (w / v) to about 1.2% (w / v) sodium chloride; b) optional hydrochloric acid or sodium hydroxide in an amount sufficient to adjust the pH to a final pH of about 4.0 to about 5.0; and c) about 0.05% (w / v) to about 2.0% (w / v) EDTA.

[0346] In certain embodiments, an aqueous formulation suitable for intranasal administration is described herein, the aqueous formulation comprising: i) about 0.9% (w / v) to about 2.0% (w / v) epinephrine; ii) water; iii) about 0.05% (w / v) to about 2.5% (w / v) dodecyl maltoside (DDM), or about 0.005% (w / v) to about 1% (w / v) benzalkonium chloride, or about 0.05% (w / v) to about 2.5% (w / v) dodecyl maltoside (DDM). a) about 0.2% (w / v) to about 1.2% (w / v) of sodium chloride; b) optional hydrochloric acid or sodium hydroxide hydrochloride in an amount sufficient to adjust the pH to a final pH of about 4.0 to about 5.0; and c) about 0.05% (w / v) to about 2.0% (w / v) of EDTA.

[0347] In certain embodiments, described herein are aqueous formulations suitable for intranasal administration, the aqueous formulations comprising: about 0.5% (w / v) to about 2.5% (w / v) epinephrine; water; about 0.05% (w / v) to about 2.5% (w / v) dodecyl maltoside (DDM); about 0.005% (w / v) to about 1% (w / v) benzalkonium chloride; about 0.2% (w / v) to about 1.2% (w / v) sodium chloride, optionally hydrochloric acid, in an amount sufficient to adjust the pH to a final pH of about 4.0 to about 5.0; and about 0.05% (w / v) to about 2.0% (w / v) EDTA.

[0348] In certain embodiments, aqueous formulations suitable for intranasal administration are described herein, the formulations comprising: epinephrine; water; one or more absorption enhancers; an isotonicity agent; a stabilizing agent; a preservative; and an optional pH adjuster to adjust the pH to a pH of 3 to 6. In certain embodiments, aqueous formulations suitable for intranasal administration are described herein, the formulations comprising: epinephrine; water; one or more absorption enhancers (e.g., dodecyl maltoside; benzalkonium chloride; or a combination of dodecyl maltoside and benzalkonium chloride); an isotonicity agent (e.g., sodium chloride); a stabilizing agent (e.g., EDTA or disodium EDTA); a preservative (e.g., benzalkonium chloride); and an optional pH adjuster to adjust the pH to a pH of 3 to 6. In certain embodiments, described herein are aqueous formulations suitable for intranasal administration, the aqueous formulations including: epinephrine; water; one or more absorption enhancers (e.g., dodecyl maltoside; benzalkonium chloride; or a combination of dodecyl maltoside and benzalkonium chloride); an isotonicity agent (e.g., sodium chloride); a stabilizer (e.g., EDTA or disodium EDTA); a preservative (e.g., benzalkonium chloride); an antioxidant; a buffering agent; and an optional pH adjusting agent to adjust the pH to between pH 3 and 6.

[0349] In certain embodiments, described herein are aqueous formulations suitable for intranasal administration, the aqueous formulations comprising: epinephrine; water; dodecyl maltoside or benzalkonium chloride, or a combination of dodecyl maltoside and benzalkonium chloride; sodium chloride; EDTA or disodium EDTA; and an optional pH adjuster to adjust the pH to between pH 3 and 6.

[0350] In certain embodiments, an aqueous formulation suitable for intranasal administration is described herein, the aqueous formulation comprising: about 0.5% (w / v) to about 2.5% (w / v) epinephrine; water; about 0.05% (w / v) to about 2.5% (w / v) dodecyl maltoside, about 0.005% (w / v) to about 1% (w / v) benzalkonium chloride, or a combination of about 0.05% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.005% (w / v) to about 1% (w / v) benzalkonium chloride; about 0.2% (w / v) to about 1.2% (w / v) sodium chloride; about 0.05% (w / v) to about 2.0% (w / v) EDTA or disodium EDTA; and an optional pH adjuster to adjust the pH to pH 3 to 6.

[0351] In some embodiments, a 100 μL sample of an aqueous formulation suitable for intranasal administration contains less than about 2.5 mg of epinephrine. In some embodiments, a 100 μL sample of an aqueous formulation suitable for intranasal administration contains about 0.5 mg to about 2.5 mg of epinephrine. In some embodiments, a 100 μL sample of an aqueous formulation suitable for intranasal administration contains about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, or about 2.5 mg of epinephrine.

[0352] <Nasal drug delivery devices and kits> Also provided is a nasal drug delivery device comprising the formulation described herein. In some embodiments, the device is pre-primed. In some embodiments, the device may be primed before use. In some embodiments, the device is operable with one hand.

[0353] Nasal delivery is considered an attractive, safe and easy to administer route for needle-free systemic drug delivery, especially when rapid absorption and efficacy are desired. In addition, nasal delivery addresses issues associated with poor bioavailability, slow absorption, drug degradation and adverse events (AEs) in the gastrointestinal tract and helps avoid first-pass metabolism in the liver.

[0354] Liquid nasal formulations are primarily aqueous solutions, but suspensions, emulsions, liposomes, and microspheres can also be delivered. Other liquid formulations may include liposomes, microspheres, mixed aqueous-organic formulations, non-aqueous formulations, dry powders, and preservatives (gels). In conventional spray pump systems, antimicrobial preservatives are typically required to maintain microbiological stability in liquid formulations. Metered dose spray pumps have dominated the market for nasal drug delivery since their introduction. Such pumps typically deliver 100 μL (25-250 μL) per spray and provide high reproducibility of emitted dose and plume geometry in in vitro studies.

[0355] Examples of standard metered dose spray pumps include the multi-dose "classic technology platform" nasal spray devices offered by Aptar Pharma, Inc., and the Accuspray™ system offered by BD Medical-Pharmaceutical Systems. Such devices include a reservoir that holds multiple doses (e.g., 50, 100, 150, 200, 60, or 120 doses) of a nasal spray formulation, a closure (e.g., screw-on, crimp-on, or snap-on), and an actuator that delivers 45-1000 μL of fluid (e.g., 50, 100, 140, 150, or 200 μL) per actuation that contains a single dose. The actuator may be configured to count doses, deliver gel formulations, deliver in an upside-down configuration, and the like.

[0356] In conventional multi-use spray pump systems, antimicrobial preservatives are typically required to maintain microbiological stability in liquid formulations. However, preservative-free systems are also available, such as the Advanced Preservative Free (APF) system from Aptar, which is vented, has a filter membrane for airflow to prevent contamination, has a metal-free fluid pathway for oxidizing the formulation, and can be used in any orientation. Additional nasal spray devices from Aptar and other devices are optimized with dispenser tips that prevent clogging (useful for high viscosity and volatile formulations), and actuators that do not require repriming if not used for extended periods of time. Additional nasal spray devices are propellant driven. Still additional nasal spray devices include dry powder inhalers.

[0357] The particle size and plume geometry vary within certain limits and depend on the pump characteristics, the formulation, the actuator orifice, and the applied force. The droplet size distribution of the nasal spray is an important parameter because it significantly affects the in vivo deposition of the drug in the nasal cavity. The droplet size is influenced by the device's operating parameters and the formulation. The typical median droplet size should be about 30 to about 100 μm. If the droplets are too large (> about 120 μm), deposition occurs mainly in the anterior part of the nose, and if the droplets are too small (< about 10 μm), they can be inhaled and reach the lungs and oral cavity, which should be avoided for safety reasons. In its performance as a surfactant, benzalkonium chloride (e.g., tetradecyl maltoside (TDM), dodecyl maltoside (DDM), etc.) can affect the surface tension of droplets from the delivered nasal spray plume, as well as the viscosity of the liquid formulation, producing spherical, or substantially spherical particles with a narrow droplet size distribution (DSD).

[0358] The plume geometry, droplet size, and DSD of the plume delivered after spraying can be measured under specific experimental and instrumental conditions by suitable, validated and / or calibrated analytical procedures known in the art. These include photography, laser diffraction, and impaction systems (cascade impaction, NGI). The plume geometry, droplet size, and DSD can be measured by C max , T max These may affect pharmacokinetic outcomes such as dose proportionality and

[0359] The droplet size distribution can be controlled with respect to the range of 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 has a D(v,50) of 30-70 μm and a D(v,90)<100 μm.

[0360] In some embodiments, the percentage of droplets less than 10 μm will be less than 10%. In some embodiments, the percentage of droplets less than 5 μm will be less than 10%. In some embodiments, the percentage of droplets less than 2 μm will be less than 10%. In some embodiments, the percentage of droplets less than 1 μm will be less than 10%.

[0361] In certain embodiments, the formulation, when dispensed from the device, will generate a uniform circular plume with an ellipticity ratio close to 1. The ellipticity ratio is the maximum diameter (D) of the spray pattern taken perpendicular to the direction of spray flow (e.g., from the "top") max ) and minimum diameter (D min ) In some embodiments, the ellipse ratio is less than ±2.0. In some embodiments, the ellipse ratio is less than ±1.5. In some embodiments, the ellipse ratio is less than ±1.3. In some embodiments, the ellipse ratio is less than ±1.2. In some embodiments, the ellipse ratio is less than ±1.1.

[0362] Details of particle generation and mechanical principles for different types of nasal aerosol devices are described. See Vidgren and Kublik, Adv. Drug Deliv. Rev. 29:157-77, 1998. Because conventional spray pumps replace the expelled liquid with air, a preservative is required to prevent contamination. However, prompted by studies suggesting the potential negative effects of preservatives, pump manufacturers have developed different spray systems that avoid the need for preservatives. These systems use collapsible bags, movable pistons, or compressed gas to compensate for the amount of liquid expelled (World Wide Web at aptar.com and World Wide Web at rexam.com). Solutions using collapsible bags and movable pistons to compensate for the amount of liquid expelled have the added advantage that they can be expelled upside down without the risk of air being sucked into the dip tube and damaging the subsequent spray. This can be useful for some products when the patient is bedridden or when head-down application is recommended. Another method used to avoid preservatives is that the air replacing the expelled liquid is filtered through a sterile air filter. In addition, some systems are equipped with a ball valve at the tip to prevent contamination of the liquid inside the applicator tip. Recently, pumps have been designed with side operation. Pumps have been designed with shortened tips to avoid contact with sensitive mucosal surfaces. New designs are available that reduce the need for priming and repriming, and incorporate pressure point features to improve dose reproducibility and dose counters, and lockout mechanisms for enhanced dose control and safety (World Wide Web at rexam.com, and World Wide Web at aptar.com).

[0363] Conventional simple single-dose, double-dose, and multi-dose metered-dose spray pumps require priming and some overfilling to maintain dose consistency for the labeled number of doses. They are well suited for drugs that are administered daily over a long period of time, but the priming procedure and limited dose limits make them unsuitable for drugs with a narrow therapeutic window for use of the device, especially when used infrequently. For expensive drugs or drugs intended for single or sporadic use where strict control of dose and formulation is important, single-dose (UDS) or double-dose spray (BDS) devices are preferred (World Wide Web at aptar.com). A simple variation of the single-dose spray device (MAD™) is offered by LMA (LMA, Salt Lake City, UT, USA; World Wide Web at lmana.com). A nosepiece with a spray tip is fitted to a standard syringe. The liquid to be delivered is first drawn into the syringe, and then the spray tip is fitted to the syringe. This device has been used in academic trials, for example, to deliver topical steroids in patients with chronic sinusitis and in vaccine trials. A prefilled device based on the same principle, in one or two doses (Accuspray™, Becton Dickinson Technologies, Research Triangle Park, NC, USA; World Wide Web at bdpharma.com), is used to deliver the influenza vaccine FluMist™ (World Wide Web at flumist.com) and is approved on the US market for both adults and children. A similar device for two doses was marketed a decade ago by a Swiss company for the delivery of another influenza vaccine.

[0364] Pre-primed one- and two-dose devices are also available and consist of a reservoir, piston, and swirl chamber (see, for example, Aptar, formerly Pfeiffer's UDS UnitDose™ and BDS BiDose™ devices). A spray is formed as the liquid is forced out through the swirl chamber. These devices are held between the second and third fingers with the thumb on the actuator. A pressure point mechanism incorporated in some devices ensures repeatability of actuation force and emitted plume characteristics. Currently, commercially available nasal migraine medications such as Imitrex® (World Wide Web at gsk.com) and Zomig® (World Wide Web at az.com; a single-dose device from Pfeiffer / Aptar), the commercially available influenza vaccine Flu-Mist (World Wide Web at flumist.com; a single-dose aerosol device from Becton Dickinson), and an intranasal formulation of naloxone for opioid overdose reversal, Narcan Nasal® (World Wide Web at narcan.com; Adapt Pharma), are delivered by this type of device.

[0365] In certain embodiments, the 90% confidence interval for the dose delivered per actuation is about ±2%. In certain embodiments, the 95% confidence interval for the dose delivered per actuation is about ±2.5%.

[0366] Historically, intranasal administration of large amounts of drugs, such as from a syringe fitted with a mucosal atomizer device (MAD), has been difficult due to the tendency of some of the formulation to drip out of the nostrils or into the nasopharynx. Thus, in certain embodiments, during nasal delivery of the pharmaceutical formulation to the patient, less than about 20% of the pharmaceutical formulation leaves the nasal cavity and enters or exits the nasopharynx via drainage. In certain embodiments, during nasal delivery of the pharmaceutical formulation to the patient, less than about 10% of the pharmaceutical formulation leaves the nasal cavity and enters or exits the nasopharynx via drainage. In certain embodiments, during nasal delivery of the pharmaceutical formulation to the patient, less than about 5% of the pharmaceutical formulation leaves the nasal cavity and enters or exits the nasopharynx via drainage.

[0367] Current container closure system designs for inhalation aerosol drug products include pre-metered presentations and device metered presentations that use mechanical or power assistance and / or energy from the patient's inhalation for the generation of the aerosol plume. Pre-metered presentations contain a pre-measured dose or dose fraction in some type of unit (e.g., single or multiple blisters or other cavities) that is subsequently inserted into the device during manufacture or by the patient prior to use. A typical device metering unit has a reservoir containing enough formulation for multiple doses that are delivered as a metered aerosol by the device itself upon actuation by the patient.

[0368] Aseptic techniques may not require the use of preservatives in pre-primed devices, but overfilling is required, resulting in waste similar to a metered multiple dose aerosol. A volume of 125 μL is filled into devices used for intranasal migraine medications Imitrex™ (sumatriptan) and Zomig™ (zolmitriptan) (Pfeiffer / Aptar single dose devices) to deliver 100 μL, and approximately half that for two dose designs. Sterile drug products can be produced using aseptic processing or terminal sterilization. Terminal sterilization typically involves filling and sealing product containers under high quality environmental conditions. Filling and sealing the product into this type of environment helps to minimize the microbial and particulate content of the in-process product to ensure the success of subsequent sterilization methods. In most cases, the product, container, and closures are low bioburden but not sterile. The product in the final container is then exposed to a sterilization process such as heat, radiation, or chemical (gas). In aseptic processing, the drug product, containers, and closures are first exposed to sterilization methods individually, if necessary, and then assembled together. Because there is no process to sterilize the product in the final container, it is important that the containers be filled and sealed in an efficient, high-quality environment. Aseptic processing involves more variables than terminal sterilization. Prior to aseptic assembly into the final product, the individual parts of the final product may typically be exposed to various sterilization steps. For example, glass containers are exposed to dry heat; rubber stoppers are exposed to moist heat; and liquid dosage forms are exposed to filtration. Each of these manufacturing steps requires validation and control.

[0369] The devices detailed herein may utilize any of the pharmaceutical formulations and are useful in the methods disclosed herein.

[0370] Thus, provided herein is a device adapted for nasal delivery of a pharmaceutical formulation to a patient, the device comprising a reservoir having a therapeutically effective amount of epinephrine.

[0371] In certain embodiments, epinephrine is the only pharma- ceutical active compound in the pharmaceutical formulation.

[0372] In certain embodiments, the volume of the pharmaceutical formulation in the reservoir is about 140 μL or less.

[0373] In certain embodiments, the volume of the pharmaceutical formulation in the reservoir is greater than about 125 μL and less than 140 μL.

[0374] In certain embodiments, about 100 μL of the pharmaceutical formulation in the reservoir is delivered to the patient in one actuation.

[0375] In some embodiments, about 100 μL of the pharmaceutical formulation in the reservoir is delivered to a patient in one actuation and contains less than about 2.5 mg of epinephrine. In some embodiments, about 100 μL of the pharmaceutical formulation in the reservoir is delivered to a patient in one actuation and contains between about 0.5 mg and 2.5 mg of epinephrine. In some embodiments, about 100 μL of the pharmaceutical formulation in the reservoir is delivered to a patient in one actuation and contains about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, or about 2.5 mg of epinephrine.

[0376] In certain embodiments, the pharmaceutical formulation further comprises one or more excipients selected from water, EDTA, and sodium chloride, hi certain embodiments, the pharmaceutical formulation further comprises benzalkonium chloride.

[0377] In some embodiments, about 100 μL of the aqueous pharmaceutical formulation in the reservoir is delivered to the patient in one actuation and contains epinephrine, dodecyl maltoside or benzalkonium chloride, or a combination of dodecyl maltoside and benzalkonium chloride, EDTA, and NaCl.

[0378] In certain embodiments, the pharmaceutical formulation is substantially free of antimicrobial preservatives.

[0379] In certain embodiments, the pharmaceutical formulation further comprises a compound that acts as a preservative, an absorption enhancer, and / or a cationic surfactant; an isotonicity agent; a stabilizer; and an acid or base in an amount sufficient to achieve a pH of about 3.5 to about 6.0. The use of absorption enhancers, such as alkyl saccharides, cyclodextrins, and chitosan, can increase the rate at which epinephrine is absorbed. In general, absorption enhancers reduce the C-reactive protein content compared to both intranasal and intramuscular formulations that do not contain an absorption enhancer. max Increase in t max Without being bound by any theory, such absorption enhancers typically operate by affecting the two major mechanisms for nasal absorption: paracellular transport through openings in tight junctions between cells, and transcellular transport or transcytosis through cells via vesicular carriers.

[0380] Some absorption enhancers can alter paracellular and / or transcellular pathways, others can extend residence time in the nasal cavity or prevent metabolic changes. Without an absorption enhancer, the molecular weight limit for nasal absorption is about 1 kDa, but administration of drugs in conjunction with an absorption enhancer can allow absorption of molecules of 1-30 kDa. However, intranasal administration of most absorption enhancers can cause nasal mucosa damage. Maggio, J. Excipients and Food Chem. 5(2):100-12, 2014. Examples of absorption enhancers include aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetylpyridinium chloride, chitosan, cyclodextrin, deoxycholic acid, decanoyl carnitine, EDTA, glycocholic acid, glycodeoxycholic acid, glycofurol, glycosylated sphingosine, glycyrrhetinic acid, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroyl carnitine, lauryl sulfate, lysophosphatidylcholine, menthol, poloxamer 407 or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, polysorbate 80, propylene glycol, quillaia saponin (quillaia saponin, salicylic acid, β-sitosterol-β-D-glucoside, sucrose coconut fatty acid, taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid, thymol, and alkyl saccharides such as dodecyl maltoside, tetradecyl maltoside, and sucrose dodecanoate.

[0381] Epinephrine may optionally be present as a pharma- ceutically acceptable salt, including pharma-ceutically acceptable acid addition salts prepared from pharma-ceutically acceptable non-toxic acids, including inorganic and organic acids. Representative acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, dichloroacetic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, and the like. Acid addition salts may be obtained as the direct product of compound synthesis. Alternatively, the free base may be dissolved in a suitable solvent with the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt from the solvent. The salts may be solvated with standard low molecular weight solvents using methods known to those skilled in the art.

[0382] In certain embodiments, the device is filled with the pharmaceutical formulation using aseptic filling.

[0383] In one embodiment, the pharmaceutical formulation is chemically storage stable at about 25° C. and about 60% relative humidity for about 12 months, and at about 40° C. and about 75% relative humidity for about 6 months.

[0384] In some embodiments, intranasal epinephrine is delivered as an aqueous solution, aqueous suspension, aqueous emulsion, non-aqueous solution, non-aqueous suspension, non-aqueous emulsion, solution with halogenated hydrocarbon propellants, or as a dry powder. In some embodiments, an aqueous formulation is sprayed into the nares. In some embodiments, an aqueous formulation is aerosolized by a liquid nebulizer that utilizes hydraulic or ultrasonic atomization. Propellant-based systems may use suitable pressurized metered dose inhalers (pMDIs). Dry powders may use dry powder inhaler devices (DPIs) that allow for effective dispersion of the drug substance.

[0385] Propellants typically used include chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, hydrocarbons, and compressed gases.

[0386] In some embodiments, intranasal epinephrine is delivered as a nasal aerosol generated by nasal metered dose inhalers (pMDIs). In some embodiments, the pMDI is a hydrofluoroalkane (HFA)-based pMDI for nasal use. Like aerosol pumps, nasal pMDIs generate localized deposition on the anterior non-ciliated epithelium of the nasal vestibule and in the anterior portion of the narrow nasal valve, but due to the rapid evaporation of the aerosol delivered by a pMDI, noticeable "drip-out" may not be a problem.

[0387] In some embodiments, epinephrine is delivered by a nebulizer, which uses compressed gas (air, oxygen, and nitrogen) or ultrasonic or mechanical forces to break up medical solutions and suspensions into small aerosol droplets that can be inhaled directly into the nose. The smaller particles and slower velocity of the aerosol mist increases penetration to target sites within the middle and upper nasal meatuses and paranasal sinuses.

[0388] In some embodiments, the epinephrine is delivered in a pulsating aerosol generated by a perforated vibrating membrane. In some embodiments, the pulsating membrane nebulizer is VibrENT (PARI Pharma GmbH). In some embodiments, the epinephrine is delivered by a pulsating aerosol in combination with a breath-in technique.

[0389] In some embodiments, epinephrine is delivered with Bi-Directional™ delivery technology (e.g., Bi-Directional™ Exhalation Delivery Systems (EDS); OptiNose).

[0390] In some embodiments, epinephrine is delivered by an atomizer. In some embodiments, the atomizer is a portable, battery-powered atomizer for nasal drug delivery. In some embodiments, the atomizer nebulizes the liquid by creating a vortex flow over the droplets as they exit the device. Such devices include the ViaNase™ atomizer (Kurve Technology Inc., Lynnwood, WA, USA). In some embodiments, the atomizer is a nasal atomizer powered by high pressure nitrogen gas.

[0391] In some embodiments, intranasal epinephrine is delivered with a nasal powder device. In some embodiments, the nasal powder device is a nasal powder inhaler, a nasal powder sprayer, or a nasal powder diffuser. A powder sprayer typically has a compressible compartment to provide pressure, which upon release creates a plume of powder particles that closely resembles a plume of liquid spray. A breath-actuated inhaler requires the user to use their breath to inhale the powder from a blister or capsule into the nostrils. A nasal diffuser device consists of a fluidly connected mouthpiece and nosepiece. Delivery occurs when the subject blows into the mouthpiece to close the velum, and the airflow carries the powder particles through the nosepiece of the device and into the nose.

[0392] In some embodiments, the nasal powder inhaler is a blister-based powder inhaler. Typically, the blister is pierced before use, and the nosepiece of the device is placed into one nostril. The subject closes the other nostril with a finger and inhales the powder into the nose. Exemplary devices include BiDose™ / Prohaler™ and Twin-lizer™.

[0393] Representative nasal powder aerosol devices include, but are not limited to, UnidoseDP™, Fit-lizer™, Monopowder™, and SoluVent™.

[0394] In some embodiments, the nasal powder sprayer is a capsule-based single dose powder device.In one such embodiment, the capsule-based single dose powder device is composed of a chamber that cuts the top and bottom of the capsule when inserted.The plastic chamber is compressed by hand, and compressed air flows through a one-way valve and the capsule during operation, releasing the powder.

[0395] In some embodiments, the nasal powder sprayer consists of an air-filled compartment that is compressed until a pin releases pressure that ruptures a membrane and releases a plume of powder.

[0396] In some embodiments, the nasal powder sprayer consists of a plunger that, when pressed, creates a positive pressure that breaks a membrane to release the powder.

[0397] In some embodiments, the nasal powder applicator requires the subject to blow into one end of a tube, while the other end is inserted into the vestibule of the nostril.

[0398] In some embodiments, intranasal epinephrine is delivered with a breath-powered Bi-Directional™ delivery device. The breath-powered Bi-Directional™ nasal delivery device utilizes exhaled air to deliver medication to the nose. The breath-powered Bi-Directional™ delivery device consists of a mouthpiece with an optimized frustoconical shape and comfortable surface that mechanically expands a first portion of the nasal valve and a sealing nosepiece. The user slides the sealing nosepiece into one nostril until the sealing nosepiece seals against the pliable soft tissue of the nostril opening, at which point it mechanically expands the narrow, slit-shaped portion of the triangular nasal valve. The user then exhales through the attached mouthpiece. Upon exhaling into the mouthpiece against the resistance of the device, the soft palate (or velum) automatically rises due to positive oropharyngeal pressure, isolating the nasal cavity from the rest of the respiratory system. Thanks to the sealing nosepiece, dynamic pressure transferred from the mouth through the device and into the nose expands the slit-like nasal passages. This "breath-powered" mechanism allows for the release of liquid or powder particles into the air stream that enters one nostril, passes completely around the nasal septum, and exits the opposite nostril. Operation of drug release in devices using this approach uses either manual triggering or an automatically flow- and / or pressure-triggered mechanism.

[0399] Single-dose devices In one embodiment, the device is a single dose device, the pharmaceutical formulation is in one reservoir, and a therapeutically effective amount of epinephrine is delivered essentially by a single actuation of the device.

[0400] Further provided herein is a disposable, pre-primed device suitable for intranasal delivery of a pharmaceutical formulation to a patient by a single actuation of the device to one nostril of the patient, the device having a single reservoir containing 100 μL of a pharmaceutical formulation disclosed herein.

[0401] In some embodiments, the device is operable with one hand.

[0402] In some embodiments, the delivery is less than about 30 seconds. In some embodiments, the delivery is less than about 25 seconds. In some embodiments, the delivery is less than about 20 seconds. In some embodiments, the delivery is less than about 15 seconds.

[0403] In certain embodiments, the 90% confidence interval for the dose delivered per actuation is about ±2%. In certain embodiments, the 95% confidence interval for the dose delivered per actuation is about ±2.5%.

[0404] In certain embodiments, upon nasal delivery of the formulation to a patient, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of the formulation leaves the nasal cavity and enters or exits the nasopharynx via drainage, as provided above.

[0405] In one embodiment, the formulation is chemically storage stable for about 12 months at about 25° C. and about 60% relative humidity, and for about 6 months at about 40° C. and about 75% relative humidity.

[0406] Two-dose device In one embodiment, the device is a two-dose device, wherein a first volume of the formulation is in a first reservoir and a second volume of the formulation is in a second reservoir, wherein a therapeutically effective amount is delivered essentially by a first actuation of the device to a first nostril of the patient and by a second actuation of the device to a second nostril of the patient.

[0407] In one embodiment, the first volume and the second volume combined equal about 380 μL or less.

[0408] In an embodiment, the first volume of the formulation of 100 μL is delivered by the first actuation.

[0409] In an embodiment, 100 μL of the second volume of the formulation is delivered by the second actuation.

[0410] In one embodiment, the dual dose device is operable with one hand.

[0411] In some embodiments, the delivery is less than about 30 seconds. In some embodiments, the delivery is less than about 25 seconds. In some embodiments, the delivery is less than about 20 seconds. In some embodiments, the delivery is less than about 15 seconds.

[0412] In certain embodiments, the 90% confidence interval for the dose delivered per actuation is about ±2%. In certain embodiments, the 95% confidence interval for the dose delivered per actuation is about ±2.5%.

[0413] In certain embodiments, upon nasal delivery of the formulation to a patient, less than about 20%, less than about 15%, less than about 10%, or less than about 5% of the formulation leaves the nasal cavity via drainage into or out of the nasopharynx.

[0414] Further embodiments are provided, any of which may be combined with one or more of the above embodiments, provided that the combinations are not mutually exclusive.

[0415] index Also provided herein are formulations and devices for use in treating adrenergic receptor-mediated diseases and / or one or more symptoms thereof, as well as methods of treating the above diseases comprising administering a formulation and using a device disclosed herein.

[0416] In one embodiment, the condition is (1) treatment of acute hypersensitivity, e.g., type 1 hypersensitivity reactions (e.g., anaphylactoid reactions (systemic allergic reactions) to foods, drugs, animal sera, insect bites and stings, and other allergens (see below)); (2) treatment of acute asthma attacks to relieve bronchospasm not controlled by inhaled or subcutaneous administration of other solutions of drugs; (3) treatment and prevention of episodes of transient atrioventricular (AV) block accompanied by cardiac arrest and / or fainting episodes (Stokes-Adams syndrome); (4) increasing mean arterial blood pressure in adult patients with hypotension associated with septic shock; and (5) induction and maintenance of pupil dilation during intraocular surgery.

[0417] In one embodiment, the type 1 hypersensitivity reaction (a generalized allergic reaction) is selected from allergic asthma, allergic conjunctivitis, allergic rhinitis (hay fever), anaphylaxis, angioedema, urticaria (hives), eosinophilia, antibiotic allergies (e.g., to penicillin or cephalosporins), and food allergies (e.g., to peanuts or shellfish).

[0418] In one embodiment, the type 1 hypersensitivity reaction (a systemic allergic reaction) is anaphylaxis.

[0419] Symptoms of anaphylaxis include hives, generalized itching, nasal congestion, wheezing, difficulty breathing, coughing, cyanosis, lightheadedness, dizziness, confusion, slurred speech, rapid pulse, palpitations, nausea and vomiting, abdominal pain or muscle cramps, redness or inflammation of the skin, nasal flaring, and intercostal retractions.

[0420] In one embodiment, symptoms of a type 1 hypersensitivity reaction (a systemic allergic reaction) are selected from generalized urticatria, itching (pruritus), flushing, swelling of affected tissues (angioedema), burning sensation of the skin (common in people with angioedema), swelling of the tongue or throat, respiratory symptoms such as shortness of breath, wheezing, or shortness of breath, coronary artery spasm, myocardial infarction, dysrhythmia or cardiac arrest (people with underlying coronary artery disease are at higher risk of cardiac effects), tachycardia, bradycardia, and the Bezold-Jarisch reflex.

[0421] In one embodiment, type 1 hypersensitivity reactions (systemic allergic reactions) are caused by stinging insects (e.g., Hymenoptera, including bees, hornets, giant carpenter bees, Japanese hornets, and fire ants), biting insects (e.g., assassin bugs and mosquitoes), allergen immunotherapy, foods, drugs, diagnostic test substances (e.g., radiocontrast media), and other allergens, as well as idiopathic or exercise-induced anaphylaxis.

[0422] In certain embodiments, the cardiac arrest is an out-of-hospital cardiac arrest.

[0423] Further embodiments are provided, any of which may be combined with one or more of the above embodiments, provided that the combinations are not mutually exclusive. EXAMPLES

[0424] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0425] Example 1. Epinephrine Formulations for Clinical Use A representative procedure for preparation of formulations for clinical use is described. Formulation excipient solutions (FES) may be made in advance (up to 7 days) and stored at room temperature. Epinephrine stock solution (ESS) must be made fresh within 72 h of administration, protected from light and excessive oxidation, and stored at 2-8 °C until 2 h prior to use. A mixture of equal amounts of sterile filtered FES and ESS results in a solution of epinephrine, dodecyl maltoside (DDM), EDTA, and benzalkonium chloride (BZK) in saline used in the following clinical protocol.

[0426] A 200 mL batch of formulation excipient solution (FES) is prepared by weighing 0.80 g EDTA (0.75-0.85 g) into a 200 mL volumetric flask and dissolving in ~150 mL sterile saline; weighing 1.00 g (0.95-1.05 g) Intravail® DDM and quantitatively transferring to the EDTA solution and mixing until dissolved (solution should be clear and colorless); if necessary, gently heat the excipient solution (40-60°C) and then allow to cool to room temperature once dissolved; add the desired amount of BZK solution (alternatively, add BZK as a solid) and add to the Intravail® / EDTA mixture for mixing; add an appropriate amount of 1 N HCl (e.g., approximately 20 mL) to reach pH 4, dilute to volume (QS) with sterile saline, and stir until mixture is homogenous. The pH of the FES solution may be measured and recorded.

[0427] Epinephrine Stock Solution (ESS) 10 mg / mL should be prepared fresh, protected from light (e.g., with foil, using brown tinted light, etc.), and protected from use within 72 hours of administration. To formulate a 100 mL batch of final 10 mg / mL product: Ensure 100 mL volumetric flask is wrapped in foil prior to addition of FES solution; Add 50 mL of FES solution to each of two foil-wrapped 100 mL flasks (50 mL per flask); Weigh and add 1.0 g (0.95-1.05 g) of epinephrine (E4250 Sigma Aldrich) to each of the two 100 mL flasks; Mix each until uniform; Measure and record the pH of each flask.

[0428] The final dose formulation (FDF) is prepared by filling a suitable nebulizer capable of delivering 100 μL per spray with the appropriate amount of ESS (e.g., approximately 5.0 mL of ESS for Aptar's multi-dose nebulizer devices or approximately 125 μL of ESS for single-dose nebulizer devices).

[0429] Representative epinephrine formulations for clinical use are presented in Tables 2, 3, and 4.

[0430] [Table 2]

[0431] [Table 3]

[0432] [Table 4]

[0433] Example 2: Clinical Protocol To evaluate the safety, optimal dosing, and pharmacokinetics of intranasal epinephrine, the following clinical protocol was or may be performed in healthy human volunteers.

[0434] Example 2A: First clinical study. Objectives: The primary objective of this study was to evaluate the relative bioavailability of epinephrine following intranasal and intramuscular administration when intramuscular epinephrine was delivered by an autoinjector device in healthy volunteers under fasting conditions. A secondary objective was to evaluate the safety and tolerability of intranasal (IN) epinephrine in healthy volunteers.

[0435] Study Design: A Phase 1, open-label, randomized, single-dose, two-treatment crossover study was conducted, consisting of a screening period, a baseline period, and an open-label treatment period. In the screening period, subjects were screened within 21 days prior to entering the open-label treatment phase of the study. In the baseline period, the first assessment was obtained within the 24-hour dosing period; in some cases, the screening and baseline visits may be combined if all assessments were completed within the 24-hour dosing period.

[0436] In the open-label treatment period, 12 eligible subjects were randomized after an overnight fast to receive a single 0.3 mg dose of intranasal epinephrine and intramuscular epinephrine delivered by a self-injection device. Blood samples were collected 360 min after dosing. Treatments were separated by a minimal 24-h washout period. Safety assessments were performed on each study day, and subjects were released after the discharge evaluation on day 1. Subjects were attended for 6 h after administration of the last dose of study medication.

[0437] Plasma samples were analyzed for all subjects who completed the two periods of the study. Blood samples for measurement of plasma concentrations of epinephrine, norepinephrine, and dihydroxyphenylglycol (DHPG) (metabolites) were collected pre-dose (0, pre-dose) and at 2, 4, 6, 8, 10, 12.5, 15, 20, 25, 45, 60, 90, 120, 150, 180, 240, and 360 min post-dose. Actual blood collection times may vary as follows: 1) ±1 min for samples from 2 to 20 min, 2) ±2 min for samples from 25 to 90 min, and 3) ±5 min for samples from 120 to 360 min. Actual sampling times were recorded.

[0438] Test Drugs and Administration. Each 100 μL IN dose of intranasal epinephrine formulation contained 0.3 mg epinephrine plus 0.25% (w / v) dodecylmaltoside (0.25 mg), 0.04% (w / v) benzalkonium chloride (BZK) (0.04 mg), and ethylenediaminetetraacetic acid (EDTA) in a 10 mM acetate buffered solution at pH 4.0. Intramuscular epinephrine delivered by an autoinjector device delivered 0.3 mg epinephrine by intramuscular injection.

[0439] Subjects were fasted prior to administration of either IN or IM epinephrine. Each 100 μL spray was administered to the left nostril via a commercially available multi-dose nasal spray device sold by Aptar Pharma. Priming of the device (5 actuations) was performed in a food or priming box within 30 minutes prior to administration to the subjects.

[0440] Participants. The study included healthy adult male volunteers (maximum 12 people) aged 18-55 years who provided written informed consent. Other inclusion criteria were: body weight greater than 50 kg; height in meters between 18 and 28 kg. 2body mass index (BMI) of 0.05; no history of hypertension or cardiovascular disease; blood pressure and heart rate within normal ranges at screening and baseline; no clinically significant abnormal findings in medical history, physical examination, electrocardiogram (QTcF < 450 milliseconds), or laboratory test results during screening; and a willingness to remain confined to one's home until the end of the study and to comply with all required study procedures.

[0441] Exclusion criteria included: history of clinically significant gastrointestinal, renal, hepatic, neurological, hematological, endocrine, oncological, respiratory, immunological, psychiatric, or circulatory disease; severe seasonal or nonseasonal allergies; absence of nasal polyps, nose piercings, or any nasal passage abnormality that may interfere with nasal spray administration; or any other illness that, in the opinion of the principal investigator, would jeopardize the subject's safety or affect the validity of the study results; smoking within 6 months prior to screening; significant trauma, major surgery, or incisional biopsy within 30 days prior to study screening; history of allergic or adverse reaction to epinephrine or any comparable or similar product; or any abnormality over the 4 weeks prior to the study. diet (such as diets that severely restrict certain staple foods [e.g., ketogenic diet], restrict calories [e.g., fasting], and / or require daily use of dietary supplements to replace foods typically eaten at mealtimes); blood or plasma donation within 30 days of the first dose of study drug; participation in a clinical trial (acceptable non-interventional studies) within 30 days prior to the first dose of study drug; inadequate or difficult venous access that could jeopardize the quality or timing of PK samples; positive blood screen for HIV, Hepatitis B surface antigen (HbSAg), or Hepatitis C, or positive urine screen for alcohol (saliva testing may be used at baseline), drug abuse, or cotinine.

[0442] In addition, during the study, subjects were not allowed to: take over-the-counter products, including vitamins and supplements, for 7 days prior to the study; use any prescription medications within 14 days prior to the first dose of study drug or during the study unless approved by the primary investigator and medical monitor; use oral and / or nasal decongestants within 14 days prior to the first dose of study drug or during the study; smoke or use tobacco products in the 6 months prior to the first dose of study drug or during the study; or engage in strenuous exercise during the study withdrawal.

[0443] Safety. Adverse events were collected and monitored to assess the safety and tolerability of intranasal (IN) epinephrine. Other safety measures included measurements of vital signs. An objective assessment of nasal irritation was assessed after each administration of study drug using a 6-point (0 to 5) score. Scoring was performed by trained observers based on evaluation of the nasal mucosa before administration (baseline), 30 (± 5 min), and 1 (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours after administration. Irritation was assessed by examining the degree of mucositis and bleeding. Subjects were requested to report any incidents of bleeding or inflammation between the actual evaluation time points.

[0444] An unconstrained visual analog scale (VAS) consisting of a 10 cm (100 mm) horizontal line was used to assess acute pain following each administration of intranasal (IN) epinephrine drug product. The ends of the scale were defined as the extremes of pain sensation: 0 = no pain, 10 = severe pain. Subjects were asked to mark the point on the scale that best represented the intensity of pain and discomfort immediately before administration (baseline) and at 15 (± 2 min), 30 (± 5 min), and 1 (± 10 min) hours after administration. The location of the mark at each time point was measured and recorded as the reported score.

[0445] Pharmacokinetic Analysis. Pharmacokinetic parameters of epinephrine, norepinephrine, and DHPG calculated using noncompartmental analysis were calculated: maximum plasma concentration (Cmax ), C max Arrival time (t max ), and the area under the curve up to the final dose at concentrations above the lower limit of quantification [AUC (0-t) ] and the area under the curve at infinity [AUC (inf) ], elimination rate constant (λz) and half-life (t 1 / 2 ), and, for epinephrine only, clearance (CL / F) and volume of distribution (Vz / F) uncorrected for bioavailability (F).

[0446] Non-GCP pharmacokinetic analysis was performed using WinNonlin version 7.0. The lower limit of quantification for the bioanalysis was 20 pg / mL. Plasma concentrations designated as BLQs were given a value of 20 pg / mL. Pharmacokinetic parameters C for epinephrine, norepinephrine, and DHPG were max , AUC (0-t) , and AUC (inf) were compared among treatments using an analysis of variance (ANOVA) model, with treatment, period, sequence, and subjects within sequence as categorical variables using the natural logarithm of the data. max is the uncorrected C max -Baseline-corrected AUC calculated from predose concentrations 0-t is the uncorrected AUC 0-t -PreDose concentration xt last Confidence intervals (90%) were constructed for the geometric mean ratios, i.e., intranasal versus intramuscular epinephrine, of the three parameters using log-transformed data and two one-sided t-test procedures. Estimates and confidence limits were exponentially scaled back to the original scale. Comparisons between intranasal (IN) and intramuscular epinephrine were assessed from the geometric mean ratios and 90% confidence intervals of the three parameters.

[0447] Results. The mean plasma concentrations of epinephrine from IN administration remained significantly below the mean plasma concentrations of epinephrine from intramuscular epinephrine delivered by the autoinjector device throughout the study, as shown in Figure 3. Intranasal administration of epinephrine using the intranasal epinephrine formulations described above resulted in significantly lower exposure (C) of parent compound epinephrine compared to intramuscular epinephrine delivered by the autoinjector device, as shown in Table 5 below. max and AUC 0-t ). No associated adverse events were reported. The pH was between 3 and 4.

[0448] [Table 5]

[0449] Example 2B: Second Clinical Study. Objectives. The primary objectives of this study were to examine the relative bioavailability of epinephrine following intranasal and intramuscular administration by injection (EpiPen®) in healthy volunteers under fasting conditions and to determine the optimal dose of intranasal epinephrine (IN-Epi) formulations used in the study to assess bioavailability. Secondary objectives were to evaluate the safety and tolerability of intranasal epinephrine formulations in healthy volunteers.

[0450] Study Design. A phase 1, dose-escalation, 12-subject, open-label, randomized, single-dose, two-treatment, two-period, crossover study was conducted as follows.

[0451] Dose escalation in three subjects was performed to determine the optimal dose of epinephrine. In the screening period, subjects were screened within 28 days prior to study entry. The three subjects were then enrolled and received IN-Epi doses of 0.5 mg, 1.0 mg, and 2.0 mg epinephrine by IN administration (formulated at pH 5.5-6.0) after an overnight fast. Blood samples were collected 360 minutes after dosing. Treatments were separated by a minimal 24-hour washout period.

[0452] The relative bioavailability of the intranasal formulation versus intramuscular injection was then evaluated in 12 subjects in an open-label, randomized, single-dose, two-treatment, two-period crossover study consisting of a screening period, a baseline period, and an open-label treatment period. In the screening period, subjects were screened within 28 days prior to study entry. During the open-label treatment period, 12 eligible subjects were randomized to receive either a 1.0 mg IN-Epi or a 0.3 mg dose of epinephrine injection administered IM (EpiPen®) after an overnight fast to receive a single dose. Blood samples were collected 360 minutes after dosing. Treatments were separated by a minimum of a 24-hour washout period.

[0453] Safety assessments were performed on each study day and subjects could be released following discharge evaluations. Subjects were attended to for 6 hours after administration of the last dose of study medication.

[0454] The study was conducted in part as disclosed above. For all parts of the study, the following procedures were performed as described below.

[0455] Test Drugs and Administration. Each 100 μL IN dose of epinephrine formulation contained 0.5 mg, 1.0 mg, or 2.0 mg (5 mg / mL, 10 mg / mL, or 20 mg / mL) of IN-Epi plus 0.25% (w / v) dodecylmaltoside (0.25 mg), 0.04% (w / v) benzalkonium chloride (BZK) (0.04 mg), and ethylenediaminetetraacetic acid (EDTA) in an acetate buffer solution at pH 4.5 (3.5-5.0). The commercially available EpiPen® delivers 0.3 mg of epinephrine via intramuscular injection.

[0456] Subjects were fasted prior to administration of either IN or IM epinephrine. Each 100 μL spray was administered to the left nostril via a commercially available multi-dose nasal spray device sold by Aptar Pharma. Priming of the device (5 actuations) was performed in a food or priming box within 30 minutes prior to administration to the subjects.

[0457] Participants. A total of 15 men were enrolled in the study. Plasma samples from all subjects who completed the study were analyzed. Blood samples for measurement of epinephrine plasma concentrations were collected pre-dose (0, pre-dose) and at 2, 4, 6, 8, 10, 12.5, 15, 20, 25, 45, 60, 90, 120, 150, 180, 240, and 360 min post-dose. Actual blood collection times may vary as follows: 1) ±1 min for 2-20 min samples, 2) ±2 min for 25-90 min samples, and 3) ±5 min for 120-360 min samples.

[0458] Inclusion criteria: Participants were males aged 18–30 years; provided written informed consent; weighed more than 50 kg and had a mean body mass of 18–28 kg / m 2have a body mass index between 0.01 and 0.25; have no family / medical history of hypertension or cardiovascular disease within the past 10 years; have blood pressure within the normal range (i.e., <140 / 90 mmHg) at the time of screening; have no clinically significant abnormal findings in the medical history, physical examination, electrocardiogram (QTcF <450 milliseconds), or laboratory test results during screening; and are willing to be confined to their home for the appropriate study period and to comply with all required study procedures.

[0459] Exclusion Criteria: Exclusion criteria were: history of clinically significant gastrointestinal, renal, hepatic, nervous system, hematological, endocrine, oncological, pulmonary, immunological, psychiatric, or circulatory disease; severe seasonal or nonseasonal allergies; nasal polyps or any nasal passage abnormality that may interfere with nasal spray administration; or any other illness that, in the opinion of the primary investigator, would jeopardize the safety of the subject or affect the validity of the study results; smoking within 6 months prior to screening; significant trauma, major surgery, or incisional biopsy within 30 days prior to study screening; history of allergic or adverse reaction to epinephrine or any comparable or similar product; Having followed an abnormal diet for a period of one week (such as a diet that severely restricts certain staple foods [e.g., ketogenic diet], restricts calories [e.g., fasting], and / or requires the daily use of dietary supplements to substitute for foods typically eaten at mealtimes); donating blood or donating plasma within 30 days of the first dose of study drug; participation in a clinical trial within 30 days of the first dose of study drug; inadequate or difficult venous access that could jeopardize the quality or timing of PK samples; positive blood screen for HIV, hepatitis B surface antigen (HbSAg), or hepatitis C, or positive urine screen for alcohol, drug abuse, or cotinine.

[0460] In addition, during the study, subjects were not allowed to: take over-the-counter products, including vitamins and supplements, for 7 days prior to the study; use any prescription medications within 14 days prior to the first dose of study drug or during the study unless approved by the primary investigator and medical monitor; use oral and / or nasal decongestants within 14 days prior to the first dose of study drug or during the study; smoke or use tobacco products in the 6 months prior to the first dose of study drug or during the study; or engage in strenuous exercise during the study withdrawal.

[0461] <Safety> Adverse events have been or will be collected and reviewed to assess the safety and tolerability of IN-Epi. Other safety measures will include vital sign measurements.

[0462] An objective assessment of nasal irritation was assessed after each administration of study drug using a 6-point score (0 to 5). Scoring was performed by medically trained observers based on evaluation of the nasal mucosa before dosing (baseline), and 30 (± 5 min) minutes, and 1 (± 10 min), 2 (± 15 min), 4 (± 30 min), and 6 (± 30 min) hours after dosing. Irritation was assessed by assessment of the degree of mucositis and bleeding. Subjects were also required to report any incidents of bleeding or inflammation during the actual assessment time points.

[0463] An unconstrained visual analog scale (VAS) consisting of a 10 cm (100 mm) horizontal line was used to assess acute pain after each dose of IN-Epi drug product. The ends of the scale were defined as the extremes of pain sensation: 0 = no pain, 10 = severe pain. Subjects were asked to mark the point on the scale that best represented the intensity of pain and discomfort immediately before dosing (baseline), and at 15 (± 2 min) and 30 (± 5 min) minutes, and 1 (± 10 min) hours after dosing. The location of the mark at each time point was measured and recorded as the reported score.

[0464] <Pharmacokinetic analysis> Pharmacokinetic parameters of epinephrine were calculated using noncompartmental analysis: maximum plasma concentration (C max ), C max Arrival time (t max ), and the area under the curve up to the final dose at concentrations above the lower limit of quantification [AUC (0-t) ] and the area under the curve at infinity [AUC (inf) ], elimination rate constant (λz) and half-life (t 1 / 2 ), and, for epinephrine only, clearance (CL / F) and volume of distribution (Vz / F) uncorrected for bioavailability (F).

[0465] Pharmacokinetic parameters of epinephrine, norepinephrine, and DHPG C max , AUC (0-t) , and AUC (inf) were compared among treatments using an analysis of variance (ANOVA) model, with treatment, period, sequence, and subjects within sequence as categorical variables using the natural logarithm of the data. Confidence intervals (90%) were constructed for the geometric mean ratios of the three parameters, IN-Epi-to-EpiPen®, using log-transformed data and two one-sided t-test procedures. Point estimates and confidence limits were exponentiated to return to the original scale. Comparisons between IN and IM epinephrine were assessed from the geometric mean ratios and 90% confidence intervals for the three parameters.

[0466] <Result> Results for the dose escalation portion of the study are provided in Table 6 below, and Figures 4, 5, 6, and 7. Three subjects were administered intranasal formulations of epinephrine, formulated as disclosed above, at doses of 0.5, 1.0, and 2.0 mg in saline at pH 4.0 (3.5-5.0, acceptable). Table 6 below shows the mean pharmacokinetic parameters for the three doses.

[0467] [Table 6]

[0468] In conclusion, all doses of intranasal epinephrine showed better efficacy than the conventional study. max is low, C max The T and AUC were higher. These trends became more pronounced as the dose increased. In particular, the 1.0 and 2.0 mg formulations each had lower T than intramuscular epinephrine delivered by an autoinjector device as used in previous studies. max , and high C max The AUC of all intranasal formulations was greater than the AUC of intramuscular epinephrine delivered by the autoinjector device at all doses.

[0469] Figures 4 and 5 show the mean VS concentration curves for 0.5, 1.0, and 2.0 mg intranasal formulations of epinephrine. Figures 6 and 7 replicate the data of Figures 4 and 5, but overlay it on the epinephrine autoinjector data from Study 2A to illustrate, for example, the pharmacokinetic differences between the 1.0 and 2.0 mg intranasal doses of epinephrine and the intramuscular epinephrine autoinjector. These figures also provide a relevant control for Figure 3, when intranasal epinephrine was formulated in an acetate buffered solution at pH 3-4.

[0470] Results from the dose escalation portion of the study, in contrast to previous studies, show that epinephrine can be formulated to achieve significant bioavailability. At a specific dose, the pharmacokinetics of formulated intranasal epinephrine appear to be superior to intramuscular epinephrine delivered by an autoinjector device, and it achieves a rapid, IM injection-like absorption rate in the first 20 minutes.

[0471] Some results of a study comparing the bioavailability of IN to IM injection are provided below in Tables 7-9c and Figures 8 and 9. Twelve subjects were administered intranasal epinephrine formulated as disclosed above at a dose of 1.0 mgm in saline at approximately pH 4.0; in addition, twelve subjects were administered intramuscular epinephrine (0.3 mg) in the thigh delivered by an autoinjector device. Table 7 below shows the mean PK parameters of IN and IM epinephrine formulated as disclosed above.

[0472] [Table 7]

[0473] 8 and 9 also show that the plasma time vs. concentration curve for 1.0 mg IN epinephrine is very similar to that of 0.3 mg IM epinephrine (EpiPen®) administered into the thigh.

[0474] Table 8 below shows the C pathway compared to the IM and IN pathways. max and partial AUC data are shown. Intranasal rates as a percent of AUC baseline are provided. The data below shows that 1.0 mg intranasal epinephrine can be formulated to closely resemble, or even better than, a 0.3 mg intramuscular injection of epinephrine.

[0475] [Table 8]

[0476] Tables 9a-9c below show the median t max , 9b)t max 9c) the distribution of values ​​that satisfy the specified conditions between intranasal and intramuscular epinephrine max The percentage of subjects with

[0477] [Table 9a]

[0478] [Table 9b]

[0479] [Table 9c]

[0480] IN-Epi appears to be safe and well tolerated, and is comparable to and in some embodiments (e.g., C max ), which showed better PK parameters.

[0481] Additionally, no significant PK differences were observed between 1.0 mg IN epinephrine and 0.3 mg IM epinephrine throughout the study.

[0482] <Other embodiments> Further provided are embodiments in which any of the above embodiments can be combined with any one or more of these embodiments, provided that the combinations are not mutually exclusive.Further provided herein are uses in the treatment of the indications disclosed herein or one or more symptoms thereof, and uses in the manufacture of medicaments for the treatment of the indications disclosed herein or one or more symptoms thereof, which are equivalent in scope to any of the disclosed embodiments, or any combination thereof that is not mutually exclusive.The methods and uses can utilize any of the devices disclosed herein, or any combination thereof that is not mutually exclusive, or any of the pharmaceutical formulations disclosed herein, or any combination thereof that is not mutually exclusive.

[0483] Although the invention has been described in the above examples with reference to specific details of particular embodiments thereof, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention.

Claims

1. A nasal spray pharmaceutical formulation, comprising about 0.40 mg to about 2.4 mg of epinephrine or a salt thereof in a single dose of the nasal spray pharmaceutical formulation.

2. 10. The nasal spray pharmaceutical formulation of claim 1, wherein intranasal administration of a single dose of the nasal spray pharmaceutical formulation to a subject results in a plasma epinephrine concentration effective for treating acute hypersensitivity reactions.

3. The nasal spray pharmaceutical formulation according to claim 1 or 2, wherein the nasal spray pharmaceutical formulation is an aqueous solution, an aqueous suspension, an aqueous emulsion, a non-aqueous solution, a non-aqueous suspension, a non-aqueous emulsion, or a dry powder.

4. The nasal spray pharmaceutical formulation of any one of claims 1 to 3, wherein intranasal administration of a single dose of the nasal spray pharmaceutical formulation to a subject results in pharmacokinetics similar to an intramuscular (IM) injection, or absorption similar to a subcutaneous (SC) injection, or something in between, when the IM injection is administered into the outer thigh.

5. Intranasal administration of a single dose of a nasal spray pharmaceutical formulation to a subject results in subcutaneous (SC)-like absorption, with the SC pharmacokinetic profile having a C of at least 100 pg / mL. ｍａｘ and 150h ＊ AUC in pg / mL ０－２４０ｍｉｎ The pharmaceutical formulation for nasal spray according to any one of claims 1 to 3,

6. The nasal spray pharmaceutical formulation of any one of claims 1 to 3, wherein intranasal administration of a single dose of the nasal spray pharmaceutical formulation to a subject results in absorption similar to that of an intramuscular (IM) injection.

7. Intranasal administration of a single dose of a nasal spray pharmaceutical formulation to a subject demonstrated the following pharmacokinetic characteristics: ・Average AUC ０－２０ｍｉｎ and AUC ０－ｔ Both are the AUCs produced by intramuscular injection of 0.3 mg. ０－２０ｍｉｎ and AUC ０－ｔ is at least 80% of ・C produced by intramuscular injection of 0.3 mg ｍａｘ At least 80% of C ｍａｘ Average C is 150% or less of ｍａｘ ; Average t less than 45 minutes ｍａｘ and IM injection-like absorption under optimal dosing conditions in the thigh A nasal spray pharmaceutical formulation according to any one of claims 1 to 3, which provides one or more of the following:

8. Intranasal administration of a single dose of a nasal spray pharmaceutical formulation to a subject demonstrated the following pharmacokinetic characteristics: ・Average AUC ０－２０ｍｉｎ and AUC ０－ｔ Both are the AUCs produced by intramuscular injection of 0.15 mg. ０－２０ｍｉｎ and AUC ０－ｔ is at least 80% of 0.15 mg intramuscular injection produces C ｍａｘ At least 80% of C ｍａｘ Average C is 150% or less of ｍａｘ ; Average t less than 45 minutes ｍａｘ and IM injection-like absorption under optimal dosing conditions in the thigh A nasal spray pharmaceutical formulation according to any one of claims 1 to 3, which provides one or more of the following:

9. Intranasal administration of a single dose of a nasal spray pharmaceutical formulation to a subject demonstrated the following pharmacokinetic characteristics: ・Average AUC ０－２０ｍｉｎ and AUC ０－ｔ Both are the AUCs produced by intramuscular injection of 0.5 mg. ０－２０ｍｉｎ and AUC ０－ｔ is at least 80% of ・C produced by intramuscular injection of 0.5 mg ｍａｘ At least 80% of C ｍａｘ Average C is 150% or less of ｍａｘ ; Average t less than 45 minutes ｍａｘ and IM injection-like absorption under optimal dosing conditions in the thigh A nasal spray pharmaceutical formulation according to any one of claims 1 to 3, which provides one or more of the following:

10. The pharmaceutical formulation according to any one of claims 1 to 9, wherein a single dose of the pharmaceutical formulation contains from about 0.5 mg to about 2.0 mg of epinephrine or a salt thereof.

11. The pharmaceutical formulation according to any one of claims 1 to 9, wherein a single dose of the pharmaceutical formulation contains from about 0.5 mg to about 1.5 mg of epinephrine or a salt thereof.

12. The pharmaceutical formulation according to any one of claims 1 to 9, wherein a single dose of the pharmaceutical formulation contains from about 0.5 mg to about 0.7 mg of epinephrine or a salt thereof.

13. 10. The nasal spray pharmaceutical formulation of claim 1, wherein a single dose of the nasal spray pharmaceutical formulation contains about 1.0 mg of epinephrine or a salt thereof.

14. The pharmaceutical formulation according to any one of claims 1 to 9, wherein a single dose of the pharmaceutical formulation contains from about 1.3 mg to about 1.5 mg of epinephrine or a salt thereof.

15. The nasal spray pharmaceutical formulation of any one of claims 1 to 14, comprising one or more absorption enhancers; and optionally one or more agents selected from isotonicity agents; stabilizers; preservatives; flavoring agents; viscosity modifiers; antioxidants; buffers and pH adjusters; wherein the pH of the nasal spray pharmaceutical formulation is from about 2.0 to about 6.

0.

16. The pharmaceutical nasal spray formulation of any one of claims 1 to 15, wherein the pharmaceutical nasal spray formulation has a pH of about 3.0 to about 5.

0.

17. 16. The pharmaceutical nasal spray formulation of claim 1, wherein the pharmaceutical nasal spray formulation has a pH of about 4.

0.

18. The nasal spray pharmaceutical formulation according to any one of claims 15 to 17, wherein the nasal spray pharmaceutical formulation comprises a pH adjuster.

19. 20. The nasal spray pharmaceutical formulation of claim 18, wherein the pH adjusting agent comprises an acid, a base, a buffer, or a combination thereof.

20. The acid is adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, or tartaric acid; The bases are sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate; and 20. The pharmaceutical nasal spray formulation of claim 19, wherein the buffer is a phosphate buffer, an acetate buffer, or a citrate buffer.

21. 16. The pharmaceutical nasal spray formulation of claim 15, wherein the pharmaceutical nasal spray formulation comprises about 0.5 to about 1.1 molar equivalents of acid for each mole of epinephrine.

22. 22. The nasal spray pharmaceutical formulation of claim 21, wherein the acid is hydrochloric acid.

23. The formulation may be selected from the group consisting of alcohol, aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetylpyridinium chloride, chitosan, cyclodextrin, deoxycholic acid, decanoyl, dimethylsulfoxide, glyceryl monooleate, glycofurol, glycosylated sphingosine, glycyrrhetinic acid, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroylcarnitine, lysophosphatidylcholine, menthol, poloxamer 407 or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, isopropyl myristate, isopropyl palmitate ... The composition further comprises one or more absorption enhancers selected from isopropyl, lanolin, light mineral oil, linoleic acid, menthol, myristic acid, myristic alcohol, oleic acid or a salt thereof, oleyl alcohol, palmitic acid, polysorbate 20, polysorbate 80, propylene glycol, polyoxyethylene alkyl ethers, polyoxylglycerides, pyrrolidone, quillaja saponin, salicylic acid, sodium salt, β-sitosterol, β-D-glucoside, sodium lauryl sulfate, sucrose cocoate, taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid, thymol, tricaprin, triolein, and alkyl saccharides.

23. A pharmaceutical nasal spray formulation according to any one of claims 15 to 22.

24. 23. The nasal spray pharmaceutical formulation of any one of claims 15 to 22, wherein the formulation comprises one or more absorption enhancers selected from dodecyl maltoside, benzalkonium chloride, oleic acid or its salts, polysorbate 20, polysorbate 80, and sodium lauryl sulfate.

25. The one or more absorption enhancers are From about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside; or about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride; or From about 0.001 (w / v) to about 1% (w / v) of oleic acid or a salt thereof; or A combination of about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001% (w / v) to about 1% (w / v) benzalkonium chloride; or A combination of about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001% (w / v) to about 1% (w / v) oleic acid or a salt thereof; or 23. The nasal spray pharmaceutical formulation of any one of claims 15 to 22, which is a combination of about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof.

26. The one or more absorption enhancers are about 0.005% (w / v) to about 0.08% (w / v) benzalkonium chloride; or about 0.01% (w / v) to about 0.06% (w / v) benzalkonium chloride; or comprising about 0.01% (w / v) to about 0.04% (w / v) benzalkonium chloride; 23. A nasal spray pharmaceutical formulation according to any one of claims 15 to 22, wherein benzalkonium chloride is the only absorption enhancer in the formulation or is present in a formulation which includes one or more additional absorption enhancers.

27. 27. The nasal spray pharmaceutical formulation of claim 15, wherein the nasal spray pharmaceutical formulation comprises a stabilizer.

28. 28. The nasal spray pharmaceutical formulation of claim 27, wherein the stabilizer is ethylenediaminetetraacetic acid (EDTA) or a salt thereof.

29. 29. The nasal spray pharmaceutical formulation of claim 28, wherein the EDTA is disodium EDTA.

30. 30. The nasal spray pharmaceutical formulation of claim 29, wherein the formulation comprises from about 0.001% (w / v) to about 1% (w / v) disodium EDTA.

31. 31. A nasal spray pharmaceutical formulation according to any one of claims 15 to 30, wherein the formulation comprises a preservative.

32. 32. The nasal spray pharmaceutical formulation of claim 31, wherein the preservative is benzalkonium chloride.

33. 33. The nasal spray pharmaceutical formulation of any one of claims 15 to 32, wherein the nasal spray pharmaceutical formulation comprises an isotonic agent.

34. 34. The nasal spray pharmaceutical formulation of claim 33, wherein the isotonic agent is dextrose, glycerin, mannitol, potassium chloride, or sodium chloride.

35. 34. The nasal spray pharmaceutical formulation of claim 33, wherein the isotonic agent is sodium chloride.

36. 36. A method for treating a disease mediated by adrenergic receptors comprising intranasal administration of a formulation according to any one of claims 1 to 35.

37. 37. The method of claim 36, wherein the disease is selected from type 1 hypersensitivity reactions (systemic allergic reactions), acute asthma attacks, cardiac arrest, and Stokes-Adams syndrome.

38. 38. The method of claim 37, wherein the disease is a type 1 hypersensitivity reaction (a systemic allergic reaction).

39. 39. The method of claim 38, wherein the type 1 hypersensitivity reaction is selected from allergic asthma, allergic conjunctivitis, allergic rhinitis, anaphylaxis, angioedema, urticaria, eosinophilia, drug allergy, and food allergy.

40. 40. The method of claim 39, wherein the drug allergy is an antibiotic allergy.

41. A nasal spray pharmaceutical formulation comprising epinephrine or a salt thereof, wherein intranasal administration of a single dose of the nasal spray pharmaceutical formulation to a subject has the following pharmacokinetic characteristics: Mean AUC resulting from 0.3 mg intramuscular injection ０－２０ｍｉｎ and mean AUC ０－ｔ A mean AUC that is at least 80% of ０－２０ｍｉｎ and AUC ０－ｔ Both; ・C produced by intramuscular injection of 0.3 mg ｍａｘ At least 80% of C ｍａｘ Average C is 150% or less of ｍａｘ ; Average t less than 45 minutes ｍａｘ and Intramuscular (IM) injection-like absorption under optimal dosing conditions in the thigh A nasal spray pharmaceutical formulation providing one or more of the following:

42. A nasal spray pharmaceutical formulation comprising epinephrine or a salt thereof, wherein intranasal administration of a single dose of the nasal spray pharmaceutical formulation to a subject has the following pharmacokinetic characteristics: Mean AUC resulting from 0.15 mg intramuscular injection ０－２０ｍｉｎ and mean AUC ０－ｔ A mean AUC that is at least 80% of ０－２０ｍｉｎ and AUC ０－ｔ Both; 0.15 mg intramuscular injection produces C ｍａｘ At least 80% of C ｍａｘ Average C is 150% or less of ｍａｘ ; Average t less than 45 minutes ｍａｘ and Intramuscular (IM) injection-like absorption under optimal dosing conditions in the thigh A nasal spray pharmaceutical formulation providing one or more of the following:

43. A nasal spray pharmaceutical formulation comprising epinephrine or a salt thereof, wherein intranasal administration of a single dose of the nasal spray pharmaceutical formulation to a subject has the following pharmacokinetic characteristics: Mean AUC resulting from 0.5 mg intramuscular injection ０－２０ｍｉｎ and mean AUC ０－ｔ A mean AUC that is at least 80% of ０－２０ｍｉｎ and AUC ０－ｔ Both; ・C produced by intramuscular injection of 0.5 mg ｍａｘ At least 80% of C ｍａｘ Average C is 150% or less of ｍａｘ ; Average t less than 45 minutes ｍａｘ and Intramuscular (IM) injection-like absorption under optimal dosing conditions in the thigh A nasal spray pharmaceutical formulation providing one or more of the following:

44. 44. The nasal spray pharmaceutical formulation of any one of claims 41 to 43, wherein intranasal administration of a single dose of the nasal spray pharmaceutical formulation to a subject results in absorption similar to that of an intramuscular (IM) injection.

45. 45. The nasal spray pharmaceutical formulation of any one of claims 41 to 44, wherein intranasal administration of a single dose of the nasal spray pharmaceutical formulation to a subject results in a plasma epinephrine concentration effective for treating an acute hypersensitivity reaction.

46. The nasal spray pharmaceutical formulation of any one of claims 41 to 45, wherein a single dose of the nasal spray pharmaceutical formulation comprises from about 0.5 mg to about 2.0 mg of epinephrine or a salt thereof.

47. The nasal spray pharmaceutical formulation of any one of claims 41 to 45, wherein a single dose of the nasal spray pharmaceutical formulation comprises from about 0.5 mg to about 1.5 mg of epinephrine or a salt thereof.

48. The nasal spray pharmaceutical formulation of any one of claims 42, 44, and 45, wherein a single dose of the nasal spray pharmaceutical formulation comprises from about 0.5 mg to about 0.7 mg of epinephrine or a salt thereof.

49. 46. ​​The nasal spray pharmaceutical formulation of any one of claims 41, 44, and 45, wherein a single dose of the nasal spray pharmaceutical formulation comprises about 1.0 mg of epinephrine or a salt thereof.

50. The nasal spray pharmaceutical formulation of any one of claims 43 to 45, wherein a single dose of the nasal spray pharmaceutical formulation contains from about 1.3 mg to about 1.5 mg of epinephrine or a salt thereof.

51. 51. The nasal spray pharmaceutical formulation of any one of claims 41 to 50, wherein the formulation is an aqueous solution, an aqueous suspension, an aqueous emulsion, a non-aqueous solution, a non-aqueous suspension, a non-aqueous emulsion, a pressurized metered dose inhaler, or a dry powder.

52. The nasal spray pharmaceutical formulation of any one of claims 41 to 51, comprising one or more absorption enhancers; and optionally one or more agents selected from isotonicity agents; stabilizers; preservatives; flavoring agents; viscosity modifiers; antioxidants; buffers and pH adjusters; wherein the pH of the nasal spray pharmaceutical formulation is from about 2.0 to about 6.

0.

53. 53. The pharmaceutical nasal spray formulation of any one of claims 41 to 52, wherein the pharmaceutical nasal spray formulation has a pH of about 3.0 to about 5.

0.

54. 53. The nasal spray pharmaceutical formulation of any one of claims 41 to 52, wherein the nasal spray pharmaceutical formulation has a pH of about 4.

0.

55. 55. The nasal spray pharmaceutical formulation of any one of claims 52 to 54, wherein the nasal spray pharmaceutical formulation comprises a pH adjuster.

56. 56. The nasal spray pharmaceutical formulation of claim 55, wherein the pH adjuster comprises an acid, a base, a buffer, or a combination thereof.

57. The acid is adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, or tartaric acid; The bases are sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate; and 57. The nasal spray pharmaceutical formulation of claim 56, wherein the buffer is a phosphate buffer, an acetate buffer, or a citrate buffer.

58. The formulation may be selected from the group consisting of alcohol, aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetylpyridinium chloride, chitosan, cyclodextrin, deoxycholic acid, decanoyl, dimethylsulfoxide, glyceryl monooleate, glycofurol, glycosylated sphingosine, glycyrrhetinic acid, 2-hydroxypropyl-β-cyclodextrin, laureth-9, lauric acid, lauroylcarnitine, lysophosphatidylcholine, menthol, poloxamer 407 or F68, poly-L-arginine, polyoxyethylene-9-lauryl ether, isopropyl myristate, isopropyl palmitate, lanolin, light mineral oil, 58. The pharmaceutical formulation of any one of claims 52 to 57, further comprising one or more absorption enhancers selected from linoleic acid, menthol, myristic acid, myristic alcohol, oleic acid or a salt thereof, oleyl alcohol, palmitic acid, polysorbate 20, polysorbate 80, propylene glycol, polyoxyethylene alkyl ethers, polyoxylglycerides, pyrrolidone, quillaja saponin, salicylic acid, sodium salt, β-sitosterol, β-D-glucoside, sodium lauryl sulfate, sucrose cocoate, taurocholic acid, taurodeoxycholic acid, taurodihydrofusidic acid, thymol, tricaprin, triolein, and alkyl saccharides.

59. 58. The nasal spray pharmaceutical formulation of any one of claims 52 to 57, wherein the formulation comprises one or more absorption enhancers selected from dodecyl maltoside, benzalkonium chloride, oleic acid or its salts, polysorbate 20, polysorbate 80, and sodium lauryl sulfate.

60. The one or more absorption enhancers are From about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside; or about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride; or From about 0.001 (w / v) to about 1% (w / v) of oleic acid or a salt thereof; or A combination of about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001% (w / v) to about 1% (w / v) benzalkonium chloride; or A combination of about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001% (w / v) to about 1% (w / v) oleic acid or a salt thereof; or 58. The nasal spray pharmaceutical formulation of any one of claims 52 to 57, which is a combination of about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof.

61. The one or more absorption enhancers are about 0.005% (w / v) to about 0.08% (w / v) benzalkonium chloride; or about 0.01% (w / v) to about 0.06% (w / v) benzalkonium chloride; or comprising about 0.01% (w / v) to about 0.04% (w / v) benzalkonium chloride; 58. A nasal spray pharmaceutical formulation according to any one of claims 52 to 57, wherein benzalkonium chloride is the only absorption enhancer in the formulation or is present in a formulation that includes one or more additional absorption enhancers.

62. 62. The nasal spray pharmaceutical formulation of any one of claims 52 to 61, wherein the nasal spray pharmaceutical formulation comprises a stabilizer.

63. 63. The nasal spray pharmaceutical formulation of claim 62, wherein the stabilizer is ethylenediaminetetraacetic acid (EDTA) or a salt thereof.

64. 64. The nasal spray pharmaceutical formulation of claim 63, wherein the EDTA is disodium EDTA.

65. 65. The nasal spray pharmaceutical formulation of claim 64, wherein the formulation comprises about 0.001% (w / v) to about 1% (w / v) disodium EDTA.

66. 66. A nasal spray pharmaceutical formulation according to any one of claims 52 to 65, wherein the formulation comprises a preservative.

67. 67. The nasal spray pharmaceutical formulation of claim 66, wherein the preservative is benzalkonium chloride.

68. 68. The nasal spray pharmaceutical formulation of any one of claims 52 to 67, wherein the nasal spray pharmaceutical formulation comprises an isotonic agent.

69. 69. The nasal spray pharmaceutical formulation of claim 68, wherein the isotonic agent is dextrose, glycerin, mannitol, potassium chloride, or sodium chloride.

70. 69. The nasal spray pharmaceutical formulation of claim 68, wherein the isotonic agent is sodium chloride.

71. 80. A method for treating a disease mediated by adrenergic receptors comprising intranasal administration of a formulation according to any one of claims 41 to 70.

72. 72. The method of claim 71, wherein the disease is selected from type 1 hypersensitivity reactions (systemic allergic reactions), acute asthma attacks, cardiac arrest, and Stokes-Adams syndrome.

73. 73. The method of claim 72, wherein the disease is a type 1 hypersensitivity reaction (a systemic allergic reaction).

74. 74. The method of claim 73, wherein the type 1 hypersensitivity reaction is selected from allergic asthma, allergic conjunctivitis, allergic rhinitis, anaphylaxis, angioedema, urticaria, eosinophilia, drug allergy, and food allergy.

75. 75. The method of claim 74, wherein the drug allergy is an antibiotic allergy.

76. 1. A method of treating anaphylaxis comprising intranasal administration of a nasal pharmaceutical formulation of epinephrine or a salt thereof in an amount of less than about 2.0 mg.

77. 77. The method of claim 76, wherein the nasal pharmaceutical formulation comprises from about 0.5 mg to about 1.5 mg of epinephrine or a salt thereof.

78. 77. The method of claim 76, wherein the nasal pharmaceutical formulation comprises from about 0.5 mg to about 0.7 mg of epinephrine or a salt thereof.

79. 77. The method of claim 76, wherein the nasal pharmaceutical formulation comprises about 1.0 mg of epinephrine or a salt thereof.

80. 77. The method of claim 76, wherein the nasal pharmaceutical formulation comprises from about 1.3 mg to about 1.5 mg of epinephrine or a salt thereof.

81. The formulation comprises: one or more absorption enhancers; Isotonicity agents; Stabilizers; Optional antioxidants; an optional buffer; Preservatives; and 81. The method of any one of claims 76 to 80, including an optional pH adjusting agent.

82. The one or more absorption enhancers include Dodecyl maltoside; Benzalkonium chloride; Oleic acid or its salts; A combination of dodecyl maltoside and benzalkonium chloride; A combination of dodecyl maltoside and oleic acid or a salt thereof; and 82. The method of claim 81, wherein the active ingredient is selected from a combination of benzalkonium chloride and oleic acid or a salt thereof.

83. The one or more absorption enhancers include From about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside; about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride; From about 0.001 (w / v) to about 1% (w / v) of oleic acid or a salt thereof; A combination of about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001% (w / v) to about 1% (w / v) benzalkonium chloride; A combination of about 0.005% (w / v) to about 2.5% (w / v) dodecyl maltoside and about 0.001% (w / v) to about 1% (w / v) oleic acid or a salt thereof; or 82. The method of claim 81, wherein the combination is selected from about 0.001 (w / v) to about 1% (w / v) benzalkonium chloride and about 0.001 (w / v) to about 1% (w / v) oleic acid or a salt thereof.

84. The formulation comprises: about 0.005% (w / v) to about 0.08% (w / v) benzalkonium chloride; about 0.01% (w / v) to about 0.06% (w / v) benzalkonium chloride; or comprising about 0.01% (w / v) to about 0.04% (w / v) benzalkonium chloride; 84. The method of any one of claims 81 to 83, wherein benzalkonium chloride is the only absorption enhancer in the formulation or is present in a formulation that includes one or more absorption enhancers.

85. 85. The method of any one of claims 81 to 84, wherein the isotonic agent is sodium chloride.

86. 86. The method of any one of claims 81 to 85, wherein the stabilizing agent is EDTA.

87. 86. The method of any one of claims 81 to 85, wherein the stabilizing agent is EDTA in an amount of about 0.001% (w / v) to about 1% (w / v).

88. 88. The method of any one of claims 81 to 87, wherein the preservative is benzalkonium chloride.

89. 88. The method of any one of claims 81 to 87, wherein the preservative is benzalkonium chloride in an amount of about 0.001% (w / v) to about 1% (w / v).

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