Claims for Patent: 11,717,571

Summary for Patent: 11,717,571

Title:	Intranasal epinephrine formulations and methods for the treatment of disease
Abstract:	Drug products adapted for nasal delivery comprising formulations with epinephrine and devices comprising such formulations are provided. Methods of treating anaphylaxis with epinephrine products are also provided.
Inventor(s):	Richard Lowenthal, Edward T. Maggio, Robert G. Bell, Pratik Shah
Assignee:	Aegis Therapeutics LLC
Application Number:	US18/049,936
Patent Claims:	1. A method of treating a type-1 hypersensitivity reaction in a human comprising an intranasal administration of a nasal spray pharmaceutical formulation to the human with the type-1 hypersensitivity reaction, wherein a single intranasally administered dose of the nasal spray pharmaceutical formulation comprises: a) between 0.1 mg and about 2.4 mg of epinephrine, wherein epinephrine is the only pharmaceutically active ingredient in the nasal spray pharmaceutical formulation; b) one or more other agents as excipients selected from the group consisting of absorption enhancement agents, isotonicity agents, stabilizing agents, antioxidants, preservatives, and pH adjustment agents; and c) water; wherein the nasal spray pharmaceutical formulation has a pH between about 3.0 and about 5.0; wherein the volume of the single intranasally administered dose of the nasal spray pharmaceutical formulation is between 25 μL and 250 μL; wherein the intranasal administration of the nasal spray pharmaceutical formulation to the human with the type-1 hypersensitivity reaction provides plasma epinephrine concentrations in the human that are efficacious for the elimination of one, more than one, or all of the symptoms of the type 1 hypersensitivity reaction in the human; or wherein the intranasal administration of the nasal spray pharmaceutical formulation to the human with the type-1 hypersensitivity reaction provides plasma epinephrine concentrations in the human that are efficacious for the prevention of the further progression of one, more than one, or all of the symptoms of the type 1 hypersensitivity reaction in the human. 2. The method of claim 1, wherein the symptoms of the type-1 hypersensitivity reaction comprise at least one symptom selected from the group consisting of generalized hives, pruritis, flushing, angioedema, a burning sensation of the skin, swelling of the tongue or throat, shortness of breath, wheezes, stridor, coronary artery spasm, myocardial infarction, dysrhythmia, cardiac arrest, tachycardia, bradycardia, and a Bezold-Jarisch reflex. 3. The method of claim 1, wherein the type-1 hypersensitivity reaction is allergic asthma, allergic conjunctivitis, allergic rhinitis, anaphylaxis, angioedema, urticaria, eosinophilia, drug allergy, or food allergy. 4. The method of claim 1, wherein the type-1 hypersensitivity reaction comprises anaphylaxis. 5. The method of claim 1, wherein the type-1 hypersensitivity reaction comprises anaphylaxis; and the symptoms of anaphylaxis are selected from the group consisting of hives, generalized itching, nasal congestion, wheezing, difficulty breathing, cough, cyanosis, lightheadedness, dizziness, confusion, slurred speech, rapid pulse, palpitations, nausea or vomiting, abdominal pain or cramping, skin redness or skin inflammation, nasal flaring, and intercostal retractions. 6. The method of claim 1, wherein the single intranasally administered dose of the nasal spray pharmaceutical formulation comprises 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, or about 2.4 mg of epinephrine in a volume of about 100 μL. 7. The method of claim 4, wherein the single intranasally administered dose of the nasal spray pharmaceutical formulation comprises about 0.3 mg, about 0.5 mg, about 1.0 mg, or about 2.0 mg of epinephrine. 8. The method of claim 1, wherein the single intranasally administered dose of the nasal spray pharmaceutical formulation comprises about 1.0 mg of epinephrine. 9. The method of claim 1, wherein the single intranasally administered dose of the nasal spray pharmaceutical formulation comprises about 2.0 mg of epinephrine. 10. The method of claim 1, wherein: the absorption enhancement agents are selected from the group consisting of surfactants, fatty acids, bile salts, cyclodextrins, phospholipids, and alcohols; the isotonicity agents are selected from the group consisting of dextrose, glycerin, mannitol, potassium chloride, and sodium chloride; and the antioxidants are selected from the group consisting of alpha tocopherol, D-α-tocopherol polyethylene glycol 1000 succinate, ascorbic acid, isoascorbic acid, butylated hydroxyanisole, citric acid monohydrate, potassium metabisulfite, sodium bisulfite, sodium metabisulfite, and sodium sulfite. 11. The method of claim 1, wherein: the absorption enhancement agents are selected from the group consisting of dodecyl maltoside, polysorbate 20, polysorbate 80, oleic acid, sodium lauryl sulfate, sodium glycocholate, sodium taurocholate, and sodium taurodihydrofusidate; the isotonicity agents are selected from the group consisting of dextrose, glycerin, mannitol, potassium chloride, and sodium chloride; and the antioxidants are selected from the group consisting of alpha tocopherol, D-α-tocopherol polyethylene glycol 1000 succinate, ascorbic acid, isoascorbic acid, butylated hydroxyanisole, citric acid monohydrate, potassium metabisulfite, sodium bisulfite, sodium metabisulfite, and sodium sulfite. 12. The method of claim 11, wherein the stabilizing agent is ethylenediaminetetraacetic acid (EDTA) or disodium salt thereof; and the preservative is benzalkonium chloride. 13. The method of claim 12, wherein the pH adjustment agents are selected from the group consisting of adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, sodium hydroxide, sodium citrate, sodium bicarbonate, and sodium carbonate. 14. The method of claim 13, wherein the volume of the single intranasally administered dose of the nasal spray pharmaceutical formulation is 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. 15. The method of claim 9, wherein the volume of the single intranasally administered dose of the nasal spray pharmaceutical formulation is about 100 μL. 16. A method of treating a type-1 hypersensitivity reaction in a human comprising an intranasal administration of a nasal spray pharmaceutical formulation to the human with the type-1 hypersensitivity reaction, wherein a single intranasally administered dose of the nasal spray pharmaceutical formulation comprises: a) 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 in a volume of about 100 μL, wherein epinephrine is the only pharmaceutically active ingredient in the nasal spray pharmaceutical formulation; b) one or more absorption enhancement agents as excipients selected from the group consisting of surfactants, fatty acids, bile salts, cyclodextrins, phospholipids, and alcohols; c) one or more isotonicity agents as excipients selected from the group consisting of dextrose, glycerin, mannitol, potassium chloride, and sodium chloride; d) a stabilizing agent as an excipient that is ethylenediaminetetraacetic acid (EDTA) or disodium salt thereof; e) benzalkonium chloride as an excipient; and f) water; wherein the nasal spray pharmaceutical formulation has a pH between about 3.0 and about 5.0; wherein the type-1 hypersensitivity reaction comprises anaphylaxis; wherein the intranasal administration of the nasal spray pharmaceutical formulation to the human with the type-1 hypersensitivity reaction provides plasma epinephrine concentrations in the human that are efficacious for the elimination of one, more than one, or all of the symptoms of the type 1 hypersensitivity reaction in the human; or wherein the intranasal administration of the nasal spray pharmaceutical formulation to the human with the type-1 hypersensitivity reaction provides a plasma epinephrine concentrations in the human that are efficacious for the prevention of the further progression of one, more than one, or all of the symptoms of the type 1 hypersensitivity reaction in the human. 17. The method of claim 16, wherein the absorption enhancement agents are selected from the group consisting of dodecyl maltoside, polysorbate 20, polysorbate 80, oleic acid, sodium lauryl sulfate, sodium glycocholate, sodium taurocholate, and sodium taurodihydrofusidate. 18. The method of claim 16, wherein the pharmaceutical formulation further comprises one or more antioxidants as excipients selected from the group consisting of alpha tocopherol, D-α-tocopherol polyethylene glycol 1000 succinate, ascorbic acid, isoascorbic acid, butylated hydroxyanisole (BHA), citric acid monohydrate, potassium metabisulfite, sodium bisulfite, sodium metabisulfite, and sodium sulfite; and wherein the pH is adjusted to the pH between about 3.0 and about 5.0 by one or more pH adjustment agents as excipients selected from the group consisting of adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, sodium hydroxide, sodium citrate, sodium bicarbonate, and sodium carbonate. 19. The method of claim 16, wherein the pH is adjusted to the pH between about 3.0 and about 5.0 by one or more pH adjustment agents as excipients selected from the group consisting of hydrochloric acid and sodium hydroxide. 20. A method of treating a type-1 hypersensitivity reaction in a human comprising an intranasal administration of a nasal spray pharmaceutical formulation to the human with the type-1 hypersensitivity reaction, wherein a single intranasally administered dose of the nasal spray pharmaceutical formulation comprises: a) between about 0.4 mg and about 2.4 mg of epinephrine, and wherein epinephrine is the only pharmaceutically active ingredient in the nasal spray pharmaceutical formulation; b) one or more absorption enhancement agents as excipients selected from the group consisting of surfactants, fatty acids, bile salts, cyclodextrins, phospholipids, and alcohols; c) a stabilizing agent as an excipient that is ethylenediaminetetraacetic acid (EDTA) or disodium salt thereof; d) benzalkonium chloride as an excipient; and e) water; wherein the nasal spray pharmaceutical formulation has a pH between about 3.0 and about 5.0; wherein the total volume of the single intranasally administered dose of the nasal spray pharmaceutical formulation is between about 50 μL and about 250 μL; wherein the type-1 hypersensitivity reaction comprises anaphylaxis; wherein the intranasal administration of the nasal spray pharmaceutical formulation to the human with the type-1 hypersensitivity reaction provides plasma epinephrine concentrations in the human that are efficacious for the elimination of one, more than one, or all of the symptoms of the type 1 hypersensitivity reaction in the human; or wherein the intranasal administration of the nasal spray pharmaceutical formulation to the human with the type-1 hypersensitivity reaction provides plasma epinephrine concentrations in the human that are efficacious for the prevention of the further progression of one, more than one, or all of the symptoms of the type 1 hypersensitivity reaction in the human. 21. The method of claim 20, wherein the absorption enhancement agents are selected from the group consisting of dodecyl maltoside, polysorbate 20, polysorbate 80, oleic acid, sodium lauryl sulfate, sodium glycocholate, sodium taurocholate, and sodium taurodihydrofusidate. 22. The method of claim 20, wherein the pharmaceutical formulation further comprises: one or more isotonicity agents as excipients selected from the group consisting of dextrose, glycerin, mannitol, potassium chloride, and sodium chloride; one or more antioxidants as excipients selected from the group consisting of alpha tocopherol, D-α-tocopherol polyethylene glycol 1000 succinate, ascorbic acid, isoascorbic acid, butylated hydroxyanisole (BHA), citric acid monohydrate, potassium metabisulfite, sodium bisulfite, sodium metabisulfite, and sodium sulfite; and wherein the pH is adjusted to the pH between about 3.0 and about 5.0 by one or more pH adjustment agents as excipients selected from the group consisting of adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, sodium hydroxide, sodium citrate, sodium bicarbonate, and sodium carbonate. 23. The method of claim 20, wherein the pH is adjusted to the pH between about 3.0 and about 5.0 by one or more pH adjustment agents as excipients selected from the group consisting of hydrochloric acid and sodium hydroxide. 24. The method of claim 20, wherein the single intranasally administered dose of the nasal spray pharmaceutical formulation comprises about 0.5 mg, about 1.0 mg, or about 2.0 mg of epinephrine. 25. The method of claim 20, wherein the single intranasally administered dose of the nasal spray pharmaceutical formulation comprises about 1.0 mg of epinephrine. 26. The method of claim 20, wherein the single intranasally administered dose of the nasal spray pharmaceutical formulation comprises about 2.0 mg of epinephrine. 27. The method of claim 20, wherein the volume of the single intranasally administered dose of the nasal spray pharmaceutical formulation is 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. 28. The method of claim 20, wherein the single intranasally administered dose of the nasal spray pharmaceutical formulation comprises 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, or about 2.4 mg of epinephrine in a volume of about 100 μL. 29. A method of treating a type-1 hypersensitivity reaction in a human comprising administering intranasally to the human in need thereof a nasal spray pharmaceutical formulation comprising between about 0.1 mg and about 2.4 mg of epinephrine, or a salt thereof, in a single dose; wherein epinephrine, or a salt thereof, is the only pharmaceutically active ingredient in the nasal spray pharmaceutical formulation; wherein the type-1 hypersensitivity reaction comprises anaphylaxis; and wherein the intranasal administration of the single dose of the nasal spray pharmaceutical formulation to the human provides plasma epinephrine concentrations in the human that are efficacious for the elimination of one, more than one, or all of the symptoms of anaphylaxis in the human; or wherein the intranasal administration of the nasal spray pharmaceutical formulation to the human provides plasma epinephrine concentrations in the human that are efficacious for the prevention of the further progression of one, more than one, or all of the symptoms of anaphylaxis in the human. 30. The method of claim 29, wherein: about 100 μL of the nasal spray pharmaceutical formulation comprises 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, or about 2.4 mg of epinephrine; and about 100 μL of the nasal spray pharmaceutical formulation is delivered to the human in one actuation of a nasal spray device.