Claims for Patent: 11,918,655

Summary for Patent: 11,918,655

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:	US18/206,881
Patent Claims:	1. A method of treating a type-1 hypersensitivity reaction in a human comprising intranasally administering to the human with the type-1 hypersensitivity reaction a nasal spray pharmaceutical formulation comprising between about 1 mg/mL and about 40 mg/mL of epinephrine, or a salt thereof, in a volume between about 25 μL and about 250 μL per 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 allergic asthma, allergic conjunctivitis, allergic rhinitis, anaphylaxis, angioedema, urticaria, eosinophilia, or combinations thereof; 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 each dose of the pharmaceutical formulation comprises between about 5 mg/mL and about 40 mg/mL of epinephrine, or a salt thereof. 3. The method of claim 1, wherein each dose of the pharmaceutical 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. 4. The method of claim 1, wherein each dose of the pharmaceutical formulation comprises 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. 5. The method of claim 1, wherein each dose of the pharmaceutical formulation comprises about 10 mg/mL of epinephrine, or a salt thereof, in a volume between about 50 μL and about 200 μL. 6. The method of claim 1, wherein each dose of the pharmaceutical formulation comprises about 20 mg/mL of epinephrine, or a salt thereof, in a volume between about 50 μL and about 200 μL. 7. The method of claim 1, wherein the pharmaceutical formulation further comprises 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 to adjust the pH to a final pH between about 3.0 and about 5.0; and water. 8. The method of claim 1, wherein the pharmaceutical formulation further comprises 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 to adjust the pH to a final pH between about 3.0 and about 5.0; and water; the absorption enhancement agents are selected from the group consisting of alkyl glycosides, 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; the stabilizing agent is ethylenediaminetetraacetic acid (EDTA) or disodium salt thereof; 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; the preservative is benzalkonium chloride; and 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. 9. The method of claim 1, wherein the salt of epinephrine is selected from the group consisting of epinephrine acetate, epinephrine hydrochloride, epinephrine tartrate, epinephrine bitartrate, epinephrine hydrogen tartrate, and epinephrine borate. 10. The method of claim 1, wherein each intranasally delivered dose of the pharmaceutical formulation comprises about 10 mg/mL or about 20 mg/mL of epinephrine, or a salt thereof, in a volume between about 50 μL and about 200 μL; dodecyl maltoside, sodium chloride, sodium metabisulfite, ethylenediaminetetraacetic acid (EDTA) or disodium salt thereof, and benzalkonium chloride as excipients; hydrochloric acid, sodium hydroxide, or both, as excipients in amounts to adjust the pH to a final pH between about 3.0 and about 5.0; and water. 11. The method of claim 1, wherein each intranasally delivered dose of the pharmaceutical formulation comprises about 20 mg/mL of epinephrine, or a salt thereof, in a volume of 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; dodecyl maltoside, sodium chloride, sodium metabisulfite, ethylenediaminetetraacetic acid (EDTA) or disodium salt thereof, and benzalkonium chloride as excipients; hydrochloric acid, sodium hydroxide, or both, as excipients in amounts to adjust the pH to a final pH between about 3.0 and about 5.0; and water. 12. The method of claim 1, wherein each intranasally delivered dose of the pharmaceutical formulation comprises about 10 mg/mL or about 20 mg/mL of epinephrine, or a salt thereof, in a volume of about 100 μL; dodecyl maltoside, sodium chloride, sodium metabisulfite, ethylenediaminetetraacetic acid (EDTA) or disodium salt thereof, and benzalkonium chloride as excipients; hydrochloric acid, sodium hydroxide, or both, as excipients in amounts to adjust the pH to a final pH between about 3.0 and about 5.0; and water. 13. The method of claim 1, wherein each intranasally delivered dose of the pharmaceutical formulation comprises about 20 mg/mL of epinephrine, or a salt thereof, in a volume of about 100 μL; dodecyl maltoside, sodium chloride, sodium metabisulfite, ethylenediaminetetraacetic acid (EDTA) or disodium salt thereof, and benzalkonium chloride as excipients; hydrochloric acid, sodium hydroxide, or both, as excipients in amounts to adjust the pH to a final pH between about 3.0 and about 5.0; and water. 14. A method of treating a type-1 hypersensitivity reaction in a human comprising intranasally administering the human with the type-1 hypersensitivity reaction a nasal spray pharmaceutical formulation comprising in each dose 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 a volume between about 50 μL and about 250 μL; wherein epinephrine, or a salt thereof, is the only pharmaceutically active ingredient in the nasal spray pharmaceutical formulation; an absorption enhancement agent as an excipient that is dodecyl maltoside; an isotonicity agent as an excipient that is sodium chloride; a stabilizing agent as an excipient that is ethylenediaminetetraacetic acid (EDTA) or disodium salt thereof; a preservative as an excipient that is benzalkonium chloride; an optional antioxidant as an excipient that is sodium metabisulfite; hydrochloric acid, sodium hydroxide, or both, as excipients in sufficient amounts to adjust the pH to a final pH between about 3.0 and about 5.0; and water; wherein the type-1 hypersensitivity reaction comprises allergic asthma, allergic conjunctivitis, allergic rhinitis, anaphylaxis, angioedema, urticaria, eosinophilia, or combinations thereof; 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. 15. The method of claim 14, 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. 16. The method of claim 14, wherein the type-1 hypersensitivity reaction comprises urticaria, or the symptoms of the type-1 hypersensitivity reaction comprise pruritis, flushing, or a burning sensation of the skin. 17. The method of claim 14, wherein each intranasally delivered dose of the pharmaceutical formulation comprises about 10 mg/mL of epinephrine, or a salt thereof, in a volume of 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. 18. The method of claim 14, wherein each intranasally delivered dose of the pharmaceutical formulation comprises about 10 mg/mL of epinephrine, or a salt thereof, in a volume of about 100 μL. 19. The method of claim 14, wherein each intranasally delivered dose of the pharmaceutical formulation comprises about 20 mg/mL of epinephrine, or a salt thereof, in a volume of 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. 20. The method of claim 14, wherein each intranasally delivered dose of the pharmaceutical formulation comprises about 20 mg/mL of epinephrine, or a salt thereof, in a volume of about 100 μL. 21. A method of treating a type-1 hypersensitivity reaction in a human comprising intranasally administering to the human with the type-1 hypersensitivity reaction a pharmaceutical formulation comprising in each dose between about 1 mg/mL and about 40 mg/mL of epinephrine as the only active moiety in the pharmaceutical formulation in a volume between about 25 μL and about 250 μL; wherein the intranasal administration of the 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 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. 22. The method of claim 21, wherein each dose of the pharmaceutical formulation comprises 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 as the only active moiety in the pharmaceutical formulation; and wherein the volume of each dose is between about 50 μL and about 250 μL. 23. The method of claim 21, wherein each dose of the pharmaceutical formulation comprises about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, or about 20 mg/mL of epinephrine as the only active moiety in the pharmaceutical formulation; and wherein the volume of each dose is between about 50 μL and about 250 μL. 24. The method of claim 21, wherein the pharmaceutical formulation further comprises 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 to adjust the pH to a final pH between about 3.0 and about 5.0; and water. 25. A method of treating a type-1 hypersensitivity reaction in a human comprising intranasally administering to the human with the type-1 hypersensitivity reaction a pharmaceutical formulation comprising in each dose between 0.1 mg and 4 mg of epinephrine as the only active moiety in the pharmaceutical formulation; wherein the intranasal administration of the 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 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. 26. The method of claim 25, wherein each dose of the pharmaceutical formulation comprises about 0.5 mg, about 1.0 mg, or about 2.0 mg of epinephrine as the only active moiety in the pharmaceutical formulation, and wherein the volume of each dose of the pharmaceutical formulation is between about 50 μL and about 250 μL. 27. The method of claim 25, wherein the pharmaceutical formulation further comprises 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 water; wherein the volume of each dose of the pharmaceutical formulation is between about 50 μL and about 250 μL. 28. The method of claim 27, wherein: the absorption enhancement agents are selected from the group consisting of alkyl glycosides, 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; the stabilizing agent is ethylenediaminetetraacetic acid (EDTA) or disodium salt thereof; 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; the preservative is benzalkonium chloride; and 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. 29. The method of claim 25, wherein the type-1 hypersensitivity reaction comprises anaphylaxis; and the symptoms of the type-1 hypersensitivity reaction 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. 30. The method of claim 25, wherein the type-1 hypersensitivity reaction comprises urticaria, and the symptoms of the type-1 hypersensitivity reaction comprise pruritis, flushing, or burning sensation of the skin. 31. A method for the treatment of anaphylaxis in a human comprising intranasally administering to the human with anaphylaxis a single dose of an aqueous pharmaceutical formulation comprising about 1.0 mg to about 2.0 mg of epinephrine as the only pharmaceutically active ingredient in the aqueous pharmaceutical formulation in a volume between about 50 μL and about 250 μL; wherein the intranasal administration of the single dose to the human with anaphylaxis 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. 32. The method of claim 31, wherein the aqueous pharmaceutical formulation further comprises one or more excipients selected from the group consisting of absorption enhancement agents, isotonicity agents, stabilizing agents, antioxidants, preservatives, and pH adjustment agents to adjust the pH to a final pH between about 3.0 and about 5.0; and wherein the single dose comprises about 1.0 mg or about 2.0 mg of epinephrine and is intranasally administered with a single-dose nasal spray device. 33. A method for the treatment of anaphylaxis in a human comprising intranasally administering to the human with anaphylaxis a single dose of an aqueous pharmaceutical formulation comprising about 2.0 mg of epinephrine as the only pharmaceutically active ingredient in a volume of about 100 μL; wherein the single dose is administered with one actuation of a single-dose nasal spray device into one nostril of the human; wherein the intranasal administration of the single dose to the human with anaphylaxis 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. 34. A method for the treatment of anaphylaxis in a human comprising intranasally administering to the human with anaphylaxis a single dose of an aqueous pharmaceutical formulation comprising: about 1.0 mg to about 2.0 mg of epinephrine as the only pharmaceutically active ingredient in the aqueous pharmaceutical formulation in a volume between about 50 μL and about 250 μL; wherein the single dose is administered with one actuation of a single-dose nasal spray device into one nostril of the human; wherein the intranasal administration of the single dose to the human with anaphylaxis 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 with a time to maximum epinephrine plasma concentrations (Tmax) of less than 45 minutes. 35. The method of claim 34, wherein the single dose comprises about 1.0 mg or about 2.0 mg of epinephrine in a volume of about 100 μL and the intranasal administration of the single dose to the human with anaphylaxis provides plasma epinephrine concentrations with a Tmax of less than 35 minutes. 36. A method for the treatment of anaphylaxis in a human comprising intranasally administering to the human with anaphylaxis a single dose of an aqueous pharmaceutical formulation comprising: about 1.0 mg to about 2.0 mg of epinephrine as the only pharmaceutically active ingredient in the aqueous pharmaceutical formulation in a volume between about 50 μL and about 250 μL, water, one or more absorption enhancement agents as excipients, and one or more additional excipients selected from the group consisting of isotonicity agents, stabilizing agents, antioxidants, preservatives, and pH adjustment agents to adjust the pH to a final pH between about 3.0 and about 5.0; wherein the intranasal administration of the single dose to the human with anaphylaxis 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 with a time to maximum epinephrine plasma concentrations (Tmax) of less than 45 minutes. 37. A method for the treatment of anaphylaxis in a human comprising intranasally administering to the human with anaphylaxis a single dose of an aqueous pharmaceutical formulation comprising: about 2.0 mg of epinephrine as the only pharmaceutically active ingredient in the aqueous pharmaceutical formulation in a volume between about 50 μL and about 250 μL, water, one or more absorption enhancement agents as excipients, and one or more additional excipients selected from the group consisting of isotonicity agents, stabilizing agents, antioxidants, preservatives, and pH adjustment agents to adjust the pH to a final pH between about 3.0 and about 5.0; wherein the single dose is administered with one actuation of a single-dose nasal spray device into one nostril of the human; wherein the intranasal administration of the single dose to the human with anaphylaxis 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 with a time to maximum epinephrine plasma concentrations (Tmax) of less than 45 minutes. 38. The method of claim 37, wherein the intranasal administration of the single dose of the aqueous pharmaceutical formulation provides plasma epinephrine concentrations with a Tmax of less than 35 minutes. 39. The method of claim 37, wherein the absorption enhancement agents are selected from the group consisting of alkyl glycosides, fatty acids, bile salts, cyclodextrins, phospholipids, and alcohols. 40. The method of claim 37, 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. 41. A method for the emergency treatment of a type-1 hypersensitivity reaction in a human comprising intranasally administering to the human with the type-1 hypersensitivity reaction a single dose of an aqueous pharmaceutical formulation comprising about 2.0 mg of epinephrine as the only pharmaceutically active ingredient in the aqueous pharmaceutical formulation in a volume of about 100 μL, water, and additional excipients comprising dodecyl maltoside, benzalkonium chloride, sodium chloride, disodium salt of ethylenediaminetetraacetic acid (EDTA), sodium metabisulfite, and hydrochloric acid or sodium hydroxide to adjust the pH to a final pH between about 3.0 and about 5.0; wherein the type-1 hypersensitivity reaction comprises anaphylaxis; wherein the single dose is administered with one actuation of a single-dose nasal spray device into one nostril of the human; wherein the intranasal administration of the single dose 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 anaphylaxis in the human with a time to maximum epinephrine plasma concentrations (Tmax) of less than 45 minutes. 42. The method of claim 41, wherein the type-1 hypersensitivity reaction is caused by stinging insects, biting insects, allergen immunotherapy, foods, drugs, diagnostic testing substances, or other allergens. 43. The method of claim 41, wherein the symptoms of the type-1 hypersensitivity reaction are selected from the group consisting of urticaria, 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 inflammation, nasal flaring, and intercostal retractions. 44. A nasal spray pharmaceutical formulation consisting of about 2.0 mg of epinephrine in a volume of about 100 μL, dodecyl maltoside, benzalkonium chloride, sodium chloride, disodium salt of ethylenediaminetetraacetic acid (EDTA), sodium A metabisulfite, hydrochloric acid or sodium hydroxide to adjust the pH to a final pH between about 3.0 and about 5.0; and water.