Intranasal epinephrine formulations and methods for the treatment of disease
Inventors
Lowenthal, Richard • Maggio, Edward T. • Bell, Robert G. • Shah, Pratik
Assignees
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Publication Number
US-11717571-B2
Publication Date
2023-08-08
Expiration Date
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.
Core Innovation
The disclosure relates to intranasal administration for treating a type-1 hypersensitivity reaction in a human using a nasal spray pharmaceutical formulation. The formulation includes epinephrine as the only pharmaceutically active ingredient, with a defined single dose volume and a formulation pH between about 3.0 and about 5.0. The intranasal administration is stated to provide plasma epinephrine concentrations efficacious for elimination of one or more symptoms or prevention of further progression of one or more symptoms.
The nasal spray pharmaceutical formulation further includes one or more excipients selected from absorption enhancement agents, isotonicity agents, stabilizing agents, antioxidants, preservatives, and pH adjustment agents, together with water. Absorption enhancement agents include alkylsaccharides, alkylglycosides, surfactants, fatty acids, bile salts, cyclodextrins, phospholipids, and alcohols, with dodecyl maltoside emphasized. Stabilizing or chelating agents include EDTA or disodium salt thereof, and benzalkonium chloride is included in narrower embodiments.
The disclosure ties the selected excipients and pH and volume parameters to achieving plasma epinephrine pharmacokinetics, including improved intranasal pharmacokinetics versus intramuscular injection in some aspects such as Cmax and faster Tmax. Aqueous intranasal formulations are described as including epinephrine, water, dodecyl maltoside or benzalkonium chloride alone or combined, sodium chloride, and EDTA or disodium EDTA, with pH adjusting agents used to reach about pH 3.5 to 6, often about pH 4 to 5. Nasal delivery device aspects and plume or droplet geometry targets are also described.
Claims Coverage
The document includes four independent claims, each directed to treating a type-1 hypersensitivity reaction, including anaphylaxis, by intranasal administration of a nasal spray pharmaceutical formulation with defined epinephrine dosing, excipient classes, formulation pH, single-dose volume, and stated plasma-epinephrine efficacy.
Single-dose intranasal epinephrine for treating type-1 hypersensitivity
A method of treating a type-1 hypersensitivity reaction in a human by intranasal administration of a nasal spray pharmaceutical formulation, where a single intranasally administered dose comprises between 0.1 mg and about 2.4 mg of epinephrine, epinephrine is the only pharmaceutically active ingredient, one or more other agents are selected from absorption enhancement agents, isotonicity agents, stabilizing agents, antioxidants, preservatives, and pH adjustment agents, the formulation includes water, the pH is between about 3.0 and about 5.0, the volume of the single intranasally administered dose is between 25 μL and 250 μL, and the intranasal administration provides plasma epinephrine concentrations efficacious for elimination of one or more symptoms or prevention of further progression of one or more symptoms.
About 0.5-2.5 mg epinephrine in about 100 μL with selected excipients for anaphylaxis
A method of treating a type-1 hypersensitivity reaction in a human by intranasal administration of a nasal spray pharmaceutical formulation, where a single intranasally administered dose comprises about 0.5 mg to about 2.5 mg of epinephrine as the only pharmaceutically active ingredient in a volume of about 100 μL; one or more absorption enhancement agents as excipients selected from surfactants, fatty acids, bile salts, cyclodextrins, phospholipids, and alcohols; one or more isotonicity agents as excipients selected from dextrose, glycerin, mannitol, potassium chloride, and sodium chloride; a stabilizing agent as an excipient that is EDTA or disodium salt thereof; benzalkonium chloride as an excipient; and water; the formulation has a pH between about 3.0 and about 5.0; the type-1 hypersensitivity reaction comprises anaphylaxis; and the intranasal administration provides plasma epinephrine concentrations efficacious for elimination of one or more symptoms or prevention of further progression of one or more symptoms.
0.4-2.4 mg epinephrine with EDTA and benzalkonium chloride in pH 3.0-5.0 for anaphylaxis
A method of treating a type-1 hypersensitivity reaction in a human by intranasal administration of a nasal spray pharmaceutical formulation, where a single intranasally administered dose comprises between about 0.4 mg and about 2.4 mg of epinephrine as the only pharmaceutically active ingredient; one or more absorption enhancement agents as excipients selected from surfactants, fatty acids, bile salts, cyclodextrins, phospholipids, and alcohols; a stabilizing agent as an excipient that is EDTA or disodium salt thereof; benzalkonium chloride as an excipient; and water; the formulation has a pH between about 3.0 and about 5.0; the total volume of the single intranasally administered dose is between about 50 μL and about 250 μL; the type-1 hypersensitivity reaction comprises anaphylaxis; and the intranasal administration provides plasma epinephrine concentrations efficacious for elimination of one or more symptoms or prevention of further progression of one or more symptoms.
Intranasal administration of anaphylaxis-dosed epinephrine-only single dose formulation
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; wherein the type-1 hypersensitivity reaction comprises anaphylaxis; and wherein the intranasal administration of the single dose provides plasma epinephrine concentrations efficacious for elimination of one or more symptoms of anaphylaxis or efficacious for prevention of further progression of one or more symptoms of anaphylaxis.
Across the independent claims, the inventive coverage is directed to intranasal treatment of type-1 hypersensitivity reaction, including anaphylaxis, using a nasal spray with epinephrine as the only pharmaceutically active ingredient, defined formulation pH of about 3.0 to about 5.0, defined single-dose volume ranges, and excipient classes including absorption enhancement agents and, in narrower embodiments, stabilizing EDTA or disodium EDTA and benzalkonium chloride, with the stated outcome of efficacious plasma epinephrine concentrations for eliminating symptoms or preventing further progression.
Stated Advantages
Provides plasma epinephrine concentrations that are efficacious for elimination of one or more symptoms of the type 1 hypersensitivity reaction or anaphylaxis.
Provides plasma epinephrine concentrations that are efficacious for prevention of further progression of one or more symptoms of the type 1 hypersensitivity reaction or anaphylaxis.
Improved intranasal pharmacokinetics versus intramuscular injection in some aspects such as Cmax and faster Tmax.
Documented Applications
Treating a type-1 hypersensitivity reaction in a human by intranasal administration of a nasal spray pharmaceutical formulation.
Treating anaphylaxis, a type-1 hypersensitivity reaction, in a human using a single intranasal dose that provides efficacious plasma epinephrine concentrations.
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