Epinephrine spray formulations
Inventors
Hartman, Steven • LOBEL, Michelle • Robben, Matthew P. • Dretchen, Kenneth L. • MESA, Michael
Assignees
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Publication Number
US-12150921-B2
Publication Date
2024-11-26
Expiration Date
Abstract
Provided herein are epinephrine spray formulations. Also provided herein are methods of treating anaphylaxis by administering epinephrine spray formulations to subjects in need of such treatment.
Core Innovation
The invention relates to an aqueous pharmaceutical nasal spray formulation comprising epinephrine, or a pharmaceutically acceptable salt thereof, in water, together with chlorobutanol or chlorobutanol hemihydrate, sodium bisulfite or sodium metabisulfite, hypromellose, citric acid or citric acid monohydrate, sodium chloride, and diethylene glycol monoethyl ether. The formulation is defined by a weight ratio of epinephrine to chlorobutanol or chlorobutanol hemihydrate of about 12:1 to about 30:1.
In the disclosed formulations, epinephrine is present at about 1% to about 10% (w/w) in water, and chlorobutanol or chlorobutanol hemihydrate is present in an amount such that the epinephrine:chlorobutanol weight ratio remains about 12:1 to about 30:1. The formulation also incorporates sulfite preservatives using sodium bisulfite or sodium metabisulfite, together with hypromellose, citric acid or citric acid monohydrate, sodium chloride, and diethylene glycol monoethyl ether as additional components.
Certain formulations further constrain the pH of the pharmaceutical nasal spray formulation to about 4.0 to about 6.5. The disclosure relates to intranasal delivery of epinephrine for treatment approaches for anaphylaxis and anaphylactic shock, and is described in the context of pharmacokinetic performance, therapeutic plasma epinephrine attainment, T_max and AUC ranges, and comparison versus intramuscular injection.
Claims Coverage
The independent claims cover an aqueous pharmaceutical nasal spray formulation of epinephrine with three inventive-feature clusters, namely the specified excipient composition, the epinephrine-to-chlorobutanol or chlorobutanol hemihydrate weight ratio, and numeric composition ranges with an optional pH range. Across the claims, the same core formulation concept is maintained.
Epinephrine aqueous nasal spray formulation with specified excipients
A pharmaceutical nasal spray formulation comprising epinephrine, or a pharmaceutically acceptable salt thereof, in water, and including chlorobutanol or chlorobutanol hemihydrate, sodium bisulfite or sodium metabisulfite, hypromellose, citric acid or citric acid monohydrate, sodium chloride, and diethylene glycol monoethyl ether.
Defined epinephrine-to-chlorobutanol weight ratio
The pharmaceutical nasal spray formulation has a weight ratio of epinephrine to chlorobutanol or chlorobutanol hemihydrate of about 12:1 to about 30:1.
Numeric composition constraints and optional formulation pH
The formulation is further defined by numeric w/w ranges for epinephrine and the excipients chlorobutanol or chlorobutanol hemihydrate, sodium bisulfite or sodium metabisulfite, hypromellose, citric acid or citric acid monohydrate, sodium chloride, and diethylene glycol monoethyl ether, and may have a pH within about 4.0 to about 6.5.
The independent claims cover an aqueous intranasal epinephrine nasal spray formulation defined by specified excipients and a specific epinephrine-to-chlorobutanol or chlorobutanol hemihydrate weight ratio of about 12:1 to about 30:1, with claim families that further constrain component concentrations and optionally pH to about 4.0 to about 6.5.
Stated Advantages
Improved pharmacokinetic performance characterized by intranasal T_max and AUC ranges and improved plasma levels compared to intramuscular injection.
Nasal delivery achieves therapeutic epinephrine plasma concentration thresholds within minutes.
Nasal congestion can enhance absorption.
Stability/quality support is indicated by stability testing, impurity/assay retention, and spray-characteristics results.
Assessment includes safety/tolerability endpoints in the documented studies.
Documented Applications
Treatment approaches for anaphylaxis and anaphylactic shock using intranasal or nasal delivery of epinephrine.
Therapeutic use for bronchial constriction and respiratory depression.
Intranasal administration of epinephrine for which pharmacokinetics and absorption are compared versus EpiPen IM.
Evaluation of nasal congestion effects on intranasal epinephrine absorption in beagle dogs.
Assessment of blood brain barrier crossing by comparing CSF versus plasma epinephrine levels.
Use of spray-characteristics and stability testing to support an epinephrine nasal spray formulation.
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