Epinephrine nasal powder stability superior to autoinjectors with comparable outcomes

Key takeaways:

• Patients may delay use of epinephrine administered via needles.
• Epinephrine absorption times for the powder and EpiPen were similar.
• Effects on blood pressure and heart rate were comparable as well.

WASHINGTON — Epinephrine formulated as nasal powder demonstrated superior stability compared with autoinjector epinephrine, according to an abstract presented at the American Academy of Allergy, Asthma & Immunology Annual Meeting.

The nasal powder also achieved plasma exposure comparable with autoinjectors, Martin Jönsson, MSc Pharm, clinical pharmacologist and clinical trial manager, Orexo AB, and colleagues wrote.

“Autoinjectors work well when used correctly, but many patients fear the needle. Worst case, these patients may not even carry the autoinjector when needed,” Jönsson told Healio. “Even if carried, use may be postponed until the anaphylactic reaction becomes severe.”

Martin Jönsson

Autoinjectors also are bulky, which may further prevent patients from carrying the drug, and accidental finger and bone injections are concerns as well, the researchers said.

Nasal epinephrine powders can address these shortcomings and serve as more accessible options for anaphylaxis, the researchers said.

Further, the researchers said, stability is poor for autoinjector epinephrine, prompting the need for storage systems that are incompatible with many activities.

Powder design, stability

Using spray-drying, researchers at Orexo AB developed four formulations of its OX640 proprietary amorphous and homogenous epinephrine powder, filled Aptar single-dose powder devices with these powders and stored them in protective storage tubes with built-in moisture protection that were custom-made.

“On a high level, the Aptar device works much like liquid nasal sprays,” Jönsson said.

Patients insert the nozzle into the nostril and press the plunger to administer a dose. The actuation pressure disperses the powder into the nose. The powder is then absorbed through the highly vascularized nasal mucosa, Jönsson said.

“There is a clever mechanical mechanism creating a reproducible actuation pressure without the use of other propellants than air,” Jönsson said. “Importantly, operation is not dependent on inhalation, and medication can be given by a family member, bystander or health care professional, even to unconscious patients.”

Baqsimi (Amphastar Pharmaceuticals), an approved glucagon nasal powder, currently uses the Aptar device, Jönsson said.

The researchers evaluated the stability of the four preservative-free powder formulations under accelerated conditions (40°C, 75% relative humidity) and compared them with the stability of EpiPen (Mylan/Viatris) autoinjectors with 0.3 mg doses of epinephrine.

“This is well below temperatures reached in a glove compartment on a hot summer day,” Jönsson said.

Over 12 months, the powder formulations were stable under these accelerated conditions with 0.65% or less total degradation, the researchers said, with full strength maintained. The EpiPens demonstrated 31.5% total degradation over the same timeframe.

This degradation included chemical degradation and racemization, or conversion to inactive S-epinephrine. The researchers also reported only 76% enantiomeric purity in the EpiPens with approximately 55% of the nominal dose remaining at 12 months.

Additionally, the powder formulations remained stable for 6 months at 50°C with less than 3% degradation, with additional data indicating that they were operational at least down to –20°C.

“Taken together, our investigations suggest properties of our development nasal powder formulations that may facilitate effective use, both in winter ski slopes and on summer beaches,” Jönsson said.

Powder effects

Using 40 healthy volunteers, the researchers also compared the bioavailability and hemodynamic response of the four powder formulations in doses of 1 mg each with 0.3 mg doses with the EpiPen.

The researchers conducted pharmacokinetic sampling at 21 time points, including three baseline samples, through 6 hours after each dose.

The patients absorbed epinephrine from the powder formulation with plasma levels that were comparable with EpiPen delivery within approximately 5 to 10 minutes, the researchers continued.

Peak and early exposures for the powders and for EpiPen were comparable as well, the researchers said, with the different powder formulations totaling about 83% to 120% of the EpiPen’s results. Also, total exposures were approximately 30% to 60% higher with the powder formulations, compared with EpiPen.

Onset of hemodynamic effects including blood pressure and heart rate were comparable between the powder formulations and EpiPen as well, the researchers said, adding that these increases were rapid. Mean peak increases included 18 to 21/11 to 14 mmHg for the powders and 11/6 mmHg for EpiPen.

In fact, the researchers said, the powder formulations had higher effects on blood pressure compared with EpiPen, with comparable onset of desired vasopressor effects despite differences in early exposure.

The powder formulations and EpiPen had similar systemic safety profiles as well. Sympathomimetic side effects were typical, commonly including headache, palpitations, tremor, hypoesthesia and hypervigilance.

One subject discontinued treatment after reoccurring ECG changes with dosing with both the powder formulations and EpiPen. Also, most subjects reported local discomfort that typically included mild nasal stinging or burning with the powder.

Conclusions, next steps

Based on these findings, the researchers concluded that their nasal powder formulations of epinephrine provided superior stability and comparable plasma exposure compared with EpiPen, as well as clinically relevant physiologic response that supports treatment.

“From a clinical perspective, we next plan to verify that our nasal powder also works in noses with ongoing allergic symptoms, to further confirm viability of the product for use in anaphylaxis,” Jönsson said.

Reference:

• Jönsson M, et al. J Allergy Clin Immunol. 2024;doi:10.1016/j.jaci.2023.11.877.
• Study shows nasal powder epinephrine provides superior stability to EpiPens. https://www.aaaai.org/about/news/news/2024/epinephrine. Published Feb. 5, 2024. Accessed Feb. 20, 2024.

For more information:

Martin Jönsson, MSc Pharm, can be reached at Martin.Jonsson@orexo.com.