Robustness of aerosol delivery of amikacin liposome inhalation suspension using the PARI eFlow® Technology

Nontuberculous mycobacterial pulmonary infection is recognized as a serious disease in immunocompetent patients. Antibiotics like amikacin are believed to have potential therapeutic effects on fighting mycobacterium species localized to the lung when administered in a sophisticated formulation utilizing an advanced inhalation delivery system. This technique allows the drug to reach the biofilms and infected macrophage cells for treatment. In 2018, amikacin liposome inhalation suspension (ALIS) with the brand name ARIKAYCE^® delivered via the Lamira^® nebulizer system was approved by the U.S. Food and Drug Administration (FDA) followed by subsequent approval in additional countries. ALIS is comprised of 590 mg of amikacin encapsulated within 200-300 nm liposomes. With a properly-designed inhaled liposomal formulation, antibiotic can then be released into the lungs at a concentration adequate to inhibit new replicating bacteria and, via liposomal phagocytosis, gain access to intracellular organisms that are otherwise sheltered inside macrophages.

In a new study by Zhili Li, Walter Perkins, and David Cipolla from Insmed Incorporated in New Jersey, the effectiveness of the Lamira system which is based on the eFlow^® Technology (PARI Pharma GmbH, Starnberg, Germany) for the delivery of the ALIS formulation was evaluated during extensive in vitro experimentation. This study was conducted to provide assurance that every batch of ALIS when used in concert with any Lamira delivery device would provide robust and consistent performance. The three key parameters included the time to generate the aerosol, the composition of the aerosol and the dose of aerosol likely to be inhaled and deposit in the airways. The key attributes regarding the composition of the aerosol included the liposome vesicle size and the percentage of encapsulated amikacin. The lung dose was estimated based on the delivered dose of amikacin in aerosol droplets less than five microns in size. The original research article is now published in the European Journal of Pharmaceutics and Biopharmaceutics.

The research team carried out experiments on 27 formulation and device combinations which included three batches of ALIS formulations and nine inhalation delivery devices covering the specification window. The three batches of ALIS spanned a range of 43 to 54 mg/mL lipid and 65.5 to 73.3 mg/mL amikacin resulting in lipid to drug ratios from 0.66 to 0.74. These ALIS batches were tested in nine Lamira nebulizer devices with aerosol heads representing a smaller, medium or larger median hole size. Different output parameters were monitored and recorded during testing to rate the delivery performance of both the ALIS and the delivery system in combination.

Insmed scientists found no meaningful differences in the critical aerosol delivery system output parameters during the nebulization process. The in vitro nebulization process occurred over a 12- to 15-minute time frame with the shortest nebulization time associated with the devices with the larger hole geometries. A design feature of around 35% of free amikacin was reproducibly generated during nebulization across all combinations of formulations and devices. The emitted dose of amikacin was around 498 mg representing 84.75% of the amount of amikacin loaded into the inhaler. The fine particle dose of amikacin, a measure of the amikacin dose in aerosol droplets that are likely to be inhaled and deposit in the airways, ranged from 244 mg to 278 mg, or 41% to 47% of the amikacin loaded into the device. This estimated lung dose from the in vitro studies agreed with the 43% mean lung dose from a referenced gamma scintigraphic study.

The new study teaches the importance in designing an inhaled formulation in concert with the attributes of the inhaler. For ALIS, the formulation and inhaler device were optimized so that there was a consistent portion of free amikacin (~35%) generated during nebulization to be immediately available to fight infection, while the majority of amikacin remained associated with the liposomes to enable access to the intracellular population of NTM. Furthermore, ALIS batches manufactured with acceptable variations in their properties were evaluated with inhaler devices that also spanned the range of their manufacturing design space. This in vitro data suggests that when a patient takes ALIS as prescribed at the labeled dose, a consistent dose is delivered