Characterization of Nebulized Liposomal Amikacin (Arikace^™) as a Function of Droplet Size

Abstract

The stress of nebulization has been shown to alter the properties of liposomal drugs. What has not been demonstrated is whether nebulized liposomes differ as a function of droplet size. Because droplet size influences lung deposition, liposomes with different properties could be deposited in different areas of the lung (e.g., central vs. peripheral). In this report, a liposomal amikacin formulation (Arikace, a registered trademark of Transave, Inc., Monmouth Junction, NJ) that is being developed as an inhaled treatment for gram negative infections was aerosolized with an eFlow (registered trademark of PARI, GmbH, Munich, Germany) nebulizer, reclaimed from the various stages of an Andersen cascade impactor (ACI) and analyzed for lipid-to-drug (L/D) (w/w) ratio, amikacin retention, and liposome size. For the nebulized solution, 99.7% of the total deposited drug was found on ACI stages 0 through 5, which have cutoff diameters of 9, 5.8, 4.7, 3.3, 2.1, and 1.1 microm, respectively. Properties were found to differ for drug reclaimed on stage 0 compared stages 1-5, which were not different from one another. For drug found on stages 1-5 (97% of total drug), the averages (n = 3) for L/D, percent encapsulated amikacin, and liposome mean diameter ranged from 0.59 to 0.68 (w/w), 71% to 75%, 248 to 282 nm, respectively. Drug found on stage 0 (2.8% of total drug) had an average L/D ratio of 0.51 and average liposome mean diameter of 375 nm. Examination of another batch of liposomal amikacin revealed no statistically significant differences between drug reclaimed on stages 0-5. Although a droplet size dependence was noted for one batch of Arikace aerosolized with the eFlow, the effect was considered to be inconsequential because the fraction in doubt represented nonrespirable particles >9 microm and accounted for <3% of the total deposited dose. The methodology applied here appears useful in evaluating aerosolized liposome systems. However, our results should not be assumed to apply to other liposome/drug compositions and nebulizers.

Pharmaceutical liposomal drug delivery: a review of new delivery systems and a look at the regulatory landscape

“…Two main types of triggers have been explored: remote triggers such as heat, ultrasound and light, and local triggers such as enzymes and pH (Bibi et al, 2012;Puri, 2014 (Li et al, 2008). The formulation is based on sustainedrelease liposomes of phospholipids (DPPC) and cholesterol encapsulating amikacin.…”

Inhaled Antibiotics for Lower Airway Infections

“…Liposomal forms of antitubercular medications such as amikacin and capreomycin are also undergoing development (51,52).…”

Emerging Opportunities for Inhaled Antibiotic Therapy

“…As discussed above, formulation of antibiotics into liposomes has the potential to provide once-daily treatment regimens [1,5,[8][9][10]19,[28][29][30][31][32][39][40][41][42]. Pulmaquin, which is a mixture of unencapsulated and liposomally encapsulated ciprofloxacin, provides a kinetic profile with a rapid peak of ciprofloxacin followed by the long tail characteristic of release from the liposomally encapsulated component [39].…”

“…Liposomal amikacin (ARIKAYCE®, Insmed) inhaled once-daily, met the noninferiority primary endpoint of relative change in FEV1 from baseline to end of study (Day 168) compared to tobramycin (TOBI®, Novartis), inhaled twice-daily [8] in a population of CF patients. From a formulation perspective, a proportion of the liposomes in ARIKAYCE are disrupted during nebulization resulting in about 30-40% of the drug leaking out of the liposomes, thus providing the patient with a mixture of unencapsulated and liposome-encapsulated antibiotic [10].…”