A Gamma Scintigraphy Study to Investigate Lung Deposition and Clearance of Inhaled Amikacin-Loaded Liposomes in Healthy Male Volunteers

Abstract

Background:The purpose of this study was to investigate the inhalation of a liposomal formulation of amikacin in healthy male volunteers in terms of pulmonary deposition, clearance, and safety following nebulization with a commercial jet nebulizer. Methods: Amikacin was encapsulated in liposomes comprised of dipalmitoyl phosphatidylcholine (DPPC) and cholesterol via a proprietary manufacturing process (20 mg/mL final amikacin concentration). The liposomes were radiolabeled with 99m Tc using the tin chloride labeling method. A nominal dose of 120 mg of drug product was loaded into a PARI LC STAR nebulizer, aerosolized using a PARI Boy compressor where subjects inhaled for 20 min. Lung deposition was determined by gamma scintigraphy in three healthy male volunteers at the following time points (0, 1, 3, 6, 12, 24, 48, and 72 h post-administration). Results: Total lung deposition, expressed as a percentage of the emitted dose, was 32.3 Ϯ 3.4%. The time-dependent retention of radiolabeled liposomes was biphasic with an initial rapid reduction in counts, followed by a slower phase to 48 h. The overall mean retention at 24 and 48 h was 60.4 and 38.3% of the initial dose deposited, respectively. The observed clearance of radiolabel is consistent with clearance of amikacin following aerosol delivery to rats. There were no clinically significant changes in laboratory parameters, vital signs, or ECG. No adverse events including cough or bronchospasm were reported. Conclusions: Inhalation of a single nominal dose of 120 mg liposomal amikacin results in prolonged retention of drug-loaded liposomes in the lungs of healthy volunteers. The treatment was well tolerated.

Design, characterization, and aerosolization of organic solution advanced spray-dried moxifloxacin and ofloxacin dipalmitoylphosphatidylcholine (DPPC) microparticulate/nanoparticulate powders for pulmonary inhalation aerosol delivery

“…[7][8][9][10][11][12][13] Targeted pulmonary delivery of antimicrobials (ie, antibacterials and antifungals) by inhalation aerosols is the subject of much recent interest in research and development, including several clinical trials. [8][9][10][11] Pulmonary liposomal aerosol delivery of antimicrobials can effectively fight infections, [14][15][16][17] and these liposomal delivery systems can be rendered into inhalable dry powder aerosols. 18 MOXI has been encapsulated in glutaraldehyde-crosslinked chitosan microspheres for intrapulmonary administration.…”

Carriers for the targeted delivery of aerosolized macromolecules for pulmonary pathologies

“…The simultaneous effects, of NPs uptake and release, were demonstrated simultaneously, when a study of multilamellar liposomes containing rifampicin and isoniazid exhibited presence in alveolar macrophages and could maintain therapeutic concentrations in the lung tissue for 5 days [77]. Antimicrobial delivery via liposomes to the lungs has been shown to be beneficial in the case of cystic fibrosis and exhibits a controlled and sustained release, and some are currently in phase II clinical trials [78]. Studies involving the delivery of macromolecules such as siRNA have also been conducted using nanocarriers, as summarized more in depth elsewhere [73].…”

An Ethanol-Based Proliposome Technology for Enhanced Delivery and Improved “Respirability” of Antiasthma Aerosols Generated Using a Micropump Vibrating-Mesh Nebulizer

“…Liposomes also significantly (P<0.05) increased the fraction of drug delivered to the lower impinge stage and decreased the deposition in the upper stage of the impinger (Fig.3b). This suggests that nebulized liposomes may not only offer a sustained and localized drug effect in the respiratory airways (Taylor et al, 1989;Saari et al, 1999;Weers et al, 2009) but can also increase the dose delivered in "respirable" fraction. Thus, liposomes may play roles beyond entrapment of drugs when the Aeroneb Pro vibrating-mesh nebulizer is employed, with inclusion of lipid having a desirable effect on drug delivery and deposition in the "FPF".…”

“…Many studies have demonstrated that liposomes are generally safe for pulmonary delivery (Kellaway and Farr, 1990). Therapeutically, liposomes can prolong the action of the entrapped drug in the respiratory tract; hence they can potentially improve the therapeutic outcome and reduce the systemic adverse effects of the drug (Taylor et al, 1989;Saari et al, 1999;Weers et al, 2009). The main limitation of liposomes is their instability in aqueous dispersions, since phospholipids are liable to hydrolysis (Kensil and Dennis, 1981) and oxidation (Hunt and Tsang, 1981); this may cause the liposomes to aggregate or fuse, resulting in leakage of the drug originally entrapped.…”