The aim of the present investigation was to prepare and evaluate the influence of adding fines on the in vitro performance of liposomal amikacin dry powder inhaler (AMK LDPI) formulations. Liposomes composed of hydrogenated soyaphosphatidylcholine, cholesterol and saturated soyaphosphatidylglycerol (AMK 1), or stearylamine (AMK 2) were prepared by a reverse phase evaporation technique, extruded to reduce size and separated from unentrapped drug. Purified liposomal dispersion was subjected to lyophilization using optimized cryoprotectant to achieve maximum percentage drug retention (PDR). Lactose carrier in varying mass ratios with or without addition of fines in different mixing sequences was used to formulate AMK LDPI formulations. AMK LDPI formulations were characterized for angle of repose, compressibility index, dispersibility index, scanning electron microscopy, and fine particle fraction (FPF). PDR was found to be 97.6% ± 2.2% for AMK1 and 98.5% ± 1.9% for AMK2 using sucrose as optimized cryoprotectant in lipid:sucrose ratio of 1:4. Lactose carrier containing 10% fines (wt/wt) was found to be the optimum blend at 1:5 mass ratio of liposome:lactose. The addition of fines and the order of mixing of fines were found to influence the FPF with significantly different device fractions. FPF of AMK LDPI formulations using Rotahaler as the delivery device at 30, 60, and 90 L/min were found to be 21.85% ± 2.2% and 24.6% ± 2.4%, 25.9% ± 1.8% and 29.2% ± 2.1%, and 29.5% ± 2.6% and 34.2% ± 2.0% for AMK1 and AMK2, respectively. From the studies performed in this investigation, it was observed that liposomal charge, addition of fines and order of mixing fines, has a significant effect (P < .05) on in vitro deposition of drug from LDPI formulation.KEYWORDS: liposomes, dry powder inhalers, amikacin, lactose, fines, fine particle fraction INTRODUCTIONAmikacin sulfate (AMK) is a broad-spectrum and potent aminoglycoside with limited clinical use owing to a high dose requirement and renal and audio-vestibular apparatus toxicity. 1-2 Major drawbacks associated with the use of earlier or conventional liposomal formulations are the tendency of liposomes to leak drug while in circulation, the extensive uptake of these liposomes by tissues of reticuloendothelial systems (RES), and the inability of liposomes to extravasate into infected tissue. 3-4 Therefore, localized liposomal AMK delivery was considered for the treatment of cystic fibrosis infections in the lungs. Liposomal encapsulation of AMK will give the required release of drug for a longer time duration at the localized site, thereby reducing both the chances of systemic side effects and the frequency of dosing.Improving drug delivery to the lungs from a dry powder inhaler (DPI) formulation is possible by various techniques such as smoothing the carrier surface, 5 reducing the particle size of the carrier, 6-7 and using a ternary powder mix formulation. 8 Addition of micronized lactose to coarse lactose carrier was found to improve the dispersion and deaggregation o...

The purpose of our study was to prepare and optimize liposomal Amphotericin B (AMB) dry powder inhaler (DPI) formulation for treatment of invasive lung fungal infection. Liposomes were prepared by reverse phase evaporation technique using ethyl acetate and ethanol (1:1) as organic solvents to avoid a possible risk for human health and to impart adequate stability of the vesicles. Drug lipid ratio was 1:10 with membrane composition of hydrogenated soyaphosphatidylcholine; cholesterol and either saturated soyaphosphatidylglycerol (7:3:0.5) or stearylamine (1:1:0.1) was used to prepare negatively (AMB1) and positively (AMB2) charged liposomes, respectively. Liposomes were extruded through 2 microm polycarbonate membrane, separated from unentrapped drug and subjected to lyophilization using Tris buffer containing cryoprotectants in various mass ratios. Sucrose was found to be the best cryoprotectant for liposomal AMB in a mass ratio of lipid: sucrose at 1:5 for AMB1 and AMB2, respectively. Sorbolac 400 and sieved Pharmatose 325 M (500#) in varying mass ratios were used as carriers to prepare the liposomal DPI formulations and subjected to determination of angle of repose, compressibility index, dispersiblity index, water content, scanning electron microscopy, and fine particle fraction (FPF). Carrier blend of Sorbolac 400 and 10% sieved Pharmatose 325 M (liposome: carrier ratio to be 1:6) resulted in 22.6 +/- 2.2% and 16.8 +/- 2.2% FPF for AMB1 and AMB2, respectively with significantly different (p >.05) device fraction. Percent dug retention studies were conducted at different storage conditions and demonstrated a shelf life over 1 year at refrigerated storage condition (2-8 degrees C).

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