Development of Liposomal Amphotericin B Dry Powder Inhaler Formulation

Abstract

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).

The Influence of Fine Excipient Particles on the Performance of Carrier-Based Dry Powder Inhalation Formulations

“…Pharmatose 325M, however, is usually used as a coarse carrier and has a typical particle size distribution of d 10% = 5.0 2m, d 50% = 54.3 2m and d 90% = 95.9 2m (25). This suggests, therefore, that even when sieved through a 25 2m sieve, the Pharmatose 325M used as fines in this work (31,32) would have had a similar, if not larger, particle size than the Sorbolac 400 used as carrier. Unfortunately, no particle size data is provided in either study to clarify this issue and so the comparability of these studies with the majority of research in this field is questionable.…”

“…Two of these studies should not be mentioned without a caveat relating to the types of lactose used as carrier (Sorbolac 400, Meggle, Germany) and fines (25 2m sieved Pharmatose 325M, DMV International, The Netherlands) (31,32,38). Sorbolac 400 is more usually used as fines and is described by its manufacturer as a fine milled lactose with Q90% of particles <32 2m diameter (39).…”

“…Further details of these studies are given in Table I. Although salbutamol sulphate has been the most frequently investigated drug, a number of other drugs have also used: beclomethasone dipropionate (5,29), bovine serum albumin (3,4), budesonide (23,37), formoterol fumarate dihydrate (37), glucagon (33), liposomal amikacin (30), liposomal amphotericin B (31,32), salmeterol xinafoate (11,12,20,26,28,35,36) and a candidate NK1 receptor antagonist (FK888) (27).…”

Physicochemical Properties and Antifungal Activity of Amphotericin B Incorporated in Cholesteryl Carbonate Esters

“…Such an approach would extend earlier work wherein AmB was being successfully delivered to the lung as nebulized dosage form, [8][9][10] and liposomal AmB was developed as a dry powder inhaler. 11 In these studies, lung delivery provided targeted therapy at the infected area, and reduced the exposure of AmB to other tissues susceptible to toxicity, for example, kidney. Additionally, with improved efficacy and tolerability, inhalation of AmB can be used prophylactically against Aspergillus infection following lung transplantation.…”

Development of Liposomal Salbutamol Sulfate Dry Powder Inhaler Formulation

“…This can reduce the leakage of SBS from the liposomes. [15][16][17] When the content of SPC was 400 mg/g, the encapsulation efficiency of liposome suspension hydrated by lactose solution (mass ratio of SPC to lactose was 1 : 4) was 80.71Ϯ 2.55% (Table 1). This was much higher than that of the liposome suspension hydrated by deionized water (57.26Ϯ 1.02%) (Fig.…”