Targeted pulmonary salmeterol and fluticasone delivery through nano- and micro-modulation of drugs and excipients

Agglomeration/microparticulation of anti-asthmatic/anti-inflammatory salmeterol (SX) and fluticasone (FP) in a single vehicle rendered inefficient pulmonary drug redispersion and site targeting. In the first part of the study, externally drug coated dual-microcarrier against single microcarrier (SX external coat/FP internal coat) systems were designed and examined for their pulmonary drug delivery/targeting profiles. Spray-dried lactose-polyethylene glycol (PEG) 3000 microcarrier were prepared with magnesium stearate lubricant added where applicable. Both single- and dual-microcarrier systems were subjected to cascade impactor analysis against microcarrier particle size and formulation attributes. Small microcarrier (~5 µm) was preferred over larger ones for SX targeting at primary to terminal bronchi. Drug-coated dual-microcarrier enhanced FP inhaled deposition at lower lung due to the absence of external SX barrier and opportunistic hydrophobic aggregation of SX with magnesium stearate-FP deposited on the same microcarrier. Dual-microcarrier increased pulmonary drug retention with a marginal rise in systemic drug levels, and reduced inflammatory lymphocytes/eosinophils/neutrophils infiltration, IL-4/5/9/13 release, mucus production and bronchoconstriction. The second part of the study designed lactose-based microcarrier of nano SX/FP as a function of particle size for tissue targeting and had SX/FP nanoencapsulated by oligochitosan conjugated/complexed with glucuronic acid and intercellular adhesion molecule-1 (anti-ICAM-1) ligands for cell targeting. Conjugate/complex was developed by carbodiimide reaction and coacervation techniques and spray drying method was adopted to produce the solid particles. Lactose-PEG 3000 microparticles (~ 5 µm) and lactose-magnesium stearate microparticles (~ 2 µm) were inclined to deliver nano SX and FP in upper and lower lungs (FPF < 4.5 μm; SX: 45.73 ± 0.52 % and FPF < 3.6 µm; FP: 41.50 ± 0.77 %). Introduction of glucuronic acid and anti-ICAM-1 on nano chitosan of SX/FP raised BEAS-2B cellular uptake of drugs via targeting, membrane permeabilization, and endocytosis (lipid raft and micropinocytosis). These nano oligochitosan-encapsulated drugs profoundly inhibited asthmatic marker (hNF-kβ p65/ERK1/2/p38/JNK/TNF-α/TGF-β/iNOS/COX-2/PGE2/IL-4/IL-5/IL-9/IL-13/IgE) expression in vitro. Rationale micro/nano particle designs increased in vivo pulmonary drug retention in relation to systemic exposure and cAMP promoter of bronchodilation, and reduced expression inflammatory marker (TL1A/PGE2) and Th-2 cytokine (IgE/IL-4/IL-5/IL-13) expression. In conclusion, dual-microcarrier systems (lactose-PEG 3000 microparticles for SX and lactose-magnesium stearate microparticles for FP), nanoencapsulation of drugs with oligochitosan, decoration of nanodrug particles with targeting ligands (glucuronic acid for nano SX and anti-ICAM-1 for FP), and nanoparticles-on-microparticles design are functional strategies to deliver SX and FP by pulmonary route in organ/tissue- and cell-specific manner.