Development and evaluation of anti-oxidant and anti-inflammatory drugs loaded lung surfactants

Abstract

Surface active liposomes containing, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and dexamethasone disodium phosphate (DXP) were developed and evaluated for potential use as lung surfactant replacement. 1,2-dipalmitoyl-sn-glycerol-3-phosphatidylcholine (DPPC) + TPGS (1 : 0.25 w/w) surfactant system (S1) and binary mixture of DPPC with 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphoglycerol ammonium salt (DPPC : POPG 9 : 1 w/w) + TPGS (1 : 0.25 w/w) surfactant system (S2) containing incremental amount of DXP in the range of 1 : 0.1–1 : 1 w/w were evaluated. S1:DXP and S2:DXP (1 : 0.1 to 1 : 1 w/w) mixed films reached 1–2 mN m⁻¹ minimum surface tension (MST) indicating surfactant functions even on concomitant addition of TPGS and DXP. Liposomal S1:DXP (1 : 0.1 to 1 : 1 w/w) attained significantly lower surface tension on adsorption, 35–29 mN m⁻¹ in one second, in comparison to 46 mN m⁻¹ attained by DPPC liposomes. Similarly, liposomes of S2:DXP (1 : 0.1–0.125 w/w) lowered surface tension on adsorption to 27–29 mN m⁻¹ in 1 second. Capillary surfactometer studies showed S1:DXP and S2:DXP (1 : 0.1–1 : 1 w/w) liposomes maintained >98% capillary patency. Rheological studies revealed that liposomal S2:DXP 1 : 0.1 and 1 : 0.125 w/w formulations (25 mg ml⁻¹) exhibited shear thinning properties and had significantly lower shear viscosities of ∼2.5 and 6.3 mPa s respectively at shear rate of 70 s⁻¹ in comparison to ∼29 mPa s for Survanta™ (25 mg ml⁻¹). S2:DXP 1 : 0.1 and 1 : 0.125 w/w liposomes were unilamellar with diameter of 200–250 and 250–350 nm respectively. Twin impinger drug deposition studies showed that on nebulization, S2:DXP 1 : 0.1 and 1 : 0.125 w/w liposomes system showed significantly higher deposition in the lower impingement chamber in comparison to that of free drug. Lipid peroxidation of Curosurf™ was reduced by 21–24% upon addition of S2:DXP liposomal formulation. The TPGS and DXP added DPPC : POPG liposomes may thus serve dual purposes of acting as a surfactant replacement and efficiently delivering antioxidant and anti-inflammatory drugs in inflammatory respiratory diseases.