Abstract:

Lower efficacy of chemotherapeutic agents through the systemic route for treatment of lung cancer is attributed to its lower concentration in the lungs. Conversely, higher concentrations of drug in the lungs can be achieved by pulmonary administration via the inhalation route. For effective deposition of the formulation at the target region (small airways and alveoli) of the lung, the aerodynamic diameter has to be controlled (1-5 μm) and its retention is of key importance. The present study attempted to design a dry powder inhalation formulation with combined benefits of micron- and nano-sized particles [nano-embedded microparticles (NEMs)], which upon redispersion, results in nanoparticles (NPs) exhibiting good retention in the lungs. The present attempt is the foremost one to utilize NEMs administered by pulmonary route for the treatment of lung cancer. Docetaxel (DTX) NPs was formulated using sonication solvent evaporation technique and characterized. Thereafter, DTX-NPs were embedded into microparticles using the spray drying technique. The NEMs exhibited the desired flow properties with Carr’s index 10.18±2.79 and Hausner ratio 1.11±0.034. The mass median aerodynamic diameter was 3.74±0.11 μm and the fine particle fraction 42.96±1.66%. Redispersed NP fraction was 47.78±4.65% with NPs retaining the desired properties. NPs demonstrated a sustained release of upto 144 h. The particle size and PDI of the redispersed NPs were unaffected. NEMs displayed stability upon charging under accelerated conditions for upto 3 months. Comparison of the cytotoxicity of DTX and DTX-NEMs revealed that the DTX-NEMs had more cytoxicity owing to the increased uptake of liberated NPs by cells. The prepared formulation could successfully entrap NPs (with mucus barrier-evading properties) in lactose microparticles, which can be deposited in the lungs and eventually, disintegrate to give back NPs under simulated lung conditions. The results suggest that the developed NEMs can be used in inhaled chemotherapy for the treatment of non-small cell lung cancer.

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