Mucus penetrating dextran microparticulate inhalable dry powder for the treatment of cystic fibrosis and mucopolysaccharidosis

Abstract

Cystic fibrosis is genetic disease that affects the lungs, pancreas, liver, kidney and intestine. Lung problems are liable to cause death in 80% of people with cystic fibrosis. Patients with cystic fibrosis lacks sulfatase enzyme, which leads to development of lysosomal storage disease i.e. Mucopolysaccharidosis. Sulfatase enzyme play important role in treating mucopolysaccharidosis because it reduces the high levels of sulfated glycosaminoglycans and glycolipids by catalyzing the hydrolysis of sulfate esters in lysosome. As there is no known cure for cystic fibrosis, various antibiotics are used to treat repetitive lung infections. Colistin sulfate is polymyxin antibiotic usually used to treat cystic fibrosis and effective against gram negative bacilli. Common side effects of colistin sulfate includes nausea, vomiting, weakness, stomach discomfort and visual disturbances. Innovative mucus penetrating dextran microparticles containing colistin sulfate and sulfatase enzyme can be used to cure both the disease. Aim of the present invention was development and evaluation of mucus penetrating dextran microparticulate inhalable dry powder for the treatment of cystic fibrosis and mucopolysaccharidosis. Lyophilization method was used to prepare microparticulate dry powder. Drug excipient compatibility was identified using FTIR spectroscopy. Optimized dextran microparticulate dry powder was evaluated for particle size, % yield, % drug content, solid state characterization, surface morphology, in-vitro lung deposition study, in-vitro drug release study and stability study. No incompatibility between drug and excipient observed that indicated by FTIR. Particle size, % yield and % drug content were found to be 3.35±0.026 μm, 94.02 % and 99.45±0.015 %. In solid state characterization, bulk density, tapped density, hausner’s ratio, carr’s index of optimized batch were found to be 0.216±0.025 g/cm3, 0.236±0.035 g/cm3, 1.09±0.026, 8.47±0.025 % and 26.10±0.029˚ respectively. Scanning Electron Microscopy (SEM) study indicates that the particles were found to be highly creased, raisin-like. A Fine Particle Fraction (FPF), Fine Particle Dose (FPD), Mass Median Aerodynamic Diameter (MMAD), Geometric Standard Deviation (GSD) and Emitted Dose were found to be 66.78%, 16.45 mg, 4.89 μm, 1.32 and 246.33 mg respectively. The % CDR of optimized batch was found to be 96.12±0.049 % within 24 hrs. The dextran microparticulate dry powder was stable at 40 ± 2˚C temperature and 75 ± 5% RH. Thus, we can conclude that the dry powder may be favorable carrier for delivery of colistin sulfate and sulfatase in combination via pulmonary route.