Nano-Liposomal Dry Powder Inhaler of Amiloride Hydrochloride

Abstract

The purpose of this study was to encapsulate Amiloride Hydrochloride into nano-liposomes, incorporate it into dry powder inhaler, and to provide prolonged effective concentration in airways to enhance mucociliary clearance and prevent secondary infection in cystic fibrosis. Liposomes were prepared by thin film hydration technique and then dispersion was passed through high pressure homogenizer to achieve size of nanometer range. Nano-liposomes were separated by centrifugation and were characterized. They were dispersed in phosphate buffer saline pH 7.4 containing carriers (lactose/sucrose/mannitol), and glycine as anti-adherent. The resultant dispersion was spray dried. The spray dried powders were characterized and in vitro drug release studies were performed using phosphate buffer saline pH 7.4. In vitro and in vivo drug pulmonary deposition was carried out using Andersen Cascade Impactor and by estimating drug in bronchial alveolar lavage and lung homogenate after intratracheal instillation in rats respectively. Nano-liposomes were found to have mean volume diameter of 198 +/- 15 nm, and 57% +/- 1.9% of drug entrapment. Mannitol based formulation was found to have low density, good flowability, particle size of 6.7 +/- 0.6 microm determined by Malvern MasterSizer, maximum fine particle fraction of 67.6 +/- 0.6%, mean mass aerodynamic diameter 2.3 +/- 0.1 microm, and geometric standard deviation 2.4 +/- 0.1. Developed formulations were found to have prolonged drug release following Higuchi's Controlled Release model and in vivo studies showed maximal retention time of drug of 12 hrs within the lungs and slow clearance from the lungs. This study provides a practical approach for direct lung delivery of Amiloride Hydrochloride encapsulated in liposomes for controlled and prolonged retention at the site of action from dry powder inhaler. It can provide a promising alternative to the presently available nebulizers in terms of prolonged pharmacological effect, reducing systemic side effects such as potassium retention due to rapid clearance of the drug from lungs in patients suffering from cystic fibrosis.