This investigation was undertaken to evaluate practical feasibility of site specific pulmonary delivery of liposomal encapsulated Dapsone (DS) dry powder inhaler for prolonged drug retention in lungs as an effective alternative in prevention of Pneumocystis carinii pneumonia (PCP) associated with immunocompromised patients. DS encapsulated liposomes were prepared by thin film evaporation technique and resultant liposomal dispersion was passed through high pressure homogenizer. DS nano-liposomes (NLs) were separated by ultra centrifugation and characterized. NLs were dispersed in phosphate buffer saline (PBS) pH 7.4 containing different carriers like lactose, sucrose, and hydrolyzed gelatin, and 15% L-leucine as antiadherent. The resultant dispersion was spray dried and spray dried formulation were characterized to ascertain its performance. In vitro pulmonary deposition was assessed using Andersen Cascade Impactor as per USP. NLs were found to have average size of 137 +/- 15 nm, 95.17 +/- 3.43% drug entrapment, and zeta potential of 0.8314 +/- 0.0827 mV. Hydrolyzed gelatin based formulation was found to have low density, good flowability, particle size of 7.9 +/- 1.1 microm, maximum fine particle fraction (FPF) of 75.6 +/- 1.6%, mean mass aerodynamic diameter (MMAD) 2.2 +/- 0.1 microm, and geometric standard deviation (GSD) 2.3 +/- 0.1. Developed formulations were found to have in vitro prolonged drug release up to 16 h, and obeys Higuchi's Controlled Release model. The investigation provides a practical approach for direct delivery of DS encapsulated in NLs for site specific controlled and prolonged release behavior at the site of action and hence, may play a promising role in prevention of PCP.

Development of dry powder inhalers involves powder recrystallization, formulation, dispersion, delivery, and deposition of the therapeutic agent in different regions of the airways in prophylaxis/ treatment/ diagnosis of pulmonary and systemic disorders. Conventional powder production by crystallization and milling has many limitations resulting into development of alternative techniques to overcome the problems. In the last decade many patents have been filed claiming improvement in aerosol performance of dry powder inhalers through the use of (i) incorporation of fines of carrier particles to occupy active sites on the surface and use of hydrophobic carriers to facilitate deaggregation through reduced surface energy and particle interaction (ii) reducing aerodynamic diameters through particle engineering and incorporating drug into porous or low particle density, and/or (iii) preparing less cohesive and adhesive particles through corrugated surfaces, low bulk density, reduced surface energy and particle interaction and hydrophobic additives. Moisture within dry powder inhaler (DPI) products has also been shown to influence aerosol performance via capillary force and electrostatic interaction. Better understanding of particle forces and surface energy has been achieved by the use of sophisticated analytical techniques. Understanding the intricacies of particle shape and surface properties influencing specific lung deposition has been further facilitated by the availability of newer and advanced softwares. A critical review of recent patents claiming different approaches to improve lung deposition of dry powder inhalers will help in deciding the focus of the research in the area of technological gaps.

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.

The present research investigates development and in vivo evaluation of oral diacerein formulations with quicker and complete absorption. In vivo, diacerein gets completely metabolized to its active metabolite rhein in gut and liver, which is the only analyte detected in plasma. Incomplete absorption of diacerein from the formulation leads to colonic availability of rhein, which is associated with increased laxative effect as one of the side effects of diacerein therapy. Thus solubility improved immediate release formulation (IR) and a gastroretentive formulation (GR) was designed to achieve rapid absorption preferentially through upper part of gastro-intestinal tract; thus controlling the amount of rhein reaching to colon and minimizing the associated increased laxative effect. In vitro drug release studies of the developed formulations revealed faster and complete release of diacerein from IR and GR formulations compared to commercially available diacerein capsule Art50. Comparative bioavailability studies conducted in healthy human volunteers revealed 1.7 fold and 1.2 fold rise in AUC(0-6h) for IR and GR formulations respectively, compared to Art50 capsules. A Levy plot analysis comparing association between the time of in vitro dissolution (Tvitro) of diacerein and time of in vivo absorption (Tvivo) of rhein confirmed faster release and absorption from upper part of gastrointestinal region for both the optimized formulations.