Bijay Kumar Padhi

Development of Dry Powder Inhalers

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.

Optimization of Formulation Components and Characterization of Large Respirable Powders Containing High Therapeutic Payload

The aim of the study was to optimize and characterize high therapeutic payload large respirable powders prepared by spray-drying technique for maximum fine particle fraction with minimum quantities of excipients. Influence of formulation components was optimized by a three-factor, five-level central composite design having different proportions of L-leucine (X1), tobramycin sulfate (X2), and poloxamer-188 (X3) as the independent variables and fine particle fraction as a response variable (Y). Large respirable powders were characterized for particle size, size distribution, moisture, crystallinity, and morphology. In vitro aerosol performance of powders was determined by an eight-stage Andersen cascade impactor using the Rotahaler. Mathematical model elucidated for Y was Y = 56.2068 + 5.7481 X1 - 3.0531 X2 + 0.8468 X3 + 1.1737 X1 X2 − 0.5012 X1 X3 − 0.7412 X2 X3 − 0.7149 X12 − 1.9212 X22 − 1.6187X32. The component of greatest influence on product performance (response variable) was found to be L-leucine. Lack of fit was not significant (p = 0.08), and regression equation predicted response for Y was in reasonably good agreement with experimental values (p = 0.01; R2 = 0.92). The optimal model predicted with a fine particle fraction of 62.8 ± 2.6% with X1, X2, X3 levels of 20, 45.71, and 5.51 respectively. Large respirable powders with TB load of 45.7% w/w were prepared; they had smooth surface texture, dimpled spherical shape, roundness value close to 1(1.048 ± 0.032) and were found to possess bulk tap densities of 0.04 g/cc, geometric particle sizes of 6–7 μm, and emitted dose of 92%. The results of the studies suggest that in vitro aerosol performance was affected significantly by small and deliberate change of specific formulation components and its proportions. It may be concluded that appropriate type and proportion of excipients is necessary to obtain maximum fine particle fraction of large respirable powders containing high therapeutic payloads.

Aerosol Performance of Large Respirable Particles of Amikacin Sulfate Produced by Spray and Freeze Drying Techniques

The purpose of the present study was to investigate the influence of method of preparation of large respirable particles of amikacin sulphate on traits and topography and in-vitro aerosol performance. Large respirable particles of amikacin sulfate (50%w/w) were produced by spray-drying and freeze-drying processes using hydrogenated soyaphosphatidylcholine, L-leucine and Poloxamer 188. Particles exhibited 0.04-0.08 g/cm3 tap densities, 7-20 microm geometric particle size, and 1 to 5 microm of mean aerodynamic diameter. Apart from the morphology and topographical features, spray-dried and freeze-dried particles had marginal difference in their solid-state characteristics. Spray-dried particles were dimpled spherical shape with roundness value close to 1(1.066 +/- 0.028), relatively smooth surface texture and produced greater aerosol dispersion with 20% higher fine particle fraction, 6.92% lower impaction loss and 13% less capsule and device retention than freeze dried particles. Traits and topographical features, such as particle size, polydispersity, elongation ratio, roundness, shape, and degree of surface roughness were found to be influenced significantly by spray-drying process and particles produced by spray-drying process showed better aerosol performance due to these differences.

Development of Novel Lyophilized Mixed Micelle Amphotericin B Formulation for Treatment of Systemic Fungal Infection

The purpose of the study was to develop a stable, controlled release Amphotericin B (Amph B) lyophilized mixed micelle (MM) formulation using hydrogenated soya phosphatidylcholine (HSPC) and bile salts in monomeric form and evaluate it for therapeutic performance and side effects. The MM formulations of Amph B were prepared using sodium deoxycholate (NDC)/sodium taurocholate (NTC)/sodium cholate (NC), and HSPC. The optimization of bile salt: HSPC ratio in the MM formulation was done using 2(4) factorial designs. MM formulations were lyophilized using sucrose as a cryoprotectant and analyzed for per cent micelle yield, per cent drug loading and per cent entrapment efficiency. Comparative in vitro diffusion studies, hemolytic activity, and minimum inhibitory concentration (MIC) of developed MM formulations and marketed formulation (Fungizone) were evaluated using cellophane membrane, human red blood cells and Candida albicans respectively. In vivo studies of MM formulations were also carried out on Candida albicans infected white albino rats and compared with Fungizone. The optimized molar ratio of bile salt: HSPC was found to be 8:11. Among all MM formulations prepared, NDC/ HSPC formulation found to have maximum per cent drug loading (4.96+/-0.8%), per cent entrapment efficiency (93.2+/-1.5%) and per cent micelle yield (96.4+/-1.4%). The in vitro drug diffusion studies of developed MM formulations show close to zero-order diffusion kinetics. All MM formulations show improved therapeutic index and reduced side effects compared to reference formulation Fungizone. The NDC/HSPC MM formulation was found to have least hemolytic activity, MIC and mortality rate at all dosage levels. Improved antifungal activity and reduced toxicity of Amph B solubilized in MM may be due to higher cellular uptake of the drug by fungal cells of infected tissues from MM formulations. Hence, Amph B MM formulation could be a safe and effective viable alternative in the treatment of systemic fungal infections.

Development and Pharmacokinetic Evaluation of Industrially Viable Self-microemulsifying Drug Delivery Systems (SMEDDS) for Terbinafine

Objective: The aim of this study was to develop a formulation for lymphatic uptake with enhanced solubility of antifungal drug, terbinafine by use of self-microemulsifying drug delivery system (SMEDDS); suitable enough to be an industrially feasible and acceptable dosage form. Methods: Fabrication of pseudo ternary phase diagram was done with suitable oils, surfactants and co-surfactants. The optimized formulation was characterised for droplet size, polydispersity index, zeta potential, cross-polarized light microscopy, thermodynamic stability, viscosity, capsule compatibility and evaluated for in vitro- in vivo parameters. The formulation was tested in animal model for lymphatic uptake with and without chylomicron blocking agent followed by the pharmacokinetic evaluation of the same. Results: The self-emulsification time, droplet size, polydispersity index of the optimized formulation remained unaffected in different media (water, 0.1N HCl and phosphate buffer pH 6.8) over stability conditions and with time. Crossed-polarized light microscopy examination of diluted SMEDDS formulation indicated that the dispersion was an isotropically stable system. The rate of dissolution for SMEDDS formulation was almost double as compared to marketed formulation (Lamisil®). Current investigation indicated a potential for lymphatic uptake of lipid based SMEDDS formulation with enhanced solubility of the candidate drug terbinafine. The optimum formulation of terbinafine SMEDDS when orally administered to rat with and without chylomicron flow blocking agent (cycloheximide) showed the area under the curve (AUC0-48hrs) as 10168.17 ng h/ml and 7425.44 ng h/ml respectively indicating the absorption through the lymphatic route. Thus, the study shows use of SMEDDS formulation for the drug delivery by lymphatic uptake.

Development and Pharmacokinetic Evaluation of New Oral Formulations of Diacerein.

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.