Effect of Food on the Pharmacokinetics of 2 Formulations of DRL-17822, a Novel Selective Cholesteryl Ester Transfer Protein (CETP) Inhibitor, in Healthy Males.

DRL-17822 is a novel selective cholesteryl ester transfer protein inhibitor that showed an increased exposure, including an increase of >20-fold of maximum concentration and area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, following a high-fat breakfast using a nanocrystal formulation. To reduce this effect of food, we generated an amorphous solid dispersion formulation. In this study, we compared the food effect of both formulations of DRL-17822 in a 2-part randomized, open-label, 4-way crossover study involving healthy adult males 18-45 years of age. In both parts of the study, 12 subjects received both formulations of DRL-17822 in both the fasted and fed states; a low-fat breakfast was provided in the first part and a high-fat breakfast in the second part. Compared to the nanocrystal formulation, the amorphous solid dispersion formulation substantially increased DRL-17822 exposure in the fasted state, including increased maximum concentration, area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, and area under plasma concentration-time curve from time zero to infinity. Following a high-fat breakfast, DRL-17822 exposure was increased to a lesser extent in the amorphous solid dispersion formulation compared to the nanocrystal formulation (P < .001). Moreover, compared to the nanocrystal formulation the amorphous solid dispersion formulation caused a more pronounced increase in high-density lipoprotein in the fasted state. Consuming breakfast increased the effect of DRL-17822 on high-density lipoprotein. Taken together, our results indicate that by improving its formulation, DRL-17822 has a favorable exposure profile and therefore a more predictable food effect profile.

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.

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 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.