Indinavir-loaded pH-sensitive microparticles for taste masking: toward extemporaneous pediatric anti-HIV/AIDS liquid formulations with improved patient compliance

Abstract

The aim of this work was to develop indinavir pediatric anti-HIV/AIDS formulations enabling convenient dose adjustment, ease of oral administration, and improved organoleptic properties by means of the generation of drug-loaded microparticles made of a polymer that is insoluble under intake conditions and dissolves fast in the stomach in order to completely release the active agent. Indinavir-loaded microparticles made of a pH-dependent polymeric excipient soluble at pH < 5, Eudragit E100, were prepared using a double emulsion solvent diffusion technique and the in vitro release profiles characterized. Finally, taste masking properties were evaluated in blind randomized sensory experiments by ten healthy human volunteers. The use of a w/o/o emulsion system resulted in indinavir loads around 90%. Thermal analysis of the microparticles by differential scanning calorimetry revealed that indinavir appeared mainly dispersed at the molecular level. Concentrations of residual organic solvents as determined by gas chromatography were below the upper limits specified by the European Pharmacopeia for pharmaceutical oral formulations. Then, the behavior of drug-containing microparticles in aqueous media at different pH values was assessed. While they selectively dissolved in gastric-like medium, in tap water (intake conditions), the matrix remained almost unchanged and efficiently prevented drug dissolution. Finally, sensoring taste tests performed by volunteers indicated that systems with indinavir loads approximately 15% displayed acceptable taste. This work explored the production of indinavir-containing microparticles based on a common pharmaceutical excipient as a means for the improvement of medicines of drugs involved in the treatment of HIV/AIDS. For systems containing about 15% drug, taste studies confirmed the acceptability of the formulation. In pediatric regimes, this composition would require an acceptable amount of formulation (0.7-1.5 g).

Fig. 1

Size range and distribution of MP20, MP40, and MP60 as determined by analytical sieving. Values of the amount retained in each sieve are expressed as % of the total sample weight

Fig. 2

Optical microscope photographs of indinavir-containing microparticles. a MP20, b MP40, and c MP60. Scale bar = 150 μm

Fig. 3

DSC thermograms of Eudragit E100, indinavir sulfate monoethanolate, and MP20, MP40, and MP60 drug-loaded microparticles

Fig. 4

Released indinavir (expressed as %) versus time for MP20 and MP40 systems. Microparticles (100 mg) were dispersed in the test medium (500 mL, pH values 1.5 and 6.8) and assayed in a dissolution test using the USP dissolution apparatus 2, at 37°C

Fig. 5

Released indinavir versus time for MP20, MP40, and MP60 microparticles (amount equivalent to 400-mg drug) under intake conditions (tap water, 125 mL), at 25°C. At time point 15 min, test samples were acidified to pH < 3 with HCl 30% in order to mimic the gastric environment