Purpose: For very low solubility (< 10 µg/mL in intestinal fluid) compounds, dissolution rate in the upper GI tract can limit absorption, even for amorphous formulations. These compounds are often formulated as amorphous solid dispersions (ASDs). The active loading of these formulations is typically limited to less than 25% in order to promote rapid dispersion of the ASD into drug-rich nanoparticles that subsequently provide rapid dissolution rate in the upper GI tract. The goal of this work is to demonstrate the feasibility of developing a formulation with higher active loading by preparing amorphous nanoparticles intrinsic to the formulation rather than relying on their formation in situ.
Methods: Itraconazole (ITZ, logP = 6, aqueous solubility < 0.01 µg/mL) was selected as a model compound. Nanoparticles of ITZ with polymers and/or surfactants were prepared by forming oil-in-water (o/w) emulsions with a high shear homogenizer (Microfluidics M110S). ITZ and selected polymers were dissolved in dichloromethane (DCM) as the oil phase and water (with or without surfactant) was the water phase. DCM was subsequently removed by rotary evaporation to create an aqueous nanoparticle suspension. Nanoparticles were then spray dried with a matrix polymer to form a dry powder and enable resuspension of the nanoparticles upon hydration. The spray dried nanoparticles (SDNPs) were tested for dissolution performance in simulated gastric and intestinal media using 0.2, 0.45, and 1 micron syringe filters.
Results: Stable nanoparticles of ITZ with ≥ 80% drug loading and a size of < 150 nm can be formed with the addition of ammonio methacrylate copolymer (Eudragit RL), which has a cationic charge density of 0.6 mmol/g from quaternary ammonium groups. When these nanoparticles are encapsulated in a reverse enteric matrix (Smartseal) at 40% active loading, the nanoparticles disperse in simulated gastric media in < 5 min with > 80% of the nanoparticles passing through 0.45 micron filter. Gastric erodible tablets can be prepared by direct compression of these powders.
Conclusion: A high concentration of amorphous nanoparticles of a low solubility compound can be delivered to the upper GI tract by preparing high loaded amorphous nanoparticles stabilized in a polymer matrix. Using this approach, very low solubility compounds may be formulated at higher loading, providing an alternative formulation approach to low loading ASDs for these challenging compounds.