Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach

Abstract

Poor water solubility of new chemical entities is considered as one of the main obstacles in drug development, as it usually leads to low bioavailability after administration. To overcome these problems, the selection of the appropriate formulation technology needs to be based on the physicochemical properties of the drug and introduced in the early stages of drug research. One example of the new potential drug substance with poor solubility is DK-I-60-3, deuterated pyrazoloquinolinone, designed for the treatment of various neuropsychiatric disorders. In this research, based on preformulation studies, nanocrystal technology was chosen to improve the oral bioavailability of DK-I-60-3. Nanocrystal dispersions stabilized by sodium lauryl sulfate and polyvinylpyrrolidone were prepared by modified wet media milling technique, with the selection of appropriate process and formulation parameters. The nanoparticles characterization included particle size and zeta potential measurements, differential scanning calorimetry, X-ray powder diffraction, dissolution and solubility study, and in vivo pharmacokinetic experiments. Developed formulations had small uniform particle sizes and were stable for three months. Nanonization caused decreased crystallite size and induced crystal defects formation, as well as a DK-I-60-3 solubility increase. Furthermore, after oral administration of the developed formulations in rats, two to three-fold bioavailability enhancement was observed in plasma and investigated organs, including the brain.

Nanosuspension-Based Dissolvable Microneedle Arrays to Enhance Diclofenac Skin Delivery

“…Among the different strategies for improving dermal application, nanocrystals are an extremely intriguing option. The term "nanocrystals" refers to nanoparticles of a pure drug lacking any sort of matrix material and having an average diameter less than 1 µm (usually between 200 and 500 nm), formulated as colloidal suspensions, also known as nanosuspensions (NS), in both water and non-water media and stabilized with either surfactants (ionic or non-ionic) or polymers [4][5][6]. The overall impact of the nanosizing procedure on the improvement of the drug's skin penetration is related to three factors: (1) an increase in the drug saturation solubility and, as a result, the concentration gradient between the formulation and the skin surface; (2) a faster dissolution process, owing to the increased particle surface area; and (3) a greater nanocrystal adherence to the skin [7].…”

Impact of multiple H/D replacements on the physicochemical properties of flurbiprofen

“…Some reports briefly describe the values of the physicochemical properties (e.g., solubility, melting point, and permeability) for both the parent drug and its deuterated form. [16][17][18] Considering the recent advancements in deuterium drug discovery, investigating the changes in physicochemical properties beyond the CYP metabolism tolerance is crucial to broaden the potential of deuterated drugs. Similar challenges are encountered in other chemical products.…”

Needle-Free Jet Injectors and Nanosuspensions: Exploring the Potential of an Unexpected Pair

“…Drug nanocrystals can be prepared by top-down or bottom-up methods, and are usually stabilized by one or more surfactants or polymers [ 21 , 22 ]. Despite the majority of marketed nanocrystals being approved for oral administration due to their efficient enhancement of bioavailability [ 23 , 24 ], the parenteral and topical routes hold great promise for the treatment of loco-regional pathologies, such as joint and muscle inflammation. In our previous works, we demonstrated the transdermal delivery of anti-inflammatory drugs formulated as nanosuspensions, either alone or in combination with medical devices (i.e., microneedle rollers) [ 25 , 26 ].…”