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

Jelena R Mitrović,Ivana Pantelić,Daniel E Knutson,Danijela V Randjelović,James M Cook,Vladimir D Dobričić,Aleksandar Kremenović,Miroslav M Savić,Jelena B Đoković,Snežana D Savić,Branka Divović-Matović

doi:10.3390/pharmaceutics13081188

Jelena R Mitrović, Ivana Pantelić + Show 9 more

Open Access

https://doi.org/10.3390/pharmaceutics13081188

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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.

Highlights

The emerging trends in the combinatorial chemistry and design of psychopharmacological drugs led to the development of drug candidates with increased lipophilicity and high molecular weight
Substance DK-I-60-3 appeared as a yellow crystalline powder, with broad particle size distribution from 2.15 to 191.16 μm (Figure 1a)
The melting peak in nanocrystalline formulations F5, F6, and F8 was around 2 ◦ C degrees lower when compared to the corresponding physical mixtures, which can be explained by smaller particle sizes [23]

Summary

Introduction

The emerging trends in the combinatorial chemistry and design of psychopharmacological drugs led to the development of drug candidates with increased lipophilicity and high molecular weight. Pharmaceutics 2021, 13, 1188 investigation, the role of the formulation scientist becomes crucial to implement advanced formulation strategies early in development processes [2]. Many attempts underachieve to overcome poor solubility due to the selection of formulation strategy driven by researchers’ experience rather than physicochemical properties of the drug substance [3]. By evaluating basic information on molecular structure, molecular weight, as well as results from preformulation studies such as solubility in water and oils, melting temperature, crystallinity, and amorphization ability, formulation steps can be determined using a knowledge-based approach. Brick dust substances are poorly soluble in an aqueous environment as well as in lipids and organic solvents, and represent ideal candidates for nanosizing, especially if amorphization is not possible [1]. Nanosizing or nanonization implies particle size reduction to the sub-micron range, obtaining nanocrystal dispersions [6]

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