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

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...

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Main Authors: Jelena R. Mitrović, Branka Divović-Matović, Daniel E. Knutson, Jelena B. Đoković, Aleksandar Kremenović, Vladimir D. Dobričić, Danijela V. Randjelović, Ivana Pantelić, James M. Cook, Miroslav M. Savić, Snežana D. Savić
Format: Article
Language:English
Published: MDPI AG 2021-07-01
Series:Pharmaceutics
Subjects:
Online Access:https://www.mdpi.com/1999-4923/13/8/1188
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author Jelena R. Mitrović
Branka Divović-Matović
Daniel E. Knutson
Jelena B. Đoković
Aleksandar Kremenović
Vladimir D. Dobričić
Danijela V. Randjelović
Ivana Pantelić
James M. Cook
Miroslav M. Savić
Snežana D. Savić
author_facet Jelena R. Mitrović
Branka Divović-Matović
Daniel E. Knutson
Jelena B. Đoković
Aleksandar Kremenović
Vladimir D. Dobričić
Danijela V. Randjelović
Ivana Pantelić
James M. Cook
Miroslav M. Savić
Snežana D. Savić
author_sort Jelena R. Mitrović
collection DOAJ
description 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.
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spelling doaj.art-5e2a79202ef0415b9129763a243ec4302023-11-22T09:14:00ZengMDPI AGPharmaceutics1999-49232021-07-01138118810.3390/pharmaceutics13081188Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based ApproachJelena R. Mitrović0Branka Divović-Matović1Daniel E. Knutson2Jelena B. Đoković3Aleksandar Kremenović4Vladimir D. Dobričić5Danijela V. Randjelović6Ivana Pantelić7James M. Cook8Miroslav M. Savić9Snežana D. Savić10Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, SerbiaDepartment of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, SerbiaDepartment of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210N. Cramer St., Milwaukee, WI 53211, USADepartment of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, SerbiaLaboratory of Crystallography, Faculty of Mining and Geology, University of Belgrade, Đušina 7, 11000 Belgrade, SerbiaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, SerbiaDepartment of Microelectronic Technologies, Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, 11000 Belgrade, SerbiaDepartment of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, SerbiaDepartment of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210N. Cramer St., Milwaukee, WI 53211, USADepartment of Pharmacology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, SerbiaDepartment of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, SerbiaPoor 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.https://www.mdpi.com/1999-4923/13/8/1188pyrazoloquinolinonesnanocrystalswet media millingfasted/fed bioavailability
spellingShingle Jelena R. Mitrović
Branka Divović-Matović
Daniel E. Knutson
Jelena B. Đoković
Aleksandar Kremenović
Vladimir D. Dobričić
Danijela V. Randjelović
Ivana Pantelić
James M. Cook
Miroslav M. Savić
Snežana D. Savić
Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach
Pharmaceutics
pyrazoloquinolinones
nanocrystals
wet media milling
fasted/fed bioavailability
title Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach
title_full Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach
title_fullStr Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach
title_full_unstemmed Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach
title_short Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach
title_sort overcoming the low oral bioavailability of deuterated pyrazoloquinolinone ligand dk i 60 3 by nanonization a knowledge based approach
topic pyrazoloquinolinones
nanocrystals
wet media milling
fasted/fed bioavailability
url https://www.mdpi.com/1999-4923/13/8/1188
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