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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2021-07-01
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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. |
first_indexed | 2024-03-10T08:29:15Z |
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id | doaj.art-5e2a79202ef0415b9129763a243ec430 |
institution | Directory Open Access Journal |
issn | 1999-4923 |
language | English |
last_indexed | 2024-03-10T08:29:15Z |
publishDate | 2021-07-01 |
publisher | MDPI AG |
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series | Pharmaceutics |
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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