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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400889/ https://www.ncbi.nlm.nih.gov/pubmed/34452149 http://dx.doi.org/10.3390/pharmaceutics13081188 |
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author | Mitrović, Jelena R. Divović-Matović, Branka Knutson, Daniel E. Đoković, Jelena B. Kremenović, Aleksandar Dobričić, Vladimir D. Randjelović, Danijela V. Pantelić, Ivana Cook, James M. Savić, Miroslav M. Savić, Snežana D. |
author_facet | Mitrović, Jelena R. Divović-Matović, Branka Knutson, Daniel E. Đoković, Jelena B. Kremenović, Aleksandar Dobričić, Vladimir D. Randjelović, Danijela V. Pantelić, Ivana Cook, James M. Savić, Miroslav M. Savić, Snežana D. |
author_sort | Mitrović, Jelena R. |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-8400889 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84008892021-08-29 Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach Mitrović, Jelena R. Divović-Matović, Branka Knutson, Daniel E. Đoković, Jelena B. Kremenović, Aleksandar Dobričić, Vladimir D. Randjelović, Danijela V. Pantelić, Ivana Cook, James M. Savić, Miroslav M. Savić, Snežana D. Pharmaceutics Article 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. MDPI 2021-07-31 /pmc/articles/PMC8400889/ /pubmed/34452149 http://dx.doi.org/10.3390/pharmaceutics13081188 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Mitrović, Jelena R. Divović-Matović, Branka Knutson, Daniel E. Đoković, Jelena B. Kremenović, Aleksandar Dobričić, Vladimir D. Randjelović, Danijela V. Pantelić, Ivana Cook, James M. Savić, Miroslav M. Savić, Snežana D. Overcoming the Low Oral Bioavailability of Deuterated Pyrazoloquinolinone Ligand DK-I-60-3 by Nanonization: A Knowledge-Based Approach |
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 | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400889/ https://www.ncbi.nlm.nih.gov/pubmed/34452149 http://dx.doi.org/10.3390/pharmaceutics13081188 |
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