Integration of In Silico, In Vitro and In Situ Tools for the Preformulation and Characterization of a Novel Cardio-Neuroprotective Compound during the Early Stages of Drug Development
The main aim of this work is the biopharmaceutical characterization of a new hybrid benzodiazepine-dihydropyridine derivative, JM-20, derived with potent anti-ischemic and neuroprotective effects. In this study, the p<i>K</i>a and the pH-solubility profile were experimentally determined....
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/1/182 |
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| author | Claudia Miranda Alejandro Ruiz-Picazo Paula Pomares Isabel Gonzalez-Alvarez Marival Bermejo Marta Gonzalez-Alvarez Alex Avdeef Miguel-Ángel Cabrera-Pérez |
| author_facet | Claudia Miranda Alejandro Ruiz-Picazo Paula Pomares Isabel Gonzalez-Alvarez Marival Bermejo Marta Gonzalez-Alvarez Alex Avdeef Miguel-Ángel Cabrera-Pérez |
| author_sort | Claudia Miranda |
| collection | DOAJ |
| description | The main aim of this work is the biopharmaceutical characterization of a new hybrid benzodiazepine-dihydropyridine derivative, JM-20, derived with potent anti-ischemic and neuroprotective effects. In this study, the p<i>K</i>a and the pH-solubility profile were experimentally determined. Additionally, effective intestinal permeability was measured using three in vitro epithelial cell lines (MDCK, MDCK-MDR1 and Caco-2) and an in situ closed-loop intestinal perfusion technique. The results indicate that JM-20 is more soluble at acidic pH (9.18 ± 0.16); however, the Dose number (Do) was greater than 1, suggesting that it is a low-solubility compound. The permeability values obtained with in vitro cell lines as well as with the in situ perfusion method show that JM-20 is a highly permeable compound (Caco-2 value 3.8 × 10<sup>−5</sup>). The presence of an absorption carrier-mediated transport mechanism was also demonstrated, as well as the efflux effect of P-glycoprotein on the permeability values. Finally, JM-20 was provisionally classified as class 2 according to the biopharmaceutical classification system (BCS) due to its high intestinal permeability and low solubility. The potential good oral absorption of this compound could be limited by its solubility. |
| first_indexed | 2024-03-10T00:42:33Z |
| format | Article |
| id | doaj.art-3a7494604785461ea4a616a3c294d50f |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T00:42:33Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-3a7494604785461ea4a616a3c294d50f2023-11-23T15:05:13ZengMDPI AGPharmaceutics1999-49232022-01-0114118210.3390/pharmaceutics14010182Integration of In Silico, In Vitro and In Situ Tools for the Preformulation and Characterization of a Novel Cardio-Neuroprotective Compound during the Early Stages of Drug DevelopmentClaudia Miranda0Alejandro Ruiz-Picazo1Paula Pomares2Isabel Gonzalez-Alvarez3Marival Bermejo4Marta Gonzalez-Alvarez5Alex Avdeef6Miguel-Ángel Cabrera-Pérez7Unit of Modeling & Experimental Biopharmaceutics, Central “Marta Abreu” de Las Villas, Centro de Bioactivos Químicos Universidad, Santa Clara 50100, CubaDepartment Engineering of Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 Alicante, SpainDepartment Engineering of Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 Alicante, SpainDepartment Engineering of Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 Alicante, SpainDepartment Engineering of Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 Alicante, SpainDepartment Engineering of Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 Alicante, SpainIn-ADME Research, 1732 First Avenue # 102, New York, NY 10128, USAUnit of Modeling & Experimental Biopharmaceutics, Central “Marta Abreu” de Las Villas, Centro de Bioactivos Químicos Universidad, Santa Clara 50100, CubaThe main aim of this work is the biopharmaceutical characterization of a new hybrid benzodiazepine-dihydropyridine derivative, JM-20, derived with potent anti-ischemic and neuroprotective effects. In this study, the p<i>K</i>a and the pH-solubility profile were experimentally determined. Additionally, effective intestinal permeability was measured using three in vitro epithelial cell lines (MDCK, MDCK-MDR1 and Caco-2) and an in situ closed-loop intestinal perfusion technique. The results indicate that JM-20 is more soluble at acidic pH (9.18 ± 0.16); however, the Dose number (Do) was greater than 1, suggesting that it is a low-solubility compound. The permeability values obtained with in vitro cell lines as well as with the in situ perfusion method show that JM-20 is a highly permeable compound (Caco-2 value 3.8 × 10<sup>−5</sup>). The presence of an absorption carrier-mediated transport mechanism was also demonstrated, as well as the efflux effect of P-glycoprotein on the permeability values. Finally, JM-20 was provisionally classified as class 2 according to the biopharmaceutical classification system (BCS) due to its high intestinal permeability and low solubility. The potential good oral absorption of this compound could be limited by its solubility.https://www.mdpi.com/1999-4923/14/1/182intestinal permeabilityCaco-2solubility-pHp<i>K</i>aBCSJM-20 |
| spellingShingle | Claudia Miranda Alejandro Ruiz-Picazo Paula Pomares Isabel Gonzalez-Alvarez Marival Bermejo Marta Gonzalez-Alvarez Alex Avdeef Miguel-Ángel Cabrera-Pérez Integration of In Silico, In Vitro and In Situ Tools for the Preformulation and Characterization of a Novel Cardio-Neuroprotective Compound during the Early Stages of Drug Development Pharmaceutics intestinal permeability Caco-2 solubility-pH p<i>K</i>a BCS JM-20 |
| title | Integration of In Silico, In Vitro and In Situ Tools for the Preformulation and Characterization of a Novel Cardio-Neuroprotective Compound during the Early Stages of Drug Development |
| title_full | Integration of In Silico, In Vitro and In Situ Tools for the Preformulation and Characterization of a Novel Cardio-Neuroprotective Compound during the Early Stages of Drug Development |
| title_fullStr | Integration of In Silico, In Vitro and In Situ Tools for the Preformulation and Characterization of a Novel Cardio-Neuroprotective Compound during the Early Stages of Drug Development |
| title_full_unstemmed | Integration of In Silico, In Vitro and In Situ Tools for the Preformulation and Characterization of a Novel Cardio-Neuroprotective Compound during the Early Stages of Drug Development |
| title_short | Integration of In Silico, In Vitro and In Situ Tools for the Preformulation and Characterization of a Novel Cardio-Neuroprotective Compound during the Early Stages of Drug Development |
| title_sort | integration of in silico in vitro and in situ tools for the preformulation and characterization of a novel cardio neuroprotective compound during the early stages of drug development |
| topic | intestinal permeability Caco-2 solubility-pH p<i>K</i>a BCS JM-20 |
| url | https://www.mdpi.com/1999-4923/14/1/182 |
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