Segmental-Dependent Solubility and Permeability as Key Factors Guiding Controlled Release Drug Product Development
The main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled...
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| Format: | Article |
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MDPI AG
2020-03-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/3/295 |
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| author | Milica Markovic Moran Zur Noa Fine-Shamir Ester Haimov Isabel González-Álvarez Arik Dahan |
| author_facet | Milica Markovic Moran Zur Noa Fine-Shamir Ester Haimov Isabel González-Álvarez Arik Dahan |
| author_sort | Milica Markovic |
| collection | DOAJ |
| description | The main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled-release (CR) drug product development. The solubility/dissolution and permeability of carvedilol (vs. metoprolol) were thoroughly studied, in vitro/in vivo (Octanol-buffer distribution coefficients (Log D), parallel artificial membrane permeability assay (PAMPA), rat intestinal perfusion), focusing on location-dependent effects. Carvedilol exhibits changing solubility in different conditions throughout the GIT, attributable to its zwitterionic nature. A biorelevant pH-dilution dissolution study for carvedilol immediate release (IR) vs. CR scenario elucidates that while the IR dose (25 mg) may dissolve in the GIT luminal conditions, higher doses used in CR products would precipitate if administered at once, highlighting the advantage of CR from the solubility/dissolution point of view. Likewise, segmental-dependent permeability was evident, with higher permeability of carvedilol vs. the low/high P<sub>eff</sub> marker metoprolol throughout the GIT, confirming it as a biopharmaceutical classification system (BCS) class II drug. Theoretical analysis of relevant physicochemical properties confirmed these results as well. A CR product may shift the carvedilol’s solubility behavior from class II to I since only a small dose portion needs to be solubilized at a given time point. The permeability of carvedilol surpasses the threshold of metoprolol jejunal permeability throughout the entire GIT, including the colon, establishing it as a suitable candidate for CR product development. Altogether, this work may serve as an analysis model in the decision process of CR formulation development and may increase our biopharmaceutical understanding of a successful CR drug product. |
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| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-04-13T00:26:22Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-16cb103f379b400084206ad226eb71e52022-12-22T03:10:35ZengMDPI AGPharmaceutics1999-49232020-03-0112329510.3390/pharmaceutics12030295pharmaceutics12030295Segmental-Dependent Solubility and Permeability as Key Factors Guiding Controlled Release Drug Product DevelopmentMilica Markovic0Moran Zur1Noa Fine-Shamir2Ester Haimov3Isabel González-Álvarez4Arik Dahan5Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, IsraelDepartment of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, IsraelDepartment of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, IsraelDepartment of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, IsraelDepartment of Pharmacokinetics and Pharmaceutical Technology, Miguel Hernandez University, 03550 San Juan de Alicante, SpainDepartment of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, IsraelThe main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled-release (CR) drug product development. The solubility/dissolution and permeability of carvedilol (vs. metoprolol) were thoroughly studied, in vitro/in vivo (Octanol-buffer distribution coefficients (Log D), parallel artificial membrane permeability assay (PAMPA), rat intestinal perfusion), focusing on location-dependent effects. Carvedilol exhibits changing solubility in different conditions throughout the GIT, attributable to its zwitterionic nature. A biorelevant pH-dilution dissolution study for carvedilol immediate release (IR) vs. CR scenario elucidates that while the IR dose (25 mg) may dissolve in the GIT luminal conditions, higher doses used in CR products would precipitate if administered at once, highlighting the advantage of CR from the solubility/dissolution point of view. Likewise, segmental-dependent permeability was evident, with higher permeability of carvedilol vs. the low/high P<sub>eff</sub> marker metoprolol throughout the GIT, confirming it as a biopharmaceutical classification system (BCS) class II drug. Theoretical analysis of relevant physicochemical properties confirmed these results as well. A CR product may shift the carvedilol’s solubility behavior from class II to I since only a small dose portion needs to be solubilized at a given time point. The permeability of carvedilol surpasses the threshold of metoprolol jejunal permeability throughout the entire GIT, including the colon, establishing it as a suitable candidate for CR product development. Altogether, this work may serve as an analysis model in the decision process of CR formulation development and may increase our biopharmaceutical understanding of a successful CR drug product.https://www.mdpi.com/1999-4923/12/3/295controlled release drug productbiopharmaceutics classification systemdrug solubilitydrug permeabilitylocation-dependent absorption |
| spellingShingle | Milica Markovic Moran Zur Noa Fine-Shamir Ester Haimov Isabel González-Álvarez Arik Dahan Segmental-Dependent Solubility and Permeability as Key Factors Guiding Controlled Release Drug Product Development Pharmaceutics controlled release drug product biopharmaceutics classification system drug solubility drug permeability location-dependent absorption |
| title | Segmental-Dependent Solubility and Permeability as Key Factors Guiding Controlled Release Drug Product Development |
| title_full | Segmental-Dependent Solubility and Permeability as Key Factors Guiding Controlled Release Drug Product Development |
| title_fullStr | Segmental-Dependent Solubility and Permeability as Key Factors Guiding Controlled Release Drug Product Development |
| title_full_unstemmed | Segmental-Dependent Solubility and Permeability as Key Factors Guiding Controlled Release Drug Product Development |
| title_short | Segmental-Dependent Solubility and Permeability as Key Factors Guiding Controlled Release Drug Product Development |
| title_sort | segmental dependent solubility and permeability as key factors guiding controlled release drug product development |
| topic | controlled release drug product biopharmaceutics classification system drug solubility drug permeability location-dependent absorption |
| url | https://www.mdpi.com/1999-4923/12/3/295 |
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