Solid lipid nanoparticles for increased oral bioavailability of acalabrutinib in chronic lymphocytic leukaemia
Abstract Acalabrutinib (ACP) is a first-line treatment for chronic lymphocytic leukemia but suffers from poor and variable oral bioavailability due to its pH-dependent solubility, CYP3A4 metabolism, and P-gp efflux. Thus, the objective of this study was to improve the solubility and dissolution beha...
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Springer
2024-12-01
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| Series: | Discover Nano |
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| Online Access: | https://doi.org/10.1186/s11671-024-04157-8 |
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| author | Swagata Sinha Punna Rao Ravi Makarand Somvanshi S. R. Rashmi |
| author_facet | Swagata Sinha Punna Rao Ravi Makarand Somvanshi S. R. Rashmi |
| author_sort | Swagata Sinha |
| collection | DOAJ |
| description | Abstract Acalabrutinib (ACP) is a first-line treatment for chronic lymphocytic leukemia but suffers from poor and variable oral bioavailability due to its pH-dependent solubility, CYP3A4 metabolism, and P-gp efflux. Thus, the objective of this study was to improve the solubility and dissolution behaviour, in turn enhancing bioavailability, by formulating solid lipid nanoparticles (SLNs). ACP loaded SLNs (ACP-SLNs) were prepared via solvent-free hot emulsification followed by a double sonication process. A combination of glyceryl di-behenate and stearyl palmitate along with Tween 80 was used as the lipid phase to dissolve ACP. A 1% w/v Poloxomer188 solution served as the aqueous phase. The optimized ACP-SLNs were spherical in shape and had particle size of 234.7–257.5 nm, PDI of 0.261–0.320 and loading efficiency of 18.70 ± 1.78%. A typical biphasic release pattern was observed from ACP-SLNs in the in vitro dissolution studies under gastrointestinal and plasma pH conditions (> 90% drug release at pH 4.5 ± 0.2, 6.8 ± 0.2 (representing GIT), and 7.4 ± 0.2 (representing plasma) at 8, 16 and 24 h, respectively). The freeze-dried product was stable when stored at 5 °C for over 6 months. Compared with the bulk drug suspension, the ACP-SLNs suspension resulted in 2.29-fold increase in oral bioavailability and more importantly 2.46-fold increase in the distribution of drug to spleen. Additionally, inhibition of lymph production and flow by administering cycloheximide resulted in 46.01% decrease in the overall absorption of ACP-SLNs, indicating the significance of lymphatic uptake process in the oral absorption of ACP-SLNs. Graphical Abstract |
| format | Article |
| id | doaj-art-2c3cb11a8e2f494da54164f04ade5ea5 |
| institution | Kabale University |
| issn | 2731-9229 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Nano |
| spelling | doaj-art-2c3cb11a8e2f494da54164f04ade5ea52025-01-05T12:43:47ZengSpringerDiscover Nano2731-92292024-12-0119112110.1186/s11671-024-04157-8Solid lipid nanoparticles for increased oral bioavailability of acalabrutinib in chronic lymphocytic leukaemiaSwagata Sinha0Punna Rao Ravi1Makarand Somvanshi2S. R. Rashmi3Department of Pharmacy, Birla Institute of Technology and Science Pilani, BITS-Pilani Hyderabad CampusDepartment of Pharmacy, Birla Institute of Technology and Science Pilani, BITS-Pilani Hyderabad CampusDepartment of Pharmacy, Birla Institute of Technology and Science Pilani, BITS-Pilani Hyderabad CampusDepartment of Pharmacy, Birla Institute of Technology and Science Pilani, BITS-Pilani Hyderabad CampusAbstract Acalabrutinib (ACP) is a first-line treatment for chronic lymphocytic leukemia but suffers from poor and variable oral bioavailability due to its pH-dependent solubility, CYP3A4 metabolism, and P-gp efflux. Thus, the objective of this study was to improve the solubility and dissolution behaviour, in turn enhancing bioavailability, by formulating solid lipid nanoparticles (SLNs). ACP loaded SLNs (ACP-SLNs) were prepared via solvent-free hot emulsification followed by a double sonication process. A combination of glyceryl di-behenate and stearyl palmitate along with Tween 80 was used as the lipid phase to dissolve ACP. A 1% w/v Poloxomer188 solution served as the aqueous phase. The optimized ACP-SLNs were spherical in shape and had particle size of 234.7–257.5 nm, PDI of 0.261–0.320 and loading efficiency of 18.70 ± 1.78%. A typical biphasic release pattern was observed from ACP-SLNs in the in vitro dissolution studies under gastrointestinal and plasma pH conditions (> 90% drug release at pH 4.5 ± 0.2, 6.8 ± 0.2 (representing GIT), and 7.4 ± 0.2 (representing plasma) at 8, 16 and 24 h, respectively). The freeze-dried product was stable when stored at 5 °C for over 6 months. Compared with the bulk drug suspension, the ACP-SLNs suspension resulted in 2.29-fold increase in oral bioavailability and more importantly 2.46-fold increase in the distribution of drug to spleen. Additionally, inhibition of lymph production and flow by administering cycloheximide resulted in 46.01% decrease in the overall absorption of ACP-SLNs, indicating the significance of lymphatic uptake process in the oral absorption of ACP-SLNs. Graphical Abstracthttps://doi.org/10.1186/s11671-024-04157-8Tyrosine kinase inhibitorSolvent-free hot emulsificationBiphasic release systemsSpleen distributionLymphatic uptake |
| spellingShingle | Swagata Sinha Punna Rao Ravi Makarand Somvanshi S. R. Rashmi Solid lipid nanoparticles for increased oral bioavailability of acalabrutinib in chronic lymphocytic leukaemia Discover Nano Tyrosine kinase inhibitor Solvent-free hot emulsification Biphasic release systems Spleen distribution Lymphatic uptake |
| title | Solid lipid nanoparticles for increased oral bioavailability of acalabrutinib in chronic lymphocytic leukaemia |
| title_full | Solid lipid nanoparticles for increased oral bioavailability of acalabrutinib in chronic lymphocytic leukaemia |
| title_fullStr | Solid lipid nanoparticles for increased oral bioavailability of acalabrutinib in chronic lymphocytic leukaemia |
| title_full_unstemmed | Solid lipid nanoparticles for increased oral bioavailability of acalabrutinib in chronic lymphocytic leukaemia |
| title_short | Solid lipid nanoparticles for increased oral bioavailability of acalabrutinib in chronic lymphocytic leukaemia |
| title_sort | solid lipid nanoparticles for increased oral bioavailability of acalabrutinib in chronic lymphocytic leukaemia |
| topic | Tyrosine kinase inhibitor Solvent-free hot emulsification Biphasic release systems Spleen distribution Lymphatic uptake |
| url | https://doi.org/10.1186/s11671-024-04157-8 |
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