Formulation, in silico, in vitro characterization, cytotoxicity and cellular uptake of cyclodextrin complexes and ion pairing/salt formation with functional excipients (azelaic acid, tartaric acid, and arginine) with raloxifene
With advancements in drug repurposing, the search for effective and less harmful anticancer agents remains a critical endeavor. Raloxifene, although not a typical anticancer drug, holds promise in this context. However, its poor solubility poses a significant challenge to its therapeutic potential a...
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Elsevier
2025-06-01
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| Series: | International Journal of Pharmaceutics: X |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590156725000210 |
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| author | Hamdy Abdelkader Adel Al-Fatease Ali H. Alamri Mai E. Shoman Hend Mohamed Abdel-Bar Zeinab Fathalla |
| author_facet | Hamdy Abdelkader Adel Al-Fatease Ali H. Alamri Mai E. Shoman Hend Mohamed Abdel-Bar Zeinab Fathalla |
| author_sort | Hamdy Abdelkader |
| collection | DOAJ |
| description | With advancements in drug repurposing, the search for effective and less harmful anticancer agents remains a critical endeavor. Raloxifene, although not a typical anticancer drug, holds promise in this context. However, its poor solubility poses a significant challenge to its therapeutic potential and formulation efficiency. Functional excipients such as cyclodextrins (e.g., β-cyclodextrin, hydroxy propyl β-cyclodextrin, and Captisol) and pH-modifying excipients (e.g., tartaric acid, azelaic acid, and arginine) were investigated to enhance solubility, dissolution, cytotoxicity and cellular uptakes employing Caco-2 cell lines through binary solid dispersions. In silico studies suggested the potential for salt formation with raloxifene-azelaic acid and raloxifene-tartaric acid, as well as inclusion complexes with cyclodextrins. Experimental results showed that pH-modifying excipients, particularly tartaric and azelaic acids, significantly improved solubility (up to an 800-fold increase), outperforming cyclodextrins (8-fold increase) compared to the untreated drug. Cytotoxicity studies on the human breast cancer (Michigan cancer foundation, MCF-7) cells revealed that raloxifene-tartaric acid significantly enhanced cell killing, achieving efficacy comparable to the standard anticancer drug Taxol. Additionally, both fluorescence-labeled raloxifene: hydroxy propyl β-cyclodextrin coprecipitated mixtures (Coppt) and raloxifene: tartaric acid Coppt exhibited concentration- and time-dependent cellular uptake, with mean fluorescence intensity increasing significantly at 24 h, indicating rapid internalization and sustained intracellular retention, especially at higher concentrations. More interestingly, the superior cellular uptake was in favor of the latter, indicating the pH-modifying excipient tartaric acid, and these findings correlated well with solubility and dissolution studies. |
| format | Article |
| id | doaj-art-8edfa1ccbcba4e4bbbc554e407923252 |
| institution | OA Journals |
| issn | 2590-1567 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal of Pharmaceutics: X |
| spelling | doaj-art-8edfa1ccbcba4e4bbbc554e4079232522025-08-20T02:09:52ZengElsevierInternational Journal of Pharmaceutics: X2590-15672025-06-01910033610.1016/j.ijpx.2025.100336Formulation, in silico, in vitro characterization, cytotoxicity and cellular uptake of cyclodextrin complexes and ion pairing/salt formation with functional excipients (azelaic acid, tartaric acid, and arginine) with raloxifeneHamdy Abdelkader0Adel Al-Fatease1Ali H. Alamri2Mai E. Shoman3Hend Mohamed Abdel-Bar4Zeinab Fathalla5Central Labs, King Khalid University, AlQura'a, Abha, P.O. Box 960, Saudi Arabia; Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia; Corresponding author at: Pharmaceutics Department, College of Pharmacy, King Khalid University, Abha, Saudi Arabia.Department of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 62529, Saudi ArabiaDepartment of Pharmaceutics, College of Pharmacy, King Khalid University, Abha 62529, Saudi ArabiaDepartment of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia, EgyptDepartment of Pharmaceutics, Faculty of Pharmacy, University of Sadat City, Sadat city, EgyptDepartment of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, EgyptWith advancements in drug repurposing, the search for effective and less harmful anticancer agents remains a critical endeavor. Raloxifene, although not a typical anticancer drug, holds promise in this context. However, its poor solubility poses a significant challenge to its therapeutic potential and formulation efficiency. Functional excipients such as cyclodextrins (e.g., β-cyclodextrin, hydroxy propyl β-cyclodextrin, and Captisol) and pH-modifying excipients (e.g., tartaric acid, azelaic acid, and arginine) were investigated to enhance solubility, dissolution, cytotoxicity and cellular uptakes employing Caco-2 cell lines through binary solid dispersions. In silico studies suggested the potential for salt formation with raloxifene-azelaic acid and raloxifene-tartaric acid, as well as inclusion complexes with cyclodextrins. Experimental results showed that pH-modifying excipients, particularly tartaric and azelaic acids, significantly improved solubility (up to an 800-fold increase), outperforming cyclodextrins (8-fold increase) compared to the untreated drug. Cytotoxicity studies on the human breast cancer (Michigan cancer foundation, MCF-7) cells revealed that raloxifene-tartaric acid significantly enhanced cell killing, achieving efficacy comparable to the standard anticancer drug Taxol. Additionally, both fluorescence-labeled raloxifene: hydroxy propyl β-cyclodextrin coprecipitated mixtures (Coppt) and raloxifene: tartaric acid Coppt exhibited concentration- and time-dependent cellular uptake, with mean fluorescence intensity increasing significantly at 24 h, indicating rapid internalization and sustained intracellular retention, especially at higher concentrations. More interestingly, the superior cellular uptake was in favor of the latter, indicating the pH-modifying excipient tartaric acid, and these findings correlated well with solubility and dissolution studies.http://www.sciencedirect.com/science/article/pii/S2590156725000210Raloxifene, functional excipientsAzelaic acidCyclodextrinsCoprecipitationAnticancerBreast cancer |
| spellingShingle | Hamdy Abdelkader Adel Al-Fatease Ali H. Alamri Mai E. Shoman Hend Mohamed Abdel-Bar Zeinab Fathalla Formulation, in silico, in vitro characterization, cytotoxicity and cellular uptake of cyclodextrin complexes and ion pairing/salt formation with functional excipients (azelaic acid, tartaric acid, and arginine) with raloxifene International Journal of Pharmaceutics: X Raloxifene, functional excipients Azelaic acid Cyclodextrins Coprecipitation Anticancer Breast cancer |
| title | Formulation, in silico, in vitro characterization, cytotoxicity and cellular uptake of cyclodextrin complexes and ion pairing/salt formation with functional excipients (azelaic acid, tartaric acid, and arginine) with raloxifene |
| title_full | Formulation, in silico, in vitro characterization, cytotoxicity and cellular uptake of cyclodextrin complexes and ion pairing/salt formation with functional excipients (azelaic acid, tartaric acid, and arginine) with raloxifene |
| title_fullStr | Formulation, in silico, in vitro characterization, cytotoxicity and cellular uptake of cyclodextrin complexes and ion pairing/salt formation with functional excipients (azelaic acid, tartaric acid, and arginine) with raloxifene |
| title_full_unstemmed | Formulation, in silico, in vitro characterization, cytotoxicity and cellular uptake of cyclodextrin complexes and ion pairing/salt formation with functional excipients (azelaic acid, tartaric acid, and arginine) with raloxifene |
| title_short | Formulation, in silico, in vitro characterization, cytotoxicity and cellular uptake of cyclodextrin complexes and ion pairing/salt formation with functional excipients (azelaic acid, tartaric acid, and arginine) with raloxifene |
| title_sort | formulation in silico in vitro characterization cytotoxicity and cellular uptake of cyclodextrin complexes and ion pairing salt formation with functional excipients azelaic acid tartaric acid and arginine with raloxifene |
| topic | Raloxifene, functional excipients Azelaic acid Cyclodextrins Coprecipitation Anticancer Breast cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2590156725000210 |
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