Improving the Solubility and Oral Bioavailability of a Novel Aromatic Aldehyde Antisickling Agent (PP10) for the Treatment of Sickle Cell Disease
Background: Aromatic aldehydes, with their ability to increase the oxygen affinity of sickle hemoglobin, have become important therapeutic agents for sickle cell disease (SCD). One such compound, voxelotor, was recently approved for SCD treatment. Methyl 6-((2-formyl-3-hydroxyphenoxy)methyl) picolin...
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| Online Access: | https://www.mdpi.com/1999-4923/13/8/1148 |
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| author | Tarek A. Ahmed Khalid M. El-Say Fathy I. Abd-Allah Abdelsattar M. Omar Moustafa E. El-Araby Yosra A. Muhammad Piyusha P. Pagare Yan Zhang Khadijah A. Mohmmad Osheiza Abdulmalik Martin K. Safo |
| author_facet | Tarek A. Ahmed Khalid M. El-Say Fathy I. Abd-Allah Abdelsattar M. Omar Moustafa E. El-Araby Yosra A. Muhammad Piyusha P. Pagare Yan Zhang Khadijah A. Mohmmad Osheiza Abdulmalik Martin K. Safo |
| author_sort | Tarek A. Ahmed |
| collection | DOAJ |
| description | Background: Aromatic aldehydes, with their ability to increase the oxygen affinity of sickle hemoglobin, have become important therapeutic agents for sickle cell disease (SCD). One such compound, voxelotor, was recently approved for SCD treatment. Methyl 6-((2-formyl-3-hydroxyphenoxy)methyl) picolinate (PP10) is another promising aromatic aldehyde, recently reported by our group. Like voxelotor, PP10 exhibits O<sub>2</sub>-dependent antisickling activity, but, unlike voxelotor, PP10 shows unique O<sub>2</sub>-independent antisickling effect. PP10, however, has limited solubility. This study therefore aimed to develop oral and parenteral formulations to improve PP10 solubility and bioavailability. Methods: Oral drug tablets with 2-hydroxypropyl beta cyclodextrin (HP-β-CD), polyvinylpyrrolidone, or Eudragit L100-55 PP10-binary system, and an intravenous (IV) formulation with <span style="font-variant: small-caps;">d</span>-α-tocopherol polyethylene glycol 1000 succinate (TPGS) or HP-β-CD, were developed. The pharmacokinetic behavior of the formulations was studied in Sprague-Dawley rats. PP10, a methylester, and its acid metabolite were also studied in vitro with sickle whole blood to determine their effect on Hb modification, Hb oxygen affinity, and sickle red blood cell inhibition. Results: Aqueous solubility of PP10 was enhanced ~5 times with the HP-β-CD binary system, while the TPGS aqueous micelle formulation was superior, with a drug concentration of 0.502 ± 0.01 mg/mL and a particle size of 26 ± 3 nm. The oral tablets showed relative and absolute bioavailabilities of 173.4% and 106.34%, respectively. The acid form of PP10 appeared to dominate in vivo, although both PP10 forms demonstrated pharmacologic effect. Conclusion: Oral and IV formulations of PP10 were successfully developed using HP-β-CD binary system and TPGS aqueous micelles, respectively, resulting in significantly improved solubility and bioavailability. |
| first_indexed | 2024-03-10T08:29:12Z |
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| id | doaj.art-53b06f2a01054c37bbf3132feeae3703 |
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| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T08:29:12Z |
| publishDate | 2021-07-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-53b06f2a01054c37bbf3132feeae37032023-11-22T09:13:10ZengMDPI AGPharmaceutics1999-49232021-07-01138114810.3390/pharmaceutics13081148Improving the Solubility and Oral Bioavailability of a Novel Aromatic Aldehyde Antisickling Agent (PP10) for the Treatment of Sickle Cell DiseaseTarek A. Ahmed0Khalid M. El-Say1Fathy I. Abd-Allah2Abdelsattar M. Omar3Moustafa E. El-Araby4Yosra A. Muhammad5Piyusha P. Pagare6Yan Zhang7Khadijah A. Mohmmad8Osheiza Abdulmalik9Martin K. Safo10Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, EgyptDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USADepartment of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USADepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDivision of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADepartment of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USABackground: Aromatic aldehydes, with their ability to increase the oxygen affinity of sickle hemoglobin, have become important therapeutic agents for sickle cell disease (SCD). One such compound, voxelotor, was recently approved for SCD treatment. Methyl 6-((2-formyl-3-hydroxyphenoxy)methyl) picolinate (PP10) is another promising aromatic aldehyde, recently reported by our group. Like voxelotor, PP10 exhibits O<sub>2</sub>-dependent antisickling activity, but, unlike voxelotor, PP10 shows unique O<sub>2</sub>-independent antisickling effect. PP10, however, has limited solubility. This study therefore aimed to develop oral and parenteral formulations to improve PP10 solubility and bioavailability. Methods: Oral drug tablets with 2-hydroxypropyl beta cyclodextrin (HP-β-CD), polyvinylpyrrolidone, or Eudragit L100-55 PP10-binary system, and an intravenous (IV) formulation with <span style="font-variant: small-caps;">d</span>-α-tocopherol polyethylene glycol 1000 succinate (TPGS) or HP-β-CD, were developed. The pharmacokinetic behavior of the formulations was studied in Sprague-Dawley rats. PP10, a methylester, and its acid metabolite were also studied in vitro with sickle whole blood to determine their effect on Hb modification, Hb oxygen affinity, and sickle red blood cell inhibition. Results: Aqueous solubility of PP10 was enhanced ~5 times with the HP-β-CD binary system, while the TPGS aqueous micelle formulation was superior, with a drug concentration of 0.502 ± 0.01 mg/mL and a particle size of 26 ± 3 nm. The oral tablets showed relative and absolute bioavailabilities of 173.4% and 106.34%, respectively. The acid form of PP10 appeared to dominate in vivo, although both PP10 forms demonstrated pharmacologic effect. Conclusion: Oral and IV formulations of PP10 were successfully developed using HP-β-CD binary system and TPGS aqueous micelles, respectively, resulting in significantly improved solubility and bioavailability.https://www.mdpi.com/1999-4923/13/8/1148PP10aromatic aldehydesickle cell diseaseinherited blood disordersoral tabletsintravenous formulation |
| spellingShingle | Tarek A. Ahmed Khalid M. El-Say Fathy I. Abd-Allah Abdelsattar M. Omar Moustafa E. El-Araby Yosra A. Muhammad Piyusha P. Pagare Yan Zhang Khadijah A. Mohmmad Osheiza Abdulmalik Martin K. Safo Improving the Solubility and Oral Bioavailability of a Novel Aromatic Aldehyde Antisickling Agent (PP10) for the Treatment of Sickle Cell Disease Pharmaceutics PP10 aromatic aldehyde sickle cell disease inherited blood disorders oral tablets intravenous formulation |
| title | Improving the Solubility and Oral Bioavailability of a Novel Aromatic Aldehyde Antisickling Agent (PP10) for the Treatment of Sickle Cell Disease |
| title_full | Improving the Solubility and Oral Bioavailability of a Novel Aromatic Aldehyde Antisickling Agent (PP10) for the Treatment of Sickle Cell Disease |
| title_fullStr | Improving the Solubility and Oral Bioavailability of a Novel Aromatic Aldehyde Antisickling Agent (PP10) for the Treatment of Sickle Cell Disease |
| title_full_unstemmed | Improving the Solubility and Oral Bioavailability of a Novel Aromatic Aldehyde Antisickling Agent (PP10) for the Treatment of Sickle Cell Disease |
| title_short | Improving the Solubility and Oral Bioavailability of a Novel Aromatic Aldehyde Antisickling Agent (PP10) for the Treatment of Sickle Cell Disease |
| title_sort | improving the solubility and oral bioavailability of a novel aromatic aldehyde antisickling agent pp10 for the treatment of sickle cell disease |
| topic | PP10 aromatic aldehyde sickle cell disease inherited blood disorders oral tablets intravenous formulation |
| url | https://www.mdpi.com/1999-4923/13/8/1148 |
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