Proniosomal encapsulation of tenofovir for improved stability and controlled release: a factorial design-based study
DOI:
https://doi.org/10.56782/pps.536Keywords:
tenofovir, proniosomes, controlled release, factorial design, encapsulation efficiencyAbstract
Tenofovir, a widely used antiviral agent, suffers from poor stability, low bioavailability, and rapid renal clearance, limiting its therapeutic efficacy. Proniosomes, a vesicular drug delivery system, offer a promising approach to enhance tenofovir's stability and controlled release. A factorial design approach was employed to optimize tenofovir-loaded proniosomes, evaluating key formulation variables such as surfactant type, cholesterol concentration, and maltodextrin concentration. The formulations were evaluated for particle size, polydispersity index (PDI), zeta potential, and encapsulation efficiency (EE%), with morphological characteristics examined through SEM and TEM imaging. In vitro, drug release studies were conducted to assess the controlled release behavior, while stability studies evaluated the formulation's robustness under different storage conditions. The optimized formulation showed a particle size of around 420 nm, a low PDI (< 0.3), a zeta potential of -28.6 mV, and an encapsulation efficiency of 87.3%, reflecting its stability and uniform vesicle distribution. The in vitro release profile showed prolonged drug release over 24 hours, beginning with an initial burst phase followed by a controlled diffusion phase. The release kinetics followed the Korsmeyer-Peppas model, suggesting a non-Fickian diffusion mechanism. Stability studies showed minimal changes in physicochemical properties over three months, confirming formulation stability. The study highlights proniosomes as an effective delivery system for tenofovir, offering enhanced stability, sustained release, and improved encapsulation efficiency. This approach presents a potential alternative for improving the pharmacokinetic profile of tenofovir, ensuring better therapeutic outcomes in antiviral therapy.
Downloads
References
1. Menéndez-Arias, L.; Delgado, R. Update and latest advances in antiretroviral therapy. Trends Pharmacol. Sci. 2022, 43(1), 16–29. DOI: 10.1016/j.tips.2021.10.004 DOI: https://doi.org/10.1016/j.tips.2021.10.004
2. Peng, Y.; Zong, Y.; Wang, D.; Chen, J.; Chen, Z.S.; Peng, F.; Liu, Z. Current drugs for HIV-1: from challenges to potential in HIV/AIDS. Front. Pharmacol. 2023, 14, Art. No: 1294966. DOI: 10.3389/fphar.2023.1294966 DOI: https://doi.org/10.3389/fphar.2023.1294966
3. Watkins, M.E.; Wring, S.; Randolph, R.; et al. Development of a novel formulation that improves preclinical bioavailability of tenofovir disoproxil fumarate. J. Pharm. Sci. 2017, 106, 906–919. DOI: 10.1016/j.xphs.2016.12.015 DOI: https://doi.org/10.1016/j.xphs.2016.12.003
4. Sangeetha, S. Formulation Design, Optimization, and Evaluation of Solid Lipid Nanoparticles Loaded With an Antiviral Drug Tenofovir Using Box–Behnken Design for Boosting Oral Bioavailability. Adv. Pharmacol. Pharm. Sci. 2024, 2024, Art. No: 5248746. DOI: 10.1155/2024/5248746 DOI: https://doi.org/10.1155/2024/5248746
5. Limenh, L.W. Advances in the transdermal delivery of antiretroviral drugs. SAGE Open Med. 2024, 12, Art. No: 20503121231223600. DOI: 10.1177/20503121231223600 DOI: https://doi.org/10.1177/20503121231223600
6. Burns, R.N.; Hendrix, C.W.; Chaturvedula, A. Population pharmacokinetics of tenofovir and tenofovir‐diphosphate in healthy women. J. Clin. Pharmacol. 2015, 55, 629–638. DOI: 10.1002/jcph.464 DOI: https://doi.org/10.1002/jcph.461
7. Hagos, Y.; Wolff, N.A. Assessment of the role of renal organic anion transporters in drug-induced nephrotoxicity. Toxins 2010, 2, 2055–2082. DOI: 10.3390/toxins2082055 DOI: https://doi.org/10.3390/toxins2082055
8. Kohler, J.J.; Hosseini, S.H.; Green, E.; et al. Tenofovir renal proximal tubular toxicity is regulated by OAT1 and MRP4 transporters. Lab. Invest. 2011, 91, 852–858. DOI: 10.1038/labinvest.2011.35 DOI: https://doi.org/10.1038/labinvest.2011.48
9. Agrahari, V.; Putty, S.; Mathes, C.; et al. Evaluation of degradation kinetics and physicochemical stability of tenofovir. Drug Test. Anal. 2015, 7, 207–213. DOI: 10.1002/dta.1659 DOI: https://doi.org/10.1002/dta.1656
10. De Clercq, E. Tenofovir alafenamide (TAF) as the successor of tenofovir disoproxil fumarate (TDF). Biochem. Pharmacol. 2016, 119, 1–7. DOI: 10.1016/j.bcp.2016.04.002 DOI: https://doi.org/10.1016/j.bcp.2016.04.015
11. Murphy, R.A.; Valentovic, M.A. Factors contributing to the antiviral effectiveness of tenofovir. J. Pharmacol. Exp. Ther. 2017, 363, 156–163. DOI: 10.1124/jpet.117.242073 DOI: https://doi.org/10.1124/jpet.117.243139
12. Singireddy, A.R.; Pedireddi, S.R. Advances in lopinavir formulations: strategies to overcome solubility, bioavailability, and stability challenges. Prospect. Pharm. Sci. 2024, 22, 105–121. DOI: 10.56782/pps.280 DOI: https://doi.org/10.56782/pps.280
13. Cobb, D.A.; Smith, N.; Deodhar, S.; et al. Transformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles. Nat. Commun. 2021, 12, Art. No: 5458. DOI: 10.1038/s41467-021-25770-4 DOI: https://doi.org/10.1038/s41467-021-25690-5
14. Safari, J.B.; Bapolisi, A.M.; Krause, R.W. Development of pH-sensitive chitosan-g-poly(acrylamide-co-acrylic acid) hydrogel for controlled drug delivery of tenofovir disoproxil fumarate. Polymers 2021, 13, Art. No: 3571. DOI: 10.3390/polym13203571 DOI: https://doi.org/10.3390/polym13203571
15. Zhang, T.; Zhang, C.; Agrahari, V.; et al. Spray drying tenofovir loaded mucoadhesive and pH-sensitive microspheres intended for HIV prevention. Antivir. Res. 2013, 97, 334–346. DOI: 10.1016/j.antiviral.2012.12.008 DOI: https://doi.org/10.1016/j.antiviral.2012.12.019
16. Pribut, N.; D’Erasmo, M.; Dasari, M.; et al. ω-Functionalized lipid prodrugs of HIV NtRTI tenofovir with enhanced pharmacokinetic properties. J. Med. Chem. 2021, 64, 12917–12937. DOI: 10.1021/acs.jmedchem.1c00928 DOI: https://doi.org/10.1021/acs.jmedchem.1c01083
17. Reddy, D.M.; Chetty, C.M.; Reddy, Y.D.; et al. Formulation and Evaluation of fast dissolving buccal patches of tenofovir disoproxil fumarate. Res. J. Pharm. Technol. 2021, 14, 225–230. DOI: 10.52711/0974-360X.2021.00038 DOI: https://doi.org/10.5958/0974-360X.2021.00039.1
18. Cazorla-Luna, R.; Notario-Pérez, F.; Martín-Illana, A.; et al. Chitosan-based mucoadhesive vaginal tablets for controlled release of the anti-HIV drug tenofovir. Pharmaceutics 2019, 11, Art. No: 20. DOI: 10.3390/pharmaceutics11010020 DOI: https://doi.org/10.3390/pharmaceutics11010020
19. Belletti, D.; Tosi, G.; Forni, F.; et al. Chemico-physical investigation of tenofovir loaded polymeric nanoparticles. Int. J. Pharm. 2012, 436, 753–763. DOI: 10.1016/j.ijpharm.2012.06.059 DOI: https://doi.org/10.1016/j.ijpharm.2012.07.070
20. Mathieu, T.; Favetta, P.; Agrofoglio, L.A. Molecularly Imprinted Polymeric Nanoparticles as Drug Delivery System for Tenofovir, an Acyclic Nucleoside Phosphonate Antiviral. Pharmaceutics 2024, 16, Art. No: 965. DOI: 10.3390/pharmaceutics16070965 DOI: https://doi.org/10.3390/pharmaceutics16070965
21. Zidan, A.S.; Spinks, C.B.; Habib, M.J.; et al. Formulation and transport properties of tenofovir loaded liposomes through Caco-2 cell model. J. Liposome Res. 2013, 23, 318–326. DOI: 10.3109/08982104.2013.814823 DOI: https://doi.org/10.3109/08982104.2013.810645
22. Spinks, C.B.; Zidan, A.S.; Khan, M.A.; et al. Pharmaceutical characterization of novel tenofovir liposomal formulations for enhanced oral drug delivery: in vitro pharmaceutics and Caco-2 permeability investigations. Clin. Pharmacol. Adv. Appl. 2017, 9, 29–38. DOI: 10.2147/CPAA.S122449 DOI: https://doi.org/10.2147/CPAA.S119875
23. Khatoon, M.; Shah, K.U.; Din, F.U.; et al. Proniosomes derived niosomes: recent advancements in drug delivery and targeting. Drug Deliv. 2017, 24, 56–69. DOI: 10.1080/10717544.2016.1230054 DOI: https://doi.org/10.1080/10717544.2017.1384520
24. Khindri, S.; Aggarwal, G.; Hari Kumar, S.L. Role of niosomes and proniosomes for enhancing bioavailability of drugs. J. Drug Deliv. Ther. 2015, 5, 28–33. DOI: 10.22270/jddt.v5i1.1004 DOI: https://doi.org/10.22270/jddt.v5i1.1043
25. Song, S.; Tian, B.; Chen, F.; et al. Potentials of proniosomes for improving the oral bioavailability of poorly water-soluble drugs. Drug Dev. Ind. Pharm. 2015, 41, 51–62. DOI: 10.3109/03639045.2013.865234 DOI: https://doi.org/10.3109/03639045.2013.845841
26. Ahmed, S.; Farag, M.M.; Attia, H.; et al. Exploring the potential of antifungal-loaded proniosomes to consolidate corneal permeation in fungal keratitis: A comprehensive investigation from laboratory characterization to microbiological evaluation. Int. J. Pharm. X 2025, 9, Art. No: 100322. DOI: 10.1016/j.ijpx.2024.100322 DOI: https://doi.org/10.1016/j.ijpx.2025.100322
27. Thongpon, P.; Intuyod, K.; Pongking, T.; et al. Curcumin-Loaded Maltodextrin-Based Proniosomes Potentially Effective against Gemcitabine-Resistant Cholangiocarcinoma. ACS Appl. Bio Mater. 2025, 8, 913-930. DOI: 10.1021/acsabm.4c01832 DOI: https://doi.org/10.1021/acsabm.4c01832
28. Anwer, K.E.; El-Sattar, N.E.; Shamaa, M.M.; et al. Design, green synthesis and tailoring of vitamin E TPGS augmented niosomal nano-carrier of pyrazolopyrimidines as potential anti-liver and breast cancer agents with accentuated oral bioavailability. Pharmaceuticals 2022, 15, Art. No: 330. DOI: 10.3390/ph15030330 DOI: https://doi.org/10.3390/ph15030330
29. Paarakh, M.P.; Jose, P.A.; Setty, C.M.; Peterchristoper, G.V. Release kinetics–concepts and applications. Int. J. Pharm. Res. Technol. 2018, 8, 12–20.
30. Askarizadeh, M.; Esfandiari, N.; Honarvar, B.; et al. Kinetic modeling to explain the release of medicine from drug delivery systems. ChemBioEng Rev. 2023, 10, 1006–1049. DOI: 10.1002/cben.202300065 DOI: https://doi.org/10.1002/cben.202300027
31. Atnip, A.; Giusti, M.M.; Sigurdson, G.T.; et al. The NCI-N87 cell line as a gastric epithelial model to study cellular uptake, trans-epithelial transport, and gastric anti-inflammatory properties of anthocyanins. Nutr. Cancer 2020, 72, 686–695. DOI: 10.1080/01635581. 2019.1655646 DOI: https://doi.org/10.1080/01635581.2019.1644354
32. Gharbavi, M.; Johari, B.; Mousazadeh, N.; et al. Hybrid of niosomes and bio-synthesized selenium nanoparticles as a novel approach in drug delivery for cancer treatment. Mol. Biol. Rep. 2020, 47, 6517–6529. DOI: 10.1007/s11033-020-05683-7 DOI: https://doi.org/10.1007/s11033-020-05704-z
33. Singireddy, A.; Pedireddi, S.R.; Subramanian, S. Optimization of reaction parameters for synthesis of Cyclodextrin nanosponges in controlled nanoscopic size dimensions. J. Polym. Res. 2019, 26, Art. No: 93. DOI: 10.1007/s10965-019-1743-3 DOI: https://doi.org/10.1007/s10965-019-1754-0
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Swarupa Arvapalli , Anka Rao Areti
This work is licensed under a Creative Commons Attribution 4.0 International License.
For all articles published in Prospects in Pharmaceutical Sciences copyright is retained by the authors. The journal publishes articles in the Open Access policy, within the CC BY 4.0 licence.
This is a human-readable summary of (and not a substitute for) the license. Disclaimer.
You are free to:
Share — copy and redistribute the material in any medium or format
Adapt — remix, transform, and build upon the material for any purpose, even commercially.
The licensor cannot revoke these freedoms as long as you follow the license terms.
Under the following terms:
Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
Notices:
You do not have to comply with the license for elements of the material in the public domain or where your use is permitted by an applicable exception or limitation.
No warranties are given. The license may not give you all of the permissions necessary for your intended use. For example, other rights such as publicity, privacy, or moral rights may limit how you use the material.
How to Cite
