Abstract
Purpose
The design, optimization, preparation, and characterization of phytosomes loaded with naringenin were the goals of the current work. The present work was intended to enhance solubility and bioavailability of naringenin.
Method
The Box-Behnken design with three factors and three levels was employed to optimize the process parameters of naringenin loaded phytosomes. In the end, the design expert software’s desirability function technique helped to identify the ideal process conditions. Reproducible techniques and independent variables, including a ratio of drug: phospholipid concentration, a processing temperature, and processing time, were used to formulate the optimized batch. Using the Box-Behnken design, the influence of these independent factors on the dependent variables, such as % entrapment efficiency and % product yield, was assessed. The optimization of the formulation was also characterized by means of tests for solubility, vesicle size, zeta potential, PDI, FTIR, XRPD, DSC, SEM, TEM, in vitro release study, in vivo bioavailability study, and stability study.
Results
It was discovered that the optimized formulation had a 64.21% product yield and a 95.26% EE. The aqueous solubility of formulated naringenin phytosomes was increased from 24.65 ± 0.46 to 176.55 ± 0.25 µg/mL. The vesicle size was found to be 161.9 nm ± 5.6, and ZP and PDI was − 22.8 mV ± 0.4 and 0.444 ± 0.07, respectively. FTIR, XRPD, and DSC confirmed the formation of phytosomes. In SEM of naringenin-loaded phytosomes, significant change in morphology and shape were observed which confirmed the absence of crystallinity of naringenin. The uniform structure and spherical shape were demonstrated by TEM. The comparative in vitro drug release study of naringenin loaded phytosomes showed the sustained release characteristics of phytosomes which reached 95.26% compared to pure naringenin reached 33.76% at the end of 12 h. Following oral administration of NGNP, the concentration of NGN in rabbit plasma at various time intervals was assessed by HPLC. The pharmacokinetic characteristics of NGNP in the rabbit were Tmax = 1.5 h, Cmax = 2.532 0.256 µg/mL, and AUC0-24 = 26.443 µg/mL·h.
Conclusion
Therefore, results demonstrated the importance of optimization of formulation development using quality by design strategy to achieve phytosomes with consistent quality.
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References
Yao W, Zhang X, Xu F, Cao C, Liu T, Xue Y. The therapeutic effects of naringenin on bronchial pneumonia in children. Pharmacol Res Perspect. 2021;9(4):1–7. https://doi.org/10.1002/prp2.825.
Tutunchi H, Naeini F, Ostadrahimi A, Hosseinzadeh-Attar MJ. Naringenin, a flavanone with antiviral and anti-inflammatory effects: a promising treatment strategy against COVID-19. Phyther Res. 2020;34(12):3137–47. https://doi.org/10.1002/ptr.6781.
Cheng IF, Breen K. On the ability of four flavonoids, baicilein, luteolin, naringenin, and quercetin, to suppress the fenton reaction of the iron-ATP complex. Biometals. 2000;13(1):77–83. https://doi.org/10.1023/A:1009229429250.
Yu Z, Liu X, Chen H, Zhu L. Naringenin-loaded dipalmitoylphosphatidylcholine phytosome dry powders for inhaled treatment of acute lung injury. J Aerosol Med Pulm Drug Deliv. 2020;33(4):194–204. https://doi.org/10.1089/jamp.2019.1569.
Wadhwa R, et al. Anti-inflammatory and anticancer activities of naringenin-loaded liquid crystalline nanoparticles in vitro. J Food Biochem. 2021;45(1):1–14. https://doi.org/10.1111/jfbc.13572.
Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK. Enhanced therapeutic potential of naringenin-phospholipid complex in rats. J Pharm Pharmacol. 2010;58(9):1227–33. https://doi.org/10.1211/jpp.58.9.0009.
Kumar R, Bhan Tiku A. “Naringenin suppresses chemically induced skin cancer in two-stage skin carcinogenesis mouse model.” Nutr Cancer. 2020;72(6):976–983. https://doi.org/10.1080/01635581.2019.1656756.
Alhakamy NA, et al. Thymoquinone-loaded soy-phospholipid-based phytosomes exhibit anticancer potential against human lung cancer cells. Pharmaceutics. 2020;12(8):1–17. https://doi.org/10.3390/pharmaceutics12080761.
Karpuz M, Gunay MS, Ozer AY. “Liposomes and phytosomes for phytoconstituents.” Adv Ave Dev Nov Carriers Bioact Biol Agents. 2020;525–553. https://doi.org/10.1016/b978-0-12-819666-3.00018-3.
Reeta RM, John M, Newton A. Fabrication and characterisation of lavender oil and plant phospholipid based sumatriptan succinate hybrid nano lipid carriers. Pharm Biomed Res. 2020;6(1):91–104. https://doi.org/10.18502/pbr.v6i1.3430.
Rodrigues K et al. “QBD approach for the development of hesperetin loaded colloidal nanosponges for sustained delivery: in-vitro, ex-vivo, and in-vivo assessment." OpenNano. 2022;7:100045. https://doi.org/10.1016/j.onano.2022.100045.
Upadhyay K, Gupta NK, Dixit VK. Development and characterization of phyto-vesicles of β-sitosterol for the treatment of androgenetic alopecia. Arch Dermatol Res. 2012;304(7):511–9. https://doi.org/10.1007/s00403-011-1199-8.
Chi C, Zhang C, Liu Y, Nie H, Zhou J, Ding Y. “Phytosome-nanosuspensions for silybin-phospholipid complex with increased bioavailability and hepatoprotection efficacy.” Eur J Pharm Sci. 2020;144:105212. https://doi.org/10.1016/j.ejps.2020.105212.
Jena SK, Singh C, Dora CP, Suresh S. Development of tamoxifen-phospholipid complex: novel approach for improving solubility and bioavailability. Int J Pharm. 2014;473(1–2):1–9. https://doi.org/10.1016/j.ijpharm.2014.06.056.
Rathee S, Kamboj A. Optimization and development of antidiabetic phytosomes by the Box-Behnken design. J Liposome Res. 2018;28(2):161–72. https://doi.org/10.1080/08982104.2017.1311913.
Freag MS, Saleh WM, Abdallah OY. Self-assembled phospholipid-based phytosomal nanocarriers as promising platforms for improving oral bioavailability of the anticancer celastrol. Int J Pharm. 2018;535(1–2):18–26. https://doi.org/10.1016/j.ijpharm.2017.10.053.
Jain P, Taleuzzaman M, Kala C, Kumar Gupta D, Ali A, Aslam M. “Quality by design (Qbd) assisted development of phytosomal gel of aloe vera extract for topical delivery.” J Liposome Res. 2021;31(4):381–388. https://doi.org/10.1080/08982104.2020.1849279.
Id SG, Usapkar P, Id NG, Nadaf S, Jena G, Id RC. “nanocarriers for enhanced delivery and therapeutic efficacy of hesperetin." 2022;1:1–15. https://doi.org/10.1371/journal.pone.0274916.
Ahmad H, et al. Phospholipid complexation of NMITLI118RT+: way to a prudent therapeutic approach for beneficial outcomes in ischemic stroke in rats. Drug Deliv. 2016;23(9):3606–18. https://doi.org/10.1080/10717544.2016.1212950.
Wang W, et al. Preparation of ursolic acid–phospholipid complex by solvent-assisted grinding method to improve dissolution and oral bioavailability. Pharm Dev Technol. 2020;25(1):68–75. https://doi.org/10.1080/10837450.2019.1671864.
International Conference on Harmonization (ICH). Guidance for industry: Q1A(R2) Stability testing of new drug substances and products. Ich Harmon Tripart Guidel. 2003;4:24. https://database.ich.org/sites/default/files/Q1A%28R2%29%20Guideline.pdf.
Psimadas D, Georgoulias P, Valotassiou V, Loudos G. Molecular nanomedicine towards cancer. J Pharm Sci. 2012;101(7):2271–80. https://doi.org/10.1002/jps.
Guo L, Chen J, Qiu Y, Zhang S, Xu B, Gao Y. Enhanced transcutaneous immunization via dissolving microneedle array loaded with liposome encapsulated antigen and adjuvant. Int J Pharm. 2013;447(1–2):22–30. https://doi.org/10.1016/j.ijpharm.2013.02.006.
Dressman JB, Reppas C. In vitro-in vivo correlations for lipophilic, poorly water-soluble drugs. Eur J Pharm Sci. 2000;11(SUPPL. 2):73–80. https://doi.org/10.1016/S0928-0987(00)00181-0.
Alharbi WS, et al. Phytosomes as an emerging nanotechnology platform for the topical delivery of bioactive phytochemicals. Pharmaceutics. 2021;13(9):1–20. https://doi.org/10.3390/pharmaceutics13091475.
Sundaresan N, Kaliappan I. Development and characterization of a nano-drug delivery system containing vasaka phospholipid complex to improve bioavailability using quality by design approach. Res Pharm Sci. 2021;16(1):103–17. https://doi.org/10.4103/1735-5362.305193.
Singh D, Rawat MSM, Semalty A, Semalty M. Chrysophanol-phospholipid complex: a drug delivery strategy in herbal novel drug delivery system (HNDDS). J Therm Anal Calorim. 2013;111(3):2069–77. https://doi.org/10.1007/s10973-012-2448-6.
Telange DR, Sohail NK, Hemke AT, Kharkar PS, Pethe AM. Phospholipid complex-loaded self-assembled phytosomal soft nanoparticles: evidence of enhanced solubility, dissolution rate, ex vivo permeability, oral bioavailability, and antioxidant potential of mangiferin. Drug Deliv Transl Res. 2021;11(3):1056–83. https://doi.org/10.1007/s13346-020-00822-4.
Saoji SD et al. “Phospholipid based colloidal nanocarriers for enhanced solubility and therapeutic efficacy of withanolides.” J Drug Deliv Sci Technol. 2022;70:103251. https://doi.org/10.1016/j.jddst.2022.103251.
Hartogh DJD, Tsiani E. Antidiabetic properties of naringenin: a citrus fruit polyphenol. Biomolecules. 2019;9(3):4–9. https://doi.org/10.3390/biom9030099.
Gracias S, Ayyanar M, Peramaiyan G, Kalaskar M, Redasani V, Gurav N, Gurav S. "Fabrication of chitosan nanocomposites loaded with biosynthetic metallic nanoparticles and their therapeutic investigation." Environ Res. 2023;234. https://doi.org/10.1016/j.envres.2023.116609
Halarnekar D, Ayyanar M, Gangapriya P, Kalaskar M, Redasani V, Gurav N, Gurav S. "Eco synthesized chitosan/zinc oxide nanocomposites as the next generation of nano-delivery for antibacterial, antioxidant, antidiabetic potential, and chronic wound repair." Int J Biol Macromol. 2023;242. https://doi.org/10.1016/j.ijbiomac.2023.124764
Acknowledgements
The authors are also grateful to VAV Life Science in Mumbai, who gifted the LS75. The authors are also grateful to the Principal, Appasaheb Birnale College of Pharmacy of Sangli, and the Principal, Adarsh College of Pharmacy, Vita, for providing laboratory and instrument facilities to carry out this research work.
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Metkari, V., Shah, R., Salunkhe, N. et al. QBD Approach for the Design, Optimization, Development, and Characterization of Naringenin-Loaded Phytosomes to Enhance Solubility and Oral Bioavailability. J Pharm Innov 18, 2083–2097 (2023). https://doi.org/10.1007/s12247-023-09775-w
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DOI: https://doi.org/10.1007/s12247-023-09775-w