Plant-derived materials are increasingly recognized for their nutritional and medicinal benefits. Rutin (RN), a bioflavonoid with phenolic antioxidant properties, is known for scavenging superoxide radicals and enhancing blood vessel permeability. Despite these benefits, rutin's oral bioavailability is low due to poor absorption. To improve rutin's antioxidant qualities and bioavailability, this study sought to create a stable nanophytosomal formulation filled with rutin. The thin-layer hydration approach was used to create rutin-loaded nanophytosomes utilizing phosphatidylcholine (PC) and cholesterol (CH). Using differential scanning calorimetry (DSC), zeta potential, scanning electron microscopy, IR spectroscopy, and particle size analysis, the physicochemical characteristics of the nanophytosomes were evaluated. For a duration of three weeks during storage, the nanophytosomes' stability was assessed. As per the findings, the lowest particle size was obtained with an RN: PC: CH molar ratio of 1:2:0.5 (F3), and the physical stability of the nanophytosomes was considerably enhanced by the addition of cholesterol. Analytical techniques confirmed the formation of Rutin-Nanophytosomes. The formulation of Rutin nanophytosomes markedly improved the antioxidant activity of Rutin by increasing its bioavailability and stability.
INTRODUCTION
Rutin, also chemically known as 3, 3´, 4´, 5, 7-pentahydroflavone-3-rhamnoglucoside, is a well-known flavonoid that is present in a wide range of plants, including the Marantaceae family member Ruta graveolens. It has a variety of pharmacological properties, including anti-inflammatory, antithrombotic, antioxidant, and antineoplastic actions (Amjadi et al., 2021; Mahmood et al., 2023; Omidfar et al., 2023). Additionally, rutin is effective in mitigating ultraviolet radiation-induced oxidative stress and inflammation, treating capillary fragility, reducing hypertension, and lowering both hepatic and blood cholesterol levels. Its anti-platelet properties further enhance its therapeutic profile (Alharbi et al., 2021; Shriram et al., 2022; Moghaddam et al., 2023; Dehnad et al., 2024).
Typically made from soy, phospholipids and naturally occurring water-soluble phytoconstituents combine to form phytosomes, which are sophisticated delivery mechanisms. Lipid-compatible molecular complexes that considerably improve absorption and bioavailability are produced when certain concentrations of phospholipids combine with phytoconstituents in a solvent (Alharbi et al., 2021; Shriram et al., 2022; Ibrahim et al., 2023; Pozos-Nonato et al., 2023; Dehnad et al., 2024). Unlike conventional herbal extracts, phytosomes offer superior bioavailability due to their enhanced absorption and systemic circulation reach. This makes phytosomes particularly advantageous for the delivery of herbal medicines, nutraceuticals, and topical skin care products (Alharbi et al., 2021; Barani et al., 2021; Susilawati et al., 2021; Kumar et al., 2023).
Rutin, also known as quercetin-3-rutinoside or sophorin, is a flavanol glycoside consisting of the flavanol quercetin and the disaccharide rutinose. It is extracted from sources like the Japanese pagoda tree, buckwheat seed, and citrus fruits such as oranges, grapefruits, and lemons (Rathee & Kamboj, 2018; Lu et al., 2019; Islam et al., 2022; Shriram et al., 2022; Tiwari et al., 2023). One innovative drug delivery system for transdermal application is the nanophytosome, a vesicular complex formed between phytoconstituents and phospholipids, resembling cell membranes with polar heads and nonpolar tails. Phytoconstituents bind to the polar head of phospholipids, typically phosphatidylcholine, to form a stable complex that improves absorption and bioavailability (Zhang et al., 2013; Sabzichi et al., 2014; Telange et al., 2017; Alhakamy et al., 2020; Bhargav et al., 2021; Jain et al., 2021; Gaikwad et al., 2023).
Phytosomes are distinct from liposomes in their structural formation; while liposomes encapsulate the active ingredient within their cavity or membrane layers, phytosomes integrate the active ingredient into the membrane itself, anchoring it through chemical bonds to the phospholipid's polar head. This structural difference grants phytosomes superior physical stability, enhancing the absorption and bioavailability of hydrophilic polar phytoconstituents and leading to greater therapeutic benefits (Huang et al., 2020; Nandhini & Ilango, 2020; Alharbi et al., 2021).
Rutin's pharmacological activities extend beyond its antioxidant properties, including anti-inflammatory, neuroprotective, cardioprotective, anti-arthritic, anti-psoriasis, antimicrobial, antiallergic, antiviral, hepatoprotective, anticancer, and gastroprotective effects. Its notable antioxidative and radical-scavenging abilities make it effective against hydroxyl, superoxide, and peroxyl radicals (Riva et al., 2019; Shriram et al., 2022). Foods originating from plants and animals both include phospholipids, which are essential parts of all cell membranes. An excellent source of choline for dietary supplements is soy lecithin, a natural phospholipid combination (Naik et al., 2006; Gnananath et al., 2017; H Shariare et al., 2020).
The objective of this research is to create and assess rutin-loaded phytosomes as a possible topical treatment for inflammatory disorders, with the goal of long-term therapeutic advantages.
MATERIALS AND METHODS
Rutin (RN) was procured from Loba Chemie, Mumbai, India. Phosphatidylcholine (PC) was acquired from Labogen, Gujarat, India, while cholesterol (CH) was sourced from Labogen, Punjab, India. All additional chemicals and solvents required for the research were obtained from Himedia Laboratories Research Lab, Mumbai, India.
Preparation of rutin nanophytosomes (RN-NPs)
RN and PC were diluted in different molar ratios (1:1, 1:2, and 1:4) to create phytosomes by the thin layer hydration technique. Dichloromethane was used to dissolve cholesterol, but ethanol was used to dissolve RN and PC. A rotary evaporator (Heidolph, Germany) was used to evaporate the solvents from the mixture and create a thin, dry layer. The mixture was put in a flask with a circular bottom. The film was exposed to nitrogen gas flow and allowed to sit at room temperature for the whole night before being hydrated to guarantee total elimination of organic solvents. Next, using a rotary evaporator set at 45°C, the film was hydrated with distilled water. Three techniques—bath sonication (Model 8852, Cole-Parmer Instrument, Chicago, IL) at 45°C, homogenization (Heidolph, Germany) at 20,000 rpm, and probe sonication (Sonix, Vibracell)—were used to decrease the size of the phytosomes (Nagpal et al., 2016; Matias et al., 2017; Deleanu et al., 2023). The graphical approach of rutin-nanophytosome production is shown in Figure 1.
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Figure 1. Schematic Illustration of the Preparation Method of Rutin Nanophytosomes (RN-NPs) |
Characterization of nanophytosomes
IR spectroscopy: Using an FT-IR spectrometer (Brucker Alpha2, Germany), FT-IR spectra were captured. Potassium bromide was added to physical mixes, rutin pure, cholesterol, phosphatidylcholine, and lyophilized nanophytosomal formulations. The particles were compacted in a hydraulic press for 10 minutes at 15 tons of pressure (Direito et al., 2019). Between 4000 and 400 cm⁻¹, scans were conducted at a resolution of 2 cm⁻¹.
Differential scanning calorimetry
Samples containing phospholipids and phytosomes were placed in aluminum crimp cells and heated at a rate of 100°C/min from 0 to 4000°C under a nitrogen atmosphere using a Perkin Elmer 4000 (Germany). The onset temperatures of peak transitions were recorded with an analyzer.
Particle size
The particle size was measured using photon correlation spectroscopy (Horiba SZ-100, Japan) through the dynamic light scattering method (Abdelkader et al., 2016; El-Menshawe et al., 2018; Permana et al., 2020). Samples were diluted in distilled water and sonicated for 5 minutes. The analysis was performed three times, and the average hydrodynamic particle size was reported as the z-average size ± SD.
Zeta potential
A Malvern Zetasizer (Horiba SZ-100) was used to estimate the surface charge of rutin nanophytosomes. Experiments were conducted at 25 °C and 149 watts after samples were diluted 50 times with distilled water. Three measurements were used to determine the average zeta potential of the nanophytosomes.
Encapsulation efficiency
Using the following formula, the rutin encapsulation efficiency in nanophytosomes was determined
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EE % = Total drug added – free non-entrapped drug / total drug added |
(1) |
W [added drug] is the amount of free drug found in the lower chamber of an Amicon Ultra-15 tube (Merck Millipore Ltd., Ireland) with a 100 kDa molecular weight cutoff following centrifugation. W [added drug] is the amount of added drug used in the creation of nanophytosomes. One milliliter of the sample was diluted with one milliliter of ethanol to dissolve any unentrapped rutin in order to separate the drug from the nanoparticles. The nanophytosomes remained in the upper chamber after the mixture was centrifuged at 5000 rpm for 10 minutes in a Hettich EBA 20 centrifugal filter in Germany. The fact that the nanophytosomes retained their stability in a 50:50 hydroethanolic solution is noteworthy. With the use of a Shimadzu 8400 S (Japan) spectrophotometer, the amount of unentrapped Rutin in the lower chamber was measured.
Scanning electron microscopy [SEM]
About 5 μL of the phytosomal suspension was placed onto a coverslip and mounted on a specimen stub. The samples were then allowed to dry, and the particle size of the formulation was examined using scanning electron microscopy (SEM) with a Hitachi 4000plus (Japan).
Transmission electron microscopy [TEM]
Prior to testing, the newly made nanoparticle solution was diluted 1:5 in ethanol and sonicated for five minutes. Samples were seen in transmission electron microscopy (TEM; JEM-2000 EX; JEOL, Japan) at magnifications ranging from 50 to 200 nm after being arranged on a copper grid covered with carbon. The form and surface morphology of the particles were ascertained using TEM. Particle size was determined by measuring the diameter of individual nanoparticles in images that were taken using a digital camera.
Anti-oxidant activity
The assay measures antioxidants by their reaction with stable free picrylhydrazyl (DPPH) (Sikarwar et al., 2008; Kim et al., 2019; Rondanelli et al., 2022). The method involves mixing the sample with DPPH in methanol/water, which helps extract antioxidant compounds. 1.0 mL of the 0.4 mM DPPH solution and 1.0 mL of each test solution concentration series were combined for the test. After a certain amount of time, the mixtures were vortexed for thirty seconds. After that, absorbance at 516 nm was measured. Pure rutin and rutin nanophytosome samples were both subjected to absorbance tests.
RESULTS AND DISCUSSION
IR spectroscopy
Spectroscopic sleuthing was employed to uncover the intricate dance between phosphatidylcholine (PC) and Rutin. Using FTIR spectroscopy, the unique functional groups and their frequencies were revealed, showcasing the key chemical components of Rutin and PC, and highlighting the emergence of novel interactions between them during the nanophytosome creation. The FTIR spectra of pure Rutin, PC, and cholesterol are shown in Figure 2, along with physical mixes and the resultant Rutin, PC, and cholesterol nanophytosomes.
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Figure 2. IR Spectrum of a) Rutin, b) Cholesterol, c) Phosphatidylcholine, d) Physical Mixture, E) RN-NPS |
Differential scanning calorimetry [DSC]
DSC thermograms were inspected in order to confirm that a complex had formed between phospholipid and rutin (Martins-Gomes et al., 2022). Figure 3 shows the rutin-loaded nanophytosomes, their physical mixing, and the DSC thermograms of pure rutin, cholesterol, and phosphatidylcholine (PC).
Cholesterol's DSC thermogram exhibited endothermic peaks at 150°C, likely indicating the melting of its non-polar hydrocarbon tail. This phase transition produced a sharp peak. The physical mixture's DSC thermogram showed a similar peak for cholesterol at around 149°C. But there were no endothermic peaks for PC or Rutin. Both compounds' crystalline states changed when PC and rutin were combined.
The melting point of pure rutin, or 192 °C, was shown as an endothermic peak on the DSC thermogram. Remarkably, the thermogram of the nanophytosomes loaded with rutin showed that this peak had vanished, indicating that rutin was completely incorporated into the matrix of the nanophytosome, which had distinct thermal characteristics from the physical mixture. The polar portion of phosphatidylcholine and the -OH group of rutin most likely formed a hydrogen bond, which is responsible for this embedding, as Figure 3 shows.
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Figure 3. DSC Spectra of a) Rutin, b) Cholesterol, c)Phosphatidylcholine, d) Physical Mixture, e) RN-NPS |
Zeta potential
Zeta potential, the electric potential at a particle's surface, is a crucial indicator of colloidal system stability (Palachai et al., 2020; Hajizadeh Moghaddam et al., 2021; Costa et al., 2022). Colloids with high absolute Zeta potential values (typically above 30 mV), whether positive or negative, are considered electrically stable. Conversely, those with low Zeta potential values are prone to coagulation or flocculation, indicating instability. Generally, higher Zeta potential values correlate with greater and more enduring particle stability.
Various factors, such as pH, ionic strength, and the type and concentration of biopolymers used, can influence a particle's Zeta potential. The surface charge analysis results, depicted in Figure 4, indicate a Zeta potential of 3.3 mV for Rutin phytosomes, pointing to their high physical stability.
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Figure 4. Zeta potential of Rutin Nanophytosomes |
Particle size and encapsulation efficiency: Table 1 below details the encapsulation effectiveness, polydispersity index (PDI) value, mean particle size, antioxidant activity, and composition of Rutin nanophytosomes made with varying molar ratios of Rutin (RN), phosphatidylcholine (PC), and cholesterol (CH). Three experiments' mean ± standard deviation are displayed as the data.
Table 1. Composition, Mean Particle Size, PDI Value, Encapsulation Efficiency, and Antioxidant Activity of Rutin Nanophytosomes
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Formulations |
RN:PC: CH |
Particle size |
Encapsulation efficiency [%] |
PDI |
IC50 |
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F1 |
1:2:0.1 |
373.31 ± 1.51 |
96.00 ± 1.00 |
0.394 |
20.34 |
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F2 |
1:2:0.3 |
177.57 ± 1.54 |
96.65 ± 0.57 |
0.456. |
30.45 |
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F3 |
1:2:0.5 |
112.32 ± 2.87 |
95.64 ± 0.57 |
0.463 |
21.63 |
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F4 |
1:2:0.7 |
201.65 ± 6.49 |
95.64± 1.13 |
0.489 |
28.67 |
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F5 |
1:2:0.9 |
391.64 ± 2.87 |
96.30 ± 0.57 |
0.762 |
29.89 |
Scanning electron microscopy
Scanning Electron Microscopy (SEM) offers valuable insights into the solid-state characteristics and surface morphology of drugs and their complexes. The SEM analysis confirms the vesicle size, as measured by the size analyzer, to be 477 nm. The drug particles are observed to be associated with the phospholipids, forming spherical, uniform, and rigid vesicles. Figure 5 displays the SEM image of Rutin, illustrating these observations.
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Figure 5. SEM of Rutin nanophytosomes |
TEM
The Rutin nanophytosome sample utilized for the TEM analysis corresponds to the Rutin formula 2 nanophytosome, which has a composition of Rutin, Phosphatidylcholine, and Cholesterol in a ratio of 1:2:0.3. This specific formulation, incorporating 1 mole of phosphatidylcholine, helps to prevent particle agglomeration, ensuring that the particles remain small. TEM observations of the Rutin formula 2 nanophytosome reveal spherical nanoparticles. The TEM micrograph, depicted in Figure 6, shows that the polar regions of the vesicles appear black, whereas the non-polar regions are indicated by transparent or colorless areas.
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Figure 6. TEM of Rutin Nanophytosomes |
Anti-oxidant activity
The IC50 values in Table 1 indicate the antioxidant capability of Rutin nanophytosomes in each formula, which range from 20 to 32 μg/ml. In particular, rutin nanophytosomes made with RN:PC:CH molar ratios of 1:2:0.5 (F3) showed IC50 values of 21.63 μg/ml. The IC50 value of pure rutin powder is 25.28 μg/ml, which is higher than these values. This finding demonstrates that rutin nanophytosomes are more effective in scavenging free radicals than coarse rutin powder. As opposed to micronized products, a substantial improvement in free radical scavenging is obtained when particle size is reduced to the nanorange, which improves surface area and concentration gradient (Omidfar et al., 2023). So, by creating its nanophytosomes, rutin's antioxidant activity is enhanced. Rutin's antioxidant capacity was found to be efficient even after being encapsulated in the formulation of the nanophytosome.
The enhancement of antioxidant activity in Rutin nanophytosomes can be attributed to several key factors. Firstly, the encapsulation of Rutin in nanophytosomes significantly increases its solubility and bioavailability. Rutin, being lipophilic, typically exhibits poor solubility in aqueous environments, limiting its effectiveness. However, when encapsulated in nanophytosomes, the phospholipid bilayer facilitates better dispersion and interaction with biological membranes, enhancing absorption and cellular uptake.
Additionally, the small particle size of the nanophytosomes ensures a larger surface area for interaction with free radicals, leading to more efficient scavenging activity. This increased surface area also allows for a more uniform distribution of Rutin in biological systems, promoting consistent antioxidant activity throughout.
Moreover, the encapsulation process protects Rutin from degradation and oxidation, preserving its antioxidant properties over time. The stability provided by the nanophytosome structure ensures that Rutin remains active and effective until it reaches its target site within the body.
The high encapsulation efficiency of Rutin in the nanophytosomes, confirmed by FTIR and DSC analyses, further supports the enhanced antioxidant activity. The formation of a stable Rutin-Phospholipid complex ensures that a substantial amount of Rutin is delivered effectively, maximizing its therapeutic potential.
Overall, the improved solubility, increased surface area, enhanced stability, and efficient delivery provided by the nanophytosome formulation collectively contribute to the significantly enhanced antioxidant activity of Rutin, making it a promising approach for various therapeutic applications.
CONCLUSION
Because rutin has so many health advantages, industrial food science is interested in incorporating rutin into food items. Rutin's lipophilic properties, however, restrict its use in the treatment of diseases including cancer, COVID-19, bacterial infections, and viral infections. Our research on preparing nanostructures loaded with high amounts of Rutin (using a rutin-to-phosphatidylcholine ratio of 1:2) advances the understanding of incorporating lipophilic herbal supplements into food and beverages. The low particle size, excellent encapsulation effectiveness, and stability of the rutin-loaded nanophytosomes were observed upon physicochemical evaluation. Rutin was successfully loaded into the phytosomes, as shown by the FTIR and DSC tests that verified the development of a rutin-phospholipid complex in the nanophytosomes. In conclusion, the development of Rutin nanophytosomes significantly enhanced the antioxidant activity of Rutin, demonstrating improved bioavailability and stability compared to its conventional form.
ACKNOWLEDGMENTS: None
CONFLICT OF INTEREST: None
FINANCIAL SUPPORT: None
ETHICS STATEMENT: None
Abdelkader, H., Longman, M. R., Alany, R. G., & Pierscionek, B. (2016). Phytosome-hyaluronic acid systems for ocular delivery of L-carnosine. International Journal of Nanomedicine, 11, 2815-2827. doi:10.2147/IJN.S104774
Alhakamy, N. A., A Fahmy, U., Badr-Eldin, S. M., Ahmed, O. A. A., Asfour, H. Z., Aldawsari, H. M., Algandaby, M. M., Eid, B. G., Abdel-Naim, A. B., Awan, Z. A., et al. (2020). Optimized icariin phytosomes exhibit enhanced cytotoxicity and apoptosis-inducing activities in ovarian cancer cells. Pharmaceutics, 12(4), 346. doi:10.3390/pharmaceutics12040346
Alharbi, W. S., Almughem, F. A., Almehmady, A. M., Jarallah, S. J., Alsharif, W. K., Alzahrani, N. M., & Alshehri, A. A. (2021). Phytosomes as an emerging nanotechnology platform for the topical delivery of bioactive phytochemicals. Pharmaceutics, 13(9), 1475. doi:10.3390/pharmaceutics13091475
Amjadi, S., Shahnaz, F., Shokouhi, B., Azarmi, Y., Siahi-Shadbad, M., Ghanbarzadeh, S., Kouhsoltani, M., Ebrahimi, A., & Hamishehkar, H. (2021). Nanophytosomes for enhancement of rutin efficacy in oral administration for diabetes treatment in streptozotocin-induced diabetic rats. International Journal of Pharmaceutics, 610, 121208. doi:10.1016/j.ijpharm.2021.121208
Barani, M., Sangiovanni, E., Angarano, M., Rajizadeh, M. A., Mehrabani, M., Piazza, S., Gangadharappa, H. V., Pardakhty, A., Mehrbani, M., Dell'Agli, M., et al. (2021). Phytosomes as innovative delivery systems for phytochemicals: A comprehensive review of literature. International Journal of Nanomedicine, 16, 6983-7022. doi:10.2147/IJN.S318416
Bhargav, E., Y, P. R., & Koteshwara, K. B. (2021). A review of development and characterization of a cost-effective targeted quality-driven antimalarial product with an emphasis on phytosomes. Current Drug Targets, 22(15), 1772-1788. doi:10.2174/1389450122666210204203132
Costa, M., Soares, C., Silva, A., Grosso, C., & Delerue-Matos, C. (2022). Characterization of codium tomentosum phytosomes and their neuroprotective potential. In Biology and Life Sciences Forum (Vol. 18, No. 1, p. 35). MDPI. doi:10.3390/Foods2022-13009
Dehnad, D., Emadzadeh, B., Ghorani, B., Rajabzadeh, G., Kharazmi, M. S., & Jafari, S. M. (2024). Nano-vesicular carriers for bioactive compounds and their applications in food formulations. Critical Reviews in Food Science and Nutrition, 64(16), 5583-5602. doi:10.1080/10408398.2022.2156474
Deleanu, M., Toma, L., Sanda, G. M., Barbălată, T., Niculescu, L. Ş., Sima, A. V., Deleanu, C., Săcărescu, L., Suciu, A., Alexandru, G., et al. (2023). Formulation of phytosomes with extracts of ginger rhizomes and rosehips with improved bioavailability, antioxidant and anti-inflammatory effects in vivo. Pharmaceutics, 15(4), 1066. doi:10.3390/pharmaceutics15041066
Direito, R., Reis, C., Roque, L., Gonçalves, M., Sanches-Silva, A., Gaspar, M. M., Pinto, R., Rocha, J., Sepodes, B., Rosário Bronze, M., et al. (2019). Phytosomes with persimmon (Diospyros kaki L.) extract: Preparation and preliminary demonstration of in vivo tolerability. Pharmaceutics, 11(6), 296. doi:10.3390/pharmaceutics11060296
El-Menshawe, S. F., Ali, A. A., Rabeh, M. A., & Khalil, N. M. (2018). Nanosized soy phytosome-based thermogel as topical anti-obesity formulation: An approach for an acceptable level of evidence of an effective novel herbal weight loss product. International Journal of Nanomedicine, 13, 307-318. doi:10.2147/IJN.S153429
Gaikwad, S. S., Morade, Y. Y., Kothule, A. M., Kshirsagar, S. J., Laddha, U. D., & Salunkhe, K. S. (2023). Overview of phytosomes in treating cancer: Advancement, challenges, and future outlook. Heliyon, 9(6), e16561. doi:10.1016/j.heliyon.2023.e16561
Gnananath, K., Sri Nataraj, K., & Ganga Rao, B. (2017). Phospholipid complex technique for superior bioavailability of phytoconstituents. Advanced Pharmaceutical Bulletin, 7(1), 35–42. doi:10.15171/apb.2017.005
H Shariare, M., Afnan, K., Iqbal, F., A Altamimi, M., Ahamad, S. R., S Aldughaim, M., K Alanazi, F., & Kazi, M. (2020). Development and optimization of epigallocatechin-3-gallate (EGCG) nano phytosome using design of experiment (DoE) and their in vivo anti-inflammatory studies. Molecules (Basel, Switzerland), 25(22), 5453. doi:10.3390/molecules25225453
Hajizadeh Moghaddam, A., Abbasalipour, H., Ranjbar, M., & Khanjani Jelodar, S. (2021). Effect of sumac nano-phytosome on memory and oxidative stress in valproic acid-induced rat model of autism spectrum disorder. Journal of Guilan University of Medical Sciences, 29(4), 102-113. doi:10.32598/jgums.29.4.950.1
Huang, Z., Brennan, C. S., Zhao, H., Liu, J., Guan, W., Mohan, M. S., Stipkovits, L., Zheng, H., & Kulasiri, D. (2020). Fabrication and assessment of milk phospholipid-complexed antioxidant phytosomes with vitamin C and E: A comparison with liposomes. Food Chemistry, 324, 126837. doi:10.1016/j.foodchem.2020.126837
Ibrahim, R., Kasabri, V., Sunoqrot, S., Shalabi, D., Alkhateeb, R., & Alhiari, Y. (2023). Preparation and characterization of rutin-encapsulated polymeric micelles and studies of synergism with bioactive benzoic acids and triazolofluoroquinolones as anticancer nanomedicines. Asian Pacific Journal of Cancer Prevention, 24(3), 977-989. doi:10.31557/APJCP.2023.24.3.977
Islam, N., Irfan, M., Hussain, T., Mushtaq, M., Khan, I. U., Yousaf, A. M., Ghori, M. U., & Shahzad, Y. (2022). Piperine phytosomes for bioavailability enhancement of domperidone. Journal of Liposome Research, 32(2), 172-180. doi:10.1080/08982104.2021.1918153
Jain, P., Taleuzzaman, M., Kala, C., Kumar Gupta, D., Ali, A., & Aslam, M. (2021). Quality by design (qbd) assisted in the development of a phytosomal gel of aloe vera extract for topical delivery. Journal of Liposome Research, 31(4), 381-388.
Kim, S. M., Jung, J. I., Chai, C., & Imm, J. Y. (2019). Characteristics and glucose uptake promoting effect of chrysin-loaded phytosomes prepared with different phospholipid matrices. Nutrients, 11(10), 2549. doi:10.3390/nu11102549
Kumar, D. S., Deivasigamani, K., & Roy, B. (2023). Development and optimization of phytosome for enhancement of therapeutic potential of epiyangambin in tinospora cordifolia extract identified by GC–MS and docking analysis. Pharmacognosy Magazine, 19(2), 371-384. doi:10.1177/09731296231157192
Lu, M., Qiu, Q., Luo, X., Liu, X., Sun, J., Wang, C., Lin, X., Deng, Y., & Song, Y. (2019). Phyto-phospholipid complexes (phytosomes): A novel strategy to improve the bioavailability of active constituents. Asian Journal of Pharmaceutical Sciences, 14(3), 265-274. doi:10.1016/j.ajps.2018.05.011
Mahmood, T. H., Al-Samydai, A., Sulaibi, M. A., Alqaraleh, M., Abed, A. I., Shalan, N., Alsanabrah, A., Alsotari, S. T., Nsairat, H., & Alshaer, W. (2023). Development of pegylated Nano-Phytosome formulation with oleuropein and rutin to compare anti-colonic cancer activity with Olea Europaea leaves extract. Chemistry & Biodiversity, 20(8), e202300534. doi:10.1002/cbdv.202300534
Martins-Gomes, C., Souto, E. B., & Silva, A. M. (2022). Nanophytosomes: A novel approach for the delivery of herbal drugs. In Systems of Nanovesicular Drug Delivery (pp. 239-257). Academic Press. doi:10.1016/B978-0-323-91864-0.00015-2
Matias, D., Rijo, P., & Reis, C. P. (2017). Phytosomes as biocompatible carriers of natural drugs. Current Medicinal Chemistry, 24(6), 568-589. doi:10.2174/0929867323666161028160855
Moghaddam, A. H., Eslami, A., Jelodar, S. K., Ranjbar, M., & Hasantabar, V. (2023). Preventive effect of quercetin-loaded nanophytosome against autistic-like damage in maternal separation model: The possible role of Caspase-3, Bax/Bcl-2 and Nrf2. Behavioral Brain Research, 441, 114300. doi:10.1016/j.bbr.2023.114300
Nagpal, N., Arora, M., Swami, G., & Kapoor, R. (2016). Designing of a phytosome dosage form with Tecomella undulata as a novel drug delivery for better utilization. Pakistan Journal of Pharmaceutical Sciences, 29(4), 1231-1235.
Naik, S. R., Pilgaonkar, V. W., & Panda, V. S. (2006). Evaluation of antioxidant activity of Ginkgo biloba phytosomes in rat brain. Phytotherapy Research: PTR, 20(11), 1013-1016. doi:10.1002/ptr.1976
Nandhini, S., & Ilango, K. (2020). Development and characterization of a nano-drug delivery system containing vasaka phospholipid complex to improve bioavailability using quality by design approach. Research in Pharmaceutical Sciences, 16(1), 103-117. doi:10.4103/1735-5362.305193
Omidfar, F., Gheybi, F., Davoodi, J., Amirinejad, M., & Badiee, A. (2023). Nanophytosomes of hesperidin and hesperetin: Preparation, characterization, and in vivo evaluation. Biotechnology and Applied Biochemistry, 70(2), 846–856. doi:10.1002/bab.2404
Palachai, N., Wattanathorn, J., Muchimapura, S., & Thukham-Mee, W. (2020). Phytosome loading the combined extract of mulberry fruit and ginger protects against cerebral ischemia in metabolic syndrome rats. Oxidative Medicine and Cellular Longevity, 2020(1), 5305437. doi:10.1155/2020/5305437
Permana, A. D., Utami, R. N., Courtenay, A. J., Manggau, M. A., Donnelly, R. F., & Rahman, L. (2020). Phytosomal nanocarriers as platforms for improved delivery of natural antioxidant and photoprotective compounds in propolis: An approach for enhanced both dissolution behavior in biorelevant media and skin retention profiles. Journal of Photochemistry and Photobiology B: Biology, 205, 111846. doi:10.1016/j.jphotobiol.2020.111846
Pozos-Nonato, S., Domínguez-Delgado, C. L., Campos-Santander, K. A., Benavides, A. A., Pacheco-Ortin, S. M., Higuera-Piedrahita, R. I., Resendiz-González, G., & Molina-Trinidad, E. M. (2023). Novel nanotechnological strategies for skin anti-aging. Current Pharmaceutical Biotechnology, 24(11), 1397-1419. doi:10.2174/1389201024666221223095315
Rathee, S., & Kamboj, A. (2018). Optimization and development of antidiabetic phytosomes by the Box-Behnken design. Journal of Liposome Research, 28(2), 161-172. doi:10.1080/08982104.2017.1311913
Riva, A., Ronchi, M., Petrangolini, G., Bosisio, S., & Allegrini, P. (2019). Improved oral absorption of quercetin from quercetin phytosome®, a new delivery system based on food grade lecithin. European Journal of Drug Metabolism and Pharmacokinetics, 44(2), 169-177. doi:10.1007/s13318-018-0517-3
Rondanelli, M., Perna, S., Gasparri, C., Petrangolini, G., Allegrini, P., Cavioni, A., Faliva, M. A., Mansueto, F., Patelli, Z., Peroni, G., et al. (2022). Promising effects of 3-month period of quercetin phytosome® supplementation in the prevention of symptomatic COVID-19 disease in healthcare workers: A pilot study. Life (Basel, Switzerland), 12(1), 66. doi:10.3390/life12010066
Sabzichi, M., Hamishehkar, H., Ramezani, F., Sharifi, S., Tabasinezhad, M., Pirouzpanah, M., Ghanbari, P., & Samadi, N. (2014). Luteolin-loaded phytosomes sensitize human breast carcinoma MDA-MB 231 cells to doxorubicin by suppressing Nrf2-mediated signaling. Asian Pacific Journal of Cancer Prevention, 15(13), 5311-5316. doi:10.7314/apjcp.2014.15.13.5311
Shriram, R. G., Moin, A., Alotaibi, H. F., Khafagy, E. S., Al Saqr, A., Abu Lila, A. S., & Charyulu, R. N. (2022). Phytosomes as a plausible nano-delivery system for enhanced oral bioavailability and improved hepatoprotective activity of silymarin. Pharmaceuticals (Basel, Switzerland), 15(7), 790. doi:10.3390/ph15070790
Sikarwar, M. S., Sharma, S., Jain, A. K., & Parial, S. D. (2008). Preparation, characterization, and evaluation of Marsupsin-phospholipid complex. AAPS PharmSciTech, 9(1), 129-137. doi:10.1208/s12249-007-9020-x
Susilawati, Y., Chaerunisa, A. Y., & Purwaningsih, H. (2021). Phytosomes drug delivery system for natural cosmeceutical compounds: Whitening agent and skin antioxidant agent. Journal of Advanced Pharmaceutical Technology & Research, 12(4), 327-334. doi:10.4103/japtr.JAPTR_100_20
Telange, D. R., Patil, A. T., Pethe, A. M., Fegade, H., Anand, S., & Dave, V. S. (2017). Formulation and characterization of an apigenin-phospholipid phytosome (APLC) for improved solubility, in vivo bioavailability, and antioxidant potential. European Journal of Pharmaceutical Sciences: Official Journal of the European Federation for Pharmaceutical Sciences, 108, 36-49. doi:10.1016/j.ejps.2016.12.009
Tiwari, R., Tiwari, G., Sharma, S., & Ramachandran, V. (2023). An exploration of herbal extracts loaded phyto-phospholipid complexes (phytosomes) against polycystic ovarian syndrome: Formulation considerations. Pharmaceutical Nanotechnology, 11(1), 44–55. doi:10.2174/2211738510666220919125434
Zhang, J., Tang, Q., Xu, X., & Li, N. (2013). Development and evaluation of a novel phytosome-loaded chitosan microsphere system for curcumin delivery. International Journal of Pharmaceutics, 448(1), 168–174. doi:10.1016/j.ijpharm.2013.03.021
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