Formulation and in vitro Evaluation of Hesperidin-Phospholipid Complex and its Antioxidant Potential

Author(s): Bhupen Kalita*, Bhargab Nath Patwary

Journal Name: Current Drug Therapy

Volume 15 , Issue 1 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: The recent trend of herbal drug delivery has been focused on developing novel drug delivery carriers to address problems related to solubility, oral bioavailability, skin permeation and stability. The phyto-phospholipid complex (phytosomes®) technology has been used to overcome the problems associated with many conventional herbal extracts.

Aim: The present work aimed to formulate phospholipid-complex of the flavanoid Hesperidin to enhance its dissolution leading to enhanced oral bioavailability.

Method: The complex was prepared by refluxing various molar ratios of hesperidin and PC followed by solvent evaporation. The prepared complexes were evaluated for saturation solubility, partition co-efficient and drug content. The free drug and phospholipid complexes were analyzed in DSC. Surface morphology of the prepared complexes was viewed using SEM images. Selected formulations were subjected to in vitro drug release study. Antioxidant effect was examined by free radical scavenging method.

Results: Solubility and partition coefficient of the prepared complexes were improved in comparison to free drug. Based on the results of solubility, partition coefficient and drug content, formulation F2 was selected as an optimized batch. DSC thermograms confirmed the formation of phospholipid complex. Free Hesperidin and Hesperidin-phospholipid complex (F2) showed 46.9 % and 78.20 % of drug release, respectively, at seven hours phosphate buffer (pH 7.4). The optimized formulation showed concentration-dependent anti-oxidant property.

Conclusion: Results of the present study suggested that the phospholipid complex of Hesperidin possesses the antioxidant potential and may be of potential use for improving the dissolution of hesperidin and hence oral bioavailability.

Keywords: Hesperidin, phospholipid complex, phytosomes, herbosomes, solubility, antioxidant.

Devi VK, Jain N, Valli KS. Importance of novel drug delivery systems in herbal medicines. Pharmacogn Rev 2010; 4(7): 27-31.
[] [PMID: 22228938]
Shivanand P, Kinjal P. Phytosomes: Technical revolution in phytomedicine. Int J Pharmatech Res 2010; 2: 627-31.
Goda T, Goto Y, Ishihara K. Cell-penetrating macromolecules: direct penetration of amphipathic phospholipid polymers across plasma membrane of living cells. Biomaterials 2010; 31(8): 2380-7.
[] [PMID: 20004016]
Bombardelli E, Curri SB, Della RL, Del Negaro P, Tubaro A, Gariboldi P. Complexes between phospholipids and vegetable derivatives of biological interests. Fitoterapia 1989; 60: 1-9.
Bombardelli E, Spelta M. Phospholipid-polyphenol complex: a new concept in skin care ingredients. Cosmetics Toiletries 1991; 106: 69-76.
Gabetta B, Bombardelli E, Pifferi G. Complexes of flavanolignanes with phospholipids, preparation thereof and associated pharmaceutical compositions. European Patent 0209038 1987.
Yanyu X, Yunmei S, Zhipeng C, Qineng P. The preparation of silybin-phospholipid complex and the study on its pharmacokinetics in rats. Int J Pharm 2006; 307(1): 77-82.
[] [PMID: 16300915]
Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK. Curcumin-phospholipid complex: Preparation, therapeutic evaluation and pharmacokinetic study in rats. Int J Pharm 2007; 330(1-2): 155-63.
[] [PMID: 17112692]
Singh C, Bhatt TD, Gill MS, Suresh S. Novel rifampicin-phospholipid complex for tubercular therapy: Synthesis, physicochemical characterization and in-vivo evaluation. Int J Pharm 2014; 460(1-2): 220-7.
[] [PMID: 24188983]
Semalty A, Semalty M, Singh D, Rawat MSM. Development and characterization of aspirin-phospholipid complex for improved drug delivery. Int J Pharm Sci Nanotechnol 2010; 3: 340-7.
Wu J, Chen D, Zhang R. Study on the bioavailability of baicalin-phospholipid complex by using HPLC. Biomed Chromatogr 1999; 13(7): 493-5.
[<493:AID-BMC915>3.0.CO;2-A] [PMID: 10534761]
Maiti K, Mukherjee K, Gantait A, Ahmed HN, Saha BP, Mukherjee PK. Enhanced therapeutic benefit of quercetin-phospholipid complex in carbon tetrachloride-induced acute liver injury in rats: a comparative study. Iran J Pharmacol Ther 2005; 4: 84-90.
Kalita B, Das MK. Rutin-phospholipid complex in polymer matrix for long-term delivery of rutin via skin for the treatment of inflammatory diseases. Artif Cells Nanomed Biotechnol 2018; 46(Suppl. 1): 41-56.
[] [PMID: 29226739]
Kalita B, Das MK. Resveratrol-phospholipid complexes (Phytosomes) with improved physicochemical properties favorable for drug delivery via skin. World J Pharm Res 2015; 4: 1497-517.
Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK. Enhanced therapeutic potential of naringenin-phospholipid complex in rats. J Pharm Pharmacol 2006; 58(9): 1227-33.
[] [PMID: 16945181]
Pathan RA, Bhandari U. Preparation & characterization of embelin-phospholipid complex as effective drug delivery tool. J Incl Phenom Macrocycl Chem 2011; 69: 139-47.
O’Neil MJ. The ‘Merck Index’ an Encyclopedia of chemicals. Drugs & Biologicals 2006; p. 807.
Anwer MK, Al-Shdefat R, Jamil S, Alam P, Abdel-Kader MS, Shakeel F. Solubility of Bioactive Compound Hesperidin in Six Pure Solvents at (298.15 to 333.15) K. J Chem Eng Data 2014; 59: 2065-9.
Galati EM, Monforte MT, Kirjavainen S, Forestieri AM, Trovato A, Tripodo MM. Biological effects of hesperidin, a citrus flavonoid. (Note I): antiinflammatory and analgesic activity. Farmaco 1994; 40(11): 709-12.
[PMID: 7832973]
Iskender H, Dokumacioglu E, Sen TM, Ince I, Kanbay Y, Saral S. The effect of hesperidin and quercetin on oxidative stress, NF-κB and SIRT1 levels in a STZ-induced experimental diabetes model. Biomed Pharmacother 2017; 90: 500-8.
[] [PMID: 28395272]
Fernández SP, Wasowski C, Loscalzo LM, et al. Central nervous system depressant action of flavonoid glycosides. Eur J Pharmacol 2006; 539(3): 168-76.
[] [PMID: 16698011]
Kamisli S, Ciftci O, Kaya K, Cetin A, Kamisli O, Ozcan C. Hesperidin protects brain and sciatic nerve tissues against cisplatin-induced oxidative, histological and electromyographical side effects in rats. Toxicol Ind Health 2015; 31(9): 841-51.
[] [PMID: 23552266]
Majumdar S, Srirangam R. Solubility, stability, physicochemical characteristics and in vitro ocular tissue permeability of hesperidin: a natural bioflavonoid. Pharm Res 2009; 26(5): 1217-25.
[] [PMID: 18810327]
Wilmsen PK, Spada DS, Salvador M. Antioxidant activity of the flavonoid hesperidin in chemical and biological systems. J Agric Food Chem 2005; 53(12): 4757-61.
[] [PMID: 15941311]
Devi SL, Kannappan S, Anuradha CV. Evaluation of in vitro antioxidant activity of Indian bay leaf, Cinnamomum tamala (Buch. -Ham.) T. Nees & Eberm using rat brain synaptosomes as model system. Indian J Exp Biol 2007; 45(9): 778-84.
[PMID: 17907743]
Nikhat F, Satyanarayan D, Subramanyam EVS. Isolation, Characterization and screening of antioxidant activity of the roots of Syzygiumcumminii (L) Skeel. Asian J Reacher Chem 2009; 2(2): 218-21.
Singh R, Singh N, Saini BS, Rao HS. In vitro antioxidant activity of pet ether extract of black pepper. Indian J Pharmacol 2008; 40(4): 147-51.
[] [PMID: 20040947]
Gacche RN, Kabaliye VN, Dhole NA, Jadhav AD. Antioxidant potential of selected vegetables commonly used in diet in India subcontinent. Indian J Nat Prod Resour 2010; 1: 306-13.
Ameer B, Weintraub RA, Johnson JV, Yost RA, Rouseff RL. Flavanone absorption after naringin, hesperidin, and citrus administration. Clin Pharmacol Ther 1996; 60(1): 34-40.
[] [PMID: 8689809]
Gil-Izquierdo A, Gil MI, Tomas-Barberan FA, Ferreres F. Influence of industrial processing on orange juice flavanone solubility and transformation to chalcones under gastrointestinal conditions. J Agric Food Chem 2003; 51(10): 3024-8.
[] [PMID: 12720386]
Ofer M, Wolffram S, Koggel A, Spahn-Langguth H, Langguth P. Modulation of drug transport by selected flavonoids: Involvement of P-gp and OCT? Eur J Pharm Sci 2005; 25(2-3): 263-71.
[] [PMID: 15911222]
Breinholt VM, Offord EA, Brouwer C, Nielsen SE, Brøsen K, Friedberg T. In vitro investigation of cytochrome P450-mediated metabolism of dietary flavonoids. Food Chem Toxicol 2002; 40(5): 609-16.
[] [PMID: 11955666]
Kobayashi S, Tanabe S, Sugiyama M, Konishi Y. Transepithelial transport of hesperetin and hesperidin in intestinal Caco-2 cell monolayers. Biochim Biophys Acta 2008; 1778(1): 33-41.
[] [PMID: 18021752]
Serra H, Mendes T, Bronze MR, Simplício AL. Prediction of intestinal absorption and metabolism of pharmacologically active flavones and flavanones. Bioorg Med Chem 2008; 16(7): 4009-18.
[] [PMID: 18249545]
Manach C, Morand C, Gil-Izquierdo A, Bouteloup-Demange C, Rémésy C. Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice. Eur J Clin Nutr 2003; 57(2): 235-42.
[] [PMID: 12571654]
Habbu P, Madagundi S, Kulkarni R, Jadav S, Vanakudri R, Kulkarni V. Preparation and evaluation of Bacopa-phospholipid complex for antiamnesic activity in rodents. Drug Invention Today 2013; 5: 13-21.
Yue PF, Yuan HL, Xie H, et al. Preparation, characterization, and bioavailability of ursodeoxycholic acid-phospholipid complex in vivo. Drug Dev Ind Pharm 2008; 34(7): 708-18.
[] [PMID: 18612911]
Qin X, Yang Y, Fan TT, Gong T, Zhang XN, Huang Y. Preparation, characterization and in vivo evaluation of bergenin-phospholipid complex. Acta Pharmacol Sin 2010; 31(1): 127-36.
[] [PMID: 19966834]
Leo A, Hansch C, Elkins D. Partition co-efficient and their uses. Chem Rev 1971; 71: 525-616.
Ai F, Ma Y, Wang J, Li Y. Preparation, Physicochemical Characterization and in vitro Dissolution Studies of Diosmin-cyclodextrin Inclusion Complexes. Iran J Pharm Res 2014; 13(4): 1115-23.
[PMID: 25587299]
Bhalekar MR, Madgulkar AR, Aswar M, Mariam G, Desale P. A comparative study of oral and topical administration of hesperidin lipid nanoparticles in rheumatoid arthritiss. Austin Arthritis 2016; 1: 1010.
Oyaizu M. Studies on products of browning reactions: Antioxidative activities of products of browning reaction prepared from glucosamine. Japanese J Nutrition 1986; 44: 307-15.
Jayanthi P, Lalitha P. Reducing power of the solvent extracts of Eichhornia crassipes (Mart) Solms. Int J Pharm Pharm Sci 2011; 3: 126-8.
Pawar HA, Bhangale BD. Phytosome as a novel biomedicine: a microencapsulated drug delivery system. J Bioanal Biomed 2015; 7: 6-12.
Jose MM, Bombardelli E. Pharmaceutical compositions containing flavanolignans and phospholipida active principles. 1987.US Patent No-EPO20903.
Maryana W, Rachmawati H, Mudhakir D. Formation of phytosome containing silymarin using thin layer-hydration technique aimed for oral delivery. Mater Today Proc 2016; 3(3): 855-66.
Ittadwar PA, Puranik PK. Novel umbelliferone phytosomes: Development and optimization using experimental design approach and evaluation of photo-protective and antioxidant activity. Int J Pharm Pharm Sci 2017; 9(1): 218-28.
Yue PF, Yuan HL, Yang M, Zhu WF. Preparation, characterization and pharmacokinetics in vivo of oxymatrine-phospholipid complex. J Bioequivalence Bioavailab 2009; 1: 99-102.
Tan Q, Liu S, Chen X, et al. Design and evaluation of a novel evodiamine-phospholipid complex for improved oral bioavailability. AAPS PharmSciTech 2012; 13(2): 534-47.
[] [PMID: 22454136]
Mei L, Qiujun Q, Xiang L, et al. Phyto-phospholipid complexes (phytosomes): a novel strategy to improve the bioavailability of active constituents. Asian J Pharmaceutical 2019; 14(3): 265-74.
Xia HJ, Zhang ZH, Jin X, Hu Q, Chen XY, Jia XB. A novel drug-phospholipid complex enriched with micelles: Preparation and evaluation in vitro and in vivo. Int J Nanomedicine 2013; 8: 545-54.
[] [PMID: 23431115]
Keerthi B, Pingali PS, Srinivas P. Formulation and Evaluation of Capsules of Ashwagandha Phytosomes. Int J Pharm Sci Rev Res 2014; 29(2): 138-42.
Abdelkader H, Longman MR, Alany RG, Pierscionek B. Phytosome-hyaluronic acid systems for ocular delivery of L-carnosine. Int J Nanomedicine 2016; 11: 2815-27.
[] [PMID: 27366062]
Semalty A, Semalty M, Singh D, Rawat MSM. Preparation and characterization of phospholipid complexes of naringenin for effective drug delivery. J Incl Phenom Macrocycl Chem 2010; 67: 253-60.
Ghaisas MM, Navghare VV. In vitro antioxidant activity of Tectonagrandis Linn. Pharmacologyonline 2008; 3: 296-305.
Ferreira ICFR, Baptista P, Vilas-Boas M, Barros L. Free-radical scavenging capacity and reducing power of wild edible mushrooms from northeast Portugal: Individual cap and stipe activity. Food Chem 2007; 100: 1511-6.
Maiti K, Mukherjee K, Murugan V, Saha BP, Mukherjee PK. Exploring the effect of Hesperetin-HSPC complex--a novel drug delivery system on the in vitro release, therapeutic efficacy and pharmacokinetics. AAPS PharmSciTech 2009; 10(3): 943-50.
[] [PMID: 19629709]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 14 January, 2020
Page: [28 - 36]
Pages: 9
DOI: 10.2174/1574885514666190226155933
Price: $65

Article Metrics

PDF: 18