Solubility, Stability, Physicochemical Characteristics and In Vitro Ocular Tissue Permeability of Hesperidin: A Natural Bioflavonoid
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Hesperidin holds potential in treating age-related macular degeneration, cataract and diabetic retinopathy. The aim of this study, constituting the first step towards efficient ocular delivery of hesperidin, was to determine its physicochemical properties and in vitro ocular tissue permeability.
pH dependent aqueous solubility and stability were investigated following standard protocols. Permeability of hesperidin across excised rabbit cornea, sclera, and sclera plus retinal pigmented epithelium (RPE) was determined using a side-bi-side diffusion apparatus.
Hesperidin demonstrated poor, pH independent, aqueous solubility. Solubility improved dramatically in the presence of 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) and the results supported 1:1 complex formation. Solutions were stable in the pH and temperature (25, 40°C) conditions tested, except for samples stored at pH 9. Transcorneal permeability in the apical-basal and basal-apical directions was 1.11 ± 0.86 × 10−6 and 1.16 ± 0.05 × 10−6 cm/s, respectively. The scleral tissue was more permeable (10.2 ± 2.1 × 10−6 cm/s). However, permeability across sclera/choroid/RPE in the sclera to retina and retina to sclera direction was 0.82 ± 0.69 × 10−6, 1.52 ± 0.78 × 10−6 cm/s, respectively, demonstrating the barrier properties of the RPE.
Our results suggest that stable ophthalmic solutions of hesperidin can be prepared and that hesperidin can efficiently permeate across the corneal tissue. Further investigation into its penetration into the back-of-the eye ocular tissues is warranted.
KEY WORDShesperetin hesperidin ocular permeability solubility
This project was supported by NIH grant numbers P20RR021929, from the National Center for Research Resources, and EY018426-01 from the National Eye Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Eye Institute, National Institutes of Health.
- 1.A. Ryskulova, K. Turczyn, D. M. Makuc, M. F. Cotch, R. J. Klein, and R. Janiszewski. Self-reported age-related eye diseases and visual impairment in the United States: results of the 2002 national health interview survey. Am. J. Public Health. 98:454–461 (2008) doi: 10.2105/AJPH.2006.098202.PubMedCrossRefGoogle Scholar
- 6.J. Zhang, R. A. Stanley, L. D. Melton, and M. A. Skinner. Inhibition of lipid oxidation by phenolic antioxidants in relation to their physicochemical properties. Pharmacologyonline. 1:180–189 (2007).Google Scholar
- 12.T. Tanaka, H. Makita, M. Ohnishi, H. Mori, K. Satoh, A. Hara, T. Sumida, K. Fukutani, T. Tanaka, and H. Ogawa. Chemoprevention of 4-nitroquinoline 1-oxide-induced oral carcinogenesis in rats by flavonoids diosmin and hesperidin, each alone and in combination. Cancer Res. 57:246–252 (1997).PubMedGoogle Scholar
- 13.T. Tanaka, H. Makita, K. Kawabata, H. Mori, M. Kakumoto, K. Satoh, A. Hara, T. Sumida, T. Tanaka, and H. Ogawa. Chemoprevention of azoxymethane-induced rat colon carcinogenesis by the naturally occurring flavonoids, diosmin and hesperidin. Carcinogenesis. 18:957–965 (1997) doi: 10.1093/carcin/18.5.957.PubMedCrossRefGoogle Scholar
- 16.T. H. Tsai, and M. C. Liu. Determination of extracellular hesperidin in blood and bile of anaesthetized rats by microdialysis with high-performance liquid chromatography: a pharmacokinetic application. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 806:161–166 (2004) doi: 10.1016/j.jchromb.2004.03.047.PubMedCrossRefGoogle Scholar
- 21.H. Serra, T. Mendes, M. R. Bronze, and A. L. Simplicio. Prediction of intestinal absorption and metabolism of pharmacologically active flavones and flavanones. Bioorg. Med. Chem. 16:4009–4018 (2008).Google Scholar
- 23.A. K. Mitra, S. Macha, and P. M. Hughes. Ophthalmic Drug Delivery Systems. Marcel Dekker, New York, 2003.Google Scholar
- 27.P. Saarinen-Savolainen, T. Jarvinen, K. Araki-Sasaki, H. Watanabe, and A. Urtti. Evaluation of cytotoxicity of various ophthalmic drugs, eye drop excipients and cyclodextrins in an immortalized human corneal epithelial cell line. Pharm. Res. 15:1275–1280 (1998) doi: 10.1023/A:1011956327987.PubMedCrossRefGoogle Scholar
- 29.S. Tommasini, M. L. Calabro, R. Stancanelli, P. Donato, C. Costa, S. Catania, V. Villari, P. Ficarra, and R. Ficarra. The inclusion complexes of hesperetin and its 7-rhamnoglucoside with (2-hydroxypropyl)-beta-cyclodextrin. J. Pharm. Biomed. Anal. 39:572–580 (2005) doi: 10.1016/j.jpba.2005.05.009.PubMedCrossRefGoogle Scholar
- 37.S. Majumdar, Y. E. Nashed, K. Patel, R. Jain, M. Itahashi, D. M. Neumann, J. M. Hill, and A. K. Mitra. Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations. J. Ocul. Pharmacol. Ther. 21:463–474 (2005) doi: 10.1089/jop.2005.21.463.PubMedCrossRefGoogle Scholar