DESIGN AND DEVELOPMENT OF NOVEL MICROEMULSION BASED TOPICAL FORMULATION OF HESPERIDIN
Objective: Bioflavonoid hesperidin is used primarily to assist treatment of capillary disorders like hemorrhoids and varicose veins, by reducing capillary permeability. There are certain limitations to the use of these bioflavonoid in the pharmaceutical formulations because of their physical properties like limited aqueous solubility, poor bioavailability and high oral dose. Therefore in the present research work micro emulsions of hesperidin were developed for improving solubility and bioavailability using topical route.
Methods: Micro emulsions of hesperidine were prepared by plotting pseudo ternary phase diagram using eucalyptus oil, Tween 80, AccononCC6 and water. The micro emulsion with optimized droplet size, polydispersity index and ex vivo diffusion ability was then converted into the ointment for ease of application. Droplet size and Polydispersity index were obtained by using Photon correlation spectroscopy. Optimized o/w microemulsion of hesperidin composed of eucalyptus oil 20%, Tween-80/Acconon CC-6(2:1) 33% and water was then converted into ointment using optimized ointment base. [a1]Â The microemulsion loaded ointment was then characterized for physicochemical parameters. Ex-vivo permeation and In-vivo bioavailability studies were carried out to check the r. release profile of drug from the prepared formulations.
Results: It was observed from ex-vivo permeation studies that flux value for optimized microemulsion was found to be 8.971Âµg/ml/cm2as compared to pure hesperidin (1.230 Âµg/ml/cm2). This formulation was then converted into ointment by using optimized base containing PEG-6000, PEG-400 and Cetyl alcohol. This microemulsion based ointment passed all the characterization tests (droplet size analysis using PCS, ex-vivo permeation studies, in-vivo bioavailability studies etc.) as well as remained stable for the period of 3 mo during stability studies as per ICH guidelines. The bioavailability studies of hesperidin microemulsion based ointment in rats showed 3 fold statistically significant (p<0.001) improvement in bioavailability as compared to microemulsion when applied topically.
Conclusion: Thus it can be concluded that components of microemulsion and ointment are contributing to improve bioavailability of hesperidin.
2. Garg A, Garg S, Zaneveld L, Singla A. Review article: chemistry and pharmacology of the citrus bioflavonoid hesperedin. Phytother Res 2001;15:655â€“69.
3. Horcajada M, Coxam V. Hesperidin, a citrus flavanone, improves bone acquisition and prevents skeletal impairment in rats in nutritional aspects of osteoporosis. 2nd ed. New York: Elsevier; 2004. p. 103â€“20.
4. Hirata A, Murakami Y, Shoji M. Kinetics of radical-scavenging activity of hesperetin and hesperidin and their inhibitory activity on COX-2 expression. Anticancer Res 2005;25:367â€“74.
5. Kanaze F, Kokkolou E, Niopas I. Thermal analysis study of flavonoid solid dispersion having enhanced solubility. J Therm Anal Calorim 2006;83:283â€“90.
6. Sansone F, Rossi A, Del Gaudio P. Hesperidin gastro-resistant microparticles by spray drying: preparation characterization and dissolution profiles. AAPS PharmSciTech 2009;10:391-401.
7. Lawrence M, Rees G. Microemulsion based media as novel drug delivery systems. Adv Drug Delivery Rev 2000;45:89â€“121.
8. Hadgraft J. Skin-The final frontier. Int J Pharm 2001;224:1â€“18.
9. Kreilgaard M. Influence of microemulsions on cutaneous drug delivery. Adv Drug Delivery Rev 2002;54 Suppl1:S77â€“S98.
10. Peltola S, Saarinen-Savolainen P, Kiesvaara J. Microemulsions for topical delivery of estradiol. Int J Pharm 2003;254:99â€“107.
11. Chen H, Chang X, Weng T. A study of microemulsion systems for transdermal delivery of triptolide. J Controlled Release 2004;98:427â€“36.
12. Chiang C, Flynn G, Weiner N. Bioavailability assessment of topical delivery systems: effect of inter-subject variability on relative in vitro deliveries of minoxidil and hydrocortisone from solution and ointment formulation. Int J Pharm 1989;50:21-6.
13. Akanksha D, Vikas G, Neetesh K, Shailendra S. Formulation and evaluation of neomycin sulphate ointment containing natural wound healing agent, curcuma longa. Int J Pharm Sci Drug Res 2009;1:116-8.
14. Kulkarni S, Kharche A. Analytical method development for Chiral separations of fruity flavonoids using rp-hplc with improved selectivity and sensitivity. J Eng Res Studies 2010;1:106-13.
15. Sudo J, Iwaseb H, Teruia J. Transdermal absorption of L-dopa from hydrogel in rats. Eur J Pharm Sci 1998;7:67â€“71.
16. Malcolmson C, Lawrence M. A comparison between nonionic micelles and microemulsions as a means of incorporating the poorly water soluble drug diazepam. J Pharm Pharmacol 1990;42:6P.
17. Garg A, Aggarwal D, Garg S. Spreading of semisolid formulations. Pharm Technol 2002;26:84â€“105.
18. Sajjadi S. Effect of mixing protocol on formation of fine emulsions. Chem Eng Sci 2006;61:3009â€“17.
19. Knop K, Hoogenboom R, Fischer D. Poly (ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew Chem Int Ed 2010;49:6288-308.
20. Abdullah, Ping Q, Liu G. Enhancing effect of essential oils on the penetration of 5-fluorouracil through rat skin. Yaoxue Xuebao 1996;31:214â€“21.
21. Shishu S, Sunita R, Kamalpreet. Development of novel microemulsion-based topical formulations of acyclovir for the treatment of cutaneous herpetic infections. AAPS PharmSciTech 2009;10:559-85.
22. Hou M, Man M. Topical hesperidin improves epidermal permeability barrier function and epidermal differentiation in normal murine skin. Exp Dermatol 2012;21:337â€“40.
23. Fanun M. Formulation and characterization of microemulsions based on mixed non-ionic surfactants and peppermint oil. J Colloid Interface Sci 2010;343:496â€“503.