An Updated Review of Pharmacological, Standardization Methods and Formulation Development of Rutin

1Rashid Latif College of Pharmacy, 35-kmFerozepur Road, Lahore, Pakistan. 2University College of Pharmacy, University of the Punjab, Lahore, Pakistan. 3School of Bioprocess Engineering, Universiti Malaysia Perlis (UniMAP), Kompleks Pusat Pengajian Jejawi 3 (KPPJ3), Kawasan Perindustrian Jejawi, 02600, Arau, Perlis, Malaysia. 4Department of Physics, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia. 5Saint-Petersburg State Chemical-Pharmaceutical Academy, Ministry of Healthcare of the Russian Federation, 14, ul. Prof. Popova, St. Petersburg, 197376 Russia.

The role of flavonoids can never be ignored in our daily life.They had a wide variety of application in our daily health care such as antioxidant 1,2 , anticancer 3 , neurodegeneration 4 and cardiovascular disease 5,6 .They are commonly available in our food such as fruits, beverages, and vegetables.There is a different class of flavonoids such as flavones, flavonols, and flavanones.Quercetin, rutin, kaempferol belongs to most common available flavonoids in our diet.This review article is based on updated information about the pharmacological potential, standardization method and recent knowledge about formulation development of rutin.Google scholar is used as a search engine to find the information from 2012 till to date.The keywords used to find the information was rutin, standardization method of rutin, pharmacological activities of rutin and formulation development of rutin in recent years (2012-2017).

Antioxidant
The recent research on rutin was based on enhancing the activity and optimization of antioxidant potential.The formation of supramolecular inclusion complexes between rutin and four cyclodextrins, namely b-cyclodextrin (b-CD), (2-hydroxypropyl)-a-cyclodextrin (HPa-CD), (2-hydroxypropyl)-b-cyclodextrin (HPb-CD) and (2-hydroxypropyl)-g-cyclodextrin (HP-g-CD), and the effects of the complexation on the stability and antioxidant activity of rutin were investigated.Formation of such an inclusion complex conferred moderate degrees of protection to rutin from degradation by heat and UV radiation during storage, and significantly enhanced its antioxidant capacity 21 .Enzymatic de-glycosylation enhance the antioxidant potential of rutin 22 .Encapsulation of rutin with lipid-based oniontype multilamellar vesicles (MLVs) optimized the antioxidant activity 23 .It considerably decreased lipid peroxidation in 6-hydroxydopamine (6-OHDA) toxicity induced in pheochromocytoma (PC-12) cells 24 .Rutin has a protective effect against hydrogen peroxide-induced oxidative stress in human lens epithelial cells 25 .

Neurodegenerative effect
Rutin can help to treat peripheral neuropathy in mice 24 .Rutin showed neuroprotective effects in streptozotocin-induced diabetic rat's retina 26 .Rutin protects dopaminergic neurons from oxidative stress in an animal model of Parkinson's disease 27 .Rutin is an effective bioflavonoid against neurotoxicity in rats by activating the mitogenactivated protein kinase (MAPK) pathway and brain-derived neurotrophic factor (BDNF) gene expression 28 .Rutin decreased the oxidative stress in seizure-induced mice by kainic acid 29 .Rutin is an effective bioactive compound against neurotoxicity caused by acrylamide 30

Antidiabetic effect
Rutin possesses the antidiabetic activity by stimulating b-cells to release more insulin 31 .It showed anti-hyperglycemic activity in streptozotocin-induced diabetic rats 32 .

Cardioprotective effect
Rutin possesses the cardioprotective effect but recent studies found that the effect was less effective than quercetin on isoproterenolinduced cardiac fibrosis in the rat 10 .It was found to be an effective as protective agent in hypercholesterolemic male rat 33 .

Wound healing activity
Rutin containing hydrogel was found to be an effective bio compound in healing the wound 11 .The roots and leaves of Tephrosia purpurea possess 2.5% of rutin and was found as an effective wound healing agent in streptozotocin-induced diabetic rats 34 .Rutin was also identified as bioactive compounds in the polyherbal formulation of Clinacanthus nutans and Elephantopus scaber in healing the wound using high-performance liquid chromatography 35 .

Nephroprotective activity
Rutin has a protective effect on hexachlorobutadiene-induced nephrotoxicity 36 .

Hepatoprotective effect
Rutin was found to be an effective flavonoid in reducing hepatotoxicity caused by CCl 4 15 and liver injury induced by biliary obstruction in rats 37 .A Recent study reveals that it alters the expression of genes in the IL-6/STAT3 pathway in reducing hepatotoxicity caused by CCl 4 38 .

Radioprotective effect
Rutin plays an important role as a radio modulator effect in Swiss albino mice when exposed to gamma radiations 13 .Monoglucosyl rutin is an enzymatically modified form of rutin that is found be an effect radioprotector in mammalian cells 39 .

Miscellaneous activities
T h e a n t i p r o l i f e r a t i o n o f r u t i n in human neuroblastoma cells LAN-5 were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay through inducing G2/M cell cycle arrest and promoting

Standardization of Rutin
Rutin in the polyherbal formulation of Azadirachta indica and Gynura procumbens ethanolic extracts was standardized by TLCdensitometry 41 .High-performance liquid chromatography was found be the most used method of standardization using C18 column.It was identified and quantified in the polyherbal formulation of Clinacanthus nutans and Elephanopus scaber using high-performance liquid chromatography.The mobile phase was a binary mixture of methanol-water, 1:1 (v/v), adjusted to pH 3.0 with glacial acetic acid was used 42 .Erythroxylum suberosum extract possesses rutin.Aqueous phosphoric acid (1%) (solvent A) and acetonitrile (solvent B) was used as a solvent system in HPLC 43 .Rutin was identified from Strychnos nux-vomica extract using High-performance thin layer chromatography (HPTLC) 44 .It was quantified from Lepidagathis prostrate using silica gel plate as a stationary phase and ethyl acetate, n-butanol, formic acid, water in the ratio (5:3:1:1) as mobile phase in HPTLC 45 .

Formulation Development of Rutin
Rutin has been used in different formulation nowadays.Rutin hydrogel was effective in healing the wound 11 .Rutin is poorly soluble in water.Liposome hydrogel can function as potential drug delivery systems to enhance transdermal permeation of the water-insoluble antioxidants such as quercetin and rutin 46 .Rutin loaded nanoemulsions were prepared by spontaneous emulsification method and highpressure homogenization (HPH) technique using sefsol 218 and tocopheryl polyethylene glycol 1000 succinate (TPGS) (1:1), solutol HS15 and transcutol P as oil phase, surfactant and co-surfactant will increase the solubility and permeability of rutin 47 .Rutin loaded nanophytosomal formulation was found to be the useful carrier to improve the bioavailability and antioxidant properties 48 .Elastic liposome containing rutin helps to improve the skin permeation effect 49 .Self-emulsifying drug delivery systems of rutin were prepared by polyethylene glycol (PEG 6000), polyvinylpyrrolidone (PVP K30 and PVP K17) or sodium desoxycholate by co-precipitation method to improve the bioavailability of bioactive compound 50 .Rutinencapsulated chitosan nanoparticles can be helpful as neuroprotective and readily available to the brain in the treatment of Cerebral Ischemia 51 .Rutin nanocrystals produced by the smart crystal help in enhancing skin penetration 52 .Nanostructured lipid carriers (NLCs) contains rutin can be useful as photoprotective cream.Apifil/TiO 2 rutin NLC is found be effective as sun protective cream 53 .

CONCLUSION
Rutin is found to be one of a member of an essential flavonoid used in our daily routine.The current research is more focus on optimization of its pharmacological activities and formulation development.There is a lot of effort going on to enhance its pharmacokinetic profile.The commercial potential of rutin is still yet to be explored.There are limited studies on a clinical trial.Most of the preclinical studies are limited on animal models.It is need of time to make use of its pharmacological activity by developing different pharmaceutical dosage form and standardization of new rutin based formulation.