Expert Opinion on Drug Delivery

ISSN: 1742-5247 (Print) 1744-7593 (Online) Journal homepage: http://www.tandfonline.com/loi/iedd20

Resveratrol: review on therapeutic potential and recent advances in drug delivery Rudra Pangeni B.Pharm, Jasjeet K Sahni, Javed Ali, Shrestha Sharma & Sanjula Baboota To cite this article: Rudra Pangeni B.Pharm, Jasjeet K Sahni, Javed Ali, Shrestha Sharma & Sanjula Baboota (2014) Resveratrol: review on therapeutic potential and recent advances in drug delivery, Expert Opinion on Drug Delivery, 11:8, 1285-1298, DOI: 10.1517/17425247.2014.919253 To link to this article: http://dx.doi.org/10.1517/17425247.2014.919253

Published online: 15 May 2014.

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Date: 28 November 2016, At: 10:18

Review

Resveratrol: review on therapeutic potential and recent advances in drug delivery 1.

Introduction

2.

Medicinal uses

3.

Bioavailability and

Rudra Pangeni, Jasjeet K Sahni, Javed Ali, Shrestha Sharma & Sanjula Baboota† †

Hamdard University (Jamia Hamdard), Department of Pharmaceutics, New Delhi, India

pharmacokinetic studies of resveratrol 4.

Solubility and bioavailability enhancement of resveratrol

5.

Clinical trials of resveratrol

6.

Conclusion

7.

Expert opinion

Introduction: Natural products have seen a wide range of acceptability for the prevention and treatment of diseases throughout history. Resveratrol, a member of the stilbene family, has been found to potentially exhibit anticancer, antiangiogenic, immunomodulatory and cardioprotective activities as well as being an antioxidant. This is in addition to its usefulness in the treatment of neurodegenerative disease, diabetes and cardiac ailments. Currently, various studies have revealed that resveratrol is a potential drug candidate with multi-spectrum therapeutic application. Areas covered: This review aims to describe the various studies supporting the wide range of pharmacological activities of resveratrol. In addition, it includes a section devoted to discussing the challenges associated with the drug and strategies to improve the properties of resveratrol such as solubility, stability and bioavailability. Expert opinion: Resveratrol demonstrated its ability to be a potential drug candidate for the treatment of different ailments due to its potent antioxidant properties. To improve the drug stability, increase the bioavailability and minimize side-effects of resveratrol, novel drug delivery systems have been formulated to bring this potential candidate to the first line of disease treatment. Keywords: antioxidant, bioavailability, resveratrol, stilbene Expert Opin. Drug Deliv. (2014) 11(8):1285-1298

1.

Introduction

Natural products have been used in the prevention and treatment of diseases throughout history due to their wide acceptability [1]. Among the various groups of natural products and plant metabolites that are available, resveratrol plays an important role in the treatment of various diseases by acting as a potent defensive antioxidant. Resveratrol is a member of the stilbene family, which is characterized by two benzene rings linked via isopropyl moiety separated by a double bond [2]. Resveratrol (Figure 1) exists as stereoisomers in cis and trans forms (Z and E) with the E form exhibiting more potential as an antioxidant and an anticancer agent [3]. Resveratrol (3,4¢,5-trans-trihydroxy-stilbene or 5-[(E)-2-(4-hydroxy phenyl)ethyl]benzene-1,3-diol; C14H12O3; MW 228.25) (Box 1) is a naturally occurring phytoalexin, a member of stilbene family of phenolic compounds, that was first isolated from the roots of white hellebore (Veratrum grandiflorum O. Loes) in 1940 [4], and later from the roots of Polygonum cuspidatum, a widely used traditional Chinese and Japanese medicine in 1960s [5,6]. Resveratrol is a polyphenolic compound distributed in particular families of plants including Vitaceae, Dipterocarpaceae, Gnetaceae, Cyperaceae and Leguminosae, which includes both edible and nonedible plants [7]. Various food and food products such as grapes, wine, grape juice, mulberries, cranberries, cranberry juice and peanuts are known to contain resveratrol in 10.1517/17425247.2014.919253 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted

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mechanism of action of resveratrol in various conditions and disease states has been described in Table 1.

Article highlights. . . . . .

Sources of resveratrol are discussed. All the pharmacological activities along with the mechanism of action of resveratrol have been discussed. There is a special focus on anticancer and antioxidant properties of resveratrol. Bioavailability and pharmacokinetics of resveratrol are discussed. Strategies for the improvement of solubility and bioavailability enhancement are provided.

This box summarizes key points contained in the article.

different concentrations [8,9]. An interesting paradox in French coined as ‘French Paradox’ almost 20 years ago suggested that lower incidence of mortality due to chronic heart disease in spite of high consumption of fatty food was due to red wine containing resveratrol [10,11]. It acts as a potent antioxidant by inhibiting reactive oxygen species (ROS) mainly by activating AMPK. Besides this it also suppresses COX-2 and lipid peroxidation [12]. ROS are continuously produced in the body as a result of various metabolic and physiological processes but when the balance between the production of ROS and inherent antioxidant activity is distorted, it leads to oxidative stress [13]. Resveratrol is a potent antioxidant capable of maintaining this oxidative stress. Therefore, it shows different pharmacological functions such as anticancer [14], antiangiogenic [15], antioxidant [16,17], antitumor [18,19] and cardioprotective activities [20]. Moreover, other therapeutic effects such as neuroprotective [21], antidiabetic [22], radioprotective and cytogenetic [23] and antiviral effects [24,25] have also been reported. Resveratrol exhibited stronger antiradical activity when compared to kaempferol and naringenin and was also found to be more efficient than a-tocopherol, catechin, myricetin and naringenin, which explains its beneficial effects in disease state [26]. It is considered as the potential candidate with non-toxic and well-tolerable properties. In spite of rapid absorption, intestinal and hepatic metabolism are the rate limiting step for the systemic bioavailability of resveratrol. High lipophilicity of resveratrol also leads to low aqueous solubility, impairing its oral bioavailability along with its metabolic stability [27]. The main aim of this paper is to focus on the various biological and therapeutic activities of resveratrol, define the problems associated with delivery of resveratrol and highlight the methods to enhance its bioavailability using various techniques such as nanotechnology and complexation.

2.

Medicinal uses

Plants containing resveratrol, a potent antioxidant, has been used widely in the treatment of various ailments [28]. It was also assumed to increase the life span, which was later proved by research [29]. Resveratrol help in the treatment of various diseases by various mechanisms. A brief description of the 1286

Antioxidant activity Free radicals from endogenous and exogenous sources play an important role in the pathogenesis of a disease caused due to oxidative stress [30]. They are considered fundamental to any biochemical process that represents an essential part of aerobic life and metabolism. Phenolic compounds have been found to have a wide range of beneficial effects as a natural antioxidant by neutralizing or scavenging the free radicals, chelating the metal ions along with the inhibition of lipid peroxidation [31-35]. Frankel et al. was the first to report the antioxidant activity of trans-resveratrol using different antioxidant assays such as 2,2-diphenylpicrylhydrazyl (DPPH) radical scavenging assay, total antioxidant activity, lipid peroxidation assay, reducing power assay and hydrogen peroxide scavenging activity assay. The results showed that DPPH-radical scavenging activity of resveratrol was 2 µmol higher as compared to the control group [36]. In another study carried out by Olas et al., the influence of trans-resveratrol on ROS generation was investigated in pig blood platelets activated by lipopolysaccharide. It was found that resveratrol (6.25 -- 100 µg/ml) inhibited the generation of ROS in blood platelets. Platelets incubated with 25 µg/ml of the drug demonstrated the strongest inhibition of oxygen radical production [37]. 2.1

Cardioprotective activity Cardioprotection includes all means and mechanisms that contribute to the protection of heart ranging from reducing or even preventing myocardial damage. Various scientific studies have proved that consumption of plant extracts containing polyphenols, especially resveratrol, like propolis and red wine reduces mortality associated with coronary heart disease [38]. Being a potent antioxidant, resveratrol inhibits the oxidation of low density lipoprotein, reduces platelet aggregation, promotes vasodilation and enhances endothelial nitric oxide synthase activity, thereby inhibiting atherosclerotic changes and showing an overall good cardioprotective effect. Histological results on Sprague--Dawley rats injected with 1 mg/kg/day i.p. of resveratrol for 4 weeks showed a potent cardioprotective effect with effective suppression of infract size. A significant improvement of left ventricle systolic and diastolic function was observed by echocardiography. Infract size after 4 weeks of myocardial infarction was evaluated and was found to be 34.2 ± 1.8% in control group and 23.2 ± 3.2% in those treated with resveratrol (1 mg/kg/day). The level of atrial natriuretic peptide and TGF-b1 mRNA expression was quantified with SYBR green real-time quantitative PCR method and was found to be higher in control rats than in those treated with resveratrol [39]. The other mechanism responsible for cardioprotection is the enhancement of NF-kB activity in human cardiac cells [40]. Resveratrol was also found to protect cardiac and vascular tissues of renal hypertensive rats by reducing the accumulation of ROS 2.2

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Resveratrol

Box 1. Drug summary. Drug name CAS No Chemical name

Resveratrol 501-36-0 3,4,5 Trihydroxy-trans-stilbene; 3,4’,5-stilbenetriol Stilbene 228.25 C14H12O3 Antioxidant, cardioprotective, immunomodulatory, anticancer, antihypertensive and anti-inflammatory activities White/off-white powder, distinctive odor 261 -- 267 C 8.1 -- 11.4 8 -- 14 min Soluble in ethanol than DMSO and water

Chemical class Molecular weight Molecular formula Indication

Appearance Melting point pKa Half-life Solubility

DMSO: Dimethyl Sulfoxide.

OH HO

OH

Figure 1. Chemical structure of resveratrol.

thereby showing potential to enhance current pharmacotherapeutic approaches [41]. Cardioprotective effect of resveratrol was found in animals treated with doxorubicin by reducing the cardiac toxicity and increasing the cytotoxic activity [42]. Recently a number of human clinical trials have also shown the cardioprotective activity of resveratrol [43]. Immunomodulatory activity Immunomodulation is a therapeutic approach of intervening auto-regulatory processes of the defense system. The level of specific antibody present in the serum is taken as a measure of the functional status of the humoral immune response, for example, hemolysin. The effect of resveratrol on regulation of hemolysin was studied using mice immunized with Sheep red blood cell and the result obtained showed a dose-dependent increase in the level of hemolysin indicating that resveratrol promoted the humoral immune response and enhanced the formation of antibody cells. Resveratrol was also found to increase CD4/CD8 ratio, T lymphocytes proliferation along with B cell mediated immune response and stimulated NK cells activity, which showed an immunomodulatory effect on mouse lymphocytic leukemia as demonstrated by Li et al. [44]. Other study carried out by Soto et al. demonstrated the dose-dependent antiproliferative activity of resveratrol on 2.3

M21 and NXS2 tumor cell lines and immunosuppressive activity on human and murine immune cells. The concentration required for the immunosuppressive activity in vitro was 25to 50-fold higher than peak plasma level achieved in mice after the oral administration showing the antitumor activity [45]. Anticancer activity Cancer remains a chronic health problem with high mortality rate till date. Carcinogenesis is a multistep process involving multiple genes. Some of the chemicals are electrophilic in nature or are metabolically activated to reactive molecules that cause alteration in DNA leading to genetic damage and mutations. Initiation, promotion and progression are the three stages of chemical carcinogenesis although recent studies have shown the occurrence of human carcinogen as an accumulation of different alterations in cancer-regulating genes [46]. A large number of studies have suggested that the diet rich in fruits and vegetables are associated with reduced incidence of cancer as these diets constitute a diverse group of polyphenolic compounds with potential anticancer activity. These compounds act as anticancer agents by induction of apoptosis, cell cycle arrest and suppression of GFR-mediated pathway, suppression of protein kinase and suppression of NF-kB activation [47]. Jang et al. identified resveratrol to inhibit COX activity of COX-1, which correlates with antitumor initiation and promotion along with its antimutagenic activity. Cancer chemopreventive activity of resveratrol was investigated in a mouse mammary gland culture model of carcinogenesis, which showed dose-dependent inhibition in development of dimethylbenz(a)anthracene-induced preneoplastic lesions with no sign of toxicity. Tumorigenesis was also studied in two-stage mouse skin cancer model for 18 weeks with the application of different concentrations (1, 5, 10 and 25 µmol) of resveratrol together with 12-O-tetradecanoylphorbol-13-acetate twice a week; a reduction in the number of skin tumors per mouse by 68, 81, 76 or 98%, respectively, was observed [48]. Subramanian et al. discussed different in vitro studies of resveratrol in a variety of tumor cell lines, which showed the drug to be antiproliferative, proapoptotic along with antiangiogeneic in certain tumor models. Resveratrol was also discussed for its low bioavailability in mammals and difference of cellular uptake between normal and tumor cells [49]. Similarly, Ndiaye et al. also discussed about the metabolism and low bioavailability of resveratrol along with the expected measures to enhance bioavailability such as inhibition of metabolism in vivo by the use of combination such as piperine, which was observed to inhibit glucuronidation and enhance bioavailability. The next measure discussed was the use of nanotechnology by encapsulation of resveratrol in liposomes or nanoparticles. Author also discussed the use of resveratrol analogues such as piceatannol found in wine and grapes for its antiproliferative activity [50]. Garcia-Zepeda et al. analyzed the antiproliferative cytostatic effect of resveratrol in different cervical cancer cell lines (C33A, CaLo, HeLa, CaSki and SiHa) where a 2.4

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Table 1. Mechanism of action of resveratrol for different activities. Role of resveratrol Antioxidant

Cardioprotective Immunomodulatory

Anticancer

Antihypertensive Anti-inflammatory

Mechanism of action

Refs

Inhibition and neutralization of ROS, chelation of metal cations and inhibition of lipid peroxidation Inhibition of ANP and TGF-b1, enhancement of NF-kB activity Promotion of humoral immune response, enhancement of formation of antibody cells, increase in CD4/CD8 ratio, T lymphocytes proliferation and B cell mediated immune response Induction of apoptosis, cell cycle arrest and suppression of GFR-mediated pathway, suppression of protein kinase and suppression of NF-kB activation Induction of gene expression of NOS, inhibition of vascular NADPH oxidase induction and inhibition of COX-2 Reduction in pro-inflammatory cytokines, TNF-a, IL-1b and COX-2, Also inhibition of NF-kB and NOS expression

[17,34]

[36,37] [41]

[44,45]

[49,50] [56-58]

ANP: Atrial natriuretic peptide; NADPH: Nicotinamide adenine dinucleotide phosphate; NOS: Nitric oxide species; ROS: Reactive oxygen species.

dose-dependent inhibition of proliferation was observed. The effect of resveratrol on the progression of cell cycle, apoptosis as well as autophagy in cancer cell lines was studied, which showed the increase in G1 phase and induced a corresponding decrease in S and G2-M phases in CaSki cells. It also showed the higher increase in the induction of apoptosis in HeLa, CaSki cells and increased lysosomal membrane permeabilization in CaLo and HeLa cell lines [51]. Aydin et al. studied the role of resveratrol on the sepsis-induced oxidative DNA damage in the lymphocytes of Wistar albino rats using the parameters such as tail length, tail intensity and tail moment for determination of DNA damage. The study showed significantly higher DNA damage in sepsis induced rats compared to control rats and the parameters were significantly decreased in resveratrol treated sepsis induced rats compared to sepsis induced rats suggesting the role of resveratrol in the prevention of sepsis induced DNA damage caused due to oxidative stress [52]. Similarly, Hu et al. discussed the role of different compounds derived from Chinese herbal medicines such as curcumin, resveratrol, silibinin, berberine, quercetin, tanshinone II-A and celastrol for the treatment of hepatocellular carcinoma. Although resveratrol was found to possess anti-hepatocellular carcinoma activity yet it has not been approved as therapeutic agent due to poor bioavailability [53]. Kil et al. determined resveratrol (80 µmol) induced reduction in viable cell count by 3-[4,5-dimethylthiazol2yl]-2,5 diphenyl tetrazolium bromide assay in 24 h. The cytotoxic activity at this concentration was associated with apoptosis. The effect of resveratrol in ROS formation was also studied in RAW264.7 cells, using specific fluorescent dye. Increase in fluorescence indicated that the treatment with 80 µmol concentration induced the formation of ROS, which was threefold higher than the untreated cells [54]. Lwuchukwu et al. studied the antiproliferative effect of resveratrol in combination with other polyphenols such as curcumin and chrysin. Combination of these compounds showed additional antiproliferative effects. Resveratrol:curcumin (20JM:40JM) 1288

combination and resveratrol:chrysin (20JM:32JM) combination showed 12-fold and 22-fold increase in mRNA expression, respectively. Significant increase in 4-MU glucuronidation with maximal mRNA induction was also observed with the combination containing chrysin [55]. Antihypertensive activity Hypertension is a lifestyle disorder disease that requires continuous attention and monitoring. The major pathway that plays an important role in hypertension is L-arginine, which also interacts with rennin-angiotensin (Ang) and eicosanoid pathways [56]. Studies have suggested that the antihypertensive activity of polyphenols is due to induction of gene expression of NOS, inhibition of vascular nicotinamide adenine dinucleotide phosphate oxidase induction and COX-2 inhibition within arterial wall [57,58]. Resveratrol improves endothelium-dependent vasorelaxation whose mechanism is still unknown. Researchers have concluded that early treatment with resveratrol lowers oxidative stress, preserves endothelial function and gradually decrease the incidence of hypertension along with the reduction in H2O2 levels and superoxide dismutase activity. Vasorelaxing effect of resveratrol was observed in spontaneously hypertensive rats (SHRs) and found to be 131.8 ± 5.18%, which was higher compared to untreated ones, 110 ± 7.16% (p < 0.05). Thus, resveratrol prevented NO scavenging and increased bioavailability in SHR by lowering oxidative stress [59]. Antihypertensive activity of resveratrol was also studied by Dolinsky et al. on SHR and Ang-II infused mice. Significant rise in systolic pressure was prevented by resveratrol although no significant effect was seen in diastolic pressure in Ang-II infused mice. The research also demonstrated enhanced vasodilatory functions, which were associated with improved NO bioavailability [60]. 2.5

Anti-inflammatory activity Inflammation is an initial response to tissue injury where the chemical signals with multifactorial network try its best to 2.6

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heal the afflicted area. The mechanism of inflammation involves the downregulation of inflammatory response through inhibition of release of various vasoactive mediators to the damaged area including leukotriene-B4, NO, TNF-a, ROS and ILs [61]. Polyphenols attenuates the oxidative and inflammatory responses in various cells [62]. As other polyphenols, resveratrol was studied for its anti-inflammatory activity. Secretion and activation of pro-inflammatory and neurotoxic mediators from microglia after the brain damage was the reason of inflammation. The effect of resveratrol in inhibiting microglia mediated neuro-inflammation was studied by Zhang et al. The research proved the anti-inflammatory property of resveratrol in the brain [63]. The effect of dietary resveratrol supplementation in chronic colonic inflammation was studied by Fidalgo et al. where the researcher used chronic dextran sulfate sodium to induce colitis. Reduction in the rise of proinflammatory cytokines, TNF-a and IL-1b along with reduction in prostaglandin E synthase-1, COX-2 and inducible NOS protein expression was observed, hence proving the beneficial role of resveratrol in treatment of chronic colitis [64]. Prabhakar evaluated resveratrol for its cerebroprotective activity through antioxidant and anti-inflammatory actions in diabetic Wistar rats. A 20 mg/kg dose of resveratrol reduced the levels of oxidative stress markers and inflammatory markers like malondialdehyde, TNF-a, IL-6 and myeloperoxidase. It also significantly increased the levels of antioxidant and antiinflammatory markers like catalase, superoxide dismutase and IL-10 hence providing the evidence of resveratrol induced cerebroprotection by reducing the percentage of infarction and abnormal histological modifications [65]. Resveratrol was also found to suppress the synthesis of PGE2 by inhibiting COX-2 enzyme activity, thus helping in the treatment of inflammation [66]. In another study, Donnelly et al. examined the effect of resveratrol on inflammation of human airway epithelial cells. They found the inhibition of release of IL-8 and GM-CSF from A549 cells with the mechanism involving the inhibition of NF-kB, activator protein-1 along with cAMP response binding protein-dependent transcription. Resveratrol was also found to inhibit NOS expression and nitrite production (IC50 = 3.6 ± 2.9 µM), GM-CSF release (IC50 = 0.44 ± 0.17 µmol), IL-8 release (IC50 = 4.7 ± 3.3 µmol) and COX-2 in human primary airway epithelial cells, thus demonstrating novel anti-inflammatory activity [67]. Leiro et al. carried out antiinflammatory activity of resveratrol in turbot (Psetta maxima), a fish species in vertebrates. The results showed the drugdependent inhibition of mRNA production, and increased TNF-a and IL-1b pre-mRNA levels thus proving its anti-inflammatory activity in vertebrates [68]. Vasorelaxing activity Vasoconstriction, which is the result of increased concentration of Ca2+ within the smooth muscle cells, causes the narrowing of blood vessels as the mechanism of regulating and maintaining the mean atrial pressure. Natural products such as polyphenols have been investigated since long back 2.7

for their vasorelaxant activity. In one study carried out by Zenebe et al., red wine polyphenols showed vasorelaxation effects on rat femoral artery by the activity of NO [69]. Resveratrol, a wine polyphenol, has been reported as a multipurpose compound that improves the endothelial function with the same mechanism of improving NO expression and vasorelaxation [70]. Various animal models such as guinea pigs and rats were used for study of vasorelaxation activity. In guinea pigs, mesenteric and uterine arteries were preconstricted using noradrenaline (10 µmol/l) or KCl (125 µmol/l) and the effects of resveratrol in inducing vasorelaxation were studied. The vasorelaxation effect of resveratrol was greater for mesenteric (resistance) arteries than that on the uterine (conductance) arteries [71]. A study carried out by Novakovic et al. on the aorta of male Wistar rats showed that the vasorelaxation induced by resveratrol was mediated by 4-aminopiridine and K+ channels present in vascular smooth muscles [72]. Similar study was carried out on human internal mammary artery (HIMA) to determine the endothelium-independent relaxation. Resveratrol was found to induce relaxation of HIMA independent to endothelium with pD2 = 4.38 ± 0.11 with maximal response of 83 ± 1%. The mechanism involved was found to be similar to that in Wistar rats [73]. Antimicrobial activity Stilbenes have been studied widely for their antimicrobial activities [74]. The antimicrobial activity of resveratrol was studied on various bacterial pathogens such as Staphylococcus aureus, Enterococcus faecalis and Pseudomonas aeruginosa along with fungal species like Trichophyton mentagrophytes, Trichophyton tonsurans, Trichophyton rubrumm, Epidermophyton floccosum and Microsporum gypseum. It was found that 171 -- 342 µg/ml of resveratrol in dimethyl sulfoxide had an inhibitory activity on the bacterial species and 25 -- 50 µg/ml on the growth of dermatophytes thereby representing a novel class of antifungal agents [75]. Nawrocki et al. studied the microbicidal activity of resveratrol in Haemophilus ducreyi, a gram negative bacterium that causes sexually transmitted disease chancroid. Both the class I and II strains of H. ducreyi were studied for the cidal concentration of resveratrol where class II strains were found to be more susceptible (250 µg/ml) compared to class I strains (500 µg/ml). The activity of drug against the natural flora of vagina (Lactobacillus species) were tested, which was unaffected by 500 µg/ml concentration, thus confirming the potential as a topical microbicidal in chancroid prevention [76]. In one study carried out by Paolillo et al., resveratrol caused time- and dosedependent reduction in NO production in U937 cells and monocytes infected by Salmonella enteric serovar Typhimurium [77]. Another antibacterial study was carried out by Paulo et al. in various strains of Helicobactor pylori, a gram negative spiral shaped bacillus and diameter of zone of inhibition and MIC were determined. The MIC ranged from 25 to 100 µg/ml with similar susceptibility patterns in most of the strains. The activity of resveratrol in urease inhibition was 2.8

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studied and found to be higher (90%), compared to the positive control strains (< 75%). Thus the research affirmed the antibacterial activity through inhibition of urease [78]. Antidiabetic activity Diabetes mellitus is a complex metabolic disorder characterized by hyperglycemia and increased resistance of insulin [79]. Resveratrol was studied for its antidiabetic activity and associated metabolic effects using mice of 5 -- 8 weeks [80]. The result showed significant decrease (p < 0.05) in the blood glucose level with the administration of 5, 15, 50 mg/kg dose and improvement in the level of insulin, with no significant change in body weight compared to control mice, which was due to the potential of Sirtuin 1 activators. In another study carried out by Su et al. in streptozotocin induced diabetic rats, reduction in plasma glucose level by 25.3 ± 4.2% and triglyceride concentration by 50.2 ± 3.2% was obtained on the 14th day of the resveratrol treatment. The drug also proved a stimulatory effect on the glucose uptake by various cells like hepatocytes and adipocytes [81]. Hypoglycemic activity of resveratrol was also confirmed in type 2 diabetic models by Minakawa et al. along with the protection of pancreatic b-cells from oxidative stress and apoptosis [82]. 2.9

Radioprotective activity Damage of living cells, mediated by the generation of free radicals and ROS, due to radiation exposure is a common problem. Various polyphenols have been studied for their radioprotective activities [83]. Activity of resveratrol in the prevention of skin damage of mouse caused by ultraviolet-B radiation was studied by Aziz et al. When 10 µmol of resveratrol was dissolved in 200 µl acetone and used topically, inhibition in increase of cellular proliferation and protein levels of epidermal COX-2 and ornithine decarboxylase was observed thus affirming radioprotective activity, which was mediated by apoptotic elimination of damaged cells [84]. Another radioprotective study carried out on resveratrol showed a reduction in chromosome aberration frequency in bone marrow cells of mouse. For this study mice were divided into four groups as no treatment, resveratrol only, radiation only, and resveratrol and radiation. After the treatment with resveratrol, mean total chromosome aberration frequency per metaphase was significantly reduced (p < 0.05), which was the first study to prove radioactivity in vivo [85]. 2.10

2.11

Neurodegenerative diseases Parkinson’s disease

2.11.1

Parkinson’s disease is a neuronal degeneration of dopaminergic neurons located in substantia nigra pars compacta. Neurodegeneration is related to various factors such as alteration in genes, mitochondrial dysfunction, oxidative stress and inflammation [86]. Different studies on resveratrol have proved its neuroprotective activity. Okawara et al. observed a protective role of resveratrol in mid-brain slice culture of Wistar rats on dopaminergic neurons. Neurodegeneration was due to the 1290

cytotoxicity of 1-methyl-4-phenyl pyridinium (MPP+), which was formed from the metabolic conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. When slice culture was applied with 30 µmol of MPP+ only, numbers of viable dopaminergic neurons were significantly decreased but when applied in combination with resveratrol, dose-dependent protection of neurons was observed. Similar cytotoxicity was shown by thrombin as MPP+ with the decrease in dopaminergic neurons in slice culture and resveratrol inhibiting the loss of neuronal numbers, which was due to antioxidative activity [87]. Similar study carried out by Blanchet et al. proved the protective potential of resveratrol for neurodegenerative disorders [88]. Alzheimer’s disease Alzheimer’s disease is also a neurological disorder characterized by progressive dementia in elderly [89]. Resveratrol was found to exhibit neuroprotective effect in animal models. Karuppagounder et al. demonstrated the protective role of resveratrol in transgenic mice with Alzheimer’s disease and found the reduction in plague pathology and brain glutathione. Nineteen Tg19959 mice of 45 days were classified into two groups; control group containing 4 males and 5 females with normal diet and treatment group containing 5 males and 5 females, which were administered with 0.2% of drug in dietary supplementation. Resveratrol was found to reduce plagues although the mechanism was unknown [90]. Potential therapeutic activity of resveratrol in Alzheimer’s disease was also reported by Marambaud et al. Dose-dependent neuroprotective activity of various polyphenols such as resveratrol, quercetin and catechin were tested where resveratrol was proved to be the best as it strongly reduced intracellular amyloid b peptides produced by different cell lines [91]. Virmani et al. discussed some of the nutritional diets containing vitamins and minerals in the protection of neurodegenerative diseases such as PD and Alzheimer’s disease caused due to free radicals and neuroinflammation. The study clarifies the ability of antioxidants (catechins, resveratrol) contained in polyphenols to modulate health status of the cell inducing apoptosis or detoxification of ROS and reactive nitrogen species. Some of the antioxidants such as a lipoic acid and coenzyme Q10 protect mitochondrial biogenesis and has protective effect on brain. Studies have also shown the activity of resveratrol to prevent brain and spinal cord damage due to ischemia-reperfusion and traumatic injury [92]. Similarly, Bocci et al. examined the biological role of oxidants and antioxidants, which are produced by all the living cells. The review also discussed the excessive and deranged production of toxic oxidant that leads to different ailments and which are not properly inhibited by the antioxidant system of the body [93]. 2.11.2

Bioavailability and pharmacokinetic studies of resveratrol

3.

Resveratrol being a potential candidate with different pharmacological activities has been extensively studied for its

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Resveratrol

pharmacokinetic parameters in different animal models and human volunteers. All the pharmacokinetic parameters, absorption, distribution, metabolism and excretion, of resveratrol are well understood. Although the drug has been found to possess high oral absorption (~ 75%), the oral bioavailability is almost negligible (< 1%) due to rapid and extensive metabolism into sulfate and glucuronide metabolites in intestine and liver [94]. Pharmacokinetic studies of resveratrol were also carried out in healthy human volunteers. Brown et al. carried out the study in healthy volunteers who were administered with different concentrations of resveratrol for 29 days (0.5, 1.0, 2.5 or 5.0 gm/day dose) and level of resveratrol and metabolites were assayed using HPLC-UV in plasma, which was taken before and up to 24 h after a dose between the 21 and 28 days. Along with the pharmacokinetic parameters, safety profile of resveratrol was observed and it was found that administration of 2.5 and 5.0 gm of dose caused mild-tomoderate gastrointestinal symptoms. The drug was highly metabolized and converted into various metabolites as resveratrol-3-O-sulfate, resveratrol-4’-O-glucuronide and resveratrol-3-O-glucuronide [95]. A similar type of study in healthy volunteers was carried out by Almeida et al. to determine the pharmacokinetic and safety profile of resveratrol. A total of 40 healthy volunteers were divided into four groups (5 males and 5 females each). Of them, 2 subjects were administered with placebo and the remaining 8 were administered with 25, 50, 100 and 150 mg of resveratrol, six times daily for 13 doses. Various pharmacokinetic parameters were determined where peak plasma concentration was found to be 0.8 -- 1.5 h. Mean Cmax and mean AUC0-t were found to be dose dependent, which was increased with the increase in dose from 25 to 150 mg [96]. Phase I study was conducted by Boocock et al. in 10 healthy volunteers with the administration of different doses of drug ranging from 0.5 to 5.0 g p.o., single dose, and similar method was used to assay the concentration of drug and the metabolite in plasma and urine. Results demonstrated that the peak plasma levels of 539 ± 384 ng/ml appeared 1.5 h after drug dosing. Mean volume of distribution of parent drug was 9,198 -- 22,226 l. Excretion of drug and its metabolites through urine was rapid, that is, 4 h after the lowest dose [97].

Solubility and bioavailability enhancement of resveratrol

4.

The poor bioavailability of many drugs is associated with the poor aqueous solubility. The aqueous solubility of resveratrol has been reported as < 1 mg/ml, which is a major drawback of the drug [98]. Studies related to metabolism of resveratrol have also shown higher first pass metabolism into glucuronide and sulfate metabolites [99] but increase in bioavailability has been reported when resveratrol in its aglycone form was administered in solution of hydroxypropyl b-cyclodextrin [100]. Different approaches have been used to improve various properties of resveratrol such as solubility, bioavailability and

stability using approaches like size reduction to micron level by preparing microparticles [101], complexation with cyclodextrins [102], formulation of different nano carrier systems like solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLCs) [103], nanosuspension [104] and nanocapsules [105]. Different vesicular systems such as liposomes [106], niosomes [107], transferosomes and ethanol containing vesicles [108] have also been reported to improve light stability, solubility and bioavailability. Microparticulate systems Microparticulate systems are the delivery vehicles for small solid particles or droplets of liquids that are surrounded by different polymers to control the release and improve bioavailability, having diameters ranging from 0.1 to 200 µm [109]. Nam et al. formulated porous polymeric microspheres of resveratrol containing cyano groups by dispersion polymerization. The improvement in antioxidant activity was observed as a result of improved stability of resveratrol in microparticulate system compared to that of pure resveratrol. Characterization of antioxidant property was carried through DPPH radical scavenging activity [110]. Resveratrol microspheres were prepared to obtain the controlled release and improve stability by Peng et al. The drug was incorporated into chitosan microspheres by emulsion cross-linking method where vanillin was used as novel cross-linker. The encapsulation efficiency of resveratrol in microspheres was up to 93.68% and mechanisms such as diffusion, swelling and erosion coexisted thus resulting in controlled release and stabilization of the drug [111]. Microencapsulation of resveratrol increased solubility in aqueous medium thereby improving bioavailability and also prevented degradation due to light and heat [112]. Microparticle formulation of resveratrol containing zinc ions as crosslinking agent and gluteraldehyde as hardening agent were prepared by Das et al. for specific delivery to colon with > 94% encapsulation efficiency. Thus, obtained formulation was found to improve the stability of resveratrol [113]. 4.1

Cyclodextrin complex Cyclodextrins are cyclic oligosaccharides formed during bacterial digestion of cellulose, which consist of (a-1,4)linked a-D-glucopyranose unit in chair conformation resulting into truncated cone rather than perfect cylinders. They are also known as cycloamyloses, cyclomaltoses and schardinger dextrins. These structurally related groups of natural products contain hydrophilic outer surface and lipophilic inner central cavity and are divided into three types as a, b and g depending on six, seven or eight glucopyranose units, respectively. Cyclodextrins are used as building blocks, which also act as a controlled dosage reservoir protecting the drug from oxidation. They are popular for their ability to form inclusion complexes, holding lipophilic drug molecules into the lipophilic inner cavity. This improves the bioavailability of poorly soluble drugs, enhancing their aqueous solubility, 4.2

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which is the result of transformation of crystalline cyclodextrins into amorphous mixtures of isomeric derivatives. This also acts as a driving force for diffusion across the biological membrane. Cyclodextrins possess both stabilizing and destabilizing effects on drugs from photolytic and hydrolytic degradation [102,114]. Resveratrol being a drug with poor bioavailability has been encapsulated in different native and modified cyclodextrins such as a-, b-, g-, 2-hydroxypropylb-, dimethyl-b-cyclodextrins forming inclusion complex. The study revealed that the formation of complex improved the dissolution rate, solubility and stability of resveratrol. Moreover 2-hydroxypropyl-b-cyclodextrin complex was found to show higher scavenging potential compared to bcyclodextrin complex [115]. A similar study was carried out by Abellan et al. and they compared the complexation of resveratrol with native a-, b- and g-cyclodextrins and modified hydroxypropyl-b-, maltosyl-b-, methyl-b-, carboxymethyl-band acetyl-b-cyclodextrins. The value of complexation constant (Kc) showed high complexation of 18,048 ± 625 M-1 for hydroxypropyl-b-cyclodextrins thus improving the solubility of the drug [116]. In another study Lu et al. prepared inclusion complex of resveratrol with b-cyclodextrins and hydroxyl-b-cyclodextrins to improve its solubility and antioxidant activity. The complexes were studied for stoichiometry and stability constant by evaluating drug--cyclodextrin interaction in solution, using phase solubility analysis. The obtained result proved to increase limited water solubility of resveratrol forming the inclusion complex with cyclodextrins. Resveratrol/hydroxy-b-cyclodextrin complex also showed higher antioxidant efficacy compared to b-cyclodextrin complex [117]. Cyclodextrin-based nanosponges were prepared by reacting cyclodextrin with crosslinker such as carbonyldiimidazole to form three-dimensional networks with the aim to increase the solubility, stability and permeation. Complexes of resveratrol with b-cyclodextrin nanosponges were prepared in different weight ratios and the interaction characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy and X-ray powder diffraction (XRPD). XRPD confirmed the decrease in crystallinity of resveratrol after encapsulation while good permeation of the complex through the pigskin was observed with the improvement in solubility and stability [118]. 4.3

Nanocarrier systems Solid lipid nanoparticles

4.3.1

SLNs as the next challenge in the field of nanotechnology are the colloidal system of diameter 50 -- 1000 nm made up of solid lipid as the matrix medium stabilized by surfactants in the aqueous media with the potential to increase drug bioavailability. The used solid lipids are the complex glyceride mixtures, highly purified triglyceride or waxes that do not melt at body temperature. SLNs have the advantage of targetspecific delivery, stability and protection from light and acid for sensitive drugs [119]. Teskac et al. formulated SLNs as a colloidal carrier for resveratrol by melt-emulsification process 1292

to investigate cellular uptake, transport and internalization in keratinocytes. Hydrodynamic diameter of loaded SLN was found to be 180 ± 8 nm, which was determined by photon correlation spectroscopy. The result confirmed improved cellular uptake of resveratrol loaded SLN with improved cellular fate. SLN were also concentrated around nuclei releasing the drug in sustained manner improving the bioavailability and stability [120]. Resveratrol loaded SLNs were prepared by high shear homogenization technique using compritol 888ATO, myglyol, poloxamer 188, tween 80 and compared with NLCs. Both formulations showed potent antioxidant activity at a concentration of 50 µM but NLC containing resveratrol penetrated deeper into the skin [121]. Nanosuspension Nanosuspensions are the submicron colloidal dispersions containing poorly water soluble drug particles in nano range stabilized by surfactants, which results in the enhancement of solubility of the drug improving its overall bioavailability [122]. Nanosuspension containing resveratrol for dermal application was formulated by Kobierski et al. using high pressure homogenization technique. The formulation contained different stabilizers as Tween 80, Poloxamer 188, Plantacare 2000 and Inutec SP1, 1 and 2% respectively. Stable nanosuspensions in the range of 150 -- 220 nm were prepared, which possessed high solubility and dissolution velocity thus improving the bioavailability [104]. 4.3.2

Vesicular systems Vesicular systems act as a novel means to deliver encapsulated drug increasing bioavailability and providing therapeutic activity for a longer duration. Vesicles are the colloidal particles containing concentric bilayer, capable of transporting both hydrophilic and hydrophobic drugs. Liposomes are prepared from natural and synthetic phospholipids whereas niosomes are made from nonionic surfactants. Some other vesicular systems are transferosome, phytosomes, ethosomes and so on [123]. 4.4

Liposomes Liposomes are colloidal, vesicular, biocompatible structures prepared from lipids with stable physicochemical properties, which can be loaded with both lipophilic and hydrophilic drugs. Resveratrol being a lipophilic drug was found to improve bioavailability when incorporated in this bilayer. In one of the studies, Bonechi et al. prepared liposomes as carrier for the polyphenolic compound, that is, resveratrol and the formulation consisted of saturated phosphatidylcholine and cholesterol. Resveratrol loaded liposomes were characterized for its size, surface charge and structural details. The results showed that resveratrol interacted with the bilayer, which were more deeply inserted in cationic liposomes than in zwitterionic liposomes. Also the liposomes showed the protection of resveratrol against biological degradation and metabolism thus improving the drug 4.4.1

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Resveratrol

bioavailability [106]. Caddeo et al. formulated a novel class of penetration enhancers containing vesicles of resveratrol which allow the penetration of drug deep into the skin along with the liposomes using phosphatidylcholine and oleic acid. Physiochemical properties, morphology, stability and antioxidant activity of both the formulations were determined, which showed that the empty vesicles were larger and with a narrower size distribution than the corresponding resveratrol loaded vesicles. Stability study showed no variation in physicochemical properties of the formulations during a 90-day period. The antioxidant activity of resveratrol was determined using in vitro DPPH assay where reduction in the concentration of stable nitrogen centered free radical was observed as a free radical scavenging activity. Moreover, the potential of resveratrol as an antioxidant remained same after the incorporation in the vesicles with any of the formulation composition [124]. Mignet et al. discussed the molecular interaction of resveratrol with the DPPC choline group (CH3) in conventional DPPC/cholesterol liposomes. When cholesterol was replaced by cationic cholesterol derivative, the effects observed showed the deeper incorporation of resveratrol in the lipid bilayer. Resveratrol when formulated as liposome was also found to prolong efficacy and improve protection from UV B [125]. Niosomes Niosomes also termed as non-ionic surfactant vesicles are the vesicular systems consisting of aqueous inner core surrounded by a membrane of non-ionic surfactants forming a closed bilayer structure. These colloidal dispersions are prepared by hydration of surfactants, which are able to entrap the required drug. Pando et al. prepared resveratrol loaded niosomes using two stage techniques: mechanical agitation followed by sonication where two different surfactants, Span 60 and Span 80, were used. Niosomes prepared from Span 80 were comparatively more stable with narrow particle size distribution and high entrapment efficiency (43.7%) proving the improvement in bioavailability [107]. 4.4.2

Transferosomes and ethosomes Transferosomes are the ultraflexible lipid-based elastic vesicles with the potential of penetrating intact skin while ethosomes are the vesicles containing phospholipids, water and ethanol with the similar action delivering drug to and through the skin into systemic circulation. Resveratrol was used as the potential drug for the preparation of vesicular system for topical application. Different surfactants and lipids were used for the preparation of transferosomes and ethosomes and were characterized for size, zeta potential, stability and permeation. The nanocarriers were found to possess a mean diameter of 83 -- 116 nm with the encapsulation efficiency of > 70%. But permeation study on porcine skin carried out on franz diffusion cells showed that ethosomes only permeated through the skin [108]. 4.4.3

Nanosponges Nanosponges are the particles with the cavities in nanometric range, capable of encapsulating a large variety of substances, that is, both lipophilic and hydrophilic, improving the solubility of poorly water soluble molecules [126]. Ahmed et al. discussed about nanosponges containing resveratrol, which was prepared by dissolving the reagents in dimethyl sulfoxide at 100 C for 4 h. The formulation was found to enhance the stability, permeation and the cytotoxicity of resveratrol [127]. 4.4.4

5.

Clinical trials of resveratrol

Resveratrol is present in different human diet and exerts a plethora of health benefits. Although the activities in vitro and animal studies (preclinical) have shown positive results, there is a question related to safety when the extrapolated dose in human is administered. A wide range of resveratrolbased neutraceuticals are being consumed worldwide with questionable clinical support. All these hypothesis related studies have led to a huge number of benefits but the activity confirmation in human are still limited. Human clinical trials with resveratrol have been conducted for colon and colorectal cancer [128,129], type 2 diabetes [130,131], hepatic metastases [132], cardioprotection [133] with their positive results. Still a number of clinical researches in resveratrol are to be conducted for a wide range of diseases. 6.

Conclusion

A wide range of pharmaceutical research using resveratrol as a potential candidate is being conducted with the aim of improving the bioavailability, increasing the stability and minimizing the toxicity related to the drug. The present review provides detailed information about the therapeutic activity of resveratrol, issues related to drug delivery along with the different approaches utilized to improve the bioavailability of the drug. Thus, it is expected that this discussion will prompt the research community to develop an ideal drug delivery system of resveratrol. 7.

Expert opinion

Compounds from natural sources have found considerable interest in the pharmaceutical industry in the last few decades and are being exploited for the development of novel formulations for improving their potential activities. Resveratrol, a natural phytoalexin first obtained from white hellebore, has been found to be tremendously useful in treatment of various diseases like inflammation, cancer, diabetes and cardiovascular and neurological disorders. The major drawback associated with oral delivery of resveratrol is its poor bioavailability, which is due to extensive metabolism in liver and intestine, although it has been found to possess high oral absorption of almost 75%. Because most of the herbal-based chemical entities suffer from the problem of low oral bioavailability,

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which leads to increase in daily dose and makes the use of herbal compound a costly affair, therefore over a period of time, a number of approaches such as complexation with cyclodextrins, microencapsulation and microspheres have been used to overcome the problems associated with poor bioavailability. Over the past few decades, use of lipid-based approaches have found significant acceptance in the market. These formulations disperse and solubilize the drug in dosage form and facilitate emulsification in gastrointestinal tract thereby increasing absorption. A number of studies on resveratrol have been conducted in order to minimize the problems associated with the drug such as low bioavailability, extensive hepatic and intestinal metabolism. Different novel approaches to develop a highly bioavailable formulation are being carried out. Also the formulations are being used in the human clinical trials to see their effects in a wide range of disease. Resveratrol being a potent antioxidant acts by inhibiting ROS. Many diseases caused due to the production/presence of ROS can be treated with the drug. In the future resveratrol Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Affiliation Rudra Pangeni1 B.Pharm, Jasjeet K Sahni3, Javed Ali3, Shrestha Sharma2 & Sanjula Baboota†3 † Author for correspondence 1 Faculty of Pharmacy, Jamia Hamdard University, Department of Pharmaceutics, New Delhi, India 2 Research Scholar, Faculty of Pharmacy, Jamia Hamdard University, Department of Pharmaceutics, New Delhi, India 3 Assistant Professor, Hamdard University (Jamia Hamdard), Department of Pharmaceutics, New Delhi-110062, India Tel: +91 9818529286; E-mail: [email protected], [email protected]