Recent Advances of Resveratrol in Nanostructured Based Delivery Systems and in the Management of HIV/AIDS Gurinder Singh, Roopa S. Pai PII: DOI: Reference:
S0168-3659(14)00620-8 doi: 10.1016/j.jconrel.2014.09.002 COREL 7367
To appear in:
Journal of Controlled Release
Received date: Accepted date:
19 June 2014 2 September 2014
Please cite this article as: Gurinder Singh, Roopa S. Pai, Recent Advances of Resveratrol in Nanostructured Based Delivery Systems and in the Management of HIV/AIDS, Journal of Controlled Release (2014), doi: 10.1016/j.jconrel.2014.09.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Recent Advances of Resveratrol in Nanostructured Based Delivery Systems and in the
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Management of HIV/AIDS
Gurinder Singh, Roopa S. Pai*
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Department of Pharmaceutics, Faculty of Pharmacy, Al-Ameen College of Pharmacy, Bangalore,
NU
SC
Karnataka, India
* Correspondence to:
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Dr. Roopa S. Pai Professor Faculty of Pharmacy
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Department of Pharmaceutics, Al-Ameen College of Pharmacy
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Near Lal Bagh Main gate, Hosur Road Bangalore 560027, Karnataka, India
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Email: [email protected], [email protected] Tel.: 080-22234619; fax: 080-22225834
1
ACCEPTED MANUSCRIPT ABSTRACT Resveratrol, a natural polyphenolic compound present in trees, in peanuts, in grapevines and exhibited multiple pharmacological activities. Extensive research in last two decades suggested
PT
that resveratrol possesses anti-inflammatory, anticancer, antiviral, anti-amyloid, antiarthritic and antioxidant properties. Some clinical reports have proposed that resveratrol might be a potential
RI
candidate for the prevention and/or treatment of HIV/AIDS and synergistically enhances the
SC
anti-HIV-1 activity. Resveratrol is not toxic to cells, and by itself reduces viral replication by 20% to 30%. With almost 12% of the world population suffering from HIV/AIDS including its
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resurgence in the developed world, better management of this global threat is highly desired. Further, various studies demonstrated several issues associated with resveratrol which account
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for its poor systemic bioavailability (almost zero) due to rapid and extensive first pass metabolism and existence of enterohepatic recirculation. In order to improve bioavailability and cellular uptake of resveratrol, various strategies have been adopted to date which includes
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resveratrol prodrug and the development of nanostructured delivery systems. Besides,
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nanostructured delivery systems are also known to inhibit the P-glycoprotein (P-gp) efflux, reduced metabolism by gut Cytochrome P-450 enzymes, and circumnavigate the hepatic first-
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pass effect, facilitating absorption of drugs via intestinal lymphatic pathways. This review paper provides an updated bird‟s-eye view account on the publications and patents study on the recent novel approaches to deliver resveratrol in order to enhance oral bioavailability, overcome first pass metabolism and trounce enterohepatic recirculation to make resveratrol therapeutically potent drug. Providing a relatively pithy overview, this paper thus presents recent advances of resveratrol for the treatment and prevention of HIV/AIDS. Keywords: Anti-retroviral drugs, bioavailability, enterohepatic recirculation, HIV/AIDS, nanostructured delivery, trans-resveratrol
2
ACCEPTED MANUSCRIPT 1. Introduction Resveratrol (3,5,4′-trihydroxystilbene) is a non-flavonoid polyphenolic compound found in peanuts, grapes, mulberries, cranberry, blueberry, red wine, in several plants and food that are
PT
usually consumed as part of human diet [1,2]. The compound was first isolated from the roots of white hellebore (Veratrum grandiflorum O. Loes) in 1940‟s [3], and later, in 1963, from the roots
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of Polygonum cuspidatum, a plant used in traditional Chinese and Japanese medicine [4,5].
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Resveratrol attracted little interest until 1992, when it was postulated to explain some of the cardioprotective effects of red wine [6]. Since then, dozens of reports have shown that resveratrol
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can prevent or slow the progression of a wide variety of illnesses, including cancer [7-12], cardiovascular disease [13], ischaemic injuries [14,15], HIV/AIDS [16,17] as well as to enhance
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stress resistance and extend the life spans of various organisms from yeast [18] to vertebrates [19,20]. These plants synthesize resveratrol as a protection in response to stress, injury, ultraviolet irradiation, fungal infection, and attack against pathogens [21,22]. Resveratrol has two
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isomers cis and trans. However, trans-resveratrol is pharmacologically active and more stable
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than cis-resveratrol [21,23]. Resveratrol is an extremely photosensitive compound and exhibits 80-90% of the trans-resveratrol in solution gets converted to cis-resveratrol if exposed to light
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for 1 h. [24].
In the last decade, resveratrol has been the focus of a number of studies scrutinizing its beneficial effects on health. Evidence has revealed that resveratrol acts as a free radical scavenger and a potent antioxidant, promotes nitric oxide production, increases HDL cholesterol, inhibits platelet aggregation and the oxidation of low-density lipoproteins [2,25]. These biological effects may be cardioprotective and contribute to the phenomenon known as the „French paradox‟: a decreased incidence of cardiovascular diseases in moderate consumers of red wines despite an intake of a high-fat diet [26,27]. Furthermore, the chemopreventive effect of resveratrol is thought to be due to inhibition of quinone reductase 2 activity, which in turn up-regulates the expression of cellular antioxidant and detoxification enzymes to improve cellular resistance to oxidative stress [28]. Resveratrol also increases the activity of SIRT 1 activity (a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent deacetylases), resulting in improved cellular stress resistance and longevity [29]. Resveratrol can also regulate the expression of hormone dependent genes 3
ACCEPTED MANUSCRIPT such as the oncosuppressor BRCA1 in breast cells, due to its structural similarity to diethylstilbestrol [30,31].
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However, therapeutic application of these beneficial effects of resveratrol remains very limited due to its short biological half-life (~8-14 min) [20,23], labile properties which account for their
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poor systemic bioavailability (almost zero) due to rapid first pass metabolism and existence of enterohepatic recirculation [32]. After an oral dose, it is demonstrated that the metabolic
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pathways leave just a little free resveratrol in blood, therefore, the bioavailability in the target tissues is very low and the concentrations used in in vitro studies are not found in tissues. The
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elimination phase for resveratrol is not well characterized because of the observed concentration increased in the terminal portion of the profiles, maybe due to enterohepatic recirculation [33].
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Resveratrol has attracted great interest in the research community, with more than 6437 publications between 1940 and 2014 referenced from PubMed service [Fig. 1]. Analysis of recent literature reveals an increasing percentage of publications [Fig. 1], which reflects the
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major interest in developing pharmaceutical forms able to increase resveratrol bioavailability as a
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step towards applying its therapeutic potential in vivo.
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Percentage of resveratrol publications over the last 74 years 1940-2000 10%
2000-2005 16%
2010-2014 45%
2005-2010 29%
Fig.1: Pictorial depiction of various publications years wise on resveratrol over the last 74 years. 4
ACCEPTED MANUSCRIPT Since 1940s, the fate of increasing resveratrol bioavailability has been employed by several researchers, resulting in the transfer of some laboratory research work to industrial setups and ultimately to clinics. Numerous international patents have been granted on diverse types of
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resveratrol formulations (for bioavailability enhancement and treatment of numerous infections
depicted in [Table 2], along with their final dosage form.
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and diseases) are depicted in [Table 1]. A recent list of some marketed resveratrol formulations is
US 2010/0297199 A1
Nanoemulsion
US 2011/0009496 A1 EP 1 829 452 A1
Liquid formulations (solutions and emulsions) Microemulsion
US 2013/0023590 A1
Aqueous solutions
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US 2013/0030518 A1
Coated device
US 2013/0046231 A1
US 2013/0115195A1 US2010/0197801 A1
Coated formulation for cutting balloon catheters Formulation (any form) of resveratrol or rice brain oil Dietary supplement Powder blends
WO2013/074948 A1 US6270780 B1
Powder blends Cosmetic
CA2748344 A1
Bioactive formulations
ZA1998/06039 (B granted National Patent)
Cosmetic
US 2013/0040920 A1
Purpose For the treatment of Itching Delivery of resveratrol through the skin For the treatment of ageing and cellular degeneration For the preparation of cosmetics, pharmaceuticals or healthcare products To improve patient compliance and bioavailability Augment solubility and stability of resveratrol Augment solubility and stability of resveratrol To reduce smooth muscle cell proliferation and platelet activity for treating or preventing atherosclerosis To improve therapeutic effect
Reference [34] [35]
Increase therapeutic potential of resveratrol Enhance efficiency To improve the oral bioavailability To enhance therapeutic benefit Useful in improving the appearance of wrinkled, lined, dry, flaky, aged or photo damaged skin Augment the water solubility and/or bioavailability of resveratrol Useful in improving the appearance of wrinkled, lined, dry, flaky, aged or photo damaged skin
[43]
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US 2004/0116386 A1
Formulation Patches or Sticking plaster Shampoo containing nano size carriers Phospholipid complex
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Patent no. US 2014/0079835 A1 US 2014/0073616 A1
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Table 1: A list of patents on the use of resveratrol in diverse formulations.
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[36] [37]
[38] [39] [40] [41]
[42]
[44] [45] [46] [47]
[48]
[49]
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US20040009197 A1
Topical (sunscreen)
US20110039945 B2
Powder or granules
US6358517 B1 WO2013056298
Cosmetic Buccal/Sublingual membranes ----------
WO2010062824
----------
WO2002072591 CA2694343 A1 US20120088829 A1
Phospholipid complex Cyclodextrin complex Stabilized aqueous formulations
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Cosmetic
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US20090035237 A1 US20100297199 B2
Enhance water solubility Enhance water solubility Can be used in the fields of food, drinks, health-care products, cosmetics and medicines Bioavailability enhancement Better penetrability and greatly improve the percutaneous absorption Enhance resveratrol stability Improve stability and good water dispersibility Improve dissolution rate and bioavailability Prolong release of resveratrol Increase the stability and halflife of the resveratrol Improve stability and solubility Enhance water solubility Enhance bioavailability
[65] [66] [67]
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EP2431023 A4
Topical (transdermal applications) Liposomes
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CA2629979 A1
[50] [51]
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EP2674155 A1
Treat skin disorders or diseases To improve solubility and bioavailability Sunscreens for protection against light having a wavelength of from 200 to 320 nm To improve solubility and bioavailability Skin care To overcome first pass metabolism by the liver Enhance the bioavailability of resveratrol Increase solubility and permeability to the skin To increase penetrability and absorption of resveratrol. To augment the water solubility and/or bioavailability of resveratrol Bioavailability enhancement Enhance water solubility To improve the water solubility and/or bioavailability of resveratrol Delivery of resveratrol through the skin Improve bioavailability
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Topical Solid dispersion
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US20020173472 A1 WO2010102245
US20100204179 B2 WO2010059628 CN102106816 A
Nanoemulsion phospholipid complex Water-soluble complex Water soluble formulation Nanometer preparation
CN101961323 A CN101874763 A
Self-emulsified soft capsule Liposomes
CN102188370 B CN102614127 A
Injection Nanoscale dispersoid
CN101703479 A
Pellets
RU02373926 C1 CN101214225 A
Particles Nano emulsion
CN102614091 A CN101292966 A WO2010124540
Nanostructured lipid carriers Solid dispersion Liposomes 6
[52]
[53] [54] [55] [56] [57] [58] [59]
[60] [61] [62]
[63] [64]
[68] [69]
[70] [71] [72] [73] [74] [75] [76] [77]
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Polymer micelles
CN102887994 A
Hydrophilic resveratrol formulation Freeze-dried albumin powder Phospholipid nano-emulsion
CN101658499 A CN101579291 B
CN101927148 A
Microcapsules
CN102766258 A
Hydrophilic conjugate
CN101693022 B
Sustained release capsule
CN101870769 B
Water soluble prodrug
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Increase solubility and stability Augment solubility, bioavailability and stability Increase solubility and bioavailability Enhance solubility and bioavailability Improve the stability and water solubility of resveratrol Improve the stability and water solubility of resveratrol Sustained-release capsule of resveratrol capable of preventing rheumatoid arthritis To change the water solubility and stability of resveratrol and improves the bioactivity.
[82] [83]
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CN101759531 B
Nano-emulsion and nanoparticles Water-soluble particles
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KR1020090132357
[78]
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CN102755298 A
Enhance absorption through small intestine and dissolution To improve the bioavailability of resveratrol Increase stability and bioavailability Enhance solubility
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CN102885780 A
Nanotechnology (nanometer granule) Pellets
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CN101317832 B
[79] [80] [81]
[84] [85] [86] [87] [88]
[89]
Table 2: A list of marketed products of resveratrol formulations manufactured by different companies. Trade name (manufacturer) REZMelts (eZMELTS) Redredwine Resveratrol (Highland Laboratories)
Resveratrol 150 (Gaia Herbs) Resveratrol Extreme Juice (Life Smart Labs Inc) Resveratrol ++ (Body By Natra) Eden Pond Resveratrol (Eden Pond) Resveratrol Platinum (Resveratrol Platinum.com) Resveratrol Gold (Nutrigold)
Marketed formulation
Strength [s]
Oral fast melting tablets
150mg
Lozenges
Herbs
25mg (Red Wine Extract (from Vitus vinifera) (standardized to 5.0% trans-resveratrol, contains 1.25 mg trans-resveratrol) 150mg
Capsules
1000mg
Capsules
35mg (low dose)
Capsules
500mg
Capsules
500mg
Capsule
500mg
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250mg
Capsule
250, 500mg
Pill
1000mg
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Softgel
Capsule
553mg (350 mg of active resveratrol) 100mg
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Tablet
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Tablet Capsule
250, 500mg
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Blend
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Softgel
100mg 40, 250mg 260mg 100mg
Softgel
100, 250, 500mg
Capsule
50, 200mg
Capsule
40mg
Self-Micro Emulsifying Drug Delivery System (SMEDDS )
---
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Capsule
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Maximum Strength Resveratrol (TruNature) Reserveage Resveratrol (Reserveage Organics) Resveratrol Premium (Resveratrol Premium) Resveratrol (ResVitale) RAW Resveratrol (Garden of Life) Resveratrol Plus (Natrol) Best trans-Resveratrol (Doctor's Best) Resveratrol (Biovea) Resveratrol & Red Wine Extract (Newton-Everett Biotech) Jarrow Formulas Resveratrol (Jarrow) Extra Strength Resveratrol (Vitamin World) Natural Resveratrol (Now Food) Resveratrol (Physician Formulas) ESTRO-TEST (Fight Labs)
A comprehensive effort was undertaken to search numerous literature findings and patents on recent advances of resveratrol for the treatment and prevention of HIV/AIDS and various types of formulations reported to date, respectively. An implicit and categorical account of literature has been accentuated here. A comparative account of various patents filed worldwide with key regulatory agencies on conventional and nanostructured delivery systems is presented in Fig. 2.
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ACCEPTED MANUSCRIPT Nanostructured based systems
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30
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25
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20
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15
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10 5
US patent
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0
World patent
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Reports on files patents on resveratrol formulation
Conventional
European Patent
Others
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Fig. 2: Pictorial depiction of various patents on conventional and nanostructured based systems of resveratrol. Unquestionably, these patents proved the versatility of different formulations in improving bioavailability of resveratrol. Also, these recent reports vouch for the application of nanostructured delivery systems in the bioavailability and solubility enhancement of resveratrol. Scope of the review
The current review paper attempts to provide a holistic account on the current innovations in nanostructured delivery systems to overcome bioavailability limitations of resveratrol and their potential for oral drug delivery, with special emphasis on the recent advances of resveratrol for the treatment and prevention of HIV/AIDS. 2. Nanostructured delivery systems for resveratrol 2.1. Rationale for nanostructured-based systems The basic concept behind the use of nanostructured delivery systems is related with the modulation of pharmacokinetics of resveratrol. With this association, the properties that govern 9
ACCEPTED MANUSCRIPT drug absorption, distribution, and elimination while in the human body are determined not by the drug properties, rather by the nanosystems physical-chemical properties, particularly surface exposed molecules and electric charge, and its particle size [90]. According to the European
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Science Foundation, nanomedicines are defined as nanometer size scale complex systems, consisting of at least two components, one of which being the active ingredient. Although
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mainstream nanotechnology explores particles between 1 and 200 nm in diameter, the size of
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individual particles tested for drug delivery of therapeutic and imaging agents may range from 1 to 1000 nm [91,92].
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Nanostructured delivery systems bring some advantages to the drug delivery field in general and oral drug delivery in particular. It allows (a) The delivery of poorly water-soluble drugs, (b)
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Specific drug targeting to gastrointestinal tract regions, (b) Transcytosis of drugs across the tight intestinal barrier and (d) Intracellular and transcellular delivery of large macromolecules [93]. Nanomedicines can increase efficacy, specificity, tolerability and therapeutic index of
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corresponding drugs [94]. Nanostructured systems must be stable, non-toxic, non-thrombogenic,
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nonimmunogenic, non-inflammatory, biodegradable, avoid uptake by reticulo-endothelial system and should be applicable to various molecules such as small drugs, proteins, vaccines or nucleic
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acids [95,96]. Besides, nanocarriers such as polymeric nanoparticles have provided a promising approach to obtain desirable biopharmaceutical and pharmacokinetic properties for drugs. Several nanostructured based products are being used and evaluated in clinical practice. Since last decade, efforts are being made to augment bioavailability, reduce metabolism and improved targeted delivery of resveratrol with the help of nanostructured based systems [16,17]. This can be achieved either by passive or active targeting. Passive targeting is based in the inherent properties of different nanosystems viz., size, particle shape, and surface charge, which can modulate resveratrol bioavailability, biodistribution and/or targeting. In the case of active targeting, nanostructured based systems are conveniently modified, most commonly by surface attachment of specific ligands that are able to recognize target cells or sites, and/or escape bioelimination processes [97]. The fate of pure resveratrol and resveratrol nanostructured systems after oral administration has been reconstituted based on various data obtained in vitro on cell cultures, ex vivo on small intestine models, and in vivo in animals and humans [Fig. 3].
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ACCEPTED MANUSCRIPT
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Fig. 3: In vivo fate of resveratrol following oral administration in pure form as well as in nanostructured form. In last few years, several reviews have been published which mainly focuses on application of nanostructured based systems (polymeric nanoparticles, solid lipid nanoparticles, Selfemulsifying drug delivery systems, liposomes, microparticles and nano emulsions) for enhancing bioavailability and therapeutic efficiency of resveratrol [37, 39, 58, 64, 67-71, 74, 75, 77, 78, 83, 84, 86, 98-104]. Their ability to incorporate, protect and/or promote the absorption of resveratrol in order to improve bioavailability [97]. In addition, protection of incorporated drug from metabolism is a favorable feature of nanosystems, allowing prolonged drug residence in the human body, thus reduces needed doses and prolongs time between administrations. 2.1. Nano-architectures for resveratrol delivery 2.1.1. Polymeric nanoparticles These are widely used delivery carriers for drug solubilization, stability, and specific targeting. Excellent stability, simplicity of administration by various routes, and possibility of loading hydrophilic and hydrophobic drugs have made their reputation as one of the most admired 11
ACCEPTED MANUSCRIPT techniques for drug encapsulation [89]. Based on the technique used for their production, two categories of systems can be formed, namely nanocapsules and nanospheres. Nanocapsules are vesicular systems in which a drug is confined to a cavity surrounded by a polymer membrane,
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whereas nanospheres are matrix systems in which the drug is physically and uniformly dispersed [89]. Over the years, various methods have been developed to engineer polymeric nanoparticles
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that can carry a variety of hydrophobic or hydrophilic drugs as well as biomolecules like proteins
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[105,106].
A large variety of synthetic and natural polymers, such as poly(D,L-lactide-co-glycolide) poly(lactide)
(PLA),
poly(glycolide)
(PGA),
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(PLGA),
poly(ε-caprolactone)
(PCL),
poly(cyanoacrylates) (PCA), polymethylmethacrylates (Eudragits), chitosan, albumin and gelatin
adsorbed on the nanoparticles surface.
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are used for the preparation of nanoparticles [102,103,107]. The drug is either encapsulated or
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Singh and Pai [98] reported sustained release of trans-resveratrol from orally administered
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PLGA nanoparticles. Drug encapsulation efficiency was ~78.25% with particle size of about ~170 nm, with polydispersity of 0.13 and -27.49 mV zeta potential. The drug was detected in the
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rats of plasma for up to 4 days resulted in a 7.17-fold higher in vivo concentration of the drug in the systemic circulation and in the organs rich in mononuclear phagocyte system (MPS) i.e. the lungs, liver and spleen for 7 days following single oral dose of nanoparticles. In contrast free drug was cleared from the plasma within 4 to 6 h. Furthermore, 6.46-fold augmentation in the values of effective permeability of trans-resveratrol was perceptible upon formulating it as nanoparticles. Study thus signifies the use of these nanoparticles for enhancing the bioavailability of resveratrol and could be a safe way to deliver resveratrol at the target; one administration every 4th day. Resveratrol loaded nanoparticles were prepared by the nanoprecipitation technique of the amphilic block copolymer methoxy poly(ethylene glycol)poly(caprolactone) and were assessed [108]. The drug encapsulation efficiency of these nanoparticles for resveratrol was found to be 90%. The average size of the nanoparticles was 90 nm, with a polydispersity index of 0.38. After an initial burst drug released of over a 50% release in 5 h, resveratrol was delivered in a sustained manner from the core-shell nanoparticles. The encapsulation process combining resveratrol and biodegradable nanoparticles efficiently demonstrated a superior ability to penetrate cell membranes and a better efficacy against glioma 12
ACCEPTED MANUSCRIPT cells than free resveratrol. Lu et al. [109] projected resveratrol-loaded nanoparticles efficiently shielded cultured PC12 cells against β-amyloid peptide-induced damage by attenuating oxidative stress and affecting apoptosis without long-term cytotoxicity. The authors hypothesized that
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administering resveratrol via an injectable and biodegradable drug delivery system might be a potential therapeutic tool. Resveratrol encapsulated in Eudragit RL 100 nanoparticles
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administered via oral route were reported [99]. Nanoparticles were prepared by the
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nanoprecipitation technique and were assessed in rat model so as to develop an effective orally administered regimen for resveratrol with enhanced bioavailability. The drug incorporation
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efficiency was found to be 83.69 %. The average size of the Eudragit RL 100 nanoparticles was 180 nm, with a polydispersity index of 0.21. The drug released in simulated intestinal fluid (SIF)
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was not more than 3% at 2 h during the entire study. Nanoparticles exhibited prolonged plasma levels up to 16 h, maintaining drug levels in the liver, spleen, heart, lungs, kidney and brain up to 24 h in comparison to free drug being cleared within 6 h. On oral administration of these
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nanoparticles to rats therapeutic levels were maintained in blood and plasma with a significant
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improvement in mean residence time as well as drug bioavailability. Eudragit RL and lecithin/chitosan nanoparticles were fabricated by co-precipitation method to enhance systemic
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bioavailability of resveratrol. Eudragit RL and lecithin/chitosan nanoparticles (submicron size) increased bioavailability to 39% and 61%, respectively [110].
Zu et al. [111] reported
carboxymethyl chitosan nanoparticles as potential carrier for augmenting the solubility and bioavailability of resveratrol. The authors developed resveratrol loaded carboxymethyl chitosan nanoparticles using emulsion cross-linking technique. The drug loaded carboxymethyl chitosan nanoparticles exhibited particle size of 155.5 nm, zeta potential -10.28 mV and encapsulation efficiency of 44.5%. The nanoparticles improved the solubility of resveratrol, thereby greatly improving the antioxidant activity of the drug. In vivo biodistribution study indicated higher localization of drug loaded carboxymethyl chitosan nanoparticles in various organs, in comparison to free resveratrol solution in PBS (pH 7.4). In comparison to free drug, the nanoparticles not only maintained the plasma levels but also improved the AUC and mean residence time (MRT), suggestive of superior pharmacokinetics of drug and showed a significant improvement in relative bioavailability in the plasma (3.516 times). The suitability of polymeric nanoparticles loaded with resveratrol for drug delivery to cochlear cells was investigated [112]. In vitro toxicity of the polymeric nanoparticles was evaluated on two cochlear cell lines: HEI13
ACCEPTED MANUSCRIPT OC1 and SVK-1 cells. The data suggests that the in vitro cytotoxicity studies showed that blank nanoparticles did not alter the viability of both cells lines in case of blank nanoparticles, except for concentrations higher than 600μg/ml. However, the cell viability was significantly decreased
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at high concentrations of native resveratrol (>50μM, p
S0168-3659(14)00620-8 doi: 10.1016/j.jconrel.2014.09.002 COREL 7367
To appear in:
Journal of Controlled Release
Received date: Accepted date:
19 June 2014 2 September 2014
Please cite this article as: Gurinder Singh, Roopa S. Pai, Recent Advances of Resveratrol in Nanostructured Based Delivery Systems and in the Management of HIV/AIDS, Journal of Controlled Release (2014), doi: 10.1016/j.jconrel.2014.09.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Recent Advances of Resveratrol in Nanostructured Based Delivery Systems and in the
PT
Management of HIV/AIDS
Gurinder Singh, Roopa S. Pai*
RI
Department of Pharmaceutics, Faculty of Pharmacy, Al-Ameen College of Pharmacy, Bangalore,
NU
SC
Karnataka, India
* Correspondence to:
MA
Dr. Roopa S. Pai Professor Faculty of Pharmacy
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Department of Pharmaceutics, Al-Ameen College of Pharmacy
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Near Lal Bagh Main gate, Hosur Road Bangalore 560027, Karnataka, India
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Email: [email protected], [email protected] Tel.: 080-22234619; fax: 080-22225834
1
ACCEPTED MANUSCRIPT ABSTRACT Resveratrol, a natural polyphenolic compound present in trees, in peanuts, in grapevines and exhibited multiple pharmacological activities. Extensive research in last two decades suggested
PT
that resveratrol possesses anti-inflammatory, anticancer, antiviral, anti-amyloid, antiarthritic and antioxidant properties. Some clinical reports have proposed that resveratrol might be a potential
RI
candidate for the prevention and/or treatment of HIV/AIDS and synergistically enhances the
SC
anti-HIV-1 activity. Resveratrol is not toxic to cells, and by itself reduces viral replication by 20% to 30%. With almost 12% of the world population suffering from HIV/AIDS including its
NU
resurgence in the developed world, better management of this global threat is highly desired. Further, various studies demonstrated several issues associated with resveratrol which account
MA
for its poor systemic bioavailability (almost zero) due to rapid and extensive first pass metabolism and existence of enterohepatic recirculation. In order to improve bioavailability and cellular uptake of resveratrol, various strategies have been adopted to date which includes
D
resveratrol prodrug and the development of nanostructured delivery systems. Besides,
TE
nanostructured delivery systems are also known to inhibit the P-glycoprotein (P-gp) efflux, reduced metabolism by gut Cytochrome P-450 enzymes, and circumnavigate the hepatic first-
AC CE P
pass effect, facilitating absorption of drugs via intestinal lymphatic pathways. This review paper provides an updated bird‟s-eye view account on the publications and patents study on the recent novel approaches to deliver resveratrol in order to enhance oral bioavailability, overcome first pass metabolism and trounce enterohepatic recirculation to make resveratrol therapeutically potent drug. Providing a relatively pithy overview, this paper thus presents recent advances of resveratrol for the treatment and prevention of HIV/AIDS. Keywords: Anti-retroviral drugs, bioavailability, enterohepatic recirculation, HIV/AIDS, nanostructured delivery, trans-resveratrol
2
ACCEPTED MANUSCRIPT 1. Introduction Resveratrol (3,5,4′-trihydroxystilbene) is a non-flavonoid polyphenolic compound found in peanuts, grapes, mulberries, cranberry, blueberry, red wine, in several plants and food that are
PT
usually consumed as part of human diet [1,2]. The compound was first isolated from the roots of white hellebore (Veratrum grandiflorum O. Loes) in 1940‟s [3], and later, in 1963, from the roots
RI
of Polygonum cuspidatum, a plant used in traditional Chinese and Japanese medicine [4,5].
SC
Resveratrol attracted little interest until 1992, when it was postulated to explain some of the cardioprotective effects of red wine [6]. Since then, dozens of reports have shown that resveratrol
NU
can prevent or slow the progression of a wide variety of illnesses, including cancer [7-12], cardiovascular disease [13], ischaemic injuries [14,15], HIV/AIDS [16,17] as well as to enhance
MA
stress resistance and extend the life spans of various organisms from yeast [18] to vertebrates [19,20]. These plants synthesize resveratrol as a protection in response to stress, injury, ultraviolet irradiation, fungal infection, and attack against pathogens [21,22]. Resveratrol has two
D
isomers cis and trans. However, trans-resveratrol is pharmacologically active and more stable
TE
than cis-resveratrol [21,23]. Resveratrol is an extremely photosensitive compound and exhibits 80-90% of the trans-resveratrol in solution gets converted to cis-resveratrol if exposed to light
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for 1 h. [24].
In the last decade, resveratrol has been the focus of a number of studies scrutinizing its beneficial effects on health. Evidence has revealed that resveratrol acts as a free radical scavenger and a potent antioxidant, promotes nitric oxide production, increases HDL cholesterol, inhibits platelet aggregation and the oxidation of low-density lipoproteins [2,25]. These biological effects may be cardioprotective and contribute to the phenomenon known as the „French paradox‟: a decreased incidence of cardiovascular diseases in moderate consumers of red wines despite an intake of a high-fat diet [26,27]. Furthermore, the chemopreventive effect of resveratrol is thought to be due to inhibition of quinone reductase 2 activity, which in turn up-regulates the expression of cellular antioxidant and detoxification enzymes to improve cellular resistance to oxidative stress [28]. Resveratrol also increases the activity of SIRT 1 activity (a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent deacetylases), resulting in improved cellular stress resistance and longevity [29]. Resveratrol can also regulate the expression of hormone dependent genes 3
ACCEPTED MANUSCRIPT such as the oncosuppressor BRCA1 in breast cells, due to its structural similarity to diethylstilbestrol [30,31].
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However, therapeutic application of these beneficial effects of resveratrol remains very limited due to its short biological half-life (~8-14 min) [20,23], labile properties which account for their
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poor systemic bioavailability (almost zero) due to rapid first pass metabolism and existence of enterohepatic recirculation [32]. After an oral dose, it is demonstrated that the metabolic
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pathways leave just a little free resveratrol in blood, therefore, the bioavailability in the target tissues is very low and the concentrations used in in vitro studies are not found in tissues. The
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elimination phase for resveratrol is not well characterized because of the observed concentration increased in the terminal portion of the profiles, maybe due to enterohepatic recirculation [33].
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Resveratrol has attracted great interest in the research community, with more than 6437 publications between 1940 and 2014 referenced from PubMed service [Fig. 1]. Analysis of recent literature reveals an increasing percentage of publications [Fig. 1], which reflects the
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major interest in developing pharmaceutical forms able to increase resveratrol bioavailability as a
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step towards applying its therapeutic potential in vivo.
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Percentage of resveratrol publications over the last 74 years 1940-2000 10%
2000-2005 16%
2010-2014 45%
2005-2010 29%
Fig.1: Pictorial depiction of various publications years wise on resveratrol over the last 74 years. 4
ACCEPTED MANUSCRIPT Since 1940s, the fate of increasing resveratrol bioavailability has been employed by several researchers, resulting in the transfer of some laboratory research work to industrial setups and ultimately to clinics. Numerous international patents have been granted on diverse types of
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resveratrol formulations (for bioavailability enhancement and treatment of numerous infections
depicted in [Table 2], along with their final dosage form.
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and diseases) are depicted in [Table 1]. A recent list of some marketed resveratrol formulations is
US 2010/0297199 A1
Nanoemulsion
US 2011/0009496 A1 EP 1 829 452 A1
Liquid formulations (solutions and emulsions) Microemulsion
US 2013/0023590 A1
Aqueous solutions
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US 2013/0030518 A1
Coated device
US 2013/0046231 A1
US 2013/0115195A1 US2010/0197801 A1
Coated formulation for cutting balloon catheters Formulation (any form) of resveratrol or rice brain oil Dietary supplement Powder blends
WO2013/074948 A1 US6270780 B1
Powder blends Cosmetic
CA2748344 A1
Bioactive formulations
ZA1998/06039 (B granted National Patent)
Cosmetic
US 2013/0040920 A1
Purpose For the treatment of Itching Delivery of resveratrol through the skin For the treatment of ageing and cellular degeneration For the preparation of cosmetics, pharmaceuticals or healthcare products To improve patient compliance and bioavailability Augment solubility and stability of resveratrol Augment solubility and stability of resveratrol To reduce smooth muscle cell proliferation and platelet activity for treating or preventing atherosclerosis To improve therapeutic effect
Reference [34] [35]
Increase therapeutic potential of resveratrol Enhance efficiency To improve the oral bioavailability To enhance therapeutic benefit Useful in improving the appearance of wrinkled, lined, dry, flaky, aged or photo damaged skin Augment the water solubility and/or bioavailability of resveratrol Useful in improving the appearance of wrinkled, lined, dry, flaky, aged or photo damaged skin
[43]
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US 2004/0116386 A1
Formulation Patches or Sticking plaster Shampoo containing nano size carriers Phospholipid complex
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Patent no. US 2014/0079835 A1 US 2014/0073616 A1
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Table 1: A list of patents on the use of resveratrol in diverse formulations.
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[36] [37]
[38] [39] [40] [41]
[42]
[44] [45] [46] [47]
[48]
[49]
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US20040009197 A1
Topical (sunscreen)
US20110039945 B2
Powder or granules
US6358517 B1 WO2013056298
Cosmetic Buccal/Sublingual membranes ----------
WO2010062824
----------
WO2002072591 CA2694343 A1 US20120088829 A1
Phospholipid complex Cyclodextrin complex Stabilized aqueous formulations
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Cosmetic
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US20090035237 A1 US20100297199 B2
Enhance water solubility Enhance water solubility Can be used in the fields of food, drinks, health-care products, cosmetics and medicines Bioavailability enhancement Better penetrability and greatly improve the percutaneous absorption Enhance resveratrol stability Improve stability and good water dispersibility Improve dissolution rate and bioavailability Prolong release of resveratrol Increase the stability and halflife of the resveratrol Improve stability and solubility Enhance water solubility Enhance bioavailability
[65] [66] [67]
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EP2431023 A4
Topical (transdermal applications) Liposomes
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CA2629979 A1
[50] [51]
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EP2674155 A1
Treat skin disorders or diseases To improve solubility and bioavailability Sunscreens for protection against light having a wavelength of from 200 to 320 nm To improve solubility and bioavailability Skin care To overcome first pass metabolism by the liver Enhance the bioavailability of resveratrol Increase solubility and permeability to the skin To increase penetrability and absorption of resveratrol. To augment the water solubility and/or bioavailability of resveratrol Bioavailability enhancement Enhance water solubility To improve the water solubility and/or bioavailability of resveratrol Delivery of resveratrol through the skin Improve bioavailability
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Topical Solid dispersion
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US20020173472 A1 WO2010102245
US20100204179 B2 WO2010059628 CN102106816 A
Nanoemulsion phospholipid complex Water-soluble complex Water soluble formulation Nanometer preparation
CN101961323 A CN101874763 A
Self-emulsified soft capsule Liposomes
CN102188370 B CN102614127 A
Injection Nanoscale dispersoid
CN101703479 A
Pellets
RU02373926 C1 CN101214225 A
Particles Nano emulsion
CN102614091 A CN101292966 A WO2010124540
Nanostructured lipid carriers Solid dispersion Liposomes 6
[52]
[53] [54] [55] [56] [57] [58] [59]
[60] [61] [62]
[63] [64]
[68] [69]
[70] [71] [72] [73] [74] [75] [76] [77]
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Polymer micelles
CN102887994 A
Hydrophilic resveratrol formulation Freeze-dried albumin powder Phospholipid nano-emulsion
CN101658499 A CN101579291 B
CN101927148 A
Microcapsules
CN102766258 A
Hydrophilic conjugate
CN101693022 B
Sustained release capsule
CN101870769 B
Water soluble prodrug
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Increase solubility and stability Augment solubility, bioavailability and stability Increase solubility and bioavailability Enhance solubility and bioavailability Improve the stability and water solubility of resveratrol Improve the stability and water solubility of resveratrol Sustained-release capsule of resveratrol capable of preventing rheumatoid arthritis To change the water solubility and stability of resveratrol and improves the bioactivity.
[82] [83]
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CN101759531 B
Nano-emulsion and nanoparticles Water-soluble particles
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KR1020090132357
[78]
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CN102755298 A
Enhance absorption through small intestine and dissolution To improve the bioavailability of resveratrol Increase stability and bioavailability Enhance solubility
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CN102885780 A
Nanotechnology (nanometer granule) Pellets
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CN101317832 B
[79] [80] [81]
[84] [85] [86] [87] [88]
[89]
Table 2: A list of marketed products of resveratrol formulations manufactured by different companies. Trade name (manufacturer) REZMelts (eZMELTS) Redredwine Resveratrol (Highland Laboratories)
Resveratrol 150 (Gaia Herbs) Resveratrol Extreme Juice (Life Smart Labs Inc) Resveratrol ++ (Body By Natra) Eden Pond Resveratrol (Eden Pond) Resveratrol Platinum (Resveratrol Platinum.com) Resveratrol Gold (Nutrigold)
Marketed formulation
Strength [s]
Oral fast melting tablets
150mg
Lozenges
Herbs
25mg (Red Wine Extract (from Vitus vinifera) (standardized to 5.0% trans-resveratrol, contains 1.25 mg trans-resveratrol) 150mg
Capsules
1000mg
Capsules
35mg (low dose)
Capsules
500mg
Capsules
500mg
Capsule
500mg
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250mg
Capsule
250, 500mg
Pill
1000mg
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Softgel
Capsule
553mg (350 mg of active resveratrol) 100mg
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Tablet
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Tablet Capsule
250, 500mg
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Blend
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Softgel
100mg 40, 250mg 260mg 100mg
Softgel
100, 250, 500mg
Capsule
50, 200mg
Capsule
40mg
Self-Micro Emulsifying Drug Delivery System (SMEDDS )
---
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Capsule
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Maximum Strength Resveratrol (TruNature) Reserveage Resveratrol (Reserveage Organics) Resveratrol Premium (Resveratrol Premium) Resveratrol (ResVitale) RAW Resveratrol (Garden of Life) Resveratrol Plus (Natrol) Best trans-Resveratrol (Doctor's Best) Resveratrol (Biovea) Resveratrol & Red Wine Extract (Newton-Everett Biotech) Jarrow Formulas Resveratrol (Jarrow) Extra Strength Resveratrol (Vitamin World) Natural Resveratrol (Now Food) Resveratrol (Physician Formulas) ESTRO-TEST (Fight Labs)
A comprehensive effort was undertaken to search numerous literature findings and patents on recent advances of resveratrol for the treatment and prevention of HIV/AIDS and various types of formulations reported to date, respectively. An implicit and categorical account of literature has been accentuated here. A comparative account of various patents filed worldwide with key regulatory agencies on conventional and nanostructured delivery systems is presented in Fig. 2.
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25
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20
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US patent
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World patent
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Reports on files patents on resveratrol formulation
Conventional
European Patent
Others
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Fig. 2: Pictorial depiction of various patents on conventional and nanostructured based systems of resveratrol. Unquestionably, these patents proved the versatility of different formulations in improving bioavailability of resveratrol. Also, these recent reports vouch for the application of nanostructured delivery systems in the bioavailability and solubility enhancement of resveratrol. Scope of the review
The current review paper attempts to provide a holistic account on the current innovations in nanostructured delivery systems to overcome bioavailability limitations of resveratrol and their potential for oral drug delivery, with special emphasis on the recent advances of resveratrol for the treatment and prevention of HIV/AIDS. 2. Nanostructured delivery systems for resveratrol 2.1. Rationale for nanostructured-based systems The basic concept behind the use of nanostructured delivery systems is related with the modulation of pharmacokinetics of resveratrol. With this association, the properties that govern 9
ACCEPTED MANUSCRIPT drug absorption, distribution, and elimination while in the human body are determined not by the drug properties, rather by the nanosystems physical-chemical properties, particularly surface exposed molecules and electric charge, and its particle size [90]. According to the European
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Science Foundation, nanomedicines are defined as nanometer size scale complex systems, consisting of at least two components, one of which being the active ingredient. Although
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mainstream nanotechnology explores particles between 1 and 200 nm in diameter, the size of
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individual particles tested for drug delivery of therapeutic and imaging agents may range from 1 to 1000 nm [91,92].
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Nanostructured delivery systems bring some advantages to the drug delivery field in general and oral drug delivery in particular. It allows (a) The delivery of poorly water-soluble drugs, (b)
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Specific drug targeting to gastrointestinal tract regions, (b) Transcytosis of drugs across the tight intestinal barrier and (d) Intracellular and transcellular delivery of large macromolecules [93]. Nanomedicines can increase efficacy, specificity, tolerability and therapeutic index of
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corresponding drugs [94]. Nanostructured systems must be stable, non-toxic, non-thrombogenic,
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nonimmunogenic, non-inflammatory, biodegradable, avoid uptake by reticulo-endothelial system and should be applicable to various molecules such as small drugs, proteins, vaccines or nucleic
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acids [95,96]. Besides, nanocarriers such as polymeric nanoparticles have provided a promising approach to obtain desirable biopharmaceutical and pharmacokinetic properties for drugs. Several nanostructured based products are being used and evaluated in clinical practice. Since last decade, efforts are being made to augment bioavailability, reduce metabolism and improved targeted delivery of resveratrol with the help of nanostructured based systems [16,17]. This can be achieved either by passive or active targeting. Passive targeting is based in the inherent properties of different nanosystems viz., size, particle shape, and surface charge, which can modulate resveratrol bioavailability, biodistribution and/or targeting. In the case of active targeting, nanostructured based systems are conveniently modified, most commonly by surface attachment of specific ligands that are able to recognize target cells or sites, and/or escape bioelimination processes [97]. The fate of pure resveratrol and resveratrol nanostructured systems after oral administration has been reconstituted based on various data obtained in vitro on cell cultures, ex vivo on small intestine models, and in vivo in animals and humans [Fig. 3].
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Fig. 3: In vivo fate of resveratrol following oral administration in pure form as well as in nanostructured form. In last few years, several reviews have been published which mainly focuses on application of nanostructured based systems (polymeric nanoparticles, solid lipid nanoparticles, Selfemulsifying drug delivery systems, liposomes, microparticles and nano emulsions) for enhancing bioavailability and therapeutic efficiency of resveratrol [37, 39, 58, 64, 67-71, 74, 75, 77, 78, 83, 84, 86, 98-104]. Their ability to incorporate, protect and/or promote the absorption of resveratrol in order to improve bioavailability [97]. In addition, protection of incorporated drug from metabolism is a favorable feature of nanosystems, allowing prolonged drug residence in the human body, thus reduces needed doses and prolongs time between administrations. 2.1. Nano-architectures for resveratrol delivery 2.1.1. Polymeric nanoparticles These are widely used delivery carriers for drug solubilization, stability, and specific targeting. Excellent stability, simplicity of administration by various routes, and possibility of loading hydrophilic and hydrophobic drugs have made their reputation as one of the most admired 11
ACCEPTED MANUSCRIPT techniques for drug encapsulation [89]. Based on the technique used for their production, two categories of systems can be formed, namely nanocapsules and nanospheres. Nanocapsules are vesicular systems in which a drug is confined to a cavity surrounded by a polymer membrane,
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whereas nanospheres are matrix systems in which the drug is physically and uniformly dispersed [89]. Over the years, various methods have been developed to engineer polymeric nanoparticles
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that can carry a variety of hydrophobic or hydrophilic drugs as well as biomolecules like proteins
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[105,106].
A large variety of synthetic and natural polymers, such as poly(D,L-lactide-co-glycolide) poly(lactide)
(PLA),
poly(glycolide)
(PGA),
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(PLGA),
poly(ε-caprolactone)
(PCL),
poly(cyanoacrylates) (PCA), polymethylmethacrylates (Eudragits), chitosan, albumin and gelatin
adsorbed on the nanoparticles surface.
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are used for the preparation of nanoparticles [102,103,107]. The drug is either encapsulated or
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Singh and Pai [98] reported sustained release of trans-resveratrol from orally administered
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PLGA nanoparticles. Drug encapsulation efficiency was ~78.25% with particle size of about ~170 nm, with polydispersity of 0.13 and -27.49 mV zeta potential. The drug was detected in the
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rats of plasma for up to 4 days resulted in a 7.17-fold higher in vivo concentration of the drug in the systemic circulation and in the organs rich in mononuclear phagocyte system (MPS) i.e. the lungs, liver and spleen for 7 days following single oral dose of nanoparticles. In contrast free drug was cleared from the plasma within 4 to 6 h. Furthermore, 6.46-fold augmentation in the values of effective permeability of trans-resveratrol was perceptible upon formulating it as nanoparticles. Study thus signifies the use of these nanoparticles for enhancing the bioavailability of resveratrol and could be a safe way to deliver resveratrol at the target; one administration every 4th day. Resveratrol loaded nanoparticles were prepared by the nanoprecipitation technique of the amphilic block copolymer methoxy poly(ethylene glycol)poly(caprolactone) and were assessed [108]. The drug encapsulation efficiency of these nanoparticles for resveratrol was found to be 90%. The average size of the nanoparticles was 90 nm, with a polydispersity index of 0.38. After an initial burst drug released of over a 50% release in 5 h, resveratrol was delivered in a sustained manner from the core-shell nanoparticles. The encapsulation process combining resveratrol and biodegradable nanoparticles efficiently demonstrated a superior ability to penetrate cell membranes and a better efficacy against glioma 12
ACCEPTED MANUSCRIPT cells than free resveratrol. Lu et al. [109] projected resveratrol-loaded nanoparticles efficiently shielded cultured PC12 cells against β-amyloid peptide-induced damage by attenuating oxidative stress and affecting apoptosis without long-term cytotoxicity. The authors hypothesized that
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administering resveratrol via an injectable and biodegradable drug delivery system might be a potential therapeutic tool. Resveratrol encapsulated in Eudragit RL 100 nanoparticles
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administered via oral route were reported [99]. Nanoparticles were prepared by the
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nanoprecipitation technique and were assessed in rat model so as to develop an effective orally administered regimen for resveratrol with enhanced bioavailability. The drug incorporation
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efficiency was found to be 83.69 %. The average size of the Eudragit RL 100 nanoparticles was 180 nm, with a polydispersity index of 0.21. The drug released in simulated intestinal fluid (SIF)
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was not more than 3% at 2 h during the entire study. Nanoparticles exhibited prolonged plasma levels up to 16 h, maintaining drug levels in the liver, spleen, heart, lungs, kidney and brain up to 24 h in comparison to free drug being cleared within 6 h. On oral administration of these
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nanoparticles to rats therapeutic levels were maintained in blood and plasma with a significant
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improvement in mean residence time as well as drug bioavailability. Eudragit RL and lecithin/chitosan nanoparticles were fabricated by co-precipitation method to enhance systemic
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bioavailability of resveratrol. Eudragit RL and lecithin/chitosan nanoparticles (submicron size) increased bioavailability to 39% and 61%, respectively [110].
Zu et al. [111] reported
carboxymethyl chitosan nanoparticles as potential carrier for augmenting the solubility and bioavailability of resveratrol. The authors developed resveratrol loaded carboxymethyl chitosan nanoparticles using emulsion cross-linking technique. The drug loaded carboxymethyl chitosan nanoparticles exhibited particle size of 155.5 nm, zeta potential -10.28 mV and encapsulation efficiency of 44.5%. The nanoparticles improved the solubility of resveratrol, thereby greatly improving the antioxidant activity of the drug. In vivo biodistribution study indicated higher localization of drug loaded carboxymethyl chitosan nanoparticles in various organs, in comparison to free resveratrol solution in PBS (pH 7.4). In comparison to free drug, the nanoparticles not only maintained the plasma levels but also improved the AUC and mean residence time (MRT), suggestive of superior pharmacokinetics of drug and showed a significant improvement in relative bioavailability in the plasma (3.516 times). The suitability of polymeric nanoparticles loaded with resveratrol for drug delivery to cochlear cells was investigated [112]. In vitro toxicity of the polymeric nanoparticles was evaluated on two cochlear cell lines: HEI13
ACCEPTED MANUSCRIPT OC1 and SVK-1 cells. The data suggests that the in vitro cytotoxicity studies showed that blank nanoparticles did not alter the viability of both cells lines in case of blank nanoparticles, except for concentrations higher than 600μg/ml. However, the cell viability was significantly decreased
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at high concentrations of native resveratrol (>50μM, p
