Journal of Controlled Release 296 (2019) 190–201

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Journal of Controlled Release

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Review article

Recent advances in topical delivery of flavonoids: A review T

⁎
Ruchika L. Nagula, Sarika Wairkar
Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKMs NMIMS, V.L.Mehta Road, Vile Parle (W), Mumbai, Maharashtra 400056, India

A R T I C LE I N FO A B S T R A C T

Keywords: Flavonoids are one of the vital classes of bioactive chemicals, abundantly found in plants. These are natural
Drug delivery systems polyphenolic compounds derived from plant metabolites. Their lipophilic nature and poor solubility lead to
Flavonoids variable and limited oral bioavailability. The substantial pharmacological properties of flavonoids include an-
Novel formulations tioxidant, anti-inflammatory, antiproliferative, photoprotective, depigmentation, anti-aging which are very
Topical route
promising in the treatment of several skin disorders. Thus, various topical delivery systems of flavonoids have
been extensively studied. Mostly, colloidal carriers of flavonoids were reported which are very efficient for
topical route with good encapsulation potential, reduced toxicity, and overcome the limitations of conventional
dosage forms. This review focuses on various formulations aspects, in vitro characterization and in vivo studies of
different classes of flavonoids administered by topical route. Although flavonoids offer tremendous potential in
healing the skin conditions categorically, its clinical translation needs in depth safety and efficacy data, meeting
established regulatory standards.

1. Introduction
Since ancient times several plants and its products are being used for
treating diseases and most of these plants are rich in bioflavonoids.
Bioflavonoids are the naturally occurring compounds which are sec-
ondary metabolites of plants having numerous therapeutic activities
[1]. They are low molecular weight polyphenolic compounds and stated
as non‑nitrogenous plant pigments. It is said that a diet rich in fruits and
vegetables is a healthy diet, flavonoids may be one of the reasons [2,3].
Flavonoids consist of C6-C3-C6 ring as basic structure, with varying
substitutes to create different subclasses such as flavones, flavanol,
flavonol, isoflavones, anthocyanins, as shown in Fig. 1 [3].
Bioflavonoids are valuable in both, for health promoting activities
and therapeutic benefits [4]. Health promoting effect improves well-
being and reduces the chances of developing risk that include beneficial
cardiovascular effect, increased eyesight, improved blood circulation,
immune system, etc. [5]. Therapeutic applications of bioflavonoids
have extensively been reported in various diseases such as inflamma-
tion, cardiovascular, respiratory, diabetes, etc. Categorically, these
biologically active compounds possess powerful antioxidant property
and act by several pathways as seen in Fig. 2 [6].
Flavonoids are highly lipophilic compounds and therefore difficult
to absorb orally. They undergo excessive first pass metabolism on oral
administration that hampers their oral bioavailability. Thus, an alter-
native topical route of administration has been explored for delivery of
several flavonoids [7]. However, stratum corneum acts as the major
barrier during skin penetration which can be addressed by preparing
various delivery systems of flavonoids such as nanoparticles, lipid na-
nocapsules, microparticle, microsponges, etc. These novel delivery
systems help in formulating both hydrophilic and lipophilic compounds
thus increasing the concentration of the drug at target site. Other ad-
vantages of topical route are controlled drug release at predetermined
rate and no interaction with the gastric and intestinal fluids, preventing
degradation of product. The topical route is also very useful in delivery
of drugs with shorter half-life and narrow therapeutic index [8]. While
designing topical formulation, various points need to be considered like
partition coefficient, pH, polymorphism, particle size, molecular
weight, vehicles, release characteristics, etc.
Several topical preparations of flavonoids have been formulated and
patented, showcasing wide range of activities as described in Table 1.
Patent overview of flavonoids would help to understand the relevant
flavonoids, their molecular targets, delivery systems and commercial
significance and thus, important to capture the gaps in flavonoids
spectrum and to decide future research strategies.
With due respect to tremendous therapeutic potential of flavonoids
combined with certain inherent limitations leads to development of
new formulations for alternative routes of administration. In this re-
view, we have attempted to take comprehensive review of topical de-
livery systems of flavonoids with recent advances and lingering chal-
lenges for their successful delivery.

⁎
Corresponding author.
E-mail address: sarikawairkar@gmail.com (S. Wairkar).

https://doi.org/10.1016/j.jconrel.2019.01.029
Received 6 December 2018; Received in revised form 18 January 2019; Accepted 18 January 2019
Available online 22 January 2019
0168-3659/ © 2019 Elsevier B.V. All rights reserved.
R.L. Nagula, S. Wairkar Journal of Controlled Release 296 (2019) 190–201

Fig. 1. Classification of flavonoids based on chemical structure.

Fig. 2. Antioxidant effect of flavonoids by (a) ROS inhibition (b) leukocyte immobilization (c) nitric oxide inhibition (d) inhibition of xanthine oxidase.

2. Structure of skin and barriers in topical delivery
The largest organ of body, skin, helps in body protection, tem-
perature regulation and acts as an organ of sensation. The skin is di-
vided into three layers namely epidermis, dermis and subcutaneous
layer as depicted in Fig. 3.
Epidermis is the outermost layer of the skin which is divided into
four layers and acts as major barrier. Stratum basalis is present next to
dermis layer and is the bottommost layer of epidermis. Second layer
above stratum basalis is stratum spinosum in which keratinocytes are
bound to each other by desmosomes which maintains the structural
integrity of skin. The next layer stratum granulosm is made up of flatter
keratinocytes and acts as the barrier to fluids such as water. Stratum
corneum is the last layer which acts as semipermeable membrane and
inhibits entry of microbes and chemicals. It is the hardest layer and
keratinocytes in this layer gets keratinized and the nucleus is lost.
Dermis is rich in blood capillaries which provide support and nu-
trition to the cells in epidermis that is divided into two layers, papillary
dermis and reticulate dermis. Papillary dermis is thin layer comprises of
loosely arranged collagen and reticulate dermis is thick portion con-
taining subcutaneous fat. The major cells in dermis layer are fibroblasts,
mast cells and macrophages. Subcutaneous layer consists of adipocytes
which provide thermoregulation and insulation to body and it also acts
as energy storage system. Adipocytes are widely distributed in

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R.L. Nagula, S. Wairkar Journal of Controlled Release 296 (2019) 190–201

Table 1
List of patents on topical delivery of flavonoids.
Patent no. Patent title Original assignee/applicant Grant date Reference

US6471973B2 Flavonide esters and their use notably in cosmetics Coletica 29-10-2002 [9]
WO2001049285A1 Flavonoid drug and dosage form, its production and use Slk Foundation 12-7-2001 [10]
US8613910B2 Flavonoids as synergists for enhancing the action of self-tanning substances Merck patent GmbH 24-12-2013 [11]
US6409996B1 Composition comprising one or more flavonoids, method of obtaining such composition Flavone Sunproducts AS 25-6-2002 [12]
and use thereof as UV-absorbing agent
EP0774249A2 Topical composition containing specific flavanones Unilever PLC, Unilever NV 21-5-1997 [13]
US8440704B2 Quercetin containing compositions Quercegen Pharmaceuticals LLC 14-5-2013 [14]
US20170020798A1 Hesperidin containing compositions and methods for treatment of skin disorders University of California 26-1-2017 [15]
WO2014090586A1 Delphinidin for combating melanoma cells Sapiotech Gmbh 19-6-2014 [16]
US20040191327A1 Methods of treating and/or preventing asthma using natural compound luteolin Council of scientific and industrial 30-09-2004 [17]
research
US20150342843A1 Topical liposome composition containing phenolic anti-inflammatory agents and their D&J Rosee Inc 3-12-2015 [18]
method of preparation
US20100069476A1 Composition and methods for reduction of cutaneous photoaging Mitsui Norin Co Ltd. 18-3-2010 [19]
US20120213842A1 Methods of making and using compositions comprising flavonoids API Genesis LLC 23-08-2012 [20]

subcutaneous layer; two types are white and brown adipocytes.
[21–23].
The major barrier for topical delivery is the complicated physiology
of the skin. Among all these layers stratum corneum acts as the major
barrier as it consists of densely packed lipid mortar and protein bricks
which limits the drug permeability. The stratum granulosm contains
desmosomes which forms the interlock with neighboring cells and acts
as barrier. It also includes keratinocytes that produce keratin and the
glycolipid and acts as water repellant. Along with this, the other in-
terruptions are the characteristics of the drug such as molecular weight,
degree of ionization, partition coefficient, diffusion coefficient, and
physicochemical nature of the drug. Drugs with only molecular weight
less than 500 Da show good permeability. The diffusion of the drug
from the vehicle is also important and so the characteristics of the ve-
hicle should also be considered.
There are different skin penetration pathways (Fig. 3) and thereby
targeting the optimum one is equally important for effective topical
delivery. In transcellular pathway, the drug passes through stratum
corneum which comprises of keratinocytes and lipid membrane thus, it
is difficult for the drug to pass through both the lipophilic and hydro-
philic layers. The alternative and the most commonly used pathway is
intercellular pathway, in this the drug travels through the space
between the corneocyte and need to cover the gap of 400 μm which
decreases the rate of permeability. Additionally, the shunt pathway is
also reported for skin transport which consists of lipophilic follicular
ducts or hydrophilic sweat glands and also called as appendageal route
[24].
3. Advances in topical drug delivery
Topical delivery is one of the most preferable routes to overcome
the drawbacks of other routes such as parenteral, oral etc. [25]. Oral
delivery of phytoceuticals is undesirable due to its characteristic taste
and odor, also there are chances of gastrointestinal (GIT) degradation of
the drug till absorption [26] whereas patient compliance is compro-
mised in parenteral route. Nevertheless, the most difficult challenge in
topical delivery is the impermeable nature of the skin. The therapeutic
effect produced by the conventional topical dosage form is not very
effective, so the research has been shifted to development of novel drug
delivery systems [23,24]. Conventionally, gels are the most commonly
used dosage form in topical delivery, mainly olegels and hydrogels but
the recent studies have reported wide range of gels such as niosomal,
proniosomal gels, emulgels, bigels, aerogels, xerogels which assists in
producing the desirable therapeutic effect [25,26,27].

Fig. 3. Structure of skin with penetration pathways.

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R.L. Nagula, S. Wairkar
Novel drug delivery of phytochemicals is the most preferred one due
to minimum side effects, less toxicity, increased solubility and bioa-
vailability. It also helps in providing site specific delivery and with
better pharmacokinetic parameters [30]. Phytochemicals possess wide
range of pharmacological properties such as anti-inflammatory, anti-
oxidant, apoptosis, photoprotective, antiproliferative and opportunely,
all these activities can be directly linked to the skin and thus, topical
delivery [31]. Extensive research has evolved in the investigation of
new carrier systems for phytochemicals such as phospholipid carriers,
nanoparticles, microparticles, liposomes, etc. [28–31]. These carriers
can later be formulated into into gels, creams and other dosage forms
which help in increasing the therapeutic line of phytochemicals [32-
36].
4. Topical delivery systems of flavonoids
Various novel formulations of flavonoids for topical route are clas-
sified as per their chemical class as mentioned below.
4.1. Flavonols
Flavonols are O-glycosidic, ketonic compounds with sugar moiety at
the 3-position. Flavonols act as antioxidants and protects reactive
oxygen species (ROS) formation. Skin is the most common target for
oxidative stress due to UV, ozone radiations, and other harmful che-
micals. The antioxidant property of flavonols is due to the combination
of conjugated double bond present in the C-ring along with neighboring
hydroxyl group in the B-ring [37]. Compounds belonging to this class
are quercetin, kaempferol, myricetin, etc.
4.1.1. Quercetin
Quercetin is a flavonol abundantly found in leafy vegetables, citrus
fruits, berries etc. Quercetin reduces inflammation by decreasing the
edema, leukocyte formation and irritation [38]. It triggers tissue re-
generation by promoting the growth of new collagen fibers and pro-
ducing ground substance to restore the skin structure [39]. Also,
quercetin inhibits various inflammatory mediators such as interleukins
(IL), prostaglandins (PGs), produced by COX, LOX, LPS. Nitric oxide
(NO) is one of the inflammatory mediators synthesized from nitric
oxide synthase which generates reactive nitrogen species such as per-
oxynitrite. An anti-inflammatory activity of quercetin and various other
flavonoids is depicted in Fig. 4. Quercetin helps in inhibiting all the
mediators which causes oxidative stress, thus producing the antioxidant
effect [40]. It prevents cell death by inhibiting caspase-3 pathway and
decreases the level of histidine decarboxylase, IL-6, monocyte che-
moattractant protein (MCP-1) by inhibiting the mast cell secretion that
leads to anti-allergic effect [41].
The poor water solubility of quercetin results in its limited bioa-
vailability. In spite of having poor bioavailability, it produces several
therapeutic benefits and it is also an important intermediary of its bio-
actives. Quercetin is unstable compound with less skin permeability. So,
it is formulated into various forms such as nanoemulsion, nanocapsules,
solid lipid nanoparticles, and microemulsion etc. which will not only
increase its solubility but also improve the skin permeability.
4.1.1.1. Quercetin lipid nanocapsules. Among the various
nanoformulations, lipid nanocapsules (LNCs) act as a promising
approach to encapsulate quercetin, due to the presence of lipid
structure. Hatahet et al. reported spherical LNCs prepared with
Cremophor EL having particle size ranged from 26 ± 3 nm -
54 ± 3 nm. Addition of Cremophor EL showed higher encapsulating
efficiency of quercetin due to its OH groups which interact with the
polar groups of quercetin. LNCs formed were perfectly spherical and the
particle size ranged from 26 ± 3 nm to 54 ± 3 nm. Quercetin loaded
LNCs exhibited 5000-fold increase in water solubility and revealed
good stability at 4 °C and 25 °C. In vitro release study of quercetin LNC
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Journal of Controlled Release 296 (2019) 190–201
showed less than 15% release after 24 h, signifying sustained behavior
in the skin. Anti-inflammatory activity of quercetin LNC (5 μg/ml) was
evaluated on THP-1 cells of human leukemic monocytes and it was
found that THP-1 cells were unharmed, as quercetin prevents
inflammation by scavenging free radical, protecting keratinocytes on
skin. It was observed that quercetin LNCs decreased ROS in cell, thus
reducing inflammation. LNCs also showed sustained release with no
toxic effect [42]. Thus, LNCs act as a good carrier for topical delivery of
quercetin and provide triple protection by preventing its degradation,
increasing the occlusive effect on skin and improving water solubility.
4.1.1.2. Quercetin nanoparticles. Nanoparticles have a greater efficiency
to permeate and accumulate within the skin to produce therapeutic
activity. Quercetin nanoparticles (QN) prepared from lecithin, chitosan,
tween 80, and TPGS had perfect round shape due to interaction
between the polycationic chitosan and negative lecithin. Lecithin
formed core and chitosan shaped the outer protective layer of
nanoparticles. The particle size of QN was 95.3 nm and zeta potential
was 10.85 ± 0.05 mV. In vitro evaluation of QN on dorsal skin of mice
showed significant amount of drug in the dermis and epidermis layer of
skin. In vivo study was performed in mice using 0.5% w/w quercetin
loaded nanoparticle suspension, the concentration of drug in dermis
and epidermis was found to be 8.4 ± 1.53 μg and 2.21 ± 0.01 μg
respectively [43]. It was seen that nanoparticles altered the skin surface
and stratum corneum and disrupted the conjugation between
corneocyte layers that resulted in increased permeation of quercetin
and also increased retention time in the skin.
4.1.1.3. Quercetin microemulsion. Roberta Censi et al. studied quercetin
microemulsions to determine its penetrability through the skin and to
evaluate drug concentration in systemic circulation. Ternary phase
diagram was plotted with Labrafil®M1944CS, Labrasol® and
Capryol™90 and Transcutol® P. The physicochemical parameters of
microemulsion such as pH, particle size distribution, % drug content
was found to be 5.3, 10-50 nm, 98.00 ± 1.70% respectively. In vitro
study through pig skin revealed the good diffusion rate of quercetin in
microemulsion formulation [44]. But the disadvantage of
microemulsions is that, their retention time in skin is very less due to
rapid transdermal absorption.
4.1.1.4. Quercetin nanostructured lipid carrier and solid lipid
nanoparticles. Lipid based nanosystems such as quercetin
nanostructured lipid carrier (NLC) and solid lipid nanoparticles (SLN)
have been a promising approach for the various hydrophobic drugs.
Quercetin NLCs prepared by probe ultrasonication method made up of
Compritol® 888. SLN was prepared in the same way except Compritol
888 was substituted with oleic acid.
Zeta potential of spherical shaped quercetin loaded NLC and SLN
was found to be −35.64 ± 1.13 mV and − 35.83 ± 2.11 mV, in-
dicating good stability. In vitro drug release of NLC was found to be
biphasic with initial burst release followed by controlled release. The
release of quercetin from NLC was approximately 55% and that of SLN
was 45% in 2 h [45]. The addition of the liquid lipid decreased the
viscosity of the NLC, resulting in the rapid release of the drug, thus
increasing the permeability. It also exhibited anti-inflammatory activity
by suppressing edema and scavenging the superoxide radicals. Hence
quercetin NLCs and SLN have proven to be good option to target topical
delivery.
4.1.1.5. Quercetin penetration enhancer containing vesicle. Penetration
enhancer containing vesicles (PEVs) act as excellent carrier due to the
presence of both, phospholipid and penetration enhancers which
provide synergistic effect on permeation. Quercetin loaded PEV's
were formulated using 4 penetration enhancers namely Transcutol® P
(Trc), Labrasol® (lab), PEG 400, PG. The size of the liposomal vesicles
containing PEG and Trc which was around 200 nm, greater than that of
R.L. Nagula, S. Wairkar
Fig. 4. Anti-inflammatory effect of flavonoids [COX: Cyclooxygenase; LOX: Lipoxygenase; PGs: Prostaglandins; LTs: Leukotrienes; I kB: Inhibitory factor Kappa B].
Lab and PG i.e. approximately 80 nm. Zeta potential value of PEG and
Trc PEV's was higher (around -50 mV), indicating high stability without
any aggregation of the vesicles but the Lab-PEVs showed lower zeta
potential (-30 mV). The outcome of rheology studies confirmed that the
shear rate increased with the increase in the shear stress and the shear
viscosity was independent of shear stress. The viscosity of the four
formulations with Trc, PG, PEG 400 and Lab-PEVs were 5, 6, 9 and 40
mPas respectively. The higher value of viscosity was attributed to the
high hydrodynamic volume occupied by the lamellar structure of the
vesicles. It was also seen that the amount of quercetin that can be
delivered decreases with the increase in the viscosity. Ex vivo study was
performed by Franz diffusion cell on skin of new born pig. Amount of
drug in various layers of the skin was evaluated i.e. stratum corneum,
epidermis, dermis and receptor fluid, the highest concentration of drug
was found in the epidermis and lowest in the stratum corneum [46].
4.1.1.6. Quercetin liposomes and PEVs. PEV's help in increasing the
permeation of the drug though the skin and promotes deposition in all
three layers of skin. In this study, 10% of quercetin was loaded in in all
three formulations such as liposomes and PEVs (5% PEG-PEVs, 10%
PEG-PEVs), prepared using Lipoid (S75) and soya lecithin. The size of
the liposomes was 100-150 nm, with zeta potential of -10 mV,
indicating poor stability. Whereas the size of 5%PEG-PEVs and 10%
PEG-PEVs was approximately 190 nm with -50 mV zeta potential
representing good stability. In in vivo anti-inflammatory study, 5%
PEG-PEV showed 4.7-fold decrease in myeloperoxidase (MPO) activity
while quercetin loaded liposome and 10%PEG-PEV showed 2.5-fold
decrease in the MPO activity. The MPO activity of the quercetin 5%v/v
PEG/ PEV was more effective than diclofenac in same PEG/PEV system
[47]. Thus, quercetin has superior anti-inflammatory activity, ROS
scavenging and increased fibroblast proliferation which helps in the
rapid wound healing. PEVs helps in localization of quercetin into the
cells at the site of inflammation which causes the degradation of the
cells by the lysosomal enzymes. Confocal images of the treated mice
skin showed large number of collagen fibers and ground substance
demonstrating healing has occurred. Hence the vesicular system is
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Journal of Controlled Release 296 (2019) 190–201
efficient for the quercetin delivery.
Quercetin being lipophilic in nature, various nanoformulations have
been developed to increase its bioavailability. There is a need of pe-
netration enhancers for quercetin topical delivery, however, the extent
of skin penetration was found to be dependent on lipid content and its
type. Also, application of quercetin in other skin disorders such as
psoriasis and atopic dermatitis can be explored in future.
4.1.2. Kaempferol
Kaempferol is mostly found in berries and plants belonging to spe-
cies of allium and brassica. Kaempferol possesses anticancer, anti-
oxidant, anti-inflammatory, and anti-allergic activity [48–51]. Kaemp-
ferol inhibits nitric oxide synthase which forms nitric oxide, a pro
inflammatory mediator to act as anti-inflammatory agent. It also in-
hibits the nuclear factor kappa B (NF-kappa B), with help of nuclear
factor inducing kinase (NIK) and mitogen activated protein kinase
(MAPKs) [52]. In addition, kaempferol obstructs COX-2 by inhibiting
nitric oxide synthase and TNF-α to produce anti-inflammatory effect.
But, kaempferol undergoes excessive first pass metabolism and there-
fore, bioavailability is only 2% and hence topical route is preferred for
its delivery.
Kaempferol acts as novel agent in treating the UVB induced tu-
morigenesis and photo-inflammation. Kaempferol was studied in skin
cancer where level of the COX 2 enzymes is found to be elevated. It
inhibits the AP-1 (Activator protein) activity by suppressing COX-2 in
JB6 P+ mouse epidermal cells. Thus, to check the transactivation of
AP-1, JB6 P+ mouse epidermal cells was transfected by the luciferase
reporter plasmid bearing AP-1 and it was found that kaempferol suc-
cessfully inhibits the COX and AP-1 activities in dose dependent manner
assisting in antitumor promoting activity. Proto-oncogene tyrosine
protein-kinase Src (Src) is the protooncogene molecule which has main
function in the cell growth, differentiation and survival. Kaempferol
competes with ATP for the Src binding site and blocks the Src activity.
Topical application of kaempferol on the dorsal skin of mouse inhibited
COX-2 expression thus, producing anti-inflammatory effect [53,54].
R.L. Nagula, S. Wairkar
4.1.2.1. Kaempferol submicron emulsion. Yun chao et al. reported
submicron emulsion of 0.1% of kaempferol, prepared by pseudo
ternary phase diagram in which ethanol or PEG 400 were used as co-
surfactant. The area of PEG 400 was very less compared to ethanol.
Hence, ethanol was preferred co-surfactant and it might help to
penetrate more easily due to its smaller chains. The size of
microemulsions was found between 75.3 and 85.4 nm and in vitro
permeation study on rat skin followed zero order kinetics [55]. Increase
in the drug deposition with the reduction in lag time was attained,
which proves that submicron emulsion act as excellent carriers along
with the increased retention time.
Research papers reported that various pharmacological activities of
kaempferol and its presence in several herbal sources Thus, a wide
range of nanoformulations like nanoemulsion, SLN, liposomes etc. can
also be evaluated further. A comprehensive clinical data is required to
decide the effective dose of kaempferol.
4.2. Flavanones
Flavanones are aromatic ketones derived from flavones, abundantly
found in many citrus fruits like oranges, lemons. Byproduct of the citrus
cultivation also yields huge amount of the hesperidin. They have cy-
totoxic activity and inhibit tumor growth and can act as anticancer
agent. Flavanones also inhibit protein tyrosine kinase which decreases
cell growth, differentiation, mitosis, apoptosis and produce anti-in-
flammatory activity [56].
4.2.1. Hesperetin and hesperidin
Hesperidin has various activities like anti-inflammatory, anti-
oxidant, Antidiabetic, neuroprotective, etc. [57–60]. Hesperetin is the
aglycone moiety of hesperidin that shows antioxidant, anti-in-
flammatory activity by interfering with arachidonic acid and also in-
hibits COX and LOX enzymes and prevents formation of inflammatory
mediators [60]. Hesperetin has the ability to reduce hyperpigmentation
caused by UV rays, producing whitening effect. Hesperetin and he-
speridin inhibits the release of histamine from mast cells to produce
anti-allergic activity. They also have the ability to reduce HMG CoA
reductase and acyl CoA, thus producing the hypolipidemic action. He-
speretin has log P value 1.7 to 2.20, which makes it lipophilic in nature
and would be difficult to absorb orally. Considering its pharmacological
actions and physicochemical properties, topical route is more suitable
for the hesperetin delivery.
4.2.1.1. Hesperetin microemulsion. Microemulsions of hesperetin were
prepared having particle size ranged from 101.5-233 μm.
Microemulsion formulations exhibits lower lag time and therefore,
increased the permeation rate and localization of hesperetin. In vitro
permeation study on rat skin exhibited distinct increase in the
permeation rate with decrease in the surfactant concentration.
Hesperetin was evaluated in vivo for the whitening effect on guinea
pigs' dorsal skin after the UV irradiation exposure [61]. UV rays cause
hyperpigmentation which leads to dark skin and application of
hesperetin microemulsion decreases hyperpigmentation. The
mechanism of action of depigmentation of hesperetin and other
flavonoids is demonstrated in Fig. 5. Additionally, hesperetin
microemulsion decreased the skin irritation and revealed anti-
inflammatory action.
4.2.1.2. Hesperetin topical film for eye delivery. Hesperetin is strong
antioxidant activity than hesperidin in scavenging ROS. It has the
property to increase the ocular blood flow and restore the retina. It is
used as dietary supplement to provide vasoprotective effect. Posterior
of the eye has unique structure which acts as physiological barrier,
therefore the treatment of back of the eye is a big challenge.
Poly ethylene oxide N10 film with 10–20% of hesperetin was pre-
pared the by melt cast method by Adellia et al. When the drug comes in
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Journal of Controlled Release 296 (2019) 190–201
Fig. 5. Depigmentation effect of flavonoids [α- MSH: Melanocyte stimulating
hormone, MC1R: Melanocortin 1 receptor, MiTF: Microphthalmia associated
transcription factor, Tyrp-1: Tyrosinase related protein 1, Tyrp-2: Tyrosinase
related protein 2, ASIP: Agouti signaling protein].
contact with physiological fluid it converts to gel. Hence high amount
of drug can be loaded without using the organic. In vitro studies,
95.3 ± 1.3% hesperetin was released within 120 min. Ex vivo study
was performed on the whole eye globes acquired from pel-Freez and
were placed in tissue culture plates containing 12-wells, with cornea on
upper side. The 10%w/w hesperetin film was applied at corneo-scleral-
limbus for 3 h and the concentration of the drug in the aqueous humor,
vitreous humor (VH), retina choroid (RC) was found to be
5.8 ± 0.2 μg/g, 5.6 ± 1.4 μg/g, 14.2 ± 3.8 μg/g of tissue. In vivo
study was performed on albino rabbits where 10%w/w and 20% w/w
HT film were kept in the conjunctival sacs. The hesperetin level for 10%
was observed in VH (0.05 ± 0.03 μg/g of tissue) RC (7.8 ± 0.2 μg/g
of tissue) and for 20% the concentration in VH (1.4 ± 0.5 μg/g of
tissue) RC (23.5 ± 6.9 μg/g of tissue) respectively which showed the
linear rise in drug concentration with the dose [62]. The film on ap-
plication transformed into gel and did not show any allergic condition
such as redness, selling, irritation, excess tear, etc.
4.2.1.3. Hesperidin microemulsions. Hesperidin has the capacity to
decrease the capillary permeability and the fragility, therefore it can
be used in treatment of various blood vessel related diseases. Yet, it is
very slightly soluble in water and unstable at the gastric pH and
undergoes hydrolysis to produce its aglycone hesperetin. But hesperidin
shows high permeability through skin which can be utilized to
formulate its topical formulations. Microemulsions based hesperidin
ointment (MBO) was prepared with eucalyptus oil acts as penetration
enhancer. The permeability and the bioavailability of MBO was more as
compared to the plain microemulsions. In vivo studies for MBO and
microemulsion on the dorsal skin surface of wistar rats demonstrated
Cmax of 30.3 and 11.3 μg/ml, the AUC of 66.7 ± 0.2 and 43.26 ± 0.1
for MBO and microemulsion correspondingly. But there was no
difference observed in Tmax of both formulations [63].
Hesperetin microemulsion has proved to be more efficient in pro-
ducing whitening effect by decreasing hyperpigmentation, therefore
various topical nano-formulations can be studied for skin. Hesperidin
shows improved bioavailability to treat venous diseases by decreasing
permeability of capillaries. Thus, vasoprotective activity of hesperetin
can be utilized by preparing ocular formulations.
4.2.2. Naringenin
Naringenin possess various activities like antioxidant, anti-in-
flammatory, antidiabetic, anticancer, etc. [64–67]. It shows antioxidant
R.L. Nagula, S. Wairkar
effect by chelating metal ions and by inhibiting the xanthine oxidase
thus preventing the formation of oxygen radicals and lipid peroxida-
tion. It also has the ability to scavenge ROS by –OH substitution. Nar-
ingenin being hydrophobic has low solubility and poor bioavailability,
so the topical route can be explored for effective formulations [68].
4.2.2.1. Naringenin submicron emulsion. Preparation of the submicron
emulsion is easy, economical and high amount of drug can be loaded
with a good stability. Naringenin submicron emulsions showed 4.5–9.4
times increased drug deposition as compared to saturated aqueous
solution of naringenin as control group. Skin irritation test did not show
any erythema and edema compared to the control and was found to be
biocompatible with skin. [69].
4.2.2.2. Naringenin gel. Naringenin based Carbopol gel (0.5%) was
evaluated topically for antioxidant and anti-inflammatory activity. In
vitro antioxidant study by the FRAP assay showed that the reducing
effect of 0.5% naringenin was 0.157 μg/ml. The IC50 value for the ABTS
[2,20-azinobis (3ethylbenzothiazoline- 6-sulfonicacid], OH radical,
iron independent LPO assay was 0.71 μg/ml, 183 μg/ml and 159 μg/
ml respectively. In vivo evaluation of naringenin in the inflammation
induced HRS/J mice inhibited the skin edema, production of the
cytokines, catalase activity and reduced glutathione levels [70].
4.2.2.3. Naringenin elastic liposome. Ming-JunTsai et al. have prepared
the naringenin loaded liposomes (5 mg/ml) and evaluated for in vitro
study permeation rate. The permeation rate of the saturated aqueous
solution (0.25 ± 0.1 μg/h/cm3) was less than that of naringenin
loaded liposomes (0.37 ± 0.15 μg/h/cm3) at 24 h. There was no skin
irritation observed after the topical application and stability study
performed at the 4 °C showed neither aggregation nor creaming,
indicating the stable formulation for three months [71].
4.2.2.4. Naringenin nanoparticles-based sunscreen cream. Naringenin
nanoparticles were prepared to explore its photo-protective and
antioxidant effect in the sunscreen cream with polyvinyl alcohol and
poly (D, L-lactide-co-glycolide). In vitro permeation study of naringenin
and naringenin nanoparticles at 12 h was found to be
124.88 ± 2.24 μg/cm2 and 184.03 ± 3.37 μg/cm2 respectively. It
was observed that the retention of the nanoparticles in epidermis was
considerably higher than plain naringenin. In vivo study was performed
on Wistar rats that displayed significant skin retention (100 ng/cm2)
without any toxicity [72].
The wide spectrum of naringenin therapeutic activities and reported
scientific evidences makes it an interesting flavonoid to be worked on.
However, it lacks the sufficient clinical data for commercial utilization.
Although above delivery systems have been reported for naringenin,
topical formulations like microsponges, nanosponges, microneedles can
be attempted for skin disorders [73].
4.3. Flavanols
They are different from the flavonol and not to be confused, they
lack ketone group. The class includes epigallocatechin-3-gallate,
proanthocyanidins, etc. They are naturally found in tea, cocoa, and
various vegetables and fruits [74]. FDA has approved the use of ca-
techins and its derivatives in various pharmaceutical formulations.
4.3.1. Catechins
The various activities of catechins include antioxidants, photo-
protective, antiaging, anti-inflammatory, anticancer, neuroprotective,
cardioprotective, antiviral and antibacterial [75–77]. Grape seed ex-
tract and tea polyphenols are rich in epigallocatechin, epicatechin. It
shows antioxidant effect by scavenging free radicals [78]. Inhibition of
the COX enzyme, PGs, NO and H2O2 production leads to the anti-in-
flammatory activity. Catechins promote the wound healing by
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Journal of Controlled Release 296 (2019) 190–201
scavenging free radicals at the site of wound.
4.3.1.1. Nano-transfersomes epigallocatechin-3-gallate and hyaluronic
acid. Epigallocatechin-3-gallate (EGCG) is abundantly found in green
tea, possessing a wide range of above said therapeutic effects [74].
Since poor absorption and low bioavailability are of major concerns of
oral catechins, the topical formulation was attempted by Avadhani
et al. for its antioxidant and anti-aging effects. Therefore, formulating
EGCG into transferosomes may increase its permeability and
bioavailability [80]. Incorporation of EGCG along with the hyaluronic
acid (HA) was studied to check synergistic effects of anti-aging and
antioxidant. In vitro cytotoxicity study in the human keratinocytes cells
was evaluated and the cell viability of the transferosomes containing
HA along with EGCG was greater compared to the EGCG
transferosomes. In vitro permeation study was performed on male
Wistar rat skin with plain EGCG, EGCG transferosomes and EGCG
with HA transferosomes. The Q12 (cumulative amount of EGCG
permeated at the end of 12 h) values were found to be
56.08 ± 4.42 μg/cm2, 159.90 ± 6.90 μg/cm2 and 199.1 ± 6.30 μg/
cm2 correspondingly. It was concluded that that HA possesses
moisturizing effect which increase deposition, retention time of
EGCG. Also, permeability of EGCG with HA transferosomes was 2.8
times greater compared to the plain EGCG [81]. In addition, topical
application of EGCG.
decreases the erythema, COX activity and decreases the level of PGs,
NO and H2O2 production.
4.3.1.2. Grape seed extract cream. Grape seed extract (GSE) is rich in
polyphenols containing proanthocyanidins [77–79] acts as a
therapeutic aid the wound healing [82-84]. The experiment was
conducted by using hydroalcoholic GSE in Eucerin base for the
wound healing and was compared against phenytoin cream for
13 days [85]. Complete wound healing was found as compared to the
control group. Wound healing was due to the presence of
proanthocyanidins (condensed tannins) which increase the tissue
oxidation at the site of wound and promotes the wound healing by
inducing apoptosis. The pathway of apoptosis for catechins and
apigenin is described in Fig. 6 [86]. Therefore, it could be used
topically for the wound contraction and closure.
Although catechins have been extensively studied for anticancer
property, the group also possesses the properties helpful in treating skin
disorders. Stability is the major disadvantage of catechins with respect
to pH, temperature and light which leads to rapid epimerization.
Fig. 6. Apoptosis by flavonoids [FADD: Fas associated death domain].
R.L. Nagula, S. Wairkar
Therefore research should be focused on improving its stability in sui-
table formulation [80].
4.4. Isoflavones
Isoflavones are the naturally occurring isoflavonoids and most
commonly found in soyabeans, soy foods and legumes. Isoflavones are
non-steroidal compounds having estrogen like activity as they mimic
17-eatradiol structure and called as phytoestrogens [87]. Most of the
compounds belonging to Fabaceae family contain isoflavones and the
common isoflavones are genistein, daidzein, glycitein, formononetin.
They show antioxidant property by scavenging free radical, protection
against lipid peroxidation and also decreases oxidative stress caused by
UV damage. Genistein has been reported to show anti-osteoporotic
activity [88]. Isoflavones being phytoestrogen and their ability for in-
creased production of hyaluronic acid which provides moisturizing ef-
fect, can be used in topical delivery.
4.4.1. Genistein and daidzein
Genistein and daidzein inhibit tyrosine kinase of the growth re-
ceptor factor which reduced cell growth and proliferation [89]. They
also have the ability to bind all the three-peroxisome proliferator-acti-
vated receptors isoforms. Isoflavones were evaluated as topical photo-
protective agent in the pig skin by Jing-Yi Lin et al. The erythema re-
sponse and the sunburn cells were studied for photoprotective effect of
isoflavones. Solutions of Isoflavones (0.5%) i.e. genistein, daidzein,
equol, biochanin A, formononetin were compared to various standard
antioxidants such as α-tocopherol, ascorbic acid, ferulic acid. Out of
which, genistein, daidzein and biochanin A showed significant photo-
protection. Genistein inhibits tyrosine receptor kinase activity and de-
creases the UV damage. Formononetin has no effect on sunburn cells
but effective for the treatment of erythema. Isoflavones act as potent
photoprotective and also the good candidate ingredient for UV damage
[90].
4.4.1.1. Effect of penetration enhancers on topical delivery of genistein and
daidzein. It is known that genistein is potent inhibitor of the protein
tyrosine kinase and possesses good topical permeability. Genistein
decreases the H2O2 level in the skin, showing radical scavenging
activity. As it belongs to polyphenolic class, they donate H-atom to
the oxygen radical and form the phenoxyl radicals which are less
reactive. Daidzein contains 1 less OH group than genistein, so it was
assumed to have less antioxidant effect which was not true [91]. Pka of
daidzein was 7.2, shows higher water solubility and decreased
permeability through skin. The retention time of genistein was more
than that of daidzein due to its lipophilicity. Log K′ of genistein and
daidzein was 0.23 and − 0.05 respectively indicating the greater
hydrophilicity of daidzein.
Subcutaneous layer acts as the major barrier for genistein and
daidzein and thus, α-terpineol and oleic acid was evaluated as pene-
tration enhancers by Zih-Rou Huanga. Melting point of the compounds
genistein, daidzein, aglycones were 305°, 338°, 238 °C but when mix-
ture was formed the melting point reduced, showing eutectic effect.
This helped to increase skin permeability as compounds in the eutectic
form have high solubility subcutaneously. In vivo study in the mouse
showed the increase in the uptake of genistein with no toxic effects and
decrease in the erythema. Daidzein also showed similar effect but in-
creased the pH of skin [92].
Genistein and daidzein were not explored earlier due to their es-
trogenic properties but later its anti-inflammatory, anti-oxidant prop-
erties were discovered. The advantage could be taken as these com-
pounds are non-steroidal but possess estrogenic property. Currently,
isoflavones are being used for cancer treatment but novel formulations
of isoflavones are very few to be used for therapeutic benefits.
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Journal of Controlled Release 296 (2019) 190–201
4.5. Flavones
Flavones provide additional nutritional value to our diet. Flavones
are having anti-microbial anti-oxidant, anti-inflammatory, and anti-
carcinogenic activity promotes apoptosis [93]. Apigenin and luteolin
have been studied in different formulations.
4.5.1. Apigenin
The most important property of apigenin is inhibition of COX and
inactivation of nuclear transcription factor (NF-kB), induces apoptosis,
activating transcription factor 3 to assist in the reduction of in-
flammation. It also acts as chemo-preventive by inhibiting enzyme
CYP2C9 and preventing the metabolism of many drugs and xenobiotics
[94].
4.5.1.1. Apigenin-phospholipid phytosome. Phytosomes are the
phospholipid carriers which help in the delivery of the poorly soluble
drugs. Oral administration leads to rapid metabolism of apigenin.
Apigenin-phospholipid phytosomes (APLC) were prepared and
evaluated in albino rats (25 mg/kg) to estimate antioxidant enzymes.
Also, hepatoprotective activity and CCl4 induced hepatotoxin
demonstrated increase in the liver marker enzymes, showing excellent
hepatoprotection. The level of several antioxidant enzymes was
elevated proving its antioxidant potential. The Cmax, Tmax, and AUC(0-
∞) of the APLC were greater than that of the aqueous solution of
apigenin, indicates enhanced bioavailability [95].
4.5.1.2. Apigenin ethosomes. Apigenin has the ability to inhibit COX
enzyme which helps in prevention of inflammation caused by UV, X-
rays. Apigenin loaded ethosomes, liposomes and deformable liposomes
formulations were prepared and studied in vivo in Sprague-dawley rats
and konmin mice. In vivo skin deposition study performed on shaved
abdominal skin of rats showed that there was highest deposition at 2 h
found with ethosomes and liposome i.e. 0.176 ± 0.010 μg/cm2 and
0.167 ± 0.047 μg/cm2 whereas deposition of deformable liposomes
was lower i.e. 0.123 ± 0.011 μg/cm2. The effect of UVB induced skin
inflammation of all formulations and plain apigenin was studied on
mice which showed inhibitory effect on COX-2 level and prevented
inflammation but the inhibitory effect of apigenin ethosomes was more
as compared to others [96].
4.5.1.3. Chamomile flower extract liposomes. Chamomile flower extract
(CFE) rich in apigenin was extracted by the percolation. Liposomes
were prepared using nattermann phospholipid and apigenin mixture
(1:2) and then incorporated into oil in water cream containing various
topical excipients. In vitro dissolution study showed increased release
compared to the non-liposomal cream containing plain CFE apigenin.
Clinical study on the 19 human volunteers between age 24–65 years
was performed and the in vivo study showed significant anti-
inflammatory activity with apigenin cream [97]. Apigenin liposomal
cream was effective, tolerated well and showed much less adverse
effects than corticosteroids.
Majority of the apigenin research include in vitro studies which
creates difficulty in drawing concrete conclusions. Therefore, more in
vivo studies of formulations can be performed to prove its safety and
efficacy in various chronic and acute skin disorders.
4.5.2. Luteolin
Luteolin is found in various plants such as celery, green pepper,
chamomile flower, etc. Although it has wide range of therapeutic ac-
tivities as other flavonoids, it shows antioxidant effect by scavenging
free radicals and nitrogen species. But the most important use of lu-
teolin is in treatment of arthritis due to its ability to inhibit IL, TNFα,
and necrosis factor [98,99]. Luteolin was evaluated on the psoriatic
skin for keratinocyte activation and the level of NF-kB factor. The effect
of luteolin (1–100 μM) on HaCaT keratinocytes showed concentration
R.L. Nagula, S. Wairkar
dependent inhibition of various mediators such as IL-6, IL-8, and VEGF
whereas its 100 μM concentration showed complete inhibition of all
three mediators. Due to the lipid solubility of luteolin, it can be used for
topical formulation for treating psoriasis [100].Luteolin has the ability
to inhibit the release of histamine from the mast cells which helps in
inhibiting inflammation and allergy. The cutaneous reaction was in-
duced in ICR mice by injecting histamine or serotonin intradermally.
Also, the contact dermatitis was induced by applying 2,4-Dinitrohlor-
obenzene (DNCB). The concentration of luteolin 2,20 and 100 μg/site
dissolved in olive oil was applied at the site of inflammation that sig-
nificantly reduced the ear swelling and thickness by inhibiting vascular
permeability, showed antagonist effect on inflammatory mediators and
also decreased the scratching behaviour [101].
4.5.2.1. Luteolin niosomes. Niosomes are a non-ionic surfactant-based
colloidal system and have ability to encapsulate hydrophobic as well as
hydrophilic drugs. Luteolin niosomes were prepared by Lubna Abidin
et al. and were formulated into the gel (niotransgel). The ex vivo study
of luteolin niosomes performed on the rat skin showed excellent
permeability with transdermal flux value 93.21 ± 13.14 mg/cm2/h.
In vitro antiarthritic study of niotransgel compared to diclofenac gel
(omnigel) showed 81.82% inhibition and the diclofenac with 85.21%
inhibition. In vivo analgesic study in rats by tail flick hot water
immersion method showed 32.6 s much greater than that of
diclofenac gel [102]. Hence, luteolin loaded niosomes can be used as
an alternative treatment of arthritis.
4.5.2.2. Luteolin nanoemulsion. Apart from aforementioned
pharmacological actions, luteolin, baicalin and alpinetin have
property to induce alkaline phosphatase which plays an important
role in hair growth. As flavonoids are lipophilic in nature, formulating
them into nano-formulation will help in increasing bioavailability.
Luteolin nanoemulsion prepared and radical scavenging activity was
evaluated using DPHH method and was compared with ascorbic acid. It
was found that ascorbic acid showed 10% inhibition at dose 250 μM
whereas luteolin nanoemulsion exhibited strong inhibitory activity in
concentration dependent manner till dose 50 μM. In vivo study for hair
growth was performed on dorsal skin of C57BL/6 mice using minoxidil
as positive control [103]. The results showed that the skin was fully
covered with soft silky hairs, showing excellent growth promoting
effect whereas minoxidil showed uneven hair growth with stiff hairs
due to epidermal keratinization. This shows that luteolin nanoemulsion
proves to be more efficient for follicular delivery.
In depth study of structural activity relationship of luteolin is re-
quired to develop a luteolin derivative with more specific activity.
Additional in vivo studies and their models should be conducted to
evaluate the inflammatory activity and use in autoimmune disease.
4.6. Anthocyanins
Anthocyanin are colored glycosylated, water-soluble pigments and
are accountable for imparting blue, red, purple colors to fruits and
vegetables. Various scientific studies have proved that anthocyanins
possess antioxidant, anti-inflammatory, depigmentation properties
[104,105].
4.6.1. Delphinidin
Delphinidin is known to inhibit osteoclastogenesis in osteoporosis,
and has antioxidant, anti-inflammatory, antitumorigenic and anti-
angiogenic properties. Delphinidin reduces the levels of inflammatory
mediators including iNOS, NO, IL-6, MCP-1, and TNF-α induced by LPS,
downregulates NF-κB pathway and MEK1/2-ERK1/2 signaling [106].
Topical application of delphinidin diminishes psoriasiform lesions in
the flaky skin mouse model by inducing epidermal differentiation and
inhibiting inflammation [107]. Delphinidin was evaluated for psoriasis
on the flaky skin mice decreased the thickness of the epidermis. Also
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Journal of Controlled Release 296 (2019) 190–201
showed down regulation of caspase 14 and infiltrating macrophages. It
also decreased the keratin-14 which causes hyperproliferation. Thus,
delphinidin acts and antiproliferative by inhibiting keratin-14. Appli-
cation of delphinidin to flaky mice skin decreases the level of patho-
logical markers of psoriasis lesions.
4.6.1.1. Anthocyanin niosome gel. Anthocyanin niosomes were prepared
and in vivo anti-inflammatory activity was evaluated on croton oil
induced inflamed ears of rats with niosomes (0.5 and 5 mg/cm2). It was
found that niosomes improved permeation rate and prolonged anti-
inflammatory effect. Percent ear edema inhibition of niosome
containing 5 mg/cm2 of anthocyanin complex was greater compared
to 0.5 mg/cm2 [108]. Thus, topical niosomes prove to be the
appropriate and potential candidate for treating inflammatory
condition.
4.6.1.2. Anthocyanin microemulsion. Purple sweet potato (Ipomoea
batatas L.) is rich in anthocyanins and possesses the ability to
scavenge free radicals. As skin is easily susceptible to free radicals,
topical treatment would be more preferable. Anthocyanins
microemulsion was prepared consisted to evaluate antioxidant
property using DPHH method for plain ethanolic extract of purple
sweet potato and microemulsion. It was found that the ethanolic extract
showed 50% inhibition whereas microemulsion containing extract
showed 80% inhibition of ROS [109].
Delphinidin is extensively used in food industry as colorants. It has
wide range of pharmacological activities and yet, more can be learnt on
the therapeutic line of anthocyanins. Development of novel formula-
tions of anthocyanin is the basic need at present as it is not been much
explored.
A brief summary of pharmacological properties of flavonoids and in
vivo/cell line study is described in Table 2.
5. Future perspective and conclusion
Current generation has become more vigilant and interested to-
wards the use of natural products. Flavonoid is an important class of
phytoproducts for its therapeutic and preventive benefits. They possess
an ability to decrease the biotic stress in the human body by acting as
phytoalexins. Their combination therapy aids in providing the sy-
nergistic effect as well as it helps in digging the ground to discover new
therapeutic activities. However, oral delivery of flavonoids is the big-
gest challenge and thus the focus of formulation development has been
shifted towards alternative route of delivery like topical route. Various
novel formulations for topical delivery have been attempted to increase
the solubility and permeability of flavonoids to cross the skin barrier,
yet there is need to overcome other limitations of topical delivery such
as inadequate residence time and sustained release profile, etc. Various
methods such as iontophoresis, electroporation, magnetophoresis, ul-
trasound, radiofrequency, microneedles can also be explored for ef-
fective topical delivery of flavonoids. Although many novel formula-
tions have been evaluated at laboratory, its scale up at commercial level
is major challenge and therefore, there is need to look at scalability of
formulation and manufacturing process.
A continuous growth in the research of flavonoids is envisioned,
however a quality research providing concrete safety, toxicity and ef-
ficacy data of flavonoids is essential. Studies on controlled, long dura-
tion clinical trials indicating important endpoints should be conducted
for determining their dosage regimen and evaluating adverse effects.
The limitations from various in vitro, animal and human studies should
be considered while making conclusions which assists in future re-
search. This can be later extrapolated to clinical conditions to reach the
actual ripening phase.
Even for oral formulations of flavonoids, the other strategies can be
adopted to increase solubility of flavonoids including co-crystallization,
modification with esters or formation of glycosides etc. At the same
R.L. Nagula, S. Wairkar Journal of Controlled Release 296 (2019) 190–201

Table 2
Pharmacological properties of flavonoids in-vivo/ cell line study.
Sr.no Formulation of flavonoid Therapeutic activity Animal/cell line Dose Ref.

Quercetin
1. Lipid nanocapsules Antioxidant, anti-inflammatory Acute monocytic leukemia cell line (THP1–1 5 μg/ml [42]
cell)
2. Nanoparticle suspension Antioxidant Mice 0.5% w/w [43]
3. Liposomes with penetration enhancing vesicles Anti-inflammatory Female CD-1 mice 5% PEG-PEV [47]
(PEV) 10%PEG-PEV

Hesperetin, hesperidin
4. Microemulsion Whitening effect Guinea pigs 2 mg/cm2 [61]
5. Topical matrix film Release of hesperetin in posterior of eye Albino rabbits 10% w/w and 20% [62]
w/w
6. Microemulsion based ointment Skin irritation Wistar rats 1 ml/g [63]

Naringenin
7. Gel Antioxidant, Anti-inflammatory HRS/J mice 0.5% [70]
8. Nanoparticles Photoprotective, antioxidant Wistar rats 2 mg/cm2 [72]

Catechins
9. Cream Wound healing Iranian rabbits 2% Grape seed extract [85]
10. Nano-transfersomes Antioxidant, antiaging effect HaCaT (human keratinocytes) cells 10 mg [81]

Apigenin
11. Apigenin phospholipid phytosome Antioxidant Albino rats 25 mg/kg [95]
12. Apigenin ethosomes Anti-inflammatory Konmin mice 0.02% w/v [96]

Luteolin
13. Luteolin in olive oil Anti-inflammatory ICR mice 2,20 and 100 μg [101]
14. Luteolin nanoemulsion Growth promoting effect C57BL/6 mice 50 μM [103]

Anthocyanin
15. Niosome gel Anti-inflammatory Male wistar rats 0.5 and 5 mg/cm2 [108]

time, suitable formulation strategies and other administration routes
can be explored as per pharmacological activity of flavonoids.
In summary, flavonoids have been established as the excellent
natural compounds, especially for topical delivery that aids in treating
various skin ailments with minimum side effects. There has been an
exponential growth in research of flavonoids for several other disorders
such as cardiovascular, neurological, diabetes and cancer which de-
monstrates deviance from synthetic drugs to healthier regimen of
dietary supplements and nutraceuticals. Topical route is the best tar-
geted route for flavonoids due to its lipophilic nature. At present a wide
range of novel drug delivery are available which show promising results
for topical delivery. Though preclinical results are promising, sub-
stantial clinical trials need to be conducted for translation of research to
commercial products.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declaration of interest
None.
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