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For decades, possessing a lighter skin color has been known as a characteristic of elegance and superiority. The use of skin lightening agents is still prevalent across the globe despite strict regulations and public health campaigns against them. This can be attributed to the misleading marketing of harmful skin bleaching agents under the name of skin brighteners, skin toners, or dark spot removal creams that are readily available. In an effort to find a safer alternative to hydroquinone and other harmful skin lighteners, extensive research culminated in the discovery of α-arbutin. It acts by inhibiting tyrosinase activity and melanosome maturation. It is one of the most popular skin lightening ingredients in the world at present and has been used in the treatment of many hyperpigmentation disorders. α-arbutin has a high market value due to its wide applicability in the cosmetics and pharmaceutical industries. In this review, we have discussed the physiochemical properties of α-arbutin and safety profile, its mechanism of action, recent advances in the delivery of α-arbutin for skin lightening, various combination treatments, and current market status. This literature review presents a futuristic scope of α-arbutin as a safer alternative to other harmful skin lightening agents.
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3502| International Journal of Pharmaceutical Research | Apr - Jun 2021 | Vol 13 | Issue 2
Review Article
Alpha Arbutin as a Skin Lightening Agent: A Review
NIKHIL CHANDORKAR1, SRUSHTI TAMBE2, PURNIMA AMIN2, CHANDU S MADANKAR1*
1Institute of Chemical Technology, Department of Oils, Oleochemicals, and Surfactants Technology,
Mumbai 400019, India
2Institute of Chemical Technology, Department of Pharmaceutical Science and Technology, Mumbai
400019, India
3Assistant Professor, Institute of Chemical Technology, Department of Oils, Oleochemicals, and
Surfactants Technology, Nathalal Parekh Marg, near Khalsa College, Matunga, Mumbai, Maharashtra
400019
*Corresponding Author
Email ID: chandumadankar@gmail.com
Received: 25.01.21, Revised: 23.02.21, Accepted: 22.03.21
ABSTRACT
For decades, possessing a lighter skin color has been known as a characteristic of elegance and superiority.
The use of skin lightening agents is still prevalent across the globe despite strict regulations and public health
campaigns against them. This can be attributed to the misleading marketing of harmful skin bleaching agents
under the name of skin brighteners, skin toners, or dark spot removal creams that are readily available. In an
effort to find a safer alternative to hydroquinone and other harmful skin lighteners, extensive research
culminated in the discovery of α-arbutin. It acts by inhibiting tyrosinase activity and melanosome maturation. It
is one of the most popular skin lightening ingredients in the world at present and has been used in the
treatment of many hyperpigmentation disorders. α-arbutin has a high market value due to its wide applicability
in the cosmetics and pharmaceutical industries. In this review, we have discussed the physiochemical
properties of α-arbutin and safety profile, its mechanism of action, recent advances in the delivery of α-arbutin
for skin lightening, various combination treatments, and current market status. This literature review presents
a futuristic scope of α-arbutin as a safer alternative to other harmful skin lightening agents.
Keywords: Alpha arbutin, skin lightening, cosmetic, hyperpigmentation, melanogenesis
INTRODUCTION
Hyperpigmentation conditions including melasma
(Rigopoulos et al., 2007), solar lentigines
(Cardinali et al., 2012), and post-inflammatory
hyperpigmentation (Davis et al., 2010) are
common causes for dermatology visits.
Hyperpigmentation is also associated with UV
exposure (Tran et al., 2008), skin aging (Ortonne,
1990), hormonal imbalance (Mahmood et al.,
2016), and skin irritation (Saeedi et al., 2019).
Dyschromatosis is another skin condition that is
marked by hypo or hyperpigmented skin lesions
giving a mottled appearance (Namitha et al.,
2015). It can occur due to changes in different
biochemical processes controlling melanogenesis.
Melanogenesis is the complicated mechanism by
which melanocytes produce pigment melanin in
melanosomes (Videira et al., 2013). Such
changes in the melanogenesis process may result
in increased melanocytes, melanosome
production, melanin synthesis, or melanocyte
hyperplasia, leading to greater deposition of
melanin in the skin (Hollinger et al., 2018). In the
last decade, pathophysiological studies on
hyperpigmentation disorders have evolved
considerably owing to the high prevalence of
hyperpigmentation. This has led to newer
treatment options, resulting in a range of
investigations and developments of several skin
lightening agents to reduce the concentration of
melanin in the epidermis layer of the skin.
Melanin is a natural skin pigment that plays a
vital role in skin pigmentation, and the biological
synthesis of melanin is primarily regulated by the
enzyme tyrosinase (Solano, 2014). Tyrosinase
enzyme inhibitors have thus become essential
components in cosmetic skin whitening
formulations. Skin lightening for cosmetic
purposes has been associated with significant
harmful effects on well-being, and negative
impact on the skin, which pose enormous
challenges for dermatologists (Charles, 2003).
Skin lightening cosmetics continue to dominate
the cosmetic market, amid existing regulations.
Skin lightening agents are possibly
underestimated for cutaneous and systemic side
effects, since a complete list of ingredients, illegal
ingredient, is rarely disclosed. Skin lightening
agents do not have high side effects with minimal
use. However, when used for extended periods or
under occlusion, the risk of adverse reactions is
increased. Traditional first-line skin lightening
ISSN 0975-2366
DOI:https://doi.org/10.31838/ijpr/2021.13.02.446
Nikhil Chandorkar et al / Alpha Arbutin as a Skin Lightening Agent: A Review
3503| International Journal of Pharmaceutical Research | Apr - Jun 2021 | Vol 13 | Issue 2
agents like hydroquinone, corticosteroids,
mercury, kojic acid, etc. are highly effective but
their long-term exposure can potentially cause
serious adverse effects on the skin such as
ochronosis, atrophy, carcinogenesis, and other
local or systemic side effects (Rendon et al.,
2012). Hydroquinone, often considered as the
gold standard for the topical treatment of
hyperpigmentation disorders may cause a
condition called exogenous ochronosis which is
characterized by paradoxical blue-gray
hyperpigmentation due to deposition of
homogentisic acid in the skin (Gandhi et al.,
2012). Squamous cell carcinoma has also been
reported after long-term use of hydroquinone
(Faye et al., 2018). Systemic absorption may
cause peripheral neuropathy (Karamagi et al.,
2001), conjunctival pigmentation (Anderson,
1947), corneal melanosis and degeneration
(DeCaprio, 1999; Naumann, 1966), impaired
wound healing (Ajose, 2005; Olumide et al.,
2008) and fish odor syndrome (trimethylaminuria)
(Tse, 2010). Super-potent corticosteroids (e.g.,
clobetasol) may lead to bacterial, viral, and
fungal skin infections due to local
immunosuppression (Valencia et al., 2003).
However, a compromised hypothalamic-pituitary
adrenal axis is one of the concerning side effects
that result due to the systemic absorption of
corticosteroids (Broersen et al., 2015). Cushing
syndrome (Broersen et al., 2015), adrenal
insufficiency (Sobngwi et al., 2003), diabetes
(Sobngwi et al., 2003), and hypertension
(Bwomda et al., 2005) are other distressing side-
effects of the use of corticosteroids.
Ophthalmologic side-effects include glaucoma
(Phulke et al., 2017) and cataracts (Fanny et al.,
2014). Mercury-containing skin lightening
formulations have been reported to cause
neuropsychiatric toxicity (Sun et al., 2017) and
nephrotoxicity (Agrawal et al., 2015), as well as
nail dyschromia, pneumonitis, and mercurial
baboon syndrome (Hamann et al., 2014).
Glutathione is a significant health issue in many
countries now due to its potential adverse effects
(Sonthalia et al., 2018). For various alcoholic liver
diseases, glutathione infusions are approved in
India whereas, in the Philippines, glutathione is
approved to be used in adjunction with cisplatin
chemotherapy. However, the FDA has not
approved their use for skin lightening (Sonthalia
et al., 2018). Significant complications of
glutathione include renal, hepatic, neurologic
toxicity, air emboli, and Stevens-Johnson
syndrome (Dadzie, 2016). Oral and topical
treatment with tranexamic acid, a synthetic
derivative of amino acid lysine has also been
carried out for skin lightening and it may cause
bloating, abdominal pain, and vascular
thrombosis (Ebrahimi et al., 2014; Tan et al.,
2017). The oral and topical use of retinoids (e.g.,
tretinoin) (Griffiths et al., 1993) has shown to
cause erythema, peeling retinoid dermatitis,
photosensitivity, teratogenic effects, fetal
complications, thyroid dysfunction, and hepatic
toxicity (Mukherjee et al., 2006). Based on the
above data, there is clearly a need for better
tolerated, yet effective, skin lightening agents that
could be used by a wider population and have
led to the investigation of several potential
botanical/natural compounds.
Arbutin is a naturally occurring skin lightening
agent and has been found in the species of
various plant families such as marjoram,
cranberry, blueberry, and several pear species.
The production of melanin is effectively reduced
by arbutin by inhibiting the tyrosinase enzyme.
Arbutin exists in its two isoforms, namely α-
arbutin (4-hydroxyphenyl-α-D-glucopyranoside)
and β-arbutin (4-hydroxyphenyl-β-D-
glucopyranoside). Both α and β-arbutin have
different rotation configurations but the same
chemical formula structure (Couteau et al.,
2016). β-arbutin is generally extracted from
leaves of various plants and fruit peels. However,
α-arbutin does not occur naturally and can be
biosynthesized by microbial enzymes or
microorganisms. Interestingly, α-arbutin is much
more efficient in inhibiting tyrosinase activity than
natural arbutin (Garcia-Jimenez et al., 2017). At
the active site of tyrosinase, the α-glucoside bond
displays greater affinity than the β-glucoside
bond. The 50% inhibitory concentration (IC 50) of
α-arbutin in human tyrosinase is 2.0 mM,
whereas, for natural arbutin, it is higher than 30
mM (Sugimoto et al., 2007; Sugimoto et al.,
2003). In the cultured melanoma cell and the
human skin model, the α-arbutin inhibitory effects
on melanin biosynthesis were examined, and
findings showed that α-arbutin effectively
inhibited melanin synthesis without any cytotoxicity
(Sugimoto et al., 2004). α-arbutin has been
shown to inhibit the tyrosinase enzyme from
mouse melanoma, and the inhibition was found
to be 10 times stronger than β-arbutin. α-arbutin
did not inhibit the growth of cultured human
melanoma cells, HMV-II, but effectively inhibited
melanin synthesis, suggesting that α-arbutin can
be effective and safe for treating
hyperpigmentation disorders (Sugimoto et al.,
2004). Because of its molecular structure, α-
arbutin works similarly to hydroquinone, but with
less irritation and melanocytotoxicity. It also does
not cause exogenous ochronosis and is less likely
to cause irritation and sensitization, making it a
Nikhil Chandorkar et al / Alpha Arbutin as a Skin Lightening Agent: A Review
3504| International Journal of Pharmaceutical Research | Apr - Jun 2021 | Vol 13 | Issue 2
more tolerable alternative to hydroquinone. This
protects skin from sun-induced pigmentation and
free radicals without increasing the skin's
sensitivity to sun exposure. It lightens skin tone by
fading discoloration caused by inflammation and
environmental stress. It also addresses glycation,
sugar-induced skin sallowness, and loss of
elasticity (Notaroberto, 2017). Commercially, α-
arbutin is synthesized by using an enzyme that
catalyzes alpha-anomer selective
transglycosylation reaction between a glucosyl
donor and hydroquinone as an acceptor. In
addition to enzymatic biosynthesis, α-arbutin can
be synthesized from hydroquinone with the help
of some microbial species (Kitao et al., 1994). In
this review, we present a novel look at α-arbutin
as a safer alternative to other harmful skin
lightening agents. The benefits of α-arbutin as a
skin lightening agent are represented in Figure 1.
Fig.1: Benefits of α-arbutin as a skin lightening agent
Physiochemical Properties of α-arbutin and
safety profile: α-Arbutin, (2R,3S,4S,5R,6R)-2-
(hydroxymethyl)-6-(4 hydroxyphenoxy)oxane-
3,4,5-triol has a molecular weight of 272.25
g/mol and appears as a white to off-white
powder (Sugimoto et al., 2007). It has a melting
point between 195° 196°C and a boiling point
of 561.6 ± 50.0 °C (Sugimoto et al., 2007). The
solubility of α-arbutin in water and DMSO
(Dimethyl sulfoxide) is 151 g/L at 20 ± 5 °C and
54 mg/mL (198.34 mM), respectively (Degen,
2016). It has a log P value of -1.49 (Pati et al.,
2011) and a log S value of -0.84. Although α-
arbutin has a strong inhibitory effect on human
tyrosinase activity, its high hydrophilicity causes
low percutaneous absorption. This limits its
permeation into the stratum basale where
melanocytes reside. The chemical structure of α-
arbutin is shown in Figure 2. The analysis of α-
arbutin can be performed by using high-
performance liquid chromatography (HPLC) (Jeon
et al., 2014). The stability of α-arbutin is pH-
dependent in a buffered aqueous solution, with
maximum stability at pH 5.0. The Scientific
Committee on Consumer Safety (SCCS) has
suggested concentrations of α-arbutin i.e., up to
2% in face creams and up to 0.5% in body lotions
for the safety of consumers that use α-arbutin
based cosmetic products (Degen, 2016). The
clinical studies supporting the safety of α-arbutin
for the treatment of hyperpigmentation are
represented in Table 1.
Nikhil Chandorkar et al / Alpha Arbutin as a Skin Lightening Agent: A Review
1| International Journal of Pharmaceutical Research | Apr - Jun 2021 | Vol 13 | Issue 2
Fig.2: The chemical structure of α-arbutin
Table 1: Clinical Studies Supporting Safety of α-arbutin (Degen, 2016)
Test
Model
Concentration
Observation
Acute oral toxicity test
Rat/Sprague-Dawley CD
5% cream
10% cream
LD50>125 mg/kg of α-arbutin
LD50>2500 mg/kg of α-arbutin
Skin irritation
New Zealand White
rabbits
0.5 g moistened with 0.5 mL
water
Non-irritant to skin
Mucous membrane
irritation / Eye irritation
New Zealand White
rabbits
10% solution
Minimally irritant to rabbit eye
Skin sensitization
Dunkin Hartley guinea
pigs
50% (w/w) solution
Non-sensitizing to the skin
Mutagenicity /
Genotoxicity
Salmonella typhimurium
and Escherichia coli
strain, Mice
50, 150, 500, and 5000 μg/plate
500, 1000 and 2000 mg/kg
bodyweight
Non-mutagenic in bacteria
Non-genotoxic (clastogenic
and/or aneugenic) in bone
marrow cells of mice.
Photo-induced toxicity
Dunkin Hartley guinea
pigs
10% in distilled water
Non-phototoxic and non -
photosensitizing.
Stability
Human female
3% gel
Conversion to hydroquinone was
negligible.
Cellular and Molecular Mechanisms of α-
arbutin
Tyrosinase (Polyphenol oxidase, EC 1.14.18.1) is
a copper-containing mixed-function enzyme. It is
widely distributed in nature, including animals,
plants, fungi, and microorganisms (Sánchez-
Ferrer et al., 1995). It contributes to melanin
production, which induces skin pigmentation and
protects the skin from UV-induced skin damage.
The enzyme tyrosinase has been reported to
catalyze two types of reaction. Firstly, it triggers
the ortho-hydroxylation of monophenols
(tyrosine), converting them into o-diphenols (L-
DOPA) (monophenolase activity). Secondly, it
catalyzes the oxidation of o-diphenols,
transforming them into o-quinones (diphenolase
activity) (Burton, 2003; Matoba et al., 2006).
During the production of melanin, the tyrosinase
enzyme plays a vital role. Melanin protects the
skin from UV-induced skin damage and is
responsible for the formation of skin color (Korner
et al., 1982; Taylor, 2002). Pigmentation
disorders (melasma, freckles, etc.), however, can
create a severe aesthetic problem in humans
(Priestley, 1993). α-arbutin is a synthetic
substance produced from enzymatic glycosylation
of hydroquinone. It inhibits the melanosomal
tyrosinase activity directly or competes with
tyrosinase for the active site by acting as a
substrate, thereby causing skin lightening effects.
The mechanism of action of α-arbutin is
represented in Figure 3. Qin et al., 2014 studied
the mechanism of action of α-arbutin by
investigating the impact of mushroom tyrosinase
on the monophenolase and diphenolase
activities. The authors reported that α-arbutin
exhibits dual effects on monophenolase and
diphenolase activities of mushroom tyrosinase. α-
arbutin inhibited the reduction of the enzyme
activity in the steady-state (suicide inactivation of
the active sites of tyrosinase) during the
monophenolase reaction. Also, a characteristic
lag period was observed during the oxidation of
tyrosine during the monophenolase activity. The
lag time showed a dose-dependent increase with
the increasing concentration of α-arbutin.
However, during the diphenolase reaction, α-
arbutin acted as an activator due to the
interaction of α-arbutin with residues located at
the entrance to the active site. Herein, no lag
Nikhil Chandorkar et al / Alpha Arbutin as a Skin Lightening Agent: A Review
1| International Journal of Pharmaceutical Research | Apr - Jun 2021 | Vol 13 | Issue 2
period was observed during the oxidation of L-
Dopa. Furthermore, it also decreased the effect of
suicide inactivation. In light of the above findings,
Garcia-Jimenez et al., 2017 carried out
experiments to gain in-depth insights into the
mechanism of action of α-arbutin. The authors
reported that the α-arbutin did not completely
inhibit tyrosinase and proposed that α-arbutin
acts as an alternative competitive substrate to the
enzyme since the enzyme is able to hydroxylate it
and does not function as an inhibitor. In another
study, Sugimoto et al., 2004 studied the inhibitory
effects of α-arbutin on melanin biosynthesis in
cultured human melanoma cells and a 3D (three-
dimensional) human skin model. The authors
reported a concentration-dependent inhibition of
melanin synthesis by α-arbutin on human
melanoma cells, HMV-II. The inhibitory effect on
melanogenesis was achieved at noncytotoxic
concentrations of α-arbutin. The authors
concluded that direct inhibition of melanosomal
tyrosinase activity by α-arbutin hampered the
melanogenesis process, rather than suppressing
tyrosinase gene expression or cell growth.
Another mechanism was proposed by
Chakraborty et al., 1998 that the inhibition of
tyrosinase activity by α-arbutin might be due to its
influence at the post-translational level.
Fig.3: Mechanism of action of α-Arbutin for skin lightening
Nikhil Chandorkar et al / Alpha Arbutin as a Skin Lightening Agent: A Review
3506| International Journal of Pharmaceutical Research | Apr - Jun 2021 | Vol 13 | Issue 2
Recent advances in the delivery of α-arbutin to
skin
α-Arbutin is one of the most widely used skin
lightening agents and less toxic as compared to
hydroquinone. It is hydrophilic in nature and has
a log P value of 1.49 and therefore exhibits
poor permeation across the skin. Since the
stratum corneum is more exclusive to hydrophobic
substances, it is difficult for hydrophilic α-arbutin
to penetrate across the skin and reach the
melanocytes. Owing to the advantages offered by
α-arbutin as compared to the other harmful skin
lightening agents, there is an urgent demand to
improve the penetration and permeation of α-
arbutin across the skin by developing various
novel delivery systems such as microneedles,
nanosystems, microsystems, lipidic systems, etc.
Various approaches that can serve as a promising
platform for the effective delivery of α-arbutin are
represented in Figure 4.
Fig.4: Various approaches to enhance the efficacy of α-arbutin as a skin lightening agent
The microneedle-based delivery system has
gained the attention of many researchers due to
its non-invasive nature and high skin penetration
property. Microneedles are being exploited by
research scientists to deliver therapeutics that
need to bypass the stratum corneum without
causing any discomfort. They are micron-sized
needles of less than 1000 μm and promote
penetration of the active compound across the
skin by creating micro-channels through the
stratum corneum without harming the skin.
Microneedles can be dissolvable or hydrogel-
forming. Dissolving microneedles (DMNs), as the
name suggests dissolve completely after the
insertion of microneedles and release the
encapsulated active moiety after coming in
contact with the interstitial fluid in the skin.
Hydrogel-forming MNs (HMNs) are fabricated by
using swellable polymers. HMNs, upon skin
insertion, pass the stratum corneum and come in
contact with the interstitial fluid within the skin.
Therein, they swell and enlarge several times,
thus releasing the active compound.
To overcome poor permeability issues of α-
arbutin, very recently, Aung et al., 2020
attempted to develop dissolvable and hydrogel-
forming microneedles using polyvinyl alcohol
(PVA) and poly (acrylic acid-co-maleic acid)
copolymer (PAMA). DMNs containing α-arbutin
showed complete dissolution within 45 min,
whereas the highest HMN swelling was observed
at 4 h. As compared to the gel and commercial
cream preparations, the developed DMNs and
HMNs showed 4.5- and 2.8-times superior
permeation, respectively. The in vivo studies also
confirmed the superior intradermal delivery of α-
arbutin by both formulations (DMNs and HMNs)
compared to the gel preparation and commercial
cream. The results suggested that DMNs and
HMNs can offer superior transdermal delivery of
α-arbutin to achieve an enhanced skin lightening
effect. In another study, Aung et al., 2020
fabricated DMNs to promote transepidermal
delivery of α-arbutin using hydroxypropyl
methylcellulose (HPMC) and polyvinylpyrrolidone
K-90 (PVP) for effective skin lightening. The
HPMC/PVP DMNs demonstrated 4.7 times
superior permeation of α-arbutin across the skin
than the gel formulation. DMNs developed using
HPMC/PVP for the delivery of α-arbutin were
proven to be a promising delivery platform to
achieve enhanced penetration of α-arbutin.
Polymeric nanoparticles have also been exploited
due to their ability to alter the drug release rate,
increase the therapeutic duration of action, and
enhance site-specific drug delivery. Ayumi et al.,
Nikhil Chandorkar et al / Alpha Arbutin as a Skin Lightening Agent: A Review
3507| International Journal of Pharmaceutical Research | Apr - Jun 2021 | Vol 13 | Issue 2
2019 developed chitosan nanoparticles (CNPs)
for topical delivery of both α-arbutin and β-
arbutin. Chitosan interacts with epidermal tight
junction proteins providing a penetration barrier
in the stratum granulosum, which is located
beneath the lipid barrier in the stratum corneum,
thus enhancing skin penetration (Ali et al., 2017).
Also, chitosan possesses a cationic charge, which
facilitates interaction with negatively charged cell
surfaces and tissues. It is reported that slightly
acidic formulations appear to be more acceptable
for dermal use because the acid mantle of normal
human skin will not be disrupted (Rajan et al.,
2012). The developed chitosan-based α-arbutin
nanoparticles ranged from 147 to 274 d.nm. It
was observed that increasing the concentration of
α-arbutin increased the size of the nanoparticles.
The α-arbutin loaded CNPs demonstrated
significantly higher release as compared to their
free form. CNPs could be a promising carrier
system for the delivery of α-arbutin across the skin
in order to improve its efficacy as a skin
lightening agent. In another study,
Patrojanasophon et al., 2020 fabricated highly
aligned cellulose acetate nanofibers containing α-
arbutin for its application as a face mask. Ideally,
a nanofibers-based face mask should provide
instant release of the active compound with a
high skin penetration rate owing to its high
surface area. Electrospun nanofibers have
outstanding characteristics, making them
desirable as carriers for several therapeutics. The
characteristics feature of nanofibers is their high
surface area which easily overcomes the
constraint of the traditional delivery systems.
Manufacturing ultrafine electrospun nanofibers
not only increase the solubility of the drug but
also promotes faster drug release. The developed
highly arranged nanofibers showed 80.0% of α-
arbutin release in 1.77 min which was
significantly faster as compared to partially
aligned (4.2 mins) and randomly aligned
nanofibers (9.4 mins). The authors successfully
demonstrated the crucial role of the orientation of
nanofibers in controlling drug release. It was
achieved due to the network meshes present in
the nanofibers with different degrees of
entanglement, which directly affected the diffusion
of drugs across the skin.
α-arbutin is one of the most popular skin
brightening compounds and less toxic as
compared to hydroquinone. With a massive
growth in the skin brightening industry today, the
supply and demand of α-arbutin are increasing
considerably. Therefore, exploring various
delivery systems such as nanoparticles,
microparticles, nanogels, nanoemulsion for
improving the efficacy of α-arbutin as a skin
brightening agent is needed.
Combination Therapy of α-arbutin
Combined active compounds with different
targeting mechanisms are used to enhance the
effectiveness of the skin lighting agent. Skin
formulations containing α-arbutin along with
other skin brighteners such as kojic acid, vitamin
C, or niacinamide have been reported to
demonstrate synergetic effects. A combination of
2% α-arbutin and 3% tranexamic acid, 2%
galactomyces ferment filtrate, and 4%
niacinamide has proven to be a safe and effective
alternative to enhance skin lightening with no
significant side effects (Santoso et al., 2018). α-
arbutin combined with 4-n butylresorcinol, and
licorice extract has been used in the therapeutic
management of melasma with improved safety,
efficacy, and tolerability (Kolbe et al., 2013).
Combination therapy with 7% α-arbutin solution
and Q-switched Nd:YAG laser demonstrated an
effective and well-tolerated treatment for
refractory melasma (Polnikorn, 2010). Very
recently, Wang et al., 2021 prepared a dissolving
microneedles array (DMNA) containing α-arbutin
and Vitamin C in a 1:1 ratio. It was observed that
this ratio exhibited maximum inhibition effects on
melanogenesis and tyrosinase activity.
Market Status of α-arbutin
Natural and herbal beauty products are
becoming extremely popular, particularly in the
United States (U.S.) and Europe. These areas are
expected to provide profitable opportunities for α-
arbutin producers. Furthermore, because of its
excellent antioxidant properties, α-arbutin has
seen an increase in demand in the
pharmaceutical industry, which is expected to
create highly profitable opportunities for
manufacturers in the coming years. North
America is the largest consumer of α-arbutin,
followed by Europe and the Asia Pacific.
Consumers' increasing preference for eco-friendly
products has prompted several US cosmetic
manufacturers, including L'Oreal and Garnier, to
develop newer and more innovative cosmetic
products. As a result, it is expected to boost
market growth in North America. In 2018, Europe
had the highest consumption of α-arbutin. An
increase in regulations aimed at reducing the use
of synthetic ingredients in cosmetic products, as
well as a rise in the geriatric population, are the
two factors that are expected to boost the market
growth (FutureWise Market Research and Reports;
2019).
CONCLUSION
Nikhil Chandorkar et al / Alpha Arbutin as a Skin Lightening Agent: A Review
3508| International Journal of Pharmaceutical Research | Apr - Jun 2021 | Vol 13 | Issue 2
α-arbutin has emerged as a popular alternative to
other harmful skin lightening agents because of
its outstanding capability to reduce
hyperpigmentation without any unwanted side
effects. Today, with massive growth in the
cosmetic and pharmaceutical industry, its supply
and demand are increasing exponentially.
Currently, α-arbutin is found as the main
ingredient in a wide range of skin lightening
products such as creams, serums, face washes,
gels, and lotions. However, owing to the
hydrophilic nature of α-arbutin, more studies are
urgently needed to enhance the penetration of α-
arbutin across the skin to achieve maximum skin
lightening effect. Lastly, more comprehensive
research investigating the long-term effects and
complexities of α-arbutin products is
recommended since they can pose a risk to the
population using skin lightening products. In this
review, we have aimed to highlight α-arbutin as a
safer alternative to many other harmful skin
lightening agents as the abuse of skin bleaching
agents remains prevalent worldwide.
Conflict of Interest: The authors declare that they
have no competing interests.
Acknowledgments: None.
Funding: This research work did not receive any
funding
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... 10,11 A highly hydrophilic and well-recognised tyrosinase inhibitor for the hyperpigmentation topical therapy, a-arbutin, was chosen as a model therapeutic due to its poor skin permeability albeit being one of the most effective whitening agents. 12,13 Having been synthesised via glycosidation of hydroquinone and is frequently linked with cosmetics, a-arbutin has also demonstrated antioxidative and free radical-scavenging properties, 14 as well as therapeutic potential in the treatment of various illnesses such as central nervous system disorders (i.e. Parkinson's and Alzheimer's diseases) 15, 16 and diabetes. ...
... The loading ability and release profiles of GBE-GG nanoparticles were investigated using a tiny hydrophilic whitening agent called a-arbutin (MW 272 Da; log P -1.49), which is known to have poor skin permeability. 12 The release profiles were examined in a pH 5 buffer, which was justified by a-arbutin maximal stability at mentioned pH condition and the fact that skin pH fluctuates between 4 and 6. 13,37 According to the data illustrated in Fig. 7, GBE-GG NPs demonstrated a sustained release, with >85% release reached within 6 h, as compared to as early as 3 h for native GG NPs. The hydrophobicity/amphiphilicity of GBE-GG perhaps prevented the entrapped hydrophilic a-arbutin from being released quickly, resulting in sustained release. ...
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Nano-colloidal systems formulated from amphiphilically-modified polysaccharides (degree of modification 16.6 %) are focus of prominent study due to their potential to augment active penetration across the skin. Here we report the synthesis of amphiphilically-modified guar gum (GBE-GG) prepared by grafting with glycidol butyl ether (GBE), which were subsequently formed into nanocarriers and loaded with α-arbutin (22.3 % loading). The monodispersed and close-to-spherical nanocarriers (size range 239–297 nm) formed via cross-linking were adequately stable mainly at low temperature (4°C) under physiological pH condition. α-arbutin was released from GBE-GG NPs in a more sustained manner and the release profiles can be accurately represented by the 1st order kinetic model. In-vitro interactions on immortalised human keratinocytes (HaCaT) cells revealed an increase in biological membrane permeability as well as the absence of cellular toxicity at application pertinent concentrations. No substantial haemolytic activity appeared and flow cytometry analysis revealed effective cellular uptake, suggesting their potential as promising nanocarriers for percutaneous delivery that warrants further comprehensive research.
... 11 ARB is the important constituent in various skin whitening products, including creams, serums, washes, gels, and lotions. 12 Cyperus rotundus essential oil (CREO) is an anti-inflammatory agent and inhibits tyrosinase activity and thus depigments keratinocytes. Because of its biological properties, CREO is useful in treating hyperpigmentation. ...
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Alpha-arbutin is one of the most efficient skin lightener agents, which shows the effect on reducing the pigmentation by competitively inhibiting human tyrosinase. However, alpha-arbutin has difficulty in skin permeability due to its hydrophilic property. The objective of this study was, therefore, to develop alpha-arbutin-loaded dissolving microneedles (DMNs) for improving the delivery of alpha-arbutin into the skin. The DMN patch was prepared using Gantrez™ S-97, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone K-90 (PVP), chitosan, and their combinations. The optimal 8% alpha-arbutin-loaded DMNs, aside from Gantrez™ S-97, was successfully formulated with combination of 8% w/w HPMC and 40% w/w PVP K-90 (HPMC/PVP) at the weight ratio of 1:1. Both DMNs had 100% of penetration into porcine skin. Over 12 h of skin permeation, the flux of Gantrez™ S-97 DMNs and the HPMC/PVP DMNs were 66.21 μg/cm²/h and 74.24 μg/cm²/h, respectively. The accumulation amount of alpha-arbutin in the skin from Gantrez™ S-97 DMNs and HPMC/PVP DMNs was 107.76 μg and 312.23 μg, respectively. In comparison to the gel formulations, Gantrez™ S-97 DMNs and HPMC/PVP DMNs increase the delivery of alpha-arbutin across the skin approximately 2 and 4.7 times, respectively. In vivo studies found that alpha-arbutin-loaded HPMC/PVP DMNs delivered more alpha-arbutin into the skin than commercial cream. Moreover, the skin can reseal naturally after removal of DMNs patch without any signs of infection and remain stable in accelerated conditions for 4 weeks. Accordingly, alpha-arbutin-loaded HPMC/PVP DMNs could be a promising delivery platform for promoting trans-epidermal delivery of alpha-arbutin for skin lightening.
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The known derivatives from hydroquinone, α and β-arbutin, are used as depigmenting agents. In this work, we demonstrate that the oxy form of tyrosinase (oxytyrosinase) hydroxylates α and β-arbutin in ortho position of the phenolic hydroxyl group, giving rise to a complex formed by met-tyrosinase with the hydroxylated α or β-arbutin. This complex could evolve in two ways: by oxidizing the originated o-diphenol to o-quinone and deoxy-tyrosinase, or by delivering the o-diphenol and met-tyrosinase to the medium, which would produce the self-activation of the system. Note that the quinones generated in both cases are unstable, so the catalysis cannot be studied quantitatively. However, if 3-methyl-2-benzothiazolinone hydrazone hydrochloride hydrate is used, the o-quinone is attacked, so that it becomes an adduct, which can be oxidized by another molecule of o-quinone, generating o-diphenol in the medium. In this way, the system reaches the steady state and originates a chromophore, which, in turn, has a high absorptivity in the visible spectrum. This reaction allowed us to characterize α and β-arbutin kinetically as substrates of tyrosinase for the first time, obtaining a Michaelis constant values of 6.5 ± 0.58 mM and 3 ± 0.19 mM, respectively. The data agree with those from docking studies that showed that the enzyme has a higher affinity for β-arbutin. Moreover, the catalytic constants obtained by the kinetic studies (catalytic constant = 4.43 ± 0.33 s⁻¹ and 3.7 ± 0.29 s⁻¹ for α and β-arbutin respectively) agree with our forecast based on 13 C NMR considerations. This kinetic characterization of α and β-arbutin as substrates of tyrosinase should be taken into account to explain possible adverse effects of these compounds.
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Hyperpigmentation is a common skin disorder caused by excessive melanogenesis and uneven dispersion of melanin in the skin. To combine multiple active agents with an efficient transdermal drug delivery system is an effective strategy to combat UV induced skin pigmentation. In this work, Arbutin (Arb) and Vitamin C (Vc) mixed in 1:1 were found to have the greatest inhibition effects on melanogenesis and tyrosinase activity in B16 murine melanoma cells. And hyaluronic acid (HA) based dissolving microneedles array (DMNA) was employed to overcome the skin barriers for improved topical drug delivery, which exhibited the most desirable features, including morphology, mechanical properties, dissolving ability, and the highest drug loading. Furthermore, DMNA could greatly increase the stability of Vc during storage without adding any antioxidant which is an important issue for Vc administration. Pharmacodynamics study showed that DMNA loaded with Arb and Vc could synergistically suppress UVB-induced hyperpigmentation in guinea pig skin. This work provides a promising treatment strategy and solution for skin pigmentation and other skin problems.
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Introduction: Light skin tone has been desired by many Asian women thus the search of effective depigmenting agent has been conducted by many researchers. Tranexamic acid, an anti-fibrinolytic drug, is now gaining popularity as a new depigmenting agent. However, studies on tranexamic acid have shown mixed result of its comparison to hydroquinone. Galactomyces ferment filtrate, niacinamide and alpha arbutin have been known of their depigmenting effect. Combined materials with different targeting mechanisms are used to enhance the effectiveness of the lighting agent Objective: To compare the skin lightening effect of combination of tranexamic acid 3%, galactomyces ferment filtrate 2%, niacinamide 4%, and alpha arbutin 2% to hydroquinone 4%. Methods: In this study, each of 30 participants applied a combination of tranexamic acid 3%, galactomyces ferment filtrate 2%, niacinamide 4%, and alpha arbutin 2% and hydroquinone 4% to the left forearm using a special patron. Subject then evaluated each week for four weeks. Clinical effects were evaluated using a chromameter including L* for skin brightness and a* for skin erythema. All measurements were taken three times, and the mean value was used. To assess the comparison of skin brightness score and pigmentation intensity between the two serum groups, the Independent T-test was used. As for assessing the change in scores based on measurement time in each serum group, Pearson's Correlation was used. The test results are significant if the value of p
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BACKGROUND: Hyperpigmentation disorders are commonly encountered in dermatology clinics. Botanical and natural ingredients have gained popularity as alternative depigmenting products.OBJECTIVE:We sought to review clinical studies evaluating the use of different natural products in treating hyperpigmentation so clinicians are better equipped to educate their patients. Specific ingredients reviewed include azelaic acid, aloesin, mulberry, licorice extracts, lignin peroxidase, kojic acid, niacinamide, ellagic acid, arbutin, green tea, turmeric, soy, and ascorbic acid.METHODS:Systematic searches of PubMed and SCOPUS databases were performed in March 2016 using the various ingredient names, "melasma"and "hyperpigmentation." Two reviewers independently screened titles, leading to the selection of 30 clinical studies.RESULTS:Review of the literature revealed few clinical trials that evaluated the treatment of hyperpigmentation with natural ingredients. Despite the limited evidence-based research, several natural ingredients did show efficacy as depigmenting agents, including azelaic acid, soy, lignin peroxidase, ascorbic acid iontophoresis, arbutin, ellagic acid, licorice extracts, niacinamide, and mulberry.CONCLUSION:The aforementioned ingredients show promise as natural treatments for patients with hyperpigmentation disorders. These agents might also provide clinicians and researchers with a way to further characterize the pathogenesis of dyschromia. However, the paucity of clinical studies is certainly a limitation. Additionally, many of thein-vivostudies are limited by the short length of the trials, and questions remain about the long-term efficacy and safety of the ingredients used in these studies. Lastly, we suggest a standardized objective scoring system be implemented in any further comparative studies.