Kojic acid applications in cosmetic and pharmaceutical preparations

Abstract

Skin color disorders can be caused by various factors, such as excessive exposure to sunlight, aging and hormonal
imbalance during pregnancy, or taking some medications. Kojic acid (KA) is a natural metabolite produced by
fungi that has the ability to inhibit tyrosinase activity in synthesis of melanin. The major applications of KA and
its derivatives in medicine are based on their biocompatibility, antimicrobial and antiviral, antitumor, antidiabetic, anticancer, anti-speck, anti-parasitic, and pesticidal and insecticidal properties. In addition, KA and its
derivatives are used as anti-oxidant, anti-proliferative, anti-inflammatory, radio protective and skin-lightening
agent in skin creams, lotions, soaps, and dental care products. KA has the ability to act as a UV protector,
suppressor of hyperpigmentation in human and restrainer of melanin formation, due to its tyrosinase inhibitory
activity. Also, KA could be developed as a chemo sensitizer to enhance efficacy of commercial antifungal drugs
or fungicides. In general, KA and its derivatives have wide applications in cosmetics and pharmaceutical industries.

Full text

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Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
Kojic acid applications in cosmetic and pharmaceutical preparations
Majid Saeedi
a
, Masoumeh Eslamifar
b,⁎
, Khadijeh Khezri
c,⁎
a
Department of Pharmaceutics, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
b
Department of Environmental Health Engineering, Faculty of Health, Mazandaran University of Medical Sciences, Sari, Iran
c
Student Research Committee, Department of Pharmaceutics, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
ARTICLE INFO
Keywords:
Melanin
Hyperpigmentation
Cosmetic
Health brightening products
Kojic acid
ABSTRACT
Skin color disorders can be caused by various factors, such as excessive exposure to sunlight, aging and hormonal
imbalance during pregnancy, or taking some medications. Kojic acid (KA) is a natural metabolite produced by
fungi that has the ability to inhibit tyrosinase activity in synthesis of melanin. The major applications of KA and
its derivatives in medicine are based on their biocompatibility, antimicrobial and antiviral, antitumor, anti-
diabetic, anticancer, anti-speck, anti-parasitic, and pesticidal and insecticidal properties. In addition, KA and its
derivatives are used as anti-oxidant, anti-proliferative, anti-inflammatory, radio protective and skin-lightening
agent in skin creams, lotions, soaps, and dental care products. KA has the ability to act as a UV protector,
suppressor of hyperpigmentation in human and restrainer of melanin formation, due to its tyrosinase inhibitory
activity. Also, KA could be developed as a chemo sensitizer to enhance efficacy of commercial antifungal drugs
or fungicides. In general, KA and its derivatives have wide applications in cosmetics and pharmaceutical in-
dustries.
1. Introduction
Skin is one of the most important organs of the body which consists
of several layers including the stratum corneum (SC), viable epidermis,
and dermis. The SC is selectively permeable to specific material such as
drugs [1,2]. The major obstacle for transdermal absorption in percu-
taneous Drug Delivery System (PDDS) is predominance of the SC bar-
rier. Several systems have been developed to enhance drug permeation
through the skin. Chemical transdermal enhancers and prodrugs are the
main paths for conquest of the SC barrier. A new intracellular screening
method in delivery of biologically active ingredients is using a protein
transduction system with a topical delivery enhancer. The combination
of naturally derived melanogenesis inhibition peptide and protein
transdermal delivery system is very useful for whitening peptides that
could be applied in cosmetics and pharmaceutical industry [3,4].
Over the past few decades, the skin has been considered as an im-
portant route in drug delivery. However, it is identified as a significant
and effective barrier [5] and is associated with some transdermal pro-
blems in drug delivery. A major advance to solving this problem, is the
novel drug delivery methods which is designed for topical, local, and
systemic treatments. Nevertheless, few number of drugs have been re-
cognized and they need to pass effectively through the layer of stratum
corneum to achieve effective blood concentration levels. Different
methods have been developed to enhance the transdermal absorption of
drugs, including drug derivatives, drug saturation systems, and che-
mical and physical enhancers. All these facilitate the penetration of
drugs through the stratum corneum layer [6,7]. Drug resistance is a big
problem in systemic chemotherapy in cancer. Therefore, delivery of
chemotherapeutic agents and anti-apoptotic genes possess advantages
to overcome this problem. The nano-carrier system prepared from kojic
acid shows effective deliveries of anti-cancer drugs, significantly in-
hibits cell proliferation and also reduces tumor growth [8,9].
Skin brighteners are a kind of therapy methods that can be used for
the treatment of skin disorders caused by hyperpigmentation. They may
inhibit the synthesis of melanin [10]. Melanin is a pigment that is
produced inside the melanocytes. They synthesize from thyrosine in a
complex process in the presence of thyrosinase and after packaging in
melanosomes immigrate to keratinocytes, the main epidermal cells
[11]. When these pigment productions are more than usual situation or
their distribution are not normal, development of skin hy-
perpigmentation occurs [12]. The use of chemical products to reduce
skin hyperpigmentation by several mechanisms such as reducing the
concentration of melanin is known as whitening of the skin. Nowadays,
brightening the skin is one of the most common procedures to improve
the hyper pigmented parts of the skin [13]. KA and its derivatives are
used to block the formation of pigment by melanocytes as one of the
most popular lightener in cosmetic products [2,14–16].
The kojic acid scaffold has an excellent structure in medicinal
https://doi.org/10.1016/j.biopha.2018.12.006
Received 20 September 2018; Received in revised form 25 November 2018; Accepted 2 December 2018
⁎
Corresponding authors at: Mazandaran University of Medical Science, Sari, Iran.
E-mail addresses: msaeedi@mazums.ac.ir (M. Saeedi), microbiologist.eslamifar@gmail.com (M. Eslamifar), Khezripnuchem@yahoo.com (K. Khezri).
Biomedicine & Pharmacotherapy 110 (2019) 582–593
0753-3322/ © 2018 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/BY/4.0/).
T

chemistry research, due to its vast biological activities. Unnatural
amino acids, that occur either naturally or synthesized chemically, are
widely used in ligand design. They represent a powerful tool in drug
discovery when incorporated into therapeutic peptidomimetics and
peptide analogs. The incorporation of unnatural amino acids could
enhance the resistance of peptides to enzymatic degradation and in-
crease peptides structural diversity as well as bioactivity. Synthesis of
novel hybrid molecules containing variety of natural products, such as
novel kojic acid amino acid hybrid natural products has made re-
markable progress over the last few years, opening new paths in
pharmacological approaches. These new amino acid derivatives con-
taining kojic acid have several reaction centers for oxidation, reduction,
alkylation, acylation, and peptide coupling reaction. Also, these com-
pound will find perfect application as tyrosinase inhibitor [17]. Tran-
scription factors, are involved in important cellular processes of some
diseases like cancers, autoimmune and inflammatory diseases [18].
Accumulation of tyrosinase and melanin in cells lead to melasma
and hyperpigmentation. Tyrosinase is the central enzyme in melanin
biosynthesis. Therefore, illumination of the molecules and pathways
that regulate tyrosinase activity could identify target areas for the de-
velopment of compounds to treat hyperpigmentation in vitro. A major
transcription factor for tyrosinase is the microphthalmia-associated
transcription factor (MITF) that increases tyrosinase expression when
upregulated and is involved in the pigmentation, proliferation, and
survival of melanocytes. Transcription factors are a class of proteins
that regulate gene expression by binding to specific DNA sequences.
Factors such as ultraviolet radiation, metal ions, free radicals, have
significantly stimulate transcription of tyrosinase gene. the inhibitory
effect of melanin formation and tyrosinase activity of kojic acid and
kojic acid esters was evaluated in B16F1 melanoma cells [19–21].
Kojic acid showed the potential inhibition of cellular NF-κB activity
in human keratinocytes. NF-κB activation is probably involved in kojic
acid induced anti-melanogenic effect [18,22].
During the past decades, fluorescent metal nanoclusters have been
widely studied because of their good photo stability, adjustable light
emission wavelength, and low bio toxicity. In particular, DNA template
fluorescent metal nanoclusters have been the center of interest [23].
Luminescent transition metal complexes have also attracted a great deal
of interest for the detection of biomolecules in scientific projects [9].
Hybrid probes are highly efficient tools used for locating biological
molecules and signals in living cells. They have great advantages based
on small molecules or fluorescent proteins and are reported to be of
great benefit in live-cell analyses of epigenetic disorders. Yet several
hybrid probes have been utilized by using that fluorescence property in
response to pH, metal ions, or gas molecules. But, there is paucity of
information on the use of hybrid probes for detecting live cells in bio
macromolecules. Particularly, there is still unsatisfied demand for
probes for direct visualization of membrane dynamics of live cells
[24–26].
Several substituents are combined into kojic acid at its 2-hydro-
xymethyl group. Some kojic acid derivatives are synthesized and
evaluated for their ability to inhibit D-amino acid oxidase (DAAO).
These analogs act as beneficial molecular probes to explore the sec-
ondary binding site, which could be used in designing more potent
inhibitors [27].
Human skin exposure to ultraviolet light can cause many skin le-
sions, such as sunburn, skin cancer, and oxidative stress, all of which
depend on the intensity and amount of UV light [28,29]. KA can be
used as a UV protector, with the ability to restrict hyperpigmentation
tyrosinase inhibitory effect [2,30–36]. Side effects of hydroquinone
(HQ) as a popular skin lightener has made KA a suitable substitution in
cosmetic products [2,37]. This review describes and discusses the ap-
plication and high capacity of KA, as a lightening agent in cosmetic and
health care preparations.
2. Investigating the background and chemical structure of KA
The KA (the name ‘kojic acid’was derived from “Koji”) is a chemical
product that is obtained from various types of fungi such as A. flavus, A.
oryzae, A. tamarii, and A. parasiticus (Table 1). It is also produced from
the fermentation of some Asian foods (e.g soy sauce and rice wine),
which acts as a primer for fungus or inoculum [38–44]. kojic Acid was
first marketed in 1955. The Charles Pfizer and Company, USA, was the
first company to try to build this product. In recent years, kojic acid-
producing companies include two in China and three companies in
Japan, Switzerland, and the USA. Rapid growth of industries and dis-
covery of the potential uses of kojic acid and its derivatives, generated
great demands for this product. KA (Fig. 1) is classified in the group of
organic acids, which is obtained from different types of fungi during
aerobic fermentation process. The common names of KA are presented
in Fig. 2 [39,41,43,45–51].
Its chemical structure is identified as 5-hydroxy-2-hydroxymethyl-γ-
pyron [38–44]. Some of these species are capable of producing KA in
Table 1
Natural sources of kojic acid from different isolates belonging to various species
of fungi [52–55].
Family Genus Organisms type species
Pleosporaceae Alternaria Alternaria alternata
Pleospora P. herbarum
Pleospora Pleospora allii
Chaetomiaceae Chaetomium Chaetomium globosum
Microascaceae Microascus Microascus brevicaulis
Stachybotryaceae Stachybotrys Stachybotrys chartarum
Stachybotrys Stachybotrys theobromae
Torulaceae Torula Torula herbarum
Hypocreaceae Trichoderma Trichoderma hamatum,Trichoderma
koningii,T. longibrachiatum,T.
polysporum
Acremonium Acremonium strictum
Nectriaceae Fusarium Fusarium aquaeductuum,
F. chlamydosporum
F. equiseti, F. lateritium
F. moniliforme, F. oxysporum
F. proliferatum, F. solani
F. subglutinans, F. tricinctum
Cunninghamellaceae Cunninghamella Cunninghamella echinulata
Mucoraceae Mucor Mucor circinelloides,
Mucor. fuscus
Syncephalastraceae Syncephalastrum Syncephalastrum racemosum
Trichocomaceae Penicillium P. Capsulatum, P. lividum, P. spinulosum
P. funiculosum, P. purpurogenum,
P. rugulosum, P. albidum, P.
atramentosum, P. aurantiogriseum
P. janthinellum, P. citrinum,
P. corylophilum, P. camemberti
P. chrysogenum, P. cyaneofulvum
P. cyclopium, P. digitatum, P. expansum
P. frequentans, P. godlewski,
P. nigricans, P. somniferum, P.
viridicatum
Trichocomaceae Aspergillus A. Candidus, A. phoenicis, A. melleus
A. Ochraceus, A. sclerotiorum
A. Sulphureus, A. fumigatus
A. flavus, A. flavus var. columnaris
A. Oryzae, A. Parasiticus
A. tamarii, A. wentii, A. aculeatus
A. niger, A. terreus, A. flavipes
A. Janus, A. sydowii A. versicolor,
A.nidulans
Fig. 1. Chemical structure of KA.
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
583

large amounts, but genetic modifications could alter their ability to
greater performance [56]. As mentioned earlier, KA as a skin
whitening, skin lightener or depigmenting agent is used in cosmetic
formulations. It is naturally produced by various species of Penicillium
and Acetobacter and various species of acetic acid bacilli [57–60].
Several methods are suggested for the analysis of KA in various
industries, including voltammetry, spectrophotometry, column chro-
matography with ultraviolet detection, thin-layer chromatography, gas
chromatography with or without flame ionization, mass spectrometry
detection, bio gel P-2 column chromatography [61], and high-perfor-
mance liquid chromatography with photodiode-array or ultraviolet
detection [58,61–73].
3. Melanin synthesis steps and its role in making pigmentation
Melanin is synthesized by melanocytes at the lower layer of epi-
dermis. Melanocytes are classified in the category of specialized den-
dritic cells that are located among epidermal keratinocytes and they
play the primary role of melanin production within an organelle called
melanosomes, and thus spread to surrounding keratinocytes. Each
melanocyte makes contact with melanosomes in different stages of the
dendritic cells and is distributed in many keratinocytes. Melanins are
complex polymers that are derived from tyrosine and other inter-
mediates. They change into black-brown eumelanin and yellow-red
pheomelanin through a multi-stage process of oxidation and complex
reactions that cause variations of color in human population [74,75].
Tyrosinase contain copper ion in the active site. When exposed to UV
rays, the copper ion commands the tyrosinase to become more active.
KA captures the copper ion, preventing that from activating the tyr-
osinase. By inhibiting the activities of tyrosinase, KA can also prevent
creating melanin (Figs. 3 and 4)[76].
More than 80 genes are involved in producing and regulating mel-
anin. Biosynthesis of melanin is controlled by various extracellular
signaling pathways, thus signals are transmitted as a cascade.
Fibroblasts are reported to be involved in this signaling. The early
stages of melanin production can occur in the skin by complex genetic
mechanisms, internal and external factors such as aging and ultraviolet
radiation and it can lead to considerable changes in synthesis of pure
melanin [77,78].
4. Transdermal penetration, depigmentation and development of
methods
The topical absorption of KA according to pharmacokinetic ab-
sorption studies in rats and human skin, is estimated to be
0.03–0.06 mg/kg/day. The genotoxic risk of KA as a skin lightening
agent for humans is less. The in vitro percutaneous absorption values of
KA in human skin resulted in 17%, and the maximum potential human
systemic exposure dose (SED) would be 1.7 mg or 0.028 mg/kg/day for
a 60 kg adult human. This SED range is based on the application area of
hands and face [79].
The results of an oral/topical pharmacokinetic study in rats showed
18% of systemic exposure after topical application. Pharmacokinetic
studies in rats after oral and subcutaneous administration to rats,
showed that KA was rapidly absorbed and metabolized. The percuta-
neous absorption of KA in human skin was investigated in vitro and
recovered
14
C-equivalents (%) were determined by liquid scintillation
counting in the skin excess (%75.8 ± 9.3), stratum corneum
(%3.7 ± 2.2), epidermis + dermis (%9.2 ± 4.3) and the receptor
fluid (7.8 ± 6.8). KA showed a significant tendency to penetrate into
the dermis and epidermis (penetration rate of 16.98 ± 10.28%, cor-
responding to 3.58 ± 2.38
14
C-mgeq/cm
2
of treated skin area) [80].
Percutaneous absorption of KA in six healthy postmenopausal
Japanese women was measured before and after applying a cream
containing 1% KA. All the concentrations in plasma were only slightly
above the quantitation limit of 1 ng/ml. So, it was proved that KA had
not the potential role for transdermal penetration into the blood [81].
The inhibition of Eumelanin (black brown) production is usually
Fig. 2. Schematic diagram of Trade Names,Technical Names and Trade Name of KA.
Fig. 3. Tyrosinase inhibitory mechanism of KA in melanin biosynthesis for creating melanin by KA.
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
584

considered the main mechanism for depigmentation agents. Cultured B-
16 melanoma cells are excellent material for confirming the melano-
genesis inhibition in vitro. Cultivation of B-16 cells in eagles MEM
containing 10% fetal bovine serum and inserting several concentrations
of depigmenting agents is one of the evaluation methods. After 5 days,
the cells are fixed by formalin and stained by ammoniacal silver nitrate,
then premelanosome stained in black. When the cells are alive, and
premelanosome stain is negative with the presence of depigmenting
agents, melanogenesis have been successfully inhibited. The effects of
melanogenesis inhibition have been established when a depigmenting
agent such as KA was added to the water in which black goldfish were
kept. After 1–2 months the black goldfish turned to yellowish brown
(Fig. 5). Later the goldfish was kept in water without KA, and it turned
back to its original black color. Therefore, KA as a highly effective and
safe ingredient inhibited melanogenesis without damaging cells nor its
function. This demonstrated that melanogenesis was inhibited [82].
5. Cellular and molecular mechanisms of kojic acid
Cosmetic performance that use skin-lightening agents to treat pig-
ment abnormalities are popular worldwide. Yet the molecular and
cellular mechanisms of these agents are mainly unknown. There are
only few skin-lightening compounds with the ability to inhibit tyr-
osinase in addition to activating or inhibiting intracellular signal
leading to the transcriptional inhibition of melanin synthesis genes.
Evidence suggest that most skin-lightening compounds reduce the
synthesis of melanin by inhibiting tyrosinase enzyme activity with low
toxicity on melanocytes. Some skin-lightening agents are believed to
regulate intracellular signaling pathways, leading to a decrease in
melanin synthesis, or increase in melanocyte cell death [85].
Malignant melanoma generally develops from the transformation
and proliferation of melanocytes in the basal cell layer of the epidermis.
The melanocytes may spread to other organs in the body (metastasis),
and disrupt the function of that organ. To better understand the mo-
lecular and cellular mechanisms of melanoma, human malignant mel-
anoma cells have been extensively used as a skin model for in vitro
examinations because they are highly reproducible, quantifiable and
facility to cultivate. It is a structural cell model that closely equals the
progression of melanoma in vivo, and also a cost-effective alternative to
clinical testing. The anti-apoptotic mechanisms regulating cell death
are involved in drug resistance in tumor cells. Therefore, further
knowledge on the signal transduction pathways leading to tumor cell
death could result in identification of new target molecules to combat
drug resistance and improve melanoma therapy. Tyrosinase catalyzes
three distinct reactions in the melanogenic pathway: hydroxylation of
monophenol (L-tyrosine), dehydrogenation of catechol (L-DOPA), and
dehydrogenation of dihydroxyindole. By contrast, catalase is a potent
inhibitor of tyrosinase that regulates the removal of H2O2. Also, per-
oxidase in the presence of H2O2 and copper ions enhance the conver-
sion of monomers to eumelanin polymers. Thus, enzymatic changes
such as modifications in protein and gene expression, affect melano-
genesis in melanomas. The complex regulatory control of the bio-
synthesis system in melanogenesis includes receptor-mediated path-
ways activated by hormones, neurotransmitters, cytokines, and growth
factors. The biological effects of kojic acid on gene and protein ex-
pression profiles of A375 human melanoma cells and cancer therapy
have been researched. The tumorigenic potential and some genotoxic
effects of kojic acid on human skin cell lines have been widely studied,
Fig. 4. Inhibiting the activities of tyrosinase by KA.
Fig. 5. Black goldfish was kept in water containing Kojic Acid,
its color tone fadedIn an initial clinical study, the cream
containing 1% KA had better therapeutic properties than the
cream containing 2.3% KA because KA in the latter crystal-
lized gradually and the effect of the improvement reduced. In
that study, cases of melasma were treated with 1% KA cream
for 6 months. Hyperpigmentation in melasma patient de-
creased significantly after the treatment period. But the
symptoms of melasma returned with exposure to sunlight
[83]. The KA as an iron chelator is applied in treatment of
depigmentation and skin aging. Nanotechnology-based drug
delivery systems, such as liquid crystalline systems (LCSs), can
improve drug permeation through the skin and efficacy of
therapeutic response for a prolonged time [84].
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
585

but its effect on gene and protein expression levels in many biological
functions of human skin has not been exactly reported. Investigating
the genes and proteins involved in melanoma may consequently im-
prove the development of early diagnostic and therapeutic applications
[86].
Melanogenesis is a process that is regulated by tyrosinase and tyr-
osinase related protein-1 and -2 (TRP-1 and TRP-2). Tyrosinase plays an
efficient role in melanin generation by the hydroxylation of tyrosine
into dihydroxyphenylalanine (DOPA) followed by further oxidation of
DOPA into DOPA Quinone. Therefore, inhibition of tyrosinase as a
common method could help in achieving skin hypopigmentation. In
addition, tyrosinase, TRP-1 and TRP-2 are transcriptionally regulated
by a microphthalmia-associated transcription factor (MITF). Skin pig-
mentation is regulated by different types of extrinsic and intrinsic fac-
tors. In particular, extracellular signal-regulated kinase (ERK) nega-
tively regulates melanogenesis in melanoma cells. It is also an effective
regulator of the activation of MITF [87].
The transcriptional level is the first step by which the expression of
tyrosinase and related melanogenic enzymes may be regulated.
Important factor in this process are the microphthalmia-associated
transcription factor (MITF) is a basic helix-loop-helix leucine zipper
transcription factor that regulates cellular melanocyte as well as the
transcription of melanogenic enzymes (tyrosinase, TYRP1 and TYRP2)
and melanosome structural proteins (MART-1 and PMEL17). There
have been substantial advances in our understanding on the cellular
and molecular mechanisms in pigment biology and the processes
causing skin pigmentation. This has led to the development of many
skin lightening agents to reduce skin hyperpigmentation. There has
been an increased interest in alternative hypo pigmenting mechanisms
and need for a standardized streamlined protocol to screen melanogenic
regulatory compounds. Cellular recognition between melanocytes and
keratinocytes is an important event involved in melanosome transfer,
because of their influence on cellular processes including intracellular
trafficking, endocytosis, and cell-cell recognition [88].
6. Chemical characterizations and applications of KA in various
industries
KA is known as a multi-agent molecule with a reactive gamma-
pyrone ring that has poor acidity. KA is reactive on its own ring in any
situation, therefore, it could be used in production of some products
with industrial value, including metal chelates, pyridones, pyridines,
ethers, azodyes, mannich base, and the products of cyanoethylation.
Many functional chemical reactions of KA have been investigated over
several decades after its separation. The hydroxyl group in the carbon 5
position from the γ-pyrene ring gives a weak acidic property to the KA
molecule, which leads to the formation of salt by some metals such as
sodium, zinc, copper, calcium, nickel, and cadmium [48–50].
Kojic acid is well-known for its wide application in various in-
dustries such as food, pharmaceuticals, cosmetics, agriculture, and en-
vironment. It is distributed naturally in traditional Asian food.
Moreover, the most striking benefit of kojic acid and its derivatives is
found in human and animal medicines as biological active compounds
(Fig. 6 and Table 2).
7. Hyperpigmentation disorders and their causes in human skin
Genetic factors, endocrine abnormalities, injuries, skin cancers,
Fig. 6. Diagrams of the key function of kojic acid and its derivatives in different industries [55,129–131].
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
586

birth control pills, pregnancies, and medications that affect melanin
production, such as chlorpromazine and hydroxychloroquine, are
amongst the effective factors for hyperpigmentation [132]. Many other
factors can also contribute to the development of hyperpigmentation.
These conditions can be very complicated and may require different
stages of treatment. In more acute cases, surgery or laser therapy may
be the only solution; but stains, melasma, spots, and small patch of light
brown color on the skin caused by post inflammatory hyperpigmenta-
tion can be effectively treated with topical products and also with
cosmetic treatment through the use of skin-whitening products. These
products are made from compounds such as KA and Arbutin, and other
substances with bleaching properties of the skin [132]. Melasma is a
Table 2
Applications of KA in various industries.
Functions Fields References
tyrosinase inhibitor (to inhibit melanin formation) Cosmetic [89]
Anti-inflammatory Cosmetic [17]
Radio protective Cosmetic [90]
Skin-lightening agent in skin creams, lotions, soaps, products Cosmetic [91]
UV protector Cosmetic [92]
Decrease the appearance of scars Cosmetic [93]
Anti-aging effect Cosmetic [94]
Antidermatophytic Cosmetic [94]
Skin whitening or depigmenting agent in cosmetics Cosmetic [79]
Radical scavenging activity Cosmetic [95]
An antioxidant Food and cosmetic [79,96]
Anti-biofilm Food and medical [97]
Anti-convulsant Medical [98]
Anti- HIV Medical [98,99]
Antimicrobial Medical [97]
An inhibitor of the growth of Gram-negative bacteria Medical [100]
antiviral Medical [101]
Biocompatibility Medical [102]
Antitumor Medical [89]
Antidiabetic Medical [103,104]
Anticancer Medical [105]
Antispeck Medical [106,107]
Anti-parasite Medical [108]
Chemo sensitizer to enhance efficacy of commercial antifungal drugs or fungicides Medical [109,110]
Pain killer Medical [55,100]
Anti-proliferative Medical [111]
Antileishmanial activity against Leishmania (L.) amazonensis both in vitro and in vivo Medical [89]
Inducing the activation of murine peritoneal macrophages by increasing reactive oxygen species (ROS)
production without causing cytotoxic effects
Medical [112]
Dental care Dentistry [113]
In the preparation of novel derivatives of kojic acid Chemistry and
cosmetic
[114,115,116,117,118,119,120,121]
Adhesives between metals and organic materials Chemistry [122]
Metal-adsorbents removing contaminating metals from water or chemicals produced by metal-catalyzed
reactions
Chemistry [122]
In chelate-forming resins Chemistry [123]
A metal chelating agent Chemistry [124]
An intermediate in synthesis Chemistry [55]
The prevention of discolouration of crustacean, meat, and fresh (0.2%) vegetables at 1.0% Food [123]
As a preservative Food [125]
As an antioxidant for fats and oils Food [126]
In flavourings at 0.2% to add luster Food [123]
In flour production at 0.1% Food [107]
In syrup at 0.05% Food [123]
Pesticide and insecticide Agriculture [127,128]
As a plant growth regulating agent to increase production Agriculture [123]
Table 3
Melasma therapies using KA alone and in various combinations (Main ingredients of bleaching or depigmenting formulas for melasma and other disorders: GA
(Glycolic acid), KA (Kojic acid), HQ (Hydroquinone), and VC(vitamin C) [135–139].
Treatment formulation given patients Duration Results Reference
2% KA, 5% GA 39 patients 3 months Highly effective in reducing the pigment in melasma patients [140]
2% KA, 10% GA, 2% HQ 40 12 weeks 60% improvement [133]
KA (0.75%),
VC (2.5%),
4% HQ
60 patients 12 weeks 4% HQ and 0.75% KA + vitamin c 2.5% are effective topical hypo pigmenting agents in the treatment of
facial melasma
[141]
1% KA
2% HQ
80 patients 12weeks 71.87 %
improvement
[142]
2% KA
2% HQ
50 3 months HQ was more suitable than KA for the treatment of melasma [143]
4% KA
2% HQ
100 women three month KA 4% was found to be more suitable in the treatment of melasma [144]
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587

common hyper pigmentation skin problem on the face which generally
happens in women. One of the most common treatments for melasma is
long-term treatment with topical agents that are used alone, or in
combinations. KA (5-hydroxy-2-hydroxymethyl-4-pyrone) is usually
combined with other agents at a concentration of 1–4% for its skin-
lightening property. The mechanism of its effect might be due to re-
ducing melanin formation in melanocytes by tyrosinase inhibition
[133].Several studies suggested the use of KA with other drugs in
melasma (Table 3). Combination of KA with other agents was also
found to be better than the monotherapy. KA combined with Hydro-
quinone (HQ) 2% showed significantly better results compared with
other formulations. In summary, efficacy of KA in melasma therapies is
yet to be understood due to lack of studies with standard drugs used in
melasma. More detailed and extensive studies on KA remain a necessity
[134].
8. Characteristics and applications of KA in cosmetic and
pharmaceutical preparations
The most important applications of KA are as follows:
a Bleaching properties and skin protection in contrast to ultraviolet
light in cosmetic products
b Dental care products
In some studies, melanogenic inhibitory properties of KA has been
proven in vitro. Due to the carcinogenicity of HQ and its prohibition in
Asia, the FDA has introduced KA as an alternative for HQ. Recently,
chelates of KA and manganese and zinc metals have been introduced as
protective agents against gamma and radio rays [14,15,37,145]. In
many studies, various derivatives of KA such as KA ester, KA laureate,
KA dipalmitate and, KA ethyl phosphonate with aldehyde have been
reported to be more effective than KA [145,146]. A schematic of cos-
metic applications of KA is shown in Fig.7. Moreover, due to the pre-
sence of a pyron ring in the structure of KA, it is used to assess iron in
mineral stones. KA metal chelates are used in controlled release in drug
delivery and catalysts.
Several studies have reported that KA acts as an antibiotic against
human tubercle bacilli,gram-negative and gram-positive microorganisms in
in vitro. In addition, the derivatives of KA called azidometalkojates are
reported to act as antifungal and antibacterial agents on several species
of Bacillus,Staphylococcus,Saccharomyces,Aspergillus,Rhizopus, and
Fusarium [147,148]. Also, zinc derivatives of azidometalkojates have
cytotoxic activity on the hella tumor cells. In addition, other derivatives
of KA act as antifungal agent on several species of Phythium graminicola,
Fusarium oxysporum, and Rhizoctonia solani. In other studies, insecticidal
properties of KA has been shown on Heliothis zea,Spodoptera frugiperda,
Musca domestica, and Drosophila melanogaster insects. It also causes
sterility in male and female species [149–153].
KA and its derivatives have become increasingly important due to
various biological activities, including antimicrobial and antiviral
[101], antitumor [154], antidiabetic [103], anticancer [105], anti-
speck [107], anti-parasitic [108], and pesticidal and insecticidal ac-
tivities [155]. In addition, KA and its derivatives are used as anti-oxi-
dant, anti-proliferative, anti-inflammatory, radio protective and skin-
lightening agent in drug and cosmetic products, due to their tyrosinase
inhibitory activity [37,156–158]. Furthermore, KA could be developed
as a chemo sensitizer to enhance efficacy of commercial antifungal
drugs or fungicides [109].
Potential application of KA and its derivatives has been studied in
veterinary medicine, cosmetic and chemical industry (Table 4–6).
[79,80,147,148,150,152,153,159–185].
9. Safety assessment of KA in cosmetics
Several studies are performed to evaluate the mechanisms of de-
pigmentation and safety of KA [193]. They suggested that the best
range of concentrations for KA topical preparation is 1% or less because
in these ranges, KA melts show effective and safe properties. Clinical
studies have shown effectiveness of 1% KA cream therapy for 6 months
in photo-hypersensitive melasma patients [193,194]. High epidermal
diffusion of KA significantly decreased its remaining in viable epi-
dermis. The absorption was modified by altering the topical preparation
base. Melasma patients who had used 1% KA cream were followed for 2
years and no significant side effect or adverse reaction was observed.
Nowadays, new depigmentation agents such as KA are known as com-
mercial cosmeceutical products and other compounds may be offered in
the future [83,195,196].
Fig. 7. Schematic diagram of cosmetic applications of KA.
Table 4
Antifungal Activities of KA.
Properties Antifungal
drugs or fungicides
Species Disease or
Infections
References
Antifungal and anti-parasite activities KA Pathogenic yeasts and
Filamentous fungi
Human invasive aspergillosis [109]
Acrylate monomers
based on KA
Candida kefyr Candida infections-
Nosocomial Bloodstream Infections
[186]
Chloro KA derivatives Candida albicans
C. parapsilosis
Invasive and non-invasive fungal infections [101]
Amino Acid and Peptide Derivatives of KA Pythium graminicola, Fusarium
Oxysporum,Rhizoctonia solani
Seedling
blight, fusarium wilt and sheath blight,
[187]
KA derivatives Dermatophytic
fungi
Skin disease [188]
KA L. amazonensis Leishmaniasis [108]
Chitosan oligosaccharide/ KA grafts Aspergillus niger
Saccharomyces cerevisiae
Aspergillosis
Crohn's disease
food-borne diseases
[189]
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
588

KA is found to be rapidly absorbed and distributed in oral admin-
istration in rats; but, its transdermal administration showed that KA is
slowly absorbed and distributed [79]. In other studies, tyrosinase in-
hibitory activity was evaluated and KA was seen to have a tyrosinase
inhibitory effect in positive control tests [30–36]. In some researches,
KA 1 and 2% not show any allergenic or ocular sensitivity [197–199].
The International Agency for research on cancer introduced KA as a
group 3 carcinogen [200–202] based on in vivo studies on genetic
toxicity of mammals [203–210]. Also, the FDA has not approved KA for
use in pharmaceutical products without prescription, but European
Commission's Scientific Committee has announced that:
1 The dose of KA should be 1% in the formulation of skin care.
2 KA is not a toxicant in acute, chronic, generative, and genotoxicity
form [79,211–215].
10. Effectiveness and risks of KA as a lightening agent
The lightening effect on visible sun damages, age spots, or scars that
lead to anti-aging outcomes on the skin are the main therapeutic effect
of KA. It is also safe to be used in cosmetics in concentration of 1%
according to the Cosmetic Ingredient Review Expert Panel (CIREP).
Besides, KA has exhibited antimicrobial properties that can eradicate
some common types of bacterial strains (E.g. acne caused bacteria) even
in small dilutions. Studies also have shown that KA has potentially
antifungal effect. Furthermore, the treating of yeast infections, candi-
diasis, and ringworm have been reported too.
Some adverse reactions and disadvantages are associated with KA in
cosmetic application. Contact dermatitis (especially for sensitive skins)
is the main side effect of KA which is accompanied by irritation, rashes,
inflamed skin, itchiness, and pain. These side effects can be observed
with a higher concentration more than 1% of KA. Another adverse re-
action may appear in long-term use of KA, such as sunburn in sensitive
skin. KA could also result in skin cancer on damaged skins. But, further
studies are needed to identify other potential benefits or risks of KA.
Table 7. shows some main applications and risks of KA as a lightening
agent.
11. New applications of KA
Different types of technology including various nanoparticles such
as polymeric micelles, noisome, dendrimers, liposomes, carbon nano-
tubes, and metal-based nanoparticles are being effectively used in drug
delivery systems. Nanoparticles coated with polymers have been ap-
plied in different biomedical fields. Biocompatible compounds for drug
delivery systems can also provide the potential to develop new medi-
cines aiming at increased bio-availability, biocompatibility, biode-
gradability, lower toxicity, higher efficiency, and controlled release. KA
products have been studied in combination with polymeric nano-
particles and liposomes. Recently, KA liposomal nano carriers’delivery
system were designed to enhance the chemotherapeutic efficacy in
tumor cell line. Despite its wide benefits, there are some challenges,
including fast elimination by the reticuloendothelial system, toxicity,
and inflammation of delivery systems [8,222]. In Nano chemical
Table 5
Some commercial applications of KA as an antimicrobial agent.
Properties Compounds Species of bacteria References
Anti
bacterial activities
Acrylate monomers based on KA Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella typhi [186]
KA crystals Proteus, Staphylococcus, Streptococcus, Pseudomonas, Bacillus, Corynebacterium, Clostridium,
Aerobacter, Escherichia,Klebsiella,
Salmonella
[190]
Natural KA Pseudmonas aeuroginosa; E. coli, Proteus vulgaris
Staphylococcus aureus; Streptococcus
pneumoniae, Bacillus subtilis
[191]
Metal Chelation of KA analogs S. aureus, E. coli and Ps. fluorescens [161]
Natural KA S. typhimurium, E. coli [80]
Chitosan oligosaccharide/ KA grafts Staphylococcus aureus, Escherichia coli [189]
Table 6
Anticancer and Anti proliferative activity of KA.
Properties Compounds Function Type of cancer cell References
Anticancer activities Pyrone-derived ligands from KA Inhibit dimer formation,
sufficient stability in aqueous solution.
Metastatic tumor cell lines [192]
Selenocyanatomethyl derivatives of
KA
Induce cellular biological changes, act as an
immunomodulatory agent, modulatory action on human
monocytes
Human skin carcinoma (A431) and
human breast carcinoma (MCF7) cells
[89]
KA derivatives,
including RHS-0110
Anti-inflammatory,
anti-proliferative,
anti-oxidative, modulate glioma cell proliferation
and Toll-like receptor
Brain
tumors C6 glioma and SYF cells
.
[105]
KA Anti-proliferative activity Breast cancer cell line, MDA MB435S
cell lines
(Breast cancer)
[190]
KA ATPase, protein binding
anti-apoptosis, hetero dimerization activity
A375 human malignant melanoma
cells
[154]
Table 7
Some main benefits and risks of KA as a lightening agent.
Advantages Lighten effect on visible sun damages, age spots [56]
Anti-aging outcomes [216]
Antimicrobial possessions [125]
Antifungal belongings [217]
Anti-acne properties [218]
Beneficial in treating yeast infections, candidiasis, and ringworm
[219]
Disadvantages Contact dermatitis (especially in sensitive skins) [220]
Long-term use of KA may make skin more susceptible to sunburn
[221]
Using KA on damaged or broken skins can result in cancer
[105,172]
M. Saeedi et al. Biomedicine & Pharmacotherapy 110 (2019) 582–593
589

promotion, liposomes are used as a minute capsule having a particle
size of 100 nm because of its superior biocompatibility and biode-
gradability. It seems to be an ideal DDS in skin and cells. The efficiency
of drug delivery is influenced by the interaction between cell and li-
posome [223–225]. The penetration of kA through skin is found to
improve using HTCC-coating liposomes. The aim of this protocol was to
improve the efficiency of fusion of liposome with cell membrane in
order to increase the absorption of drug [226].
Researchers are trying to improve the disadvantages and challenges
of this system by developing biocompatible products and bio ther-
apeutics. Drug discovery and drug delivery nanoparticles not only in-
crease the effectiveness of active compounds but also improve infection
control, particularly when organisms show multidrug resistant. Coated
magnetic nanoparticles loaded with anticancer drugs such as bio-
compatible product can localize and reduce tumor cells with low side
effects. KA is a poly functional compound without any hazardous side
effects that approve the development of biologically natural compounds
and pharmaceuticals. KA-coated liposome could be used in drug de-
livery in melanoma to its higher fusion ability with cell membrane, high
water solubility and lower toxicity. These liposomal nano carriers can
be applicable for transdermal drug delivery, cancer chemotherapy, and
gene delivery [226,227]. Further researches are suggested to focus on
application of drug-delivery systems with bio therapeutics that include
delivery of several types of nucleic acids such as plasmids, nucleotides
or RNA, antibody–drug conjugates and combination of KA derivate and
liposome, to develop new type of nano carriers for drug delivery in the
future.
12. Conclusion
Generally, KA is popular for its applications in various purposes
such as pharmaceuticals, cosmetics, agriculture, food, and chemical
industry. The most significant advantage of KA is its wide applications
in cosmetics and medical industry. It acts as a brightening ingredient in
whitening creams, skin lotions, and bleaching soaps, and also in dental
and medical care products. In conclusion, and today with massive
growth in this industry, its supply and demand is increasing con-
siderably. Therefore, more clinical studies are needed for designing and
developing new products based on KA.
Acknowledgements
This study is a research project and involves receiving a research
score with approval number 86, supported by Student Research
Committee of the Mazandaran University of Medical Sciences.
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