Comprehensive review of the skin use of bakuchiol: physicochemical properties, sources, bioactivities, nanotechnology delivery systems, regulatory and toxicological concerns

Abstract

Bakuchiol is a meroterpene that has recently aroused great interest in the cosmetic and pharmaceutical industries. Its main source is the seeds of Psoralea corylifolia, a medicinal plant native to Asia, despite having a wide geographical distribution. However, this medicinal herb faces endangerment due to low seed germination rates and high seedling mortality. In this context, this review article highlights studies that have focused on describing plant regeneration from root fragments. Subsequently, given its morphological similarity to other species, a technique that can be used to verify the authenticity of the plant and prevent counterfeiting is also mentioned and explored. Additionally, a “green” extraction method for obtaining bakuchiol is presented, and the possibility of obtaining bakuchiol through chemical synthesis routes is also explored. Furthermore, we provide an exhaustive description of bakuchiol's wide range of biological activities, with particular relevance to the skin. The main skin bioactivities of bakuchiol include antifungal, antibacterial, antioxidant, anti-inflammatory, antiaging, depigmenting, and anticancer. However, the particular physicochemical properties of bakuchiol require and benefit from the development of innovative skin delivery systems that allow its encapsulation. These include micro- and nano-sized systems for therapeutic and cosmetic applications, which are also carefully described in this review article. Finally, regulatory issues, metabolic considerations, and toxicological concerns related to the use of bakuchiol in cosmetic and dermopharmaceutical formulations will be addressed, relating not only to the user but also to the environment.

Graphical abstract

Full text

Comprehensive review of the skin use of bakuchiol:
physicochemical properties, sources, bioactivities,
nanotechnology delivery systems, regulatory
and toxicological concerns
Filipa Mascarenhas-Melo .Mariana Marques Ribeiro .Kaveh Hatami Kahkesh .
Sagarika Parida .Kiran D. Pawar .K. Velsankar .Niraj Kumar Jha .
Fouad Damiri .Gustavo Costa .Francisco Veiga .Ana Cla
´udia Paiva-Santos
Received: 25 May 2023 / Accepted: 28 January 2024 / Published online: 1 March 2024
ÓThe Author(s) 2024
Abstract Bakuchiol is a meroterpene that has
recently aroused great interest in the cosmetic and
pharmaceutical industries. Its main source is the seeds
of Psoralea corylifolia, a medicinal plant native to
Asia, despite having a wide geographical distribution.
However, this medicinal herb faces endangerment due
to low seed germination rates and high seedling
mortality. In this context, this review article highlights
studies that have focused on describing plant regen-
eration from root fragments. Subsequently, given its
morphological similarity to other species, a technique
that can be used to verify the authenticity of the plant
and prevent counterfeiting is also mentioned and
explored. Additionally, a ‘‘green’’ extraction method
for obtaining bakuchiol is presented, and the possibil-
ity of obtaining bakuchiol through chemical synthesis
routes is also explored. Furthermore, we provide an
exhaustive description of bakuchiol’s wide range of
biological activities, with particular relevance to the
skin. The main skin bioactivities of bakuchiol include
antifungal, antibacterial, antioxidant, anti-inflamma-
tory, antiaging, depigmenting, and anticancer. How-
ever, the particular physicochemical properties of
bakuchiol require and benefit from the development of
innovative skin delivery systems that allow its encap-
sulation. These include micro- and nano-sized systems
for therapeutic and cosmetic applications, which are
also carefully described in this review article. Finally,
regulatory issues, metabolic considerations, and tox-
icological concerns related to the use of bakuchiol in
cosmetic and dermopharmaceutical formulations will
be addressed, relating not only to the user but also to
the environment.
F. Mascarenhas-Melo (&)F. Veiga 
A. C. Paiva-Santos
REQUIMTE/LAQV, Group of Pharmaceutical
Technology, Faculty of Pharmacy, University of Coimbra,
Po
´lo das Cie
ˆncias da Sau
´de, Azinhaga de Santa Comba,
3000-548 Coimbra, Portugal
e-mail: filipamelo@ff.uc.pt
F. Veiga
e-mail: fveiga@ff.uc.pt
F. Mascarenhas-Melo
Higher School of Health, Polytechnic Institute of Guarda,
Rua da Cadeia, 6300 – 307 Guarda, Portugal
M. M. Ribeiro F. Veiga A. C. Paiva-Santos (&)
Drug Development and Technology Laboratory, Faculty
of Pharmacy of the University of Coimbra, University of
Coimbra, Po
´lo das Cie
ˆncias da Sau
´de, Azinhaga de Santa
Comba, 3000-548 Coimbra, Portugal
e-mail: acsantos@ff.uc.pt
M. M. Ribeiro
e-mail: marianasmribeiro99@gmail.com
K. H. Kahkesh
Department of Basic Medical Science, Faculty of
Veterinary Medicine, Shahrekord University, Shahrekord,
Iran
e-mail: kavehhatamikahkesh@gmail.com
123
Phytochem Rev (2024) 23:1377–1413
https://doi.org/10.1007/s11101-024-09926-y(0123456789().,-volV)(0123456789().,-volV)
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Graphical abstract
Keywords Bakuchiol Delivery system 
Nanotechnology Regulatory Skin bioactivity 
Toxicology
Abbreviations
AQP3 Aquaporin 3
BAK Bakuchiol
b-CD b-Cyclodextrin
b-
CDNS
b-Cyclodextrin-based nanosponge
BGM Bakuchiol, Ginkgo biloba extract, and
mannitol
BO Babchi essential oil
BOMS Babchi essential oil in microsponge
BONS Babchi essential oil in nanosponge
CLL Collagen
DEJ Dermal-epidermal junction
EC Ethyl cellulose
S. Parida
Department of Botany, School of Applied Sciences,
Centurion University of Technology and Management,
Bhubaneswar, Odisha 752050, India
e-mail: sagarika.parida@cutm.ac.in
K. D. Pawar
School of Nanoscience and Biotechnology, Shivaji
University, Kolhapur, Maharashtra, India
e-mail: kdp.snst@unishivaji.ac.in
K. Velsankar
Department of Plant Pathology, Agricultural College,
Guizhou University, Guiyang 550025, People’s Republic
of China
e-mail: velsankark@gmail.com
N. K. Jha
Centre for Global Health Research, Saveetha Medical
College, Saveetha Institute of Medical and Technical
Sciences, Saveetha University, Chennai, India
e-mail: nirajkumarjha2011@gmail.com
N. K. Jha
Centre of Research Impact and Outreach, Chitkara
University Institute of Engineering and Technology,
Chitkara University, Punjab, India
N. K. Jha
School of Bioengineering & Biosciences, Lovely
Professional University, Phagwara 144411, India
F. Damiri
Laboratory of Analytical and Molecular Chemistry
(LCAM), University Hassan II of Casablanca,
20000 Casablanca, Morocco
e-mail: fouad.damiri@outlook.fr
F. Damiri
Chemical Science and Engineering Research Team
(ERSIC), Polydisciplinary Faculty of Beni Mellal
(FPBM), University Sultan Moulay Slimane (USMS),
Beni Mellal, Morocco
G. Costa
Coimbra Institute for Clinical and Biomedical Research
(iCBR), Faculty of Medicine; CNC.IBILI Consortium and
CIBB Consortium, University of Coimbra, Coimbra,
Portugal
e-mail: costagff@gmail.com
123
1378 Phytochem Rev (2024) 23:1377–1413
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ECM Extracellular matrix
EMA European Medicines Agency
FDA Food and Drug Administration
GAG Glycosaminoglycan
GC-MS Gas chromatography-mass spectrometry
HDF Human dermal fibroblast
IL-8 Interleukin-8
iNOS Inducible nitric oxide synthase
LPS Lipopolysaccharide
MIF Macrophage migration inhibitory factor
MMP Matrix metalloproteinase
MRSA Methicillin-resistant Staphylococcus
aureus
MS Microsponge
NF-kB Nuclear transcription factor-Kb
NO Nitric oxide
NS Nanosponge
PGE
2
Prostaglandin E
2
POFR Phenolic oxygen free radical
PVA Polyvinyl alcohol
RET Retinol
ROS Reactive oxygen species
SC Stratum corneum
TDNA Percentage of fragmented DNA
TMOM Tail moment
UV Ultraviolet
Introduction
Plant-derived products have been widely used for
many years, thanks to their cost-effectiveness and easy
accessibility. Psoralea corylifolia is a widely recog-
nized plant, particularly among Chinese and Indian
populations, owing to its natural geographic distribu-
tion. Given the decades of ethnobotanical use and its
diverse chemical composition, several properties have
been ascribed to P. corylifolia, encompassing estro-
genic, antidepressant, hepatoprotective, immunomod-
ulatory, osteoblastic, neuroprotective, and pesticidal
activities (Alam et al. 2018; Chopra et al. 2013; Koul
et al. 2019; Li et al. 2016b). It is the source of more
than a hundred compounds (Alam et al. 2018;
Khushboo et al. 2010; Koul et al. 2019; Li et al.
2016b). Among these compounds, the renowned
psoralen stands out, and it has been employed in the
treatment of psoriasis since the 1970s (Reid and
Griffiths 2020). Bakuchiol (BAK) is also considered
one of its main compounds (Chaudhuri and Boja-
nowski 2014; Chen et al. 2012; Cui et al. 2015;
Ferra
´ndiz et al. 1996; Jafernik et al. 2021; Madrid et al.
2015; Majeed et al. 2012; Zhuang et al. 2013). From a
chemical standpoint, it has an aromatic ring and a long
hydrocarbon chain which negatively influences its
water solubility, a relevant aspect for its practical
application in carrier systems (Adarsh Krishna et al.
2022). In addition, the BAK molecule has other
specific physicochemical properties responsible for its
main biological activities.
Over the years, various extraction methods have
been described, with one notable approach being an
‘‘environmentally friendly’’ technique utilizing super-
critical extraction to acquire BAK (Lewin
´ska et al.
2021). Extracting plant-derived products can be a
challenge due to the large number of active com-
pounds present. Frequently, plant extraction and
isolation methods yield low quantities of the desired
substances. In these cases, chemical synthesis can be
used as an alternative. Despite certain challenging
steps, several scientists have reported diverse syn-
thetic chemical pathways for BAK (Lystvan et al.
2010).
The organisms constituting the skin‘s microbiota,
known as commensal organisms, play a crucial role in
maintaining homeostasis and contribute to reinforcing
the skin‘s immune capacity (Byrd et al. 2018; Parlet
et al. 2019). Disturbances in the commensal balance
can lead to the overgrowth of fungal and bacterial
species. Several in vivo and in vitro studies have
confirmed the effectiveness of BAK in addressing
these disorders (Cui et al. 2015; Hsu et al. 2009; Lau
et al. 2010,2014; Parlet et al. 2019; Pfaller et al. 2006).
Staphylococcus aureus, an opportunistic pathogen, is
implicated in the majority of acute and chronic
bacterial skin infections. It is estimated that approx-
imately 20 to 30% of healthy adults carry S. aureus
asymptomatically. Moreover, about 76% of skin
infections are attributed to S. aureus (Parlet et al.
2019). In the face of increasing antibiotic resistance,
the antibacterial properties of BAK become especially
valuable (Pola
´kova
´et al. 2015).
Furthermore, the antioxidant and anti-inflammatory
properties can be beneficial in slowing down the
natural aging process (Bluemke et al. 2022; Heidari
et al. 2022; Zafar et al. 2022). Free radicals are
naturally produced during biological processes
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Phytochem Rev (2024) 23:1377–1413 1379
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(Surveswaran et al. 2007). Acute overexposure to solar
radiation can lead to sunburn, while chronic exposure
may induce skin changes such as wrinkle formation,
plaque-like thickening, deep furrowing, and a reduc-
tion in skin tone. This condition, commonly referred to
as ‘‘photoaged skin’’ or ‘‘solar scar’’, has a particularly
negative effect due to the generation of reactive
oxygen species (ROS) associated with cellular oxida-
tive damage (Fayad et al. 2017) in DNA, lipids, and
proteins, ultimately resulting in a decline in cell
viability (Cadet and Wagner 2013; Lau et al. 2014;
Slimen et al. 2014). Human exposure to factors such as
allergens, microbes, and pollutants contributes to an
increased generation of ROS. Maintaining a balance in
oxidation-antioxidation processes, along with the
presence of systems that monitor the formation of
these radicals and facilitate their elimination, is crucial
(Bouayed and Bohn 2010; Surveswaran et al. 2007).
In the human body, macrophages play a crucial role
in the innate immune response, exhibiting
immunomodulatory properties essential for inflamma-
tory response and immune surveillance. Activation of
macrophages, typically induced by lipopolysaccha-
rides (LPSs), initiates the activation of transcription
factors, such as mitogen-activated protein kinase,
nuclear transcription factor-kB (NF-kB), and the
secretion of cytokines and proinflammatory media-
tors, including nitric oxide (NO), prostaglandin E
2
(PGE
2
), tumor necrosis factor a, interleukin-1b, and
interleukin-6 (Mitra et al. 2022; Qin et al. 2022;
Taciak et al. 2018). Blood-circulating monocytes
serve as the primary source of skin macrophages,
undergoing tissue maturation and differentiation,
although they are not found in the epidermis (Kashem
et al. 2017; Pae et al. 2001). Macrophages may act as
inflammatory mediators in certain inflammatory skin
diseases, such as atopic dermatitis (Eichenfield et al.
2014; Weidinger and Novak 2016) and psoriasis
(Deng et al. 2016), making them attractive targets for
therapeutic interventions aimed at suppressing inap-
propriate or excessive activation (Chen et al. 2017). In
this context, several studies have been conducted to
demonstrate the anti-inflammatory capacity associ-
ated with BAK.
Among skin cancers, melanoma stands out as one
of the most lethal and invasive types. Once it reaches
the metastatic stage, its control becomes challenging,
often leading to high mortality rates due to a limited
response to treatment. The difficulty in obtaining
effective anticancer therapy sometimes results in
inadequate targeting, resulting in a cytotoxic effect
on normal cells. Early diagnosis substantially
enhances the prospects of successful treatment
(Madrid et al. 2015; Movagharnezhad et al. 2022;
Raza et al. 2022). The constant need to search for
novel molecules provided the opportunity to discover
more about BAK and its potential anticancer proper-
ties. As the largest organ in the human body, the skin
serves as an excellent avenue for drug delivery.
However, molecules with low penetration capacity
often require modifications to facilitate this delivery
(Lewin
´ska et al. 2021). Particle size reduction is one of
the strategies. Micro and nanosponges formulations,
as well as nanoemulsions, offer solutions to overcome
limiting characteristics such as volatility, hydropho-
bicity, and viscosity. Additionally, these formulations
enhance physical stability and extend the release time
of the drug, enabling dose reduction and minimizing
side effects (Kumar et al. 2018; Lewin
´ska et al. 2021;
Wadhwa et al. 2019).
Regulatory issues play a pivotal role in ensuring the
safe use of nanosystems. Regulatory organizations
must clarify specific regulations related to the manu-
facturing process, determination of pharmacodynamic
and pharmacokinetic profiles, and evaluation of tox-
icological profiles. This is crucial to ensure the
efficiency and safety of these nanoformulations,
thereby securing sustained approval for their market
availability (Mascarenhas-Melo et al. 2022).
Physicochemical properties of bakuchiol
BAK’s unique chemical composition, structure and
molecular arrangement give rise to numerous biolog-
ical activities (Nazir et al. 2021). Its chemical structure
comprises phenolic and terpenoid components, clas-
sifying BAK as a meroterpene phenol. The chemical
skeleton consists of an aromatic ring with a hydroxyl
group and, at the para position, an unsaturated long
hydrocarbon chain containing three alkenes and one
all-carbon (tetra-alkylated) quaternary stereocenter
(Adarsh Krishna et al. 2022). BAK possesses an
asymmetric stereocenter and its absolute configuration
has been shown to exhibit (S)-chirality (as illustrated
in Fig. 1).
Table 1summarizes the physicochemical proper-
ties of BAK. Due to its long hydrophobic chain, BAK
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has low aqueous solubility and poor bioavailability.
Additionally, BAK undergoes a significant degree of
first-pass metabolism, due to its easy formation of
covalent bonds with endogenous molecules such as
glycine and glucuronic acid through the phenolic
hydroxyl group (Adarsh Krishna et al. 2022; Li et al.
2021).
Sources of bakuchiol
Natural sources
BAK exhibits structural and chemical diversity. In
plants, it is synthesized through a mixed pathway that
combines amino acids and isoprene. This synthesis
leads to molecular chemical variations in terms of
stereocenters and different functional groups con-
tributing to its various biological activities (Adarsh
Krishna et al. 2022). Since 1977, efforts have been
undertaken to understand the biosynthetic pathways
responsible for BAK production. Notable research
groups, such as those led by Banerji and Chintalwar, as
well as Risinger et al., have contributed significantly to
understanding the natural formation of BAK (Banerji
and Chintalwar 1983,1984; Risinger et al. 1978). In a
1978 study, Risinger et al.proposed novel biosynthetic
pathways for irregular terpenes, including BAK,
suggesting a pivotal role for 2-(1-hydroxy-2-pheny-
lethyl) thiamine as the intermediary in their formation
(Risinger et al. 1978). In 1983, Banerji and Chintalwar
reported the synthesis pathway of BAK in P. coryli-
folia. They used mevalonic acid and phenylalanine as
substrates, demonstrating that BAK has a mixed
origin, derived from two isoprenoid units and one
phenylpropane (with the loss of the carboxyl carbon)
(Banerji and Chintalwar 1983). Subsequently, the
same researchers highlighted L-phenylalanine as the
preferred precursor over L-tyrosine in BAK biosyn-
thesis, proposing that BAK originates from pheny-
lalanine through p-coumaric and cinnamic acids
(Banerji and Chintalwar 1984). These findings laid
the foundations for recent studies, suggesting that
BAK belongs to a distinct group of rare terpenoids,
with its aromatic ring derived from the phenylpropane
pathway. This phenolic compound has a carbon side
chain (monoterpene chain) derived from the meval-
onate pathway (Adarsh Krishna et al. 2022; Chaudhuri
and Bojanowski 2014). Figure 1schematically repre-
sents one of the described biosynthesis pathways. This
mixed pathway starts with phenylalanine and leads to
p-coumaric acid. Simultaneously, the reaction
between acetyl CoA and acetoacetyl CoA produces
geranyl pyrophosphate. Finally, the interaction of
these two compounds results in the formation of BAK.
While BAK is typically associated with Psoralea
corylifolia, it has also been extracted from various
other species. Examples include Pimelea drupacea
(Lystvan et al. 2010), Psoralidium tenuiflorum (Hsu
et al. 2009), Prosopis glandulosa (Backhouse et al.
2001; Labbe
´et al. 1996), Piper longum (Ohno et al.
2010), Aerva sangulnolenta (Jafernik et al. 2021),
Otholobium pubescens (Krenisky et al. 1999), Ulmus
davidiana (Choi et al. 2010; Lee et al. 2021).
The first isolation of BAK occurred in 1973 by
Mehta et al.from P. corylifolia seeds (Damodaran and
Dev 1967). P. corylifolia is recognized as the primary
source of BAK (Jafernik et al. 2021) and it is also
recognized as a synonym of Cullen corylifolium (L.)
Medik (Jafernik et al. 2021; Kim et al. 2018; Liu et al.
2021; Ren et al. 2020; Sharifi-Rad et al. 2020).
Table 2provides an overview of some extraction
methods described for obtaining BAK from natural
sources.
Fig. 1 Biosynthesis of bakuchiol and its molecular structure
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Table 1 Physicochemical properties of bakuchiol
Physicochemical properties References
Molecular
formula
C
18
H
24
O (Adarsh Krishna et al. 2022; Hsu et al. 2009; NCBI 2022; Takao
et al. 2012)
Chemical name 4-[(1E,3S)-3-ethenyl-3,7-dimethylocta-1,6-dien-1-
yl] phenol
(ECHA 2022a; Madrid et al. 2012; NCBI 2022)
CAS 10,309–37-2 (NCBI 2022)
Molecular
weight
256.38 g mol
-1
(Alalaiwe et al. 2018; Hsu et al. 2009; Husain et al. 2018;
Jiangning et al. 2005; NCBI 2022; Takao et al. 2012)
Molecular
volume
238.38 cm
3
. mol
-1
(Alalaiwe et al. 2018)
Organoleptic
characteristics
A
Pale yellow oil
Viscous liquid. Brownish-yellow, odor characteristic
of aromatic compounds
(Adarsh Krishna et al. 2022; Alalaiwe et al. 2018; Hsu et al. 2009;
Jiangning et al. 2005; Madrid et al. 2012; Takao et al. 2012;Xu
et al. 2013)
(ECHA 2022b)
Boiling point
B
[260 8C (ECHA 2022c)
Flash point
C
184 8C (ECHA 2022d)
Partition
coefficient
D
5.09 (octanol–water) (ECHA 2022e)
Explosiveness No exothermic decomposition peak was observed up
to 430 °C, the test item is considered to be
nonexplosive
(ECHA 2022f)
Solubility in 20%
PEG400
0.02 mM (Alalaiwe et al. 2018)
Water solubility
E
Slightly soluble (0.1–100 mg/L) (ECHA 2022g)
Density
F
0.969 g/cm
3
(ECHA 2022h)
Rotatable bond 6 (Adarsh Krishna et al. 2022; Husain et al. 2018; NCBI 2022)
Bioavailability
score
0,55 (Husain et al. 2018)
Maximum
absorption UV
262 nm (Hsu et al. 2009; Jiangning et al. 2005)
Optical rotation
G
?37.28(Hsu et al. 2009)
iLog P
H
3.54 (Adarsh Krishna et al. 2022; Husain et al. 2018)
Alog P
I
5,35 (Alalaiwe et al. 2018)
Log K
J
0,73 (Alalaiwe et al. 2018)
Molar
Refractivity
84.10 (Adarsh Krishna et al. 2022)
Polar Surface
Area
20.23 A
˚
2
(Alalaiwe et al. 2018; NCBI 2022)
Surface tension
K
43.92 mN/m (ECHA 2022i)
Hydrogen bond
accept number
1 (Adarsh Krishna et al. 2022; Alalaiwe et al. 2018; Husain et al.
2018; NCBI 2022)
Hydrogen bond
donor number
1 (Adarsh Krishna et al. 2022; Alalaiwe et al. 2018; Husain et al.
2018; NCBI 2022)
A
Organoleptic characteristics, determined at 208C.
B
Boiling point, determined at 300 mm Hg atmospheric pressure.
C
Flash point,
determined at 760 mm Hg atmospheric pressure.
D
Partition coefficient (log Pow), determined at 20 °C, 6.31 pH, by HPLC.
E
Water
solubility, determined at 20 °C, 5 pH.
F
Density, determined at 20 °C.
G
Optical rotation, [a]
30D
=?37.2°, exhibited by ( ?)-BAK.
H
iLog P is the n-octanol/water partition coefficient, accepted as a measure of the lipophilicity of a substance.
I
Alog P is the partition
coefficient, determined by molecular modeling.
J
Log K is the logarithm of t
r
-t
0
, where tr is the retention time of the compost peak and
t
0
is the retention time of the solvent peak.
K
Surface tension, determined at 20 °C (1 g/L)
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Table 2 Main extraction methods for obtaining BAK from natural sources
Plant material Extraction method Extraction conditions References
Psoralidium
tenuiflorum
(whole plants)
Ethyl acetate extraction The sample was extracted with ethyl acetate and dried (rotary
evaporation)
The ethyl acetate extract was partitioned between hexane and aqueous
methanol
The methanol fraction was diluted with water and subsequently
extracted with dichloromethane
Evaporation of solvents yielded two fractions: bioactive
dichloromethane and methanol fractions, and an inactive hexane
fraction
Bioactive fractions were combined, chromatographed, and eluted with
increasing quantities of methanol in water
Bioactive fractions were combined, chromatographed, and eluted with
increasing amounts of ethyl acetate in hexane
The most active ethyl acetate fraction was subjected to reverse-phase
PTLC with aqueous methanol
(Hsu et al.
2009)
P. corylifolia
(fruits)
Ethanol extraction The sample was extracted with 95% ethanol under reflux and
evaporated to dryness
The ethanolic extract was sequentially partitioned with n-hexane,
dichloromethane, ethyl acetate, and n-butanol
The hexane fraction was subjected to chromatography and eluted with a
mixture of hexane and ethyl acetate (9:1), followed by elution with
methanol and water (7:3)
(Lau et al.
2010)
P. corylifolia
(fruits)
Ultrasound-assisted
extraction
The sample was mixed with an extraction solvent (methanol and
concentrated hydrochloric acid (5:1))
Ultrasound extraction was carried out at 20 °C for 45 min
The mixture was left at room temperature for 30 min
The extract was centrifuged at 3000 g for 20 min
The supernatant was collected, diluted with the extraction solvent, and
stored in a refrigerator at 4 °C
(Chen et al.
2012)
P. glandulosa
(aerial parts)
Dichloromethane
extraction
The sample was immersed in dichloromethane for 30 s at room
temperature
The filtered solution was concentrated under reduced pressure
The resin extract was subjected to chromatography and eluted with a
mixture of ethyl acetate and hexane
(Madrid
et al.
2012)
P. corylifolia
(fruits)
n-hexane, ethyl acetate,
and methanol extraction
The sample was successively extracted with n-hexane, ethyl acetate,
and methanol
The ethyl acetate extract was subjected to chromatography and
purification by HPLC and TLC
(Cui et al.
2015)
P. corylifolia
L(fruits)
Methanol extraction The sample was extracted with methanol for 3 days
The extract was concentrated under reduced pressure at 35 °C
The residue was partitioned between ethyl acetate and water (1:1)
The ethyl acetate-soluble fraction was subjected to several
chromatographs, eluted with a mixture of ethyl acetate and hexane
and purified by preparative TLC
(Chen et al.
2017)
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Regeneration and authenticity of P. corylifolia,
and extraction and detection of bakuchiol
Despite being a valuable source of constituents such as
BAK, P. corylifolia faces the threat of endangerment.
Given this problem, is crucial to understand how we
can produce and conserve this species, preventing
overexploitation and mitigating the risk of extinction
(Jani et al. 2015; Koul et al. 2019). In addition, factors
including geographical location, climatic variations,
and environmental conditions introduce variability in
the chemical composition, potentially influencing its
pharmacological effects (Wu et al. 2020). Ensuring the
production of high-quality products is essential to
guaranteeing customer safety and the desired thera-
peutic effect (Heinrich 2015; WHO 2022). The use of
standardized techniques to verify the authenticity and
prevent counterfeiting becomes necessary, especially
with species like Abutilon theophrasti Medic. and
Crotalaria pallida. Despite their morphological sim-
ilarities, these species exhibit distinct characteristics
in terms of chemical composition (Wu et al. 2020).
Lewin
´ska et al.reported a new ‘‘green’’ method
with various advantages, including low extraction
temperature and short operating times. This approach
effectively reduces thermal degradation and oxygen
decomposition of bioactive compounds. Additionally,
pure CO
2
serves as an appealing solvent due to its
odorless, inert, non-toxic, and non-inflammable prop-
erties. It is cost-effective and facilitates the solubility
of hydrophobic compounds. The technique employs
the static-dynamic method, involving alternating
cycles of static extraction (10 to 15 min) and dynamic
extraction (15 to 50 min). This method enables the
extraction of a high BAK content with a lower
percentage of psoralens and isopsoralen, which typi-
cally require higher pressure and temperature values.
The highest yield, about 8.58%, was obtained with
10/20 intervals at 280 bar for 330 min. Since BAK
extraction occurs at the initial stages of the process, a
high process yield is not required to obtain a BAK-rich
extract. Therefore, the key to obtaining high BAK
contents lies in optimizing the extraction process
conditions (Lewin
´ska et al. 2021). Several separation
techniques have already been documented and,
depending on the chosen method, different com-
pounds can be extracted and isolated. Chen et al.
further explored this issue, suggesting that high-
performance liquid chromatography coupled with
electrochemical detection is the most suitable tech-
nique for the separation, identification, and quantifi-
cation of BAK due to its high sensitivity (Chen et al.
2012).
Table 3summarizes the key findings from studies
regarding the previously mentioned issues.
Table 2 continued
Plant material Extraction method Extraction conditions References
P. corylifolia
(fruits)
Ultrasound-assisted
extraction
The sample was extracted with ethanol for 30 min, filtered, and cooled
to room temperature
The extracted solution was dried, concentrated under reduced pressure
at 50 °C, and dissolved in methanol
The extract was subjected to HSCCC with a two-phase solvent system
of n-hexane–ethyl acetate–methanol-water (5:5.5:6.5:5, v/v/v/v)
(Wu et al.
2020)
P. corylifolia
(seeds)
Supercritical Fluid
Extraction
The sample was extracted at 280 bar and 40 °C with pure CO
2
at a flow
rate of 4 L NPT/min (equivalent to 3.6 g/min)
The extraction static/dynamic cycles (10 min in static mode and 20 min
in dynamic mode), total extraction duration: 330 min
The extract was stored in the dark at -20 °C
(Lewin
´ska
et al.
2021)
HPLC High-performance liquid chromatography, HSCCC High-speed countercurrent chromatography, PTLC Preparative thin layer
chromatography, TLC Thin layer chromatography
123
1384 Phytochem Rev (2024) 23:1377–1413
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Chemical synthesis
BAK can be isolated from various plant species, but it
is also obtained through chemical synthesis. Since its
discovery in 1966, several approaches to the chemical
synthesis of BAK have been explored. However, these
pathways are complex and often result in racemic
BAK ( ±) instead of the optically active ( ?)-isomer
found in nature (Lystvan et al. 2010). Total synthesis
involves achieving crucial stereochemistry and an all-
Table 3 Summary of research studies on in vitro regeneration and authenticity of P.corylifolia, and extraction and detection of
bakuchiol
Background Hypothesis Desired result Results References
P. corylifolia
regeneration
in vitro
This medicinal herb is
difficult to propagate
due to low seed
germination, and
elevated seedling
mortality
Supplement the
medium with
growth regulators:
6-
Benzylaminopurine
and Kinetin
to regenerate P.
corylifolia in vitro
from root
fragments
Obtain in vitro
high shoot
bud/explant and
elongated shoot
from root
fragments
Maximal response
(65.57%) was
observed when the
medium was
supplemented with
2.22 lM
6-Benzylaminopurine
and 6.98 lM Kinetin.
They exert a positive
synergistic effect
(Jani et al.
2015;
Koul
et al.
2019)
Prove the
authenticity of
P. corylifolia
Therapeutic activities
and active ingredient
concentration are
directly related to
plant quality. Low-
quality products
compromise customer
safety and the
intended therapeutic
effect
The analytical
method
High-Speed
Countercurrent
Chromatography
might serve as a
fingerprint
Use a standard
technique to
verify the
authenticity and
prevent
counterfeiting
Chromatograms present
six peaks that amount
to certain marker
compounds for
inferring plant quality
(Heinrich
2015;
WHO
2022;
Wu et al.
2020)
‘‘Green’’Extraction
of BAK
An extensive range of
extraction techniques
with different
methods, solvents, and
experimental
conditions has been
described to obtain
BAK from P.
corylifolia seeds
Extract BAK from P.
corylifolia seeds
through a
Supercritical Fluid
Extraction
with pure carbon
dioxide
Found a
sustainable
alternative to
conventional
solvent-based
extraction
methods
SCFE performed at
280 bar and 40 °C
with a CO
2
flow rate
equivalent to 3.6 g/
min, allows to obtain
nearly 80% of BAK
(Lewin
´ska
et al.
2021)
Achieve a final
product of
excellence
To achieve a final
product of excellence,
it is necessary to
establish quality
standards, such as
qualitative and
quantitative
composition, that must
be compliant with an
acceptable range of
values
The most common
technique is
High-Performance
Liquid
Chromatography,
which can be
coupled to varying
detectors
Choose the
detector that is
most
suitable for the
separation,
identification,
and
quantification of
BAK
HPLC coupled with
electrochemical
detection seems to be
the most appropriate
technique for the
separation,
identification, and
quantification of BAK
due to its high
sensitivity
(Chen
et al.
2012)
BAK Bakuchiol, HPLC High-performance liquid chromatography; SCFE Supercritical fluid extraction
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Table 4 Chronologically-ordered synthetic pathways of bakuchiol
Year Final product Reactional first steps and brief general notes References
1967 Rac-bakuchiol
methyl ether
Geraniol interacts with ethyl vinyl ether
First chemical synthesis
Three-step synthesis
(Adarsh Krishna et al. 2022;
Damodaran and Dev 1967)
1967 Rac-bakuchiol Geraniol reacts with p-methoxyacetophenone diethyl acetal
First total synthesis of rac-bakuchiol
Prepared in situ Claisen rearrangement: a key step to obtain the
bakuchiol skeleton
(Adarsh Krishna et al. 2022; Araki
and Bustugan 1991; Carnduff and
Miller 1967)
1990 (?)-
bakuchiol
(S)–O-benzylglycidol reacts with methyl
First enantioselective synthesis of ( ?)-bakuchiol
Twelve-steps synthesis
(Adarsh Krishna et al. 2022; Takano
et al. 1990)
1991 Rac-bakuchiol Geranylindium sesquibromide reacts with 2-(4-methoxyphenyl)
acetaldehyde
Synthesis via a geranylindium reagent. Three-step synthesis
(Adarsh Krishna et al. 2022; Araki
and Bustugan 1991)
1999 (?)-
bakuchiol
Sequential alkylation of cyclohexanone with Lithium
diisopropylamide-allyl bromide and Lithium diisopropylamide -
methyl iodide
Synthesis via stereoselective alkylation using silyl group to obtain
the chiral quaternary carbon center. Sixteen steps with an overall
yield of 5%
(Adarsh Krishna et al. 2022;
Sakakiyama et al. 1999)
2008 (?)-
bakuchiol
Chiral Michael’s acceptor reacts with Copper-Lithium reagent
Synthesis via stereoselective alkylation using silyl group. 1,4
addition using vinylcopper (I) reagents. Ten-step synthesis
(Adarsh Krishna et al. 2022; Esumi
et al. 2008)
2008 Rac-bakuchiol Intermediate prepared with vinyl magnesium bromide and Grignard
reagent
Synthesis via 1,4 addition of citral, with vinylmagnesium bromide
under Cu (I) catalyst. Four-step synthesis
(Adarsh Krishna et al. 2022; Chen
and Li 2008)
2008 (S)-bakuchiol
(R)-bakuchiol
Geraniol undergoes Sharpless epoxidation
Method of obtaining chiral center. Synthesis of (S)-enantiomer in ten
steps. Synthesis of (R)-enantiomer in nine steps
(Adarsh Krishna et al. 2022; Du et al.
2008)
2009 (?)-
bakuchiol
Conversion of (-)-citronellol into citronellol-based chiral q-sulfone
Synthesis via intramolecular diazosulfonate obtaining C–H bond
(Adarsh Krishna et al. 2022;
Bequette et al. 2009)
2010 (?)-
bakuchiol
Geraniol phosphonation
Synthesis via Ni Catalyzed NCH–Cu enantioselective allylic
substitution reaction
(Adarsh Krishna et al. 2022; Gao
et al. 2010)
2012 (?)-
bakuchiol
Geraniol reacts with N-propioloyl camphorsultam (Michael addition
reaction)
Synthesis via sulfur-based chiral auxiliaries-mediated Claisen
rearrangement
(Adarsh Krishna et al. 2022; Takao
et al. 2012)
2013 (S)-bakuchiol Geranic acid reacts with triethylamine and pivaloyl chloride
Synthesis via asymmetric 1,4-addition
(Adarsh Krishna et al. 2022; Esumi
et al. 2013)
2013 (S)-bakuchiol Stereo-selective unconjugated alkylation of an a,b-unsaturated
imide
Asymmetric synthesis routes. An approach using Evans’ auxiliary
(Adarsh Krishna et al. 2022; Xu et al.
2013)
2016 (S)-bakuchiol Geranial diazo is added to 4-methoxy phenyl boronic acid solution
Synthesis of bakuchiol precursor in one single operation, using an
interactive coupling method
(Adarsh Krishna et al. 2022;
Battilocchio et al. 2016)
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1386 Phytochem Rev (2024) 23:1377–1413
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carbon quaternary (tetra-alkylated) stereocenter.
Moreover, obtaining alkenyl groups between carbons
17 and 18, a sterically hindered position, entails a
specific challenge (Adarsh Krishna et al. 2022;
Choudhury et al. 2017; Harding 2006; Hawner and
Alexakis 2010; Quasdorf and Overman 2014).
Table 4presents the synthetic pathways reported by
various authors over time in chronological order. This
table offers a succinct overview of the different
approaches, accompanied by brief explanations of
the respective processes.
Skin bioactivities of bakuchiol
Antifungal activity
BAK exhibits remarkable antifungal properties, evi-
denced by lower minimum inhibitory concentration
values compared to traditional antifungals. Studies
evaluating the antifungal efficacy of BAK against
species such as Candida guilliermondii and Tri-
chophyton mentagrophytes have demonstrated highly
promising results, surpassing the effectiveness of
conventional antifungals. C. guilliermondii is com-
monly associated with superficial skin infections
(Pfaller et al. 2006), while T. mentagrophytes is a
dermatophyte linked to athlete’s foot, also known as
tinea pedis (Bell-Syer et al. 2012; Ilkit and Durdu
2015). Additional parameters indicating the effective-
ness of BAK include an increased permeability of the
fungal membrane, as demonstrated by Lau et al.
leading to fungal death due to an increase in ROS and
not as a consequence of DNA fragmentation (Lau et al.
2014). The primary outcomes of various studies on the
antifungal properties of BAK are summarized in
Table 5.
Antibacterial activity
BAK also demonstrates significant antibacterial activ-
ity, as pointed out by Yin et al., who considered BAK
as a ‘‘well-known natural antimicrobial agent’’. In
their study, BAK was used as a positive control, with
minimum inhibitory concentration values of 0.018 and
0.037 mM observed for Staphylococcus epidermidis
and S. aureus, respectively (Yin et al. 2004). S.
epidermidis is a common bacteria found on healthy
human skin (Brown and Horswill 2020) and can be the
causative agent of certain opportunistic skin infections
(Natsis and Cohen 2018; Nguyen et al. 2017).
Methicillin-resistant S. aureus (MRSA) has also been
associated with skin infections (Lee et al. 2018).
Trompezinski et al.evaluated the efficacy of the
biological complex BAK, Ginkgo biloba extract, and
mannitol (BGM), and compared it with benzoyl
peroxide and zinc gluconate. Benzoyl peroxide, a
topical agent commonly used as a first-line treatment
for acne, generates free radicals to damage the
bacterial cell walls of Cutibacterium acnes (also
known as Propionibacterium acnes) (Eichenfield
et al. 2021). Zinc gluconate has a bacteriostatic effect
against C. acnes and is also employed in acne
management (Yee et al. 2020). Table 6summarizes
the main results of some studies, emphasizing the
lower inhibitory concentration values exhibited by
Table 4 continued
Year Final product Reactional first steps and brief general notes References
2016 (S)-bakuchiol Chiral oxazoline sulfonamide ligand and a chromium salt provide
allylation products
Asymmetric allylation to obtaining quaternary
center
Method through chromium-catalyst
(Adarsh Krishna et al. 2022; Xiong
and Zhang 2016)
2017 (S)-bakuchiol
methyl ether
Rhodium-catalyzed hydroboration of pinacolborane with allylic
phosphonates
Strategy via enantioselective rhodium-catalyzed hydroboration
(Adarsh Krishna et al. 2022;
Chakrabarty and Takacs 2017)
2020 Rac-bakuchiol Tertiary allylic carbonate reacts with sulfinate salt
Used a regioselective molybdenum-catalyzed and allylic substitution
(Adarsh Krishna et al. 2022; Salman
et al. 2020)
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Table 5 Main results of studies conducted to evaluate the antifungal activity of bakuchiol
Bakuchiol
source
Study models Positive
Controls
Results Conclusions References
P.
glandulosa
(aerial parts)
In vitro
Microdilution
method for
yeast
Fluconazole,
ketoconazole,
and
itraconazole
BAK showed ;MIC
80
MIC
80
: BAK = 0.125 lg/mL
Fluconazole = 0.5 lg/mL
Ketoconazole = 0.5 lg/mL
Itraconazole = 4.0 lg/mL
BAK exhibited better activity
against C. guilliermondii than
the other antifungals tested
(Madrid
et al.
2012)
P.
corylifolia
(dried ripe
fruit)
In vitro
Broth dilution
method
Fluconazole BAK showed ;MIC
MIC: BAK = 3.83 lM
Fluconazole = 52.20 lM
BAK exhibited better activity
against T. mentagrophytes than
the other antifungal tested
(Lau et al.
2010)
P.
corylifolia
(dried ripe
fruit)
In vitro
Broth dilution
method
Terbinafine and
nystatin
BAK showed :fungal
membrane permeability and
:ROS levels
Fungal membrane permeability:
BAK [Terbinafine [Nystatin
ROS levels in fungal cells:
Nystatin [BAK [Terbinafine
BAK does not induce DNA
fragmentation in T.
mentagrophytes
BAK increases fungal
membrane permeability dose-
dependently and generates
ROS
(Lau et al.
2014)
P.
corylifolia
(dried ripe
fruit)
In vivo
Hartley
guinea pigs
LamisilÒcream
(Terbinafine)
BAK (aqueous cream)
eradicates fungal hyphae and
eliminates the fungal burden in
guinea pigspaws but was not
as effective as LamisilÒ
The discrepancy between the
activity of BAK and LamisilÒ
was attributed to the absence
of transdermal enhancers or
formulation issues that
compromise appropriate drug
delivery
(Lau et al.
2014)
BAK Bakuchiol, MIC Minimum inhibitory concentration, ROS Reactive oxygen species
Table 6 Main results of studies conducted to evaluate the antibacterial activity of bakuchiol
Bakuchiol
source
Study
models
Positive
Controls
Results Conclusions References
P. corylifolia
(fruits)
In vitro
Liquid
dilution
method
NA BAK showed ;MIC against
MRSA (strains) compared to
flavones, isoflavones,
meroterpenes, and coumarins
BAK exhibited activity against both
MRSA strains (OM481 and OM584)
This antibacterial activity depends on
the presence of phenolic hydroxyl
groups and lipophilicity provided by
the benzene ring
(Cui et al.
2015)
P.
tenuiflorum
(Ethyl
acetate
extract)
In vitro
Agar
well
diffusion
method
NA IC
12
: BAK = 123 ±11 lg/mL BAK displayed cytotoxicity against S.
epidermidis
(Hsu et al.
2009)
BAK Bakuchiol, BGM Bakuchiol, Ginkgo biloba extract, and mannitol, IC Inhibitory concentration; MIC Minimum inhibitory
concentration, MRSA Methicillin-Resistant S. aureus;NA Not applicable
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BAK compared to other compounds, underscoring its
antibacterial potential.
Antioxidant activity
The antioxidant properties of BAK result from the
presence of hydrogen in the terpenoid chain, located
conveniently adjacent to the trisubstituted alkene
group and readily available for abstraction. Addi-
tionally, the antioxidant activity is influenced by the
enthalpy of dissociation of the phenolic bond
(Adhikari et al. 2003). Another critical factor that
increases antioxidant activity is the presence of
hydroxyl groups in the aromatic ring, along with
the reinforcement of electron-donating groups, espe-
cially in the ortho-andpara-positions. Conversely,
electron withdrawal diminishes these antioxidant
properties. Additionally, the stereo-hindering effect
of hydroxyl groups, especially in the ortho-position,
modulates antioxidant activity.
Jiangning et al.characterized BAK as an unhin-
dered phenol, emphasizing the absence of substituted
groups in the ortho-positions of the hydroxyl group. A
pivotal double bond links the phenol of the phenolic
hydroxyl group in the para-position. This structural
configuration enables the extension of BAK’s pheno-
lic oxygen free radical (POFR) conjugation system
after the donation of a hydrogen atom to active free
radicals. As a result, the resonance structure stabilizes
POFR, reinforcing its antioxidant efficacy (Jiangning
et al. 2005). Studies have been conducted to elucidate
the antioxidant activity of BAK.
C. acnes absorbs ultraviolet (UV) and visible
radiation, resulting in the photo-oxidation of squa-
lene, a sebaceous lipid prone to oxidation due to its
chemical structure with six double bonds. Squalene
peroxides play a role in various skin conditions,
including acne (Cibrian et al. 2020). The skin
naturally produces vitamin E, a lipophilic antioxidant
present in normal human sebum, to prevent squalene
oxidation. Vitamin E production is directly corre-
lated to the amount of squalene. In individuals with
acne, low levels of vitamin E contribute to increased
levels of oxidized squalene (Thiele et al. 1999;
Trompezinski et al. 2016).
Trompezinski et al. also evaluated the efficacy of
the BGM complex in treating acne vulgaris, while
Bluemke et al.explored the multidimensional and
holistic impact of BAK on cellular aging. BAK
demonstrates the ability to protect biological compo-
nents, specifically proteins and lipids, from oxidative
damage. Furthermore, BAK exhibits a superior ability
to eliminate free radicals compared to retinol (RET).
ROS trigger an inflammatory cascade that results in
reduced cell viability in both dermal and epidermal
cells, leading to extracellular matrix (ECM) damage—
a recognized cornerstone of skin aging. These findings
support the antiaging effect of BAK through its strong
antioxidant activity (Bluemke et al. 2022).
Table 7brings together the results from various
research groups regarding the antioxidant properties of
BAK.
Anti-inflammatory activity
Pro-inflammatory cytokines, such as interferon-cand
LPS, have the ability to stimulate the expression of
inducible nitric oxide synthase (iNOS). The iNOS
gene comprises a promoter and a repeated initial
sequence that facilitates the binding of transcription
factors, including NF-kB, associated with stimuli
triggering iNOS expression. After synthesis, iNOS
generates high and sustained levels of NO, a crucial
inflammatory mediator for host defense. The quantifi-
cation of NO synthesis can be obtained by measuring
the accumulation of nitrite in the culture medium.
However, its sustained production has been implicated
in the pathogenesis of inflammatory diseases. The
anti-inflammatory response is related to the suppres-
sion of NO activity (Pae et al. 2001).
Both PGE
2
and macrophage migration inhibitory
factor (MIF) are pro-inflammatory cytokines. High
levels of these cytokines are observed in aging skin
due to chronic exposure to UVA and UVB irradiation.
Despite this similarity, they follow distinct signaling
pathways. PGE
2
, the main prostaglandin produced in
human skin, has the capacity to reduce collagen (CLL)
synthesis and increase the expression of matrix
metalloproteinase (MMP) in fibroblasts (Bluemke
et al. 2022). On the other hand, MIF is expressed in
the skin, particularly in fibroblasts and keratinocytes.
Acting as a potent macrophage activator, MIF posi-
tively regulates UVA-induced MMP-1 in fibroblasts
(Shimizu 2005). BAK effectively reduces the levels of
these cytokines, which demonstrates its anti-inflam-
matory activity and underlines its antiaging effects
(Bluemke et al. 2022).
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Chen et al. conducted a screening for potential
natural anti-inflammatory agents, using RAW 264.7
cells previously exposed to LPS to induce NO
production (Chen et al. 2017). Other studies, partic-
ularly those by Pae et al.explored the inhibition of
iNOS gene expression (Pae et al. 2001). Bluemke et al.
focused their research on assessing the anti-inflam-
matory capacity of BAK, examining its effect on
reducing two pro-inflammatory cytokines, PGE
2
and
MIF (Bluemke et al. 2022).
Table 8summarizes the main results of these
studies focusing on the anti-inflammatory activities of
BAK.
Antiaging activity
Several factors contribute to skin aging, including
exposure to UV radiation throughout life. The degra-
dation of ECM is one of the main signs of aging. This
damage causes the degeneration of dermal connective
tissue and is marked by the degradation of CLL fibers,
elastic fibers, and hyaluronic acid (Fayad et al. 2017).
BAK has the potential to prevent skin aging through
different pathways, delaying the appearance of signs
of aging. While comparable to RET, BAK’s efficacy
surpasses that of this well-known compound. In
addition, it should be noted that the antioxidant and
anti-inflammatory activities of BAK produced promis-
ing results, demonstrating an impact on the aging
process.
BAK’s anti-aging effects can be attributed to its
‘‘retinol-like’’ activity, since BAK acts as a functional
analog of RET. However, its anti-aging effect may
also be associated with other mechanisms termed
‘‘non-retinol-like’’, which will be described below.
Non-retinol-like activity
Bacqueville et al.studied the in vitro benefits of BAK
in preventing skin photoaging. The actin network
serves as an aging marker that facilitates morpholog-
ical analysis. After UVA irradiation, actin staining
showed that human dermal fibroblasts (HDFs) lose
their star-shaped pattern and acquire a fusiform
pattern. Incubation with 0.5 lg/mL BAK effectively
prevented the morphological changes in fibroblasts,
with results comparable to those of the non-irradiated/
non-treated control. Furthermore, after UVA irradia-
tion, there was an increase in the expression of
interleukin-8 (IL-8) and P16 protein, both indicative of
Table 7 Main results of studies conducted to evaluate the antioxidant activity of bakuchiol
Bakuchiol
source
Study models Positive
Controls
Results Conclusions References
BGM
complex
(cream)
In vitro
Squalene oxidation
Vitamin
E
Prevention of
squalene
oxidation:
At 3.9 mM At
19 mM
BAK–30.0%
BAK–36.9%
Vit E–15.2% Vit
E–40.3%
The protective index of BAK
squalene was 2x:that of vitamin E
(Trompezinski
et al. 2016)
SytenolÒA
(from
Sytheon
Ltd)
In vitro
DPPH reduction and
electron spin resonance
Retinol Antioxidant
power:
BAK—12,125
antioxidative
unit
RET—848
antioxidative
unit
BAK exhibits :antioxidant capacity
and power than RET
(Bluemke et al.
2022)
BAK Bakuchiol, BGM Bakuchiol, Ginkgo biloba extract, and mannitol; DPPH 2,2-diphenyl-1-picrylhydrazyl, RET Retinol, Vit E
Vitamin E
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skin aging. Incubation with BAK led to a reduction in
the expression of IL-8, associated with inflammation,
and P16, linked to cellular senescence (Fig. 2A)
(Bacqueville et al. 2020).
Subsequently, the authors investigated the benefits
of Vanilla tahitensis extract (VTE) and BAK, explor-
ing the potential of the compounds alone and in
combination to prevent skin photoaging. In in vitro
studies, the combined compounds showed a signifi-
cant synergistic effect, resulting in a remarkable
reduction of 95.1% in IL-8 expression. While the
individual reductions were 88.3% for BAK and 83.8%
for VTE, the combined impact was notably higher.
There was also a reduction in P16 levels of around
95.2%, with individual reductions of 44.4% and 29.2%
for BAK and VTE, respectively (Fig. 2B) (Bac-
queville et al. 2020). It is noteworthy that, despite
the synergistic effect, both results showed the superior
efficacy of BAK when used alone.
To better understand the advantages of this com-
bination, a dermo-cosmetic serum was formulated
(1.5% BAK ?1% VTE), and an ex vivo study was
conducted using a model of photodamaged human
skin induced by chronic UVA irradiation. Gly-
cosaminoglycan (GAG) was used as an ECM marker
to assess dermal density. GAG is located near the
dermo-epidermal junctions (DEJ) and the underlying
papillary dermis. Chronic exposure to UVA radiation
Table 8 Main results of studies conducted to evaluate the anti-inflammatory activity of bakuchiol
Bakuchiol
source
Study models Positive Controls Results Conclusions References
P.
corylifolia
(dried
fruits)
In vitro
Murine
macrophage
cell line
RAW264.7
Quercetin BAK showed ;IC
50
IC
50
: BAK = 21.57 lM
Quercetin = 33.08 lM
BAK inhibits NO generation LPS-
induced, without cytotoxicity
(cell viability [93%)
(Chen
et al.
2017)
P.
corylifolia
(seeds)
In vitro
Murine
macrophage
cell line
RAW264.7
Pyrrolidine
dithiocarbamate
Inhibition of NF-kB
activation
(measured through nitrite
accumulation)
Pyrrolidine – potent
inhibition
BAK – similar inhibition,
slightly higher
BAK acts at the transcriptional
level to regulate iNOS gene
expression, through NF-kB
binding dose-dependently
inhibition
(Pae et al.
2001)
Transcriptional regulation
(measured through
expression of iNOS
mRNA)
INF-c/LPS—considerably
increase
BAK—decrease its
expression
P.
corylifolia
(seeds)
In vitro
Human
dermal
fibroblasts
Diclofenac PGE
2
levels:
BAK considerably reduced
the PGE
2
level and at10
lM had a similar reduction
as a positive control
MIF protein levels:
BAK considerably reduced
MIF levels
BAK proved to considerably
reduce the expression of two pro-
inflammatory cytokines (PGE
2
and MIF)
(Bluemke
et al.
2022)
BAK Bakuchiol, IC Inhibitory concentration, INF-cInterferon gamma, iNOS Inducible nitric oxide synthase, LPS
Lipopolysaccharides, MIF Macrophage migration inhibitory factor, NF-kB Nuclear factor kappa B, NO Nitric oxide; PGE
2
Prostaglandin E2
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Fig. 2 Antiaging effect of BAK. AImmunofluorescence stain-
ing of actin network, interleukin-8, and p16 protein as markers
of morphology, inflammation, and senescence, respectively.
Performed in human dermal fibroblasts. Analyzed by laser
scanning confocal microscopy; BQuantitative analyses of IL-8
and p16 immunolabelling; CEvaluation of dermal density in an
ex vivo human skin aging assay. Analyzed by photon
microscopy. Arrows indicate GAG (intense blue network) loss
at the dermo-epidermal junction; DFull-face macrophotographs
show improvement of radiance after 28 days (?26%) and
56 days (?44%); ESkin firmness improvement, analyzed by
DynaskinÒ. Cross-section showing the depth of skin deforma-
tion reduced after 28 and 56 days. In the image below, from day
1 to day 56, skin deformation depth 56 days (30.4%), and skin
deformation volume 56 days (36.7%); FFacescanÒ, ptosis
volume decreased 56 days (22.8%). Defined face contour,
showing a remodeling effect of the product. Adapted from
(Bacqueville et al. 2020)
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induces photoaging stress, resulting in a decline in
ECM production, particularly in GAGs, and disrupts
the network, leading to less intense and more diffuse
staining (Fig. 2C). The loss of GAGs is correlated with
changes in the CLL and elastic fibers in the papillary
dermis. The application of this serum demonstrated
the ability to restore GAG content and network
organization, thereby improving dermal density. The
results were comparable to the non-irradiated/ non-
treated control, indicating that the serum exhibited a
re-densifying effect and protected the skin from UVA-
induced changes in GAGs (Bacqueville et al. 2020;
Lee et al. 2016; Naylor et al. 2011).
The researchers concluded the serum evaluation
with a clinical trial involving 43 healthy women,
where skin radiance through photographs, firmness
using DynaSKINÒ, and skin remodeling with FaceS-
canÒwere assessed. The clinical trial revealed
significant outcomes in skin radiance, with an overall
improvement of approximately 20% observed in 80%
of individuals after 56 days (Fig. 2D). The dermato-
logical assessment revealed an improvement in skin
firmness in 95% of individuals, evidenced by a
decrease in skin deformation of 17% and 16% in
depth and volume, respectively (Fig. 2E). Further-
more, after 56 days, 63% of individuals reported a
significant remodeling effect, characterized by a more
defined facial contour line (Fig. 2F). The results for
tolerance and overall safety rated the serum as ‘‘very
good’’ (Bacqueville et al. 2020).
Additionally, the main results of the studies by
Bacqueville et al. are found in Table 9, as well as the
results of the in vivo study by Bluemke et al., where
the efficacy of 0.5% BAK cream was compared with
its vehicle involving 34 healthy individuals (Bluemke
et al. 2022).
Retinol-like activity Retinoids play a crucial role in
maintaining skin health, and any deficiency or excess
of these compounds can disrupt the natural balance of
the skin, leading to disturbances in homeostasis and
impairment of the skin’s barrier function (Fisher and
Voorhees 1996). Within this group of natural
compounds, retinol (vitamin A alcohol), retinal
(vitamin A aldehyde) and retinoic acid (vitamin A
acid) are the most important elements (Bailly et al.
1998; Chaudhuri and Bojanowski 2014). As active
derivatives of vitamin A, they play key roles in various
stages of the cell life cycle, including differentiation,
proliferation, and apoptosis (Bastien and Rochette-
Egly 2004).
Due to the importance of RET in controlling and
regulating homeostasis and natural cellular processes,
along with the reported side effects associated with its
use, a current fundamental premise is to identify an
alternative molecule that can exert similar effects with
minimal adverse effects. Despite lacking structural
similarities with retinoids, BAK has the ability to
perform similar functions, earning its classification as
a functional analog (Chaudhuri and Bojanowski
2014).
Chaudhuri et al.conducted an investigation into the
relationship between BAK and retinoids, revealing
their structural dissimilarity, as illustrated in Fig. 3.In
an effort to identify potential RET-like compounds,
the study involved a comparison of gene expression
profiles with the known RET profile. The results of this
genome-wide analysis are represented by a volcano
plot for both BAK and RET (Fig. 4A), where signif-
icant changes in DNA microarray data are highlighted.
The positively regulated genes are situated on the
right, while negatively regulated genes are on the left.
The general similarity in the shapes of the volcano
diagrams for both compounds served as evidence of
the functional analogy between these molecules. This
was further confirmed by the similar modulation of
genes involved in retinoid-binding and metabolism
(Chaudhuri and Bojanowski 2014).
RET positively regulates nuclear retinoid receptors,
responsible for translating retinoid signals (Bastien
and Rochette-Egly 2004), whereas BAK does not
influence their modulation. This suggests potential
advantages in terms of adverse effects (Napoli 2017).
BAK significantly up-regulates lecithin-retinol acyl-
transferase, responsible for the esterification of RET
with a long chain of fatty acids, essential for the
absorption and storage of RET. Furthermore, both
BAK and RET up-regulated the retinoic acid receptor
responsive gene, typically down-regulated in acne,
psoriasis, rosacea, and multiple human cancers, mak-
ing BAK an attractive candidate for the treatment of
these health conditions. These results not only indicate
that BAK increases the endogenous bioavailability of
RET, but also highlight its role as a functional analog
of it (Chaudhuri and Bojanowski 2014).
Moreover, BAK has been shown to up-regulate
genes encoding ECM components in DEJ, specifically
those associated with CLL fibrils and elastin
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microfibrils. The degradation of these components is
directly linked to the appearance of wrinkles and fine
lines, as they play a significant role in the tensile
strength and elasticity of the skin’s support structure
(Tsamis et al. 2013).
BAK also demonstrated a notable up-regulation of
the genes encoding fibronectin-like, hyaluronan syn-
thase 3, and aquaporin 3 (AQP3), surpassing the
effects observed with RET. Fibronectin contributes to
the stability of the matrix and is indispensable for
Table 9 Main results of studies conducted to evaluate the anti-aging activity of bakuchiol, including non-retinol-like and retinol-like
activity
Bakuchiol
source
Study models Results References
Non-
retinol-
like
activity
P.
corylifolia
(seeds)
In vitro
Human dermal
fibroblasts
BAK reduced the expression of IL-8, p16 protein and prevented
fibroblast morphological changes
(Bacqueville
et al. 2020)
Ex vivo
Human skin
explants
BAK exhibits a re-densifying effect and protects skin from GAG
alterations UVA-induced in human skin photodamaged model
In vivo
Human
volunteers
BAK exhibits a remodeling effect, reduced depth and volume,
and improved skin firmness and radiance
P.
corylifolia
(seeds)
In vivo
Human
volunteers
BAK was well tolerated and improved the perceived appearance
of the skin regarding radiance, freshness, and signs of skin
aging
(Bluemke et al.
2022)
Retinol-like
activity
P.
corylifolia
(seeds)
In vitro
DNA
microarrays
Up and downregulation of genes (ECM and DEJ). Similar RET
gene modulation profile
(Chaudhuri and
Bojanowski
2014)
Ex vivo
Human
EpiDermFT
skin substitute
BAK increased collagen synthesis and metabolic activation in
mature fibroblasts and AQP3 expression
In vivo
Human
volunteers
BAK improved photodamage signs (skin elasticity, tone,
brightening, dryness, wrinkles)
P.
corylifolia
(seeds)
In vivo
Human
volunteers
BAK exhibit good efficacy (clarity, radiance, overall global
photoaging, overall skin appearance, tactile softness, and
visual smoothness) and tolerability (redness, peeling, burning,
itching, dryness, tightness, erythema, flaking, irritation,
roughness, stinging) in sensitive skin, with an excellent
tolerability profile
(Draelos et al.
2020)
AQP3 Aquaporin-3, BAK Bakuchiol, DEJ Dermo-epidermal junctions, ECM Extracellular matrix, GAG Glycosaminoglycans, IL-8
Interleukin 8, RET Retinol, UVA Ultraviolet A
Fig. 3 A Structure of Bakuchiol; BStructure of Retinol
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maintaining the shape of cells, while hyaluronan
preserves tissue hydration. AQP3, a channel protein
present in the epidermis, is involved in water/glycerol
transport, contributing to skin hydration, barrier
recovery, and elasticity (Chaudhuri and Bojanowski
2014). BAK also promoted the positive regulation of
certain genes in DEJ, which provide cohesion between
the epidermis and dermis, namely CLL a-6 (IV),
involved in cellular processes such as migration,
proliferation, and adhesion, and CLL a-2 (XVII),
Fig. 4 A Volcanic plot of DNA microarray data for RET and
BAK; BRET band BAK ceffect on collagen IV expression in
human EpidermFT (full thickness), ais the control. Arrows
indicate DEJ, where collagen IV is localized. Darker bands in
band cconfirm collagen expression; CRET band BAK ceffect
on AQP-3 expression in human EpidermFT (full thickness), ais
the control. Arrows indicate AQP-3 staining in the basal layer,
where is mainly localized; DSubjective evaluation by experts
Eand individuals I(% improvement vs. baseline); ERight view
day zero VS 12-week treatment; FResults of silicone replica
analysis using profilometry: % reduction vs. baseline. Adapted
from (Chaudhuri and Bojanowski 2014)
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which strengthens the bond between the two skin
layers (Chaudhuri and Bojanowski 2014). On the other
hand, BAK also positively regulated components of
hemidesmosomes, such as plectin I and integrins,
which play roles in cellular functions, such as
cytoskeleton organization. Additionally, BAK influ-
enced laminin, a key protein in the lamina densa,
associated with cell survival and phenotypes (Chaud-
huri and Bojanowski 2014).
It is crucial to highlight that RET is renowned for its
ability to inhibit natural aging signals, such as
morphological flattening and thinning of the skin,
which result from the physiological weakening of the
ECM and DEJ. BAK emerges as a promising candi-
date in the realm of anti-aging, showcasing a gene up-
regulation profile that, in most instances, surpasses
that of RET (Chaudhuri and Bojanowski 2014). In
photodamaged and aged skin, the synthesis of CLL
decreases as a result of the quantitative and qualitative
reduction of fibroblasts. BAK stimulated the expres-
sion of CLL in a mature fibroblast model by 147%,
150%, and 119% for type I, II, and IV, respectively,
whereas the RET results were 119%, 148%, and
100%, respectively, under identical conditions
(Chaudhuri and Bojanowski 2014).
BAK and RET were incubated at 10 lg/mL with a
3D model of a skin tissue substitute (EpiDerm FT) to
assess whether the stimulation of type IV CLL
corresponded to robust CLL expression. The result
revealed a strong signal near the DEJ, visible when
using an anti-type IV CLL antibody (Fig. 4B), suggest
that CLL synthesis results from selective metabolic
activation in fibroblasts, as BAK does not promote cell
proliferation (Chaudhuri and Bojanowski 2014). Epi-
dermal water homeostasis is crucial for the hydration
of the stratum corneum (SC), which is essential for
maintaining protective function, mechanical proper-
ties, and a healthy appearance of the skin. Dehydration
of the SC is common in photoaged skin and diseases
like psoriasis, eczema, and atopic dermatitis. Epi-
DermFT, when incubated with BAK, exhibited an
increase in the expression of the AQP3 gene in DNA
microarrays, correlating with an elevation in the
protein’s quantity (Fig. 4C) (Chaudhuri and Boja-
nowski 2014).
It is also important to note that when RET
undergoes oxidation in the skin, it produces retinoic
acid, which mimics its effects but is noticeably less
irritating. Even at the usual concentration of RET, less
than or equal to 0.1%, some irritation can occur. In this
context, BAK exhibits better acceptability and toler-
ability on the skin. Chaudhuri et al.concluded their
research with a clinical study involving 16 subjects
who applied the 0.5% BAK formulation twice a day
for 12 weeks. Experts and individuals evaluated
parameters such as skin elasticity, tone, brightness,
dryness, wrinkles, radiance, and eye area appearance,
using a semi-quantitative scale, where 0 corresponds
to none and 4 to severe. Experts gave higher ratings to
radiance, roughness, and the percentage of improve-
ment in dryness, while individuals gave higher ratings
to the eye area appearance, fine lines, and wrinkles. A
pronounced improvement in most parameters was
observed at week 8 compared to week 4, suggesting
cumulative beneficial effects of BAK over time
(Fig. 4D) (Chaudhuri and Bojanowski 2014). The
study also evaluated profilometry, analyzing wrinkle
depth and skin roughness using a silicone replica. The
reduction in wrinkle depth was 7%, 13%, and 20%
after 4, 8, and 12 weeks, respectively. Similarly, the
reduction in skin roughness was 2%, 10%, and 21%
after 4, 8, and 12 weeks, respectively (Figs. 4E and
4F). All these significant improvements in photodam-
age signs observed 12 weeks after treatment with
BAK corroborate the in vitro results, supporting its
therapeutic potential as a valid alternative to RET
(Chaudhuri and Bojanowski 2014).
Topical retinoids have been used for many years,
often associated with frequently reported adverse
effects, including irritation, burning sensation at
application sites, erythema, pruritus, and flaking
(Mukherjee et al. 2006). Individuals with sensitive
skin may experience even more pronounced effects.
Addressing these concerns, Draelos et al.(Draelos
et al. 2020) conducted a clinical evaluation of BAK as
a nature-based antiaging product. The study included
60 women with three dermatologic conditions: 20 with
atopic dermatitis/eczema, characterized by a break-
down of the barrier, 20 with rosacea, associated with
vascular hyperreactivity, and another 20 with cosmetic
intolerance syndrome, defined as individuals with a
history of harmful sensory stimuli in response to
topical applications. BAK demonstrated retinoid-like
effects due to RET-like genetic modulation, but with a
significantly improved tolerance profile compared to
retinoids and without the need for dose scaling. In this
study, a cleanser and antiaging moisturizer based on
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BAK (1% w/w) were used and the main results are also
presented in Table 9(Draelos et al. 2020).
Depigmenting
A study conducted by Kang et al.evaluated the effect
of the UP256 cream, composed of 77.02% BAK, on
reducing hyperpigmentation. The effect of UP256 in
inhibiting melanin synthesis was assessed in vitro
using normal human epidermal melanocytes and
compared with phenylthiourea, a melanogenesis
inhibitor. UP256 at 5 lM demonstrated a similar
inhibition of melanin production as phenylthiourea at
10 lM. Additionally, tyrosinase activity was detected
in situ by staining with L-3,4-dihydroxyphenylala-
nine. An increase in UP256 concentration led to a
reduction in the stained area. Western blot analysis
revealed a decrease in the expression of melanogenic
enzymes and the pull-down assay showed a pro-
nounced inhibition of the activation of the GTP-
binding protein, which is involved in the formation of
melanocyte dendrites. The authors also analyzed the
effect of UP256 in vivo, using an embryonic zebrafish
model, and ex vivo, in a 3D human skin model. The
results showed a clear inhibition of melanogenesis by
UP256 in both models (Kang et al. 2020).
Lyons et al.conducted an in vivo assessment of the
anti-hyperpigmentation effect of BAK. The study
involved 20 individuals with acne-induced post-
inflammatory hyperpigmentation, characterized by
hypermelanosis that occurs after the resolution of skin
conditions such as acne, eczema, and psoriasis,
following infections, contact dermatitis, allergic reac-
tions, medication use, inflammatory diseases, and
burns. The results showed significant improvements in
acne-induced post-inflammatory hyperpigmentation
lesions after treatment with BAK (Lyons et al.
2020). Table 10 presents the main findings from these
studies focusing on the depigmenting activity of BAK.
Anticancer
Madrid et al.investigated the in vitro anticancer
potential of BAK against human melanoma cell lines
(A2058) and fibroblasts. BAK exhibited significant
inhibition of A2058 cell viability without affecting the
cell viability of fibroblasts. The authors concluded that
cytotoxicity was not attributed to cell membrane
rupture. As there was no evidence of cell damage, it
was suggested that the inhibition was related to
apoptosis (Madrid et al. 2015). Human cancer cells
often resist programmed cell death (apoptosis), a
natural defense mechanism against tumoral develop-
ment (Hanahan and Weinberg 2011). This resistance
allows tumor progression, making cancer cells resis-
tant to human defense mechanisms and therapeutic
interventions (Madrid et al. 2015). Detailed analysis of
DNA fragmentation patterns enables the differentia-
tion of necrotic from apoptotic cells. The percentage
of fragmented DNA (TDNA) and tail moment
(TMOM) are parameters used to determine DNA
damage. The results showed an increase in TDNA and
TMOM, implying that BAK induces cell death
through apoptosis (Madrid et al. 2015). The increase
in caspase-3 enzyme activity, correlated with BAK
concentration, reinforced the idea of apoptosis induc-
tion. Active caspases inhibit cell growth and are
involved in the cleavage of proteins crucial for
apoptosis. Additionally, western blot analysis assessed
the expression of the p53 family, functioning as a
stress sensor in the cell and promoting the activation of
pro-apoptotic genes and specific proteins, including
the pro-apoptotic protein Bax and the anti-apoptotic
Bcl-2 family. The Bax/Bcl-2 ratio, reflecting the
propensity for apoptosis, demonstrated an increase in
Bax protein values and a decrease in Bcl-2 values.
In vitro studies showed a down-regulation of Bcl-2
expression and an up-regulation of p53 and Bax in
A2058 cells when incubated with BAK. Finally, a
concentration-dependent rise in ROS levels (initiating
the apoptosis cascade) was observed following the
incubation of A2058 cells with BAK (Madrid et al.
2015). Therefore, the results indicate that BAK is
effective in vitro in reducing the viability of A2058
cancer cells and exhibits good biocompatibility due to
its selective toxicity against cancer cells.
Skin delivery systems for the encapsulation
of bakuchiol
The skin, recognized as the largest organ in the human
body, serves as an appealing avenue for topical
delivery, offering advantages over oral, parenteral,
and intravenous administration, particularly in terms
of user comfort (minimal pain and invasiveness).
Despite their therapeutic or cosmetic applications,
active molecules face some challenges, particularly
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their limited ability to penetrate through the SC, thus
compromising their permeation (Lewin
´ska et al.
2021). Several strategies have been explored to
overcome this problem.
BAK demonstrates potential as a therapeutic sub-
stance for skin application, with its use currently
restricted to cosmetics and personal care products, as
defined by the European Chemicals (ECHA 2022j).
Formulations incorporating BAK as a cosmetic
ingredient are already available on the market,
specifically designed to reduce fine lines and wrinkles,
improve skin elasticity, increase CLL synthesis, and
even out skin tone, among other benefits. Table 11
provides examples, summarizing their main charac-
teristics and claims. Unfortunately, the specific deliv-
ery systems for these formulations are not publicly
known. This section will look at three nanosystems for
topical delivery, offering detailed descriptions that
will contribute to future studies on skin BAK delivery.
Bakuchiol-loaded microsponges
Wadakwa et al.explored a new approach for deliver-
ing the essential oil of P. corylifolia (Babchi) (BO) to
the skin by encapsulating it in microsponges (MS).
Babchi essential oil, widely employed in traditional
medicine, poses challenges due to its volatile nature,
low solubility, and stability (Wadhwa et al. 2019). The
production of Babchi oil microsponges (BOMS), as
described by Pawar et al., followed the quasi-emulsion
solvent evaporation method, utilizing ethyl cellulose
(EC) as a hydrophobic, non-swellable cellulose
derivative for structural integrity. Polyvinyl alcohol
(PVA) served as an emulsifier and stabilizer, while
dichloromethane acted as a solvent (Pawar et al.
2015). Gas chromatography-mass spectrometry (GC–
MS) confirmed BAK as the main constituent of BO.
Essential oils compositions can vary slightly based on
factors such as the growing environment, harvest and
collection time, and extraction technique, among other
considerations (Wadhwa et al. 2019).
The MS structures are predominantly spherical and
highly porous, with multiple null spaces for BO
encapsulation (Wadhwa et al. 2019). After confirming
the viability and stability of the BO in the microstruc-
tures, the researchers analyzed the in vitro drug release
profile. In general, the cumulative percentages of drug
release are inversely proportional to the concentra-
tions of the polymer and emulsifier. Increased con-
centrations of EC and PVA led to a decrease in the
extent of drug release. For instance, higher EC content
reduces the surface accumulation of the drug (drug
accumulated in the polymeric matrix), delaying the
release rate. A low amount of EC results in small MS
with a high surface area, increasing the release rate
(Wadhwa et al. 2019).
Despite the excellent properties of some essential
oils, certain ones have shown skin toxicity and
irritation. The results of the BOMS compatibility
studies conducted by Wadakwa et al.are shown in
Table 10 Main results of studies conducted to evaluate the depigmenting activity of bakuchiol
Bakuchiol
source
Study models Conclusions References
P.
corylifolia
(seeds)
In vitro
Normal human
epidermal
melanocytes
UP256 cream (77.02% BAK) inhibited melanin production through inhibition
of tyrosinase activity, reduction of the expression of TRP 1 and 2, MITF,
and a-PAK, inhibition of Rac1 and Cdc42 activation
(Kang et al.
2020)
P.
corylifolia
(seeds)
In vivo
Zebrafish model
Ex vivo
3D human skin model
BAK inhibited melanogenesis and exhibited a better depigmenting effect on
the skin than the zebrafish model
P.
corylifolia
(seeds)
In vitro
Normal human
epidermal
melanocytes
BAK improved acne-induced post-inflammatory hyperpigmentation lesions (Lyons
et al.
2020)
BAK Bakuchiol, MITF Microphthalmia-associated transcription factor, TRP Tyrosinase-related protein
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Table 11 Commercialized products containing bakuchiol and their claims
Concerns Product
categories
Activity claims of bakuchiol Commercial
Brands
References
Fine lines &
wrinkles
Serum
Cream
Gel-
Cream
RET-like effect by its action on
CLL I synthesis stimulation
Laboratoires Lierac
Paris
(Cica-filler)
(Lierac 2022a; 2022b; 2022c)
Imperfections Gel ;sebum secretion (acts on shine) Laboratoires Lierac
Paris
(Se
´bologie)
(Lierac 2022d)
Imperfections/
acne-prone
skin
Cream Part of SeboRestore technology;
Helps restore natural sebum quality
Bioderma
(Se
´bium global)
(Bioderma 2022; Pola
´kova
´et al. 2015;
Trompezinski et al. 2016)
Fine lines &
wrinkles
Serum Restoring skin elasticity and
firmness (stimulation on CLLs
and elastin fibers synthesis);
;fine lines appearance and
wrinkles
ISDIN
(Melatonik)
(Goldberg et al. 2019,2020; ISDIN
2022; Narda et al. 2018,2020)
Fine lines &
wrinkles/
Maturing
skin
Cream Moisturizer;
:collagen production;
Improves skin texture and tone
Skintensive
(Bakuchiol ?Retinol)
(Skintensive 2022)
Fine lines &
wrinkles
Cream Improves skin firmness and
elasticity;
;fine lines appearance and
wrinkles;
Improve skin tone
TheInkeyList
(Bakuchiol
Moisturizer)
(Theinkeylist 2022)
Fine lines &
wrinkles
Cream
Serum
;fine lines appearance and
wrinkles;
Improves skin elasticity;
Improve even skin tone and smooth
texture
Olehenriksen
(Transform Plus)
(Olehenriksen 2022a;2022b)
Eye Gel-
Cream
Fades the look of lines around the
eyes;
;fine lines appearance and
wrinkles;
Improves even skin tone and
smooth texture;
Improves skin firmness, elasticity
and the look of dark circles
Olehenriksen
(Transform)
(Olehenriksen 2022c)
Fine lines &
wrinkles
Serum ;CLL degradation and :its
synthesis;
Improves skin firmness;
;expression lines and wrinkles;
Regulates sebum and evens out
skin tone;
;hyperpigmentation and
imperfections, correct the dark
spots
Be beauty
(Bakuchiol)
(Olehenriksen 2022d)
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Table 12. In general, the developed microformulation
demonstrated greater safety on keratinocytes com-
pared to free BO, showcasing compatibility with skin
cells (Wadhwa et al. 2019). Previous studies have
highlighted the antibacterial effect of BAK against a
variety of bacteria, particularly S. aureus and S.
epidermidis (Chopra et al. 2013), MRSA (Cui et al.
2015), Pseudomonas aeruginosa, and Escherichia coli
(Li et al. 2021). In vitro, BOMS displayed robust
antimicrobial activity, comparable to streptomycin
(standard drug), and notably superior when compared
to free BO (Wadhwa et al. 2019).
Furthermore, photodegradation studies suggest that
BOMS are more photostable than free BO, which is
attributed to the encapsulation of BO in the MS system
forming a physical barrier. This protects the BO from
UVA-induced photolysis, improving its photostabil-
ity. These findings hold significance for pharmaceu-
tical applications, since microencapsulation can
safeguard bioactive substances from degradation by
UVA radiation. Additionally, stability studies indicate
no color change in the MS over 3 months, implying no
significant difference in their content (Wadhwa et al.
2019).
Thus, the MS system proves to be an effective and
stable approach for the dermal delivery of BO. Beyond
its demonstrated antibacterial properties and minimal
propensity for antibiotic resistance, MS could offer a
promising strategy for treating dermatological infec-
tious disorders. The use of the MS system allows the
main limiting characteristics of BO to be overcome,
such as its volatile nature, hydrophobicity, high
Table 11 continued
Concerns Product
categories
Activity claims of bakuchiol Commercial
Brands
References
Skin tone &
elasticity
Serum :skin elasticity and even out skin
tone
Rituals
(Natural Booster)
(Rituals 2022)
Fine lines &
wrinkles
Night
cream
Day
cream
Defines the contours;
Regenerates the skin;
;deep wrinkles;
Activate cellular CLL;
Redensifies and strengthens the
skin’s support fibers
NIVEA
(Cellular expert lift)
(Nivea 2022a;2022b)
Anti-Aging/
Brown spots
Serum Stimulates the effect of retinol;
;discoloration;
Fades brown spots and evens out a
patchy skin tone
Paula’s Choice
(Clinical)
(Paula’s 2022a)
Anti-Aging Cream Improves skin tone and texture;
Fades brown spots;
;fine lines appearance and
wrinkles
Paula’s Choice
(Clinical)
(Paula’s 2022b)
Anti-Aging Serum RET-like effect;
;fine lines appearance and
wrinkles;
;discoloration;
Improves skin firmness
Biossance
(Squalane ?phyto-
retinol)
(Biossance 2022)
Anti-Aging Serum
Booster
Eye
Cream
Oil
Improves skin hydration, firmness
and elasticity;
;fine lines appearance and
wrinkles;
Improve skin tone
Allies of Skin
(Bakuchiol)
(Allies
2022a,2022b,2022c,2022d,2022e)
CLL Collagen, RET Retinol
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Table 12 Summary of main properties and characteristics of skin delivery systems for Bakuchiol
Formulation Pharmaceutical
form
Characterization Preparation
method
Composition Bakuchiol
content
EE
(%)
LE
(%)
P. corylifolia
(Babchi)
essential oil,
encapsulated
in
microsponges
(BOMS)
Microsponges Spherical uniform
shape with a
highly porous
microstructure
Quasi-emulsion
solvent
evaporation
method
-Babchi essential
oil
-Ethyl cellulose
(polymer)
-Polyvinyl alcohol
(emulsifier and
stabilizer)
-Dichloromethane
(solvent)
65,37% 55.28
to
87.70
NA
Babchi essential
oil
encapsulated
in b-
cyclodextrin-
based
nanosponges
(BONS)
Nanosponges Fluffy powder
with a highly
porous structure
losing its
crystallinity
Blank b-
cyclodextrin
nanosponges:
Melt method
Essential oil
loading:
Freeze-drying
method
-Babchi essential
oil
-Diphenyl
carbonate
(crosslinker)
65,37% 50.43
to
93.05
14.23
to
21.47
Bakuchiol
loaded in
nanoemulsions
Nanoemulsions Oil-in-water;
Spherical
nanostructures
with roughly
uniform sizes,
non-aggregated
and good
droplet
distribution
Spontaneous and
sustainable self-
assembly
process between
Bakuchiol and
surfaction and
coco-betaine
-Bakuchiol
-Surfactin and
coco-betaine
(stabilizers)
-Oil
-Water
80% NA NA
Formulation Particle
size
Zeta potential
(mV)
Poly Dispersity
Index
Release
profile
(in vitro)
Cytotoxicity Antibacterial
activity
Inhibition
zone
(mm)
Reference
P. corylifolia
(Babchi)
essential oil,
encapsulated
in
microsponges
(BOMS)
20.44
to
41.75 lm
NA NA 58.35 to
86.21%
(after
8h)
?In
immortalized
human
keratinocytes
Free Babchi oil
at 320 lg/mL
caused
51.05%
inhibition
BOMS at
320 lg/mL
caused
26.34%
inhibition
BOMS did not
have a
significant
cellular
cytotoxic
effect
Free Babchi
oil:
P.
aeruginosa
11.67
E. coli 11.33
S. aureus
12.67
BOMS:
P.
aeruginosa
16.77
E. coli 15.33
S. aureus
16.67
(Wadhwa
et al.
2019)
123
Phytochem Rev (2024) 23:1377–1413 1401
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Table 12 continued
Formulation Particle
size
Zeta potential
(mV)
Poly Dispersity
Index
Release
profile
(in vitro)
Cytotoxicity Antibacterial
activity
Inhibition
zone
(mm)
Reference
Babchi essential
oil
encapsulated
in b-
cyclodextrin-
based
nanosponges
(BONS)
234
to
484 nm
-22.0 to -15.5
:values:
(:repulsive
forces)
greater
stability
with less
aggregation
trend
0.188 to 0.509
;values: homogeneous
and
stable nanocolloidal
suspensions
NA ?In
immortalized
human
keratinocytes
Free Babchi oil
the IC
50
value
was 172.3 lg/
mL
BONS the IC
50
value was
191.4 lg/mL
BONS
formulation is
safer than free
Babchi oil for
human skin
cells
Free Babchi
oil:
P.
aeruginosa
12.33
E. coli 12.00
S. aureus
12.33
BONS:
P.
aeruginosa
16.00
E. coli 17.00
S. aureus
16.00
(Kumar
et al.
2018)
Bakuchiol
loaded in
nanoemulsions
200
to
243 nm
-73 to -66 0.182 to 0.276 NA ?In human
dermal
fibroblasts and
in immortalized
human
keratinocytes
Bakuchiol [0.02
and 0.5] mg/
mL showed
low
cytotoxicity,
even at
0.5 mg/mL,
the higher
concentration
Cell viability
was reduced
by about 60%
after 24 h and
55% after
48 h
Between 0.02 to
0.2 mg/mL
there was a
beneficial
effect,
accompanied
by excellent
cell survival
NA (Lewin
´ska
et al.
2021)
BOMS Babchi oil microsponges, BONS Babchi oil nanosponges, EE Encapsulation efficiency, IC Inhibitory concentration, LE
Loading efficiency, NA Not available
123
1402 Phytochem Rev (2024) 23:1377–1413
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viscosity, and susceptibility to degradation during
storage due to low stability to air, light, and high
temperatures. These challenges hinder its utilization in
dermopharmaceutical applications. Apart from
enhancing stability, the MS system mitigates dermal
toxicity, a crucial aspect of therapy adherence. It has
shown no cytotoxicity, which is in line with its
compatibility with skin cells. The dermatological
potential of BOMS can be further optimized by
incorporating them into creams, gels, lotions, or other
suitable dermal carriers, reinforcing the skin benefits
of BO and contributing even more to avoiding skin
toxicity problems resulting from direct contact with
BO. This delivery system allows for an extended drug
release time, thus reducing dosage and potential side
effects. Simultaneously, it improves cost-effective-
ness and payload (Wadhwa et al. 2019).
Bakuchiol-loaded nanosponges
Following the studies carried out by Wadhwa et al.on
BOMS, Kumar and Rao, expanded the research and
developed a delivery system for this essential oil,
transitioning from the microscale to the nanoscale
(Kumar et al. 2018; Wadhwa et al. 2019). Kumar et al.
focused on the encapsulation of BO in nanosponges
(NS) (BONS) based on b-cyclodextrin (b-CD) (b-
CDNSs) (Kumar et al. 2018). The nanocavities within
the solid mesh network of b-CD allow for the
entrapment of complex chemical substances. NSs are
generally highly efficient and significantly enhance
stability (Pawar et al. 2019).
Once again, GC–MS confirmed that BAK was the
predominant component. The NSs were synthesized
using the b-cyclodextrin melt method, which was
cross-linked with diphenyl carbonate. Subsequently,
the NSs were loaded with essential oil using the
freeze-drying method. Thermogravimetry showed that
the degradation of cross-linked structures exhibited
good thermal stability, and X-ray powder diffraction
revealed a loss of crystallinity after freeze-drying,
resulting in a fluffy powder characterized by a highly
porous structure (Kumar et al. 2018). The main results
of the cytotoxicity studies of b-CDNSs are presented
in Table 12, indicating that BONSs are generally safer
on keratinocytes than free BO, demonstrating com-
patibility with skin cells (Kumar et al. 2018).
Furthermore, photodegradation studies suggest that
BONS are more photostable than free BO due to the
encapsulation of BO in the NS system. This protective
mechanism delays the photolysis process of the BO
induced by UVA radiation, enhancing its photostabil-
ity. These findings offer additional value for der-
mopharmaceutical applications, as nanoencapsulation
can protect bioactive substances from degradation
caused by UVA radiation (Kumar et al. 2018).
In the context of antimicrobial efficacy against
various bacteria, including E. coli, P. aeruginosa, and
S. aureus, the performance of BO stands out. BONS
also exhibited greater antimicrobial activity in vitro
compared to free BO. This significant improvement is
attributed to the increased water solubility of BO after
its encapsulation in CDNSs, overcoming the limita-
tions of free BO such as volatility and insolubility
(Kumar et al. 2018).
The advantages of this formulation are similar to
those of MS, serving as a skin delivery system
designed to overcome the challenges associated with
essential oils. The prolonged drug release time enables
a reduction in dosage and drug consumption, thus
minimizing the side effects resulting from targeted
drug release in the skin. This system reinforces the
BOs dermatological potential while avoiding skin
irritation and toxicity. In fact, scale reduction can be
advantageous for improving parameters such as sol-
ubility and permeability, depending on the intended
purpose, due to the substantial increase in the surface
area of the particles (Kumar et al. 2018).
Bakuchiol-loaded nanoemulsions
Lewinska et al. recently conducted a comprehensive
investigation into ‘‘environmentally-friendly’’
nanoemulsions as a potential strategy to improve the
transdermal delivery of BAK. The ‘‘green’’ nanosys-
tem consists of an oil-in-water nanoemulsion with two
hybrid-surface active agents (stabilizers), surfactin
and coco-betaine (1:4). The inclusion of these ionic
surfactants allows for the development of stable for-
mulations (Lewin
´ska et al. 2021).
The prepared nanoemulsions showed high kinetic
stability, featuring spherical nanostructures with well-
distributed and nearly uniform sizes. In addition, there
was no aggregation of nanodroplets, avoiding
123
Phytochem Rev (2024) 23:1377–1413 1403
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processes such as flocculation or coalescence. The
formulation containing BAK was subsequently sub-
jected to ex vivo permeation studies, in vitro cytotox-
icity, and in vivo contact studies (Lewin
´ska et al.
2021).
The ex vivo study was carried out on Franz cells
(full-thickness pig skin). Analysis of the fluid in the
acceptor chamber did not detect the presence of
surfactants. Subsequently, microscopic analysis
revealed that the BAK formulation penetrated the
epidermal barrier. The carrier remained intact and
provided stable transport (Lewin
´ska et al. 2021). The
in vitro study showed that the encapsulated BAK
formulation exhibited low cytotoxicity on immortal-
ized human keratinocytes and HDF. BAK proved to be
biocompatible in both cell lines (Lewin
´ska et al.
2021). In the in vivo study, which involved male and
female volunteers aged between 30 and 50 years, the
efficacy of the nanoemulsion (BAK at 0.05 mg/mL)
on capillaries, skin discoloration, and wrinkles was
evaluated. Younger individuals typically show milder
signs of skin deterioration, with softer changes
expected. Skin changes in individuals over 40 are
usually visible to the naked eye. From the age of 50,
some changes become permanent. The results showed
that the BAK formulation improved skin condition by
reducing the depth of wrinkles and blood vessels in
subjects of all ages. Regarding discoloration, there
was a significant reduction in subjects aged 30 and 50,
which was more evident in those aged 50 (Lewin
´ska
et al. 2021). This promising nanoemulsion can
increase the solubility and effectiveness of hydropho-
bic compounds due to its surface-to-volume. In
addition to its excellent physical stability, the presence
of biosurfactants protects the system from degradation
during production and storage. Finally, nanoemulsions
are potential systems for the effective delivery of
active ingredients, such as BAK, to deeper layers of
the skin, as they can penetrate the epidermis, while
maintaining its integrity (Lewin
´ska et al. 2021).
Table 12 brings together some of the most impor-
tant aspects of formulations for delivering BAK to the
skin, such as pharmaceutical form, characterization,
preparation method, composition, content of BAK,
encapsulation efficiency, loading capacity, particle
size, polydispersity index, drug release profile, as well
as cytotoxicity and antibacterial activity.
Safety of bakuchiol for skin: regulatory
and toxicological concerns
Regulatory organizations, including the European
Medicines Agency (EMA) and the Food and Drug
Administration (FDA), are responsible for developing
guidelines for toxicity assessment. In the European
Union, the EMA supervises the use of medicines,
monitoring their risk–benefit ratio and safety. In
addition, all nanocarriers require a full risk assessment
evaluation and prior authorization before use (Mas-
carenhas-Melo et al. 2022). In Europe, EU Directive
2001/83/EC regulates medical products, and EU
Directive 93/42/EEC regulates medical devices. One
of the critical points is deciding whether nanotech-
nology-based formulations are medical products or
devices (Santos et al. 2020). The toxicity assessment
provides efficacy and safety results that determine
whether regulatory approval is accepted or denied.
The International Organization for Standardization,
associated with the Organization for Economic Coop-
eration and Development, has developed industry
standards for assessing the toxicity of nanoformula-
tions. However, these regulations were specifically
designed for industrial applications (Cla
´udia Paiva-
Santos et al. 2022; Li et al. 2016a,2019; Santos et al.
2020). The FDA‘s draft guidance on industrial nano-
materials is not clear on toxicity assessment. It only
refers to the importance of establishing a safety profile
(Santos et al. 2020).
Concerning BAK, the European Chemicals Agency
has compiled a variety of information. The results for
the classification of physical hazards were conclusive,
but insufficient to classify almost all parameters as
explosive or self-reactive substances, except in the
case of desensitized explosives, where the reason for
non-classification was a lack of data. Concerning
health risks, skin irritation/corrosion was assessed in
111 individuals using a patch test, revealing no
irritation, and similar results were observed for skin
sensitization. The results were conclusive, but insuf-
ficient to classify skin sensitization and irritation/cor-
rosion. Additionally, acute dermal toxicity was not
classified due to a lack of data (ECHA 2022k).
Although it is suggested that BAK may offer advan-
tages over retinoids, potentially preventing side effects
such as redness, peeling, itching, erythema, irritation,
roughness, and stinging, the reported cases neverthe-
less indicated adverse reactions. A 33-year-old woman
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1404 Phytochem Rev (2024) 23:1377–1413
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with no previous atopic history experienced itchy and
erythematous plaques, mainly located on the neck,
perioral area, and eyelids. Patch tests were performed
on the products used, and Noreva Exfoliac Global 6
cream showed a positive result. All ingredients were
subjected to patch tests, read on the 3rd and 7th days.
BAK was evaluated at 0.1%, corresponding to its
concentration in the cream. The result was positive
(???) on the 3rd day. The patient was counseled to
avoid products containing BAK (Malinauskiene et al.
2019). In another case, a 23-year-old woman with a
history of seasonal rhinoconjunctivitis frequently
experienced facial eczema. The woman reported
recurrent flares of edematous and erythematous itchy
lesions. This coincided with the application of
DermAbsolu Soin, an anti-aging eye cream. Patch
tests were conducted and read on the 2nd and 4th days,
with negative results for all patches. The eye cream
was investigated using the repeated open application
test, revealing positive results from day one, showing a
follicular inflammatory pattern. BAK was evaluated at
1%, corresponding to its concentration in the cream. In
the end, only the BAK test was positive (??). The
patient was counseled to avoid products containing
this compound (Raison-Peyron and Dereure 2020).
The environmental risks classified BAK as ‘‘very
toxic to aquatic life’’, in the short-term (category acute
1) and ‘‘with long-lasting effects’’, in the long-term
(category chronic 1). BAK labeling includes an
environment hazard pictogram (GHS09) (ECHA
2022l,2022m). Short-term toxicity (ECHA 2022n)
was assessed in aquatic invertebrates (Daphnia
magna), and the results were read after 48 h. The
effect concentration (EC
50
) was around 0.2 mg/L. The
toxicity results for algae and cyanobacteria (Raphido-
celis subcapitata) were read after 72 h, and EC
50
/
NOEC was [2.108 mg/L (ECHA 2022o). The com-
plete environmental impact of BAK remains
unknown, lacking data on aspects such as photodegra-
dation or bioaccumulation (ECHA 2022p). Biodegra-
dation studies in water were conducted using a sample
from the Daman Ganga river as an inoculum. The
percentage of degradation was estimated by monitor-
ing the consumption of dissolved oxygen over 28 days
(the initial concentration was 7.98 mg/L). The results
were read on days 7, 14, 21, and 28, and the values
obtained were 34.72, 66.89, 77.62, and 87.66%,
respectively. BAK was considered not easily
biodegradable. Potassium hydrogen phthalate was
the reference substance (toxicity control) and showed
similar degradation values. The study concluded that
BAK had no adverse effects on the inoculum (ECHA
2022p).
Toxicity is closely related to structural and physic-
ochemical properties, including size, shape, tendency
to agglomerate, and surface charge (Paiva-Santos et al.
2021). The nanometric dimension entails potential
risks. On the one hand, it increases the possibility of
achieving systemic circulation and, on the other, it
increases the contact surface area. Therefore, more
interactions with biological systems are expected,
making them more reactive and with a greater
potential for toxicity, especially in vivo (Cla
´udia
Paiva-Santos et al. 2022). In addition, cytotoxicity
depends on the exposure time and the concentration of
the nanosystem, and potential contamination during
the manufacturing process should be taken into
account (Paiva-Santos et al. 2021). However, more
attention should be given to the toxic characteristics of
the surface material, since it can influence the
surrounding environment (Mascarenhas-Melo et al.
2022). Depending on their ratio, the presence of
surfactants may also induce some adverse effects,
including irritation, erythema, or toxicity (Santos et al.
2020). Some strategies, including the coating of
nanosystems, have been designed to mitigate these
toxic effects (Prajitha et al. 2019). However, more
studies are required to establish the safety and
toxicological profiles of BAK skin delivery systems,
both in the short and long-term (Cla
´udia Paiva-Santos
et al. 2022).
Despite all the advantages and great potential of
nanoformulations for therapeutic and cosmetic appli-
cations, their practical usefulness depends entirely on
their favorable safety profile. It is, therefore, necessary
to establish a regulatory framework for nanotechnol-
ogy-based formulations, encompassing specific man-
ufacturing regulations, determining
pharmacodynamic and pharmacokinetic profiles, and
evaluating toxicological profiles. Only in this way can
the efficacy and safety of these nanoformulations be
guaranteed, allowing sustained approval for their
placement on the market (Paiva-Santos et al. 2021).
It is also important to remember that, although it is
intended for topical application, it is essential to know
about BAK metabolic pathways. The human liver
microsomes, which include several isoenzymes such
as CYP2C9, CYP2C19, and CYP3A4, are responsible
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Phytochem Rev (2024) 23:1377–1413 1405
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for BAK metabolism. This issue is highly relevant due
to potential interactions, which can result in adverse
reactions or a lack of therapeutic efficacy. It is
important to consider the possibility of coadministra-
tion of molecules capable of activating or inhibiting
any of these isoforms, such as glycyrrhetinic acid, the
active metabolite of licorice, which can increase the
toxicity of BAK by inhibiting its detoxification
enzymes. The inhibition of cytochrome P450 isoen-
zymes ultimately delays metabolic detoxification,
prolonging the time that the drug remains in the body.
This can be dangerous due to the increased potential
for bioaccumulation and cytotoxicity (Li et al. 2016a).
It should also be noted that salt processing reduces the
toxicity of P. corylifolia extract on the renal and
cardiovascular systems. This is attributed to a reduc-
tion in volatile compounds, one of which is BAK,
resulting from the heating process (Li et al. 2019).
Hsu et al., in their study on the antibacterial effect
of BAK, found a curious aspect about its long-term
storage. After 8 months at room temperature, BAK
degraded into 4-hydroxybenzaldehyde, and showed no
antibacterial effect against S. epidermidis (Hsu et al.
2009). This compound formed is inactive. These
results demonstrate the need for further studies to
predict these changes and assess their toxic potential,
as well as the possible occurrence of unexpected
biological effects.
Conclusions and future perspectives
This review article addresses the main physicochem-
ical properties, natural sources, synthesis routes,
biological effects, skin delivery carriers, and toxicity
of BAK. It also highlights the existence of a promising
‘‘green’’ method for its isolation, which already has a
very successful yield. As far as chemical methods are
concerned, none of them stand out for their better
performance, so existing methods could be improved,
especially from a sustainable perspective. Further-
more, the main skin activities of BAK found in the
literature were thoroughly described and discussed,
and the results were promising, especially as an anti-
aging agent and as a bio-retinol-like agent. BAK
appears to be an alternative to RET without its
associated adverse effects, even in individuals with
sensitive skin. Moreover, it has shown potential
antioxidant, anti-inflammatory, and depigmenting
effects. Evidence about its anticancer potential is still
scarce, but seems promising. BAK also showed
antibacterial and antifungal activity against C. guil-
liermondii, MRSA, S. epidermidis and C. acnes,
among others. It can be considered a valuable
therapeutic weapon, given the emerging antibacterial
resistance. However, its mechanisms of action require
further clarification. Concerning BAK skin delivery
technology, the delivery systems described are
promising in overcoming limiting characteristics such
as volatility, hydrophobicity, viscosity and suscepti-
bility to degradation. Future research should expand
on the results already found, as well as try to find other
delivery systems for BAK, since the alternatives found
in the literature are still scarce. In addition, a challenge
for the years ahead will be to explore whether there
can be a link between the type of nanosystem and its
therapeutic or cosmetic use in order to further
personalize the therapy. In this review we highlight
the main benefits of using nanosystems as reducing
dermal toxicity and prolonging the release time of
BAK, thus reducing the dose and side effects, as well
as having the ability to deliver BAK to deeper layers of
the skin. However, both these and other strategies for
delivering BAK should be the subject of future
research, since the biological properties of BAK are
already known. It is therefore necessary to take ‘‘better
advantage’’ of these nanosystems in order to increase
the bioavailability of BAK and strengthen its derma-
tological potential, by introducing them into creams,
gels, lotions, or other suitable dermal formulations.
Assessing the risks of nanosystems and controlling
them are fundamental requirements, and this is still a
gap. In order to accurately measure toxicity, it is
necessary to develop new clinical trials, since most
in vitro toxicology studies focus only on one cell line
and do not reproduce reality in humans. Nevertheless,
it is necessary to create concrete guidelines to confirm
the results and develop good models to predict the
effect of nanosystems on mammals. In addition, future
tests should be performed, both in vitro and in vivo, on
damaged skin rather than healthy skin. Once the
barrier capacity is compromised, this is reflected in
increased permeability, consequently, a variation in
pharmacodynamic and pharmacokinetic profiles is
expected. In the real skin conditions in which BAK is
intended to be applied, the actual skin penetration
capacity of these systems, the dwell time and the
occurrence of any potential problems they may cause
123
1406 Phytochem Rev (2024) 23:1377–1413
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

are not yet fully known. Finally, it is essential to
conduct studies to assess and determine the ecotoxi-
city of these BAK nanosystems more accurately.
Funding Open access funding provided by FCT|FCCN (b-
on).
Open Access This article is licensed under a Creative
Commons Attribution 4.0 International License, which permits
use, sharing, adaptation, distribution and reproduction in any
medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative
Commons licence, and indicate if changes were made. The
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the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not
included in the article’s Creative Commons licence and your
intended use is not permitted by statutory regulation or exceeds
the permitted use, you will need to obtain permission directly
from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/.
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