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Azadirachta indica (Neem) as a Potential Natural Active for Dermocosmetic and Topical Products: A Narrative Review

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Azadirachta indica (Neem) is a large tree that is native to India and is traditionally used due to its several properties, mainly to treat skin diseases, as well as its “herbicidal” activity. Its bark, leaves, seeds, fruits and flowers are widely used in medicinal treatment due to the presence of active secondary metabolites with biological effects, mainly limonoids and tetranortriterpenoids, such as azadirachtin. Thus, A. indica was studied in a variety of conditions, such as anticancer, antiseptic, anti-inflammatory and chemopreventive agents, as well as a biopesticide. Furthermore, differentiated cell tissue in A. indica cultivation was reported to produce active metabolites for different purposes. However, only a few studies have been developed regarding its potential use in cosmetics. For instance, most studies explained the antimicrobial properties in health conditions, such as acne, dandruff and personal health care. Here, we summarized not only the most common cosmetic claims to treat acne but also mitigating other skin disorders related to inflammatory and oxidant processes in recent in vivo studies and patents to aid researchers and industrialists to select A. indica derivatives as novel cosmetic ingredients.
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Citation: Baby, A.R.; Freire, T.B.;
Marques, G.d.A.; Rijo, P.; Lima, F.V.;
Carvalho, J.C.M.d.; Rojas, J.;
Magalhães, W.V.; Velasco, M.V.R.;
Morocho-Jácome, A.L. Azadirachta
indica (Neem) as a Potential Natural
Active for Dermocosmetic and
Topical Products: A Narrative
Review. Cosmetics 2022,9, 58.
https://doi.org/10.3390/
cosmetics9030058
Academic Editors: Carmen Garcia-
Jares and Laura Rubio
Received: 19 April 2022
Accepted: 26 May 2022
Published: 2 June 2022
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cosmetics
Review
Azadirachta indica (Neem) as a Potential Natural Active for
Dermocosmetic and Topical Products: A Narrative Review
AndréRolim Baby 1, * , Thamires Batello Freire 1, Gabriela de Argollo Marques 1, Patricia Rijo 2,
Fabiana Vieira Lima 1,3 , João Carlos Monteiro de Carvalho 4, John Rojas 5, Wagner Vidal Magalhães 6,
Maria Valéria Robles Velasco 1and Ana Lucía Morocho-Jácome 1,*
1Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of São Paulo,
São Paulo 05508-000, Brazil; tbfreire@usp.br (T.B.F.); gabriela.argollo@usp.br (G.d.A.M.);
fabianavlimag@gmail.com (F.V.L.); mvrobles@usp.br (M.V.R.V.)
2CBIOS—Universidade Lusófona’s Research Center for Biosciences and Health Technologies,
1749-024 Lisbon, Portugal; patricia.rijo@ulusofona.pt
3Health Sciences Department, Faculty of Pharmacy, Federal University of Espírito Santo,
São Mateus 29932-540, Brazil
4
Department of Biochemical Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of São
Paulo, São Paulo 05508-000, Brazil; jcmdcarv@usp.br
5Department of Pharmacy, School of Pharmaceutical and Food Sciences, University of Antioquia,
Medellin 050010, Colombia; jrojasca@gmail.com
6In Vitro Laboratory, Chemyunion Ltda. Sorocaba, São Paulo 18087-101, Brazil;
wagner.magalhaes@chemyunion.com
*Correspondence: andrerb@usp.br (A.R.B.); anamorochojacome@gmail.com or
anamorochoj@usp.br (A.L.M.-J.)
Abstract:
Azadirachta indica (Neem) is a large tree that is native to India and is traditionally used due
to its several properties, mainly to treat skin diseases, as well as its “herbicidal” activity. Its bark,
leaves, seeds, fruits and flowers are widely used in medicinal treatment due to the presence of active
secondary metabolites with biological effects, mainly limonoids and tetranortriterpenoids, such as
azadirachtin. Thus, A. indica was studied in a variety of conditions, such as anticancer, antiseptic,
anti-inflammatory and chemopreventive agents, as well as a biopesticide. Furthermore, differentiated
cell tissue in A. indica cultivation was reported to produce active metabolites for different purposes.
However, only a few studies have been developed regarding its potential use in cosmetics. For
instance, most studies explained the antimicrobial properties in health conditions, such as acne,
dandruff and personal health care. Here, we summarized not only the most common cosmetic claims
to treat acne but also mitigating other skin disorders related to inflammatory and oxidant processes
in recent
in vivo
studies and patents to aid researchers and industrialists to select A. indica derivatives
as novel cosmetic ingredients.
Keywords:
acne treatment; antiaging effect; anti-dandruff; natural cosmetics; Neem biocompounds;
oral care; skin disorders; skin-whitening
1. Introduction
Azadirachta indica A. Juss, traditionally named Neem (Meliaceae), has been widely
known for centuries as a source of active ingredients to develop products for health
providers in remote areas. Thus, primary healthcare in developing countries has included
treatments with this tree or its parts [
1
]. For instance, Indian traditional medicine reported
cases of success that were not always scientifically tested [
2
]. A. indica is considered a
multipurpose medicinal tree. Outstanding for its wide distribution in nature, as well as
its low toxicity, Neem can be considered a natural source of cosmetic raw material for
large-scale production. This tree is biologically close to Mahogany and all its parts (root,
gum, leaves, flowers and fruits) can be used in agriculture, medicine and cosmetology since
Cosmetics 2022,9, 58. https://doi.org/10.3390/cosmetics9030058 https://www.mdpi.com/journal/cosmetics
Cosmetics 2022,9, 58 2 of 17
the seeds and leaves have a higher concentration of secondary metabolites, which are more
accessible through different extraction processes. Therefore, its beneficial effects can be
attributed to one or more phytochemicals, including flavonoids, for instance. In general, it
has a better effect through the synergism of its constituents [3].
The concentration of phytocomponents may vary according to the mode of harvest,
storage, moisture content, light, temperature and variations in pH. In recent literature,
antiseptic, anti-inflammatory and chemopreventive activities were described [
4
]. Moreover,
other pharmacological features, such as antidiabetic, hypolipidemic, hepatoprotective,
antipyretic, antifertility, hypoglycemic, cardioprotective, antiulcer, neuroprotective, antiox-
idant, microbicidal, nematicidal and antileishmaniasis properties were described [
1
]. In
addition, more recent scientific reports remarked on the possibility of using it as a biopesti-
cide [
1
,
5
,
6
]. However, there are few studies describing its use in topical products for human
health. For instance, it was evaluated in terms of the
in vitro
SPF (sun protection factor)
values of creams containing A. indica oil in a recent study. The SPF values were higher
than the commercial cream, thus, revealing this plant as an alternative for the production
of multifunctional sunscreens. Moreover, such cream was inoffensive to representative
skin flora [
7
]. Likewise, until the present date, there have been only a few efforts of
in vivo
testing with cosmetic samples containing A. indica ethanolic extract with satisfactory safety
results [8].
As an interesting technological development, plant biotechnology is currently used to
produce targeted compounds with extraction advantages beyond the traditional ones [
9
].
Furthermore, some reports highlighted the importance of culturing A. indica to enhance the
production of useful targeted compounds [
9
,
10
]. Although there are some previous studies
about A. indica general uses, this review not only focused on the main dermatological effects
of A. indica but also on the new possibilities claimed in patents to produce dermocosmetics
with enhanced attributes. Hence, we aimed to aid in the scientific selection of novel
ingredients derived from plant resources and meeting the increasing consumers’ demand
for naturally derived ingredients, including in the cosmetic market.
2. Phytochemical Composition
The major representative phytochemical compounds are oxidized tetranortriterpenoids,
such as azadirachtin A (azadirachtin), azadirachtin B (3-tigloylazadirachtol), azadirachtin
D (1-tigloyl-3-acetyl-11-hydroxy-meliacarpin), azadirachtin H (11-demethoxycarbonyl
azadirachtin), azadirachtin I (1-tigloyl-3acetyl-11-hydroxy-11-demethoxycarbonyl meli-
acarpin), azadirachtanin, azadiriadione, azadirachtolide, deacetylnimbin, epoxyazadira-
dione, isoazadirolide, margosinolide, nimbin, nimbolin A, nimbandiol, nimocinol, nim-
binene, nimbocinone, nimbocinolide, nimocin, nimbolide, salannin and related deriva-
tives [
3
,
11
13
]. Many of these have specific physiological functions, mainly in the de-
fense against harmful environmental factors, such as light, predators, microorganisms
and insects. Moreover, the different parts of Neem trees were used to isolate more
than
135 phytocompounds
. At least nine limonoids are triterpenes. Limonoids named
azadirachtin A–G (produced in leaves) are the most studied and they have activities that
allow them to be used as potent insecticides. Moreover, the bark is rich in lignans [3].
Other biological activities found in Neem oil studies are attributed to the following
compounds: salannin, nimbin, meliantriol, meliacin, tignic acid, gedunin (also present
in leaves), nimbidin, nimbidic acid, nimbidinin, nimbolide (found in leaves), valassin,
meliacin, deacetylnimbin, linoleic acid, stearic acid, palmitic acid, oleic acid, azadiradione,
hexadecanoic acid, caryophyllene oxide, linalool oxide, mahmoodin, margolone, azadirone,
nimbolin, nimbinene and nimbosterol. Neem kernels have 30–50% oil, which is mainly
used in soaps, biopesticides and pharmaceuticals [3,1113].
Furthermore, it can be mentioned that the following nonisoprenoid compounds are
present: proteins (amino acids), sulfurous compounds, carbohydrates (polysaccharides),
polyphenolics such as flavonoids and their glycosides, rutin, dihydrochalcone, quercetin,
carotenoids, catechin, ferulic acid,
β
-sitosterol, steroids (produced in leaves and/or bark),
Cosmetics 2022,9, 58 3 of 17
coumarin and tannins (produced in the bark), aliphatic compounds, ellagic acid, lupeol,
saponins (leave), alkaloids (leave), resins, gums, margisine, cyclic trisulphide, steroids and
ketones [3,4,13,14]. Hence, Table 1shows the main secondary metabolites that are used in
cosmetics and topical products with the corresponding reported biological activities.
Table 1.
Phytochemical structures of Azadirachta indica (Neem) parts with their cosmetic or
topical applications.
Phytochemical Neem Part Structural Formula Biological Activity References
Nimbolide Oil from leaves and
seeds, fruit
Cosmetics 2022, 9, x FOR PEER REVIEW 3 of 17
carotenoids, catechin, ferulic acid, β-sitosterol, steroids (produced in leaves and/or bark),
coumarin and tannins (produced in the bark), aliphatic compounds, ellagic acid, lupeol,
saponins (leave), alkaloids (leave), resins, gums, margisine, cyclic trisulphide, steroids
and ketones [3,4,13,14]. Hence, Table 1 shows the main secondary metabolites that are
used in cosmetics and topical products with the corresponding reported biological activ-
ities.
Table 1. Phytochemical structures of Azadirachta indica (Neem) parts with their cosmetic or topical
applications.
Phytochemical Neem Part Structural Formula Biological Activity References
Nimbolide Oil from leaves
and seeds, fruit
Psoriasis, antibacterial [15,16]
Gedunin Oil from leaves
and seeds
Antifungal [15,16]
Mahmoodin Oil from seeds
Antibacterial [15]
Margolone Oil from seeds
and stem bark
Antibacterial [15,16]
Psoriasis, antibacterial [15,16]
Gedunin Oil from leaves
and seeds
Cosmetics 2022, 9, x FOR PEER REVIEW 3 of 17
carotenoids, catechin, ferulic acid, β-sitosterol, steroids (produced in leaves and/or bark),
coumarin and tannins (produced in the bark), aliphatic compounds, ellagic acid, lupeol,
saponins (leave), alkaloids (leave), resins, gums, margisine, cyclic trisulphide, steroids
and ketones [3,4,13,14]. Hence, Table 1 shows the main secondary metabolites that are
used in cosmetics and topical products with the corresponding reported biological activ-
ities.
Table 1. Phytochemical structures of Azadirachta indica (Neem) parts with their cosmetic or topical
applications.
Phytochemical Neem Part Structural Formula Biological Activity References
Nimbolide Oil from leaves
and seeds, fruit
Psoriasis, antibacterial [15,16]
Gedunin Oil from leaves
and seeds
Antifungal [15,16]
Mahmoodin Oil from seeds
Antibacterial [15]
Margolone Oil from seeds
and stem bark
Antibacterial [15,16]
Antifungal [15,16]
Mahmoodin Oil from seeds
Cosmetics 2022, 9, x FOR PEER REVIEW 3 of 17
carotenoids, catechin, ferulic acid, β-sitosterol, steroids (produced in leaves and/or bark),
coumarin and tannins (produced in the bark), aliphatic compounds, ellagic acid, lupeol,
saponins (leave), alkaloids (leave), resins, gums, margisine, cyclic trisulphide, steroids
and ketones [3,4,13,14]. Hence, Table 1 shows the main secondary metabolites that are
used in cosmetics and topical products with the corresponding reported biological activ-
ities.
Table 1. Phytochemical structures of Azadirachta indica (Neem) parts with their cosmetic or topical
applications.
Phytochemical Neem Part Structural Formula Biological Activity References
Nimbolide Oil from leaves
and seeds, fruit
Psoriasis, antibacterial [15,16]
Gedunin Oil from leaves
and seeds
Antifungal [15,16]
Mahmoodin Oil from seeds
Antibacterial [15]
Margolone Oil from seeds
and stem bark
Antibacterial [15,16]
Antibacterial [15]
Margolone Oil from seeds and
stem bark
Cosmetics 2022, 9, x FOR PEER REVIEW 3 of 17
carotenoids, catechin, ferulic acid, β-sitosterol, steroids (produced in leaves and/or bark),
coumarin and tannins (produced in the bark), aliphatic compounds, ellagic acid, lupeol,
saponins (leave), alkaloids (leave), resins, gums, margisine, cyclic trisulphide, steroids
and ketones [3,4,13,14]. Hence, Table 1 shows the main secondary metabolites that are
used in cosmetics and topical products with the corresponding reported biological activ-
ities.
Table 1. Phytochemical structures of Azadirachta indica (Neem) parts with their cosmetic or topical
applications.
Phytochemical Neem Part Structural Formula Biological Activity References
Nimbolide Oil from leaves
and seeds, fruit
Psoriasis, antibacterial [15,16]
Gedunin Oil from leaves
and seeds
Antifungal [15,16]
Mahmoodin Oil from seeds
Antibacterial [15]
Margolone Oil from seeds
and stem bark
Antibacterial [15,16]
Antibacterial [15,16]
Cyclic trisulphide Oil from seeds
and leaves
Cosmetics 2022, 9, x FOR PEER REVIEW 4 of 17
Cyclic trisul-
phide
Oil from seeds
and leaves
Antifungal [16]
4 azadiradione-
type limonoids Leaf extract
Melanogenesis inhibition [17]
2 salannin-type
limonoids Leaf extract
Melanogenesis inhibition [17]
5 nimbin-type
limonoids Root extract
Melanogenesis inhibition [17]
Limonoid Leaves extract
Anti-inflammatory [18]
3. Recent Developments in Cell Culture to Produce Molecules for Cosmetic Use
The biotechnological aspects of differentiated plant cell tissue in A. indica cultivation,
as well as the biosynthesis of interesting secondary metabolites under different nutritional
and environmental conditions, are well described in the literature. Recent efforts have fo-
cused on modifying the nutritional necessities of cells, optimizing the culture medium
composition, and evaluating the amount of both the elicitor and precursor, which could
improve not only cell growth but also secondary metabolites formation. Such studies in-
tended to produce enhanced azadirachtin and related limonoids (AZRL) [5]. However,
this review focused on the production of possible cosmeceutical ingredients derived from
A. indica.
Antifungal [16]
Cosmetics 2022,9, 58 4 of 17
Table 1. Cont.
Phytochemical Neem Part Structural Formula Biological Activity References
4 azadiradione-type
limonoids Leaf extract
Cosmetics 2022, 9, x FOR PEER REVIEW 4 of 17
Cyclic trisul-
phide
Oil from seeds
and leaves
Antifungal [16]
4 azadiradione-
type limonoids Leaf extract
Melanogenesis inhibition [17]
2 salannin-type
limonoids Leaf extract
Melanogenesis inhibition [17]
5 nimbin-type
limonoids Root extract
Melanogenesis inhibition [17]
Limonoid Leaves extract
Anti-inflammatory [18]
3. Recent Developments in Cell Culture to Produce Molecules for Cosmetic Use
The biotechnological aspects of differentiated plant cell tissue in A. indica cultivation,
as well as the biosynthesis of interesting secondary metabolites under different nutritional
and environmental conditions, are well described in the literature. Recent efforts have fo-
cused on modifying the nutritional necessities of cells, optimizing the culture medium
composition, and evaluating the amount of both the elicitor and precursor, which could
improve not only cell growth but also secondary metabolites formation. Such studies in-
tended to produce enhanced azadirachtin and related limonoids (AZRL) [5]. However,
this review focused on the production of possible cosmeceutical ingredients derived from
A. indica.
Melanogenesis
inhibition [17]
2 salannin-type
limonoids Leaf extract
Cosmetics 2022, 9, x FOR PEER REVIEW 4 of 17
Cyclic trisul-
phide
Oil from seeds
and leaves
Antifungal [16]
4 azadiradione-
type limonoids Leaf extract
Melanogenesis inhibition [17]
2 salannin-type
limonoids Leaf extract
Melanogenesis inhibition [17]
5 nimbin-type
limonoids Root extract
Melanogenesis inhibition [17]
Limonoid Leaves extract
Anti-inflammatory [18]
3. Recent Developments in Cell Culture to Produce Molecules for Cosmetic Use
The biotechnological aspects of differentiated plant cell tissue in A. indica cultivation,
as well as the biosynthesis of interesting secondary metabolites under different nutritional
and environmental conditions, are well described in the literature. Recent efforts have fo-
cused on modifying the nutritional necessities of cells, optimizing the culture medium
composition, and evaluating the amount of both the elicitor and precursor, which could
improve not only cell growth but also secondary metabolites formation. Such studies in-
tended to produce enhanced azadirachtin and related limonoids (AZRL) [5]. However,
this review focused on the production of possible cosmeceutical ingredients derived from
A. indica.
Melanogenesis
inhibition [17]
5 nimbin-type
limonoids Root extract
Melanogenesis
inhibition [17]
Limonoid Leaves extract
Cosmetics 2022, 9, x FOR PEER REVIEW 4 of 17
Cyclic trisul-
phide
Oil from seeds
and leaves
Antifungal [16]
4 azadiradione-
type limonoids Leaf extract
Melanogenesis inhibition [17]
2 salannin-type
limonoids Leaf extract
Melanogenesis inhibition [17]
5 nimbin-type
limonoids Root extract
Melanogenesis inhibition [17]
Limonoid Leaves extract
Anti-inflammatory [18]
3. Recent Developments in Cell Culture to Produce Molecules for Cosmetic Use
The biotechnological aspects of differentiated plant cell tissue in A. indica cultivation,
as well as the biosynthesis of interesting secondary metabolites under different nutritional
and environmental conditions, are well described in the literature. Recent efforts have fo-
cused on modifying the nutritional necessities of cells, optimizing the culture medium
composition, and evaluating the amount of both the elicitor and precursor, which could
improve not only cell growth but also secondary metabolites formation. Such studies in-
tended to produce enhanced azadirachtin and related limonoids (AZRL) [5]. However,
this review focused on the production of possible cosmeceutical ingredients derived from
A. indica.
Anti-inflammatory [18]
3. Recent Developments in Cell Culture to Produce Molecules for Cosmetic Use
The biotechnological aspects of differentiated plant cell tissue in A. indica cultivation,
as well as the biosynthesis of interesting secondary metabolites under different nutritional
and environmental conditions, are well described in the literature. Recent efforts have
focused on modifying the nutritional necessities of cells, optimizing the culture medium
composition, and evaluating the amount of both the elicitor and precursor, which could
improve not only cell growth but also secondary metabolites formation. Such studies
intended to produce enhanced azadirachtin and related limonoids (AZRL) [
5
]. However,
this review focused on the production of possible cosmeceutical ingredients derived from
A. indica.
The rheological properties with their main parameters, such as the Reynolds num-
ber, apparent viscosity, volumetric power and phase state of A. indica cell cultures, were
evaluated in 250 mL shake flasks that were 5 cm in diameter. The morphological aspects
were evaluated and it was demonstrated that the isodiametric round shape of their huge
individual cells, as well as their tendency to produce cell clusters, determined the capacity
of such cell cultures to store secondary metabolites with high commercial interest in terms
of developing both pharmaceuticals and cosmetics [
19
]. Moreover, the culturing of plant
cells of A. indica was developed to continuously produce its principal secondary metabo-
lites in recent years [
9
,
10
]. For instance, azadirachtin, mevalonic acid and squalene were
Cosmetics 2022,9, 58 5 of 17
successfully extracted from an A. indica cell suspension culture by using a green analytical
method for ultrasound-assisted extraction with ethanol as solvent [9].
Another recent study investigated the effect of different culture types, as well as some
concentrations of both cytokinins and auxins on cell biomass production, cell growth and
azadirachtin production with further accumulation in cell suspension, as well as callus
cultures of A. indica [10].
Furthermore, an A. indica culture as a cell suspension was carried out in shake flasks
and bioreactors using a modified culture medium, as well as precursors and elicitors.
They achieved an increase from 0.77 to 4.52 mg limonoids/g dry cell weight (DCW), with
the consequent limonoids volumetric production increasing more than threefold using
a two-stage culture (the one-stage process produced 13.82 mg limonoids/L, while the
two-stage one produced 41.44 mg/L) in the bioreactors [
20
]. Thus, hydrodynamic stress
under different agitation speeds was evaluated in A. indica cultivations using shake flasks.
Some interesting parameters, such as limonoid concentration, cell viability and growth,
reactive oxygen species (ROS) production and glutathione peroxidase (GPx) enzymatic
activity, confirmed the effect of mechanical stimulus on the production of specific secondary
metabolites. In addition to this, the most suitable agitation was 400 rpm with no cell
integrity damage and a maximum biomass concentration of 10.53
±
1.03 g DW containing
82.66 ±32.96 mg limonoid/g DW [21].
4. In Vitro Tests with Dermocosmetic Applications
4.1. Antimicrobial Activity
Plants have substances called secondary metabolites that can develop antibacterial,
antifungal and/or antioxidant activities (such as glycosides, alkaloids, flavonoids, saponins,
among others), and can be also part of a defense mechanism against pathogens [
14
,
22
].
Such phytochemicals are extracted according to the molecule polarity and the character-
istics of the vegetable part used. Thus, studies with methanolic extracts from A. indica
leaves inhibited the action of Bacillus, while oils from seeds, bark and leaves could in-
hibit the growth and/or viability of Gram-negative and Gram-positive bacteria. Among
Gram-positive bacteria, we highlight the strains of M. pyogenes, Streptococcus mutans and
Staphylococcus aureus, which are commonly found on the skin’s surface [4].
Moreover,
β
-sitosterol is recognized for its wide spectrum in treating skin diseases [
4
]. In
addition to the compounds mentioned above, nimbolide and nimbidin were found in A. indica,
which showed antibacterial activity against the following species:
Staphylococcus coagulase
,
S. aureus
,Staphylococcus sp. and Serratia. Moreover, various concentrations of an aque-
ous extract of Neem leaves inhibited the growth of Bacteroides intermedius,B. gingivalis,
Streptococcus viridans
and S. salivarius
in vitro
[
23
]. Furthermore, nimbidin isolated from
bark showed antifungal activity [4,14].
A. indica was classified as the most effective medicinal plant for dermatophytosis in
traditional treatment due to its components. A study revealed the minimum fungicidal
concentration (MFC) and the minimum inhibitory concentration (MIC) for the leaf and seed
extracts of A. indica against various dermatophytes, such as Trichophyton mentagrophytes,
T. rubrum
and Microsporum nanum. The growth curve of such dermatophytes was affected
in the presence of A. indica extracts, whose effect was unexpected when compared with the
dermatophytes without extracts [24].
Moreover, gedunin has antifungal activity and deoxygedunin has moderate antibac-
terial action, both of which were isolated from Neem seed oil [
4
]. A. indica leaf and seed
grain extracts were effective against the human fungi Candida, Geotrichum,Epidermophyton,
Trichophyton,Microsporum and Trichosporon [14].
In addition to this, the antifungal properties of A. indica leaf extracts were attributed
to the inhibition of dermatophytes. The effect was attributed due to the presence of
quercetin [
14
]. Thus, various concentrations of petroleum ether extracts of the Neem
leaves inhibited the growth of Microsporum canis, M. gypseum, Epidermophyton floccosum,
Trichophyton concentricum, T. rubrum and T. violaceum [
24
]. Furthermore, the leaf extracts
Cosmetics 2022,9, 58 6 of 17
and seed oil inhibited the growth of E. floccosum T. mentagrophytes, M. canis and T. rubrum,
where the extract from Neem leaves had the highest antifungal activity of both [25].
Sulfur-containing compounds isolated from the steam distillation of fresh and ripe
Neem leaves revealed antifungal activity against Trichophyton mentagrophytes [
4
]. In ad-
dition, some A. indica extracts that contained flavonoids with known antioxidant activity
were evaluated. For instance, rutin was one of the flavonoids found in A. indica leaves,
where the antibacterial action of quercetin combined with rutin was superior in relation to
the same isolates [14].
Studies demonstrated that tetranortriterpenoid and some other phytocompounds,
such as azadiradione, 6-deacetylnimbin, salannin, nimbin and epoxyazadiradione, were
the main antifungal compounds from A. indica. However, the triterpenoids from Neem oil
in its pure form (separately) showed basically no antifungal activity, while the combined
effect was demonstrated against the three fungi tested, which may be indicative of such
compounds having additive or synergistic effects [26].
Furthermore, nimbolide showed the greatest zone of inhibition against some bacteria
species, such as S. epidermis, S. aureus, P. aeruginosa, K. pneumoniae and S. aureus (MR
—methicillin
resistant), in agar diffusion assay. The highest inhibition level was found
against K. pneumonia, as well as the synergistic action of nimbolide, when combined with
the pre-existing antibiotics cephalexin (97% pure) and cefazolin (98% pure). Thus, a greater
antimicrobial effect in the synergy with these antibiotics compared to the other tested
compounds (such as deacetylnimbin) was shown [27].
4.2. Antioxidant Activity
It is known that ROS and free radicals are involved in cancer, DNA damage and even
aging [
1
], and the addition of antioxidants in dermocosmetics can minimize these effects.
Thus, some extracts that contained flavonoids with known antioxidant effects and other
extracts derived from A. indica flowers and young leaves showed strong antioxidant poten-
tial [
4
]. Moreover, the aqueous fraction of the Neem bark had greater antioxidant activity
than the leaf extract because of the higher concentration of phenolic compounds [28].
The topical application of A. indica leaf ethanolic extract was tested on hairless mice
exposed to UVB irradiation to prevent the formation of wrinkles. To carry out this study,
dry Neem leaves (10 g) were used, which were pulverized and extracted three times with
1 L
of 50% ethanol over 24 h at room temperature. Then, the extract was analyzed via liquid
chromatography, using methanol as the mobile phase. Moreover, a significant amount of
rutin was found in the dried leaf extract, showing a high capacity to eliminate free radicals,
which indicated the antioxidant activity. Finally, it was found that mice exposed to UVB
irradiation and received the treatment with A. indica leaf extract had less wrinkle formation
than the other groups, indicating a possible antiaging effect of the A. indica extracts [29].
4.3. Skin-Soothing and Melanogenesis Inhibition Activities
A detailed investigation of two species from Meliaceae plants, namely,
Azadirachta indica
(Neem, AI) and Azadirachta indica var. siamensis (Siamese Neem, AIS), isolated and cat-
egorized 81 limonoids, 11 flavonoids and 1 diterpenoid, and revealed inhibitory activity
against melanogenesis in B16 and tumor promoter assay (TPA)-induced inflammation in
mice [17].
As it is well known, skin color depends mainly on the pigment melanin. The biosyn-
thetic pathway named melanogenesis is responsible for melanin production in human
skin. Furthermore, a form of hyperpigmentation condition named melasma was often
reported as brown or gray patches on facial skin. Thus, there is an increasing demand
for dermocosmetics to diminish skin hyperpigmentation, e.g., those containing melano-
genesis inhibitors. Many of the AI and AIS compounds have revealed inhibitory activity
against melanogenesis in B16 4A5 (mouse melanoma cells) stimulated with [
30
] or with-
out
α
-melanocyte-stimulating hormone (
α
-MSH) [
31
]. Hair and skin pigmentation are a
response to the stimulation of
α
-MSH. Among the AI and AIS compounds, some of them
Cosmetics 2022,9, 58 7 of 17
(4 azadiradione-type limonoids, 5 nimbin-type limonoids and 2 salannin-type limonoids)
showed higher melanogenesis inhibition (79.1–108.1% cell viabilities) than the reference
arbutin (4-hydroxyphenyl
β
-D-glucopyranoside; 100.1% cell viabilities), which was used as
a depigmentation alternative in skin whitening for the cosmetic sector. Likewise, tyrosinase,
which catalyzes the oxidation of L-DOPA to L-DOPA quinone, as well as the hydroxylation
of L-tyrosine to L-(3,4-dihydroxyphenyl) alanine (L-DOPA), tyrosinase-related protein-
1 (TRP-1), TRP-2 and tyrosinase, are involved in melanin biosynthesis. Furthermore, a
nimbin-type limonoid from an AIS root extract, which was reported as the most abundant
limonoid, was the most effective melanogenesis inhibitor [17].
Furthermore, the TPA-induced inflammatory ear edema in mice was studied to inves-
tigate the limonoids from AI and AIS extracts. A single application of TPA induced skin
inflammation that was mainly defined by edema, polymorphonuclear leukocyte infiltra-
tion and erythema. The tested limonoids showed higher anti-inflammatory activity (50%
inhibitory dose, ID50 = 0.19–0.75
µ
mol/ear) than indomethacin (ID50 = 0.91
µ
mol/ear) [
17
].
5. In Vivo Tests (Subjects) for Cosmetic Applications
Some preclinical trials that investigated the antidiabetic, anti-inflammatory, analgesic,
antinociceptive and insecticidal/pesticidal activities of A. indica extracts using different
parts are described in the literature [
1
]. Thus, we discuss the first attempts with volunteers
for new cosmetics development in the next paragraphs.
Neem oil was used in an emollient cream to assess its photoprotective effect, rheologi-
cal characterization, toxicity and effect on the natural cutaneous flora health. Volunteers
were used as donors of their skin’s bacterial flora, rubbing it with sterile swabs and grown
on agar with nutrients and incubated for 24 h at 37
C. As a result, the rheological character-
ization was similar to the commercial creams. Such Neem formulation had no cytotoxicity
in 3T3 cell lines, as well as no damage to the natural cutaneous flora. In addition to this,
when titanium dioxide was added to this cream, it showed greater photoprotective activity
than the commercial product [7].
A randomized double-blind study with a commercial nutritional supplementation
using turmeric polyherbal formulation decreased facial redness compared with the turmeric
or placebo in volunteers in a study within 4 weeks. The turmeric polyherbal tablets
included 500 mg of a blend of the following certified organic herbs: A. indica (Neem) leaf,
H. indicus (anantamul) root, C. longa (turmeric) root, R. cordifola (manjistha) root, C. asiatica
(brahmi/gotu kola) leaf, Glycyrrhiza glabra (licorice) root, Tinospora cordifolia (guduchi) stem,
P. amarus (bhumyamalaki) herb and P. emblica (amalaki) fruit. Thus, the beneficial effects of
this formulation were attributed to a synergic effect of each plant, such as anti-inflammatory,
antioxidant, photoprotective and anti-aging properties, which enhance both the prevention
and treatment of different skin conditions with different origins [32].
A polyherbal cream was developed as a vaginal cream containing A. indica (Neem)
dry seed extract, Sapindus pericarp extract and quinine hydrochloride, which gave the
cream a spermicidal action, as well as antimicrobial properties. The mentioned ingredients
were incorporated into a water-soluble cream base and stabilized with the addition of
antioxidant and preservative components. Then, an
in vivo
test was performed with
intravaginal application in both rabbits and monkeys. Finally, such cream was tested and
considered devoid of both sensitization and irritation with the Draize test using a 21-day
duration cumulative skin sensitivity test in volunteers [33].
In a more recent study, a polyherbal gel was developed with ethanolic extracts
of the following species: A. indica, Piper betle, Adhatoda vasica, Pongamia pinnata and
Ocimum tenuiflorum
to evaluate its antimicrobial action. Moreover, its drug content, physi-
cal appearance, viscosity, pH, spreadability, washing ability and skin irritation were tested.
To do so, twenty healthy volunteers were submitted to the patch test, which was applied
in the forearm of each participant to detect the possible reactions to formulations A, B,
C (with 0.1, 0.3 and 0.5% ethanolic extracts, respectively) and the control after 48 h. It
was concluded that the combination of ethanolic extracts did not demonstrate any serious
Cosmetics 2022,9, 58 8 of 17
adverse reaction, and thus, they are considered safe in those conditions. In addition, the
most effective concentration tested was 0.5% [8].
Furthermore, a 6-week study was performed to evaluate the effectiveness of Neem
extract dental gel with a positive control containing chlorhexidine gluconate (0.2% w/v)
mouthwash. It showed that the Neem extract dental gel exhibited a higher reduction in the
bacterial presence, as well as the plaque index than the control group [34].
6. Alternative Dermatological Effects
Other dermatological properties of A. indica included its use as a wound healer. The
healing activity of methanolic extracts from leaves of both A. indica and Tinospora cordifolia
was evaluated using models of excision and incision of wounds in rats. It was concluded
that the extracts had healing activity both in the excision and in the incision, with the
first presenting greater healing potential than the second. There was greater resistance to
traction of the scar tissue, as well as a higher proportion of wound contraction [35].
Organic Neem oil has been used to treat other skin disorders, such as acne, psoriasis,
eczema, mycosis and warts. Indeed, the Indian Siddha medicine has been using Neem oil
and leaves since ancient times to treat skin diseases, mainly psoriasis [36,37].
In addition, new technologies involving Neem and its dermatological effects are
emerging with interesting results that could be used for the improvement of new dermo-
cosmetics. For instance, the antidermatophytic activity of leaves and seeds of A. indica,
as well as the effect on growth patterns in dermatophytes, were performed. After the
extraction of compounds from Neem leaves and seeds, the fungi Trichophyton mentagrophyte,
Microsporum nanum and T. rubrum were inoculated. The MIC and MFC values were deter-
mined, where the first is considered the lowest extract concentration that did not reveal
any viable growth after incubation (21 days), while the second is the lowest extract con-
centration that inhibits the fungal growth in the solid medium. The growth pattern of the
tested fungi with Neem extract on an agar medium was compared with the control. Thus,
it was identified that the extract of Neem leaves and seeds had high antidermatophytic
properties [24].
On the other hand, the potential of A. indica in microspheres with a mucoadhesive
polymer, which were prepared using an ionotropic gelation method, was evaluated as an
oral controlled drug delivery system. The
in vivo
pharmacokinetic studies using rabbits
revealed an increase in mean residence time by 75% and relative bioavailability by 1.5 times,
meaning that it is a good option for oral controlled drug delivery systems [38].
Furthermore, the Neem constituents were deemed effective against several cancer
types, including both connective tissue and skin cancer using
in vivo
and
in vitro
models.
Animal studies showed anti-cancer activity from nimbolide. For instance, nimbolide
isolated from Neem at 5 and 20 mg/kg significantly reduced the growth of colorectal
cancer xenografts in mice. Xenografts are tissues that are transplanted from one species to
another. Moreover, a significant decreased in tumorigenic protein, such as those related
to proliferation, survival, invasion, metastasis and angiogenesis, were also reported in the
mice xenograft treated with nimbolide [39].
An ethosomal formulation with soy lecithin (300 mg), ethanol (35%), luliconazole (
100 m
g)
and Neem extract was more effective against Candida parapsilosis than
Aspergillus niger
in fungal
culture tubes. In the same study, the
in vitro
drug permeation test with Wistar albino rat
skin model demonstrated the release of 83.45
±
2.51% in 24 h. Thus, luliconazole and Neem
extract showed synergistic effects against fungal infections [40].
Interestingly, A. indica was reported as a nutritional strategy for psoriasis in a recent
study since it is rich in nimbidin. A significant reduction in the PASI (psoriasis area
and severity index) score was observed after 12 weeks of consuming three capsules/day
of
A. indica
in an RCT (randomized controlled trial) of 50 patients. According to the
authors, this may have been due to the inhibition of prostaglandin synthetase by nimbidin,
which is a secondary metabolite found in the A. indica essential oil [
41
]. Hence, Figure 1
Cosmetics 2022,9, 58 9 of 17
summarizes the mentioned biological activities of A. indica parts with the corresponding
dermocosmetic attributes.
Cosmetics 2022, 9, x FOR PEER REVIEW 9 of 17
Animal studies showed anti-cancer activity from nimbolide. For instance, nimbolide iso-
lated from Neem at 5 and 20 mg/kg significantly reduced the growth of colorectal cancer
xenografts in mice. Xenografts are tissues that are transplanted from one species to an-
other. Moreover, a significant decreased in tumorigenic protein, such as those related to
proliferation, survival, invasion, metastasis and angiogenesis, were also reported in the
mice xenograft treated with nimbolide [39].
An ethosomal formulation with soy lecithin (300 mg), ethanol (35%), luliconazole
(100 mg) and Neem extract was more effective against Candida parapsilosis than Aspergillus
niger in fungal culture tubes. In the same study, the in vitro drug permeation test with
Wistar albino rat skin model demonstrated the release of 83.45 ± 2.51% in 24 h. Thus, lu-
liconazole and Neem extract showed synergistic effects against fungal infections [40].
Interestingly, A. indica was reported as a nutritional strategy for psoriasis in a recent
study since it is rich in nimbidin. A significant reduction in the PASI (psoriasis area and
severity index) score was observed after 12 weeks of consuming three capsules/day of A.
indica in an RCT (randomized controlled trial) of 50 patients. According to the authors,
this may have been due to the inhibition of prostaglandin synthetase by nimbidin, which
is a secondary metabolite found in the A. indica essential oil [41]. Hence, Figure 1 summa-
rizes the mentioned biological activities of A. indica parts with the corresponding dermo-
cosmetic attributes.
Figure 1. Main A. indica biological activities with their dermocosmetic attributes.
7. Toxicology Issues
Regarding the toxicological profile of A. indica species, recorded data refers to the
extracts of the leaf and bark, the limonoids and the oil from seeds [42]. The first and prin-
cipal data came mainly from scientific studies conducted on animals, as they were in a
period before the current evolution of alternative methods in scientific research. Further-
more, most of this data was registered at REACH (Registration, Evaluation, Authoriza-
tion, and Restriction of Chemicals), which is an institution regulated by the European Un-
ion. These data are freely accessible and can be used to understand the toxicological pro-
file of A. indica and its phytochemical components, exempting the need to repeat safety
tests that have already been performed [43].
Considering the A. indica safety for human health, the principal tests for Neem and
its components described by the Organization for Economic Cooperation and Develop-
Figure 1. Main A. indica biological activities with their dermocosmetic attributes.
7. Toxicology Issues
Regarding the toxicological profile of A. indica species, recorded data refers to the ex-
tracts of the leaf and bark, the limonoids and the oil from seeds [
42
]. The first and principal
data came mainly from scientific studies conducted on animals, as they were in a period
before the current evolution of alternative methods in scientific research. Furthermore,
most of this data was registered at REACH (Registration, Evaluation, Authorization, and
Restriction of Chemicals), which is an institution regulated by the European Union. These
data are freely accessible and can be used to understand the toxicological profile of A. indica
and its phytochemical components, exempting the need to repeat safety tests that have
already been performed [43].
Considering the A. indica safety for human health, the principal tests for Neem and its
components described by the Organization for Economic Cooperation and Development
(OECD) found the following results: ocular irritation, skin sensitization and irritation, acute
oral toxicity, subacute oral toxicity, acute dermal toxicity, reproductive toxicity, teratogenic-
ity, inhalation toxicity, mutagenicity and genotoxicity. Concerning the ocular irritation
classification, a study revealed that when 0.1 mg of an ethanolic extract of Neem seed
or an aqueous solution of 1 or 5% sodium nimbidinate was applied in the eyes of male
New Zealand albino rabbits, no severe eye damage or irritation reaction was observed [
44
].
Moreover, a complementary study under the same conditions mentioned above with a 10%
aqueous solution of sodium nimbidinate revealed that the substance applied to the eyes
of guinea pigs did not show any irritating reaction [
45
]. Therefore, there is no scientific
evidence for the potential eye irritant action of A. indica.
Some toxicological studies of different parts of A. indica were recently described [
1
]. In
addition, a complementary study showed that Margosan-O
®
, an approved Neem-based
insecticide, which included a concentrated ethanolic extract of Neem seeds at 3000 ppm
azadirachtin (
±
10%), caused low-to-moderate primary skin irritation when intradermally
administered to albino rabbits [
46
]. Additionally, there is a record of the classification of
the substance azadirachtin (CAS number 11141-17-6, with 95% purity) in category 1B of the
GHS (Globally Harmonized System of Classification and Labeling of Chemicals) for skin
Cosmetics 2022,9, 58 10 of 17
sensitization. This category indicates that the substance, under the conditions evaluated, is
a skin sensitizer [47].
Acute oral toxicity studies showed that methanolic extracts of Neem leaf and peel,
administered orally in rats, showed an LD50 (50% oral lethal dose) of about 13 g/kg of
the animal, leading to the death of mice by terminal seizure [
48
]. Moreover, the study
noted that the animals that survived had gastrointestinal spasms, hypothermia and apathy,
and refused water and feed. These data on acute oral toxicity in rodents corroborated
another study in which Neem seed oil was orally administered to rats and rabbits, and the
measured LD50 of 24 h was 14 and 24 mL/kg, respectively [49].
According to a study that assessed the subacute oral toxicity in rodents, adult Holtz-
man rats received a single daily dose of an alcoholic solution of nimbidin at concentrations
of 25, 50, and 100 mg/kg in their diets for 6 weeks. The trial revealed that the rodents did
not show any severe toxic symptoms during the study period [
50
]. Moreover, acute dermal
toxicity data published on the administration of concentrated ethanolic extract Margosan-
O
®
in albino rabbits indicated that the substance had an LC50 (lethal concentration 50%)
greater than 2 mL/kg [46].
Concerning reproductive toxicity, a study evaluated the administration of an aque-
ous extract of A. indica wood ash in male albino mice in three different doses (5, 50 and
100 mg/kg
body weight). The parameters evaluated were the following: gonadosomatic
index, sperm count, sperm motility, sperm morphological analysis, serum quantifica-
tion of follicle-stimulating (FSH) and luteinizing (LH) hormones, testosterone assay and
histopathological observations of the testicles. The results concluded that even without
a toxic effect on testicular weight, testosterone, and the hormones FSH and LH, there
was a significant reduction in motility and sperm count [
51
]. Furthermore, another study
evaluated the effect on reproductive toxicity in quails (Coturnix coturnix japonica L.) fed
with Neem seeds incorporated in the feed in the proportions of 0, 5, 10, 20 and 40% for
60 days. The study concluded that there were significant changes in sperm concentration,
seminal volume, vigor, motility and sperm viability [
52
]. Thus, in both studies, the authors
concluded that A. indica should impair reproduction, presenting a considerable degree of
reproductive toxicity.
Furthermore, another study evaluated the teratogenic profile of nimbidin. It assessed
the effects of the oral administration of a 10% aqueous solution of nimbidin at 25, 50 and
100 mg/kg in fertile rats mated for 13 days. The evaluated parameter was the presence of
severe anatomical fetal abnormalities. This study concluded that even the highest applied
doses did not cause any deformity in the organs of the born pups. Thus, there was no
subsequent adverse effect on breeding performance. In conclusion, nimbidin did not have
a potential teratogenic action [50].
Toxicological data identified for A. indica, as well as its phytochemical components,
indicated that these substances were susceptible to applications in dermocosmetic formu-
lations since there was no evidence of risks to human health for the intended application.
However, there were no scientific reports on the safety of A. indica and its components re-
garding carcinogenicity and phototoxicity, for example. Thus, additional toxicological tests
are still necessary to expand the coverage of the safety of these substances. Furthermore,
all dermocosmetic information, even if supported by toxicological data of the individual
components, must present evidence of the toxicological safety of the integral formula,
previous safety of potential synergism or potentiation of toxic effects associated with the
substance. In contrast, a survey of toxicological data on the safety of A. indica for the envi-
ronment revealed that this substance and its components could be quite aggressive to the
environment [
42
,
53
], unlike the toxicological records identified for their safety concerning
human health.
Additionally, a recent review on the latest
in vivo
toxicity of A. indica extracts is
presented in two major sections: (a) aquatic species toxicity and (b) mammalian (rats,
rabbits, etc.) toxicity, with the corresponding final application as a pesticide or a possible
new therapeutic drug, respectively [54].
Cosmetics 2022,9, 58 11 of 17
Above all, scientific reports showed and recognized the medicinal properties of
A. indica
, even naming it the “village pharmacy” or the “doctor’s tree”. Hence, A. indica is
an excellent candidate for exploratory tests for dermocosmetic effectiveness.
8. Patents Applications
In this section, our research group used three free databases, namely, Espacenet
®
,
Google Patents
®
and PatentScope
®
, to search patents within a 10-year period (
2010–2020
).
To standardize the web research, we used the keywords Azadirachta indica with
two refined
options, namely, title and title + abstract, on the same day (16 July 2020). The main results
are summarized in Table 2.
Table 2.
Patents found in 3 databases with the keywords Azadirachta indica in the title or
title + abstract.
Keywords No. of Patents
Espacenet®Google Patents®PatentScope®
Azadirachta indica (title) 24 5 4
Azadirachta indica
(title + abstract) 204 27 23
In summary, we found patents regarding interesting topics about inducing methods for
hairy roots of A. indica cell cultures, novel methods to prepare extracts, herbal compositions
with different health claims and further pharmaceutical and cosmetic products. Outstand-
ingly, azadirachtin, nimbolide and salannin from Neem are well described in biopesticides
preparations and repellent formulations. Other remarkable innovations also described
the powdered plant in association with other plants to eliminate bacteria from clothes, as
well as insects with an additional advantage on the clothes’ softness. Some documents
concerning medical applications of herbal mixtures containing A. indica claimed the en-
hancement of the immune systems, as well as cancer treatment, in particular for skin-related
malignancies. Furthermore, different drugs were related to ameliorate metabolic syndrome
with inhibition of the increment of body fat, as well as anti-inflammatory compounds for
dental care.
Regarding cosmetic applications, the main patents that involved the use of different
A. indica parts and extracts are summarized in Table 3. Some cosmetic formulations
were developed to ensure the claimed effect reported in each document. We remark that
the synergic effects of the combination of different herbs, their parts or their extracts
were the most common strategy found in the formulations to achieve good results. Only
two products
were developed with a sole A. indica seed extract, which were shampoos that
claimed to provide a desquamation treatment, as well as anti-dandruff properties [
55
,
56
].
The most common cosmetic effect claimed was to treat acne, as well as mitigate other skin
disorders related to inflammatory processes.
Table 3.
Phytochemical structures of Azadirachta indica (Neem) parts with their cosmetic or
topical applications.
A. indica Part(s) Other Main Plants
in Formulations Claims in Cosmetics Patent
Seed extract with n-hexane NI * Bacteria-killing agent in the skin CN109805037A [57]
Extract Mentha canadensis extract
and holy basil
Inhibits the expression of
inflammatory cytokines (IL-8, IL-6)
caused by fine dust, thus alleviating
skin irritation and skin inflammation;
acne prevention and alleviation;
flushing alleviation; and dermatitis
prevention and alleviation
WO2018021777A1 [58]
Cosmetics 2022,9, 58 12 of 17
Table 3. Cont.
A. indica Part(s) Other Main Plants
in Formulations Claims in Cosmetics Patent
Leaf extract
1–10% NI * Skin rejuvenation and fungi and
bacteria treatment MX2013004928A [59]
4–7% of bark aqueous extract
0.5–4% extract of Berberis
aristata, Jasminum officinale,
Glycyrrhiza glabra, Picrorhiza
kurroa, Rubia cordifolia,
Pongamia pinnata, Saussurea
lappa, Stellata wild and
Terminalia chebula; 6–9%
Curcuma longa and
Trichosanthes diocia
Topical wound healing formulation NZ578363A [60]
0.1–5% aqueous extract
0.1–5% Cymbopogon
martyinii oil, 0.1–5% aqueous
extract of A. indica or
Phyllanthus emblica or both
Anti-dandruff composition
(shampoo) WO2020020539A1 [61]
5–8% folium extract
0.1–0.5% Sophorae
flavescentis, 3–10%
Hammamelis extract, 5–10%
Chinese radix Rehmanniae
extract, 3–5% radix
Scutellariae extract, 3–5%
heartleaf Houttuynia herb
extract and 5–8% Glycine soja
seed extract
Acne-removing compound, removes
redness and eliminates swelling in the
skin and acne bacillus on the surface
of a human body cannot generate
drug resistance to the acne-removing
compound preparation
CN110613658A [62]
Flower and fruit extract
Coconut extract, shea butter
fruit oil, Sambucus chinensis
extract and Eucheuma
gelatinae extract
Lipstick, good moistening and
antioxidant effect, and can be
protected so that it can be stored for
one year without bacteria breeding
CN110101628A [63]
Folium extract
Herba violae extract,
Lactobacillus/pear juice
fermented product filtrate and
Polygonum cuspidatum
extract.
Multiple-effect facial mask that has
good repair effects for acne and the
bad symptoms, including rough skin,
scars, hyperpigmentation, etc.,
accompanying the acne
CN108904432A [64]
Folium extract
Lactobacillus/pear juice
fermented product,
Phellodendron bark extract,
white willow bark extract, a
western pear extract,
Scutellariae root extract and
Herba houttuyniae extract
Antioxidant components and inhibits
monophenyl oxidase, where the
acne-removing effect was remarkable
CN108888678A [65]
Leaf extract
Houttuynia cordata extract,
wild soybean seed extract,
Phellodendron bark extract
and Scutellaria
baicalensis extract
Acne-removing skincare product
treatment was mild, non-irritant, easy
to absorb, not greasy, safe
and efficient
CN108434032A [66]
Leaf extract
Dioscoreae bulbiferae bark
extract, Sophorae flavescentis
extract and Salviae
miltiorrhizae extract
Inhibits acne inflammation CN108158972A [67]
Cosmetics 2022,9, 58 13 of 17
Table 3. Cont.
A. indica Part(s) Other Main Plants
in Formulations Claims in Cosmetics Patent
Folium extracts
Sea sludge extracts, amur cork
tree bark extracts, white
willow bark extracts, China
Rehmannia extracts and
Scutellaria extracts
Acne-removing function with a
remarkable oil control effect. CN105770160A [68]
Seed extract
Gleditsia australis extract,
Sapindus mukurossi extract
and Camellia extract
Cleaning skin with a role in inhibiting
and killing bacteria and fungi,
capable of eliminating smells and
resisting corrosion, skin friendly and
soluble in water
CN105769710A [69]
* NI—no information available.
9. Trends in Dermocosmetic Formulations
In this section, we suggest dermocosmetic formulations according to the principal
benefits related to the biochemical composition of A. indica.
Acne: Suppression of the ability of the Propionibacterium acnes pathogen to induce ROS
and pro-inflammatory cytokines. Antibacterial action of A. indica oil was demonstrated
in vitro
against pathogenic bacteria by inhibiting bacterial cell membrane synthesis.
A. indica
contained nimbolid (antibacterial), gedunin (antifungal), mahmoodin (an-
tibacterial), margolone (antibacterial) and cyclic trisulphide (antifungal) [3].
Anti-aging: A. indica stimulated collagen production, promoted soft and supple skin,
aided in reducing old scars and supported healing [12].
Anti-dandruff: A. indica produced antibacterial, antifungal, pain-relieving and another
specific phytocompounds to avoid dandruff [70].
Oral care: Reduction in plaque and treatment of gingivitis and periodontitis (dental
gel) [
3
]. Dental gel with Neem extract reduced plaque and bacteria more than the
commercial mouthwash (chlorhexidine gluconate 0.2% w/v). Furthermore, Neem
could reverse incipient carious lesions and inhibit Streptococcus mutans (bacterium
causing tooth decay) [4].
Health and personal care products: A. indica could be used for nail care (nail oils and
polish), hair care (hair oils and shampoo), oral hygiene (toothpaste and Neem twigs),
skin cleanser, soaps and insect repellent (spray and lotion) [4,14,71,72].
Pediculosis treatment: shampoo with A. indica seed extract was more active than
permethrin-based shampoo against head lice [73].
Scabies treatment: A. indica oil was used in soap production and was indicated
to scabies.
Skin disorders: A. indica could treat lice and scabies. Neem in a paste combination with
Curcuma longa treated scabies and 97% of the volunteers were cured after application
(3 to 15 days) with no adverse effects. Neem was used for diabetic foot, dry psoriasis
and wounds [4,12].
Skin-whitening: A. indica inhibited 47% of tyrosinase with no anti-wrinkle effect, with
it being best for young skin [74].
Wound healing: the presence of tannins could favor the healing of wounds [4].
10. Perspectives and Conclusions
For centuries, the production and commercialization of herbal medicines have faced
many challenges worldwide, mainly in developing countries. Thus, some issues must be
considered as problems to be solved to offer plants or extracts as qualified raw materials for
several industries, such as quality, processing and harvesting issues, and even mainly clini-
Cosmetics 2022,9, 58 14 of 17
cal trials [
2
]. Fortunately, plant biotechnology has emerged to aid in secondary metabolite
production in in vitro controlled conditions, mainly via cell suspension cultures [9].
On the other hand, the most accepted biopesticides are those containing Neem deriva-
tives, e.g., azadirachtin, which is currently established as an essential insecticidal ingre-
dient [
3
,
5
,
6
,
75
]. It acts as a repellent, antifeedant and repugnant agent that also induces
sterility in insects by interrupting sperm production, as well as preventing oviposition in
males. Therefore, more alternative strategies for pest resistance are evolving to develop
more specific nanocarriers aiding in environmental conservation [75].
Most recently, nanotechnology-based plants are used in many scientific domains, such
as controlling pollutants and biomedical fields [
76
]. For instance, metal oxide nanoparticles
were shown to enhance both the antimicrobial activity and photocatalytic potential of the
aqueous leaves extract of A. indica in a recent review [
77
]. Regarding skin disorders, a
simple green route to synthesize silver nanoparticles containing the aqueous extracts of
A. indica leaves had greater antibacterial and free-radical scavenging efficacy. Moreover,
a hydrogel with such nanoparticles was described as a low-toxic, eco-friendly delivery
vehicle with interesting potential in wound healing due to the presence of phenolic com-
pounds, flavonoids, terpenoids and terpenes using topical wounds in rats [
78
]. Therefore,
formulating topical products with A. indica nanoparticles can be a novel choice to produce
safer topical products with proven dermocosmetic attributes.
Indeed, some industries are developing many efforts to establish “green chemistry” to
reduce or avoid both the use and creation of substances that are dangerous to the environ-
ment and even human health. Therefore, such new technologies enhance the production
of targeted biocompounds that are to be incorporated as cosmeceutical ingredients with
some advantages, such as a less cultivation time, high concentration/extraction of targeted
compounds and less environmental damage.
Finally, plant derivatives, mainly A. indica (Neem) byproducts, can be carefully used
in cosmetics for skin and hair care after all the specific safety and efficacy assessments to
offer skin benefits described in our review with good cutaneous tolerance.
Author Contributions: Conceptualization, A.L.M.-J. and A.R.B.; methodology, T.B.F., G.d.A.M. and
A.L.M.-J.; validation, A.R.B. and P.R.; formal analysis, M.V.R.V.; investigation, A.L.M.-J., J.R. and
W.V.M.; resources, J.C.M.d.C. and P.R.; data curation, A.L.M.-J., F.V.L. and A.R.B.; writing—original
draft preparation, A.L.M.-J., T.B.F. and G.d.A.M.; writing—review and editing, A.R.B. and A.L.M.-J.;
supervision, A.L.M.-J.; project administration, A.L.M.-J.; funding acquisition, A.R.B. and A.L.M.-J.
All authors have read and agreed to the published version of the manuscript.
Funding:
This research was funded by the São Paulo Research Foundation (FAPESP, Process
2019/16169-0) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Pro-
cess 305250/2019-1). This study was also financed in part by Coordenação de Aperfeiçoamento
de Pessoal de Nível Superior—Brazil (CAPES, Finance Code 001 and Programa Nacional de Pós-
Doutorado, PNPD).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Saleem, S.; Muhammad, G.; Hussain, M.A.; Bukhari, S.N.A. A comprehensive review of phytochemical profile, bioactives for
pharmaceuticals, and pharmacological attributes of Azadirachta indica.Phyther. Res. 2018,32, 1241–1272. [CrossRef] [PubMed]
2.
Sen, S.; Chakraborty, R. Revival, modernization and integration of Indian traditional herbal medicine in clinical practice:
Importance, challenges and future. J. Tradit. Complement. Med. 2017,7, 234–244. [CrossRef] [PubMed]
3.
Mossini, S.A.G.; Kemmelmeier, C. A árvore Nim (Azadirachta indica A. Juss): Múltiplos Usos. Acta Farm. Bonaer.
2005
,24, 139–148.
4.
Biswas, K.; Chattopadhyay, I.; Banerjee, R.K.; Bandyopadhyay, U. Biological activities and medicinal properties of Neem
(Azadirachta indica). Curr. Sci. 2002,82, 1336–1345.
Cosmetics 2022,9, 58 15 of 17
5.
Thakore, D.; Srivastava, A.K. Production of biopesticide azadirachtin using plant cell and hairy root cultures. Eng. Life Sci.
2017
,
17, 997–1005. [CrossRef]
6.
Gonzalez-Coloma, A.; Reina, M.; Diaz, C.E.; Fraga, B.M. Natural Product-Based Biopesticides for Insect Control. In Comprehensive
Natural Products II; Mander, L., Liu, H.-W., Eds.; Elsevier: Amsterdam, The Netherlands, 2010; pp. 237–268.
7.
Banerjee, K.; Thiagarajan, N.; Thiagarajan, P. Formulation optimization, rheological characterization and suitability studies of
polyglucoside-based Azadirachta indica A. Juss emollient cream as a dermal base for sun protection application. Indian J. Pharm.
Sci. 2017,79, 914–922. [CrossRef]
8.
Bhinge, S.D.; Bhutkar, M.A.; Randive, D.S.; Wadkar, G.H.; Kamble, S.Y.; Kalel, P.D.; Kadam, S.S. Formulation and evaluation of
polyherbal gel containing extracts of Azadirachta indica,Adhatoda vasica,Piper betle,Ocimum tenuiflorum and Pongamia pinnata.J.
Res. Pharm. 2019,23, 44–54. [CrossRef]
9.
Farjaminezhad, R.; Garoosi, G. Establishment of green analytical method for ultrasound-assisted extraction of azadirachtin,
mevalonic acid and squalene from cell suspension culture of Azadirachta indica using response surface methodology. Ind. Crops
Prod. 2020,144, 111946. [CrossRef]
10.
Farjaminezhad, R.; Garoosi, G. New biological trends on cell and callus growth and azadirachtin production in Azadirachta indica.
3 Biotech 2019,9, 309. [CrossRef]
11.
Chaturvedi, R.; Razdan, M.K.; Bhojwani, S.S. An efficient protocol for the production of triploid plants from endosperm callus of
Neem, Azadirachta indica A. Juss. J. Plant Physiol 2003,160, 557–564. [CrossRef]
12.
Mak-Mensah, E.; Firempong, C. Chemical characteristics of toilet soap prepared from Neem (Azadirachta indica A. Juss) seed oil.
Asian J. Plant Sci. Res. 2011,1, 1–7.
13.
Gupta, A.; Malviya, R.; Singh, T.P.; Sharma, P.K. Indian medicinal plants used in hair care cosmetics: A short review. Pharmacogn.
J. 2010,2, 361–364. [CrossRef]
14.
Shivanand, P.; Nilam, M.; Viral, D. Herbs play an important role in the field of cosmetics. Int. J. PharmTech Res. CODEN
2010
,
2, 632–639.
15.
Hatti, K.S.; Muralitharan, L.; Hegde, R.; Kush, A. NeeMDB: Convenient database for Neem secondary metabolites. Bioinformation
2014,10, 314–315. [CrossRef] [PubMed]
16.
Pimple, B.P.; Badole, S.L.; Menaa, F. Exploring Neem (Azadirachta indica) for antidermatophytic activity. In Bioactive Dietary Factors
and Plant Extracts in Dermatology; Watson, R., Zibadi, S., Eds.; Humana Press Inc.: Totowa, NJ, USA, 2013; pp. 459–470.
17.
Akihisa, T.; Zhang, J.; Manosroi, A.; Kikuchi, T.; Manosroi, J.; Abe, M. Limonoids and other secondary metabolites of
Azadirachta indica
(Neem) and Azadirachta indica var. siamensis (Siamese Neem), and their bioactivities. In Studies in Natu-
ral Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier B.V.: Amsterdam, The Netherlands, 2021; Volume 68, pp. 29–65.
18.
Gerolino, E.F.; Chierrito, T.P.C.; Santana Filho, A.; Souto, E.R.; Gonçalves, R.A.C.; Oliveira, A.J.B. Evaluation of limonoid
production in suspension cell culture of Citrus sinensis.Rev. Bras. Farmacogn. 2015,25, 455–461. [CrossRef]
19. Alvarez-Yela, A.C.; Chiquiza-Montaño, L.N.; Hoyos, R.; Orozco-Sánchez, F. Rheology and mixing analysis of plant cell cultures
(Azadirachta indica,Borojoa patinoi and Thevetia peruviana) in shake flasks. Biochem. Eng. J. 2016,114, 18–25. [CrossRef]
20.
Vásquez-Rivera, A.; Chicaiza-Finley, D.; Hoyos, R.A.; Orozco-Sánchez, F. Production of Limonoids with insect antifeedant
activity in a two-stage bioreactor process with cell suspension culture of Azadirachta indica.Appl. Biochem. Biotechnol.
2015
,177,
334–345. [CrossRef]
21.
Villegas-Velásquez, S.; Martínez-Mira, A.D.; Hoyos, R.; Rojano, B.; Orozco-Sánchez, F. Hydrodynamic stress and limonoid
production in Azadirachta indica cell culture. Biochem. Eng. J. 2017,122, 75–84. [CrossRef]
22.
Amadioha, A.C. Controlling rice blast
in vitro
and
in vivo
with extracts of Azadirachta indica.Crop Prot.
2000
,19,
287–290. [CrossRef]
23.
Wolinsky, L.E.; Mania, S.; Nachnani, S.; Ling, S. The inhibiting effect of aqueous Azadirachta indica (Neem) extract upon bacterial
properties influencing in vitro plaque formation. J. Dent. Res. 1996,75, 816–822. [CrossRef]
24.
Natarajan, V.; Venugopal, P.V.; Menon, T. Effect of Azadirachta indica (neem) on the growth pattern of dermatophytes. Indian J.
Med. Microbiol. 2003,21, 98–101. [CrossRef]
25.
Ospina Salazar, D.I.; Hoyos Sánchez, R.A.; Orozco Sánchez, F.; Arango Arteaga, M.; Gómez Londoño, L.F. Antifungal activity of
Neem (Azadirachta indica: Meliaceae) extracts against dermatophytes. Acta Biológica Colomb. 2015,20, 201–207. [CrossRef]
26.
Govindachari, T.R.; Suresh, G.; Gopalakrishnan, G.; Banumathy, B.; Masilamani, S. Identification of antifungal compounds from
the seed oil of Azadirachta indica.Phytoparasitica 1998,26, 109–116. [CrossRef]
27.
Dhanya, S.R.; Kumar, S.N.; Sankar, V.; Raghu, K.G.; Kumar, B.S.D.; Nair, M.S. Nimbolide from Azadirachta indica and its derivatives
plus first-generation cephalosporin antibiotics: A novel drug combination for wound-infecting pathogens. RSC Adv.
2015
,5,
89503–89514. [CrossRef]
28.
Ghimeray, A.K.; Jin, C.-W.; Ghimire, B.K.; Cho, D.H. Antioxidant activity and quantitative estimation of azadirachtin and nimbin
in Azadirachta indica A. Juss grown in foothills of Nepal. African J. Biotechnol. 2009,8, 3084–3091.
29.
Ngo, H.T.T.; Hwang, E.; Seo, S.A.; Park, B.; Sun, Z.W.; Zhang, M.; Shin, Y.K.; Yi, T.H. Topical application of Neem leaves prevents
wrinkles formation in UVB-exposed hairless mice. J. Photochem. Photobiol. B Biol. 2017,169, 161–170. [CrossRef] [PubMed]
30.
Akihisa, T.; Horiuchi, M.; Matsumoto, M.; Ogihara, E.; Ishii, K.; Zhang, J. Melanogenesis-inhibitory activities of isomeric C-seco
limonoids and deesterified limonoids. Chem. Biodivers. 2016,13, 1410–1421. [CrossRef] [PubMed]
Cosmetics 2022,9, 58 16 of 17
31.
Akihisa, T.; Takahashi, A.; Kikuchi, T.; Takagi, M.; Watanabe, K.; Fukatsu, M.; Fujita, Y.; Banno, N.; Tokuda, H.; Yasukawa, K. The
melanogenesis-inhibitory, anti-inflammatory, and chemopreventive effects of limonoids in n-hexane extract of Azadirachta indica
A. Juss. (Neem) Seeds. J. Oleo Sci. 2011,60, 53–59. [CrossRef] [PubMed]
32.
Vaughn, A.R.; Pourang, A.; Clark, A.K.; Burney, W.; Sivamani, R.K. Dietary supplementation withturmeric polyherbal formulation
decreases facial redness: A randomized double-blind controlled pilot study. J. Integr. Med.
2019
,17, 20–23. [CrossRef] [PubMed]
33.
Garg, S.; Taluja, V.; Upadhyay, S.; Talwar, G. Studies on the contraceptive efficacy of Praneem polyherbal cream. Contraception
1993,48, 591–596. [CrossRef]
34.
Alzohairy, M.A. Therapeutics role of Azadirachta indica (Neem) and their active constituents in diseases prevention and treatment.
Evid. -Based Complement. Altern. Med. 2016,2016, 7382506. [CrossRef] [PubMed]
35.
Barua, C.C.; Talukdar, A.; Barua, A.G.; Chakraborty, A.; Sarma, R.K.; Bora, R.S. Evaluation of the wound healing activity of
methanolic extract of Azadirachta indica (Neem) and Tinospora cordifolia (guduchi) in rats. Pharmacologyonline 2010,1, 70–77.
36.
Kumar, V.S.; Navaratnam, V. Neem (Azadirachta indica): Prehistory to contemporary medicinal uses to humankind. Asian Pac. J.
Trop. Biomed. 2013,3, 505–514. [CrossRef]
37.
Thas, J.J. Siddha Medicine—background and principles and the application for skin diseases. Clin. Dermatol.
2008
,26,
62–78. [CrossRef]
38.
Vijayavani, S.C.; Vidyavathi, M. Azadirachita indica gum based sildenafil citrate mucoadhesive microspheres—Design and
optimization. J. Drug Deliv. Sci. Technol. 2018,47, 499–513. [CrossRef]
39.
Gupta, S.C.; Prasad, S.; Tyagi, A.K.; Kunnumakkara, A.B.; Aggarwal, B.B. Neem (Azadirachta indica): An Indian traditional
panacea with modern molecular basis. Phytomedicine 2017,34, 14–20. [CrossRef]
40.
Dave, V.; Bhardwaj, N.; Gupta, N.; Tak, K. Herbal ethosomal gel containing luliconazole for productive relevance in the field of
biomedicine. 3 Biotech 2020,10, 97. [CrossRef]
41.
Zuccotti, E.; Oliveri, M.; Girometta, C.; Ratto, D.; Di Iorio, C.; Occhinegro, A.; Rossi, P. Nutritional strategies for psoriasis: Current
scientific evidence in clinical trials. Eur. Rev. Med. Pharmacol. Sci. 2018,22, 8537–8551.
42.
Van der Nat, J.; Van der Sluis, W.; Silva, K.T.; Labadie, R. Ethnopharmacognostical survey of Azadirachta indica A. Juss (Meliaceae).
J. Ethnopharmacol. 1991,35, 1–24. [CrossRef]
43.
ECHA Undestanging REACH. Available online: https://echa.europa.eu/regulations/reach/understanding-reach (accessed on
13 October 2020).
44. Gaitonde, B.B.; Sheth, U.K. Pharmacological studies of sodium nimbidinate. Indian J. Med. Sci. 1958,12, 156–161.
45.
Bhide, N.K.; Mehta, D.J.; Altekar, W.W.; Lewis, R.A. Toxicity of sodium nimbidinate. Indian J. Med. Sci.
1958
,12,
146–149. [PubMed]
46.
NAP. Neem: A Tree for Solving Global Problems, 1st ed.; Press, T.N.A., Ed.; National Academies Press: Washington, DC, USA, 1992.
47.
ACS Molecule of the Week Archive: Azadirachtin. Available online: https://www.acs.org/content/acs/en/molecule-of-the-
week/archive/a/azadirachtin.html?cid=home_motw (accessed on 5 April 2021).
48. Raj, A. Toxicological effect of Azadirachta indica.Asian J. Multidiscip. Stud. 2014,2, 29–33.
49.
Gandhi, M.; Lal, R.; Sankaranarayanan, A.; Banerjee, C.K.; Sharma, P.L. Acute toxicity study of the oil from Azadirachta indica seed
(Neem oil). J. Ethnopharmacol. 1988,23, 39–51. [CrossRef]
50. Pillai, N.; Santhakumari, G. Toxicity studies on nimbidin, a potential antiulcer drug. Planta Med. 1984,50, 146–148. [CrossRef]
51.
Auta, T.; Hassan, A.T. Reproductive toxicity of aqueous wood-ash extract of Azadirachta indica (Neem) on male albino mice. Asian
Pacific J. Reprod. 2016,5, 111–115. [CrossRef]
52.
Góis, R.C.S.; Silva, L.A.; Júnior, H.N.A.; Silva, J.B.; Cavalcante, T.V.; Olinda, R.G.; Viana, G.A.; Araujo, M.S.; Moura, G.H.F.;
Silva, I.A.A.; et al
. Reproductive toxicity of neem seeds (Azadirachta indica) in male quail (Coturnix coturnix japonica). Cienc. Rural
2019,49, e20180484. [CrossRef]
53. Subrahmanyam, B. Azadirachtin—A naturally occurring insect growth regulator. Proc. Anim. Sci. 1990,99, 277–288. [CrossRef]
54.
Braga, T.M.; Rocha, L.; Chung, T.Y.; Oliveira, R.F.; Pinho, C.; Oliveira, A.I.; Morgado, J.; Cruz, A. Azadirachta indica Juss
in vivo
toxicity-An updated review. Molecules 2021,26, 252. [CrossRef]
55.
Wanxiang, Z.; Ganwei, T.; Hai, C.; Jian, C.; Na, H. A Kind of Desquamation Compositions and Its Application. CN107349122A,
15 June 2017.
56.
Wanxiang, Z.; Ganwei, T.; Hai, C.; Na, H.; Jia, Z. A Kind of Anti-Dandruff Silk Quality Lubrication is Without Silicone Oil
Shampoo. CN107468563A, 9 August 2017.
57.
Beibei, L.; Lin, W.; Lixu, P.; Xin, C.; Pan, P.; Niqing, F. A Method for the Preparation and Application of Azadirachta and
Fungicides. CN109805037A, 27 February 2019.
58.
Kyung-Eun, L.; Seung-Hyun, K.; Yeon-Joon, K. Composition for Alleviating Skin Irritation and Skin Inflammation Caused
by Fine Dust, Containing, as Active Ingredient, Mixture of Holy Basil, Mentha canadensis, and Azadirachta indica Extracts.
WO2018021777A1, 29 July 2016.
59.
Gutierrez Miceli, F.A.; Gutiérrez Oliva, V.F. Topic Cosmetic Composition Based on Extracts of Neem Leaves (Azadirachta indica
Juss) for Promoting the Skin Rejuvenation and Treating Fungi and Bacteria Infections. MX2013004928A, 2 May 2013.
60. Saxena, M. Herbal Formulation for Wound Healing Containing Azadirachta indica. NZ578363A, 24 February 2012.
61.
Barchha, N.; Desai, D.H.; Gangopadhyay, M.; Rajagopalan, S.; Serai, P.S.; Serrao, G. An Antidandruff Composition.
WO2020020539A1, 18 June 2019.
Cosmetics 2022,9, 58 17 of 17
62. Zesen, L.; Changchi, L.; Yong, H. A Preparation Method of Acne Dispelling Compound. CN110613658A, 9 October 2019.
63. Manzhi, L. A Lipstick without Castor Oil. CN110101628A, 3 April 2019.
64.
Cang, L.; Guosheng, F.; Xiaoyan, W. A Kind of Multi-Effect Mask which has the Function of Tender Skin and Removing Acne.
CN108904432A, 2 August 2018.
65.
Yuye, J.; Furong, Z. An Extract of Acne Essence Containing Extract of Lactobacillus, Houttuynia cordata and Bark of Willow.
CN108888678A, 29 July 2018.
66. Ishima; Zhilong, L. An Anti-Acne Skin Care Product and Its Preparation Method. CN108434032A, 27 April 2018.
67.
Yuefeng, D.; Wenshu, K.; Guangwen, H.; Shaowei, Y. Composition and Cosmetic Containing the Composition to Suppress Acne
Inflammation. CN108158972A, 28 March 2018.
68. Chunling, C. Skin Care Composition with Acne Removing Function. CN105770160A, 15 April 2016.
69. Guofeng, C. Botanic Preservative. CN105769710A, 15 April 2016.
70. Laxmi, S.; Josh, H.A.P. Herbal Cosmetics and Cosmeceuticals: An Overview. Nat. Prod. Chem. Res. 2015,3, 1000169.
71.
Pandey, G.; Verma, K.; Singh, M. Evaluation of phytochemical, antibacterial and free radical scavenging properties of
Azadirachta indica (neem) leaves. Int. J. Pharm. Pharm. Sci. 2014,6, 444–447.
72.
Gediya, S.K.; Mistry, R.B.; Patel, U.K.; Blessy, M.; Jain, H.N. Herbal Plants: Used as cosmetics. J. Nat. Prod. Plant Resour
2011
,
1, 24–32.
73.
Ogbuewu, I.P.; Odoemenam, Y.U.; Obikaonu, H.O.; Opara, M.N.; Emenalom, O.O.; Uchegbu, M.C.; Okoli, I.C.; Esonu, B.O.; Iloeje,
M.U. The growing importance of Neem (Azadirachta indica A. Juss) in agriculture, industry, medicine and environment: A review.
Res. J. Med. Plant 2011,5, 230–245. [CrossRef]
74.
Chiocchio, I.; Mandrone, M.; Sanna, C.; Maxia, A.; Tacchini, M.; Poli, F. Screening of a hundred plant extracts as tyrosinase and
elastase inhibitors, two enzymatic targets of cosmetic interest. Ind. Crops Prod. 2018,122, 498–505. [CrossRef]
75.
Chaudhary, S.; Kanwar, R.K.; Sehgal, A.; Cahill, D.M.; Barrow, C.J.; Sehgal, R.; Kanwar, J.R. Progress on Azadirachta indica based
biopesticides in replacing synthetic toxic pesticides. Front. Plant Sci. 2017,8, 1–13. [CrossRef]
76.
Asimuddin, M.; Shaik, M.R.; Adil, S.F.; Siddiqui, M.R.H.; Alwarthan, A.; Jamil, K.; Khan, M. Azadirachta indica based biosyn-
thesis of silver nanoparticles and evaluation of their antibacterial and cytotoxic effects. J. King Saud Univ.-Sci.
2020
,32,
648–656. [CrossRef]
77.
Patil, S.P.; Chaudhari, R.Y.; Nemade, M.S. Azadirachta indica leaves mediated green synthesis of metal oxide nanoparticles: A
review. Talanta Open 2022,5, 100083. [CrossRef]
78.
Chinnasamy, G.; Chandrasekharan, S.; Koh, T.W.; Bhatnagar, S. Synthesis, characterization, antibacterial and wound healing
efficacy of silver nanoparticles from Azadirachta indica.Front. Microbiol. 2021,12, 1–14. [CrossRef]
ResearchGate has not been able to resolve any citations for this publication.
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Various attempts have been made for green synthesis of metal oxide nanoparticles; revealing the significance of plant extracts in reducing metal source to nanoparticles and applications in various scientific domains. Azadirachta indica (Neem) is evergreen tree, belonging to family Meliaceae. It's leaves are reported to contain several phytochemicals like flavonoids, glycosides, terpenes and triterpenes. This article focus on applications of Azadirachta indica leafs extract in fabrication of nanoparticles of various metal oxides like calcium oxide, chromic oxide, cobalt oxide, cupric oxide, iron oxide, manganese oxide, molybdate oxide, titanium dioxide, zinc oxide. In respective research attempts, these metal oxide nanoparticles were evaluated for one or more applications like antibacterial, anti-cancer activity, photocatalytic activity. Use of aqueous extract of neem leaves indicated involvement of its polar phyto-compounds in reducing the metal oxides and stabilizing their nanoparticles. In conclusion, it could be noted that, metal oxide nanoparticles have better anti-microbial activity and photocatalytic potential over aqueous leaves extract.
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Plants of the Meliaceae family have been well documented for their ability to metabolize structurally diverse and biologically significant limonoids. To search for potential bioactive compounds from Meliaceae plants, we have investigated the limonoids and other secondary metabolites of Azadirachta indica A. Juss. (AI; neem tree) and Azadirachta indica A. Juss. var. siamensis Valeton (AIS; Siamese neem tree), and have isolated and characterized 81 limonoids, 1 diterpenoid, and 11 flavonoids. These compounds have been demonstrated potent bioactivities, including melanogenesis-inhibitory activity in B16 melanoma cells, inhibitory potential against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced Epstein–Barr virus early antigen (EBV-EA) activation, a primary screening for inhibitors of tumor promotion, cytotoxic activities against human cancer cell lines, inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 cells, a primary screening for antiinflammatory agents, and antiinflammatory activity against TPA-induced inflammation in mice. In this review chapter, isolation, characterization, and bioactivities, including melanogenesis-inhibitory activity, cancer chemopreventive property, cytotoxic activity, and antiinflammatory activity, of limonoids and other secondary metabolites of AI and AIS, which are mostly the results of our investigations are presented.
Article
This study includes development, characterization, and optimization of herbal ethosomal formulation. The aim of the present study is to develop drug loaded ethosomes capped with Azadirachta indica (neem) which, was further incorporated in Carbopol 934 K thereby, resulting in the formation of ethosomal gel. The formulation is aimed to express effective treatment against fungal infection. The build was formulated using drug (Luliconazole), soyalecithin, ethanolic neem extract and propylene glycol. In total nine ethosomal, formulations of distinct concentrations of ingredients were processed, to determine out the optimized formulation among the all. Further the prepared drug loaded ethosomes were subjected to various evaluation parameters like particle size, zeta potential, polydispersity index (PDI) and % entrapment efficiency. For the evaluation of its surface morphology, transmission electron microscopy was executed whereas, atomic force microscopy was carried out which contributes in detail and depth information of surface morphology. For the analysis of thermal behavior Thermal gravimetric analysis graph was obtained for luliconazole, soyalecithin, neem extract, physical mixture and optimized formulation (LF5). Attenuated total internal reflection Fourier transforms infra-red spectroscopy was performed for luliconazole, soyalecithin, neem extract, physical mixture, and optimized formulation (LF5) to examine the interaction between the drug and the excipients. Viscosity, pH, spreadability and extrudability of the ethosomal gel were calculated to determine the suitability of the formulation for topical application. In vitro drug permeation study and antifungal activity was executed out with the aid of Wistar albino rat skin model and tube dilution assay respectively. The complete study wrap up, that this herbal ethosomal approach provides advanced sustained and targeted delivery of luliconazole. On analyzing the results, ethosomal formulation LF5 was found to be optimized one, due to its optimum concentration of soyalecithin (300 mg) and ethanol (35%). Hence it has maximum entrapment efficiency of 86.56 ± 0.74%. Optimum vesicle size, zeta potential, and PDI were found to be 155.30 ± 1.2 nm, − 42.20 ± 0.3 mV, and 0.186 ± 0.07 respectively. In vitro drug permeation study expresses release of 83.45 ± 2.51 in 24 h whereas; the in vivo activity proved that LF5 is more active and effective against Candida parapsilosis in comparison to Aspergillus niger. In the end, it was estimated that ethosomal suspension and lyophilized ethosomal suspension was utmost stable at 4 °C/60 ± 5 RH. The complete study clearly indicates that the buildup of ethosomal formulation with luliconazole and neem extract show synergistic effect thereby, expressing excellent result against the treatment of fungal infection.
Article
Azadirachta indica is used as a medicinal plant and its biological activity have been studied, but the extraction of its secondary metabolites was not clearly optimized. In this study, response surface methodology was applied for optimization of extraction of azadirachtin, mevalonic acid and squalene from cell suspension culture of A. indica. The Box-Behnken Design was used for the optimization of factors. The azadirachtin, mevalonic acid, and squalene were recognized by HPLC-DAD. Results showed that the optimal condition (solvent, temperature and ultrasonication time) obtained by response surface methodology for target compounds from cell suspension culture of A. indica were as following. Azadirachtin: water, temperature 35 °C and ultrasonication time 20 min, obtained 86.445 mg/g DW; mevalonic acid: 50 % ethanol, temperature 45 °C and ultrasonication time 30 min, provided 33.671 mg/g DW; and squalene: 50 % ethanol, temperature 55 °C and ultrasonication time 10 min, achieved 8.278 mg/g DW.
Article
Azadirachtin is an important secondary metabolite from Azadirachta indica used as a natural biopesticide. This study is the first comprehensive report concerning the influence of plant growth regulators on callus induction, cell suspension growth, and azadirachtin accumulation and production in cell suspension cultures of A. indica. We investigated the effect of plant growth regulators including different types of auxins and cytokinins and their combinations on callus induction, cell suspension growth, and azadirachtin accumulation and production. The highest percentage of callusing (100%) obtained at different combinations of plant growth regulators on MS medium supplemented with 1 mg/L picloram and 2 mg/L kinetin and the highest fresh weight of callus (264.50 mg) was observed in MS medium containing 1.5 mg/L NAA and 3 mg/L kinetin. In cell suspension cultures, the maximum cell density, SCV, and PCV were 2.44 × 106 cells per mL, 97.95%, and 81.46%, respectively, obtained in the MS medium containing 1.5 mg/L 2,4-D and 3 mg/L zeatin riboside. The highest average growth rate (0.25 days) was on MS medium containing 1.5 mg/L NAA and 3 mg/L zeatin riboside. The MS medium supplemented with 1 mg/L picloram and 2 mg/L kinetin produced the highest amount of fresh cell weight (493.02 g/L), dry cell weight (77.27 g/L), azadirachtin accumulation (3.69 mg/gDW), and azadirachtin production (285.64 mg/L). The results showed that all measured indices had positive correlation with together except FCW and DCW with azadirachtin accumulation.
Article
Objective: Several nutritional strategies for the management of psoriasis are promising. Even if recent data support that nutrition may play a pivotal role in prevention and co-treatment and despite patient's concerns regarding the best nutritional habits, the consensus regarding the nutritional strategies to be adopted lacks in clinical settings. In this manuscript, the effects of several nutritional strategies for psoriasis patients such as hypocaloric diet, vitamin D, fish oil, selenium, and zinc supplementation were systematically reviewed. Randomized controlled trials (RCTs) on beneficial botanical oral supplements were also included in the analysis. Materials and methods: For each topic, a search was conducted in MEDLINE electronic databases for articles published in English between January 1, 1990 and September 2018. Two independent reviewers assessed and extracted the data. Only controlled clinical trials were selected. Results: The evidence regarding the current nutritional strategies for psoriasis patients were summarized and translated into a global, comprehensible recommendation. Conclusions: Weight loss combined with a healthy lifestyle was shown to be very beneficial for patients with moderate to severe disease with a significant reduction of the Psoriasis Area and Severity Index (PASI) score. Currently, oral vitamin D supplementation for prevention or treatment of psoriasis in adults with normal vitamin D levels is not recommended; however, psoriasis patients with a deficit in plasma vitamin D levels are advised to complement with oral supplements to prevent psoriasis-related comorbidities. Instead of zinc, selenium, and omega 3 supplements have been proven beneficial for psoriasis patients. Among botanical species, Dunaliella bardawil (D. bardawil), Tripterygium wilfordii (T. wilfordii), Azadirachta indica (A. indica), Curcuma longa (C. longa), and HESA-A are the most beneficial. In conclusion, a close cooperation between nutritionists and dermatologists may be useful for the management of psoriasis.