molecules

Review
A Mini-Review on Solid Lipid Nanoparticles and
Nanostructured Lipid Carriers: Topical Delivery of
Phytochemicals for the Treatment of Acne Vulgaris
Romchat Chutoprapat 1, * , Peerawas Kopongpanich 1 and Lai Wah Chan 2

1 Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn

University, Bangkok 10330, Thailand; [email protected]
2 Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Singapore;
[email protected]
* Correspondence: [email protected]

Abstract: Acne vulgaris (acne) is one of the most common dermatological problems affecting ado-
lescents and young adults. Although acne may not lead to serious medical complications, its psy-
chosocial effects are tremendous and scientifically proven. The first-line treatment for acne is topical
medications composed of synthetic compounds, which usually cause skin irritation, dryness and
itch. Therefore, naturally occurring constituents from plants (phytochemicals), which are generally
regarded as safe, have received much attention as an alternative source of treatment. However, the
degradation of phytochemicals under high temperature, light and oxygen, and their poor penetration
across the skin barrier limit their application in dermatology. Encapsulation in lipid nanoparticles is
one of the strategies commonly used to deliver drugs and phytochemicals because it allows appropri-
ate concentrations of these substances to be delivered to the site of action with minimal side effects.
Citation: Chutoprapat, R.;
Kopongpanich, P.; Chan, L.W. A
Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are promising delivery
Mini-Review on Solid Lipid systems developed from the combination of lipid and emulsifier. They have numerous advantages
Nanoparticles and Nanostructured that include biocompatibility and biodegradability of lipid materials, enhancement of drug solubility
Lipid Carriers: Topical Delivery of and stability, ease of modulation of drug release, ease of scale-up, feasibility of incorporation of both
Phytochemicals for the Treatment of hydrophilic and lipophilic drugs and occlusive moisturization, which make them very attractive
Acne Vulgaris. Molecules 2022, 27, carriers for delivery of bioactive compounds for treating skin ailments such as acne. In this review,
3460. https://doi.org/10.3390/ the concepts of SLNs and NLCs, methods of preparation, characterization, and their application in
molecules27113460 the encapsulation of anti-acne phytochemicals will be discussed.
Academic Editors: Christian Mayer
and Jessica Rosenholm Keywords: solid lipid nanoparticles; nanostructured lipid carriers; topical application; phytochemicals;
acne vulgaris
Received: 24 April 2022
Accepted: 25 May 2022
Published: 27 May 2022

Publisher’s Note: MDPI stays neutral 1. Introduction

with regard to jurisdictional claims in
The cause of acne is multifactorial, with four primary factors including excess sebum
published maps and institutional affil-
production, Cutibacterium acnes (formerly Propionibacterium acnes (P. acnes)) colonization,
iations.
follicular hyperkeratinization, and release of inflammatory mediators into the skin. There
are standard acne treatments that vary according to the stage or severity of the disease. The
first-line treatment for mild to moderate acne vulgaris is topical medications composed of
Copyright: © 2022 by the authors.
synthetic compounds or their combination with oral antibiotics. However, most of these
Licensee MDPI, Basel, Switzerland. topical medications usually cause side effects such as irritation, dryness, scaling and itch to
This article is an open access article the skin. Therefore, the use of phytochemicals has been studied as an alternative treatment
distributed under the terms and to resolve unpleasant side effects due to the synthetic compounds. For example, α- and
conditions of the Creative Commons γ-mangostins, the active compounds in mangosteen, were able to reduce the proliferation
Attribution (CC BY) license (https:// of keratinocytes induced by P. acnes and suppress P. acnes-induced inflammation [1]. In
creativecommons.org/licenses/by/ another study, eucalyptus oil was found to decrease sebum production in a rat sebaceous
4.0/).

Molecules 2022, 27, 3460. https://doi.org/10.3390/molecules27113460 https://www.mdpi.com/journal/molecules

Molecules 2022, 27, 3460 2 of 16

gland model and inhibit secondary infection caused by other strains of bacteria [2]. Resver-
atrol, a natural compound produced in some fruits such as grapes, has been shown to
be effective in reducing the number of acne lesions in a clinical study [3]. Nevertheless,
the major challenges of phytochemicals derived from the plants are their instability and
poor penetration across the skin barrier which may limit their application in dermatology.
The use of lipid carriers, such as solid lipid nanoparticles (SLNs) and nanostructured lipid
carriers (NLCs), can increase the absorption rate and facilitate the sustained release of
active substances. Moreover, these carriers can protect the active substances from degrada-
tion [4]. Solid lipid nanoparticles (SLNs) are nanospheres prepared from solid lipids and
surfactants. SLNs have been applied in a wide variety of cosmetics and pharmaceutical
preparations due to their various advantages such as good stability, rigid morphology, good
biocompatibility, ease of scale-up, ease of modulation of drug release, and the avoidance
of organic solvents in the preparation [5,6]. Moreover, SLNs have an occlusive property
which can reduce the trans-epidermal water loss and make the skin hydrated [7]. However,
SLNs show a low drug loading capacity. Therefore, nanostructured lipid carriers (NLCs),
the second generation of lipid nanoparticles, were developed to address this problem of
SLNs. NLCs are prepared by incorporating liquid lipid to solid lipid in order to impart
imperfections to the crystal order of the solid lipid, thereby facilitating the incorporation
of higher amount of drug while preserving the stability of the NLCs [6]. Both SLNs and
NLCs can play an important role in anti-acne therapy owing to their ability to penetrate
into the hair follicle and sebaceous gland, occlusive and skin hydration effects [8].
The focus of this review work is to provide a concise overview of solid lipid nanopar-
ticles (SLNs) and nanostructured lipid carriers (NLCs) as promising carrier systems for
topical delivery and to highlight the application of SLNs and NLCs in the encapsulation
of anti-acne phytochemicals. The concepts of SLNs and NLCs, their recent application
in the encapsulation of anti-acne phytochemicals as well as methods of preparation and
characterization have been reviewed and discussed below.

2. Solid Lipid Nanoparticles (SLNs)

SLNs were introduced in 1990s as an alternative to conventional colloidal carriers
such as liposomes and polymeric nanoparticles due to the possibility of production at
large industrial scale [9]. Moreover, SLNs have gained much interest in pharmaceutical
sciences for drug delivery applications because of their flexibility in modulating the drug
release, high drug loading capacity, and protecting the drugs from physical and chemical
degradation [10]. The SLNs are nanosized lipid particles comprising solid lipids dispersed
in aqueous surfactant media. The lipids commonly used in the preparation of SLNs are
biodegradable lipids with high melting point such as triglycerides, partial glycerides,
fatty acids, fatty alcohols, and waxes [11]. Surfactants are used to stabilize the structure
of SLNs by decreasing surface tension between aqueous media and lipid [12]. It was
reported that the higher the surfactant concentration, the smaller the particle size of SLNs
obtained. However, a high concentration of surfactants may cause toxicity [13]. Therefore,
the surfactant concentration used in the development of SLNs has to be optimized. Particle
size of SLNs is one of the most important parameters affecting the drug delivery efficiency.
Some studies have shown that the skin permeability of SLNs increases when their particle
size decreases, and the sub-100 nm size range is optimal for skin delivery because they
can penetrate into deeper skin layers through hair follicles [14]. In addition, SLNs may
enhance the penetration of drugs through the stratum corneum due to their occlusive
property [7]. The incorporation of drugs into SLNs can be described by three models,
namely homogeneous matrix, drug-enriched shell, and drug-enriched core (Figure 1).
• Homogeneous matrix model: the drug is dispersed in lipid matrix without the use of
solubilizers or surfactants. This model is usually prepared by the cold homogenization
technique [15].
• The drug-enriched shell model: a mixture of lipid and drug is heated at temperature
above the melting point of the lipid. On rapid cooling, lipid precipitates at the core
Molecules 2022, 27, 3460 3 of 16

whereas the drug is concentrated at the outer melted lipid. The drug-enriched shell is
completely formed when the melted mixture is cooled to room temperature [16].
• The drug-enriched core model: the concentration of drug in the melted lipid is close to
its saturation solubility. The cooling process creates supersaturation of the drug in the
melted lipid, resulting in drug precipitation at the core prior to lipid crystallization.
Further cooling will lead to the crystallization of the lipid surrounding the drug core
as a shell [17]. The drug-enriched shell and the drug-enriched core models are usually
produced by hot homogenization technique.

Figure 1. The drug incorporation models of SLNs (A) homogeneous matrix, (B) drug-enriched shell,
(C) drug-enriched core.

Advantages of SLNs [18] are:

• SLNs are biodegradable and biocompatible.
• They can modulate the drug release.
• SLNs can enhance the penetration of drugs through the stratum corneum.
• They have occlusive property which can increase skin hydration.
• SLNs can be sterilized using the autoclave. The high temperature (121 ◦ C) during
sterilization by autoclaving certainly causes a hot o/w microemulsion. On subsequent
cooling, the SLNs reformed. However, it should be noted that the average particle size
of SLNs is usually increased after sterilization by heating.
• Ease of large-scale production and low production cost.
• They are safe because of avoidance of organic solvents in the preparation.
• Incorporation of lipophilic and hydrophilic drugs is feasible.
• They can increase storage stability of loaded drug.
Limitations of SLNs [7,19] are:
• Low loading capacity and drug expulsion during storage. Since the lipids crystallize
in high energy modification (α form) during the preparation, they can transform to
more organized, lower energy modification (β form) during storage. This modifi-
cation resulted in fewer imperfections of lipid matrix for drug loading leading to
drug expulsion.
• The irreversible transformation of a low viscous SLNs dispersion into a viscous gel,
known as gelation phenomena, may occur rapidly and is unpredictable upon storage.
In this circumstance, the surfactants can no longer stabilize the new surfaces, and
hence the particle aggregation occurred. It has been reported that the addition of co-
emulsifying surfactants with high mobility such as glycocholate can retard a gelation
in SLNs.
• Irritation and sensitizing potential of some surfactants. Three surfactant types includ-
ing cationic (such as cetylpyridinium chloride, cetyltrimethyl ammonium bromide),
anionic (such as sodium dodecyl sulfate, sodium glycocholate), and non-ionic (such as
poloxamer, Tween, phospholipid, Cremophor) are generally used in the preparation
of both SLNs and NLCs. They are chosen based on their hydrophile-lipophile balance
(HLB) values, effects on the particle size and lipid modification of the lipid carriers, as
Molecules 2022, 27, 3460 4 of 16

well as the route of administration of the lipid carriers [20]. It has been reported that
the type and concentration of surfactants exert influence on the potential toxicity of
these lipid carriers. According to the studies of Scholer et al. (2001), SLN formulation
containing cetylpyridinium chloride exhibited strong cytotoxic effect on murine peri-
toneal macrophages, whereas other SLN formulations containing poloxamer, Tween,
phospholipid, and sodium dodecyl sulfate at the same concentration, reduced cell via-
bility slightly [21]. Furthermore, cationic and anionic surfactants are broadly regarded
as potent irritants to human skin, with cationic surfactants being more cytotoxic than
anionic surfactants. In contrast, non-ionic surfactants are considered to be safe (low-
est irritation potential) [22]. Therefore, the safety test of SLNs and NLCs should be
investigated prior to in vivo use of these lipid carriers.

3. Nanostructured Lipid Carriers (NLCs)

Nanostructured lipids carriers (NLCs) were developed to improve encapsulation
capacity and storage stability of SLNs. The NLCs are composed of a mixture of solid and
liquid lipids, with typical percentage of liquid lipid in the range of 10–30%. The presence of
liquid lipid in the lipid mixture produces a nanostructure matrix which can accommodate a
greater load of drug [23]. In addition, the high loading capacity of NLCs will enable a high
drug concentration gradient on the skin, which will in turn improve drug permeation [7].
NLCs also have various advantages similar to SLNs such as the use of biodegradable and
biocompatible lipids, controlled drug release, enhanced drug penetration and stability, ease
of fabrication and avoidance of organic solvents in preparation [24]. Based on the nature
of lipid content and ratios of solid and liquid lipids, NLCs can be classified into three
types including imperfect crystal type, amorphous type, and multiple oil-in-fat-in-water
(O/F/W) type (Figure 2) [25].
• Imperfect crystal type: this type involves mixing of spatially different liquid lipids
such as glycerides and solid lipids which introduce imperfections in the crystal order
leading to more space for drug loading. The imperfection can be increased by using a
mixture of various glycerides which vary in saturation and length of carbon chains.
• Amorphous type: this type is formed by incorporating special liquid oils such as
isopropyl myristate or hydroxyoctacosanyl hydroxystearate in a lipid matrix. The
matrix will solidify in an amorphous form that potentially reduces the expulsion of
the loaded drug by delaying the crystallization of lipids during the preparation and
storage of the NLCs
• Multiple O/F/W type: this type is formed by adding high amount of liquid lipid
beyond its solubility in the lipid matrix. This will create oil nanocompartments
distributed in the solid matrix. Drug solubility in oil nanocompartment is higher than
in solid matrix which enables higher drug loading. Moreover, a solid lipid matrix
around the oil nanocompartments acts as a barrier that prevents drug leakage and
provides controlled drug release.
Advantages of NLCs over SLNs [26,27] are:
• Higher drug loading capacity by the formation of imperfect matrix and greater drug
solubility in liquid lipid in the matrix.
• NLCs reduce drug expulsion during long-term storage. As known, drug expulsion
has been occurred during the ongoing crystallization process of the lipid matrix. By
mixing the special liquid oil in NLCs formulation, it forms amorphous structure which
limits the crystallization of lipid matrix leading to a reduction of drug expulsion. More
flexibility for modulation of drug release by modifying the types and amounts of
liquid lipids or surfactants.
Limitations of NLCs [28] are:
• Irritation and sensitizing potential of some surfactants. Hwang et al. (2014) revealed
that NLC formulation with cationic surfactants induced cell death and the release of
inflammatory mediators [29].
Molecules 2022, 27, 3460 5 of 16

Figure 2. Types of NLCs (A) imperfect crystal type, (B) amorphous type, (C) multiple oil-in-fat-in-
water type.

4. Preparation Methods of SLNs and NLCs

Several methods have been applied for the preparation of SLNs and NLCs, including
hot homogenization, cold homogenization, ultrasonication or high shear homogeniza-
tion, double-emulsion, micro-emulsification, solvent emulsification/evaporation, solvent
diffusion and injection, membrane contractor technique, phase inversion technique, and
supercritical fluid extraction of emulsions (SFEE) [19].
• Hot homogenization
The drug is dissolved or dispersed in the melted lipid. Then, the drug loaded lipid is
dispersed in a hot aqueous surfactant phase with continuous stirring by high-shear mixer
to make the pre-emulsion. The resulting pre-emulsion is subjected to high-pressure homog-
enization at a temperature above the lipid melting point to obtain hot oil-in-water (o/w)
nanoemulsion. After the homogenization step, the nanoemulsion obtained is solidified by
cooling to room temperature to form SLNs. However, high-pressure homogenization can
increase the temperature of the mixture resulting in the degradation of heat-sensitive drug.
• Cold homogenization
This technique was developed to overcome the problems of hot homogenization,
including drug degradation, drug partitioning into the aqueous phase during pre-emulsion
step and crystallization of the nanoemulsion which can lead to a low drug loading ef-
ficiency [11]. Briefly, the drug is dissolved or dispersed in the melted lipid to make
pre-emulsion which is then rapidly cooled by dry ice or liquid nitrogen. The resulting
solidified drug-loaded lipid is ground using a powder mill to obtain microparticles. The
latter is dispersed in a chilled surfactant solution and homogenized at high-pressure at
or below room temperature. The nanoparticles obtained generally have larger size and
broader size distribution compared to those prepared by hot homogenization [30].
• Ultrasonication or high-shear homogenization
Compared to high-pressure homogenization, this method is more rapid and simple to
perform. The drug-loaded melted lipid and an aqueous phase containing surfactant are
separately heated at a temperature above the lipid melting point. The aqueous phase is
then added to the lipid phase and homogenized using an ultrasonic probe sonicator or
high-shear homogenizer. The use of proper amount and type of surfactant will allow the
formation of lipid nanoparticles using a simple ultrasonication or high-shear homogeniza-
tion method [31]. However, metal contamination has to be considered when an ultrasonic
probe sonicator is used [30].
• Micro-emulsification
This technique is based on the dilution of microemulsions. The drug-loaded melted
lipid and an aqueous phase containing surfactant/co-surfactants are separately heated at
the temperature above the lipid melting point. Hot o/w microemulsion is produced by
Molecules 2022, 27, 3460 6 of 16

adding lipid phase into aqueous phase. The resulting hot microemulsion is then diluted
with cold water (2–10 ◦ C) under gentle stirring to form lipid nanoparticles. Typically,
the ratio of microemulsion to cold water lies in the range of 1:25 to 1:50. Due to the
dilution, the nanoparticles obtained will have lower lipid content than those prepared by
the homogenization method [30]. Furthermore, this method is useful for encapsulating
drugs which are sensitive to mechanical stress [19,32].
• Double-emulsion
This method was developed for the encapsulation of highly hydrophilic drugs in lipid
matrix of nanoparticles. In this method, the drug is dissolved in water while the lipid is
dissolved in an organic solvent. The water phase is added into the organic phase to form
a primary w/o emulsion which is subsequently dispersed in the external water phase to
form a double emulsion (w/o/w). The organic solvent is then removed, resulting in the
formation of lipid nanoparticles [19].
• Solvent emulsification/evaporation
This technique is based on the precipitation of particles in o/w emulsion. First, the
lipid and drug are dissolved in water-immiscible organic solvent, then emulsified with an
aqueous phase to form an o/w emulsion. The organic solvent is then evaporated leading
to the precipitation of lipid in the aqueous medium and formation of nanoparticles. The
advantage of this method is the avoidance of heat exposure. Its main disadvantage is the
use of organic solvent [30].
• Solvent diffusion and injection
The lipid and drug are dissolved in an organic solvent. The resulting solution is then
injected through a syringe into an aqueous phase containing surfactant under continuous
stirring. Surfactant reduces interfacial tension between water and solvent leading to the
formation of small droplets of solvent phase at the injection site. The solvent will then
diffuse out of the droplets into the aqueous phase resulting in a droplet size reduction
and local supersaturation of lipid within the droplets. Nanoparticle dispersion is formed
due to lipid precipitation after solvent evaporation. The advantages of this method are
avoidance of heat exposure and small particle size obtained. However, the possibility of
having residual organic solvent in the nanoparticles produced is a disadvantage of this
method [19].
• Membrane contractor technique
The melted lipid phase is pressed through the pores of a membrane at a temperature
above the melting point of the lipid to form small droplets which are detached from the
membrane pore outlet by the tangential flow of water. SLNs are formed by cooling of the
dispersion of droplets to room temperature [33].
• Phase inversion technique
This technique is based on the phase inversion temperature (PIT) of some non-ionic
polyethoxylated surfactants. The surfactants will form w/o emulsions at temperature
above PIT and o/w emulsions at temperature below PIT. In this method, the lipid, drug,
and water (containing surfactants) are mixed and heated at a temperature above PIT under
constant stirring to form a w/o microemulsion. The microemulsion is then rapidly cooled
to a temperature below PIT to form an o/w nanoemulsion, followed by the formation of
SLNs at a temperature below the melting point of the lipid [32].
• Supercritical fluid extraction of emulsions (SFEE)
SFEE is a novel method for the preparation of SLNs and NLCs. This method uses
a supercritical fluid, such as carbon dioxide, to remove the organic solvent from an o/w
emulsion, leading to the precipitation of the lipid with the drug as composite particles. For-
mation of nanoparticles with narrow size distributions can be achieved by this method [6].
Molecules 2022, 27, 3460 7 of 16

5. Characterization of SLNs and NLCs

In order to assure the quality and stability of SLNs and NLCs, their properties such as
drug loading, entrapment efficiency, particle size and size distribution, zeta potential, de-
gree of crystallinity and co-existence of additional colloidal structures need to be evaluated.
Each characterization method mentioned above is summarized below.
• Drug loading and entrapment efficiency:
Drug loading (DL) refers to the amount of drug loaded per unit weight of the nanopar-
ticles, indicating the mass of the nanoparticles contributed by the encapsulated drug. Drug
loading is calculated using the following equation.

%DL = (Weight of entrapped drug/Weight of nanoparticles) × 100 (1)

Encapsulation efficiency is the percentage of drug that is successfully entrapped in

the nanoparticles. It can be determined as the ratio between the amount of entrapped
drug and the amount of drug added in the preparation of the nanoparticles [18]. EE can
also be determined from the amount of drug found in the non-lipid phase (free drug) as
shown below:

%EE = (Weight of entrapped drug/Weight of drug added) × 100 (2)

%EE = [(Weight of drug added − Weight of free drug)/Weight of drug added] × 100 (3)
The entrapped drug in particles can be separated from free drug by using various tech-
niques, such as ultracentrifugation. The sedimented particles are collected and dissolved
with suitable solvent. The resulting solution is subjected to proper analytical method such
as high-performance liquid chromatography (HPLC), spectrophotometrically in order to
quantify the entrapped drug. For free drug content, it can be obtained by analyzing the
separated supernatant [34].
• Particle size and size distribution
Dynamic light scattering (DLS) and laser diffraction are established techniques for
the characterization of particle size. These methods can measure particle size across
the range of 0.1 nm to 10 µm and 0.01 to 3500 µm, respectively. In DLS, the intensity
fluctuations of scatter light from particle motion are measured and used to determine the
diffusion coefficient and the particle size. The smaller particles show faster fluctuations
of scattered light than larger particles. For laser diffraction, it measures the intensity of
light scattered at various angles as a laser beam passes through a dispersion which is then
analyzed to calculate the particle size. Large particles scatter light at small angles, whereas
small particles scatter light at large angles. Polydispersity index (PDI or PI), a parameter
calculated from DLS, is used to indicate particle size distribution. A PDI value of 0.3 and
below is considered to be acceptable for representing monodispersity of nanoparticles [30].
• Zeta potential:
Zeta potential is the net charge on the particle surface. A greater zeta potential will
result in electrostatic repulsion between dispersed particles, thus preventing particle aggre-
gation. Zeta potential can be measured by electrophoretic light scattering. A zeta potential
value of ±30 mV is generally considered to result in sufficient electrostatic repulsion force
to ensure better physical stability of nanoparticle dispersion [18].
• Degree of crystallinity:
The crystallinity behavior of lipid nanoparticles affects the mobility of the entrapped
drug. The lower crystallization degree can result in faster drug release due to high mobility
of the drug. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) are com-
monly used to investigate crystallinity behavior of lipid carriers. In DSC, the heat energy
uptake in a sample is compared to a reference and applied to monitor the changes of phase
Molecules 2022, 27, 3460 8 of 16

transitions. For XRD, the sample is irradiated with X-rays and the intensity of the radiation
scattered at different angles is analyzed. XRD provides structural information such as
phases, crystal orientations, crystallinity, and crystal defects of the lipid nanoparticles [30].
• Co-existence of different colloidal species:
The co-existence of different colloidal species such as micelles, mixed micelles, and
liposomes can solubilize drug, serve as an alternative location for drug incorporation,
and affect the stability and release kinetics of the incorporated drug. Therefore, the co-
existing colloidal species should be taken into consideration for the development of SLN
or NLC formulations and the interpretation of their analytical results. Nuclear magnetic
resonance (NMR) is a useful technique to investigate dynamic phenomena and the presence
of nano-oil compartments in the colloidal lipid dispersions. NMR can differentiate between
different nuclei, elements, and isotopes due to the fact that each specific nuclide will
absorb electromagnetic radiation at a very specific frequency [30]. NMR spectra can
provide information concerning the number of nuclei and the interaction of nuclei with
the surrounding environment. For those who want to get more details regarding the
applications of NMR to the study of physicochemical properties of different types of
surfactant aggregates, micelles, and related system, many excellent publications should be
consulted [35,36].
• In vitro drug release:
This characteristic can be measured by dialysis bag diffusion technique. In dialysis
technique, lipid dispersion is added into a dialysis bag and then immersed in a dissolution
medium at controlled temperature under continuous stirring. The aliquots of the disso-
lution medium are withdrawn at appropriate time intervals and simultaneously replace
with same volume of fresh dissolution medium. The concentration of drug in the aliquots
is analyzed by appropriate methods such as UV-Vis spectrophotometer and HPLC [37].

6. SLNs and NLCs as Topical Carriers for Anti-Acne Phytochemicals

SLNs and NLCs were broadly studied and used in a wide variety of pharmaceutical
and cosmetic applications including anti-acne. Raza et al. (2013) prepared isotretinoin (ITR)-
loaded SLNs and NLCs. They evaluated skin transport characteristics and antimicrobial
activity against P. acnes of these nanoparticles [38,39]. The ITR-loaded SLNs and ITR-loaded
NLCs had much lower minimum inhibitory concentration compared to isotretinoin alone.
In skin permeation and retention studies, the SLNs and NLCs gave higher permeation flux
and skin retention values than those of the marketed product. Liu et al. (2007) reported
that SLNs improved skin accumulation of ITR with no penetration through skin, thus
avoiding systemic uptake of drug [40]. According to the work of Pokharkar et al. (2014),
benzoyl peroxide-loaded SLNs exhibited strong anti-P. acne activity with controlled drug
release, thereby reducing irritation potential when compared to marketed product [41].
SLNs loaded with triamcinolone acetonide (TA) exhibited prolonged drug release for 24 h.
Moreover, the developed TA-loaded SLNs mainly accumulated in the epidermis which
might avoid undesirable systemic side effect [42]. Gel containing mometasone furoate-
loaded SLN showed significantly superior sustained release and skin deposition than
both mometasone furoate-loaded gel (without SLNs) and commercialized product [43].
Pople et al. (2006) reported that SLNs provided prolonged release of vitamin A palmitate
up to 24 h, and the SLNs-enriched gel demonstrated a better localization of the drug in
the skin than conventional gel [44]. Spironolactone-loaded NLCs in carbopol gels were
developed by Kelidari et al. (2016). Their clinical study was performed in patients with
mild to moderate acne for 8 weeks. It was found that the NLCs-based gel enabled high
tolerance, high skin hydration, and high efficacy against acne compared to spironolactone
alcoholic gels [45]. The efficacies and safety of topical anti-acne drugs, such as clindamycin,
adapalene, azelaic acid, isotretinoin, salicylic acid, and retinyl palmitate, were improved
by incorporating these drugs into SLNs and NLCs [46–51]. The encapsulation of various
Molecules 2022, 27, 3460 9 of 16

anti-acne phytochemicals in SLNs and NLCs was also studied by several research groups
as described in the following sections.

6.1. SLNs as a Promising Carrier System for the Topical Delivery of Anti-Acne Phytochemicals
SLNs loaded with resveratrol, vitamin E, and epigallocatechin gallate (EGCG) for skin-
care applications have been developed by Chen et al. in 2017. The study showed that lipid
nanoparticles provided protective effect against UV-induced degradation of resveratrol
and vitamin E and improved skin penetration of resveratrol [52]. Previous studies showed
that the topical formulations containing resveratrol and EGCG were effective in reducing
inflammation, sebum production, and the viability of P. acnes [53] as well as reducing
the severity of acne vulgaris in patients [54]. Shrotriya et al. (2018) developed SLNs gel
loaded with curcumin with the aim of improving its efficacy. Curcumin is a phytochemical
extracted from the rhizome of Curcuma longa (Zingiberaceae family). Curcumin has anti-
inflammatory and antimicrobial activities which may combat the bacteria that contribute
to acne. The results demonstrated that SLNs-based gel gave better occlusive effects and
skin accumulation of curcumin compared to plain gel. The optimized curcumin-loaded
SLNs had mean particle size of 51 nm and entrapment efficiency of 93% [55]. According
to Kakkar et al. (2018), SLNs loaded with tetrahydrocurcumin (THC), a partially reduced
derivative of curcumin, provided great occlusive effect. The THC- loaded SLNs in gel
formulation demonstrated better therapeutic effects than free THC [56]. It was also found
that the formulation containing just 10% SLNs resulted in better occlusion properties than
the gold standard (Vaseline) [57]. Talarico et al. (2021) reported that the controlled release of
Quercetin, a poorly water-soluble flavonoid, over 26 h was achieved with SLNs composed
of stearic acid as core lipid and Arabic Gum as stabilizer. In addition, the SLNs were found
to enhance antioxidant activity compared to free Quercetin [58]. Eugenol is a natural com-
pound widely found in many aromatic plant species such as clove, holy basils, and betel
vine. It has shown anti-acne activity by suppressing P. acnes-induced inflammatory reac-
tion [59]. Garg et al. (2014) studied the permeation of hydrogel containing eugenol-loaded
SLNs in the epidermis of human cadaver skin. It was found that the SLNs could enhance
the accumulation of eugenol in the epidermis compared to plain hydrogel. Eugenol-loaded
SLNs also exerted greater occlusion and hydration to the skin than eugenol oil and plain
hydrogel [60]. Resveratrol (3,5,40 -trihydroxystilbene) is a polyphenolic compound found
naturally in grapes, wine, peanuts, cocoa, and some berries and it has multiple biological
effects including antimicrobial properties against P. acne [61]. According to Rigon et al.
(2016), resveratrol (RES)-loaded SLNs could be used for administration of RES to improve
its efficacy in skin disorders such as hyperpigmentation and aging [62].

6.2. NLCs as a Promising Carrier System for the Topical Delivery of Anti-Acne Phytochemicals
Rapalli et al. (2020) developed curcumin-loaded NLCs with the aim of improving
its skin permeability. The results indicated that the skin permeation of curcumin-loaded
NLCs was three times higher than that of curcumin alone. Moreover, curcumin loaded-
NLCs showed extended in vitro release up to 48 h [63]. Lacatusu et al. (2017) studied the
anti-inflammatory activity of the marigold extract and azelaic acid co-loaded NLCs. The
results showed that the NLCs could reduce inflammatory IL-6 and IL-1β cytokines tested
by ELISA method and paw edema in rats challenged with carrageenan [64]. Moreover,
a synergistic effect of carrot extract (CE) combined with azelaic acid (AA) in NLCs on
anti-inflammatory and anti-acne activities was observed by Lacatusu et al. (2020). The
results revealed that the NLCs exerted superior anti-inflammatory effect compared with
the commercial product. Furthermore, the expression of inflammatory IL-1β and TNF-α
cytokines was decreased in the cells treated with CE-AA loaded NLCs [65,66]. Salicin is
an alcoholic β-glucoside found in willow bark extract which is used to treat skin diseases
such as acne due to its anti-inflammatory and high comedolytic activities. According to
Arsenie et al. (2020), NLCs loaded with a mixture of white willow bark extract (WBE),
azelaic acid and panthenol were able to improve the epidermal cell reconstruction. The
Molecules 2022, 27, 3460 10 of 16

gel containing the NLCs gave a degree of hydration of 84 % in the T-zone for type-III
skin (predisposed to acne) [67]. Asiaticoside, madecasosside, asiatic acid, and madecas-
sic acid are the phytochemicals found in Centella asiatica which exhibit multi-therapeutic
effects including antioxidant, anti-inflammatory, antimicrobial, and anticarcinogenic ac-
tivities [68]. NLCs were found to enhance the membrane fluidity of stratum corneum
which enabled the asiaticoside in Centella asiatica to penetrate the skin [69]. Singh et al.
(2016) studied the anti-inflammatory effect of silymarin- loaded NLCs. Silymarin is a
phytochemical extracted from Silybum marianum (milk thistle) fruit. It has comedolytic
activity and reduces the production of fatty acid [70,71]. It was found that silymarin-
loaded NLCs could reduce the swelling and inflammation of mouse skin induced by
7,12-dimethylbenz[a]anthracene (DMBA). The NLCs also improved the stability of sily-
marin [72]. Rosli et al. (2015) reported that NLCs loaded with Zingiber zerumbet oil, a
phytochemical found in Zingiber zerumbet (pinecone or shampoo ginger), were stable and
suitable for transdermal delivery systems [73]. Zingiber zerumbet oil itself was found to
have anti-P. acnes activity (MIC ≥ 125 µg/mL), great antioxidant and anti-biofilm forma-
tion activities [74]. Origanum vulgare L. or oregano is an aromatic plant containing high
amounts of carvacrol and thymol essential oil. It possesses antimicrobial activity against
P. acnes with MIC of 0.34 mg/mL [7,18]. According to Carbone et al. (2018), NLCs loaded
with this essential oil exhibited antioxidant and anti-inflammatory effects and promising
drug solubility and stability enhancement properties [75]. Bose et al. (2021) studied the
effect of α-terpineol- loaded NLCs against Pseudomonas aeruginosa in the murine model.
Alpha-terpineol is a phytochemical found in tea tree oil that strongly inhibits P. acnes
with MIC of 2.5%. It was found that topical application of α-terpineol-loaded NLCs
could reduce bacterial count in the infected tissue and decrease the levels of various
inflammatory markers [39,76]. Cannabidiol (CBD) is a non-psychoactive phytocannabi-
noid found in Cannabis sativa. CBD is one of the promising anti-acne phytochemicals
due to its anti-inflammatory and sebostatic activities [30]. Esposito et al. (2016) devel-
oped and optimized the formulation of CBD-loaded NLCs prepared by ultrasonication
method and initiated its clinical trial [77]. Cinnamon oil is an essential oil obtained from
Cinnamomum zeylanicum or cinnamon bark. The main components of cinnamon oil are
cinnamaldehyde and eugenol [23]. Cinnamon oil exerts anti-P. acnes activity with MIC
of 5 mg/mL. Wen et al. (2018) developed cinnamon-loaded NLCs for promoting wound
healing. The study showed that NLCs containing cinnamon oil had antimicrobial activities
against antibiotic-resistant P. aeruginosa and Burkholderia cepacia complex. The NLCs also
enhanced skin permeation of cinnamon oil and could shorten the treatment time [78].
Essential oil from bergamot or Citrus medica L. var. sarcodactyl has shown anti-acne activity
by promoting apoptosis of sebaceous glands and inhibiting the accumulation of triglyc-
erides and inflammation [79]. Bergamot oil-loaded NLCs were developed and studied for
the photodynamic treatment of vitiligo. Research findings suggested that bergamot oil
was successfully loaded into NLCs, which provided sustained release of bergamot oil for
24 h [80].
In addition to the above information, brief details of various formulations and their
respective findings are mentioned in Table 1.

Table 1. Examples of SLNs and NLCs loaded with anti-acne phytochemicals.

Lipid Carriers Phytochemicals Compositions Findings References

The penetration through the stratum
corneum of quercetin via
Tristearin,
SLNs Quercetin quercetin-loaded SLNs in topical [81]
phosphatidylcholine
emulsion (21.2 ± 2.9%) was greater than
that of control emulsion (18.1 ± 2.3%).
Molecules 2022, 27, 3460 11 of 16

Table 1. Cont.

Lipid Carriers Phytochemicals Compositions Findings References

Beeswax, Tween 80, The formulation showed a sustained
SLNs Curcuminoids [82]
lecithin release with first order kinetics.
Entrapment efficiency (EE) of neem
oil-loaded SLNs was in the range of
67.23–82.10%.
Soya lecithin, EE increased when the concentrations of
SLNs Neem oil [83]
cholesterol, Tween80 lecithin and tween 80
increased.
SLNs showed burst
release (3.56–30.05%) within first 30 min.
Mean particle size of SLNs and NLCs
Glyceryl behenate
were 287.2 nm ± 5.1 and 110.5 nm ± 1.3,
(Compritol 888),
respectively.
poloxamer 188
SLNs Resveratrol The drug entrapment [84]
(Pluronic F68),
efficiency was 18% higher in NLCs.
Tween 80,
NLCs penetrated deeper
Miglyol® 812
into the skin than SLNs.
Glyceryl The PFs-loaded SLNs exhibited prolonged
monostearate, drug release for 24 h and prolonged
Propolis
SLNs soy lecithin, anti-inflammatory properties. No [85]
flavonoids (PFs)
PEG400, cytotoxicity
Tween80 observed.
All NLC formulations showed a slow
Cetyl palmitate, degradation of
sesame oil, tween 80 resveratrol over 24 h while resveratrol
Glyceryl behenate solution showed rapid degradation in the
(Compritol 888), first 8 h.
NLCs Resveratrol [52]
sesame oil, tween 80 Phospholipon-based NLCs showed
Phospholipid sustained release of resveratrol over 24 h
(Phospholipon80), and improved the penetration of
sesame oil, Tween 80 resveratrol through
stratum corneum.
Cetyl palmitate,
lavender oil, α -Mangostin-loaded
Montanov 82, NLC reduced the levels of inflammatory
NLCs α-Mangostin Polyoxyethylene (20) mediators including [86]
sorbitanmonolaurate, nitric oxide and TNF-α in macrophages
poloxamer and induced by lipopolysaccharide.
glycerol
All NLC formulations showed good
bioadhesive properties.
Eucalyptus
Cocoa butter, Eucalyptus oil-loaded NLCs
essential oils or
NLCs olive oil or sesame oil, prepared with [87]
Rosemaryessential
lecithin olive oil showed
oils
antimicrobial and wound healing
properties.
Lycopene-loaded NLCs
gave a biphasic release profile (a relatively
fast release during the first 6 h, followed
Eumulgin SG, by a sustained release during
NLCs Lycopene orange wax, the next 18 h). [88]
rice oil The occlusive properties of NLC increased
with increasing lycopene loading.
The utilization of NLC increased the
stability of lycopene.
Molecules 2022, 27, 3460 12 of 16

For this mini-review, the references cited are more specific to the application of SLNs
and NLCs to topical delivery of phytochemicals for the treatment of acne vulgaris. Readers
can however refer to the literature to find out more about the materials and methods used
for the production of SLNs and NLCs, as well as their other applications in topical, dermal,
and transdermal drug delivery. Such information can be obtained from many insightful
review articles previously published [6,16,89–98].

7. Conclusions
The SLNs and NLCs are attractive and promising lipid nanocarriers for topical de-
livery of phytochemicals due to their desirable properties that include skin penetration
enhancement, promising occlusive effect, possibility to modulate drug release kinetics,
ability to prevent the degradation of phytochemicals and suitability as carriers for both
hydrophilic and lipophilic active substances. Moreover, the SLNs and NLCs can be applied
onto damaged or inflamed skin because they are composed of biocompatible and non-toxic
lipids. However, it is worth highlighting that although remarkable results of SLNs and
NLCs as delivery systems for anti-acne phytochemicals have been demonstrated by many
research groups, their in vivo efficacy in treating acne has not been fully established yet.
Hence, further investigation on the potential of these lipid carriers in clinical setting is
highly warranted and strongly encouraged. This would bring a new perspective on SLNs
and NLCs as phytochemical carriers for topical treatment of acne.

Author Contributions: Writing—review and editing and supervision, R.C.; writing—original draft
preparation, P.K.; editing and supervision, L.W.C. All authors have read and agreed to the published
version of the manuscript.
Funding: This research was funded by the Temasek Foundation—National University of Singapore
STEM for University Educators Programme in ASEAN.
Acknowledgments: The authors gratefully acknowledge the support from Department of Pharmacy,
Faculty of Science, National University of Singapore and Department of Pharmaceutics and Industrial
Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Xu, N.; Deng, W.; He, G.; Gan, X.; Gao, S.; Chen, Y.; Gao, Y.; Xu, K.; Qi, J.; Lin, H.; et al. Alpha- and gamma-mangostins exhibit
anti-acne activities via multiple mechanisms. Immunopharmacol. Immunotoxicol. 2018, 40, 415–422. [CrossRef] [PubMed]
2. Bhatt, D.; Sachan, A.K.; Jain, S.; Barik, R. Studies on inhibitory effect of Eucalyptus oil on sebaceous glands for the management
of acne. Indian J. Nat. Prod. Resour. 2011, 2, 345–349.
3. Fabbrocini, G.; Staibano, S.; De Rosa, G.; Battimiello, V.; Fardella, N.; Ilardi, G.; La Rotonda, M.M.; Longobardi, A.; Mazzella, M.;
Siano, M.; et al. Resveratrol-containing gel for the treatment of acne vulgaris: A single-blind, vehicle-controlled, pilot study. Am. J.
Clin. Dermatol. 2011, 12, 133–141. [CrossRef] [PubMed]
4. Garg, T. Current nanotechnological approaches for an effective delivery of bio-active drug molecules in the treatment of acne.
Artif. Cells Nanomed. Biotechnol. 2016, 44, 98–105. [CrossRef]
5. Battaglia, L.; Gallarate, M. Lipid nanoparticles: State of the art, new preparation methods and challenges in drug delivery. Expert
Opin. Drug Deliv. 2012, 9, 497–508. [CrossRef]
6. Beloqui, A.; Solinís, M.; Rodríguez-Gascón, A.; Almeida, A.J.; Préat, V. Nanostructured lipid carriers: Promising drug delivery
systems for future clinics. Nanomedicine 2016, 12, 143–161. [CrossRef]
7. Jain, S.; Patel, N.; Shah, M.K.; Khatri, P.; Vora, N. Recent advances in lipid-based vesicles and particulate carriers for topical and
transdermal application. J. Pharm. Sci. 2017, 106, 423–445. [CrossRef]
8. Verma, S.; Utreja, P.; Duvedi, D.R.; Prasad, D.; Kumar, L. Nanotechnological carriers for treatment of acne. Recent Pat. Antiinfect
Drug Discov. 2018, 13, 105–126. [CrossRef]
9. Müller, R.H.; Mehnert, W.; Lucks, J.S.; Schwarz, C.; Zur Mühlen, A.; Weyhers, H.; Freitas, C.; Rühl, D. Solid lipid nanoparticles
(SLN)—An alternative colloidal carrier system for controlled drug delivery. Eur. J. Pharm. Biopharm. 1995, 41, 62–69.
10. Müller, R.H.; Lippacher, A.; Gohla, S. Solid lipid nanoparticles (SLN) as a carrier system for the controlled release of drugs. In
Handbook of Pharmaceutical Controlled Release Technology; Wise, D., Ed.; Marcel Dekker: New York, NY, USA, 2000; pp. 377–392.
11. Mukherjee, S.; Ray, S.; Thakur, R.S. Solid lipid nanoparticles: A modern formulation approach in drug delivery system. Indian J.
Pharm. Sci. 2009, 71, 349–358. [CrossRef]
Molecules 2022, 27, 3460 13 of 16

12. Mishra, V.; Bansal, K.K.; Verma, A.; Yadav, N.; Thakur, S.; Sudhakar, K.; Rosenholm, J.M. Solid lipid nanoparticles: Emerging
colloidal nano drug delivery systems. Pharmaceutics 2018, 10, 191. [CrossRef]
13. Smith, T.; Affram, K.; Nottingham, E.L.; Han, B.; Amissah, F.; Krishnan, S.; Trevino, J.; Agyare, E. Application of smart solid lipid
nanoparticles to enhance the efficacy of 5-fluorouracil in the treatment of colorectal cancer. Sci. Rep. 2020, 10, 16989. [CrossRef]
14. Mardhiah Adib, Z.; Ghanbarzadeh, S.; Kouhsoltani, M.; Khosroshahi, A.Y.; Hamishehkar, H. The effect of particle size on the
deposition of solid lipid nanoparticles in different skin layers: A histological study. Adv. Pharm. Bull. 2016, 6, 31–36. [CrossRef]
15. Zur Mühlen, A.; Mehnert, W. Drug release and release mechanisms of prednisolone loaded solid lipid nanoparticles. Pharmazie
1998, 53, 552–555.
16. Müller, R.H.; Radtke, M.; Wissing, S.A. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and
dermatological preparations. Adv. Drug Deliv. Rev. 2002, 54 (Suppl. S1), S131–S155. [CrossRef]
17. Wissing, S.A.; Muller, R.H. The influence of the crystallinity of lipid nanoparticles on their occlusive properties. Int. J. Pharm.
2002, 242, 377–379. [CrossRef]
18. Scalia, S.; Young, P.M.; Traini, D. Solid lipid microparticles as an approach to drug delivery. Expert Opin. Drug Deliv. 2015, 12,
583–599. [CrossRef]
19. Borges, A.; Freitas, V.; Mateus, N.; Fernandes, I.; Oliveira, J. Solid lipid nanoparticles as carriers of natural phenolic compounds.
Antioxidants 2020, 9, 998. [CrossRef]
20. Chauhan, I.; Yasir, M.; Verma, M.; Singh, A.P. Nanostructured Lipid Carriers: A Groundbreaking Approach for Transdermal Drug
Delivery. Adv. Pharm. Bull. 2020, 10, 150–165. [CrossRef]
21. Scholer, N.; Olbrich, C.; Tabbatt, K.; Muller, R.H.; Hahn, H.; Liesenfeld, O. Surfactant, but not the size of solid lipid nanoparticles
(SLN) influences viability and cytokine production of macrophages. Int. J. Pharm. 2001, 221, 57–67. [CrossRef]
22. Effendy, I.; Maibach, H.I. Surfactants and experimental irritant contact dermatitis. Contact Dermat. 1995, 33, 217–225. [CrossRef]
[PubMed]
23. Iqbal, M.A.; Md, S.; Sahni, J.K.; Baboota, S.; Dang, S.; Ali, J. Nanostructured lipid carriers system: Recent advances in drug
delivery. J. Drug Target. 2012, 20, 813–830. [CrossRef] [PubMed]
24. Liu, C.H.; Wu, C.T. Optimization of nanostructured lipid carriers for lutein delivery. Coll. Surf. A Physicochem. Eng. Asp. 2010, 353,
149–156. [CrossRef]
25. Khosa, A.; Reddi, S.; Saha, R.N. Nanostructured lipid carriers for site-specific drug delivery. Biomed. Pharmacother. 2018, 103,
598–613. [CrossRef]
26. Vyas, A.; Kumar Sonker, A.; Gidwani, B. Carrier-based drug delivery system for treatment of acne. Sci. World J. 2014, 2014, 276260.
[CrossRef]
27. Subramaniam, B.; Siddik, Z.H.; Nagoor, N.H. Optimization of nanostructured lipid carriers: Understanding the types, designs,
and parameters in the process of formulations. J. Nanopart. Res. 2020, 22, 141. [CrossRef]
28. Jaiswal, P.; Gidwani, B.; Vyas, A. Nanostructured lipid carriers and their current application in targeted drug delivery. Artif. Cells
Nanomed. Biotechnol. 2016, 44, 27–40. [CrossRef]
29. Hwang, T.L.; Aljuffali, I.A.; Lin, C.F.; Chang, Y.T.; Fang, J.Y. Cationic additives in nanosystems activate cytotoxicity and
inflammatory response of human neutrophils: Lipid nanoparticles versus polymeric nanoparticles. Int. J. Nanomed. 2015, 10,
371–385.
30. Oláh, A.; Tóth, B.I.; Borbíró, I.; Sugawara, K.; Szöllõsi, A.G.; Czifra, G.; Pál, B.; Ambrus, L.; Kloepper, J.; Camera, E.; et al.
Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. J. Clin. Investig. 2014, 124, 3713–3724. [CrossRef]
31. Carlotti, M.E.; Sapino, S.; Trotta, M.; Battaglia, L.; Vione, D.; Pelizzetti, E. Photostability and stability over time of retinyl palmitate
in an o/w emulsion and in SLN introduced in the emulsion. J. Disper. Sci. Technol. 2005, 26, 125–138. [CrossRef]
32. Battaglia, L.; Gallarate, M.; Panciani, P.P.; Ugazio, E.; Sapino, S.; Peira, E.; Chirio, D. Techniques for the preparation of solid
lipid nano and microparticles. In Application of Nanotechnology in Drug Delivery; Sezer, A.D., Ed.; IntechOpen: London, UK, 2014;
pp. 51–75.
33. Charcosse, C.; El-Harati, A.; Fessi, H. Preparation of solid lipid nanoparticles using a membrane contactor. J. Control. Release 2005,
108, 112–120. [CrossRef]
34. Opatha, S.A.T.; Titapiwatanakun, V.; Chutoprapat, R. Transfersomes: A promising nanoencapsulation technique for transdermal
drug delivery. Pharmaceutics 2020, 12, 855. [CrossRef]
35. Söderman, O.; Stilbs, P.; Price, W.S. NMR studies of surfactants. Concept Magn. Reason. Part A 2004, 23, 121–135. [CrossRef]
36. Furó, I. NMR spectroscopy of micelles and related systems. J. Mol. Liq. 2005, 117, 117–137. [CrossRef]
37. Üner, M.; Karaman, E.F.; Aydoğmuş, Z. Solid lipid nanoparticles and nanostructured lipid carriers of loratadine for topical
application: Physicochemical stability and drug penetration through rat skin. Trop. J. Pharm. Res. 2014, 13, 653–660. [CrossRef]
38. Raza, K.; Singh, B.; Singal, P.; Wadhwa, S.; Katare, O.P. Systematically optimized biocompatible isotretinoin-loaded solid lipid
nanoparticles (SLNs) for topical treatment of acne. Coll. Surf. B 2013, 105, 67–74. [CrossRef]
39. Raza, K.; Singh, B.; Singla, S.; Wadhwa, S.; Garg, B.; Chhibber, S.; Katare, O.P. Nanocolloidal carriers of isotretinoin: Antimicrobial
activity against Propionibacterium acnes and dermatokinetic modeling. Mol. Pharm. 2013, 10, 1958–1963. [CrossRef]
40. Liu, J.; Hu, W.; Chen, H.; Ni, Q.; Xu, H.; Yang, X. Isotretinoin-loaded solid lipid nanoparticles with skin targeting for topical
delivery. Int. J. Pharm. 2007, 328, 191–195. [CrossRef]
Molecules 2022, 27, 3460 14 of 16

41. Pokharkar, V.B.; Mendiratta, C.; Kyadarkunte, A.Y.; Bhosale, S.H.; Barhate, G.A. Skin delivery aspects of benzoyl peroxide-loaded
solid lipid nanoparticles for acne treatment. Ther. Deliv. 2014, 5, 635–652. [CrossRef]
42. Pradhan, M.; Singh, D.; Singh, M.R. Influence of selected variables on fabrication of Triamcinolone acetonide loaded solid lipid
nanoparticles for topical treatment of dermal disorders. Artif. Cells Nanomed. Biotechnol. 2016, 44, 392–400. [CrossRef]
43. Madan, J.R.; Khude, P.A.; Dua, K. Development and evaluation of solid lipid nanoparticles of mometasone furoate for topical
delivery. Int. J. Pharm. Res. 2014, 4, 60. [CrossRef] [PubMed]
44. Pople, P.V.; Singh, K.K. Development and evaluation of topical formulation containing solid lipid nanoparticles of vitamin A.
Aaps Pharmscitech 2006, 7, E63–E69. [CrossRef]
45. Kelidari, H.R.; Saeedi, M.; Hajheydari, Z.; Akbari, J.; Morteza-Semnani, K.; Akhtari, J.; Valizadeh, H.; Asare-Addo, K.; Nokhodchi,
A. Spironolactone loaded nanostructured lipid carrier gel for effective treatment of mild and moderate acne vulgaris: A randomized,
double-blind, prospective trial. Colloids Surf. B 2016, 146, 47–53. [CrossRef] [PubMed]
46. Fatima, N.; Rehman, S.; Nabi, B.; Baboota, S.; Ali, J. Harnessing nanotechnology for enhanced topical delivery of clindamycin
phosphate. J. Drug Deliv. Sci. Technol. 2019, 54, 101253. [CrossRef]
47. Jain, A.; Garg, N.K.; Jain, A.; Kesharwani, P.; Jain, A.K.; Nirbhavane, P.; Tyagi, R.K. A synergistic approach of adapalene-loaded
nanostructured lipid carriers, and vitamin C co-administration for treating acne. Drug Dev. Ind. Pharm. 2016, 42, 897–905.
[CrossRef] [PubMed]
48. Malik, D.S.; Kaur, G. Exploring therapeutic potential of azelaic acid loaded NLCs for the treatment of acne vulgaris. J. Drug Deliv.
Sci. Technol. 2020, 55, 101418. [CrossRef]
49. Patwekar, S.L.; Pedewad, S.R.; Gattani, S. Development and evaluation of nanostructured lipid carriers-based gel of isotretinoin.
Part. Sci. Technol. 2018, 36, 832–843. [CrossRef]
50. Woo, J.O.; Misran, M.; Lee, P.F.; Tan, L.P. Development of a controlled release of salicylic acid loaded stearic acid-oleic acid
nanoparticles in cream for topical delivery. Sci. World J. 2014, 2014, 205703. [CrossRef]
51. AlZahabi, S.; Sakr, O.S.; Ramadan, A.A. Nanostructured lipid carriers incorporating prickly pear seed oil for the encapsulation of
vitamin A. J. Cosmet. Dermatol. 2019, 18, 1875–1884. [CrossRef]
52. Chen, J.; Wei, N.; Lopez-Garcia, M.; Ambrose, D.; Lee, J.; Annelin, C.; Peterson, T. Development and evaluation of resveratrol,
Vitamin E, and epigallocatechin gallate loaded lipid nanoparticles for skin care applications. Eur. J. Pharm. Biopharm. 2017, 117,
286–291. [CrossRef]
53. Yoon, J.Y.; Kwon, H.H.; Min, S.U.; Thiboutot, D.M.; Suh, D.H. Epigallocatechin-3-gallate improves acne in humans by modulating
intracellular molecular targets and inhibiting P. acnes.. J. Investig. Dermatol. 2013, 133, 429–440. [CrossRef]
54. Szulc-Musioł, B.; Sarecka-Hujar, B. The use of micro- and nanocarriers for resveratrol delivery into and across the skin in different
skin diseases—A Literature Review. Pharmaceutics 2021, 13, 451. [CrossRef]
55. Shrotriya, S.; Ranpise, N.; Satpute, P.; Vidhate, B. Skin targeting of curcumin solid lipid nanoparticles-engrossed topical gel for the
treatment of pigmentation and irritant contact dermatitis. Artif. Cells Nanomed. Biotechnol. 2018, 46, 1471–1482. [CrossRef]
56. Kakkar, V.; Kaur, I.P.; Kaur, A.P.; Saini, K.; Singh, K.K. Topical delivery of tetrahydrocurcumin lipid nanoparticles effectively
inhibits skin inflammation: In vitro and in vivo study. Drug Dev. Ind. Pharm. 2018, 44, 1701–1712. [CrossRef]
57. Hamishehkar, H.; Same, S.; Adibkia, K.; Zarza, K.; Shokri, J.; Taghaee, M.; Kouhsoltani, M. A comparative histological study on
the skin occlusion performance of a cream made of solid lipid nanoparticles and Vaseline. Res. Pharm. Sci. 2015, 10, 378–387.
58. Talarico, L.; Consumi, M.; Leone, G.; Tamasi, G.; Magnani, A. Solid lipid nanoparticles produced via a coacervation method as
promising carriers for controlled release of Quercetin. Molecules 2021, 26, 2694. [CrossRef]
59. Tsai, T.H.; Huang, W.C.; Lien, T.J.; Huang, Y.H.; Chang, H.; Yu, C.H.; Tsai, P.J. Clove extract and eugenol suppress inflammatory
responses elicited by Propionibacterium acnes in vitro and in vivo. Food Agric. Immunol. 2017, 28, 916–931. [CrossRef]
60. Garg, A.; Singh, S. Targeting of eugenol-loaded solid lipid nanoparticles to the epidermal layer of human skin. Nanomedicine 2014,
9, 1223–1238. [CrossRef]
61. Taylor, E.J.M.; Yu, Y.; Champer, J.; Kim, J. Resveratrol demonstrates antimicrobial effects against Propionibacterium acnes in vitro.
Dermatol. Ther. 2014, 4, 249–257. [CrossRef]
62. Rigon, R.B.; Fachinetti, N.; Severino, P.; Santana, M.H.; Chorilli, M. Skin delivery and in vitro biological evaluation of trans-
resveratrol-loaded solid lipid nanoparticles for skin disorder therapies. Molecules 2016, 21, 116. [CrossRef]
63. Rapalli, V.K.; Kaul, V.; Waghule, T.; Gorantla, S.; Sharma, S.; Roy, A.; Dubey, S.K.; Singhvi, G. Curcumin loaded nanostructured
lipid carriers for enhanced skin retained topical delivery: Optimization, scale-up, in-vitro characterization and assessment of
ex-vivo skin deposition. Eur. J. Pharm. Sci. 2020, 152, 105438. [CrossRef] [PubMed]
64. Lacatusu, I.; Badea, G.; Popescu, M.; Bordei, N.; Istrati, D.; Moldovan, L.; Seciu, A.M.; Panteli, M.I.; Rasit, I.; Badea, N. Marigold
extract, azelaic acid and black caraway oil into lipid nanocarriers provides a strong anti-inflammatory effect in vivo. Ind. Crops
Prod. 2017, 109, 141–150. [CrossRef]
65. Lacatusu, I.; Istrati, D.; Bordei, N.; Popescu, M.; Seciu, A.M.; Panteli, L.M.; Badea, N. Synergism of plant extract and vegetable
oils-based lipid nanocarriers: Emerging trends in development of advanced cosmetic prototype products. Mater. Sci. Eng. C 2020,
108, 110412. [CrossRef]
66. Istrati, D.; Lacatusu, I.; Bordei, N.; Badea, G.; Oprea, O.; Stefan, L.M.; Stan, R.; Badea, N.; Meghea, A. Phyto-mediated
nanostructured carriers based on dual vegetable actives involved in the prevention of cellular damage. Mater. Sci. Eng. C 2016, 64,
249–259. [CrossRef] [PubMed]
Molecules 2022, 27, 3460 15 of 16

67. Arsenie, L.V.; Lacatusu, I.; Oprea, O.; Bordei, N.; Bacalum, M.; Badea, N. Azelaic acid-willow bark extract-panthenol—Loaded
lipid nanocarriers improve the hydration effect and antioxidant action of cosmetic formulations. Ind. Crops Prod. 2020, 154,
112658. [CrossRef]
68. Sun, B.; Wu, L.; Wu, Y.; Zhang, C.; Qin, L.; Hayashi, M.; Kudo, M.; Gao, M.; Liu, T. Therapeutic potential of Centella asiatica and its
triterpenes: A review. Front. Pharmacol. 2020, 11, 568032. [CrossRef] [PubMed]
69. Da Rocha, P.B.R.; Souza, B.S.; Andrade, L.M.; Dos Anjos, J.L.V.; Mendanha, S.A.; Alonso, A.; Marreto, R.N.; Taveira, S.F. Enhanced
asiaticoside skin permeation by Centella asiatica-loaded lipid nanoparticles: Effects of extract type and study of stratum corneum
lipid dynamics. J. Drug Deliv. Sci. Technol. 2019, 50, 305–312. [CrossRef]
70. Fontao, F.; Von Engelbrechten, M.; Seilaz, C.; Sorg, O.; Saurat, J.H. Microcomedones in non-lesional acne prone skin. New
orientations on comedogenesis and its prevention. J. Eur. Acad. Dermatol. Venereol. 2020, 34, 357–364. [CrossRef]
71. Nocera, T.; Josse, G.; Garidou, L.; Rizz, N.C.; Bessou-Touya, S.; Saurat, J.H. 15410 Efficacy and tolerability of a new formulation
containing Silybum marianum fruit extract in young adults with acne-prone skin: A comparative controlled study. J. Am. Acad.
Dermatol. 2020, 83, AB150. [CrossRef]
72. Singh, P.; Arya, M.; Kanoujia, J.; Singh, M.; Gupta, K.P.; Saraf, S.A. Design of topical nanostructured lipid carrier of silymarin
and its effect on 7,12-dimethylbenz[a]anthracene (DMBA) induced cellular differentiation in mouse skin. RSC Adv. 2016, 6,
84965–84977. [CrossRef]
73. Rosli, N.A.; Hasham, R.; Aziz, A.A.; Aziz, R. Formulation and characterization of nanostructured lipid carrier encapsulated
Zingiber zerumbet oil using ultrasonication technique. J. Adv. Res. Appl. Mech. 2015, 11, 16–23.
74. Yob, N.J.; Jofrry SMohd Meor Mohd Affandi, M.M.R.; Teh, L.K.; Salleh, M.Z.; Zakaria, Z.A. Zingiber zerumbet (L.) Smith: A Review
of Its Ethnomedicinal, Chemical, and Pharmacological Uses. Evid. Based Complement. Altern. Med. 2011, 2011, 543216. [CrossRef]
75. Carbone, C.; Martins-Gomes, C.; Caddeo, C.; Silva, A.M.; Musumeci, T.; Pignatello, R.; Puglisi, G.; Souto, E.B. Mediterranean
essential oils as precious matrix components and active ingredients of lipid nanoparticles. Int. J. Pharm. 2018, 548, 217–226.
[CrossRef]
76. Bose, K.S.; Sharma, K.; Chhibber, S.; Harjai, K. Therapeutic potential of nanolipoidal α-terpineol in combating keratitis induced
by Pseudomonas aeruginosa in the murine model. Int. J. Pharm. 2021, 594, 120175. [CrossRef]
77. Esposito, E.; Drechsler, M.; Cortesi, R.; Nastruzzi, C. Encapsulation of cannabinoid drugs in nanostructured lipid carriers. Eur. J.
Pharm. Biopharm. 2016, 102, 87–91. [CrossRef]
78. Wen, M.M.; El-Zahaby, S.A.; Abdelwahab, I. Nanostructured lipid carriers: A promising topical system for delivering cinnamon
oil in wound care treatment. In Proceedings of the Fifth Euro-Mediterranean conference of Natural Products, Pharma and
Complementary Medicine, Limassol, Cyprus, 1 March 2018.
79. Sun, P.; Zhao, L.; Zhang, N.; Wang, C.; Wu, W.; Mehmood, A.; Zhang, L.; Ji, B.; Zhou, F. Essential oil and juice from bergamot and
sweet orange improve acne vulgaris caused by excessive androgen secretion. Mediat. Inflamm. 2020, 2020, 8868107. [CrossRef]
80. Shaaban, M.; Nasr, M.; Tawfik, A.A.; Fadel, M.; Sammour, O. Bergamot oil as an integral component of nanostructured lipid
carriers and a photosensitizer for photodynamic treatment of vitiligo: Characterization and clinical experimentation. Expert Opin.
Drug Deliv. 2021, 18, 139–150. [CrossRef]
81. Scalia, S.; Franceschinis, E.; Bertelli, D.; Iannuccelli, V. Comparative evaluation of the effect of permeation enhancers, lipid
nanoparticles and colloidal silica on in vivo human skin penetration of quercetin. Skin Pharmacol. Physiol. 2013, 26, 57–67.
[CrossRef]
82. Zamarioli, C.M.; Martins, R.M.; Carvalho, E.C.; Freitas, L.A.P. Nanoparticles containing curcuminoids (Curcuma longa): Develop-
ment of topical delivery formulation. Rev. Bras. Farmacogn. 2015, 25, 53–60. [CrossRef]
83. Vijayan, V.; Aafreen, S.; Sakthivel, S.; Reddy, K.R. Formulation and characterization of solid lipid nanoparticles loaded Neem oil
for topical treatment of acne. J. Acute Dis. 2013, 2, 282–286. [CrossRef]
84. Gokce, E.H.; Korkmaz, E.; Dellera, E.; Sandri, G.; Bonferoni, M.C.; Ozer, O. Resveratrol-loaded solid lipid nanoparticles versus
nanostructured lipid carriers: Evaluation of antioxidant potential for dermal applications. Int. J. Nanomed. 2012, 7, 1841–1850.
[CrossRef] [PubMed]
85. Afra, B.; Mohammadi, M.; Soleimani, M.; Mahjub, R. Preparation, statistical optimization, in vitro characterization, and in vivo
pharmacological evaluation of solid lipid nanoparticles encapsulating propolis flavonoids: A novel treatment for skin edema.
Drug Dev. Ind. Pharm. 2020, 46, 1163–1176. [CrossRef] [PubMed]
86. Yostawonkul, J.; Surassmo, S.; Namdee, K.; Khongkow, M.; Boonthum, C.; Pagseesing, S.; Saengkrit, N.; Ruktanonchai, U.R.;
Chatdarong, K.; Ponglowhapan, S.; et al. Nanocarrier-mediated delivery of α-mangostin for non-surgical castration of male
animals. Sci. Rep. 2017, 7, 16234. [CrossRef] [PubMed]
87. Saporito, F.; Sandri, G.; Bonferoni, M.C.; Rossi, S.; Boselli, C.; Cornaglia, A.I.; Mannucci, B.; Grisoli, P.; Vigani, B.; Ferrari, F.
Essential oil-loaded lipid nanoparticles for wound healing. Int. J. Nanomed. 2018, 13, 175–186. [CrossRef]
88. Okonogi, S.; Riangjanapatee, P. Physicochemical characterization of lycopene-loaded nanostructured lipid carrier formulations
for topical administration. Int. J. Pharm. 2015, 478, 726–735. [CrossRef] [PubMed]
89. Muller, R.H.; Mader, K.; Gohla, S. Solid lipid nanoparticles (SLN) for controlled drug delivery—A review of the state of the art.
Eur. J. Pharm. Biopharm. 2000, 50, 161–177. [CrossRef]
90. Schäfer-Korting, M.; Mehnert, W.; Korting, H.C. Lipid nanoparticles for improved topical application of drugs for skin diseases.
Adv. Drug Deliv. Rev. 2007, 59, 427–443. [CrossRef] [PubMed]
Molecules 2022, 27, 3460 16 of 16

91. Pardeike, J.; Hommoss, A.; Muller, R.H. Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products. Int. J.
Pharm. 2009, 366, 170–184. [CrossRef]
92. Muller, R.H.; Shegokar, R.; Keck, C.M. 20 years of lipid nanoparticles (SLN and NLC): Present state of development and industrial
applications. Curr. Drug Discov. Technol. 2011, 8, 207–227. [CrossRef]
93. Naseri, N.; Valizadeh, H.; Milani, P.Z. Solid lipid nanoparticles and nanostructured lipid carriers: Structure, preparation and
application. Adv. Pharm. Bull. 2015, 5, 305–313. [CrossRef]
94. Lauterbach, A.; Müller-Goymann, C.C. Applications and limitations of lipid nanoparticles in dermal and transdermal drug
delivery via the follicular route. Eur. J. Pharm. Biopharm. 2015, 97, 152–163. [CrossRef]
95. Garcês, A.; Amaral, M.H.; Sousa Lobo, J.M.; Silva, A.C. Formulations based on solid lipid nanoparticles (SLN) and nanostructured
lipid carriers (NLC) for cutaneous use: A review. Eur. J. Pharm. Sci. 2018, 112, 159–167. [CrossRef]
96. Montoto, S.S.; Muraca, G.; Ruiz, M.E. Solid lipid nanoparticles for drug delivery: Pharmacological and biopharmaceutical aspects.
Front. Mol. Biosci. 2020, 7, 587997. [CrossRef]
97. Souto, E.B.; Baldim, I.; Oliveira, W.P.; Rao, R.; Yadav, N.; Gama, F.M.; Mahant, S. SLN and NLC for topical, dermal, and
transdermal drug delivery. Rev. Expert Opin. Drug Deliv. 2020, 17, 357–377. [CrossRef]
98. Dhiman, N.; Awasthi, R.; Sharma, B.; Kharkwal, H.; Kulkarni, G.T. Lipid nanoparticles as carriers for bioactive delivery. Front.
Chem. 2021, 9, 580118. [CrossRef]