Review

Nanoemulgel: A Novel Nano Carrier as a Tool for Topical

Drug Delivery
Mahipal Reddy Donthi 1,‡, Siva Ram Munnangi 1,2,†,‡, Kowthavarapu Venkata Krishna 1,3,†,
Ranendra Narayan Saha 1, Gautam Singhvi 1 and Sunil Kumar Dubey 1,4,*,†

1 Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS-PILANI), Pilani Campus,
Rajasthan 333031, India
2 Department of Pharmaceutics and Drug Delivery, School of Pharmacy, The University of Mississippi,

Oxford, MS 38677, USA

3 Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of

Pharmacy, University of Florida, Orlando, FL 32827, USA

4 R&D Healthcare Division Emami Ltd., 13, BT Road, Kolkata 700056, India

* Correspondence: [email protected]; Tel.: +91-8239703734

† Current Affiliation: Department of Pharmacy, Birla Institute of Technology and Science,
Pilani (BITS-PILANI), Pilani Campus, Rajasthan 333031, India
‡ These authors contributed equally to this work.

Abstract: Nano-emulgel is an emerging drug delivery system intended to enhance the therapeutic
profile of lipophilic drugs. Lipophilic formulations have a variety of limitations, which includes
poor solubility, unpredictable absorption, and low oral bioavailability. Nano-emulgel, an amalga-
mated preparation of different systems aims to deal with these limitations. The novel system pre-
pared by the incorporation of nano-emulsion into gel improves stability and enables drug delivery
for both immediate and controlled release. The focus on nano-emulgel has also increased due to its
ability to achieve targeted delivery, ease of application, absence of gastrointestinal degradation or
the first pass metabolism, and safety profile. This review focuses on the formulation components of
nano-emulgel for topical drug delivery, pharmacokinetics and safety profiles.

Keywords: nano emulgel; topical delivery; permeation; surfactant; bioavailability

Citation: Donthi, M.R.; Munnangi,
S.R.; Krishna, K.V.; Saha, R.N.;
Singhvi, G.; Dubey, S.K.
Nanoemulgel: A Novel Nano
1. Introduction
Carrier as a Tool for Topical Drug
Delivery. Pharmaceutics 2023, 15, 164.
The recent progress in drug synthesis and high throughput screening have steered
https://doi.org/10.3390/ drug discovery and development toward lipophilic drug moieties. Currently, 90% of
pharmaceutics15010164 drugs in the discovery pipeline and more than 40% of the drugs present in the market are
of lipophilic nature [1]. The lipophilic nature of the drugs leads to problems like poor
Academic Editors: Silvia Tampucci
solubility, unpredictable absorption, and inter and intra-subject variability concerning
and Daniela Monti
pharmacokinetics. Various techniques have been employed to increase the solubility of
Received: 20 November 2022 active moieties. These techniques include physical and chemical modification of API
Revised: 24 December 2022 along with formulation strategies, which include particle size reduction, complexation,
Accepted: 27 December 2022 amorphization, and nano-carrier drug delivery systems as represented in Figure 1 [2–4].
Published: 3 January 2023 Despite of employing various technologies for enhancing the solubility, delivering
the drugs via the oral route is not always feasible owing to their low bioavailability
associated with poor absorption, first-pass metabolism, chemical and enzymatic
Copyright: © 2023 by the authors. Li-
censee MDPI, Basel, Switzerland.
degradation [5,6]. In addition, clinical complications and low concentrations of the drug
This article is an open access article at the site of action hinder drug delivery through the oral route. For example, the oral
distributed under the terms and con- administration of Disease-modifying anti-rheumatic drugs (DMARDs) used in the
ditions of the Creative Commons At-
tribution (CC BY) license (https://cre- treatment of arthritis are associated with various side effects like carcinogenicity,
ativecommons.org/licenses/by/4.0/). hepatotoxicity, and hematologic toxicity [7,8]. These clinical complications can be
mitigated by delivering the drug through the topical route [9].

Pharmaceutics 2023, 15, 164. https://doi.org/10.3390/pharmaceutics15010164 www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2023, 15, 164 2 of 28

Figure 1. Strategies to improve solubility and bioavailability of lipophilic drugs.

In topical delivery, skin being a fundamental defense layer, considers the API’s as
external components and restricts their entry into the body. The outer most layer of epi-
dermis called stratum corneum is the first and firm layer to overcome for drug penetration
into the skin [10]. Various mechanisms have been explored to enhance the drug permea-
tion. One such mechanism involves disruption of skin layer structure, which can be
achieved using techniques such as chemical penetration enhancers, ultrasound, iontopho-
resis, sonophoresis, electroporation and microneedles [11]. In contrary, the use of nanocar-
riers was observed to be an effective strategy for circumventing the SC barrier without
exacerbating skin damage and achieving efficient drug penetration. They facilitate the
drug delivery through the skin utilizing intra and inter cellular transport mechanisms,
interacting with skin components to mediate transport or to create depots of the drug for
sustained or stimuli-induced release. These novel carrier for topical administration in-
cludes but not limited to emulsions (nano/micro), micelles, dendrimers, liposomes, solid
lipid nanoparticles and nano-structured lipid carriers [12–14]. Among these, nano-emul-
sions are found to be a potential drug delivery system because of their high drug-loading
capacities, solubilizing capacities, ease of manufacturability, stability and controlled re-
lease patterns. These nano-emulsions owing to their lipophilic core allow the movement
of more lipophilic molecules across the topical membranes compared to the liposomes
[15]. In addition, liposomes stability has always been an issue, as they disintegrate during
the penetration process. Likewise, the low drug loading capacity and uncontrolled release
hinders the application of solid-lipid nanoparticles in dermal drug delivery. Similarly,
micelles exhibit poor stability and encapsulation efficiency. In the same way, the toxicity
and poor controlled release behavior of dendrimers limits its topical application [16].
Nano-emulsions are heterogeneous colloidal mixtures of oil and water, with one
component as a dispersed phase and the other as a continuous phase. A surfactant known
as an emulsifier is adsorbed at the interface between the dispersed and continuous phases,
lowering the surface tension and thus stabilizing the system. These systems possess high
Pharmaceutics 2023, 15, 164 3 of 28

thermodynamic stability leading to longer shelf life compared to simple emulsions, mi-
celles or suspensions, etc. Despite having various advantages, nano-emulsions are limited
by their low viscosity leading to low retention time and spreadability [17]. These problems
can be resolved by modifying the nano-emulsion into a nano-emulgel by using a suitable
gelling agent [18].
The nano-emulgel acts as a colloidal system consisting of a mixture of emulsion and
gel. The emulsion part protects the drug from enzymatic degradation, and hydrolysis and
improves the permeation like other nano-carriers. Besides enhancing the penetration of
the drug through the skin, it is equally important to retain the therapeutic concentrations
of the drug for a sufficient period of time. The gel part improves the viscosity and spread-
ability resulting in improved retention time, and also reduces the surface and interfacial
tension, thus improving the thermodynamic stability. Nano-emulgel possesses various
advantages having high drug loading capacity, better penetration, diffusion, and low skin
irritation compared to other nano-carriers [19,20].
This article aims to provide insight into the selection of formulation ingredients of a
nano-emulgel, characteristics and formulation aspects, advantages, pharmacokinetics and
pharmacodynamics, and safety of the same. The objective here is to give an overview of
the future and rationale behind the nano-emulgel drug delivery system.

2. Drug Delivery through a Topical Route

The characteristics of any ideal formulation are patient compliance, self-administra-
tion, non-invasiveness, fewer side effects, and better pharmacological action. The topical
route administering formulations possess most of the aforementioned characteristics [21].
The benefits of the topical route of administration comprise of avoiding the hepatic first-
pass effect, decreased side effects due to the local site of action, enhancement in percuta-
neous absorption and topical usage may even increase bioavailability with a sustained
deposition [22]. Further, the reduced drug loss due to metabolism or decomposition, and
the ability to specifically target the drug at the desired site are also some of the advantages.
Minimization of drug breakdown coupled with constant delivery of drug for a prolonged
period results in prominent movement of the drug across the barrier of stratum corneum,
leading to improved bioavailability [23,24].
An increase in the bioavailability of drugs via the topical route has been proved in
various research works. For example, Flurbiprofen nano-emulsion showed 4.4 times in-
crement in bioavailability upon topical administration compared to oral delivery [25].
Zhou et al. prepared the nano-emulsion of nile red dye, which displayed 10-fold increase
in the penetration of dye across the skin compared to an emulsion formulation [26]. Gannu
et al. reported a 3.5-fold increase in Lacidipine bioavailability via the transdermal route of
administration using microemulsions. The group reported that this improvement could
be due to the avoidance of the first-pass effect on the drug upon topical application [24].
Further, an enhancement in the therapeutic and pharmacological effect of therapeutically
active agents has been demonstrated with topical formulations.
Conventional topical formulations that are used are solutions, ointments, lotions,
creams, patches, gels, etc. [27]. But these topical formulations have to traverse the remark-
ably effective and competent stratum corneum barrier along with viable epidermis of the
skin as shown in Figure 2. The SC is a 10–20 µ m thick lipid-interspersed matrix of termi-
nally formed keratinocytes, which causes a huge challenge for the delivery of therapeuti-
cally active agents via the topical or transdermal route of administration [28–30]. Thus,
reducing the amount of drug reaching the target site. This is reflected in the marketed
topical preparations possessing low permeation leading to poor therapeutic effect [31–33].
Therefore, research in this area mainly focuses on the development of topical formulations
with appropriate permeability and ensuring delivery by numerous mechanisms. The di-
rection of research work in recent years has shifted towards novel carrier systems with
the intent to alter the permeability of hydrophobic drugs through the skin. New formula-
tion development techniques and strategies are emerging in recent years but the main
Pharmaceutics 2023, 15, 164 4 of 28

drawback of the recent strategies is the usage of chemicals and non-green solvents for
enhancing the permeation. The usage of these preparations for a long period would lead
to various skin complications [34,35]. Besides, various limitations posed by the skin, there
are certain characteristics that an active moiety should possess in order to be suitable for
the topical route of administration as represented in Table 1 [36,37].

Figure 2. Skin morphology.

Table 1. Primary requirement of active moiety for topical delivery.

Properties Conditions
t1/2 ≤10 h
≤500 Daltons
Molecular mass
The limit can be exceeded by altering the permeability of skin
Molecular size Small
Polarity Non-polar is desirable
Log P 0.8–5
pKa Higher
Irritation on skin Non-irritating
Skin Permeability coefficient ≥0.5 × 10–3 cm/h

3. Nano Emulsions in Topical Delivery

An upgrade and innovation of topical and transdermal drug delivery systems led to
the development of lipid-based nano-formulations. Though there are various formula-
tions, research has deepened pertaining to nano-emulsions due to the aforementioned ad-
vantages and their ability to deliver hydrophobic drugs non-invasively and without the
need for a penetration enhancer [38]. Nano-emulsions are an isotropic biphasic mixture
consisting of two portions: water and oil, where one phase is dispersed in the other as
nanosized droplets. The system is stabilized by the utilization of an interfacial layer of
surfactants [39]. The difference between nano-emulsions and traditional emulsions is that
the former has decreased propensity to undergo phase separation [40,41]. A prominent
Pharmaceutics 2023, 15, 164 5 of 28

number of in-vivo studies have been carried out demonstrating the applications and fea-
sibility of topical micro and nano-emulsions. In-vitro works have also supported the use
of these topical lipidic formulations [42,43]. These nano-emulsion systems possess a trans-
lucent or transparent appearance. The thermodynamic stability of nano-emulsions is
greater than other lipid carriers. Nano-emulsions exhibit an increased solubilization ca-
pacity as compared to solutions of simple micelles [29,44]. These formulations can solu-
bilize and incorporate large amounts of active drug substances due to the increased sur-
face area because of the nano-size of oil droplets [45]. The phenomena of creaming or sed-
imentation are the general issues faced in an emulsion. The improved stability in a nano-
emulsion is due to Brownian motion and less gravitational force acting on the particles
because of their nano-size, thus preventing the stability issues like sedimentation and
creaming [46]. Numerous studies have demonstrated the enhanced permeation of drugs
upon administered as nano-emulsion systems in comparison to other formulations like
emulsions, creams, and ointment gels [47–49]. The enhanced permeation is because of the
ability of nano-emulsion to overcome the firmly bonded lipid bi-layers, thus able to pen-
etrate deep into the skin and deliver the drug to systemic circulation because of smaller
sized dispersed droplets, which facilitate transcellular in addition to paracellular
transport [18].

4. Nano-Emulgel Drug Delivery System

Despite possessing many advantages, nano-emulsions lack spreadability because of
their low viscosity resulting in poor retention of formulation over the skin [50]. This limi-
tation hampers the clinical applications of nano-emulsions [51]. This issue has been re-
solved by incorporating a gelling agent into the nano-emulsion, thus forming a nano-
emulgel [52]. Huge quantities of aqueous or hydroalcoholic bases are employed in a col-
loidal particulate system to prepare gels [53]. Nano-emulgel is formed by incorporating
the nano-emulsion into a hydrogel matrix, which reduces the thermodynamic instability
of the emulsion. The improved thermodynamic stability is due to the reduction in the
portability of the non-aqueous phase because of the increased consistency of the external
medium. The increased retention time and thermodynamic stability enable the formula-
tion to release the drug over a period, making nano-emulgel a controlled release dosage
form for topical administration benefiting the drugs with a short half-life [19,54].
The incorporation of nano-emulsion into a gelling system helps to annihilate the dis-
advantages of both individual systems. The combined nano-emulgel enjoys the properties
of a gel with the refined characteristics of a nano-emulsion. The Table 2 discloses the ad-
vantages of nano-emulgel over conventional emulgel owing to its particle size and ther-
modynamic stability. The variety of benefits offered by nano-emulgels is enhanced skin
permeation, greater loading of an active moiety, less irritation, and greater spreadability.
This is apparent in comparison with different nano-carriers such as solid lipid nanoparti-
cles and liposomes. The nano-emulsion is made suitable for topical use due to the in-
creased viscosity of the gel. To achieve the same, various gelling agents compatible with
skin like xanthan gum, carbomer 980, Pluronic’s, carrageenan, and carbomer 934 are used
for topical application [55]. Acceptable localization and drug dispersion through adequate
percutaneous absorption across the skin is achieved in nano-emulsions. This helps to in-
crease the efficacy locally and also systematically via the skin. This system can also be
used to deliver drugs to the central nervous system (CNS) due to its ability to cross the
blood-brain barrier when applied through the nasal route [56,57]. Non-irritant and non-
greasy nature of nano-emulgel facilitates better patient compliance [53] In addition, phar-
macokinetic properties like enhanced bioavailability and decreased side effects are added
advantages for these systems [58]. The hydrogel matrix, consistency, and homogeneity
have added to the growing focus on nano-emulgels. Furthermore, various studies have
shown that nanoemulgel has increased stability due to less Oswalt ripening caused by
decreased mobility of oil globules in gel matrix [59]. For instance, Kaur et al. developed a
Pharmaceutics 2023, 15, 164 6 of 28

topical nanoemulgel loaded with TPGS containing mefenamic acid. In the pharmacody-
namic investigation, the optimized nanoemulgel inhibited inflammation and enhanced
percent reaction time with improved analgesic efficacy. The formulated nanoemulgel out-
performed other traditional topical formulations in terms of long-term stability and drug
penetration [60].

Table 2. Comparison between conventional emulgel and nano-emulgel.

Parameter Conventional Emulgel Nano-Emulgel

Not stable because of natural Stable–because of their smaller particle size,
Thermodynamic stability tendence of coalescence leading to Brownian motion provides enough stability against
sedimentation or creaming [61] gravity, preventing sedimentation or creaming [54]
Particle size Greater than >500 nm [18] Less than 100 nm [62]
Comparatively less bioavailable than Enhanced bioavailability, attributed to small size
Bioavailability
Nano-emulgel [63] and large surface area [64]
High permeation owing to its lower particle size
Permeation Comparatively lower permeation [65]
[54,65]
It can be prepared either by using high or low
Preparation Require high energy techniques [66]
energy techniques [20]
Higher compared to conventional emulgel due to
Systemic absorption Very minimal
the small particle size and large surface area [54]
Ability to cross BBB Cannot cross BBB [67] Can Cross BBB because of its small particle size [68]

Besides these, nano-emulgel is devoid of other formulation stability limitations like

the problem of destabilization faced with conventional emulgels, the problem of moisture
entrapment faced with powders, the problem of cake formation faced with suspensions,
the problem of coalescence of oil globules, formation of agglomerates in case of suspen-
sions, along with the problem of poor adherence and excessive spreadability that is faced
with nano-emulsions [53]. Due to these factors, nano-emulgel is often thought of as an
improved and different topical drug delivery approach over the standard marketed dos-
age forms. This novel formulation is welcome for research targeting various skin diseases
and disorders. Nano-emulgel will soon be capturing the market in the topical delivery
segment as a favorable substitute over conventional forms and some are currently being
marketed as in Table 3. Many preclinical (Table 4) and clinical studies (Table 5) are being
conducted to evaluate the efficacy of nanoemulgel.

Table 3. Examples of marketed emulgels for topical application.

Marketed Product Active Pharmaceutical Ingredient Manufacturing Company

Voltaren Emulgel Diclofenac diethylamine GlaxoSmithKline
Isofen Emulgel Ibuprofen Beit Jala Pharmaceutical Co.
Benzolait Emulgel Benzoyl peroxide & Biguanide Roydermal
Miconaz-H Emulgel Miconazole nitrate & Hydrocartisone Medical Union Pharmaceuticals
Derma Feet Urea Herbitas
Diclofenac diethylamine, Methyl Salicylate &
Adwiflam Emulgel Saja Pharmaceuticals
Menthol
Nucoxia Emulgel Etoricoxib Zydus Cadila Healthcare LTD

Table 4. Pre-clinical Studies on the nano-emulgel dosage form.

Active Route of
Composition In Vivo Model Therapeutic Outcome Reference
Ingredient Administration
Oil: Labrofac PG + Psoriatic mice treated with the
Curcumin BALB/c mice Topical [69]
transcutol HP curcumin nano-emulgel showed
Pharmaceutics 2023, 15, 164 7 of 28

Surfactant mixture: faster and earlier healing than

Tween 20 + solutol those treated with curcumin plus
HS15 betamethasone-17-valerate gel
Gelling agent:
Carbopol 934
Oil: Black seed oil
Surfactant mixture: Nano-emulgel administration of
Kolliphor EL + thymoquinone improves its
Thymoquinone Wistar rat Topical [70]
transcutol HP therapeutic efficiency in wound
Gelling agent: healing studies in Wistar rats
Carbopol 940
Curcumin and resveratrol nano-
emulgel technology revealed
drastically increased curcumin
and resveratrol deposition in
skin layers. The in-vivo
Oil: Labrofac PG investigation revealed that the
Surfactant mixture: NEG formulation resulted in
Curcumin and
Tween 80 Wistar rat Topical improved burn healing, with [71]
Resveratrol
Gelling agent: histological findings comparable
Carbopol to standard control skin.
Thymoquinone nano-emulgel
delivery method improves
thymoquinone therapeutic
effectiveness in wound healing
studies in Wistar rats.
Oil: Myrrh oil
Surfactant mixture: Brucine-loaded nanoemulgel has
Tween 80 + PEG 400 BALB/c mice and shown improved anti-
Brucine Topical [72]
Gelling agent: Wistar rats inflammatory and anti-
Carboxymethylcellu nociceptive efficacy.
lose sodium
Oil: Labrofac PG Curcumin nanoemulgel
Surfactant mixture: improved the wound-healing
Curcumin Tween 80 + PEG 400 Albino rats Topical efficacy of curcumin compared [69]
Gelling agent: to the conventional gel
Carbopol 940 formulation.
Raloxifene hydrochloride (RH)
Oil: Peceol
loaded nanoemulgel formulation
Surfactant mixture:
for enhanced bioavailability and
Raloxifene Tween 20 +
Wistar rats Topical anti-anti-osteoporotic efficacy of [73]
hydrochloride transcutol HP
RH. The bioavailability
Gelling agent:
improved by 26-fold compared
Chitosan
oral marketed product.
Oil: Castor oil Naoemulgel formulation
Surfactant mixture: showed improved skin
Eprinomectin Tween 80 + Labrasol Wistar rats Topical permeability of 1.45-fold [74]
Gelling agent: compared to emulgel and had no
Carbomer 940-1 skin-irritating property
Improved pharmacokinetic
Amisulpride Oil: Maisine CC Wistar rats Intranasal [75]
profile. The Cmax of API in brain
Pharmaceutics 2023, 15, 164 8 of 28

Surfactant mixture: after administering through in-

Labrosol + situ nano-emulgel improved by
transcutol HP 3.39-fold compared to
Gelling agent: intravenous administration of
Poloxamer 407, nano-emulsion.
Gellan gum
Oil: Ethyl oleate
Improved survival rate of rats
Surfactant mixture:
and reduced tumor progression
Tween 80 +
Sprague Dawley (Glioblastoma). The survival
Disulfiram transcutol HP Intranasal [76]
rats time of in-situ nano-emulgel
Gelling agent:
treated group is 1.6 times higher
Deacetylated gellan
than control group
gum

Table 5. Clinical studies on emulgel dosage form.

Identifier No Active Constituent Titile of the Study Conditions Referance

Topical Metformin Emulgel VS
Metformin and salicylic
NCT05536193 Salicylic Acid Peeling in Treatment of Acne Vulgaris [77]
acid
Acne Vulgaris
Comparison of the Bioavailability of
Diclofenac in a Combination Product
(Diclofenac 2% + Capsaicin 0.075%
Diclofenac sodium &
NCT03074162 Topical Gel) With Two Diclofenac Inflammatory [78]
Capsaicin
Only Products, Diclofenac Mono Gel
2% and Voltarol® 12 Hour Emulgel
2.32% Gel, in Healthy Volunteers
Effects of Visnadin, Ethyl Ximeninate, Female Sexual
Visnadin, ethyl
Coleus Barbatus and Millet in FunctionVulvovaginal
NCT04579991 ximeninate, coleus [79]
Emulgel on Sexual Function in AtrophyPostmenopaus
barbatus
Postmenopausal Women al Atrophic Vaginitis
Clinical Assessment of Voriconazole
NCT04110860 Voriconazole Self Nano Emulsifying Drug Delivery Tinea Versicolor [80]
System Intermediate Gel
Clinical Assessment of Itraconazole
NCT04110834 Itraconazole Self Nano Emulsifying Drug Delivery Tinea Versicolor [81]
System Intermediate Gel
Evaluation of the Clinical Efficacy and
Tolerability of SYSTANE Complete in
Propylene glycol-based
NCT03492541 Adult Patients With Dry Eye Disease Dry eye disease [82]
eye drops
Following Topical Ocular Use for 4
Weeks: A Multicenter Trial
Effect of Topical Diclofenac on
Carbamide Clinical Outcome in Breast Cancer Hand and Foot
NCT05641246 [83]
diclofenac Patients Treated With Capecitabine: A Syndrome
Randomized Controlled Trial.

5. Formulation Components
Nano-emulgels are made up of two individual systems; the gelling agent and the
nano-emulsion i.e., emulsion consisting of nano droplets which are of o/w or w/o type.
Both emulsion types possess an aqueous and an oily phase. The gel base consists of poly-
mers that can swell on the absorption of a liquid. The various components in the nano-
Pharmaceutics 2023, 15, 164 9 of 28

emulgel formulation are provided in Table 6 [53,84]. The overview of the selection criteria
of the essential components in a nano-emulgel have been discussed below.

Table 6. Details of commonly used excipients in nano-emulgel formulations.

Active Composition
Disease/
S.No Pharmaceutica References
Disorder Oil Surfactant Co-Surfactant Gelling Agent
l Ingredient
Cremophor Labrafil
1 Anti-inflammatory Curcumin Emu oil Carbopol [85]
RH40 M2125CS
Diclofenac Isopropyl Labrafil
2 Anti-inflammatory Tween 20 Carbopol 980 [86]
sodium myristate M2125CS
Almond and
3 Anti-inflammatory Meloxicam peppermint oil Tween 80 Ethanol Carbopol 940 [87]
(1:2)
Antimicrobial and
4 Anti- Quercetin Cinnamon oil Tween 80 Carbitol Poloxamer [88]
Inflammatory
TranscutolP,
5 Antifungal Itraconazole Eugenol Labrasol Carbolpol [89]
Lecithin
6 Antifungal Fluconazole Capmul MCM Tween 80 Transcutol P Carbopol 934 [90]
Diethylene
Labrafac: glycol
7 Anti-hyperglycemic Glibenclamide Tween 80 Carbopol 934 [91]
Triacetin (1:1) monoethyl
ether
Oleic acid: IPM
8 Antihypertensive Carvedilol Tween 20 Carbitol Carbopol-934 [92]
(3:1)
Immunosuppressiv
9 Cyclosporine Oleic acid Tween 80 Transcutol P Guar gum. [93]
e agent
10 Anti-cancer Chrysin Capryol 90 Tween 80 Transcutol HP Pluronic F127 [94]
Sodium
Atorvastatin Propylene
11 Wound Healing Liquid Paraffin Tween 80 carboxymethyl [95]
Calcium glycol
cellulose
Sodium
12 Anti-inflammatory Curcumin Myrrh Oil Tween 80 Ethanol carboxymethyl [96]
cellulose
Propylene
13 Wound Healing Curcumin Labrofac PG Tween 80 Carbopol 940 [69]
glycol 400
Terbinafine
14 Anti-fungal Peceol oil Tween 80 Propanol Carbopol 940 [97]
HCl
Soluphus
Dimethylaceta (10% w/v) &
15 Anti-fungal Ebselen Captex Kolliphor ELP [98]
mide HPMC K4M
(2.5% w/v)

5.1. Oil Phase

The selection of oil and its quantity depends on the application and utility of the
nano-emulgel. The permeability, stability, and viscosity of the prepared nano-emulsion
depends on the type and quantity of chosen lipid component, i.e., oil phase. Primarily in
case of pharmaceutical and cosmetic applications, the oil phase is made up of either nat-
urally or synthetically originated lipids, unless the oil phase itself is an active ingredient.
Pharmaceutics 2023, 15, 164 10 of 28

The consistency of the lipids may vary from liquid to high molecular solids. The hydro-
phobicity of an oil plays a crucial role in forming a stable emulsion, wherein poor hydro-
phobicity of the oil is shown to increase the emulsification, concurrently affecting the sol-
ubility of lipophilic moieties [99]. Thus, choosing an oil is an essential prerequisite for
nano-emulgel development as a novel drug delivery system [100].
Natural oils exhibit an additional medicinal significance leading to an increase in the
researcher’s interest to use these additive properties supporting the pharmacological ac-
tion of the active moiety. For example, oleic acid is frequently used oil in nano-emulgel
formulations and is obtained from vegetable and animal sources. It is a biodegradable and
biocompatible omega-nine fatty acid and has elevated solubilization characteristics along
with improving percutaneous absorption [101]. Antioxidants present in oleic acid contrib-
ute to cellular membrane integrity. It also repairs cell damage and showcases formulation
stabilization [55,102]. Arora et al. confirmed that an increase in oleic acid content in the
preparation increases the rate of permeation. In their study, using 6% oleic acid instead of
3% in the preparation nanoemulgel of drastically improved the permeability of keto-
profen [55].
Another natural oil called Emu oil is being appreciated for its analgesic, antipruritic,
and antioxidant characteristics. Jeengar and group prepared nano-emulgel of curcumin
with emu oil to treat the disease of joint synovium, the formulation demonstrated en-
hanced permeability and better pharmacological activity compared to pure curcumin
[85,103]. The use of emu oil has been encouraged in the cosmetic field as well [85]. It mois-
turizes the skin and has high amounts of unsaturated fatty acids like oleic acid, thus im-
proving the penetration of the drug [104].
The therapeutically active agent may also be used as the oil component in nano-
emulgel preparation. Active moieties from Swietenia macrophylla have anti-inflamma-
tory action and are self-employed as an oily phase in nano-emulgel. The therapeutic effect
was found to be better in this nano-carrier preparation as opposed to the parent form [44].
Further, the edible oils considered to be the preferred lipid excipient of choice for the de-
velopment of emulsions, are not frequently chosen due to their poor ability to dissolve
large amounts of lipophilic drugs. Therefore, these oils are chemical modification or hy-
drolyzed to form an appropriate oil, which upon combining with a suitable surfactant
enhances the solubility of hydrophobic compounds for nano-emulgel formulation [104].

5.2. Surfactant System

Surfactants are an essential ingredient in nano-emulsion, which are utilized in the
stabilization of the unstable mix of two immiscible phases. This is achieved by a decreas-
ing the interfacial tension amongst the two phases and alteration of dispersion entropy.
The surfactant should show quick adsorption along the interface of the liquids. The final
result is a decrease of interfacial tension and inhibition of coalescence of the individual
nano-sized droplets [105].
The HLB value of the surfactant is an important variable for selecting the proper sur-
factant. The surfactants are either w/o type (HLB of 3–8) or o/w type (HLB of 8–16). In w/o
emulsions, low HLB value surfactants i.e., less than 8 are utilized. Alternately Spans and
Tweens are used for o/w emulsion as their HLB value is more than 8. A mixture of Span
and Tween provides better stability to an emulsion system compared to pure Span or
Tween containing preparations. Thus, using a proper mixture of surface-active agents is
essential to formulate an ideal nano-emulsion. Based on the charge, the surfactants are of
four main categories i.e., cationic, non-ionic, anionic, and zwitterionic nature. Examples
of cationic surfactants are hexadecyl trimethyl ammonium bromide, cetyl trimethyl am-
monium bromide, quaternary ammonium compounds, and dodecyl dimethyl ammonium
bromide [106,107]. Poloxamer 124 and 188, Tween 20 and Caproyl 90 are some of the non-
ionic surfactants [108,109]. Anionic surfactants are sodium dodecyl sulphate and sodium
bis-2-ethylhexylsulfosuccinate [110]. Phospholipids such as phosphatidylcholine are part
Pharmaceutics 2023, 15, 164 11 of 28

of zwitterion surfactants [111]. Toxicity should be considered while selecting the surfac-
tant as it may lead to irritation of the gastrointestinal tract or skin based on the route of
administration. Ionic surfactants are usually not preferred due to their toxicity and non-
biocompatibility. The safety, biocompatibility and being unaffected by pH or ionic
strength alteration make non-ionic surfactants an appropriate choice [112].
The surfactants derived from natural sources such as bacteria, fungi, and animals are
being considered as a potential option, due to their safety, biodegradability, and biocom-
patibility. Bio-surfactants show a similar mechanism in decreasing surface tension along
the interface due to amphiphilic properties. This is mainly due to the presence of non-
polar short fatty acids and polar functionalities as the tail and head respectively [113].
They are more bio-compatible and safer than synthetic surfactants.

5.3. Co-Surfactant System

Co-surfactants support surfactants during the emulsification of oil in the water
phase. Co-surfactants are required for decreasing the interfacial tension and improving
the emulsification [114]. Flexibility is added to the interfacial film along with attaining
transient negative interfacial tension due to co-surfactants. The association between the
surfactant and co-surfactant along with the partitioning of the drug in immiscible phases
decides the drug release from the nano-emulgel. Hence co-surfactant selection is equally
important as surfactant. The commonly used co-surfactants are PEG- 400, transcutol® HP,
absolute ethyl alcohol, and carbitol [115]. Alcohol based co-surfactants are most preferred
because of their ability to partition between the oil and water phase thereby improving
their miscibility.
The concentration of co-surfactant being used has to be chosen cautiously, since it
may affect the emulsification by surfactant. Also, a combination of surfactant and co-sur-
factant with closer HLB values does not produce a stable emulsion as produced by non-
ionic surfactants with different HLB values. The reason may be due to the solubilization
of higher HLB value surfactants in the aqueous phase. Whereas, lower HLB value surfac-
tants solubilize in the non-aqueous phase, enabling more intense association with the mix-
ture of surfactant and co-surfactant [116]. Therefore, the choice of various formulation
components and the rationale behind them is a very demanding and stimulating exercise.

5.4. Gelling Agents

Gelling agents upon addition to the appropriate media as a colloidal mixture forms
a weakly cohesive three-dimensional structural network with a high degree of cross-link-
ing either physically or chemically providing consistency to nano-emulgel [117–119]. In
topical applications, these agents are used to stabilize the formulation, to attain optimum
delivery of the drug across the skin. They play an important role in determining various
parameters of the formulation like consistency, rheological properties, bio-adhesive prop-
erties, pharmacokinetics, spreadability, and extrudability. Based on the origin, these gel-
ling agents are divided into natural, synthetic, and semi-synthetic. The Table 7 gives in-
formation on the concentration and pharmaceutical adaptability of various gelling agents
used to prepare nano-emulgel. Natural gelling agents are bio-polysaccharides or their de-
rivatives and proteins. The pectin, carrageenan, alginic acid, locust bean gum, and gela-
tine, etc., are bio-polysaccharides, while xanthan gum, starch, dextran, and acacia gum,
etc., are derivatives of bio-polysaccharides. Though they provide excellent biocompatibil-
ity and biodegradability, the major limitation of natural gelling agents is microbial degra-
dation [119,120]. Like natural gelling agents, semisynthetic gelling agents also offer good
biocompatibility and biodegradability [121]. These agents are usually the derivatives of
cellulose like hydroxypropyl cellulose, ethyl cellulose, sodium alginate, etc. The semisyn-
thetic agents are comparatively more stable than natural gelling agents and are more re-
sponsive to chemical, biological and environmental changes like pH and temperature
[122]. Synthetic gelling agents are prepared by chemical synthesis, some of them are FDA-
approved e.g., carbomers and poloxamers [123,124]. Carbomers are polymerized acrylic
Pharmaceutics 2023, 15, 164 12 of 28

acids, while poloxamers are triblock non-iconic copolymers comprising two hydrophilic
units of polyoxyethylene attached to a central hydrophobic chain of polypropylene
[124,125]. The FDA-approved synthetic agents are non-toxic and offer a wide range of
rheological properties based on the molecular weight of the polymer, thus suitable for a
wide range of applications.

Table 7. Various gelling agents and their pharmaceutical adaptability for use in topical emulgel.

Concentration
Gelling Agent Pharmaceutical Adaptability Reference
Range (%w/w)
• Forms neutral gels
HPMC 2–6% • Can provide good stability [126,127]
• Resists microbial growth
• Forms high viscous gel
Carbomer (Carbopol)
• Forms gel at very low concentration
Grades–ETD 2020, 171, 910, 934, 0.1–1.5% [126,128]
• Provides controlled release
934P, 940, 1342 NF, 1971P
• pH dependent gelling
• It withstands autoclaving. Therefore, can be used
NaCMC 3–6% in sterile gels [129,130]
• Stable between pH 2 to 10
• Possess better solubility in cold water
Poloxamer
20–30% • Thermoreverisble gelation–gel at room tempera- [131,132]
Grades–124, 182, 188, 407
ture and liquid at refrigerated conditions
Combination of HPMC & • Combination can improve stability of emulsion
1.2% [133,134]
Carbopol compared to individual components

6. Preparation of Nano-Emulgel
Nano-emulgel is a non-equilibrium formulation of structured liquids requiring en-
ergy, surfactant, or both for its preparation. They are spontaneously formulated by mixing
the components. This is undertaken by introducing energy in the biphasic system or de-
creasing the interfacial tension between the interfaces of the two immiscible phases [135].
There are various nano-emulgel preparation methods reported based on the order of
mixing of oil and aqueous phase [136]. Lupi et al. (2014) as illustrated in Figure 3A solu-
bilized the drug in the oil phase and gelling agent in the water phase separately. The oil
phase is added to the aqueous gel phase under stirring followed by homogenization to
form an emulsion. The sol form of gelling agent in the emulsion is converted to gel by
various mechanisms like adding a complexing agent or adjusting to the required pH [137].
Dong et al. (2015) as illustrated in Figure 3B divided the total quantity of water required
for the preparation into two parts. One part of the divided quantity is used to prepare pre-
emulsion and the other part is used for the preparation of gel. Later, these two components
are mixed together under stirring [138]. Jeengar et al. (2016) prepared the emulsion and
gel separately, followed by mixing them together in a 1:1 w/w ratio [85].
Pharmaceutics 2023, 15, 164 13 of 28

Figure 3. Schematic representation for the preparation of nano-emulgel by (A) adding Oil (oil +
drug) phase to aqueous (water + gelling agent) phase (B) adding nano-emulsion to aqueous (water
+ gelling agent) phase.

Nano-emulgel formulation preparation can be further divided into two types based
on the implementation of high-energy and low-energy emulsification techniques. High
energy method involves the use of mechanical devices to produce a highly disruptive
force in which both phases undergo size reduction. Hence this method may lead to the
heating up of components in the formulation causing thermodynamic instability of the
formulation and making it not suitable for thermo-labile drugs. Microfluidizers, high-
pressure homogenizers, and ultrasonicated are high-energy methods employed to obtain
a nanosized emulsion. This method is used for preparing nano-formulation of sizes of
about 1 nm.
Phase inversion, self-emulsification, temperature, and phase transition are tech-
niques of low energy approach. These methods provide the required thermodynamic sta-
bility to the nano-emulsion. The spontaneous method involves mixing oil, surfactant, and
water in the best ratio possible and is most applicable for thermolabile compounds. The
Pharmaceutics 2023, 15, 164 14 of 28

emulsification process is based on the surfactant and co-surfactant characteristics and

their order of addition. Temperature-based alterations in HLB are utilized for non-ionic
surfactants like Tween 20 Tween 60, Tween 80, Labrasol [139]. This method is mostly uti-
lized for phase transition during phase inversion. Application of cooling with constant
stirring will lead to a reversal of emulsion prepared at inversion temperature. Reduction
in phase inversion temperature facilitates the inclusion of thermolabile components using
this technique [140]. The second step incorporates gelling agent to change the liquid state
to gel in the nano-emulsion. The thixotropic nature of the gelling agent facilitates the gel-
solution conversion when shear stress is applied to the preparation keeping the volume
constant. This leads to thickening in o/w nano-emulsion because of the creation of a gelled
structure.

7. Permeability of Nano-Emulgel
In the preparation of emulsion-based gels, it is necessary to examine the important
process parameters that have a significant effect on the size and formulation stability. In
order to accomplish this, we must select the proper preparation process at the early stages.
Emulsions are developed using various techniques, such as mechanical (or rotor-stator),
high-pressure, microfluidization, and ultrasonic methods. The mechanical system com-
prises a colloid mill, that has a complex geometry, and the droplets of an emulsion gener-
ated by this system are several microns in size, making it the least desirable approach for
manufacturing nanoemulsions [141]. Achieving an optimum droplet size is highly chal-
lenging. However, a droplet size of less than a micron can be achieved using high-pres-
sure homogenization and sonication techniques, which in turn helps extend the shelf life
of emulsions by lowering the creaming rate. For this reason, homogenization and soni-
cation are considered to be efficient methods for the development of nanoemulsion
[142,143]. In addition, increasing the homogenization speed or duration by itself is not
enough to decrease the size of the globules, however, the use of the optimum concentra-
tion of an emulsifier is necessary to maintain control over the re-coalescence of the emul-
sion. For instance, Sabna Kotta et al. made a nanoemulsion utilizing the phase inversion
and homogenization methods. In this formulation, gelucire 44/14 was used as a surfactant
and transcutol-HP as a co-surfactant. They employed both the proposed techniques to
produce nano-sized emulsion globules. In the case of homogenization, the large globule
size was observed, despite increased pressure, and increased cycles at lower concentra-
tions of an emulsifier. This demonstrates that the globule size of the formulation could not
be decreased by homogenization alone. When the optimum concentration of an emulsifier
is combined with increasing homogenization pressure and cycles, the size of the globules
decreases. Because homogenization alone can break down globule size to nano, but with
a lower concentration of surfactant, the newly formed globule surface would be improp-
erly covered with a surfactant, resulting in re-coalescence. With the optimum concentra-
tion of an emulsifier and increased homogenization pressure and cycles, a smaller globule
size with a good polydispersity index could be achieved. As a result, the author came to
the conclusion that, throughout the preparation process, the desired particle size was ob-
tained with a lower PDI by the combination of the surfactant, homogenization pressure,
and cycle duration [142].
Mohammed S. et al. used ultrasonication to develop a thymoquinone-loaded topical
nanoemulgel for wound healing. They used black seed oil (oil vehicle), Kolliphor El (sur-
factant), and Transcutol HP (co-surfactant). Nanoemulgel was prepared using different
time intervals (3, 5, and 10 min) of ultrasonication at a 40% amplitude. When the concen-
tration of surfactant decreased with 10 min of ultrasonication, the globular size increased.
Meanwhile, increasing the concentration of surfactant with 10 min of sonication time re-
sulted in a smaller globular size. The authors concluded that sonication is more effective
when the appropriate concentration is used [70]. Monitoring the process control parame-
ters and taking into account the composition of the excipients is both necessary steps in
the process of optimizing the formulation.
Pharmaceutics 2023, 15, 164 15 of 28

8. Permeability of Nano-Emulgel
Skin shows an inherent property of acting as a protective barrier against external
agents. Therefore, penetration through the skin is a major complication associated with
topical delivery systems. The outermost layer of skin is the stratum corneum, which is
followed by stratum granulosum and stratum lucidum. The stratum corneum is loosely
composed of keratinized cells, waxy lipids, fatty acids, and cholesterol. All these constit-
uents of stratum corneum help in retaining moisture and provide a hydrophobic barrier
over the skin [18]. After the stratum corneum, there is the epidermis which is followed by
dermis and subcutaneous layer. After crossing the subcutaneous layer, the active moiety
will finally reach the systemic circulation. The primary hurdle for the drug moiety after
reaching out from gel matrix is crossing the stratum corneum, from here the nano sized
droplet due to the virtue of small diameter traverses basically through two different path-
ways as shown in Figure 4. One is cell to cell transfer involving concentration gradient-
based movement called transcellular transport or intracellar transport, while the other is
a passage through intercellular spaces or paracellular transport [118]. Whereas there is a
third pathways called transappendageal transport, its influence on drug penetration is
limited because hair follicles and glandular ducts make up negligible portion of the total
surface area of the skin [16].

Figure 4. Graphical representation of entry of nano-emulgel into skin [144]. Adapted from Nano-
medicine, 3 December 2010; 5(9): 1385–1399. Copyright (2010) Future Science Group.

Generally, ex-vivo permeation studies involve the examination of nano-emulgel for-

mulation on isolated tissue in a simulated biological medium. Ex-vivo studies give a com-
parative analysis of penetration with different types of topical dosage forms and an idea
about the flux rate of the drug inside the skin. Jeengar et al. made a nano-emulsion with
emu oil as the oil phase. Optimized nanoemulsion was amalgamated with Carbopol gel
to form nano emulgel and used for topical delivery of curcumin as an anti-inflammatory
agent in rheumatoid arthritis. Ex-vivo permeation studies showed that permeation
through the skin was higher for nano-emulgel as the retention of the formulation was
higher compared to the nano-emulsion [145,146]. Elmateeshy and group formulated
Pharmaceutics 2023, 15, 164 16 of 28

nano-emulgel by incorporating terbinafine HCl (TB) nano-emulsion formed from peceol

as oil phase and (TWEEN 80/propanolol) as surfactant mixture and Carbopol as a gelling
agent. The enhanced permeation of peceol oil-based nano-emulgel was observed in ex-
vivo studies compared to available marketed products [97]. Similarly, Mulia et al. devel-
oped nano-emulgel for mangosteen extract composed of o/w nano-emulsion with virgin
coconut oil as the oil phase and Tween 80/SPAN 80 as surfactant mixtures. The gel base
was made with xanthan gum and phenoxyethanol was supplemented as a preservative.
In vitro permeation studies demonstrated elevated penetration compared to nano-emul-
sion [29,147,148]. In addition, Bhattacharya et al., formulated celecoxib nano-emulgel with
carbopol-940 hydrogel base, while Tween 80 and Acconon MC8-2EP as surfactants. Both
in-vitro drug release and ex-vivo studies showed positive results. After the twelfth hour
of diffusion, the optimized formulation displayed 95.5% cumulative release of the drug,
whereas the commercially available formulation showed only 56.90% release. A higher
penetration coefficient is displayed by nano-emulgel compared to commercial formula-
tion [149]. In the same way, Chin et al. also developed a nano-emulgel of telmisartan for
intranasal delivery using different molecular weight chitosan polymers. The ex-vivo pen-
etration studies showed an improved permeation profile. The group also demonstrated
the improvement in permeation is attributed to the molecular weight of the polymer,
where the medium molecular weight chitosan provides higher permeation [150].
A nano-emulgel preparation for delivery through the transdermal route of tacroli-
mus was formulated by Begur et al. using almond gum as gel and oleic acid as the lipo-
philic phase. Cremophor was used as a surfactant to improve penetration. Examinations
on rat abdominal skin showed a substantial increase in penetration [34]. Similarly, buten-
afine an antifungal agent available as a cream in the market, Syamala et al. prepared a
nano-emulgel formulation for the same drug and found considerable results. Ex-vivo pen-
etration studies showed a substantial increase in permeation over marketed creams [97].
In the same way, an increment in permeation of ketoconazole by about 53% was observed
by delivering the drug in nano-emulgel formulation compared to normal marketed cream.
The quality of life of the patient could be improved by implementing these types of dosage
forms [151]. These studies showcase the ability of nano-emulgel in enhancing the perme-
ation of the active moiety compared to nano-emulsion and conventional topical dosage
forms. The permeation of the nano-emulgel is affected by various factors like gelling
agents, surfactants, and permeation enhancers, etc. The gelling agents improve the per-
meation by improving the adherence of formulation upon the skin. While the surfactant
alone or in combination with a co-surfactant will improve the permeation by disrupting
the lipid bilayer. All these components can improve the permeation of active moiety.

9. Characterization Studies of Nano-Emulgel

The pharmaceutical product must be evaluated to ensure quality and consistency be-
tween different batches. These tests help in understanding the product’s behavior and
stability. According to USP, there are few universal tests for any given dosage form e.g.,
description, identification, assay, and impurities. A topical dosage form should undergo
a few specific tests set by USP on a case-by-case basis: uniformity of dosage units, water
content, microbial limits, antimicrobial and antioxidant content, pH, particle size, sterility,
and API’s polymorphic nature. Apart from the tests required for topical dosage form,
nanoemulgel consists of nanosized globules, which need to be evaluated for zeta poten-
tial, droplet size and polydispersity index (PDI). Along with these physiochemical tests, a
dosage form needs to be evaluated for its in-vitro release, spreadability, bio-adhesive tests,
skin-irritation, ex-vivo permeability and in-vivo bioavailability can be performed to un-
derstand the behavior of nanoemulgel. Methods and techniques for analyzing significant
properties of a nanoemulgel are briefly described below:
Pharmaceutics 2023, 15, 164 17 of 28

9.1. Zeta Potential

The particles in a solution usually possess a layer of ions on their surface, referred to
as the stern layer. Adjacent to the stern layer, there exists a diffuse layer of loosely
bounded ions, which along with the stern layer collectively called an electrical double
layer. There is a boundary between the ions in the diffuse layer that move with the particle
and the ions that remain with the bulk dispersant. The zeta potential is the electrostatic
potential at this “slipping plane” boundary [152]. Zeta potential measurement provides
an indirect measure of the net charge and is a tool to compare batch-to-batch consistency.
The higher the zeta potential, the greater the repulsion resulting in increased stability of
the formulation. For example, the high zeta potential of emulsion globules prevents them
from coalescing. A surface charge modifier may also be used to adjust the surface charge.
For instance, if a negatively charged surface modifier is used, the zeta-potential value be-
comes negative, and vice-versa [153,154]. Surface active ingredients (such as anionic or
cationic surfactants) thus play an important role in emulsion stability, and the zeta poten-
tial can be measured using various instruments such as the ZC-2000 (Zeecom-2000, Mi-
crotec Co. Ltd., Chiba, Japan), Malvern Nanosizer/Zetasizer® nano-ZS ZEN 3600 (Malvern
Instruments, Westborough, MA, USA), and others.

9.2. Droplet Size Measurement and Polydispersity Index (PDI)

The size of globule in nanoemulgel is referred as its hydrodynamic diameter, which
is a diameter of equivalent hard sphere that diffuses at the same rate as the active moiety
[155]. The PDI determines the distribution of droplet size and is defined as the standard
deviation of droplet size divided by mean droplet size. The droplet size and the polydis-
persity index are closely connected to the stability and drug release, as well as the ex-vivo
and in-vivo performance of the dosage form. In addition, it is important to measure con-
sistency between different batches. The globule size and PDI of the formulation can be
measured using a zeta sizer or master sizer. The globule size of the emulsion can be de-
termined using the principle of dynamic light scattering, in which the transitional diffu-
sion coefficient is measured by monitoring the interaction between the laser beam and
dispersion, as well as the Polydispersity index [156,157].

9.3. Rheological Characterizations

Rheology is the study of the deformation and flow of materials. The rheological char-
acterization of materials reveals the influence of excipient concentrations like oils, surfac-
tants, and gelling agents on the formulation’s viscoelastic flow behavior. If a formulation’s
viscosity and flow characteristics vary, this may influence its stability, drug release, and
other in-vivo parameters. In this instance, the formulation’s shear thinning tendency gen-
erates a thin layer on the skin surface, improving permeability, whereas a thicker formu-
lation decreases permeation. Therefore, the rheological behavior is an extremely im-
portant factor in the formulation of nanoemulgel and several unique types of viscometers
can be used to determine the rheological behavior [20]. FDA recommends the evaluation
of complete flow curves whenever possible, plotted as both heat stress versus shear rate
and viscosity versus shear rate across multiple shear rates until low or high plateaus are
observed. If a formulation exhibits plastic flow, yield stress values should be evaluated.

9.4. Spreadability Testing

The spreadability property of the topical dosage form ensures the evenly spreading
of the dosage form, thus delivering a stranded dose subsequently affecting the efficacy.
The viscosity of the nanoemulgel greatly affects the spreadability property [158]. To date,
no standard method has been established for measuring the spreadability of the dosage
form. A few tests, that are commonly used for a good approximation of spreadability are
a parallel-plate method and human subject assessment etc. The parallel-plate method (slip
and drag method) is a widely employed technique because of its simplicity and relatively
Pharmaceutics 2023, 15, 164 18 of 28

economic [158]. The instrumental setup consists of two glass slides of the same length, one
of which is stationarily attached to the wooden block, and the other glass slide is mobile
attached to a pulley at one end to measure spreadability. Spreadability is determined by
the emulgel’s ‘Slip’ and ‘Drag’ qualities. The nanoemulgel dosage form will be placed on
a stationary glass slide, which is then squeezed in between stationary and mobile glass
slides. The formulation is squeezed firmly for uniformly spreading formulation between
two slides and to remove any air bubbles. The known weights are added to the pulley
until the upper slide slips off from the lower slide. The time required for slipping off is
recorded, which is used to calculate spreadability using the following equation [159].

𝑆 = 𝑀 ∗ 𝐿/𝑇
where, S, M, L and T respectively represent the spreadability, weight bounded to the up-
per slide, Length of the slide, and Time taken to detach the slides.

9.5. In-Vitro Release Test (IVRT)

The efficacy and safety of the API are associated with drug release from the dosage
form. The IVRT serves as a tool for assessing the quality of the drug product [160]. Ac-
cording to FDA, the IVRT studies for semi-solid dosage forms are conducted using either
the vertical diffusion cell or an immersion cell. The vertical diffusion cell consists of re-
ceptor and donor chambers, separated by a receptor membrane. The donor chamber holds
the sample of dosage form, while the receptor chamber holds the receptor media. The
receptor media can be a buffer or hydro-alcoholic solution, selected based on the solubil-
ity, sink condition, and stability of the API. The skin-like receptor membrane is selected
based on the effective pore size, high permeability and expected inertness towards the
API. If necessary, the receptor membrane should be saturated with release media. The
temperature of the media should be maintained around 32 °C ± 1 °C for topical adminis-
tering products, for products intended for mucosal membrane the temperature should be
37 °C ± 1 °C. A Teflon-coated magnetic stirrer is used for stirring the receptor media. While
the immersion cell model has a cell body, which acts as a reservoir [161]. The cell body is
covered with a membrane and closed using a leakproof seal (retaining ring cap) that en-
sures no leakage of the dosage form. The retaining ring cap possesses an opening on the
top, and it should be adjusted in such a way that the membrane is in contact with the
dosage form on the bottom and release media on the top. The whole setup is used along
with the USP-2 apparatus, wherein the immersion cell is placed in flat bottomed dissolu-
tion vessel with a usual volume of 150–200 mL. A mini spin-paddle is used for stirring or
agitating the media [162].

9.6. Bio-Adhesive Property

Bio-adhesive strength is used to determine the force required to detach the drug car-
rier system from a biological surface. This property is important for a topical dosage form
if prolonged contact is required [163]. This test is usually performed using rat or pig skin,
the latter is preferred because of its resemblance to human skin. There are various tech-
niques to measure this property but none of them is approved by FDA. The texture ana-
lyzer is one such technique, where the upper mobile probe and stationary lower base plate
will be covered with skin. The dosage form is placed on the skin of the base plate. The
upper probe is lowered to contact the lower base plate and the contact is maintained for
at least a minute. The upper probe is lifted slowly until the separation of skin sheets. The
force required to separate the two skin sheets will be measured by the instrument and
represented as the area under the force-distance curve [164].
Pharmaceutics 2023, 15, 164 19 of 28

10. Safety Issues

One of the crucial concerns while developing a skin-related formulation is toxicity
and skin irritation [165]. Impairment of enzyme activity, disturbance in normal physio-
logical functions, and sometimes carcinogenic effects (For e.g., being caused by Sodium
do-decyl benzene sulfonate) are some common toxicity issues related to surfactants [166].
Smith and the group analyzed the effect of two surface active agents’ sodium dodecyl
sulfate and dodecyl trimethyl ammonium bromide on penetration and skin perturbation.
They concluded that disruption in the layer of skin is primarily caused by elevated con-
centrations of micelle agglomerate and monomers [167].
Irritation caused by topical nano-emulgel can be examined by applying it on the
shaven skin of a rat, then observation of redness and other signs of inflammation on the
skin were made and then graded based on the number of eurythmic spots to assess their
clinical implication as give in Table 8 [167]. In general, a grade scale up to 2 is safe. Azeem
et al. prepared ropinirole nano-emulgel using caproyl 90, tween 20 and carbital. The skin
irritation studies showed a grade 2 erythema index, which is safe [168]. Gannu et al. also
performed skin irritation studies of nano-emulgel prepared using non-ionic surfactant the
Tween 80 and co-surfactant labrasol. They observed no signs of skin irritation as the used
surfactants are generally considered safe [25]. Usually, major toxic effects are observed
with cationic surfactants so they are avoided in preparations associated with topical de-
livery. While nonionic surfactants are mostly preferred as they cause minimum perturba-
tion of the skin layer [151,166].

Table 8. Skin irritation grading scale and their clinical implications.

Clinical Portrayal Grade

No erythema 0
Slight erythema that is barely perceptible 1
Moderate erythema that is visible 2
Erythema and papules 3
Severe Edema 4
Erythema, edema, and papules 5
Vesicular eruption 6
Strong reaction spreading beyond the application sight 7

11. Challenges
The impartment of large drug entities with molecular weight exceeding 400 Dalton
is hindered in this dosage form, as they show difficulty during size reduction and are
found to leach out of the gel mesh network. A limited number of safe surfactants and co-
surfactants are available for emulgel preparation. Not much maneuvering can be done
with the selection of surfactant as it can have hazardous consequences. The abundance of
surfactant in emulgel can lead to skin problems like contact dermatitis, erythema, redness
of skin, skin layer perturbation [169]. High susceptibility of the gelling agent toward var-
iations in pH and temperature can lead to the breaking of gel structure and the leaching
of chemicals [170].
Capriciousness in nano-emulsion is caused due to Ostwald ripening, which is asso-
ciated with nano size of oil droplets, preferably nano-emulsion is prepared shortly before
its application. Optimizing the speed of the stirrer in the homogenizer (as required to pro-
duce an inflexible and non-cracking gel), mixing appropriate quantities of surface-active
agents, and selecting a reliable packing material are very pivotal tasks associated with the
stability of nano-emulgel [171]. Highly specialized instruments are required for size re-
duction to nanoscale, which requires handling by skilled labour. Expensive sustenance of
high energy homogenizers and production cost is one of the critical limitations associated
with scale up of nano-emulgel formulation. Besides these disadvantages, the comforting
Pharmaceutics 2023, 15, 164 20 of 28

prospect of nano-emulgel is increased adherent property and elevated embranglement of

the drug in the gel mesh [53]. Also, prevalent drawbacks associated with conventional
topical dosage forms i.e., emulsion, ointment, lotions etc. such as creaming, phase disrup-
tion, oxidation induced degradation of ointments are overcome by forming emulgel [44].

12. Current and Future Prospects of Nanoemulgel

Delivering hydrophobic drugs to the biological systems has been a major challenge
in formulation development owing to their low solubility, leading to poor bioavailability.
Some of the topical formulations include creams, ointments, and lotions. They possess
good emollient characteristics, however, has slow drug release kinetics due to the pres-
ence of hydrophobic oleaginous bases such as petrolatum, beeswax, and vegetable oils,
which inhibit the incorporation of water or aqueous phase. On contrary, topical aqueous-
based formulations like gels enhance the drug release from the medication since it pro-
vides an aqueous environment for medicament. Therefore, hydrophobic APIs are blended
with oily bases to form an emulgel, which further undergoes nanonization to form a
nanoemulgel with enhanced properties. The superior properties of a nanoemulgel like
thermodynamic stability, permeation enhancement, and sustained release make it an ex-
cellent dosage form. There are several marketed emulgels and patents being filed (Table
9) for the same, demonstrating its tremendous progress in this field. By making advance-
ments in the ongoing research, nanoemulgel, as a delivery system would outshine, in for-
mulating the drugs that are being eliminated from the development pipeline owing to
their poor bioavailability, therapeutic non-efficacy, etc. Despite these advantages, the
manufacturing of nano-emulsion limits its commercialization. However, with the pro-
gressing technology, commercially feasible and profitable manufacturing techniques
could be possible in the future. With the advantages of nano-emulgel over other formula-
tions, a tremendous increase in the production of nano-emulgel can be foreseen.

Table 9. Recent patents on nano-emulgel.

Current Granted
Disease
Patent Number API Title Assignee/Invent /Publication Reference
Indication
ors Year
Transdermal non-
Aromatase aqueous nanoemulgels
US11185504B2 breast cancer Qatar University 2021 [172]
inhibitors
for systemic delivery of
aromatase inhibitor
Methods of treating
Anti-
inflammatory disorders
inflammatory
and global inflammation
nutraceuticals
with compositions Nanosphere
e.g., resveratrol, Inflammatory
CA3050535C comprising phospholipid Health Sciences 2021 [173]
cinnamaldehyde Disorders
nanoparticle Inc
, green tea
encapsulations of anti-
polyphenols,
inflammatory
lipoic acid etc.
nutraceuticals
Immune diseases
Tripterygium glycosides Second Military
e.g., clinical
Tripterygium nanoemulsion gel and Medical
CN107303263B rheumatoid 2020 [174]
glycosides preparation method University
arthritis and
thereof SMMU
psoriasis etc.
Besifloxacin for the
Vyome
EP3099301B1 Besifloxacin treatment of resistant Acne vulgaris 2019 [175]
Therapeutics Ltd.
acne
Pharmaceutics 2023, 15, 164 21 of 28

Hemant
In-situ gelling
WO2020240451 Hanumant
Brinzolamide nanoemulsion of glaucoma 2020 [176]
A1 BHALERAO,
brinzolamide
Sajeev Chandran
Sudha suresh Dr.
WO2020121329 Minoxidil and Minoxidil and castor oil androgenic
Rathodsoniya 2020 [177]
A1 castor oil nanoemulgel for alopecia alopecia
ramesh devasani
Nanoemulgel based on
ucúuba fat (Virola
BR102019014044 surinamensis) for Rayanne Rocha
Ketoconazole Onychomycosis 2021 [178]
A2 transungual Pereira et al.
administration of
antimicotics

13. Conclusions
The selection of ingredients and their appropriate ratios play a vital role in deciding
the properties of a nano-emulgel. Deviation from this could affect the conversion of a
nano-emulsion to a nano-emulgel and its thermodynamic stability. The nano-emulgel is
more stable compared to that of a nano-emulsion mainly due to its less mobile dispersed
phase and the decreased interfacial tension. Thus, the former is a better alternative in de-
livering lipophilic moieties mainly due to improved permeation, and better pharmacoki-
netics, which subsequently improves the pharmacological effect. Patient compliance is
also elevated due to its non-greasy and improved spreading properties on topical admin-
istration. Despite of its advantages, nano-emulgel is still at its infancy in the prospect of
the pharmaceutical industry. However, various emulgels are being marketed e.g., Voltron
emulgel, which holds out hope for the commercialization of nano-emulgel in near future.
Hence it has the potential to become a center of attention due to its safety, efficacy, and
user-friendly nature for topical drug delivery. Despite some disadvantages, nano-emulgel
is a tool for the future which may be an alternative to traditional formulations.

Author Contributions: Writing—original draft, M.R.D.; Writing—review & editing, S.R.M.; Writ-
ing, review & editing, K.V.K.; Resources, Supervision, R.N.S.; editing, Resources, Supervision, G.S.;
Conceptualization, Review & editing, Resources, Supervision S.K.D. All authors have read and
agreed to the published version of the manuscript.
Funding: This review received no external funding.
Conflicts of Interest: The authors declare that they have no known competing financial interests or
personal relationships that could have appeared to influence the work reported in this paper.

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