Accepted Manuscript

Recent update on nanoemulgel as topical drug delivery system

Hira Choudhury, Bapi Gorain, Manisha Pandey, Lipika Alok Chatterjee, Pinaki
Sengupta, Arindam Das, Nagashekhara Molugulu, Prashant Kesharwani

PII: S0022-3549(17)30232-0
DOI: 10.1016/j.xphs.2017.03.042
Reference: XPHS 722

To appear in: Journal of Pharmaceutical Sciences

Received Date: 6 February 2017

Revised Date: 11 March 2017
Accepted Date: 30 March 2017

Please cite this article as: Choudhury H, Gorain B, Pandey M, Chatterjee LA, Sengupta P, Das A,
Molugulu N, Kesharwani P, Recent update on nanoemulgel as topical drug delivery system, Journal of
Pharmaceutical Sciences (2017), doi: 10.1016/j.xphs.2017.03.042.

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 ACCEPTED MANUSCRIPT
Recent update on nanoemulgel as topical drug delivery system

Hira Choudhurya, Bapi Gorainb*, Manisha Pandeya, Lipika Alok Chatterjeea, Pinaki

Senguptac, Arindam Dasb, Nagashekhara Molugulua, Prashant Kesharwanid*

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a
Department of Pharmaceutical Technology, School of Pharmacy, International Medical
University, Malaysia

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b
Faculty of Pharmacy, Lincoln University College, Kuala Lumpur, Malaysia
c
Kulliyyah of Pharmacy, International Islamic University of Malaysia, Pahang, Malaysia

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d
Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, UP, 226031
India

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*Author for correspondence:

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Dr. Prashant Kesharwani Dr. Bapi Gorain

Pharmaceutics Division, Lincoln University College
CSIR-Central Drug Research Institute, 47301 Petaling Jaya, Kuala Lumpur
Lucknow, UP, 226031 India MALAYSIA
Email: prashantdops@gmail.com Email: bapi@lincoln.edu.my
Prashant_pharmacy04@rediffmail.com bapi.gn@gmail.com
Tel./Fax: +91-7582-244432 Office: +603-7806-3478
Fax: +603-7806-3479
Disclosures: There is no conflict of interest and disclosures associated with the manuscript.

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ABSTRACT:

Being an emerging transdermal delivery tool, nanoemulgel, has proved to show surprising

upshots for the lipophilic drugs over other formulations. This lipophilic nature of majority of

the newer drugs developed in this modern era resulting in poor oral bioavailability, erratic

absorption and pharmacokinetic variations. Therefore, this novel transdermal delivery system

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has been proved to be advantageous over other oral and/or topical drug delivery to avoid such

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disturbances. These nanoemulgels are basically oil-in-water nanoemulsions gelled with the

use of some gelling agent in it. This gel phase in the formulation is non-greasy which favors

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user compliance and stabilize the formulation through reduction in surface as well as

interfacial tension. Simultaneously, it can be targeted more specifically to the site of action

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and can avoid first pass metabolism and relieve the user from gastric/systemic
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incompatibilities. This brief review is focused on nanoemulgel as a better topical drug
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delivery system including its components screening, formulation method and recent

pharmacokinetic and pharmacodynamic advancement in research studies carried out by the

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scientists all over the world. Therefore, at the end of this survey it could be inferred that
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nanoemulgel can be a better and effective drug delivery tool for the topical system.
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Keywords: Nanoemulgel; Nanoemulsion; Transdermal drug delivery; Pharmacokinetic

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improvement.
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1. Introduction

Since the dawn in pharmaceutical culture in Mesopotamia (2600 B.C.) by the use of
water, and plant for the treatment of ailment, pharmacists are able to develop the era of
modern dosing systems [1]. Researches in this field have introduced several routes of
administration to deliver the developed modern dosage forms. The dosage forms are mostly

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dependent on the physicochemical characteristics of the active compound. Recent trend of
synthesis drug development or during high throughput screening leads towards development

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of lipophilic active pharmaceutical agents [2]. Recent statistical reports on poor aqueous
solubility of new chemical entities (NCE) (70%)[3] has crossed the initial report of around

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40% NCE with poor solubility [4–9]. Lipophilic characteristics of the newly developed drug
molecules manifest the problems like poor oral bioavailability, erratic absorption, intra- and
inter-subject pharmacokinetic variations and lack of dose proportionality [10]. To overcome

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those issues to focus on solubility enhancement, formulation approach is a continuous
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developing process. Different strategies such as physical modification, chemical modification
and formulation development (Figure 1) can be used to improve the solubility of poorly
soluble drugs. There have been numerous formulation approaches to improve the solubility of
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poorly aqueous soluble drugs such as particle size reduction to deliver through nanocarrier
system, crystal engineering, amorphous formulation [11–15], several lipid formulations
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approaches [16], etc. Newer lipid formulation techniques, viz: incorporation of lipophilic
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component in inert lipid vehicle [17,18], formation of microemulsion or nanoemulsions [19],

self-emulsifying formulations, liposomes, solid lipid nanoparticles or lipid nanocarriers [20–
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22] are becoming increasingly popular to overcome these problems of lipophilic properties of
compounds. Consequently, several route of administration have been explored to deliver
those formulations based on its distinct advantages and disadvantages on target site, severity
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of disease, patients’ age and condition, available dosage form and finally for the compliance
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of the users.

Oral route is the most preferred route anchored in patient compliance, however, oral
administration is more prone to result in hepatic first pass metabolism, leading towards
requirement of higher dose [23,24]. Further, gastric irritation is the major limitations for the
presence of surfactants in the lipid based formulations [25], simultaneously the distribution of
drug throughout the body can lead to unavoidable side effects. Hence, to stay away from such
unacceptable issues, the non-invasive, non-paining, non-irritating topical delivery of

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formulation is an alternate way associated with several advantages such as delivery of drug to
specific site of action with reduced systemic toxicity, avoidance of first pass metabolism and
gastric irritation, increasing release rate of drug from formulation to improve percutaneous
absorption and sometime topical application related to increase bioavailability with sustained
release profile [26,27].

Besides its advantages described, traditional transdermal formulations, viz: ointments,

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creams, lotions are in accord with many disadvantages such as sticky nature, lack of spreadibility,
stability issue, etc., ultimately leading to patient incompliance. Modernization of transdermal

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delivery by the formulation revealed transparent gel and emulgel with greater patient compliance
and improved efficacy. Thus, these formulations are gaining interest both in cosmetics industries,

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as well as in pharmaceutical industries. In spite of lots of advantages of gel and emulgel
formulations, delivery of hydrophobic drug still remains a big hurdle to cross over. Moreover,

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skin penetration through stratum corneum is also a great concern to the researchers for the
systemic activity of the transdermal delivery. Literatures suggest that nanosized topical
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formulations can enhance permeability of the active moiety by disrupting the lipid bilayer as
evident from the distinct void and empty spaces in the nanoemulsion treated skin samples
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[28] and extent retention of the drug at the site of action [29,30]. Nanoemulsion bears much
hope being isotropic, transparent (or translucent) heterogeneous mixture composed of two
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media (oil and aqueous), one phase is dispersed in another and stabilized by an interfacial
film of surfactant molecules [31]. Studies suggested that nanoemulsions have a higher drug
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solubilization capacity than simple micellar solutions, and their thermodynamic stability
offers advantages over unstable dispersions, such as emulsions and suspensions, because they
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can be manufactured with little energy input (heat or mixing) and have a longer shelf-life
[18]. Regardless of lots of advantages of nanoemulsion, topical application is limited due to
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its low viscosity and spreadibility [32]. Researchers have solved the problems associated with
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nanoemulsion for transdermal delivery through a simple conversion of nanoemulsion to

nanoemulgel. Nanoemulgels are nanoemulsion, either of oil-in-water (o/w) or water-in-oil (w/o)
type which further convert to nanoemulgel by using gelling agent [33]. Nanoemulgel possesses
gel characteristic with improved nanoemulsion properties for transdermal application. Other
advantages of nanoemulgel include its low skin irritation, increase permeability, and high
drug-loading capacity for topical delivery when compared with the other carriers such as
microemulsions, liposomes or solid lipid nanoparticles [34–36]. This colloidal delivery
system can be utilized to incorporate drug compounds to target on bioavailability

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improvement, increase stability plateau and reducing their side effects [37]. Nanoemulsion
ensures adequate localization and dispersion of the drug by adequate percutaneous absorption
within the skin to enhance its local efficacy and/or through the skin to the circulation to
polish its systemic effect and even can cross the rigid blood-brain-barrier to offer added
advantages in CNS activity [38].

Hanging on the researcher’s interest, patient acceptance and interesting research

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outcomes in the field of pharmaceutical formulation development, study on nanoemulgel
focuses on development of vast number of delivery system viz: transdermal, dental, vaginal,

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ocular, nose to brain nanoemulgel for treatment of various local as well as systemic ailments
[39–45]. There are a very few review articles available in the literature mainly focusing on

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formulation overview and penetration aspects of emulgel [46], characterization of the
nanoemulgel [47], current market products on nanoemulgels and its advantages [48] and

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delivery of antifungal agents through nanoemulgel delivery [27]. Present article is an
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extensive review covering components screening for nanoemulgel formulation combined
with its formulation overview and pharmacokinetic and pharmacodynamic parameters of the
published research works on nanoemulgel with different pharmaceutical products. Therefore,
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the aim of the present study is to give an overview on the selection criteria of the basic
component for nanoemulgel and its positive/negative role in experimental results on
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pharmacokinetics, pharmacodynamics, and safety of the drug. Connecting section of the

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article will reveal the components and selection criteria for the achievement of targeted
objective.
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2. Formulation components consideration

Either of o/w or w/o nanoemulsion is composed of an oil phase and aqueous phase,
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where the tiny dispersed phase is enervated by a thin layer of surfactant, which sometimes
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augmented by the presence of co-surfactant. Overview of oil selection strategies to utilize

several inherent properties of the incorporating oil has been apprehended in the connecting
section.

2.1. Oil selection

One of the important components of the nanoemulgel is the lipid component, i.e., oil.
There is requirement of several investigations to select an appropriate oil phase based on
viscosity, permeability, and stability of the formulated nanoemulsion. Sometimes selection of

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oil phase is also dependent on utilization of the medicinal property of some natural oils [49].
Based on the source of the oil, it has been observed that vegetable oils (of long-chain fatty
acids) had poor emulsification properties, therefore result in unstable nanoemulsion [50,51].
On the other hand, emulsification property was found to be better when the oil was with less
hydrophobic property [52]. Contrary, increased hydrophobicity affects the solubility of the
lipophilic drugs in it. Therefore, selection of appropriate oil is a critical step in formulation

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development. A selection strategy of an appropriate oil phase for a nanoemulgel to plan is
represented in Figure 2.

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Oleic acid, a biocompatible and biodegradable omega-nine fatty acid, available from
many vegetables source and animal products, is widely used as an oil phase in nanoemulgel

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formulation not only due to its high solubilization properties, but also for its well-known
percutaneous absorption enhancer property [53] and formulation stabilization property

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[54,55]. Additionally, reach antioxidants in oleic acid known to strengthen the cell membrane
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integrity, helps in replacing cells and tissues damage. Due to presence of such advantageous
properties, this oleic acid has been used as a permeation enhancer for many drugs [54], for
the development of topical nanoemulgel with piroxicam [55]. Dhawan and its group reported
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that there is improved permeation rate with increased percentage of oleic acid in the
formulation. Further, enhancement of ketoprofen permeability was observed [54] by
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increasing oleic acid from 3% to 6%. On analyzing, it has been observed that lipid
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fluidization and lipid phase separation are the two mechanism by which oleic acid increases
the permeability and easily permeate within lipid bilayers of the stratum corneum [56,57].
However, high concentration of oleic acid could decrease the permeation rate which might be
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due to aggregation of oil [55]. Besides, incorporation of oleic acid in diclofenac diethyl amine
nanoemulgel could be one of the possible reasons for the increased cumulative percentage
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permeated through stratum corneum [58].

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Thus, oils from natural sources have proved to contain additional medicinal value(s)
and now-a-days scientists all over the world are more focused to utilize such supplementary
benefit in therapeutic effect. Another oil from emu bird, emu oil also gained interest in
pharmaceutical industry for its anti-inflammatory, analgesic, anesthetic, antipruritic and
antioxidant properties [59]. Such important therapeutic activities of emu oil were utilized by
the Jeengar and team. They manufactured curcumin nanoemulgel with improved permeability
in the ailment of joint synovium [59]. Parenteral medicaments are also gaining attention to

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deliver through transdermal route with the utilization of its penetration enhancing properties
to the site of action for a prolonged period. Excellent hypoglycemic activity of insulin had
been reported by the researchers in experimental rabbits when it was delivered through
percutaneous emulgel delivery [60]. Uses of emu oil is not only cornered in pharmaceutical
industries, it is also gaining importance in cosmetic industries due to its moisturizing benefits
to the skin [61]. Its’ resemblance to skin composition due its high percentage of unsaturated

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fatty acid with major percentage of oleic acid [62,63] further helps in penetration
enhancement of drug through skin.

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Furthermore, another natural oil – tea tree oil, is well known for their broad spectrum
antimicrobial activity [64]. Thus, use of tea tree oil as a formulation ingredient can be

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beneficialin application on fungal and bacterial infection. The stable and thermo sensitive
nanoemulgel of itraconazole, an azole antifungal agent, with tea tree oil was reported with

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synergistic effect against vaginal candidiasis [42]. Drug loading in tea tree oil was improved
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using organic solvent during nanoemulgel formulation development. Skin penetration of
itraconazole was improved through nanoemulgel delivery, which might be due to the
presence of nano sized droplet of tea tree oil and its major component terpinen-4-ol [65].
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Instead of its various advantages, use of tea tree oil as a formulation component is limited for
transdermal delivery due to its allergic properties [66,67]. Further evaluation revealed that,
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1,8-cineole, a component of tea tree oil has known to cause skin irritation, provided its
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content should have≥28% [66]. But we are fortunate enough to know that tea tree oil has only
15% 1,8-cineole. So whenever developing a formulation with tea tree oil as a component,
judicious selection of tea tree oil concentration will be an important factor. Itraconazole
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nanoemulgel with tea tree oil did not produce any irritation potential and any sign of
abnormality in histopathology study due to low percentage of tea tree oil (10% in
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nanoemulgel) [42]. Another nanoemulgel of synthetic trizole antifungal drug, fluconazole,

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has been reported by Pathak and team for topical application. They reported that ocular
application of the nanoemulgel formulated with Capmul MCM as an oil phase due to its high
solubilization potential for fluconazole, adequate water solubility and well tolerance to the
eye [68,69].

Eugenol, a phenolic compound obtained from Eugenia aromatica, is well known for
its analgesic, local anesthetic, anti-inflammatory, and antibacterial properties [70]. Srivatava
and team had been utilized eugenol as an oil phase in ketoprofen nanoemulgel formulation

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[43,70]. They observed a supra-additive synergistic antibacterial activity of ketoprofen in
eugenol nanoemulgel formulation against Staphylococcus aureus and Escherichia coli which
is due to the nano delivery of ketoprofen as well as due to presence of eugenol in formulation
[70].

Occasionally, the target compound or the active ingredient was employed as an oil
phase in nanoemulgel development. One of such component is swieteniamacrophylla

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nanoemulgel where swieteniamacrophylla is used as an oil phase. It has been revealed that
the anti-inflammatory property of swieteniamacrophylla was higher when delivered through

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nanoemulgel formulation compared to its parent form [71].

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As discussed earlier, the edible/vegetable oils are not frequently useful due to their poor
ability to dissolve large quantity of lipophilic drugs and poor emulsification properties.
Therefore, chemically modified oils, like medium-chain triglycerides or mono- or diglyceride

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are frequently used as an oil phase in formulation development to deliver poorly water
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soluble drugs [72]. Capryol 90 is one of such example with hydrophilic lipophilic balance of
5, due to its lipophilicity easily solubilize drugs with less polar area. Published literature
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revealed that the presence of the numerous advantageous properties, Capryol 90 has been
used as an oil phase for the development of nanoemulsion for various lipophilic compounds
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to target improvement of their pharmacokinetic/pharmacodynamic properties [33,73].

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Medium chain triglycerides are suitable for encapsulating drugs with log-P value
ranging from 2 to 4 [74]. Labrafac is another example of medium-chain triglyceride used as
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fat phase in nanoemulsion preparation [75,76]. Among the available variety of it, Labrafac™
Lipophile WL1349 was used for the development of nanoemulgel for transangual delivery of
ketoprofen [77]. An additional medium chain triglyceride Capmul MCM found to be widely
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used in pharmaceutical research. It has HLB value of 5 to 6, therefore, reported to have good
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solubility with water. It has also proven to be an appropriate oil phase for ocular
nanoemulsion formulation due to its non-irritating properties on human eye [68]. A different
medium chain triglyceride, Miglyol 812, is also preferred for ocular delivery through
nanoemulgel formulation as it is too well tolerated with human eyes. In spite of the non-
irritability property of Miglyol 812 for ocular delivery, use of it is limited due to less
nanoemulsifying area in pseudoternery phase diagram which might be due to its higher
molecular volume and smaller alkyl chain [78]. Nevertheless, suitable combination and
composition with an appropriate surfactant might result a stable nanoformulation [79] for the

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improvement of solubility of poorly water soluble drugs. In their research, Tayel et al.
developed non-irritant ocular nanoemulgel of terbenafine hydrochloride with Miglyol 812
and achieved a thermodynamically stable, sustained released and improved bioavailable
formulation [79].

2.2. Surfactant and co-surfactant selection

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2.2.1. Surfactant

Surfactants are integral component of nanoemulsion system which is used to stabilize

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the thermodynamically unstable mixture of two immiscible liquids by reducing the interfacial
tension between them and change the dispersion entropy. Safety, stability and high drug

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loading capacity along with good emulsification properties are the basic requirements for the
surfactants integrated in nanoemulsion development, [51]. A suitable surfactant used in

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nanoemulsion formulation should be adsorbed rapidly onto the interface of the two
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immiscible phases leading to dramatically reduction of interfacial tension and prevents
coalescence of the nano droplets [80].
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Due to the presence of ionic nature, these stabilizing systems are classified into the
following categories: cationic surfactant (amines and quaternary ammonium compounds,
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cetyl trimethyl ammonium bromide, lecithin, hexadecyl trimethyl ammonium bromide,

dodecyl dimethyl ammonium bromide, etc.), anionic surfactant (containing carboxylate
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group, sodium bis-2-ethylhexylsulfosuccinate, sodium dodecyl sulfate), zwitterionic

surfactant (phospholipid), and non-ionic surfactant (Capryol 90, Labrafil CS, Labrasol,
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Gelucire 44/14, 50/13, Cremophor RH 40, Cremophor EL, Imwitor 191, 742, 780 k, 928, 988
M, 2125 CS, Lauroglycol 90, PEG MW > 4000, Plurol Oleique CC 497, Poloxamer 124 and
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188, Softigen 701, 767, Tween 20, Tween 60, and Tween 80, etc). Their working mechanism
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based on the repulsion force between nano droplets, because presence of similar ionic charge
on the head of the surfactant molecule on the interface of the dispersed and continuous phase
prevents aggregation of droplets leading to thermodynamically stable nanoemulsion [81].

There are various factors which governs the selection of surfactants. The first and
most important feature is the associated toxicity of the surfactant used. Proper selection of
surfactant is important due to large amount of surfactant may cause irritation to skin and GI
tract when administered topically and orally, respectively. So it was advocated to incorporate
minimum amount of surfactant in formulation. Another selection criteria include the HLB

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value of the surfactant. Based on the hydrophilic-lipophilic balance (HLB) values of the
available surfactants, they are classified as w/o emulsifying agent (HLB 3-8) and o/w
emulsifying agent (HLB 8-16) [82,83]. Therefore, to develop an o/w nanoemulsion, HLB
value of the selected surfactant should be greater than 10. Thus, in o/w emulsion, Tweens and
Spans having HLB value more than 8 are used. Additionally, combination of Span 20 and
Tween 20 contribute towards greater stability of the emulsions as compared with pure Tween

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or Span systems [84,85]. Conversely, to stabilize w/o emulsion, surfactants having HLB
value less than 8 are used [86]. However, formation of stable nanoemulsion can be obtained

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from appropriate mixing of low and high HLB surfactants. On the similar concept, Noor El-
Din et al. prepared water-in-diesel fuel nanoemulsion by using mixture of Tween 80 (HLB-

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15) and Span 80 (HLB-4.3) [87]. In such system, the hydrophilic and lipophilic emulsifiers
are thought to align alongside each other imparting more rigidity and strength to the
emulsifier film through hydrogen bonding and making nanoemulsion more stable. Several

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authors affirmed that surfactant mixtures could provide more stable emulsions with the
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minimum size of dispersed droplets than use of any one [88,89]. These surfactants improves
stability of nanoemulsion by lowering the needed energy to formulate nanoemulsion [90,91].
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An additional criteria of surfactant selection is the type and nature of surfactants; typically,
nonionic surfactants are preferred because of biocompatibility, safety, less affected by pH and
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changes in ionic strength. In contrast, ionic surfactants are less preferred due to toxicological
concerns [92]. Furthermore, solubilization of oil with the surfactant is also an important
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factor for surfactant selection, like Abdelaziz et al. selected Tween 20 and propylene glycol
as surfactant and co-surfactant respectively on the basis of solubility of Indomethacin [93].
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Likewise, Azeem et al., [72] and Arora et al. [54] identified Tween 20 and Tween 80 as the
surfactant having highest solubility for oil phase Capryol 90 and oleic acid, respectively.
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However Pund et al., screened Tween 20, Tween 80, Labrasol, Cremophor RH 40 and
Cremophor EL as surfactant where Capryol 90 used as oil phase [33]. Finally, they selected
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the surfactant on the basis of miscibility with oil phase along with solubility of drug
(Leflunomide) in surfactant (Cremophor EL). Similarly, Shakeel et al. [94], elected Tween 80
as surfactant and Transcutol P as co-surfactant based on solubility of aceclofenac for phase
study.

Natural surfactants generally from animal source, microbial cells like bacteria, few
yeast and fungi are gaining research interest day by day due to their less toxic in nature,
biocompatibility, environ compatibility and biodegradability. Biosurfactant are amphiphilic

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in nature and they also reduce the interfacial tension by the same mechanism. Their polar
head groups and short fatty acid tail has affinity to both hydrophilic and hydrophobic
[49,95,96]. Bai and McClements used rhamnolipids as biosurfactant in formulation of
nanoemulsion and they reported that rhamnolipids are effective natural surfactants which
may be explored to replace synthetic surfactants in certain commercial applications [97,98].
On the other hand, Rosa et al. developed an stable o/w emulsion of d-tocotrienol-rich oil

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using saponin-rich extract from Brazilian ginseng roots as a biosurfactant [99]. Similarly,
Cerón-Camacho et al. synthesized alkyl-O-glucoside and -cellobioside biosurfactants with a

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long fatty chain (C8–C18) in order to prepare stable and low viscous o/w emulsions of a
Mexican heavy crude oil [100].

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2.2.2. Co-surfactant

Co-surfactant helps surfactant in the nanoemulsion system to emulsify oil in aqueous

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phase. In such system, co-surfactant combines with surfactant and penetrates into the
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surfactant layer, thereby disrupts the interfacial film, and confers required fluidity, lower the
interfacial tension, and help emulsification process [72]. Usually transient negative interfacial
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tension and fluid interfacial film cannot be achieved by using surfactant only, so
incorporation of co-surfactant provide flexibility to the interfacial film. Co-surfactants may
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also help in solubilization of the oil by modification of the curvature of the oil-water interface
[101]. Selection of co-surfactant is important because release of therapeutic agent or
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lipophilic drugs affected by its partitioning in aqueous and oil phase by interaction between
surfactant and co surfactant [33]. Transcutol HP, 1,2-propylene glycol, PEG- 400,carbitol,
®
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absolute ethyl alcohol, propanol, butanol are used frequently as co-surfactants in

nanoemulgel and nanoemulsion system [54,102]. Alcohols may increase the miscibility of the
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aqueous and oily phases due to its partitioning between these phases. Therefore, ethanol,
isopropyl alcohol, 1-butanol, and propylene glycol are being selected as co-surfactants. PEG
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400 and carbitol were also selected, as they show increased permeation when incorporated
into formulations and are relatively tolerable [72]. The criterion of selecting surfactant and
co-surfactant in nanoemulsion formulation is of their percent transmittance [103]. Arora et al.
screened Tween 80, Labrasol, Labrafac as surfactant and Transcutol P, propylene glycol,
ethanol as co surfactant using oleic acid as oil phase. In their formulations, Tween 80
revealed 96.34 ± 0.24% transmittance whereas the other surfactants labrasol and labrafac
showed 89.41±0.66% and 72.66±0.69%, respectively [54]. Likewise, Transcutol P resulted in

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higher percent transmittance than propylene glycol and ethanol and therefore, selected for the
formulation development. Furthermore, Transcutol P was found to be advantageous as an
efficient permeation enhancer [104]. Thus, it has been established that the concentration of
co-surfactant influence the performance of surfactant in emulsification process. An
assessment criterion for selection of co-surfactant is to evaluate the nanoemulsion area in
phase diagram. Nanoemulsification efficiency of surfactant and co-surfactant ratio depends

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largely on the size of the nanoemulsion area in phase diagram. It had been reported that
increased in carbon chain length on structure increased the nanoemulsion area [72].

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On the other hand, mass ratio of surfactant and co-surfactant had also been found to
be another key factor influencing the phase diagram properties, i.e., size and position of

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nanoemulsion region [105]. Abdelaziz et al. [93] and Azeem et al. [72] studied with Tween
20 and propylene glycol/carbitol as surfactant and co-surfactant respectively, reported that if

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co-surfactant is absent (1:0) or present at lower concentrations, the surfactant is not able to
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sufficiently reduce the interfacial tension. However, equal amount of surfactant and co-
surfactant (1:1) leads to higher nanoemulsion region due to reduction in interfacial tension.
On further increment of surfactant amount (2:1) increased the nanoemulsion area initially,
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followed by decrease in nanoemulsion area (3:1). This indicated that maximum

emulsification reached at 2:1 ratio. Above findings were in coherence with Attwood et al.
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who also reported that location of nanoemulsion area in phase diagram changed with
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changing the ratio of surfactant (polysorbate 40) and co-surfactant (sorbitol) from 1:1 to
1:3.5. In the same way, Shakeel et al. found an increment of surfactant ratio upto 2:1
nanoemulsion area increased but further increase in surfactant concentration (3:1) leads to
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decrease in nanoemulsion area [94]. In contrast, Arora et al. [54] revealed that surfactant
(Tween 80) alone showed significant nanoemulsion area in psuedoternary phase diagram,
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however, higher concentration of surfactant has also been reported to cause skin irritation
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[106]. So, it has been justified that incorporation of co-surfactant with surfactant leads to
large nanoemulsification area due to good penetration of the oil phase in the hydrophobic
region of the surfactant monomers. On the other hand, Bali et al. [92] grouped two
formulations with Capryol 90 as oil phase with surfactant and co-surfactant of low (Labrasol
and Transcutol® P) and high HLB (Tween 20 and PEG 400). They observed that an
appreciable nanoemulsion region was obtained when high HLB surfactant (Tween 20) was
used alone where incorporation of co-surfactant in equal quantity (1:1) nanoemulsion region
was somewhat reduced. Conversely, in second group where surfactant and co-surfactant were

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of low HLB values, small amount of oil was emulsified using high quantity of surfactant
while addition of co-surfactant in equal quantity tremendously increase the nanoemulsion
area [92].

Further, it has been reported that co-surfactant concentration is inversely proportional

to the nanoemulsion region in phase diagram. Shafiq et al. [107] who investigated the
nanoemulsion area in phase diagram was found to be decreased on increasing the co-

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surfactant concentration ratio in the mixture of Tween 80 (surfactant) and carbital(co-
surfactant). Similarly, [93] also observed that the increase in concentration of co-surfactant

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with respect to surfactant (1:2) could result in decreased nanoemulsion area compared to 1:1
ratio. It was reported that two non-ionic surfactants with different HLB values able to

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produced more stable emulsion in comparison to mixture of surfactant and co surfactant of
having close HLB values. This may be attributable to the fact that surfactants with higher

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HLB values solubilize in the aqueous phase, whereas lower HLB values solubilize in oil that
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enable to work more strongly with surfactant and co-surfactant mixture [85,108]. Based on
same concept, Shakeel et al. [94], selected Tween 80 having HLB value of 15 along with
Transcutol P, which has an HLB value of 4.2 to produce stable nanoemulsion.
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Thus, it has been observed that selection of ideal components for a nanoemulsion is a
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challenging part of research. In the connecting section of the article, we will discuss on the
different formulation procedure aspects to formulate nanoemulsion in the laboratory and the
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use of diverse hydrogels to change the physical status of the formulated nanoemulsion.
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3. Preparation of nanoemulsion and change its physical state by addition of gelling agent:

Nanoemulgels are manufactured undergoing two steps, where in the first step nanoemulsion
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will be manufactured whereas nanoemulsion will be introduced in the gelling agent during
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the second step (Figure 3). Nanoemulsions are spontaneously prepared by mixing the
compositions by reducing the interfacial tension between oil/water interfaces or may be
prepared by application of external energy into the heterogenous mixture [109,110]. Thus, a
thermodynamically stable nanoemulsion can be prepared basically by adopting high energy
and low-energy emulsification methods.
Step 1:

High-Energy Emulsification Method

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High shear force produced by ultrasonicators, high pressure homogenisers, microfluidizers,

etc., are used rupture the oil phase to form nanosized droplets in the aqueous phase by

optimizing required time, temperature and component properties to minimize size of the

dispersed to the nano-range [98,111,112]. Therefore, this methods of preparation of

nanoemulsion require input of external energy which makes the developed formulations

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thermodynamically unstable due to the presence of free energy into it [73,113]. Further, this

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method is advantageous to obtain the size of the dispersed phase as low as 1 nm through

component changing, whereas it is inapplicable for thermolabile components [19].

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Low Energy Emulsification Method

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Low-energy method for preparation of nanoemulsions include spontaneous method and phase
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inversion method, which are found to be advantageous over high energy emulsification

technique in terms of thermodynamic stability of the final formulation due to incorporation of

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high energy during manufacturing process [10,19]. Mixing of oil, water and surfactant in a

perfect ratio could formulate the nanoemulsion spontaneously, alternatively by addition of

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aqueous phase with or without surfactant in the oil phase without or with surfactant,
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respectively could generate desired nano-structured droplets dispersed in the continuous

phase. The order of addition of the basic components, pH of the medium, properties of
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incorporated surfactant and co-surfactant affect the emulsification process [19]. Specifically,

temperature dependent change in HLB for certain non-ionic surfactants, mostly poly-
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ethoxylated surfactants (e.g., Tween 80, Tween 60, Tween 20, Cremophor EL, Labrasol,

etc.) are utilized under this method [114,115]. Spontaneous method is most suitable for the
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thermolabile components to be incorporated into the nanoemulsion. Alternatively,

temperature dependent spontaneous twist of non-ionic surfactants is used for phase transition

during phase inversion method. The emulsion formed at phase inversion temperature will be

reversed on cooling with continuous stirring. This process is also limited to incorporate

thermolabile components, although this limitation could be reverted by approaching

decreased phase inversion temperature by suitably selecting the surfactant(s) [19,116].

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Step 2:

Nanoemulsion prepared by adopting any of the above methods can be converted to

nanoemulgel using gelling agents. Purpose of use of jelling agent in the nanoemulsion
formulation is to change its physical state, from liquid to gel. Addition of gelling agent to an
o/w nanoemulsion system thickens the formulation by forming gelled like structure. This is

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due to the thixotropic nature of the agent which helps in the gel-solution transition during
application of shear stress to the formulation without changing its volume. Further, on
standing, there will be an automatic reversal of the state from solution to gel. Some

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commonly used gelling agents are used in the preparation of nanoemulsion gel, which
includes carbomer 940 [54], chitosan [117], carbopol 934 [39,42,118], carbopol 940

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[32,40,119], carbopol-980 [120], Poloxamer 407 [42], methyl cellulose [121], carbopol 971
[58] etc. Incorporation of gelling agent in the nanoemulsion had been shown to affect the

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pharmacokinetic properties of the drug incorporated into this nanocarrier system. Gelling
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media is prepared by dissolving gelling agents into an aqueous media with continuous stirring
at a constant rate at specified conditions for specific time to obtain complete swelling.
Finally, the emulsion will be introduced into the prepared gel at a particular ratio with
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continuous mixing for homogeneity [59]. Impact of nanoemulgel development in the

pharmacokinetic and pharmacodynamic properties of the drug has been summarized in the
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following section of the article.

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4. Brief testimony of published nanoemulgel formulations and its impact on pharmacology

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Incorporation of hydrogel matrix in nanoemulsion could have a high impact on the

pharmacokinetic properties of the drug. Lipophilic drugs are mostly incorporated into the
lipid phase before preparation of the nanoemulsion. Screening of lipid phase for perfect
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choice for the incorporated drug as well as estimation of entrapment of the pharmaceutical
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component into the nanoemulsion specially determines using modern analytical instruments,
like HPLC [9,122]. In a recent study by Dasgupta et al. reported the development and
optimization of lornoxicam nanoemulgel [76]. However, instead of directly adding optimized
nanoemulsion to gelling agent, as described earlier (1% w/w Carbopol 934), here the
researchers adopted a different strategy. They added the selected oil, Labrafac, first to the
dispersed phase of gelling agent followed by addition of triethanolamine to neutralize the gel.
Selected surfactant (Tween 80) and co-surfactant (Pluronic F68) were slowly integrated into
the gel and thus nanoemulgel was formed by adding rest of the aqueous phase. The pH of

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developed nanoemulgel was found to be 6–7 following neutralization using 0.5% w/w
triethanolamine, and it has also reported that the neutral pH is appropriate for cutaneous
application [55]. In vitro release and permeation flux through skin are significantly higher
for nanoemulsion and nanoemulgel compared to marketed gel formulation whereas in vitro
release and permeation flux of lornoxicam was found to be maximum in nanoemulsion
formulation. Less flux of nanoemulgel compared to nanoemulsion may result in prolonged

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drug release behavior of nanoemulgel. Hence pharmacodynamic study revealed that both
nanoemulsion and nanoemulgel remained superior to the marketed product in its ability to

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suppress edema in Complete Fraund’s Adjuvent induced paw edema model in male Wistar
rats [76]. In another study by Khurana and team revealed the sustained release and enhanced

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permeation properties of the meloxicam carrier gel through skin, simultaneously, the developed
formulation was found to be non-irritant, hemo-compatible, and non-toxic with significant anti-
inflammatory activity [119].

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Study by Pund et al. disclosed nanoemulgel as potential carrier for the treatment of
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psoriatic arthritis and melanoma affected skin. The research team had successfully improved ex-
vivo permeability of the drug through rat skin, to mimic the transdermal permeability of the
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formulation. Further, developed formulation was found to cause cell specific cytotoxicity towards
human melanoma cell lines, which further proves the safety of the formulation towards normal
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cells. They had postulated that this transdermal delivery could be targeted to site specific
treatment thereby it will reduce the dose of the drug, leading to be economically helpful as well
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as minimize systemic adverse events [33]. Histopathological sections of the rat skin showed no
alteration of the skin architecture following 12 hour of exposure with nanoemulsion (Figure 4c),
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whereas positive control group with nitric oxide (Figure 4b) showed marked alteration of the
epithelium as compared to negative control (Figure 4a). In vitro study on A375 and SK-MEL-2
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cell line demonstrate the upregulation of the aryl hydrocarbon receptors and antiproliferative
activity in the test cell lines through activation of the transcriptional activity [33]. Similar
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approach towards mycological cure with nystatin nanoemulgel resulted in highest drug release
when compared with solid dispersion or marketed cream formulation [121]. Carbopol 934 was
employed by Aparna and team during preparation of nanoemulsion of telmisartan, an
antihypertensive agent. In their study, the ex-vivo skin permeation results were found to be
correlated with the in vivo findings. Both the studies showed significant increase in the drug
permeability. This could be possible due the enormous increase in the surface area of the drug in
the nanoemulsion which further enhances its solubility as well as its permeation through the
lipidic tissue barriers [39].

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Another study by Elosaily et al. reported the prepared nanoemulsion of nystatin by
spontaneous emulsification technique and further modified to nanoemulgel by adding to
viscous solution of 5% methyl cellulose. The group compared the formulated nanoemulgel to
solid dispersion gel of the drug and observed that the release of nanoemulgel is higher
compared to solid dispersion gel. Besides, it is relevant to mention that the nanoemulgel of
nystatin also showed increased efficacy and better tolerability against cutaneous candidiasis

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in clinical trial compared to the Nystatin® cream [123].

In another study, itraconazole nanoemulgel was developed by Sampathi et al. where

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they developed the nanoemulsion by ultrasonication after dissolving the drug in eugenol by
heating with lecithine and sodium cholate as surfactants. Optimized nanoemulsion was

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converted to nanoemulgel by using carbopol 934 and the pH was adjusted by triethylamine
[124]. Here, the researchers used 0.1% limonene in the formulation as permeation enhancer

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as well as odor masking agent. Nanoemulsion based hydrogel of itraconazole showed
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promising penetration and in vitro release when compared to the drug solution. Interestingly,
the formulation showed sustained release profile which might be helpful in reduction of the
dosing frequency [124]. In a similar type of study, Mirza et al. also developed nanoemulgel
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formulation of itraconazole with tea tree oil using Tween 20, labrasol, and carbopol 934 as
surfactant, co-surfactant and gelling agent, respectively. Findings of their study revealed that
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in spite of similar polymer content, a higher flux and improved permeability of the drug can
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be achieved with nanoemulgel formulation than the conventional gel. Additionally,

preparation of nanoemulgel of itraconazole in tea tree oil (as proposed to have antimicrobial
activity) potentiates the antimicrobial property of the drug due to synergistic effect [42].
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Eid and team had developed a nanoemulsion formulation of Swietenia macrophylla

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oil, using an oil phase to observe its therapeutic efficacy by phase inversion method followed
by self-emulsification. Optimized nanoemulsion was further modified to gel by using
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carbopol 940 as gelling agent. Swietenia macrophylla oil nanoemulgel was shown to have
significant anti-inflammatory activity in carrageenan induced rat paw edema compared to
Swietenia macrophylla oil solution [71]. A brief summary of transdermal nanoemulgels for
its components, droplet size of the dispersed phase and overview of reported pharmacological
properties have been summarized in Table 1.

Full epidermis layer of our skin provides a protective barrier for any hazardous
substance to enter into the body. Thus, penetration of hydrophilic drugs and high molecular

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weight compounds having size >500 Da are limited through intact skin [125]. Being larger in
size and peculiar problems associated with oral delivery, viz: poor aqueous solubility, poor
permeability and acidic degradation [126], amphotericin B is available as parenteral dosage
form. To overcome the limitations of clinical application including potential nephrotoxicity
of amphotecin B, an approach in formulation development has been accomplished by
Hussain and team [127]. Topical route has been chosen for the new formulations to acquire

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antifungal activity as well as to avoid serious systemic complications of the drug. The
researchers developed the nanoemulgel of amphotericin B by incorporating formulated

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nanoemulsion to the dispersed polymeric gelling agent (carbopol-980) followed by vigorous
homogenization. In the optimization of nanoemulsion sefsol 218 and dimethyl sulfoxide in

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1:1 ratio has been selected as appropriate oil phase. Triethylamine was added to the dispersed
gelling agent and kept overnight for air removal and for cross linking the polymer with
triethylamine. Experimental in vitro results on release, skin permeation and hemolysis studies

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were satisfactory and further skin irritation test in Wistar albino rats did not result in
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erythema or edema as observed at different time points after application of the formulation.
Additionally, to clarify in vitro permeability outcomes, in vivo study for skin penetration was
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performed by incorporating Rhodamine 123 (a tracer dye) in nanoemulgel and nanoemulsion

to observe the penetration of drug through skin by using Fluorescence Correlation
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Microscope [127]. Low viscosity of nanoemulgel and nanoemulsion of amphotericin B

resulted in slow release/sustained release in initial hours compare to the solution. Further,
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sustained release pattern of nanoformulation follow zero order kinetics whereas release of
drug from solution follows first order kinetics. Interestingly cumulative drug permeation of
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nanoemulgel is higher compare to nanoemulsion and conventional gel. It will be very

commendable that combination of transcutol-P and tween 80 have synergistic effect on
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improvement of drug permeation through skin, even to the high molecular weight drugs.
Finally, pharmacodynamic efficacy of the formulation was established by in vitro antifungal
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activity, thus the safety pattern revealed its effectiveness over oral delivery of amphotericin B
[127].

Arora and team had formulated a novel nanoemulsion with ketoprofen using low
energy method where carbomer 940 was used to convert nanoemulsion to nanoemulgel. The
group selected the excipients based on solubility studies, transmittance and further
formulation was optimized based on thermodynamic stability, drug content, spreadability,
rheological properties, ex vivo drug permeation study and sustainability studies at stress

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conditions. Nanoemulgel was surprisingly found to significant higher permeation and flux
with lower lag time than the marketed formulation and solution [54] which further inspire
the researcher to work on nanoemulgel to ensure the commercialization of nanoemulgel. It is
interesting to mention that the concentration of surfactant-co-surfactant is inversely
proportional to the penetrability. In this experimentation, the researchers mentioned that upon
reduction of surfactant-co-surfactant concentration from 75% to less than half (35%), the

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penetration rate was doubled. This statement was also supported by another team of
researchers [106]. Researchers further commented that salvation of α-keratin layer of the skin

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and formation of hydrogen bonding property of transcutol P could further help in penetration
of the drug through the intact skin [54,104]. Study of stratifin and acetylsalicylic acid loaded

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nanoemulgel showed a sustained release profile of the drugs which dramatically improve the
wound healing on rabbit ear with a daily basis dressing. With this decreased number of
application of this formulation over the wound bed, it was found to reduce epidermal

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hypertrophy better than the CMC gel of the drugs and a significant reduction in both collagen
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density and tissue cellularity [45].

Low energy method was employed by Yang and group for the preparation of
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microemulgel of diclofenac sodium using chitosan and cationic polymer polylysine. On

evaluating it was found that the skin permeation rate of the drug from the optimized
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formulation was 1.86- and 5.76- folds higher, respectively than that of the commercial
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emulgel and hydrogel formulation of the same drug. Interestingly, self-preserving activity of
the reported micro-emulgel was an immense observation by the authors when used polylysine
in the formulation [128].
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Delivery of nanoemulgel is not only limited to the transdermal application, it has

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gained interest by the researchers towards application in periodontitis disease, ocular

delivery, cosmetology, vaginal infection etc. Srivastava et al. [43] had developed
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nanoemulgel of a non-steroidal anti-inflammatory agent (NSAID), ketoprofen, for

periodontics disease where they used eugenol as an oil and Carbopol 934P and Polaxamer
407 as gelling agents. They observed that high concentration of polaxamer 407 results in
slower burst release of drug from nanoemulgel. On evaluation of the pharmacodynamic
efficacy in periodontitis, it was observed that ketoprofen nanoemulgel significantly reduced
gingival index, tooth mobility, alveolar bone loss [70]. Pharmacodynamic activity was
reflected by the decreased levels of cytokine close to the normal in ketoprofen nanoemulgel

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treated group. Additionally, significant reduction in inflammatory cell infiltration, alveolar
bones resorption and cementum were evident from the histopathological analysis of the
experimental molar teeth as observed with ketoprofen nanoemulgel treated group. Eugenol
oil used in formulation development has shown synergistic effect to ketoprofen in the control
of periodontitis [70].

For the remedial action on arthritic disorder, Jeenger et al. recently reported the

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development of Curcumin nanoemulsion formulated with emu oil. This delivery of Curcumin
loaded nanoemulsion loaded in carbopol gel was found to solve the poor penetration and low

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solubility characteristics of curcumin. In the experimental model of adjuvant induced
arthritis, it was observed that the destruction of bone was significantly reduced as evidenced

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by the decrease in radiological scoring through application of low and high dose curcumin
nanoemulsion loaded gel (Figure 5). The findings were further proved through inhibition of

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cartilage damage, decrease in cellular infiltration in synovial cavity, prevention of damage
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and narrowing of synovial space, and pannus formation. Figure 6 represents the
histopathological diagram on improvement of arthritic condition in the experimentally
induced arthritic rats [59].
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Nanoemulgel is also considered to be a promising alternative drug delivery to the

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conventional eye drops. Due to gel like droplet of nanoemulgel formulation, sufficient drug
quantity can be incorporated and delivered to the cornea and the aqueous humor parts of the
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eye. Tayel and team had developed a controlled release ocular nanoemulgel of terbinafine, an
allylamine antifungal compound, where the researchers used Miglyol 812 as oil phase and
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Cremophor EL, PEG 400 and gellan gum as surfactant, co-surfactant and gelling agent,
respectively [44]. Aqueous solution of gellan gum was heated to 50°C and 0.5% drug loaded
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nanoemulgel was prepared by mixing optimized nanoemulsion formulation to the gellan gum
solution. Special property of gellan gum attracted its use in ocular nanoemulgel delivery.
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Gellan gum cross links with the tear fluid electrolytes and proteins allowing in-situ gelation,
as assessed by using simulated tear fluid, thereby provides a prolonged release. The
optimized nanoemulgel was sterilized by using gamma radiation in presence of dry ice [44].
Pharmacokinetic findings in rabbit plasma revealed significantly higher Cmax, delayed Tmax,
prolonged mean residence time and increased bioavailability profile of the drug.
Interestingly, the ocular irritation potential of the drug in nanoemulgel was found to be very
less [44,79]. Pathak and his coworkers also developed an ocular nanoemulgel formulation of

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fluconazole, a triazole antifungal agent, using capmul MCM as oil phase, emulsified with
tween 80 and transcutol P and gelled with carbopol 934. The in vitro antifungal activity of the
nanoemulgel formulation showed to have higher antifungal activity as compared to the
fluconazole solution. Additionally, a 3.71 folds higher cumulative amount of fluconazole
permeation was observed from nanoemulgel formulation compared to commercial eye drop
preparation [69]. A higher rate of cumulative drug permeation has also been reported from

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diclofenac diethylamine nonoemulgel formulation when formulated with oleic acid as oil
base, Polysorbate 20 and ethanol as surfactants and carbopol 971 as gelling agent [129].

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Incorporation of nanotechnology is common in cosmetology. Harwansh et al.
developed a nanoemulgel with ferulic acid, a strong UV absorber that prevents UV induced

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skin damage, by dispersing the pre-soaked gelling agent (carbopol 940) in distilled water into
the optimized nanoemulsion which was developed by adopting low pressure method [40]. In

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order to obtain a homogeneous dispersion of gel, the researchers incorporated components
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like polyethylene glycol 400, propylene glycol, isopropyl alcohol and triethanolamine into
the nanoemulgel. In vitro permeability of the formulated nanoemulgel was found to be
directly comparable to the droplet size in the formulations. Further, the improved
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permeability and controlled release property was found to be effective against UV exposure
even after 4 h of application to the skin surface [40]. Introduction of nanotechnology through
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adaptation of nanoemulgel approach for vaginal, dental, ocular and transangual application
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has been summarized in Table 2.

5. Concluding remark and future prospect:

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Nanoemulgel contains various constituents and the nature of selection along with
determination of desired concentration of such components requires a skilled knowledge
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because the properties of these are varying from components to components, whether it is
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surfactant, co-surfactant, oil and/or gelling agent. Further, different manufacturing

methodologies have distinct advantages which affect the characteristics of the final
formulation. Thus, development of a thermodynamically stable nanoemulsion and
nanoemulsion to nanoemulgel is solely depending on suitable selection of its components and
the primary methodology. Formulating hydrogel thickened nanoemulgel from nanoemulsion
has found to be better compatible and efficient than the ordinary nanoemulsions for
transdermal delivery. This viscous formulation could be more thermodynamically stable than
nanoemulsion due to reduction of interfacial tension and decreased mobility of the dispersed

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phase, thus could result in better and successful topical delivery system of pharmaceutical
agents, particularly for lipophilic drug molecules with the aim of enhanced skin permeation
across the deeper layer of the skin due to improved contact time, formation of thin layer over
the skin and by hydrating the skin. Marketed formulations for this nanoemulgels are pointing
towards potential improvement in therapeutic aspects and research interest of this novel
dosage forms.

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Successful incorporation of nanoemulsion in hydrogel with improved therapeutic
response in various pathophysiological condition suggesting a significant progress of

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formulation scientists in pharmaceutical industry. Nevertheless, it creates a center of attention
for user acceptability due to the non-greasy-gel like sustained release property following

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topical administration. Incorporation of active components against bacterial, fungal, viral
infections or even for melanoma can be extrapolated successfully through development of

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nanoemulgel, however more molecular assessment on absorption process of the drugs should
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be necessary. Therefore, this novel transdermal dosage form is open for research to target
specific dermatological disorders as well as in the improvement of various systemic ailments.
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Figure captions:

Figure 1: Possible strategies to improve bioavailability of poorly water soluble drugs.

Figure 2: Strategies for oil phase selection in the course of nanoemulgel formulation
development.
Figure 3: Schematic representation of nanoemulgel preparation: Step 1 - Preparation of
nanoemulsion; Step 2 - Conversion of nanoemulsion to nanoemulgel.
Figure 4: Histopathological sections of rat abdominal skin (magnification 40x) (a) negative

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control, untreated skin, (b) positive control, skin treated with nitric acid (37% v/v) for 2 h, and
(c) test specimen, skin treated with leflunomide nanoemulgel for 12 h. [33].
Figure 5: (A) Radiological scoring of adjuvant arthritic and treated rats. All the values are

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expressed as mean ±SEM (n = 6).***P < 0.001and *p < 0.05 vs. Adjuvant induced arthritis
(AIA); control; %%%p< 0.001, %%p < 0.01 vs. standard (STD; indomethacin) group; ###p <

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0.001, ##p < 0.01 vs. BF. (B) Radiographic changes in ankle joints; normal, no evidence of
pathological changes was observed in normal animals, AIA control group showing severe
inflammation with diffused joint space, cartilage destruction and bone deformity along with

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bone erosion; STD, Clear joint space and no evidence of inflammation and bone loss in
standard diclofenac treated group; BF, blank nano emulsion loaded gel treated group also
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showed severe inflammation and bone loss moderate deformity; CFL, curcumin
nanoemulsion loaded gel (low dose) and CFH, curcumin nano emulsion loaded gel (high
dose) both groups showed recovery and was similar to standard group. S, soft tissue swelling;
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D, deformity; E, erosion [59].

Figure 6: Effect of treatment of diclofenac gel and curcumin nano emulsion loaded gel on
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tibiotarsal joint histology in different groups of rats. Sections were cut sagittally,stained with
hematoxylin/eosin and photographed at magnification of 100x. Ti, tibia; Ta, talus; SS,
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synovial space; C, cartilage; ST, synovial tissue; CI, cellular infiltrate [59].
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Table captions:

Table 1: Summary of reported transdermal nanoemulgels for its components, formulation

droplet size and overview of reported pharmacological properties with rationalisation in the
findings.
Table 2: Summary of reported vaginal, dental, ocular and transangual nanoemulgels for its
components, formulation droplet size and overview of reported pharmacological properties
with rationalisation in the findings.

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Table 1

Drug Oil Surfactant Gelling Droplet Safety Efficacy Skin permeation Remarks Ref.
Co surfactant agent size

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Curcumin Emu oil Cremophor carbopol 62.06 ± - significant Increased permeation, anti- [59]
RH40 and gel 0.52 nm improvement in inflammatory, analgesic
Labrafil antiinflammatory activity is due to nano

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M2125CS activity droplet and presence of
emu oil in nanoemulgel.
oil:surfactant:cos

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urfatant:: 2:5:3
Ketoprofen Oleic acid Tween 80 Carbomer 55.40 ± - - The nanoemulgel had Oleic acid, Transcutol P [54]
( 6% w/w) Transcutol P 940 0.58 nm higher flux, high was reported as

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(35% w/w) permeation potential, permeation enhancer.
lower local (Note: with very high

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accumulation concentration of oleic acid:
efficiency compared to permeation decrease due to
solution and marketed aggregation of oil)

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formulation.
Capsaicin Glycerol Poloxamer 407 Carbopol 170.30± Produce no Not reported Capsaicin Shear rate had a positive [130]
monooleate and Glycerol 940 7.81 nm observable skin Permeability in correlation with

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irritation in nanoemulgel was 2.80- entrapment efficiency and
rabbits within fold greater flux values a negative correlation with

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72h. than conventional particle size and
ointment after 24 h. polydispersity index.
Ferulic acid Isostearyl Labrasol, Carbopol 105 ± 0.14 The nano-gel Sustained release The nanogel Drug loaded nanogel [40]
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isostearate and plurol 940 nm was found to be effect against UV formulation exhibited exhibited better UV
isostearique stable, safe and A exposure with better permeation protection activity even
effective for enhanced UV profile (96.95%) in after 4 h of application to
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topical protection comparison with the skin surface due to its

application activity. conventional gel (61%) improved permeability and
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against UV. at sustained-release profile.

24h.

Lornoxicam Labrafac Tween 80 and Carbopol 102 to 200 - The formulation The steady-state flux Composition like tween 80 [76]
Pluronic F68 934 nm found to be and permeability and labrafac also act as a
superior to the coefficient permeationenhancer
marketed product were significantly through skin.
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Drug Oil Surfactant Gelling Droplet Safety Efficacy Skin permeation Remarks Ref.
Co surfactant agent size
in its ability to increased in
suppress paw nanoemulsions gel
edema. formulation as

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compared with normal
gel.
Amphotericin Sefsol-218 Tween 80 and Carbopol- 76.2±1.4 No severe In vivo The flux rate of Significant [127]

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B Transcutol-P 980 nm irritation histopathological nonoemulgel found to enhancement of the
symptoms such examination be 3.9- 3.5 fold higher permeation was achieved

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as erythema and suggested that the with respect to the by the use of
edema observed formulation is solution. 5% DMSO.
to the rat skin. more efficacious
than oral delivery

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for cutaneous

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infection.
Meloxicam Cetyl Tween 80 and Carbopol 239.33 ± Solid lipid Effectively Meloxicam deposited [32]
palmitate Propylene glycol 940 0.88 nm nanoparticle gel suppressed in varying amount at
did not result in carrageenan different layer of the

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any marked induced paw skin.
changes in edema and Epidermis> Dermis>

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normal histology sustained activity Subcutaneous layer
and no was observed

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inflammation in with solid lipid
skin nanoparticle gel
Nystatin Labrafil M Tween 80 and Methyl - Clinical trial Showed to have - In a clinical trial study, [123]
ethanol cellulose showed the significantly nanoemulgel of nystatin
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nanoemulgel higher rates of has been proved a
was more mycological cure. promising drug delivery
efficacious and against cutaneous
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better tolerated candidiasis.

than
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commercially
available cream
for the treatment
of cutaneous
candidiasis.
Itraconazole Eugenol Lecithine and Carbopol 154.3 to Non-irritant to - Compared to solution, [124]
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Drug Oil Surfactant Gelling Droplet Safety Efficacy Skin permeation Remarks Ref.
Co surfactant agent size
sodium cholate 934 223.9 nm skin of the skin permeation and
experimental rat penetration ability was
and safe to be more pronounced with

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applied for the nanoemulgel.
intended period
of time.

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Leflunomide Capryol 90 Cremophor EL Pluronic 98.7– No hemolytic Cytotoxicity Ex vivo studies Leflunimide nanoemulgel [33]
and Transcutol F127 280.92 nm and local tissue studies showed demonstrated that showed effective

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HP toxicity was enhanced nanoemulsification localization which may
observed. therapeutic significantly promoted result in dose reduction
response against the transcutaneous and reduction in systemic
psoriasis and penetration and skin toxicity.

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melanoma . deposition of the drug.

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Swietenia Swietenia sucrose laureate Carbopol 113 to 117 - Significant anti- The group proved that [71]
macrophylla macrophylla (20%), glycerol 940 nm inflammatory carbopol 940 is superior
oil oil (50%) (30%) activity was than carbopol 934 as a
observed in viscosity modifier for

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nanoemulgel nanoemulgel formulation.
treated group in

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carrageenan
induced paw

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edema model.
Diclofenac Oleic acid Polysorbate 20 Carbopol 59.97±3.22 - - The cumulative amount [129]
diethylamine and ethanol 971P nm of drug permeation was
higher in nonoemulgel.
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Table 2

Drug Oil Surfactant Gelling Droplet Safety Efficacy Skin permeation Remarks Ref.
Co surfactant agent size

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Vaginal nanoemulgel
Itraconazole Tea tree oil Tween 20 and Carbopol Average The optimized The dual loading In spite of similar Despite being low [42]
Labrasol 934 diameter gel was also of Itraconazole polymer content, a higher solubility of Itraconazole

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42.13 nm found without and tea tree oil in flux was obtained with in tea tree oil, a
any sign of a single nanoemulgel formulation homogeneou, transparent
toxicity. formulation than the conventional and stable solution of both

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showed to be gel. was created by co-
more effective as solvency using
antimicrobials. chloroform.

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Dental nanoemulgel
Ketoprofen Eugenol Cremophore EL Carbopol 37.230 ± Not irraitant to Suitable Box–Behnken [43,

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(13%) and Transcutol 934P 0.210 nm mucous formulation for experimental design (3- 70]
HP (37%) and membrane periodontal factor 3-level) was used
Polaxamer (evaluated disease in respect for the optimization of

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407 invitro using of syringibility, nanoemulsion. Due to
HET-CAM mucoadhesivity antibacterial, analgesic
method): and rheology. and anesthetic properties

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Suitable for of eugenol, synergistic
intrapocket Nanoemulgel potential of ketoprofen

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delivery. significantly and eugenol was observed
prevent in periodontitis
periodontitis by
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preventing like
gingival index,
tooth mobility,
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alveolar bone
loss.
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Ocular nanoemulgel
Terbinafine Miglyol 812 Cremophor EL: Gellan gum Less than Showed no Nonoemulgel showed the [44]
hydrochloride and PEG 400 30 nm histopathological least ocular irritation
alteration in the potential and significantly
cornea, iris, higher Cmax, delayed Tmax,
retina or sclera prolonged mean residence
in rabbit. time and increased
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Drug Oil Surfactant Gelling Droplet Safety Efficacy Skin permeation Remarks Ref.
Co surfactant agent size
bioavailability
Fluconazole Capmul Tween 80 and Carbopol 19.09 ± Ex-vivo corneal In-vitro anti- A 3.71 folds higher The droplet size decreased [69]

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MCM Transcutol P 934 1.93 nm toxicity study fungal activity cumulative amount of with increasing surfactant
demonstrated showed to have fluconazole permeation to cosurfactant ratio.
ocular safety of better antifungal was observed from
the formulation. activity of the nanoemulgel compared

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nanoemulgel to commercial eye drop.
compared to the

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solution.
Transangual
Ketoconazole Labrafac™ Tween 80 Carbopol® 77.52 ± After 48 hour of Exvivo trasungual Nanoemulgel could be a [77]

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Lipophile and PEG 400 Ultrez 21 0.92 nm incubation permeation study was better choice for the
WL1349 showed a carried out using goat treatment of

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significant area of hoof membrane. onychomycosis
zone of inhibition Improved permeation for
for T. rubrum and nanomulsion and
C. albicans) due nanoemulgel was

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to slow diffusion observed in compare to
of nano droplet aqueous suspension of

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into the medium ketoconazole.
although duiing

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first 24 hour
nanoemulgel
exhibited similar
activity
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like drug solution
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