Accepted Manuscript

Recent update on nanoemulgel as topical drug delivery system

Hira Choudhury, Bapi Gorain, Manisha Pandey, Lipika Alok Chatterjee, PinakiSengupta, 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 ofPharmaceutical Sciences (2017), doi: 10.1016/j.xphs.2017.03.042.

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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*

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

b Faculty of Pharmacy, Lincoln University College, Kuala Lumpur, Malaysia c Kulliyyah of Pharmacy, International Islamic University of Malaysia, Pahang, Malaysia d Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, UP, 226031

India

*Author for correspondence: Dr. Prashant Kesharwani Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, UP, 226031 India Email: prashantdops@gmail.com Prashant_pharmacy04@rediffmail.com Tel./Fax: +91-7582-244432

Dr. Bapi Gorain Lincoln University College 47301 Petaling Jaya, Kuala Lumpur MALAYSIA Email: bapi@lincoln.edu.my bapi.gn@gmail.com 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

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

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

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

and can avoid first pass metabolism and relieve the user from gastric/systemic

incompatibilities. This brief review is focused on nanoemulgel as a better topical drug

delivery system including its components screening, formulation method and recent

pharmacokinetic and pharmacodynamic advancement in research studies carried out by the

scientists all over the world. Therefore, at the end of this survey it could be inferred that

nanoemulgel can be a better and effective drug delivery tool for the topical system.

Keywords: Nanoemulgel; Nanoemulsion; Transdermal drug delivery; Pharmacokinetic

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

dependent on the physicochemical characteristics of the active compound. Recent trend of

synthesis drug development or during high throughput screening leads towards development

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

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

those issues to focus on solubility enhancement, formulation approach is a continuous

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

poorly aqueous soluble drugs such as particle size reduction to deliver through nanocarrier

system, crystal engineering, amorphous formulation [11–15], several lipid formulations

approaches [16], etc. Newer lipid formulation techniques, viz: incorporation of lipophilic

component in inert lipid vehicle [17,18], formation of microemulsion or nanoemulsions [19],

self-emulsifying formulations, liposomes, solid lipid nanoparticles or lipid nanocarriers [20–

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

of disease, patients’ age and condition, available dosage form and finally for the compliance

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,

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

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,

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,

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

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

[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

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

solubilization capacity than simple micellar solutions, and their thermodynamic stability

offers advantages over unstable dispersions, such as emulsions and suspensions, because they

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

its low viscosity and spreadibility [32]. Researchers have solved the problems associated with

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

outcomes in the field of pharmaceutical formulation development, study on nanoemulgel

focuses on development of vast number of delivery system viz: transdermal, dental, vaginal,

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

formulation overview and penetration aspects of emulgel [46], characterization of the

nanoemulgel [47], current market products on nanoemulgels and its advantages [48] and

delivery of antifungal agents through nanoemulgel delivery [27]. Present article is an

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,

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

pharmacokinetics, pharmacodynamics, and safety of the drug. Connecting section of the

article will reveal the components and selection criteria for the achievement of targeted

objective.

2. Formulation components consideration

Either of o/w or w/o nanoemulsion is composed of an oil phase and aqueous phase,

where the tiny dispersed phase is enervated by a thin layer of surfactant, which sometimes

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

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

represented in Figure 2.

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

formulation not only due to its high solubilization properties, but also for its well-known

percutaneous absorption enhancer property [53] and formulation stabilization property

[54,55]. Additionally, reach antioxidants in oleic acid known to strengthen the cell membrane

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

that there is improved permeation rate with increased percentage of oleic acid in the

formulation. Further, enhancement of ketoprofen permeability was observed [54] by

increasing oleic acid from 3% to 6%. On analyzing, it has been observed that lipid

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

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

permeated through stratum corneum [58].

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

fatty acid with major percentage of oleic acid [62,63] further helps in penetration

enhancement of drug through skin.

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

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

synergistic effect against vaginal candidiasis [42]. Drug loading in tea tree oil was improved

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].

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,

1,8-cineole, a component of tea tree oil has known to cause skin irritation, provided its

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

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

nanoemulgel) [42]. Another nanoemulgel of synthetic trizole antifungal drug, fluconazole,

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

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

nanoemulgel formulation compared to its parent form [71].

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

are frequently used as an oil phase in formulation development to deliver poorly water

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

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

to target improvement of their pharmacokinetic/pharmacodynamic properties [33,73].

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

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

used in pharmaceutical research. It has HLB value of 5 to 6, therefore, reported to have good

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

2.2.1. Surfactant

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

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

loading capacity along with good emulsification properties are the basic requirements for the

surfactants integrated in nanoemulsion development, [51]. A suitable surfactant used in

nanoemulsion formulation should be adsorbed rapidly onto the interface of the two

immiscible phases leading to dramatically reduction of interfacial tension and prevents

coalescence of the nano droplets [80].

Due to the presence of ionic nature, these stabilizing systems are classified into the

following categories: cationic surfactant (amines and quaternary ammonium compounds,

cetyl trimethyl ammonium bromide, lecithin, hexadecyl trimethyl ammonium bromide,

dodecyl dimethyl ammonium bromide, etc.), anionic surfactant (containing carboxylate

group, sodium bis-2-ethylhexylsulfosuccinate, sodium dodecyl sulfate), zwitterionic

surfactant (phospholipid), and non-ionic surfactant (Capryol 90, Labrafil CS, Labrasol,

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

188, Softigen 701, 767, Tween 20, Tween 60, and Tween 80, etc). Their working mechanism

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

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

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-

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

authors affirmed that surfactant mixtures could provide more stable emulsions with the

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].

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

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

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].

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.

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

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

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

long fatty chain (C8–C18) in order to prepare stable and low viscous o/w emulsions of a

Mexican heavy crude oil [100].

2.2.2. Co-surfactant

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

phase. In such system, co-surfactant combines with surfactant and penetrates into the

surfactant layer, thereby disrupts the interfacial film, and confers required fluidity, lower the

interfacial tension, and help emulsification process [72]. Usually transient negative interfacial

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

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

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,

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

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

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

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].

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

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

co-surfactant is absent (1:0) or present at lower concentrations, the surfactant is not able to

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,

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.

who also reported that location of nanoemulsion area in phase diagram changed with

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

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,

however, higher concentration of surfactant has also been reported to cause skin irritation

[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-

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

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

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

HLB values solubilize in the aqueous phase, whereas lower HLB values solubilize in oil that

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.

Thus, it has been observed that selection of ideal components for a nanoemulsion is a

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

use of diverse hydrogels to change the physical status of the formulated nanoemulsion.

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

will be manufactured whereas nanoemulsion will be introduced in the gelling agent during

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

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

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].

Low Energy Emulsification Method

Low-energy method for preparation of nanoemulsions include spontaneous method and phase

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

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

aqueous phase with or without surfactant in the oil phase without or with surfactant,

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

incorporated surfactant and co-surfactant affect the emulsification process [19]. Specifically,

temperature dependent change in HLB for certain non-ionic surfactants, mostly poly-

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

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

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

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

[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

pharmacokinetic properties of the drug incorporated into this nanocarrier system. Gelling

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

continuous mixing for homogeneity [59]. Impact of nanoemulgel development in the

pharmacokinetic and pharmacodynamic properties of the drug has been summarized in the

following section of the article.

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

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

choice for the incorporated drug as well as estimation of entrapment of the pharmaceutical

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

drug release behavior of nanoemulgel. Hence pharmacodynamic study revealed that both

nanoemulsion and nanoemulgel remained superior to the marketed product in its ability to

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

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].

Study by Pund et al. disclosed nanoemulgel as potential carrier for the treatment of

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

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

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

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),

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

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

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

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

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

they developed the nanoemulsion by ultrasonication after dissolving the drug in eugenol by

heating with lecithine and sodium cholate as surfactants. Optimized nanoemulsion was

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

as well as odor masking agent. Nanoemulsion based hydrogel of itraconazole showed

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

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

in spite of similar polymer content, a higher flux and improved permeability of the drug can

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].

Eid and team had developed a nanoemulsion formulation of Swietenia macrophylla

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

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

antifungal activity as well as to avoid serious systemic complications of the drug. The

researchers developed the nanoemulgel of amphotericin B by incorporating formulated

nanoemulsion to the dispersed polymeric gelling agent (carbopol-980) followed by vigorous

homogenization. In the optimization of nanoemulsion sefsol 218 and dimethyl sulfoxide in

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

were satisfactory and further skin irritation test in Wistar albino rats did not result in

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

performed by incorporating Rhodamine 123 (a tracer dye) in nanoemulgel and nanoemulsion

to observe the penetration of drug through skin by using Fluorescence Correlation

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,

sustained release pattern of nanoformulation follow zero order kinetics whereas release of

drug from solution follows first order kinetics. Interestingly cumulative drug permeation of

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

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

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

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

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

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

hypertrophy better than the CMC gel of the drugs and a significant reduction in both collagen

density and tissue cellularity [45].

Low energy method was employed by Yang and group for the preparation of

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

formulation was 1.86- and 5.76- folds higher, respectively than that of the commercial

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].

Delivery of nanoemulgel is not only limited to the transdermal application, it has

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

delivery, cosmetology, vaginal infection etc. Srivastava et al. [43] had developed

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

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

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

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

cartilage damage, decrease in cellular infiltration in synovial cavity, prevention of damage

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].

Nanoemulgel is also considered to be a promising alternative drug delivery to the

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

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

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

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.

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

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].

Incorporation of nanotechnology is common in cosmetology. Harwansh et al.

developed a nanoemulgel with ferulic acid, a strong UV absorber that prevents UV induced

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

order to obtain a homogeneous dispersion of gel, the researchers incorporated components

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

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

adaptation of nanoemulgel approach for vaginal, dental, ocular and transangual application

has been summarized in Table 2.

5. Concluding remark and future prospect:

Nanoemulgel contains various constituents and the nature of selection along with

determination of desired concentration of such components requires a skilled knowledge

because the properties of these are varying from components to components, whether it is

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.

Successful incorporation of nanoemulsion in hydrogel with improved therapeutic

response in various pathophysiological condition suggesting a significant progress of

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

topical administration. Incorporation of active components against bacterial, fungal, viral

infections or even for melanoma can be extrapolated successfully through development of

nanoemulgel, however more molecular assessment on absorption process of the drugs should

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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[130] M.L. Tang, L.H. Chen, D.S. Zhou, W.F. Zhu, Y.M. Guan, J.S. Li, Optimized Preparation of Capsaicin-Loaded Nanoparticles Gel by Box-Behnken Design, Adv. Mater. Res. 1061–1062 (2014) 359–368. doi:10.4028/www.scientific.net/AMR.1061-1062.359.

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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 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 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 < 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 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 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; D, deformity; E, erosion [59]. Figure 6: Effect of treatment of diclofenac gel and curcumin nano emulsion loaded gel on 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, 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 Co surfactant

Gelling agent

Droplet size

Safety Efficacy Skin permeation Remarks Ref.

Curcumin Emu oil Cremophor RH40 and Labrafil M2125CS oil:surfactant:cosurfatant:: 2:5:3

carbopol gel

62.06 ± 0.52 nm

- significant improvement in antiinflammatory activity

Increased permeation, anti-inflammatory, analgesic activity is due to nano droplet and presence of emu oil in nanoemulgel.

[59]

Ketoprofen Oleic acid ( 6% w/w)

Tween 80 Transcutol P (35% w/w)

Carbomer 940

55.40 ± 0.58 nm

- - The nanoemulgel had higher flux, high permeation potential, lower local accumulation efficiency compared to solution and marketed formulation.

Oleic acid, Transcutol P was reported as permeation enhancer. (Note: with very high concentration of oleic acid: permeation decrease due to aggregation of oil)

[54]

Capsaicin Glycerol monooleate

Poloxamer 407 and Glycerol

Carbopol 940

170.30± 7.81 nm

Produce no observable skin irritation in rabbits within 72h.

Not reported Capsaicin Permeability in nanoemulgel was 2.80-fold greater flux values than conventional ointment after 24 h.

Shear rate had a positive correlation with entrapment efficiency and a negative correlation with particle size and polydispersity index.

[130]

Ferulic acid Isostearyl isostearate

Labrasol, and plurol isostearique

Carbopol 940

105 ± 0.14 nm

The nano-gel was found to be stable, safe and effective for topical application against UV.

Sustained release effect against UV A exposure with enhanced UV protection activity.

The nanogel formulation exhibited better permeation profile (96.95%) in comparison with conventional gel (61%) at 24h.

Drug loaded nanogel exhibited better UV protection activity even after 4 h of application to the skin surface due to its improved permeability and sustained-release profile.

[40]

Lornoxicam Labrafac Tween 80 and Pluronic F68

Carbopol 934

102 to 200 nm

- The formulation found to be superior to the marketed product

The steady-state flux and permeability coefficient were significantly

Composition like tween 80 and labrafac also act as a permeationenhancer through skin.

[76]

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Drug Oil Surfactant Co surfactant

Gelling agent

Droplet size

Safety Efficacy Skin permeation Remarks Ref.

in its ability to suppress paw edema.

increased in nanoemulsions gel formulation as compared with normal gel.

Amphotericin B

Sefsol-218 Tween 80 and Transcutol-P

Carbopol-980

76.2±1.4 nm

No severe irritation symptoms such as erythema and edema observed to the rat skin.

In vivo histopathological examination suggested that the formulation is more efficacious than oral delivery for cutaneous infection.

The flux rate of nonoemulgel found to be 3.9- 3.5 fold higher with respect to the solution.

Significant enhancement of the permeation was achieved by the use of 5% DMSO.

[127]

Meloxicam Cetyl palmitate

Tween 80 and Propylene glycol

Carbopol 940

239.33 ± 0.88 nm

Solid lipid nanoparticle gel did not result in any marked changes in normal histology and no inflammation in skin

Effectively suppressed carrageenan induced paw edema and sustained activity was observed with solid lipid nanoparticle gel

Meloxicam deposited in varying amount at different layer of the skin. Epidermis> Dermis> Subcutaneous layer

[32]

Nystatin Labrafil M Tween 80 and ethanol

Methyl cellulose

- Clinical trial showed the nanoemulgel was more efficacious and better tolerated than commercially available cream for the treatment of cutaneous candidiasis.

Showed to have significantly higher rates of mycological cure.

- In a clinical trial study, nanoemulgel of nystatin has been proved a promising drug delivery against cutaneous candidiasis.

[123]

Itraconazole Eugenol Lecithine and Carbopol 154.3 to Non-irritant to - Compared to solution, [124]

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Drug Oil Surfactant Co surfactant

Gelling agent

Droplet size

Safety Efficacy Skin permeation Remarks Ref.

sodium cholate 934 223.9 nm skin of experimental rat and safe to be applied for the intended period of time.

the skin permeation and penetration ability was more pronounced with nanoemulgel.

Leflunomide Capryol 90 Cremophor EL and Transcutol HP

Pluronic F127

98.7–280.92 nm

No hemolytic and local tissue toxicity was observed.

Cytotoxicity studies showed enhanced therapeutic response against psoriasis and melanoma .

Ex vivo studies demonstrated that nanoemulsification significantly promoted the transcutaneous penetration and skin deposition of the drug.

Leflunimide nanoemulgel showed effective localization which may result in dose reduction and reduction in systemic toxicity.

[33]

Swietenia macrophylla oil

Swietenia macrophylla oil (50%)

sucrose laureate (20%), glycerol (30%)

Carbopol 940

113 to 117 nm

- Significant anti-inflammatory activity was observed in nanoemulgel treated group in carrageenan induced paw edema model.

The group proved that carbopol 940 is superior than carbopol 934 as a viscosity modifier for nanoemulgel formulation.

[71]

Diclofenac diethylamine

Oleic acid Polysorbate 20 and ethanol

Carbopol 971P

59.97±3.22 nm

- - The cumulative amount of drug permeation was higher in nonoemulgel.

[129]

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Table 2

Drug Oil Surfactant Co surfactant

Gelling agent

Droplet size

Safety Efficacy Skin permeation Remarks Ref.

Vaginal nanoemulgel Itraconazole Tea tree oil Tween 20 and

Labrasol Carbopol 934

Average diameter 42.13 nm

The optimized gel was also found without any sign of toxicity.

The dual loading of Itraconazole and tea tree oil in a single formulation showed to be more effective as antimicrobials.

In spite of similar polymer content, a higher flux was obtained with nanoemulgel formulation than the conventional gel.

Despite being low solubility of Itraconazole in tea tree oil, a homogeneou, transparent and stable solution of both was created by co-solvency using chloroform.

[42]

Dental nanoemulgel Ketoprofen Eugenol

(13%) Cremophore EL and Transcutol HP (37%)

Carbopol 934P and Polaxamer 407

37.230 ± 0.210 nm

Not irraitant to mucous membrane (evaluated invitro using HET-CAM method): Suitable for intrapocket delivery.

Suitable formulation for periodontal disease in respect of syringibility, mucoadhesivity and rheology. Nanoemulgel significantly prevent periodontitis by preventing like gingival index, tooth mobility, alveolar bone loss.

Box–Behnken experimental design (3-factor 3-level) was used for the optimization of nanoemulsion. Due to antibacterial, analgesic and anesthetic properties of eugenol, synergistic potential of ketoprofen and eugenol was observed in periodontitis

[43,70]

Ocular nanoemulgel Terbinafine hydrochloride

Miglyol 812 Cremophor EL: and PEG 400

Gellan gum Less than 30 nm

Showed no histopathological alteration in the cornea, iris, retina or sclera in rabbit.

Nonoemulgel showed the least ocular irritation potential and significantly higher Cmax, delayed Tmax, prolonged mean residence time and increased

[44]

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Drug Oil Surfactant Co surfactant

Gelling agent

Droplet size

Safety Efficacy Skin permeation Remarks Ref.

bioavailability Fluconazole Capmul

MCM Tween 80 and Transcutol P

Carbopol 934

19.09 ± 1.93 nm

Ex-vivo corneal toxicity study demonstrated ocular safety of the formulation.

In-vitro anti-fungal activity showed to have better antifungal activity of the nanoemulgel compared to the solution.

A 3.71 folds higher cumulative amount of fluconazole permeation was observed from nanoemulgel compared to commercial eye drop.

The droplet size decreased with increasing surfactant to cosurfactant ratio.

[69]

Transangual Ketoconazole Labrafac™

Lipophile WL1349

Tween 80 and PEG 400

Carbopol® Ultrez 21

77.52 ± 0.92 nm

After 48 hour of incubation showed a significant area of zone of inhibition for T. rubrum and C. albicans) due to slow diffusion of nano droplet into the medium although duiing first 24 hour nanoemulgel exhibited similar activity like drug solution

Exvivo trasungual permeation study was carried out using goat hoof membrane. Improved permeation for nanomulsion and nanoemulgel was observed in compare to aqueous suspension of ketoconazole.

Nanoemulgel could be a better choice for the treatment of onychomycosis

[77]

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