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\def\RunningAuthor{Ramesh K. et al.}
\firstPage{859}
\articleType{Original Article}
\receivedDate{09 Nov 2020}
\acceptedDate{20 Dec 2020}
\revisedDate{14 Dec 2020}
\journalVolume{2020, 11 (SPL4)}
\journalDoi{ijrps.v11iSPL4.4086}
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\title{\textbf{Recent Analysis on new Nanoemulgel Transdermal Drug Delivery System use for Skin Disease Treatment}}
\author{Ramesh~K.\textsuperscript{*}\textsuperscript{1},  
            Venkateswara~Rao~J.\textsuperscript{2},  
            Srinivasan~M.K.\textsuperscript{3}, 
            Sravanathi~P.\textsuperscript{3}~\\[5pt]{\textsuperscript{1}Department of DVL, Konaseema Institute of Medical Sciences Research Foundation, Amalapuram, Andhra Pradesh, India}~\\{\textsuperscript{2}Department of OBG, Konaseema Institute of Medical Sciences Research Foundation, Amalapuram, Andhra Pradesh, India}~\\{\textsuperscript{3}Department of ENT, Meenakshi Academy of Higher Education and Research, Chennai, Tamilnadu, India}}

\begin{abstract}
Nanoemulsions have the potential in medical industries due to transparency at high droplet volume division, higher bio availability rate and expanded shelf life of drugs. The ``Nano emulsion-based gel" is a very interesting transdermal delivery framework as it has double delivery control framework, i.e., nano emulsion \& hydrogel. The Nano emulgel having nanosized emulsion goes from 10-100\ensuremath{\mu }m may quickly enter and convey dynamic substance more profound and faster. The gelling limit of this compound permits the definition of stable emulsion and creams by diminishing surface and interfacial pressure simultaneously expanding the consistency of watery stage. Regardless of the many preferred position of gels, a significant restriction is in delivery of hydrophobic medication. So to defeat this constraint, an emulsion-based methodology is being utilized to that even a hydrophobic moiety might appreciate exceptional property of gel. They have clingy causing distress, less spreading coefficient, scouring is a requirement for application to the skin, and they show the issue of solidness for detailing. Due to all these disadvantages, gels are selected for both cosmetic as well as a pharmaceutical formulation. Despite several benefits of gels, the main drawback is with the delivery of hydrophobic therapeutic moiety. So, emulgel based approach is used to overcome this drawback; by this, even a hydrophobic drug might be included and delivered successfully. When emulsions and gels are mixed than that dosage form is mentioned as emulgel. In fact, the existence of a gelling agent changes conventional emulsion into an emulgel in the water phase.  
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Nanoemulsion,\newline emulgel,\newline Nanoemulgel,\newline drug delivery framework
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Ramesh~K.~\\ Phone:\ 9912391909~\\  Email:\ ramesh@gmail.com
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\section{Introduction}
Nanoemulsions are the novel medication delivery framework that permits continued or controlled release of medication such as genetic materials \&biological active ingredient and so on. The Nanoemulsion contains oil, surfactant and a fluid stage, and they are isotropically clear and thermo-progressively stable fluid arrangement, ordinarily with bead width in the scopes of 10 {\textendash} 500nm \unskip~\citep{978975:21180868}. Numerous skin specialists, like moisturizer, salve, cream are generally utilized have different hindrances. These emulgel have various benefits over novel drug delivery systems as well as on conventional drug delivery systems in numerous aspects. One of the promising ways for drug organization is skin due to accessibility of huge surface region \unskip~\citep{978975:21180888,978975:21180874,978975:21180893}. Medication conveyance through the skin to the foundational dissemination is advantageous for various clinical conditions because of which there has been an impressive enthusiasm for this zone. It offers the benefit of consistent state-controlled medication conveyance over a broadened timeframe, with self-organization additionally being conceivable, which may not be the situation with a parenteral course \unskip~\citep{978975:21180889}.

\textbf{Nanoemulsion and Nanoemulgel}

Nanoemulsions are isotropic scattered frameworks of two non-miscible fluids, ordinarily comprises of a slick framework scattered in a watery framework, or a watery framework scattered in a sleek framework however shaping beads or other slick periods of nanometric size. Nanoemulsion-gel has a decent bond and high solubilising property, the medication in the oil stage prompts bigger fixation inclination towards the skin that further increment skin entrance of medication. Likewise, understanding consistency is improved because of expanded spared ability, diminished tenacity contrast with creams and balms \unskip~\citep{978975:21180884}.

\textbf{Types of Nanoemulsion}

Depending on composition


  
  \begin{enumerate}
  \item \relax O/W Nanoemulsions: oil droplets are dispersed in a continuous water phase.
  \item \relax W/O Nanoemulsions: water droplets are dispersed in the continuous oil phase.
  \item \relax Bi-continuous Nanoemulsions: water and oil are dispersed with each other \unskip~\citep{978975:21180879}
  \end{enumerate}
  \textbf{Components of Nanoemulgel}

\textbf{Oils}

Oils utilized in Nanoemulsion are commonly mineral oils utilized as the vehicle for drugs, e.g. Castor oils and different fixed oils (maize oils, cottonseed oil, Arachis oil) Olive Oil, eucalyptus oil, Coconut Oil, rose oil, clove oil and so on. 

\textbf{Aqueous Phase}

For the organization of hydrogel \& nanoemulsion, refined water is utilized as an aqueous stage. 

\textbf{Surfactant and Co-Surfactant}

Surfactants are utilized both to give emulsification at the hour of definition and control everyday dependability during the time frame of realistic usability of arranged nanoemulsion. E.g. Range 80 (Sorbitanmonooleate), Polyethylene-glycol-40-stearate, Labrasol, Stearic corrosive, PlurolOleique, Tween 80 (Polyoxyethylene-sorbitan-monooleate), Labrafil, Sodium stearate, Where specialists like Transcutol, Captex, Cammul, Migyol, and so on can be used as co-surfactant or co-solvents. 

\textbf{Gelling Agent}

Polymers are basic to give the basic organization for the planning of gels are known as gelling specialists, e.g. Common - Agar, Tragacanth, Guar gum, Xanthan Gum, Semi-engineered and Synthetic Carbapol, Poloxamer, HPMC (cellulose subsidiaries). 

\textbf{Permeation Enhancers}

They communicate with various skin constituents to deliver a reversible temporarily increment in penetrability \unskip~\citep{978975:21180884}.

\textbf{Advantages of Nanoemulsion}


  
  \begin{enumerate}
  \item \relax Increases bio availability.
  \item \relax Enhances the absorption rate.
  \item \relax Gives aqueous dosage form for water-insoluble drugs.
  \item \relax Eliminates variability in absorption.
  \item \relax Quick and effective penetration of drug moiety.
  \item \relax Nanoemulsion formulation required less amount of surfactant compare 
  \item \relax Nanoemulsions are the thermodynamically stable framework, and stability 
  \item \relax Nanoemulsion is not exposed to attack by air \& water.
  \item \relax Less amount of energy requirement \unskip~\citep{978975:21180886}
  \end{enumerate}
  \textbf{Disadvantages of Nanoemulsion}


  
  \begin{enumerate}
  \item \relax Nanoemulsion is having the inadequate solubilizing capability for high melting substances.
  \item \relax The high concentration of co-surfactant \& surfactant and essential for solubilizing the nanodroplets.
  \item \relax Nanoemulsion stability is affected by environmental factor like Ph \& temperature.
  \item \relax The surfactant should be nontoxic for utilizing pharmaceutical application \unskip~\citep{978975:21180894}
  \end{enumerate}
  \textbf{Application}

\textbf{Topical Delivery}

Topical organization of medications might have benefits over diverse techniques for some reasons; it will evade the hepatic first-pass metabolism of medication and related toxicity impacts. They directly target \& delivery medication to the influenced area of eyes or skin. 

The nanoemulsion might accomplish an elevated level of effective antimicrobial action is recently proficient by fundamental anti-toxins. The nanoemulsion has extensive range movement against microscopic organisms (like S. aureus, E.coli,) growths (like Dermatophytes, Candida) \unskip~\citep{978975:21180891,978975:21180879}.

\textbf{Antimicrobial activity}

Essential oil like Thymus daenensis produces nanoemulsion which is generally used as antibacterial and also increase the ability nanoemulsion of Thymus daenensis essential oil created by high-intensity ultrasound method signifies bigger antibacterial activity with enhanced capability to disrupt cell membrane integrity of E.coli, a food-borne pathogen.

\textbf{In Cosmetic}

Nanoemulsions are used for lipophilic drug transport and it also helps the skin penetration of active ingredients \& hence enhances their concentration in the skin \unskip~\citep{978975:21180870}. Recently significance of nanoemulsions has become enhancing as best vehicles for cosmetics controlled delivery and for optimized dispersion of active ingredients in specific skin layers.

In nanoemulsion there is no sedimentation, inherent creaming, flocculation is noticed with macro emulsion, so nanoemulsion is acceptable in cosmetics. 

\textbf{Nanoemulsion to improve skin penetration}

The organic solvents have been utilized to upgrade the skin infiltration of poor efficacious medications. Yet, these solvents actuate some antagonistic impacts on the skin, for example, skin disturbance, poisonousness and refinement. To evade these unfriendly impacts, the drug is captured in the o/w nanoemulsion without utilizing skin natural solvents. Furthermore, o/w nanoemulsion permits high solvent limit with regards to water-insoluble topically dynamic medicaments and furthermore helps in conveying water, a magnificent conditioner, to the skin, e.g. Diazepam, NSAIDs, \ensuremath{\alpha }-tocopherol, antifungal medications (econazole or miconazole nitrate).

\textbf{Transdermal Drug Delivery (TDD) System}

The TDD might be described as the application of a medication to skin for local or systemic action \unskip~\citep{978975:21180875}. They are recognized to remove oral gastrointestinal (GI) adverse effects and handle the level of plasma drug for a longer time and appropriate for chronic disease's long treatment of \unskip~\citep{978975:21180882}.

The TDD frameworks are a stable source of interest due to the advantages they afford in overcoming numerous disadvantages connected with other drug delivery modes (i.e., intravenous, oral). Due to skin impermeable nature, designing a proper`` drug delivery vehicle'', which penetrates the skin barrier is challenging \unskip~\citep{978975:21180872}.
    
\section{\textbf{REVIEW OF LITERATURE}}
Drais \textit{et al., }investigated Piroxicamnanoemulsion gel of as topical dosage form to enhance the solubility of Piroxicam \& diminish gastrointestinal side effect, which intend to increase therapeutic activity \& Piroxicam bioavailability in Table~\ref{tw-eda6d23f1873}. They resulted in pseudo- ternary phase plot that has a big area of nanoemulsion is surfactant mixture ratio (3:1) and used for nanoemulsion formulas further to formulate nanoemulsion gel. They finished that nanoemulsion gel is an effective alternative for Piroxicamtopical delivery \unskip~\citep{978975:21180877}.

Karthikeyan \textit{et al., }developed nanoemulsion coating by using Azadirachta Indica (neem oil) as substitution of organic solvent, utilizing neem oil \& tween 20 as an emulsifier. They reported mean droplet size ranging from 31.03 - 251.43nm. 

Then the prepared stable emulsion loaded for coating on steel surface by using method electrophoretic deposition method, the atomic force microscopy images the formulation confirmed the nano emulsified coated on steel \unskip~\citep{978975:21180890}.

Khullar \textit{et al., }developed emulgel by using Mefenamic acid as a model drug. They used Carbopol 940 as mentha oil, gelling agent and clove oil as penetration enhancers. 

The formulations are assessed for rheological surveys, bio adhesion strength, spreading coefficient surveys, \textit{in-Vitro} release, skin irritation studies, and reported that Mefenamic acid topical emulgel possess an effective analgesic activity \& anti-inflammatory \unskip~\citep{978975:21180883}.


\begingroup
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\begin{longtable}{p{\dimexpr.05265714285714284\linewidth-2\tabcolsep}p{\dimexpr.13465714285714284\linewidth-2\tabcolsep}p{\dimexpr.14515714285714292\linewidth-2\tabcolsep}p{\dimexpr.1406\linewidth-2\tabcolsep}p{\dimexpr.16768571428571434\linewidth-2\tabcolsep}p{\dimexpr.17122857142857146\linewidth-2\tabcolsep}p{\dimexpr.1880142857142858\linewidth-2\tabcolsep}}
\caption{\boldmath {Recently reported Nanoemulsion for transdermal drug delivery system} }
\label{tw-eda6d23f1873}
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  \cAlignHack PEG 200 &
  \cAlignHack Aqueous titration method &
  \cAlignHack Nanoemulsion of Ketacanazole can be used for topical application for \mbox{}\protect\newline fungal diseases. \unskip~\citep{978975:21180871}\\
 &
   &
   &
   &
   &
   &
  \\
\cAlignHack 2. &
  \cAlignHack Piroxicam &
  \cAlignHack Oleic acid &
  \cAlignHack Tween -80 &
  \cAlignHack Ethanol &
  \cAlignHack Aqueoustit-ration &
  \cAlignHack The new piroxicam nano emul gel with appropriate viscosity and utilized for transdermal application \unskip~\citep{978975:21180892}.\\
 &
   &
   &
   &
   &
   &
  \\
\cAlignHack 3. &
  \cAlignHack Carvedilol &
  \cAlignHack Oleic acid, IPM &
  \cAlignHack Tween 20 &
  \cAlignHack Carbitol &
  \cAlignHack Spontaneous emulsification &
  \cAlignHack Nanoemulsion have enhanced bioavailability for transdermal and eliminate first-pass effect \unskip~\citep{978975:21180878}.\\
 &
   &
   &
   &
   &
   &
  \\
\cAlignHack 4. &
  \cAlignHack Clozapine &
  \cAlignHack Oleic acid &
  \cAlignHack Tween 20 &
  \cAlignHack Transcutolp &
  \cAlignHack Spontaneous emulsification &
  \cAlignHack Nanoemulsion have significantly enhanced bioavailability for transdermal and eliminated first-pass metabolism \unskip~\citep{978975:21180876}.\\
 &
   &
   &
   &
   &
   &
  \\
\cAlignHack 5. &
  \cAlignHack Amisulpride &
  \cAlignHack Oleic acid, IPM &
  \cAlignHack Labrasol, Tween-20 &
  \cAlignHack PEG-400 &
  \cAlignHack Ultra sonication method &
  \cAlignHack Nanoemulsion showed significant increases \mbox{}\protect\newline \textit{invivo} bioavailability \unskip~\citep{978975:21180885}.\\
 &
   &
   &
   &
   &
   &
  \\
\cAlignHack 6. &
  \cAlignHack Micanazole nitrate &
  \cAlignHack Clove oil &
  \cAlignHack Tween 20 &
  \cAlignHack Ethanol &
  \cAlignHack Spontaneous emulsification &
  \cAlignHack Nanoemulsion was stable at room temperature and effectively delivered micanazole transdermally compared with marketed gel \unskip~\citep{978975:21180869}.\\
 &
   &
   &
   &
   &
   &
  \\
\cAlignHack 7. &
  \cAlignHack Etoricoxib, Methyl salicylate &
  \cAlignHack Oleic acid &
  \cAlignHack Tween 80 &
  \cAlignHack Propylene glycol &
  \cAlignHack Low energy method &
  \cAlignHack Nanoemulgel is efficient, secure, \& promising for inflammatory conditions treatment \unskip~\citep{978975:21180881}.\\
 &
   &
   &
   &
   &
   &
  \\
\cAlignHack 8. &
  \cAlignHack Mefanamic Acid &
  \cAlignHack Capryol 90 &
  \cAlignHack Tween 60 &
  \cAlignHack Transcutolp &
  \cAlignHack Aqueous titration method &
  \cAlignHack Topical nanoemulgel of mefanamic acid be a promising choice over conventional topical \mbox{}\protect\newline formulation \unskip~\citep{978975:21180880}\\
 &
   &
   &
   &
   &
   &
  \\
\cAlignHack 9. &
  \cAlignHack Ketoprofen &
  \cAlignHack Oleic acid &
  \cAlignHack Tween 80 &
  \cAlignHack Transcutolp &
  \cAlignHack Titration method &
  \cAlignHack New ketoprofen nanoemulgel with proper viscosity is effectively formulated for transdermal application \unskip~\citep{978975:21180887}.\\
 &
   &
   &
   &
   &
   &
  \\
\cAlignHack 10. &
  \cAlignHack Astaxanthin &
  \cAlignHack Sunflower oil &
  \cAlignHack Kolliphor RH40 &
  \cAlignHack PEG 400 &
  \cAlignHack Self- nano emulsifying (SNE) method &
  \cAlignHack Nanoemulsion can serve as a potential vehicle for improved transdermal delivery of \mbox{}\protect\newline astaxanthin.\unskip~\citep{978975:21180895}\\
\tblbottomrule 
\end{longtable}
\endgroup
\makeatletter\@ifundefined{TwoColDocument}{}{\twocolumn}\makeatother 
Brajesh \textit{et al}., Developed nanoemulsion gel containing carvedilol for transdermal drug delivery system they used spontaneous emulsification method, after constructing a pseudo ternary phase diagram. They have used oil, surfactant, co-surfactant and reported oleic acid act as a powerful enhancer of the transdermal drug delivery system. Further in their study, they have reported a mean droplet size of 71.8nm and then nanoemulsion formulation shows the highest flux at 24hrs. Finally, they have concluded that nanoemulsion gel formulation has a greater potential to improve the bioavailability of carvedilol by transdermal drug delivery framework \unskip~\citep{978975:21180873}.

Gupta \textit{et al., }developed a nanoemulsion based transdermal patches of Diclofenac Diethylamine, by using solvent evaporation technique. Nanoemulsion was categorized for diverse physicochemical factors. They concluded that nanoemulsion comprising transdermal patches might be a promising device for improving Diclofenac Diethylaminepercutaneous delivery.

Arora \textit{et al.,} developed nanoemulgel as a transdermal delivery framework for poorly water-soluble drug, Ketoprofen, to overcome problems related to its oral delivery. They constructed Pseudo-ternary phase diagrams utilizing titration technique to figure out the components concentration range. Their results revealed that nanoemulsion signified best physical stability during storage at room temperature with better antibacterial activity. 

Thakkar \textit{et al.,} studied Itraconazolenanoemulsion by the method of speed stirring method, by using capmul mono-diglyceride of medium-chain fatty acid (MCM) C8 as oil, pluronic F68 as co-surfactant and cremophore EL as a surfactant, and then followed by sonication. 

Sharma \textit{et al. }developed nanoemulsion gel of Tenoxicam and reported the particle size with nano range. They used the emulsification method using ethyl oleate, tween- 80 and propylene glycol, surfactants and co-surfactants. They concluded that Tenoxicam has better efficacy and transdermal application.

Majeed \textit{et al.,} developed Eugenol loaded nanoemulsions, emulsified with changed starch by high-pressure homogenizer at 150Mpa pressure, 5processing cycles and study their apoptotic potential against liver and colon cancer cells and were surveyed in comparison with bulk eugenol. In this study, they concluded that reactive oxygen species perform the main role in apoptosis in HTB37\&HB8065 cells.

Vatsraj \textit{et al., }developed a new ``oil-in-water (O/W) nanoemulsion'' framework having the capability to function as a carrier for poorly soluble drugs with Clarithromycin as model antibiotic. They utilized ``3-level 3-factorial central composite investigational design'' to conduct investigates. They investigated selected variables effects, polysorbate 80, olive oil content \& polyvinyl alcohol concentration. Their results revealed that nanoemulsion revealed best physical stability through storage at room temperature with better antibacterial activity.
    
\section{Conclusion}
The topical Nanoemulgels have demonstrated a better choice for compelling and helpful medication delivery framework{\textemdash}Nanoemulgel where medication is joined into oil period of Nanoemulsion and afterwards converged with a gel base. Nanoemulsion stacked gel gives higher viability in some effective issues. The eventual fate of Nanoemulsion-Gel based definitions may give a superior and dependable answer for the conveyance of hydrophobic medications. An extensive parcel of drugs used as a piece of the treatment of skin disease.

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest for this study.

\textbf{Funding Support}

The authors declare that they have no funding support for this study.
    

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