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\begin{document}


\def\RunningAuthor{Gangadhara R et al.}
\firstPage{1798}
\articleType{Original Article}
\receivedDate{19 Feb 2021}
\acceptedDate{26 Mar 2021}
\revisedDate{22 Mar 2021}
\journalVolume{2021, 12}
\journalIssue{3}
\journalDoi{ijrps.v12i3.4841}
\copyrightYear{2021}
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\def\journalTitle{International Journal of Research in Pharmaceutical Sciences}

\title{\textbf{Formulation and Invitro characterization of Flurbiprofen loaded Nanosponges}}
\author{Gangadhara~R\textsuperscript{*}\textsuperscript{1},  
            Satheesh~K~P\textsuperscript{1},  
            Devanna~N\textsuperscript{2},  
            Sasikala~L\textsuperscript{3}, 
            Vandavasi~Koteswara~Rao\textsuperscript{3}~\\[5pt]{\textsuperscript{1}Department of Chemistry, Jawaharlal Nehru Technological University Anantapuramu, Anantapur, Andhra Pradesh, India}~\\{\textsuperscript{2}Oil Technological and Pharmaceutical Research Institute, Ananthapuramu, Andhra Pradesh, India}~\\{\textsuperscript{3}Department of Chemistry, Gandhi Institute of Technology and Management, Hyderabad, Telangana, India}}

\begin{abstract}
The aim of this analysis is to see how effective a Nanosponge-loaded topical gel is at distributing flurbiprofen through the skin. Flurbiprofen was entrapped in Nanosponge and formulated into a gel for this purpose. Flurbiprofen Nanosponges were developed by solvent evaporation using pluronic F68 and ethyl cellulose. The particle size and entrapment quality were discovered to be in the range of 200-410 nm and 90.94\% to 98.68\%, respectively. For gel formulation, Nanopsonges with high entrapment efficiency and the smallest particle size (F3) were chosen based on the characterization. Using Guar gum, Carbopol, and HPMC K4M, a total of 6 formulations were produced to determine the sustained drug release and were tested for physiochemical tests, producing positive results. According to the findings of the above in vitro drug release trials, formulations containing carbopol release more drug at the end of 11 hours than other formulations and follow a zero-order with case II transport mechanism.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Flurbiprofen,\newline Carbopol,\newline Pluronic F68,\newline Ethyl cellulose
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Gangadhara~R~\\ Phone:\ +91 9700353324~\\  Email:\ phdchemistry16@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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        \makeatother
        
    
\section{Introduction}
In recent years, much focus has been put on the development of novel Nanosponge-based drug delivery mechanisms in order to regulate and monitor drug release actions. It is possible to adjust the therapeutic index and length of drug action by integrating it into a carrier system \unskip~\citep{1124173:22401915}. Nanosponges are a new form of hyper-crosslinked polymer-based colloidal structure that consists of colloidal-sized dense nanoparticles and nanosized cavities \unskip~\citep{1124173:22401913}. They increase drug stability, decrease side effects, and change drug release. The outer surface is generally porous, allowing for long-term drug release. They're also used to handle topical drugs \unskip~\citep{1124173:22401914,1124173:22401916}. Topical medications in their conventional forms concentrate excessively in the epidermis and dermis. Nanosponge stops the active ingredient from circulating in the dermis and epidermis. The nanosponge method decreases the irritation of working medications without compromising their effectiveness \unskip~\citep{1124173:22401923}. They can be used to target medications to particular sites and to protect drugs and proteins from degrading. These tiny sponges will circulate across the body until they come across a certain target spot, where they bind to the surface and start releasing the substance in a coordinated and predictable fashion. The most challenging aspect of topical drug distribution is the skin's membrane function, which prohibits most medications from penetrating \unskip~\citep{1124173:22401918,1124173:22401926}. Nanosponges can be successfully integrated into a topical hydrogel drug delivery system to improve drug release and penetration through the skin, as well as to reduce drug exposure and enhance patient safety by extending dose intervals \unskip~\citep{1124173:22401911,1124173:22401912}. 

Flurbiprofen, a propionic acid analogue, is an antipyretic and analgesic nonsteroidal anti-inflammatory drug (NSAIA). The aim of this analysis is to see how effective a nanosponge-loaded topical gel is at distributing flurbiprofen through the skin. Flurbiprofen was entrapped in a nanosponge and incorporated into a gel for this purpose, and the in vitro permeation tests were analysed \unskip~\citep{1124173:22401926}.
    
\section{Materials and Methods}
Flurbiprofen was obtained as a gift sample from Sun Pharma from India. Pluronic F-68, Ethyl Cellulose, Guar gum, Carbopol, HPMC K4M was procured from BMR Chemicals, Hyd. and other suppliers. All of the other compounds were of analytical consistency.

\textbf{Formulation of Flurbiprofen Nanosponges}

Nanosponges using different proportions of Ethyl cellulose, Pluronic F-68 as rate restricting polymer and co-polymers like polyvinyl alcohol were prepared by a solvent evaporation method. Flurbiprofen and the required amount of polymers were dissolved in 20 mL solvent (Methanol: Dichloromethane) and slowly applied to a particular amount of PVA in 100 mL of continuous aqueous phase prepared with a magnetic stirrer. 

The reaction mixture was stirring it up at 1000 RPM for 2 hours on a magnetic stirrer and kept on a hot plate until the organic solvent was completely extracted from the formulation. Filtration through Whatman filter paper and collect the dried Nanosponges produced \unskip~\citep{1124173:22401926,1124173:22401913,1124173:22401924} (Table~\ref{tw-1f84e3a95a4b}).


\begin{table*}[!htbp]
\caption{\boldmath {Formulation table of Flurbiprofen loaded Nanosponges} }
\label{tw-1f84e3a95a4b}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.22970000000000002\linewidth-2\tabcolsep}p{\dimexpr.1411\linewidth-2\tabcolsep}p{\dimexpr.13450000000000001\linewidth-2\tabcolsep}p{\dimexpr.1335\linewidth-2\tabcolsep}p{\dimexpr.12580000000000002\linewidth-2\tabcolsep}p{\dimexpr.1148\linewidth-2\tabcolsep}p{\dimexpr.1206\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Excipients & \cAlignHack F1 & \cAlignHack F2 & \cAlignHack F3 & \cAlignHack F4 & \cAlignHack F5 & \cAlignHack F6\\
\tblmidrule 
\cAlignHack Flurbiprofen (g) &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1\\
\cAlignHack Pluronic F-68 (g) &
  \cAlignHack 0.5 &
  \cAlignHack 1 &
  \cAlignHack 1.5 &
  \cAlignHack -- &
  \cAlignHack -- &
  \cAlignHack --\\
\cAlignHack Ethyl Cellulose (g) &
  \cAlignHack -- &
  \cAlignHack -- &
  \cAlignHack -- &
  \cAlignHack 0.5 &
  \cAlignHack 1 &
  \cAlignHack 1.5\\
\cAlignHack PVA (mg) &
  \cAlignHack 500 &
  \cAlignHack 500 &
  \cAlignHack 500 &
  \cAlignHack 500 &
  \cAlignHack 500 &
  \cAlignHack 500\\
\cAlignHack DCM:Ethanol  &
  \cAlignHack 20 &
  \cAlignHack 20 &
  \cAlignHack 20 &
  \cAlignHack 20 &
  \cAlignHack 20 &
  \cAlignHack 20\\
\cAlignHack Water (mL) &
  \cAlignHack 100 &
  \cAlignHack 100 &
  \cAlignHack 100 &
  \cAlignHack 100 &
  \cAlignHack 100 &
  \cAlignHack 100\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Formulation of Flurbiprofen nanosponges loaded gels} }
\label{tw-2158b9179d95}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.31390000000000008\linewidth-2\tabcolsep}p{\dimexpr.13350000000000001\linewidth-2\tabcolsep}p{\dimexpr.11809999999999999\linewidth-2\tabcolsep}p{\dimexpr.1127\linewidth-2\tabcolsep}p{\dimexpr.1104\linewidth-2\tabcolsep}p{\dimexpr.1105\linewidth-2\tabcolsep}p{\dimexpr.1009\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Ingredients & \cAlignHack F3G1 & \cAlignHack F3G2 & \cAlignHack F3G3 & \cAlignHack F3G4 & \cAlignHack F3G5 & \cAlignHack F3G6\\
\tblmidrule 
\cAlignHack Optimize Nanosponge  \mbox{}\protect\newline (weight equivalent in \%w/w)  &
  \cAlignHack 2.5\% &
  \cAlignHack 2.5\%  &
  \cAlignHack 2.5\%  &
  \cAlignHack 2.5\% &
  \cAlignHack 2.5\% &
  \cAlignHack 2.5\%\\
\cAlignHack Guar gum (gm) &
  \cAlignHack 1 &
  \cAlignHack 2 &
  \cAlignHack -- &
  \cAlignHack -- &
  \cAlignHack -- &
  \cAlignHack --\\
\cAlignHack Carbopol (gm) &
  \cAlignHack -- &
  \cAlignHack -- &
  \cAlignHack 1 &
  \cAlignHack 2 &
  \cAlignHack -- &
  \cAlignHack --\\
\cAlignHack HPMC K4M (gm) &
  \cAlignHack -- &
  \cAlignHack -- &
  \cAlignHack -- &
  \cAlignHack -- &
  \cAlignHack 1 &
  \cAlignHack 2\\
\cAlignHack Propylene Glycol (ml) &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1\\
\cAlignHack Distilled Water (ml) &
  \cAlignHack Q.S &
  \cAlignHack Q.S &
  \cAlignHack Q.S &
  \cAlignHack Q.S &
  \cAlignHack Q.S &
  \cAlignHack Q.S\\
\cAlignHack Triethanolamine (2\%v/v) (ml) &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1 &
  \cAlignHack 1\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Formulation of Nanosponge loaded gel}

To ensure smooth dispersion, the polymer was first immersed in water for 2 hours before being stirred at 600rpm with a magnetic stirrer. To neutralise the pH, triethanolamine (2 percent v/v) was applied. Permeation enhancers (Propylene glycol) were applied to the aqueous dispersion as a methanolic solution \unskip~\citep{1124173:22401919,1124173:22401920,1124173:22401917}. (Table~\ref{tw-2158b9179d95}).

\textbf{Evaluation parameters}

\textbf{Entrapment efficiency}

By dissolving 100mg of Flurbiprofen weight equal Nanosponge in 10ml of Methanol, the sample was analysed. Once the substance has been dissolved, take 10ml of the dissolved drug. After that, a UV-Spectrophotometric process at 246 nm was used to detect the concentration of the drug in the water phase (U.V Spectrophotometer). The calibration curve is used to assess the drug's concentration. By subtracting the amount of drug in the aqueous phase from the overall amount of drug in the Nanosponges, the amount of drug within the particles was determined. \unskip~\citep{1124173:22401917,1124173:22401919}

\textbf{pH}

A pH meter was used to calculate the pH of the prepared in-situ gelling method after completion of the process \unskip~\citep{1124173:22401919,1124173:22401921,1124173:22401917}

\textbf{Dr}\textbf{ug} \textbf{ content uniformity}

The Spectrophotometric approach was used to verify the drug content uniformity of the prepared gels. Pipetting 1 ml of optimised formulations and diluting it up to 100 ml of pH 7.4 was used to test these formulations. The formulas were shaken for 2-3 minutes before a transparent gel solution was obtained. The absorbance was measured at 246 nm using a UV-Visible spectrophotometer after the sample was purified into Millipore membrane filtrate (0.45um) \unskip~\citep{1124173:22401920,1124173:22401925}.

\textbf{Rheological Studies}

The viscosity of the formulation is an important element in defining the drug's residence time in the eye. The viscosity was measured using a Brookfield viscometer (Brookfield DV+Pro, Brookfield Engineering Laboratories, Middleboro, MA, USA) after the formulated solutions had gelled at physiological temperature. \unskip~\citep{1124173:22401925,1124173:22401917}.

\textbf{In-vitro Drug Release studies of Nanosponge gel formulations}

For testing the dissolution release of gels via a cellophane membrane, diffusion tests of the prepared gels may be carried out in the Franz diffusion cell. The diffusion experiments were carried out at 37\ensuremath{\pm} 0.5\ensuremath{^\circ}C using 40 ml of phosphate buffer (pH 7.4) as the dissolution medium and a gel sample (1g) in a cellophane membrane. At daily intervals, one millilitre of each sample was extracted, and each sample was supplemented with an equivalent amount of fresh dissolution medium. The substance was tested using a UV spectrophotometer calibrated to 246nm \unskip~\citep{1124173:22401920,1124173:22401925,1124173:22401922}. 
    
\section{Results and Discussion}
\textbf{Entrapment Efficiency}

It is measured to assess the utility of any process, which aids in the selection of the most suitable production method. After preparing the formulations, the functional yield was determined by dividing the number of Nanosponges recovered from each preparation by the total amount of starting material. (Theoretical yield). (Table~\ref{tw-c72c298f75ff})


\begin{table*}[!htbp]
\caption{\boldmath {Entrapment Efficiency of Flurbiprofen Nanosponges (F1-F6)} }
\label{tw-c72c298f75ff}
\centering 
\begin{threeparttable}

\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.5019\linewidth-2\tabcolsep}p{\dimexpr.4981\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Formulation code  & \cAlignHack \% Entrapment Efficiency \\
\tblmidrule 
\cAlignHack F1  &
  \cAlignHack 93.02\\
\cAlignHack F2  &
  \cAlignHack 96.42\\
\cAlignHack F3  &
  \cAlignHack 98.68\\
\cAlignHack F4  &
  \cAlignHack 90.94\\
\cAlignHack F5  &
  \cAlignHack 96.35\\
\cAlignHack F6  &
  \cAlignHack 97.04\\
\tblbottomrule 
\end{tabulary}\par 
\begin{tablenotes}\footnotesize 
    
\item{Formulation F1-F6's entrapment efficiency was found to be between 90.94 and 98.68 \%.}
\end{tablenotes}
\end{threeparttable}

\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Physicochemical evaluation of Nanosponges Loaded Gels} }
\label{tw-b69f7e0ea6aa}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1969\linewidth-2\tabcolsep}p{\dimexpr.2031\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\cAlignHack Formulation & \cAlignHack pH & \cAlignHack Drug content & \multicolumn{2}{p{\dimexpr(.40\linewidth-2\tabcolsep)}}{\cAlignHack Angular Velocity}\\
\rowcolor{kwdboxcolor}\cAlignHack code & \cAlignHack  & \cAlignHack (\%) & \cAlignHack 10 (rpm) & \cAlignHack 100 (rpm)\\
\tblmidrule 
\cAlignHack F3G1 &
  \cAlignHack 7.4 &
  \cAlignHack 95.02 &
  \cAlignHack 650 &
  \cAlignHack 320\\
\cAlignHack F3G2 &
  \cAlignHack 7.3 &
  \cAlignHack 96.43 &
  \cAlignHack 830 &
  \cAlignHack 590\\
\cAlignHack F3G3 &
  \cAlignHack 7.6 &
  \cAlignHack 98.65 &
  \cAlignHack 880 &
  \cAlignHack 460\\
\cAlignHack F3G4 &
  \cAlignHack 7.5 &
  \cAlignHack 97.02 &
  \cAlignHack 1260 &
  \cAlignHack 620\\
\cAlignHack F3G5 &
  \cAlignHack 7.2 &
  \cAlignHack 98.42 &
  \cAlignHack 620 &
  \cAlignHack 340\\
\cAlignHack F3G6 &
  \cAlignHack 7.3 &
  \cAlignHack 96.02 &
  \cAlignHack 940 &
  \cAlignHack 460\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Morphology determination by scanning electron microscopy (SEM)}


\bgroup
\fixFloatSize{images/6848de76-1bbd-4e84-b17b-a19cb75dfbaf-upicture1.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/6848de76-1bbd-4e84-b17b-a19cb75dfbaf-upicture1.png}{\includegraphics{images/6848de76-1bbd-4e84-b17b-a19cb75dfbaf-upicture1.png}}{}
\makeatother 
\caption{\boldmath {Nanosponges structure optimized formulation (F3)}}
\label{f-c09329a430b1}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/c3a2b199-652f-4ded-85c6-3c640e108748-upicture2.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/c3a2b199-652f-4ded-85c6-3c640e108748-upicture2.png}{\includegraphics{images/c3a2b199-652f-4ded-85c6-3c640e108748-upicture2.png}}{}
\makeatother 
\caption{\boldmath {In-vitro drug release graphs of formulation (F3G1-F3G6)}}
\label{f-efffb5f802f1}
\end{figure}
\egroup
Both formulated topical gels had tested their physicochemical properties. The physicochemical properties of gel formulations, such as viscosity, pH, and drug material, were calculated and tabulated in Table~\ref{tw-b69f7e0ea6aa}. Both of the formulations have a pH level of 7.1 to 7.6, which is ideal for topical use. 

The formulated gels' drug quality was found to be adequate, varying from 95.02 to 98.65 percent. Many of the formulations had viscosities ranging from 320cps to 1260cps.

\textbf{In-vitro drug release of Flurbiprofen nanosponges loaded gels}

Using Guar gum, Carbopol, and HPMC K4M, a total of 6 formulations were produced to assess the sustained drug release. 

According to the findings of the above in vitro drug release trials, the formulation containing Carbopol has the largest drug release at the end of 11 hours than the other formulations. 

As a result, the formulation F3G4 containing Carbopol was selected as the best. (Figure~\ref{f-c09329a430b1} and Figure~\ref{f-efffb5f802f1})

\textbf{Release Kinetics of Flurbiprofen Nanosponges loaded gels}

The release was discovered to be in zero-order, with an R2 value similar to null. Zero-order kinetics is used in the formulation. 

The drug release mechanism was discovered to be a case II transport mechanism.
    
\section{Conclusion}
The present study was aimed to develop Flurbiprofen Nanosponges loaded gels for targeting drug delivery systems. Flurbiprofen Nanosponges were formulated using ethyl cellulose, Pluronic F68 with different ratios. Developed Nanosponges were further evaluated for particle size morphology in which F3 formulation containing Pluronic F68 shows the spongy structure with minute pores of 200nm particle size shows good entrapment efficiency than remaining formulations. So further F3 formulation was incorporated as a topical gel by using 3 different rate retarding polymers in which F3G4 formulation containing carbopol revealed sustained drug release upto 11hrs and follows zero-order with case II transport mechanism.
\section*{Acknowledgement}The authors would like to thank Dr V. Anuradha, HOD of Science and Humanities, Stanley College of Engineering \& Technology for Women, Hyderabad, for continued support. The authors also extend their sincere thanks to Dr Sridhar, Mr Waseem and Mr. Mahesh of Spectrum Pharma labs for permitting to conduct the study and research.

\textbf{Funding Support}

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

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest.
    

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