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\def\RunningAuthor{Khairnar Akshay  et al.}
\firstPage{1403}
\articleType{Original Article}
\receivedDate{21 Nov 2019}
\acceptedDate{13 Dec 2019}
\revisedDate{31 Jan 2020}
\journalVolume{2020, 11}
\journalIssue{2}
\journalDoi{ijrps.v11i2.2006}
\copyrightYear{2020}
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\title{Mucoadhesive Potential of Whey Protein Concentrate in Miconazole Mucoadhesive Prolong Release Tablets}
\author{Khairnar~Akshay\textsuperscript{*}\textsuperscript{1},  
            Salunkhe~Kishor\textsuperscript{2},  
            Chavan~M~J\textsuperscript{1}, 
            Chintamani~Ravindra\textsuperscript{1}~\\[5pt]{\textsuperscript{1}Department of Pharmaceutics, Amrutvahini College of Pharmacy, Sangamner, Ahmednagar -422608, Maharashtra, India}~\\{\textsuperscript{2}Sanjivani College of Pharmaceutical Education and Research, Sahajanaandnagar, Shinganapur, Kopargaon, Ahmednagar-423603 , Maharashtra, India}}

\begin{abstract}
Orophygial candidiasis (OPC) is one of the most frequent \textit{Candida }infections of the oral cavity this condition is common in patients with malnutrition, having chemotherapy, administrating immunosuppressive agents, or severe disease such as HIV. Prolong local administration of Miconazole is a must to treat OPC conditions in patients, which required the prolong mucoadhesion of the dosage form to provide local delivery of drugs for an extended time period with good mucoadhesion. Miconazole is synthetic imidazole antifungal agent, various prescription and over the counter product available like Miconazole Gel, Topical cream, Immediate release Tablet available in the market but that lack in the prolonged period of action to the local mucosa. In the present study combination of Whey protein concentrate (WPC), Hydroxypropyl methylcellulose (HPMC) and Lactose were evaluated as a potential buccal adhesive tablet. The various combination of Whey protein concentrate with release controlling polymer was tested using a Miconazole as a potential antifungal agent. The mucoadhesive potential of WPC evaluated using Tensiometer by calculating the detachment force and drug release of Miconazole was performed to study the prolong release activity of Tablet. The optimized combination of WPC/HPMC/Lactose through a statistical study showed significant bioadhesion to the porcine mucosa and prolong drug release for 10hrs. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Buccal Tablets,\newline Hydroxypropyl methylcellulose,\newline Miconazole,\newline Whey Protein
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Khairnar~Akshay~\\ Phone:\ 91 9890424466~\\  Email:\ akshaykhairnar@gmail.com 
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{ Introduction}
In recent years the effectiveness of formulation has been achieved through the controlled drug delivery platforms. Most of the work has been carried out in the area of bio adhesion, particularly the mucoadhesive drug delivery system, to improve the efficacy of drugs through oral, buccal, nasal route of administration \unskip~\citep{723851:17171369}. Common polymers that have been used as mucoadhesive drugs carrier are polyethylene oxide \unskip~\citep{723851:17171368}, Lecithin \unskip~\citep{723851:17171361}, Chitosan, Poly-methyl acrylates, Carbapol, Poly-carbophil, Sodium CMC \unskip~\citep{723851:17171367}.

However, most of the polymers used in mucoadhesive drug delivery cause mucosal irritation limits its use in the therapeutic system \unskip~\citep{723851:17171366}. 

In the present study, an attempt has been made to evaluate the potential of Whey protein concentrate as a mucoadhesive agent in combination with Hydroxypropyl methylcellulose as release controlling agent \unskip~\citep{723851:17171365} for the Prolong delivery of Miconazole is an antifungal agent \unskip~\citep{723851:17171364}. 

Miconazole is a synthetic imidazole antifungal agent and most of the various prescription and over-the-counter products have been approved under various dosage forms like vaginal formulation \unskip~\citep{723851:17171363}, dermal formulations, oral, gel, topical formulations which can be administered orally, intravenously and intrathecally.

Miconazole also indicated for the treatment of Orophygial candidiasis (OPC) one of the most frequent \textit{Candida }infections of the oral cavity. If it is left untreated, it may invade the esophagus or further progress to induce systemic complications. This condition is common in patients with malnutrition, having chemotherapy, administrating immunosuppressive agents, or severe diseases such as HIV \unskip~\citep{723851:17171362}. 

Prolong local administration of Miconazole is a must to treat OPC conditions in patients, which required the prolong mucoadhesion of the dosage form to provide local delivery of drugs for an extended time period with good mucoadhesion.

The Buccal administrations of drugs have gained interest as the oral cavity in disease conditions like OPC forms a convenient and easily accessible site for local and systemic delivery of the drug. 

The present invention provides a carrier system with whey protein concentrate as a mucoadhesive agent to provide prolonged release bioadhesive therapeutic system that is essential for producing a long residence time in the locations of the infection in contrast to the usual local forms (mouthwashes, gel, pistils, lozenges) which have a transitional effect \unskip~\citep{723851:17171358}.

The Whey protein concentrate in combination with hydroxypropyl methylcellulose (HPMC) as a release controlling agent and Lactose monohydrate as a diluent come pore former have been evaluated in the present study as potential buccal bioadhesive tablets. The objective was to investigate the mucoadhesive potential of Whey protein concentrate in various combinations with release controlling polymer. 

The bioadhesive strength of the WPC investigated and drug release characteristics evaluated with Miconazole as a potential antifungal drug. 

The final combination of the polymer was optimized through the design of experiments using Mini Tab. 
    
\section{Materials and Methods}
Miconazole API received from Gufic biosciences as a gift sample, Whey protein concentrate (WPC) purchased from NZMP, Hydroxypropyl methylcellulose (Methocel K15 LV) from Colorcon Ltd, Lactose monohydrate 450M from Armor Pharma, Microcrystalline cellulose (Avicel PH 102) from FMC, Colloidal silicon dioxide (Roqquete ), Magnesium stearate (Merck), Talc (Merck)

\textbf{Preparation of the Buccal Tablets}

After some preliminary trials, the following excipients were finalize for the preparation of tablets, wherein Miconazole dose kept as 50mg and tablet weight finalized as 115mg. The list of ingredients listed in Table~\ref{tw-028406b151fd}.


\begin{table*}[!htbp]
\caption{\boldmath {\textbf{List of ingredient }} }
\label{tw-028406b151fd}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.13450000000000003\linewidth-2\tabcolsep}p{\dimexpr.5255\linewidth-2\tabcolsep}p{\dimexpr.34\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No & Ingredient & Functionality\\
\tblmidrule 
1 &
  Miconazole  &
  Active Pharmaceutical ingredient \\
2 &
  Whey protein concentrate (WPC) &
  Mucoadhesive agent\\
3 &
  Hydroxy propyl methyl cellulose (HYpromellose HPMC K15LV) &
  Release controlling polymer \\
4 &
  Lactose Monohydrate (450M) &
  Diluent/Pore former \\
5 &
  Microcrystalline cellulose (Avicel PH 102) &
  Diluent\\
6 &
  Talc &
  Glidant\\
7 &
  Magnesium stearate &
  Lubricant\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
The various combination of WPC, HPMC and Lactose have been performed through the design of experiments (DOE) full factorial design. 

The selection of design is based on the impacts of the factor for that full factorial design is chosen with three center points. Design details are as below mention Table~\ref{tw-3cb914064b21} and the design of trials in Table~\ref{tw-b26dc15e2396} \textbf{.}


\begin{table*}[!htbp]
\caption{\boldmath {\textbf{Design details of factors }} }
\label{tw-3cb914064b21}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.225\linewidth-2\tabcolsep}p{\dimexpr.175\linewidth-2\tabcolsep}p{\dimexpr.1252\linewidth-2\tabcolsep}p{\dimexpr.297\linewidth-2\tabcolsep}p{\dimexpr.1778\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Factors & \multicolumn{2}{p{\dimexpr(.3002\linewidth-2\tabcolsep)}}{3} & Base Design & 3, 8\\
\tblmidrule 
Runs &
  \multicolumn{2}{p{\dimexpr(.3002\linewidth-2\tabcolsep)}}{11} &
  Replicates &
  1\\
Blocks &
  \multicolumn{2}{p{\dimexpr(.3002\linewidth-2\tabcolsep)}}{1} &
  Centre pts (total) &
  3\\
\multicolumn{3}{p{\dimexpr(.52519999999999996\linewidth-2\tabcolsep)}}{\cAlignHack Factors } &
  \multicolumn{2}{p{\dimexpr(.47480000000000004\linewidth-2\tabcolsep)}}{\cAlignHack Responses }\\
Factors &
  \multicolumn{2}{p{\dimexpr(.3002\linewidth-2\tabcolsep)}}{Level } &
  Responses  &
  Target \\
HPMC K 15  &
  18 &
  22 &
  Detachment Force  &
  Maximum\\
WPC  &
  28 &
  32 &
  Dissolution at 3 Hr. &
  30 \ensuremath{\pm} 10\\
Lactose &
  6 &
  10 &
  Dissolution at 6 Hr.  &
  65 \ensuremath{\pm} 10\\
 &
   &
   &
  Dissolution at 8 Hr &
  At least 80 \%\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{\space }

\textbf{\space }


\begin{table*}[!htbp]
\caption{\boldmath {\textbf{ Design of trials (run)}} }
\label{tw-b26dc15e2396}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.182\linewidth-2\tabcolsep}p{\dimexpr.218\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}p{\dimexpr.20\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Std Order & Run Order & \multicolumn{3}{p{\dimexpr(.60\linewidth-2\tabcolsep)}}{\cAlignHack Factors (mg/tablet)}\\
\rowcolor{kwdboxcolor} &  & HPMC K 15LV & WPC & Lactose\\
\tblmidrule 
1 &
  1 &
  18 &
  28 &
  6\\
2 &
  2 &
  22 &
  28 &
  6\\
3 &
  3 &
  18 &
  32 &
  6\\
4 &
  4 &
  22 &
  32 &
  6\\
5 &
  5 &
  18 &
  28 &
  10\\
6 &
  6 &
  22 &
  28 &
  10\\
7 &
  7 &
  18 &
  32 &
  10\\
8 &
  8 &
  22 &
  32 &
  10\\
9 &
  9 &
  20 &
  30 &
  8\\
10 &
  10 &
  20 &
  30 &
  8\\
11 &
  11 &
  20 &
  30 &
  8\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Bioadhesion and Drug release } }
\label{tw-caa71932bac4}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{LLLLLLLLL}
\tbltoprule \rowcolor{kwdboxcolor}Std Order & Run Order & \multicolumn{3}{p{\dimexpr(\mcWidth{3}+\mcWidth{4}+\mcWidth{5})}}{\cAlignHack Factors} & \multicolumn{4}{p{\dimexpr(\mcWidth{6}+\mcWidth{7}+\mcWidth{8}+\mcWidth{9})}}{\cAlignHack Response}\\
\rowcolor{kwdboxcolor} &  & HPMC K 15 & WPC & Lactose & Detachment Force & Disso at 3 Hr & Disso at 6 Hr & Disso at 8 Hr\\
\tblmidrule 
1 &
  1 &
  18 &
  28 &
  6 &
  4.8 &
  38 &
  70 &
  95\\
2 &
  2 &
  22 &
  28 &
  6 &
  4.5 &
  26 &
  53 &
  80\\
3 &
  3 &
  18 &
  32 &
  6 &
  6.7 &
  35 &
  74 &
  95\\
4 &
  4 &
  22 &
  32 &
  6 &
  5.8 &
  22 &
  51 &
  79\\
5 &
  5 &
  18 &
  28 &
  10 &
  5.3 &
  32 &
  71 &
  90\\
6 &
  6 &
  22 &
  28 &
  10 &
  5.3 &
  32 &
  58 &
  92\\
7 &
  7 &
  18 &
  32 &
  10 &
  6.2 &
  35 &
  74 &
  93\\
8 &
  8 &
  22 &
  32 &
  10 &
  6.1 &
  29 &
  64 &
  82\\
9 &
  9 &
  20 &
  30 &
  8 &
  6.5 &
  28 &
  55 &
  86\\
10 &
  10 &
  20 &
  30 &
  8 &
  6.7 &
  32 &
  58 &
  90\\
11 &
  11 &
  20 &
  30 &
  8 &
  6.8 &
  29 &
  62 &
  88\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Factorial Regression: Detachment Force versus HPMC K15, WPC, Lactose, Centre Pt} }
\label{tw-77c976d21324}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2137\linewidth-2\tabcolsep}p{\dimexpr.2534\linewidth-2\tabcolsep}p{\dimexpr.26730000000000004\linewidth-2\tabcolsep}p{\dimexpr.2656\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S & R-sq & R-sq(adj) & R-sq(pred)\\
\tblmidrule 
0.152753 &
  99.28\% &
  96.40\% &
  *\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Analysis of Variance} }
\label{tw-753c9d75d5bd}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.3177\linewidth-2\tabcolsep}p{\dimexpr.079700000000000015\linewidth-2\tabcolsep}p{\dimexpr.15040000000000001\linewidth-2\tabcolsep}p{\dimexpr.15719999999999999\linewidth-2\tabcolsep}p{\dimexpr.1434\linewidth-2\tabcolsep}p{\dimexpr.1516\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Source & DF & Adj SS & Adj MS & F-Value & P-Value\\
\tblmidrule 
Model &
  8 &
  6.42970 &
  0.80371 &
  34.44 &
  0.029\\
Linear &
  3 &
  3.36375 &
  1.12125 &
  48.05 &
  0.020\\
HPMC K 15 &
  1 &
  0.21125 &
  0.21125 &
  9.05 &
  0.095\\
WPC &
  1 &
  3.00125 &
  3.00125 &
  128.62 &
  0.008\\
Lactose &
  1 &
  0.15125 &
  0.15125 &
  6.48 &
  0.126\\
2-Way Interactions &
  3 &
  0.49375 &
  0.16458 &
  7.05 &
  0.127\\
HPMC K 15*WPC &
  1 &
  0.06125 &
  0.06125 &
  2.63 &
  0.247\\
HPMC K 15*Lactose &
  1 &
  0.15125 &
  0.15125 &
  6.48 &
  0.126\\
WPC*Lactose &
  1 &
  0.28125 &
  0.28125 &
  12.05 &
  0.074\\
3-Way Interactions &
  1 &
  0.03125 &
  0.03125 &
  1.34 &
  0.367\\
HPMC K 15*WPC*Lactose &
  1 &
  0.03125 &
  0.03125 &
  1.34 &
  0.367\\
Curvature &
  1 &
  2.54095 &
  2.54095 &
  108.90 &
  0.009\\
Error &
  2 &
  0.04667 &
  0.02333 &
   &
  \\
Total &
  10 &
  6.47636 &
   &
   &
  \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/56ddecb5-976c-4a59-a67f-b83fa545ee3d-upicture1.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/56ddecb5-976c-4a59-a67f-b83fa545ee3d-upicture1.png}{\includegraphics{images/56ddecb5-976c-4a59-a67f-b83fa545ee3d-upicture1.png}}{}
\makeatother 
\caption{\boldmath {Half Normal Plot of detachment force}}
\label{f-74478f92d43d}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/955ac3ac-ac49-4c7d-899b-0429d4e8293d-upicture2.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/955ac3ac-ac49-4c7d-899b-0429d4e8293d-upicture2.png}{\includegraphics{images/955ac3ac-ac49-4c7d-899b-0429d4e8293d-upicture2.png}}{}
\makeatother 
\caption{\boldmath {Pareto Chart of Detachment Force}}
\label{f-4ca0ecf80297}
\end{figure}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Model Summary} }
\label{tw-7eb8dda3309b}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.20680000000000003\linewidth-2\tabcolsep}p{\dimexpr.26549999999999997\linewidth-2\tabcolsep}p{\dimexpr.31230000000000004\linewidth-2\tabcolsep}p{\dimexpr.2154\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S & R-sq & R-sq(adj) & R-sq(pred)\\
\tblmidrule 
2.08167 &
  95.80\% &
  78.98\% &
  *\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Analysis of Variance} }
\label{tw-28764295585c}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.175\linewidth-2\tabcolsep}p{\dimexpr.0966\linewidth-2\tabcolsep}p{\dimexpr.0884\linewidth-2\tabcolsep}p{\dimexpr.12\linewidth-2\tabcolsep}p{\dimexpr.12\linewidth-2\tabcolsep}p{\dimexpr.0404\linewidth-2\tabcolsep}p{\dimexpr.1996\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{Source} & DF & Adj SS & \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{Adj MS} & F-Value & P-Value\\
\tblmidrule 
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{Model} &
  8 &
  197.515 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{24.689} &
  5.70 &
  0.158\\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{Linear} &
  3 &
  132.375 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{44.125} &
  10.18 &
  0.091\\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{HPMC K 15} &
  1 &
  120.125 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{120.125} &
  27.72 &
  0.034\\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{WPC} &
  1 &
  6.125 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{6.125} &
  1.41 &
  0.357\\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{Lactose} &
  1 &
  6.125 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{6.125} &
  1.41 &
  0.357\\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{2-Way Interactions} &
  3 &
  57.375 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{19.125} &
  4.41 &
  0.190\\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{HPMC K 15*WPC} &
  1 &
  6.125 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{6.125} &
  1.41 &
  0.357\\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{HPMC K 15*Lactose} &
  1 &
  45.125 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{45.125} &
  10.41 &
  0.084\\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{WPC*Lactose} &
  1 &
  6.125 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{6.125} &
  1.41 &
  0.357\\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{3-Way Interactions} &
  1 &
  3.125 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{3.125} &
  0.72 &
  0.485\\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{HPMC K 15*WPC*Lactose} &
  1 &
  3.125 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{3.125} &
  0.72 &
  0.485\\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{Curvature} &
  1 &
  4.640 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{4.640} &
  1.07 &
  0.409\\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{Error} &
  2 &
  8.667 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{4.333} &
   &
  \\
\multicolumn{2}{p{\dimexpr(.2716\linewidth-2\tabcolsep)}}{Total} &
  10 &
  206.182 &
  \multicolumn{2}{p{\dimexpr(.1604\linewidth-2\tabcolsep)}}{} &
   &
  \\
\multicolumn{8}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Regression Equation in Uncoded Units }\\
Disso at 3 Hr  &
  = &
  \multicolumn{6}{p{\dimexpr(.7284\linewidth-2\tabcolsep)}}{471 - 18.9 HPMC K 15 - 10.3 WPC - 64.9 Lactose + 0.406 HPMC K 15*WPC + 2.94 HPMC K 15*Lactose + 1.78              WPC*Lactose - 0.0781 HPMC K 15*WPC*Lactose - 1.46 Ct Pt}\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/47997d56-6ad7-458f-91d4-2cff5d2cc08d-upicture3.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/47997d56-6ad7-458f-91d4-2cff5d2cc08d-upicture3.png}{\includegraphics{images/47997d56-6ad7-458f-91d4-2cff5d2cc08d-upicture3.png}}{}
\makeatother 
\caption{\boldmath {Half Normal plot }}
\label{f-8af297937d96}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/20b9b292-2814-4f66-ab84-f45c2fdc77ce-upicture4.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/20b9b292-2814-4f66-ab84-f45c2fdc77ce-upicture4.png}{\includegraphics{images/20b9b292-2814-4f66-ab84-f45c2fdc77ce-upicture4.png}}{}
\makeatother 
\caption{\boldmath {Pareto Chart }}
\label{f-e9127cd34a25}
\end{figure}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Model Summary} }
\label{tw-cce9231d6f66}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.21200000000000003\linewidth-2\tabcolsep}p{\dimexpr.26889999999999997\linewidth-2\tabcolsep}p{\dimexpr.2466\linewidth-2\tabcolsep}p{\dimexpr.2725\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S & R-sq & R-sq(adj) & R-sq(pred)\\
\tblmidrule 
3.51188 &
  96.55\% &
  82.73\% &
  *\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Regression Equation in Uncoded Units} }
\label{tw-8a2de5b60232}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{LLL}
\tbltoprule 
Disso at 6 Hr &
  \cAlignHack = &
  -481 + 28.4 HPMC K 15 + 23.3 WPC + 68.4 Lactose - 1.22 HPMC K 15*WPC - 3.69 HPMC K 15*Lactose - 2.59 WPC*Lactose + 0.141 HPMC K 15*WPC*Lactose - 6.04 Ct Pt\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/d2400e60-331e-4a13-97b0-75e61b31c865-upicture5.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/d2400e60-331e-4a13-97b0-75e61b31c865-upicture5.png}{\includegraphics{images/d2400e60-331e-4a13-97b0-75e61b31c865-upicture5.png}}{}
\makeatother 
\caption{\boldmath {Half Normal Plot }}
\label{f-6430d7fff98c}
\end{figure}
\egroup

\bgroup
\fixFloatSize{images/54feca00-da50-47c9-adc0-5e6ffc29c335-upicture6.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/54feca00-da50-47c9-adc0-5e6ffc29c335-upicture6.png}{\includegraphics{images/54feca00-da50-47c9-adc0-5e6ffc29c335-upicture6.png}}{}
\makeatother 
\caption{\boldmath {Pareto Chart }}
\label{f-f740b4892dd2}
\end{figure}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Model Summary} }
\label{tw-e5b32b118911}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2016\linewidth-2\tabcolsep}p{\dimexpr.2707\linewidth-2\tabcolsep}p{\dimexpr.3019\linewidth-2\tabcolsep}p{\dimexpr.2258\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S & R-sq & R-sq(adj) & R-sq(pred)\\
\tblmidrule 
2 &
  97.59\% &
  87.94\% &
  *\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Analysis of Variance} }
\label{tw-4c6bef898519}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1729\linewidth-2\tabcolsep}p{\dimexpr.10859999999999998\linewidth-2\tabcolsep}p{\dimexpr.10129999999999999\linewidth-2\tabcolsep}p{\dimexpr.1055\linewidth-2\tabcolsep}p{\dimexpr.05880000000000001\linewidth-2\tabcolsep}p{\dimexpr.1729\linewidth-2\tabcolsep}p{\dimexpr.12\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{Source} & DF & Adj SS & \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{Adj MS} & F-Value & P-Value\\
\tblmidrule 
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{Model} &
  8 &
  323.636 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{40.455} &
  10.11 &
  0.093\\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{Linear} &
  3 &
  216.000 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{72.000} &
  18.00 &
  0.053\\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{HPMC K 15} &
  1 &
  200.000 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{200.000} &
  50.00 &
  0.019\\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{WPC} &
  1 &
  8.000 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{8.000} &
  2.00 &
  0.293\\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{Lactose} &
  1 &
  8.000 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{8.000} &
  2.00 &
  0.293\\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{2-Way Interactions} &
  3 &
  89.500 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{29.833} &
  7.46 &
  0.121\\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{HPMC K 15*WPC} &
  1 &
  24.500 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{24.500} &
  6.12 &
  0.132\\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{HPMC K 15*Lactose} &
  1 &
  60.500 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{60.500} &
  15.13 &
  0.060\\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{WPC*Lactose} &
  1 &
  4.500 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{4.500} &
  1.13 &
  0.400\\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{3-Way Interactions} &
  1 &
  18.000 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{18.000} &
  4.50 &
  0.168\\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{HPMC K 15*WPC*Lactose} &
  1 &
  18.000 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{18.000} &
  4.50 &
  0.168\\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{Curvature} &
  1 &
  0.136 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{0.136} &
  0.03 &
  0.871\\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{Error} &
  2 &
  8.000 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{4.000} &
   &
  \\
\multicolumn{2}{p{\dimexpr(.2815\linewidth-2\tabcolsep)}}{Total} &
  10 &
  331.636 &
  \multicolumn{2}{p{\dimexpr(.2317\linewidth-2\tabcolsep)}}{} &
   &
  \\
\multicolumn{8}{p{\dimexpr(1\linewidth-2\tabcolsep)}}{\cAlignHack Regression Equation in Uncoded Units }\\
Disso at 8 Hr &
  \cAlignHack = &
  \multicolumn{6}{p{\dimexpr(.7185\linewidth-2\tabcolsep)}}{852 - 39.9 HPMC K 15 - 20.3 WPC - 120.1 Lactose + 1.063 HPMC K 15*WPC + 6.31 HPMC K 15*Lactose + 3.56 WPC*Lactose - 0.1875 HPMC K 15*WPC*Lactose - 0.25 Ct Pt}\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\bgroup
\fixFloatSize{images/4f0dec22-44e2-4e17-bfcc-cf04c8871dc6-upicture7.png}
\begin{figure}[!htbp]
\centering \makeatletter\IfFileExists{images/4f0dec22-44e2-4e17-bfcc-cf04c8871dc6-upicture7.png}{\includegraphics{images/4f0dec22-44e2-4e17-bfcc-cf04c8871dc6-upicture7.png}}{}
\makeatother 
\caption{\boldmath {Half Normal Plot }}
\label{f-c2e1b0f1fc5e}
\end{figure}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Parameters for Optimization } }
\label{tw-30cb105edb12}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1489\linewidth-2\tabcolsep}p{\dimexpr.136\linewidth-2\tabcolsep}p{\dimexpr.13709999999999999\linewidth-2\tabcolsep}p{\dimexpr.14200000000000001\linewidth-2\tabcolsep}p{\dimexpr.1449\linewidth-2\tabcolsep}p{\dimexpr.1548\linewidth-2\tabcolsep}p{\dimexpr.13629999999999999\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Response & Goal & Lower & Target & Upper & Weight & Importance\\
\tblmidrule 
Disso at 8 Hr &
  Target &
  79.0 &
  80.0 &
  95 &
  1 &
  1\\
Disso at 6 Hr &
  Maximum &
  51.0 &
  74.0 &
   &
  1 &
  1\\
Disso at 3 Hr &
  Maximum &
  22.0 &
  38.0 &
   &
  1 &
  1\\
Detachment Force &
  Maximum &
  4.5 &
  6.8 &
   &
  1 &
  1\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Solution for optimization } }
\label{tw-7731316ab63f}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.0923\linewidth-2\tabcolsep}p{\dimexpr.1243\linewidth-2\tabcolsep}p{\dimexpr.0976\linewidth-2\tabcolsep}p{\dimexpr.08879999999999999\linewidth-2\tabcolsep}p{\dimexpr.14240000000000004\linewidth-2\tabcolsep}p{\dimexpr.14779999999999998\linewidth-2\tabcolsep}p{\dimexpr.14329999999999998\linewidth-2\tabcolsep}p{\dimexpr.1635\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Solution & HPMC K 15 & WPC & Lactose & Disso at 8 Hr Fit & Disso at 6 Hr Fit & Disso at 3 Hr Fit & Detachment Force Fit\\
\tblmidrule 
1 &
  22 &
  32 &
  10 &
  82 &
  64 &
  29 &
  6.1\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Multiple Response Prediction} }
\label{tw-c54ddac74e7b}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.22536\linewidth-2\tabcolsep}p{\dimexpr.14396\linewidth-2\tabcolsep}p{\dimexpr.20356\linewidth-2\tabcolsep}p{\dimexpr.20356\linewidth-2\tabcolsep}p{\dimexpr.22356\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Variable & Setting &  &  & \\
\tblmidrule 
HPMC K 15 &
  22 &
   &
   &
  \\
WPC &
  32 &
   &
   &
  \\
Lactose &
  10 &
   &
   &
  \\\cline{1-1}\cline{2-2}\cline{3-3}\cline{4-4}\cline{5-5}
Response &
  Fit &
  SE Fit &
  95\% CI &
  95\% PI\\\cline{1-1}\cline{2-2}\cline{3-3}\cline{4-4}\cline{5-5}
Disso at 8 Hr &
  82.00 &
  2.00 &
  (73.39, 90.61) &
  (69.83, 94.17)\\
Disso at 6 Hr &
  64.00 &
  3.51 &
  (48.89, 79.11) &
  (42.63, 85.37)\\
Disso at 3 Hr &
  29.00 &
  2.08 &
  (20.04, 37.96) &
  (16.33, 41.67)\\
Detachment Force &
  6.100 &
  0.153 &
  (5.443, 6.757) &
  (5.171, 7.029)\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Actual Trial Results } }
\label{tw-387c87a54ac4}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.1018\linewidth-2\tabcolsep}p{\dimexpr.127\linewidth-2\tabcolsep}p{\dimexpr.1182\linewidth-2\tabcolsep}p{\dimexpr.11139999999999999\linewidth-2\tabcolsep}p{\dimexpr.1416\linewidth-2\tabcolsep}p{\dimexpr.12\linewidth-2\tabcolsep}p{\dimexpr.12\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Solution & HPMC K 15 & WPC & Lactose & Disso at 8 Hr Fit & Disso at 6 Hr Fit & Disso at 3 Hr Fit & Detachment Force Fit\\
\tblmidrule 
1 &
  22 &
  32 &
  10 &
  80 &
  65 &
  39 &
  6\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Manufacturing process }

Miconazole, Whey protein concentrate (WPC), Hydroxypropyl methylcellulose (Hypromellose HPMC K15LV), Lactose Monohydrate (450M) mixed and granulated using purified water in High shear mixture granulator (HSMG) followed by drying, Milling and milled granules were lubricated with Microcrystalline cellulose (Avicel PH 102) 11mg/tablet or adjusted quantity, talc (1mg/tablet) and Magnesium stearate (1mg/tablet). 

Tablet weight kept as 115mg and weight compensation done with Microcrystalline cellulose (Avicel PH102)

Compression of the tablets performed using Tablet compression machine (Cad Mach Single rotory 8 Station) with specially designed 8 mm tooling having concave at one side and flat at other.

The compression force was kept in the range of 6-8KP.  

\textbf{Evaluation/Characterization}

\textbf{Determination of physical parameters of tablets }

Tablet thickness, Hardness, weight variation, friability test \BreakURLText{(www.usp.org} \guilsinglright document \guilsinglright gen-chapter) performed as per USP and recorded. 

\textit{\textbf{Ex- Vivo}} \textbf{ determination of bio adhesion }

\textit{In Vitro} comparative bio adhesion study (peak detachment force) through Tensiometer \unskip~\citep{723851:17171359}.

Porcine gingiva was obtained from slaughterhouse the mucosPO4,8.0g NaCl a were stored at\ensuremath{-}20 \ensuremath{^{\ensuremath{\circ }}}C in isotonic buffered saline pH 7.4 (2.38 g Na2HPO4\ensuremath{\cdot}H2O, 0.19 g KH2PO4,8.0g) NaCl made up to 1000 ml with demineralized water. The porcine gingival tissue was attached with glue to the plate of the tensiometer. After hydrating the mucosa with 15\_l of the isotonic phosphate-buffered saline, the tablet was fixed on the mucosa applying a force of 0.5N for 5 min. After the initial contact, the thermostatic beaker (37 \ensuremath{^{\ensuremath{\circ }}}C) was filled with 125 ml isotonic buffered saline pH 7.4 at 37 \ensuremath{^{\ensuremath{\circ }}}C. Next, the tablet and mucosa were pulled apart at a speed of 5mmmin\ensuremath{-}1 until a complete ru and detachment force was recorded listed in Table~\ref{tw-caa71932bac4}.

\textbf{Drug Release studies }

Dissolution of all tablets was performed at the following condition \BreakURLText{(www.accessdata.fda.gov).}

Apparatus USP I~Basket, RPM 50, Medium pH 6.5 phosphate buffer with 0.5 \% Sodium Lauryl Sulphate, Volume 1000mL,Time points 1Hrs, 3Hrs, 4Hrs, 6Hrs, 8Hrs and 10hrs. Results of the same shown in Table~\ref{tw-caa71932bac4}.
    
\section{Results and Discussion}
\textbf{Physical parameters of Tablets}

Thickness: Avg : 2.2mm (n:12), Hardness : 3.1kp (n:12) ,Weight: 115.3 (n:12), Friability  0.06 \%

\textbf{Interpretation}

From the above plots half-normal plot, Pareto chart and Interaction plot, it can be depicting that WPC is the most impacting factor on the Detachment force. As the concentration of the WPC increase, then Detachment force is also increasing Tables~\ref{tw-77c976d21324} and~\ref{tw-753c9d75d5bd}, Figure~\ref{f-74478f92d43d} and Figure~\ref{f-4ca0ecf80297}.

\textbf{Dissolution at 3hrs }

Impact of dissolution at 3hrs shown in Tables~\ref{tw-7eb8dda3309b} and~\ref{tw-28764295585c}, Figure~\ref{f-8af297937d96}and Figure~\ref{f-e9127cd34a25}.

\textbf{Interpretation}

From the above plots half-normal plot, Pareto chart and Interaction plot, it can be depicting that HPMC K 15 is the most impacting factor on Dissolution at 3 Hr. As the concentration of the HPMC increase, then Dissolution is also increasing.  

\textbf{Dissolution at 6 Hr}

Impact of dissolution at 6hrs shown in Tables~\ref{tw-cce9231d6f66} and~\ref{tw-8a2de5b60232}, Figure~\ref{f-6430d7fff98c}and Figure~\ref{f-f740b4892dd2}.

\textbf{Interpretation}

From the above plots half-normal plot, Pareto chart and Interaction plot, it can be depicting that HPMC K 15 is the most impacting factor on Dissolution at 6 Hr. As the concentration of the HPMC increase, then Dissolution is also increasing.  

\textbf{Response}

\textbf{Dissolution at 8 Hr}

Impact of dissolution at 6hrs shown in Tables~\ref{tw-e5b32b118911} and~\ref{tw-4c6bef898519}, Figure~\ref{f-c2e1b0f1fc5e}.

\textbf{Interpretation }

From the above plots half-normal plot, Pareto chart and Interaction plot, it can be depicting that HPMC K 15 is the most impacting factor on Dissolution at 8 Hr. As the concentration of the HPMC increase then Dissolution is also increasing.

\textbf{Optimization }

Optimized parameters were shown in Tables~\ref{tw-30cb105edb12}, \ref{tw-7731316ab63f}, \ref{tw-c54ddac74e7b} and~\ref{tw-387c87a54ac4}.

\textbf{Inference}

Above mention Trail was conducted for optimization predicted results and actual results are well within the limit. Hence it can be said that the product is optimized from above setting parameters with 95\% CI.
    
\section{Conclusions}
The mucoadhesive potential of Whey protein concentrate has been investigated using Miconazole as a Model antifungal drug through the various combination with HPMC K15LV as a release controlling polymer. The optimized quantity of Whey protein 32mg/tablet) found to be providing good bioadhesive/mucoadhesive strength calculated using a tensiometer. The prolonged-release of Miconazole was obtained and an optimized combination of Whey protein, HPMC and Lactose have been established, which can be used as a platform technology for mucoadhesive drug delivery.
    
\section{Acknowledgement}
Mr. Mandar Kor for supporting in statistical evaluation of data.
    

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