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\def\RunningAuthor{Gowda D V et al.}
\firstPage{176}
\articleType{Review Article}
\receivedDate{13.07.2019}
\acceptedDate{15.10.2019}
\revisedDate{01.10.2019}
\journalVolume{2020, 11}
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\journalDoi{ijrps.v11i1.1804}
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\def\journalTitle{International Journal of Research in Pharmaceutical Sciences}

\title{\textbf{Recent developments in nano micelles as drug delivery system}}
\author{Pooja~Mallya,  
            Gowda~D~V\textsuperscript{*},  
            Mahendran~B,  
            Bhavya~M~V, 
            Vikas~Jain~\\[5pt]{Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education \& Research, Sri Shivarathreeshwara Nagar, Mysuru - 570015, Karnataka, India}}

\begin{abstract}
Targeting of the drug directly to the cells, tissues, or organs with no impact on healthy cells is a challenge. In the current era, it's been made possible by therapeutic interventions. The novel drug delivery systems such as nano particulates, liposomes, aquasomes, phytosomes, dendrimers, nano sponges, nano micelles are developed. Nano micelles are developed for efficient targeting and are currently in trend as therapeutic carriers of water-insoluble drugs. Micelles are self-assembling Nano-sized colloidal particles with a hydrophobic core and hydrophilic shell. Among the micelle-forming compounds, amphiphilic copolymers, i.e., polymers consisting of hydrophobic block and hydrophilic block, are gaining increasing attention. Polymeric micelles possess high stability both \textit{in vitro} and \textit{in vivo} with good biocompatibility. Nano micelles are used widely because of the smaller size range of 10 to 100nm, with greater drug loading capacity. Advantages over other dosage forms include solubilization of poorly soluble drugs, sustained release, protection of drugs from degradation and metabolism. The property discussed includes CMC, size, and aggregation number, and stability. CMC is the minimum polymer concentration required for micelle formation. Aggregation number (Nₐ) is the number of polymeric chains required to form micelles, and it ranges between tens to hundreds. Thermodynamic stability is based on size, the optical clarity of solution, viscosity, and surface tension. Kinetic stability accounts for micellar integrity. This review will discuss some recent trends in using micelles as pharmaceutical carriers such as to deliver drugs in conditions such as TB, cancer, ocular complications, etc. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Amphiphiles,\newline Block copolymers,\newline Drug delivery,\newline Polyion complexes,\newline Solubilisation
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Gowda~D~V~\\ Phone:\ +91 9663162455~\\  Email:\ dvgowda@jssuni.edu.in
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
In order to ameliorate the discrete delivery of drugs with low therapeutic index, assorted drug carriers such as liposomes, microparticles, nano-associates, nanoparticle, and drug polymer-consolidates and polymeric micelles have been flourished. Nano micelles were developed for the first time in 1984 \unskip~\citep{628393:14701924}. The polymers utilized to construct nano-micelles must be biodegradable. Extensively employed polymers counts poly (lactide), poly (propylene oxide) (PPO), poly (glycolide), poly (lactide-co-glycolide), and poly (\ensuremath{\epsilon}-caprolactone) (PCL) among which ubiquitously utilized hydrophilic polymer being Polyethylene glycol (PEG).

Research on nano-micelles is propelling and is a provocative field of drug delivery for solubilization, stabilization, and delivery of definite drugs. Polymeric micelles possess attributes such as small size, distinctive nanoscopic architecture, stability, compatibility with the drugs. The attributes of micelles scrutinized include critical micellization concentration (CMC), micellar aggregation number, structure, dimensions, and thermodynamic and kinetic stability. Polymeric micelles affiliate to the set of amphiphilic copolymers, which on clustering form nano-scale (1{\textendash}200 nm) assemblage. The outer shell modulates in-vivo pharmacokinetic attributes, whilst inner core rehires the drug, conserves stability, and drug delivery profile. The distinctiveness of the polymeric micelles is that they can encapsulate hydrophobic drugs in the core while the exterior can be refined correspondingly \unskip~\citep{628393:14720046,628393:14720047}. They offer advantages such as facile composition, biocompatible, and considerable efficacy \unskip~\citep{628393:14720048}, porter for the abjectly-water soluble medication in their hydrophobic core \unskip~\citep{628393:14720049} and target specificity \unskip~\citep{628393:14720050}. Nano micelles are expensive and provide rise to toxicity issues\unskip~\citep{628393:14720051}. 

\textbf{Requisites for the formulation of Nano micell}

\textbf{Polymers}

\unskip~\citep{628393:14720052}Table~\ref{tw-a139a29116a4} depicts the polymers used in the formulation of nano micelles.


\begin{table*}[!htbp]
\caption{\boldmath {Polymers used in the formulation of nano micelles} }
\label{tw-a139a29116a4}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.4442\linewidth-2\tabcolsep}p{\dimexpr.38709999999999994\linewidth-2\tabcolsep}p{\dimexpr.16869999999999997\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Polymers & Curative agent & Size\\
\tblmidrule 
Peo-ppo-peo  &
  Lacz gene contained in plasmid dna  &
  155 \ensuremath{\pm} 44 nm \\
PEG 40 stearate &
  Cyclosporine A &
  200 nm\\
Sympatene AS  &
  Cyclosporine A  &
  9.7 \ensuremath{\pm} 0.05 nm \\
Sympatene AS and Sympatene ACS &
  Cyclosporine A &
  9 {\textendash} 12 nm\\
Pluronic F127 with chitosan  &
  Dexamethasone  &
  25.4 {\textendash} 28.7 nm \\
Quaternary ammonium palmito-glycol chitosan &
  Prednisolone &
  10 {\textendash} 100 nm\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Approaches for the development of nano micelles}

By contemplating the physical and chemical attributes of the polymer chain length and monomer features, nano micelles are composed in two ways,


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\caption{\boldmath {Direct dissolution approach for the preparation of nano micelles}}
\label{f-5d542016deb7}
\end{figure*}
\egroup

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\caption{\boldmath {Dialysis technique for the preparation of nano micelles where in polymers and drugs are passed through the dialysis membrane}}
\label{f-c716fa398601}
\end{figure*}
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\caption{\boldmath {(o/w emulsion method) depicts the method involved in the preparation of nano micelles}}
\label{f-2cabef60b846}
\end{figure*}
\egroup

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\makeatother 
\caption{\boldmath {solution casting approach in which the thin film formation by polymer leads to micelle formation by redispersion}}
\label{f-0d6cb5e61206}
\end{figure*}
\egroup

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\makeatother 
\caption{\boldmath {lyophilization technique where the solution is freeze-dried to obtain nano micelles which needs reconstitution}}
\label{f-3f98ebe5558d}
\end{figure*}
\egroup

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\makeatother 
\caption{\boldmath {Three phases of wound healing }}
\label{f-e34130ff7c6a}
\end{figure*}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Recent developments in nano micelles as drug delivery systems used to deliver a drug into the eyes} }
\label{tw-c804186997f2}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2569\linewidth-2\tabcolsep}p{\dimexpr.212\linewidth-2\tabcolsep}p{\dimexpr.231\linewidth-2\tabcolsep}p{\dimexpr.30010000000000005\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Polymer or surfactant & Medicament & Size domain & Observation\\
\tblmidrule 
Pluronicpolymer   &
  Drug-Pilocarpine  &
  23.3\ensuremath{\pm}0.5nm in water,30.3 \ensuremath{\pm}o.3nm in 7.4 pH buffer  &
  63.9\% raise in Area under the curve alongst vital protracted miotic activity  \unskip~\citep{628393:14720062}.\\
Poloxamine (tetronic T1107) &
  Alpha tocopherol-drug &
  30.5-39.5nm &
  Nano micelles remained firm for days under 3-4{\textdegree}C \unskip~\citep{628393:14720063}.\\
Poloxamine (tetronic T908, T1107, t1307)  &
  Ethoxzolamide   &
  Several faceted dispensation  &
  Tuneable medicinal substance delivery profile attained by variegated nano micelle organization \unskip~\citep{628393:14720064}.\\
m-Polyethyleneglycol+ hex poly(lactic acid) &
  Cyclosporine A &
  53\ensuremath{\pm}2nm &
  Improved penetrability across cornea \unskip~\citep{628393:14720065,628393:14720066,628393:14720067,628393:14720068}.\\
mPEG - PDLLA  &
  Pirezepine HCl  &
  PEG/PLA size   \mbox{}\protect\newline  (nm)   \mbox{}\protect\newline 80/20 152.5  \mbox{}\protect\newline 50/50 89.6   &
  Intraocular drug extent inflated in rabbit scrutinization {\textendash} in vitro biocompatibility review on topical introduction \unskip~\citep{628393:14720069}.\\
Pluronic F127 with chitosan &
  Dexamethasone &
  25.4 {\textendash} 28.9nm &
  Remarkable pharmacological reciprocation on instillation \unskip~\citep{628393:14720070}.\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Developments been made in nano micelles for treating tuberculosis} }
\label{tw-7f23b8962763}
\def\arraystretch{1.1}
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\tbltoprule \rowcolor{kwdboxcolor}Researchers & Drug & Polymer used & Evaluation\\
\tblmidrule 
\unskip~\citep{628393:14720091} &
  Rifampicin  &
  Stearic acid and the amine group of branched polyethylenimine adsorbed by covalent bond  &
  The average size range of 218nm  \mbox{}\protect\newline zeta potential = 16.7mv  \mbox{}\protect\newline Drug loading efficiency = 99\%  \mbox{}\protect\newline Drug release = 85\% for 24 hr  \mbox{}\protect\newline In vitro cytotoxicity studies to check biocompatibility in which 80\% of cells out of the population was found viable. \\
\unskip~\citep{628393:14720092} &
  Rifampicin &
  Block copolymer of polyethylene oxide complexed withdistearoyl phosphatidyl-ethanolamine &
  Effectiveness of encapsulation was 83.5 {\textendash} 103.9\%\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
1. \textbf{Direct dissolution approach}

Employed for hydrophobic block copolymers like block copolymers of poly (butyl acrylate) and poloxamers \unskip~\citep{628393:14720053}. Figure~\ref{f-5d542016deb7} describes the direct dissolution technique employed in the preparation of nano micelles.\textbf{\space }

2. \textbf{Solvent casting approach}

Methodologies include dialysis, o/w emulsion method, solution casting, and freeze-drying.

\textbf{Dialysis}

Principle: Application of high boiling point and the use of water-soluble organic solvents. Dimethylsulfoxide (DMSO) is a solvent of choice. Figure~\ref{f-c716fa398601} shows the dialysis technique wherein the mixture is charged into a chemical analysis membrane bag for dialysis averse to water for a minimum period of 12hr with successive water substitution at a definite period of time. Evaporation of organic solvent entails the evolution of drug enriched micelles.

Constraints include drug mislaying and weak potency of encapsulation.

\textbf{Oil in water emulsion methodology}

Drug and copolymer are solubilized in oil miscible liquids along with water for entrapment. Vaporization of organic solvent on stirring incites evolution of hydrophobic drug entrapped nano micelle \unskip~\citep{628393:14720054}. Figure~\ref{f-2cabef60b846} shows o/w emulsion method involved in preparing nano micelles \unskip~\citep{628393:14720055}. 

\textbf{Solution casting approach}

\unskip~\citep{628393:14720056,628393:14720057,628393:14720058,628393:14720059}. Figure~\ref{f-0d6cb5e61206} illustrates the solution casting approach where redispersion of thin-film yields nano micelles\unskip~\citep{628393:14720060}.

\textbf{Freeze-drying / Lyophilisation approach }

Single pace operation of yielding micelles where the therapeutic entity and copolymers are solubilised in tertiary-butanol together with lyophilized to obtain fine ice crystals. Sublimation of these crystals, as shown in Figure~\ref{f-3f98ebe5558d}, generates freeze-thawed cake, which upon rehydration yields drug-stacked nano-micelles \unskip~\citep{628393:14720061}.

\ensuremath{^{}}\textbf{Recent Developments}

\textbf{Ocular Drug Delivery }

Nano micelles can be used to deliver drug intraocularly to improve corneal permeability and improve the ocular bioavailability. Table~\ref{tw-c804186997f2} indicates the advancements in the treatment of ocular disorders along with the polymers used.

\textbf{Cancer}

\textbf{Gene therapy}

Gene therapy comprises of nucleic acid {\textendash} pluronic polyplex complex that exhibits improved stability by encapsulation of gene rather than adaptation chemically, thus defending against serum degradation \unskip~\citep{628393:14720071,628393:14720072}. Mode of action is by clathrin-mediated endocytosis.

\textbf{Glioma}

Glioma is the recurrent and fatal tumour of the brain, and the rate of prognosis is poor \unskip~\citep{628393:14720073}. Quercetin nanomicelles were used in the treatment of glioma. Mechanism of action is by hindering the expression of the mutant p53 gene \unskip~\citep{628393:14720074} and elevating the rate of apoptosis in glioma affected cells \unskip~\citep{628393:14720075}. Quercetin loaded nanomicelles were composed by the solvent- evaporation technique and analyzed by HPLC \unskip~\citep{628393:14720076}.

\textbf{Melanoma}

Clotrimazole (CLT) loaded nanomicelles are used in the treatment of melanoma and acts on calcium, potassium channel, and apoptosis \unskip~\citep{628393:14720077}. 

\textbf{Increased tumour vaccination by in situ nano micelle - provoking microneedles}

Resiquimod (R848) nano micelles are proven to increase the tumour vaccination \textit{in situ}. Resiquimod is an imidazoquinoline derivative that falls under the category of an immunomodulator. Resiquimod exhibits specificity for a person's toll-like receptor 7 and 8 conveyed on dendritic cells, macrophages, NK cells, and B-lymphocytes \unskip~\citep{628393:14720078}.

\textbf{Atherosclerosis}

Iron oxide super paramagnetic Nano micelles, a de-novo magnetic probe, is the method of treatment employed.

Principle: Magnetic resonance imaging (MRI) \unskip~\citep{628393:14720079} The Nano probes act by passive accumulation in the process of engulfment by the macrophages \unskip~\citep{628393:14720080}.

 Criteria for targeting atherosclerotic plaques,


  
  \begin{enumerate}
  \item \relax PC-stabilised Nano micelle protein corona of ApoB-100, a protein responsible for plaque development \unskip~\citep{628393:14720081}
  \item \relax  A greater degree of PC-PLC expression in atherosclerotic lesions 
  \item \relax  De-esterification amidst PC glycerol and phosphate moieties, which are mediated by natural PC-PLC \unskip~\citep{628393:14720082}, 89Zr, a radioelement, helps in the detection of the amount of Nano micelles in target tissues \unskip~\citep{628393:14720083}.
  \end{enumerate}
  \textbf{Nano micelle-in-nano fibre system providing long term dual controlled release in antibacterial medical dressings}

Wound healing is a tidy clinical condition in which tissues respond to injury and self heals and can be disserted into 3 phases, as shown in Figure~\ref{f-e34130ff7c6a}\unskip~\citep{628393:14720083,628393:14720084,628393:14720085}.

Pluronic F127 micellar solution was prepared by the film dispersion hydration technique. AMX 40mg and pluronic F127 200mg were weighed and dissolved in 30ml methanol contained in 100ml flask, which was stirred up to 4hrs until a homogenous solution was formed. Eliminate excess organic solvent using a rotary evaporator maintained at15rpm, 60{\textdegree}C to form a thin film. Reconstitute the film by 10ml deionized water and stir at 100rpm for 1.5hr and perform membrane filtration. Transfer this micellar solution to 5ml vials containing 2\%w/w mannitol (lyoprotectant) and subject for freeze-drying. The next step is coaxial electrospinning maintained at 16kv voltage, 25\ensuremath{\pm}3{\textdegree}C, and 55\ensuremath{\pm}5\% RH in order to enclose drug-carrying nano micelles in Nano fibres. Collect the fibres and vacuum dry for 24 hours.

Evaluation of nano micelle-in-nano fibre system,


  
  \begin{enumerate}
  \item \relax ANOVA is employed for statistical analysis.
  \item \relax  Encapsulation efficiency 
  \item \relax  Percentage of drug loading capacity
  \item \relax  Antibacterial test \unskip~\citep{628393:14720086}
  \end{enumerate}
  \textbf{Osteoporosis}

Osteoporosis is a bone disorder characterized by diminished bone formation, thus condensing the period of survival of bone cells \unskip~\citep{628393:14720087,628393:14720088}. This is caused by estrogenic deficiency. Raloxifene HCl (RH) nano micelles can be used to treat osteoporosis. The nano micelles were prepared using the Ipegal and condensed form of poly oxythylenee. Nonyl-phenyl ether (C95H184O41) was used as a non-ionic, non-denaturing surfactant with HLB 17, relative mass 1981.99. Raloxifene HCl is a selective oestrogen-receptor modulator (SERM) - non-steroidal agonist \unskip~\citep{628393:14720089,628393:14720090}.

\textbf{Tuberculosis}

Tuberculosis is an infectious disease affecting the lungs. It is caused by Mycobacterium tuberculosis. The symptoms of TB may include weight loss, loss of apetite, coughing up blood or mucus, fatigue, fever, and night sweats. Nanomicelles of Rifampicin plays an important role in the treatment of tuberculosis. Table~\ref{tw-7f23b8962763} shows the research work in Rifampicin nano micelles been made in the treatment of tuberculosis.

\textbf{Anti-fungal activity}

Amphoterecin B nanomicelles were prepared using polyethyleneoxide-b-p [6-HHA] and Polyethylene-b-p [HASA]. Analysed by chromatographic technique {\textendash}HPLC \unskip~\citep{628393:14720093}.

\textbf{Antibiotics}

Nanomicelles of Thiamphenicol (TAP) and its fluorinated derivative, florfenicol (FF), are employed in veterinary practice \unskip~\citep{628393:14720094}. Polymers used was Chitosan-stearic acid (CS-SA), which serves as a carrier for the delivery of antibiotics.
    
\section{Conclusions}
Nanotechnology, a sophisticated area of great value and perspective, deals with the control, manipulation, synthesis, and biofunctionalization of structures/devices at the nanometre scale. Several pharmaceutical applications of Nano micelles are based on their specific physicochemical and biological properties regarding size (diameter), surface (porosity), pH, solubility, complexation (binding/ ligand capacity), bioavailability, toxicity, and cellular and molecular effects. Polymers play an important role in designing of nano micelles due to their widespread availability, renewability, low cost, versatility, biocompatibility, biodegradability, and lack of toxicity. Direct dissolution and solvent casting (freeze-drying, solution casting, and emulsification) are the main mechanisms applicable for the preparation of Nano micelles. In recent decades, interdisciplinary researches and instantaneous development of nanotechnology for diagnosis (imaging), drug delivery, and targeting of extremely serious disorders, such as cancer, Parkinson and Alzheimer diseases, chronic inflammations, ocular dysfunctions, and microbial/viral infections. 

Current research is also focused on developing modern Nanosystems, including noisome, polymeric nanoparticles, Nanocomposite (colloidal) hydrogels, polymeric micelles, dendrimers, aptamers, capsosomes, Nano needles, molecularly imprinted polymers, stimuli-responsive polymers, therapeutic polymers (polymer-drug conjugates), and polymeric, artificial cells. 
    

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