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\begin{document}


\def\RunningAuthor{Jawahar Natarajan et al.}
\firstPage{1130}
\articleType{Review Article}
\receivedDate{24.08.2019}
\acceptedDate{11.11.2019}
\revisedDate{02.11.2019}
\journalVolume{2020, 11}
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\journalDoi{ijrps.v11i1.1946}
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\title{A review of the preparation, characterization and application of nanostructured lipid carriers}
\author{Asha~Spandana~K~M\textsuperscript{1},  
            Jawahar~Natarajan\textsuperscript{*}\textsuperscript{2},  
            Shailesh~Thirumaleshwar\textsuperscript{1}, 
            Hemanth~Kumar~S\textsuperscript{1}~\\[5pt]{\textsuperscript{1}Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, SS Nagara, Mysuru, Karnataka, India}~\\{\textsuperscript{2}Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education \& Research, Ooty, Nilgiris, Tamil Nadu, India}}

\begin{abstract}
Lipid Nanoparticles have gained increased attention during the last few decades. These carrier systems offer many advantages over conventional drug delivery system, including protection of the entrapped active ingredient from environmental (pH) or physiological (immune system, enzymes) degradations, improved bioavailability, prolonged circulation time, sustained release of drug and site specific drug delivery, reduced dose and side effects. Solid Lipid Nanoparticles (SLN), has been reported as an alternative carrier system to liposomes. However, SLN show some disadvantages such as drug expulsion during storage, low drug loading and aggregation of the particles. Nanostructured lipid carriers are evolved as second generation lipid nanoparticles to overcome the limitations of SLN, by modifying SLN by incorporating liquid lipid to the solid matrix for better drug accommodation to increase drug loading and prevent drug leakage while preserving the physical stability of the formulation. This article describes the features, various preparation techniques, characterization techniques and the therapeutic applications of NLCs in topical drug delivery, brain, oral and pulmonary delivery.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Nanostructured lipid carriers,\newline solid lipids,\newline liquid lipids,\newline surfactants
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Jawahar~Natarajan~\\ Phone:\ +91-9791439545~\\  Email:\ jajupharma@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
In the past few decades, Lipid-based drug delivery systems gained increased attention due to their biodegradable and biocompatible property, non-toxicity, ability to improve safety, efficacy, and ability to penetrate through physiological barriers which can present challenges for drug delivery particularly blood-brain barrier \unskip~\citep{649866:15269545}. Additionally, improved stability and easy scale-up of nanoparticle \unskip~\citep{649866:15269559} makes lipid nanoparticle as a promising delivery system for a variety of drug molecules and other agents.

The first generation Solid lipid nanoparticles(SLN) was formulated at the beginning of 1990 as an alternate carrier system to other colloidal carrier systems \unskip~\citep{649866:15269556}. Advantages of SLNs include enhanced bioavailability, protection of entrapped active ingredient from the outer environment (water, light), and controlled-release of a drug, use of physiological lipids, no use of organic solvents \unskip~\citep{649866:15269554}. However, SLN show some disadvantages like low drug-loading capacity due to the crystalline structure of solid lipids, stability problems because the expulsion of active pharmaceuticals following the polymeric transition, particle growth during storage \unskip~\citep{649866:15269567}. To overcome these limitations of SLN, the Nanostructured lipid carriers (NLCs) are evolved as second-generation lipid nanoparticles developed by incorporating liquid lipid to the solid matrix to increase the number of imperfection in the solid matrix, thus to increase the drug loading, while preserving the physical stability of the formulation \unskip~\citep{649866:15269541}.
    
\section{Materials and Methods}
\textbf{High-pressure homogenization method (HPH)}

Hot HPH\textbf{\space }is suitable for insoluble and lipophilic drugs and rarely suitable for hydrophilic drugs, it involves the melting of solid lipid materials initially and then mixing with liquid lipid and drugs. The molten liquid thus formed is dispersed uniformly in the aqueous phase containing surfactants, later the mixture is stirred continuously until an emulsion is formed, which is further broken into nanoparticles by to high shear force \unskip~\citep{649866:15269560}.

In the Cold HPH, the\textbf{\space }solid and liquid lipids are melted at the temperature higher than the melting point of solid lipid. The drug is dispersed in the melted lipid, which is then subjected to high-pressure homogenization to form an emulsion, and the emulsion is rapidly cooled by using liquid nitrogen to yield solid mass. The solid mass thus obtained is size reduced to microparticles, the microparticles are distributed in the cold aqueous phase containing a surfactant, the aqueous phase is further subjected to homogenization with high shear to obtain NLCs \unskip~\citep{649866:15269560}. 

\textbf{Emulsification-ultrasonication method}

The method involves mixing of a drug, liquid, and solid lipids and melting at a temperature higher than the melting point of solid lipid. An aqueous phase is prepared by heating distilled water along with surfactants at the same temperature of lipid melt. The aqueous phase is slowly added into lipid phase to get a pre-emulsion, which is further homogenized at high shear followed by ultrasonication, the emulsion is added to a specified quantity of water, cooled, solidified at room temperature to form NLCs \unskip~\citep{649866:15269560}.

\textbf{Solvent diffusion method}

In this method, the NLC's are prepared by incorporating the drug in organic solvents along with lipid mixture and lipophilic surfactant at elevated temperature, then the resulting organic solution containing drug is instantly dispersed with high mechanical agitation at 25 \ensuremath{^\circ}C until the NLC's are obtained. The residual organic solvent from the prepared dispersion is evaporated by placing the dispersion in vacuum desiccators for 24 hours \unskip~\citep{649866:15269560}.

\textbf{Solvent emulsification evaporation method}

The method involves the preparation of NLC by dissolving the polymer in an organic solvent and then dispersing the drug in the polymer solution to form an organic phase. The organic phase is then slowly poured to the aqueous phase and emulsified by using an emulsifier or surface-active agent to form an oil-in-water system. The organic solvent is evaporated form the prepared emulsion by heating under reduced pressure \unskip~\citep{649866:15269560}.

\textbf{Film-ultrasonication method}

This method involves the preparation of NLCs by probe ultrasonication in which the melted lipid, polymer, and drug are dispersed in an aqueous solution containing a surfactant. The resulting dispersion is allowed to cool and then solidified to get NLCs \unskip~\citep{649866:15269560}.

\textbf{Microemulsion method}

In this method, the drug, emulsifier, auxiliary emulsifier, and deionized water are added to previously melted lipid to form a thermodynamically stable transparent microemulsion. The obtained microemulsion is immediately dispersed in ice water (0-4 \ensuremath{^\circ}C) to form an NLC dispersion \unskip~\citep{649866:15269560}.

\textbf{Hot-melt extrusion technology}

Hot-melt extrusion with twin-screw extruder is a new technology for NLC preparation. The extruder has three feeding ports, the first to add lipid drug mix, the second to add liquid lipid, and the third to add aqueous phase.  Solid lipid and drug mix are added in first port through a volumetric feeder, the heated liquid lipid is added through the second port by using a peristaltic pump. As the solid lipid, drug, and liquid lipid is introduced into the extrusion barrel, it undergoes melting and mixing. The Third port is selected for inclusion of preheated aqueous phase containing surfactant by using a peristaltic pump and mixed at the optimum speed to form pre-emulsion. That obtained pre-emulsion is extruded into a vessel attached with probe sonicator to obtain NLCs \unskip~\citep{649866:15269560}.
    
\section{Results and Discussion}
\textbf{Lipids and surfactants used in nanostructured lipid carriers production}

The major components of NLC are lipids, surfactants, and water. Lipid core comprises of a blend of solid lipid and liquid lipid. The surfactant is added to stabilize the system. Table~\ref{tw-7f3dbb488090} indicates the various formulation ingredients used in the NLC formulation


\begin{table*}[!htbp]
\caption{\boldmath {Various formulation ingredients used in the formulation of NLC} }
\label{tw-7f3dbb488090}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.20540000000000003\linewidth-2\tabcolsep}p{\dimexpr.439\linewidth-2\tabcolsep}p{\dimexpr.3556\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Formulation Ingredient & Examples & Reference\\
\tblmidrule 
Solid Lipids &
  Stearic acid, cetyl palmitate Glyceryl Behenate,  \mbox{}\protect\newline Glyceryl Monostearate, Gelucire Ovucire WL 2944, Grades of Softisan, Grades of Dynasans, Lauric Acid Cutina CP, Palmic acid Witepsol E 85 &
  \unskip~\citep{649866:15269561,649866:15269550,649866:15269562,649866:15269558}\\
Liquid Lipid &
  Oleic acid Castor oil, Labrasol, Isopropyl myristate, Cremophore EL olive oil, soybean oil, sunflower oil peanut oil, sesame oil, corn oil, Almond oil, Cetiol, Corn oil Mygliol 812 N, Tegosoft M, and Tegosoft P &
  \unskip~\citep{649866:15269561,649866:15269550,649866:15269562,649866:15269558}\\
Surfactants &
  Pluronic F-68 and Tween 80 Tween 20, Span 80, Pluronic F 188 and Pluronic F 127 Cremophor, Solutol{\textsuperscript{\textregistered}} HS 15, Poloxamer 188 Eumulgin SLM 20, Lutrol F68, Span 85 &
  \unskip~\citep{649866:15269561,649866:15269550,649866:15269562,649866:15269558}\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {NLC formulations for different routes of administration} }
\label{tw-f991b1b62cd7}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.16\linewidth-2\tabcolsep}p{\dimexpr.2027\linewidth-2\tabcolsep}p{\dimexpr.1415\linewidth-2\tabcolsep}p{\dimexpr.20499999999999993\linewidth-2\tabcolsep}p{\dimexpr.15769999999999996\linewidth-2\tabcolsep}p{\dimexpr.13309999999999999\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Therapeutic Applications & Therapeutic Agent & Purpose & NLC Composition & Outcome & References\\
\tblmidrule 
Oral \mbox{}\protect\newline delivery  &
  Exemestane &
  Breast cancer &
  Precirol{\textsuperscript{\textregistered}} ATO 5 \mbox{}\protect\newline flaxseed oil \mbox{}\protect\newline Poloxamer 188, \mbox{}\protect\newline Tween 80, and Tween 20 &
  3.9-fold enhancement in bioavailability &
  \unskip~\citep{649866:15269564}\\
Topical delivery  &
  Flurbiprofen &
  NA &
  stearic acid \mbox{}\protect\newline glyceryl behenate \mbox{}\protect\newline castoroil \mbox{}\protect\newline Tween 80 &
  Delayed and sustained permeation of Flurbiprofen &
  \unskip~\citep{649866:15269548}\\
Pulmonary delivery  &
  Doxorubicin and siRNA &
  Lung cancer &
  Precirol ATO 5 \mbox{}\protect\newline Soybean phosphatidylcholine \mbox{}\protect\newline Squalene, Tween-80 &
  Enhanced antitumor activity when compared with intravenous treatment &
  \unskip~\citep{649866:15269565}\\
CNS Delivery  &
  Protein &
  Neuro \mbox{}\protect\newline degenerative diseases &
  Precirol ATO5 and Dynasan 114) \mbox{}\protect\newline Precirol ATO5 \mbox{}\protect\newline Poloxamer 188 \mbox{}\protect\newline Tween 80 \mbox{}\protect\newline Chitosan. &
  Effective delivery of protein to the brain. Prolonged retention time of CS-NLCs in the nasal epithelium. &
  \unskip~\citep{649866:15269549}\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{Characterization of nanostructured lipid carriers}

\textbf{Particle size and Polydispersity index}

Particle size and the polydispersity index indicates the quality of nanoparticle with respect to size distribution. Rate of drug release, bio distribution profile, mucoadhesion, cellular uptake of water and buffer exchange to the interior of the nanoparticles, and protein diffusion affected by particle size \unskip~\citep{649866:15269542}. And also the particle size is a crucial factor in producing nano-sized particles, which describes the stability of the formulation, narrow size should be maintained during storage, increased size indicates agglomerates during storage \unskip~\citep{649866:15269563}. The delivery of some therapeutic agent to specific sites of the disease and their release profile is also affected by particle size \unskip~\citep{649866:15269557}.  Photon correlation spectroscopy (PCS) and laser diffraction (LD) are the widely used methods for the particle size measurements \unskip~\citep{649866:15269552}. 

Polydispersity index describes the degree of non-uniformity of a size distribution of particles. Value of less than 0.5 are considered to be acceptable in practice for lipid nanoparticles, indicates monodisperse and homogenous. Values greater than 0.7 indicate that the sample has a very broad size distribution. PDI of nanoparticles measured using the Microscopy method, diffraction and scattering techniques, and hydrodynamic techniques \unskip~\citep{649866:15269546}.

\textbf{Zeta potential }

Zeta Potential (ZP) analysis is a technique for determining the surface charge of nanoparticles in solution (colloids), obtaining information about their stability and surface interaction with other molecules. Suitable ZP provides drug delivery to the targeted by improving the possibility of actives interaction with target cells \unskip~\citep{649866:15269551}. Unlike particle size, ZP is a property involving not only the particles but also their environments such as pH, ionic strength, and even the type of ions \unskip~\citep{649866:15269566}. Generally, ZP values higher than positive 25 mV or less than negative 25 mV typically have high degrees of stability \unskip~\citep{649866:15269543}. Hence zeta potential is one of the important parameters to be assessed since it affects the stability and also the permeability through the membrane because of the surface charge.

\textbf{Shape and morphology}

Particle shape and morphology are important parameters influences various biological and processes, including biodistribution, cellular uptake, and subsequent trafficking within cells \unskip~\citep{649866:15269568}. It has been reported that the toxicity of the nanoparticle depends on the shape of the nanoparticles. The shape and morphology of Nanoparticles can be determined using \textit{Scanning electron microscopy, Transmission electron microscopy, and Atomic force microscopy}\unskip~\citep{649866:15375673}.

\textbf{Drug - lipid (excipient) interaction}

Fourier Transform Infrared (FTIR) spectrometer is used to identify possible interactions between the drug, lipid, and other excipients for the formulation of nanostructured lipid carriers \unskip~\citep{649866:15269540}. This study supports successive drug delivery design by ensuring the absences of drug interaction with the other excipients and stability of the drug in the formulation \unskip~\citep{649866:15269544}.

\textbf{Crystallization behaviour and lipid polymorphism}

Crystallization behavior and lipid polymorphism are the two important parameters to be assessed in lipid-based nanoparticles to obtain stable NLC because crystallization behavior and lipid modification influence the entrapment efficiency and release profiles of the drug. Thermodynamic stability and lipid packing density increase, and drug encapsulation efficiencies decrease in the following order: supercooled melt; \ensuremath{\alpha }-modification; \ensuremath{\beta }'-modification; \ensuremath{\beta } {\textendash}modification \unskip~\citep{649866:15269555}. Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) for the determination of the degree of crystallinity of the particle dispersion \unskip~\citep{649866:15269547}.

\textbf{Applications of NLC}

NLCs can be used in a wide variety of drug delivery systems such as oral delivery, Topical delivery, Pulmonary delivery, CNS delivery because of their increased solubility, bioavailability, improved stability, protection of actives from toxicity, enhanced pharmacological activity and, sustained delivery and targeted delivery and well-established biocompatibility. Some of the NLC formulations for different routes of administration are discussed in Table~\ref{tw-f991b1b62cd7}.
    
\section{Conclusions}
Nanostructured lipid carrier (NLC) is the second generation of solid lipid drug carriers composed of both solid and liquid lipids as a core matrix. NLCs offer many advantages over conventional carriers for drug therapy, including  increased solubility, bioavailability, improved stability, protection of actives from toxicity, enhanced pharmacological activity and intracellular uptake, improved tissue macrophages distribution, sustained delivery and targeted delivery. NLC can be easily scaled up and can be modified to alter the drug delivery rate, stability, and drug loading. NLC holds significant promise for effective therapeutic delivery of drugs administered via different routes of administration. Taking all these factors into consideration, it can be concluded that NLC could be a promising approach for the delivery of a variety of drug molecules and other agents.
    

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