nano-lipid carriers: a formidable drug delivery system

www.wjpps.com Vol 6, Issue 3, 2017.

396

Subharaj et al. World Journal of Pharmacy and Pharmaceutical Sciences

NANO-LIPID CARRIERS: A FORMIDABLE DRUG DELIVERY

SYSTEM

Subharaj Saha1*, Nagasamy Venkatesh D.

2 and Annesha Deb

3

*1,2,3

Department of Pharmaceutics, JSS College of Pharmacy, (A Constituent College of JSS

University, Mysore) Ooty – 643 001. Tamil Nadu.

ABSTRACT

Lipid nanoparticles (LNPs) have attracted special interest during the last

few decades. Nano lipid carriers (NLCs) are one of the major types of

lipid-based nanoparticles. Nano lipid carriers (NLCs) are drug-delivery

systems comprises of both solid and liquid lipids as the core matrix. It

was seen that NLCs reveal some merits for drug therapy over the

conventional carriers, including enhancing solubility, the ability to

increase storage stability, improved permeability and bioavailability,

decreased adverse effect, prolonged half-life, and tissue-targeted

delivery. NLCs have attracted increasing attention in recent years. This

review illustrates recent developments in drug delivery arena using

NLCs strategies. The structural features, preparation techniques and

physicochemical characterization of NLCs are systematically explained

in this review. The next generation lipid nanoparticle i.e. NLCs are

modified SLNs which improve the stability and loading capacity. Three structural models of

NLCs have been proposed. These LNPs have enormous applications in drug delivery field,

research, cosmetics, clinical medicine, etc.

KEYWORDS- LNPs, SLNs, increased solubility, SLNs, stability.

INTRODUCTION

Rapid advances in the ability to generate nanoparticles of uniform size, shape, and

composition have begun a revolution in the field of sciences. The strategy of lipid based drug

carriers has attracted great attention over the last few years. Since the beginning of 20th

century, nanotechnology has seen enhanced growing interest in the pharmaceutical

technology research groups worldwide. It practically made its influence in all the technical

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 6.647

Volume 6, Issue 3, 396-421 Review Article ISSN 2278 – 4357

*Corresponding Author

Subharaj Saha

Department of

Pharmaceutics, JSS

College of Pharmacy, (A

Constituent College of

JSS University, Mysore)

Ooty – 643 001. Tamil

Nadu.

Article Received on

29 Dec. 2016,

Revised on 19 Jan. 2017,

Accepted on 08 Feb. 2017

DOI: 10.20959/wjpps20173-8709


397


fields. Industrial data suggests that approximately 40% of lipophilic drug fails due to

solubility, stability and formulation issues, which has been tried to solve by various novel and

advanced lipophilic drug delivery technologies.[1]

The lipids which are used to prepare lipid

nanoparticles are usually physiological lipids (biocompatible and biodegradable) so, that the

drugs can be reached at the site of action with controlled release having low acute and

chronic toxicity.[2]

Nanotechnology is being used extensively to provide site targeting drug

therapy, diagnostics, tissue regeneration, cell culture, biosensors and other tools in the field of

molecular biology. To overcome the demerits linked to the traditional colloidal systems such

as emulsions, liposomes and polymeric nanoparticles, various nanotechnology platforms like

nano lipid carrier, fullerenes, nanotubes, quantum dots, nano pores, dendrimers, liposomes,

magnetic nano probes and radio controlled nanoparticles are being developed.

NLC AS COMPARED TO SLN

Nano lipid carrier, the next generation state of the art lipid nanoparticle which as a fictive

carrier system has been prepared to swipe some demerits of the solid lipid nanoparticle. To

overthrow this drug exclusion at the time of storage, lipid fusions were preferred because

they don’t cast a notably organized crystalline arrangement which is desired. Matrixes of

NLCs are prepared by blending spatially organized varied lipid molecules, typically a fusion

of solid and liquid lipid, presents deformities in the matrix to aggregate more drug molecules

than SLN. Alternative to the existence of liquid lipid, NLC matrix is solid at room

temperature. NLCs are nothing but a blend of solid lipid and liquid lipid and reside in the

solid state by regulating the content of liquid lipid. NLCs can thoroughly paralyse the drugs

and prohibit the particles from coagulating by means of the solid matrix correlated to

emulsions. NLC has enhanced scientific and commercial attention midst of the last few years

due to the decreased risk of systemic side effects.[3,4]

Also, the exclusion of drug entrapped in

NLC during storage is decreased or avoided. This comprises of high amounts of drug

payload, enhanced drug stability, the chances to control drug release and targeting and

avoidance of organic solvents.[5]


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Fig-1: Triggered release of drug from NLC the transform form of SLN

NLCs are made up of biocompatible solid lipid matrices and liquid lipid which have varied

chemical structure than that of the solid lipid.[6]

Furthermore, NLCs have the usual particle

diameter ranging 10–1000 nm. Nano lipid carriers (NLC) are the next generation SLN

comprised of solid lipid matrix which is integrated with liquid lipids.[7]

Amidst the nano lipid

carriers that comprises of solid lipids together with liquid oils are, Miglyol®, α-tocopherol,

etc.[8]

The existence of liquid lipids with varied fatty acid C-chains yields NLC with less

classified crystalline structure and thus provides better loading capacity for drug.[9]

Liquid

lipids are said to be the good solubilizers of drugs than solid lipids. These carriers comprises

of physiological and biodegradable lipids showing less systemic toxicity and less

cytotoxicity.[10]

Most of the lipids have a suggested status or are excipients used in commercially available

pharmaceutical preparations. The small size of the lipid particles ensures close contact to

stratum corneum and can enhance the amount of drug penetrating into mucosa or skin. Due to

their solid lipid matrix, a controlled release from these carriers is possible. This becomes an

important tool when it is necessary to supply the drug over a long period of time, to reduce

systemic absorption, and when drug produces irritation in high concentrations.[11,12,13]

NLC

have been shown to exhibit a controlled release behavior for various active ingredients such

as ascorbyl palmitate, clotrimazole, ketoconazole and other antifungal agents.

MERITS OF NLCs

Better physical stability,

Ease of preparation and scale-up,

Increased dispersability in an aqueous medium,

High entrapment of lipophilic drugs and hydrophilic drugs,


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Controlled particle size,

An advanced and efficient carrier system in particular for substances,

Increase of skin occlusion,

Extended release of the drug,

One of the carriers of choice for topically applied drugs because their lipid components

have an approved status or are excipients used in commercially available topical cosmetic

or pharmaceutical preparations,

Small size of the lipid particles ensures close contact to the stratum corneum thus

enhancing drug penetration into the mucosa or skin,

Improve benefit/risk ratio,

Increase of skin hydration and elasticity

These carriers are highly efficient systems due to their solid lipid matrices, which are also

Generally recognized as safe or have a regulatory accepted status.[14]

DEMERITS OF NLCs

Although there is great potential of NLCs in targeted delivery, but they also poses some

limitations like:

Cytotoxic activities according to the type of matrix and concentration.

Irritative and sensitizing response of some surfactants.

Functioning and efficiency in case of protein and peptide drugs and gene delivery systems

still need to be explored.

Lack of sufficient preclinical and clinical studies with these nanoparticles in case of bone

repair.[15]

STRUCTURES AND PREPARATIONS OF NLCS

Materials for NLCs

The important elements for NLCs include lipids, water, and emulsifiers. Both solid and liquid

lipids are embodied in NLCs for designing the inner cores. The solid lipids generally used for

NLCs are glyceryl behenate (Compritol® 888 ATO), glyceryl palmitostearate (Precirol®

ATO 5), fatty acids (e.g. stearic acid), triglycerides (e.g. tristearin), steroids (e.g. cholesterol),

and waxes (e.g. cetyl palmitate). This lipids in room temperature stays at solid state. They

melt at high temperatures (e.g. > 80°C) at the time of preparation process. Liquid oils

typically used for NLCs consist of digestible oils from natural sources. The medium chain


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triglycerides, such as Miglyol® 812, are generally employed as the ingredients of liquid

lipids because of their same structures as that of Compritol®.[18]

Other oily ingredients such

as paraffin oil, 2-octyl dodecanol, propylene glycol dicaprylocaprate (Labrafac®), isopropyl

myristate and squalene are there. Alternately, the fatty acids, such as oleic acid, linoleic acid,

and decanoic acid, are included in NLCs for their value of having oily components and as

being penetration enhancers of topical delivery. Generally, these lipids are already approved

by European and American regulatory authorities for clinical applications and for their

―generally recognized as safe‖ (GRAS) status. Necessity is there for novel and biocompatible

oils which are cost-effective, non-irritating, and accomplishes of being sterilized before

application. Vitamin E (α-tocopherol) and other tocols are used as materials for nano

emulsions.[19]

Tocols also serves as a choice of oils for NLCs by virtue of their stability, ease

of production on a large scale, and good solubility in lipophilic drugs[20]

. NLCs procured

using natural oils from plants are also accepted. Averina et al. [21, 22]

had used Siberian pine

seed oil and fish oil from Baikal Lake as the liquid oils after all they show desirable physical

and chemical stability of NLCs. The emulsifiers are used to stabilize the lipid dispersions.

Mostly the investigations employs hydrophilic emulsifiers such as Pluronic F68 (poloxamer-

188), polysorbates (Tween), polyvinyl alcohol, and sodium deoxycholate.[23–25].

Lipophilic or

amphiphilic emulsifiers such as Span 80 and lecithin are also used for fabrication of NLCs if

required. It was also found that the combination of emulsifiers can prohibit particle

aggregation more efficiently.[16]

Polyethylene glycol (PEG), at times added in NLCs, dwells

on the nanoparticulate shell to restrict uptake by the reticuloendothelial system (RES) and to

lengthen the circulation time of drugs.[26]

Table 1 summarizes the thorough information

related to the materials used for NLCs. Another requisite for NLCs’ stability is the ability for

preservation. The preservatives can worsen the physical stability of lipid dispersions. Obeidat

et al.[27]

exhibit that Hydrolite® 5 is proved convenient for the preservation of coenzyme

Q10-loaded NLCs. They have suggested that the morphological examination by light

microscopy provides a fast and cost-efficient method for preservative screening.

Table 1- The excipients for composing nanostructured lipid carriers (NLCs).

Ingredient Materials

Solid Lipids

Tristearin, stearic acid, cetyl palmitate, cholesterol, Precirol® ATO 5,

Compritol® 888 ATO, Dynasan® 116, Dynasan® 118, Softisan® 154,

Cutina® CP, Imwitor® 900 P, Geleol®, Gelot® 64, Emulcire® 61


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Liquid Lipids

Medium chain triglycerides, paraffin oil, 2-octyl dodecanol, oleic acid,

squalene, isopropyl myristate, vitamin E, Miglyol® 812, Transcutol®

HP, Labrafil Lipofile® WL 1349, Labrafac® PG, Lauroglycol® FCC,

Capryol® 90

Hydrophobic emulsifiers

Pluronic® F68 (poloxamer 188), Pluronic® F127 (poloxamer 407),

Tween 20, Tween 40, Tween 80, polyvinyl alcohol, Solutol® HS15,

trehalose, sodium deoxycholate, sodium glycocholate, sodium oleate,

polyglycerol methyl glucose distearate

Lipophilic emulsifiers Myverol® 18-04K, Span 20, Span 40, Span 60

Amphiphilic emulsifiers Egg lecithin, soya lecithin, phosphatidylcholines,

phosphatidylethanolamines, Gelucire® 50/13

Structures of NLCs

SLNs when made from solid lipids, the matrix aims to form a relatively perfect crystal lattice,

leaving narrow space to accommodate the active ingredients. Fig. (1) shows the expected

structure of the inner cores of SLNs. Accordingly, using of a lipid blend including solid and

liquid forms can hamper the production of a perfect crystal. The particle matrix contains

imperfections, providing space to accommodate the drug molecules in amorphous clusters.

Fig. (1). It has also been suggested that NLCs are composed of oily droplets encapsulated in a

solid lipid matrix. The morphology of particles of NLCs is not always spherical.

Preparation Methods for NLCs

Three different methods are mainly used to prepare NLCs: hot homogenization, cold

homogenization, and microemulsion. Hot homogenization is operated at temperatures over

the melting point of the lipids. As listed in Fig. (2), firstly, the lipid and aqueous phase are

prepared distinctly. The lipid phase comprises of solid, liquid lipids and lipophilic

emulsifiers, while the aqueous phase consists of double-distilled water and hydrophilic

emulsifiers. Both phases are then heated separately to a high temperature for a period of time.

The aqueous phase is then added to the lipid phase and mixed. The mixture can be condensed

by a high-shear homogenizer. Sometimes, the mixture can be further treated using a water-

bath or probe-type sonicator to get the smaller and more-regular size distribution. The high-

temperature high-pressure homogenization technique may cause detoriation of thermo-labile

drugs. Therefore an upgraded process is required to decrease the chemical instability. A

simple method is to reduce the heating temperature.

Hung et al.[28]

have minimized the processing temperature from 85°C to 60°C. It is found that

32% of vitamin E is detoriated in NLCs made using the conventional technique after a 90-day


402


storage period. Whereas, no degradation is seen in NLCs prepared in the lower-temperature

condition. Such similar result is observed in the case of β-carotene. In the cold

homogenization method, the melted lipid is cooled and the solid lipid is ground to lipid

microparticles Fig. (2). These microparticles are dispersed in a cold emulsifier solution to get

a pre-suspension. Subsequently, the suspension is condensed at or below room temperature.

The cavitation force is high to rupture the microparticles directly to NLCs. This process can

prevent the melting of the lipids and therefore minimize loss of the hydrophilic drugs to the

aqueous phase [17]

. A transparent and thermodynamically stable dispersion, so-called

microemulsion, can be prepared when the melted lipids, emulsifiers, and water are mixed in a

correct ratio. The further addition of the microemulsion to water leads to precipitation of the

lipid phase forming fine particles [29]

. Large-scale production of lipid nanoparticles by the

microemulsion technique appears feasible for the pharmaceutical industry. Since dilute

nanoparticle dispersion is produced, sometimes the product needs to be concentrated by

ultrafiltration or Lyophilization.[30]

Fig. (1)- Nanoparticulate structures of solid lipid nanoparticles (SLNs), nanostructured

lipid carriers (NLCs), and oil-in-water nanoemulsions (NEs).

PREPARATION PROCEDURES FOR NLCs

There many methods for the preparation of lipid nanoparticulate DDS. The method used is

dictated by the type of drug especially its solubility and stability, the lipid matrix, route of

administration, etc.

High Pressure Homogenization Technique

HPH has been used as a reliable and powerful technique for the large-scale production of

NLCs, lipid drug conjugate, SLNs, and parenteral emulsions. In High Pressure

Homogenization technique lipid are pushed with high pressure (100-200bars) through a


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narrow gap of few micron ranges. So shear stress and cavitation are the forces which cause

the disruption of particle to submicron range. Normally the lipid contents are in the range of

5-10%. In contrast to other preparation technique High Pressure Homogenization does not

show scaling up problem. Basically there are two approaches for production by high pressure

homogenization, hot and cold homogenization techniques.[31]

For both the techniques drug is

dissolved in the lipid being melted at approximately 5- 10º C above the melting point.

Hot Homogenization Technique

In this technique the drug along with melted lipid is dispersed under constant stirring by a

high shear device in the aqueous surfactant solution of same temperature. The pre-emulsion

obtained is homogenized by using a piston gap homogenizer and the obtained nanoemulsion

is cooled down to room temperature where the lipid recrystallizes and leads to formation of

nanoparticles.[32]

Cold homogenization technique

Cold homogenization is carried out with the solid lipid containing drug. Cold homogenization

has been developed to overcome the problems of the hot homogenization technique such as,

temperature mediated accelerated degradation of the drug payload, partitioning and hence

loss of drug into the aqueous phase during homogenization.

The first step of both the cold and hot homogenization methods is the same. In the subsequent

step, the melt containing drug is cooled rapidly using ice or liquid nitrogen for distribution of

drug in the lipid matrix as shown in the Figure 2. Cold homogenization minimizes the

thermal exposure of the sample.[33]

Fig. (2). Preparation procedures of nanostructured lipid carriers (NLCs): hot

homogenization, cold homogenization.


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PHYSICOCHEMICAL CHARACTERIZATION OF NLCS

The physicochemical characterization for NLCs is essential to confirm quality control and

stability. Both physical and chemical properties can be determined for NLCs. The most

frequent parameters for determining NLCs are particle size and zeta potential. In addition, the

lipid nanoparticles are characterized by differential-scanning calorimetry (DSC), X ray,

nuclear magnetic resonance (NMR), and Raman spectroscopy. As the drug is incorporated

into NLCs, the encapsulation efficiency and drug-release behavior provide important

information to judge the feasibility of NLCs as drug delivery systems.

Particle Size

Photon correlation spectroscopy (PCS) and laser diffraction are the most powerful methods

for routine measurement of particle size. PCS is also known as dynamic light scattering.

It measures the fluctuation of the scattered light intensity produced by particle movement.

This technique covers a determined size range from several nm to 3 μm.[16]

The larger size

can be detected by laser diffraction. This determination is based on the dependence of the

diffraction angle on a particle radius. The types and ratios of lipid and emulsifier used in

NLCs greatly influence particle size. The addition of more emulsifiers always facilitates more

complete emulsification and more rigid structure; thus the size can be reduced.[18]

Zeta Potential

The measurement of surface charge is used to assess the dispersion and aggregation processes

affecting particle stability in application. In general, particle aggregation or fusion is less

likely to occur for charged particles because of the electrostatic repulsion. A positively

charged surface of NLCs is efficient for entering the blood brain barrier (BBB) because of

binding to the paracellular area of the BBB, an area rich in anionic sites [34]

. Zeta potential

determination is helpful for formulation design to check if the cationic surface is achieved.

Sometimes a negative charge of particulate surface is needed to stabilize the nanoparticulate

systems during storage.

Electron Microscopy

The particulate radius and size distribution of NLCs can also be measured by scanning

electron microscopy (SEM) and transmission electron microscopy (TEM). In addition, the

electron microscopy is beneficial in observing the shape and morphology of the particles.

SEM employs electrons transmitted from the surface of the sample, while TEM uses


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electrons transmitted through the specimen. SEM possesses high resolution and easy

preparation of the samples. TEM allows visualization of nanoparticles after freeze-drying or

freeze-thawing.

Atomic Force Microscopy (AFM)

AFM is optimal for measuring morphological and surface features that are extremely small.

AFM does not use photons or electrons but a very small sharp-tipped probe located at the free

end of a cantilever driven by interatomic repulsive or attractive forces between the tip and

surface of the specimen [35]

. Although electron microscopy is still frequently used, the AFM

technique offers substantial benefits: real quantitative data acquisition in three dimensions,

minimal sample preparation times, flexibility in ambient operating conditions, and effective

magnifications at the nano levels.[36]

Surface Tension

The surface tension of water at 20°C is 72.8 dynes/cm. The addition of lipids and emulsifiers

can significantly reduce the surface tension to a lower value. The surface tension decreases

following the increase of emulsifier concentration due to the emulsification process of the

whole system. Surface tension of the lipid nanoparticles is often measured by the Wilhemy

plate method. The measurement of the contact angle is another method for detecting surface

tension of the nanoparticulate systems.[37]

Differential Scanning Calorimetry (DSC)

DSC gives an insight into the melting and recrystallization behavior of the solid lipids from

SLNs and NLCs. DSC determination uses the fact that various lipid modifications have

various melting points and enthalpies. The degree of crystallinity of NLCs is calculated from

the ratio of NLCs enthalpy to bulk lipid enthalpy, which is calculated on the basis of total

weight taken [38]

.The crystallinity degree of nanoparticles decreases with increasing liquid

lipid ratio in the particles. This result presents the evidence that the liquid oil is the main

factor lowering the crystallinity and increasing the less-ordered structure of NLCs. The

decline of enthalpy and reduction of the melting point of the lipids occur in the NLCs that

have a smaller size, a higher surface area, and a greater number of emulsifiers. The loading of

liquid oil leads to crystal order disturbance, resulting in more space to include drug

molecules. DSC profiles are advantageous to suggest the preferential drug dissolution in solid

or liquid lipids.[39]


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X-ray Diffraction

Both DSC and X-ray diffraction are widely used to investigate the status of lipids. The lipid

molecules composed of a long hydrocarbon chain have been known to possess

polyphorphism.[40]

The crystalline order of NLCs can be elucidated by wide-angle X-ray

diffraction. The polymorphism status of the nanoparticles detected by X-ray can be utilized to

confirm DSC results.[41]

By means of X-ray scattering, it is possible to assess the length of the

long and short spacing of the lipid lattice.

Parelectric Spectroscopy

Parelectric spectroscopy is based on the frequency dependency of dipole density and mobility

when exposed to a change of electromagnetic field. This approach is employed to recognize

the structure and dynamics of SLNs and NLCs. Parelectric spectroscopy is proven to be a

versatile tool as it offers insight into experimental details and function of open ended coaxial

probes to be used when performing measurements on liquid dispersions, and even when

testing living material for medical diagnostic aims.[43, 42]

Nuclear Magnetic Resonance (NMR)

Proton NMR spectroscopy is performed to investigate the mobility of the materials in the

inner core of NLCs. The mobility of the solid and liquid lipids is related to the width at half

amplitude of the signals.[44]

Broad signals and small amplitudes are characteristics of

molecules with restricted mobility and strong interactions [45]

. The higher line width of NLCs

compared to the physical mixture of the materials added in NLCs indicates the interaction of

liquid oil with the solid lipid. Immobilization of the nanoparticles of NLCs is stronger

compared to SLNs with totally crystallized cores.

Raman Spectroscopy

Raman spectroscopy detects vibrations of molecules after excitation by a strong laser beam.

Water causes only broad peaks at 3500 cm-1. With regard to the aspect of oil incorporation in

a crystalline lattice, the bands indicating order of lipid chains are of interest [46]

. The

symmetric stretching modes of the methylene groups at 2840 cm-1 and the sharp band of the

asymmetric stretching mode at 2880 cm-1 are both indicators of a high degree of

conformational order of hydrocarbon chains occurring in NLCs.[47]


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Molecular environment

The lipophilic fluorescent dye Nile red can be used as a marker determined by fluorometric

spectroscopy. The molecular environment or polarity of NLCs is elucidated because of the

solvatochromism of Nile red [47]

. Nile red is a lipophilic benzophenoxazone known to show

strong fluorescence in organic solvents and lipid environments. Corresponding to a high

lipophilicity, the emission maximum of Nile red is near 600 nm. The emission spectra of Nile

red can shift to shorter wavelengths with decreasing environmental polarity. On the other

hand, the emission maximum moves to a longer wavelength, and the reduction of the

fluorescence intensity is observed when Nile red is relocated into a more polar environment

such as an aqueous phase or nanoparticulate shell [48]

. In NLCs, Nile red is preferentially

located in the fluid lipid phase.

Drug Encapsulation Efficiency

Determination of drug-loading efficiency is very important for NLCs since it affects the

release characteristics.[49]

The lipophilic drug molecules may homogeneously distribute in the

lipid matrix or enrich the core or particulate shell. Aqueous and interfacial phases are the

main locations for loading hydrophilic drugs. The prerequisite to achieving high loading

capacity is sufficient solubility of the drug in the lipids. The solubility should be higher than

required because it decreases when cooling down the melt and may even be lower in the solid

lipids.[17]

The encapsulation percentage of the drugs in NLCs is based on the separation of the

internal and external phases. To separate the dispersions, different techniques such as

ultrafiltration, ultracentrifugation, gel filtration by Sephadex, and dialysis are commonly used

[43]. As compared to SLNs, the incorporation of liquid oil to solid lipid in NLCs leads to

massive crystal order disturbance. The resulting matrix indicates great imperfection in the

lattice and leaves more space to accommodate the drugs. The entrapment efficiency and

loading capacity of the drugs are thus improved.

Drug Release

The controlled or sustained release of the drugs from NLCs can result in the prolonged half-

life and retarded enzymatic attack in systematic circulation. The drug release behavior from

NLCs is dependent upon the production temperature, emulsifier composition, and oil

percentage incorporated in the lipid matrix [38]

.The drug amount in the outer shell of the

nanoparticles and on the particulate surface is released in a burst manner, while the drug

incorporated into the particulate core is released in a prolonged way. Sustained release of the


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drugs can be explained considering both drug partitioning between the lipid matrix and water,

as well as the barrier function of the interfacial membrane.[39]

The dialysis method and the

utilization of the Franz cell are the modes for measuring in vitro drug release from

nanoparticles. The interpretation of in vitro drug release profiles should consider the specific

environment in the in vivo status. Enzymatic degradation of lipid nanoparticles may be

influenced to a relevant extent by the composition of the particles.

MECHANISM OF SKIN PENETRATION OF NLCs

Nanosized particles can make close contact with superficial junctions of SC and furrows

between corneocyte islands, allowing superficial spreading of the active agents. Following

the evaporation of water from the nanosystems applied to the skin surface, particles form an

adhesive layer occluding the skin. Hydration of SC thus increases to reduce corneocyte

packing and widen inter-corneocyte gaps. Hydration also influences partitioning of the drug

into SC.[50]

Intact nanoparticles sized above 100 nm are not considered to permeate the SC because of

their dimensions and rigidity.[51]

Although the particles do not penetrate across SC, uptake of

the components is to be expected. Since epidermal lipids are rich in SC, lipid nanoparticles

attaching to the skin surface would allow lipid exchange between SC and the nano carriers

[52]. Lipid nanoparticles have the potential to deliver drugs via the follicles.

[53] Furthermore,

each follicle is associated with sebaceous glands, which release sebum creating an

environment enriched in lipids.[54]

This environment is beneficial for trapping of lipid

nanoparticles. The possible mechanisms involved in skin permeation enhancement by NLCs

are depicted in Fig.[6]

APPLICATION OF NLCs

Oral drug delivery- Interest in NLCs for oral administration of drugs has been increasing in

recent years. Increased bioavailability and prolonged plasma levels are described for per oral

administration of NLCs. The lipid nano-carriers can protect the drugs from the harsh

environment of the gastrointestinal tract. Repaglinide, an anti-diabetic agent with poor water

solubility, has low oral bioavailability and a short half-life.[55]

It is suitable to load into NLCs

for improving oral delivery. Date et al.[56]

prepare repaglinide NLCs with Gelucire 50/13 as

an amphiphilic lipid excipient. Gelucire 50/13(stearoyl macrogolglycerides) has been

previously used for the preparation of solid dispersions for improving the aqueous solubility

of lipophilic drugs.[57]

DSC studies indicate that Gelucire 50/13 interacts with Precirol® and


409


that this interaction suppresses polymorphic transitions of both components. The NLCs

exhibit a significantly greater decrease of the blood glucose level (about 2-fold) in rats

compared to marketed repaglinide tablets. The chemotherapeutic agent etoposide is used as a

model drug. Etoposide is a poorly water-soluble drug and a substrate of P-glycoprotein with a

considerable intra- and inter patient variation of oral bioavailability. The formulations with

smaller size are easier to penetrate across the intestine wall. A pharmacokinetic study is

conducted in rats. After oral administration at a drug dose of 180 mg/kg, the relative

bioavailability etoposide from standard NLCs, PEG-containing NLCs, and DSPE-PEG-

containing NLCs is enhanced 1.8-, 3.0-and 3.5-fold, respectively, compared with control

dispersion. DSPE-PEG-containing NLCs display the highest cytotoxicity against lung

carcinoma cells among all carriers tested.

Figure 6: Possible mechanisms for skin permeation enhancement of drugs or active

ingredients from Nanostructure lipid carriers (NLCs).

Drug delivery to brain- Brain targeting not only increases the cerebrospinal fluid

concentration of the drug but also reduces the frequency of dosing and side effects. The major

advantages of this administration route are avoidance of first pass metabolism and rapid onset

of action as compared to oral administration. LNC (e.g. NLC) of this generation are

considered to be one of the major strategies for drug delivery without any modification to the

drug molecule because of their rapid uptake by the brain, bioacceptability and


410


biodegradability. Further, the feasibility in scale-up and absence of burst effect make them

more promising carriers for drug delivery. In addition, NLC further enhanced the intranasal

drug delivery of duloxetine in the brain for the treatment of major depressive disorder.

Nanostructured Lipid Carriers (NLCs) of Asenapine maleate to improve the bioavailability

and enhance the uptake of ASN to the brain.[58]

In bromocriptine loaded NLCs the in‐vivo

results showed bromocriptine NLCs have rapid onset of action and longer duration and

higher brain levels as compared to that of solution, entrapment efficiency was also

increased.[59]

Topical drug delivery- Tacrolimus – loaded NLCs were successful prepared. The

penetration rate of these NLCs through the skin of a hairless mouse was greater than that of

Prototopic®. In vitro penetration tests revealed that the tacrolimus-loaded NLCs have a

penetration rate that is 1.64 times that of the commercial tacrolimus ointment,

Protopic®.[60]

An increase of skin penetration was reported for coenzyme Q 10 (Q10)-loaded

SLN compared toQ10 in liquid paraffin and isopropanol. The cumulative amounts of Q10

were determined performing a tape stripping test. After five strips the cumulative amount of

Q10 was 1%, 28%and 53% of the applied amount from the liquid paraffin, the isopropanol

and the SLN formulation, respectively. similar results were achieved by another study for

Q10- loaded NLC.

Pulmonary drug delivery- Inhalation drug delivery represents a potential delivery route for

the treatment of several pulmonary disorders. NLCs have greater stability against the shear

forces generated during nebulization compared to polymeric nanoparticles, liposomes and

emulsions. NLCs are comprised of an inner oil core surrounded by an outer solid shell and

hence allow the high payload of a lipophilic drug8. NLCs in pulmonary disorders seems to be

promising strategy (discussed in table 2) since lung epithelium can be directly reached

resulting in faster onset of action, desired dose and dosing frequency can be reduced as

compared to other administered routes like oral and undesirable side effects of drugs can be

avoided. Bio-adhesive properties of NLCs are due to their small particle size as well

lipophilic character lead to longer residence time in lungs.[61, 62]

Cancer Chemotherapy- In supplement, the function of NLC in cancer chemotherapy is

presented and hotspots in research are emphasized. It is foreseen that, in the beside future,


411


nano-structured lipid carriers will be further advanced to consign cytotoxic anticancer

compounds in a more efficient, exact and protected manner. ZER into NLC did not

compromise the anti-proliferative effect of ZER. Both ZER and ZER-NLC significantly

induced apoptosis via the intrinsic pathway in time-dependent manner. The proposed

mechanism of apoptosis of cancer cells induced by ZER and ZER-NLC is via activation of

caspase-9 and caspase-3, inhibition of anti-apoptotic protein, and stimulation of proapoptotic

protein expressions. Loading of ZER into NLC will increase the bioavailability of the

insoluble ZER in the treatment of cancers [63]

.g l-arginine lauril ester (AL) into nanostructure

lipid carriers (NLCs) and then coating with bovine serum albumin (BSA),pH-sensitive

membranolytic and lysosomolytic nanocarriers (BSAAL- NLCs) were developed to improve

the anti-cancer effect y render more nanocarriers lysosomolytic capability with lower

cytotoxicity, as well as improved therapeutic index of loaded active agents.[64]

Parasitic treatment- Novel colloidal delivery systems have gained considerable interest for

anti‐parasitic agents with focus on 3 major parasitic diseases viz. malaria, leishmaniasis and

trypanosomiasis. Lipid Nanoparticles combine advantages of traditional colloidal drug carrier

systems like liposome, polymeric nanoparticles and emulsions but at the same time avoid or

minimize the drawbacks associated with them. The delivery system should be designed in

such a way that physico‐chemical properties and pharmacokinetic properties are modulated

of the anti‐parasitic agents (formulated as NLCs shown in table 5) in order to improve

biospecificity (targetablity) rather than bioavailability with minimization in the adverse

effects associated with it. SLNs and NLCs have ability to deliver hydrophobic and

hydrophilic drug with more physical biocompatibility. For example- Dihydroartemisnin

(Anti-malarial) loaded NLCs, the drug release behaviour from the NLC exhibited a biphasic

pattern with burst release at the initial stage and sustained release subsequently.[65]

Ocular delivery- The characteristic features of SLNs and NLCs for ocular application are the

improved local tolerance and less astringent regulatory requirements due to the use of

physiologically acceptable lipids. The other benefits include the ability to entrap lipophilic

drugs, protection of labile compounds, and modulation of release behavior.[66]

SLNs have

been used for ocular drug delivery in the last decades. Recently, further investigations

employing NLCs as ocular delivery systems have become known in cyclosporine loaded

NLCs the mucoadhesive properties of the thiolated non‐ionic surfactant cysteine polyethylene

glycol stearate (Cys‐ PEG‐SA) and NLC modified by this thiolated agent were evaluated.


412


Cys‐PEG‐SA and its resultant NLC provided a promising system with prolonged residence

time.[67]

Lutein- loaded NLCs could protect the entrapped lutein in the presence of simulated

gastric fluid and slowly released lutein in simulated intestinal fluid in an in‐vitro study.[68]

Triamcinoloe acetonide (TA) - loaded NLCs increased ocular absorption and enhanced

prolonged drug residence time in the ocular surface and conjunctival sac, by sustained drug

release from the delivery system, it also reduced precorneal drug loss.[69]

Intranasal drug delivery- The use of nanocarriers provides suitable way for the nasal

delivery of antigenic molecules. These represent the key factors in the optimal processing and

presentation of the antigen. Nasal administration is the promising alternative noninvasive

route of drug administration due to fast absorption and rapid onset of action, avoiding

degradation of labile drugs (peptides and proteins) in the GI tract and insufficient transport

across epithelial cell layers. The development of a stable nanostructured lipid carrier (NLC)

system as a carrier for curcumin (CRM) bio-distribution studies showed higher drug

concentration in brain after intranasal administration of NLCs than PDS. The results of the

study also suggest that CRM-NLC is a promising drug delivery system for brain cancer

therapy [70]

. In addition; NLC further enhanced the intranasal drug delivery of duloxetine in

the brain for the treatment of major depressive disorder. Nanostructured Lipid Carriers

(NLCs) of asenapine maleate to improve the bioavailability and enhance the uptake of ASN

to the brain.[60]

Parenteral drug delivery- The nano-drug delivery systems such as nanomicelles,

nanoemulsions and nanoparticles has displayed a great potential in improved parenteral

delivery of the hydrophobic agents since last two decades. NLC has been considered as an

alternative to liposomes and emulsions due to improved properties such as ease in

manufacturing, high drug loading, increased flexibility in modulating drug release profile and

along with these, their aqueous nature and biocompatibility of the excipients has enabled

intravenous delivery of the drug with passive targeting ability and easy abolishment. Another

reported example is NLCs of artemether (Nanoject) that offers significant improvement in the

anti-malarial activity and duration of action as compared to the conventional injectable

formulation. Nanoject can be considered as a viable alternative to the current injectable

intramuscular (IM) formulation.[71, 72]

Bufadienolides a class C-24 steroid also proved to be

effective in terms of enhanced hemolytic activity and cytotoxicity with reduced side effects

when incorporated in NLCs.[73]


413


Nanostructured lipid carriers (NLCs) were prepared and optimized for the intravenous

delivery of β- Elemene (β-E) β-E-NLCs showed a significantly higher bioavailability and

anti-tumor efficacy than Elemene injection. β-E-NLCs described in this study are well-suited

for the intravenous delivery of β-E.[74]

Cardiovascular treatment- Lipid nanoparticles as a carrier system has superiorities mainly

prolonged circulation time and increased area under the curve (AUC) with manageable burst

effect. NLCs would provide highly desirable physic‐chemical characteristics as a delivery

vehicle for lipophilic drugs. Drug loading and stability were improved. Tashinone (TA)

loaded NLCs the in‐vitro incubation tests confirmed that TA‐NLC could bind to apo A‐I

specifically. Macrophage studies demonstrated that TA‐NLC incubated with native HDL

could turn endogenous by association to apo‐lipoproteins, which cannot trigger

immunological responses and could escape from recognition by macrophages.[75]

Nifedipine

loaded NLCs Nanoparticle suspensions were formulated with negatively charged

phospholipid, dipalmitoyl phosphatidyl glycerol in preventing coagulation to improve

solubility and hence bioavailability of drug.[76]

In Lovastatin loaded NLCs, NLCs were

developed to promote oral absorption of lovastatin. More than 70% lovastatin was entrapped

in the NLCs. The in‐vitro release kinetics demonstrated that lovastatin release could be

reduced by up to 60% with lipid nanoparticles containing Myverol as the lipophilic

emulsifier. NLCs showing the slowest delivery. The oral lovastatin bioavailability was

enhanced from 4% to 24% and 13% when the drug was administered from NLCs containing

Myverol and SPC as surfactants respectively.[77]

Cosmetic Applications of NLC- Lipid nanoparticles—SLN and NLC—can be used to

formulate active compounds in cosmetics, e.g. prolonged release of perfumes. Incorporation

of cosmetic compounds and modulation of release is even more flexible when using NLC. In

addition, the release of insect repellents has been described.[78,79]

A feature of general interest

is the stabilization of chemically labile compounds. The solid matrix of the lipid nanoparticle

protects them against chemical degradation, e.g. Retinol.[80]

and coenzyme Q10. A recently

discovered feature is the sunscreen blocking effect of lipid nanoparticles. Similar to particles

such as titanium dioxide the crystalline lipid particles scatter UV light, thus protecting against

UV irradiation. In addition, it was found that incorporation of sunscreens leads to a

synergistic UV blocking effect of the particulate blocker lipid nanoparticle and the molecular

blocker. In vitro, crystalline lipid nanoparticles with the same sunscreen concentration


414


exhibited twice the UV protection effect compared with an O/W emulsion loaded with the

sunscreen.

CURRENT & FUTURE DEVELOPMENTS

The selection of vehicles is important for drug delivery to exert maximum activity and cause

minimal adverse effects. Some novel nano-carriers are studied to load drugs for therapy.

Among them, NLCs have gained much interest in recent years because of the satisfied drug

carrier potency and safety. This review summarizes recent advances in drug delivery by

NLCs. In addition to intravenous administration, topical and oral routes are possible

pathways for drug delivery from NLCs. Drawbacks of clinically used vehicles can be

resolved by using lipid nanoparticles. It is expected that the utility of NLCs in basic research

and the clinical setting will be more extensive in the future because of urgent needs to

discover new therapies such as treatments for cancer, neurodegenerative disease, and

inflammation. Many investigations have examined lipid nanoparticle design for fewer side

effects, longer half-life and higher bioavailability compared to conventional carriers.

However, only a few NLCs have been used in current clinical practice. The cosmetic

products are the most commonly used NLCs on the market. Also, clinical trials investigating

NLCs for drugs are limited. It is suggested that more results in animal and clinical studies

will encourage future application of drug therapy using the lipid nanocarriers. Although most

of the ingredients for composing NLCs are biodegradable, the possible toxicity of

nanoparticles still cannot be ignored in the development of NLCs. Nanomaterials are thought

to have more-serious adverse effects on organisms than materials of a larger size due to their

tiny size and corresponding higher surface areas. Information regarding the health concerns

of materials at the nano-level is still limited. Intravenous injection and topical delivery are the

main routes for drug administration by NLCs. The effort to develop alternative routes and to

treat other diseases with NLCs should be continued to extend their applications. Permeation

via the gastrointestinal tract and BBB may be a future trend. The combination of two

therapeutically active agents to be included in a single nanosystem is another consideration

for future development. Although some advantages of NLCs for drug delivery are

demonstrated, the mechanisms for enhanced efficacy are not fully understood. Hence, these

mechanisms should be further explored with the goal of elucidation and efficacy

enhancement.


415


CONCLUSION

In the20th century, Paul Ehrlich envisioned his magic bullet concept; the idea that drugs

reaches the right site in the body, at the right time, at right concentration. The aim has been to

developed therapeutic nanotechnology undertaking, particularly for targeted drug therapy The

smart NLCs as the new generation offer much more flexibility in drug loading, modulation of

release and improved performance in producing final dosage forms such as creams, tablets,

capsules and injectables. The effort to develop alternative routes and to treat other diseases

with NLCs should be continued to extend their applications. Permeation via the

gastrointestinal tract and BBB may be a future trend. The combination of two therapeutically

active agents to be included in a single nanosystem is another consideration for future

development.

Ethical Issues

Not applicable.

Conflict of Interest

The authors report no conflicts of interest.

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