NANO-LIPID CARRIERS: A FORMIDABLE DRUG DELIVERY SYSTEM
Transcript of NANO-LIPID CARRIERS: A FORMIDABLE DRUG DELIVERY SYSTEM
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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
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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
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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
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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
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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,
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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.
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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]
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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
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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.
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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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