WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Dilip et al.

World Journal of Pharmacy and Pharmaceutical Sciences

Volume 2, Issue 3, 921-938.

Review Article

ISSN 2278 4357

NANOSTRUCTURED LIPID CARRIER (NLC) A MODERN

APPROACH FOR TOPICAL DELIVERY: A REVIEW
Dilip K. Patel1*, Surendra Tripathy1, Suresh K. Nair1, Roohi Kesharwani1
1

Chandra Shekhar Singh College of Pharmacy, Kausambi, Allahabad, U.P. INDIA.

Article Received on
17 March 2013,
Revised on 27 April 2013,
Accepted on 28 May 2013

ABSTRACT
Solid lipid nanoparticles (SLN) were developed at the beginning of the
1990s as an alternative carrier system to emulsions, liposomes and
polymeric nanoparticles. The paper reviews advantages also potential
limitations of SLN for the use in topical pharmaceutical formulations.

*Correspondence for

Features discussed include stabilisation of incorporated compounds,

Author:

controlled release, occlusivity, film formation on skin including in vivo

* Dilip K. Patel
Chandra Shekhar Singh

effects on the skin. As a novel type of lipid nanoparticles with solid

College of Pharmacy,

matrix, the nanostructured lipid carriers (NLC) are presented, the

Kausambi, Allahabad, U.P.

structural specialities described and improvements discussed, for

INDIA.

example, increase in loading capacity, physical and chemical long-term

dilippatel87@rediffmail.com,

stability, triggered release and potentially supersaturated topical

formulations. For NLC, the technologies to produce the final topical

formulation are described, especially the production of highly concentrated lipid nanoparticle
dispersions. 3080% lipid content.
Keywords: Nanostructured lipid carriers, NLC, Nanoparticle, Topical delivery.
INTRODUCTION
Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are the two main
types of lipid nanoparticles. The research activities in SLN and NLC in the last two decades
focused mainly on pharmaceutical non dermal administration routes, i.e. parenteral peroral,
ocular and pulmonary administration. During the last 5 years SLN and NLC have been
intensively investigated for dermal application because of many positive features that have
been reported after their application to the skin. Due to the lipid matrix, the small particle size
and related adhesive properties, the residence time of SLN and NLC on the skin is
prolonged2,3,5. The development of SLN overcame many problems related to traditional

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nanoparticulate carrier technologies which limited the use (e.g. liposomes, i.v. emulsions) or
even prevented the introduction to the market (e.g. polymeric nanoparticles). SLN can be
prepared from regulatory accepted excipients, these excipients are well tolerated, large scale
production by high pressure homogenization is possible even using existing production lines
for i.v. emulsions, and the technology and the product itself are low cost. Lipid nanoparticles
with solid particle matrix are derived from o/w emulsions by simply replacing the liquid lipid
(oil) by a solid lipid, i.e. being solid at body temperature. The first generation of solid lipid
nanoparticles (SLN) was developed at the beginning of the nineties. They were produced
from a solid lipid only. In the second generation technology of the nanostructured lipid
carriers (NLC), the particles are produced by using a blend of a solid lipid with a liquid lipid,
this blend also being solid at body temperature2.
WHY LIPID NANOPARTICLES?

Better control over release kinetics of encapsulated compound

a. Engineering via size and lipid composition.

b. Melting can serve as trigger.
Enhanced bioavailability of entrapped bioactive.
Chemical protection of labile incorporated compounds.
Much easier to manufacture than biopolymeric nanoparticles.
No special solvents required.
Wider range of base materials (lipids).
Conventional emulsion manufacturing methods applicable.
Raw materials essential the same as in emulsions.
Very high long-term stability.
Application versatility:
a. Can be subjected to commercial sterilization procedures.
b. Can be freeze-dried to produce powdered formulation.
ADVANTAGES

OF

SLN/NLC

OVER

CONVENTIONAL

PARTICULATE

CARRIERS
Their small size and relatively narrow size distribution permits site-specific drug delivery.
Controlled and Sustained release of active drug can be achieved.
The incorporated drug is protected from the onslaughts of biochemical degradation.
High drug payload.
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Incorporation of lipophilic and hydrophilic drugs feasible

Can be sterilized by autoclave or gamma radiation.
Can be lyophilizes and spray dried.
Do not generate any toxic metabolites.
Relatively cheap and stable.
Easy of industrial scale production by hot dispersion technique.
Surface modification can be easily performed.
POTENTIAL PROBLEMS ASSOCIATED WITH SLN AND ITS PRODUCTION
TECHNOLOGY
The review by Mehnert high lights these aspects3 4.
Pay-load for a number of drugs too low
Drug expulsion during storage (Figure. 1)
High water content of SLN dispersions

Figure 1: Mechanism of drug expulsion during storage of SLN dispersions, transition to

highly ordered lipid crystal 6.
NLC have been developed to overcome the drawbacks associated with SLN. They are
considered to be the second generation of lipid nanoparticles. Compared to SLN, NLC show
a higher loading capacity for active compounds by creating a less ordered solid lipid matrix,
i.e. by blending a liquid lipid with the solid lipid, a higher particle drug loading can be
achieved. Therefore, the NLC have an increased drug loading capacity in comparison to SLN
and the possibility of drug expulsion during storage is less 7,8,910.

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THE NEW CONCEPT OF NLC

The three types of NLC can be summarized
1. The imperfect type
2. The amorphous type
3. The multiple type
A potential problem in SLN is the formation of a perfect crystal, which can be compared to a
dense brick wall. Using different molecules, i.e. different stones to build the matrix or
wall leaves enough imperfections to accommodate the drug (Fig. 2, 3). Drug load in SLN is
limited due to the formation of the lipid crystal. Drug expulsion is caused by an ongoing
crystallization process towards a perfect crystal. Thus, by avoiding crystallization, one can
avoid these obstacleswhich is realised in the NLC type 2. The lipid matrix is solid but not
crystalline it is in an amorphous state (Fig. 4). This can be achieved by mixing special lipids,
e.g. hydroxyoctacosanylhydroxystearate with isopropylmyristate. The solid character of the
particles was proven by NMR measurements and the lack of crystallinity by DSC analysis10.
The third type of NLC is a multiple system, being comparable to w/o/w emulsions. In this
case it is an oil-in-solid lipid-in-water dispersion. The solid lipid matrix contains tiny liquid
oil nanocompartments This NLC type uses the fact that for a number of drugs, the solubility
in oils is higher than their solubility in solid lipids (fig. 5).

Figure 2: Perfect crystal in SLN comparable with a brick wall (upper) and structure
with imperfections due to spacially very different molecules in NLC type 1 6.

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Figure 3: Crystallisation process during storage to perfect crystal in SLN (left) and
unchanged remaining NLC I structure with imperfections 9.

Figure 4: Structureless type II of NLC the lipid solidifies in the solid but amorphous
state9.

Figure 5: Theoretical proposed structure of multiple type NLC (oil-in-solid fat-in-water,

O/F/W)9.
PRODUCTION PROCESSES FOR SLN/NLC
1: High-Shear Homogenization and Ultrasound
High-shear homogenization and ultrasound were initially used for the production of lipid
nanodispersions. Both methods are widespread and easy to handle. However, in many cases,
bimodal size distributions are obtained with one population in the micrometer range. In

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addition, metal contamination has to be considered if ultrasound is used. Ahlin et al. used a
rotor-stator homogenizer to produce SLN/NLC by melt-emulsification. They investigated the
influence of different process parameters including emulsification time, stirring rate, and
cooling conditions on the particle size and the zeta potential. In most cases, average particle
sizes in the range of 100 to 200 nm were obtained using stirring rates of 20,000 to 25,000 rpm
for 8 to 10 min and controlled cooling with a stirring rate of 5,000 rpm11,12.
2: High-Pressure Homogenization
HPH has emerged as a reliable and powerful technique for the preparation of SLN/NLC.
High-pressure homogenizers push a liquid with high pressure (10 to 200 MPa) through a
narrow gap (in the range of few microns). The fluid accelerates on a very short distance to
very high velocity (over 1000 km/h). Very high-shear forces disrupt the particles down to the
submicron range. Typical lipid contents range between 5 to 10% of the fluid and represent no
problem to the homogenizer. Even lipid concentrations up to 40% have been homogenized to
lipid nanodispersions. Two general approaches of the homogenization step, the hot and the
cold homogenization techniques, can be used for the production of SLN/NLC. In both cases,
a preparatory step involves incorporating the drug into the bulk lipid by dissolving or
dispersing the drug in the lipid melt13,14.
2.1: Hot Homogenization
Hot homogenization is carried out at temperatures above the melting point of the lipid and
can therefore be regarded as the homogenization of an emulsion. A pre-emulsion of the drugloaded lipid melt and the aqueous emulsifier phase (same temperature) is obtained by a highshear mixing device (Ultra-Turrax). The quality of the pre emulsion affects the quality of the
final product to a large extent, and obtaining droplets in the size range of a few micrometers
is desirable. HPH of the pre emulsion is carried out at temperatures above the melting point
of the lipid. In general, higher temperatures result in lower particle sizes because of the
decreased viscosity of the inner phase15. However, high temperatures may also increase the
degradation rate of the drug and the carrier. Furthermore, many surfactants have decreased
solubilitys and HLB values at a higher temperature, which might have a negative impact on
homogenization efficacy. The homogenization step can be repeated several times. It should
always be kept in mind that HPH increases the temperature of the sample (approximately
10C for 500 bar). In most cases, 3 to 5 homogenization cycles at 500 to 1500 bar are
sufficient. Increasing the homogenization pressure or the number of cycles often results in an

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increase of the particle size because of particle coalescence, which occurs as a result of the
high kinetic energy of the particles. The primary product of the hot homogenization is a
nanoemulsion resulting from the liquid state of the lipid. Solid particles are expected to be
formed by the cooling of the sample to room temperature or below.
2.2: Cold Homogenization
Cold homogenization is carried out with the solid lipid and can therefore by regarded as a
high-pressure milling of a lipid suspension. Effective temperature control and regulation is
needed to ensure the unmolten state of the lipid because of the increase in temperature during
homogenization16. Cold homogenization has been developed to overcome the following three
problems of the hot homogenization technique:
Temperature-induced drug degradation
Drug distribution into the aqueous phase during homogenization
Complexity of the crystallization step of the nanoemulsion leading to several
modifications or supercooled melts.
The first preparatory step is the same as in the hot homogenization procedure and includes
the solubilization or dispersing of the drug in the melt of the bulk lipid. However, different
steps follow. The drug-containing melt is cooled very rapidly (e.g., by means of dry ice or
liquid nitrogen). The high cooling rate favors a homogenous distribution of the drug within
the lipid matrix. The solid, drug-containing lipid is milled by means of ball or mortar milling
in the range of 50 to 100 nm. Low temperatures increase the fragility of the lipid and,
therefore, favor particle disruption. The solid lipid microparticles are dispersed in a chilled
emulsifier solution. The presuspension is subjected to HPH at or below room temperature. In
general, compared with hot homogenization, larger particle sizes and a broader size
distribution are observed in cold homogenized samples14.
3: SLN/NLC Prepared by Solvent Emulsification/Evaporation
Sjostrom and Bergenstahl used a solvent emulsification/evaporation method to prepare solid
lipid nanodispersions. The lipophilic material is dissolved in a water immiscible organic
solvent (e.g., cyclohexane) that is emulsified in an aqueous phase to give an oil/water (o/w)
emulsion. On evaporation of the solvent by reduced pressure, solid lipid Nanoparticle
dispersion is formed. The mean diameter of the obtained particles was 25 nm, with
cholesterol acetate as the model drug and using a lecithin/sodium glycocholate blend as the
emulsifier. The reproducibility of these results was confirmed by Siekmann and Westesen,
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who also prepared nanoparticles of tripalmitin by dissolving triglyceride in chloroform. Mean

particle sizes of the final particles ranged from 30 to 100 nm, depending on the
lecithin/cosurfactant blend. The advantage of this procedure over the cold homogenization
process described before is the avoidance of any thermal stress. A clear disadvantage is the
use of organic solvents17,18.
4: Solvent Injection Method
The production of polymeric nanoparticles by dilution of polymer solutions in water has been
described by De Labouret19. The process also can be easily used for the production of lipid
nanodispersions. A requirement is the solubility of the lipid in the polar organic solvent,
which limits the application range of this procedure. A further disadvantage is the low
concentration of the lipid nanoparticles (typically 1% or less). Higher amounts of the organic
solvent increase the solubility of the lipid in the aqueous phase and lead to an increase in
particle size resulting from Ostwald ripening. The main advantage of the method is the
avoidance of thermal stress20.
5: Micro emulsion-Based SLN/NLC Preparations
SLN preparation techniques that are based on the dilution of microemulsions have been
developed by Gasco21. It should be mentioned that there are different definitions and opinions
about the structure and dynamics of microemulsion in the scientific community. An extended
review has recently been published by Moulik and Paul22. Gasco and other scientists describe
microemulsions as two-phase systems composed of an inner and outer phase (e.g., o/w
microemulsions). Microemulsions are made by stirring at 65 to 70C an optically transparent
mixture that is typically composed of a low-melting fatty acid (e.g., stearic acid), an
emulsifier (e.g., polysorbate 20, polysorbate 60, soy phosphatidylcholine, taurodeoxycholic
acid sodium salt), coemulsifiers (e.g. butanol, sodium monooctylphosphate), and water. The
hot microemulsion is dispersed in cold water (2 to 3C) under stirring. Typical volume ratios
of the hot microemulsion to cold water are in the range of 1:25 to 1:50. The dilution process
is critically determined by the composition of the microemulsion. According to the literature
Boltri Gasco21,23, the droplet structure is already contained in the microemulsion, and,
therefore, no energy is required to achieve submicron particle sizes. In addition to the
composition, the temperature gradient and the pH value are key parameters for the quality of
the final lipid nanosuspension. High-temperature gradients facilitate rapid lipid crystallization

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and prevent aggregation. Because of the dilution step, achievable lipid contents are
considerably lower compared with the HPH-based formulations.24
NLC AS TOPICAL DRUG DELIVERY SYSTEMS
Topical drug application has been introduced since long time to achieve several purposes on
different levels (skin surface, epidermis, dermis and hypodermis). However, several problems
have been reported with the conventional topical preparations e.g. low uptake due to the
barrier function of the stratum corneum and absorption to the systemic circulation. A lot of
research groups paid attention to the topical application of the SLN and NLC. Many features,
which these carrier systems exhibit for dermal application of cosmetics and pharmaceutics,
have been pointed out. SLN and NLC are composed of physiological and biodegradable
lipids that show low toxicity. The small size ensures a close contact to the stratum corneum
and can increase the amount of drug penetrated into the skin. Due to the occlusive properties
of lipid nanoparticles, an increased skin hydration effect is observed. Furthermore, lipid
nanoparticles are able to enhance the chemical stability of compounds sensitive to light,
oxidation and hydrolysis8.
TOPICAL BENEFIT OF NLC
Increase of skin occlusion: The lipid film formation on the top of the skin and the
subsequent occlusion effect was reported for lipid nanoparticles25,26. By using very small
lipid particles, which are produced from highly crystalline and low melting point lipids, the
highest occlusion will be reached. Particles smaller than 400 nm containing at least 35% lipid
of high cystallinity have been most effective27. Souto et al. found a higher occlusive factor
for SLN in comparison to NLC of the same lipid content. Comparing NLC with different oil
content showed that an increase in oil content leads to a decrease of the occlusive factor 28,29.
Increase of skin hydration and elasticity: The reduction of trans epidermal water loss
(TEWL) caused by occlusion leads to an increase in skin hydration after dermal application
of SLN, NLC or formulations containing them. An in vivo study showed that the SLNcontaining o/w cream increased the skin hydration significantly more than the conventional
o/w cream. In this study the skin hydration effect after repetitive application of an o/w cream
containing SLN and a conventional o/w cream was investigated for 28 days26. A significant
higher increase in skin hydration was found by Mller et al. for an NLC-containing cream
compared to conventional cream30.

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Enhancement of skin permeation and drug targeting: The stratum corneum in healthy
skin has typically a water content of 20% and provides relatively an effective barrier against
percutaneous absorption of exogenous substances. Skin hydration after applying SLN or NLC
leads to a reduction of corneocytes packing and an increase in the size of the corneocytes
gaps. This will facilitate the percutanious absorption and drug penetration to the deeper skin
layers31.
An increase of skin penetration was reported for coenzyme Q 10 (Q10)-loaded SLN
compared to Q10 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 NLC formulation, respectively. Jenning et al. showed that enhanced penetration of retinol
with epidermal targeting of this active could be achieved by applying retinol-loaded NLC10.32.
Ricci et al. investigated the in vitro penetration of indomethacin from NLC-containing gel
and gel without NLC through the stratum corneum and epidermis. He also investigated the in
vivo indomethacin release by tape-stripping test and the in vivo anti-inflammatory activity
using the UV-B induced erythrema model. In this work it was found that the antiinflammatory effect following the topical application of indomethacin was more prolonged
with indomethacin-loaded NLC gel. In the tape stripping test higher amounts of indomethacin
were found in the stratum corneum after application of the indomethacin-loaded NLC gel.
The in vitro permeation through the stratum corneum and epidermis from indomethacinloaded NLC gel was less than from gel without NLC33.
Improve benefit/risk ratio: Skin atrophy and systemic side effect occurred after applying
conventional prednicarbate cream could be avoided when this drug was formulated as lipid
nanoparticle. Predinicarbate uptake was enhanced and it was accumulated in the epidermis
with a low concentration in the dermis31,34.
Tretinoin loaded-SLN formulation was studied by Shah et al concerning skin irritation. One
of the major disadvantages associated with the topical application of tretinoin is the local skin
irritation such as erythrema, peeling and burning as well as increased sensitivity to sunlight.
In the in vitro permeation studies through rat skin they found that SLN based tretinoin gel has
a permeation profile comparable to that of the market tretinoin cream. But on the other hand,
Draize patch test showed that SLN based tretinoin gel resulted in remarkably less erythremic

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episodes compared to the currently marketed tretinoin cream and hence, a better benefit/risk
ratio is expected for the formulations containing tretinoin-loaded SLN. Conclusively,
applying SLN or NLC can enhance skin penetration of incorporated actives, promote the
epidermal targeting and minimize the systemic side effects and therefore, the benefit/risk
ratio is improved35.
Enhancement of chemical stability of chemically labile compounds: Enhancement of
chemical stability after incorporation into lipid nanocarriers was proven for many cosmetic
actives, e.g. coenzyme Q 10, ascorbyl palmitate, and retinol (vitamin A)32,36,37.
Regulatory status of excipients: One hurdle for a formulation to be introduced to the market
is the use of excipients having no accepted status. For topical SLN, all excipients used in
current topical cosmetic and dermal pharmaceutical products can be used. In addition, GRAS
substances and substances with accepted GRAS status can be used (Code of Federal
Regulations, Food and Drugs 21).
TOPICAL TREATMENT OF SKIN DISEASE: POTENTIAL AND PROBLEMS
Topical treatment of skin diseases is very attractive, since systemic load of active
pharmaceutical ingredients (API) and thus also systemic side effects are reduced as compared
to parenteral or oral drug administration. Hence application of drugs (preparations of API) to
the skin surface was and still is not only used for skin disease but also for local antirheumatic
therapy to control gastrointestinal side effects of nonsteroidal anti-inflammatory drugs.
Moreover, drug application to the skin surface avoids the major fluctuations of plasma levels
typical for repeated administration of rapidly eliminated drugs while it also allows to
circumvent the first passage of API through liver after intestinal absorption. Thus transdermal
drug application has gained still increasing importance for systemic treatment, e.g. with drugs
subject to extensive first-pass elimination such as glyceryl trinitrate or estrogens as well as
for the sustained suppression of chronic pain38.
SKIN MORPHOLOGY: BARRIER AND RESERVOIR FUNCTION
Drug molecules in contact with the skin surface can penetrate by either three potential
pathways: through the sweat ducts, via the hair follicles and sebaceous glands (collectively
called the shunt or appendageal route), or directly across the stratum corneum (Fig.7). The
relative importance of the shunt or appendageal route versus transport across the stratum
corneum has been debated by scientists over the years and is further complicated by the lack

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of a suitable experimental model to permit separation of the three pathways. In vitro

experiments tend to involve the use of hydrated skin or epidermal membranes so that
appendages are closed by the swelling associated with hydration. Scheuplein and colleagues
proposed that a follicular shunt route was responsible for the pre steady-state permeation of
polar molecules and flux of large polar molecules or ions that have difficulty diffusing across
the intact stratum corneum39,40,41.
A molecule traversing via the transcellular route must partition into and diffuse through the
keratinocyte, but in order to move to the next keratinocyte, the molecule must partition into
and diffuse through the estimated lipid lamellae between each keratinocyte. This series of
partitioning into and diffusing across multiple hydrophilic and hydrophobic domains is
unfavorable for most drugs. Consequently,
The intercellular route is now considered to be the major pathway for permeation of most
drugs across the stratum corneum.

Figure 6: Simplified representation of skin showing routes of penetration Traditionally

it was thought that hydrophilic chemicals diffuse within the aqueous regions near the
outer surface of intracellular keratin filaments (intracellular or transcellular route)
whilst lipophilic chemicals diffuse through the lipid matrix between the filaments
(intercellular route)39.

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Figure 7: Diagrammatic representation of the stratum corneum and the intercellular

and transcellular routes of penetration39.
The three main factors determining the transdermal permeation of drugs are the mobility of
drug in the vehicle, release of drug from the vehicle, and permeation of drug into the skin.
These factors affect either the thermodynamic activity that drives the drug into the skin or the
permeability of drug in the skin, particularly stratum corneum. NLC based gel improve the
transdermal delivery of several drugs over the conventional topical preparations such as
emulsions, and gels42,43. Among the physical properties that make NLC based gel attractive
as transdermal drug delivery vehicles is their transparent nature, which means that the
product is not only aesthetically pleasing, but allows easy visualization of any contamination.
Significantly the small droplet size provides a large interfacial area for rapid drug release, and
so the drug should exhibit an enhanced bioavailability, enabling a reduction in dose, more
consistent temporal profiles of drug absorption, and the protection of drugs from the hostile
environment of the body. In addition to increasing the rate of drug release, NLC can also be
used as a reservoir and actually slow the release of drug and prolong its effect, thereby
avoiding high concentrations in the blood. Whether a drug is rapidly or slowly released from
NLC depends very much on the affinity of the drug for the NLC. Since NLC contain
surfactants (co-surfactants) and other excipients, they may serve to increase the membrane
permeation of drug by.

Disrupting the intercellular bilayer lipid structure

Interacting with the intracellular proteins of the stratum corneum

Improving the partitioning of a drug into the stratum corneum44.

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Aceclofenac is a potent analgesic, antipyretic and anti-inflammatory agent has been approved
for the treatment of various kinds of pain, osteoarthritis and rheumatoid arthritis. An arthritic
condition demands a controlled release drug delivery system for a prolong period so that can
satisfy the goals of the treatment like reduction of the pain and inflammation, slowing the
disease progression and prevention of adverse reaction. The requirement for designing of a
topical drug delivery system of aceclofenac, which could not only increase the presence of
the drug locally, and for a prolonged period but also reduce the risk of systemic toxicity. NLC
have been shown to exhibit a controlled release behavior for various active ingredients such
as ascorbyl palmitate, clotrimazole and other antifungal agents. As an alternative route for
aceclofenac transdermal administration eliminate these systemic side effects, which also offer
many advantages, such as patient compliance and possibility of continuous and controlled
drug absorptio45,46,47.
CONCLUSION
SLN and NLC have shown many advantages for dermal delivery of drugs but unfortunately
up to now there are no pharmaceutical products on the market containing lipid nanoparticles.
It could be shown already for various drugs that topical formulations containing lipid
nanoparticles can enhance the penetration into the skin increasing treatment efficiency, target
the epidermis, reduce systemic absorption and side effects. Furthermore, increased activities
as well as prolonged activity was reported while the benefit/ risk ratio was increased for
many drugs. Due to the superior performance of lipid nanoparticles containing topical
formulations compared to market formulations, the market introduction of pharmaceutical
topical formulations is expected in the near future.
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