International Journal of Pharmaceutics: Lipid Nanoparticles (SLN, NLC) in Cosmetic and Pharmaceutical Dermal Products

International Journal of Pharmaceutics 366 (2009) 170–184
Contents lists available at ScienceDirect
International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm
Pharmaceutical Nanotechnology
Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products

Jana Pardeike, Aiman Hommoss, Rainer H. Müller ∗
Department of Pharmaceutical Technology, Biopharmaceutics and Nutricosmetics, Freie Universität Berlin, Kelchstraße 31, 12169 Berlin, Germany
a r t i c l e i n f o a b s t r a c t
Article history: Solid lipid nanoparticles (SLN) are distinguishable from nanostructured lipid carriers (NLC) by the compo-
Received 31 July 2008 sition of the solid particle matrix. Both are an alternative carrier system to liposomes and emulsions. This
Received in revised form 2 October 2008 review paper focuses on lipid nanoparticles for dermal application. Production of lipid nanoparticles and
Accepted 3 October 2008
final products containing lipid nanoparticles is feasible by well-established production methods. SLN and
Available online 17 October 2008
NLC exhibit many features for dermal application of cosmetics and pharmaceutics, i.e. controlled release
of actives, drug targeting, occlusion and associated with it penetration enhancement and increase of skin
Keywords:
hydration. Due to the production of lipid nanoparticles from physiological and/or biodegradable lipids,
Solid lipid nanoparticles (SLN)
Nanostructured lipid carriers (NLC)
this carrier system exhibits an excellent tolerability. The lipid nanoparticles are a “nanosafe” carrier. Fur-
Dermal application thermore, an overview of the cosmetic products currently on the market is given and the improvement
Cosmetic use of the benefit/risk ratio of the topical therapy is shown.
Pharmaceutical use © 2008 Elsevier B.V. All rights reserved.
Dermal safety
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
2. What exactly are lipid nanoparticles? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
3. Production and incorporation into creams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
4. Science-based cosmetics: formulations and products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
5. Pharmaceutical formulations and benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
5.1. Topical glucocorticoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
5.2. Antiandrogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
5.3. Vitamin A derivates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
5.4. PUVA-therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
5.5. Non-steroidal anti-inflammatory drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
5.6. Traditional Chinese medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
5.7. Antimycotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
5.8. Podophyllotoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
6. Lipid nanoparticles: a “nanosave” carrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
7. Conclusion and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
1. Introduction Currently more than 20 research groups are working on lipid

nanoparticles world wide, estimated by the published articles. This
At the beginning of the 1990s there were only the research proves the increasing interest in the field of lipid nanoparticles.
groups of Müller (Berlin, Germany), Gasco (Turin, Italy) and West- Lipid nanoparticles have been investigated for various pharmaceu-
esen (Braunschweig, Germany) working on lipid nanoparticles. tical applications, e.g. parenteral (Wissing et al., 2004a; Blasi et
al., 2007; Bondi et al., 2007; Brioschi et al., 2007), peroral (Müller
et al., 2006; Martins et al., 2007; Sarmento et al., 2007; Yuan et
∗ Corresponding author. Tel.: +49 30 838 678; fax: +49 30 838 616. al., 2007), dermal (Müller et al., 2002; Priano et al., 2007), ocu-
E-mail address: [email protected] (R.H. Müller). lar (Ugazio et al., 2002; Attama and Müller-Goymann, 2008) and
0378-5173/$ – see front matter © 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.ijpharm.2008.10.003
J. Pardeike et al. / International Journal of Pharmaceutics 366 (2009) 170–184 171
pulmonary (Xiang et al., 2007; Liu et al., 2008) administration.

Moreover, since the last decade, they have been studied intensively
for dermal application, both in pharmaceutical and cosmetic uses.
This review paper provides an overview of the ongoing research
in cosmetic and pharmaceutical dermal preparations containing
SLN or NLC. The production technology of these lipid nanoparticles
and preparation of lipid nanoparticles containing products for der-
mal application is presented. Furthermore, the excellent tolerability
of these carriers for dermal application is outlined and discussed
based on available data.
2. What exactly are lipid nanoparticles?

Fig. 1. Formation of an almost perfect crystalline structure in SLN (left) by identically
shaped molecules similar to a brick wall with limited loading capacity for actives.
Solid lipid nanoparticles (SLN) were developed at the beginning Formation of a solid particle matrix of NLC (right) with many imperfections compa-
of the 1990s as an alternative carrier system to emulsions, lipo- rable to building a wall from very differently shaped stones, the increased number of
somes and polymeric nanoparticles. SLN are produced by replacing imperfections leads to an increased loading capacity for active compounds (modified
the liquid lipid (oil) of an o/w emulsion by a solid lipid or a blend after Müller et al. (2002)).
of solid lipids, i.e. the lipid particle matrix being solid at both room
and body temperature (Lucks and Müller, 1991). SLN are composed to a dermal formulation produced with a reduced amount of
of 0.1% (w/w) to 30% (w/w) solid lipid dispersed in an aqueous water.
medium and if necessary stabilized with preferably 0.5% (w/w)
to 5% (w/w) surfactant. The incorporation of cosmetic and phar- 3. Production and incorporation into creams
maceutical actives is feasible. The mean particle size of SLN is in
the submicron rage, ranging from about 40 to 1000 nm (Lucks and Many different techniques for the production of lipid nanopar-
Müller, 1991). ticles have been described in the literature. These methods are high
In the second generation of the lipid nanoparticle technology, pressure homogenization (Liedtke et al., 2000; Mehnert and Mäder,
the particles are produced using blends of solid lipids and liquid 2001; Wissing et al., 2004a), microemulsion technique (Gasco,
lipids (oils). To obtain the blends for the particles matrix, solid lipids 1993, 1997; Priano et al., 2007), emulsification-solvent evaporation
are mixed with liquid lipids (oils), preferably in a ratio of 70:30 up (Sjöström and Bergenstahl, 1992), emulsification-solvent diffusion
to a ratio of 99.9:0.1. Due to the oil in these mixtures a melting method (Hu et al., 2002; Trotta et al., 2003), solvent injection
point depression compared to the pure solid lipid is observed, but (or solvent displacement) method (Schubert and Müller-Goymann,
the blends obtained are also solid at body temperature (Müller and 2003), phase inversion (Heurtault et al., 2002), multiple emulsion
Olbrich, 2000b). This second generation of nanoparticles is called technique (Garcý-Fuentes et al., 2002), ultrasonication (Pietkiewicz
nanostructured lipid carriers (NLC). The overall solid content of NLC and Sznitowska, 2004; Puglia et al., 2008) and membrane contrac-
could be increased up to 95% (Müller et al., 1999). These second tor technique (Charcosset et al., 2005; El-Harati et al., 2006).
generation of submicron particles can be loaded with cosmetic and However, high pressure homogenization technique has many
pharmaceutical actives as well. advantages compared to the other methods, e.g. easy scale up,
NLC were developed to overcome some potential limitations avoidance of organic solvents and short production time. High pres-
associated with SLN. Compared to SLN, NLC show a higher loading sure homogenizers are widely used in many industries including
capacity for a number of active compounds, a lower water content the pharmaceutical industry, e.g. for the production of emulsions
of the particle suspension and avoid/minimize potential expulsion for parenteral nutrition. Therefore, no regulatory problems exist
of active compounds during storage (Mehnert and Mäder, 2001). for the production of topical pharmaceutical and cosmetic prepa-
SLN are produced from solid lipids only and after preparation at rations using this production technique. It can be considered as
least a part of the particles crystallizes in a higher energy modifi- being industrially the most feasible one.
cation (␣ or ␤ ). During storage, these modifications can transform Lipid nanoparticles can be produced by either the hot or cold
to the low energy, more ordered ␤ modification. Due to its high high pressure homogenization technique. Fig. 2 shows schemat-
degree of order, the number of imperfections in the crystal lattice ically the steps of these two methods. The active compound is
is reduced leading to drug expulsion. By creating a less ordered dissolved or dispersed in melted solid lipid for SLN or in a mixture of
solid lipid matrix, i.e. by blending a solid lipid with a liquid lipid, liquid lipid (oil) and melted solid lipid for NLC. In the hot homog-
a higher active load of the particles can be achieved. In general, enization method the lipid melt containing the active compound
the drug (or cosmetic active) can be located in between the fatty is dispersed in a hot surfactant solution of the same temperature
acid chains or in between the lipid layers and also in imperfections (5–10 ◦ C above the melting point of the solid lipid or lipid blend)
of the lipid matrix (e.g. amorphous drug clusters). In case of very by high speed stirring. The obtained emulsion (generally called
similar lipid molecules, especially when highly purified monoacid pre-emulsion) is then passed through a high pressure homoge-
glycerides are used, the drug loading is very limited and drug expul- nizer adjusted to the same temperature generally applying three
sion occurs within a short time due to the formation of the well cycles at 500 bar or two cycles at 800 bar. In the cold homoge-
ordered ␤ modification (Fig. 1). Therefore, the production of NLC nization method, the active containing lipid melt is cooled down.
yields to an increase of the loading capacity of the active compounds After solidification the mass is crushed and ground to obtain lipid
in the particles and also avoids or minimizes the expulsion of the microparticles. The lipid microparticles are then dispersed in a cold
active compound during storage. SLN are dispersions having typ- surfactant solution yielding a cold pre-suspension of micronized
ically water contents of 70–99.9% which might lead to problems lipid particles. This suspension is passed through a high pressure
regarding the SLN content in a potential final topical formula- homogenizer at room temperature applying typically 5–10 cycles
tion. NLC concentrates with higher lipid content can be produced, at 1500 bar.
which simplifies the incorporation into a final product. An NLC For the production of lipid nanoparticles by high pressure
concentrate (e.g. 40–50% solid contend (w/w)) is simply admixed homogenization there are many machines available on the mar-
172 J. Pardeike et al. / International Journal of Pharmaceutics 366 (2009) 170–184
Fig. 2. Production process of lipid nanoparticles using cold (light gray background) and hot (dark gray background) high pressure homogenization technique.
ket. For some technical reasons, e.g. temperature control and cost of Addition of SLN or NLC to an existing product, e.g. cream or
large-scale equipment, piston-gap homogenizers are preferred over lotion, is realized by replacing a part of the water phase with con-
jet-stream homogenizers (Müller et al., 2005). Piston-gap homoge- centrated SLN or NLC dispersion. To maintain the lipid content of
nizers are available with different production capacities. Therefore, the original cream or lotion, the lipid content of the original formu-
production on laboratory scale up to large scale is possible with lation can be reduced about the amount of incorporated lipid from
the same dispersion principle. With a minimum batch size of 3 ml the lipid nanoparticles (Müller et al., 2002). The creams and lotions
an EmulsiFlex-B3 (Avestin, Ottawa, Canada) can be used for the are produced using the established way of production, cooled to
laboratory scale production with limited new chemical entities or about 30 ◦ C, and the concentrated lipid nanoparticles suspension is
very expensive active materials. The Micron LAB 40 (APV Deutsch- then admixed applying gentle stirring.
land GmbH, Unna, Germany) is a laboratory scale high pressure Instabilities of lipid nanoparticles in cosmetic or pharmaceuti-
homogenizer with a maximum batch size of 40 ml if operated dis- cal creams or lotions containing oil droplets that might occur are
continuously and a batch size range from 200 to 1000 ml when aggregation or dissolution. The presence of solid lipid in such for-
modified to work continuously. Another laboratory scale homog- mulations can be proven by differential scanning calorimetry (DSC)
enizer is the Panda (tabletop homogenizer) (Niro Soavi, Lübeck, (Müller and Dingler, 1998). The particle size can be determined
Germany). It is used for feasibility testing and process development. using photon correlation spectroscopy (PCS) or laser diffractometry
The batch size ranges from 500 ml to 2 l. Medium scale batches (up (LD) (Pardeike and Müller, 2007b).
to 10 l) can be produced using a Micron LAB 60 (APV Deutschland Hydrogel formulations (xanthan gum, hydroxyethylcellulose
GmbH, Unna, Germany). Examples of high pressure homogeniz- 4000, Carbopol 943 and chitosan) containing SLN or NLC were
ers for large scale production are the Gaulin 5.5 (APV Deutschland investigated regarding the physical stability of the lipid nanopar-
GmbH, Unna, Germany) and the Rannie 118 (APV Deutschland ticles. For both lipid nanocarriers a good physical stability was
GmbH, Unna, Germany). These machines have a homogenization reported (Shahgaldian et al., 2003; Souto et al., 2004b).
capacity of 150 and 2000 l/h, respectively (also depending on the Using high lipid concentrations a final product can be pro-
pressure applied) (Gohla and Dingler, 2001; Müller et al., 2002). duced in one step. These particle dispersions have a relatively high
In general the formulation of topical products containing SLN consistency; they are cream like or almost solid. By PCS, LD and
or NLC is identical for both of them. Products can be obtained electron microscopy the existence of intact particles can be proven
by admixing SLN/NLC to existing products, addition of viscosity (Lippacher et al., 2001; Radtke and Müller, 2001).
enhancers to the aqueous phase of SLN/NLC to obtain a gel or the Comparing lipid nanoparticle formulations for dermal appli-
direct production of a final product containing only nanoparticles cation in the pharmaceutical and the cosmetics field, the
in a one-step process. technological aspects are similar if not identical (e.g. incorporation
Fig. 5. Increase in skin hydration after application of formulation A (cream without

Fig. 3. The %age remaining retinol in the lipid nanoparticles (solid lipid Elfacos or
SLN) and formulation B (cream with SLN) for 28 days (with permission from Wissing
Compritol) and Miglyol nanoemulsion with 0.5% (w/w) retinol loading stored at
and Müller (2003b)).
room temperature for 6 months (10% lipid, 1.5% Miranol 32 as stabilizer) (n = 3)
(modified after Jenning (1999)).
ing at least 35% lipid of high cystallinity have been most effective
of actives into particles, incorporation of particles into cream, sta- (Fig. 4) (Wissing et al., 2001a; Wissing and Müller, 2002a). Con-
bility in cream, etc.). However, the time for product development sequently Souto et al., found a higher occlusive factor for SLN in
and market introduction for cosmetic products is much shorter due comparison to NLC of the same lipid content (Souto et al., 2004a).
to the more complex regulations for the development of a pharma- Comparing NLC with different oil content led to the conclusion that
ceutical product. Therefore, analogously to liposomes, the first lipid an increase in oil content leads to a decrease of the occlusive factor
nanoparticles product on the market was a cosmetic product. (Teeranachaideekul et al., 2008).
Due to the reduced water loss caused by occlusion, the skin
4. Science-based cosmetics: formulations and products hydration is increased after dermal application of SLN or NLC or
lipid nanoparticles-containing formulations. Wissing and Müller
Both NLC and SLN have many features that are advantageous performed an in vivo study investigating the skin hydration effect
for dermal application. They are colloidal carriers providing con- after repetitive application of an o/w cream containing SLN and a
trolled release profiles for many substances. They are composed of conventional o/w cream for 28 days. The SLN containing o/w cream
physiological and biodegradable lipids exhibiting low toxicity and increased the skin hydration significantly more than conventional
low cytotoxicity, that means an excellent tolerability. The small size o/w cream (Wissing and Müller, 2003b) (Fig. 5). A significant higher
ensures a close contact to the stratum corneum and can increase increase in skin hydration was found by Pardeike and Müller for an
the amount of drug penetrated into the skin. Due to the occlusive NLC-containing cream compared to conventional cream (Pardeike
properties of lipid nanoparticles, an increased skin hydration effect and Müller, 2006).
is observed. Furthermore, lipid nanoparticles are able to enhance In healthy skin the stratum corneum has typically a water
the chemical stability of compounds sensitive to light, oxidation content of 20% and provides a relative effective barrier against per-
and hydrolysis. Enhancement of chemical stability after incorpora- cutaneous absorption of exogenous substances. Skin occlusion can
tion into lipid nanocarriers was proven for many cosmetic actives, increase the stratum corneum hydration and therefore influence
e.g. coenzyme Q10 (Dingler, 1998; Puglia et al., 2006), ascorbyl percutanious absorption (Zhai and Maibach, 2001). For cosmetic
palmitate (Teeranachaideekul et al., 2007a), tocopherol (vitamin products it is important that the cosmetic active is not systemi-
E) (Dingler, 1998) and retinol (vitamin A) (Fig. 3) (Jenning, 1999; cally absorbed. But a certain penetration into the skin is needed
Jenning and Gohla, 2001; Jee et al., 2006). to obtain a cosmetic effect. In general lipid nanoparticles do not
Film formation on the skin and subsequent occlusion effect was penetrate the horny layer (Schäfer-Korting et al., 2007) but a follic-
reported for lipid nanoparticles. It was found by Wissing et al., ular uptake by the hair follicles has been reported for particulate
that the highest occlusion will be reached using low melting lipids, systems (Lademann et al., 2007). Improved dermal uptake of active
highly crystalline particles and very small particles. Nanoparticles compounds loaded to lipid nanoparticles might also result from an
have been found to be 15-folds more occlusive than microparticles increased contact surface of the active compound with the corneo-
(de Vringer, 1992, 1999). Particles smaller than 400 nm contain- cytes, a rapid or a steady release and surfactants (Schäfer-Korting
Fig. 4. The occlusion factor of lipid nanoparticles depends on various factors: at identical lipid content, reducing the particle size leads to an increase in particle number, the
film becomes denser (left) and therefore the occlusion factor increases. At a given particle size, increasing the lipid concentration increases particle number and density of
the film (right) which also leads to a higher occlusion factor (with permission from Müller et al. (2007a)).
Fig. 6. Models of incorporated actives in lipid nanoparticles, homogeneous matrix (left), active-free lipid core with active-enriched shell (middle) and active-enriched core
with active-free lipid shell (right) (modified after Müller et al. (2000b)).
et al., 2007). The distribution of the active compound within the al. showed a prolonged release of the perfume Kenzo from NLC
lipid particles can vary considerably (Fig. 6) and hence its influence compared to emulsion and conventional shampoo (Müller et al.,
on the percutanious uptake (Müller et al., 2000b; Wissing et al., 2007b). Hommoss et al. studied the effect of changing the solid
2004b). Therefore, each system has to be studied separately consid- lipid of the perfume-loaded lipid nanoparticles on the release pro-
ering its influence on percutanious absorption (Sivaramakrishnan file of the incorporated perfume (Hommoss and Müller, 2006). It
et al., 2004; Lombardi Borgia et al., 2005; Stecova et al., 2007). Burst could be concluded that by selecting a solid lipid that can enclose
release as well as sustained release has been reported for SLN and the perfume in its solid matrix a controlled perfume released can be
NLC dispersions (Müller et al., 2000a). For dermal application both achieved (Fig. 7). Furthermore, it was found that the release of per-
features are of interest. Burst release might improve the penetra- fume depends on the lipid matrix composition, the perfume load
tion of active compounds. Sustained release becomes important and the surfactant type (Hommoss et al., 2007a).
for active ingredients that are irritating at high concentrations or A prolonged release is also desired for insect repellents. With
to supply the skin over a prolonged period of time with an active SLN and NLC a prolonged release can be achieved. The natural insect
compound (e.g. antimycotics). repellent lemon oil and the synthetic insect repellent DEET (N,N-
Comparing the release profiles of retinol-loaded SLN and diethyltoluamide) were successfully incorporated into SLN (Iscan
nanoemulsion as well as retinol-loaded SLN and nanoemulsion et al., 2005). A prolonged release of the insect repellent from SLN
incorporated in xanthan gum hydrogel or o/w cream, it was found could be shown (Fig. 8) (Wissing et al., 2000b; Wissing, 2002).
that the SLN formulations showed a controlled release over the It was found by Wissing et al. that SLN can act as a phys-
first 6 h. After longer periods (12–24 h) the release rate increased ical UV blocker themselves and are able to improve the UV
and even exceeded the release rate of the formulations contain- protection in combination with organic sunscreens such as 2-
ing retinol-loaded nanoemulsions (Jenning et al., 2000b). In in hydroxy-4-methoxy benzophenone which allows a reduction of
vitro penetration studies using porcine skin retinol-loaded SLN and the concentration of the UV absorber (Wissing and Müller, 2001b;
retinol-loaded nanoemuslion were compared. High concentrations Müller et al., 2002; Wissing and Müller, 2002b). These findings were
of retinol were found in the upper skin layers following the applica- confirmed by Song and Lui comparing UV absorption properties
tion of SLN preparation, whereas the deeper regions showed very of 3,4,5-trimethoxybenzochitin-loaded SLN and SLN free system
low retinol levels. Therefore, a localization effect in upper skin lay- (Song and Liu, 2005). Comparing SLN to a conventional emulsion,
ers was suggested (Jenning et al., 2000a). the amount of molecular sunscreen can be reduced by 50% in
Teeranachaideekul et al. compared the release profile of Q10- the SLN formulation maintaining the protective level of the con-
loaded NLC and nanoemulsion. The Q10-loaded NLC exhibit a ventional emulsion (Wissing and Müller, 2003a). Furthermore, a
biphasic release pattern. NLC provided a fast initial release fol- significant increase in SPF up to about 50 was reported after the
lowed by slow release while the Q10-loaded nanoemulsion showed encapsulation of titanium dioxide into NLC (Villalobos-Hernandez
a constant release over the time (Teeranachaideekul et al., 2007b).
An increase of skin penetration was reported for coenzyme
Q10-loaded SLN and NLC compared to nanoemulsion and liquid
paraffin or isopropanol respectively, performing a tape strip-
ping test (Dingler, 1998; Pardeike and Müller, 2007a). Using the
fluorescence dye Nile red as a marker, it could be shown by Teer-
anachaideekul et al. that the penetration depth and the amount
penetrated into the skin depends on the oil content used in NLC
(Teeranachaideekul et al., 2008). It was found that the degree of epi-
dermal targeting depends on the oil content, and associated with
the oil content, the occlusive factor.
A prolonged release is of interest for perfumes as well as for
perfumes incorporated into cosmetic products. Wissing et al. found
that SLN loaded with the perfume Allure (Chanel) yield a prolonged
release of the perfume from the solid lipid matrix of SLN. Compar-
ing the release of the perfume from an emulsion and SLN, after
Fig. 7. A prolonged release can be seen for the perfume CA from two different lipid
6 h 100% of the perfume were released from the emulsion but only nanoparticle formulations (Preifac, Apifil) compared to a fast releasing nanoemul-
75% was released from the SLN (Wissing et al., 2000a). Müller et sion (modified after Hommoss and Müller (2006)).
and Müller-Goymann, 2005). Encapsulation of inorganic sun-

screens into NLC is therefore a promising approach to obtain well
tolerable sunscreens with high SPF.
The positive features of lipid nanoparticles leaded to the market
introduction of a number of cosmetic products. Table 1 provides an
overview of cosmetic products containing lipid nanoparticles (NLC)
currently on the market.
Investigations on Cutanova Cream NanoRepair Q10 (Dr. Rimpler
GmbH, Wedemark, Germany), being the first lipid nanoparticles-
based cosmetic product introduced to the market in 2005, have
proven that the NLC containing cream is superior with regard to
skin hydration in comparison to a conventional o/w cream having
the same composition (Pardeike and Müller, 2006). Fig. 9 shows
the increase in skin hydration after repetitive application of both
creams for 42 days by 30 female volunteers. The evaluation of the
Fig. 8. Evaporation profile of lemon oil upon storage at 32 ◦ C for 6 h. A prolonged occlusive factor of the NLC dispersion used in the final product and
release of the insect repellent DEET was observed from lipid nanoparticles compared an o/w emulsion (obtained by replacing the solid lipid by Miglyol
to emulsion (modified after Wissing et al. (2000b)).
812), at the same concentration level as in the final product, showed
a five-times higher occlusive factor for the NLC dispersion than for
the o/w emulsion (Pardeike and Müller, 2007a). Furthermore, the
Table 1
Examples of cosmetic products currently on the market containing lipid nanoparticles.
Product name Producer/distibuter Market introduction Main active ingredients
Cutanova Cream Nano Repair Q10 Dr. Rimpler 10/2005 Q 10, polypeptide, hibiscus extract, ginger extract,
ketosugar
Intensive Serum NanoRepair Q10 10/2005 Q 10, polypeptide, mafane extract
Cutanova Cream NanoVital Q10 06/2006 Q 10, TiO2, polypeptide, ursolic acid, oleanolic acid,
sunflower seed extract
SURMER Crème Legère Nano-Protection Isabelle Lancray 11/2006 Kukuinut oil, Monoi Tiare Tahiti® , pseudopeptide, milk
extract from coconut, wild indigo, noni extract
SURMER Crème Riche Nano-Restructurante Kukuinut oil, Monoi Tiare Tahiti® , pseudopeptide, milk
SURMER Elixir du Beauté Nano-Vitalisant Kukuinut oil, Monoi Tiare Tahiti® , pseudopeptide, milk
SURMER Masque Crème Nano-Hydratant Kukuinut oil, Monoi Tiare Tahiti® , pseudopeptide, milk
NanoLipid Restore CLR Chemisches Laboratorium 04/2006 Black currant seed oil containing ␻-3 and ␻-6 unsaturated
fatty acids
Nanolipid Q10 CLR Dr. Kurt Richter, (CLR) 07/2006 Coenzyme Q10 and black currant seed oil
Nanolipid Basic CLR 07/2006 Caprylic/capric triglycerides
NanoLipid Repair CLR 02/2007 Black currant seed oil and manuka oil
IOPE SuperVital Amore Pacific 09/2006 Coenzyme Q10, ␻-3 und ␻-6 unsaturated fatty acids
Cream
Serum
Eye cream
Extra moist softener
Extra moist emulsion
NLC Deep Effect Eye Serum Beate Johnen 12/2006 Coenzyme Q10, highly active oligo saccharides
NLC Deep Effect Repair Cream Q10, TiO2 , highly active oligo saccharides
NLC Deep Effect Reconstruction Cream Q10, acetyl hexapeptide-3, micronized plant collagen, high
active oligosaccharides in polysaccharide matrix
NLC Deep Effect Reconstruction Serum
Regenerationscreme Intensiv Scholl 6/2007 Macadamia ternifolia seed oil, avocado oil, urea, black
currant seed oil
Swiss Cellular White Illuminating Eye Essence La prairie 1/2007 Glycoprotiens, panax ginseng root extract, equisetum
arvense extract, Camellia sinensis leaf extract, viola tricolor
extract
Swiss Cellular White Intensive Ampoules 1/2007 Glycoprotiens, panax ginseng root extract, equisetum
arvense extract, Camellia sinensis leaf extract, viola tricolor
extract
SURMER Creme Contour Des Yeux Nano-Remodelante Isabelle Lancray 03/2008 Kukuinut oil, Monoi Tiare Tahiti® , pseudopeptide,
hydrolized wheet protein
Olivenöl Anti Falten Pflegekonzentrat Dr. Theiss 02/2008 Olea europaea oil, panthenol, acacia senegal, tocopheryl
acetate
Olivenöl Augenpflegebalsam Olea Europaea oil, prunus amygdalus dulcis oil, hydrolized
milk protein, tocopheryl acetate, rhodiola rosea root
extract, caffeine
Fig. 9. The increase in human skin hydration after application of Cutanova Cream
Fig. 11. Distribution of prednicarbate and its metabolites in human skin after 24 h.
NanoRepair Q10 and a cream having the same composition but replacing the NLC
Mean value ± S.D. (n = 3) (modified after Santos Maia et al. (2000)).
by o/w emulsion for 42 day (modified after Müller et al. (2007c)).
penetration of coenzyme Q10 into the stratum corneum from the

5. Pharmaceutical formulations and benefits
NLC used in Cutanova Cream NanoRepair Q10 was evaluated by tape
stripping test on human female volunteers and compared with an
Topical treatment of skin diseases has the advantage that
o/w emulsion having the same coenzyme Q10 and lipid content. The
high drug levels can be achieved at the site of disease and sys-
cumulative amount of coenzyme Q10 found in nine tape strips was
temic side effects can be reduced compared to oral or parenteral
21% for the NLC dispersion and 16% for the o/w emulsion, related to
drug administration. Topical drug administration is still a chal-
the applied amount of coenzyme Q10 (Pardeike and Müller, 2007a).
lenge in pharmaceutics due to the difficulties in controlling and
NanoLipid Restore CLR (Chemisches Laboratorium Dr. Kurt
determining the exact amount of drug that reaches the different
Richter, Berlin, Germany) is a semi-finished cosmetic product based
skin layers. The drugs and the vehicles physicochemical prop-
on lipid nanoparticles. The easily oxidized black currant seed oil
erties are considered to be the main features responsible for
(BCO) is incorporated in NLC. NLC are able to protect BCO against
the drug differential distribution in the skin. Lipid nanoparticles
oxidation, which enhances the stability of the final product. This
have been investigated to improve the treatment of skin diseases
was proven by performing an oxidation stress test comparing
such as atopic eczema, psoriasis, acne, skin mycosis and inflam-
NanoLipid Restore CLR with a reference nanoemulsion (containing
mations. Apart from the treatment of skin diseases by topical
Miglyol 812) (Petersen et al., 2006). It was found, that the BCO is bet-
application, e.g. gastrointestinal side effects of non-steroidal anti-
ter stabilized against oxidation in the NanoLipid Restore CLR than
inflammatory drugs can be decreased by topical antirheumatic
in the reference emulsion (Fig. 10). The stability of coenzyme Q10 in
therapy. Drugs under investigations for dermal application using
NanoLipid Restore CLR was also assessed and results showed that
lipid nanoparticles at the present are for instance glucocorticoids,
the NLC lead to an enhanced stability of coenzyme Q10 (Hommoss
retinoids, non-steroidal anti-inflammatory drugs, COX-2 inhibitors
et al., 2007b). NanoLipid Restore CLR was used in the prestigious
and antimycotics. It was show that it is possible to enhance the
cosmetic product line IOPE (Amore Pacific, Seoul, South Korea)
percutaneous absorption with lipid nanoparticles. These carriers
introduced to the market in September 2006.
may even allow drug targeting to the skin or even to its sub-
In the cosmetic products line Surmer (Dr. Rimpler GmbH,
structures. Thus they might have the potential to improve the
Wedemark, Germany) the lipid nanoparticles were used for their
benefit/risk ratio of topical drug therapy (Schäfer-Korting et al.,
occlusive properties. It was possible to increase the occlusion of a
2007).
day cream without changing its light character, i.e. achieving higher
occlusive properties without having the glossy skin appearance
5.1. Topical glucocorticoids
associated with the high occlusive night creams.
Topical corticosteroids are the first-line therapy of acute exacer-

bations of atopic dermatitis and contact dermatitis. Prednicarbate
is superior to the halogenated glucocorticoids because of an
improved benefit/risk ratio. However, at the present the separation
of desired anti-inflammatory effects and undesired antiprolifer-
ative effects is still not satisfying. Therefore, lipid nanoparticles
were investigated as a delivery system for prednicarbate. Santos
et al. reported an improved extent of prednicarbate uptake by
human skin in vitro, if applied as SLN dispersion or cream contain-
ing prednicarbate-loaded SLN (Fig. 11) (Santos Maia et al., 2000).
The authors found that a prednicarbate targeting to the epider-
mis occurred (Santos Maia et al., 2002). This is particular relevant
because prednicarbate in the dermis is responsible for the induc-
tion of irreversible skin atrophy while the inflammatory process
is most pronounced within the epidermis (Schäfer-Korting et al.,
Fig. 10. The peroxide value results of the oxidative stress test for NanoLipid Restore
2007). Therefore, a better benefit/risk ratio is expected for the
CLR and the reference emulsion at day 1 and after 9 days. The BCO in the NLC-based
formula was better stabilized against peroxidation (modified after Hommoss et al. application of pretnicarbate in SLN containing topical formula-
(2007b)). tions.
Fig. 12. 0.05% Cyproterone acetate containing dispersion of drug carriers (NE = nanoemulsion, n = 3 donors, SLN n = 7 donors, NLC-O = NLC containing olic acid, n = 5 donors,
NLC-M = NLC containing Miglyol, n = 3 donors, MS = microspheres, n = 2 donors) were applied to cryoconserved human skin for 6 h and the penetration into human skin
was investigated. Particulate dispersions were tested in parallel to o/w cream (n = 7 donors) using 2–4 skin tissue specimen per donor for each preparation. Except for
NE, cyproterone acetate amounts in the first layer exceed amounts following the cream, moreover penetration ratios of the layers 0–100 and 100–200 mm differed for all
preparations except for NLC-M (p ≤ 0.05). (*) Differences in CPA-ratios (over cream) between the particulate systems (p ≤ 0.05) (with permission from Stecova et al. (2007)).
5.2. Antiandrogen into rat skin of isotretinoin was investigated from SLN and ethanolic
solution. For the isotretinoin-loaded SLN in comparison to ethano-
The oral application of cyproterone acetate can be used to reduce lic solution, no penetration through rat skin was found. Therefore,
sebum secretion rate and acne lesions. For female patients a com- isotretionin-loaded SLN formulation can avoid systemic uptake of
bination of cyproterone acetate and ethinyl estradiol is given to the drug. For the SLN a high accumulative amount of isotretinoin
exclude teratogenic effects of cyproternoe acetate (feminization of was found in the skin, showing a skin targeting effect (Liu et al.,
the male fetus). In male patients loss of libido, gynecomastia, vaso- 2007).
motor flushing and loss of bone mineral density can be observed
as cyproterone acetate side effects, which is acceptable when used 5.4. PUVA-therapy
for metastatic prostate cancer but not for acne treatment. To avoid
systemic antiandrogen effects a topical application is preferable PUVA-therapy involves the application of a psoralen in com-
(Iraji et al., 2006). Application of cyproterone acetate-loaded SLN bination with long-wavelength UV light (UV-A). It is used for
increased the skin penetration at least four-folds over the uptake the treatment of skin diseases like psoriasis, mycosis fungoides
from cream and emulsion (Fig. 12), whereas the drug amount found and vitiligo. Fang et al. studied the permeation of psoralens from
in the dermis was low for all preparations. No difference was seen SLN, NLC, emulsion and aqueous suspension through nude mice
in the penetration profiles into intact and stripped skin. Cypro- skin with and without introduction of hyperproliferative skin
terone acetate-loaded SLN enhanced skin absorption resulting in by repeated tape stripping (Fang et al., 2008). The permeation
therapeutic drug levels within the target tissue while reducing sys- of psoralens increased in the order 8-methoxypsoralen > 5-
temic side effects compared to the oral administration (Stecova et methoxypsoralen > 4,5,8-trimethylpsoralen for all formulations
al., 2007). tested. If was found that the drug flux through nude mice skin
was highest for the NLC formulations while SLN were not able to
5.3. Vitamin A derivates improve the skin permeation over the aqueous suspension. The
flux of the emulsion was the lowest. No difference was found in
Tretinoin, a metabolite of vitamin A is used for topical treatment the permeation behavior of 8-methoxypsoralen through hyperpro-
of various proliferateive and inflammatory skin diseases such as liferative skin and normal nude mice skin while the permeation
psoriasis, acne, photo aging, epidermotropic T-cell lymphomas and through hyperproliferative skin was significantly reduced for the
epithelial skin cancer. One of the major disadvantages associated other formulations.
with the topical application of tretinoin is local skin irritation such
as erythrema, peeling and burning as well as increased sensitivity 5.5. Non-steroidal anti-inflammatory drugs
to sunlight. To overcome this problems tretinoin was incorporated
into SLN by Shah et al. (Shah et al., 2007). In vitro permeation studies The non-steroidal anti-inflammatory drugs celecoxib and vale-
through rat skin indicated that SLN-based tretinoin gel has a per- coxib acting by selective inhibition of COX-2 have been investigated
meation profile comparable to that of the market tretinoin cream. for dermal application using NLC-based delivery systems. Cele-
Furthermore, Draize patch test showed that SLN-based tretinoin coxib is widely used for the treatment of rheumatoid arthritis,
gel resulted in remarkably less erythremic episodes compared to osteoarthritis, acute pain, familial adenomatous polyposis and pri-
the currently marketed tretinoin cream (Fig. 13). Therefore, also for mary dysmenorrheal. Furthermore, topical formulations of COX-2
formulations containing tretinoin-loaded SLN a better benefit/risk inhibitors have been developed for the treatment of COX-2 medi-
ratio is expected. ated skin diseases like inflammation, pain and nociception, skin
Isotretinoin, a derivate of retinoic acid, is used for the treatment tumors, injury and wounds (Lee et al., 2003). Joshi et al. compared
of severe acne and other dermatological diseases. The marketed a NLC-based gel of celecoxib with a micellar gel with the same
products such as isotretinoin cream show significant skin irrita- composition regarding the in vitro skin penetration using rat skin
tion and systemic absorption, which is associated with side effects and the pharmacodynamic efficiency by Aerosil induced rat paw
(Queille-Roussel et al., 2001). Penetration through and permeation edema (Joshi and Patravale, 2008). The in vitro permeation of cele-
Fig. 13. Pictures of Draize skin irritation studies carried out on New Zealand rabbits 24 h after application of (A) control (no application); (B) marketed formulation (Retino-A®
cream); (C) SLN-based gel without tretinoin; (D) SLN-based gel containing tretinoin (0.05%, w/w). The Marketed tretinoin cream clearly shows erythemal lesions, which are
not visible in SLN based tretinoin gel (with permission from Shah et al. (2007)).
coxib from NLC gel was less than the permetration from the micellar rated into Carbopol gel were investigated regarding in vitro release,
based gel, which confirms findings about nanoparticles leading to skin irritation using the Draize patch test and efficacy using Aerosil-
a drug deposit in the skin resulting in sustained release. The in vivo induced rat paw edema model and compared to a market product
comparison of the percentage edema inhibition produced by NLC (Joshi and Patravale, 2006). In vitro the NLC gel showed burst release
and micellar gel showed a significant higher inhibition after appli- followed by steady release while the market formulation showed
cation of the NLC based gel up to 24 h (Fig. 14) (Joshi and Patravale, 100% release within 1 h. In the Draize patch test the NLC contain-
2008). ing gel showed no skin irritation while the market gel showed
Valdecoxib is used for the treatment of inflammation and arthri- slight irritation after 48 h. The NLC-based gel showed prolonged
tis. The topical marketed valdecoxib formulation contains 56% activity up to 24 h while the activity of the market gel was much
alcohol, which may have a drying effect on the skin after repet- shorter. This indicates better skin tolerability and longer activity of
itive application. Therefore, an alcohol free delivery system with the NLC-formulation compared to the marketed formulation.
faster onset and prolonged action was targeted by developing a gel Indomethacin is one of the most potent non-steroidal anti-
based on valdecoxib-loaded NLC. Valdecoxib-loaded NLC incorpo- inflammatory drugs, widely used topically for the treatment of
dermatitis and rheumatic diseases. Ricci et al. investigated the in
vitro penetration of indomethacin from NLC containing gel and
gel without NLC through the stratum corneum and epidermis,
the in vivo indomethacin release by tape-stripping test and the in
vivo anti-inflammatory activity using the UV-B induced erythrema
model (Ricci et al., 2005). It was found, that the anti-inflammatory
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 indomethacin-loaded NLC gel was less than from gel without
NLC.
Ketoprofen and naproxen are non-steroidal anti-inflammatory
drugs used for the treatment of musculoskeletal disorders, e.g.
rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.
Puglia et al. prepared ketoprofen-loaded NLC and naproxen-loaded
NLC which were incorporated into gels and compared to refer-
ence gels containing ketoprofen or naproxen solution, respectively.
Fig. 14. In vivo comparison of the percentage inhibition observed after application
of NLC-based celecoxib gel, micellar gel and marketed gel in the aerosil-induced rat The in vitro percutaneous absorption, the in vivo active localiza-
paw edema method (with permission from Joshi and Patravale (2008)). tion in the stratum corneum and the anti-inflammatory effect were
5.7. Antimycotics
SLN and NLC have been investigated for topical delivery of anti-
fungals like clotrimazole and ketoconazol (Souto et al., 2004a;
Souto, 2005; Souto and Müller, 2006). Ketoconazol is widely used in
topical formulations for the treatment of human mycotic infections.
Adverse effects like severe irritation, pruritus and stinging have
been reported. Up to now it could be shown by Souto and Müller
that stable lipid nanoparticles for topical delivery of ketoconazol
can be prepared (Souto and Müller, 2005). Further investigations
regarding the skin permeation, skin penetration and reduction of
adverse effects need to be done.
For clotrimazole it was found, that SLN and NLC can be poten-
tial topical delivery systems. Good stability over a storage time of
3 months was reported. NLC loaded with clotrimazole showed a
Fig. 15. Permeation profiles of flurbiprofen through rat skin from NLC () and sat-
urated physiological saline () (with permission from Han et al. (2008)).
faster drug release than SLN loaded with clotrimazole. Further-
more, it was found, that the release rate of clotrimazole depends
on the drug concentration. A fast release was reported using low
studied. NLC were able to reduce the drug penetration through drug concentrations while a higher drug concentration prolonged
excised human skin while it was found by tape-striping test that the release (Souto et al., 2004a).
the drug permeation and drug accumulation in the horny layer Sanna et al. investigated econazole nitrate-loaded SLN incor-
was increased. Furthermore, a prolonged anti-inflammatory effect porated into hydrogels for topical application (Sanna et al., 2007).
could be shown for drug-loaded NLC compared to drug solution In an ex vivo permeation test using porcine stratum corneum the
(Puglia et al., 2008). authors showed controlled drug release properties of SLN whereby
Flurbiprofen, another non-steroidal anti-inflammatory drug, is the release rate depended upon the lipid content of the nanoparti-
used for the treatment of gout, osteoarthritis, rheumatoid arthri- cles. In in vivo tape-stripping tests it was found that SLN promote a
tis and sunburn. In order to avoid irritation of the gastrointestinal rapid penetration of econazol nitrate through the stratum corneum
tract which might occur after oral administration of flurbiprofen, after 1 h and improve the penetration of the drug into deeper skin
drug administration via the skin is targeted. Han et al. investigated layers after 3 h of application compared to reference gel.
the physical stability and the permeated amount of flurbiprofen
from NLC through rat skin. The authors found that the investigated 5.8. Podophyllotoxin
flurbiprofen containing NLC formulation was stable over the obser-
vation period. Comparing the permeation of flurbiprofen through Podophyllotoxin is used for the treatment of genital warts
rat skin after 12 h a 4.5-folds increased permeation was reported and for the inhibition of growth of epithelial cells infected by
from the NLC formulation compared to phosphate buffered saline human papilloma virus in the epidermis. Commercially available
(Fig. 15) (Han et al., 2008). Therefore, NLC might be promising as a podophyllotoxin tinctures and creams can lead to systemic absorp-
delivery system for transdermal delivery of flurbiprofen. tion which results in severe side effects. Chen et al. compared
The non-steroidal agent ketorolac, with powerful analgesic and podophyllotoxin-loaded SLN with podophyllotoxin tincture with
low anti-inflammatory activity, is widely used for the treatment of regards to skin permeation, skin penetration and epidermal target-
moderate and severe pain. Puglia et al. studied the in vitro deliv- ing effect (Chen et al., 2006). It was found that podophyllotoxin was
ery of ketorolac through human epidermis (Puglia et al., 2006). able to permeate porcine skin from the tincture while no perme-
The formulations under investigation were Carbopol 934P gel con- ation was found for drug-loaded SLN. For one SLN-formulation an
taining an alcoholic solution of ketorolac, alcoholic solutions of increased penetration into porcine skin up to 3.48-times over tinc-
ketorolac prodrugs (polyoxyethylene glycol ester derivates with ture was reported. Furthermore, it was found, that podophyllotoxin
different amounts of polyovxethylene units), ketorolac-loaded NLC was located in the epidermis and hair follicles when applied as SLN-
and blank NLC together with free ketorolac. The authors found that formulation. No drug was found in the dermis after SLN application
the penetration of the ester prodrugs was significantly enhanced while podophyllotoxin after tincture application was distributed in
apart from the pentaethylene glycol ester, the ester with the longest each layer of the skin. Therefore, a localization effect in the epi-
ethylene glycol unit tested. The NLC-containing formulations dermis was suggested and a reduction in systemic side effects is
gave the lowest ketorolac permeation rate among the formu- expected after application of podophyllotoxin using a formulation
lations tested. However, NLC seemed appropriate for sustained containing SLN.
release due to the possible formulation of a drug reservoir in the
skin. 6. Lipid nanoparticles: a “nanosave” carrier
5.6. Traditional Chinese medicine During the last decade there was an increasing hype about
nanotechnology in almost any discipline, ranging from computer
Triptolide is a purified compound of a traditional Chinese technology via products of daily life (e.g. coating of clothes, supra-
medicine, showing anti-inflamatory, immunosuppressive, anti- tex) to cosmetic and pharmaceutical formulations and products.
fertility and anti-neoplastic activity. The transdermal delivery Nanotechnology seemed to open unexpected perspectives (what
and anti-inflammatory activity was evaluated by Mei et al. using indeed many nanotechnology products are doing!). Within this
triptolide-loaded SLN and microemulsion. SLN were found to enthusiasm about nanotechnology, the potential “dark side” of each
increase the triptolide penetration into the skin as well as the anti- technology was forgotten. In the last years there was an increasing
inflammatory activity (Mei et al., 2003). This strategy improved the awareness about potential toxicity of nanosized materials. This con-
bioavailability at the site of action, reduces the required dose and siders that limited experience is available how nanosized materials
the dose-dependent side effects like irritation and stinging. interact with the body. Due to their nanosize nanoparticles have
completely different possibilities to interact with cells in the body, least when selecting lipid matrix materials which are composed
they can use “infiltration routes” and utilize certain mechanisms, of fatty acids being present in the body, e.g. using fatty acids from
which are not accessible by micrometer material. For example, emulsions for parenteral nutrition).
injected polymeric microparticles with a size around 50 ␮m can- To judge about the safety or toxicity of carriers systems like lipid
not be phagocytosed by immune cells. This is completely different nanoparticles it is important to perform studies comparing the
when having material in the range of few micrometers or in the toxicity of lipid nanoparticles with other nanoparticulate carrier
nanorange. Internalization of such material can cause release of cer- systems and to compare lipid nanoparticles composed of different
tain cytokines (Schöler et al., 2000a) and also cause death of cells. excipients with each other.
Smith and Hunneyball described already in the 1980s the cytotoxi- Nanoparticles can cause cytotoxicity by adherence of the par-
city of small polymeric microparticles made from poly(lactide acid) ticle to the cell membrane, degradation and subsequent release of
(Smith and Hunneyball, 1985). The intention was to treat arthritis in cytotoxic degradation products (Lherm et al., 1992). Another mech-
joints by injecting prednisolone-loaded polymeric microparticles. anism is the internalization of nanoparticles by cells, intracellular
In cell cultures they discovered that the amount of the polymeric degradation and subsequent toxic effects inside the cell. There are
microparticles required for administration of an efficient dose led quite a number of different cell culture studies looking at the viabil-
to the death of cells. ity of cells evaluating either the damage of the cell membrane, e.g.
Schroeder et al. determined the acute effects of polystyrene by neutral red uptake or LDH release or other factors like activity
microspheres with a size of 3, 8, 15 and 25 ␮m upon intravenous of the mitochondrial succinate dehydrogenases of living cells (MTT
administration to beagle dogs. Four weeks after application they test).
found that all 25 and 15 ␮m particles and the major part of the 8 ␮m It was shown by Müller et al. that the phagocytic uptake of SLN
particles were accumulated in the lung. Traces of the 8 ␮m particles is low applying them to human granulocytes. At 2.5% SLN concen-
could also be found in the liver, spleen, heart and kidneys. The main tration no toxic effects were observed on these cells. That shows,
part of the 3 ␮m particles was found in the liver, followed by spleen that SLN do not exhibit any extracellular toxic effect. Compar-
and lung. Traces of these particles were detectable in the kidneys ing the internalization effect of SLN and PLA/GA nanoparticles by
and the heard (Schroeder et al., 1978a). The histological evaluation human granulocytes, it was found that the effect is similar for both
of the tissue samples showed no evidence of damage that could be nanoparticles. Nevertheless, the toxicity of SLN was much lower.
attributed to the presence of microspheres in the organs (Schroeder Comparing the toxicity of SLN composed of Compritol and cetyl-
et al., 1978b). These results were confirmed by Kanke et al. Fur- palmitate the effect was similar for both systems indicating a good
thermore, these authors found that large microspheres (12 ␮m) are tolerability (Müller et al., 1997a).
not phagocytized within 4 weeks after intravascular administra- Schöler et al. found that the cytotoxicity of SLN assessed by MTT
tion to beagle dogs whereas smaller sphere sizes are phagocytized, test on murine peritoneal macrophages is concentration dependent
implying a size limit for phagocytosis (Kanke et al., 1980). and influenced by the lipid matrix. SLN composed of stearic acid or
However, nowadays the discussion about nanotoxicity seems dimethyl-dioctadecylammonium bromide showed toxic effects at
to go into a wrong direction. At the beginning we had the equa- concentrations of 0.01%, whereas SLN composed of triglycerides,
tion “nano = good”, nowadays it appears that we are rather moving cetylpalmitate and paraffin did not exhibit major cytotoxic effects
towards a witch hunt for everything which is nano. It is the time to at the same concentration (Schöler et al., 2002). Furthermore, it was
essentially assess the benefits and risks on scientific, neutral and found that the size of SLN did not affect the cytotoxicity (Schöler et
emotionless basis. al., 2001, 2002).
The most important factor for potential nanotoxicity is the lack Müller et al. analyzed the influence of nanoparticulate carrier,
of biodegradability of many nanomaterials. After generation of the lipid matrix of SLN and surfactants on the cytotoxicity using
these nanomaterials, they will stay for ever and pollute the envi- HL60 cells (Müller et al., 1997b). It was found that SLN show lower
ronment and, considering the circle in the environment, finally end toxicity compared to polyalkylcyanoacrylate and PLA/GA nanopar-
up in the human body. Examples for such materials are Fullerenes ticles. The nature of the lipid (Dynasan 114, Compritol ATO 888) had
and carbon nanotubes. At the beginning the Fullerenes were even no influence on the viability of HL60 cells. In a concentration range
considered to be used as “hollow spheres” for transporting drugs of 0.015–1.5% SLN no significant difference in viability was found
to their target sites, but it was completely forgotten that they can- compared to reference cells. Distinct differences were found for
not be biodegraded. The same is valid for carbon nanotubes. To surfactants (Poloxamer 407, Tween 80, Soya lecithin and sodium
illustrate the potential dangers of such non-biodegradable nano- dodecyl sulfate). The cell damaging effect of surfactants depends
material, it is simply referred to the clarification plants for sewage on the status of the molecules, i.e. free in solution or bounded to
water. Clearing of the water from suspended particulate mate- surfaces. Binding of the surfactant to the SLN surface was found
rial is performed by sedimentation process. After sedimentation to reduce the toxicity. The same effect was observed by Olbrich
of the particles, the water supernatant is being removed. However, et al. using RAW 264.7 cells (Olbrich et al., 2004). This was con-
nanoparticles will never sediment, in a normal clarification plant firmed by Kristl et al., assessing the effect on cell viability of the
they will stay in the water forever, and of course with the water surfactant Tyloxapol in solution and an SLN-dispersion stabilized
they will finally end up in the drinking water for humans. It might with the same surfactant using Jurkat and HEK 293 cells. It was
be that in the future for clearing water from nanomaterial, spe- found, that both the solution of Tyloxapol and the SLN showed an
cial processes have to be developed, e.g. further development of initial unfavorable effect, while longer incubation periods result in
controlled flocculation by addition of flocculants (however many cell recovery after application of Tyloxapol stabilized SLN whereas
flocculants are also toxicologically dubious). Tyloxapol solution caused cell death (Kristl et al., 2008).
The outstanding advantage of lipid nanoparticles is their easy In another study comparing the cytotoxicity of magnetite-
and complete biodegradation. Lipids are natural materials, glyc- loaded polylactide (PLA) nanoparticles, polylactide/glycolide
erides are easily degraded by natural processes such as enzymes. (PLA/GA) nanoparticles and SLN using human granulocytes, the
The time for degrading lipid nanoparticles is depending on the effective concentration to reduce the cell viability in the MTT test to
nature of the lipid and the stabilizers used (Olbrich and Müller, 50% was 0.38% for high molecular weight PLA, 0.30% for low molec-
1998; Olbrich, 2002). The degradation products, fatty acids and ular weight PLA, 0.15% for PLA/GA and over 10% for SLN. That means
glycerol, are natural compounds present in the human body (at SLN were the least cytotoxic formulation (Müller et al., 1996).
Weyenberg et al. investigated the influence of SLN formulated Even assuming that some lipid nanoparticles might arrive in the
using different lipids and different surfactants on cell viability of systemic blood circulation, they will be very well tolerated. Based
J774 macrophages, mouse 3T3 fibroblasts and HaCaT keratinocytes on their composition they are rather a kind of parenteral nutrition.
using the MTT test (Weyenberg et al., 2007). The surfactant had In the 1990s in vivo studies showed that intravenously injected lipid
a big impact on the toxicity of SLN. SLN formulated with lecithin, nanoparticle suspensions were very well tolerated (Weyhers, 1995;
sodium taurocholate, phosphatidylserine and polysorbate 80 did Weyhers et al., 1995).
not affect the viability of the three cell lines while the cell viability Weyhers et al. performed i.v. injections of SLN composed of
was significantly reduced by stearylamine. SLN formulated with either Compritol or cetylpalmiate in mice. The administered dose
stearic acid were toxic for all cell lines exhibiting the most toxic was extremely high, 400 ␮g SLN dispersion with lipid content of
effect on macrophages. Viability of >90% was observed when semi- 10%, six times bolus injection within 20 days. This does correspon-
synthetic glycerides or hard fat was used to formulate SLN. dents to 100 g of lipid given six-fold to men (75 kg) in a bolus
Membrane damage and MTT reduction are relatively good injection. Using SLN as a drug carrier the does of lipid would be
parameters to assess cytotoxicity. However, it is more appropriate distinctly lower (e.g. single does of 1 g lipid, corresponding to 10 ml
and more sensitive to look at the release of cytokines. of 10% SLN dispersion). For the cetylpalmitate SLN no pathological
Schöler et al. showed that the interaction of Compritol and cetyl- effects were obtained even in this high concentration. SLN com-
palmitate SLN with murine peritoneal macrophages does not cause posed of Compritol led to an accumulation of the lipid in liver and
stimulation of pro-inflammatory cytokines (IL-6, IL-12 and TNF- spleen and subsequently to pathological alterations which were
␣) responses. At higher concentration levels of SLN a significant partially reversible within 6 weeks after i.v. administration. These
decrease in IL-6 production caused by cytotoxic effects of SLN was side effects were attributed to the slow degradation of the Compri-
observed (Schöler et al., 2000a). This was confirmed in other stud- tol matrix. Administration of Compritol SLN in a lower dose (200 ␮l
ies, where it was also found that the size of SLN did not influence SLN dispersion, lipid content 2.5%) led to a good tolerability. All in all
the cytokine production (Schöler et al., 2001, 2002). this in vivo study of SLN indicated a good tolerability of this carrier
Furthermore, it was found by Schöler et al. that SLN preserved system (Weyhers et al., 2005).
with thiomersal did neither cause an increase in cytotoxic effects on The tolerability of lipid nanoparticles was also investigated
the murine peritoneal macrophages nor led to secretion of proin- intramuscularly. They were injected i.m. and the tissue reactions
flammatory cytokines by these cells compared to unpreserved SLN were compared with non-biodegradable aluminum hydroxide
(Schöler et al., 2000b). (Müller et al., 2000b). Also these data prove good tolerability of
Comparing all these data, and considering the biodegradabil- the lipid nanoparticles.
ity without toxic degradation products, the lipid nanoparticles are The use of solid lipid matrices is known in pharmacy for many
really very well tolerated at the cellular level. years, e.g. drug release from lipid pellets. Solid lipid mircoparticles
In general mucosal surfaces can be considered as being more were introduced by Speiser et al. (Speiser, 1990; Eldem et al., 1991).
sensitive towards toxic effects compared to the skin, being pro- In the next step the size of the particles was further reduced to the
tected by the stratum corneum and having in general the function to nanosize yielding the lipid nanoparticles, the SLN and as a further
protect against the environment. Recently the pulmonary cytotoxi- development of the SLN the NLC. For topical applied lipid nanopar-
city of lipid nanoparticles was investigated. Nassimi et al. compared ticles all excipients, which used in the current topical cosmetic and
the in vitro cytotoxicity on human alveolar epithelial cancer cell line dermal pharmaceutical products, can be used. In addition, GRAS
(A549) by MTT test and neutral red assay and the ex vivo toxicity substances and substances with accepted GRAS status can be used.
on murine precision cut lung slices. SLN reduced the cell viability The choice of the lipid matrix and surfactant is essential in order
in a concentration dependent manner. The in vitro toxic dose of to formulate an optimal safe and stable formulation (Weyenberg et
SLN was approximately 2000 ␮g/ml. While the ex vivo toxic dose al., 2007).
was 500 ␮g/ml. For efficient pharmaceutical drug delivery lower Despite nanoparticles being biodegradable and leading to non-
concentrations are expected to be needed (Nassimi et al., 2008). toxic degradation products, the particle itself might interact in
Therefore, the lipid nanoparticles are a promising new drug deliv- an undesired way with the body prior to its degradation. Lipid
ery system for the lungs. Considering the good tolerability of the nanoparticles were investigated intensively regarding their effects
lipid nanoparticles in the lung at the simultaneously higher sensi- on skin when the cosmetic products were introduced to the market.
tivity of the alveolar epithelial cells, especially when administering In Europe such products undergo certain tests. Animal tests like the
the lipid nanoparticles to the normal skin, they will be very well Draize skin irritation test or Draize rabbit eye test are prohibited for
tolerated and are safe for dermal application. cosmetic products in Europe (Verordnung über kosmetische Mittel,
For topically applied nanoparticles a frequently discussed ques- 2008). To ensure the safety of cosmetic products alternative tests
tion is if and to which extent the nanoparticles might penetrate are performed, e.g. the Epikutan test, the human patch test, the
deeply into the epidermis, maybe reaching dermis and finally the EPISKIN test, the HET-CAM test and cell culture tests (Spielmann,
systemic circulation. At present there is an increased concern that 1992; Prinsen, 1999; ZEBET, 2001; Liebsch et al., 2004; Hartung,
very small nanoparticles might penetrate via the hydrophilic chan- 2007; Vinardell and Mitjans, 2008). That means, thanks to the cos-
nels (about 50 nm sized) into the skin. This is especially valid for metic products, broad skin irritation studies have been successfully
example for titanium dioxide nanoparticles used in sunscreens performed prior to placing lipid nanoparticle products on the mar-
which have sizes about 10–20 nm. Of course the quantity will be ket.
definitely very low but the titanium dioxide nanoparticles are not To evaluate the skin irritation potential and the eye irritation
biodegradable. In addition even low particle quantities can interact potential of SLN and dendritic core-multishell nanoparticles the
with the immune system. Regarding this one will be on the safe side EPISKIN test and HET-CAM test were performed by Küchler et al.
with lipid nanoparticles because typically the size is around 200 nm (2008). No irritation potential according to EU classification system
and therefore well above the 50 nm. Even if smaller lipid nanopar- R38 was found for both carriers with the EPISKIN test. In the HET-
ticles should be present in the formulation, the material can be CAM test no eye irritation potential was found for both SLN and
biodegraded. In addition the theoretical potential amounts in the dentritic core-multishell nanoparticles.
skin are so low that they are few dimensions below the concentra- The evaluation of cell viability by MTT test on human fibrob-
tions which caused an effect on cytokine production and release. lasts and keratinocytes after application of SLN and SLN containing
prednicarbate showed a viability >90%. Cell viability evaluated by de Vringer, T., 1999. Topical preparation containing a suspension of solid lipid par-
MTT test after application of prednicarbate containing SLN to recon- ticles. USA patent 91-200,664.
Dingler, A., 1998. Feste Lipid-Nanopartikel als kolloidale Wirstoffträgersysteme zur
structed epidermis was 94.5% (Santos Maia et al., 2000). This shows dermalen Applikation. Institut für Pharmazie. Freie Universität, Berlin.
a good tolerability of the carrier system by the skin. Eldem, T., Speiser, P., Hincal, A., 1991. Optimization of spray-dried and -congealed
It can be summarized that it might be difficult to find a nanopar- lipid micropellets and characterization of their surface morphology by scanning
electron microscopy. Pharm. Res. 8, 47–54.
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excipients (lipids, surfactants and stabilizers) are available than for lipid nanoparticles prepared with a membrane contactor. Pharm. Dev. Technol.
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International Journal of Pharmaceutics: Lipid Nanoparticles (SLN, NLC) in Cosmetic and Pharmaceutical Dermal Products

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International Journal of Pharmaceutics 366 (2009) 170–184

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products

1. Introduction Currently more than 20 research groups are working on lipid

pulmonary (Xiang et al., 2007; Liu et al., 2008) administration.

2. What exactly are lipid nanoparticles?

Fig. 5. Increase in skin hydration after application of formulation A (cream without

and Müller-Goymann, 2005). Encapsulation of inorganic sun-

Product name Producer/distibuter Market introduction Main active ingredients

penetration of coenzyme Q10 into the stratum corneum from the

Topical corticosteroids are the ﬁrst-line therapy of acute exacer-

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