J. DRUG DEL. SCI. TECH.

, 14 (6) 423-434 2004

Novel colloidal delivery systems for dermal application

M.A. Schubert, C.C. Müller-Goymann*

Institut für Pharmazeutische Technologie, Technische Universität Braunschweig,

Mendelssohnstr. 1, 38106 Braunschweig, Germany
*Correspondence: c.mueller-goymann@tu-braunschweig.de

The human skin, especially the stratum corneum, is the main barrier for dermal and transdermal drug delivery. In order to assist, manipulate
or even overcome this barrier a variety of different formulations has been developed over the last two decades. At the beginning, the skin structure
and composition with regard to drug delivery is reviewed then promising drug delivery systems like surfactant free emulsions, reverse micelles,
liquid crystals, vesicles, lipid nanoparticles and supercooled melts are introduced focussing on sustained or enhanced drug release, improved
stability and mode of action of the respective drug delivery system.

Key words: Dermal drug delivery – Reverse micelles – Liquid crystals – Vesicles – Supercooled melts – Surfactant free emulsions – Lipid nano-
particles.

I. INTRODUCTION
Drug delivery to and/or through human skin is still a
challenge for formulation scientists due to the unique barrier
function of this tissue. For that reason, it is necessary to have
a basic knowledge and understanding of skin structure and
composition, in order to formulate efficient dosage forms.
1. Skin structure and composition
The human skin is the largest organ of the human body,
providing around 10% of the body mass and covering an area up
to two square meters. Such a large and easily accessible organ
apparently offers ideal and multiple sites to administer therapeutic
agents for both local and systemic effects. Unfortunately, the
human skin is a highly efficient self-repairing barrier designed
to protect the body from environmental influences. The reason
of the effective barrier function of human skin is based on its
structure. The human skin can be categorised into four main
layers: the outer stratum corneum, the epidermis, the dermis,
and the innermost subcutaneous fat layer (hypodermis) [1].
The stratum corneum, as the superficial layer of the epi-
dermis, is the final product of epidermal cell differentiation. It
comprises several layers (10-25) of dead cells embedded in a
lipid matrix and acts as the main barrier to transdermal drug
delivery. The stratum corneum is only around 10 µm thick in
the non-hydrated state, although it may swell to a manifold
of this thickness when wet [2]. This thin membrane serves to
regulate water loss from the body and vice versa prevents the
entry of harmful substances, including microorganisms. The
barrier function of the stratum corneum depends substantially on
its unique composition. On a dry weight basis, 75-80% consist
of protein, 5-15% of lipids and 5-10% of unidentified material
(3). The protein is located primarily within the corneocytes and
is predominantly constituted as fibrous α-keratin (around 70%)
and amorphous β-keratin (approximately 10%) surrounded by
a proteinaceous cell envelope (around 5%) [4, 5]. The lipid
composition is devoid of phospholipids and consists mostly of
ceramides (41%), cholesterols (27%), cholesteryl esters (10%)
and fatty acids (9%) with a small fraction of cholesterol sulphate
(2%) [6]. The stratum corneum is often represented as a «brick
and mortar» model [7, 8] in which the corneocytes forming the
bricks are embedded in the intercellular lipid as mortar. The
extracellular lipids between the corneocytes are arranged in
multiple lamellar structures forming continuous lipid phases
that occupy approximately 20% of the total stratum corneum
volume [9]. All these components together make the corneocyte
dense and almost impermeable for solutes.
Situated beneath the stratum corneum is the viable epider-
mis, a complex multiply layered membrane characterised by
various stages of keratinocyte differentiation. The epidermis
ranges in thickness from 75 to 150 µm and contains no blood
vessels. Hence, molecules permeating across the epidermis must
diffuse successively across the stratum lucidum, the stratum
granulosum, the stratum spinosum and the stratum basale in
order to be cleared into the systemic circulation in the dermis.
The cellular structure of the viable epidermis is predominantly
hydrophilic throughout its various layers and substances can
be transported in its intercellular fluids. Especially for polar
substances, the resistance to permeation is considerably lower
than in the stratum corneum [10].
The dermis, a 3-5 mm thick layer, contains a rich supply
of capillaries, nerves, sweat glands, sebaceous glands and hair
follicles that are embedded into a network of connective tissue,
predominantly collagen fibrils, providing support and flexibility
[3]. In terms of transdermal drug delivery, this layer is often
viewed as gelled water, and thus provides a minimal barrier for
the delivery of polar drugs, although the dermal barrier may
be significant for the diffusion of highly lipophilic molecules.
Chemicals reaching the dermis are readily absorbed into the
blood stream and diluted systemically, ensuring «sink condi-
tions» as the driving force behind diffusion.
The subcutaneous fat layer, or hypodermis, bridges between
the overlying dermis and the underlying body constituents. This
layer is relatively thick and serves to insulate the body and to
provide mechanical protection against physical shock.

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J. DRUG DEL. SCI. TECH., 14 (6) 423-434 2004
2. Topical application of drugs
Considering transdermal therapy, the unique barrier func-
tion of the skin is the biggest obstacle. Besides, there may
be pharmacodynamic, physiological and/or physicochemical
limitations. For example, compounds may act as irritants (so-
diumlauryl sulphate), may cause allergic sensitisation (some
antibiotics), hyperpigmentation (bleomycin), or be keratolytic
(salicylates). Despite, topical application of drugs for systemic
therapy offers several advantages in comparison to the conven-
tional oral route, e.g. circumventing gastro-intestinal absorp-
tion, eliminating systemic first pass metabolism, constant drug
administration even for drugs with short biological half-lives,
etc. [11].
Drug absorption across the skin is believed to be passive
[12]. Transdermal permeation through shunt pathways like
hair follicles or ecrine glands is possible in principle, but is
considered to be of minor importance because these skin ap-
pendages occupy only 0.1% of the total human skin surface
[2]. Percutaneous absorption via the transepidermal pathway
involves diffusion through the stratum corneum and the viable
cell layers of epidermis, and finally through the upper layer of
dermis into the microcirculation [13]. The rate determining step
in percutaneous absorption of most drugs is their permeation
across the stratum corneum providing the major portion of
resistance. Only for very lipophilic drugs the essential aqueous
nature of viable epidermis may provide a significant barrier.
In theory, two potential pathways exist for substances to cross
the stratum corneum: the transcellular (across the corneocytes
and the lipid matrix) and the intercellular (via the lipid domains
between the corneocytes) [14]. The intercellular route is believed
to provide the principal pathway of permeation of most drugs
and only sufficiently hydrophilic ones may penetrate through
the hydrophilic regions of both the corneocytes (presumably
water associated with keratin) and the lipid matrix [15].
3. Drug delivery systems for topical application
It is commonly accepted that the pharmacological effects
of a drug are related to the entire formulation and therefore
an optimized galenic vehicle is a necessary prerequisite. The
objective of dermal formulations can be divided in two major
areas. Firstly, to modulate or assist the barrier function and/or to
deliver active ingredients locally, i.e. corticoids, disinfectants,
antibiotics, etc.. Secondly, to deliver active ingredients like
hormones systemically. For transdermal drug delivery, it would
be desirable to have drug carrier systems which can overcome
this unique barrier without affecting the skin structure and be
more potent than classical vehicles like lotions, creams, oint-
ments, etc.
Colloidal drug carrier systems such as micellar solutions,
vesicle and liquid crystal dispersions, as well as nanoparticle dis-
persions show promise as topical drug delivery systems (DDS).
Nanoparticles are in the submicron size range possessing particle
sizes between a few nanometers up to 1000 nm; above 1000 nm,
particles are considered as microparticles. When developing
these formulations, the goal is to obtain systems with optimized
drug loading and release properties, long shelf life and low
toxicity. Since the properties of colloidally dispersed materials
may differ significantly from those in the bulk, comprehensive
424
Novel colloidal delivery systems for dermal application
M.A. Schubert, C.C. Müller-Goymann
structural investigations are necessary to achieve this goal [16].
The incorporated drug participates in the microstructure of the
system, and may even influence it due to molecular interactions,
especially if the drug possesses amphiphilic and/or mesogenic
properties. These properties are met by a variety of compounds
such as some nonsteroidal anti-inflammatory drugs (NSAID)
[17, 18], which are widely used for dermal application. The
present contribution mainly focuses on colloidal systems for
topical administration. Besides, surfactant free drug delivery
systems are introduced in this review offering a promising al-
ternative DDS in comparison to traditional formulations due
to the lack of emulsifier.
II. SURFACTANT FREE EMULSIONS
Most skin care products represent a mixture of two or more
compounds that are only partially miscible in each other. For
that reason, they are inherently unstable according to the second
law of thermodynamics and require the addition of suitable
stabilizers to guarantee an appropriate shelf life. Traditionally,
ionic or non-ionic surfactants are used as emulsifiers. However,
such low molecular weight amphiphiles are known to cause
skin irritations [19]. Therefore, the pharmaceutical industry has
been seeking for surfactant-free emulsions as alternatives to
conventional formulations. The most promising alternatives are
polymeric emulsifiers and solid particles as stabilizers [20].
1. Polymer stabilization of emulsions
In contrast to the traditional formulation concept, emulsions
can also be stabilized by appropriate macromolecules without
using any low molecular weight surfactant. By adding polymers
like polyacrylic acid to the continuous phase of an emulsion,
the viscosity is increased and at the same time the physical
stability against creaming and coalescence is improved by the
reduced droplet mobility. These systems often named as «quasi
emulsions» consist of small amounts of finely dispersed lipids
in a hydrogel.
For the preparation of emulsions with higher amounts of
lipid it is necessary to employ surface active polymers, e.g.
carbomer 1342 (Permulen) or hydroxypropylmethylcellulose
(HPMC) [22]. In contrast to most polymers, these polymers
are able to interact at the o/w and w/o interface, respectively,
and form structured interfacial films, which effectively prevent
the coalescence of oil drops. In this case, the increase in vis-
cosity of the external phase plays only a minor role in terms
of stabilization. From a physicochemical point of view these
formulations cannot be claimed as emulsifier free because any
substance that lowers the interfacial tension is an emulsifier ac-
cording to the IUPAC definition [23]. This formulation concept
is often named as hydrolipid dispersion and hydro dispersion
gel, respectively. It is often employed for sun care products
because the polymeric emulsifiers are unable to penetrate the
stratum corneum due to their high molecular weights. For
that reason, the irritating potential of polymeric emulsifiers is
distinctively reduced in comparison to traditional emulsifiers,
and unwanted interactions, such as Mallorca acne, are not to
be expected [21].
In aqueous media with low electrolyte concentration car-
bomer polymeric emulsifiers form thick protective gel layers
Novel colloidal delivery systems for dermal application
M.A. Schubert, C.C. Müller-Goymann
around each oil droplet with the hydrophobic alkyl chains an-
chored in the oil phase. This allows emulsifying up to 20% of
oil with typical usage levels of only 0.1 to 0.3% of the polymeric
emulsifier. Upon contact with the electrolyte-containing skin
surface, such emulsions become unstable because the protective
gel layer collapses instantly. Following water evaporation, the
oil phase is released and a thin oil film deposits on the skin.
This mechanism allows an easy formulation of sun care prod-
ucts which are waterproof despite their hydrophilic properties
during application [20].
In contrast, hydrolipid dispersions with carbomer 1342
polymeric emulsifiers, preparations with HPMC as polymeric
emulsifier are less sensitive to electrolytes. Therefore o/w
emulsions with a normal saline solution as external phase are
still stable on storage. When applied on the skin, the mechani-
cal stress may cause a partial breakdown of these emulsions
and a thin oil film spreads onto the skin, thus reducing the
wettability of the skin. After water evaporation, the emulsion
remains partially on the skin and forms a flexible film where oil
droplets are embedded into a polymer matrix. HPMC-stabilized
nanoemulsions from liquid lipid phases can be processed cold
[24]. The aqueous polymer solution and the liquid oil phase
are mixed at room-temperature to yield a crude pre-emulsion.
The final nanoemulsion is obtained by passing the pre-emul-
sion several times through a high-pressure homogeniser. High
pressure homogeniser should be used carefully to avoid both
mechanical degradation of the high molecular weight polymeric
emulsifier and overprocessing [25, 26].
Another special feature of HPMC-stabilized emulsions is
that they survive sterilization in an autoclave without substan-
tial impact on quality [22]. This is due to the phenomenon of
thermally reversible sol-gel transition. Above 60°C, the external
phase gels and immobilizes the dispersed oil drops. The droplets
cannot collide and the rate of coalescence is almost negligible.
Thus, formulators have the opportunity to formulate a preserva-
tive-free o/w emulsion, presuming that a recontamination proof
packaging is used.
2. Solid particle stabilization of emulsions
Alternatively, surfactant free emulsions might be formulated
as so called Pickering emulsions by using solid particles as
stabilizers at the interface [27]. In this formulation concept, a
stable interfacial film providing good protection against coa-
lescence can be achieved by densely packed solid particles at
the o/w interface. For manufacturing, both phases are simply
mixed and the pH is adjusted. A wide variety of solid materi-
als has been used as stabilizers of either water-in-oil (w/o) or
oil-in-water (o/w) emulsions including iron oxides, hydroxides,
metal sulphates, clay, silica, carbon, fat crystals and latex par-
ticles [28]. Recently, colloidal precipitates of ethylcellulose
have been established as a new type of emulsion stabilizer for
solid stabilized emulsions [29].
Ethylcellulose as stabilizer offers the opportunity to prepare
either o/w emulsions or w/o emulsions depending on tempera-
ture during preparation. The emulsion type is believed to be
determined by particle wettability, wherein the more poorly
wetting liquid becomes the dispersed phase [30]. The wet-
tability of the solid particles can be expressed in terms of the
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J. DRUG DEL. SCI. TECH., 14 (6) 423-434 2004
contact angle θ. In the case of colloidal ethylcellulose particles,
their affinity towards the oily and aqueous phase, respectively,
changes depending on temperature: o/w systems form at tem-
peratures below 20°C whereas w/o systems form above 20°C.
Interestingly, the phase volume is of no influence on emulsion
type [29]. For TiO2 particles it has been shown, however, that
coating with different materials leads to either o/w emulsions or
w/o emulsions in dependence on hydrophobicity of the particles
[28].
As a prerequisite, Pickering emulsions require sufficiently
small particles which are able to arrange at the o/w or w/o
interface. For that reason, the solid particles are usually at
least 10-fold smaller in size than the dispersed droplets of the
emulsion. According to Mennon and Wasan [31] the stability of
Pickering emulsions is mainly influenced by the contact angle,
the particle size, the solid concentration and interparticulate
interaction. Further critical parameters are the nature of the oil,
the phase volume fraction and the preparation processing.
Particle-stabilized emulsions may be of great interest for
the formulation of sun care products, especially if physical
sun screens like TiO2 or ZnO are used. With this formulation
concept it might be possible to distribute these filters in the
emulsion uniformly, avoid agglomeration and in addition they
can act simultaneously as emulsion stabilizers.
III. REVERSE MICELLES
Amphiphilic molecules such as surfactants associate to form
micelles beyond the critical micelle concentration (CMC) of
the compound in an aqueous solution. Micellar solutions not
only exist in aqueous systems but also form in oily systems.
In this case, reverse micelles are formed with the lipophilic
part of the surfactant molecule facing the oily medium and the
hydrophilic part representing the inner core of the associate. A
widely used excipient in drug development is lecithin, which is
able to form reverse micelles in different oily media. Normal
micelles of lecithin do not exist, instead liposomes are formed
when phospholipids are dispersed in aqueous media.
Solubilization of drug molecules is possible both in normal
micelles and in reverse micelles. While the solubilization within
normal micelles improves the bioavailability of poorly soluble
drugs [32], the use of reverse micelles allows sustained drug
release. Upon contact of a reverse micellar solution with aque-
ous body fluids the reverse micellar solution transforms into
a liquid crystalline phase or vesicle dispersion which reduces
the release rate of the solubilized drug molecules [33].
The therapy of a chronic disease requires repeated drug
administration. In the case of a short biological half-life, the
drug has to be administered within short intervals up to several
times daily. To reduce application frequency sustained formu-
lations have been developed. Liquid crystalline excipients are
appropriate candidates for this purpose, because in a liquid
crystalline vehicle the drug diffusion is reduced by factor 10
to 1000 in comparison with a liquid vehicle such as a solution
[33-35]. The factor depends on the kind of liquid crystal being
used.
A further possibility is the formation of liquid crystals (see
also Section IV) upon contact with body fluids at the site of
application. The drug solution interacts with body fluids such
J. DRUG DEL. SCI. TECH., 14 (6) 423-434 2004
as plasma, tear fluid or skin lipids, and undergoes a phase
transition into a mono- or multiphasic system of liquid crys-
tals (Figure 1). An example of this is oily solutions of reverse
micellar phospholipids, which solubilize additional drug and
transform into liquid crystalline lamellar phases by absorbing
water upon mucosal application. Drug release is controlled
by the liquid crystals because the diffusion within the liquid
crystalline phase is slowest and is thus the rate-controlling
step [35]. This principle can be used for ophthalmological ad-
ministration as well as for nasal, oromucosal, rectal, vaginal
or even parenteral subcutaneous application [36, 37]. The oral
administration of such reverse micellar solutions either directly
or encapsulated within soft gelatine capsules, is not recom-
mended however [38], because the sustained release effect is
limited by interindividual variations in digestion. This results
from differences in the amount and composition of the gastric
fluid as well as the ability of the gastric fluid to emulsify and
dissolve the dose prior to absorption.
Lecithin
Water
Figure 1 - Application induced transformation of a reverse micellar solu-
tion into a liquid crystal upon contact with aqueous media [38].
IV. LIQUID CRYSTALS
The liquid crystalline state combines properties of both liquid
and solid states. The liquid state is associated with the ability to
flow whereas solids have an ordered, crystalline structure [39].
Liquid crystals show at least orientational long-range order and
may show short-range order whereas the positional long-range
order as characteristic in real crystals has disappeared [40].
Therefore, liquid crystalline phases represent intermediate states
and are also called mesophases. A pre-requirement for the for-
mation of liquid crystalline phases is an anisometric molecular
shape, which is generally associated with a marked anisotropy
of the polarisability. Molecules that can form mesophases are
called mesogens. The latter are often excipients of drugs, e.g.
surfactants. Even drug compounds themselves, e.g. the salts of
organic acids or bases with anisometric molecular shape, may
fulfil the requirements for the liquid crystal formation [41].
Starting with the crystalline state, the mesophase is reached
either by increasing the temperature or by adding a solvent.
Accordingly, thermotropic or lyotropic liquid crystals form.
As with thermotropic liquid crystals, variation in temperature
can also cause a phase transformation between different mes-
ophases of lyotropic liquid crystals. Lyotropic liquid crystals
426
Novel colloidal delivery systems for dermal application
M.A. Schubert, C.C. Müller-Goymann
arise from mesogens that are not the molecules themselves but
their hydrates or solvates as well as associates of hydrated or
solvated molecules. Water or a mixture of water and organic
solvent are the most important solvents for drug molecules, and
the degree of hydration or solvation depends on the amphiphilic
properties of a drug molecule. Hydration or solvation of a mostly
rod-shaped molecule results in different geometries, i.e. cone
or cylinder [42].
Cylinders arrange in layers. This results in a lamellar phase
with alternating polar and nonpolar layers. Water and aqueous
drug solutions can be included in the polar layers, resulting in
an increase in layer thickness. Analogously, molecules with
appropriate affinity can be included in the non-polar layers. In
addition to the increased layer thickness of the lamellar phase,
lateral inclusion between molecules is also possible with an
increase in the solvent concentration, which transforms the
rod shape of the solvated molecules to a cone shape. This leads
to a phase change. Depending on the polarity of the solvating
agent and the molecule itself, the transition results in a hex-
agonal or inverse hexagonal phase. The hexagonal phase is
named after the hexagonally packed rod micelles of solvated
molecules, whereby their polar functional groups either point
to the outside or the inside of the structure. In the hexagonal
phase, the additional amount of water or nonpolar solvent that
can be included is limited. As the molecular geometry changes
further during solvation, a cubic (type I) or inverse cubic form
(type IV) develops, consisting of spherical or ellipsoidal micelles
and/or inverse micelles.
In addition to the cubic and/or inverse cubic forms described
above, further transitional forms exist between the lamellar
phase and hexagonal (cubic, type II) or inverse hexagonal
mesophases (cubic, type III). In contrast to the discontinuous
type I and IV phases, type II and III cubic mesophases form
bicontinuous phases. A range of lyotropic mesophases is pos-
sible depending on the mesogen concentration, the lipophilic
or hydrophilic characteristics of the solvent and the molecule
itself [43]. However, not all theoretically possible mesophases
may occur in practice.
1. Liquid crystalline drug substances
Some drug substances are able to form mesophases either
together with a solvent (lyotropic liquid crystals) or alone (ther-
motropic liquid crystals) [17, 18, 44-49]. Thermotropic and/or
lyotropic liquid crystalline mesophases of drug substances may
interact with mesomorphous vehicles as well as with liquid
crystalline structures present in humans. Table I presents drug
substances that have been proven to exhibit either thermotropic
or lyotropic mesomorphism.
The molecular structure of arsphenamine is a typical repre-
sentative of a thermotropic mesogen [44]. With its symmetrical
arrangement of the atoms, the same holds for disodium cro-
moglicinate DNCG [45] which forms both thermotropic liquid
crystals and additionally lyotropic mesophases with water. If
micronized DNCG powder is applied to nasal or bronchial
mucosa, the powder will absorb water due to the high relative
humidity of the respiratory tract. It will then transform into a
lyotropic mesophase, followed by solution formation, depend-
ing on the amount of water available.
Novel colloidal delivery systems for dermal application
M.A. Schubert, C.C. Müller-Goymann
Table I - Liquid crystalline drug substances.
Drug Type of liquid crystal
Arsphenamine nematic
Disodium cromoglicinate nematic, hexagonal
Nafoxidin HCl hexagonal, cubic, lamellar
Diethylammonium flufenamate lamellar
NSAID salts
fenoprofen lamellar
ketoprofen lamellar
ibuprofen lamellar
flurbiprofen lamellar
pirprofen lamellar
diclofenac lamellar
Peptide hormone LH-RH
analogue
For therapeutic purposes, a frequently used group of drug
compounds are the non-steroidal anti inflammatory drugs
(NSAID). One of the best known representatives of the aryl
acetic acid derivatives is diclofenac, and ibuprofen is an aryl
propionic acid derivative. As both have acidic properties, they
dissociate while being dissolved and may form salts with am-
phiphilic properties. Together with appropriate counter ions
these amphiphilic organic acids may form lyotropic mesophases
with water at room or body temperature, e.g. diclofenac di-
ethylamine or ibuprofen lysinate [17, 18]. Furthermore, some
NSAID anhydrates exhibit thermotropic mesomorphism after
thermal dehydration of the crystalline salt, e.g. fenoprofen
calcium [49]. All the other drug substances listed in Table I
have not yet been used for therapeutic purposes.
2. Liquid crystalline formulations for dermal
application
Since drug molecules with amphiphilic character may form
lyotropic mesophases, amphiphilic excipients in drug formula-
tions also form lyotropic liquid crystals [50]. This is particularly
so for surfactants, which are commonly used as emulsifiers in
dermal formulations, and associate to form micelles after dis-
solving in a solvent. With increasing concentration the prob-
ability of interaction between the micelles increases and thus
liquid crystals form.
2.1. Surfactant gels
The use of monophasic systems of lyotropic liquid crystals
is relatively seldom and is limited to gels. A variety of polar
surfactants (e.g. ethoxylated fatty alcohols) hydrate in the
presence of water and form spherical or ellipsoidal micelles.
At high surfactant concentrations these associates are densely
packed and are identified as cubic liquid crystals [51].
Cubic liquid crystalline surfactant gels are optically
transparent. If agitated mechanically, their elastic properties
become evident. Due to resonance effects in the audible range,
they are also called ringing gels. These gels are composed of
the lipophilic components solubilized together with the active
ingredients in hydrated associates of the surfactants. However,
the solubilization capacity of lipophilic components is gener-
ally limited, and any excess disperses dropwise in the liquid
crystalline phase. Such systems exhibit a white appearance
according to the change in refractive index at the interface
J. DRUG DEL. SCI. TECH., 14 (6) 423-434 2004
between continuous liquid crystalline and dispersed oil phase.
Ref. The dispersed drops are mechanically stabilized because the
44 liquid crystalline phase of either hexagonal or cubic character
45 has a high yield value.
46 Ringing gels with cubic liquid crystalline microstructure
47 are marketed as commercial drug formulations, especially for
topical NSAID formulations. Examples on the German mar-
17 ket include Contrheuma Gel Forte N, Trauma-Dolgit Gel and
17
Dolgit Mikrogel. The latter was introduced in 1996 and contains
17
17 ibuprofen as active ingredient. The high surfactant concentra-
17 tion of such gels is necessary to verify the liquid crystalline
18 microstructure, on one hand, and, on the other hand, influences
the microstructure of the stratum corneum lipids, increasing
48 permeability. Increased permeability is also achieved by alcohol,
which is also solubilized in the formulation. In permeation tests
with excised human stratum corneum, the amount of ibuprofen
permeating a specific surface area over time was even much
higher for Dolgit Mikrogel than for an aqueous mixed micellar
solution of the drug [41]. Although relatively high permeation
rates are possible for liquid preparation, the commercial formu-
lation is significantly more effective since the high surfactant
content and the alcohol lead to a high permeability. Compari-
sons between different commercial formulations revealed the
superiority of the ringing gel [52].
A ringing surfactant gel of liquid crystalline microstructure
containing the antimycotic bifonazole was introduced on the
German market in 1995 (Bifomyk Gel). Like surfactant gels
containing NSAIDs, improved penetration of the active ingre-
dient is desired in antifungal therapy of the dermis. However,
since the liquid crystal structure only forms with a relatively
high surfactant concentration, the positive effect of improved
penetration must be considered together with the potential for
irritation. The objective is to improve penetration as much as
possible via a change in skin structure, while minimising ir-
ritation. Since hyphae of fungi (mycelium) can penetrate deep
into the epidermal layers by sliding past the corneocytes of
the horney layer, improvement of the antimycotic therapy is
of particular importance. The same holds for the penetration of
NSAIDs through several epidermal layers, because they have
to reach the muscle and joint tissue located more deeply.
2.2. Ointments and creams
Commonly, the surfactant concentration in ointments
and creams is significantly lower than in surfactant gels.
Ointments are non-aqueous preparations, whereas creams
result from adding water to ointments. If a liquid crystalline
network or matrix is formed by amphiphilic molecules, the
microstructure of ointments or creams may be liquid crystal-
line. In this situation, the system is more easily deformed by
shear stress. Such formulations show plastic and thixotropic
flow behaviour. Systems with a liquid crystalline matrix ex-
hibit a short regeneration time after shearing. In comparison,
a crystalline matrix is usually destroyed irreversibly by shear.
To obtain a liquid crystalline matrix, amphiphilic surfactants
that form lyotropic liquid crystals at room temperature must be
selected. It is preferred if lamellar liquid crystals are formed,
which are able to solubilize high amounts of other ingredients
and spread through the whole formulation as a network-form-
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J. DRUG DEL. SCI. TECH., 14 (6) 423-434 2004
ing cross-linked matrix. In contrast, ointments which contain
long-chain fatty alcohols such as cetyl and/or stearyl alcohol,
have a crystalline structure at room temperature [53].
Although the α-phase of the fatty alcohols, a thermotropic
smectic-B liquid crystal with hexagonal arrangement of the
molecules within double layers, is initially formed from the
melt during the manufacturing process, it normally transforms
into a crystalline modification as it cools. However, crystal-
lization of the gel matrix can be avoided if the α-phase is kept
stable as it cools to room temperature. This can be achieved by
combining appropriate surfactants such as myristyl or lauryl
alcohol and cholesterol, which mix to form a lamellar liquid
crystal at room temperature [54].
The polar character of a surfactant molecule enables the
addition of water to form creams. Depending on whether
the surfactant or the surfactant mixture has a strong or weak
polar character, an o/w or w/o cream will form, respectively.
Creams of w/o type are produced from systems which are
solely stabilized with weakly polar surfactants such as fatty
alcohols, cholesterol, glycerol monostearate, or sorbitan fatty
acid esters. The surfactants or surfactant mixtures are adsorbed
at the interface between the dispersed aqueous and continuous
lipophilic phase. Even multiple layers of the surfactants are
adsorbed if the concentration of mesogenic molecules is high
enough to form their own liquid crystalline phase. Apart from
the reduction of the surface tension and/or surface energy, the
liquid crystalline interface also has a mechanically stabilizing
effect on the emulsion drops.
Surfactants such as sulphated fatty alcohols may be hy-
drated to a higher extent than the fatty alcohols alone and thus
stabilize o/w emulsions. The combination of an anionic and a
nonionic surfactant has proven to be particularly effective, since
the electrostatic repulsion forces between the ionic surfactant
molecules at the interface are reduced by the incorporation
of nonionic molecules, thus improving the emulsion stability.
The combination of cetyl/stearyl sulfate (Lanette E) and cetyl/
stearyl alcohol (Lanette O) to yield an emulsifying cetyl/stearyl
alcohol (Lanette N) is an example of this approach. The polar
properties of this surfactant mixture are dominant, and there-
fore o/w creams are formed. In contrast to w/o systems, the
stabilizing effect of the surfactant mixture is only partly due to
adsorption at the interface. Instead, the mixed surfactants are
highly hydrated and form a lamellar network, that is dispersed
throughout the continuous aqueous phase, and the dispersed
lipophilic components are immobilized within the gel network.
However, this hydrated gel matrix is not crystalline at room
temperature as is the case for corresponding w/o creams with
cetyl/stearyl alcohol, but is in its α-phase, which belongs to
the thermotropic smectic liquid crystals and exhibits a strong
similarity to lyotropic lamellar liquid crystals.
Analogous gel matrices of liquid crystalline lamellar
phases can also be formed with nonionic mesogens, e.g. with
the combination of cetyl/stearyl alcohol and ethoxylated fatty
alcohol, provided that the hydrophilic and lipophilic properties
of the surfactant molecules are more or less balanced to favour
the formation of lamellar structures. New possibilities for the
development of controlled drug delivery systems of lamellar
lyotropic liquid-crystalline systems are introduced due to their
428
Novel colloidal delivery systems for dermal application
M.A. Schubert, C.C. Müller-Goymann
stability and special, skin-friendly structure [55]. Sugar based
emulsifiers so called glucolipids like alkylpolyglucosides may
be promising alternatives to traditionally used polyoxyethlene
derivates offering better skin hydration and barrier improvement
[56, 57].
V. VESICLES
With some molecules, a high concentration results in a
lamellar phase but no additional mesophases are formed if the
concentration is reduced. The lamellar phase is dispersed as
concentric layered particles in an excess of solvent (water or
aqueous solution). This results in a vesicular dispersion. If the
mesogenic material consists of phospholipids, the vesicular
dispersion is called a liposomal dispersion [56]. In principle,
the liposomes may be dispersed in oily continuous media,
too. However, the latter systems are of minor interest in drug
formulation.
Liposomes consist either of many, a few or just one phospholi-
pid bilayer. Therefore multilamellar vesicles (MLV), oligolamel-
lar vesicles (OLV), small unilamellar (SUV), and large unila-
mellar vesicles (LUV) have to be distinguished. Furthermore,
multivesicular liposomes (MVL) may be formed. The polar
character of the liposomal core enables polar drug molecules
to be encapsulated. Amphiphilic and lipophilic molecules are
solubilized within the phospholipid bilayer according to their
affinity towards the phospholipids. Participation of non-ionic
surfactants instead of phospholipids in the bilayer formation
results in niosomes. The term sphingosome is suggested for
vesicles from sphingolipids. However, nomenclature is not
consistent, i.e. the term liposome is used as a general term,
although vesicles would be the better choice.
The standard manufacturing procedure of liposomes is
the film-forming method. Alternatively, solvent injection
and reverse phase dialysis are appropriate procedures for the
formation of SUV and LUV. Freeze thaw procedures enable
drug loading of the liposomes and also offer an evaluation of
the stability of the vesicular dispersion. Further information is
available elsewhere [56, 57].
1. Vesicle dispersions for topical application
Although liposomes have been studied intensely since 1970,
only a few commercial drug formulations contain liposomes as
drug carriers [60, 61]. The first commercial drug formulation with
liposomes for topical administration was registered in Italy. The
antimycotic econazole was encapsulated in liposomes dispersed
in a hydrogel (Ecosom Liposomengel, formerly Pevaryl Lipo-
gel). A highly hydrated gel network of the hydrophilic polymer
forms, and liposomes are immobilized within the gel network
and thus mechanically stabilized. This stabilization via gelation
of the continuous aqueous phase can also be applied to other
disperse systems, e.g. suspensions or emulsions. An example of
such an emulsion/hydrogel combination that contains heparin
sodium as the active ingredient and, since 1995, liposomes as
an additional dispersed phase is Hepaplus Liposom. Voltaren
Emulgel is a formulation with an analogous emulsion/hydrogel
combination but without additional liposomes. The continuous
aqueous phase is again a hydrogel derived from polyacrylate,
in which the dispersed lipophilic phase is immobilized. The
Novel colloidal delivery systems for dermal application
M.A. Schubert, C.C. Müller-Goymann
interface consists of multilamellar layers consisting of both
surfactant and drug molecules. Thus, the hydrogel is not
only stabilized by the hydrogel network itself but also by the
liquid crystalline interface. The active ingredient, diclofenac
diethylamine, diffuses slowly from the dispersed phase via the
multilamellar interface into the continuous phase from where
it penetrates into the epidermis.
Similar to Voltaren Emulgel, oil droplets of an eutectic mix-
ture of lidocaine and prilocaine are dispersed in a hydrogel to
provide local anæsthesia of the skin for injections and surgical
treatment (Emla cream). A further possibility is the dermal
administration of a liposome dispersion as a spray (Heparin
PUR ratiopharm Sprühgel). After administration, water and
isopropyl alcohol evaporate partially, increasing the liposome
concentration and a transition from the initial liposome disper-
sion into a lamellar liquid crystal occurs [62]. The therapeutic
effect thus appears to be influenced favourably by the presence
of lecithin alone, rather than by the degree of dispersion of the
liposomes.
2. Elastic vesicles for topical application
Elastic vesicles are a novel development in vesicular de-
sign for dermal and transdermal drug delivery. In contrast to
conventional vesicles, elastic vesicles are composed of both a
bilayer forming substance like phosphatidylcholine and at least
one micelle forming surfactant such as polysorbate 80, sodium
dodecyl sulphate, sodium cholate, etc. [63]. The presence of
different stabilizing molecules and their tendency to redistribute
in the bilayers enables these vesicles to be more elastic than
normal vesicles.
Studies have suggested that these vesicles are superior to
rigid vesicles in terms of both therapeutic effects and in terms
of interactions with human skin [63, 64]. Skin permeation
studies were performed using a wide variety of drugs includ-
ing insulin, lidocaine, oestradiol, 5-fluorouracil, diclofenac
and pergolide [65-70]. It is proposed that these vesicles are
able to deform when applied to the skin. This behaviour is
expected to facilitate partitioning into the stratum corneum and
to increase the permeation rate of drugs across the skin. Cevc
and Blume suggested that – under non-occlusive applications
– elastic vesicles (Transfersomes) are able to penetrate through
intact stratum corneum under the influence of a transepidermal
osmotic gradient and a hydration force [63]. It has been further
postulated that irregularities within the intercellular lipid packing
of stratum corneum can act as virtual channels through which
elastic vesicles can penetrate [71] and are even transported
intact through the skin [63].
The interactions of elastic and rigid vesicles with mammalian
skin in vitro and in vivo were investigated by Van den Bergh et
al. (64,72) and Honeywell-Nguyen et al. (73-75). In contrast to
the results reported by Cevc et al., these studies did not show
any evidence that elastic vesicles could penetrate through the
stratum corneum into the viable epidermis in large quantity.
Instead, after treatment with elastic vesicles, a fast penetration
of intact elastic vesicles into the stratum corneum was observed
and lamellar stacks of elastic vesicles were found in the intercel-
lular lipid spaces. However, 4 h after non-occlusive treatment,
vesicle appearance changed and extensive vesicle fusion was
429
J. DRUG DEL. SCI. TECH., 14 (6) 423-434 2004
seen. Besides, it was shown that elastic vesicles altered the in
vitro penetration pathway of a lipophilic fluorescent marker;
the transport of the fluorescent label was via a fine network of
thread-like channels whereas rigid vesicles and micelles showed
a homogeneous intercellular penetration of the fluorescence
label [64].
VI. LIPID NANOPARTICLES
Nanoparticles are in the solid state, and either amorphous
or crystalline. They are able to adsorb and/or encapsulate a
drug, thus protecting it against chemical and enzymatic deg-
radation. Furthermore the encapsulated drug may be prevented
from crystallisation, thus forming a solid solution. However,
it has been shown that the drug, as a foreign material, is only
incorporated to a limited extent in the different crystal lattice
of the nanoparticle carrier material, due to a limited solubility
of the respective drug in the stable crystal modification. The
loading capacity of solid lipid nanoparticles is lower than that
of an equally concentrated nanoemulsion [76, 77]. Depending
on drug solubility in the carrier, a drug load varying from only
a few percent up to 50%, as in the case of ubidecarenone, has
been reported [77]. In this context, drug nanodispersions and
nanoparticles of supercooled drug melts consisting of pure drug
in either a crystalline or amorphous state are gaining increasing
interest [78].
Nanoparticles as drug carriers can be formed from different
materials. In addition to solid lipids, both biodegradable poly-
mers and non-biodegradable polymers have been used as carrier
materials [79-82]. Polymer nanoparticles are most commonly
prepared by precipitation via solvent displacement, salting-out,
and pH variation, and also polymerisation from microemulsions
and mixed micelles [83, 84]. Preparation techniques for lipid na-
noparticles involve high pressure homogenisation, precipitation
from microemulsions and solvent evaporation [82]. Recently,
it has been reported that lipid nanoparticles were successfully
prepared by solvent injection, which is also appropriate for the
preparation of vesicle dispersions [85].
Solid lipid nanoparticles (SLN) have gained increasing
interest as pharmaceutical and cosmetic formulations recently
[86-110]. Due to their small particle size and consequent high
surface area they possess strong adhesive properties. This
leads to film formation on the skin, which may help to restore
a previously damaged protective lipid film on the skin and
increase the moisturising effect via occlusion [86-88, 91, 102].
Furthermore, SLN have been proposed as novel carriers for
sunscreens [89-93].
Incorporation of active ingredients into the solid lipid matrix
offers protection against chemical degradation of the active
compound [106], as well as allowing either immediate or sus-
tained release, depending on the polymorphic transitions of the
lipid matrix [101]. Sustained release is important with active
ingredients that are irritating at high concentrations or when
supply of a drug to the skin over a prolonged period of time is
desired, whereas immediate release can be useful to improve
drug penetration. According to Jenning et al. [101] sustained
release is often related to the metastable betaʼ polymorph of
the lipid matrix (glyceryl behenate in the present study). Drug
expulsion is explained by a reduction of amorphous regions in
J. DRUG DEL. SCI. TECH., 14 (6) 423-434 2004
the carrier lattice due to a betaʼ to beta(i) polymorphic transition.
This transformation can be controlled with surfactant mixtures
or, in the case of a hydrogel or an oil/water cream, with gelling
agents or humectants. Thus, the release rate for the topical route
of application can be adjusted.
Stability enhancement was reported for vitamin E [100]
and retinol [106] by encapsulation of retinoids in solid lipid
nanoparticles. Different lipids were compared, and glyceryl
behenate gave superior entrapment compared to tripalmitate,
cetyl palmitate and solid paraffin [106]. Three drugs were com-
pared, and entrapment increased with decreasing polarity of the
molecule (tretinoin < retinol < retinyl palmitate). Encapsulation
efficacy was enhanced by formulating SLN from mixtures of
liquid and solid lipids. These particles were solid and provided
better protection for sensitive drugs than an emulsion. X-ray
investigations revealed that good encapsulation was correlated
with a low degree of crystallinity and lattice defects. With highly
ordered crystals, as in the case of cetyl palmitate, drug expul-
sion from the carrier was more pronounced.
Based on the experiences with solid lipid nanoparticles,
a new type of solid lipid nanoparticle has been developed by
incorporating triglyceride containing oils in the solid shell of
the particle [104, 105]. A medium chain triglyceride oil was
successfully incorporated into a solid long chain glyceride
matrix. The crystal order was greatly disturbed, but the carrier
remained solid. The oil inside the particle remained in a liquid
state and induced a slight shift from the betaʼ polymorph to the
beta(i) form of the crystalline lipid. Long spacings varied within
0.1 nm with increasing oil loads. There was a linear relationship
between oil supplementation and melting point depression of the
glyceryl behenate. From 1H-NMR measurements it was found
[105] that the mobility of the oil molecules inside the particles
was considerably lower than that of the emulsified oil. Moreover,
two different chemical shifts for each of the lipid signals were
observed indicating two different chemical environments. The
experimental data are in line with a model describing uniform
distribution of the oil molecules in the glyceryl behenate for
low oil loads. However, at higher oil loads oil clusters appear to
form within the solid nanoparticle. Nanoparticles with low oil
concentrations showed sustained release properties. Improved
drug load levels were achieved by lipid particles supplemented
with oily constituents.
In a recent publication, the term nanostructured lipid carrier
(NLC) has been suggested for the oil-loaded SLN with supe-
rior drug-loading capacity and controlled-release characteristics
[110, 111]. Proton nuclear magnetic resonance spectroscopy,
electron spin resonance experiments and transmission electron
microscopy were performed to investigate component mobility,
the molecular environment of model drugs and NLC structure
in comparison to SLN and nanoemulsions. NLC nanoparticles
differ from nanoemulsions and SLN by forming a liquid com-
partment that strongly interacts with the solid lipid. The electron
spin resonance model drug was found to be accommodated
either on the particle surface with close water contact (SLN)
or additionally in the oil (NLC). From these data, the authors
suggested that NLC are not spherical solid lipid particles with
embedded liquid droplets, but exhibit an intraparticulate phase
separation and are composed of rather solid platelets with oil
430
Novel colloidal delivery systems for dermal application
M.A. Schubert, C.C. Müller-Goymann
spots sticking on the surface. Bunjes et al. [112] observed similar
structures for SLN loaded with the highly lipophilic drug ubi-
decarenone forming liquid caps of supercooled ubidecarenone
on one of the large faces of the platelet. In contrast to previous
results, Jores et al. [110, 111] found that neither SLN nor NLC
lipid nanoparticles showed any advantage with respect to the
incorporation rate or retarded accessibility of the drug compared
with conventional nanoemulsions. Other disadvantages of SLN
are their particle growth, their unpredictable gelation tendency
and their unexpected dynamics of polymorphic transitions [76,
113-115].
While most published data deal with glyceride SLN, little
knowledge is reported on wax carriers. A comparison of the
two substances was made with respect to retinol encapsulation
efficacy, particle size distribution after production and storage,
and crystal packing [103]. Glyceride SLN showed good drug
encapsulation, while physical stability was poor. In contrast,
wax SLN possessed good physical stability but lacked sufficient
drug encapsulation in the solidified state. These differences
were attributed in part to different crystal packing. Less ordered
crystal lattices favour successful drug inclusion, as in the case of
glyceryl monostearate and glyceryl behenate SLN. The highly
ordered crystal packing of wax SLN, comprised of beeswax or
cetyl palmitate, for instance, leads to drug expulsion, but also
to superior physical stability.
Besides dermal application, delivery to the eye of nanopar-
ticles is possible and has demonstrated promising results over
the last ten years. A recent review on cyclosporin A delivery
to the eye summarizes a variety of different carrier systems
including nanoparticles and other colloidal carriers [116].
VII. SUPERCOOLED SMETIC NANOPARTICLES
A novel colloidal drug delivery system based on the highly
supercooled thermotropic liquid crystalline smectic phase of
cholesterol esters was developed by Bunjes et al. [117]. Such
nanoparticle dispersions can be prepared from mesogenic
cholesterol esters and their mixtures and may be an alterna-
tive drug delivery system especially for poorly water soluble
drugs. These systems are prepared by high pressure homog-
enisation, either by melt homogenisation of the molten lipid
in a hot aqueous phase or by homogenisation of a solution
of cholesterol esters in cyclohexane in a cold aqueous phase,
evaporation of the organic solvent after homogenisation and
subsequent heating of the dispersion above the melting point
of the lipid matrix. Depending on the emulsifier composition
and preparation method, particle sizes down to 50 nm or even
below are obtained. Investigations of cholesteryl myristate by
freeze fracture and cryoelectron microscopy reveal the presence
of particles with cylindrical and/or spherical shape. In some
of the cholesteryl myristate particles, a concentrically layered
structure was detected by freeze fracture electron microscopy.
Due to the layered structure of the smectic mesophase, a cy-
lindrical shape of the smectic nanoparticles is assumed to be
more favourable than a spherical shape [118].
In comparison to bulk, the smetic mesophase of cholesteryl
myristate of the nanodispersions is much more stable and can
be preserved upon storage for several months or even years.
By using cholesterol ester blends the crystallisation tendency
Novel colloidal delivery systems for dermal application
M.A. Schubert, C.C. Müller-Goymann
can be further suppressed from about 20°C down to 0°C [119].
Due to the high transition temperature of the smetic phase of
8.
cholesteryl myristate the particles retain their liquid crystalline
state at body temperature. This makes these systems interest- 9.
ing for drug delivery purposes because the highly viscous and
ordered, but still mobile, structure of thermotropic mesophases
10.
may offer a compromise between loading capacity and im-
mobilisation potential of lipophilic drugs. The model drugs 11.
ibuprofen, etomiate and miconazole could be incorporated in
the dispersions at concentrations of 10% with respect to the
12.
lipid matrix without destroying the liquid crystalline state of the
nanoparticles and without precipitating drug crystals. In addi- 13.
tion, some drugs, e.g. ubidecarone, can be formulated directly
as colloidal supercooled melts [78]. However, it has to be kept
14.
in mind, that dispersions of supercooled melts are metastable
formulations not only with respect to their dispersity but also 15.
concerning the physical state of the dispersed phase.
* 16.
* *
The most superficial layer of the human skin, the stratum 17.
corneum, is the major barrier for dermal and transdermal drug
delivery. In order to increase the efficiency of drugs delivered
to and/or through skin there is a demand for new dermal drug 18.
delivery systems. Over the last two decades colloidal drug
delivery systems have been developed and explored as po- 19.
tential carriers for dermal/transdermal drug delivery offering
superior properties in this context and, thus, may be the carriers
of choice. Meanwhile, a broad knowledge of physicochemical
20.
characteristics of the different colloidal carriers relevant for
topical delivery is available, providing in most cases a better
understanding of the mode of action of the respective systems. 21.
Surfactant free emulsions, stabilized either by particles or surface
22.
active polymers, are an alternative carrier system when skin
irritations due to interactions of emulsifiers with the human skin
have to be reduced. Nevertheless, drug delivery systems have
to be optimally developed, depending on the therapy require- 23.
ments.
24.
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MANUSCRIPT
Received 15 July 2004, accepted for publication 27 August 2004.