Original Contributions

Formulations of hydrogels and lipogels with vitamin E

Blackwell Publishing, Ltd.

V Gallardo, M Muoz & M A Ruz

Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada, 18071 Granada, Spain

Summary Vitamin E, a topically administered antioxidant, reduces erythema, photoaging, photo-

carcinogenesis, edema, and skin hypersensitivity associated with exposure to ultraviolet
B (UVB) radiation. Virgin olive oil, which also has antioxidant properties, reduces the
number of, and delays the onset of skin cancer induced by UVB radiation when used after
sunbathing. Topical use after sunbathing of formulations that contain virgin olive oil and
vitamin E may therefore reduce the number and delay the onset of UVB-related skin
cancer in humans. We designed formulations of gels with olive oil (lipogels) and hydrogels
containing 2% tocopherol. The formulations were optimized on the basis of rheological,
organoleptic, biopharmaceutical, and cosmetic criteria. Different formulae for hydrogels
with vitamin E were ideal for application after exposure to solar radiation because of their
good organoleptic properties. Vitamin E lipogels are of potential use in cosmetics such as
locally acting anti-aging treatments because of the antioxidant effects of vitamin E.
Keywords: hydrogels, lipogels, vitamin E

in acute overexposure. Repeated exposure can lead to

Introduction
Recent studies have shown that the topical application
of vitamin E, an antioxidant, significantly reduces
erythema, edema, and skin hypersensitivity associated
with ultraviolet B (UVB) radiation resulting from solar
exposure to solar radiation. 1,2 Vitamin E stabilizes
biological membranes, especially those that contain large
amounts of polyunsaturated fatty acids.3 It also delays
the appearance of skin cancer induced by UV radiation in
mice.4 Because of its emollient properties, nonirritant
nature, and ability to favor permeation, this molecule is
highly compatible with the skin.5
Ultraviolet solar radiation (UV-A from 320 to 400 nm,
UV-B from 290 to 320 nm of the solar spectrum) gives
rise, through the formation of free radicals (oxygen-
reactive species), to erythema and cutaneous edema
Correspondence: V Gallardo, University of Granada Department of
Pharmacy and Pharmaceutical Technology, Campus de Cartuja Granada
18071, Spain, E-mail: vglara@ugr.es
Accepted for publication June 25, 2005
photoaging, cutaneous photocarcinogenesis because of
DNA alterations6 and immunosuppression.3
Topical administration in dermatological therapy7
or for cosmetic purposes has practical advantages
over systemic use, mainly in that it facilitates delivery
of the active principle directly to the damaged organ.
This occurs when the substance is able to penetrate the
skin in sufficient amounts to ensure a pharmacological
effect.8,9
An ideal topical antioxidant should satisfy the
following requirements:
antioxidant activity
ability to penetrate the skin
prolonged action in the skin
protection from oxidative damage
Virgin olive oil10,11 has been shown to have antioxi-
dant effects that reduce the number and delay the appear-
ance of skin cancer induced by UVB radiation when
applied to the skin after exposure to sunlight.12 However,
pretreatment with olive oil and pre- and/or post-
treatment neither delays nor reduces the appearance
of skin cancer in mice irradiated with UV light.4

2005 Blackwell Publishing Journal of Cosmetic Dermatology, 4, 187192 187

Hydrogels and lipogels with vitamin E V Gallardo et al.
Thus the simultaneous topical administration of virgin
olive oil and vitamin E after sunbathing can delay and
reduce the development of skin cancer induced by UV
radiation in humans. This effect is probably because of
the decreased formation of free radicals and 8-hydroxy-
deoxyguanosine (8-OHdG), a molecule that can cause
gene mutations.
Optimization of the formulations tested here was based
on previously published criteria for rheology,13 orga-
noleptic properties,14 and biopharmaceutical properties
and cosmetic quality.15 We designed gel formulations16
prepared from olive oil (lipogels),1719 and hydrogels that
incorporated 2.0% tocopherol acetate.20
We describe the validation process for the analytical
method used to measure tocopherol acetate with UV
spectrophotometry, and report the results of release
assays for the active principle in each formulation.
Materials and methods
The products used as components in the formulations
were as follows:
Analytical grade citric acid ACS 131808. Batch 68154LLN,
supplied by Panreac Qumica S.A. (Barcelona, Spain)
Olive oil, Ph Eur (8001-25-0) 75343. Acidity index
1.1; water content < 0.1%. Batch 422297/130701,
supplied by Fluka Chemica. (Steinheim, Switzerland)
Distilled deionized water, Milli-Q water purification
system. (Millipore, USA)
Ethyl alcohol, CEE No. 603-002-00-5. Registro
sanitario (Spanish health registry) No. 303174-CO.
Supplied by Albus. (Crdoba, Spain)
Carbopol ETD 2001. Batch EC8N1EC007, supplied
by BF Goodrich. (Brussels, Belgium)
Ethyl cellulose (9004-57-3). Ethoxyl content 4849.5%,
viscosity in toluene or alcohol (5% solution) 0.045
Newton second/m 2, supplied by ICN. (Barcelona,
Spain)
Olivem products: Olivem 700 (PEG-4 olive oil). Batch
DF1019, and Olivem 900 (sorbitan olivate), Batch
DN1924. Emulgents, supplied by Quimibios, S.L.
(Barcelona, Spain)
Polyethylene glycol 400 (PEG 400); 100% purity.
Batch 3821297, supplied by Roig Farma, S.A.
(Terrasa, Spain)
Polyethylene glycol 1500 (PEG 1500); pH (5%) = 6.2.
Batch 2000997. Roig Farma, S.A. (Terrasa, Spain)
Propylene glycol USP; m.p. (1.03 C), > 99.5% purity,
dens. 1038. Batch 1770696. Roig Farma, S.A.
(Terrasa, Spain)
Sodium hydroxide flakes (1310-73-2). Batch 029.
Supplied by Guinama. (Valencia, Spain)
188
Triethanolamine (TEA) 85%, 181110. Batch 8290.
Supplied by Probus S.A., Badalona. (Barcelona, Spain)
Tween 80 Polysorbate 80, polyoxyethylene (20)
sorbitan monooleate, Batch 014. Supplied by Guinama.
(Valencia, Spain)
Vitamin E (DL-alpha-tocopherol acetate), Batch 042.
Supplied by Guinama. (Valencia, Spain)
Preparation of formulations
The importance of and interest in incorporating vitamins
in cosmetic formulations are well known. However,
vitamin release from cosmetic products to the stratum
corneum of the skin requires a specific type of contact.
This biopharmaceutical phase of release of the active
principle to the skin surface is a factor that limits
subsequent transdermal permeation a more complex
process. It is often useful for topical administration
formulations to facilitate the rapid release of the active
principle, with as little time as possible of contact with
the skin until penetration of the product to the stratum
corneum. This study of the release phase is, from our
opinion, a matter that has not always been clarified
in other studies of vitamin E topical formulations. We
are convinced it is an important event of the cosmetic
preparation so it can be able to access to the stratum
corneum and to be accumulated in the upper skin layers
in order to perform the antioxidant effect.
Our aim was to design a series of formulations contain-
ing vitamin E (2%) but differing qualitatively and quanti-
tatively in some components or in the production process,
in order to compare their abilities to release the active
ingredient. The composition of the different formulae
tested here is summarized in Table 1. Two types of prepa-
rations have been chosen, lipogels and hydrogels, to
be vehicles of vitamin E acetate and representing two
kinds of physicochemical behavior, hydrophobic and
hydrophilic respectively. The aim is to choose those
formulae that present an adequate release profile of the
vitamin considering that the release phase is very often
influenced by the physicochemical character of the active
molecule and its interaction with the vehicle.
Lipogel formulations
Lipogels are a kind of preparations based on vegetable,
mineral, or animal oils gellified by gelling agents such
as cellulose derivatives. They are cosmetics themselves
because of their lipidic composition that serves as a
barrier between the skin and the outside ambient. When
necessary, they help to regenerate the stratum corneum
because of their rich content in fatty acids (i.e., oleic fatty
2005 Blackwell Publishing Journal of Cosmetic Dermatology, 4, 187192

Table 1 Composition of vitamin E lipogel for topical application.
Ethylcellulose Olivem 700
Lipogel 1-A 3% 5%
Lipogel 1-B 3% 5%
Lipogel 2-A 3%
Lipogel 2-B 3%
*Method 1: Vitamin E added during lipogel synthesis.
**Method 2: Vitamin E added after lipogel synthesis.
acid) which are usually compatible with the epidermis.
In this sense, they can prevent some kinds of allergies
caused by contact with some cosmetic compounds,
because it is demonstrated that the appropriate
physiology of the stratum corneum can minimize the
risk of contact allergies. Nonetheless they are commonly
used as vehicles to incorporate active compounds to a
therapeutic or cosmetic use. In both cases, the bigger the
capacity of releasing the active molecule to the stratum
corneum, the better the formulation is. The method used
to produce lipogels was based on the findings of Fukasawa
and Aiache for the gelling of vegetable oils. We modified
these procedures for synthesis as necessary for our purposes.
The gelation process for lipogels began with the addi-
tion of a surfactant and ethyl cellulose21 to the oil phase,
which was heated to 100 C with constant shaking. Once
the mixture was homogeneous, heating was stopped but
shaking continued until the material had cooled to room
temperature. A 48-h settling period then ensued to allow
the reticular structure of the lipogel to stabilize. Gentle
manual shaking is recommended to verify homogeneity
of the formula and check for the appearance of oil exu-
dates not fully interposed within the gel structure, or
granules that denote incomplete melting of the ethyl
cellulose. The main difficulty with these gels is in melting
the cellulose in the oil phase. This material does not melt
at temperatures used to produce the gel (melting point
120 C), but instead appears to dissolve in the oil and
disappear completely.
Two methods were used to incorporate vitamin E into
the lipogel. Formula 1 consisted of adding vitamin E to
the oil phase (olive oil) during production, after ethyl cel-
lulose had been added for gelation. In formula 2 we added
the vitamin at room temperature to the finished lipogel.
The olive oil derivative Olivem 700 (PEG 4 olivate) is
a nonionic O/A emulgent able to stabilize emulsions
through the formation of a liquid crystal structure (in
contrast to systems that consist of spherical micelles).22
Using Olivem 700 prevents lipid oxidation, stabilizes the
emulsion, and has notable hydrating properties because
2005 Blackwell Publishing Journal of Cosmetic Dermatology, 4, 187192
Hydrogels and lipogels with vitamin E V Gallardo et al.
Olivem 900 Vitamin E Olive oil
2% method 1* to 100%
2% method 2** to 100%
5% 2% method 1 to 100%
5% 2% method 2 to 100%
it reduces water loss through the skin. In this study we
used Olivem at a concentration of 15% depending on
the preparation.
Olivem 900 (sorbitan olivate) is a nonionic A/O
emulgent. 23,24 At a concentration of 510%, this
ingredient gives rise to a stable product thanks to the
low or moderate polarity of its oil phase. Like Olivem 700,
it is biodegradable and nontoxic.
At higher vitamin E concentrations (20%),25 lipogels
can also be used to reduce allergies and irritant contact
dermatitis because they stabilize keratinocytes and have
other new and interesting properties that make them of
potential interest for this indication.
Hydrogel formulations
Hydrogels are aqueous preparations mainly formed by
distilled water and a polymer as a gelling agentcellulose
derivatives, gums, agar, etc. Because of such a simple
composition they do not have the capacity to regenerate
lipidic membranes as lipogels do. However, they are much
more accepted in the market because of their nonoily
touch and the advantage of being water-washable.
Moreover, those patients with oily skin would be better
advised to use these kinds of hydrophilic preparations in
order not to increase the lipidic composition of their
epicutaneous emulsion. The hydrogels we tested were
prepared with a single method. Vitamin E (2%) was mixed
with a surfactant (Olivem 700, a combination of PEG26,27
or Tween 80,28 depending on the formulation). This
mixture was then added to an appropriate amount of the
previously prepared carbopol gel.
The surfactant Tween 80 forms an emulsion at concen-
trations of 115%, solubilizes active principles normally
poorly soluble in lipophilic bases (110%), and wets
active principles normally insoluble in lipophilic bases
(0.13%). It is well tolerated, only mildly irritant, and has
very low toxicity. In these studies we used Tween 80 at
concentrations of 2% and 4% to prepare formulas 3 and
4, respectively. (Table 2)
189
Hydrogels and lipogels with vitamin E V Gallardo et al.

Table 2 Composition of vitamin E hydrogels for topical application.

Olivem 700 Tween 80 PEG (1500 : 400) Vitamin E* Carbopol gel**

Hydrogel 1 1% 2% to 100%
Hydrogel 2 3% 2% to 100%
Hydrogel 3 2% 2% to 100%
Hydrogel 4 4% 2% to 100%
Hydrogel 5 3% 2% to 100%
Hydrogel 6 5% 2% to 100%

*Vitamin E, mixed with surfactant, added to carbopol gel.

**Carbopol gel prepared with Carbopol ETD 2001.

Nonionic polymers (PEG) are highly inert, a benefit for Table 3 Equations for the six calibration plots for vitamin E and
formulations with vitamin E as they adhere the vitamin correlation coefficients (r).
to the reticular structure without altering the vitamin.
y = ax + b r
Moreover, PEGs are compatible with skin. These polymers
are thus ideal for our aim of developing topical applica- PLOT1 y = 0.035x + 0.005 0.991
tion formulations.29 PLOT2 y = 0.036x + 0.005 0.990
Combining polymers is a strategy intended to obtain PLOT3 y = 0.037x + 0.006 0.991
a synergetic effect in terms of rheological behavior. PLOT4 y = 0.034x + 0.005 0.991
The consistency of a binary gel is greater than the sum of PLOT5 y = 0.032x + 0.006 0.992
consistencies of individual gels. In the present study we PLOT6 y = 0.040x + 0.005 0.990
used low, equal proportions of two different polymers:
PEG 1500 : 400 at 3% in Formula 5 and at 5% in Formula 6.
As a result there was little variation in the consistency of
the carbopol gel (the major component). Table 3 shows the equations for the regression lines
Release assays with each formulation were done with a calculated for each series of dilutions. For all calculations
thermostated water bath to select those formulations we used MS Excel, an Office 98 software.
with the best kinetics. The settings for the water bath For precision studies we accepted as valid all values
were chosen to emulate normal conditions of topical of the CV (coefficient of variation) lower than 510%.
administration at a temperature 37 0.1 C (physiological Table 4 shows the mean, standard deviation, and
temperature) at shaking at 60 r.p.m. coefficient of variation for different absorbance values
The analytical method used for tocopherol acetate obtained with different concentrations of vitamin E.
was validated spectrophometrically with a Perkin Elmer
Lambda 40 apparatus. Earlier studies20 and the spectrum
Vitamin E release from different formulations
used here (200 400 nm) indicated maximum absorption at
284 nm. The procedure for release assays consisted of spreading
To ensure physicochemical stability the most widely 1 g of each formulation on a slide immersed in 100 mL of
used form of alfa-tocopherol is the esterified prodrug.3 In solution medium (citrate/citrate buffer at pH 5.5 with
our experiments we used alfa-tocopherol acetate. 1% Tween). Samples (3 mL) were obtained for analysis
after 5, 10, 15, 30, and 60 min, and hourly thereafter
until the 8th hour. After 24 h, the volume of medium was
Results and discussion
replaced after each sample was removed. The water bath
was kept at 37 C and 60 r.p.m.
Validation of the analytical method
The results of the release assays showed that Formulae
The method we used to measure tocopherol acetate in 1 and 2 (which differed only in the proportion of Olivem
ethanol satisfied the criteria for linearity, accuracy, and 700) had the fastest release kinetics (Fig. 1), and led to
precision over the range of concentrations from 1.25 to concentrations in the medium 1 h after time 0 (t = 1) of
60 g/mL (1.25, 2.5, 5, 10, 20, 40, 60 g/mL). 111.2 g/mL in Formula 1, and 106.8 g/mL in Formula 2.
For linearity analyses we considered valid all values The differences between the two formulae were negligible
of r (the linear regression coefficient) greater than 0.99. throughout the assay.

190 2005 Blackwell Publishing Journal of Cosmetic Dermatology, 4, 187192

 Hydrogels and lipogels with vitamin E V Gallardo et al.

Table 4 Standard deviation (St. dev.), mean and coefficient of variation (C.V.) for spectrophotometric absorbance obtained with each
concentration of vitamin E from the calibration plots.

CONC. PLOT1 PLOT2 PLOT3 PLOT4 PLOT5 PLOT6 ST.DEV. MEAN C.V.(%)

0.00 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.000 0.00
1.25 0.040 0.045 0.045 0.040 0.040 0.050 0.004 0.043 9.45
2.50 0.060 0.066 0.067 0.060 0.060 0.067 0.003 0.063 5.80
5.00 0.081 0.076 0.081 0.078 0.079 0.080 0.002 0.078 2.87
10.00 0.103 0.098 0.100 0.102 0.105 0.100 0.002 0.101 2.47
20.00 0.155 0.150 0.148 0.147 0.140 0.140 0.005 0.146 3.70
40.00 0.270 0.270 0.270 0.245 0.260 0.240 0.013 0.258 5.24
60.00 0.370 0.360 0.370 0.370 0.390 0.330 0.020 0.365 5.61

which vitamin E was added during gel synthesis, yielded

a concentration 73.6 g/mL at t = 1 h.
In Lipogel 1-B and 2-B, to which vitamin E was added
after the gel had been formed, release was slower:
50.6 g/mL and 47.8 g/mL, respectively, after 1 h.
Regarding the percent release at different sampling
times, after 1 h, release was 24% in the formulae in
which vitamin E was added after the gel was formed,
but was 37% in formulae in which the vitamin had been
added during gel synthesis.

Figure 1 Vitamin E concentration in the medium in release assays
with hydrogel Formulae 16.
Formulae 3 and 4, which contained different propor-
tions of Tween 80, had slower release kinetics, with con-
centrations at t = 1 h of 98.5 g/mL for Formula 3 and
99.7 g/mL for Formula 4. The differences between the
two were negligible throughout the 24-h assay period.
The slowest kinetic release was seen in Formulae 5
and 6, which contained a mixture of PEGs. After 1 h, con-
centration of the active principle in the medium was
80.89 g/mL for Formula 5 and 81.06 g/mL for Formula 6.
The highest percent release rates were seen for Formulae
1 and 2 (mean 54% at t = 1 h), followed by Formulae 3
and 4 (mean 49%). Formulae 5 and 6 showed a slower
release rate (mean 40% after 1 h).
In lipogels the release kinetics were slower, as
expected,30 probably because of the lower affinity of oil-
based vehicles for the acqeous release medium at pH 5.5.
Lipogel 1-A, which contained Olivem 700 and in
which vitamin E was added during gel synthesis, yielded
a concentration in the medium of 75.3 g/mL at t = 1 h,
whereas Lipogel 2-A, which contained Olivem 900 and in
Conclusions
The results showed the best formulae of hydrogels with
vitamin E to be those prepared with Tween 80: hydrogels
3 and 4. These formulas showed the best organoleptic
properties (consistency and spreadability) and good release
kinetics. From these findings we assume that these formula-
tions should present no impediments to accumulation
and/or permeation of vitamin E into the skin. They can be
considered adequate cosmetic preparations for topical
post-sunbath application with an antioxidant function.
Their aim therefore is to perform an efficient protective
action from the UV-radiation oxidative damage.
Lipogels, because of their spreadability and persistence
on the skin, were considered suitable for local use for
cosmetic anti-aging treatment with vitamin E as an
antioxidant agent. The compatibility of these types of
lipophilic vehicles with the skin makes them especially
appropriate for vitamin E topical administration. Regard-
ing that a photodamaged and/or age-damaged skin is
characterized not only by the presence of radical oxygen
species but also by a lower quantity of lipids, it is advisable
to use preparations that contribute to reestablishing the
lipidic equilibrium of the stratum corneum as well as
having some kind of molecules such as vitamin E with
an antioxidant effect or similar kinds of radical agents.

2005 Blackwell Publishing Journal of Cosmetic Dermatology, 4, 187192 191

Hydrogels and lipogels with vitamin E V Gallardo et al.
Acknowledgements
This work was supported in part by the Caja Rural
Provincial de Granada (Spain) through contract no.
541 A-609. We thank K. Shashok for translating the
original manuscript into English.
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