International Journal of Pharmaceutics 490 (2015) 180–189

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International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Characterization of gelation process and drug release profile of

thermosensitive liquid lecithin/poloxamer 407 based gels as carriers
for percutaneous delivery of ibuprofen
Ljiljana Djekic * , Danina Krajisnik, Martina Martinovic, Dragana Djordjevic,
Marija Primorac
Department of Pharmaceutical Technology and Cosmetology, University of Belgrade—Faculty of Pharmacy, Vojvode Stepe 450, P.O. Box 146, 11221 Belgrade,
Serbia

A R T I C L E I N F O A B S T R A C T

Article history: Suitability of liquid lecithin (i.e., solution of lecithin in soy bean oil with
60% w/w of phospholipids) for
Received 9 March 2015 formation of gels, upon addition of water solution of poloxamer 407, was investigated, and formulated
Received in revised form 24 April 2015 systems were evaluated as carriers for percutaneous delivery of ibuprofen. Formulation study of pseudo-
Accepted 13 May 2015
ternary system liquid lecithin/poloxamer 407/water at constant liquid lecithin/poloxamer 407 mass ratio
Available online 19 May 2015
(2.0) revealed that minimum concentrations of liquid lecithin and poloxamer 407 required for formation
of gel like systems were 15.75% w/w and 13.13% w/w, respectively, while the maximum content of water
Keywords:
was 60.62% w/w. The systems comprising water concentrations in a range from 55 to 60.62% w/w were
Liquid lecithin
Poloxamer 407
soft semisolids suitable for topical application, and they were selected for physicochemical and
Thermosensitive gels biopharmaceutical evaluation. Analysis of conductivity results and light microscopy examination
Gelation process revealed that investigated systems were water dilutable dispersions of spherical oligolamellar associates
Sustained drug release of phospholipids and triglyceride molecules in the copolymer water solution. Rheological behavior
Ibuprofen evaluation results indicated that the investigated gels were thermosensitive shear thinning systems.
Ibuprofen (5% w/w) was incorporated by dispersing into the previously prepared carriers. Drug-loaded
systems were physically stable at storage temperature from 5  3  C to 40  2  C, for 30 days. In vitro
ibuprofen release was in accordance with the Higuchi model (rH > 0.95) and sustained for 12 h. The
obtained results implicated that formulated LLPBGs, optimized regarding drug release and organoleptic
properties, represent promising carriers for sustained percutaneous drug delivery of poorly soluble
drugs.
ã2015 Elsevier B.V. All rights reserved.

1. Introduction emulsifier, stabilizer, dispersing agent and penetration enhancer in

The interest on evaluation of lecithin based gels as drug delivery
carriers has grown in the last decade due to low risk for skin
irritation and promising potential for cutaneous or percutaneous
delivery of molecules with different physico-chemical properties
(Elnaggar et al., 2014; Narasimha Murthy and Shivakumar, 2010;
Murdan, 2005; Willimann and Luisi, 1991). Lecithin (1,2-diacyl-sn-
glycero-3-phosphocholine) is an excipient classified by FDA as
Generally Recognized as Safe (GRAS) (http://www.fda.gov/food/
ingredientspackaginglabeling/gras/scogs/ucm260453.htm) and as
a member of Inactive Ingredients database (http://www.access-
data.fda.gov/scripts/cder/iig/getiigWEB.cfm). It is widely used as
* Corresponding author. Tel.: +381 113951359.
E-mail address: ljiljanadjek@gmail.com (L. Djekic).
a numerous pharmaceutical products. The main natural sources of
lecithin are soy bean and egg yolk. It is brown to light yellow
powder to semisolid, practically insoluble in water, polar solvents,
and cold vegetable and animal oils (Szuhaj, 1989). In the late 1980s,
Scartazzini and Luisi with coworkers (Luisi et al., 1990; Scartazzini
and Luisi, 1988) were first who described a spontaneous formation
of a jelly-like systems (lecithin organogels) from nonviscous
solutions of lecithin in organic solvents, upon addition of a small
amount of water. Preparation of the oil solution of lecithin in an oil
is actually a time consuming melting at 55–70  C, and requires
procedures with avoidance of incorporation of air and suitable
mixing equipment (Belgamwar et al., 2008; Murdan, 2005; Russet,
2004). Only highly purified (95%) lecithin of natural origin
enables the formation of lecithin organogels (Kumar and Katare,
2005; Scartazzini and Luisi, 1988; Schurtenberger and Cavaco,
1994; Schurtenberger et al., 1990), and that increases their cost and

http://dx.doi.org/10.1016/j.ijpharm.2015.05.040
0378-5173/ ã 2015 Elsevier B.V. All rights reserved.
 L. Djekic et al. / International Journal of Pharmaceutics 490 (2015) 180–189
susceptibility for oxidation. Furthermore, powder lecithin is a
hygroscopic compound, thus the percentages of the components
producing the gel state are variable and depend on the dryness of
lecithin (Russet, 2004; Shchipunov and Shumilina, 1996; Trotta
et al., 1999). Current market offers liquid lecithins (or fluid
lecithins), which represent solutions of lecithin in vegetable oils
with at least 50% of phospholipids (Russet, 2004). Usage of liquid
lecithin is potentially preferable to overcome the drawbacks of
powder lecithin, therefore there is a particular interest to
formulate gels in multicomponent systems comprising such raw
materials. Inclusion of poloxamer 407 (polyoxyethylene101-poly-
oxypropylene56-polyoxyethylene101 block-copolymer) makes the
organogelling feasible with lecithin of relatively lesser purity.
Poloxamers are biocompatible synthetic long chain polyoxy-
ethylene-polyoxypropylene-polyoxyethylene block-copolymers,
widely used as emulsifiers, solubilizers, and wetting agents in
drug delivery systems for different routes of administration
(Collett, 2009). Poloxamer/lecithin based gels, frequently de-
scribed as poloxamer/lecithin organogels (PLOs), have been
studied by different authors as dermal an transdermal drug
delivery carriers (Agrawal et al., 2004; Almeida et al., 2012;
Belgamwar et al., 2008; Dreher et al., 1997; Kumar and Katare,
2005; Murdan, 2005; Shchipunov, 2001). PLOs offer advantages of:
biocompatibility, semisolid consistency suitable for application on
the defined skin area, coexistence of oil and aqueous phases, which
are available for solubilization of hydrophilic and lipophilic drug
molecules, and superior potential for improvement of effective-
ness of topically applied drugs over the conventional vehicles such
as creams, ointments, and hydrogels (Choukse and Sangames-
waran, 2012; Finch et al., 2009; Flores et al., 1998; Giordano et al.,
1998; Shchipunov et al., 2001). Several studies, including clinical
evaluations, have demonstrated promissing potential for
percutaneous delivery of nonsteroidal antiinflammatory drugs
(ketoprofen, diclofenac, and flurbiprofen), from the lecithin based
organogels in treatment of rheumatic deseases (e.g., osteoarthritis
of the knee, lateral epicondylitis) (Burnham et al., 1998; Choukse
and Sangameswaran, 2012; Grace et al., 1999; Richards et al.,
2006). In spite of the promising potential of lecithin based
organogels as dermal and transdermal drug delivery vehicles,
several drawbacks are identified, including time consuming
preparation (Belgamwar et al., 2008; Murdan, 2005), a lack of
scientific knowledge on their physical stability, morphology,
molecular organization, specific interactions and internal mobility
of constituents (Shapiro, 2011; Vintiloiu and Leroux, 2008), and
scarcely characterized influence of carrier design variables on drug
release kinetics.
The subject of the current study was to develop liquid lecithin/
poloxamer 407 based gels (LLPBGs) and evaluate their potential as
carriers for topical administration of a model drug substance
ibuprofen (5% w/w). Ibuprofen is a weakly acidic propionic acid
derivative (pKa = 4.38) with a small hydrophobic molecule (Mr =
206; log Pn-octanol/water = 3.91) (Meloun et al., 2007). The solubility of
ibuprofen in water is extremely low in acidic media, but it is pH
dependent, and increases in neutral and moderately alkaline
aqueous media (Ghorab and Adeyeye, 2001; Glowka, 2000; Shaw
et al., 2005). Although peroral administration of this non-steroidal
Table 1
Composition of the prepared liquid lecithin (LL)/poloxamer 407 (P)/water (W) samples A–J.
Composition Sample
A B C D
Liquid lecithin (% w/w) 50.00 45.00 40.00 35.00
Poloxamer 407 (% w/w) 25.00 22.50 20.00 17.50
Water (% w/w) 25.00 32.50 40.00 47.50
181
anti-inflammatory drug for treatment of pain and inflammation is
effective, dose-dependent side effects, particularly gastrointestinal
irritation, are common in long-term therapy of rheumatic diseases,
osteoarthritis, and ankylosing spondylitis. Transdermal application
provides the possibility to reduce side effects while achieving
therapeutic drug concentrations in blood. However, skin perme-
ability for ibuprofen is low (Yano et al., 1986), and there is a
permanent research work on the development of novel carriers that
would enhance its transdermal delivery (Chen et al., 2006; Djekic
et al., 2012, 2011; Heard et al., 2003; Iervolino et al., 2000; Park et al.,
2000; Perioli et al., 2004; Saino et al., 2010; Stott et al., 1998;
Takahashi et al., 2002). This investigation focuses on characteriza-
tion of gelation process and morphology of the LLPBGs, and
assessment of physicochemical properties, physical stability and in
vitro drug release kinetics of ibuprofen from such carriers.
2. Materials and methods
2.1. Materials
The excipients used as the components of the investigated
LLPBGs were: liquid lecithin (Topcithin1 NGM, Cargill, USA),
poloxamer 407 (Kolliphor1 P 407, BASF, Germany), and water,
purified (Ph. Eur. 8.0 grade). Topcithin1 NGM comprises a
minimum of 60% w/w of phospholipids (phosphatidylcholine
min. 12% w/w, phosphatidylethanolamine min. 8% w/w, phospha-
tidylinositol min. 10% w/w, and phosphatidic acid max. 7% w/w),
dissolved in soy bean oil. The specified maximum viscosity of this
ingredient was 12.5 Pa s at 25  C. Sorbic acid and potassium sorbate
(Sigma–Aldrich, Germany) were used as preservatives for oil and
water phase of ibuprofen-loaded LLPBGs, respectively. Ibuprofen
(racemate) was a product of BASF, Germany, and obtained as a gift
from Galenika a.d., Serbia. The ingredients of the phosphate buffer
pH 7.2 (potassium dihydrogen phosphate and sodium hydroxide),
were purchased from Sigma–Aldrich, USA. All the substances were
used as received.
2.2. Design and characterization of LLPBGs
The initial stage in design of LLPBGs was a formulation study in
pseudo-ternary system comprising liquid lecithin, poloxamer
407 and water, at room temperature. Liquid lecithin was a
pseudo-component comprising phospholipids and soy bean oil
at a constant mass ratio of
1.5. After the formulation and
preparation, the selected LLPBGs were checked visually and
subjected to conductivity measurement, rheological behavior
characterization, and optical microscopy, in order to elucidate
their morphology and mechanism and dynamic of the gelation
process as a function of concentrations of water and gelators
(liquid lecithin and poloxamer 407), and temperature.
2.2.1. Formulation study in pseudo-ternary systems liquid lecithin/
poloxamer 407/water
Formulation study included preparation and examination of ten
samples (Table 1) which differed in terms of the concentration of
water, which was varied in the range of 25–62.5% w/w.
E F G H I J
33.30 30.00 28.75 27.50 26.25 25.00
16.70 15.00 14.37 13.75 13.13 12.50
50.00 55.00 56.88 58.75 60.62 62.50
182 L. Djekic et al. / International Journal of Pharmaceutics 490 (2015) 180–189
The corresponding concentration range of the mixture of liquid
lecithin and poloxamer 407 was 37.5–75% w/w. The mass ratio of
liquid lecithin and poloxamer 407 was 2.0 in all samples. The
samples were prepared by careful mixing of the appropriate
amounts of a solution of poloxamer 407 in water with liquid
lecithin. The water solutions of poloxamer 407 were prepared
previously, following the cold process preparation method
(Kolliphor1 P Grades, Technical Information 03_111136e-03,
2013), i.e., the required amounts of poloxamer 407 were dissolved
in water pre-cooled to a temperature of 5  3  C. For complete
dissolution of the copolymer, the solutions were stored in a
refrigerator for at least 12 h before use. The prepared pseudo-
ternary mixtures were stored in tightly closed glass containers for
24 h prior characterization.
2.2.2. Conductivity measurements
The conductivity (s ) of the samples was determined by using a
conductivity meter CDM 230 (Radiometer, Denmark) calibrated
before the measurements using a 0.01 M potassium chloride
solution. Measurements were carried out at a frequency of 94 Hz
and a temperature of 20  3  C.
2.2.3. Rheological measurements
Rheological measurements were performed for the selected
LLPBGs using rotational and oscillatory rheometer (Rheolab MC
120, Paar Physica, Stuttgart, Germany) coupled with the cone and
plate measuring device MK 22 (diameter 50 mm, 1 angle, gap
50 mm) and MK 24 (diameter 75 mm, 1 angle, gap 50 mm).
Rotational tests were performed at 10  0.2  C, 15  0.2  C,
20  0.2  C and 32  0.2  C, whereas oscillatory tests were per-
formed at 15  0.2  C, 20  0.2  C and 32  0.2  C. All the measure-
ments were performed in triplicate.
The CSR (controlled shear rate) procedure was selected for flow
curve evaluation. Continuous (rotational) flow tests were per-
formed by increasing a shear rate from 0 to 200 s1 and back to 0,
each stage lasting 100 s. Oscillatory (dynamic) measurements were
performed in order to determine linear viscoelastic region of the
samples (amplitude sweep). The investigations were carried out at
constant frequency of 1 Hz and amplitude sweep ramp from 0.6 to
100%. Afterwards, a frequency sweep ramp from 0.1 to 10 Hz was
performed at the constant strain of 1%, within the previously
determined linear viscoelastic region for all the samples. For the
yield point determination, an oscillatory stress sweep test at
constant frequency of 1 Hz was performed.
2.2.4. Optical microscopy
Morphology of the selected LLPBGs was observed in a thin layer
of the sample on a microscope slide, covered with a cover slip, by
using light microscopy system with fluorescence imaging (Olym-
pus System microscope BX50/Olympus Reflected Light Fluores-
cence Attachment BX-FLA, Japan). The image was captured with
attached digital camera (Sony Power HAD, 3CCD Color Video
Camera, DXC-950P model, Japan).
2.3. Preparation of ibuprofen—loaded LLPBGs
The selected LLPBGs were prepared and loaded with 5% w/w of
ibuprofen. The hydrosoluble preservative potassium sorbate (0.1%
w/w) was previously dissolved in water, at room temperature, and
the obtained solution was used further to prepare the solution of
poloxamer 407, in accordance with the cold process method, as
described earlier. Sorbic acid (0.1% w/w) was dissolved in the
required amount of liquid lecithin, at room temperature. The block-
copolymer solution was admixed to the previously measured
liquid lecithin, until the formation of a homogeneous system. The
drug substance was accurately measured and homogeneously
mixed with the prepared LLPBG carriers. The drug-loaded samples
were stored in tightly closed glass containers, for 24 h at room
temperature (20  3  C), and after that, the characterization tests
were carried out.
2.4. Characterization of ibuprofen—loaded LLPBGs
Characterization of the ibuprofen-loaded LLPBGs included
evaluation of organoleptic properties (color, odor, homogeneity,
spreadability and skin feel) and physical stability, and determina-
tion of their morphology, pH, conductivity, apparent viscosity, flow
behavior, and in vitro drug release profile. The morphology of the
samples was analyzed by light microscopy, as previously
described. Conductivity, apparent viscosity and flow behavior
were characterized by applying the same techniques and protocols
as described previously for the drug-unloaded LLPBGs.
2.4.1. Physical stability evaluation
The samples of ibuprofen-loaded LLPBGs were prepared and
stored in tightly closed glass containers, under ambient conditions
(20  3  C), for 30 days. Their physical stability was assessed by
organoleptic examination of color, odor, consistency, homogeneity
and spreadability on the skin surface, and by centrifugation test
using a laboratory centrifuge MPW 56/MPW (Med. Instruments,
Poland) for 2  15 min at a speed of 3000 rpm. The assessment was
performed after 48 h, 7 days, 14 days and 30 days. Simultaneously,
the second series of the investigated samples was prepared, and
they were exposed to the temperature cycling at 5  3  C (in the
refrigerator) (24 h), 20  3  C (ambient conditions) (24 h), and
40  2  C (in the thermostatic chamber) (24 h), during the ten
cycles, for a period of 30 days. During the temperature cycling, it
has been was observed whether the gel-to-sol and sol-to-gel
transitions occurred, at the temperatures of the refrigerator,
thermostatic chamber, or under the ambient conditions. The
duration of the physical stability assessment was set in accordance
with the recommendation of the USP Chapter 795 for beyond-
use date for nonsterile compounded water-containing topical/
dermal semisolid drug preparations in the absence of stability
information (not later than 30 days from the date when the
preparation is compounded).
2.4.2. pH measurement
The pH of the investigated samples was measured by a
pH-meter HI 9321 (Hanna Instruments, USA) at a temperature
of 20  3  C. Prior to the measurement of the pH value, the
apparatus was calibrated with the standard buffer solutions of pH
4.0 and 7.0.
2.4.3. In vitro drug release testing
In vitro testing of ibuprofen release was performed as the paddle
over ehancer cell method by using the 4 cm2 surface area
polytetrafluoroethylene (PTFE) enhancer cell (Vankel Industries,
Inc., USA) which was attached to a dissolution apparatus Erweka
DT 70 (Erweka, Germany). The precisely weighed amount (2.0 g) of
the ibuprofen-loaded LLPBG sample was placed into the cell and
covered with a regenerated cellulose membrane. The cell was
dipped into 750 ml of phosphate buffer pH 7.2 (the acceptor
medium) which was thermostated at 32  1  C and continuously
stirred (a paddle speed of 100 rpm) through the experiment. The
small volumes (
4 ml) of the acceptor medium were sampled each
hour during the period of 12 h and the concentration of the drug
substance in the collected samples was determined spectrophoto-
metrically (Evolution 300, Thermo Scientific, USA) at the
wavelength of maximum absorption of ibuprofen (l = 220 nm).
The test was performed in triplicate for each sample. The drug
release profiles were analyzed by applying model-dependent
 L. Djekic et al. / International Journal of Pharmaceutics 490 (2015) 180–189 183

approach including Higuchi, zero-order and first-order kinetics for a gel formation (i.e., at water content >60.62% w/w), the
mathematical equations. Release data was statistically analyzed formation of homogenous liquids was observed. In this case, after
using a one way ANOVA to determine significance of differences applying small amounts on an inert surface, at room temperature,
regarding the release rate and cumulative amount of the drug they were spread spontaneously. That may indicate a certain risk of
released after 12 h from the beginning of the experiment. spilling of such samples during the administration as well as out of
Statistical significance was set at p 0.01. the area of application. The samples which had most suitable
semisolid consistency and spreadability were F, G, H, and I, in
3. Results and discussion which the water concentration was ranged from 55% w/w to
60.62% w/w (surrounded by the blue line in Fig. 1).
3.1. Selection of LLPBGs from the pseudo-ternary mixtures liquid
lecithin/poloxamer 407/water 3.2. Influence of water content and temperature on gelation process in
LLPBGs
In order to elucidate the gelation process we have considered
the effect of the concentrations of the components on consistency In the prepared ten samples conductivity was measured and the
of the prepared pseudo-ternary mixtures liquid lecithin/polox- values are shown as a function of the water content (Fig. 2).
amer 407/water (A–J). Their appearance is presented in Fig. 1. The conductivity value increases gradually as the water concen-
The content of the water in the samples ranged from 25 to 62.5% tration increases within the range from32.5% w/w to 58.75% w/w. The
w/w, while the concentrations of lecithin (phospholipids) and conductivity of the samples with higher contents of water
poloxamer 407 ranged from
15 to 30% w/w, and 12.5 to 25% w/w, (W > 58.75% w/w) increases steeply, as illustrates the terminal
respectively. Thus, the phospholipids/poloxamer 407 mass ratio segment of conductivity-water concentration curve in Fig. 2.
was
1.2. The homogeneous systems formed within few minutes The maximum apparent viscosity of the samples was deter-
after addition of water under moderate mixing. The prepared mined and presented as a function of water concentration in Fig. 3.
samples were opaque, and their color and consistency varied from The apparent viscosity values decrease with increase in
dark ochre stiff semisolids to bright yellow soft semisolids, as concentrations of water up to approximately 30% w/w, however,
content of water increases from 25% w/w (A) up to 60.62% w/w (J) the values of this parameter remained almost unchanged in the
(Fig. 1). All mixtures had a mild odor of lecithin. The samples systems comprising 32.5–58.75% w/w of water. The apparent
prepared with less than 50% w/w of water had a darker color and
they were not suitable for gentle smearing on the skin. The
mixtures comprising water in concentrations >50% w/w, were
lighter in color and with softer consistency. The samples were
considered as gels if they were semisolids and do not spread
spontaneously over the inert surface when applied a small amount,
at room temperature. The minimum concentrations of lecithin and
poloxamer 407 required for formation of the homogenous system
with gel like consistency were 15% w/w and 12.5% w/w,
respectively. The results of recent study of Bhatia et al. (2013)
also indicate the critical importance of concentration of lecithin
and lecithin/poloxamer 407 mass ratio for formation of PLOs, and
they observed that the gel was formed at lecithin/poloxamer
407 mass ratio
2.33 and with the concentration of lecithin of 35%,
while at lecithin/poloxamer mass ratio 0.67 and lecithin content of
20%, there was no gel formation. The formulation of liquid lecithin/
poloxamer 407 based gel-like systems in the current study was
achieved with significantly lower level of amphiphiles at the Fig. 2. Conductivity of the investigated liquid lecithin/poloxamer 407 based
systems as a function of water content. The intersections of the linear regression
customized liquid lecithin/poloxamer 407 mass ratio of 2.0. At trend lines represents the positions of the first (W1) and the second (W2)
concentrations of the amphiphiles lower than minimum required percolation thresholds.

Fig. 1. The appearance of the prepared liquid lecithin (LL)/poloxamer 407 (P)/water (W) samples at room temperature. The appearance of the four samples selected for further
characterization is presented within the squares surrounded with the blue and red lines.
184 L. Djekic et al. / International Journal of Pharmaceutics 490 (2015) 180–189
Fig. 3. Apparent viscosity of the investigated liquid lecithin/poloxamer 407 based
systems as a function of water content. The intersection of the linear regression
trend lines represent the position of the percolation threshold W0.
viscosity values of the samples prepared with 60% w/w of water
were significantly decreased. For instance, values determined for
the sample prepared with 62.5% w/w of water (114 Pa s) was more
than 20 fold lower than for the sample comprising 25% w/w of
water (5.25 Pa s).
The described changes of conductivity and apparent viscosity
were interpreted by percolation theory, which is found suitable for
description of phenomenon such as structural transitions in
systems comprising oil phase, water phase and amphiphiles, under
continuous increase in content of the dispersed phase (Mehta et al.,
2009; Milner and Safran, 1987). Taking into account this point of
view, the segments of the conductivity and apparent viscosity
curves (Figs. 2 and 3, respectively) were analyzed by applying
linear regression in order to determine the critical concentrations
of water (i.e., percolation thresholds). The analysis of conductivity-
water concentration data revealed two percolation thresholds at
37% w/w (W1) and 57.5% w/w (W2) of water. It could mean that the
structure of the investigated liquid lecithin/poloxamer 407 based
systems gradually changes from the one that has the complex
organization with predominantly bound water molecules (at
W < W1), through structures with a fraction of free water (at water
contents W1 < W < W2), up to the structure with the large fraction
of free water and weak attraction between the dispersed phase in a
water continuous system (at W > W2). The apparent viscosity-
water concentration curve showed a percolation threshold (W0 ) at
57% w/w of water, which coincide well with the value of second
percolation threshold W2 which was determined from the
conductivity-water concentration data analysis. Although the
sharp decrease of apparent viscosity was observed as the
concentration of water was increased from 25% w/w to 32.5%
w/w, which was followed by the platou between 32.5% w/w and
W0, there were a lack of data in initial segment of maximum
apparent viscosity-water concentration curve for linear regression
analysis and determination of the position of the additional
percolation threshold. Bentley et al. (1999) reported in their study
that the increase in the lecithin content in PLOs, increase their
apparent viscosity. However, we observed the platou i.e., the
almost unaffected value of the apparent viscosity with the
concentrations of the gelators, which likely corresponded with a
gradually evolving structure in the investigated system. It is well
established that in aqueous solutions of poloxamer 407 above the
critical micellar concentration (CMC) and the critical micelle
temperature (CMT) micellization occurs, based on hydrophobic
interactions among polypropylene oxide (PPO) blocks which form
hydrophobic core, while the polyethylene oxide (PEO) blocks form
hydrophilic corona of the spherical micelles, available for hydrogen
bonding with surrounding water molecules. As reported (Castile
et al., 2001 Escobar-Chávez et al., 2006), CMT of poloxamer 407 at
infinite dilution is 29.23  0.39  C, and decreases linearly to

18  C as concentrations of the copolymer increase up to
10% w/v. Furthermore, at higher poloxamer 407 concentrations
(16–30% w/w), micelles can order into a lattice, and the gels formed
at room temperature. In the systems investigated in the present
study, at W < W1, concentrations of poloxamer 407 were >21% w/w.
In accordance with the previous data analysis, we proposed the
model of the structure of the investigated LLPBGs. It was
reasonable to consider that the block-copolymer used for
preparation of these samples was in the form of micelles or even
micelle aggregates. Generally, high conductivity indicate that the
water phase in the investigated systems has the characteristics of
the continuous phase. When solution of poloxamer 407 was mixed
with liquid lecithin, there was expected formation of associates of
the molecules of phospholipids and soy bean oil triglycerides,
which were immersed in the surrounding water phase. The
structure of the investigated systems at water concentrations
beyond the first percolation threshold (W1) up to the second
percolation threshold (W2), was related with the gradual increase
in the distances between the dispersed associates and formation of
percolative aqueous domains. The increase in conductivity and
almost unchanged viscosity between W1 and W2 may indicate an
increase in the mobility of the charge carriers in the system with
likely percolative network of water channels. The assumed
structural model was supported by observation of Ezrahi et al.
(1998) which put forward the claim that changes in the course of
percolative curves could be interpreted as a structural transfor-
mation (without phase inversion), during which increases the
mobility of the water phase and electrical conductivity.
Further increase of the concentration of water, beyond the second
percolation threshold, may induce gel-sol transition at 60% w/w
of water. At this stage, as the relative content of the amphiphiles
decreases, the hydrophobic interactions and hydrogen bonds were
weakened. Therefore, the concentration of the unbound water was
significantly increased, while the number of poloxamer
407 micelles decreased, and that reflected with enhanced
conductivity and suddenly decreased viscosity of the investigated
systems.
In order to elucidate morphology and the gelation process in the
investigated liquid lecithin/poloxamer 407 pseudo-ternary
systems, further investigation was focused on the sample H
near the second percolation threshold which was prepared with
58.75% w/w of water (surrounded by the red square in Fig. 1), by
applying light microscopy and rheological characterization. The
photomicrographs of the investigated LLPBG sample are presented
in Fig. 4.
The photomicrograph in Fig. 4a revealed the homogeneous
structure with highly concentrated dispersed phase surrounded by
the aqueous phase, which was observed as brighter network or
channels throughout the sample. Additionally, microscopic as-
sessment was performed in the sample which was diluted with
water up to W 95% w/w, and as presented in Fig. 4b–c, the
dispersion of the spherical or oval entities in water was detected.
The size of the entities was on a micro-scale and it was up to 10 mm.
The related study of Bentley et al. (1999) described the formation of
micellar structures following the addition of lecithin into the
poloxamer 407 based gels, while Nakagawa et al. (2012) suggested
the bilayer geometry of associates of phospholipids and hydro-
phobic molecules in the presence of water phase. The results
obtained in this study, particularly in Fig. 5c, pointed that the
structure of the dispersed entities was vesicular and most likely
oligolamellar. Furthermore, the latter results confirmed the
previous assumption that the structure of the investigated LLPBGs
was water continuous and that they were suitable for dilution with
 L. Djekic et al. / International Journal of Pharmaceutics 490 (2015) 180–189
Fig. 4. Photomicrographs of the LLPBG H prepared with 58.75% w/w of water: (a)
undiluted (magnification 1000); (b) diluted with water (W 95% w/w) (magnifica-
tion 400); (c) diluted with water (W 95% w/w) (magnification 1000).
increase in water content (i.e., decrease in liquid lecithin and
poloxamer 407 concentrations), without compromising molecular
organization of the dispersed phase.
Rheological characterization of the sample H at different
temperatures, revealed the non-Newtonian, shear thinning flow
behavior (Tadros, 2004), with a moderately (at 10  C and 15  C), or a
significantly pronounced (at 20  C and 32  0.2  C) thixotropy
(Fig. 5).
The significant influence of storage temperature on investigated
rheological parameters could be clearly seen (Table 2).
The most significant change in maximal apparent viscosity was
observed at lower temperatures (10  C and 15  C), while it was less
pronounced at higher storage temperatures (20  C and 32  C).
Considerably larger hysteresis area at higher temperatures
indicated the enhancement of gel strength (Lee et al., 2009).
Furthermore, at 10  C was observed a drastic reduction in viscosity
(i.e., the consistency of the sample was transformed from gel to
185
sol). Although rotational experiments provide information con-
cerning the flow properties of a system such as apparent viscosity,
thixotropy, and steady flow curve, they are only a part of the
complete rheological characterization. The more detail analysis of
temperature influence on rheological properties was performed
using dynamic rheology. Dynamic oscillation testing is a much
more powerful tool for revealing the microscopic structure of a
viscoelastic material. This test was not applicable at 10  C due to
gel-to-sol transition of the investigated sample. The comparative
plots of the storage (G0 ) and viscous—loss (G00 ) moduli at 15  C,
20  C, and 32  C, as a function of the oscillation frequency sweep,
are shown in Fig. 6.
It could be seen that G0 was higher than G00 at 20  C and 32  C and
that both moduli were independent of the oscillation frequency,
suggesting that the molecules of phospholipids, triglycerides and
poloxamer 407 act as true gelators in the investigated LLPBG. On
the other hand, at 15  C, gel structure was weakening since loss
modulus was above storage modulus and slightly increasing with
increasing frequency. The values of elastic – storage (G0 ) modulus,
viscous – loss (G00 ), complex (G*) modulus and tan d different
temperatures at 1.13 Hz are listed in Table 3.
Dynamic tests showed that the increase in G0 , G00 and G* values
with increasing temperature (15  C < 20  C < 32  C) followed the
same order as the increase in apparent viscosities obtained in
rotational measurements (Table 2), indicating that the LLPBG
became stronger as the temperature increased. The significant
increase in elasticity when the temperature was increased from
15  C to 20  C was related with the thermoreversible sol-to-gel
transition. As reported, aqueous solutions comprising 16–30% w/w
of poloxamer 407 have the characteristic of reverse thermal
gelation (sol-to-gel transition) upon warming up to the temper-
atures in the range of 30–60  C (Kolliphor1 P Grades, Technical
Information 03_111136e-03, 2013). Although the concentration of
poloxamer 407 in the investigated LLPBG sample was 13.75% w/w,
it was sufficient for thermoreversible phenomenon, likely due to
the simultaneous influence of lecithin on rheological behavior of
the system. Han et al. (2013) described organogels from lecithin,
sitosterol, and sunflower oil, which became stronger at higher
storage temperatures (25  C), than at lower storage temperatures
(5  C and 15  C) due to formation of internal elastic structure. We
assumed that the observed gel/sol transitions in the investigated
LLPBG were based on thermally dependent competition between
the hydrophobic interactions among the PPO chains of the
copolymer and lipid molecules, on the one side, and hydration
of POE chains of the copolymer, on the other side. At lower
temperatures, POE interaction with water prevailed, the gel
strength was decreased, and it transformed into a liquid state.
At higher temperatures, the hydrogen bonds established between
water and hydrophilic chains of the copolymer, were reduced,
while the enhanced hydrophobic association and interactions lead
to gelation. The presence of lipid molecules shifted the gelation
temperature to the lower temperatures, in comparison with the
pure poloxamer 407 solutions, thus at room temperature (
20  C)
the LLPBG was soft semisolid suitable for topical application, but at
the skin surface (32  C) the gel becomes slightly stronger.
3.3. Physicochemical properties of the ibuprofen-loaded LLPBGs
With the aim to elucidate the drug carrier performances of the
liquid lecithin/poloxamer 407 based gels, further investigation was
focused on the selected LLPBGs, which were prepared with water
concentration of 55% w/w (F), 56.88% w/w (G), 58.75% w/w (H), and
60.62% w/w (I). The model drug ibuprofen was incorporated by
dispersing into the previously prepared gels. The incorporation of
ibuprofen did not affect the color, odor, consistency and
homogeneity in comparison with the drug-unloaded carriers.
186 L. Djekic et al. / International Journal of Pharmaceutics 490 (2015) 180–189

The ibuprofen-loaded LLPBGs samples which were stored at

room temperature (20  3  C) did not change in terms of
organoleptic characteristics as well as after centrifugation. Storage
of the second series of the ibuprofen-loaded LLPBGs samples at
40  2  C, also did not changed their organoleptic features. As
expected from the observations of previous rheological character-
ization, after storing at 5  3  C, a reversible transformation from
gel to sol state was observed for all samples. When they were again
held at room temperature, they transformed from sol to gel and
their consistency was as the original, without signs of phase
separation or drug precipitation. The investigated ibuprofen-
loaded LLPBGs showed thermoreversibility under the cyclic
temperature changes, while their physical stability was regarded
as satisfactory. Their texture and consistency at ambient conditions
were suitable to be spread easily over the skin, while at a skin
temperature of the application site, their rheological properties
Fig. 5. Rheograms of the LLPBG H prepared with 58.75% w/w of water at different changes so that the risk of an undesirable smearing on the larger
temperatures (10  C (&), 15  C (&), 20  C (~), and 32  C (D)). surface area is reduced. Additionally, storage on the lower
temperatures may allow the softening of the gel, which becomes
Table 2 suitable for application on large areas.
Values of maximal (hmax) and minimal (hmin) apparent viscosity, yield stress (s 0) Microscopic examination of the ibuprofen-loaded LLPBGs
and hysteresis area of the LLPBG prepared with 58.75% w/w of water at different revealed the uniform dispersion of individual crystals of ibuprofen
temperatures (T). suspended within a homogenous carrier. For example, Fig. 7
T ( C) hmax (Pa s) hmin (mPa s) s0 Hysteresis area illustrates the photomicrographs of the ibuprofen-loaded
D = 4.1 s1 D = 200.0 s1 (Pa) (Pa/s) sample H, in undiluted state and after dilution with water
10 3.7  0.2 1.35  0.08 n/aa 830  5 (up to W 95% w/w).
15 80  2 4.9  0.1 62 190  10 The photomicrograph recorded on the diluted ibuprofen-
20 170  20 4.7  0.8 510  10 50140  2000 loaded LLPBG H (Fig. 7b) shows the undisturbed structural
32 220  10 6.3  0.9 620  20 58260  3000
organization of the carrier and absence of agglomeration the drug
a
Not applicable.

Fig. 6. Effect of temperature on G0 (filled symbols) and G00 (open symbols) modulus
for the LLPBG H prepared with 58.75% w/w of water, at 15  C (~ and D), 20  C (&
and &), and 32  C (* and ), during a frequency scan from 0.1 to 10 Hz.

Table 3
The elastic – storage (G0 ) modulus, viscous – loss (G00 ), complex (G*) modulus and
tan d for the LLPBG prepared with 58.75% w/w of water, at different temperatures at
1.13 Hz.

T ( C) G0 (KPa) G00 (KPa) G* (KPa) tan d

15 0.17  0.005 0.24  0.01 0.29  0.01 1.40  0.05
20 16.0  0.8 1.29  0.06 15.3  0.7 0.08  0.01
32 18.2  0.7 1.31  0.05 18.3  0.9 0.07  0.01

They were soft and aqueous in touch, without visible particles,

lumps or air bubbles. Ibuprofen-loaded LLPBGs were also easy
spreadable on the skin, with smooth and cool feel, without visible
Fig. 7. Photomicrographs of the ibuprofen-loaded LLPBG H:(a) undiluted, and (b)
residues or occlusion. diluted with water (W 95% w/w) (magnification 100).
 L. Djekic et al. / International Journal of Pharmaceutics 490 (2015) 180–189
particles. By adding of water in excess (W 95% w/w), the sample
was simply diluted and the structure of the dispersion of
supramolecular associates was not disturbed.
The results of determination of physicochemical parameters
(pH, the conductivity and the apparent viscosity values) of the
ibuprofen-loaded samples, with and without ibuprofen, are
presented in Table 4.
The pH values of the investigated drug-unloaded and ibupro-
fen-loaded LLPBGs were in the range of 5.57–5.70, and 5.30–5.35,
respectively, which are well within the physiological pH range of
human skin (typically from 4.5 to 6.0) (Chikakane and Takahashi,
1995). Regrading the pH values, ibuprofen-loaded LLPBGs were
acceptable for topical administration without the addition of the
pH adjusting agents. The pH values in the presence of ibuprofen
were slightly decreased, while the conductivity was significantly
increased. The latter observation was ascribed to the ionisation of
the dissolved fraction of the ibuprofen molecules which increased
the level of hydrogen ions as well as the overall content of the
charge carriers within the water phase of the LLPBGs. The
investigated ibuprofen-loaded LLPBGs also had shear thinning
plastic flow behavior with thixotropy, which was observed for the
corresponding drug-unloaded LLPBGs. The drug loading has
increased apparent viscosity in all samples (Table 4). The increase
in apparent viscosity was primarily the result of dispersing the
solid substance in the vehicle at a relatively high concentration.
However, also it was assumed that the solubilization and
penetration of the hydrophobic molecules of ibuprofen within
the phospholipid bilayers, could affected their size, number and
strength of mutual interactions, thus affecting the apparent
viscosity. As reported, solubility of ibuprofen in soybean oil is

9 % w/w, however in aqueous solution of poloxamer 188 is less
than 0.1% (Roni and Jalil, 2011; Zaghloul et al., 2011). From the
results of physicochemical characterization of the ibuprofen-
loaded LLPBGs and related literature data, it was concluded that
most of the incorporated amount of ibuprofen was suspended,
while the small fraction was in the molecular state, mainly
solubilized within the phospholipide associates and partially
dissolved in the continuous water phase.
3.4. Drug release kinetics from ibuprofen-loaded LLPBGs
Model dependent analysis of the release profiles shows that the
ibuprofen release was in accordance with the Higuchi model
(rH > 0.95), wherein the amount of released substance (Qt) linearly
depended on the square root of time (t), and the slope of the curve
(kH) is the rate constant of the drug, according to the Eq. (1):
pffiffi
Q t ¼ kH t (1)
The release profiles of ibuprofen from the tested LLPBGs F, G, H,
and I, are shown as cumulative amount of the released drug as a
function of square root of time in Fig. 8.
This release model describes a system in which: (1) the drug is
suspended in a carrier matrix, i.e., the initial concentration of the
drug substance is much higher than its solubility; (2) swelling and
Table 4
Physicochemical characterististics (pH, conductivity (s ), and apparent viscosity (h))
for the investigated drug-unloaded and ibuprofen-loaded LLPBGs.
Sample pH pHIB s s IB h hIB
(mS cm1) (mS cm1) (Pa s) (Pa s)
F 5.67 5.35 456 744 34.1  0.6 100.3  2.2
G 5.71 5.33 580 983 31.2  0.7 94.9  1.9
H 5.70 5.30 620 1089 30.5  0.4 86.9  1.5
I 5.57 5.32 794 1147 15.5  0.2 41.7  1.3
187
Fig. 8. The drug release profiles for the investigated ibuprofen-loaded LLPBGs (F: ,
G: , H: , I: *).
dissolution of the carrier matrix is negligible; and (3) the dissolved
drug substance is released from the carrier by diffusion with the
diffusion rate which is characteristic of the system. The parameters
of the ibuprofen release kinetics are summarized in Table 5.
The ibuprofen release rate (kH) ranged from 992 to
1215 mgh0.5cm2. One way ANOVA test showed that at the end
of the in vitro assessment there was no significant difference
(F < 7.6; p > 0.01) regarding the release rate (F 1.2) and total amount
of the drug released (F 2.1) from the investigated LLPBGs. Although
without statistical significance, the release rate and the cumulative
amount of ibuprofen released after 12 h (Q12h) were slightly
increased as the water concentration in the carrier increases, and
their apparent viscosity values were decreased. Several related
studies also have shown that the diffusion coefficient of the drug
substance from the gels on the basis of poloxamer 407 decreases
with increasing polymer content due to an increase in the viscosity
and thixotropy of the gel, while in vitro release rate of lipophilic
drugs was reversely correlated with the lecithin concentration in
lecithin organogels (Bentley et al., 1999; Nasser et al., 2003; Pandey
et al., 2009; Surjyanarayan et al., 2010; Vintiloiu and Leroux, 2008).
In line with these reports, as water concentration in the samples
increases, and the concentration of the gelators decreases, their
strength and apparent viscosity decrease, while thermodynamic
activity of ibuprofen molecules within the carrier may enhances.
However, the release of ibuprofen molecules from the investigated
LLPBGs was slow and sustained for 12 h, generally. There was taken
into account the thermally induced increase in viscosity of the
LLPBGs, due to their thermosensitivity, in the initial phase of the in
vitro release test performance. Furthermore, the results of
evaluation of the LLPBGs morphology revealed that the differences
in water content among the investigated LLPBGs, may have only
small influence on their capacity for solubilization of ibuprofen.
Additionally, penetration of water molecules from the acceptor
medium, during the in vitro release test, could not affect
Table 5
Parameters of ibuprofen release kinethics (release constant (kH), cumulative
amount of drug released after 12 h (Q12h), and correlation coefficient for Higuchi
drug release model (rH)) for the investigated LLPBGs.
Sample kH Q12h rH
(mg h0.5 cm2) (%)
F 992 13.3 0.9794
G 1063 14.4 0.9868
H 1122 15.2 0.9866
I 1215 16.45 0.9926
188 L. Djekic et al. / International Journal of Pharmaceutics 490 (2015) 180–189
significantly the capacity of the carriers for ibuprofen solubiliza-
tion. Finally, the concentration of ibuprofen which was dissolved in
the aqueous phase of the gel, maintained constant due to a
chemical equilibrium with the suspended drug particles. In this
way the designed LLPBGs were classified as controlled drug release
carriers, which could provide the prolonged release of ibuprofen at
a constant rate.
4. Conclusion
Liquid lecithin with
60% w/w of phospholipids dissolved in
soybean oil, combined with poloxamer 407, at the mass ratio of 2.0,
can be used for the preparation of gels upon addition of water in
the concentration range from 25% w/w up to 60.62% w/w, at room
temperature. They were concentrated dispersions of oligolamellar
vesicles of phospholipids and soybean oil constituents in an
aqueous solution of the block-copolymer. The systems were
physically stable in the temperature range of 5  3  C to
40  2  C, which is common for the storage and application of
pharmaceuticals. Their rheological behavior depend on the
temperature and concentration of liquid lecithin and poloxamer
407, most likely due to variations in the degree of hydrophobic
interactions in the system. The sol/gel transition occurred near
15  C, and with increasing temperature, increases the viscosity and
thixotropy of the system, providing retention at the site of
application. The structure of the systems was unaltered within the
temperature range from 5 to 32  C as well as upon dilution with
water up to 95% w/w. The in vitro release profiles obtained for
LLPBGs comprising 55–60.62% w/w of water demonstrated
ibuprofen release controlled by the carrier. Release kinetics was
in accordance with the Higuchi model for at least 12 h. The
optimized LLPBG, regarding both, drug release and organoleptic
properties, was prepared with 58.75% w/w of water. The obtained
results encourage further evaluation of the designed LLPBGs
potential for improvement of percutaneous drug delivery.
Acknowledgements
This study was financially supported by the Ministry of
Education, Science and Technological Development as a part of
the projects III 46010 and TR 34007. The authors are also thankful
to BASF (Germany) and Cargill (USA) for their kind donation of the
pharmaceutical excipients used in this study.
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