a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 8 ( 2 0 1 3 ) 4 8 e5 7

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Original Research Paper

Organogels, hydrogels and bigels as transdermal delivery

systems for diltiazem hydrochloride

Mahmoud Mokhtar Ibrahim a,b,*, Salma A. Hafez a, Mahmoud M. Mahdy a

a
Department of Pharmaceutics, Faculty of pharmacy, Zagazig University, Zagazig, Egypt
b
Department of Pharmaceutics, Faculty of Pharmacy, Najran University, Najran, Saudi Arabia

article info abstract

Article history: In the present study, gel formulations of organogels, hydrogels, and oleo-hydrogel (bigels)
Received 16 January 2013 were evaluated as transdermal drug delivery systems for diltiazem HCL (DH). Organogels were
Received in revised form prepared using soya-bean oil (SO) as a solvent and span 60 (Sp 60), cetyl alcohol (CA) or lecithin-
10 February 2013 pluronic (PLO) as organogelators without and with different surfactants (2% w/w) namely span
Accepted 15 February 2013 80 (Sp80), tween 20 (T20) and tween 80 (T80). On the other hand, hydrogels were formulated
using Hydroxypropyl-methylcellulose (HPMC) polymer and bigels were prepared by mixing
Keywords: organogels with HPMC hydrogels. The prepared gels were analyzed microscopically, ther-
Organogels mally by DTA and for pH, and viscosity. The effect of gelator used, surfactant types and pH of
Hydrogels the sink on DH release from cellophane membrane was investigated. In addition, the DH
Bigels permeability across the rabbit skin was evaluated. Finally, the in vivo performance of various
Lecithin gel formulations was assessed based on the hypotensive effects of the drug using hypertensive
Span albino male rat models. The microscopical analysis indicated that the solid fibers formed by
gelator particles form the backbone of the organogels while bigels appeared as emulsion like.
The addition of surfactants showed an increase in organogel viscosity. The thermal analysis of
organogels indicated that the drug present in amorphous not in crystalline form. The release
studies indicated that DH release from organogels, hydrogels and bigels could be controlled.
The included surfactants decreased the DH release and permeation from organogels
compared to those without surfactants using either Sp60 or CA. HPMC hydrogel and Bigels
showed higher DH release and permeation rates when compared to organogels. The percent
DH released in different pH values was in the following descending order:
pH5.5>pH1.2>pH6.8>pH7.4. The in vivo antihypertensive activity of DH using different
transdermal gels is arranged as following: hydrogels > PLO organogel > bigel> Sp 60 organogel.
ª 2013 Shenyang Pharmaceutical University. Production and hosting by Elsevier B.V. All
rights reserved.

* Corresponding author. Department of Pharmaceutics, Faculty of pharmacy, Zagazig University, Zagazig, Egypt. Tel.: þ20 552303266.
E-mail address: mahmoud_dsky@zu.edu.eg (M.M. Ibrahim).
Peer review under responsibility of Shenyang Pharmaceutical University

Production and hosting by Elsevier

1818-0876/$ e see front matter ª 2013 Shenyang Pharmaceutical University. Production and hosting by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ajps.2013.07.006
 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 8 ( 2 0 1 3 ) 4 8 e5 7
1. Introduction
The development of new drug molecules is time consuming
and expensive. On the other hand, the existing marketed and
patented drug substances with known therapeutic effects can
be used with the modification of their pharmacotherapeutic
characteristics. This was achieved by incorporating the drug
in a suitable drug delivery system [1]. Diltiazem HCl (DH) is a
calcium channel blocker belonging to the benzothiazepine
family. It is widely prescribed for the treatment of hyperten-
sion and angina [2]. Although DH is well absorbed from the
gastrointestinal tract, it undergoes substantial hepatic first-
pass effect. Therefore, DH elimination half-life is very short
(3e4.5 h) and frequent administration of the drug required to
maintain therapeutic effect. The drug dosage is reported to be
30 mg 4 times a day and may increase as necessary up to
360 mg/day in divided doses in order to maintain adequate
plasma levels [3]. Transdermal application of the drug was our
target of this investigation to minimize the frequency of DH
administration and overcome its side effects after oral
administration of conventional dosage forms.
The transdermal route of drug administration is definitely
one of the potential routes for local and systemic delivery.
This route provides a controlled diffusion of drugs into the
systemic circulation, breaks many barriers in medical therapy
like the need of assistance, intermediate dosing and uncom-
fortable administration and improves patient compliance
[4,5]. In general, gel-based products may be categorized either
as hydrogels or organogels depending on the polarity of the
external liquid component. Water is the external liquid
component of hydrogels while organogels were formulated
using non-polar solvents such as hexane, isopropyl myristate,
sunflower oil, corn oil or others.
Hydrogels are prepared using natural or synthetic hy-
drophilic polymers which form a colloidal network of
polymer chains in water. They possess a degree of flexibility
which is very similar to natural tissue. Moreover, hydrogels
are of many uses such as essential controlled drug delivery
systems, in cell culture, dressing for healing of wounds.
Their easy way of preparation and availability made them of
high value in the pharmaceutical field [6]. On the other
hand, the use of organogel based products is increasing due
to their easy method of preparation and inherent long-term
stability [7]. Depending on the mechanism of the formation
of the three dimensional gel skeleton, the organogels are
considered as fluid-filled structures and solid-fiber based
gels [8]. They are thermoreversible and have the ability to
accommodate both hydrophilic and hydrophobic com-
pounds within the gel structure. This property has also
widened the scope of the organogels uses as controlled drug
delivery systems which can be taken via several routes of
administration. The gelators which compose the major
skeleton of an organogel are generally amphiphilic sub-
stances, such as sorbitan monostearate (Sp60) and sorbitan
monopalmitate (Sp40). Moreover, Lecithin organogels can be
obtained by the addition of a critical amount of water to its
non-aqueous solutions [9]. Recent reports have also sug-
gested the incorporation of synthetic polymers (e.g. Plur-
onics) into Lecithin organogels as cosurfactants and
49
stabilizers that makes gelation feasible with lecithin of a
relative lower purity. The formulation has referred to as
Pluronic lecithin organogels (PLOs) [10]. Oleogel/hydrogel
mixtures (bigels) were also synthesized as topical formula-
tions based on mixing hydrogels (aqueous systems) with
oleogels (lipophilic systems) [11]. The aim of the present
investigation was to enhance the transdermal permeability
of the highly water soluble drug DH. Different gel types
namely hydrogels, organogels and bigels were formulated
and subjected to in vitro evaluation. The drug hypotensive
effects were also assessed after transdermal application of
DH gels on hypertensive rat models.
2. Materials and methods
2.1. Materials
Diltiazem HCl (DH) was a gift from Egyptian Pharmaceutical
industrial company (E.P.I.Co), Egypt. Sp60, Sp80, T20, T80, CA,
Pluronic F127, HPMC, and SO were purchased from Sigma
chemical Co., St. Louis, MO, USA. The Epikuron 200 phospho-
lipids (>92% SPC) were a gift from Lucas Meyer, Hamburg, Ger-
many. All other chemicals were of analytical grades and
obtained from the El-Nasr Company for pharmaceutical chem-
icals, Cairo, Egypt.
2.2. Gels preparation
Different organogels, hydrogels and bigels were prepared by
different procedures which are briefly described below and
the formulations are listed in Table 1. The final DH concen-
tration was adjusted to be 150 mg/g in all the formulations.
2.2.1. Organogels
Organogels were prepared by dissolving 10% w/w of Sp60 or
CA in SO vehicle into the SO in wide mouth vials, without or
with additional 2% w/w of different surfactants such as Sp80,
T20 or T80. The vials were kept in a water bath at 60  C, until a
homogenous clear solution was obtained. The hot solutions
were allowed to cool down at room temperature so as to allow
organogel formation.
150 mg of DH was loaded into each 1 g of the organogel
formulations by the mixing 0.2 ml of heated DH (60  C) solu-
tion (750 mg/ml) in distilled water with the surfactant hot oily
solution while magnetic stirring at 500 rpm. The mixture was
allowed to cool giving the medicated organogel formulas [12].
2.2.2. PLO gels
The aqueous phase (10% w/w Pluronic F127 solution in water)
of PLO was prepared by the cold process reported by Murdan
[10]. PLO gels were obtained by adding the oil phase (solution
of PC in SO) to the aqueous phase with vigorous stirring. The
hydrophilic DH solution was added to the aqueous phase with
stirring before the addition of the oil phase [10].
2.2.3. Hydrogels
HPMC hydrogels were prepared by allowing the weighed
quantities of HPMC (10% w/w) to be soaked in distilled water
50 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 8 ( 2 0 1 3 ) 4 8 e5 7

Table 1 e Composition and proportion of different gel formulation.

Formulation Concentration of various compositions (w/w) (Total weight ¼ 10 g)

Sp60 CA Sp80 T20 T80 Lecithin Pluronic HPMC SO Water DH Solution

(g) (g) (g) (g) (g) (g) (g) (g) (g) (g) (750 mg/ml)

Sp60/SO organogel 1 e e e e e e e 7 e 2
Sp60/Sp80 orgaanogel 1 e 0.2 e e e e e 6.8 e 2
Sp60/T20 organogel 1 e e 0.2 e e e e 6.8 e 2
Sp60/T80 organogel 1 e e e 0.2 e e e 6.8 e 2
CA/SO organogel e 1 e e e e e e 7 e 2
CA/Sp80 organogel e 1 0.2 e e e e e 6.8 e 2
CA/T20 organogel e 1 e 0.2 e e e e 6.8 e 2
CA/T80 organogel e 1 e e 0.2 e e e 6.8 e 2
PLO e e e e e 1 0.5 e 4 2.5 2
HPMC hydrogel e e e e e e e 1 e 7 2
Sp60/HPMC bigel 0.5 e e e e e e 0.5 2.5 4.5 2
Sp60/Sp80/HPMC bigel 0.5 e 0.1 e e e e 0.5 2.4 4.5 2
Sp60/T20/HPMC bigel 0.5 e e 0.1 e e e 0.5 2.4 4.5 2
Sp60/T80/HPMC bigel 0.5 e e e 0.1 e e 0.5 2.4 4.5 2
CA/HPMC bigel e 0.5 e e e e e 0.5 2.5 4.5 2
CA/Sp80/HPMC bigel e 0.5 0.1 e e e e 0.5 2.4 4.5 2
CA/T80/HPMC bigel e 0.5 e e 0.1 e e 0.5 2.4 4.5 2

for a period of 2 h until complete hydration and gel formation.
DH solution (750 mg/ml) was added to the dispersions with
continuous stirring until homogenous gel was formed and the
drug concentration was adjusted to be 150 mg/1 g.
2.2.4. Bigels
The prepared gels were stored separately at 4  C for at least
24 h, then bigels were prepared by mixing HPMC hydrogels
with the Sp60 or CA organogels (1:1 w/w) prepared without or
with different surfactants.
2.3. Microscopic study
A compound optical microscope (Olympus B 41) was used for
analyzing the microstructure of the organogel, hydrogel and
bigels. Attempts were used to understand the mechanism of
the gel formation by varying the composition and proportion
of the ingredients used and analyzing their microstructure.
2.7. In vitro release study
In vitro release of DH from different gel formulations was per-
formed using shaker water bath (Serve well Instruments and
Equipment, Pvt. Ltd. India) maintained at temperature of
32  C  1  C and allowed to agitate at 50 rpm. One gram of the gel
was weighed in plastic holders then attached to a permeation
cell previously specified by Mahmoud et al. and covered with
the cellophane membrane (soaked in phosphate buffer pH 5.5
for 24 h before use) [14]. The cell was immersed to the depth of
1 cm below the surface of the phosphate buffer (pH 5.5) in the
receptor compartment (50 ml). Samples of 3 ml each from the
receptor compartment was taken at various time intervals of
15, 30, 60, 120, 180, 240, 300 and 360 min and assayed for DH at
237 nm using UVeVisible Spectrophotometer (Shimadzu-UV-
1201, Japan). To maintain sink condition, the sample volume
was replaced with equal volume of the fresh buffer maintained
at 32  C. Each experiment was carried out in triplicate.

2.4. Thermal analysis

Thermal properties of organogels were studied using differ-
entials thermal analysis (TA-50 thermal analyzer, Shimadzu,
Japan). Samples were heated from 0  C up to 600  C, at a rate of
6  C/min.
2.5. pH measurement
The pH of the organogel, hydrogel and bigel samples was
detected by using digital pH meter (Cole-parmer instrument
Co., U.S.A). The pH of the gels was measured by bringing the
probe of the pH meter in contact with the sample [13].
2.6. Determination of viscosity
The viscosity of all the gel formulations was determined by
using Visco Star-R FUNGILAB viscometer, sample spindle (R6)
and speed of 10 rpm at 25  C. The value of the viscosity is
displayed in the form of cP.
2.8. In vitro skin permeation studies
Abdominal skin of male rabbits (2e2.5 kg) was used in this
study. Before the permeation study, the skin was hydrated in
phosphate buffer pH 5.5 at 4  C overnight and the adipose
tissue layer of the skin was removed by rubbing with a cotton
swab [15]. The permeation experiments were run by using the
same cells previously described in the in vitro release studies
but the abdominal rabbit skin rather than semi-permeable
cellophane membrane was used to cover the gel preparation
with the stratum corneum side face [16]. The experiment was
continued as described above. The cumulative amount of DH
permeated per unit surface area was plotted vs. time.
2.9. In vivo study of DH as transdermally applied
antihypertensive agent
This study was done using adult albino male rats weighing
250e300 g obtained from the animal breading center, Faculty
 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 8 ( 2 0 1 3 ) 4 8 e5 7
of Veterinary medicine, Zagazig University, Egypt. Animals
were treated according to Ethical committee of animal
handling in Zagazig University “ECAHZU”. Firstly, hyperten-
sion was induced in rats by complete left renal artery ligation
according to the method described by Cangiano et al. [17].
Postoperatively, the rats were given penicillin G (100,000 units
I.M.) per rat for three successive days, and were allowed free
access to food and water for 28 days till the complete induc-
tion of hypertension [18]. In vivo studies were done using DH
formulations of Sp60/SO organogel, HPMC hydrogel, PLO and
Sp60/HPMC bigel to evaluate their antihypertensive effects
when administered transdermally. Results were compared
with that of the non treated rats as negative controls and
those administered oral DH solution as positive controls.
Animals were divided into six groups as listed in Table 2. Each
group consisting of six rats (n ¼ 6) and allowed the application
of 0.2 g of different gel formulations which containing 30 mg of
DH on the hairless skin of the abdomen region (about 4 cm2 in
size). The negative control group was received placebo
hydrogel free from drug. The positive control group (300 g
weighed rats) received the dose of 0.027 ml of oral DH solution
which containing 2.025 mg of DH.
The oral dose calculated according to Paget’s equation [19]:
The therapeutic dose for rat weighing 200 g
18  Adult human therapeutic dose ð75 mgÞ
¼ ¼ 1:35 mg
1000
On the other hand, according to Fick’s first low, the drug
efflux increased across the skin as the concentration gradient
increased [20]. To reach the maximum thermodynamic ac-
tivity, the drug concentration in the donor compartment
applied transdermally must be maximum or in the saturation
state. Accordingly, DH concentration in the transdermal gels
to be tested was kept as high as possible (30 mg/0.2 g gel).
The blood pressure measurements were done using
Oscillograph (Washington, 400 MD 4C, Bio Science, Sheerness,
Kent, U.K) at time intervals from 0 to 6 h. The rats were
anaesthetized with urethane (ethyl carbamate) in a dose of
1.75e2.0 g/kg body weight then injected I.P as 25% freshly
prepared aqueous solution. Intra arterial cannulation was
done and the systemic arterial blood pressure was recorded
and the blood pressure of rats was determined employing the
method of Burden et al. [21].
Table 2 e Classification of in vivo transdermal and oral
groups.
Groups Formulation
Group (I) Control and received placebo gels
free from drug (ve control).
Group (II) Received 0.2 g of Sp60/SO organogel
which containing 30 mg of DH.
roup (III) Received 0.2 g PLO about which
containing 30 mg of DH.
Group (IV) Received 0.2 g of SP60/HPMC bigel
which containing 30 mg of DH.
Group (V) Received 0.2 g of HPMC hydrogel
which containing 30 mg of DH.
Group (VI) Received 0.027 g of oral solution
which containing 2.025 mg of DH (þve control)
51
The antihypertensive effects of the selected formulations
were studied after induction of hypertension into rats and the
results were compared to that of the control (group I). For
in vivo performance, gels which showed the highest release
rates both through the cellophane membrane and the
permeability across rabbit skin were selected. The antihy-
pertensive activity was studied at different time intervals after
application (1, 2, 3, 4, 5 and 6 h) to differentiate between the
onset of action of the oral DH solution and transdermal gel
formulations. The mean arterial blood pressure was calcu-
lated according to the following equation [22]:
Mean arterial B:P ¼ Diastolic B:P
ðSystolic B:P  Diastolic B:PÞ
þ
3
2.10. Statistical analysis
All values were expressed as mean  SD. Data were analyzed
statistically using one way analysis of variance (ANOVA) test.
The level of significance was considered at P < 0.05.
3. Results and discussion
Different organogelators were dissolved in the hot oil phase
until a clear homogenous solution was obtained. As the tem-
perature cooled down, the gelators precipitated in the oil due to
changes in the solubility parameters. The precipitated gelators
grown in size as fibers or reverse cylindrical micelles. The fibers
or the micelles physically entangled with each other to form a
three dimensional networked structure [23]. The gel containers
were then inverted and observed for any flow (Fig. 1). Samples
were considered as organogels if they did not flow [12]. All the
prepared gels except those of the PLO were white to pale yellow
in color, oily in touch, opaque in nature and no odor.
Concerning PLO, it was jelly like in appearance with yellow
color, and aqueous touch. On the other hand, the prepared DH
hydrogel was transparent, homogenous, clear and smooth
with aqueous touch because the liquid compartment is water.
In addition, bigels (combined forms of hydrogels with orga-
nogels) were white in color, creamy in appearance with ho-
mogenous smooth non oily touch. It is well known that a large
number of emulsifiers could affect the properties of lamellar
lipids of the intracellular matrix of the SC, resulting in the
increased transepidermal water loss and several irritant re-
actions [24]. However, the simple composition of organogels,
bigels and hydrogels is therefore beneficial considering the
safety of these formulations.
3.1. Gel morphology
The variations in the microstructure of organogels were
studied as the gelator and/or surfactant types changed (Fig. 2).
The results showed the presence of needle shaped clusters of
Sp60 when 10% (w/w) gelator concentration was used (Fig. 2).
As another surfactant added such as T80, T20, or Sp80, these
clusters aggregated to form fiber-like structures. These fiber-
like structures were in the form of networked skeleton
which could help in the immobilization of the oil. Hydrogel
52 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 8 ( 2 0 1 3 ) 4 8 e5 7

Fig. 1 e Gelation process of the organogel (a) Clear solution after heating; (b) Uniform, cloudy suspension upon cooling and
standing; (c) Opaque, semi-solid gel upon further standing.

showed Blank pictures where bigels appeared emulsion like
with the oil phase dispersed in a continuous aqueous one.
3.2. Thermal analysis
The thermogram of DH showed a single sharp endothermic
peak at 207.55  C and another broad one at 245.50  C
(Fig. 3(a)). The sharp endothermic peak is corresponding to
the melting point of the drug where the broad one is cor-
responding to its decomposition [25]. Also, Fig. 3 (b and c)
showed strong endothermic peaks at 48.78  C and 50.93  C
which indicated the melting points of CA and Sp60,
respectively. DTA-thermogram of DH-CA organogel showed
a small and broad peak of DH appeared at 208  C (Fig. 3(d)).
However, Sp60-DH organogel showed shifting of DH peak
from 207  C to 188  C and become smaller than that of pure
DH. This indicated the interaction of the gel clusters of Sp60
and DH which pointed to the presence of the drug in the
amorphous nature (Fig. 3(e)). These results agree with that
of Sultana et al., who found that the endothermic peak of
DH in alginate microspheres was not distinctive indicating
that, the drug was no longer present in the crystalline
form [26].
3.3. Measurements of the gel pH and viscosity
The pH values of the organogels, hydrogels and bigels were
found to be in the range of 4.66e5.91 (Table 3), which were
close to skin pH 4.5e7 [27]. This enhances a safe application to
the skin without irritation problems. All gel formulations were
found to have viscosities in the range of 870 cP to 34900 cP, and
as a general observation, the incorporation of surfactants

Fig. 2 e Microscopic study of different gel formulations, a) Sp60/SO organogel. b) Sp60/Sp80 organogel. c) HPMC hydrogel. d)
microstructure of bigel.
 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 8 ( 2 0 1 3 ) 4 8 e5 7 53

70
CA
60 Sp 60

% Diltiazem HCl released

Lecithin/Pluronic
50

40

30

20

10

0
Fig. 3 e Thermal analysis, a) Pure DH, b) Pure CA, c) Pure 0 50 100 150 200 250 300 350 400
Sp60, d) DH-CA organogel and e) DH-Sp60 organogel. Time (min)

Fig. 4 e Effect of different organogelators on DH release.

such as T80, T20, or Sp80 resulted in increasing the viscosity of

the gel as listed in Table 3.
50.93  C and 48.78  C for Sp60 and CA, respectively). Con-
3.4. In vitro release of DH across semi-permeable cerning PLO, the significant lower DH release rate may be
cellophane membrane (pH 5.5) attributed to the high affinity between the freely water soluble
DH and PLO surfactants concentrated on the emulsion inter-
For transdermal drug delivery, in vitro drug release tests are face. A similar study showed the release of 81.56% piroxicam
often performed before transdermal permeation studies. at 48 h from PLO organogels, however the solubility of pirox-
From the in vitro release studies it is possible to determine how icam in water was low [30]. The authors attributed the result
the viscosity and the ingredients of the vehicle affected the to the amphiphilic nature of pluronic and the weak affinity
drug release profiles of each formulation [28]. The release of between pluronic and piroxicam which may facilitate the
DH from organogels of SO formulated using different gelling release of poor water soluble drugs from organogels.
agents is demonstrated in Fig. 4. From Fig. 4, it is clearly Inclusion of surface active agents into gels is well known to
illustrated that DH was slowly released from organogels affect drug release and permeability across biological mem-
where different gelators used. About 43.7%, 49.4, and 50.4% of branes [31]. Different surfactants of different acyl chain
the drug was released after 360 min from organogels of the lengths and unsaturation such as Sp80, T20 or T80 were used
PLO, Sp60, and CA gelators, respectively. The drug release was in concentrations of 2% w/w to modify the release profile of
dependent on the solid skeleton network formed by the DH from the organogels of Sp60/SO or CA/SO. From Fig. 5(a
gelator molecules [29,30]. CA and Sp60 organogels exhibited a and b), it was observed that the percentage DH released after
similar drug release pattern (no significant difference; P > 0.05) 360 min from different organogels containing 2% of Sp80, T20,
due to the similarity in their transition temperatures (about or T80 were 38.48%, 33.80%, and 27.56%, respectively with
Sp60/SO organogels and was 44.21%, 40.04% and 39.52%,
respectively with CA/SO organogels. Generally, all surfactants
had significantly decreased the drug release (P < 0.05) from
Table 3 e The pH and viscosity values of various gel organogels compared to those without surfactants in both
formulations. Sp60 and CA. This result might be due to the participated in-
Formulation Viscosity (cP) pH verse tubular aggregation of Sp60 or CA that increased the
viscosity and gel strength [32]. On the other hand, incorpora-
Sp60/SO organogel 1000 5.61  0.32
tion of Sp80 into organogels resulted in a significant higher DH
Sp60/Sp80 orgaanogel 1800 5.29  0.21
Sp60/T20 organogel 8000 4.98  0.15 release rate when compared to Tween incorporated gels for
Sp60/T80 organogel 32,100 5.11  0.40 both Sp60 and CA organogels. The result might be due to the
CA/SO organogel 3400 5.04  0.30 high degree of lipophilicity of spans compared to Tweens and
CA/Sp80 organogel 7000 4.98  0.15 this could lead to lower affinities to hydrophilic drugs [33]. The
CA/T20 organogel 7200 4.85  0.13 viscosity of the prepared gel might be another reason for the
CA/T80 organogel 7400 4.90  0.18
deviations recorded in drug release rates from different gels.
PLO 1900 4.66  0.19
HPMC hydrogel 870 5.66  0.33
The viscosity of organogels containing Sp80 was found too low
Sp60/HPMC bigel 14,400 5.87  0.40 when compared to those containing T80 or T20. Moreover, the
Sp60/Sp80/HPMC bigel 9900 5.66  0.17 lower DH release from organogels containing Tween surfac-
Sp60/T20/HPMC bigel 27,000 5.14  0.30 tants may be ascribed to the longer fiber length of Tween
Sp60/T80/HPMC bigel 34,900 5.23  0.15 surfactant which can cause an increased area of overlap and
CA/HPMC bigel 14,900 5.91  0.23
cross-linking, producing high gel strengths [30]. T20 has a
CA/Sp80/HPMC bigel 8900 5.82  0.18
comparatively lower gel-strengthening effect and showed
CA/T80/HPMC bigel 15,900 5.15  0.12
higher fluxes than T80 [32]. The active participation of Tweens
54 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 8 ( 2 0 1 3 ) 4 8 e5 7

a 70 b 70
HPM C hydrogel HPM C hydrogel
60 Sp60 CA
Sp60/2%Sp80 60
% Diltiazem HCl released
CA/2% sp 80
Sp60/2%T20

% Diltiazem HCl released

50 CA/2%T20
Sp60/2%T80 50 CA/2% T80
40 40

30 30

20 20

10 10

0 0
0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400
Time (min) Time (min)

c 70 d 80

60 70
% Diltiazem HCl released

60

% Diltiazem HCl released

50
50
40
40
30
30
Sp60/HPM C
20 CA/HPM C
Sp60/Sp80/HPM C 20 CA/Sp80/HPM C
10 Sp60/T20/HPM C CA/T80/HPM C
Sp60/T80/HPM C 10
0 0
0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400
Time (min) Time (min)

Fig. 5 e Release profiles of DH from different vehicles. (a) Sp60 organogels vs. HPMC gel, (b) CA organogels vs. HPMC gel, (c)
Bigels of Sp60, and (d) Bigels of CA.

in micelle formation produced an increased area of micellar shown in Fig. 5(d). It is clear that all bigels gave significantly
overlap might be the reason for linear increase in the viscosity higher release rates than organogels (P < 0.05). This may be
of the organogel [34]. attributed to the fact that organogels are W/O type emulsions
The release of DH from HPMC hydrogel was also included having an external lipid phase [11], while a bigel is a w/o/w
in this study and compared with organogels. The percentage type emulsion due to the incorporation of the organogel inside
DH released from HPMC hydrogel was 55.64% after 360 min as the hydrogel which have an external aqueous phase and
shown in Fig. 5 (a and b). The hydrogels are three dimensional capable of incorporating large amounts of water [35]. The
polymeric networks with chemical or physical cross links hydrophilic nature of the external aqueous environment of a
which can control the drug delivery via controlling the base bigel facilitates the release of the hydrophilic drug from the
viscosity [35]. The amount of DH released from hydrogels of external aqueous phase. The release would be faster for a
HPMC was higher than that from all organogels. This may be hydrophilic drug in case of o/w emulsion, since it is in the
due to the aqueous liquid component of hydrogels which can continuum region. The diffusion is difficult when DH incor-
impede large amount of water or biological fluid [35]. On the porated in w/o type emulsion base, since it gets trapped in
other hand, organogels has a liquid organic (lipophilic) me- water droplets. The reverse is true for hydrophobic drugs [36].
dium which make the release of freely water soluble drug To show the effect of the pH of the external sink on DH
more difficult. release, CA/SO organogel and CA/HPMC bigel were formulated
Several formulations of bigels prepared by using different and tested for DH release in different pH values. Fig. 6(a)
organogels of Sp60 or CA with SO with or without different showed that the percentage DH released from CA/SO orga-
surfactants (Sp80, T20 or T80) and mixed with HPMC hydrogel. nogel and CA/HPMC bigel after 360 min was 50.4 and 72.28%
From Fig. 5(c), it was illustrated that the percentage DH when pH was 5.5, 33.80% and 51.48% at pH 1.2, 24.96% and
released after 360 min from different bigels of Sp60/HPMC, 32.68% at pH 6.8, and 14.66% and 18.09% at pH 7.4, respec-
Sp60/Sp80/HPMC, Sp60/T20/HPMC and Sp60/T80/HPMC were tively. The amount of DH released in different pH values was
59.80%, 55.12%, 48.36% and 46.28%, respectively. While, in the following descending order: pH 5.5 > pH 1.2 > pH
72.28%, 54.60% and 41.08% of DH were released from bigels of 6.8 > pH 7.4. Diltiazem is a basic drug and should be more
CA/HPMC, CA/Sp80/HPMC and CA/T80/HPMC, respectively as soluble in the acidic media than neutral and alkaline media.
 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 8 ( 2 0 1 3 ) 4 8 e5 7
a 100
CA/HPMC (pH 5.5)
90 CA organogel (pH 5.5)
CA/HPMC (pH 1.2)
CA organogel (pH 1.2)
80 CA/HPMC (pH 6.8)
CA organogel (pH 6.8)
% Diltiazem Hcl released
70 CA/HPMC (pH 7.4)
CA organogel (pH 7.4)
60
50
40
30
20
10
0 0
0 50 100 150 200 250
Time (min)
Fig. 6 e (a) represents the release of DH from CA organogels and bigels in different pH values and (b) represents the
permeation of DH from hydrogel, PLO, bigel and organogel formulations across Rabbit skin.
However, the decline in the DH solubility in HCl buffer pH 1.2
was attributed to the common ion effect, which provided
unexpected trend in solubility of this medicament in the
presence of chloride ion in the medium [37]. On the other
hand, high amounts of DH were released in pH 5.5 which in
turn were gradually decreased at pH 6.8 and 7.4. The result
might be due to the acidic nature of DH salt of a basic drug
having pka of 7.7 and the molecule is freely soluble in water.
The high the release profile of DH can be attributed to rapid
ionization and higher solubility of the drug in pH 5.5, however
the reduced release rate of DH in pH 7.4 could be due to the
reduced the extent of ionization and solubility of DH in basic
media [37].
3.5. In vitro rabbit skin permeation study
The aim of this study was to examine the possibility of using
organogels, hydrogels and bigels as transdermal delivery forms.
Fig. 6(b) shows the cumulative amount of DH expressed in mg/
cm2 transferred from different gel formulations to the receptor
compartment (phosphate buffer pH 5.5). Throughout the
experiment period, the hydrogel of HPMC showed higher
amount of DH skin permeability than other organogel formu-
lations. After 360 min, about 1569.50, 1286.28, 1121.07, 1062.0,
979.46 and 483.83 mg/cm2 of DH were permeated across rabbit
skin from HPMC hydrogel, PLO, Sp60/HPMC bigel, CA/HPMC
bigel, Sp60/SO and CA/SO organogel formulations, respectively.
Firstly, it must be taken into consideration that the partitioning
of a drug between the skin and the reservoir favors more lipo-
philic drug because skin act as an organic phase [38]. Skin is a
horny layer so penetration of drugs is very less. To improve the
penetration of a drug into the skin, chemical enhancers are
added. Incorporation of HPMC enhances the flux of drugs [39].
Hydrogel consists of an aqueous phase which facilitates the
penetration of hydrophilic drug. Also, lower gel viscosity might
be another reason for higher amount of DH permeated the
55
b
2000
HPMC hydrogel
1800
PLO
1600 Sp60/HPMC
Amount DH permeated (µg/cm2)
CA/HPMC
1400 Sp60/SO
CA/SO
1200
1000
800
600
400
200
300 350 400 0 50 100 150 200 250 300 350 400
Time (min)
rabbit skin using hydrogels of DH. Concerning PLO organogel,
the amount of DH permeated was higher than Sp60/SO and CA/
SO organogels due to the aqueous external compartment and
the amphiphilic nature of phospholipids which can enhance
skin penetration and absorption of both lipophilic and hydro-
philic drugs [40]. The phospholipid tail of micelles could interact
with the lipids in SC causing their rearrangement and thus
facilitated drug penetration between epidermal cells into sys-
temic circulation [41]. Also, bigels of Sp60/HPMC and CA/HPMC
gave higher penetration rates than their organogels and this
could be as discussed before due to the external aqueous phase
of bigel as well as the surfactant activity of CA and Sp60. CA/SO
organogel gave the lowest fluxes which may be ascribed to its
lower surface activity and higher viscosity (3400 cP) when
compared to Sp60/SO organogel (1000 cP).
3.6. In vivo study of DH
Fig. 7 shows the significant decrease in the mean arterial blood
pressure in all hypertensive rats receiving transdermal DH gels
compared to the group I (ve control) at all time intervals. The
one way ANOVA test revealed that the difference between the
antihypertensive effects of DH in all transdermal groups was
statistically significant (P < 0.05) when compared to control
group at all time intervals of the experiment. Group VI which
received oral doses of DH solution showed a sharp decrease in
blood pressure after 1 h (92 mmHg) then gradually increased
after the fourth hour. A statistical significant difference
(P < 0.05) was found between oral solution group and all
transdermal groups during the first 2 h. Meanwhile, no statis-
tical significance (P > 0.05) was observed after 3 h till the end of
the experiment between transdermally applied organogels,
bigels and oral DH solution. On the other hand, group V which
received HPMC hydrogel showed a statistical significant dif-
ference (P < 0.05) compared with oral solution group after 4 h till
the end of the experiment. This result may be attributed to the
56 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 8 ( 2 0 1 3 ) 4 8 e5 7
180
160
Mean arterial B.P (mmHg)
140
120
100
80
Control
60 Sp60/SO organogel
PLO
40 Sp60/HPM C bigel
20 HPM C hydrogel
DH oral solution
0 1999;13(2):145e153.
0 2
Time (h)
Fig. 7 e Mean arterial blood pressure of rat groups received
different DH gel formulations via the transdermal route
compared with non treated group and those taken DH
solution via the oral route. Data represented as mean ± SD
(n [ 6).
fact that the hydrogel gives faster antihypertensive effect when
compared with other transdermal groups as it decreased the
blood pressure gradually and maintained it. From these results
all transdermal gels can give comparable results to oral solution
and reveal a sustained antihypertensive effect. A statistical
significant difference (P < 0.05) between group V (hydrogel) and
group II (Sp60 organogel) was observed at all times of the
experiment. However, groups III (PLO) and IV (bigel) showed no
statistical difference (P > 0.05) at all times of experiment. The
results which obtained with all transdermal groups revealed
that, the antihypertensive effects of DH could be arranged in
the following order: hydrogel > PLO > bigel > Sp60 organogel.
As explained previously, this may be attributed to the external
aqueous phase of hydrogels which facilitate DH release from
the formula in contrast to organogels which has an external
lipophilic phase that hinder the DH release. In addition the
aqueous external phase provides epidermal cell hydration and
swelling which enhances hydrophilic drug diffusion across SC.
PLO and bigels both contain external aqueous phase facilitating
the release of DH in addition to surface active components
which can enhance skin penetration ability.
4. Conclusion
The above mentioned results revealed that, the natures of the
active drug and other ingredients of the gels, as well as the vis-
cosity of the matrix, will affect the drug release profiles from
different gels. In vitro release and permeation studies indicated
prolonged release of DH from the tested organogels, hydrogels
and bigels. Hydrogel formulation gave better results among
other tested formulations. In vivo studies indicated that all
transdermal formulations can give sustained antihypertensive
effects. Organogels can effectively enhance the hydrophilic drug
delivery across the skin however this investigation revealed that
they could not be suggested as the vehicle of choice for trans-
dermal application of hydrophilic drugs. Conversely, watery gel
systems like hydrogels, PLO and bigels may be tried as matrices
which hold good promise for transdermal drug delivery of DH.
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