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Research article Rapports De Pharmacie Vol.

2 (4), 2016, 309-314


ISSN: 2455-0507
FORMULATION AND EVALUATION OF TERBINAFINE
HYDROCHLORIDE ORGANOGELS FOR TOPICAL DELIVERY
Shankrayya M*, Hajaratumar Doddamani, and Sreenivasa GM
S.C.S. College of Pharmacy, Harapanahalli, Karnataka. India

ABSTRACT
The objective of present study was to develop sorbitan monostearate (span 20) and sunflower oil (SO) based
organogels for topical drug delivery. The organogels were prepared by dissolving sorbitan monostearate in
sunflower oil (60°C). Terbinafine HCl was used as a model antifungal drug. The formulated organogels were
evaluated for their appearance, pH, viscosity, gel to sol transition study, drug content, in-vitro diffusion study,
antifungal activity and stability studies. The pH range of the organogels was simulated to the skin pH
conditions and the gel-sol transition study indicated that as the concentration of the gelator was increased,
there was a subsequent increase in the transition temperature. As the concentration of Span 60 increased, there
was a proportionate decrease in drug release pattern and the drug release profile of all the formulations were
followed zero order kinetic model and the mechanism of drug release were found to be non-fickian diffusion
controlled. All the formulations were able to restrict the growth of Candida albicans efficiently as comparable
to the marketed product. Based on the results, the developed organogels can be used as an efficient drug
carrier for the topical delivery of Terbinafine HCl.
Keywords: Terbinafine HCL, Sunflower oil, Span-60, Organogels.
INTRODUCTION
Fungal infections of skin are one of the common formulating them in an advantageous way [2].
dermatological problems. It has been estimated that In a recent development, organogels have been
about 40 million people have suffered from fungal shown to provide a very promising topical drug
infections in developing and under developed delivery vehicle. Organogel, a viscoelastic system,
nations. The progression of fungal infections can be can be regarded as a semi-solid preparation which
rapid and serious due to compromising with immune has an immobilized external a polar phase. The polar
function. Dermatophytes are one of the most phase gets immobilized within spaces of the three-
frequent causes of tinea and onchomycosis. dimensional networked structure formed due to the
Candidal infections are also among the most physical interactions amongst the self assembled
widespread superficial cutaneous fungal infections. structures of compounds regarded as gelators. In
Even, candida can invade deeper tissues as well as general, organogels are thermodynamically stable in
the blood which leads to life threating systemic nature and have been explored as matrices for the
candidiasis, when the immune system is weakened. delivery of bioactive agents [3].
[1] A wide variety of vehicles ranging from solid to Organogels have been investigated successfully as
semisolids and liquid preparations are available for dermal pharmaceutical formulations. The
topical treatment of dermatological diseases. Topical formulations designed for topical applications
drug administration is a localized drug delivery should be able to interact with the skin, which acts
system anywhere in the body through ophthalmic, as an anatomical and biological barrier for drug
rectal, vaginal and skin as topical route. However, penetration to the systemic circulation. Many
the major barrier of the skin is the stratum corneum, organic substances, like lipids, work as a penetration
the top layer of the epidermis. Low molecular enhancer. The cosmetics industry employs
weight (≤500 Da), lipophilicity, and effectiveness at organogels in personal care products like sunscreens,
a low dosage are the ideal characteristics of the lipsticks, and moisturizers. The food industry
drugs for transdermal delivery. Thus, the therapeutic utilizes organogel-based products for structuring
effectiveness of the existing drugs is improved by edible oils at low concentrations of the gelator
Address for correspondence: molecules. The commonly used organo gelators
Dr. Shankrayya.M include monoacylglycerols, diacylglycerols,
P.G. Dept. of Pharmaceutics, triacylglycerols, fatty acids, fatty alcohols, waxes,
S.C.S College of Pharmacy, wax esters and sorbitan monostearate.
Harpanahalli-583131. Karnataka. India. Sorbitan monostearate is a non-ionic surfactant
E-mail:guruscs1008@rediffmail.com which is hydrophobic in nature and forms organogel
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Shankrayya et al,: Terbinafine hydrochloride organogels for topical delivery

of organic solvents (e.g., hexadecane, isopropyl shown in Table 1. The hot mixture when cooled to
myristate, and a range of vegetable oils like sesame room temperature forms organogel at the sorbitan
oil, groundnut oil, olive oil, soybean oil, sunflower monostearate concentration ≥CGC. The
oil). Sorbitan monostearate based organogels have formulations which did not show flow on inversion
also been developed for pharmaceutical applications were selected as the representative samples for
[4] . further characterization. Terbinafine hydrochloride
Sunflower oil is the non-volatile oil compressed was added to the organogels as a model antifungal
from the seeds of sunflower (Helianthus annuus). drug at a concentration of 1% w/w.[4]
Sunflower oil is commonly used in food as frying Table-1: Composition of Organogel Formulations
oil, and in cosmetic formulations as an emollient [5]. Formulation Span60 Sunflower oil
Terbinafine HCl is most commonly prescribed Code (%) (%)
antifungal drug. Terbinafine HCl is emerging as the F1 1.5 8.5
good treatment option for virtually all forms of F2 2.0 8.0
susceptible Candida infections in both immune F3 2.5 7.5
competent and immune compromised hosts. It acts F4 3.0 7.0
by blocking the synthesis of ergosterol, an essential F5 3.5 6.5
component of the fungal cell membrane. Clinical EVALUATION STUDIES
efficacy of topical antifungal therapy depends on the Drug-polymer compatibility studies:
drug ability to penetrate into the SC and the duration Compatibility studies of pure drug, Span 60 and the
of treatment. Hence, organogel formulations mixture of both drug and Span 60 were carried out
appeared to be a viable approach for topical delivery using Fourier Transform Infrared Spectrophotometer
of terbinafine HCl. The solubilisation of terbinafine (Shimadzu FT-IR 8400-S ) in the range of 400-
HCl in organogel would improve its topical 4000cm-1 by KBr disc method.[7]
availability [6]. Physical appearance:
Keeping these facts into consideration, the current The prepared organogels formulations were
study reports the development of organogels using observed for their colour, homogenecity,
sorbitan monostearate as the organo gelator and consistency, appearance and texture.[8]
sunflower oil as the organic phase. The presence of pH determination:
sunflower oil may impart its beneficial effects when The pH was measured for each organogel using a pH
the organogel is applied topically to provide more meter (Hanna-213, Portugal) by direct immersion of
sustained topical antifungal effect of Terbinafine the electrode.[8]
HCl. Determination of viscosity:
MATERIALS AND METHODS: The viscosity of prepared organogels was
Materials: determined using a Brook field viscometer. The
Terbinafine hydrochloride was purchased from sample holder taken for the viscosity measurement
Yarrow. Chem. Product. Ltd. Mumbai, Sorbitan was filled with the sample and then inserted into the
monostearate (Span 60) from SD Fine chem. Ltd. flow jacket mounted on the viscometer. The sample
Mumbai, Sunflower Oil from Kaleesuwari. Refinery. adapter (spindle LV 64) rotated at optimum speed to
Pvt. Ltd and all other chemicals used were of measure the viscosity of the preparation.[9]
analytical grade. Gel-Sol Transition study:
Preparation of organogels: Organogels were incubated at various temperatures
The required quantity of sorbitan monostearate was in the range of 30°C and 60°C in a constant
dissolved in sunflower oil (60°C, 500 RPM). The temperature water bath. An increment of 5°C was
stirring was continued for 15 min under similar made after 5 min incubation at previous temperature.
experimental condition to obtain a homogenous Samples were analyzed by inverted test tube method
transparent mixture. The optimization of the after each incubation period. The temperature at
composition of the organogel was done by varying which samples started flowing was recorded as gel-
the concentration of sorbitan monostearate from sol transition temperature (Tg).[10]
1.5% w/w to 3.5% w/w. The minimum gelator Drug Content:
(SMS) concentration required for inducing gelation Drug content was determined using a UV
is called the critical gelator concentration (CGC). Spectrophotometric method by measuring the
The compositions tested for the gel formation are absorbance at 282 nm. 10mg of gel was dissolved in
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Shankrayya et al,: Terbinafine hydrochloride organogels for topical delivery

100ml of methanol. The absorbance was measured RESULT AND DISCUSSION


after suitable dilution against the corresponding Preparation of the Organogels:
blank solution.[10] The formulations containing lower concentrations of
span 60 (<1.5% w/w) resulted in the phase
In-vitro diffusion study:
separation. The formulations did not form
The in vitro diffusion study of the organogels was
organogels when cooled to room temperature
performed using dialysis membrane (Sigma Inc,).
(25°C). At a gelator concentration ≥1.5% (w/w),
The membrane soaked in phosphate buffer, pH 7.4
organogels were formed when the hot mixture of
(PB) for 6-8 h was clamped carefully to one end of
sorbitan monostearate and sunflower oil was slowly
the hollow glass tube of dialysis cell. 20ml of
cooled down to room temperature. The solution of
phosphate buffer was taken in a beaker, which was
sorbitan monostearate and sunflower oil was
used as receptor compartment. Then 1g of gel was
transparent when hot, which slowly turned turbid
spread uniformly on the membrane. The donor
and finally converted into organogel (opaque).
compartment was kept in contact with the receptor
All the formulations were found to be opaque in
compartment and the temperature was maintained at
nature and creamish yellow in colour due to the
37±0.5° C. The solutions on the receptor side were
slight yellow colour of the sunflower oil. They were
stirred by externally driven Teflon-coated magnetic
smooth, uniform and contained no lumps. They were
bars. At predetermined time intervals, pipetted out 5
easily and uniformly extrudable from the collapsible
ml of solution from the receptor compartment and
tube. The pH of the organogels was measured at
immediately replaced with the fresh 5 ml phosphate
room temperature by using a digital pH meter. The
buffer. The drug concentration of the receptor fluid
pH of all the formulations was found to be in the
was determined spectrophotometrically (Shimadzu,
range of 6.08±0.114 to 7.42±0.216, indicating their
Tokyo, Japan) against appropriate blank. The
utility of the formulation as transdermal or topical
experiment was carried out in triplicate.[11]
products. Viscosity of the organogels indicated that
Antifungal Activity:
as the rpm increases the viscosity decreases,
The antifungal efficacy studies were carried out to
confirming the shear thinning nature of the
ascertain the biological activity of optimized
formulations. The viscosity of all the formulations
organogel formulation (F5), in comparison with
increased with the increase in gelator concentration.
marketed Terbinafine hydrochloride cream
The results are tabulated in Table 2.
against Candida albicans as the test
The FT-IR spectra of physical mixture (Terbinafine
microorganisms. This is determined by agar
hydrochloride:Span 60) 1:1 ratio have shown the
diffusion test employing ‘Cup plate’ technique. A
characteristic peaks of pure drug indicating that
layer of Potato dextrose agar media (20 ml) seeded
there were no interactions between the drug and
with the test microorganisms were allowed to
Span 60 (Figures 1 and 2).
solidify in the petri dishes. Cups were made on the
Drug content of all the prepared formulations was
solidified agar layer with the help of sterile borer (5
found to range from 67.76±0.136 to 88.87±0.315 %
mm). 0.5 ml of oragnogel (1 μg of drug) was filled
as shown in Table 2. These results indicate complete
into one cup (i.e., hole) which is marked with ‘F’
distribution of the drug throughout the organogel
and 0.5 ml of marketed gel (1 μg of drug) is filled
base.
into the second cup (i.e., hole) which is marked with
The release study indicated that the rate of drug
‘M’. After keeping the petri dishes at room
release was higher in the organogels containing
temperature for 1 h, the plates were incubated at 37±
lower gelator concentration. The percentage release
20C for 48 hours. After the incubation period, the
of the drug decreased when the concentration of
plates were observed for zone of inhibition by using
sorbitan monostearate was increased from 1.5% to
zone reader.[12]
3.5% w/w. The gelator network might have hindered
Stability studies:
the diffusion of the drug, resulting in its lower
The stability study was carried out for the most
release with the increase in the gelator concentration.
satisfactory formulation. The most satisfactory
The release studies suggested that the release of the
formulations were packed in a collapse tubes and
drug can be controlled by tailoring the concentration
stored at room temperature for 3 months. At the end
of sorbitan monostearate in the organogels. Hence,
of each month the samples were analyzed for their
the developed organogels can be considered as
physical properties like appearance, pH, viscosity
potential matrices for controlled release applications.
and drug content by procedure stated earlier.[13]
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Shankrayya et al,: Terbinafine hydrochloride organogels for topical delivery

Figure-1: FT -IR Spectra of pure Terbinafine Hydrochloride

Figure-2: FT-IR Spectra of optimized formulation

Figure-3: Gelation process of organogel


(a) Clear solution after heating;
(b) Uniform, cloudy suspension upon cooling and standing;
(c) Opaque, semi-solid gel upon further standing.
Table -2: Evaluation studies of Organogels
Gel-Sol
Formulation Drug content Viscosity
pH Transition
Code (%) (cps)
temperature
F1 6.93±0.096 84.72±0.324 5911088±325 ±500C
F2 6.08±0.114 67.76±0.136 15600011±547 ±500C
F3 7.15±0.125 88.87±0.315 25200008±623 ±500C
F4 6.33±0.105 69.75±0.368 37899391±564 ±600C
F5 7.42±0.216 67.86±0.421 48919664±352 ±600C

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Shankrayya et al,: Terbinafine hydrochloride organogels for topical delivery

150
F1

% Cumulative Drug Release


F2
100 F3
F4
F5
50

0
0 5 10 15
Time(mins)

Figure- 4: In-vitro drug release profile of Terbinafine HCl organogels

Table- 3: Observations of the Antifungal activity


Mean zone of inhibition
(in mm)*
Sl. No Formulation Code
Candida albicans
5mcg/ml 10mcg/ml
Marketed Terbinafine HCl
01 20 24
cream
02 F5 21 25

The release behaviors of the drug from the thoroughly by investigating various properties. The
organogels were subjected using various release organogels were stable, smooth and the mechanical
kinetic models. The release of the drug followed properties (viscosity) increased with the increase in
zero-order release kinetics in all the organogels. The the organogelator (sorbitan monostearate)
type of drug diffusion from the organogels was concentration. The Terbinafine hydrochloride loaded
estimated by fitting the released data in the organogels showed diffusion-mediated release of
Korsmeyer–Peppas model. The diffusion coefficient drug from the organogel matrix. The antifungal
(n value) of the organogels varied from 0.61 to 0.78, activity showed a good inhibitory action of the drug-
which suggested a non-Fickian release behavior. loaded organogels against Candida albicans .
The optimized organogel (F5) formulation showed Hence, the developed organogels can be considered
antifungal activity when tested microbiologically by as probable matrices for a controlled release of the
cup plate technique. The values of the zone of antimicrobials for topical application.
inhibition produced by optimized organogel (F5) ACKNOWLEDGEMENTS
and marketed cream were shown in the table 3. It is The authors are highly indebted to President,
obviously clear that anti-fungal activity optimized Secretary, TMAE Society, and Principal, S. C. S.
organogel (F5) is higher than the marketed cream. College of Pharmacy, Harapanahalli, Karnataka,
Stability studies indicated that the optimized India for providing necessary facilities to carry out
formulation was stable at room temperature with no the study.
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