Characterization
Niosomes were
characterized for microscopic characteristics, entrapment efficiency, vesicle
size and zeta potential.
Microscopic
examination51
Niosomal suspension was
examined for structure and lamellarity under motic plus 2.0 microscope at magnification power of 10X and
45X and photomicrographs were recorded.
Entrapment efficiency
Niosomes encapsulation efficiency was determined by dialysis technique for
separating un-entrapped drug. 52 Quantity of drug loaded niosomal dispersion equal to 2 mL
was placed into dialysis bag and exhaustively dialyzed against 200 mL of pH 3 citrate buffer, magnetically stirred at 150 rpm
and 37±0.5ΊC for 5 hours. Vesicles were disrupted with 4 mL
of isopropyl alcohol and diluted to 10 mL with pH 3
citrate buffer and sonicated for 15 min. Quantity of
resultant dispersion equal to 1 mL was diluted up to
25 mL with pH 3 citrate buffer and drug content was
estimated by the UV spectroscopy.40Amount of terbinafine
hydrochloride entrapped in vesicles was determined using following
equation.
EE
(%) = [(Ct-Cf)/Ct] 100
Where, Ct is concentration of
total terbinafine hydrochloride, Cf
is concentration of free terbinafine hydrochloride
Measurement of vesicle size53
The
mean particle size diameter and size distribution (polydispersity
index, PI) was determined by Malvern zetasizer nano. Each sample was run 3 times and analysis was carried
out at 25ΊC with an angle of detection 173°.
Measurement of zeta potential53
The
zeta potential was determined by Malvern zetasizer nano after suitable dilutions. Each sample was run 3 times
and the analysis was carried out at 25ΊC with an angle of detection 173°.
Stability studies56
The
physical stability studies were carried out to investigate the leaching of drug
from niosomes during storage. The niosomal
formulations were sealed in 20 mL glass vials. The
stability studies of vesicular dispersions were carried out at refrigerator
temperature (4-8ΊC) and at room temperature for 45 days. The effects of
temperature on the % EE were monitored at 0, 15, 30, 45 and 60 days for
vesicular dispersion.
Preparation
of gels
Vesicular
gel
Aqueous dispersion of 1.5 %w/w carbopol-934P was
prepared and niosomal suspension was incorporated
with gentle shaking to prevent breakage of vesicles. To it, 0.2g and 0.02 g
methyl paraben and propyl paraben respectively were incorporated and pH was adjusted
to 6.8 to 7 by addition of triethnolamine.
Conventional
gel
Conventional gel was prepared by dispersing micronised drug equal to 100 mg in aqueous dispersion of
carbopol-934P.
Evaluation
of vesicular gel
The appearance, drug content, pH, viscosity and spreadability of vesicular gel were determined.
Study
of in vitro antifungal activity
Sabourd dextrose agar
(SDA) media was used for the cultivation of pathogenic fungi. In it candida albicans was inoculated
and incubated at 25ΊC for 3 days.
The in vitro
antifungal activity of niosomal gel and conventional
gel were carried out against candida albicans using cup plate method. The antifungal assay agar
was used for the assay of antifungal activity. The quantity of fungal culture
equal to 1 mL was inoculated to antifungal assay agar
media and uniformly poured into a sterile petridish.
The agar medium was left to solidify to and 5 holes were made by cork-borer
having diameter of 1 cm and agar disk was removed. The quantity of gel
formulations equal to 30 mg were sampled in cup. It was allowed to diffuse at
room temperature for 1 hour. The plates were placed in incubator at 25ΊC. The diameter of growth inhibition zones were measured after every 24
hours for 3 days.
Ex vivo percutaneous
permeation and skin uptake behavior
Ex vivo permeation
studies were carried out using the abdominal skin of Sprague Dawley rat mounted on static vertical Franz diffusion cells
with dermal-side in contact with receptor phase. The diffusion cell with an
effective diffusion area of 3.14 cm2 and diffusion medium pH 7.4
phosphate buffer.The test system was equilibrated at
37ΊC. Terbinafine hydrochloride accumulation in
skin was assessed after 24 hours treatment with vesicular gels (tween 60, tween 80, span 60 and
span 80), and conventional gel.
The skin content of drug was determined using
methanol by sonication which was analyzed by UV
visible spectroscopy at 282 nm.
RESULTS:
Preformulation
studies
Fourier transform Infrared (FT-IR)
spectroscopy
The FT-IR spectrum
of terbinafine hydrochloride is shown in figure 1.
Figure 1 FT-IR spectrum of terbinafine
hydrochloride in methanol
Drug-Excipients
interaction
FT-IR spectras of terbinafine hydrochloride in combination with excipients (figure 2,3,4 and 5) were compared with FT-IR
spectrum of the terbinafine hydrochloride (figure 1).
Figure 2 FT-IR spectras of terbinafine hydrochloride, cholesterol and tween 60
Figure 3 FT-IRspectras of terbinafine hydrochloride, cholesterol and span 60
Figure
4 FT-IR spectras of terbinafine
hydrochloride, cholesterol and span 80
Figure 5
FT-IR spectras of terbinafine
hydrochloride, cholesterol and tween 80
Cumulative drug dialyzed
The cumulative % amount of dialysed terbinafine
hydrochloride is shown in the table 2.
Table 2 Cumulative % drug
dialyzed with respect to time
|
Time (Hours)
|
Cumulative % drug released (Mean±
SD)
|
|
0.5
|
34.777 ± 0.052
|
|
1
|
57.542 ± 0.223
|
|
2
|
63.851 ± 0.524
|
|
3
|
76.111 ± 0.263
|
|
4
|
81.147 ± 0.994
|
|
5
|
86.296 ± 0.313
|
|
6
|
82.962 ± 0.209
|
|
7
|
81.517 ± 0.156
|
SD-Standard
deviation
From the table 2 it can be observed that
more than 85% drug was dialyzed at the end of 5 hours.
Formulation development
Preparation of terbinafine
hydrochloride loaded niosomes
Vesicle
forming ability of surfactant
It has been reported that niosomes
prepared without cholesterol forms a gel and only on addition of cholesterol,
homogenous niosomal dispersion obtained.27
Thus, in this study, cholesterol was added at 0.5, 1 and 1.5 molar ratios, and
amount of surfactant and drug was kept constant. As shown in table I,
surfactants were able to form vesicles at cholesterol ratios studied.
Characterization of vesicles
Microscopy
The morphological characteristics of terbinafine hydrochloride loaded niosomes
are shown in figures 6, 7, 8, 9, 10 and 11.
Figure 6 Photomicrograph of niosomes
containing tween at 45X magnification
Figure 7 Photomicrograph of niosomes
containing tween at 10X magnification
Figure 8 Photomicrograph of niosomes containing span at 45X magnification .
Figure 9 Photomicragraph of niosomes containing span at 10X magnification.
Figure 10 Photomicrograph
of niosomes containing span at 45X magnification
Figure 11 Photomicrograph of niosomes
containing span at 45X magnification
As observed from
photomicrographs at various magnifications (figure 7, 8, 9, 10, 11 and 12) terbinafine hydrochloride loaded niosomal
vesicles were found to be well identified perfect spherical structures in size range of 0.24 to 9.4 μm
and multilamellar in nature formulated by classic
thin film hydration method and no aggregation of vesicles was observed.
Entrapment efficiency
Effect of cholesterol on niosomal
formulation
The
effect of cholesterol on terbinafine hydrochloride
entrapment was found to vary according to nonionic surfactant used and
cholesterol was found to have an insignificant effect on drug entrapment into sorbitan esters (span) niosomes
(figure 12). For tweens, entrapment of drug was found
to increase with increase of cholesterol ratio from 0 to 1.5. As HLB value of
surfactant was increased above 10, minimum amount of cholesterol necessary to
form vesicles was increased.13
Figure 12 Effect of
cholesterol molar ratio on the entrapment efficiency of terbinafine hydrochloride into niosomes
(n = 3)
In formulations prepared with sorbitan monoesters, span 60 showed maximum entrapment
efficiency at 1 molar ratio of cholesterol.
Vesicle size
The mean vesicle diameters along
with polydispersity index of the optimized
formulations are shown in table 3.
All vesicles
formed were in mean area-number diameters (dAN)
ranging from 0.24 μm to 9.4 μm.
While comparing formulations that had shown maximum entrapment efficiencies,
larger size was observed of those vesicles that had surfactants with a
saturated alkyl chain. As observed from table III, in case of vesicles containing
surfactants with saturated alkyl chain, size of niosomes
containing span 60 (1754 nm) were larger than tween
60 containing niosomes (1332 nm) and for vesicles
containing surfactants with unsaturated alkyl chain, niosomes
containing span 80 (807.23 nm) were larger in size than those containing tween 80 (756.2 nm).
Table 3
Particle
diameter (nm) and polydispersity index (PDI) of
optimized formulations (n=3)
SD- Standard deviation; PDI- Polydispersity
index
Zeta potential
As
shown in table 4, the formulations containing the sorbitan
esters, zeta potential value of formulation containing span 60 (HLB 4.7) was
found to be higher than, span 80 (HLB 4.3).Similarly zeta potential value of
the formulation containing tween 80 (HLB 15) was
found to be higher than formulation containing tween
60 (HLB 14.9).
Table 4
Zeta
potential of optimized formulations (n=3)
SD-Standard
deviation
Stability study
A direct relationship between
percentage drug leaching out of vesicles and ageing was observed. With increase
in storage period, the degree of leaching was also increased
Figure
13 Effect of storage
time and temperature on the entrapment efficiency of vesicle
From
figure 13, it was observed that span 60 and tween 80 niosomal suspensions has shown higher stability in terms of
entrapment efficiency over other niosomal
suspensions. It was observed that niosomal suspension
containing tween 60 showed low stability. Vesicular
dispersions were found to be more stable at low temperature and should be stored
at low temperature.
In-vitro antifungal activity
The results of in vitro antifungal activity are shown
in figure 15 and table 5.
Figure
14 Zone of inhibition
of terbinafine hydrochloride containing niosomal gels and conventional gel against candida albicans (n=3)
Table 5 In
vitro antifungal activity of terbinafine
hydrochloride containing niosomal gels and conventional gel against candida albicans (n=3).
Terbinafine hydrochloride was found to be active against Candida albicans. The vesicular formulations of terbinafine
hydrochloride were found to be more effective than conventional formulation, as
they were found to have larger zone of inhibition. The vesicular formulations
containing tween 60 and span 80 were found to have
maximum zone of inhibition followed by span 60 and tween
80.
Ex
vivo percutaneous permeation and skin uptake behaviors
From
figure 15, better ex vivo permeation
and skin partitioning of drug by niosomal gel was
observed as compared to conventional gel.
Figure 15.Ex vivo
permeation studies of niosomal
formulations
The
superior skin permeation was observed with formulations containing tween 80 and span 80 as compared to formulations containing
tween 60 and span 60. From figure16, it was clearly
indicated that drug deposition in excised rat skin from vesicular gels were
greater than conventional gels.
Figure 16 Drug Deposition in rat skin from
different formulations, (Mean±SD) (n=3).
DISCUSSION:
Drug excipients
interaction
From FT-IR spectrum of physical mixture of drug and excipients, excipients were found
to be compatible with terbinafine hydrochloride.
Characterization
of vesicles
Entrapment
efficiency
Effect
of cholesterol on niosomal formulation
The effect of
cholesterol on terbinafine hydrochloride entrapment was found to be varying
according to nonionic surfactant used. Cholesterol was found to have
insignificant effect on terbinafine hydrochloride
entrapment into sorbitan esters (span) niosomes (figure 13). For tweens,
entrapment of terbinafine hydrochloride was found to
increase with increase of cholesterol ratio from 0 to 1.5. As HLB value of
surfactant was increased above 10, minimum amount of cholesterol necessary to
form vesicles was increased.13 More amount of cholesterol was
necessary to compensate for larger head group. In present study, tweens have highest HLB value indicating low hydrocarbon
chain volume in comparison with hydrophilic surface area. Thus, increased
cholesterol content might have increased the lipophilic
behavior and crystallinity of lipid bilayer of niosomes containing
tweens.13 .Hence, higher drug entrapment of niosomes
containing tween was observed in presence of higher
content of cholesterol. In niosomal
formulations prepared with sorbitan monoesters, span
60 showed maximum entrapment efficiency at 1
molar ratio of cholesterol. Increasing cholesterol content from 0 to 1 molar
ratio leads to an increase in entrapment efficiency of sorbitan
ester niosomes. The improvements in drug entrapment with increased cholesterol content (01)
and major reduction in drug entrapment when
the cholesterol content was further increased (11.5)
may be due to two conflicting factors: (1) with increased cholesterol, bilayer hydrophobicity and
stability was found to increase135 and permeability was decreased136 which may lead to efficiently
trapping of hydrophobic drug into bilayers as the
vesicles were formed. (2) In contrast, the higher amounts of cholesterol may compete with drug for packing space within
the bilayer, hence excluding
the drug as amphiphiles assemble into vesicles.28,
30
Span
60 was found to have significantly higher entrapment efficiency than span 80.
This could be due to surfactant chemical structure. All spans have same head
group and different alkyl chain. Increasing alkyl chain length leads to higher
entrapment efficiency.41 The span 60 and span 80 have same head
groups but span 80 have an unsaturated alkyl chain, 137 demonstrated that introduction of a double bonds into the
paraffin chains caused a marked enhancement in permeability of niosomes, possibly explaining lower entrapment efficiency
of span 80 formulation. In addition, span 80 have lowest transition temperature
(Tc =−12ΊC) amongst all spans.138
Span 60 having highest phase transition temperature provided highest entrapment
of drug and vice versa.27
Vesicle size
It
had been widely known that diameter of vesicles depends on length of alkyl
chain of surfactants. Surfactants with longer alkyl chains generally gave the
larger vesicles.13
The
size distribution was observed from polydispersity
index shown in table III, a polydispersity index of 1 indicates
large variations in particle size and a value of 0 means size variation is absent. It indicates that all niosomal formulations were multidispersed.
While comparing formulations that had shown the maximum entrapment
efficiencies, polydispersity index was found to be 1
for niosomal formulations containing span 60 and tween 80 surfactants and niosomal
formulations containing tween 60 (PI 0.994) was found
to be more polydispersed as compared to span 80 (PI
0.744). Among all formulations, span 80 (1.5:1) showed least degree of variation in particle size (PI 0.203).
Zeta
potential
Zeta potential of
niosomal formulations containing span was increased
with increase in hydrophilicity of surfactants. This
could be due increased surface free energy of span surfactants with increased
HLB value.32 Similar kind of results were observed in case of polyoxyethylene sorbitan esters,
zeta potential value of formulation containing tween
80 (HLB 15) was found to be higher than that of formulation containing tween 60 (HLB 14.9).
Evaluation
of antifungal gel
Ex vivo percutaneous permeation and skin uptake
behaviors
Surfactant in
formulations acts as a permeation enhancer, which might partly contribute to
enhancement of terbinafine hydrochloride permeation
from niosomes.1140 The niosomes fused at
interface of stratum cornium, and high local drug
concentration in bilayers generates a high
thermodynamic activity of drug in upper part of the stratum cornium.141,
142
The
superior skin permeation was observed with formulations containing tween 80 and span 80 as compared to formulations containing
tween 60 and span 60. This could be due to better
release of drugs from tween 80 and span 80 niosomes due to low phase transition temperature of these
surfactants and smaller size of niosomes.27 The packing nature of
unsaturated fatty acids changed the fluidity of the stratum corneum
lipid structure and facilitated skin permeation of drug.143 Moreover, it was reported that sorbitan ester niosomes exhibit
an alkyl chain length dependent drug release; the higher the chain length, the
lower the release rate.106, 100
CONCLUSION:
Niosomes entrapped with terbinafine
hydrochloride were prepared by film hydration method for topical skin fungal
infection. The niosomal gel was found to improve the
antifungal activity as compared to conventional gels. This study provided the
evidence that niosomal vesicles are valuable as
topical delivery carrier to enhance the penetration and deposition of terbinafine hydrochloride in skin.
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