Journal of Drug Delivery Science and Technology 66 (2021) 102928

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Journal of Drug Delivery Science and Technology

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

Development and characterization of Novel topical oil/PEG creams of

voriconazole for the treatment of fungal infections
Abhishek Shettar a, Vijay Kumar Shankar a, Srinivas Ajjarapu a, Vijay I. Kulkarni b,
Micheal A. Repka a, S. Narasimha Murthy a, c, *
a
Department of Pharmaceutics of Drug Delivery, University of Mississippi, University Park, Oxford, MS, USA
b
Pharmaceutical Development Center, STEERLife India Pvt. Ltd., Bangalore, Karnataka, India
c
Institute for Drug Delivery and Biomedical Research, Mahalaxmipuram, Bangalore, India

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

Keywords: Voriconazole (VRC), a second generation triazole derivative emerged as a promising candidate for the treatment
Topical of fungal infections. Voriconazole is commercially available as oral and intravenous formulations, however
Voriconazole administration through these routes is associated with several side effects like hepatotoxicity, photopsia and
Creams
abdominal pain. Hence, percutaneous delivery of voriconazole through creams or hydrogels would be beneficial
Melt-extrusion
for preventing side effects due to other routes of administration. Voriconazole may potentially undergo degra­
Stability
dation in formulations containing water. The objective of the study was to prepare a stable biphasic semisolid
formulation using oil and PEG. The melt extrusion process was used as a continuous manufacturing technique for
preparation of oil/PEG cream. Formulation composition and processing conditions were optimized based on the
compatibility and pre-formulation studies. The developed creams were characterized for content uniformity,
viscosity and in vitro drug release. The effect of Transcutol® P and camphor: menthol (1:1) on the permeation of
voriconazole was evaluated by ex vivo permeation studies. The voriconazole in oil/PEG formulation (93.44 ±
1.59%) were stable for 3 months compared to control voriconazole hydrogel formulation (10.67 ± 0.03%) at
25 ◦ C (60% RH). The formulation with Transcutol® P used as a permeation enhancer increased voriconazole
permeation 9 folds compared to formulation without permeation enhancer. In conclusion, a stable oil/PEG
voriconazole cream was successfully developed using continuous manufacturing process and can be used as
alternate for intravenous/oral voriconazole for treatment of fungal skin infections.

1. Introduction immunocompromised patients. However, there are several adverse ef­

Voriconazole is a triazole antifungal drug approved by USFDA for
treatment of invasive aspergillosis, Candidemia, esophageal candidiasis,
and refractory infections of Scedosporium apiospermum and Fusarium
species. Voriconazole inhibits the biosynthesis of ergosterol and disrupts
fungal cell wall formation to exert its antifungal activity. Voriconazole
shows better fungistatic activity against Aspergillus fumigatus, Scedo­
sporium apiospermum and cryptococcus neoformans compared to other
approved antifungal drugs (itraconazole, fluconazole, miconazole and
posaconazole). Voriconazole prescribed as oral and intravenous for­
mulations for treatment of invasive fungal infections in
fects reported on systemic exposure of voriconazole leading to hep­
atoxicity, photopsia, abdominal pain and visual disturbances [1] [–] [4].
The topical delivery of voriconazole would be a better alternative to
overcome adverse effects associated with oral and intravenous routes for
treatment of Aspergillus fumigatus and Scedosporium apiospermum
infections.
The cream or hydrogel formulation are most commonly used topical
formulation to deliver the drugs for treatment of various dermatological
disorders. Voriconazole has a poor aqueous solubility. The better option
of topically delivering poor aqueous soluble drugs is by incorporating
the drugs into O/W or W/O creams. Voriconazole in aqueous solvents

Abbreviations: vrc, voriconazole; peg, polyethylene glycol; do/di, outer diameter to inner diameter ratio; hplc, high-performance liquid chromatography; rpm,
revolutions per minute; ivrt, in vitro release testing; ivpt, in vitro permeation testing; jmax, maximum flux; auc0-24, area under the curve of flux versus time plot.
* Corresponding author. Professor-Pharmaceutics and Drug Delivery 113 Faser Hall, The University of MississippiUniversity, MS, 38677, USA.
E-mail addresses: ashettar@go.olemiss.edu (A. Shettar), vshankar@go.olemiss.edu (V.K. Shankar), shankarsrinivasajjarapu@gmail.com (S. Ajjarapu), Vijay.
Kulkarni@steerlife.com (V.I. Kulkarni), marepka@olemiss.edu (M.A. Repka), murthy@olemiss.edu (S.N. Murthy).

https://doi.org/10.1016/j.jddst.2021.102928
Received 30 May 2021; Received in revised form 4 September 2021; Accepted 16 October 2021
Available online 21 October 2021
1773-2247/© 2021 Elsevier B.V. All rights reserved.
A. Shettar et al. Journal of Drug Delivery Science and Technology 66 (2021) 102928

undergoes hydrolysis resulting in formation of an inactive enantiomer Table 1

by recombination of retro-aldol products [5] [–] [9]. The aqueous The formulation composition, F1–F32 (% w/w).
instability of drugs limits the preparation of O/W or W/O cream for the Formulation (Labrafil M 1944 PEG PEG PEG PEG PEG
topical delivery. CS/Light Mineral oil) 1450 2000 3350 4500 400
Therefore, there are reports on development of nano lipid carriers F1/F2 8.5 – – – 48.5
and microemulsion to prevent the degradation of voriconazole in F3/F4 12 – – – 45
aqueous solvent [10]. The extemporaneously prepared voriconazole F5/F6 17 – – – 40
creams were stable at refrigerated conditions for 90 days. But on the F7/F8 28.5 – – – 28.5
F9/F10 8.5 48.5
other hand, at room temperature phase separation was observed as early
– – –
F11/12 – 12 – – 45
as 21st day [11]. In the current project it was hypothesized that devel­ F13/F14 – 17 – – 40
opment of cream formulations devoid of aqueous solvent would be F15/F16 – 28.5 – – 28.5
beneficial to deliver the moisture sensitive drugs topically to treat F17/F18 – – 8.5 – 48.5
F19/F20 12 45
dermal ailments. – – –
F21/F22 – – 17 – 40
The approach investigated in this project is to develop a cream F23/F24 – – 28.5 – 28.5
formulation using non-aqueous hydrophilic component polyethylene F25/F26 – – – 8.5 48.5
glycol (PEG) to preserve voriconazole in topical formulation. PEG is a F27/F28 – – – 12 45
product of condensed ethylene oxide and hydrophilic in nature and are F29/F30 – – – 17 40
F31/F32 28.5 28.5
generally used as drug penetration enhancers and solubilizers in cream
– – –

preparation. In the current study, the feasibility of incorporating PEG as
a dispersed phase in preparation of creams to prevent the degradation of
moisture sensitive drugs was explored [12]. In addition, the feasibility of
using melt extrusion process as potential continuous manufacturing
process for preparation of oil in PEG creams was also explored [13].
2. Materials and methods
2.1. Materials
PEG 4500 and light mineral oil were purchased from PCCA (Houston,
USA). PEG 2000 was purchased from Millipore Sigma (Darmstadt,
Germany). PEG 400 was gift sample obtained from BASF (New Jersey,
USA). Labrafil M1944 CS, Tefose 63 and Transcutol® P were gift sam­
ples obtained from Gattefosse (Saint Priest, France). Menthol and
Camphor were purchased from Ward’s Science (New York, USA) and
voriconazole was purchased from TCI chemicals (Oregon, USA). Meth­
anol and acetonitrile used were of HPLC grade. All other chemicals used
for studies were of research grades.
Note: All creams consist of 3% Voriconazole, 8% propylene glycol, 7.5%
Transcutol or camphor/menthol (1:1), 5% Tefose 63 and 20% oil (Labrafil M
1944 CS/Light mineral oil).
The screw with diameter ratio (Do/Di) of 1.71 and barrel diameter of 10
mm was selected for the extrusion process. The processing parameters
barrel temperature (70 ◦ C at feeding zone and 40 ◦ C at zone 2), screw
speed (200 rpm) and torque (0–3 Nm/shaft) of hot melt extruder was
set. The feeder speed was set to 30 rpm to feed the material at rate of 1.8
g/min. The oil phase was introduced at zone 2 to facilitate the adequate
mixing of both oil and aqueous phase. The flow rate of aqueous and oil
phase at feeding zone and zone 2, respectively was optimized using
peristaltic pump. The flow rate was fixed to dispense accurate quantities
of oil/aqueous phase per minute to maintain the desired composition of
creams. At the end zone (collecting zone) creams, were collected in a
container (double-walled, wide mouth, polypropylene with a poly­
ethylene foam layer, cream jars were used), and allowed to cool down to
room temperature [16]. The creams were then refrigerated and used for
further study.

2.2. Preparation of voriconazole creams

2.3. Characterization of Oil/PEG creams

2.2.1. Optimization of Oil/PEG cream

2.3.1. Fourier transform infrared spectroscopy (FTIR)
The Oil/PEG 3% w/w voriconazole creams F1 through F32 was
FTIR analysis of voriconazole, excipients (PEG 2000, PEG 400,
prepared using fusion method. The composition of voriconazole, pro­
camphor, menthol, tefose 63, labrafil M1944 CS, Transcutol® P, pro­
pylene glycol, Labrafil M 1944 CS, Transcutol® P, light mineral oil, and
pylene glycol and light mineral oil) and physical mixtures were per­
Tefose 63 were constant in all creams and the amount of PEGs (high
formed using Cary 600 series Fourier transform infrared spectrometer,
molecular weight/solid PEG 4500, PEG 3350, PEG 2000, and PEG 1450
Agilent Technologies. The scanning range used was 450–4000 cm− 1 and
and low molecular weight/liquid PEG 400) in formulation was varied as
the resolution was set at 1 cm− 1.
shown in Table 1 to prepare a stable formulation. The voriconazole API
was dissolved in the propylene glycol and then incorporated in aqueous
2.3.2. Voriconazole content uniformity
phase. The oil phase containing Tefose 63 (emulsifier) was heated at
The content uniformity was determined by collecting 10 mg of cream
70 ◦ C on a hot plate. The oil phase was added to the hydrophilic phase
samples from three different (top, middle and bottom) regions of the
maintained at 70 ◦ C in Silverson Homogenizer, homogenized at 100 rpm
cream container and dissolved in 1 ml of DMSO (dimethyl sulfoxide).
for 15 min at 70 ◦ C and allowed to cool with continuous homogenization
The mixtures were vortexed for 15 min then subjected to sonication for
at 100 rpm for 15 min [14]. The prepared creams were subjected to
10 min. After sonication, the mixtures were centrifuged for 10 min at
freeze thaw stability studies, where the creams were exposed to 3
13,000 rpm and 100 μl of supernatant samples were collected and
freeze-thaw cycles (24 h at room temperature: 24 h at − 20 ◦ C: 24 at
diluted up-to 1 ml with DMSO. The concentration of the samples was
room temperature: 24 h at 45 ◦ C: 24 h at room temperature) [15].
analyzed using High Performance Liquid Chromatography (HPLC). All
samples were analyzed in triplicate and drug content uniformity was
2.2.2. Continuous manufacturing of Oil/PEG creams using hot melt
determined by using the following formula
extruder
The formulation composition of creams, which are stable during Actual Drug content
% Drug Content = × 100
freeze-thaw cycles were selected for continuous manufacturing. The Theoretical Drug content
creams were manufactured by using co-rotating twin screw extruder
(OMICRON 10, STEER Life) as shown in Fig. 1. All the ingredients of 2.3.3. Differential scanning calorimetry (DSC) analysis
aqueous phase and oil phase were weighed separately. Oil phase and The DSC profile of drug, excipients and formulations was determined
aqueous phase was heated on a hot plate and maintained at 70 ± 5 ◦ C. using TA Instruments discovery series DSC 25. Analysis was performed

2
A. Shettar et al.
Fig. 1. Pictorial representation of Oil in PEG cream preparation using HME.
over the temperature range of 20–200 ◦ C at 10 ◦ C increments and ni­
trogen purge were set at 20 ◦ C/min. Samples were weighed (approxi­
mately 5 mg) in an aluminum pan, sealed with a hermetic lid [17].
TRIOS software was used to analyze the thermal behavior of vor­
iconazole in the formulations.
2.3.4. Viscosity measurement
The viscosity of the prepared formulations was determined using a
Brookfield viscometer (DV-II+) at 32 ◦ C temperature and with spindle
(3.2 cm) speed of 0.3 RPM. LV-4 spindle was fit near the shipping cap of
viscometer and the formulations were placed on the guard leg, and the
spindle was immersed into a glass vial. The instrument was allowed to
stabilize for 15 min and readings were noted for each cream formulation
in triplicate.
2.4. In-vitro release testing (IVRT)
2.4.1. Screening of receptor media
Voriconazole solubility in different solvents were evaluated to
identify ideal receptor media to maintain sink conditions for release and
permeation studies. The saturation solubility of voriconazole in 0.2% w/
v Brij S20, 0.5% w/v Brij S20, 1% w/v Brij S20, 2% w/v Brij in 10% v/v
PG, 0.2% w/v Brij C20 (AP), 2% v/v PEG 400, 1% v/v tween 80, 1% v/v
tween 20 and 10% v/v propylene glycol in PBS was determined. Vor­
iconazole was added to tubes containing above solvents and placed on
mechanical shaker for 24 h. These Samples were subjected to centrifu­
gation at 13,000 rpm for 15 min. The supernatants were collected and
diluted appropriately and subjected to HPLC analysis.
2.4.2. Drug-stability in receptor media
The drug in receptor media used for ex vivo permeation studies or
IVRT should be stable for period of the study performed. The stability of
voriconazole in receptor media was evaluated at 100 μg/mL con­
certation for 48 h at 32 ◦ C. After specified time period, 0.5 mL of
acetonitrile was added to 0.5 mL of drug solution in receptor media.
These samples were vortexed and centrifuged at 13,000 rpm for 15 min.
The supernatant was analyzed using HPLC.
2.4.3. Membrane inertness
Membrane inertness test was performed to evaluate non-specific
binding characteristics of voriconazole to membrane used for IVRT
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Journal of Drug Delivery Science and Technology 66 (2021) 102928
studies. The membrane selected for IVRT should offer free resistance for
drug diffusion [19]. The membrane inertness testing was performed at
50, 250 and 500 μg/mL concentrations of voriconazole. The nylon
membrane with pore size of 0.22 μm was soaked in the scintillation tube
and kept aside for 24 h. After 24 h, 200 μl of sample was withdrawn from
each tube and these samples were analyzed using HPLC to determine the
amount of drug bound to membranes.
2.4.4. In-vitro drug release test
The Vertical Franz diffusion cells (Logan Instruments Corp, USA)
with an active diffusion area 0.64 cm2 were used to determine the in vitro
drug release profile of voriconazole from the formulations. The tem­
perature of Franz cells was maintained at 32 ± 0.5 ◦ C for IVRT studies.
Nylon membranes with pore size of 0.22 μm was used for the release
study, these membranes were placed between the donor and receiver
compartment and clamped. The receiver compartment was filled with 5
mL receptor media and stirred with the magnetic stir bar at 600 rpm. In
the donor compartment 300 mg of cream was loaded. At pre-determined
time intervals (0, 1, 2, 3, 4, 5 and 6 h), aliquots of 0.3 ml of the media
were withdrawn from the receptor chambers and replenished with fresh
media. The IVRT samples were analyzed using HPLC.
2.5. Ex-vivo permeation testing
The human cadaver skin (New York fire fighters skin bank, NY, USA)
was used for ex vivo permeation studies. The formulations with good
release profile were selected for ex vivo permeation testing. The
permeation studies were performed with formulations without perme­
ation enhancer (negative control), with camphor: menthol (positive
control) [7], and 7.5% w/v Transcutol® P as permeation enhancers in
optimized formulation.
The ex-vivo skin permeation study was performed using Franz
diffusion cells with an effective diffusion area of 0.64 cm2. A human
cadaver skin was sandwiched between the donor and receiver media
with the stratum corneum (SC) facing the donor compartment. The
receiver compartment was filled with 5 ml of receptor media and tem­
perature was maintained at 32 ± 0.5 ◦ C. The drug loaded in donor
compartment for finite dose study was 10 mg/0.64 cm2. During the
permeation studies, at pre-determined time points (0, 4, 8, 12, 18 and
24 h) aliquots of 0.2 ml of the media were withdrawn from the receptor
chambers and replenished with fresh media. The amount of
A. Shettar et al.
voriconazole in these samples was quantified using HPLC. The average
flux was calculated and plotted to determine the maximum flux (J max)
and AUC0-t [20,21].
2.6. Stability studies
The optimized voriconazole cream and hydrogel (control) formula­
tions were stored at stability chamber at stability conditions (25 ◦ C/60%
RH and 40 ◦ C/75% RH) for the period of 3 months. The stored formu­
lations were analyzed for drug content uniformity and appearance after
3 months.
2.7. HPLC analysis of voriconazole
Analysis of voriconazole was performed using a Waters HPLC system
(Water 600 Controller, USA) equipped with a 600-pump unit, a 717 plus
auto sampler and 2487 dual absorbance UV detector. The chromato­
graphic separation was done using the reversed-phase C18 column (25
cm × 4.6 mm i.d., particle size 5 μm). An isocratic HPLC method was
used for eluting voriconazole [6,18]. The mobile phase consisted of a
mixture of acetonitrile and water (50:50, v/v), voriconazole was eluted
at flow rate of 1.0 mL min− 1 and eluent was monitored at 252 nm. The
Peak area integration was performed using Breeze software.
2.8. Statistical analysis
All the data were analyzed by GraphPad Prism 7 using student’s t-test
for single unpaired comparison between two groups. The difference was
considered significant when p-value < 0.05.
3. Results and discussion
3.1. Preparation of creams
3.1.1. Optimization of Oil/PEG creams
Initial studies demonstrated creams containing <8.5% w/w of PEG
2000 led to lesser than desired consistency. The preliminary screening of
F1 to F32 formulations were performed based on visual examination of
creams subjected to 3 cycles of freeze thaw stability. In formulations,
F1–F8 there was separation of dispersed and continuous phases which
could be due to use of low molecular weight PEG (1450) in preparation
of creams. Formulations F11–F32 resulted in paste like consistency
(8–10 × 104 cP) this is likely due to larger percentage of high molecular
weight PEG’s (2000, 3350, and 4500) in creams. Whereas, formulations
F9 and F10 containing PEG2000: PEG400 (15:85) had an acceptable
consistency. The oil phase used in F9 and F10 formulations were Labrafil
M 1944 CS and light mineral oil, respectively. Hence, F9 and F10
formulation composition was selected for continuous manufacturing
using twin-screw processor. The final compositions of F9 and F10
creams was, PEG 2000 (8.5% w/w), PEG 400 (48% w/w), propylene
glycol (8% w/w), permeation enhancers (7.5% w/w), voriconazole (3%
w/w), Labrafil M 1944CS (20% w/w) and Tefose 63 (5% w/w).
3.1.2. Continuous manufacturing of Oil/PEG creams using hot melt
extruder
Conventionally creams are prepared by homogenization of the in­
gredients, which involves applying sufficient energy to disperse one
phase into another and stabilizing the formulation using an emulsifier in
a batch process [22]. Preparation of oil in PEG creams employing
continuous manufacturing process would decrease the problems asso­
ciated with batch process.
The schematic representation of cream preparation using twin-screw
processor is depicted in Fig. 1. The flow rate of peristaltic pump was
optimized to dispense the desired composition of oil and aqueous phase
to prepare F9 and F10 creams. The peristaltic pump was set at a flow rate
of 45 and 20 rpm to dispense the aqueous (75% w/w) and oil phase
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Journal of Drug Delivery Science and Technology 66 (2021) 102928
(25% w/w) at feeding zone and zone 2, respectively. The F9 and F10
formulation prepared by using Hot melt extruder was subjected to
characterization.
3.2. Characterization of Oil/PEG creams
3.2.1. Fourier transform infrared spectroscopy (FTIR)
Physicochemical interactions of an active pharmaceutical ingredient
(API) and pharmaceutically inactive ingredients (excipients) in the
dosage forms is an integral part of pre-formulation studies, to develop a
dosage form. Although excipients are pharmacologically inert, they can
interact with drugs chemically in the dosage form to affect drug product
stability [23]. The FTIR spectra of the voriconazole, excipients and
formulations were analyzed to determine the physical (H-bonding) or
chemical interactions between API and excipients. The voriconazole
powder exhibited IR absorption bands at 3191 cm− 1 corresponding to
the stretching vibrations of OH− groups in the molecule. The bands at
3000–2850, 1600–1400, and 1360–1250 cm− 1 were corresponding to
the alkane CH, C = C aromatic and aryl C–N stretches of voriconazole
[24] [–] [26] as shown in Fig. 2. The formulations showed no major
shifting of any bands compared to drug and excipients spectra alone. The
IR spectra demonstrates that there are no drug-excipient interactions in
the formulations.
3.2.2. Drug content uniformity
In bulk manufacturing of topical formulations achieving a drug
content uniformity is challenging tasks. Uniformity of drug content
demonstrates the efficiency of mixing process and the low relative
standard deviation (RSD) of the drug content is a good indication of the
content uniformity of the creams. In this study, we found that the drug
content in the prepared creams were within the acceptable limits of
>90%, the limit set by the USP. The voriconazole content in F9 and F10
formulations were 101 ± 0.45% and 103 ± 1.78%, respectively. In
addition, the RSD of the drug concentration calculated based on samples
taken from different regions of the creams from cream jars was less than
3.5%, indicating acceptable uniformity of the drug in the creams [27,
28].
3.2.3. Differential scanning calorimetry (DSC)
The thermogram of voriconazole API demonstrated single endo­
thermic peak at 134 ◦ C, which shows that voriconazole exists in one
polymorphic form. The thermogram of F9 and F10 formulations showed
complete disappearance of drug peak (Fig. 3) suggesting conversion of
voriconazole from crystalline to amorphous form indicating the drug in
creams are in dissolved forms.
3.2.4. Viscosity measurements
Increase in viscosity of topical formulation decreases the drug
diffusivity and could potentially influence the drug release from
formulation. The viscosity of marketed topical formulations i.e., lotions,
gels and creams range from 10 to 60 × 104 cP [29,30]. Viscosity of F9
and F10 formulations were 34.3 ± 3.00 and 27.5 ± 1.33 × 104 cP,
respectively. The viscosity of formulations containing Labrafil M 1944
CS was relatively higher compared to formulations containing light
mineral oil.
3.3. In-vitro release testing (IVRT)
3.3.1. Drug solubility studies (receptor media selection)
As shown in Table 2, the solubility of voriconazole was in the range
of 648–1369 μg/mL in Brij™ S-20 (0.2, 0.5, 1 and 2%) in 10% propylene
glycol and 1% Tween 20. The solubility of voriconazole was higher
(1369 μg/mL) in 2% w/v Brij™ S-20 in 10% propylene glycol compared
to other solvents used to enhance solubilization. Hence 2% w/v Brij™ S-
20 in 10% propylene glycol was selected as the receptor medium for
IVRT and permeation studies.
A. Shettar et al. Journal of Drug Delivery Science and Technology 66 (2021) 102928

Fig. 2. The FTIR spectra of voriconazole, excipients, physical mixtures and optimized formulations.

Fig. 3. The DSC thermogram of voriconazole, excipients and optimized formulations.

adsorption of API to the nylon membrane on exposure to the drug so­

Table 2
lution. The amount of drug adsorbed on the membrane was 0.86 ±
The solubility of voriconazole in different solvents (mean ± SD) n =
1.28%, 0.70 ± 0.07% and 0.10 ± 3.90% on the exposure of membrane to
3.
solutions containing 50, 250 and 500 μg/ml of voriconazole, respec­
Media Solubility (μg/ml) tively. Thus, demonstrating nylon membrane does not act as a rate
0.2% Brij S20 648 ± 19.3 controlling barrier and the drug release would be absolutely attributed
0.5% Brij S20 794 ± 5 .04 to formulation properties.
1% Brij S20 1034 ± 8.39
2% Brij S20 in 10% PG 1369 ± 3.63
0.2% Brij C20 (AP) 570 ± 7.01 3.3.4. In-vitro drug release test
2% PEG 400 489 ± 4.84 The IVRT study results (Fig. 4) showed that F9 and F10 oil/PEG
1% Tween 80 694 ± 157 cream formulations prepared by the hot melt extrusion process followed
1% Tween 20 789 ± 3.79 Higuchi’s release profile. In vitro release rate of the F9 and F10 formu­
10% Propylene glycol 656 ± 6.66
PBS 477 ± 10.3
lations were 2561 ± 282 and 6504 ± 380 μg/cm2/h, respectively. The in
vitro release rate of F10 (6504 ± 380 μg/cm2/h), F10P1 (7410 ± 685 μg/
cm2/h) and F10P2 (6758 ± 319 μg/cm2/h) formulations were signifi­
3.3.2. Drug-stability in the receiver medium cantly (p < 0.05) higher compared to F9 (2561 ± 282 μg/cm2/h), F9P1
Stability studies demonstrated voriconazole in 2% w/v Brij™ S-20 in (3054 ± 603 μg/cm2/h) and F9P2 (2775.81 ± 286 μg/cm2/h) formu­
10% propylene glycol at 100 μg/ml concentration was 98.7 ± 4.77% lations. Approximately 2.53-fold increase in release rate of voriconazole
stable at 32 ◦ C for 48h. These study results demonstrate voriconazole from F10 compared to F9 formulations could be attributed to lower
would remain stable in receiver media intended for IVRT and perme­ viscosity and different oil phase/permeation enhancers used in F10
ation study. compared to F9 formulations.

3.3.3. Membrane inertness

Membrane inertness test demonstrated that there was negligible

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A. Shettar et al. Journal of Drug Delivery Science and Technology 66 (2021) 102928

Fig. 4. The In-vitro drug release profile of voriconazole from F9, F9P1, F9P2 and F10, F10P1, F10P2 formulations (mean ± SD) n = 3.

3.4. Ex-vivo permeation testing
Drug permeation through skin under ex vivo conditions can be used
to predict percutaneous absorption in humans [31]. The optimized
formulations without permeation enhancers (F9 and F10), with
permeation enhancer camphor: menthol (F9P1 and F10P1) and Trans­
cutol® P (F9P2 and F10P2) were studied. The ex vivo permeation profile
(Fig. 5) and data (Table 3) demonstrates formulation with permeation
enhancer (F9P1, F10P1, F9P2 and F10P2) increases permeation of
voriconazole across human cadaver skin compared to formulation
without permeation enhancers (F9 and F10). The cumulative amount
permeated and Jmax (Table 3) of formulations was in the order of F9P2
> F10P2 > F10P1 > F9P1 > F9 > F10. The permeation of voriconazole
across human cadaver skin from F9P1 and F10P1 (with camphor:
menthol) formulation was 2.27 and 10.0-fold higher compared to F9 and
F10 formulations (without permeation enhancers), respectively. Previ­
ously reported studies have demonstrated incorporation of camphor:
menthol (1:1) in formulation enhances the permeation of voriconazole
across the skin [32].
When enhancers were incorporated, the permeation of voriconazole

Fig. 5. The Ex vivo drug permeation profile of the formulations with and without permeation enhancers across human cadaver skin (mean ± SD) n = 3.

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A. Shettar et al. Journal of Drug Delivery Science and Technology 66 (2021) 102928

Table 3 Table 4
The cumulative amount of drug permeated and flux of voriconazole formula­ The stability of F9P1, F9P2, F10P1 and F10P2 formulations at 25 ◦ C (60% RH)
tions at finite dosing (mean ± SD) n = 3. and 40 ◦ C (75% RH) for 3 months (mean ± SD) n = 3.
Formulation ID Cumulative amount permeated (μg/cm2) Jmax (μg/cm2/h) Conditions Formulations Parameters

F9 0.81 ± 0.02 0.18 ± 0.10 Content Viscosity pH Appearance

F10 0.56 ± 0.05 0.12 ± 0.08 uniformity (cP X 104)
F9P1 2.20 ± 0.43 0.36 ± 0.26 (%)
F9P2 9.31 ± 0.89 0.91 ± 0.30
25 ◦ C/60% F9P1 94.2 ± 0.89 27.13 ± 6.53 No change
F10P1 5.62 ± 1.22 0.55 ± 0.39
RH 1.23 ±
F10P2 8.75 ± 2.46 0.87 ± 0.75
0.13
F9P2 93.5 ± 1.59 24.13 ± 6.25 No change
0.50 ±
from F9P2 and F10P2 formulations (containing Transcutol® P) were 0.09
4.23 and 1.56-fold higher compared to F9P1 and F10P1 formulations, F10P1 93.8 ± 0.45 26.54 ± 6.41 No change
respectively. The current study demonstrates higher potential of 2.31 ±
Transcutol® P to increase the permeation of voriconazole across human 0.12
F10P2 95.1 ± 1.25 27.53 ± 5.76 No change
cadaver skin compared to camphor: menthol. Transcutol® P is an
1.33 ±
excellent solvent to enhance the solubility and penetration of lipophilic 0.11
drugs envisioned for topical delivery. Transcutol® P increases the Hydrogel 10.7 ± 3.58 13.67 ± 6.78 No change
permeation by modifying stratum corneum barrier properties, which 1.71 ±
0.04
enhances the penetration of drug into viable epidermis (Osborne and
40 ◦ C/75% F9P1 78.7 ± 1.30 25.27 ± 6.59 No change
Musakhanian, 2018). It is safe to use and has low irritancy inferred by RH 1.04 ±
numerous toxicological studies and precedence of use in approved 0.10
topical medicines [33,34]. The study results indicate formulation con­ F9P2 73.9 ± 1.50 22.72 ± 6.49 No change
taining Transcutol® P increases the permeation of voriconazole signif­ 0.77 ±
0.06
icantly compared to formulation containing camphor: menthol,
F10P1 77.7 ± 3.38 23.90 ± 6.55 No change
irrespective of oil phase in the formulations. 1.91 ±
0.07
3.5. Stability studies F10P2 78.5 ± 3.69 25.83 ± 5.81 No change
1.51 ±
0.09
The long term and accelerated stability of voriconazole products Hydrogel 4.28 ± 0.20 9.89 ± 6.12 No change
were evaluated. Study results demonstrated there was no significant 0.91 ±
variation (p < 0.05) physical appearance of the formulation for the 0.10
period of 3 months. The voriconazole in cream formulations were
relatively stable compared to hydrogel formulation at 25 ◦ C (60% RH)
Declaration of interests
and 40 ◦ C (75% RH) (Table 4). However, voriconazole percentage in
hydrogel (control) was significantly declined after 3-month stability
The authors declare that they have no known competing financial
studies as shown in Table 4. The study shows Oil/PEG formulation
interests or personal relationships that could have appeared to influence
would be better approach to prevent the hydrolysis of voriconazole in
the work reported in this paper.
topical formulations. Previous reported studies have demonstrated
The authors declare the following financial interests/personal re­
thermal degradation of voriconazole, same was evident in current
lationships which may be considered as potential competing interests:
studies where voriconazole formulations were less stable at 40 ◦ C (75%
RH) compared to 25 ◦ C (60% RH) [6,35].
CRediT authorship contribution statement
4. Conclusion
Abhishek Shettar: Conceptualization, Methodology, Validation,
Investigation, Writing – original draft, Writing – review & editing. Vijay
The Oil/PEG creams of voriconazole were successfully developed
Kumar Shankar: Methodology, Validation, Supervision, Writing – re­
using melt extrusion as a continuous manufacturing process. The
view & editing. Srinivas Ajjarapu: Methodology, Writing – review &
Transcutol® P in creams increased the permeation of voriconazole
editing. Vijay I. Kulkarni: Supervision, Writing – review & editing.
across the human cadaver skin compared to creams without enhancers
Micheal A. Repka: Supervision, Writing – review & editing. S. Nar­
and with camphor: menthol (1:1). The study demonstrates voriconazole
asimha Murthy: Conceptualization, Supervision, Methodology, Vali­
oil/PEG creams can be better alternative for intravenous or oral vor­
dation, Writing – review & editing.
iconazole for treatment fungal skin infections. The voriconazole in Oil/
PEG creams were stable compared to voriconazole in hydrogel control
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