Journal of Drug Delivery Science and Technology 39 (2017) 210e216

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Journal of Drug Delivery Science and Technology

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

Development and evaluation of a polyvinyl alcohol based topical gel

Arunprasad Sivaraman a, Sindhu S. Ganti a, Hiep X. Nguyen a, Gudrun Birk b,
Alena Wieber b, Dieter Lubda b, Ajay K. Banga a, *
a
Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA, USA
b
Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany

a r t i c l e i n f o a b s t r a c t

Article history: Topical drug delivery systems provide localized drug action. A hydrophilic polymer such as polyvinyl
Received 19 February 2017 alcohol is a multi-faceted excipient that can be used as a coating agent, lubricant, stability enhancer and
Received in revised form viscosity-increasing agent. The objective of our study was to evaluate the use of polyvinyl alcohol
21 March 2017
polymer in preparing a topical gel with a diclofenac salt as the pharmaceutical active. The gel was
Accepted 26 March 2017
Available online 27 March 2017
characterized for its rheological and other properties and its effectiveness to deliver drug through der-
matomed human skin compared to a similar commercially available topical gel. Topical polyvinyl alcohol
based gel was prepared with propylene glycol, isopropyl alcohol, hydroxypropyl cellulose, and Trans-
Keywords:
Polyvinyl alcohol
cutol® P. Formulation was tested for pH, rheology, adhesion, spreadability, skin irritation, in vitro drug
Topical gel distribution in skin, and permeation. The formulated topical gel delivered an average cumulative drug
Diclofenac salts amount of 22.85 ± 9.41 mg/cm2 across skin and delivered 10.30 ± 9.09 mg/cm2 in the skin over 24 h. The
Hydroxypropyl cellulose mean cell viability value of 107.41± 40.81% rendered by in vitro skin irritation test confirmed the
Skin irritation formulated gel to be non-irritant to human skin. In conclusion, a safe efficacious and rheologically
Rheology competent polyvinyl alcohol polymer based topical diclofenac gel was developed and characterized
successfully.
© 2017 Elsevier B.V. All rights reserved.

1. Introduction fluctuation in drug levels and avoidance of systemic side effects by

The increasing interest in topical drug delivery we see today is a
reflection of its advantages and opportunity to create reformula-
tions of established drugs. The rise in demand for convenient self-
administrating drug delivery options poses major opportunities for
the advancement of topical formulations. Furthermore, advances in
modern technologies and polymer sciences are resulting in a larger
number of pharmaceuticals being delivered topically for dermal
and transdermal delivery. Topical drug delivery systems to treat
superficial disorders, systemic ailments and for use as cosmetics are
copiously varied, complex, multicomponent, heterogeneous com-
positions that requires extensive experimentation to attain the final
desired formulation. It allows application onto the site of action
resulting in numerous advantages: the ability to deliver pharma-
ceuticals more selectively to the site of interest, improved patient
compliance, self-administration, sustained release, reduced
* Corresponding author. College of Pharmacy, Department of Pharmaceutical
Sciences, Mercer University, Atlanta, GA, USA.
E-mail address: banga_ak@mercer.edu (A.K. Banga).
bypassing gastrointestinal track and first pass metabolism [1]. As a
result, several topical semi-solid preparations such as gels, oint-
ments, lotions and creams are currently on the market. Among
these, gels are semi-solid preparations that comprise of a disper-
sion phase of inorganic or organic molecules interspersed by liquid
in a three dimensional matrix [2]. Apart from many advantages of
topical delivery, gels have a cooling effect upon application, provide
quick onset of action and significant long-term efficacy compared
to conventional treatments along with good safety profile and high
patient satisfaction [3].
The rigidity of a gel structure originates from a network
composed by physical or chemical interlinking of particles and the
type of force responsible for interlinking determines the structure
and properties of gel. While there can be many components in a gel,
the fundamental component required to form the structural
network of the gel are polymers. Topical gels can be prepared with
naturally occurring polymers, natural polymers that are chemically
modified or chemically synthesized polymers. Drug release from
gel mainly depends upon the physicochemical properties of the
drug and its polymer. Polymer blends have been used to control
drug release rates and polymers can be blended in different ratios

http://dx.doi.org/10.1016/j.jddst.2017.03.021
1773-2247/© 2017 Elsevier B.V. All rights reserved.
 A. Sivaraman et al. / Journal of Drug Delivery Science and Technology 39 (2017) 210e216
to combine the advantages of individual polymers [4,5]. In order to
achieve a high degree of swelling, synthetic polymers like polyvinyl
alcohol (PVA) that are water-soluble when in non-cross-linked
form are commonly used [6,7]. Physical properties of PVA such as
solubility, flexibility, tensile strength, adhesiveness, pH, viscosity,
loss on drying, melting point, refractive index, heavy metals and
residue on ignition vary with their molecular weight
(20,000e200,000) and grade used. PVA polymer due to its exten-
sive range of physical properties and good biocompatibility has
been used in biomedical applications such as wound dressing,
wound management, drug delivery systems, artificial organs and
contact lenses [7e13]. Despite its appealing properties, its use is
limited to topical patches and jellies, tablets and ophthalmic solu-
tions [14].
In recent years, a combination of polymers have proven to be
successful in obtaining polymeric structures of specific properties.
For example, research has demonstrated the blending of PVA with
natural biopolymers such as hydroxypropyl cellulose (HPC) can
change the micro-molecular and macromolecular structure of the
gel leading to improved thermal stability and decreased crystalline
nature of the polymeric blend. Previous investigations have re-
ported the advantages of using HPC alone or in combination with
PVA to formulate gels. HPC belongs to the group of cellulose ethers
soluble in water as well as in polar organic solvents, which makes it
versatile to combine aqueous and non-aqueous solvents [15,16].
In our current study, we used the combination of PVA and HPC
to formulate a diclofenac sodium topical gel to provide local and
systemic anti-inflammatory effects. Diclofenac, a member of non-
steroidal anti-inflammatory drug (NSAID), is used by more than
one billion patients and ranks as the eighth largest selling drug in
the world [17]. The aim of the study was further extended to
evaluate the physicochemical properties of the formulated gel and
compare the in vitro drug distribution and permeation to
commercially available Voltaren® gel using dermatomed human
skin.
2. Material and methods
2.1. Materials
PVA polymer [1.41350 PVA 4 - 88 EMPROVE ® exp Ph Eur, USP,
JPE - Viscosity (4%, water) - 3.4e4.6 mPa s; MW: ~31,000 Da,
1.41352 PVA 26 - 88 - EMPROVE ® exp Ph Eur, USP, JPE - Viscosity
(4%, water) - 22.1e29.9 mPa s; MW: ~160,000 Da and 1.41353 PVA
40 - 88 EMPROVE ® exp Ph Eur, USP, JPE - Viscosity (4%, water) -
34e46 mPa s; MW: ~205,000 Da] was kindly gifted by Milli-
poreSigma, a business of Merck KGaA (Darmstadt, Germany).
Diclofenac epolamine was obtained from BOC Sciences (Shirley, NY,
USA). Diclofenac sodium and diethylamine were obtained from
Sigma-Aldrich (St. Louis, MO, USA). Isopropyl alcohol and Trans-
cutol® P were obtained from PHARMCO-AAPER (Brookfield, CT,
USA) and Gattefosse  (Saint-Priest Cedex, France) respectively.
Propylene glycol and pH 7.4 phosphate buffer saline were obtained
from EKI Industries (Joliet, IL, USA) and Fisher Scientific (Fairlawn,
NJ, USA) respectively. Hydroxypropyl cellulose was kindly gifted by
BASF - The Chemical Company (Tarrytown, NY, USA). All other re-
agents of analytical grade were used.
2.2. Formulation preparation
Gels were formulated using three different grades of PVA
[1.41350 PVA 26-88 - 1.41352 PVA 26 - 88 and 1.41353 PVA 40 - 88].
PVA (12% w/v) polymer solution using each of the three grades
were prepared by heating deionized water to 95
C followed by
gradual addition of polymer and mixed for 4 h until a homogenous
211
solution was formed. The drug was solubilized in a solvent mix of
propylene glycol, isopropyl alcohol and Transcutol® P. HPC was then
gradually added to the drug-solvent mixture and homogenized
using a Tissue Homogenizer (THq, Omni International, Kennesaw,
GA, USA). Previously prepared PVA solution was then added to this
homogenized mixture and further blended with low shear mixing
overnight using a rotating mixer (Gilson, Lewis Center, OH, USA) to
form a clear gel.
2.3. Rheological evaluation
Viscoelastic parameters such as elastic property or storage (G0 )
modulus, viscous or loss (G00 ) modulus and overall change in the
viscoelastic property or complex viscosity (h*) of PVA based gel and
innovator gels were measured using a rheometer (Anton Paar USA,
Ashland, VA, USA) at skin temperature (32
C). Amplitude sweep
test followed by frequency sweep test were conducted with an
angular frequency (u) ranging from 100 to 0.1 radians/second using
a rheometer spindle PP25/S of 24.987 mm surface diameter and a
gap setting of 0.1 mm to assess the viscoelasticity of the
formulations.
2.4. Tack and spreading efficiency
The adhesion and spreading efficiency of PVA and innovator gel
was evaluated using a texture analyzer (Texture Technologies Corp,
Marietta, GA, USA) with a 2.5 cm diameter probe. The instrument
was calibrated for force and height and the parameters such as
contact force and hold time were optimized with a return speed of
5 mm/s before testing. The probe was allowed to adhere to the
substrate at an approaching speed of 0.5 mm/s with a contact force
and hold time of 20 g and 10 s respectively. Subsequent pulling of
the probe from the gel resulted in debonding between the surfaces,
at which point the adhesion value was recorded. The spreading
efficiency was evaluated and recorded based upon the distance
spread by the gel because of the force and hold time applied by the
probe on the substrate.
2.5. Skin resistance and thickness
Dermatomed human skin (New York Fire Fighters, NY, USA) was
tested for thickness using material thickness gauge (0-1in/0-
25 mm, Electromatic Equipment Co., Inc. Cedarhurst, NY, USA) and
skin barrier property was measured to ensure the integrity using
electrical resistance. Skin resistance was measured using silver/
silver chloride electrodes, Agilent 33220 A, 20 MHz Function/
arbitrary waveform generator and 34410 A 6 ½ digital multimeter
(Agilent Technologies, CA, USA). Skin was mounted between the
receptor compartment of vertical Franz diffusion cells containing
10 mM phosphate buffer solution (PBS) at pH 7.4 and a donor
compartment containing 0.3 mL of the same. The tip of the silver
chloride electrode was placed in the donor compartment without
touching the skin and the silver wire was placed in the receptor
compartment. A frequency of 10 Hz, amplitude of 100 mV and a
load resistor of 100 kU (RL) were connected in series. The drop in
voltage across the circuit (VO) and skin (VS) was recorded as dis-
played on the multimeter. Skin resistance (RS) was calculated and
recorded in kU/cm2.
2.6. In vitro permeation study
The in vitro permeation study was conducted using vertical
Franz diffusion cells for 24 h. The thickness and integrity tested and
approved skin samples were placed on the receptor compartment
of Franz diffusion cells that contained 5 mL of 10 mM pH 7.4 PBS
212 A. Sivaraman et al. / Journal of Drug Delivery Science and Technology 39 (2017) 210e216
with a magnetic stirrer at a rotational speed of 600 rpm. The re-
ceptor chamber was surrounded by water jacket maintained at
37
C. The donor chamber was placed on the skin allowing a
diffusion area of 0.64 cm2, followed by application of 6.4 mg of the
drug formulation using a positive displacement pipette. Samples
were withdrawn periodically and fresh PBS was replaced after
sampling to maintain 5 mL of 10 mM PBS in the receptor
compartment. Samples were filtered through a 0.2 mm filter and
analyzed by HPLC quantification.
2.7. Drug distribution in the skin
The skin samples were carefully removed from the donor after
the permeation study. Samples were cleaned twice with dry q-tips
and twice with q-tips soaked in 10 mM PBS to remove any excess
drug formulation remaining on the surface of skin samples and
then followed by tape stripping (D-Squame stripping adhesive
tape, D101, CuDerm, Dallas, TX, USA). Twenty tapes (Tapes 1-5,
tapes 6-10 and tapes 11-20) were collected individually in 6-well
plates (Becton Dickinson, Franklin Lakes, NJ, USA). The epidermis
was then separated from the dermis layer using forceps, minced
with surgical scissors and placed in a separate 6-well plate followed
by addition of ethanol (2 mL) in each well. The 6-well plates with
the solvent were then placed overnight on a shaker at 100 rpm,
filtered through a 0.2 mm filter and analyzed by HPLC quantification.
2.8. Skin irritation
A validated in vitro EpiDerm™ skin irritation test (EPI-200-SIT)
with a 3D in vitro reconstructed epidermis (RhE) model (MatTek
Corporation 200 Homer Ave, Ashland, MA 01721) was used to
determine the cell viability of skin using methyl thiazolyl tetrazo-
lium assay. Around 30 mL of the sample was applied onto the skin
inserts for testing any potential skin irritation of the topical gel and
was compared to a positive (5% sodium dodecyl sulfate) and
negative (Dulbecco's phosphate buffered saline) control. After the
sample formulation was removed from the surface of tissue inserts,
the inserts were washed using PBS and transferred to a fresh assay
medium for a 24 h incubation and again for an 18 h incubation after
a fresh medium was replaced. The inserts were then transferred
into yellow methyl thiazolyl tetrazolium solution and incubated for
3 h. During the 3 h incubation, mitochondrial metabolism occurred
with formation of purple-blue formazan salt. The plate with the
inserts were filled with 2 mL of isopropyl alcohol and kept in a
shaker at 120 rpm for 2e3 h. The aliquots were then transferred to a
96 well ELISA plate and the optical density of the extracted for-
mazan was measured at 560 nm by a Synergy HT plate reader
(BioTek Instruments, Inc, Winooski, VT, USA).
2.9. HPLC analysis
Waters alliance HPLC system (e2695 Separating Module)
equipped with photodiode array detector (Waters Co., Milford, MA,
USA) was used to detect the drug in the Franz cell receptor and skin
at 276 nm wavelength. The composition of methanol (66% v/v) and
10 mM sodium di-hydrogen phosphate buffer (pH 2.5, 34% v/v)
were used to separate and quantify drug in an injection volume of
20 mL. This mobile phase was conducted at a flow rate of 1.2 mL/min
through a luna C8 column of 5 mm particle size and 4.6  250 mm
dimensions (Phenomenex, Torrance, CA, USA).
2.10. Statistical analysis
Statistical analysis was conducted for in vitro drug permeation
studies using t-test. A probability level of 0.05 (p < 0.05) was
considered to be significantly different for the tested formulations.
3. Results and discussion
3.1. Formulation preparation
Three different grades of PVA polymers were tested for the
formulation of topical gel. Based upon the preliminary studies, PVA
26 - 88 polymer demonstrated optimum viscosity and consistency
for a gel formulation in comparison to the other two polymers,
hence, this grade of the polymer was chosen for all further studies.
The gel formulations (Table 1) were prepared using diclofenac salts
including sodium, epolamine and diethylamine along with iso-
propyl alcohol, propylene glycol, HPC, Transcutol® P and PVA in
deionized water. Drug crystals developed in the gel formulation
containing diclofenac epolamine and diclofenac diethylamine as
shown in Fig. 1 (A) and (B) respectively. There were no drug crystals
observed in the gel formulation containing diclofenac sodium
hence this formulation was chosen for further characterization and
in vitro permeation studies.
Typically, crosslinked acrylic acid based carbopol polymers are
used in preparation of transdermal and topical gels because of their
thickening, suspending and stabilizing properties [18]. Previous
investigations have demonstrated superior permeation of diclofe-
nac salt from an aqueous based topical formulation that are in
combination with an organic base [19]. In the present study, PVA
polymer was used in combination with HPC to formulate the
topical gel. HPC was used to enhance the viscosity of the formu-
lation while PVA with HPC reduced the formation of drug crystals.
In addition, PVA-HPC blend formulation did not require a neutral-
izer for gelation while carbopol polymer based gels require a
neutralizer.
Solvents such as Transcutol® P, propylene glycol and isopropyl
alcohol increased the solubility of the drug. The resulting gel
formulation was found to have a pH of 7.1, which being closer to the
pH of water can be considered safe for topical application.
3.2. Rheological evaluation
The preparation and processing conditions such as high shear
homogenization or the addition of multiple excipients especially
the solvent based excipients can alter the viscoelastic properties of
the formulations. These properties govern the suitability of the gel
formulations for the desired application. Therefore it is important
to evaluate the viscoelastic properties of gels and this can be
analyzed by rheological assessment using a rheometer.
PVA, the primary agent in our formulation is a semi-crystalline
pharmaceutical polymer and the degree of crystallization is an
important factor in determining the solubility and swelling prop-
erties. PVA polymers are highly cross-linked three-dimensional
hydrophilic polymers with a glass to rubber transition at around
85
C. As a result of its structure and crystallinity, PVA is a highly
stable and chemically inert polymer [20]. The grade of PVA used in
Table 1
Formulation components of polyvinyl alcohol gel.
Formulation components % w/w
Diclofenac sodium 1.00
Propylene Glycol 10.00
Isopropyl alcohol 10.00
Hydroxypropyl cellulose 4.50
Transcutol® P 10.00
Polyvinyl alcohol (12%) in deionized water 64.50
Total 100.00
 A. Sivaraman et al. / Journal of Drug Delivery Science and Technology 39 (2017) 210e216
Fig. 1. Microscopy observation of diclofenac crystals in PVA gel formulations.
(A) Microscopic image of diclofenac epolamine crystals.
(B) Microscopic image of diclofenac diethylamine crystals.
our study for rheological evaluation has a degree of hydrolysis of
85e89%. The viscoelastic modulus of PVA based gels can be
increased with an increase in degree of hydrolysis but this results in
formation of crystallites [21,22]. Hence choosing the appropriate
grade of PVA with ideal degree of hydrolysis to prevent crystals but
with sufficient viscoelastic properties is vital. The viscoelastic
properties such as G0 , G00 and h * with u ranging from 100 to 0.1
radians/second were significantly higher for the formulated PVA
based gel over the innovator gel as shown in Table 2. The rubbery
nature and degree of crystallinity of PVA gel could have contributed
to this increase in viscoelastic properties. Greater drug diffusion can
be achieved from high viscosity semi-solid dosage forms compared
to a lower viscosity semi-solid dosage form [23]. As represented in
Table 2, PVA based gel exhibited substantially higher complex
viscosity at low angular frequency compared to the innovator gel.
No crossover points were observed for PVA based gel and
innovator gel as shown in Fig. 2 (A) and (B) which substantiates that
both the gels maintained their matrix structure with the applied
rheological stress parameters.
3.3. Tack and spreading efficiency
Evaluation of adhesion and spreading efficiency of a gel
formulation is an important criterion as these factors can directly
influence drug delivery. Apart from the material properties of the
formulation components, the experimental parameters (contact
force and hold time) used to assess adhesive strength also play a
critical role in evaluating the adhesion and spreading efficiency
[24]. The resulting average tack value (n ¼ 3) and spreading effi-
ciency value (n ¼ 3) for the formulated PVA based gel was found to
be 627.83 ± 189.52 g and 1.03 ± 0.15 cm respectively while that of
innovator gel was 301.63 ± 46.38 g and 1.10 ± 0.10 cm respectively
as represented in Fig. 3(A) and (B). The adhesive strength of PVA
depends upon its molecular structure and its degree of
Table 2
®
Rheological values of polyvinyl alcohol gel and Voltaren gel.
Viscoelastic parameters Angular frequency (rad/s)
Complex Viscosity [Pa.s] 100
10
0.1
G0 Storage Modulus (Pa) 100
10
0.1
G00 Loss Modulus (Pa) 100
10
0.1
213
polymerization. Viscoelastic properties and adhesive strength of
the PVA blend both affect the spreading efficiency of the gel [25].
Hence these parameters need to be harmonized to get good
adhesion with suitable spreading efficiency. Based on our results,
the PVA based gel formulation provided a comparatively higher
adhesion with similar spreading efficiency to that of the innovator
gel.
3.4. Skin resistance and thickness
Before performing in vitro drug permeation studies using der-
matomed human skin, it is important to assess the integrity of skin
samples to ensure skin was not compromised during handling [26].
Measuring the electrical resistance offered by skin can assess skin
integrity. The electrical resistance was measured with silver, silver
chloride electrodes, a voltage sensitive waveform generator and a
digital multimeter for read out according to our previously pub-
lished method in Sivaraman et al. [27]. Thickness of skin samples
were measured to minimize variations. The average skin thickness
and resistance were found to be 0.211 ± 0.05 mm and 20 ± 15 kU/
cm2 respectively. The range of values of skin resistance observed in
this study were in concordance with previous literature and skin
samples with resistance less than or equal to 3.4 kU/cm2 were
replaced [28].
3.5. In vitro drug permeation
In vitro drug permeation was performed using vertical Franz
diffusion cell to comparatively analyze the skin permeation of
diclofenac sodium from the prepared PVA based gel and the
commercially available innovator gel. Each vertical Franz diffusion
cell (n ¼ 4) comprised of a receptor compartment containing PBS of
pH 7.4 maintained at 37
C to mimic the in-vivo physiological
condition and a donor compartment containing the drug
Polyvinyl alcohol topical gel Innovator gel
40.6 4.0
250.0 26.9
7970.0 2190.0
3810.0 390.0
2340.0 268.0
604.0 217.0
1410.0 69.6
884.0 29.0
520.0 27.9
214 A. Sivaraman et al. / Journal of Drug Delivery Science and Technology 39 (2017) 210e216

®
Fig. 2. Rheological property of the topical formulations (A) PVA gel (B) Voltaren gel.

formulation [27]. Human dermatomed skin was clamped between
the two compartments and samples were withdrawn periodically
from the sample port in the receptor compartment. Since diclofe-
nac sodium is soluble in water (50 mg/mL), and PBS pH 7.2 (6 mg/
mL), the finite dose (6.4 mg) of drug formulation added in the donor
compartment has sufficient solubility in 5 mL of 10 mM pH 7.4
phosphate buffer solution maintaining sink conditions without
saturation of the solution [29]. The samples were then analyzed by
HPLC to quantitate the amount of drug permeated. The average
cumulative drug permeation (Fig. 4) from PVA based gel and Vol-
taren® (commercial innovator) gel over 24 h was 22.85 ± 9.41 mg/
cm2 and 26.41 ± 10.07 mg/cm2 respectively while the average flux
was 1.02 ± 0.57 mg/cm2/h and 1.14 ± 0.55 mg/cm2/h for the same.
Statistical comparison of cumulative drug permeation and flux of
the PVA based gel and innovator gel showed no statistical differ-
ence. PVA based gel showed an earlier onset of drug delivery than
the innovator gel and this can be beneficial for drug delivery of
certain medications especially the ones administered for pain.
 A. Sivaraman et al. / Journal of Drug Delivery Science and Technology 39 (2017) 210e216 215

®
Fig. 3. Tack testing of the topical formulations (A) PVA gel (B) Voltaren gel.

®
Fig. 4. In vitro cumulative permeation of diclofenac sodium from PVA gel and Voltaren gel.

Minghetti et al. reported that water behaved better than the non-
aqueous based formulations in enhancing the delivery of diclofe-
nac [19]. Since PVA based gel formulation is largely an aqueous
based formulation, this could be one of the contributing factors for
the rapid onset of drug delivery observed in this study.

3.6. Drug distribution in the skin

Tape stripping is a useful technique to investigate the amount of

drug in stratum corneum and the underlying layers of skin samples.
The combined amount of drug in the epidermal and dermal layers
was considered as the total quantity of drug in skin. The total
amount of diclofenac sodium in the skin for PVA based gel and
innovator gel was 10.30 ± 9.09 mg/sq.cm and 3.46 ± 1.10 mg/sq.cm
respectively. However, no statistically significant difference was
observed in drug distribution between the PVA based gel and
innovator gel formulations.
3.7. Skin irritation test
Considering topical drug delivery systems are applied on the site
of action that is skin, it is essential to evaluate the skin irritancy
potential of the formulated PVA based topical gel. The active
pharmaceutical ingredient and other formulation components such
as the excipients can cause potential skin irritation [30]. The drug
concentration, contact area and total time of application can
significantly contribute to the severity of irritation [31,32]. Ac-
cording to the in vitro EpiDerm™ skin irritation test (EPI-200-SIT),
the formulation resulting in more than 50% cell viability is
considered to be non-irritant to skin. The tested PVA based topical
gel resulted in a mean relative cell viability of 107.41 ± 40.81% while
the positive and negative control showed cell viability of
8.59 ± 1.00% and 100.00 ± 5.71% respectively as shown in Fig. 5.
Fig. 5. Skin irritation data.
Negative control is considered to be a non-irritant and the positive
control is a skin irritant. Since the PVA gel shows a cell viability of
above 50% and is closer to the negative non-irritant control, it can
be categorized as non-irritant to skin. Diclofenac sodium has been
incorporated into many topical dosage forms and is considered
largely non-irritant on intact skin. The major component of the gel
formulation apart from the drug is PVA polymer. Considering PVA is
a water-soluble polymer and the gel formulation is largely aqueous
based, these attributes add to the non-irritant nature of the
formulation. Moreover, previous literature reports PVA based for-
mulations to be non-toxic, non-carcinogenic and bioadhesive in
nature [33].
4. Conclusion
In our study, PVA polymer was used in combination with HPC to
prepare a topical diclofenac sodium gel. The resulting PVA based gel
216 A. Sivaraman et al. / Journal of Drug Delivery Science and Technology 39 (2017) 210e216
was characteristically evaluated based on its viscoelastic properties,
adhesive strength, spreading efficiency and safety to develop a non-
irritant, topical gel with suitable adhesion, rheology, and spread-
ability. Our study further compared the in vitro drug distribution
and in vitro drug permeation of the PVA based gel and Voltaren® gel
through dermatomed human skin to determine the efficiency and
competency of the formulated gel. Although there was no statisti-
cally significant difference observed between the drug permeation
and drug distribution between the two gels, PVA based gel showed
greater viscoelastic properties and produced an earlier onset of
drug delivery. In conclusion, a safe, rheologically competent, topical
gel using PVA polymer was successfully formulated with a drug
permeation profile similar to its analogous commercially used
innovator gel. Our investigation and findings can open new avenues
for the application of PVA polymer in not just topical drug delivery
but can also extend to other delivery systems.
Acknowledgement
This project was funded by Merck KGaA, 64271 Darmstadt,
Germany. The authors would like to acknowledge Pooja Nazar
Bakshi of Mercer University for her assistance with the skin irri-
tation test.
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