Development and evaluation of a polyvinyl alcohol

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 b

Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University, Atlanta, GA, USA 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: Received 19 February 2017 Received in revised form 21 March 2017 Accepted 26 March 2017 Available online 27 March 2017

Topical drug delivery systems provide localized drug action. A hydrophilic polymer such as polyvinyl alcohol is a multi-faceted excipient that can be used as a coating agent, lubricant, stability enhancer and viscosity-increasing agent. The objective of our study was to evaluate the use of polyvinyl alcohol polymer in preparing a topical gel with a diclofenac salt as the pharmaceutical active. The gel was characterized for its rheological and other properties and its effectiveness to deliver drug through dermatomed 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 Transcutol® P. Formulation was tested for pH, rheology, adhesion, spreadability, skin irritation, in vitro drug distribution in skin, and permeation. The formulated topical gel delivered an average cumulative drug 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 mean cell viability value of 107.41± 40.81% rendered by in vitro skin irritation test confirmed the formulated gel to be non-irritant to human skin. In conclusion, a safe efficacious and rheologically competent polyvinyl alcohol polymer based topical diclofenac gel was developed and characterized successfully. © 2017 Elsevier B.V. All rights reserved.

Keywords: Polyvinyl alcohol Topical gel Diclofenac salts Hydroxypropyl cellulose Skin irritation Rheology

1. Introduction The increasing interest in topical drug delivery we see today is a reflection of its advantages and opportunity to create reformulations of established drugs. The rise in demand for convenient selfadministrating 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 compositions 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 pharmaceuticals 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: [email protected] (A.K. Banga). http://dx.doi.org/10.1016/j.jddst.2017.03.021 1773-2247/© 2017 Elsevier B.V. All rights reserved.

fluctuation in drug levels and avoidance of systemic side effects by bypassing gastrointestinal track and first pass metabolism [1]. As a result, several topical semi-solid preparations such as gels, ointments, lotions and creams are currently on the market. Among these, gels are semi-solid preparations that comprise of a dispersion 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

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 extensive 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 solutions [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 reported 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 nonsteroidal 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.

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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

2. Material and methods

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.

2.1. Materials

2.5. Skin resistance and thickness

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 MilliporeSigma, 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 Transcutol® P were obtained from PHARMCO-AAPER (Brookfield, CT, (Saint-Priest Cedex, France) respectively. USA) and Gattefosse 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 reagents of analytical grade were used.

Dermatomed human skin (New York Fire Fighters, NY, USA) was tested for thickness using material thickness gauge (0-1in/025 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 displayed on the multimeter. Skin resistance (RS) was calculated and recorded in kU/cm2.

2.2. Formulation preparation 2.6. In vitro permeation study 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

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

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with a magnetic stirrer at a rotational speed of 600 rpm. The receptor 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 tetrazolium 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 formazan 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 isopropyl 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 diclofenac 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 formulation while PVA with HPC reduced the formation of drug crystals. In addition, PVA-HPC blend formulation did not require a neutralizer 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 properties. 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 Propylene Glycol Isopropyl alcohol Hydroxypropyl cellulose Transcutol® P Polyvinyl alcohol (12%) in deionized water Total

1.00 10.00 10.00 4.50 10.00 64.50 100.00


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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 efficiency 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

®

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 dermatomed 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 published 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

gel.

Viscoelastic parameters

Angular frequency (rad/s)

Polyvinyl alcohol topical gel

Innovator gel

Complex Viscosity [Pa.s]

100 10 0.1 100 10 0.1 100 10 0.1

40.6 250.0 7970.0 3810.0 2340.0 604.0 1410.0 884.0 520.0

4.0 26.9 2190.0 390.0 268.0 217.0 69.6 29.0 27.9

G0 Storage Modulus (Pa)

G00 Loss Modulus (Pa)

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

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 diclofenac 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

®

gel.

cumulative drug permeation (Fig. 4) from PVA based gel and Voltaren® (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 difference. 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.


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

®

215

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 nonaqueous based formulations in enhancing the delivery of diclofenac [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]. According 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 formulations 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

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was characteristically evaluated based on its viscoelastic properties, adhesive strength, spreading efficiency and safety to develop a nonirritant, topical gel with suitable adhesion, rheology, and spreadability. 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 statistically 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 irritation test. References [1] Michael N. Pastore, Y.N. Kalia, Michael Horstmann, M.S. Roberts, Transdermal patches: history, development and pharmacology, Br. J. Pharmacol. 172 (9) (May 2015) 2179e2209. [2] Topical and transdermal drug products, Pharmacopeial Forum 35 (3) (MayeJune 2009) 750e764. [3] Anil Kurain, M.N and Benjamin Barankin. Delivery vehicle advances in dermatology, updated December 2016, Available from: http://www. skintherapyletter.com/fp/2011/7.2/2.html. [4] Sudhir Bharadwaj, G.D. Gupta, V.K. Sharma, Topical gel: a novel approach for drug delivery, J. Chem. Biol. Phys. Sci. 2 (2) (2012) 856e867. [5] Loveleen Preet Kaur, Tarun Kumar Guleri, Topical gel: a recent approach for novel drug delivery, Asian J. Biomed. Pharm. Sci. 3 (17) (2013) 1e5. , History and ap[6] N. Chirani, L. Yahia, L. Gritsch, F.L. Motta, S. Chirani, S. Fare plications of hydrogels, ResearchGate 4 (2) (2015 Dec 1) 13e23. [7] E.A. Kamoun, X. Chen, Mohy Eldin MS, Kenawy E-RS. Crosslinked poly(vinyl alcohol) hydrogels for wound dressing applications: a review of remarkably blended polymers, Arab. J. Chem. 8 (1) (2015 Jan) 1e14. [8] C.C. DeMerlis, D.R. Schoneker, Review of the oral toxicity of polyvinyl alcohol (PVA), Food Chem. Toxicol. 41 (3) (2003 Mar) 319e326. [9] E.-R. Kenawy, E.A. Kamoun, M.S. Mohy Eldin, M.A. El-Meligy, Physically crosslinked poly(vinyl alcohol)-hydroxyethyl starch blend hydrogel membranes: synthesis and characterization for biomedical applications, Arab. J. Chem. 7 (3) (2014 Jul) 372e380. [10] L. Zhao, H. Mitomo, M. Zhai, F. Yoshii, N. Nagasawa, T. Kume, Synthesis of antibacterial PVA/CM-chitosan blend hydrogels with electron beam irradiation, Carbohydr. Polym. 53 (4) (2003 Sep 1) 439e446. [11] D.S. Muggli, A.K. Burkoth, K.S. Anseth, Crosslinked polyanhydrides for use in orthopedic applications: degradation behavior and mechanics, J. Biomed. Mater. Res. 46 (2) (1999 Aug) 271e278.

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