Iraqi J Pharm Sci, Vol.32( 1 ) 2023 Ondansetron hydrochloride transdermal patches DOI: https://doi.org/10.31351/vol32iss1pp147-155 147 Preparation and in Vitro Evaluation for Different Types of Ondansetron Hydrochloride Transdermal Patches Karima Abd Allatif *,1 and Jameela Ali Hasian** Department of Pharmaceutical Technology, Damascus University, Syria.  Department of Pharmaceutics, Faculty of Pharmacy, Damascus University, Syria. Abstract This research aims to develop transdermal patches of Ondansetron hydrochloride (OSH) with different types of polymers as ethyl cellulose and polyvinyl pyrrolidone k30 in a ratio (3:0.5,3:1,3:2,2:1,1:1) with propylene glycol 20%w/w as a plasticizer by the solvent evaporation technique. Prepared transdermal patches were evaluated for physical properties. The compatibility between the drug and excipients was studied by differential scanning calorimetry (DSC), where there is no interaction between the drug and polymers. From the statistical study, there is a statistical difference between all the prepared formulations p<0.05. In-vitro release study of transdermal patches was performed by using a paddle over the disc. The release profile of OSH followed Korsmeyer - Peppas model in P2 (EC:PVP 3:1, P4 EC:PVP 3:2) formulations and, Higuchi model in P1, P3, P5 formulations. The best formulation P6 carrying EC:PVP in ratio1:1 released 96.47% of ondansetron hydrochloride during 12 hr. The release profile of P6 followed the Higuchi model and correlation coefficient (r2 = 0.9815) Keywords: Ondansetron hydrochloride, Transdermal patches, Ethyl cellulose, Propylene glycol, Polyvinyl pyrrolidone. تحضير وتقييم في الزجاج ألنماط مختلفة من اللصاقات الجلدية من مادة األوندانسيترون هيدروكلورايد **جميلة حسيانو 1، *كريمة عبد اللطيف قسم الصيدالنيات والتكنولوجيا الصيدلية, كلية الصيدلة, جامعة دمشق . * جامعة دمشق. -كلية الصيدلة - قسم الصيدالنيات والتكنولوجيا الصيدلية ** ةالخالص لتحضير البحث هذا نسب الصقات يهدف باستخدام هيدروكلورايد األوندانسيترون مادة تحوي الماتريكس نمط من من جلدية مختلفة . تم w/w%20لماء والبولي فينيل بيروليدون المحب للماء باستخدام البروبلين غليكول كملدن بنسبة المحب لغير ايتيل سيللوز إمزيج البوليميرات ل المسح الحراري تمت دراسة التوافق بين السواغات والدواء من خال. الصقات األوندانسيترون هيدروكلورايد من ناحية الخواص الفيزيائيةتقييم التفاضلي حيث ال يوجد تداخل بين البوليميرات المستخدمة والدواء. أظهرت الدراسة اإلحصائية وجود فارق إحصائي بين جميع الصيغ المحضرة عة حيث سا 12لمدة paddle over the diskتم اجراء اختبار التحرر في الزجاج باستخدام جهاز المجداف فوق القرص P<0.05 . حيث كانت الصيغ الصيغ P2, P4تان حررت وحررت , بيباس ماير كورس نمط من الصيغة P1, P3, P5الدواء كانت هيغوتشي. نمط من P6الدواء . 0.98152r=هيغوشي وكانت قيمة ساعة بنمط تحرر 12خالل من الدواء %96.47قد حررت 1:1بنسبة EC: PVPالمكونة من بروبيلين غليكول ,بولي فينيل بيروليدون, ايتيل سيللوز, اللصاقات الجلدية, نسيترون هيدروكلورايداألونداالكلمات المفتاحية : Introduction Chemotherapy-induced nausea and vomiting (CINV) cause unpleasant side effects that affect the quality of life in patients and their compliance to chemotherapy(1). Serotonin receptor blockers are used in the treatment of nausea and vomiting caused by chemotherapy in the acute phase, which extends from 0 to 24 hr(1). Ondansetron hydrochloride (OSH) is a first- generation competitive serotonin receptor blocker used in the treatment of postoperative or chemotherapy-induced nausea and vomiting(2). Orally administered of ondansetron hydrochloride (OSH) undergoes extensive metabolism in the liver by cytochrome enzymes P450, which explains a short biological half-life and reduced bioavailability(3). The bioavailability of ondansetron hydrochloride is 60% after oral administration, and the half-life is 3-4 hr. Ondansetron hydrochloride has a low molecular weight(293.36 Da) and good transdermal penetration, so it has ideal properties to be introduced into the transdermal drug delivery system(4). Transdermal therapeutic systems are defined as discrete dosage forms applied to intact skin where the drugs are delivered through the skin to the systemic circulation(5). There are three types of transdermal patches: Single-layer Drug-in- Adhesive, the adhesive layer contains the drug and is responsible for releasing the drug. Reservoir, the drug layer is a liquid in a separate compartment in the form of a solution or suspension. The Matrix system is a semi-solid matrix that contains the drug in the form of a solution or suspension, where the adhesive layer surrounds the drug layer(6). 1Corresponding author E-mail: karimaabd523@gmail.com Received: 15/2 /2022 Accepted: 10/5 /2022 Iraqi Journal of Pharmaceutical Science https://doi.org/10.31351/vol32iss1pp147-155 Iraqi J Pharm Sci, Vol.32( 1 ) 2023 Ondansetron hydrochloride transdermal patches 148 The first generation is designed for drug delivery at low doses, the second generation has enhanced transdermal drug penetration with chemical permeability enhancers. The skin is the most common organ that receives one-third of the blood supply to all parts of the body. The skin was not known to be a systemic drug delivery route until the late twentieth century(7). Transdermal drug delivery systems deliver the drug into systemic circulation at a controlled rate to maintain constant drug concentrations in the plasma for long periods(8). Transdermal drug delivery systems avoid the first hepatic passage of drugs, reduce gastrointestinal side effects, and increase patient compliance(8). The first transdermal system containing scopolamine was approved in the United States in 1979; the US Food and Drug Administration (FDA) approved nicotine patches in 1984. A decade later, transdermal patches for pain relief, analgesic activity, contraception, and hormone replacement therapy were FDA approved and marketed (9). Materials and Methods Materials Ondansetron hydrochloride supplied from mahrshee laboratories pvt ltd panoli, India. Ethyl cellulose and polyvinyl pyrrolidone were obtained from SIGMA-ALDRICH. Chloroform and propylene glycol were obtained from warehouse chemicals of the College of the Pharmacy/ University of Damascus. Methods Solubility study The solubility of ondansetron hydrochloride was determined using different pH grades from a phosphate buffer pH 5.8, 6.8, 7.4 at 37° C. A saturated solution was prepared from Ondansetron hydrochloride by taking 1 g in 10 ml of each solution and placing it in a 50 ml plastic tube in a mechanical shaker for 24 hours. The solution was filtered, 1 ml was taken, and the absorbance was measured with a spectrophotometer at a wavelength of 310 nm(10,11). Spectrophotometric analysis Determination of λ max of ondansetron hydrochloride: The λ max was determined in phosphate buffer pH 5.8 by spectrophotometric scanning of OSH solution with a spectrophotometer in the range 200-400 nm. Preparation of standard solution: A stock solution of 1000 mcg/ml was prepared by taking 100 mg of the drug in a calibrated 100 mL volumetric flask and dilute it with a phosphate buffer with pH = 5.8. 1 ml was taken from the first stock solution and extended to 10 ml with a 10 ml calibrated volumetric flask to obtain a solution with a concentration of 100 mcg /ml(10), from this solution standard series with concentrations ranging from 5-30 mcg/ml was prepared and the absorption was measured with a spectrophotometer at a wavelength of 310 nm.The graph was drawn between the concentrations and the absorbance in phosphate buffer solution at pH 5.8. Preparation of backing film for the transdermal patch An aqueous solution of 4% polyvinyl alcohol was prepared by taking 4g of polyvinyl alcohol and add it to 100 ml of distilled water. It was placed in a water bath at 80 C° with stirring for two hr until a clear solution was obtained. After cooling the solution, 4 ml of the solution was poured into an Aluminum foil mold and dried at room temperature for 24 hr (12). Figure 1. Aluminum foil mold Preparation of transdermal patches The polymers were weighed as in table 1, added to 10 ml of chloroform, and kept aside until the polymers were completely dissolved for 12 hr. Then propylene glycol was added with stirring for 30 min, then 16 mg of OSH was added with stirring for another 30 min. The polymer solution was poured over the supporting layer and dried at room temperature for 24 hr. The molds were covered with inverted glass funnels to control the evaporation of the solvent(13). Table 1. Formulations of OSH Transdermal Patches P1 P2 P3 P4 P5 P6 EC 0.3g 0.3g 0.3g 0.3g 0.3g 0.3g PVP 0.05g 0.1g 0.15g 0.2g 0.25g 0.3g PG 0.067ml 0.076ml 0.086ml 0.096ml 0.10ml 0.11ml OSH 16mg 16mg 16mg 16mg 16mg 16mg solvent Chloroform Chloroform Chloroform Chloroform Chloroform Chloroform Up to 10ml Up to 10ml Up to 10ml Up to 10ml Up to 10ml Up to 10ml *EC-Ethyl cellulose; PVP-Polyvinyl pyrrolidone; OSH-Ondansetron hydrochloride; PG-Propylene glycol. Iraqi J Pharm Sci, Vol.32( 1 ) 2023 Ondansetron hydrochloride transdermal patches 149 Evaluation of Transdermal Patches Physical appearance The prepared transdermal patches were evaluated for morphology, transparency and, flexibility of the film(14). Folding endurance Three transdermal patches were evaluated, so the patch was folded into a specific piece several times until it broke. Foldability is determined by the number of times the patch is folded without breaking(15). Uniformity of weight Ten transdermal patches were weighed from each formulation individually on a sensitive scale and the standard deviation from the mean was calculated(16). The thickness of the patch The thickness of the film was determined by using a micrometer screw gauge device at several points of the film, then the average readings and standard deviation were calculated(17). Moisture uptake(14) Three transdermal patches were selected from each formulation. Each patch was weighed before starting the test and then placed in a desiccator containing a saturated solution of potassium chloride, which gives relative humidity of 84% w/w. The weight of the patches was then taken for 3 days, then the uptake percentage was calculated from the following relationship: M%= [Final weight – Initial weight / Initial weight] × 100. Moisture content(18) Three transdermal patches were selected from each formulation, where each patch was weighed before the start of the test, then it was placed in a desiccator containing Activated Calcium Chloride. The weight of the patches was taken for 3 days and moisture content was calculated from the relationship: M%= [Initial weight – Final weight / Final weight] × 100. Drug content determination: One cm2 of the film was weighed and dissolved in 10 mL of mixture of methanol and ethanol, then filled up with phosphate buffer solution to 100 mL. It was stirred for 24 hr, then the solution was filtered and the absorbance was measured at wavelength 310 nm maximum absorbance. The drug concentration was determined by the absorption equation from the standard graph(19). In vitro release study: The test was performed using a USP apparatus V (paddle over the disc). 500 ml of phosphate buffer solution was used at pH = 5.8, the device was set at a temperature of 32 + 0.5 ° C and a paddle speed of 50 rpm. The film was fixed on a circular glass disc by a stainless steel mesh and stainless steel clips then placed into the dissolution medium, so that it was 2.5 cm away from the paddle according to the requirements of the American Pharmacopeia. 5 ml were withdrawn after the following intervals of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 hr and replaced with phosphate buffer pH=5.8. The absorbance of samples was then measured using a spectrophotometer at wavelength 310 nm(20). Figure 2. Fixed transdermal patch Figure 3. Paddle over the disc Statistical analysis The statistical study was performed using a one-way ANOVA analysis through the statistical analysis program Graph Pad Prism 9 to study the effect of polymer and its percentage on the release of the drug. After applying the test, the p-value was calculated and the results were interpreted. Post-hoc Tukey-HSD (Honestly Significant Difference) test was performed where p< 0.05. Differential scanning calorimetry (DSC) study Thermal differential scanning of ondansetron hydrochloride, ethyl cellulose, polyvinyl pyrrolidone and, the physical mixture of the drug with the excipients was performed to determine any incompatibility between them. A device (DSC131, SITARAM, France) was used, and the samples taken with a quantity of 5 mg were placed in an open aluminum chamber against Iraqi J Pharm Sci, Vol.32( 1 ) 2023 Ondansetron hydrochloride transdermal patches 150 another aluminum chamber used as a reference, then the temperature was raised from (25 to350) C° at a rate of 10 degrees per min(21). Results and Discussions Solubility study Ondansetron was soluble within the PBS buffer pH 5.6. The solubility results are shown in Table 2. Table 2. Solubility of Ondansetron Hydrochloride. n=3 The solubility of ondansetron hydrochloride exhibits high solubility at low pH (pH 5.8, this degree is considered close to the skin’s pH so that the patch does not cause irritation to the skin ) at 37°C because of Ondansetron HCl is a weakly basic drug belongs to BCS Class-II and it is showing distinct pH-dependent solubility ; however, it exhibits poor solubility at higher pH (6.8 pH phosphate buffer) at 37°C. These results were parallel with the findings of Anilkumar et al where the solubility in phosphate buffer pH=6.8 was found to 36 µg/ml (22) . Spectrophotometric analysis Standard graph of OSH in PBS pH 5.8 The estimated λ max is 310nm that's agreed with the reported values figure. 4. Figure 5 showed the calibration curve within the involved media.The standard graph showed good linearity with R2 =0.999 which indicates that it obeys “Beer- Lambert’s” law. Figure 4. λ max of OSH in phosphate buffer pH=5.8 Figure 5. Standard curve of OSH in phosphate buffer pH=5.8 Evaluation prepared transdermal patches A smooth, non-broken and, thin matrix was obtained. Table 4 shows the results of physical tests for the prepared formulations, where the results of the foldability test ranged between (22- 100) times(4), which indicates that the use of propylene glycol as a plasticizer gave the unbroken film. For the weight test, there is no specific constitutional value for weights of transdermal patches. The weights of the patches ranged between (0.32-0.54) g, and we notice a small difference in the standard deviation values ranging between (0.003-0.01), which indicates uniformity of weight. For drug content uniformity test, results were found in the range (92-99) %, which indicates a homogeneous distribution of the drug within the patch. Table 3. Physical evaluation of ondansetron hydrochloride films Folding endurance ±SD Thickness (mm) ±SD Drug content (%)±SD Weight variation (g) ±SD Patch code 22±2.16 0.1mm 98.49±0.7 0.32±0.004 P1 26±1.24 0.2mm 94.55±0.95 0.433±0.004 P2 46±1.24 0.2mm 97.89±0.24 0.443±0.012 P3 71±1.35 0.3mm 92.88±1.02 0.495±0.005 P4 97±2.05 0.3mm 96.67±0.56 0.545±0.003 P5 106±1 0.3mm 99.21±1.78 0.565±0.007 P6 n=3, SD= Standard Deviation. Solubility(µg/ml) Time duration(hr) Solubility medium 515±0.01 µg/ml 24 Phosphate buffer Ph=5.8 23±0.12 µg/ml 24 Phosphate buffer Ph=6.8 insoluble 24 Phosphate buffer Ph=7.4 Iraqi J Pharm Sci, Vol.32( 1 ) 2023 Ondansetron hydrochloride transdermal patches 151 Moisture uptake and moisture content Table 5 shows the results of the moisture uptake test for all prepared formulations. The formula P1 is the lowest among all formulations due to the decrease in the amount of PVP in the formula, which amounted to 3.29±0.05, while the moisture uptake percentage increases with the increase in the amount of PVP in the formula, and this is explained by its hygroscopic nature. In addition, the plasticizer works to separate the polymer chains from each other, which facilitates the absorption of water into the matrix, These results are in agreement with sheba et al where PG containing patches have higher percentage of moisture content and water absorption (> 1)(3). The moisture content test showed an increase in moisture content with the increase in the amount of PVP in the formula. P6 gave the largest value of 6.82±0.18 after72 hours because it contained the largest amount of PVP unlike formula P1, which has the lowest value. Table 4. Moisture uptake and moisture content of OSH films. Patch code Moisture uptake 72hr±SD Moisture content 72hr±SD P1 3.29±0.05 4.45±0.16 P2 5.21±0.48 4.83±0.05 P3 5.6±0.19 5.14±1 P4 6.17±0.15 5.52±1.82 P5 7.01±0.13 6.7±1.82 P6 7.21±0.48 6.82±0.18 *72 h: test after 72 hr, SD= Standard Deviation. In vitro release study The cumulative % of ondansetron hydrochloride release were shown in Table 5, and release curves of ondansetron hydrochloride were shown in Figure 6. There is an initial release from all formulations after 30 min and it lasted for 12 hr. The release of the drug from formulations P1-P6 gradually increases with the increase in the amount of PVP while the amount of EC remains constant, this is explained by the hydrophilic nature of PVP which facilitates absorption of water to the matrix enhances the release of the drug, in addition, the PVP works to form pores in the matrix structure that facilitates drug particles leave to the dissolving medium(3). Furthermore, the presence of PVP in patches with chloroform as casting solvent reduce the crystalline state of the drug, which leads to an increase in drug release. These results are in agreement with mutalic et al where the formulation with EC:PVP (3:2) exhibited the greatest percentage of drug release value (71.25 %±8.55) compared to the lowest value observed with the formulation containing EC:PVP (4.5:0.5) (47.65%±9.55)(23). . Formulation P6 gave the highest release rate when using EC and PVP with a ratio of 1:1. One- way ANOVA analysis produced statistically significant differences among all formulations where p=0.001, (p<0.05). Table 5. In vitro drug release from P1 to P6. Time hr P1 P2 P3 P4 P5 P6 0 0 0 0 0 0 0 0.5 16.2±0.75 24.25±0.68 35.9±0.75 33.46±0.12 34.31±0.14 32.92±0.39 1 20.23±1.97 28.8±0.21 41.73±1.09 41.4±0.02 42.53±0.47 37.40±0.02 2 29.34±0.96 34.71±1.72 56.44±0.16 46.84±0.23 52.09±0.66 47.30±0.19 3 34.33±0.11 37.46±1.28 57.11±0.35 48.53±0.67 59.85±0.09 54.55±0.96 4 37.01±0.18 41.77±0.18 59.63±0.82 52.86±0.82 63.24±0.31 60.77±0.1 5 40.01±0.42 44.1±0.48 60.01±0.55 55.36±0.77 66.06±0.45 66.23±0.56 6 41.47±1.29 45.17±1.31 60.61±0.35 56.93±0.43 67.56±0.37 69.79±0.54 7 41.96±0.91 47.39±0.68 60.97±0.55 58.51±0.14 68.65±0.96 74.03±0.03 8 45.94±0.27 51.77±0.79 63.31±0.67 63.79±0.37 73.25±0.85 79.02±0.35 10 50.15±0.76 59.4±0.68 64.94±0.79 73.45±0.36 80.1±0,45 88.81±0.39 12 53.93±0.47 65.82±0.77 68.72±0.63 83.21±0.10 87.18±0.83 96.47±0.23 n=3, Mean ±SD= Standard deviation. Iraqi J Pharm Sci, Vol.32( 1 ) 2023 Ondansetron hydrochloride transdermal patches 152 Figure 6. Release curves of ondansetron hydrochloride films. Kinetic modeling of drug release Several models describe the kinetics of drug release from the pharmaceutical form, such as Korsmeyer- Peppas, Higuchi, zero order and first order. Table 7 shows the value of correlation coefficient R2 for the release models of zero order, first order, Higuchi and Korsmeyer- Peppas. The formulations (P2, P4) gave a release from the Korsmeyer- Peppas model, where the value of the correlation coefficient R2 was maximum and the value of the exponential coefficient n was calculated, it was less than 0.5, this indicates that the mechanism of drug release is diffusion from a non swellable matrix. The formulations (P1, P3, P5, P6) also gave release from the Higuchi model, where the value of the correlation coefficient was greater compared to the rest of the types, that is, the release of the drug from the matrix is proportional to the square root of the time. It also indicates that the process of diffusion through the matrix is the main mechanism to release the drug. Table 6. Kinetics study of prepared transdermal patches Korsmeyer - Peppas Higuchi First order Zero order Patch code R2 n R2 slope R2 slope R2 slope 0.9167 0.1772 0.972 14.689 0.861 0.0454 0.8205 3.6506 P1 0.9576 0.0381 0.954 16.222 0.9301 0.0336 0.8315 4.0967 P2 0.7154 0.0217 0.7772 16.069 0.7154 0.0217 0.5299 3.5891 P3 0.9447 0.0325 0.9142 19.264 0.9447 0.0325 0.7808 4.8155 P4 0.8835 0.0338 0.9269 21.72 0.8835 0.0338 0.7443 5.2648 P5 0.9555 0.0439 0.9815 25.449 0.9555 0.0439 0.8636 6.4571 P6 Table 7.Value of n and drug release mechanism(24). Release exponent (n) Drug transport Mechanism Rate as a function of time Drug release mechanism n< 0.5 Quasi – Fickian diffusion tn Non swellable matrix diffusion 0.5 Fickian diffusion t0.5 0.5 < n < 1.0 Anomalous (Non -fickian transport) tn-1 For both diffusion and relaxation ( erosion ) 1 Case II transport (time – independent) Zero order release Higher than 1 Super case II transport Tn-1 (relaxation / erosion ) Differential scanning calorimetry (DSC) study The DSC thermogram of ondansetron HCl showed a sharp endothermic peak at 187.47C with a starting point of 180.97C and an endpoint of 240.06C as shown in Figure7a which corresponds to the melting point of the substance and indicates that the substance is pure and has a crystalline shape. The DSC thermograms of ethyl cellulose and PVP K30 showed endothermic peaks at 348.66°C as shown in figure 7b and 87.04°C as shown in figure 7c, respectively. The DSC thermograms of physical mixture OSH +PVPK30 as shown in figure 7d and physical mixture of OSH+ EC as shown in figure 7e, showed endothermic peaks separately, not overlapping with each other and without changing the melting point of the active substance, which indicates that there is no interaction between Ondansetron and used excipients. Iraqi J Pharm Sci, Vol.32( 1 ) 2023 Ondansetron hydrochloride transdermal patches 153 Figure 7a. DSC of ondansetron hydrochloride. Figure 7b. DSC of PVP k30 Figure 7c. DSC of EC -25 -20 -15 -10 -5 0 5 10 15 0 50 100 150 200 250 300 350 400 450 Temperture/Cº Onset point:64.87Cº Endset point:139.04Cº Peak 1 top: 100.90Cº Enthalpy / J/g :293.97 Onset point:182.12Cº Endset point:231.33Cº Peak 1 top: 187.47Cº Enthalpy / J/g :153.7799 -12 -10 -8 -6 -4 -2 0 0 50 100 150 200 250 300 350 400 450 Temperture/Cº Onset point:43.09Cº Endset point:125.45Cº Peak 1 top: 87.04Cº Enthalpy / J/g :336.1625 -6 -5 -4 -3 -2 -1 0 0 50 100 150 200 250 300 350 400 450 Temperture/Cº Onset point:28.30Cº Endset point:88.83Cº Peak 1 top: 53.79Cº Enthalpy / J/g :29.7998 Onset point:272.50Cº Endset point:301.24Cº Peak 1 top: 286.38Cº Enthalpy / J/g :31.2577 Onset point:218.25Cº Endset point:249.06Cº Peak 1 top: 237.51Cº Enthalpy / J/g :17.5069 Iraqi J Pharm Sci, Vol.32( 1 ) 2023 Ondansetron hydrochloride transdermal patches 154 Figure 7d. DSC of OSH+PVP K30. Figure 7e. DSC of OSH+EC Conclusion Ondansetron hydrochloride transdermal patches were prepared using two different types of polymers, polyvinyl pyrrolidone and, ethyl cellulose . Formula P6 gave the highest release rate among the prepared formulas, reaching to 96% w/v (cumulative drug release) after 12 hr. The release kinetics of all formulations were studied and the P6 formula followed the Higuchi model. Formula P6 can be nominated for further studies in animal models and pharmacokinetic studies. References 1. Smith C, Smith M, Cunningham R, Davis S. Recent Advances in Antiemetics: New Formulations of 5-HT3 Receptor Antagonists in Adults. Cancer Nurs. 2020;43(4):E217–28. 2. Huddart R, Altman RB, Klein TE. PharmGKB summary: Ondansetron and tropisetron pathways, pharmacokinetics and pharmacodynamics. Pharmacogenet Genomics. 2019;29(4):91–7. 3. David SRN, Rajabalaya R, Zhia ES. 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Release Kinetics – Concepts and Applications. Int J Pharm Res Technol. 2019;8(1):12–20. This work is licensed under a Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/