Introduction  

Topical drug delivery is a localized drug administration anywhere through rectal, vaginal, ophthalmic, and skin. Topical drug administration through the skin can be defined ‎as the application of drug contains formulation directly to the skin for prophylactic, protective, ‎or therapeutic purposes [1-4]. The topical drug delivery has many advantages: avoidance of first-pass metabolism, GIT irritation, and varied absorption conditions such as ‎pH changes, gastric emptying, and presence of enzymes [5]. The gel is a semisolid network ‎composed of a liquid phase constrained inside a three-dimensional matrix of natural or ‎synthetic polymer. A high degree of chemical or physical cross-linking is established [6]. The main advantages of gel are easy to formulate, non-greasy, providing controlled ‎release, and can be used for polar and non-polar drug administration [7]. 5-Fluorouracil (5FU) ‎is an antineoplastic agent used to treat skin diseases such as actinic keratosis ‎psoriasis, cutaneous premalignant, malignant lesions, and basal-cell carcinoma, 5-FU ‎available in different dosage forms like cream: 0.5%, 1%,5% and injection:50 mg/mL.  ‎Chemically 5-FU is a white crystalline powder with a melting point of 282 ᵒC. It is slightly ‎soluble in ethanol, sparingly soluble in water, practically insoluble in chloroform and ether. It has a chemical formula C4H3FN2O2 with  MW=130.1 [8]. The aim of this work was development a gel formulation of 5-FU using a Na carboxymethylcellulose (NaCMC) and polyvinyl alcohol (PVA) as a gelling agent. the ‎influence of type and concentration of gelling agent was investigated, drug content, pH, ‎spreadability, extrudability viscosity and In -vitro drug release of the prepared gel were ‎evaluated.‎‎

Materials and Methods ‎

Materials

‎5-FU was purchased from  Hyper-chem Ltd Co. China, NaCMC from Baerlocher, GMBH, ‎Germany, PVA from H.I. media laboratories, India, glycerin and Methyl hydroxyl benzoate  ‎obtained from Gain Land chemical community, U.K.All other reagents and chemicals used ‎were of analytical grade.‎

Construction calibration curve of 5-FU ‎

A stock solution of 5-FU at a concentration (1mg/ml) in buffer pH5.5 was prepared and ‎diluted to a series of standard solutions at a concentration range from (2.5,5,10,15, and 17.5 ‎‎µg/ml). The absorbance of these standard solutions was measured at 5-FU λ max 266 ‎nm by using a U.V spectrophotometer. After that, the absorbance of each prepared standard ‎solution was plotted against the concentrations.‎

Preparation of 5-FU gel ‎

Six formulations (F1-F6) were prepared, as shown in Table 1, using different NaCMC and PVA concentrations as a gelling agent. NaCMC formulations (F1-F3) were prepared by ‎dispersed the desired amount of NaCMC insufficient quantity of D.W, which contain 0.2gm ‎methyl hydroxyl benzoate as a preservative and 5ml glycerin as a humectant and increasing ‎the gel spreadability. The dispersed solution was homogenized by the magnetics stirrer then ‎left at room temperature for one day to complete the polymer swelling [9]. PVA ‎formulations (F4-F6) were prepared by using the hot method in which 70ml D.W that contain ‎‎0.2gm methyl hydroxyl benzoate and 5ml Glycerin heated to 70 ᵒC in a beaker for 10 min ‎followed by slow addition of PVA amount, then complete the volume to 100 ml by D.W. Finally the PVA dispersion was left to cool at room temperature for a viscous clear ‎dispersion production [10].

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Evaluation of 5-FU ‎

Visual examination ‎

This test was considered for visual characteristics, which include homogeneity, clarity, and ‎consistency [10].‎

pH determination

The pH of 5-FU gel was measured at room temperature using a digital pH meter, and the ‎reading was taken in triplicate [11].‎

Drug content

A sample of 1gm of prepared gel, which is equivalent to 5mg 5-FU, was taken in a100ml ‎buffer pH 5.5 of volumetric flask followed by flask sonication to get complete drug ‎solubility and filtration through 0.45µm membrane filter. One ml of the filtered ‎solution was diluted to 10 ml buffer pH 5.5 and analyzed at λ max 266 nm by a U.V ‎spectrophotometer using the buffer pH 5.5 as blank [12].‎

Extrudability ‎

A sample (15 gm) of the gel of each formulation was placed in a 60 ml feeding syringe, followed by applied one gram pressure. The time required for the gel to be completely ‎extruded from the syringe was recorded, an average of three readings was taken [13].

Spreadability

One of the important gel criteria to get the ideal quantities is to possess good ‎spreadability. The term expressed the degree of an extended area in which the gel spreads  ‎quickly on the affected skin part. A sample weighted one gram of each formula was pressed ‎between two slides with 500mg weight, then left for five minutes when no further spreading ‎was expected; after that, the diameters of spread circles were measured in cm and used as ‎spreadability comparative values; this test is done in triplicate and takes the average ‎values [14].

Viscosity study ‎

The viscosity is considered an important evaluation test of rheological study in semisolid ‎dosage form, the determination of viscosity was done using a digital viscometer Myr ‎VR3000 with spindle no. R7 at room temperature with an optimum speeds 2.5,4,6,10,20,30 ‎and 50 rpm [15].

In vitro drug release study

Each formulation's sample (1 gm) was weighed using a digital balance and uniformly ‎spread on the watch glass surface and, after that, gently lowered throughout 500ml buffer pH ‎‎5.5 as a dissolution media. The paddle's dissolution apparatus was positioned around 2.5 cm ‎above the watch glass; the paddle rotates at 50 rpm and maintains at 37 ± 0.5 °C. At ‎specified time intervals, an aliquot of 5ml dissolution media withdrawal is replaced ‎immediately by the same dissolution media volume over three h. The samples were filtered ‎through 0.45 mm filter paper and analyzed at appropriate λmax 266nm of 5-FU by using  ‎a UV-visible spectrophotometer to obtain the % drug release at each time interval [16].

Fourier-transformed infrared (FTIR) spectroscopic analysis

FTIR spectra of pure5-FU and physical mixture at ratio (1:1) of 5-FU and NaCMC were ‎analyzed between 400 and 4000 cm–1 by KBr disc method, using FTIR lambda 7600-‎Australia spectroscopy [17].

Statistical analysis ‎

Student t-test was used for statistical analysis when p<0.05. A significant statistical difference was considered, and the study was done in triplicate, where the data ‎represent mean ± standard deviation.‎

Results and Discussion

Physical appearance ‎

The six prepared gel formulations were vicious, homogenous, smooth, and glossy ‎with no phase separations; as shown in Table 2, NaCMC formulations show ‎translucent appearance. In contrast, the PVA formulation shows a white appearance.

pH determination

the pH of all formulations was between the range (6.27 - 6.45) as seen in Table 2 so that it ‎has the pH near the pH of the skin (4-5.5) and does not cause any skin irritation [18].‎

Drug content ‎

The data of Drug content analysis from the six prepared formulations range between (90.06-‎‎97.2), as shown in Table 2, indicating the homogenous 5-FU distribution within the ‎prepared gels.‎

Extrudability

The extrudability depends on the type and concentration of the polymer used, as depicted in Figure 1. As the concentration of polymer increases, the extrusion time will increase ‎, and from the obtained results, the PVA gel was quickly extrudable than NaCMC gel. ‎

Spreadability ‎

The spreadability values for 5-FU gel ranged from 4.5cm with gel prepared by NaCMC ‎to 8 cm with gel prepared by PVA, indicating the ease of spreadability ‎using a small shear amount. The result data indicate that the PVA gel is more spreadable ‎than the  NaCMC gel, also as the concentration of NaCMC polymer increase (F1-F3), the ‎spreadability will decrease this is due to as polymer concentration increase, the chains ‎repulsion and the cross-linking between the chains will increase so that the spreadability of ‎the polymer will reduce [19], the same result seen in  PVA based formulas.

Viscosity ‎

From the obtained results for NaCMC based formulas, as the concentration of NaCMC ‎increases, the viscosity of gel increases at the same velocity; this is due to the particles of the ‎gel linked together by Vander Waals forces or H- bonding to produce an interlaced network ‎, thus give the rigidity to the gel structure so that as the gelling agent concentration increase ‎lead to increasing the gel viscosity [20]. Also from the result, it was seen, the viscosity ‎decrease as the speed of spindle increase due to disarranged molecules caused to align their ‎long axes in the flow direction so that this orientations reduce the internal resistance of the ‎substances and thus reduce the viscosity [21], the same result was obtained with  PVA based ‎formulas, so that all formulas show non-Newtonian pseudoplastic flow behavior and the obtained viscosities for different 5-FUgels formulas, at low and high shearing rate indicate ‎that  NaCMC based formulas produced the high viscosity values than PVA based formulas.

It was found that F1 exhibit ‎pseudoplastic with the time-dependent flow (thixotropic behavior) in which the down curve ‎show displacement concerning the up curve and the down curve producing at any shear ‎rate lower shear stress than on the up curve as result hysteresis loop formed between the ‎up and down curve, this thixotropic behavior occur due to the gel needs time to rebuild to ‎its original structure which destroys throughout the continuous measurement of the shear [19].

In vitro drug release study ‎

The release profile of 5-FU gel from different prepared formulations in phosphate buffer pH ‎‎5.5 was study and the graphical representation of the drug release is shown in Figure 2; in the case ‎of NaCMC based formulas, the 5-FU release can be ranked with following order F1> F2>F3 ‎with (98.12, 93.5, 86.63) % drug release respectively, while for PVA based formulas the5-‎F.U. release can be ranked with following order F4> F5>F6 with (73.93,70.75,66.25) % drug ‎release respectively. From the obtained data, it was found that the release of the drug significantly depended on the concentration and type of the polymer used; regarding the ‎polymer concentration, it was seen as the polymer concentration increase, the drug release ‎from the gel would decrease, this is due to as the polymer concentration increase leads to ‎increasing the polymer cross-linking and reducing the migration of drug molecules [22]. ‎Regarding the polymer types, NaCMC based formulas showed more drug release than PVA-based formulas; this is due to the three-dimension, and physical structural network of the PVA polymer since 5-FU entrapment within these structural networks revealed the high ‎capability of PVA compared with NaCMC [20, 23].

FTIR spectroscopic analysis

The infrared spectra for pure 5-FU and Physical mixture of drug and NaCMC (1:1) were ‎shown in Figures 3 and 4. The presence of characteristic peak of the drug in the physical mixture ‎as seen in Table 3, indicates no interaction between the drug and the polymer used.