Development and Evaluation of Floating Bilayer Tablet Containing Combination of Oxethazine and Cefixime Trihydrate

Introduction

Oral route is most effective for drug administration. Tablets are the most popular oral formulations in the market, and they are preferred by both patients and physicians. In long term therapy for the treatment of chronic disease conditions, a conventional formulation is required to be administered in multiple doses, and therefore lacks patient compliance.¹

Sustained-release tablet formulations are highly desirable and preferred for such treatments because they improve patient compliance, maintain uniform drug levels, reduce dosage and side effects, and increase the safety margin for new potency drugs^.2

Oral drug delivery is becoming more popular as formulation scientists look for strategies to control drug release and improve patient convenience. However developing oral sustained-release tablets with sustained release rates for water-soluble drugs has been difficult for pharmaceutical chemists. Most of these water-soluble medications, if not correctly prepared, can rapidly release the drug and produce toxic drug concentrations when given orally.³

The pharmaceutical industry has become more interested in the formulation of two or more active pharmaceutical ingredients (API) into a single dosage form (bilayer tablet) over the last ten years. Bilayer tablets allow for the design and modification of dissolution and release properties.⁴

The term bilayer tablets include subunits that can be either identical (one layer of drug for immediate release and the other layer for sustained release) or different (heterologous: combining two drugs) or both (separation of heterogeneous substances).⁵

The primary benefit of bilayer tablets lies in their capability to integrate diverse release layers, such as immediate release and sustained release layers, within a single tablet. This feature becomes particularly advantageous for addressing chronic conditions, as it enables the maintenance of potent effects, precise dosing, and enhanced safety. Blood levels of the drug can be maintained at a constant therapeutic level for better drug delivery and reduction of adverse effects.^6,7

Oxetacaine, also referred as Oxethazine, is N, N-bis- (N-methyl-N-phenyl-t-butyl-acetamide)-beta-hydroxyethyl amine. It has been demonstrated to ease duodenal ulcers, chronic gastritis, and pain from reflux and dysphagia.⁸

Cefixime is a third-generation antibiotic like ceftriaxone and cefotaxime. Cefixime is stable in the presence of beta-lactamase enzyme. Many organisms that are resistant to penicillin and some cephalosporins may become susceptible to cefixime because of the presence of beta-lactamase. Cefixime inhibits the production of mucopeptides in the bacterial cell wall, which has an antibacterial effect.

Materials and Method

In this study, the chemicals used were pure drugs such as Oxethazine and Cefixime trihydrate obtained from Yarrow chemicals Mumbai, as well as polymers such as HPMC K100, xanthan gum, guar gum, karaya gum, and other excipients such as microcrystalline cellulose, magnesium stearate, sodium bicarbonate, and citric acid. All materials and solvents used in this study were of standard grade.

Preparation of floating bilayer tablets

The components for the immediate release layer, as listed in Table 1, were sieved through a 60 # size mesh before formulating the dosage form. The quantities needed to produce 50 tablets were individually weighed and blended comprehensively for a duration of 10 minutes. The resulting mixture for the first layer underwent slight compression using a ten-station rotary tablet machine. Likewise, the drug and excipients intended for the sustained release layer, outlined in Table 2, were also sieved through a 60 # size mesh prior to preparing the dosage form. All constituents were separately weighed and meticulously mixed for a period of 10 minutes. These mixtures were placed over the first layer and compressed to produce a tablet with a hardness of 6±0.5 kg/cm² . Bilayer tablets containing immediate release layer (IR) and sustained release layer (SR) were termed as formulations F1, F2, F3, and so on.

Evaluation Parameters

Evaluation of flow properties

The prepared powder mixture of different formulations was evaluated for angle of repose, loose bulk density, tapped bulk density and compressibility index.

Hardness test

To measure the tablet hardness, Monsanto hardness tester was used. The tablet was placed between two jaws, one fixed and one movable. The scale was reset to zero, and the load was gradually increased until the tablet fractured. The value at that point indicated the hardness of the tablet. The unit of hardness was measured in kg/ cm²

Friability test

The friability of the tablet was assessed using the Roche friabilator. Initially, ten tablets were weighed and the total weight was recorded. The tablets were then poured into a friabilator and rotated for 100 revolutions. The weight of ten tablets after rotation was recorded, and the percentage friability was calculated. The formula for calculating percentage friability is as follows

% F = {1-(Wt/W)} ×100

Where, % F = Friability in percentage

W = Initial weight of tablets

Wt = Weight of tablets after revolution

Weight variation

To assess tablet weight consistency, an initial step involved weighing ten individual tablets separately. Subsequently, the average weight was computed. By comparing each tablet's weight to the calculated average, the disparity for each individual tablet was determined, and the resulting percentage deviation was documented.

Drug content uniformity

To ascertain the drug content, a random selection of three tablets was made, and these were then powdered. The resulting powdered material, equivalent to 100 mg of the tablet, was placed into a 100 mL volumetric flask. The volume was adjusted to 100 mL using pH 6.8 phosphate buffer solution. From the primary stock solution, 1 mL of the solution was drawn and diluted with 6.8 pH buffer solution to achieve the desired concentration of 10 g/mL. Subsequently, the absorbance was gauged using a UV spectrophotometer.

In vitro drug release

In vitro drug release from floating bilayer tablets was determined by using dissolution type-II test apparatus. The dissolution test was carried out with 900 mL of 0.1N HCl solution at 37±0.5ºC temperature at 50 rpm. To keep the volume constant, samples of 5 mL were taken from the dissolution medium and replaced with fresh medium at predetermined time intervals. The samples were filtered and diluted with 0.1 N HCl to the desired concentration. The absorbance of the diluted samples was measured using UV spectrophotometer. Standard curve equation was used to calculate the cumulative percentage drug release. Dissolution test was continued for 12 hours using pH 1.2 N HCL buffer.

Results

FTIR spectroscopy

The FTIR spectroscopy of drug and polymers are mentioned in Figures 1-5.

Floating properties

Determination of floating lag time

Evaluation of pre-compression parameters

Evaluation of post compressional parameters

In vitro drug release studies

Discussion

Floating property study

The duration taken for the dosage form to emerge on surface of medium is called buoyancy lag time (BLT). Total floating time (TFT) is the amount of time it takes for the dosage form to constantly emerge on the surface of the medium. Tablets were placed in a 400 mL flask of pH 1.2; the time needed to go upward and float on the surface of the liquid and the floating duration were determined.

FTIR spectroscopy

The FTIR spectroscopy of drug and polymers are depicted in Figure 1-5. There was no substantial difference in the functional groups between the IR spectra of the pure drug and the selected formulations, and no new peaks were seen. This demonstrates that there was no interaction between the drug and the excipients.

Evaluation of pre-compression parameters

Pre-compression data are reported in Table 3. The bulk density of immediate release was found in the range of 0.284 g/cm³ and for sustained release layer, it was found in the range of 0.468 gm/cm³ to 0.598 gm/cm³ . This value of bulk density indicated good packing characteristic. The tapped density for IR layer was 0.418 g/cm³ and for sustained release layer, it was found between 0.545 to 0.653 g/cm³ . The bulk and tapped density were used to calculate compressibility index and Hausner’s ratio. The Carr’s compressibility index for IR layer was 12.96 and for sustained release layer was in the range of 11.23 to 14.63 suggesting good compressibility of blend. The values of Hausner ratio for IR layer was 1.18 and for sustained release layer was in the range of 1.12 to 1.19 suggesting good flow ability of powder blend. The angle of repose for IR layer was 23.89 and for sustained release layer, the angle of repose of the entire blend was within range of 22.56 to 25.20 indicating excellent flow property of powder blend.

Evaluation of post-compression parameters

Each value was represented as mean±SD of three determinants.

The hardness, thickness, friability, and drug content uniformity of the bilayer tablets were all evaluated. The hardness ranged from 6.3 to 7.6 kg/cm² , which is consistent with the bi-layer tablet. The thickness range of 3.51 to 3.62 mm suggested that the thickness of the bi-layer tablet was uniform. The fact that the friability was less than 1% indicated that the layer flowed well. The content uniformity ranged from 97.02 to 99.65%, indicating uniform tablet dispersion in the layer.

In vitro drug release studies

The floating release layer of Oxethazine and Cefixime trihydrate tablet were designed using individual HPMC K100, xanthan gum, guar gum, locust bean gum and karaya gum alone and also in combination with two polymers (3:1 HPMC K100: guar gum (Natural polymer). The total weight of the polymers used in the formulation was 46.75% of total weight of SR layer. All the batches of formulated layers were produced under similar conditions to avoid processing variables. The in vitro release study was conducted in 0.1N HCl for 12 hours. The in vitro release data is shown in Table 5. The in vitro release is dependent on nature of drug, nature of polymer, drug to polymer concentration and the medium used. In the present work, HPMC K100, xanthan gum, guar gum, locust bean gum and karaya gum were used as hydrophilic polymers in the preparation of sustained release layer. The highest release for 12 hours was observed with HPMC K100 which is a commonly used hydrophilic matrix which gets swelled, forming viscous gel, thereby rapidly releasing the drug. Among all the formulations, F5 contained 15% of total weight of tablet of HPMC K100 and 5% of total weight of the guar gum released 99.88% of drug up to 12 hours. The results of drug release are shown in Figures 1-12.

In vitro release drug release kinetics

The in vitro release data from bilayer tablet was processed to plot different kinetic approaches. The kinetics of in vitro drug release from the entire formulated bilayer tablet obeyed Higuchi release with the high regression r2 value of 0.99 as compared to others. Since the employed polymers acted as matrix materials, the application of the Higuchi model was appropriate. This model displayed favorable linearity, with a high regression value of 0.99. This result implies that the release mechanism was governed by diffusion control. Values of n between 0.45 and 0.89 can be used to predict both phenomena (anomalous transport). The n value of optimized formulation F5 was 0.309 and it was clear that all formulations had n values below 0.45. This indicates that the drug release majorly depends on diffusion-controlled phenomenon.

Conclusion

The floating bilayer tablets were prepared using one synthetic polymer and five natural polymers in order to achieve sustained release of drug. As the concentration of the super disintegrant in the immediate-release layer rises, there is a corresponding increase in the release percentage of Oxethazine. The release of Cefixime trihydrate for the sustained release was found to be 99.88% in 12 hrs. The formulation F5 showed better drug release, which was achieved by combining two polymers such as HPMC K-100 and guar gum which released the drug at a controlled rate at regular time intervals in appropriate concentrations as per the limits. Hence formulation F5 was selected. Therefore, it can be implied that combination of HPMC K100 with natural polymers guar gum can be successfully used to develop floating sustained release tablets.

Conflict of interest

None

Acknowledgment

The authors are thankful to the management of Shree Siddaganga College of Pharmacy for providing the necessary resources to complete this work.