Formulation and Optimization of Esomeprazole Magnesium Buccal Films for Effective Treatment of Gastric Acid Reflux Disease.

Esomeprazole is a proton pump inhibitor (PPI) used for the treatment of gastric ulcers, gastroesophageal reflux disease (GERD), Zollinger Ellison syndrome, erosive esophagitis long-term management of patients suffering from peptic ulcer and Helicobacter pylori infections alone or associated with other drugs such as non-steroidal anti-inflammatory drugs.[1], The intragastric pH-monitoring data for esomeprazole, 20 mg once daily, show improvement over omeprazole, 20 mg once daily, but the esomeprazole, 40 mg once daily, intragastric pH data show a further convincing gain in control of gastric pH. [2]. Buccal films represent a recent advancement in buccal drug delivery, serving as semi-solid dosage forms that are applied to the buccal region and allowed to dissolve. [3], Following administration, they directly enter the systemic circulation. These films have quickly gained recognition as a novel administration route, offering improved safety and an enhanced onset of action. Buccal films are an elegant and efficient dosage form, providing superior bioavailability compared to other buccal dosage forms like buccal tablets, lozenges, and wafers. [4], This is achieved by bypassing the hepatic first-pass metabolism. Upon administration, these films dissolve within the patient's buccal mucosa. The oral mucosa serves as the site of drug administration and is further divided into buccal and sublingual mucosa. [5]

MATERIAL AND METHODS:

Materials:

Esomeprazole magnesium, polyvinyl pyrrolidine K30 (PVP K30), and aspartame were purchased from Yarrow Chem Products Ltd, Mumbai, India. Polyvinyl alcohol (PVA) and polyethylene glycol 400 (PEG 400) were purchased from Central Drug House (p) LTD, New Delhi. Citric acid was purchased from Thermo Fisher Scientific India Pvt. Ltd, Mumbai. Ethanol and distilled water were purchased from Sigma–Aldrich Chemicals Ltd, Bangalore, India. All chemicals used were of analytical grade.

PRE-FORMULATION STUDIES:

Determination of the melting point of the drug:

The drug's melting point was determined by placing a small amount in a capillary tube closed at one end and placing it in Thiels' melting point apparatus. The temperature at which the drug melts was noted and the Reading was taken.

Solubility determination of drug:

The solubility of the Esomeprazole magnesium was dissolved in distilled water, methanol, ether, chloroform, and pH 6.8.

Drug excipients compatibility study:

Excipients are integral components of almost all pharmaceutical dosage forms. The successful formulation of a stable and effective dosage form depends on the careful selection of the excipients, which are added to facilitate administration, promote the consistent release and bioavailability of the drug, and protect it from degradation. Infrared Spectroscopy is one of the most powerful analytical techniques to identify the functional group of a drug.

Method:

The pure drug and its formulation were subjected to IR studies. In the present study, the potassium bromide disc (pellet) method was employed.

Fourier-Transform Infrared Spectroscopy (FT-IR):

During preparation, the drug and the polymer may interact as they will be in close contact with each other which would affect the stability of the drug. The pure drug, polymer, and drug-polymer combinations and formulations were exposed to FT IR studies. The drug and/or polymer in a 1:1 ratio was taken. In the sample holder of the instrument, the mixtures were placed and the spectra were run from 4000 to 400 cm-1 wave number. The FT-IR spectrum obtained for the pure drug was compared to the FT-IR spectrum of the drug with polymer.

Determination of absorption maximum (? max) of the drug:

Preparation of stock solution:

A stock solution of 20 µg/ml was prepared by dissolving 10 mg of esomeprazole into 100 ml of phosphate buffer. Then 20 ml of this solution was diluted to 100 ml with phosphate buffer 6.8, the calibration curve was prepared using an aliquot 2-20 µg/ml from the stock solution.

Preparation of standard solution:

Accurate weight quantity of standard esomeprazole in 10 ml of 6.8 phosphate buffer, further diluted to get a working standard solution of 200 µg/ml. Then 1,2,3,4… 10 ml, of working standard solution were transferred into a series of 10 ml volumetric flasks. Volume made up of 6,8 phosphate buffer solution. Then the sample was scanned in the UV range (200 – 400) peak maxima were observed at 300.0 nm by using a UV-spectra photometer. The absorbance of the solution was measured at 300.0 nm against a blank and the calibration curve was plotted.

Method:

Solvent casting technique:

The mucoadhesive buccal film of Esomeprazole magnesium was prepared by a solvent-casting technique using a film-forming mucoadhesive polymer as per the formula given in Table 1. Initially, the polymers PVP K30 and PVA were weighed accurately and dissolved in 2 ml ethanol and 3 ml distilled water. The beaker containing polymers, ethanol, and water was kept aside for 15 min for swelling of polymers marketed as solution A. Then the polymeric solution was stirred for 1h on the magnetic stirrer to get a clear and bubbles-free solution. Plasticizer PEG 400 was added to the polymeric solution A with continuous stirring. In another beaker, Esomeprazole magnesium with aspartame and citric acid was dissolved in a sufficient quantity of solvent (Ethanol: water 1:1) marketed as solution B. The solution was continuously stirred for 4 h. Then the drug-containing solution B and polymeric solution A with other excipients were mixed gently with the help of a magnetic stirrer to form the homogeneous casting solution. The whole solution was poured into the pre-lubricated glass petri-plate at 40 ?C and left for 12 h. The film was removed carefully after drying and cut into 2×2 cm?2;. The film was stored in butter paper covered with aluminum foil and stored at room temperature.

Table. No.1: Composition of mucoadhesive buccal films:

Evaluation of mucoadhesive oral films:

Thickness

It can be measured using a micrometer screw gauge at various locations. It is vital to assess the uniformity in film thickness as it directly impacts the accuracy of dosage in the strip.

Folding endurance:

The flexibility of the thin film is important when considering its breakage-free administration. The flexibility of the polymeric thin films can be measured by assessing their folding endurance. Folding endurance is determined by repetitively folding the film at a 180° angle in the same spot until it breaks. A film that exhibits a folding endurance value of 300 or more is considered to have excellent flexibility. [6]

Surface pH:

To determine the surface pH, a combination of glass electrodes is utilized. The patches are placed in contact with 5 ml of distilled water for 1 hour. The pH can be determined by bringing the electrode near the surface of the formulations and allowing it to equilibrate for 1 minute. [7], [8]

Organoleptic properties:

The desired sensory characteristics such as color, flavor, and taste can be evaluated through visual inspection of the film composition. E-tongue software helps assess the flavor intensity and determine the amount of flavor added, or if further adjustment is required. Uniformity in color and aroma, as well as an acceptable taste, enhance patient acceptance. [9]

Swelling study:

The oral patches are individually weighed (designated as W1) and placed in separate 2% agar gel plates, which are then incubated at 37°C ± 1°C. The patches are periodically removed from the gel plates and excess surface water is carefully eliminated using filter paper. The swollen patches are then reweighed (W2), and the swelling index (SI) is calculated using the following formula. [10]

Drug Content Uniformity:

Drug content uniformity is determined by dissolving each patch in 10 ml of solvent and filtering it using Whitman filter paper (0.45 ?m). The filtrate is evaporated, and the remaining drug residue is dissolved in 100 ml of phosphate buffer (pH 6.8). A 5 ml solution is diluted with phosphate buffer (pH 6.8) up to 20 ml, filtered through a 0.45-?m Whitman filter paper, and the absorbance is measured using a UV Spectrophotometer against pH 6.8 phosphate buffer used as a blank. The experiments are conducted in triplicate, and the average values are reported. [11], [12]

In-vitro Drug Release Studies:

In vitro, drug diffusion investigations were carried out utilizing a Franz diffusion cell with a receptor compartment capacity of 150 ml. The dialysis membrane was installed in the diffusion cell's donor and receptor compartments. After positioning the film on the cellulose acetate membrane, it was wrapped in aluminum foil. Phosphate buffer, pH 6.8, was put into the diffusion cell's receptor compartment. [13]

Organoleptic properties

The melting point of the obtained drug was found to be 168, which is within the reported range of 168–169. It complies with the standards, thus indicating the purity of the drug.

Solubility Determination:

Esomeprazole Magnesium was found to be insoluble in water. Esomeprazole magnesium is freely soluble in Methanol, Ethanol, and 6.8 pH phosphate buffer. Solubility analysis is important because the drug has to be dissolved in the solvents and also in the dissolution medium used.

FTIR spectra of pure drug, polymer, and their physical mixtures (stored at 40°C 2°C / 75%+5% RH for 2 months) were recorded. The polymer and physical mixtures of drugs and polymers were scanned for absorbance which is shown in Figure 2, Figure 3, and Figure 4.  The spectra obtained from the physical mixtures showed all the principal peaks at or around the requisite wave number of pure drugs. Thus, it may be inferred that there was no interaction between the drug and polymer, the purity and integrity of the drug was maintained in the physical mixtures.

Standard calibration curve of Esomeprazole in Phosphate buffer pH 6.8

It was found that the estimation of Esomeprazole Magnesium by UV Spectrophotometrically method at max 285 nm in 6.8 pH phosphate Buffer had good reproducibility and this method was used in the study. The correlation coefficient for the standard curve was found to be closer to 1 which is 0.9992, at the concentration range 10-60 µg/ml. The regression equation generated was 0.011.

Film Thickness:

The thickness of the film-developed formulations F1 to F7 varied from 0.23 to 0.33 mm and was found to be uniform. The thickness increased with an increase in PVA concentration. The SD values were less than 1 for all formulations, an indication of more uniform films as shown (Table No.5).

Folding Endurance:

Folding Endurance of the developed formulations F1 to F7 varied from 114-165 as shown (Table No.5). Folding Endurance of the film increases with an increase in the PVA and PVP K30 Proportion.

Drug content uniformity:

Good uniformity in drug content was observed in all buccal films as shown (Table No.5). The drug content ranged from 93.82% - to 98.73%. Hence it was concluded that the drug was uniformly distributed in all the formulations.

Swelling index:

Figure No.26 shows the comparison of the Swelling index of the developed formulation F1 to F7 varied from 84.09% - to 95.03%. The Water Content remaining in F7 was found to be more so the formulation F7 which has a high % Swelling index was found to be 95.03%. The formulation F2 which has less % Swelling index was found to be 85.12% (Table No.5).

Surface pH

The surface pH was found to be in the range of 6.23 - 6.87 which is close to salivary pH, which indicates that films may have less potential to irritate the oral mucosa. The results are given in Table. No.5.

Disintegration time

Disintegration time of the developed formulations F1 to F7 varied from 25-44 as shown (Table No.5). Disintegration time of the film increases with an increase for the effect of polymers such as PVA and PVP K30 Proportion.