Development and Assessment of Mucoadhesive Buccal Patches of Ondansetron Hydrochloride for Sustained Drug Delivery

In recent years, there has been a significant change in the preferred routes for administering    therapeutic agents. Considerable research has been dedicated to developing drug delivery systems that target specific areas of the body, aiming to enhance drug bioavailability while reducing side effects related to dosage. Buccal drug delivery offers a promising alternative to traditional systemic administration methods, as the buccal mucosa has good permeability, a rich blood supply, and serves as an effective site for drug absorption.

The oral mucosa is quite distinct from the rest of the gastrointestinal tract and, in terms of structure, more closely resembles the skin. While skin is commonly known for its low permeability, it's often overlooked that the oral mucosa does not possess the high permeability seen in the intestinal lining.

The buccal cavity offers easy access for self-medication, making it a safe and user-friendly method of drug administration. Buccal patches are easy to apply and can be removed effortlessly from the site of application, allowing drug delivery to be stopped at any time. Additionally, buccal patches offer greater flexibility compared to many other drug delivery systems.

Ondansetron hydrochloride, marketed under various brand names, is a selective serotonin 5-HT? receptor antagonist Ondansetron functions by inhibiting the effects of serotonin, a natural chemical in the body that can trigger nausea and vomiting. It is mainly used to control and prevent nausea and vomiting resulting from chemotherapy, radiation therapy, and surgical procedures. It is indicated for use in adults and pediatric patients (as young as 6 months old, depending on the formulation and route of administration) and is available in oral tablets, orally disintegrating tablets (ODT), oral solution, and injectable formulations. Ondansetron is commonly prescribed in combination with other supportive therapies to enhance its antiemetic effects and improve patient comfort during cancer treatment or post-operative recovery.

Although various formulations of Ondansetron HCl buccal patches have been explored in the literature, no previous studies have reported the use of Sodium Alginate (SA) in combination with three mucoadhesive, release-retardant polymers—Methyl Cellulose, Sodium Carboxymethyl Cellulose (NaCMC), and Hydroxypropyl Methylcellulose (HPMC). Both NaCMC and HPMC possess sustained-release properties, which can significantly prolong the drug release when incorporated into buccal patches. Therefore, developing Ondansetron HCl buccal patches using these polymers has the potential to offer extended drug release, enhancing therapeutic efficacy and patient compliance over an extended period.

Buccal patches of Ondansetron HCl may offer sustained drug delivery over an extended period and serve as an effective approach to bypass extensive hepatic first-pass metabolism, enhancing therapeutic efficacy in the management of nausea and vomiting.

ORAL MUCOSA:

The total surface area of the oral cavity is approximately 100 cm², with around 33% of this region comprising the buccal mucosa, which is characterized by an epithelial layer roughly 0.5 mm thick. The primary function of the oral mucosa is to protect the underlying tissues. This protection is largely due to lipid-based permeability barriers within the epithelium, which help prevent fluid loss and shield the tissues from harmful environmental agents such as microbial toxins, antigens, carcinogens, and enzymes. The regeneration time of oral epithelial cells is estimated to be 5 to 6 days.

The lips, cheeks, hard and soft palates, and the floor of the mouth are among the anatomical components that make up the oral cavity. It is divided structurally into two main sections:

• The oral vestibule is the area that is bounded on the inside by the teeth and gingiva and on the outside by the lips and cheeks.
• The oral cavity proper extends back to the oropharyngeal aperture, past the teeth and gums. The tongue rises from its floor and contributes to speech, taste, and food movement, while the hard and soft palates form its top border.

Drug transport across the buccal mucosa

• Transcellular (or intracellular) route, where the drug passes directly through the epithelial cells, navigating both lipid and aqueous regions of the cell membrane.
• Paracellular (or intercellular) route, which involves passive diffusion of the drug between cells, through the extracellular lipid matrix.

Mechanism of Mucus adhesion:

The first contact stage and the consolidation stage are the two main stages of Mucus adhesion, according to the mechanisms of Mucus adhesion. To facilitate tighter contact and adhesion to the mucus layer, the mucoadhesive material first comes into touch with the mucosal surface, allowing it to spread and start to swell.

Preparation Method of Buccal Patches

Mucoadhesive buccal patches were developed using the solvent casting technique.

To prepare the fast-dissolving buccal patch, the film-forming polymer HPMC 15cps and methyl cellulose was first dissolved in water. Glycerol was then added as a plasticizer to the polymer solution. The mixture was continuously stirred on a magnetic stirrer for 4 hours to achieve thorough uniformity. After thorough mixing, the solution was placed in a vacuum desiccator to eliminate any entrapped air bubble. In a separate beaker, Ondansetron HCl along with other excipients was dissolved and allowed to stand undisturbed for 45 minutes. The drug solution was then combined with the polymer mixture and stirred again on the magnetic stirrer for an additional 1 hour to achieve a uniform blend. The prepared solution was transferred into Petri dishes and placed in a hot air oven at 50°C for 24 hours to allow for complete drying. Once dried, the resulting film was carefully cut into the required size and stored in aluminum foil inside an airtight container to preserve its integrity. Table 1 shows mucoadhesive patch composition.

Table 1 shows Mucoadhesive patch composition

1. Preparation of pH 6.8 Phosphate Buffer:

To formulate a phosphate buffer with a pH of 6.8, dissolve 28.8 g of disodium hydrogen phosphate and 11.45 g of potassium dihydrogen phosphate in 1000 ml of distilled water.

2. Calibration curve Ondansetron Hcl : -

10mg of pure drug was taken in a 10ml standard flask and to this add 6.8 pH phosphate buffer and shake vigorously. From this stock solution with draw 1ml of solution and dilute to 100ml with phosphate buffer. Finally, various concentrations were prepared, including 2 µg/ml, 4 µg/ml, 6 µg/ml, 8 µg/ml, and 10 µg/ml. These are further diluted, and samples were subjected to spectrophotometric analysis (UV-Visible) to determine absorbance at ?max of 306nm. From the curve obtained, a line equation and regression analysis were determined.

Mathematical Models Drug Release Kinetics

The in-vitro diffusion data of the buccal patches were analyzed using various kinetic models, including Zero-order (percentage of cumulative drug release vs. time) and Higuchi’s model (percentage of cumulative drug release vs. the square root of time).

However, these models were inadequate in fully explaining the drug release behavior, particularly due to the swelling of the matrix upon hydration and its gradual erosion during the release process. To better understand the release mechanism, the data were further evaluated using the Korsmeyer-Peppas semi-empirical model, described by the equation:

log (Mt/M∞) = log k + n log t

Where:

• M∞ represents the maximum amount of drug that would be released after an infinite period.
• k is the release rate constant, reflecting the structural and geometrical properties of the buccal patches.
• n is the diffusion exponent, which indicates the nature of the drug release mechanism.

Drug release kinetics models help explain and predict how a drug is released from various dosage forms, including buccal patches. These models are based on specific assumptions about the release mechanism and are used to interpret experimental data on drug release behavior. Below is a summary of three widely used kinetic models:

1. Zero-Order Kinetics:

In a zero-order release model, the drug is released at a uniform rate over time, meaning the release does not depend on the remaining concentration of the drug in the formulation. This results in a steady and linear drug release profile. The equation representing zero-order kinetics is:

Q=k0×t

Where:

• Q is the quantity of drug released at time t
• K0 is the zero-order rate constant

2.First-Order Kinetics Model:

 In the first-order release model, the drug is released at a rate that is directly dependent on the concentration of the drug remaining in the dosage form. As a result, the release rate decreases over time in an exponential manner. The mathematical expression for this model is:

ln?(Q0−Qt) =−kt

Where:  

• Q0 is the initial drug content in the dosage form
• Qt is the amount of drug released at time t
• K is the first-order release rate constant

3. Higuchi Kinetic Model:

The Higuchi model explains drug release from matrix-based systems, where the release rate is related to the square root of time. It is often applied to solid and semi-solid dosage forms, such as transdermal patches. The Higuchi equation is represented as:

Q=kH \sqrt{t}

Where:

• ? is the quantity of drug released at time t
• kH is the Higuchi diffusion rate constant

4. Korsmeyer-Peppas Model:

This model is commonly used to assess the drug release behavior by applying the experimental data to the equation:

Mt/M = Kt?

Where:

• Mt/M represents the fraction of drug released at a specific time t
• K is a constant that characterizes the drug release rate
• n is the diffusion exponent, which helps determine the type of release mechanism and varies based on the geometry and design of the dosage form.

Evaluation of buccal patch:

1] Folding Endurance

Folding endurance refers to the number of times a film can be folded at the same spot without tearing or forming visible cracks. It serves as an indicator of the film's flexibility and resistance to brittleness. A higher number of folds before breaking reflects greater folding endurance.

2] Thickness of the Film

The thickness of the prepared medicated films (MDFs) was measured using a calibrated digital Vernier caliper. Each film was measured individually, and all measurements were taken in triplicate to ensure accuracy and consistency.

3] Drug Entrapment and Content Uniformity of Patches:

To evaluate content uniformity, patches measuring 2×2 cm² were cut and placed in a 100 ml volumetric flask containing pH 6.8 phosphate buffer. The flask was kept undisturbed for 24 hours to ensure complete dissolution of the patch. If required, the resulting solution was appropriately diluted, and the absorbance was measured at 306 nm using a blank solution as the reference.

4] In-Vitro Drug Release Studies:

The in-vitro drug release was evaluated using the open-ended cylinder method with a semi-permeable membrane. This setup consists of two compartments: the donor and the receptor. The upper end of the donor compartment remained open to the environment, and a piece of cellophane paper, serving as the semi-permeable membrane, was used to separate it from the receptor compartment.

A phosphate buffer solution (pH 6.8) was used as the diffusion medium. The film samples were placed in the donor compartment and separated from the receptor compartment by the cellophane membrane, which had been pre-soaked in a glycerin-water mixture to enhance permeability.

The system was maintained at a constant temperature of 37°C with a stirring speed of 50 rpm. At intervals of every 30 minutes for a total duration of 6 hours, 10 ml samples were withdrawn from the receptor compartment. Each time a sample was removed, it was replaced with an equal volume of fresh buffer solution. The amount of drug released was measured using a UV spectrophotometer at 306 nm.

5] Surface PH:

Surface pH was assessed by placing three films from each formulation onto an agar plate, allowing them to swell for 2 hours. After swelling, pH paper was gently applied to the surface of each film to measure the ph. The surface pH was obtained by taking the mean of three separate readings recorded from each formulation.

6] Excipient- Compatibility studies:

FT-IR analysis was conducted using Ondansetron HCL   buccal patch to investigate potential     interactions between the pure drug and the polymer.

7] Percentage humidity Loss (PHL)

Films measuring 2 cm × 2 cm were first weighed and placed in a desiccator containing calcium chloride to maintain a low- moisture terrain. After a period of three days, the films were removed and reweighed. The average humidity loss was calculated using the formula below

Percentage humidity Loss (PHL) = (original Weight – Final Weight)/ original Weight × 100

RESULTS AND DISCUSSION :

Fig- 01 Spectrum of Ondansetron HCL by UV – Spectrophotometry

Figure: 02 Calibration curve Ondansetron HCL

Table 01: Calibration curve Ondansetron HCL

2] Drug and Excipient Compatibility studies by FTIR

Figure: 03 FTIR (Fourier Transform Infrared) Spectroscopic Analysis of Ondansetron HCl.

Figure:04 FTIR (Fourier Transform Infrared) Spectroscopic Analysis of Ondansetron HCl + polymer

Table 07: FTIR Spectral Data of Ondansetron HCl and Buccal Patch

The retention of major functional group peaks in the buccal patch spectra indicates that the drug remains chemically intact within the polymeric matrix. Minor shifts, such as the broadening of the N–H stretch around 3425 cm?¹, can be attributed to hydrogen bonding between the drug and excipients, but no new peaks or disappearance of existing peaks were observed. This confirms the absence of significant chemical interactions between Ondansetron HCl, and the polymers used. Thus, FTIR analysis demonstrates good compatibility of the drug with the selected excipients in the buccal patch formulation.

3. Evaluation Results of prepared Ondansetron HCL Buccal patches:

1. Weight variation:

The weight variation test was conducted, and the patches were found to weigh between 150 ± 0.01 g and 184 ± 0.30 g. All formulations successfully met the weight variation criteria. The results are presented in Table 2.”

2.Thickness:

The thickness of the formulations ranged from 0.36 mm to 0.53 mm, as presented in Table 2.”

3. Folding endurance:

“Folding endurance, which reflects the fragility of the film, was determined by manually folding the prepared strips. A 2×2 cm film section was repeatedly folded at the same location until breakage occurred, and the number of folds sustained provided the folding endurance value. as presented in Table 2.”

4. Surface pH determination:

Acidic or alkaline pH may cause irritation to the buccal mucosa and influence the degree of hydration of polymers. The surface pH of the patches ranged between 5.85± 0.15 and 7.05 ± 0.11. The results were found to be close to neutral in all the formulations, and this means that they have less potential to irritate the buccal mucosa. Result is shown in Table No.2

5. Drug content uniformity:

The medication content (%) ranged from 85.60 ± 2.36% to 95.65 ± 0.51% in all formulations. This suggests that the medication was evenly distributed throughout the polymeric patches. Result is shown in Table No.2 and Absorbance to % drug content 

6. Percent moisture absorption:

To determine the film's physical stability under high humidity levels and its integrity under dry conditions, moisture interaction studies are required. According to the results of the three-day investigation on the percentage of moisture absorption, the results ranged from 2.48% ±0.07% to 5.85% ±1.15%. It was discovered that as the polymer concentration and viscosity (HPMC 10CPS, Methyl Cellulose) increased, so did the moisture absorption. To prevent microbiological contamination and the bulkiness of the patches, the formulation's low moisture content is greatly appreciated. Furthermore, formulations with a low moisture level are less likely to become brittle and totally dry. Result is shown in Table No.2

7. Percent moisture loss:

The percent moisture loss (PML) varied between 1.03% ±0.95% and 2.20% ±0.31%. The polymer's moisture retention capacity increased as its viscosity increased, which progressive decrease in PML.  Result is shown in Table No.2

 8. Ex-Vivo permeability study of F5batch performed as it was the most satisfactory batch among all. It found that the more than 90% drug was release in 8 hours. The batch was showing good permeability also. Result is shown in Table No.3

9. Excipient – compatibility studies

"FT-IR analysis was conducted using Ondansetron HCL buccal patch to investigate potential interactions between the pure drug and the polymer

Table No. 02: Evaluation studies of formulated buccal patches

Table 3 The results of permeability study and the release profile also shown below

Figure 05:  In Vivo Permeability Study of Ondansetron HCL Buccal patch[F5]

Kinetic model:

Table 5 Drug release kinetics of   Ondansetron HCL buccal patch

Table 6 kinetic model

Figure 06: Zero order release kinetics of Ondansetron HCL Buccal patch[F5]

Figure 07: First order release kinetics of Ondansetron HCL Buccal patch[F5]

Figure 08: Higuchi model for Ondansetron HCL Buccal patch [F5]

Figure 09: Korsmeyer- Peppas model of Ondansetron HCL buccal patch [ F5]