Formulation and Evaluation of Mucoadhesive Buccal Tablets of Repaglinide Using Primary Polymers: Carbopol 934P and HPMC K4M

Conventional oral drug delivery remains the most common and convenient route of administration due to its ease of use and patient compliance. However, it poses significant challenges for drugs that undergo extensive first-pass metabolism, exhibit pH sensitivity, or are degraded by gastrointestinal enzymes—leading to reduced bioavailability and therapeutic efficacy. Repaglinide, a short-acting oral hypoglycemic agent used for managing postprandial blood glucose in Type II Diabetes Mellitus, is one such drug. Despite its rapid onset of action, Repaglinide has poor oral bioavailability (~56%) and a short half-life (~1 hour) due to extensive hepatic first-pass metabolism, necessitating frequent dosing.

To overcome these limitations, buccal drug delivery systems have gained attention as effective alternatives. Buccal administration involves placing a drug formulation in the buccal cavity, where it adheres to the mucosa and is absorbed directly into systemic circulation, bypassing hepatic metabolism. This route offers multiple advantages such as non-invasiveness, ease of administration, improved bioavailability, and the potential for sustained drug release.

Mucoadhesive buccal tablets are particularly promising for systemic delivery of drugs like Repaglinide. These systems utilize bioadhesive polymers that enhance residence time at the site of absorption, enabling controlled drug release. Among various polymers, Carbopol 934P and HPMC K4M have demonstrated excellent mucoadhesive and matrix-forming properties, making them ideal candidates for buccal formulations.

This study aims to formulate and evaluate mucoadhesive buccal tablets of Repaglinide using Carbopol 934P and HPMC K4M as primary polymers. The goal is to enhance bioavailability, prolong drug release, and improve therapeutic efficacy through a non-invasive, patient-friendly drug delivery system.

OBJECTIVES

Mucoadhesive drug delivery systems, including tablets, patches, films, and gels, have the potential to prolong residence time at the absorption site, providing sustained and controlled drug release. This approach is particularly valuable for drugs like Repaglinide, a short-acting oral hypoglycemic agent used in the treatment of Type II Diabetes Mellitus. Despite its rapid onset of action, Repaglinide exhibits limited oral bioavailability (~50%) due to significant first-pass hepatic metabolism, necessitating frequent dosing.

To address these challenges, the present study aims to develop and evaluate mucoadhesive buccal tablets of Repaglinide using Carbopol 934P and HPMC K4M as primary mucoadhesive polymers, with Sodium alginate and Chitosan as secondary polymers to optimize drug release and adhesion properties.

Specific Objectives of the Study:

1. To overcome the bioavailability limitations of Repaglinide by delivering it via the buccal route, thereby bypassing first-pass hepatic metabolism and potentially reducing the required dosage.
2. To enhance therapeutic efficacy and patient compliance through sustained drug release from a mucoadhesive buccal tablet formulation.
3. To formulate mucoadhesive buccal tablets of Repaglinide using Carbopol 934P and HPMC K4M as primary polymers, in combination with Sodium alginate and Chitosan as secondary polymers for improved mucoadhesive performance and release modulation.
4. To evaluate the physicochemical and performance parameters of the prepared buccal tablets, including:
   1. Hardness
   2. Thickness
   3. Weight variation
   4. Friability
   5. Drug content uniformity
   6. Surface pH
   7. Swelling index
   8. In-vitro drug release profile
   1. Mucoadhesive strength
   10. Short-term stability under accelerated conditions (40?±?2?°C / 75?±?5% RH for 3 months)
5. To assess drug–polymer compatibility and formulation integrity using Fourier Transform Infrared (FTIR) spectroscopy.

MATERIALS AND METHODS

Materials

The materials and chemicals used in this study are listed in Table 4. Repaglinide, the active pharmaceutical ingredient (API), was received as a gift sample from Cadila Pharmaceuticals Ltd., Ahmedabad. Primary polymers—Carbopol 934P and HPMC K4M—were used for matrix formation and mucoadhesion, while Chitosan and Sodium Alginate were employed as secondary polymers for further modulation of drug release and mucoadhesive properties.

Excipients such as mannitol (diluent), microcrystalline cellulose (MCC) (binder), sodium saccharin (sweetener), and magnesium stearate (lubricant) were used to ensure proper tablet characteristics. Analytical-grade reagents including methanol, Tween 80, sodium hydroxide, and potassium dihydrogen orthophosphate were used for buffer preparation and spectrophotometric analysis.

Table 1: Materials Used in the Study

Instruments and Equipment

The instruments used for formulation and evaluation are summarized in Table 5. Direct compression was performed using a 10-station rotary tablet compression machine. Analytical evaluations were conducted using standard equipment including a UV-Visible spectrophotometer, digital balance, dissolution apparatus, and FTIR spectrophotometer. All instruments were calibrated prior to use.

Table 2: Equipment Used in the Study

Preparation of Calibration Curve of Repaglinide

a) Determination of λmax of Repaglinide

A 10 mg quantity of Repaglinide was dissolved in 60% methanol to obtain a 1 mg/mL (1000 µg/mL) stock solution. This was diluted using phosphate buffer (pH 6.8) to achieve a final concentration of 10 µg/mL. The solution was scanned between 200–400 nm using a UV-Visible spectrophotometer (Model T80), and the λmax was determined at 237 nm, which was used for further drug estimation.

b) Preparation of Standard Calibration Curve

• Stock Solution: 10 mg of Repaglinide was dissolved in 60% methanol and diluted to 10 mL to obtain a 1 mg/mL solution.
• Working Solution: 1 mL of the stock was diluted to 10 mL with phosphate buffer (pH 6.8) to obtain 100 µg/mL.
• Calibration Standards: Aliquots of 0.5 to 2.5 mL of the working solution were diluted to 10 mL to yield 5–25 µg/mL concentrations.

Absorbance values of these standards were measured at 237 nm against phosphate buffer as blank, and a calibration curve was plotted. (Include Table 10 here if absorbance data is available.)

Method of Preparation of Mucoadhesive Buccal Tablets

Repaglinide mucoadhesive buccal tablets were prepared by direct compression using Carbopol 934P and HPMC K4M as primary polymers, with Chitosan and Sodium Alginate included in some formulations as secondary polymers.

Procedure:

1. Weighing and Sieving: All ingredients were accurately weighed and passed through a #40 mesh sieve.
2. Blending: The drug and excipients (excluding lubricants) were blended manually in a polyethylene pouch for 10 minutes to ensure uniform mixing.
3. Lubrication: Magnesium stearate was added to the blend and mixed for an additional 2 minutes.
4. Compression: The lubricated blend was compressed using a 7 mm flat-faced punch on a rotary tablet press (Rimek Minipress).

Tablets were stored in airtight containers at room temperature for further evaluation.

Composition of Buccal Tablets

Table 3: Composition of Buccal Tablets of Repaglinide

Pre-Compression Parameters

Before tablet compression, the prepared powder blends of each formulation were evaluated for flow properties using standard pre-compression parameters such as angle of repose, bulk density, tapped density, and Carr’s index. These parameters help assess the flowability and compressibility of the physical mixtures, which are critical for ensuring uniform die filling and consistent tablet weight.          

Angle of Repose (θ)

The angle of repose indicates the internal friction or cohesion between powder particles and reflects the flow behavior of the formulation blend.

The angle was determined using a fixed-height funnel method. The powder blend was allowed to flow through the funnel and form a conical heap. The height (h) and the radius (r) of the resulting pile were measured, and the angle was calculated using the following formula:

θ=tan⁻¹ (h/r)

Where:               

• θ = Angle of repose
• h = Height of the heap (cm)
• r = Radius of the heap at the base (cm)

A smaller angle of repose indicates better flowability. Magnesium stearate was used as a lubricant to improve flow when necessary.

Bulk Density (Db)

Bulk density was determined by gently pouring a known weight of powder (previously passed through sieve #40) into a graduated measuring cylinder without compacting the powder. The bulk volume was recorded, and the density was calculated using:

Tapped Density (Dt)

Tapped density was determined by placing 2 g of powder into a 10 mL measuring cylinder. The cylinder was tapped from a height of 2.5 cm at 2-second intervals until no further volume change was observed. Tapped volume was recorded, and tapped density was calculated using:

Carr’s Index (Compressibility Index)

Carr’s index is a measure of powder compressibility and is used to predict flow behavior. It was calculated using the bulk and tapped density values as follows:

Where:

• Dt = Tapped density
• Db = Bulk density

Evaluation of Mucoadhesive Buccal Tablets of Repaglinide

Hardness Test

Tablet hardness is a critical parameter that affects tablet integrity, disintegration, and drug release. The hardness of three randomly selected tablets from each batch was determined using a Monsanto hardness tester, and results were expressed in kg/cm². The mean and standard deviation were calculated.

Thickness          

Tablet thickness was measured for three tablets per batch using a screw gauge. Consistent thickness ensures uniformity in dose and packaging compatibility.

Friability Test

Friability indicates the tablet’s ability to resist abrasion during handling and transport. Twenty tablets from each formulation were weighed (W_initial), placed in a Roche friabilator and rotated at 25 rpm for 4 minutes (100 revolutions). Tablets were then dusted and reweighed (W_final). Friability (%) was calculated using:

A value below 1% was considered acceptable.

Weight Variation

Twenty tablets were randomly selected from each batch and individually weighed. The mean and standard deviation were calculated, and the percentage deviation from the mean was assessed according to IP specifications for uniformity of weight.

Drug Content Uniformity

Five tablets were powdered, and an amount equivalent to 10 mg of Repaglinide was extracted using 60% methanol, filtered, and diluted using phosphate buffer (pH 6.8) to obtain a 10 µg/mL solution. Absorbance was measured at 248 nm using a UV-Visible spectrophotometer. Drug content was determined from the calibration curve.

Surface pH        

The surface pH was evaluated to ensure that the formulation does not irritate the buccal mucosa. Each tablet was allowed to swell for 2 hours in 1 mL of phosphate buffer pH 6.8 at room temperature. A combined glass electrode pH meter was used to record the pH after equilibrating for 1 minute on the tablet surface.

Swelling Index

Swelling behavior was assessed in phosphate buffer pH 6.8. The initial tablet weight (W?) was recorded, and tablets were placed in buffer at 37 ± 1°C. At predetermined intervals (0.5 to 8 hours), tablets were removed, blotted, and reweighed (W?). Swelling index was calculated as:

Mucoadhesive Strength

Mucoadhesive strength was evaluated using a modified physical balance with sheep buccal mucosa as a model membrane (Figure-7). A tablet was attached to a glass stopper with adhesive and placed in contact with the mucosal tissue (mounted over a beaker) under a preload of 5 g for 3 minutes. Weights were added incrementally until detachment occurred. The mucoadhesive force was recorded as the excess weight required for detachment. The test was repeated three times for each formulation, and mean values were reported.

In-vitro Drug Release Study

Drug release was studied using a USP Type II dissolution apparatus (Campbell Electronics DR-6), with paddle rotation at 50 rpm in 900 mL phosphate buffer (pH 6.8) containing 0.5% Tween 80, maintained at 37 ± 0.5°C. Samples (5 mL) were withdrawn at regular intervals, filtered through a 0.25 µm membrane, and analyzed at 248 nm using a UV-Visible spectrophotometer.

Release Kinetics

Data were analyzed using the following kinetic models:

1. Zero-order: Cumulative % drug release vs. time
2. First-order: Log cumulative % drug remaining vs. time
3. Higuchi model: Cumulative % drug release vs. √time
4. Korsmeyer-Peppas model: Log cumulative % drug release vs. log time

Where Q = % drug release, K = kinetic constant, n = release exponent

• n = 0.45 indicates Fickian diffusion
• 0.45 < n < 0.89 suggests anomalous transport
• n = 0.89 implies zero-order release

Short-Term Stability Study

Optimized formulations were packed in amber-colored screw cap bottles, sealed with aluminum foil, and stored in a stability chamber at 40 ± 2°C / 75 ± 5% RH for 3 months. Samples were evaluated monthly for drug content and in-vitro release.

Drug-Polymer Interaction Studies

FTIR spectroscopy (Shimadzu 8400-S, Japan) was used to assess drug-polymer and polymer-polymer interactions. Characteristic peaks of pure drug and physical mixtures were analyzed to detect any changes indicative of interaction.

RESULTS AND DISCUSSION

1. Determination of λmax of Repaglinide in Phosphate Buffer (pH 6.8)

Repaglinide was analyzed spectrophotometrically to determine its maximum absorbance wavelength (λmax) in phosphate buffer pH 6.8. As shown in Table 9, the UV spectrum revealed a peak absorbance at 236 nm, which was selected as the λmax for subsequent spectrophotometric analysis and calibration curve generation.

Table 4: Determination of λmax of Repaglinide in Phosphate Buffer (pH 6.8)

2. Standard Calibration Curve of Repaglinide

A standard calibration curve of Repaglinide was constructed in phosphate buffer (pH 6.8). As shown in Table 10, absorbance values increased linearly with concentration. The calibration curve (Figure-9) showed excellent linearity with a correlation coefficient (r = 0.999), validating the method’s reliability for drug estimation.

Table 5: Standard Calibration Curve of Repaglinide in Phosphate Buffer (pH 6.8)

Figure-1: Standard calibration curve of Repaglinide in pH 6.8 phosphate buffer

This figure illustrates the linear relationship between the concentration of Repaglinide and its corresponding absorbance at λmax (236 nm) in phosphate buffer pH 6.8. The curve demonstrates excellent linearity with a correlation coefficient (r) of 0.999, confirming the suitability of the method for quantitative analysis of Repaglinide.

3. Pre-Compression Parameters

Flow properties of the powder blends were evaluated using standard pre-compression parameters. The angle of repose ranged from 23.47° to 25.85°, indicating good flow. Carr’s Index values ranged from 13.41% to 18.07%, further supporting good compressibility of the blends. These properties ensured uniform die filling during tablet compression.

Table 6: Pre-Compression Parameters of Repaglinide Buccal Tablet Formulations (Values expressed as Mean ± SD; n = 3)

All formulations exhibited acceptable flow properties conducive to consistent tablet production.

4. Post-Compression Evaluation

The formulated buccal tablets were evaluated for hardness, thickness, friability, weight variation, drug content, surface pH, swelling index, and mucoadhesive strength. Results are shown in Table 12.

• Hardness ranged between 4.5 to 7.0 kg/cm², indicating good mechanical strength.
• Thickness remained consistent (3.20–3.46 mm), ensuring uniform size.
• Friability values were <1% for all batches, indicating satisfactory resistance to abrasion.
• Weight variation and drug content were within pharmacopeial limits.
• Surface pH ranged from 6.6 to 6.9, close to the physiological pH of the buccal cavity, indicating low risk of mucosal irritation.
• Swelling Index increased with polymer concentration, enhancing the mucoadhesive interface.
• Mucoadhesive Strength ranged from 4.0 g to 8.0 g, demonstrating effective adhesion suitable for buccal retention.

Table 7: Post-Compression Parameters of Repaglinide Buccal Tablets (Values expressed as Mean ± SD; n = 3)

Among all, CP3 showed the highest mucoadhesive strength (8.0 g) and swelling index (75.12), indicating strong mucoadhesion and potential for prolonged retention.

In-vitro Drug Release Study

The in-vitro release profiles of Repaglinide from various mucoadhesive buccal tablet formulations (CP1–CP3 and HP1–HP3) were studied over an 8-hour period using phosphate buffer (pH 6.8) with 0.5% Tween 80. The cumulative percent drug release was plotted against time to evaluate release performance, and data were further analyzed using kinetic models to determine the release mechanism.

Formulations with Carbopol 934P (CP1–CP3)

• CP1 exhibited a sustained release profile, with 95.36% of drug released at the end of 8 hours. The drug release was gradual, indicating effective matrix formation and mucoadhesion. The t??%, t??%, and t??% values were approximately 3.41 h, 6.17 h, and 7.34 h, respectively.
• CP2 showed slightly slower release with 92.47% drug released in 8 hours, possibly due to increased polymer concentration enhancing the gel strength.
• CP3, containing the highest concentration of Carbopol 934P, exhibited the slowest release (86.28% in 8 h), demonstrating a clear inverse relationship between polymer content and drug release rate, likely due to increased viscosity and matrix density.

Formulations with HPMC K4M (HP1–HP3)

• HP1 demonstrated a comparatively faster release among HPMC-based formulations, with 99.00% drug release in 8 hours, and t??%, t??%, and t??% values of 3.20 h, 5.48 h, and 7.16 h, respectively.
• HP2 showed slightly prolonged release (91.23% in 8 h), attributed to the moderate increase in polymer content.
• HP3, with the highest HPMC content, released 85.45% of the drug by the end of 8 hours, suggesting effective retardation of drug diffusion.

These results clearly indicate that increasing the concentration of Carbopol 934P or HPMC K4M decreases the rate of drug release, due to enhanced gel layer formation and matrix integrity, which increases the diffusion path length.

Table-8:In-vitro drug release data of formulation CP1

^*Average of three determinations

Table-9: In-vitro drug release data of formulation CP2

^*Average of three determinations

Table-10: In-vitro drug release data of formulation CP3

^*Average of three determinations

Table-11: In-vitro drug release data of formulation HP1

^*Average of three determinations

Table-12: In-vitro drug release data of formulation HP2

^*Average of three determinations

Table-13: In-vitro drug release data of formulation HP3

^*Average of three determinations

Figure-2: Cumulative percent drug released vs time plots (zero order) of formulations CP1, CP2and CP3

Figure-3: Log cumulative percent drug remaining vs time plots (first order) of formulations CP1, CP2and CP3

Figure -4: Cumulative percent drug released vs square root of time (Higuchi plots) of formulations CP1, CP2and CP3

Figure-5: Log cumulative percent drug released vs Log time (Peppas plots)offormulations CP1, CP2and CP3

Figure -6: Cumulative percent drug released vs time plots (zero order) of formulations HP1, HP2and HP3

Figure -7: Log cumulative percent drug remaining vs time plots (first order) of formulations HP1, HP2and HP3

Figure -8: Cumulative percent drug released vs square root of time (Higuchi plots) of formulations HP1, HP2and HP3

Figure-9: Log cumulative percent drug released vs Log time (Peppas plots)of formulationsHP1, HP2and HP3

Table-14: Dissolution parameters for the formulations

Figure-10: Comparison of dissolution parameters (t_50%, t_70% and t_90%)of Buccal tablets of Repaglinide

Table-15: Kinetic data of the formulations

Table-16: Drug content data of stability formulation (CP1)

Table-17: Statistical analysis of drug content data for the stability formulation (CP1)

Table-18: In-vitro drug release data of the stability formulation (CP1)