Implementing the Design of Experiments (DoE) Concept into the Development of Mucoadhesive Tablets Containing Orange Peel Extract as a Potential Concept for the Treatment of Oral Infections

Abstract

This study explores for the first time the impact of chitosan (CS) with varying molecular weights (MW), orange peel extract concentration, and hydroxypropyl methylcellulose (HPMC) content on the formulation of buccal tablets for treating oral infections. Utilizing a statistical design of experiments (DoE), nine different formulations were evaluated for mechanical properties, dissolution behavior, mucoadhesion, and biological activity. A formulation with high CS MW, 60% orange peel extract, and 8% HPMC, emerged as the optimal formulation, demonstrating superior tabletability, compressibility, and compactibility. Dissolution studies indicated that hesperidin release followed the Higuchi model, with higher extract content enhancing this phenomenon. Mucoadhesion improved with increased HPMC and CS concentrations, although higher extract content reduced bioadhesion. Biological assays showed that higher extract levels boosted antioxidant activity, while CS primarily contributed to anti-inflammatory effects. The optimized formulation exhibited broad antimicrobial activity against key oral pathogens, surpassing the effectiveness of the individual components. Principal component analysis (PCA) further confirmed the significant influence of extract content on tablet properties. These findings suggest that the optimized tablet formulation holds promise for effective buccal delivery in the treatment of oral infections, warranting further investigation in clinical settings.

Keywords: buccal tablets; chitosan; dissolution; hydroxypropyl methylcellulose; mucoadhesion; oral cavity infections; orange peel extract; statistical design of experiments.

Figure 1

ATR-IR spectra for orange peel extract [15], CS [26], and HPMC [8] (a), and formulation F1–F9 (b).

Figure 2

Tabletability (a), compressibility (b), and compactibility (c) profiles of tablets produced from systems 1–9.

Figure 3

Hesperidin dissolution profiles for tablets F1–F9 for both compression pressures (′ for lower compression pressure and ″ for higher compression pressure).

Figure 4

Swelling index for tablets F1–F9 for both compression pressures (′ for lower compression pressure and ″ for higher compression pressure).

Figure 5

Component of bioadhesion of formulations F1–F9.

Figure 6

Prediction based on effects with positive signs (true density, porosity, dissolution after 6 h expressed in mg, swelling index, component of mucoadhesion) (a) and with negative signs (antioxidant and anti-inflammatory activities) (b).

Figure 7

Principal component analysis (PCA) showing the factor loading plot considering true density, porosity, dissolution after 6 h expressed in mg, swelling index, component of mucoadhesion (=Muco), and antioxidant (=DPPH) and anti-inflammatory activities (=Hyal).