Hexyl alginate derivative, an amphiphilic innovative buccal film-forming material of promising mechanical and release characteristics for the improvement of repaglinide bioavailability

Abstract

Background: Association of long hydrocarbon chain with alginate molecule imparts surface active properties and increases chain flexibility.

Purpose: This work studied the efficacy of synthesized hexyl alginate derivative as a film-forming material with unique amphiphilic and mechanical properties for the preparation of rapidly disintegrating repaglinide oral films with higher drug release rate and improved bioavailability.

Methods: Alginate hexyl amide derivative was prepared and used in the formulation of oral films by solvent casting technique. Using Box-Behnken experimental design, formulations were optimized at different polymer, plasticizer, and disintegrant levels as independent variables for maximum drug release rate, higher tensile strength, and shortest disintegration time as responses. Optimized film formulae were fully evaluated and subjected to further in vivo bioavailability studies in rabbits.

Results: Higher dependency of response results on the selected variables was observed. Optimized formula showed satisfactory tensile strength (145.862 g/cm²), rapid disintegration (22.2 seconds), and higher drug release rate (97.799% within 30 minutes). The drug bioavailability was significantly improved in comparison with plain drug and conventional alginate oral films, where the AUC and C_max values reached 296.072 μg.h/mL and 116.932 μg/mL in comparison with 164.917 μg.h/mL and 56.568 μg/mL for alginate film and 95.368 μg.h/mL and 31.925 μg/mL for plain drug, respectively. T_max also showed significant reduction to be only 30 minutes in comparison with 60 minutes for other forms.

Conclusion: This led to the final conclusion that the synthesized alginate derivative is an innovative promising film-forming material with unique mechanical and drug release properties for application in buccal drug delivery especially of Biopharmaceutics Classification System (BCS) class II drugs to increase solubility and improve bioavailability.

Keywords: BCS class II drugs; Box–Behnken; amphiphilic derivatives of alginate; oral films; repaglinide.

Figure 1

Three dimensional response surface (A–C) and perturbation plot (D) showing the effect of different independent variables on REP release rate (R₁). Abbreviations: REP, repaglinide; AHAD, alginate hexyl amide derivative.

Figure 2

Three dimensional response surface (A–C) and perturbation plot (D) showing the effect of different independent variables on tensile strength (R₂). Abbreviations: REP, repaglinide; AHAD, alginate hexyl amide derivative.

Figure 3

Three dimensional response surface (A–C) and perturbation plot (D) showing the effect of different independent variables on disintegration time (R₃). Abbreviations: REP, repaglinide; AHAD, alginate hexyl amide derivative.

Figure 4

Dissolution profiles of REP from optimized AHAD film formulae in comparison with alginate film and plain drug. Abbreviations: AHAD, alginate hexyl amide derivative; REP, repaglinide; Alg, alginate.

Figure 5

Characterization of optimized film formula (F4) using (A) DSC, (B) FTIR, and (C) scanning electron microscopy. Abbreviation: DSC, differential scanning calorimetry; FTIR, Fourier-transform infrared spectroscopy.

Figure 6

Mean plasma concentration–time curves for optimized film formula (F4) in comparison with conventional alginate film and plain drug in rabbits. Abbreviations: REP, repaglinide; AHAD, alginate hexyl amide derivative.