Fabrication and characterization of glimepiride nanosuspension by ultrasonication-assisted precipitation for improvement of oral bioavailability and in vitro α-glucosidase inhibition

Abstract

Purpose: We aimed to enhance the solubility, dissolution rate, oral bioavailability, and α-glucosidase inhibition of glimepiride (Glm) by fabricating its nanosuspension using a precipitation-ultrasonication approach.

Methods: Glm nanosuspensions were fabricated using optimized processing conditions. Characterization of Glm was performed using Malvern Zetasizer, scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry, and powder X-ray diffraction. Minimum particle size and polydispersity index (PDI) values were found to be 152.4±2.42 nm and 0.23±0.01, respectively, using hydroxypropyl methylcellulose: 6 cPs, 1% w/v, polyvinylpyrrolidone K30 1% w/v, and sodium lauryl sulfate 0.12% w/v, keeping ultrasonication power input at 400 W, with 15 minutes' processing at 3-second pauses. In vivo oral bioavailability was assessed using rabbits as a model.

Results: The saturation solubility of the Glm nanosuspensions was substantially enhanced 3.14-fold and 5.77-fold compared to unprocessed drug in stabilizer solution and unprocessed active pharmaceutical ingredient. Also, the dissolution rate of the nanosuspensions ws substantially boosted when compared to the marketed formulation and unprocessed drug candidate. The results showed that >85% of Glm nanosuspensions dissolved in the first 10 minutes compared to 10.17% of unprocessed Glm), 42.19% of microsuspensions, and 19.94% of marketed tablets. In-vivo studies conducted in animals, i.e. rabbits, demonstrated that maximum concentration and AUC_0-24 with oral dosing were twofold (5 mg/kg) and 1.74-fold (2.5 mg/kg) and 1.80-fold (5 mg/kg) and 1.63-fold (2.5 mg/kg), respectively, and compared with the unprocessed drug formulation. In-vitro α-glucosidase inhibition results showed that fabricated nanosuspensions had a pronounced effect compared to unprocessed drug.

Conclusion: The optimized batch fabricated by ultrasonication-assisted precipitation can be useful in boosting oral bioavailability, which may be accredited to enhanced solubility and dissolution rate of Glm, ultimately resulting in its faster rate of absorption due to nanonization.

Keywords: boosted bioavailability; glimepiride nanosuspension; precipitation–ultrasonication approach.

Figure 1

Chemical structure of glimepiride.

Figure 4

SEM of raw glimepiride (Glm) (A); TEM of Glm nanosuspension (B). Abbreviations: SEM, scanning electron microscopy; TEM, transmission electron microscopy; HV, high vacuum; WD, working distance.

Figure 2

Influence of polymer concentration on particle size. Abbreviations: HPMC, hydroxypropyl methylcellulose; PVP, polyvinylpyrrolidone; SLS, sodium lauryl sulfate.

Figure 3

Impact of ultrasonic energy power input (A) and time length (B) on particle size of fabricated GN. Abbreviation: GN, glimepiride nanosuspension.

Figure 5

DSC thermogram of GN and unprocessed Glm. Abbreviations: DSC, differential scanning calorimetry; Glm, glimepiride; GN, Glm nanosuspension.

Figure 6

P-XRD patterns of GN, unprocessed Glm, and PM. Abbreviations: P-CRD, powder X-ray diffraction; Glm, glimepiride (unprocessed); GN, Glm nanosuspension; PM, physical mixture.

Figure 7

Solubility of Glm, GN in aqueous medium, and Glm in stabilizer solution. Abbreviations: Glm, glimepiride; GN, glimepiride nanosuspension.

Figure 8

Physical stability of GN in terms of P.S and PDI at (A) 2°C–8°C, (B) 25°C, and (C) 40°C. Abbreviations: GN, glimepiride nanosuspension; PDI, polydispersity index.

Figure 9

ζ-potential of glimepiride nanosuspension (GN).

Figure 10

Comparative in vitro dissolution profiles of raw glimepiride (Glm), Glm nano suspension (GN), and marketed tablets.

Figure 11

Plasma drug concentration versus time after oral administration of GN and Glm. Abbreviations: Glm, glimepiride; GN, Glm nanosuspension.