Development and optimization of vildagliptin solid lipid nanoparticles loaded ocuserts for controlled ocular delivery: A promising approach towards treating diabetic retinopathy

Abstract

Diabetes mellitus (DM) is the most prevalent cause of diabetic retinopathy (DRP). DRP has been recognized for a long time as a microvascular disease. Many drugs were used to treat DRP, including vildagliptin (VLD). In addition to its hypoglycemic effect, VLD minimizes ocular inflammation and improves retinal blood flow for individuals with type 2 diabetes mellitus. Nevertheless, VLD can cause upper respiratory tract infections, diarrhea, nausea, hypoglycemia, and poor tolerability when taken orally regularly due to its high water solubility and permeability. Effective ocular administration of VLD is achieved using solid lipid nanoparticles (SLNPs), which improve corneal absorption, prolonged retention, and extended drug release. Ocuserts (OCUs) are sterile, long-acting ocular dosage forms that diminish the need for frequent dosing while improving residence time and stability. Therefore, this study intends to develop VLD solid lipid nanoparticle OCUs (VLD-SLNPs-OCUs) to circumvent the issues commonly associated with VLD. SLNPs were prepared using the double-emulsion/melt dispersion technique. The optimal formula has been implemented in OCUs. Optimization and development of VLD-SLNPs-OCUs were performed using a Box-Behnken Design (BBD). VLD-SLNPs-OCUs loading efficiency was 95.28 ± 2.87%, and differential scanning calorimetry data (DSC) showed the full transformation of VLD to an amorphous state and the excellent distribution in the prepared OCUs matrices. The in vivo release of VLD from the optimized OCUs after 24 h was 35.12 ± 2.47%, consistent with in vitro drug release data of 36.89 ± 3.11. The optimized OCUs are safe to use in the eye, as shown by the ocular irritation test. VLD-SLNPs-OCUs provide extended VLD release, an advantageous alternative to conventional oral dose forms, resulting in fewer systemic adverse effects and less variation in plasma drug levels. VLD-SLNPs-OCUs might benefit retinal microvascular blood flow beyond blood glucose control and may be considered a promising approach to treating diabetic retinopathy.

Keywords: Diabetic retinopathy; Double emulsion/ melt dispersion technique; Ocuserts; Solid lipid nanoparticles; Solvent casting technique; Vildagliptin.

Graphical abstract

Fig. 1

Schematic depiction of procedures that comprise the preparation of VLD-SLNPs.

Fig. 2

The comparative dissolution profiles of VLD-SLNPs formulations and pure VLD in phosphate buffer, pH 7.4.

Fig. 3

The SEM imaging of VLD-SLNPs formulation, Run 3.

Fig. 4

Percentage of moisture absorption, moisture loss, and swelling index of various vildagliptin-solid lipid nanoparticles loaded ocuserts formulations.

Fig. 5

(a) 3D and response surface plots for the effect of HPMC, PVA, and Eudragit RL100 (R₁, R₂, and R₃) on MAT (Z₁), (b) The contour plot for the effect of HPMC, PVA, and Eudragit RL100 (R1, R2, and R3) on MAT (Z1).

Fig. 6

In vitro release profiles of various VLD-SLNPs-OCUs in phosphate buffer, pH 7.4.

Fig. 7

(a) 3D and response surface plot for the effect of HPMC, PVA, and Eudragit RL100 (R₁, R₂, and R₃) on the cumulative VLD% released after 24 h (Z₂), (b) The contour plot for the effect of HPMC, PVA, and Eudragit RL100 (R₁, R₂, and R₃) on the cumulative VLD % released after 24 h (Z₂).

Fig. 8

Plots of a: in vitro and b: in vivo, cumulative VLD percent amount released versus time for the optimized VLD-SLNPs-OCUs formulation (VOS-0).