Drug Delivery Letters - Volume 15, Issue 2, 2025

The study aims to develop a 3^rd generation amorphous solid dispersion (ASD) of Apremilast (APST) employing the Design of Experiment (DoE) methodology, followed by a thorough assessment including in silico pharmacokinetics.

APST, classified as a BCS-Class IV molecule due to its low solubility and permeability, exhibits highly variable oral bioavailability across different species.

In this study, a 3^rd generation ASD of APST was developed using the DoE approach.

The miscibility of APST within polymers was assessed using solubility parameters and Flory Huggin equation. Phase solubility studies were conducted to identify the most suitable polymer-surfactant combination for maximizing drug solubility. The produced solid dispersions were characterized using FTIR, DSC, XRD, DVS, and SEM.

The combination of APST and Soluplus^® in a 1:5 ratio resulted in the highest improvement in solubility and dissolution, with vitamin E TGPS being identified as the most efficient surfactant. Stability studies were carried out, and findings revealed that the ASD remained stable under accelerated conditions for up to 3 months, suggesting its suitability for scaling up for industrial applications. In silico predictions of the pharmacokinetics of APST following oral administration of solid dispersion formulations were determined by PBBM using GastroPlus™.

The simulation of oral absorption profiles for APST showed a significant improvement in both Cmax and AUC for the solid dispersion formulations compared to plain drugs. This study makes a significant contribution to the field of pharmaceutical science by addressing the formulation complexities inherent in poorly water-soluble compounds like APST.

Berberine is an isoquinoline alkaloid with potent anti-inflammatory effects. However, its therapeutic efficacy is often restricted by its poor solubility, absorption, and permeability, especially in topical applications. Transferosomes are elastic vesicular carriers with high skin permeability values and retention, making them suitable for encapsulating hydrophilic and lipophilic actives.

The objective of this research was to develop a transferosome-based topical gel formulation of Berberine hydrochloride (BER) to improve its skin permeability and anti-inflammatory efficacy.

The thin film hydration method was used to formulate the BER transferosomes. The effects of independent variables, amount of BER in lipid phase (X1), and lipid (Phospholipon 90G) to surfactant ratio (X2) on BER entrapment and vesicle size were studied using face-centered central composite design. The characterization was performed using differential scanning calorimetry, transmission electron microscopy, and X-ray diffraction. The optimized batch (F5) was incorporated in Carbopol gel and further investigated for viscosity, in vitro and ex-vivo diffusion, skin retention by tape stripping, and in-vivo anti-inflammatory efficiency.

The formulation optimized with 50 mg of drug and a 5:1 lipid-to-surfactant ratio (F5) demonstrated higher drug entrapment efficiency (72.11%) and lower vesicle size (77.9 nm). TEM validated the spherical vesicle morphology, whereas DSC and XRD analysis confirmed the molecular entrapment of BER within the phospholipid vesicles. The transferosomal gel demonstrated improved BER diffusion (0.63 mg/cm²) confirmed by in vitro and ex-vivo diffusion experiments that revealed a 6-fold increase in flux and permeability coefficient (0.1053 mg. cm^-2.h^-1). The drug release from transferosome gel was non-Fickian in nature (n = 0.6575), indicating an integration of diffusion and erosion processes. Furthermore, BER transferosomal gel displayed substantial anti-inflammatory activity in rats (p < 0.001).

The findings demonstrated the potential of transferosomal gel as a promising approach for efficient drug delivery and therapeutic efficacy.

Flurbiprofen, a non-selective COX inhibitor utilized for managing mild to moderate pain and inflammation, operates through reversible inhibition of both COX-1 and COX-2 pathways. However, as a BCS class II drug, it exhibits limited aqueous solubility, leading to suboptimal ocular bioavailability and a brief corneal contact.

The goal of this study was to amplify the aqueous solubility of Flurbiprofen by formulating it into a nanosuspension, which was subsequently incorporated into an in-situ gelling system so as to extend the ocular residence time and to achieve sustained drug release.

Nanosuspensions were crafted through the anti-solvent precipitation ultra-sonication method. The assessment included parameters, such as particle size, surface morphology, XRD, and FT-IR. The optimized nanosuspension was then incorporated into a pH-sensitive in-situ gel.

The developed formulation was stable and showed enhanced contact time, minimizing the frequency of administration. Morphological analysis unveiled spherical drug nanoparticles in the nanosuspension without any signs of aggregation, supported by high-resolution transmission electron microscopy. The ex vivo permeation studies showed a drug release of 83.48%, indicating good permeation and histopathology, and isotonicity indicated no ocular irritation and tissue damage.

The design and development of Flurbiprofen nanosuspension were found to be liquid at the formulated pH and formed gel due to changes in bonds between polymers. In-situ ocular gels minimize the risk of systemic absorption of the drug, as they are designed to stay localized on the ocular surface and within the eye. An optimum point can be reached in the shortest time with minimum efforts to achieve desirable rheological and in-vitro release properties for in-situ gelling systems.