Establishment of In Vitro Dissolution Based on Similarity with In Vivo Dissolution: A Case Study on Aripiprazole.

In vitro dissolution that predicts the in vivo performance of solid preparations is extremely important in formulation optimization. Fraction absorbed (Fa) has been used to screen in vitro dissolution protocols based on the idea of in vitro-in vivo correlation (IVIVC) but failed to increase the success rate due to the inaccuracy of the Fa. The essence of IVIVC is the correlation between in vitro dissolution and in vivo dissolution. We tried to establish in vitro dissolution protocol via similarity with in vivo dissolution using aripiprazole (APZ) as a model drug. Hybrid APZ crystals (APZ-HCs) were prepared by physically embedding aggregation-caused quenching (ACQ) fluorophores inside the lattice to measure the in vivo dissolution. The process did not change the physicochemical properties and crystallinity of APZ. The fluorophore illuminated APZ crystals but was quenched upon dissolution of APZ-HCs in aqueous media, enabling monitoring intact APZ-HCs in real-time. The good correlation between fluorescent quenching and dissolution of APZ-HCs justified reliable quantification of intact APZ crystals. The residual percentage of fluorescence intensity in rats treated by APZ-HCs was recorded with time, which was converted to in vivo dissolution by the difference from 100%. The in vivo dissolution was validated with the Fa. The in vitro dissolution profile of APZ was set up via a similarity factor larger than 50 in comparison with the in vivo dissolution. The study provides a novel idea and method to establish in vitro dissolution protocol.

Engineered small extracellular vesicles as a versatile platform to efficiently load ferulic acid via an "esterase-responsive active loading" strategy.

As nano-drug carriers, small extracellular vesicles (sEVs) have shown unique advantages, but their drug loading and encapsulation efficiency are far from being satisfied, especially for the loading of hydrophilic small-molecule drugs. Inspired by the strategies of active loading of liposomal nanomedicines, pre-drug design and immobilization enzyme, here we developed a new platform, named "Esterase-responsive Active Loading" (EAL), for the efficient and stable drug encapsulation of sEVs. Widely used ferulic acid ester derivatives were chosen as prodrugs based on the EAL of engineered sEVs to establish a continuous transmembrane ion gradient for achieving efficient loading of active molecule ferulic acid into sEVs. The EAL showed that the drug loading and encapsulation efficiency were around 6-fold and 5-fold higher than passive loading, respectively. Moreover, characterization by nano-flow cytometry and Malvern particle size analyzer showed that differential ultracentrifugation combined with multiple types of membrane filtration methods can achieve large-scale and high-quality production of sEVs. Finally, extracellular and intracellular assessments further confirmed the superior performance of the EAL-prepared sEVs-loaded ferulic acid preparation in terms of slow release and low toxicity. Taken together, these findings will provide an instructive insight into the development of sEV-based delivery systems.

The Study of Ginger-Derived Extracellular Vesicles as a Natural Nanoscale Drug Carrier and Their Intestinal Absorption in Rats.

Extracellular vesicles have been widely used in drug delivery systems and clinical studies as a new natural nanoscale drug carrier. Most of these studies focused on the extracellular vesicles from animals, but few involved in the extracellular vesicles from edible plants. This study was the first to explore the potential and value of ginger-derived extracellular vesicles (GDEVs) as drug carrier by using the content ratio method and to further study their intestinal absorption in rats. In this experiment, GDEVs were extracted and purified by ultrahigh-speed centrifugation. GDEVs were saucer-like with a particle size of 70.09±19.24 nm and a zeta potential of -27.70±12.20 mV. In this experiment, high-performance liquid chromatography was used to explore the difference in gingerol content between GDEVs and ginger slices. Under the same mass, the contents of 6-gingerol (6G), 8-gingerol (8G), and 10-gingerol (10G) in GDEVs were 10.21-fold, 22.69-fold, and 32.36-fold of those in ginger slices, respectively. In this experiment, the absorption kinetics and absorption site of GDEVs were investigated using in situ single-pass intestinal perfusion method in rats. GDEVs could be absorbed by the small intestine in the concentration range of 15-60 mg/mL, and the absorption trend of different intestinal segments was duodenum > jejunum > ileum. These results indicated that GDEVs had good loading capacity and significant prospects as a carrier of the drug delivery system. At the same time, combining the oil-water partition coefficient (6G < 8G < 10G) of three gingerol compounds, we speculated that the loading capacity of GDEVs increased with the increase of the lipid solubility of the compounds. This study fully demonstrated the potential and value of ginger-derived extracellular vesicles as natural nanocarrier and provided an important reference for the further application of plant-derived extracellular vesicles in the drug delivery system.

Techniques and Applications of Animal- and Plant-Derived Exosome-Based Drug Delivery System.

Exosomes are a kind of extracellular vesicle, has a particle size of 50-150 nm. Exosomes derived from different cell types are thought to participate in the regulation of cellular communication. On account of the ability of exosomes to deliver various cargos to a corresponding target site, they are often used to deliver therapeutic cargos for treatment. This review summarizes the origins and composition of exosomes, and provides a detailed overview of the current methods for exosome isolation and drug loading as well as the application of exosomes to drug delivery systems (DDSs) to provide practical suggestions for exosome studies. Moreover, this review also highlights the research progresses on plant-derived exosomes in determining their commonalities with and distinctions from animal-derived exosomes, and the advantages and challenges faced by plant-derived exosomes as drug delivery carriers are also discussed to contribute to the further application of plant-derived exosomes.