Development of an Oral Delivery System for Ileo-Colonic Release of a Diospyros kaki leaf extract

Following the COVID-19 pandemic, interest in complementary approaches to disease prevention and health promotion has increased, particularly in nutraceuticals containing plant-derived bioactive compounds. Among these, polyphenols have attracted attention for their antioxidant, anti-inflammatory and immunomodulatory properties, as well as for their positive impact on the gut microbiota1. Diospyros kaki (DK), particularly its leaves, is a promising source of flavonoids and condensed tannins. However, the limited stability of polyphenols in the upper gastrointestinal tract may reduce systemic absorption and, also, their availability in the ileo-colonic region for microbiota interaction and biological activity on intestinal mucosa. The aim of the present study was to develop and characterize an oral delivery system for ileo-colonic release of a dried ethanolic extract from DK leaves, consisting of extract-loaded tablet cores coated with a low-viscosity hydroxypropyl methylcellulose (HPMC) layer and a methacrylic acid copolymer outer film. The inner layer was intended to delay the onset of release for a lag time consistent with ileo-colonic release, while the outer film would protect the system from gastric fluid, thus ruling out the influence of unpredictable stomach emptying on the site of delivery2. Preliminary physico-technological characterization of the DK leaf extract pointed out a highly cohesive powder with poor flow properties (Carr’s index 39%). To overcome processability issues, formulation studies were performed. The extract (50%) was finally blended with microcrystalline cellulose (25.8%), lactose monohydrate (11%), sodium starch glycolate (6%), magnesium stearate (1%), talc (6%) and colloidal silica (0.2%). 5 mm tablet cores containing 35 mg of DK extract were obtained, exhibiting disintegration time below 10 min, while no breaking force was recorded due to plastic deformation on mechanical testing. When subjected to aqueous HPMC spray-coating, swelling and partial disintegration of the cores were observed. To prevent exposure of tablets to the coating formulation, a sealing layer was applied up to 4% weight gain using a copovidone ethanolic solution. In was thereby possible to obtain coated units having HPMC and polymethacrylate weight gains of 43 and 7%, respectively. The final multilayer systems showed no release in acidic medium and a reproducible lag phase of 77±8 min in phosphate buffer pH 6.8, followed by rapid and complete release as desired. Reversed-Phase Ultra-High Performance Liquid Chromatography - Diode Array Detector (RP-UHPLC-DAD) analysis of kaempferol-3-O-glucoside confirmed that compression did not affect integrity, whereas copovidone/HPMC coating reduced recovery of approximately 10%. No additional loss occurred after enteric coating. Overall, these findings demonstrate the feasibility of developing an ileo-colonic delivery system of DK leaf extract.