Phytotherapeutics self-microemulsifying systems in pellet dosage form for enhanced intestinal drug delivery: formulation, stability, and in-vivo performance.

Abstract

Self-microemulsifying drug delivery systems (SMEDDS) containing volatile phytotherapeutics such as thymol (T), carvacrol (C), and eugenol (E) present significant formulation challenges, even when solidified. Their instability and interactions with coatings often hinder intestinal delivery. To address these limitations, we developed solid SMEDDS consisting of pellets (microcrystalline cellulose/magnesium aluminometasilicate/chitosan) and enteric capsules (CEC) for enhanced intestinal delivery. Based on solubility and pseudo-ternary phase diagrams, SMEDDS formulations (SES1-3) differing in component ratios (glycerol monooleate/caprylocaproyl macrogol-8 glycerides/diethylene glycol monoethyl ether) with 5% w/w of each drug were identified, demonstrating nano-scale droplet sizes (PDI <0.4) and showing no phase separation over 6 months. Thermodynamic stability and liquid-state NMR revealed particle size variations with preserved structural integrity. The lead formulation SES1 exhibited superior ex-vivo intestinal permeation (T-SES1). CECs filled with T-, C-, and E-loaded SES1 pellets, respectively, prepared via extrusion/spheronization, exhibited in-vitro gastro-resistant release, and achieved > 85% drug release within 120  min after a pH change to 6.8 during a one-year stability study (25 °C; 60% RH). FTIR-ATR analysis of the CEC internal surface confirmed the temperature-dependent restructuring of hypromellose and E sorption, a phenomenon not observed with C or T, which is likely attributable to physicochemical distinctions. Oral administration of CEC with T-SES1-pellets (0.5  mg/kg) in piglets demonstrated a delayed peak plasma concentration (C_max 11.67  ng/mL at 9 h) and sustained systemic exposure (AUC 119.8 ng·h/mL). These in-vivo findings substantiate the gastro-protective effect and enhanced intestinal absorption, positioning the pellet/CEC system as a promising strategy for the application of volatile phytotherapeutics in current pharmacotherapy.