Key Takeaways & Executive Findings
- •• • The optimized Dio-Reb A-SNM achieved 93.59±0.63% encapsulation efficiency and 5.65±0.07% drug loading with a particle size of 25.66±1.76 nm, enabling rapid gastrointestinal mucus penetration and enhanced cellular uptake. This sub-30 nm size is critical for avoiding first-pass metabolism and improving oral absorption. • • Relative oral bioavailability of diosgenin increased 6.82-fold compared to free diosgenin, surpassing previous formulations such as albumin nanoparticles (3.77-fold), dripping pills (4.53-fold), and amorphous solid dispersions (5.69-fold). This positions Dio-Reb A-SNM as a superior delivery system for diosgenin. • • In T2DM rats, Dio-Reb A-SNM (30 mg/kg) produced a highly significant reduction in blood glucose (P<0.01) at week 4, along with significant decreases in AST, ALT, urea nitrogen, and creatinine (P<0.01), indicating improved glycemic control and reduced hepatic and renal injury. • • The nanomicelles exhibited sustained release with 90.94% cumulative release at 18 h, following a Weibull model, combining rapid onset (tmax 2.06±0.29 h) and prolonged action (t1/2 8.39±1.94 h). This release profile supports both immediate and maintained therapeutic effects.
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Abstract
Diosgenin (Dio) suffers from poor aqueous solubility and low oral bioavailability, limiting its clinical translation. This study developed diosgenin-rebaudioside A self-assembled nanomicelles (Dio-Reb A-SNM) using a combined drug-excipient strategy. Box-Behnken design-response surface methodology optimized the formulation: rebaudioside A to diosgenin ratio 12.32:1, diosgenin concentration 1.97 mg/mL, ultrasonic time 20.20 min. The optimized Dio-Reb A-SNM exhibited an encapsulation efficiency of 93.59±0.63%, drug loading of 5.65±0.07%, particle size of 25.66±1.76 nm, and zeta potential of -24.59±1.18 mV. Transmission electron microscopy revealed spherical morphology, and X-ray powder diffraction confirmed amorphization of diosgenin. The nanomicelles significantly enhanced saturated solubility across pH media and demonstrated sustained release (90.94% cumulative release at 18 h) fitting a Weibull model. Pharmacokinetic studies in SD rats showed that Dio-Reb A-SNM achieved a tmax of 2.06±0.29 h, t1/2 of 8.39±1.94 h, and increased Cmax and relative bioavailability by 3.59-fold and 6.82-fold, respectively, compared to free diosgenin. In a type 2 diabetes mellitus rat model, Dio-Reb A-SNM (30 mg/kg) significantly reduced blood glucose (P<0.01) and serum AST, ALT, urea nitrogen, and creatinine levels (P<0.01), with attenuated hepatic and renal pathological injury. These findings demonstrate that Dio-Reb A-SNM markedly improves oral absorption and hypoglycemic efficacy of diosgenin, providing a promising formulation strategy.
1. Introduction
Diosgenin, a steroidal sapogenin with documented hypoglycemic, anti-inflammatory, and hypolipidemic activities, faces a critical pharmaceutical bottleneck: its aqueous solubility is negligible, and oral bioavailability is extremely low, primarily due to poor dissolution and extensive first-pass metabolism. Conventional formulation approaches—including solid dispersions, nanoparticles, and lipid-based systems—have achieved only modest improvements, with relative bioavailability typically not exceeding 5.69-fold. These limitations have stalled the clinical translation of diosgenin as an oral antidiabetic agent.
This study addresses the bottleneck by employing a 'combined drug-excipient' strategy, using rebaudioside A—a natural sweetener with intrinsic hypoglycemic activity—as both carrier and functional excipient. The self-assembled nanomicelles (Dio-Reb A-SNM) were optimized via Box-Behnken design, yielding a formulation with high encapsulation efficiency, small particle size, and amorphous drug state. The resulting nanomicelles significantly enhanced solubility, modulated release kinetics, and improved oral bioavailability and hypoglycemic efficacy in a type 2 diabetes rat model, offering a scalable and cost-effective solution for diosgenin delivery.
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CAI Lijun, WANG Haijun, ZHANG Li, DING Shuming, JUE Lili (2026). Preparation, Pharmacokinetics and Hypoglycemic Effects Evaluation of Diosgenin-Rebaudioside A Self-Assembled Nanomicelles Based on the 'Combined Drug-Excipient' Strategy. Chinese Traditional and Herbal Drugs. https://doi.org/10.7501/j.issn.0253-2670.2026.16.20261610
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Frequently Asked Questions
What is the physical stability of Dio-Reb A-SNM under gastrointestinal stress, and does the amorphous state risk recrystallization during storage?
XRPD confirmed that diosgenin is amorphous in the lyophilized powder, and the nanomicelles remained stable in different pH media. However, long-term stability data were not provided; recrystallization could occur under high humidity or temperature, potentially compromising dissolution and bioavailability. Accelerated stability studies are warranted.
How does the relative bioavailability of 6.82-fold compare to other advanced delivery systems, and what is the industrial scalability of the ultrasonic-assisted self-assembly process?
The 6.82-fold increase exceeds reported values for albumin nanoparticles (3.77-fold), dripping pills (4.53-fold), and amorphous solid dispersions (5.69-fold). The process uses ultrasonic time of 20.20 min and a drug-to-excipient ratio of 12.32:1, which is amenable to scale-up, but ultrasonic energy input and batch uniformity need validation in pilot-scale equipment.
Does rebaudioside A contribute synergistically to the hypoglycemic effect, or is it solely a carrier? What is the evidence?
Rebaudioside A itself possesses hypoglycemic activity, and the study acknowledges potential synergy but does not isolate its contribution. The improved efficacy may stem from both enhanced bioavailability and intrinsic activity of rebaudioside A. Further studies with rebaudioside A alone and combination index analysis are required to confirm synergy.
What are the failure mechanisms under stress conditions, such as high shear or freeze-drying, and how do they affect encapsulation efficiency?
High shear or freeze-drying could disrupt the micellar structure, leading to drug leakage and reduced encapsulation efficiency. The optimized formulation achieved 93.59% EE, but no stress testing data are reported. Robustness studies under mechanical stress and lyophilization cycles are necessary to ensure batch consistency.
What is the cost parity of Dio-Reb A-SNM against legacy formulations, considering the use of rebaudioside A and the ultrasonic process?
Rebaudioside A is a natural, low-cost excipient compared to synthetic polymers, and the process avoids organic solvents. However, ultrasonic equipment and energy consumption may add capital and operational costs. A detailed techno-economic analysis is required to assess cost parity with solid dispersions or nanoparticles.
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