(M1330-09-58) Berberine Hydrochloride Amorphous Solid Dispersion via Hot-Melt Extrusion for Taste Masking and Bioavailability Enhancement

Purpose: Berberine hydrochloride (BH) is a multi-target, multifunctional natural isoquinoline alkaloid[1] with broad therapeutic potential for the treatment of metabolic[2], inflammatory[3], infectious diseases[4], and various tumors[5]. However, its intensely bitter taste and classification as a Biopharmaceutics Classification System (BCS) Class III compound—characterized by high solubility but low permeability[6]—significantly hinder its therapeutic efficacy and patient compliance, presenting major challenges for clinical use and commercialization. To overcome these limitations, we developed an amorphous solid dispersion (ASD) of berberine hydrochloride using hot-melt extrusion technology.

Methods: BH, Kollicoat® MAE 100-55 (MAE 100-55, polymer), polyethylene glycol 8000 (PEG 8000, plasticizer), and citric acid (CA) were uniformly blended prior to hot-melt extrusion. The extrusion process was carried out at 145 °C with a screw speed of 60 rpm and a feeding rate of 5–6 g/min. The resulting extrudate was cooled to room temperature, milled, passed through a 60-mesh sieve, and stored in a desiccator. The prepared samples were characterized using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FT-IR). In vitro dissolution studies of the BH amorphous solid dispersion (BH-ASD) were performed in physiologically relevant media: pH 1.2 HCl, pH 6.8 phosphate-buffered saline (PBS), and simulated salivary fluid. Oral bioavailability of BH-ASD was assessed in rats following intragastric administration. Additionally, a human volunteer taste test was conducted to evaluate the effectiveness of BH-ASD in masking the bitterness of BH.

Results: BH was successfully formulated into an amorphous solid dispersion using hot-melt extrusion. The PXRD pattern (Fig. 1) of pure BH exhibited distinct diffraction peaks at 8.50°, 8.99°, 20.20°, 20.79°, 25.30°, and 26.18°, confirming its crystalline nature. In contrast, these characteristic peaks were completely absent in BH-ASD, indicating that BH was converted into a stable amorphous form. FT-IR (Fig. 2a) spectra of Kollicoat® MAE 100-55 exhibited ester and carboxylic C=O stretching vibrations at 1727 cm⁻¹ and 1694 cm⁻¹, respectively, with the latter showing greater intensity. In the BH-ASD formulation, the intensity of the carboxylic C=O peak decreased relative to the ester peak, and the C–N⁺ stretching band broadened and shifted to 1340 cm⁻¹, suggesting the formation of ionic interactions between BH and the polymer. Differential scanning calorimetry (DSC) of pure BH showed three endothermic peaks at approximately 87.5 °C, 127.7 °C, and 198.1 °C. In BH-ASD, no melting peak corresponding to BH was detected (Fig 2b), further confirming the complete amorphization of the drug. Fig. 3 shows that in vitro dissolution from BH-ASD significantly suppressed drug release in simulated gastric fluid, with only 15.2% of the BH released at 2 hours, compared to pure BH. In simulated salivary fluid, the dissolution of BH-ASD was only 6.5% in 5min, indicating effective taste masking. Although the pH in the intestinal fluid is pH 6.8 too, it had a higher buffering capability, ensuring the dissociation between BH and MAE 100-55 and causing a faster dissolution. In vivo pharmacokinetic studies in rats confirmed improved oral bioavailability of BH-ASD over pure BH, BH-ASD demonstrated a relative bioavailability of 220.5% in comparison to the original BH.

Conclusion: PXRD, DSC, and FT-IR analyses confirmed the successful preparation of an BH-ASD via hot-melt extrusion. The BH-ASD formulation demonstrated reduced dissolution in gastric conditions, enabling targeted release in the intestine—the primary site of BH absorption—and thereby significantly improving its oral bioavailability, which resulted in a 2.2-fold increase in the relative oral bioavailability of BER. These results highlight the potential of the ASD approach as an effective strategy for enhancing the bioavailability of poorly permeable drugs. Moreover, the BH-ASD formulation effectively masked the intense bitterness of commercial BH, supporting its promise as a patient-friendly oral dosage form for future clinical development.

References: [1] Caliceti C, Franco P, Spinozzi S, et al. Berberine: new insights from pharmacological aspects to clinical evidences in the management of metabolic disorders. 2016, 23: 1460-76.
[2] Lin X, Zhang J, Chu Y, et al. Berberine prevents NAFLD and HCC by modulating metabolic disorders. Pharmacology & Therapeutics, 2024, 254: 108593.
[3] Poudel A, Zhou J, Massey S, et al. Berberine Hydrochloride Protects Cytokine-Induced Inflammation through Multiple Pathways. Diabetes, 2018, 67: 1985-P.
[4] Zhao R, Tan P, Han Y, et al. Preparation and Performance Evaluation of Antibacterial Melt-Spun Polyurethane Fiber Loaded with Berberine Hydrochloride. 2021, 13: 2336.
[5] Imenshahidi M, Hosseinzadeh H. Berberine and barberry: A clinical review. Phytotherapy Research, 2019, 33: 504-23.
[6] Chen W, Miao Y-Q, Fan D-J, et al. Bioavailability Study of Berberine and the Enhancing Effects of TPGS on Intestinal Absorption in Rats. AAPS PharmSciTech, 2011, 12: 705-11.

Figure 1. XRPD diffractograms of BH, MAE 100-55, PEG 8000, CA, physical mixture (PM), and BH-ASD.

Figure 2. (a) FT-IR and (b) DSC of BH, MAE 100-55, PEG 8000, CA, PM, and BH-ASD.

Figure 3. The dissolution curves of the BH, PM and BH-ASD in (a) the simulated salivary fluid (pH = 6.8, n = 3), (b) the simulated intestinal fluid (pH = 6.8, n = 3), (c) the simulated gastric fluid (pH = 1.2, n = 3) and (d) plasma concentration–time plots of original BER, PM and BH-ASD (n = 6).