A bigel co-delivering highly hydrophilic and hydrophobic natural compounds for enhanced ulcerative colitis therapy

Abstract

Bigel, formed by high-speed shearing of hydrogel and oleogel, is suited to deliver both lipophilic and hydrophilic active compounds. patchouli oil and paeoniflorin, despite their potential in treating ulcerative colitis, face challenges due to patchouli oil’s poor aqueous solubility and paeoniflorin’s high solubility but low permeability. In this study, we developed an oral colon-targeted bigel system to co-deliver patchouli oil and paeoniflorin for treating ulcerative colitis. Patchouli oil served as both an therapeutic agent and an oil phase (excipient). The bigel system enhanced mechanical stability, prolonging retention at the colon and enabling effective colon-targeted drug delivery. Compared to oleogel, bigel significantly alleviated symptoms in DSS-induced colitis in mice, reduced inflammatory cytokine release, repairs intestinal mucosal damage, and regulates immune cell populations in the gut. The combination of patchouli oil and paeoniflorin in the bigel exerted a synergistic effect on ulcerative colitis treatment. This work underscores the efficacy of bigel in delivering a combination of hydrophilic and lipophilic drugs, offering a novel strategy for enhanced drug delivery in ulcerative colitis. It also provides a delivery platform technology for volatile oils.

Introduction

Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease (IBD), is characterized by recurrent, diffusive inflammation of the intestinal mucosa that continuously extends from the colon to the proximal rectum (Du et al., 2022).

The inflammatory microenvironment compromises the structure and function of intestinal epithelial intercellular junctions, affecting intestinal epithelial barrier properties and mucosal integrity (Vos et al., 2012). The compromised colonic mucus barrier is thought to be an early manifestation of the pathogenesis of ulcerative colitis (van der Post et al., 2019). Patchouli oil (PO), the essential oil of Pogostemonis Herba, with therapeutic potential in treating ulcerative colitis by reducing inflammation and oxidative stress (Huang et al., 2025). Paeoniflorin (PAE), an active terpene glycoside component isolated from Paeonia lactiflora Pall, effectively repairs the intestinal barrier, reduces colonic tissue inflammation, and exhibits protective activity against colitis (Cao et al., 2021, Li et al., 2021). However, the therapeutic application is hindered by their unfavorable physicochemical properties: the poor water solubility and low oral bioavailability of PO (Chen et al., 2024, Liu et al., 2024), the high water solubility and low membrane permeability of PAE (He et al., 2025, Shen et al., 2021). In addition, how to deliver them to the colon for site-specific action is also a difficulty. Traditional encapsulation techniques for volatile oils have some problems, such as limited loading capacity, complicated preparation process, and instability (Oliveira Brito Pereira Bezerra Martins et al., 2020, Suvarna and Chippa, 2023).

For UC treatment, oral administration is widely used due to its low cost, convenience, and safety (Zu et al., 2021). However, gastrointestinal pH, metabolic enzymes, colon contents, and drug solubility hinder colonic drug delivery, making it difficult to maintain adequate drug concentrations in colon lesions (Naeem et al., 2020). Colon-specific drug delivery drugs can improve therapeutic efficacy by taking action locally and reducing side effects caused by systemic exposure (Zhao et al., 2023). The oral colon-targeted drug delivery system is usually in a form of nanoparticles (Zhang and Merlin, 2018), microspheres (Du et al., 2024, Jing et al., 2023), or hydrogels (Wang et al., 2023a), and these systems take advantages of different triggering mechanisms, such as pH response and enzymatic degradation, to achieve efficient drug delivery (Amidon et al., 2015).

Bigel presents an innovative biphasic system, a hybrid of hydrogel and oleogel, and is characterized by the properties of both the aqueous and oil phases. The structure (gel type) of bigel can generally be categorized as oleogel-encapsulating hydrogel (O/W), hydrogel-encapsulating oleogel (W/O), or bicontinuous/semi-continuous/substrate structure (complexes) (Zampouni et al., 2024). Bigel offers superior performance compared to single-phase gels and exhibits advantages of accommodating hydrophobic and hydrophilic drugs (Martín-Illana et al., 2022). By adjusting formulation compositions (e.g., a ratio between hydrogel and oleogel, various types of oleogel factors and hydrogel factors) and process parameters, mechanical properties of bigel can be finetuned, including thermodynamic behavior, rheological behavior, and textural properties (Chao et al., 2024), so that it can be applied for different applications such as site-specific delivery.

Bigel benefits from ease of preparation, excellent spreadability, good physical stability, and long shelf life (Mao et al., 2020). Bigel differs from emulsions and latexes, needless of surfactants, and excels as a topical drug delivery vehicle due to its enhanced mechanical stability over conventional hydrogels (Hu et al., 2015, Wakhet et al., 2015).

The preparation of an oleogel often involves an oil phase and an oleogel factor (Kirtane et al., 2022). In this study, PO served as not only the active compounds but an oil phase, while hard fat was used as an oleogel factor. Moreover, konjac glucomannan (KGM) and gelatin were applied for preparing PAE-loaded hydrogel. KGM is a soluble dietary fiber known for its resilience against degradation by gastric juices and small intestinal fluids, but readiness for degradation by β-mannanase produced by colon microbes (Ye et al., 2021, Zhang et al., 2014). This can enable the sustained-release drug delivery in the colon. In addition, the adhesive properties of KGM enable defensive coverings on the mucosa and the repairing the damaged mucosal barrier (Kapoor et al., 2024). This bigel system was characterized and its treatment efficacy evaluated in a murine UC model.

Materials

PO was purchased from Zhongyi Pharmaceutical Co (Fujian, China). PAE (purity > 98 %), Gelatin (type B), simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and simulated colonic fluid (SCF) were purchased from Shanghai Yuanye Bio-Technology Co., Ltd (Shanghai, China). Konjac powder was purchased from Vokai Biotechnology Co (Beijing, China). The hard fat, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, mono and diglycerides, and behenoyl polyoxyl-8 glycerides.

Yueqian Wu, Yuting Jiang, Yihao He, YanLi Luo, Zhiwen Gu, Yanfeng Xiu, Bing Wang, Yongzhuo Huang, A bigel co-delivering highly hydrophilic and hydrophobic natural compounds for enhanced ulcerative colitis therapy, International Journal of Pharmaceutics, 2025, 125706, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125706.