Jul 2026· International journal of pharmaceutics· Vol 702, pp.
127196
· 0 citations· 33 references
Medicine
TL;DR
A thermoresponsive and mucoadhesive dual-functionality enema system that enables injectable administration, in situ gelation, strong mucosal adhesion, and gradual release of 5-ASA while maintaining enhanced mucoadhesion and rectal retention, thereby improving retention and therapeutic potential.
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by abdominal pain and diarrhea. Although 5-aminosalicylic acid (5-ASA) enemas are widely used, conventional formulations can result in rectal leakage and poor retention, substantially impairing the therapeutic efficacy and quality of life (QOL) of patients. To address these limitations, in this study, we developed a thermoresponsive and mucoadhesive dual-functionality enema system by combining poloxamer with carbopol (CP). This study optimized a thermoresponsive and mucoadhesive rectal gel formulation for 5-ASA and evaluated its physicochemical properties and therapeutic efficacy in experimental ulcerative colitis. The formulation exhibited a gelation temperature of 30-35 °C, indicating its suitability for situ gel formation in the colon. The 1H NMR analysis confirmed minimal interactions between 5-ASA and the polymers. Increasing the CP concentration markedly delayed drug release, likely due to enhanced network entanglement within the gel. Ex vivo evaluation using porcine colonic mucosa indicated reduced leakage and improved adhesion compared with a commercial formulation. Furthermore, in vitro studies using Caco-2 cells showed enhanced retention of the active compounds. These findings indicate that the proposed system enables injectable administration, in situ gelation, strong mucosal adhesion, and gradual release of 5-ASA while maintaining enhanced mucoadhesion and rectal retention, thereby improving retention and therapeutic potential. Furthermore, the administration of the formulation to rats with UC led to a significantly higher anti-inflammatory effect. Thus, the developed approach represents a promising strategy for enhancing treatment efficacy and patient compliance in ulcerative colitis.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease for which effective oral colon-targeted therapies remain limited. Sinapic acid (Sin), a dietary polyphenol, has demonstrated therapeutic potential in UC due to its antioxidant and anti-inflammatory properties; however, its clinical application is hindered by poor stability and low water solubility. To address these limitations, we designed a smart macromolecular double-network hydrogel based on quaternized chitosan (QCTS) derivatives and glycyrrhizic acid (GA) self-assembled hydrogel to enhance targeted Sin delivery for UC treatment. Specifically, Sin was conjugated to QCTS via reduction-cleavable disulfide linkages and dynamically crosslinked with aldehyde-functionalized GA through Schiff-base reactions, yielding the double-network hydrogel, QSAG. QSAG demonstrated structural robustness, colon-targeting capability, and reduction-responsive drug release under inflammatory conditions, which was evidenced by swelling equilibrium within 120 min, 94.23% degradation in simulated colonic fluid within 24 h, and a cumulative Sin release of 83.66% under 10 mM GSH. In vivo imaging confirmed prolonged colonic retention of QSAG in the inflamed colon for at least 24 h and localized drug accumulation. Therapeutic efficacy was evaluated in a 3% DSS-induced UC mouse model following 5 days of treatment. Both in vitro and in vivo studies revealed that QSAG effectively alleviated colitis by suppressing oxidative stress and inflammation while promoting intestinal barrier repair. Collectively, this dual-crosslinked QSAG hydrogel, with its structural stability and inflammation-responsive drug release, represents a promising oral platform for targeted and enhanced UC therapy.
Mengqi Shen, Shuai Sun, Huilin Zhu et al.· International Journal of Bio...· 0 citations
Background: Psoriasis is a chronic inflammatory skin disease that severely impacts patients' quality of life. Traditional topical deliveries of salicylic acid (SA) often cause localized irritation and face systemic limitations due to the formidable barrier properties.
Objective: This study aimed to formulate, optimize, and evaluate an ultra-deformable vesicular carrier system—transfersomes—incorporated into a carbopol hydrogel base for the sustained and enhanced topical delivery of salicylic acid.
Methods: Salicylic acid-loaded transfersomes were prepared via the thin-film hydration technique utilizing Soya-phosphatidylcholine (PC) and Span 80 in varying ratios. The prepared vesicles were characterized for particle size, zeta potential, and entrapment efficiency (%EE). The optimized formulation (TF4) was successfully incorporated into three different concentrations of Carbopol 934 gel bases (0.5%, 1.0%, and 2.0% w/w). The hydrogels were extensively evaluated for their organoleptic parameters, pH, viscosity, spreadability, drug content, and in-vitro drug diffusion kinetics via a modified Franz diffusion cell over 14 hours.
Results: The vesicle sizes of the prepared transfersomes ranged from 161.08 nm to 552.8 nm with an encapsulation efficiency between 63.70% and 90.89%. The optimized formulation, TF4, presented a vesicle size of 269.00 nm, high entrapment efficiency of 73.70%, and a stable zeta potential of -35.6 mV. The formulated hydrogels displayed excellent homogeneity and acceptable pH ranges (6.9 to 7.3). In-vitro diffusion profiling revealed that formulation TF2 (1.0% w/w Carbopol) exhibited the most balanced, controlled release profile, reaching 94.08% drug delivery at the end of 14 hours. Mathematical modeling demonstrated compliance with zero-order kinetics and a non-Fickian anomalous transport mechanism (0.5 < n < 1.0).
Conclusion: The developed transfersomal hydrogel serves as an advanced, highly elastic vesicular platform that effectively bypasses the skin barrier, offering sustained release while potentially reducing the localized toxicity associated with standard salicylic acid treatments.
Adarsh Jedhe, Neelima Naneriya, S. Jain et al.· International journal of pha...· 0 citations
OBJECTIVE
This study aimed to design and evaluate pH-sensitive pellets loaded with 5-aminosalicylic acid (5-ASA) for targeted colon delivery in ulcerative colitis (UC) therapy.
SIGNIFICANCE
The proposed formulation leverages glyceryl monooleate (GMO) and linoleic acid (LA) as liquid crystal precursors to achieve site-specific drug release.
METHODS
Liquid crystal nanoparticles (LCNPs) were prepared from a GMO bulk phase using a top-down method, with LA added for pH sensitivity. The formulations were then evaluated for drug loading, encapsulation efficiency, and structure by polarized light microscopy, with drug release tested at pH 1.2 and 6.8. The LCNPs dispersions were then used to make pellets using the extrusion-spheronisation technique. Drug-excipient interactions were examined by FTIR and DSC. The pellet formulations were finally tested in a rat ulcerative colitis (UC) model by comparing colon damage scores across treatment groups.
RESULTS
The pH-sensitive pellets containing LCNPs exhibited a uniform morphology, desirable aspect ratio, and sufficient mechanical strength. The in vitro release profile demonstrated a 5.7-fold higher drug release at pH 6.8 compared to pH 1.2. This targeted release was ascribed to a pH-triggered phase transition of the LA and electrostatic repulsion between the ionized drug and the carrier. The in vivo results confirmed that the pH-sensitive pellets elicited the most pronounced and statistically significant (p < 0.05) reduction in colon damage scores.
CONCLUSION
The developed pellet system, which encapsulates 5-ASA within GMO/LA-based liquid crystal nanoparticles, presents a highly promising platform for targeted drug delivery in the treatment of ulcerative colitis.
A. Khakshur, A. Akhgari, Hosseinzadeh Zahra et al.· Drug Development and Industr...· 0 citations
Budesonide (BUD) enema therapy for ulcerative colitis (UC) is limited by poor solubility, inadequate bio-adhesion, and rapid clearance due to intestinal peristalsis. To address the limitations of conventional budesonide enemas, we designed a water-triggered in situ phase-transition phospholipid formulation (termed PG oil). This system comprises soybean phosphatidylcholine (PC-98), glyceryl dioleate (GDO), propylene glycol, and anhydrous ethanol, and achieves markedly enhanced BUD solubilization (35 mg/mL), in contrast to its negligible aqueous solubility (0.021 mg/mL). Upon contact with colonic fluid, PG oil rapidly underwent sol-gel transition, forming a bio-adhesive lamellar liquid crystalline gel that serves as both a physical mucosal barrier and a sustained-release drug depot. In a dextran sulfate sodium (DSS)-induced colitis mouse model, rectal administration of BUD-PG oil (0.3 mg/kg) significantly outperformed free BUD suspension, as evidenced by restored body weight, reduced disease activity index, normalized colon length, and decreased spleen index. Immunohistochemistry revealed marked suppression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β, MCP-1) in colonic tissue. Histological analysis demonstrated that BUD-PG promoted favorable mucosal repair characterized by reduced collagen deposition (Masson's trichrome: from 48.5% to 16.7%) while restoring gut barrier integrity through replenishment of goblet cells and upregulation of tight junction proteins (ZO-1, Occludin-1, Claudin-5, β-catenin). Collectively, this water-responsive in situ gelling phospholipid oil platform addresses critical limitations of conventional BUD enemas by combining sustained local drug delivery with physical mucosal protection, offering a promising therapeutic strategy for comprehensive mucosal healing in UC.
Ting Ouyang, Yumo Chen, Yiying Jia et al.· International Journal of Pha...· 0 citations
ABSTRACT Ulcerative colitis remains challenging to treat due to the need for localized control of inflammation, restoration of mucosal integrity, and avoidance of systemic toxicity. Here, we report a rectally administered, sprayable, thermo‐responsive hyaluronic acid‐based copolymer platform for the localized co‐delivery of probiotic‐derived extracellular vesicles (ProEVs) and 5‐aminosalicylic acid. This system enables enhanced retention and sustained presentation of therapeutics at inflamed colonic sites. The combined formulation demonstrates improved therapeutic efficacy compared to individual treatments, promoting mucosal recovery and intestinal homeostasis. Mechanistically, the platform modulates inflammatory responses, supports epithelial barrier function, and contributes to microbiota rebalancing. Notably, extracellular vesicles provide a more effective and consistent therapeutic modality compared to live probiotics. Importantly, the formulation is designed for clinical translation, offering localized administration, minimal toxicity, and stability upon lyophilization, enabling off‐the‐shelf use. These findings highlight the potential of integrating extracellular vesicles with biomaterial‐based delivery systems as a multifunctional therapeutic strategy for inflammatory bowel disease.
Ayushi Mairal, Ubaid Tariq, Shreya Mehrotra et al.· Advancement of science· 0 citations
Ulcerative colitis (UC) is an immune-mediated chronic inflammatory bowel disease that severely impairs patients’ quality of life. Efficient oral colon-targeted delivery systems are urgently needed to improve local therapeutic efficacy while minimizing systemic exposure. Herein, we developed a pH-responsive Eudragit S100-coated coacervate microdroplet system for the oral delivery of natural Bletilla striata polysaccharide (BSP), termed BSP@EU-Coac. The optimized BSP@EU-Coac microdroplets exhibited a spherical morphology with an average hydrodynamic diameter of 3.86 ± 0.82 μm, an encapsulation efficiency of 85.03 ± 3.66%, and a drug loading capacity of 9.29 ± 0.93%. In vitro release studies showed that BSP@EU-Coac effectively limited premature BSP release under simulated gastric and small intestinal conditions, while achieving pH-triggered sustained release in simulated colonic medium, with a cumulative release of approximately 88.25% within 96 h. In vitro assays further demonstrated that BSP@EU-Coac showed good cytocompatibility at the working concentration and markedly reduced intracellular ROS levels, with ROS fluorescence intensity decreased by 53.95% and 51.13% in RAW264.7 macrophages and Caco-2 cells, respectively. After oral administration, fluorescence imaging confirmed that BSP@EU-Coac preferentially accumulated in the inflamed colon and maintained detectable colonic retention for up to 24 h. In a DSS-induced colitis mouse model, BSP@EU-Coac significantly alleviated UC symptoms, as evidenced by improved body weight recovery, reduced disease activity index, and restoration of colon length from 4.99 ± 1.23 cm in the model group to 8.66 ± 1.92 cm. Mechanistically, BSP@EU-Coac modulated macrophage polarization by reducing the M1-like CD86⁺CD206⁻ population from 29.26% to 8.95% and increasing the M2-like CD86⁻CD206⁺ population to 20.70%, accompanied by suppressed pro-inflammatory cytokine expression, enhanced tight junction protein expression, reduced oxidative stress, and partial restoration of gut microbiota homeostasis. Overall, this study demonstrates that BSP@EU-Coac is a promising oral colon-targeted polysaccharide delivery platform for UC therapy through integrated regulation of oxidative stress, immune response, epithelial barrier repair, and gut microbiota.
Qiantao Zhang, L. Chai, Hui Liu et al.· Journal of Nanobiotechnology· 0 citations