Polysaccharide-based emulsion gels for the prevention of postoperative adhesions and as a drug delivery system using 5-fluorouracil

Abstract

Postoperative tissue adhesion is a well-recognized and common complication. Despite ongoing developments in anti-adhesion agents, complete prevention remains a challenge in clinical practice. Colorectal cancer necessitates both adhesion prevention and postoperative chemotherapy. Accordingly, drug-loading into an anti-adhesion agent could be employed as a treatment strategy to maximize the drug effects through local application and minimize side effects. Herein, we introduce an anti-adhesion agent that functions as a drug delivery system by loading drugs within an emulsion that forms a gel matrix in the presence of polysaccharides, xanthan gum, and pectin. Based on the rheological analysis, the xanthan gum-containing emulsion gel formed a gel matrix with suitable strength and mucosal adhesiveness. In vitro dissolution tests demonstrated sustained drug release over 12 h, while in vivo pharmacokinetic studies revealed a significant increase in the T_max (up to 4.03 times) and area under the curve (up to 2.62 times). However, most of the drug was released within one day, distributing systemically and raising toxicity concerns, thus limiting its efficacy as a controlled drug delivery system. According to in vivo anti-adhesion efficacy evaluations, the xanthan gum/pectin emulsion gels, particularly F2 and F3, exhibited remarkable anti-adhesion capacity (P < 0.01). The emulsion gel formulation exhibited no cytotoxicity against fibroblasts or epithelial cell lines. Thus, the xanthan gum/pectin emulsion gel exhibits excellent anti-adhesion properties and could be developed as a drug delivery system.

Introduction

Surgical procedures play a vital role in the treatment of various medical conditions and often involve the removal of underlying diseases or causative factors. However, surgery is associated with a wide range of adverse effects. Surgical wounds, such as incisions, tissue ablations, or infections leading to inflammation, can result in undesirable adhesions between the wound tissue and the healthy surrounding tissue during the recovery process (Krafts, 2010). Tissues injured during surgery undergo fibrosis as a part of the rapid recovery process, and adhesion can develop as an integral aspect of this process at the wound site (He et al., 2016). Adhesions have been found to occur in approximately 90 % of patients undergoing open surgery and have the potential to cause complications such as organ obstruction and chronic pain (Rajab et al., 2010, van Goor, 2007). Moreover, for patients requiring subsequent surgeries, the presence of adhesions can lead to prolonged operation times and negatively affect surgical outcomes (Brüggmann et al., 2010, Lang et al., 2015, Torres-De La Roche et al., 2019).

In clinical practice, anti-adhesion agents such as films, hydrogels, and liquid formulations are employed to prevent post-surgical adhesions (Ahmed, 2015, Wallwiener et al., 2006). These agents minimize adhesion to healthy tissues, creating a physical barrier in the wound area characterized by high viscoelasticity and osmotic pressure (Fan et al., 2021). Film formulations form a transparent physical barrier and are highly effective in preventing adhesions post-surgery, particularly in open surgery (Mayes et al., 2020). However, the increasing popularity of minimally invasive surgeries such as laparoscopy presents challenges for their application. Consequently, there is a growing demand for anti-adhesion solutions or gels suitable for diverse surgical settings. Currently, commercially available hydrogels using hyaluronic acid and sodium carboxymethyl cellulose (Na-CMC) and thermodynamic hydrogels utilizing poloxamer 188 or poloxamer 407 exhibit limited viscoelasticity. These formulations are unable to effectively maintain a physical barrier over an extended period and poorly adhere to the wound area (Chen and Liu, 2016). Owing to their tendency to detach and flow downward under the influence of gravity, they are often unable to function as effective anti-adhesion agents (An et al., 2021).

Recently, the use of emulsions as anti-adhesion agents has also been researched. Emulsions based on fish oil and soybean oil have been shown to significantly reduce intraperitoneal adhesions (Sirovy et al., 2023). Additionally, soybean oil has been reported to act as a lubricant within the body and to possess inherent anti-adhesion properties (Dag et al., 2015). However, a disadvantage of emulsions is their inability to form a solid physical barrier. Polysaccharides present a potential solution to this challenge, enhancing the anti-adhesive properties of emulsions. Biocompatible and biodegradable polysaccharides exhibit enhancing viscoelasticity and mucoadhesive property owing to wettability and swelling properties in response to body fluids present in mucous membranes (Alexander et al., 2011, Boddupalli et al., 2010).

We have developed an emulsion gel using xanthan gum and pectin among polysaccharides. Xanthan gum is a polysaccharide composed of glucose, mannose, and glucuronic acid, featuring a linear-linked (1–4) β-D-glucose backbone with a trisaccharide chain residue of D-mannose-D-glucuronic acid-D-mannose attached at glucose C-3 (Jansson et al., 1975, Palaniraj and Jayaraman, 2011). Xanthan gum is widely used as a thickening agent in the food and pharmaceutical industries, and is also utilized in the management of oropharyngeal dysphagia (Hadde et al., 2021). Xanthan gum provides strong viscoelasticity among polysaccharides, enhancing the structural integrity of the emulsion matrix. Pectin is a component of the plant cell wall, composed of an α-linear chain (1–4) backbone of D-galacturonic acid with residues such as D-xylose or D-apiose (Mohnen, 2008). Pectin is used as a gelling and stabilizing agent and has been extensively researched in relation to wound dressing due to its wound healing and anti-inflammatory effects (Amante et al., 2023, Muthulakshmi and Rajarajeswari, 2021, Nordin et al., 2022, Ouyang et al., 2024). The combined use of xanthan gum and pectin can form an appropriate gel matrix in the emulsion and is expected to aid in post-operative wound healing and anti-inflammatory effects.

Emulsion gel can be developed as a drug delivery system that incorporates both hydrophilic and hydrophobic drugs. Recently, emulsion gels have been utilized as novel drug delivery systems for applications such as topical and intraarticular delivery (Das et al., 2023, Milutinov et al., 2023). Emulsion gels incorporating gallic acid and chitosan have been reported to enhance the cellular uptake of hydrophobic drugs, in addition to their anti-inflammatory effects (Li et al., 2023).

5-FU is a widely used anticancer drug, particularly in colorectal cancer chemotherapy (Grem, 2000). Typically, cancer treatment involves surgical tumor removal, followed by adjuvant chemotherapy and/or radiotherapy (Koppe et al., 2006, Young and Rea, 2000). However, complete eradication of cancer through surgery alone is often challenging, and residual cancer cells may metastasize, leading to cancer recurrence (Markman and Shiao, 2015). A local delivery system using a poloxamer-alginate hydrogel loaded with 5-FU significantly suppressed tumors (Al Sabbagh et al., 2020). Previously, we reported a thermodynamic hydrogel loaded with 5-fluorouracil (5-FU) by crosslinking carrageenan and a poloxamer (Dinh et al., 2022), evaluating the rheological properties, anti-adhesion efficacy, and characteristics of the hydrogel as a potential drug delivery system.

In this study, we developed a novel 5-FU loaded polysaccharide-based emulsion gel, introducing muco-adhesiveness to the emulsion by incorporating xanthan gum and pectin to address the limitations of currently available anti-adhesion gels. By incorporating an anticancer drug as the anti-adhesion agent, we could achieve localized chemotherapeutic effects, thereby affording an alternative to systemic chemotherapy.

Materials

5-FU and polyethylene glycol (PEG) 4000 were purchased from Sigma-Aldrich (St. Louis, MO, USA). GENU® pectin (citrus) type USP/200 and Keldent® Xanthan Gum were gifted by CP Kelco U.S., Inc. (Georgia, USA). Kolliphor P 407 (Poloxamer 407) and Kollisolv® PEG E 400 were kindly gifted from BASF Co., Ltd (Ludwigshafen, Germany). Soybean oil was purchased from Lipoid GmbH (Ludwigshafen, Germany). MontanoxTM 80 (polysorbate 80) was a gift from Seppic Inc. (Courbevoie, France).

Jong-Ju Lee, Linh Dinh, Haneul Kim, Jooyeon Lee, Juseung Lee, Yulseung Sung, Sooho Yeo, Sung-Joo Hwang,
Polysaccharide-based emulsion gels for the prevention of postoperative adhesions and as a drug delivery system using 5-fluorouracil, International Journal of Pharmaceutics, 2024, 124386, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124386.