Poloxamer/HPMC/Carbopol-Based Thermosensitive Hydrogel Loaded with Ibuprofen for Potential Vaginal Drug Release

Abstract

Vaginal drug delivery offers a critical route for local treatments but is limited by short formulation residence times. This study describes a thermosensitive in situ gel prepared by the cold-dissolution method from a ternary blend of Pluronic F127, Carbopol 940, and HPMC for localized vaginal therapy. We used ibuprofen as a model drug selected for its reported anti-inflammatory and antiproliferative activity. The hydrogels exhibited a constant gelation temperature of 28 °C and high viscosity under simulated physiological conditions; ibuprofen incorporation further reduced susceptibility to gravitational leakage. FTIR, XRD, and DSC analyses confirmed stable physical cross-linking of the polymer network and amorphous molecular dispersion of ibuprofen. Peppas–Sahlin modelling revealed a controlled, sustained release profile (>50% over 24 h) predominantly governed by Fickian diffusion (69%). The blank hydrogel exhibited high biocompatibility (>75% viability). In contrast, the ibuprofen-loaded matrix exhibited a concentration-dependent cytotoxic effect on HeLa cervical cancer cells, reducing cell viability to ~12% at the full extract concentration. Overall, this ternary hydrogel platform represents a stable, promising vehicle for sustained local administration of ibuprofen in the vaginal microenvironment.

Introduction

Vaginal drug delivery is a critical route for the treatment of local conditions, including infections, inflammation, and hormonal imbalances. This route is favoured due to its large surface area, rich vascularization, and ability to bypass first-pass hepatic metabolism [1]. The high permeability of the cervicovaginal epithelium facilitates drug absorption; however, this can be influenced by physiological factors, including pH, the mucosal barrier, the immune system, microbiota, and hormones. These factors can make it challenging to achieve optimal therapeutic concentrations at the desired site [2,3]. Consequently, the development of controlled drug-delivery systems is crucial to enhance local bioavailability, reduce systemic toxicity, and improve delivery of therapeutic agents [4].

A range of vaginal delivery platforms has been investigated, each with its own limitations. Tablets, suppositories, and conventional gels tend to be rapidly cleared by vaginal secretions [5,6,7]. Thin films are limited by their drug-loading capacity, while inserts or rings may cause local discomfort, particularly during short-course therapies [8,9]. Complex nanocarriers, such as liposomes and nanoparticles, can improve mucosal targeting, but they face challenges in translation and scale-up for broader use [10]. In contrast, in situ gelling hydrogels offer a promising alternative to overcome these limitations. These innovative formulations remain as low-viscosity liquids at room temperature and undergo a sol–gel transition, thereby simplifying administration. Upon exposure to physiological conditions, they change into a solid-like gel, enabling longer residence time and improved drug retention [11,12].

Among the polymers used to develop in situ gelling systems, poloxamers have emerged as among the most promising materials due to their reversible thermogelation and biocompatibility [13,14,15]. They are triblock copolymers composed of poly(ethylene oxide)–poly(propylene oxide)–polythylene oxide) (PEO–PPO–PEO) that self-assemble via micellization and can interact with both hydrophilic and hydrophobic drugs, thereby enabling their use as controlled-release systems [16]. In particular, Poloxamer 407 (Pluronic® F127; designated herein as PF127) is approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a pharmaceutical excipient, making it attractive for the formulation of vaginal delivery systems [17].

Nevertheless, pure poloxamer-based gels often exhibit weak mechanical strength and rapid erosion [18]. To overcome these limitations, incorporating secondary polymers, such as Carbopol 940 and hydroxypropyl methylcellulose (HPMC), can significantly enhance mucoadhesive strength, mechanical stability, and drug release control, and stabilize the drug through synergistic matrix interactions [19].

Carbopol® 940 (Lubrizol Corp., Wickliffe, OH, USA; referred to as CP940) is a synthetic homopolymer of polyacrylic acid crosslinked with allyl sucrose or allyl pentaerythritol, polymerized in a cosolvent system [20]. CP940 is widely recognized for forming pH-sensitive hydrogels that rapidly develop viscosity and mechanical strength upon neutralization. These properties facilitate sustained drug release and stable therapeutic levels over the desired period [19].

HPMC is a semi-synthetic, non-ionic cellulose derivative that has gained attention as a low-cost, renewable alternative to synthetic polymers [21]. Widely used as a pharmaceutical excipient, it forms stable hydrogel films and matrices that enable fine-tuning of drug release kinetics [19].

Beyond designing the delivery platform, the choice of active pharmaceutical ingredients is equally critical for achieving the desired therapeutic outcome. Vaginal inflammation plays a pivotal role in the pathophysiology of multiple gynaecological diseases [22], including recurrent infections [23], epithelial alterations [24], and neoplastic processes [25], in which sustained production of pro-inflammatory mediators drives tissue damage and pathology [26]. Chronic inflammation is also a crucial driver of cervical carcinogenesis, contributing to increased prostaglandin production, cell proliferation, angiogenesis, and resistance to apoptosis [27].

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), is commonly employed to manage pain and inflammation. Additionally, it represents an attractive candidate for localized vaginal delivery due to its dual anti-inflammatory and anticancer properties. Its primary mechanism of action involves inhibiting cyclooxygenase (COX) enzymes, thereby reducing the synthesis of pro-inflammatory prostaglandins derived from arachidonic acid [28,29,30]. In addition to COX inhibition, ibuprofen modulates inflammation-related tumorigenic pathways and demonstrates antiproliferative effects on HeLa cervical cancer cells by decreasing viability and inducing apoptosis [31]. Based on this dual mechanism, ibuprofen has been proposed in the literature as a candidate for combined local anti-inflammatory and antiproliferative therapy [27], which motivated its selection for the present delivery platform. Furthermore, local vaginal administration may enhance drug concentrations at the target site while minimizing the gastrointestinal, renal, and cardiovascular adverse effects commonly associated with oral or parenteral NSAID therapy [31,32].

Ibuprofen has been used clinically for the topical treatment of vulvovaginal inflammation, particularly as ibuprofen isobutanolammonium vaginal solutions (Ginenorm®). However, these liquid formulations have a limited residence time in the vaginal cavity [33]. Therefore, thermosensitive hydrogels represent a promising strategy to prolong drug retention and enhance local bioavailability [34].

Binary systems such as poloxamer/HPMC [35] and poloxamer/Carbopol [36] have been evaluated as in situ-forming thermosensitive hydrogels, and the ternary F127/HPMC/CP940 combination has also demonstrated potential for an in situ gel system for the sustained release of anti-tuberculosis drugs [19]. However, the ternary combination remains unexplored for vaginal drug delivery. In this context, integrating these polymers offers a promising approach to developing in situ gelling systems with optimized thermoresponsiveness, enhanced mucoadhesion, and controlled release.

The purpose of this work was to characterize a thermosensitive hydrogel platform based on a ternary blend of PF127, CP940, and HPMC, tailored for localized vaginal administration of ibuprofen. Ibuprofen was selected as a model drug to assess the system’s performance. The study includes comprehensive physicochemical characterization, including evaluation of pH, viscosity, chemical interactions, and structural information obtained by Fourier Transform Infrared Spectroscopy (FTIR) and X-ray diffraction (XRD). The thermal profile was also evaluated by differential scanning calorimetry and thermogravimetric analysis (DSC/TGA), along with the swelling capacity of the formulations. We also assessed critical functional parameters that determine clinical applicability were assessed, such as gelation time and temperature, gel persistence, spreadability, and adhesive properties. We analyzed the in vitro drug release profile in simulated vaginal fluid (SVF) using the Peppas–Sahlin kinetic model to decouple the release mechanisms. Finally, we evaluated the biological activity of the formulations in a two-dimensional (2D) HeLa cancer cell culture model.

To the best of our knowledge, this is the first report to adapt the PF127/HPMC/CP940 system to incorporate ibuprofen within the matrix, highlighting its potential as a vaginal delivery system.

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Materials

PF127 (Pluronic F127®, powder, pharmaceutical grade, Sigma-Aldrich, St. Louis, MO, USA), hydroxypropyl methylcellulose (METHOCEL® K100 Premium, hypromellose 2208, USP grade, Sigma-Aldrich, St. Louis, MO, USA), Carbopol® 940 (pharmaceutical grade, Lubrizol Advanced Materials, Cleveland, OH, USA), ibuprofen salt (α-methyl-4-(isobutyl)phenylacetic acid sodium salt, analytical standard, ≥98% purity, Sigma-Aldrich, St. Louis, MO, USA), analytical-grade triethanolamine (TEA; ≥99.0% purity, Sigma-Aldrich, St. Louis, MO, USA), human cervical cancer cell line HeLa (ATCC®, CCL-2, American Type Culture Collection, Manassas, VA, USA), Dulbecco’s Modified Eagle Medium (DMEM; high glucose, with L-glutamine, cell culture grade, Sigma-Aldrich, St. Louis, MO, USA), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT; ≥98% purity, Sigma-Aldrich, St. Louis, MO, USA) and Dimethyl sulfoxide (DMSO; sterile-filtered, cell culture grade, ≥99.7% purity, Sigma-Aldrich, St. Louis, MO, USA).

Politrón Zepeda, G.A.; Tinajero-Díaz, E.; Ilarduya, A.M.d.; Rodríguez Rodríguez, R.; Arízaga, G.G.C.; Escalera, A.C.; Vasquez Martínez, N.; Velázquez, M.M.; Carvajal, Z.Y.G. Poloxamer/HPMC/Carbopol-Based Thermosensitive Hydrogel Loaded with Ibuprofen for Potential Vaginal Drug Release. Gels 2026, 12, 807. https://doi.org/10.3390/gels12090807