Formulation Optimization of a Thermosensitive Curcumin Hydrogel for Localized Drug Delivery Using Response Surface Methodology

Abstract

Curcumin has been widely reported to exhibit anticancer potential; however, its clinical application is limited by poor aqueous solubility and lowpermeability. This study aimed to develop a thermoresponsive hydrogel systembased on Poloxamer 407 and hydroxypropyl methylcellulose (HPMC) for localizedcurcumin delivery through sol–gel transition at physiological temperature. Curcuminnanoparticles were prepared via ionic gelation and incorporated into hydrogelmatrices containing varying ratios of Poloxamer 407 and HPMC. Optimization wasperformed using Response Surface Methodology. pH, gelation time, and viscositywere selected as critical quality attributes reflecting the applicability of in situhydrogels. The evaluated responses included pH (5–7), gelation time (9–11 min), andviscosity (2000–5000 mPa·s), with model validation based on lack-of-fit > 0.05, highR², a difference between adjusted and predicted R² < 0.2, and adequate precision >4. Nano-curcumin exhibited a particle size of 423.03 ± 27.80 nm, PDI of 0.59 ± 0.08,and a zeta potential of −12.47 ± 0.74 mV. The optimized formulation (17.067%Poloxamer 407 and 4% HPMC) achieved a desirability value of 0.86, with a pH of 5.85,gelation time of 9 minutes, and viscosity of 4389.76 mPa·s. In vitro release followedthe Korsmeyer–Peppas model, indicating diffusion-controlled release and suggestingthe suitability of the optimized thermosensitive hydrogel as a localized curcumindelivery platform. These findings provide a basis for further investigation of thesystem’s stability and performance under extended conditions.

Introduction

Localized delivery Current therapeutic approaches are often associated with systemic side effects, drug resistance, and limited selectivity toward malignant cells (1). Curcumin, the principal bioactive compound of Curcuma longa L., has attracted considerable attention due to its reported antiproliferative and pro-apoptotic activities in localized delivery models (2, 3).

Despite these promising biological properties, the clinical translation of curcumin remains challenging due to its unfavorable physicochemical characteristics. According to the Biopharmaceutical Classification System (BCS), curcumin is categorized as a Class IV compound, exhibiting poor aqueous solubility and low permeability (4). In addition, curcumin exhibits limited stability under physiological conditions, further limiting its potential delivery (5). These characteristics highlight the importance of formulation strategies to improve drug stability and support localized delivery approaches.

Localized drug delivery systems have emerged as a promising strategy to enhance drug concentration at the intended site while minimizing systemic exposure (7). Among these systems, thermosensitive hydrogels represent an attractive platform because they remain in a sol state at room temperature and undergo sol–gel transition at physiological temperature (~37 °C). This in situ gelation behavior enables minimally invasive administration and the formation of a local depot that supports sustained and controlled drug release (8).

In thermosensitive hydrogel formulations, physicochemical parameters such as pH, gelation time, and viscosity play essential roles in determining system performance. The pH influences drug stability and formulation compatibility, gelation time governs the sol–gel transition at physiological temperature, enabling in situ depot formation, and viscosity affects pre-administration handling while contributing to matrix integrity and sustained release (5, 6). Within this context, the present study focuses on the formulation and optimization of a localized thermoresponsive delivery system rather than investigating cancer biology itself, aiming to enhance curcumin stability and site-specific retention. Therefore, controlling these parameters is fundamental to achieving reproducible and functional localized delivery systems.

Poloxamer 407 (Pluronic F127) is a thermosensitive polymer capable of reversible sol–gel transition at physiological temperature; however, its relatively low mechanical strength may limit its performance as a standalone matrix (9, 10). The incorporation of hydroxypropyl methylcellulose (HPMC) can enhance viscosity, modulate gelation behavior, and reinforce the gel network, thereby improving formulation stability (11). The Poloxamer 407–HPMC system has been widely investigated as a thermoresponsive platform for localized drug delivery due to its tunable physicochemical properties (12). However, studies integrating nanoparticle-stabilized curcumin with statistically optimized Poloxamer 407–HPMC thermosensitive hydrogels remain limited, particularly in the context of systematic formulation optimization.

Optimizing the composition of thermosensitive hydrogel formulations is essential to obtain well-defined physicochemical characteristics and predictable gelation behavior. Response Surface Methodology (RSM) provides a systematic statistical approach to evaluate the linear, quadratic, and interaction effects of formulation variables, specifically Poloxamer 407 and HPMC concentrations, on critical responses such as pH, gelation time, and viscosity (13, 14). Compared with conventional trial-and-error approaches, RSM reduces the number of experimental runs while enabling the development of statistically validated predictive models and desirability functions to determine optimal formulation conditions (12, 15). Although RSM relies on localized model assumptions, careful selection of factor ranges and experimental design enhances model reliability and interpretability (16, 17).

Therefore, this study focuses on the statistical optimization of a Poloxamer 407–HPMC thermosensitive hydrogel incorporating curcumin nanoparticles to achieve controlled gelation and viscosity suitable for potential localized administration. The objective is to establish a rational formulation framework that supports physicochemical stability and controlled drug release, providing a basis for future evaluation in localized delivery applications.

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Materials

Curcumin analytical grade (pro analysis) obtained from PTMerck, Indonesia, was used as the active compound innanoparticle preparation and hydrogel formulation. Curcumin from PT Haldin Pacific Semesta was used as areference material for comparison. Hydroxypropylmethylcellulose (HPMC) and Poloxamer 407 (Kolliphor®P407, BASF) were obtained from PT Sampharindo Perdana,Indonesia. All excipients were of pharmaceutical grade andused without further purification.

Azis Ikhsanudin, Teuku Nanda Saifullah Sulaiman, Khadijah Zai, Navista Sri Octa Ujiantari, Formulation Optimization of a ThermosensitiveCurcumin Hydrogel for Localized Drug Delivery UsingResponse Surface Methodology, The author informations are in the declarations section. This article is published by ETFLIN in Sciences of Pharmacy, Volume5, Issue 2, 2026, Page 189-199. DOI:10.58920/sciphar0501554

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