Development and Optimization of Gastroretentive Floating Microspheres of Glabridin Using Box–Behnken Design-Based Response Surface Methodology.

One of the most common gastrointestinal conditions in the world, peptic ulcer disease is characterized by mucosal erosion in the stomach or duodenum due to an imbalance between the protective mechanisms of the gastric mucosa and aggressive factors like gastric acid, pepsin, alcohol, stress, Helicobacter pylori infection, and nonsteroidal anti-inflammatory drugs. Proton pump inhibitors, H2_22-receptor antagonists, and antacids are examples of standard anti-ulcer medicines that are available; nevertheless, long-term use of these drugs is frequently linked to side effects, recurrence, drug resistance, and incomplete mucosal repair. The development of innovative gastroretentive medication delivery methods that incorporate phytoconstituents with strong gastroprotective action is therefore gaining attention (Banerjee et a., 2010).

Glabridin, a prenylated isoflavane that was extracted from Glycyrrhiza glabra (licorice), has drawn a lot of interest because of its many pharmacological effects, which include cytoprotective, antioxidant, anti-inflammatory, antibacterial, and anti-ulcer qualities. By scavenging reactive oxygen species, preventing lipid peroxidation, lowering inflammatory mediators, and strengthening mucosal defense mechanisms, glabridin has been shown in numerous investigations to protect against stomach mucosal damage. However, glabridin's short gastric residence time, poor water solubility, and instability in gastrointestinal fluids limit its therapeutic efficacy after oral treatment, resulting in decreased bioavailability and insufficient localized activity in the stomach (Zhang et al., 2003).

For medications that are preferentially absorbed in the upper gastrointestinal tract or designed for localized gastric action, gastroretentive drug delivery systems (GRDDS) have become a successful method for extending gastric residence duration and enhancing the bioavailability. Because of their low density, extended buoyancy, controlled drug release properties, and improved patient compliance, floating microspheres have garnered a lot of attention among the several GRDDS techniques. Floating microspheres increase stomach retention and maintain medication release at the site of action by remaining buoyant on gastric fluids for a prolonged period of time. Additionally, microsphere-based systems offer benefits like consistent drug distribution, fewer doses, less variation in plasma drug concentration, and enhanced therapeutic efficacy (Dwivedi et al., 2025).

For gastroretentive microspheres to be developed successfully, formulation variable optimization is essential. Conventional optimization methods are frequently tedious, time-consuming, and unable to assess the impact of variable interactions. In contrast, a methodical and effective approach to formulation optimization is offered by statistical experimental design approaches like Box-Behnken Design (BBD) in conjunction with Response Surface Methodology (RSM). While RSM makes it easier to describe and anticipate ideal conditions mathematically, BBD makes it possible to assess the individual and combined effects of several independent variables with fewer experimental runs. This method improves formulation reproducibility, lowers experimental error, and makes it possible to accurately anticipate important quality aspects. Therefore, the present study was designed to develop, optimize, and evaluate gastroretentive floating microspheres of glabridin using BBD-based Response Surface.

Table 1: Design builds information using Design-Expert^®

Table 2: List of independent variables selected in experimental design

Table 3: List of response or dependent variables selected in experimental design

Table 4: BBD Experimental Design for Gastroretentive Floating Microsphere

Using BBD and Design-Expert-13®, the formulation of Glabridin Gastroretentive Floating Microsphere (GFM) was optimized. According to the experimental design, a total of fifteen runs were prepared in a randomized fashion. We looked into how the response variables were affected by various levels of independent factors. The linear model was recommended by Design as the best fit for both response variables. Table 5.7 displays the impact of independent variables on the response variables. Additionally, R2, adjusted R2, predicted R2, standard deviation, and percentage coefficient of variance were calculated using the ANOVA test for statistical validity.

Table 5: Effect of independent variables on response variables

Table 6: Statistical Data of ANOVA for Responses R1, R2, R3, and R4

Fig. 1: 3D Surface Plots.

Numerical optimization and experimental evaluation were used to successfully validate the improved formulation of Glabridin gastroretentive floating microspheres. Polymer concentration (10.84%), plasticizer concentration (24.62%), and enhancer concentration (4.78%) were the optimum independent variables that together generated the desired physicochemical and release properties. The validated formulation showed excellent mechanical integrity and flexibility of the microsphere system, with a suitable thickness of 0.23 mm and a tensile strength of 4.86 kg/cm². With a drug concentration of 94.21%, drug content analysis showed that Glabridin was uniformly distributed throughout the formulation, indicating effective integration and little drug loss during preparation.

With a cumulative drug release of 88.76%, the improved formulation also demonstrated sustained drug release behavior, demonstrating efficient controlled-release qualities appropriate for gastroretentive delivery. Excellent gastroretentive qualities were confirmed by the high buoyancy % and extended floating period of over 12 hours, which allowed for a longer stomach residence time and improved absorption of Glabridin in the upper gastrointestinal tract. The bioactive chemical was effectively encapsulated within the polymeric matrix when the entrapment efficiency was more than 95%. The optimization model for the creation of Glabridin gastroretentive floating microspheres meant to treat peptic ulcers was found to be reliable, robust, and reproducible. Overall, the validated formulation demonstrated excellent agreement between predicted and experimental responses.

Table 7: Validated Values of Independent Variables and Response Variables for Glabridin Gastroretentive Floating Microsphere

The present study successfully developed and optimized gastroretentive floating microspheres of glabridin using Box–Behnken Design-based Response Surface Methodology. The optimized formulation demonstrated excellent drug release, indicating its potential for prolonged gastric retention and improved therapeutic efficacy in the management of gastric ulcer disorders.