Design, Optimization And In-Vitro–Ex-Vivo Evaluation Of Enteric-Coated Nanocarriers For Enhanced Oral Bioavailability Of A Poorly Soluble Drug

Abstract

The present study aimed to design, optimize, and evaluate enteric-coated nanocarriers to enhance the oral bioavailability of Rifaximin, a poorly soluble and P-glycoprotein–susceptible drug. Preformulation studies, including organoleptic assessment, solubility profiling, FTIR, DSC, partition coefficient, hygroscopicity analysis, and micromeritic evaluation, confirmed the physicochemical suitability and compatibility of Rifaximin with glyceryl monostearate, Pluronic F68, and Eudragit L100. Solid lipid nanoparticles were prepared using a solvent-injection method and subsequently coated to obtain enteric-protected RFN-EC-SLNs. A Quality-by-Design–enabled Box–Behnken Design (BBD) was employed by varying lipid concentration, surfactant level, and polymer content to optimize critical quality attributes: particle size, entrapment efficiency, and drug release. Statistical modeling revealed significant effects of lipid and polymer levels on nanoparticle characteristics, and the optimized formulation (F6) achieved a particle size of 154 ± 14 nm, entrapment efficiency of 82 ± 0.9%, and drug release of 86 ± 1.2%.

In-vitro release studies demonstrated effective gastric protection at pH 1.2 and sustained intestinal release at pH 6.8, confirming the enteric functionality of Eudragit L100. Ex-vivo permeation across sheep intestinal mucosa showed enhanced permeation and reduced efflux, indicating improved trans-epithelial transport and P-gp modulation. Stability studies conducted under ICH conditions established the robustness, physicochemical stability, and retention of functional properties of the optimized formulation. Overall, the developed enteric-coated nanocarriers significantly improved the solubility, intestinal release, and permeation profile of Rifaximin, supporting their potential as an effective oral delivery platform for poorly soluble drugs.

Introduction

Rifaximin is a semi-synthetic, poorly water-soluble antibiotic widely used for the management of gastrointestinal infections, hepatic encephalopathy, traveler’s diarrhea, and irritable bowel syndrome.1-5 Despite its broad therapeutic utility and excellent safety profile, its clinical effectiveness is significantly limited by poor aqueous solubility and minimal systemic absorption following oral administration. The drug exhibits a Biopharmaceutics Classification System (BCS) Class IV profile characterized by low solubility and poor permeability which contributes to inadequate intestinal absorption and inconsistent therapeutic concentrations at the target site.6-12 Moreover, Rifaximin is a known substrate of P-glycoprotein (P-gp), an efflux transporter abundantly expressed in the intestinal epithelium. This efflux activity restricts the trans-epithelial movement of the drug, further reducing its bioavailability and limiting therapeutic performance. Therefore, designing an efficient oral delivery system capable of enhancing solubility, modulating efflux, and improving intestinal permeability is essential.13-18

Lipid-based nanocarriers, particularly solid lipid nanoparticles (SLNs), have gained significant interest as promising drug-delivery systems for poorly soluble drugs. SLNs offer advantages such as biocompatibility, controlled release behavior, high drug-loading efficiency, and protection of labile compounds from degradation. Their nano-sized structure enhances interfacial interaction with the intestinal mucosa, facilitating improved absorption and permeability. However, for drugs like Rifaximin that are unstable or incompletely released in acidic gastric conditions, the incorporation of enteric-coated polymers provides substantial benefits. An enteric-coated SLN system can protect the drug from early degradation in the stomach, ensure targeted release in the intestine, and support optimal absorption where therapeutic activity is required. Eudragit L100, an anionic pH-dependent polymer, is particularly suitable for such systems due to its selective solubility at intestinal pH and its ability to maintain formulation integrity under acidic conditions.19-22

The application of Quality by Design (QbD) principles in pharmaceutical development has further strengthened formulation optimization by introducing systematic design approaches, risk assessment strategies, and statistically driven experimentation. The Box–Behnken Design (BBD), a key response surface methodology, enables efficient evaluation of critical formulation variables, reducing development complexity while improving product quality and predictability. In the context of SLN systems, factors such as lipid concentration, surfactant level, and polymer content significantly influence critical quality attributes, including particle size, drug entrapment efficiency, and release behavior. Through QbD-driven optimization, robust and reproducible nanocarriers can be achieved.23-29

Given these considerations, the development of Rifaximin-loaded enteric-coated solid lipid nanoparticles (RFN-EC-SLNs) presents a promising strategy to overcome the drug’s inherent limitations. Such a system not only enhances solubility and stability but also improves intestinal permeability and potentially reduces P-gp–mediated efflux, leading to better therapeutic outcomes. This research focuses on the formulation, optimization, characterization, and evaluation of RFN-EC-SLNs using a QbD framework, with the aim of improving oral bioavailability and establishing a reliable delivery platform for Rifaximin and other poorly soluble therapeutic agents.

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Materials

Rifaximin was received as a gift sample from Cipla Pharmaceuticals Ltd., Mumbai. Glyceryl monostearate (GMS) and Eudragit L100 were procured from Loba Chemie and Evonik India Pvt. Ltd., respectively. Pluronic F68 was sourced from Sigma-Aldrich, USA. All solvents and reagents used, including ethanol, methanol, and acetone, were of analytical grade and purchased from Merck, Mumbai.

Dr. Subhranshu Panda, Shubham Tikait*, Dr. Swati Deshmukh, (2025) Design, Optimization And In-Vitro–Ex-Vivo Evaluation Of Enteric-Coated Nanocarriers For Enhanced Oral Bioavailability Of A Poorly Soluble Drug, Vascular and Endovascular Review, Vol.8, No.14s, 265-282.