(M1530-05-32) Effect of Mucin on Drug Dissolution in Lipid–Surfactant Systems During Digestion

Purpose: Mucins, the primary glycoproteins in mucus, play a crucial role in modulating drug delivery behavior in the gastrointestinal (GI) tract. Their interactions with formulation components can influence drug solubility, stability, and absorption (J. Pharm. Sci. 113, 2024, 3272–3278; J. Drug Deliv. Sci. Technol. 78, 2022, 103973). This study aimed to investigate how mucin interacts with formulation ingredients, such as surfactants and lipids, and how these interactions affect the dissolution and solubilization of poorly water-soluble drugs under simulated digestive conditions.

Methods: Dissolution studies were conducted using three model drugs—griseofulvin (GRIS), celecoxib (CEL), and cyclosporine A (CsA)—in formulations containing polysorbate 80 (P80) and triolein. Experiments were performed in simulated intestinal fluid (FaS) with and without 0.2% mucin, and in the presence or absence of pancreatic extract to simulate digestion. Drug solubility was measured under these conditions to evaluate the impact of mucin and digestion on drug dissolution behavior.

Results: All three drugs exhibited higher solubility in FaS containing 0.2% mucin compared to FaS alone (Figure 1). The presence of mucin led to enhanced drug solubilization, attributed to synergistic interactions with bile salts that promote micelle formation. This effect was most pronounced for CsA, the most lipophilic compound, due to its stronger affinity for mucin and bile components. The addition of P80 further improved drug dissolution, likely through the formation of micelles and solubilizing complexes (data not shown). Mucin enhanced this effect by providing hydrophobic patches that interact with poorly soluble drugs and forming a hydrated gel-like matrix that stabilizes them in colloidal or molecular form. Mucin also interacts with triolein via its hydrophobic domains and stabilizes the resulting lipid–drug assemblies within its hydrated gel network, thereby enhancing drug solubilization (data not shown). Triolein and P80 acted synergistically to enhance drug solubilization by forming stable colloidal structures, and mucin further increased this effect through steric stabilization and electrostatic repulsion (Figure 2). During digestion, drug dissolution generally decreased, indicating that enzymatic degradation of mucin by pancreatin disrupts the mucin network, affecting drug solubilization (data not shown). However, in the presence of lipid and surfactant, mucin still enhanced drug dissolution, suggesting that mucin can stabilize digestion products to form micelle and prevent drug precipitation even under proteolytic stress (Figure 3).

Conclusion: Mucin significantly enhances drug solubility and dissolution through synergistic interactions with bile salts, surfactants, and lipids. It plays a critical role in stabilizing colloidal drug carriers, especially in undigested systems. While digestion may degrade mucin and reduce its effect, mucin can still provide solubilization benefits when combined with surfactants like P80 or digestion products. These findings highlight the importance of considering mucin–formulation interactions when designing oral delivery systems for poorly soluble drugs.

References: 1. Tania Ng et al. Evaluation of the impact of mucin on supersaturation and permeation of BCS class2 basic drugs. J. Pharm. Sci. 113, 2024, 3272–32.
2. Weijun Liu et al. The effect of mucin on supersaturation of poorly water-soluble drugs with different crystallization behavior and in vitro-in vivo correlation. J. Drug Deliv. Sci. Technol. 78, 2022, 103973

Acknowledgements: This work was financially supported by the National Institutes of Health.

Figure 1: Drug Solubility in FaS with and without mucin.

Figure 2: Drug dissolution profiles with formulation components.

Figure 3: Effect of digestion on drug dissolution in mucin-containing media.