Safety of Surfactant Excipients in Oral Drug Formulations

Abstract

Surfactants are a diverse group of compounds that share the capacity to adsorb at the boundary between distinct phases of matter. They are used as pharmaceutical excipients, food additives, emulsifiers in cosmetics, and as household/industrial detergents. This review outlines the interaction of surfactant-type excipients present in oral pharmaceutical dosage forms with the intestinal epithelium of the gastrointestinal (GI) tract. Many surfactants permitted for human consumption in oral products reduce intestinal epithelial cell viability in vitro and alter barrier integrity in epithelial cell monolayers, isolated GI tissue mucosae, and in animal models. This suggests a degree of mismatch for predicting safety issues in humans from such models. Recent controversial preclinical research also infers that some widely used emulsifiers used in oral products may be linked to ulcerative colitis, some metabolic disorders, and cancers. We review a wide range of surfactant excipients in oral dosage forms regarding their interactions with the GI tract. Safety data is reviewed across in vitro, ex vivo, pre-clinical animal, and human studies. The factors that may mitigate against some of the potentially abrasive effects of surfactants on GI epithelia observed in pre-clinical studies are summarised. We conclude with a perspective on the overall safety of surfactants in oral pharmaceutical dosage forms, which has relevance for delivery system development.

Introduction

Surfactants are amphiphilic molecules that accumulate at the boundary between distinct forms of matter where they lower surface tension. This feature makes amphiphiles useful as pharmaceutical excipients, food additives, and as components of cosmetics. In oral pharmaceutical dosage forms, surfactants are included as wetting agents, dispersants, emulsifiers, foaming agents, solubilizers, glidants, lubricants, and preservatives.

Surfactants used in oral pharmaceutical dosage forms are considered safe for human consumption by regulators when used within acceptable dose limits. Although surfactants are synonymous with detergency and solubilization, the orally ingested ones cause mild effects compared to household and industrial detergents, which cause extensive GI toxicity even at low concentrations [1]. Still, many soluble surfactants used as oral formulation excipients can disrupt biological membranes [2], [3], [4], causing an alteration to intestinal epithelial permeability in in vitro models [5]. It is unclear, however, if the quantities used in oral formulations can reach and sustain the threshold concentrations at the intestinal mucosa to cause epithelial barrier reduction in vivo. There is also controversy over whether they may contribute to the development of autoimmune disease as a result of barrier dysregulation, microbiome changes, and changes in mucus overlying the epithelium [6], [7]. Recent publications based on data in mouse models have presented concerns that commonly used surfactants might be implicated in ulcerative colitis [8], colon cancer [9], and metabolic disorders [8].

Increasing evidence suggests that synthetic surfactants that increase GI permeability might play a role in the increasing rates of allergic and autoimmune diseases [10], [11]. This article reviews the safety data for surfactants used as excipients in oral drug formulations. Included is a summary of the structure and function of surfactants to detail how some surfactants damage biological membranes while others have no observable effect. As the safety data on surfactants is derived largely from pre-clinical models, (with perhaps limited prediction for human exposure), a section is outlined on the factors that may give rise to differences in the effects observed in humans compared to those models. Five case studies are included to provide a focal point for important themes related to surfactant safety. The cases highlight oral formulations with high surfactant concentrations and also contextualise surfactant safety. The article concludes with an overall perspective on the safety of surfactants used in oral pharmaceutical dosage forms in the GI tract.

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Sam Maher, Caroline Geoghegan, David J. Brayden, Safety of Surfactant Excipients in Oral Drug Formulations, Advanced Drug Delivery Reviews, 2023, 115086, ISSN 0169-409X, https://doi.org/10.1016/j.addr.2023.115086.