Natural product-based excipients for topical green formulations

Abstract

The industry has been paying more attention to the quality of excipients since they play a fundamental role in the efficacy, safety, and acceptability of pharmaceutical products. However, in the case of topical products synthetic compounds have been a concern for consumers, since they can lead to sensitization reactions, disturbance of the microbiota, and impairment in the skin barrier function. Consequently, the pharmaceutical industry has been looking for safer, cheaper, more effective, and more eco-friendly alternatives, and so natural raw materials (or natural ingredients) are good candidates to meet this demand. This narrative review aims to present studies that use natural excipients and describe their advantages, disadvantages and overall performance. In topical formulations, natural ingredients can be found in the form of emulsifiers, emollients, preservatives, gelling agents, humectants, and permeation enhancers. The studies show that they fulfill their role in formulations, demonstrating rheological and stable characteristics, as well as not being toxic to skin cells and the microbiota. Moreover, many natural raw materials are biodegradable, being less harmful to the environment. More studies are still needed to effectively replace synthetic excipients with natural ones, while maintaining quality control. These raw materials present themselves as a potential alternative and there are vast resources still little explored, and those already used are highly effective and safe.

Introduction

In the 15th century, Paracelsus said that any substance has adverse effects if administered in sufficient doses. Synthetic excipients have infrequent and mild adverse effects, as they are generally selected based on their low toxicity. Their adverse effects can be attributed to direct toxicity, immunotoxicity, allergy or intolerance, and, despite the low frequency, the increased use of these products has raised concerns since the beginning of the 20th century (Pifferi and Restani, 2003). Along with concerns about the environment, green products are an increasing market in a variety of industries, including food, cosmetic and pharmaceutical (Carriço et al., 2018; Santos et al., 2021), encouraging the search for new alternatives to make safer and eco-friendly products. In this context, the pharmaceutical industry is now paying greater attention to the nature of excipients. When it comes to products for topical use, there is great concern about sensitivity reactions (Bujak et al., 2015, 2020; Liu and Lunter, 2020; Ma et al., 2021), and impairment of the skin barrier function (Hirata et al., 2014; Musazzi et al., 2018; Simonsson et al., 2011) and disturbance of its microbiota (Wang et al., 2019), which can be triggered by the action of generally synthetic excipients.

For thousands of years, nature has been a source of vital ingredients for treatments, which have been used not only as complex mixtures with a variable composition, but also as pure, quantifiable and chemically known compounds (Seabra et al., 2002). In fact, there is an estimation that approximately 50% of the new drugs introduced since 1994 were derived from natural sources (Li and Vederas, 2009). Apart from being used as active pharmaceutical ingredients (APIs) or inspiring synthetic molecules in formulations (Newman and Cragg, 2020), green substances can act as pharmaceutical aids and excipients (Pal et al., 2019).

Pharmaceutical excipients were traditionally defined as inactive components crucial to guarantee an adequate quality, safety, and efficacy of APIs, which are derived from different sources, such as biological, mineral, vegetal, and chemical synthesis-based (Darji et al., 2018; Ionova and Wilson, 2020). On the other hand, the International Pharmaceutical Excipients Councils (IPEC) defines excipients in a more complete and adequate way, as any substance, other than the API, which has had its safety assessed and can be included in the pharmaceutical dosage form (Elder et al., 2016). As a matter of fact, excipients are employed in pharmaceutical formulations to facilitate the production and the identification of products, namely: to correctly stabilize and preserve a preparation’s appearance and physicochemical and/or microbiological characteristics; to modify drug release profile: and optimize the bioavailability of the API (Bejarano et al., 2019; Vasconcelos et al., 2017). Depending on their role, excipients can be grouped into different categories and they are used to prepare a wide variety of dosage forms, such as tablets, capsules, oral liquids, ointments, creams, gels, transdermal patches, injectable preparations, implants, suppositories, and inhalers (Abrantes et al., 2016; Veeravalli et al., 2020). Over the years, the point of view of the pharmaceutical industry has evolved, moving from focusing only on the standard of the active ingredients to a broader look, that not only involves the standard of the excipients but also the production process itself, contributing to the quality improvement of the final product (Elder et al., 2016; Garcia-Fernandez et al., 2016; Kozarewicz and Loftsson, 2018).

Based on the increased concern about synthetic excipients, there is interest devoted to looking for new green, eco-friendly and sustainable alternatives. This way, this narrative review aims to present studies that use natural ingredients as a source of excipients for the development of topical formulations, critically discussing their advantages and disadvantages, and the overall performance in comparison to synthetic versions.