The dawning era of oral thin films for nutraceutical delivery: From laboratory to clinic

Abstract

Oral thin films (OTFs) are innovative dosage forms that have gained tremendous attention for the delivery of nutraceuticals. They are ultra-thin, flexible sheets that can be easily placed on the tongue, sublingual or buccal mucosa (inner lining of the cheek). These thin films possess several advantages for nutraceutical delivery including ease of administration, rapid disintegration, fast absorption, rapid onset of action, bypass first-pass hepatic metabolism, accurate dosing, enhanced stability, portability, discreetness, dose flexibility and most importantly consumer acceptance. This review highlights the utilization OTFs for nutraceutical delivery, their composition, criteria for excipient selection, methods of development and quality-based design (QbD) approach to achieve quality product. We have also provided recent case studies representing OTFs as promising platform in delivery of nutraceuticals (plant extracts, bioactive molecules, vitamins, minerals and protein/peptides) and probiotics. Finally, we provided advancement in technologies, recent patents, market analysis, challenges and future perspectives associated with this unique dosage form.

Introduction

Nutraceutical is an amalgamated term of “nutrition” and “pharmaceutical”, generally defined as substances having health-promoting nutritional components (such as bioactive peptides, polyphenols, phytosterols, carotenoids, vitamins and minerals etc.) that provide therapeutic and physiological benefits beyond the basic nutritional needs (DeFelice, 1995; Dhritlahre et al., 2021; Gonçalves et al., 2018). They have gained tremendous attention in recent years because of their high safety, low side-effects and multiple pharmacological benefits (including antioxidant, antibacterial, anti-inflammatory, anticancer, anti-aging etc.) (Sun et al., 2023).

Despite having diverse pharmacological benefits, their successful translation from laboratory to clinics/market is constrained by several factors including chemical instability during processing/ storage (e.g., sensitivity towards oxygen, heat and light) or within gastro-intestinal tract (GIT) (e.g., easily degraded by enzymes and/or pH) and therapeutic limitations (such as poor aqueous solubility, low permeability, chemical degradation, hepatic – first pass metabolism, and efflux transporter specificity). All these factors affect nutraceutical’s functionality, bioavailability and consequently therapeutic efficacy which lead to negligible effect even when ingested at higher dosage (Ali et al., 2019; Dhritlahre et al., 2021; Gonçalves et al., 2018; Velikov and Pelan, 2008). Numerous attempts have been made by the researchers to address these nutraceutical-related limitations; however efficient nutraceutical delivery still requires the investigation of cutting-edge technology and practical administration methods.

Among all the administration routes, the oral route remains the most popular and preferred one which still holds a significant market share (holding 52% of overall delivery market) owing to their ease of applicability, non-invasiveness, convenience, and flexibility with low production cost (Brown et al., 2020; De Robertis et al., 2015). The traditional oral dosage forms (the form in which medicaments are present in the market) including solid dosage forms (such as capsules and tablets) and liquid dosage forms (emulsion, suspension and syrups etc.), are usually associated with incompliance and inconvenience to consumers. Additionally, they impose problem in swallowing, choking, dosage inaccuracy, and therapy insufficiency accompanied by systemic adverse effects due to their unspecified bio-distribution and uncontrolled release of the therapeutics (Borges et al., 2015b). Furthermore, conventional delivery systems have been found to impose several constraints including higher doses and repeated administration (Laffleur and Keckeis, 2020).

To tackle these challenges and hurdles associated with traditional dosage forms, researchers and scientists from nutraceutical formulations domain has shifted their views towards more innovative and patient-centric dosage forms. In this context, oral thin films (OTFs) have acquired considerable importance which is designed with the aim of fast release of nutraceuticals. The dispersed nutraceutical get absorbed via oral mucosa and directly reaches to systemic circulation and thereby providing the benefit of bypassing the first-pass hepatic metabolism, accurate dosing, and fast onset of action (Alqahtani et al., 2021). Additionally, they also offer several other benefits such as ease of administration, high consumer acceptance and convenience, ease of transportation and storage (in comparison to friable oral dispersible tablets), and provides flexibility in dose as compared to conventional dosage forms (tablets and capsules) (Fig. 1). OTFs are most convenient and innovative dosage form for pediatric, geriatric, bedridden and emetic patient population with special needs (such as dysphagia, oral cancer, oral ulcerative mucositis induced by chemotherapy or radiotherapy, Parkinson’s disease and/or other central nervous system disorders and any patient with considerable problems in swallowing and fear of choking/suffocation etc.) (Musazzi et al., 2020; Orlu et al., 2017; Pacheco et al., 2021). In a randomized controlled clinical trial on different age groups (2–28 days, 9 days −5 months and 6–12 months), OTFs are demonstrated to be a promising, safe and convenient alternative dosage form even for the young children (neonates and infants) (Klingmann et al., 2020).

Most importantly, unlike traditional solid dosage forms, OTFs do not require the action of mastication and consumption of water (Gupta et al., 2021b). The OTFs hold dual advantages of good stability like as solid oral dosage form and bioavailability similar to liquid oral dosage form which makes them ideal and superior over the traditional oral dosage form.

The OTFs technique, which has its roots in pharmaceutical research, has opened up new perspectives and expertise in the field of food science, improving the bioavailability and rapid onset of nutraceuticals, therefore demonstrating the vast potential of this formulation strategy (Park et al., 2022). Several drugs such as benzocaine (Chloraseptic®), clonazepam (Klonopin wafers), dexatromethorphan (Theraflu) and diphenhydramine (Triaminic) have been commercialized as OTF formulations (Bala et al., 2013). Now-a-days, OTFs has gained special consideration of researchers for utilizing them as carriers for the delivery of various nutraceuticals (including herbal extracts, bioactive molecules, vitamins, minerals and protein/peptides). Despite of numerous original works and patented technologies available in the literature, a more in-depth study is still required to precisely optimize the performance of OTFs for nutraceutical delivery. Lack of proper guidelines for the production, characterization, and quality control of thin films has prompted the need for sufficient clinical research in this field. Therefore, this paper will contribute to generate insights on significant points of OTFs design: key compositions & their impact on OTFs performance, critical quality attributes (CQA), technological platforms, manufacturing strategies, characterizations, and various evaluation parameters of OTFs. Finally, we also covered market outlook, current challenges, and future perspective of this unique platform for nutraceutical delivery.