The oral administration of therapeutic peptides and proteins is favoured from a patient and commercial point of view. In order to reach the systemic circulation after oral administration, these drugs have to overcome numerous barriers including the enzymatic, sulfhydryl, mucus and epithelial barrier. The development of oral formulations for therapeutic peptides and proteins is therefore necessary. Among the most promising formulation approaches are lipid-based nanocarriers such as oil-in-water nanoemulsions, self-emulsifying drug delivery systems (SEDDS), solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), liposomes and micelles. As the lipophilic character of therapeutic peptides and proteins can be tremendously increased such as by the formation of hydrophobic ion pairs (HIP) with hydrophobic counter ions, they can be incorporated in the lipophilic phase of these carriers. Since gastrointestinal (GI) peptidases as well as sulfhydryl compounds such as glutathione and dietary proteins are too hydrophilic to enter the lipophilic phase of these carriers, the incorporated therapeutic peptide or protein is protected towards enzymatic degradation as well as unintended thiol/disulfide exchange reactions. Stability of lipid-based nanocarriers towards lipases can be provided by the use to excipients that are not or just poorly degraded by these enzymes. Nanocarriers with a size <200 nm and a mucoinert surface such as PEG or zwitterionic surfaces exhibit high mucus permeating properties. Having reached the underlying absorption membrane, lipid-based nanocarriers enable paracellular and lymphatic drug uptake, induce endocytosis and transcytosis or simply fuse with the cell membrane releasing their payload into the systemic circulation. Numerous in vivo studies provide evidence for the potential of these delivery systems. Within this review we provide an overview about the different barriers for oral peptide and protein delivery, highlight the progress made on lipid-based nanocarriers in order to overcome them and discuss strengths and weaknesses of these delivery systems in comparison to other technologies.

Poorly water-soluble drugs continue to be a problematic, yet important class of pharmaceutical compounds for treatment of a wide range of diseases. Their prevalence in discovery is still high, and their development is usually limited by our lack of a complete understanding of how the complex chemical, physiological and biochemical processes that occur between administration and absorption individually and together impact on bioavailability. This review defines the challenge presented by these drugs, outlines contemporary strategies to solve this challenge, and consequent in silico and in vitro evaluation of the delivery technologies for poorly water-soluble drugs. The next steps and unmet needs are proposed to present a roadmap for future studies for the field to consider enabling progress in delivery of poorly water-soluble compounds.

Cyclodextrins (CD) and derivatives are functional excipients that can improve the bioavailability of numerous drugs. Because of their drug solubility improving properties they are used in many pharmaceutical products. Furthermore, the stability of small molecular drugs can be improved by the incorporation in CDs and an unpleasant taste and smell can be masked. In addition to well-established CD derivatives including hydroxypropyl-β-CD, hydroxypropyl-γ-CD, methylated- β-CD and sulfobutylated- β-CD, there are promising new derivatives in development. In particular, CD-based polyrotaxanes exhibiting cellular uptake enhancing properties, CD-polymer conjugates providing sustained drug release, enhanced cellular uptake, and mucoadhesive properties, and thiolated CDs showing mucoadhesive, in situ gelling, as well as permeation and cellular uptake enhancing properties will likely result in innovative new drug delivery systems. Relevant clinical trials showed various new applications of CDs such as the formation of CD-based nanoparticles, stabilizing properties for protein drugs or the development of ready-to-use injection systems. Advanced products are making use of various benefical properties of CDs at the same time. Within this review we provide an overview on these recent developments and take an outlook on how this class of excipients will further shape the landscape of drug delivery.