Peptide therapeutics are on the rise due to their high potency, specific mode of action and safety. Currently, more than 60 peptides are available on the market. About 140 are in clinical trials and 500 are in preclinical development (Fosgerau and Hoffmann, 2015).
Around 70% of marketed peptides are delivered via injection. However, needles are unpopular with patients and alternative routes are being explored, including oral. For effective oral administration, peptides need to withstand the harsh conditions of the gastrointestinal (GI) tract to be delivered to their site of action in an active form (Richard, 2017; Leonaviciute and Bernkop-Schnürch, 2015).
Among the various solutions explored, the simplicity of formulation, biopharmaceutical advantages and precedence of use of self emulsifying drug delivery systems (SEDDS) make them an interesting option.
Challenges of oral peptide delivery
Peptides – and proteins – are part of our diet. Our body developed numerous strategies to digest them into amino acids suitable for absorption, while preventing their direct entry into systemic circulation. For oral peptide therapeutics to be effective, formulations must prevent this naturally occurring digestion and promote peptide permeability through the GI tract.
Challenge #1: prevent degradation
Variations in pH throughout the GI tract lead to peptide hydrolysis with consequent loss of activity. They also induce changes in ionization, hence peptide solubility.
Numerous enzymes, such as pepsin, chymotrypsin, endopeptidase and exopeptidase, attack the peptides, contributing to proteolysis of their structure.
Glutathione, endogenous or originating from food, affects some peptides through reduction of disulfide bonds, leading to their inactivation.
Only a limited fraction of the ingested therapeutic peptide reaches the enterocytes in an active form.
Challenge #2: promote permeability
A mucus layer covers the epithelial cell in the lumen where proteases and antibodies fight against any intrusion. It acts as a filter and limits the penetration of molecules. Its viscosity slows down the diffusion of molecules.
However some molecules do penetrate and cross mucosal barriers to reach the systemic circulation, either via the enterocyte (transcellular) or between cells (paracellular). The transcellular pathway requires specific binding to receptors for active transport or passive diffusion for molecules having suitable properties (ie. low molecular weight, high LogP). Tight junctions between cells control the paracellular transport of molecules to the systemic system.
A very small fraction of active peptide actually crosses the epithelial membrane to reach the systemic circulation.
Figure: Hoops and hurdles in oral peptide delivery
SEDDS: a simple and efficient platform
Among the various strategies developed for oral peptide delivery, SEDDS are interesting due to their simplicity, efficiency and biopharmaceutical advantages.
#1. A simple platform
SEDDS consists of a mixture of oils, surfactants and solvents, designed to solubilize the drug throughout the digestion process and deliver the active ingredient at the absorption site. SEDDS have a long history of use, using well characterized excipients with worldwide precedence of use (Table 1).
Table1: Excipients commonly used in SEDDS formulation (From Jannin, 2015).
Lauroyl polyoxyl-32 glycerides
Caprylo caproyl polyoxyl-8 glycerides
Polyethylene-20 sorbitan oleate
Polyethylene-40 hydrogenated castor oil
Kolliphor® RH 40
Oleoyl polyoxyl-6 monocaprylate
Labrafil®M 1944 CS
Propylene glycol monocaprylate
Propylene glycol monolaurate
Medium chain triglycerides
Labrafac™ Lipophile WL 1349
Diethylene glycol monoethylether
SEDDS have been formulated for decades and are described in many scientific articles. For comprehensive and updated information on lipid-based formulations, including SEDDS, please refer to Feeney et al (2016) for an in-depth scientific review and LePree (2017) for a practical overview.
#2. Proven efficacy
Effective protection of the peptide from degradation
The resistance of peptides to digestive enzymes has been shown in several studies as reported in the review by Leonaviciute and Bernkop-Schnürch (Table 2).
Table 2: Enzyme resistance of peptides loaded in SEDDS (from Leonaviciute and Bernkop-Schnürch, 2015)
The explanation is that hydrophilic enzymes cannot enter the SEDDS to hydrolyze the peptide. Therefore as long as the peptide is maintained in the oil droplet it is protected.
Hetenyi et al (2017) showed that SEDDS could provide a complete protective effect towards protease degradation and deactivation by glutathione.
Efficient permeation through the intestinal mucus gel layer and membrane cell
Mucus permeation properties of SEDDS have been demonstrated both in vitro and in vivo, as reviewed by Leonaviciute and Bernkop-Schnürch. Using Transwell diffusion system, it was shown that SEDDS droplet size is a critical parameter. The smaller the droplet size, the greater the permeability.
Moreover the surfactants used in SEDDS have the capacity to open tight junctions, increasing intestinal epithelial permeability. Several in vivo studies listed by Leonaviciute and Bernkop-Schnürch confirm the increase of permeability on different peptides.
High loading capacity
Pairing the hydrosoluble cationic peptide with an anionic counterion enables its incorporation in lipophilic SEDDS. Using this technique (hydrophobic ion pairing), Griesser et al (2017) showed on three model peptides (leuprorelin, insulin and desmopressin) that the LogP of the ion-paired peptides was greatly increased. Consequently, the peptides are slowly released out of the SEDDS and a better protection towards enzymes and glutathione is achieved. With this technique they obtained the highest peptide load in SEDDS: more than 10% of paired peptide.
Gattefossé areas of research
Gattefosse is currently focusing on three areas of research on oral peptide delivery:
To understand how SEDDS can be formulated to effectively protect the peptides and achieve high load
To demonstrate that peptides are effectively delivered and absorbed at the epithelial membrane with increased bioavailability
To facilitate mucosal absorption via nanomaterial as carriers
Listen to Vincent Jannin, Ph.D., research director, pharmaceuticals at Gattefossé, explaining the company’s latest studies on oral peptide delivery.
SEDDS is a simple and efficient platform to answer the growing need for oral peptide delivery. This technology is well-established for small molecules and has also successfully been applied for oral peptide delivery: Cyclosporin A (Neoral) is a SEDDS marked since the 1980’s.
Recent findings using hydrophobic ion pairing further encourage the exploration of SEDDS for oral peptide delivery, due to the high drug load achieved.
Feeney OM, Crum MF, McEvoy CL, Trevaskis NL, Williams HD, Pouton CW, Charman WN, Bergström CAS, Porter CJH. 50 years of oral lipid-based formulations: Provenance, progress and future perspectives. Adv Drug Deliv Rev. (2016) Jun 1;101:167-194.
Fosgerau K. and Hoffmann T. Peptide therapeutics: current status and future directions, Drug Discovery Today (2015), Volume 20, Number 1
Griesser J., Hetényi G., Moser M., Demarne F., Jannin V., Bernkop-Schnürch A. Hydrophobic ion pairing: Key to highly payloaded self-emulsifying peptide drug delivery systems, International Journal of Pharmaceutics, Volume 520, Issues 1–2, 30 March 2017, Pages 267–274
Hetényi G., Griesser J., Moser M., Demarne F., Jannin V., Bernkop-Schnürch A. Comparison of the protective effect of self-emulsifying peptide drug delivery systems towards intestinal proteases and glutathione, International Journal of Pharmaceutics, Volume 523, Issue 1, 15 May 2017, Pages 357–365
Jannin V., Chevrier S., Michenaud M., Dumont C., Belotti S., Chavant Y., Demarne F., Development of self emulsifying lipid formulations of BCS class II drugs with low to medium lipophilicity, International Journal of Pharmaceutics, Volume 495, Issue 1, 10 November 2015, Pages 385-392
Leonaviciute G. and Bernkop-Schnürch A. Self-emulsifying drug delivery systems in oral (poly)peptide drug delivery, Expert opinion (2015) 10.1517/17425247.2015.1068287
LePree J. (2017) LIPID-BASED DELIVERY – Are Lipid-Based Drug Delivery Systems in Your Formulation Toolbox? Drug Development & Delivery, Issue: October 2017, Posted Date: 9/29/2017
Richard J. Challenges in oral peptide delivery: lessons learnt from the clinic and future prospects, Ther. Deliv. (2017) 8(8), 663–684