scholarly journals Intestinal Permeation Enhancers for Oral Delivery of Macromolecules: A Comparison between Salcaprozate Sodium (SNAC) and Sodium Caprate (C10)

Pharmaceutics ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 78 ◽  
Author(s):  
Caroline Twarog ◽  
Sarinj Fattah ◽  
Joanne Heade ◽  
Sam Maher ◽  
Elias Fattal ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Oral Delivery ◽  
Long Term Effects ◽  
Permeation Enhancers ◽  
Single Digit ◽  
Sodium Caprate ◽  
Intestinal Epithelia ◽  
Intestinal Permeation ◽  
Intestinal Permeation Enhancers

Salcaprozate sodium (SNAC) and sodium caprate (C10) are two of the most advanced intestinal permeation enhancers (PEs) that have been tested in clinical trials for oral delivery of macromolecules. Their effects on intestinal epithelia were studied for over 30 years, yet there is still debate over their mechanisms of action. C10 acts via openings of epithelial tight junctions and/or membrane perturbation, while for decades SNAC was thought to increase passive transcellular permeation across small intestinal epithelia based on increased lipophilicity arising from non-covalent macromolecule complexation. More recently, an additional mechanism for SNAC associated with a pH-elevating, monomer-inducing, and pepsin-inhibiting effect in the stomach for oral delivery of semaglutide was advocated. Comparing the two surfactants, we found equivocal evidence for discrete mechanisms at the level of epithelial interactions in the small intestine, especially at the high doses used in vivo. Evidence that one agent is more efficacious compared to the other is not convincing, with tablets containing these PEs inducing single-digit highly variable increases in oral bioavailability of payloads in human trials, although this may be adequate for potent macromolecules. Regarding safety, SNAC has generally regarded as safe (GRAS) status and is Food and Drug Administration (FDA)-approved as a medical food (Eligen®-Vitamin B12, Emisphere, Roseland, NJ, USA), whereas C10 has a long history of use in man, and has food additive status. Evidence for co-absorption of microorganisms in the presence of either SNAC or C10 has not emerged from clinical trials to date, and long-term effects from repeat dosing beyond six months have yet to be assessed. Since there are no obvious scientific reasons to prefer SNAC over C10 in orally delivering a poorly permeable macromolecule, then formulation, manufacturing, and commercial considerations are the key drivers in decision-making.

Abstract 13307: An Oral Antisense Oligonucleotide for PCSK9 Inhibition in Humans

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Peter Gennemark ◽  
Katrin Walter ◽  
Niclas Clemmensen ◽  
Dinko Rekic ◽  
Catarina Nilsson ◽  
...  
Keyword(s):  
Steady State ◽  
Oral Administration ◽  
Antisense Oligonucleotide ◽  
Oral Delivery ◽  
Permeation Enhancers ◽  
Pcsk9 Inhibitors ◽  
Liver Uptake ◽  
Pcsk9 Inhibition ◽  
Intestinal Permeation ◽  
Intestinal Permeation Enhancers

Current PCSK9 inhibitors are administered via subcutaneous (SC) injection. Here, we present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier ASO chemistries and intestinal permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by tri-antennary N -acetyl galactosamine (GalNAc) conjugation make this ASO highly potent. A single SC dose of 90 mg reduces PCSK9 by >90% in humans with elevated LDL-C (A), and a once monthly SC dose of 25 mg ([20, 30], 90% CI) is predicted to reduce PCKS9 by 80% at steady-state. To investigate the feasibility of oral administration, we developed an oral solid tablet wherein the ASO is co-formulated with a transient permeation enhancer. Repeated oral daily dosing of tablets to dogs resulted in a bioavailability of 7% in the liver (target organ), approximately 5-fold greater than the plasma bioavailability (B). Favourable liver uptake following oral administration is supported by similar bioavailability in plasma and kidney. Since the ASO is not active in rodents or dogs, we used a rat-specific GalNAc- Malat-1 ASO with the same chemistry to confirm target engagement. Intrajejunal administration resulted in ≥78% mRNA knockdown in the liver for single doses of 3-40 mg/kg. A monkey tolerability study of the PCSK9 ASO further supports oral feasibility with all tested doses (28-56 mg/day) significantly reducing LDL-C already after 7 days of daily oral dosing. Based on available animal and human data, and an assumption of 5% oral bioavailability in humans, a daily dose of 15 mg ([10, 20], 90% CI) in man is predicted to reduce PCSK9 in plasma by 80% at steady-state. This supports the development of the compound for subcutaneous and oral administration to treat dyslipidemia.

scholarly journals From Farm to Pharmacy: Strawberry-Enabled Oral Delivery of Protein Drugs

2020 ◽  
Author(s):  
Nicholas G. Lamson ◽  
Katherine C. Fein ◽  
John P. Gleeson ◽  
Sijie Xian ◽  
Alexandra Newby ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Oral Delivery ◽  
Oral Drug Delivery ◽  
Oral Drug ◽  
Protein Drugs ◽  
Permeation Enhancers ◽  
Intestinal Permeation ◽  
Macromolecular Permeability ◽  
Intestinal Permeation Enhancers

AbstractAlthough oral drug delivery is preferred by patients, it is not possible for proteins because the gastrointestinal tract is not sufficiently permeable. To enable the non-toxic oral uptake of protein drugs, we investigated plant-based foods as intestinal permeation enhancers, hypothesizing that compounds found in food would be well-tolerated by the gastrointestinal tract. Following a screen of over 100 fruits, vegetables, herbs, and fungi, we identified strawberry as a potent enhancer of macromolecular permeability in vitro and in mice. Natural product chemistry techniques identified pelargonidin, an anthocyanidin, as the active compound. In mice, insulin was orally administered with pelargonidin to induce sustained pharmacodynamic effects with doses as low as 1 U/kg and bioactivity of over 100% relative to the current gold standard of subcutaneous injection. Pelargonidin-induced permeability was reversible within two hours of treatment, and one month of daily dosing did not adversely affect mice as determined by weight tracking, serum concentrations of inflammatory markers, and tight junction gene expression. Results underscore the utility of plant-based foods in biomedical applications and demonstrate pelargonidin as an especially potent enhancer for the oral delivery of biologics.

scholarly journals In Vitro, Ex Vivo and In Vivo Evaluation of Microcontainers for Oral Delivery of Insulin

Pharmaceutics ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 48 ◽  
Author(s):  
Jacob Rune Jørgensen ◽  
Feiyang Yu ◽  
Ramakrishnan Venkatasubramanian ◽  
Line Hagner Nielsen ◽  
Hanne Mørck Nielsen ◽  
...  
Keyword(s):  
Oral Delivery ◽  
Ex Vivo ◽  
Sodium Dodecyl ◽  
Insulin Absorption ◽  
Oral Gavage ◽  
In Vivo Evaluation ◽  
Sodium Caprate ◽  
Intestinal Membrane

Enhancing the oral bioavailability of peptides has received a lot of attention for decades but remains challenging, partly due to low intestinal membrane permeability. Combining a permeation enhancer (PE) with unidirectionally releasing microcontainers (MCs) has previously been shown to increase insulin permeation across Caco-2 cell monolayers. In the present work, this setup was further employed to compare three common PEs—sodium caprate (C10), sodium dodecyl sulfate (SDS), and lauroyl carnitine. The concept was also studied using porcine intestinal tissue with the inclusion of 70 kDa fluorescein isothiocyanate-dextran (FD70) as a pathogen marker. Moreover, a combined proteolysis and Caco-2 cell permeation setup was developed to investigate the effect of soybean trypsin inhibitor (STI) in the MCs. Lastly, in vivo performance of the MCs was tested in an oral gavage study in rats by monitoring blood glucose and insulin absorption. SDS proved to be the most potent PE without increasing the ex vivo uptake of FD70, while the implementation of STI further improved insulin permeation in the combined proteolysis Caco-2 cell setup. However, no insulin absorption in rats was observed upon oral gavage of MCs loaded with insulin, PE and STI. Post-mortem microscopic examination of their gastrointestinal tract indicated lack of intestinal retention and optimal orientation by the MCs, possibly precluding the potential advantage of unidirectional release.

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