Transient Permeation Enhancer® (TPE®) technology for oral delivery of octreotide: a technological evaluation

Abstract

Introduction:The FDA approval of oral semaglutide for type 2 diabetes (2019) and oral octreotide for acromegaly ( 2020) is evidence that selected niche peptides can be administered orally if formulated with selected intestinal permeation enhancers. Areas covered:We evaluated the oral octreotide formulation, MYCAPSSA ® (Chiasma Pharmaceuticals, Needham, MA, USA). An outline of the current standard of care in acromegaly and the benefits of oral octreotide versus depot injections is provided. We discuss the Transient Permeation Enhancer (TPE ® ) technology used and detail the safety and efficacy data from animal models and clinical trials.Expert opinion: TPE ® is an oily suspension of octreotide that includes a number of excipients that can transiently alter epithelial barrier integrity by opening of intestinal epithelial tight junctions arising from transcellular perturbation. Phase I studies using 20 mg octreotide capsules yielded a relative oral bioavailability of ~0.7% and primary endpoints were achieved in two Phase III studies. The oral octreotide dose required to achieve these endpoints was over 200 times that of the 0.1 mg immediaterelease subcutaneous injection, a reminder of the difficulty in achieving oral absorption of macromolecules. Many acromegaly patients will prefer a convenient twice-daily oral formulation of octreotide compared to monthly depot injections.

Oral delivery of protein and peptide drugs: from non-specific formulation approaches to intestinal cell targeting strategies

“…Currently, Phase I studies of octreotide capsules resulted in an oral bioavailability of about 0.7% and primary endpoints were achieved in two Phase III studies. The oral octreotide dose required to achieve these endpoints was over 200 times that of the 0.1 mg subcutaneous injection, which demonstrated a big achievement of this promising oral form 101 .…”

“…Moreover, several peptides have been incorporated into TPE ® including teriparatide, leuprolide, insulin and octreotide. However, a main concern in application of TPE ® , the intestinal tight junction opening that cause toxicity, or the use of food emulsifiers or other excipients might initiate autoimmune disease 101 , 102 . Currently, Phase I studies of octreotide capsules resulted in an oral bioavailability of about 0.7% and primary endpoints were achieved in two Phase III studies.…”

The Centenary of the Discovery of Insulin: An Update on the Quest for Oral Delivery

“…Much credit is due for the recent FDA approvals of oral semaglutide in 2019 (Rybelsus ® , Novo Nordisk, Bagsvaerd, Denmark) (Anderson et al, 2020) and of oral octreotide in 2020 (Mycappsa ® , Chiasma Pharma, Needham, MA, United States) (Samson et al, 2020). These formulations of highly potent peptides with a degree of intestinal stability are both based on intestinal permeation enhancers (Brayden et al, 2020), Rybelsus ® with salcaprozate sodium (SNAC) (Buckley et al, 2018), and Mycappsa ® with sodium caprylate in an oily suspension (Brayden and Maher, 2021). While they achieved the required respective changes in plasma biomarkers for Type 2 diabetes and acromegaly, typical oral bioavailability values in humans for both peptides averaged <1%, and with large coefficients of variation.…”

Intestinal Absorption of FITC-Dextrans and Macromolecular Model Drugs in the Rat Intestinal Instillation Model

“…There has been some recent success using permeation enhancers with the approval of oral semaglutide and oral octreotide, but bioavailability remains low and variable. 1 , 2 It is still not well understood how to best formulate permeation enhancers for oral administration of macromolecules. Sodium caprate (C10) is one of the most widely studied permeation enhancers and has been evaluated in several clinical studies.…”

“…Oral administration of macromolecules remains of high interest in the drug delivery field to offer patients an alternative to injections. There has been some recent success using permeation enhancers with the approval of oral semaglutide and oral octreotide, but bioavailability remains low and variable. , It is still not well understood how to best formulate permeation enhancers for oral administration of macromolecules. Sodium caprate (C10) is one of the most widely studied permeation enhancers and has been evaluated in several clinical studies. − C10 is believed to work by enhancing both the paracellular and transcellular transport of co-presented macromolecules. − We recently used the rat intestinal instillation model to better understand the absorption mechanism of C10 .…”