Systems Biology and Peptide Engineering to Overcome Absorption Barriers for Oral Peptide Delivery: Dosage Form Optimization Case Study Preceding Clinical Translation

Figure 4. Plasma concentration–time profiles of individual animals dosed with Formulation 5. Formulation 5 = 1 ng/mL is shown as a red dashed line. All values below LLOQ were plotted as ½ LLOQ for illustration purposes.

Abstract

Oral delivery of peptides and biological molecules promises significant benefits to patients as an alternative to daily injections, but the development of these formulations is challenging due to their low bioavailability and high pharmacokinetic variability. Our earlier work focused on the discovery of MEDI7219, a stabilized, lipidated, glucagon-like peptide 1 agonist peptide, and the selection of sodium chenodeoxycholate (Na CDC) and propyl gallate (PG) as permeation enhancer combinations. We hereby describe the development of the MEDI7219 tablet formulations and composition optimization via in vivo studies in dogs. We designed the MEDI7219 immediate-release tablets with the permeation enhancers Na CDC and PG. Immediate-release tablets were coated with an enteric coating that dissolves at pH ≥ 5.5 to target the upper duodenal region of the gastrointestinal tract and sustained-release tablets with a Carbopol bioadhesive polymer were coated with an enteric coating that dissolves at pH ≥ 7.0 to provide a longer presence at the absorption site in the gastrointestinal tract. In addition to immediate- and enteric-coated formulations, we also tested a proprietary delayed release erodible barrier layer tablet (OralogiK^TM) to deliver the payload to the target site in the gastrointestinal tract. The design of tablet dosage forms based on the optimization of formulations resulted in up to 10.1% absolute oral bioavailability in dogs with variability as low as 26% for MEDI7219, paving the way for its clinical development.

Introduction

Oral delivery of proteins and peptides has been gaining predominance since the 1970s, when it was observed in the clinic that intact macromolecules can be absorbed from the gastrointestinal (GI) tract. Despite the challenges posed by the barrier mechanisms within the GI tract, oral delivery of macromolecules can provide many benefits to patients over injections [1]. Efforts have continued over the years in both academia and industry to achieve absorption of large molecules in therapeutically meaningful doses orally that could potentially change the standard of care. To date, most approaches to the oral delivery of protein therapeutics have relied on the protection of the peptide and protein molecules from enzymatic degradation in the GI tract. Extensive structural alterations have been made to these macromolecules in general, and to peptides in particular, to obtain valuable information on their degradation in vivo [2].
In general, orally delivered peptides and proteins are absorbed via paracellular and transcellular routes. During paracellular transport, the opening of the tight junctions facilitates the entry of proteins and peptides. This route has been widely studied due to the availability of chemical permeation enhancers, many of which have reached the clinic for peptides such as calcitonin [3] and octreotide [4]. During transcellular transport, the molecule diffuses through lipid membranes or uses carrier- or receptor-mediated transport mechanisms. The transcellular route is of less interest than the paracellular route, owing to the considerable effort that is required to explore formulation development for this route [5]. Furthermore, transcellular transport is not expected to be the main contributor to improve delivery of hydrophilic drugs such as peptides [6].

Various permeation enhancer dependent oral peptide delivery formulations have reached the clinic, out of which insulin and glucagon-like peptide 1 (GLP-1) are predominant (Table 1). Other peptides that have advanced to the clinic in an oral presentation include parathyroid hormone, calcitonin, and octreotide.

Table 1. Clinically advanced technologies for oral peptide delivery using permeation enhancers. Source: PharmaCircle. Interested readers are encouraged to refer to the National Library of Medicine’s clinical trials database (ClinicalTrials.gov) for the most recent updates. Abbreviations: FDA, U.S. Food and Drug Administration; GIPET, gastrointestinal permeation enhancement technology; GLP-1, glucagon-like peptide 1; POD, peptide oral delivery.

Here we describe the comprehensive optimization of the oral tablet formulations of a glucagon-like peptide 1 (GLP-1) receptor agonist a molecule, MEDI7219, (Figure 1) using various controlled-release technologies to enable absorption at the site of interest. In an earlier publication, we described our work on the early preclinical development of oral MEDI7219 [12]. GLP-1 RAs provide clinically viable reductions in elevated blood sugar, glycated hemoglobin, body weight, blood pressure, and cardiovascular risk in patients with type 2 diabetes and obesity [13]. MEDI7219 was stabilized against gastrointestinal peptidases and proteases by the introduction of unnatural amino acids at protease degradation hotspots. Further, side-chain lipidation was added to MEDI7219 to increase its half-life via an albumin reversible binding mechanism. MEDI7219 has been tested in in vitro and in vivo studies for receptor binding and pharmacodynamic effects in rodent models. The MEDI7219 stabilized lipidated peptide has good solubility and great proteolytic stability. Furthermore, potency in cell cultures and in rodent obesity and diabetes models was comparable to semaglutide [12]. To increase systemic bioavailability upon oral administration, we have identified Na CDC and a combination of Na CDC and PG permeation enhancers in Caco-2 screens and confirmed their effect in vivo after intraduodenal administration in rats. In vivo administration of a non-optimized tablet formulation of this combination in dogs resulted in bioavailability of approximately 4%, as well as decreased blood glucose excursion and reduced food consumption in an HF/HF dog model [12].

Figure 1. Chemical structure of MEDI7219. For details about the chemical structure, please see [12].

We conducted in vivo studies to achieve the additional optimization of MEDI7219 tablets in beagle dogs. The aim of these studies was to maximize MEDI7219 exposure while minimizing pharmacokinetic variability and to use minimal amounts of peptide and permeation enhancers while still achieving pharmacologically relevant MEDI7219 exposure. Based on the results of our prior site-of-absorption studies [12], we designed tablet formulations to deliver the peptide to the optimal absorption site by using a pH-specific enteric coating and immediate-release and time delayed-release formulations. Our results demonstrate the optimization of peptide content and the ratio of permeation enhancers in the tablet to maximize bioavailability and minimize the use of permeation enhancers in each tablet. To the best of our knowledge, this is a first-of-its-kind study of this magnitude that compared three distinctive release profiles of a target peptide at different sites of absorption.

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Materials

MEDI7219 was manufactured by Bachem (Bubendorf, Switzerland). The permeation enhancers Na CDC and PG were purchased from Sigma-Aldrich (St. Louis, MO, USA). Eudragit polymers and PlasACRYL HTP 20 were purchased from Evonik (Allentown, PA, USA). Mucoadhesive polymer Carbopol 71G was purchased from Lubrizol (Wickliffe, OH, USA). HPMC Hypromellose K4M and Acryl-eze 93A were purchased from Colorcon (Harleysville, PA, USA). Glyceryl behenate was purchased from Gattefossé (Eschbach, Germany). Hydrogenated castor oil was purchased from BASF (Ludwigshafen, Germany). Low-substituted hydroxypropyl cellulose (LH-21 and LH-32) was purchased from Shin-Etsu (Tokyo, Japan). Simethicone was purchased from Basildon (Abingdon, UK). All other ingredients were purchased from Sigma-Aldrich. The OralogiK time-delayed tablets were designed and manufactured by BDD Pharma (Scotland, UK).

Tyagi, P.; Patel, C.; Gibson, K.; MacDougall, F.; Pechenov, S.Y.; Will, S.; Revell, J.; Huang, Y.; Rosenbaum, A.I.; Balic, K.; et al. Systems Biology and Peptide Engineering to Overcome Absorption Barriers for Oral Peptide Delivery: Dosage Form Optimization Case Study Preceding Clinical Translation. Pharmaceutics 2023, 15, 2436. https://doi.org/10.3390/pharmaceutics15102436

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