Oral Absorption of Middle-to-Large Molecules and Its Improvement, with a Focus on New Modality Drugs

Abstract

To meet unmet medical needs, middle-to-large molecules, including peptides and oligonucleotides, have emerged as new therapeutic modalities. Owing to their middle-to-large molecular sizes, middle-to-large molecules are not suitable for oral absorption, but there are high expectations around orally bioavailable macromolecular drugs, since oral administration is the most convenient dosing route. Therefore, extensive efforts have been made to create bioavailable middle-to-large molecules or develop absorption enhancement technology, from which some successes have recently been reported. For example, Rybelsus^® tablets and Mycapssa^® capsules, both of which contain absorption enhancers, were approved as oral medications for type 2 diabetes and acromegaly, respectively. The oral administration of Rybelsus and Mycapssa exposes their pharmacologically active peptides with molecular weights greater than 1000, namely, semaglutide and octreotide, respectively, into systemic circulation. Although these two medications represent major achievements in the development of orally absorbable peptide formulations, the oral bioavailability of peptides after taking Rybelsus and Mycapssa is still only around 1%. In this article, we review the approaches and recent advances of orally bioavailable middle-to-large molecules and discuss challenges for improving their oral absorption.

Keywords: C10; C8; Lipinski’s rule of five; SNAC; absorption enhancer; antisense oligonucleotide; cyclic peptide; middle-to-large molecule; new modality; target protein degrader.

Figure 1

Chemical structure and physicochemical properties of octreotide. MW: molecular weight, HBD: number of hydrogen bond donors, HBA: number of hydrogen bond acceptors, TPSA: topological polar surface area, and cLogP: calculated octanol-water partition coefficient.

Figure 2

Chemical structure and physicochemical properties of cyclosporin. MW: molecular weight, HBD: number of hydrogen bond donors, HBA: number of hydrogen bond acceptors, TPSA: topological polar surface area, and cLogP: calculated octanol-water partition coefficient.

Figure 3

Schematic representation of the conformational basis of the membrane permeability of cyclic peptides (chameleonic property). Adapted with permission from [43]. Copyright (2006) American Chemical Society.

Figure 4

Chemical structures of C8 (A), C10 (B), and SNAC (C).

Figure 5

Chemical structures of cyclic peptide A ((A) MW: 1091) and its de-ethylated form ((B) MW: 1063). The above figure was cited from [121].

Figure 6

Pharmacokinetics of cyclic decapeptide A (MW: 1091) in mouse plasma after its oral administration at 1 mg/kg with or without ABT (P450 inhibitor) and/or GF (P-gp inhibitor). Plasma concentrations of cyclic decapeptide A were determined by LC-MS/MS and plotted. Each point represents the mean ± SD of three animals. (A) Normal plot; (B) semi-log plot. ABT and GF represent 1-aminobenzotriazole and GF120918, respectively. The above figure was cited from [121].

Figure 7

Metabolite identification of cyclic decapeptide A (MW: 1091) after incubation with hepatic and intestinal microsomes from mice. Ms represent microsomes. The above figure was cited from [121].

Figure 8

Synergic elimination of cyclic decapeptide A (MW: 1091) by P-gp and P450. The above figure was cited from [121].

Figure 9

Chemical structures of TPDs ((A) ARV-110 (MW: 812); (B) ARV-471 (MW: 724)).

Figure 10

Chemical structures of other representative middle-to-large molecules. (A) Rifampicin (MW: 823), (B) venetoclax (MW: 868), (C) erythromycin (MW: 734), and (D) simeprevir (MW: 750).

Figure 11

Chemical structure of daptomycin (MW: 1621).

Figure 12

Pharmacokinetics of daptomycin (MW: 1621) in male rat plasma after its oral administration at 10 mg/kg with or without SNAC at doses ranging from 10 to 1000 mg/kg. Plasma concentration of daptomycin was determined by LC-MS/MS and plotted. Each point represents the mean ± SD of three animals. (A) Normal plot; (B) semi-log plot. The above figure was cited from [148].

Figure 13

Time-dependent changes in the concentrations of daptomycin (MW: 1621) in monkey (A) and dog (B) plasma after its oral administration at 10 (A) and 5 (B) mg/kg with or without SNAC at 200 mg/kg. Plasma concentrations of daptomycin were determined by LC-MS/MS and plotted. Each point represents the mean of two animals. The above figure was cited from [121].

Figure 14

Chemical structures of octreotide ((A) MW: 1019), lanreotide ((B) MW: 1096), and pasireotide ((C) MW: 1047).

Figure 15

Time-dependent changes in the concentrations of octreotide ((A) MW: 1019), lanreotide ((B) MW: 1096), and pasireotide ((C) MW: 1047) in rat plasma after their oral administration at 5 mg/kg with or without SNAC at 200 mg/kg. Plasma concentrations of octreotide, lanreotide, and pasireotide were determined by LC-MS/MS and plotted. Each point represents the mean ± SD of three animals. The above figure was cited from [148].

Figure 16

Chemical structures of liraglutide ((A) MW: ca. 3800) and semaglutide ((B) MW: ca. 4100).