Gastrointestinal Permeation Enhancers Beyond Sodium Caprate and SNAC – What is Coming Next?

Oral peptide delivery is trending again. Among the possible reasons are the recent approvals of two oral peptide formulations, which represent a huge stride in the field. For the first time, gastrointestinal (GI) permeation enhancers (PEs) are leveraged to overcome the main limitation of oral peptide delivery—low permeability through the intestinal epithelium. Despite some success, the application of current PEs, such as salcaprozate sodium (SNAC), sodium caprylate (C8), and sodium caprate (C10), is generally resulting in relatively low oral bioavailabilities (BAs)—even for carefully selected therapeutics. With several hundred peptide-based drugs presently in the pipeline, there is a huge unmet need for more effective PEs. Aiming to provide useful insights for the development of novel PEs, this review summarizes the biological hurdles to oral peptide delivery with special emphasis on the epithelial barrier. It describes the concepts and action modes of PEs and mentions possible new targets. It further states the benchmark that is set by current PEs, while critically assessing and evaluating emerging PEs regarding translatability, safety, and efficacy. Additionally, examples of novel PEs under preclinical and clinical evaluation and future directions are discussed.

Introduction

The recent commercialization of two oral peptide formulations could be seen as a breakthrough in oral peptide delivery. In 2019, the Food and Drug Administration (FDA) approved the oral dosage form of semaglutide (Rybelsus) developed by Novo Nordisk for the treatment of type 2 diabetes[1] followed by the octreotide capsule (Mycapssa), developed through Chiasma’s Transient Permeation Enhancer (TPE) technology for the treatment of acromegaly in 2020.[2] These two oral peptide products represent a milestone in the field because formulations allowing the successful oral delivery of macromolecular peptide drugs have been desired for decades.

Peptide-based drugs offer tremendous therapeutic potential for a broad variety of ailments, including cancer, metabolic, and cardiovascular diseases.[3] To date, there are already over 80 peptide drugs approved, >150 compounds in clinical development, and over 600 in preclinical studies. However, most peptide-based therapeutics have one major drawback: they must be administered via injection, either intravenously (i.v.), subcutaneously (s.c.), or intramuscularly (i.m.).[4] While oral administration is the most convenient, patient-friendly, and easiest mode of drug delivery (Table 1), it is most of the time characterized by low peptide BA and subtherapeutic concentrations.[5]

Table 1. Benefits of oral peptide delivery over conventional parenteral administration.

• Ease of use: it does not require any expertise, special equipment, or trained medical personal.
• Convenience and patient acceptance favor adherence and compliance, especially for treatments that are used chronically and require frequent dosing.
• Avoidance of certain side effects such as pain and discomfort, scarring, (allergic) reactions at the injection site, and cutaneous infections associated with injections.
• Reduction of healthcare expenditures by removing the need for complex auto-injectors or healthcare professionals to deliver parental formulations.
• Reformulation into an oral formulation can expand the commercial life cycle for marketed injectable peptide-based drugs and can generate large market sales.
• No need for sterilization (might not apply for microneedle-based formulations), potentially offsetting higher costs associated with large quantities of peptide needed.
• Oral peptide formulations can be used for new therapeutic indications previously not considered due to the frequency of administration and/or psychological injection barrier (fear of needles).

Upon oral administration, the absorption of most peptide drugs is strongly limited by GI barriers formed by digestion, mucus, and the epithelium. Huge efforts have been made to overcome these hurdles and ultimately increase oral BAs.[6, 7] A plethora of technologies using physical modes such as direct injection, jetting, ultrasounds, and iontophoresis have been investigated to overcome the intestinal epithelial barrier. Numerous recent reviews provide a comprehensive overview of this field.[8-14] While some physical approaches revealed promising preclinical and clinical results regarding the enhancement of oral BAs of peptide therapeutics, the translatability remains, at this stage, questionable due to complexity, issues with reliability, uncertain regulatory pathways, and potential safety concerns.

To date, the most extensively investigated and most successful approach remains the use of PEs to increase the permeability of the epithelial barrier.

PEs are an inhomogeneous class of substances ranging from small molecules to biologics that transiently alter the GI epithelial barrier to facilitate permeation of macromolecules.[15] Rybelsus and Mycapssa are formulated with the PEs sodium salcaprozate (SNAC) as a tablet and sodium caprylate (C8) as a lipidic capsule, respectively. They are, so far, the only marketed oral peptide-based drugs relying on a PE-based absorption process.[1, 2] Even though PEs have been intensively studied and many have been shown to efficiently increase GI permeability in pre-clinical settings, only a few have progressed to clinical trials. Of those, modest, single-digit (mostly around 1–5%, highest 9%) increases in oral BAs of peptides with high variability have been achieved.[15, 16] While average BA values of ca. 1% were sufficient for semaglutide and octreotide, for other peptides this might be too low, calling for the development of more potent PEs.[17, 18] Next-generation PEs must be compatible with a wide range of macromolecular drugs, should ideally approach oral BAs in the double-digit range (10%), be safe with a transient mode of action, and, in a perfect scenario, deliver precise and reproducible peptide doses. If successful, these advances would completely break open the field of oral peptide delivery.[6, 7]

Here, we describe the biological barriers to oral peptide delivery with a special focus on the epithelium, summarize peptide characteristics that favor oral administration, comprehensively discuss possible modes of PE action, and highlight new targets. Finally, achievements and limitations of current PEs are outlined and approaches under preclinical or clinical investigation are critically assessed and evaluated in regard to translatability, safety, and efficacy. Overall, this review aims to provide a critical yet focused perspective on the field of intestinal PEs, commenting on translatability, outlying general controversies, highlighting recent advantages, and ultimately suggesting further directions.

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6.2. Transcellular PEs

Similarly, only a few new transcellular PEs emerged in the lastyears. Of those, none exhibited superiority over C10 (Table 4).Sucrose laurate (SL), a food additive, was found to hamper mem-brane integrity leading to TJ opening. The concentrations thatenhanced flux in Caco-2 cells also caused cytotoxicity. 1 mm SLreduced TEER < 20% within 20 min incubation and increased14 C-mannitol permeability by 10-fold. In rat intrajejunal instilla-tions, 50 and 100 mm SL co-administered with insulin achieveda relative to s.c. BA of 1.3% and 2.5%, respectively. In the sameexperimental setup, 50 and 100 mm C10 achieved 4.4% and 3.3%relative to s.c. BA, respectively. [164] The authors concluded that SLcan therefore be added to the list of potential PEs but no furtherinvestigations have been reported since.

Another well-known excipient that gained attention as a PE isLabrasol which constitutes a mixture of mono-, di- and triglyc-erides and mono- and di-fatty acid esters of PEG-8 and free PEG-8, with caprylic (C8)- and capric acid (C10) as the main fattyacids. Originally, Labrasol was investigated as a compound of self-microemulsifying drug delivery systems (SMEDDS) to im-prove oral BA of lipophilic drugs. SMEDDS are isotropic mix-tures of drugs with oil, surfactant, and co-surfactant which canform oil-in-water (o/w) microemulsions. It was hypothesizedthat SMEDDS act by altering membrane permeability and openTJs. In vitro studies confirmed the redistribution of ZO-1 andactin upon 2 h exposure to SMEEDDS containing Maisine 35-1, Kolliphor EL, Labrasol, and Transcutol (diethylene glycol mo-noethyl ether). [181] In another study, an aqueous solution con-taining 1% of Labrasol reduced TEER to 40% within 30 minand increased mannitol flux by 30-fold.[181] In rat intrajejunal in-stillations, 40 mg mL−1 Labrasol co-administered with insulinachieved a relative to s.c. BA of 6.7%. [165] Labrasol was also testedwith MK-0616 in a Phase 1 clinical trial (10 to 300 mg of MK-0616 formulated with 1800 mg Labrasol). Despite C10 (200 mgMK-0616 and 360 mg C10) and Labrasol (200 mg MK-0616 and1800 mg Labrasol) showing comparable permeation enhance-ment effects that increased overall drug exposure by 2- to 3-fold,the development progressed with C10. [127,128]

AMT-101 and AMT-126 developed by Applied MolecularTransport, operating as Cyclo Therapeutics, Inc. as of 21 st September 2023 (San Francisco, USA), are formulations lever-aging toxin-inspired, peptide-based transcellular PEs. Both arebased on a recombinant biologic fusion protein of humaninterleukin-1 and interleukin-22, respectively, and a toxin-basedcarrier protein that mediates transcytosis through intestinal en-terocytes. Despite oral IL-10 (ATM-101) successfully conclud-ing a Phase 2 trial for the treatment of chronic pouchitis and AMT-126 having completed a Phase 1 trial, the development seems to be discontinued. [182,183] The PE mechanism is basedon a non-toxic form of cholix. Cholix is an exotoxin secreted by Vibrio cholerae which can traverse the epithelium via vesicu-lar transcytosis. [182,184] However, the aim of those formulations differs significantly from conventional oral delivery approaches. The overarching goal is to overcome the challenge of local ad-ministration of interleukins to the region below the intestinalepithelium (lamina propria) without significant systemic expo-sure. Therefore, the amount that is required to cross the in-testinal epithelium and achieve local effects is lower than what would be needed to achieve therapeutic systemic effects. Applied Molecular Transport seems, however, to have ceased its drug delivery activities following the recent merger with another company. [185]

An approach aiming for systemic peptide delivery which is currently tested in clinical trials is the Peptelligence technology of Enteris Biopharma (Boonton, USA). It is based on a multi-modal mode of action comprising an enteric coating, a sub-coatthat allows simultaneous excipient release, citric acid granules,and in some cases surfactant-type PEs (an acylcarnitine or bilesalt). Acylcarnitines and bile salts are amphiphilic, surfactant-type transcellular PEs that alter the cell membrane and can alsoaffect TJ proteins such as ZO-1 and claudins-1, -3, and -5.[158] Al-ready in 2013, it was tested in a clinical trial to deliver recombi-nant human parathyroid hormone [rhPTH(1-31)NH2] orally butwas inferior to the s.c. drug and was not further developed. [167] Another attempt in 2015 with oral salmon calcitonin (formerly known as TBRIA) was successful and met clinical endpoints ina Phase 3 study (ORCAL trial). [186] However, TBRIA was neverapproved possibly due to the lack of efficacy of the drug in pre-venting fractures,[187] and a coincidental warning from the FDA regarding the use of nasal salmon calcitonin. [188] To date, the Peptelligence technology is also part of clinical trials with leupro-lide and difelikefalin. Enteris Biopharma is developing oral le-uprolide (Ovarest) and Cara Therapeutics (Stamford, USA) oral difelikefalin (Korsuva).[28]

Source: Marilena Bohley, Jean-Christophe Leroux, Gastrointestinal Permeation Enhancers Beyond Sodium Caprate and SNAC – What is Coming Next?, First published: 17 June 2024 https://doi.org/10.1002/advs.202400843

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Read also our introduction article on Mannitol here: