Peptide drugs have demonstrated revolutionary potential in metabolic diseases, oncology, and neurological disorders due to their high specificity, potent efficacy, and favorable safety profile. However, their oral bioavailability is generally below 1%, which has become the most significant bottleneck limiting their clinical application. This article explores the core challenges faced by oral peptides and outlines strategies for overcoming these challenges through formulation approaches, supported by literature reviews and case analyses.

I. Core Challenges in Oral Peptide Therapy

1. Enzymatic barrier:

The gastrointestinal tract is essentially an efficient protein hydrolysis "reactor." The oral degradation of peptides is not the action of a single enzyme but rather a serial, complementary cascade reaction process: under the strongly acidic gastric environment (pH 1.5-3.0), pepsin preferentially hydrolyzes peptide bonds between hydrophobic/aromatic amino acids. Upon entering the near-neutral small intestinal environment, trypsin, chymotrypsin, and elastase secreted by the pancreas form the core attack network. Additionally, carboxypeptidases A and B perform exocutaneous degradation from the C-terminus. As the peptide approaches the absorption site, aminopeptidase N (AP-N) and dipeptidyl peptidase IV (DPP-IV) on the brush border of intestinal epithelial cells degrade the peptide. Many therapeutic peptides (e.g., GLP-1 analogs) are natural substrates of DPP-IV. A minority of peptides that enter cells via transmembrane action are further degraded by proteases such as histone proteases in endosomes/lysosomes. In the jejunum, intraluminal degradation contributes less than 3% of total degradation, while brush border and intracellular degradation dominate (over 95%). This explains why simple use of enteric-coated formulations to bypass gastric acid still fails to achieve effective oral delivery.

2. Physical and Transport Barriers:

The gastrointestinal epithelium is covered by a layer of viscoelastic mucus, whose main component, mucin, carries a negative charge and traps positively charged polypeptides within the mucus network until they are renewed by mucus or cleared by enzymes. Intestinal epithelial cells form a tight physical barrier through tight junctions, allowing only small molecules (<200-300 Da) to pass through, while polypeptides with molecular weights ranging from hundreds to thousands of daltons are unable to squeeze through the intercellular spaces. Transcellular transport is further hindered by the strong hydrophilicity of polypeptides and the lack of effective transporters. Even small amounts of polypeptides that enter the cells may be "pumped" back into the intestinal lumen by efflux transporters such as P-glycoprotein (P-gp). Polypeptides that successfully enter the bloodstream must undergo first-pass metabolism in the liver and are further metabolized and degraded.

3. Conflict between Molecular Properties and the "Five Rules of Drug-like Molecules"

The physicochemical properties of peptides are at odds with the ideal requirements for oral absorption. They typically violate Lipinski's Rule of Five: molecular weight>500 Da, hydrogen bond donors>5, hydrogen bond acceptors>10, and low LogP values. These characteristics result in poor membrane permeability, a tendency to form intermolecular hydrogen bond aggregates, and make them ideal substrates for various digestive enzymes.

II. Formulation Delivery Strategies and Case Analysis

Strategy 1: Self-nanoemulsified Drug Delivery System (SNEDDS)

SNEDDS is an isotropic mixture composed of oil phase, surfactant, and cosurfactant, which spontaneously forms oil/water nanodroplets with particle sizes less than 300 nm (ideally <100 nm) under gastrointestinal peristalsis. It can solubilize peptides in the oil phase or interfacial membrane, significantly enhancing their apparent solubility. Additionally, the large specific surface area provided by the nanoscale size reduces the distance for drug diffusion to the absorption membrane. The formed oil-phase microenvironment physically isolates proteases in the aqueous phase, and surfactant molecules can sometimes non-specifically interfere with enzyme active sites. Long-chain triglycerides promote chylomicron formation, guiding drug absorption through the mesenteric lymphatic system and bypassing the first-pass effect of the liver. Certain surfactants (e.g., Labrasol®) can modulate the phosphorylation state of tight junction proteins (such as Occludin), reversibly increasing the pore size of cell junctions. Some nonionic surfactants have been reported to inhibit P-gp.

Case Analysis: Cyclosporine A Microemulsion (Neoral®)

Although cyclosporine A is a hydrophobic cyclic peptide, the successful commercialization of Neoral® represents a milestone in the SNEDDS technology platform. It utilizes a medium-chain triglyceride and hydrogenated castor oil derivative (Cremophor® EL) system to form droplets approximately 100 nm in size, enhancing the oral bioavailability of cyclosporine A from about 30% in conventional formulations to over 40%, with significantly reduced interindividual variability. This demonstrates the strong potential of lipid nanosystems in improving the oral performance of macromolecular, poorly absorbed drugs, paving the way for subsequent SNEDDS development of hydrophilic peptides.

Strategy 2: Hydrophobic Interaction Pairs (HIP)

The core mechanism of HIP involves the electrostatic interaction between charged hydrophilic peptides and counter-ions with opposite charges, forming ion-pair complexes with enhanced lipophilicity. On one hand, the counter-ions neutralize the surface charges of the peptides and introduce their own hydrophobic chains (e.g., alkyl chains, steroid frameworks), significantly increasing the apparent partition coefficient (LogP) of the complex, thereby enabling efficient distribution into the oil phase of SNEDDS. On the other hand, the enzyme active site often relies on interactions with specific substrate charges. After charge masking, the sensitivity of the peptides to certain enzymes (e.g., trypsin) decreases.

Case Analysis: Octreotide-Sodium Deoxycholic Acid Ion Pair for SEDDS

The study formed a HIP complex by combining the somatostatin analog octreotide with sodium deoxycholate in a molar ratio of 1:3, followed by loading it into SEDDS. In pharmacokinetic experiments in pigs, the oral bioavailability of this formulation reached 2.1%, which was 17.9 times that of the free octreotide solution. More importantly, the HIP complex remained stable during formulation and storage, and rapidly dissociated in the receiving medium at physiological pH, releasing octreotide with intact biological activity. This perfectly exemplifies the HIP design concept of "in vitro stability, in vivo release."

Strategy 3: 3D Printing Pharmaceutical Technology

3D printing, particularly fused deposition modeling (FDM) and stereolithography (SLA), enables digital programming control of the geometric structure, composition, and release kinetics of pharmaceutical formulations through precise layer-by-layer material stacking. Multilayer tablets can be printed with an outer layer of enteric-coated polymer and an inner layer containing a drug-loaded matrix for rapid or sustained release, achieving colon-targeted or timed pulse release. By adjusting the filling density and pattern, the drug's surface area and diffusion pathway can be precisely controlled to customize the release profile. Different spatial regions within a single dosage form can be loaded with peptide drugs, penetration enhancers, or enzyme inhibitors. Sequential release can be achieved by designing the dissolution rates of each region: first releasing the excipient to facilitate drug absorption, followed by the drug itself. The drug content in the printed model can be directly adjusted via software to enable dose individualization, which is particularly crucial for peptide drugs with narrow therapeutic windows.

Case Analysis: Dual-Release Capsules for Synergistic Delivery of Peptides and Osmolality Promoters

Xu et al. designed and printed a dual-chamber capsule. Chamber A loaded the model peptide, encapsulated by a thicker sustained-release polymer wall; Chamber B loaded the permeation enhancer C10, encapsulated by a thinner rapid-release polymer wall. After oral administration, Chamber B rapidly dissolved, allowing C10 to be released first and act on the local intestinal epithelium, temporarily and reversibly opening tight junctions. Subsequently, Chamber A slowly dissolved to release the peptide, at which point intestinal barrier permeability had increased, significantly enhancing the transmembrane absorption of the peptide. This spatiotemporal programmed synergy is unachievable with traditional formulation processes.

III. Future Outlook:

Oral peptide delivery represents a complex systems engineering process spanning molecular, cellular, tissue, and even organ levels. Future advanced formulations may integrate the "HIP-SNEDDS-3D printing" triad: first, peptides are lipophilized via HIP technology; then, they are efficiently loaded into SNEDDS; finally, optimized SNEDDS formulations are integrated with controlled-release structures using 3D printing technology to produce intelligent dosage forms with gastric retention, intestinal targeting, or pulse-release capabilities. 3D-printed microfluidic chips can enable continuous, high-throughput, and homogeneous production of SNEDDS or nano-lipid carriers, addressing the stability and scalability challenges of traditional batch processes. Despite its promising prospects, practical challenges such as cost and compliance in large-scale production, safety evaluation of novel lipid/polymer excipients, and significant interindividual gastrointestinal physiological variations must be addressed. This requires close collaboration among pharmaceutists, materials scientists, clinicians, and regulatory agencies. References:

1.B. Öngoren,A Kara,D.R. Serrano,Novel enabling strategies for oral peptide delivery,International Journal of Pharmaceutics,Volume 681,2025.

2.Baral, K.C., Choi, K.Y., 2025. Barriers and strategies for oral peptide and protein therapeutics delivery: update on clinical advances. Pharmaceutics 17, 397.

3.Bonengel, S., Jelkmann, M., Abdulkarim, M.,Impact of different hydrophobic ion pairs of octreotide on its oral bioavailability in pigs. J. Control. Release 273, 21–29.2018

4.Xu, P., Nguyen, H., Huang, S., Tran, H.Development of 3Dprinted twocompartment capsular devices for pulsatile release of peptide and permeation enhancerPharmaceutical ResearchVol. 41, pp. 2259–2270，2024

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