Cracking the Oral Peptide Code

Once limited by poor bioavailability and enzymatic degradation, oral peptides are now on the cusp of becoming the next blockbuster class, reveal Hong Li and Lixia Zhang from BioDuro.

Peptide therapeutics are proving to be a promising prospect in the modern biopharmaceutical landscape. Combining targeted potency and biocompatibility with lower manufacturing costs, peptide therapeutics have the potential to reach blockbuster status. 

However, transitioning peptides from subcutaneous injections to more convenient oral solid dosage forms is challenging as a result of biochemical obstacles from the gastrointestinal (GI) tract, complex manufacturing sensitivities, and tricky analytical matrix interferences. To explore how formulation and analytical teams are overcoming these hurdles, The Pharma Navigator sat down with Hong Li, Head of Formulation, and Lixia Zhang, Director of Analytical Service, CMC, both from BioDuro.

Potentially Useful Strategies

TPN: Peptide therapeutics have the potential to become blockbusters on a scale that was previously seen within the monoclonal antibody space thanks to their effectiveness and biocompatibility. However, peptides also present development challenges, particularly for oral delivery, as they are susceptible to hydrolysis and enzymatic degradation and have poor bioavailability. What potential strategies are available to overcome these obstacles to formulating a broader range of oral peptide therapies?

Li: Peptides readily undergo hydrolysis and get broken down by digestive enzymes, while weak intestinal permeability further complicates oral absorption. Hydrophilic peptides barely cross epithelial membranes. Clinically proven permeation enhancer sodium caprate temporarily loosens tight junctions and disrupts membrane lipids; SNAC [sodium N-(8-[2-hydroxybenzoyl] amino) caprylate] improves transcellular peptide transport via local‑pH‑modulation and peptide monomerization, to boost paracellular and transcellular peptide transport.

Co-administered protease inhibitors have been explored for oral peptides, yet clinical adoption remains limited by safety and formulation-synchronization issues; current strategies instead favor physical shielding via lipid carriers or high-concentration permeation enhancers.

Enteric coatings paired with pH-modulating excipients shield peptides from gastric acid and deliver drugs to less enzymatically active, more permeable intestinal segments. 

Lipid carriers such as SNEDDS [self-nanoemulsifying drug delivery systems] provide substantial, though not absolute, GI protection against enzymatic degradation. In some cases, they also facilitate lymphatic absorption to mitigate hepatic first-pass metabolism. For poorly soluble hydrophobic peptides, solubilization approaches — salt screening, pH adjustment, surfactants, amorphous dispersions, and nanomilling — elevate dissolution and sustain supersaturation for oral and injectable products.

Single technologies cannot address all delivery defects. Rational combinations of permeation enhancers, enzyme inhibitors, enteric layers and lipid vehicles are required. Fine-tuned excipient matching maximizes bioavailability while minimizing intestinal mucosal irritation.

Optimized Synchronization

TPN: Focusing on permeation enhancers for a moment, these need to dissolve in a coordinated way along with the peptide in order to work. How can developers optimize a matrix to achieve such synchronicity?

Li: To achieve synchronized dissolution of peptides and permeation enhancers (PEs), formulators construct tailored matrix systems to eliminate release lag via four validated approaches supported by pharmaceutical studies. 

Copovidone-based co-amorphous ternary solid dispersions form uniformly hydrating gel matrices that offset two-fold intrinsic dissolution disparities between hydrophilic peptides and lipophilic PEs like SNAC, enabling complete synchronous payload release within 10–25 minutes. 

Lipid SNEDDS nanoformulations co-encapsulate peptides and fatty-acid PEs through hydrophobic ion pairing; upon intestinal fluid dilution, nanodroplets co-deliver both actives under controlled HLB [hydrophilic–lipophilic balance] values, while lymphatic absorption further elevates oral bioavailability. 

Thiolated chitosan mucoadhesive matrices form slowly eroding scaffolds cross-linked to intestinal mucus via disulfide bonds, extending simultaneous exposure of peptides and PEs and mitigating mucosal irritation induced by concentrated enhancers. 

HPMC-AS [hydroxypropyl methylcellulose acetate succinate] pH-triggered enteric composites with internal buffers disintegrate fully only under neutral small‑intestinal pH to avoid premature gastric phase separation and achieve matched peptide‑PE co‑release in the distal gut.

Optimized synchronization requires rational screening of polymers, lipid blends and pH regulators based on peptide physicochemical traits; integrated matrix architecture, rather than simple physical powder blending, has become the mainstream development paradigm for oral peptide delivery.

Low-Stress Manufacturing

TPN: Developers aren’t only faced with formulation challenges with oral peptides, as the molecules’ fragilities aren’t compatible with traditional OSD unit operations. Therefore, what process adaptations or alternative manufacturing pathways, such as continuous direct compression or specialized fluid bed processing, are required to handle peptides?

Li: Peptides suffer conformational degradation from moisture, heat, and high shear in traditional oral solid dosage manufacturing, requiring redesigned low-stress processes. 

Direct compression avoids wet granulation’s aqueous and thermal risks; MCC/PVP blends have demonstrated capacity to preserve the stability of certain model peptides (e.g., insulin) under 100–200 MPa compaction in academic studies, though commercial application to longer‑chain peptides remains challenging and requires careful excipient selection. Mild fluid-bed layering coats multi-particulates sequentially with peptides, permeation enhancers, and polymers for controllable release kinetics. Continuous direct compression drastically cuts material residence time to reduce oxidation and hydrolysis. Lipid SEDDS solubilize peptides in lipid excipients through hydrophobic ion pairing, protecting molecules from gut enzymes, while long‑chain lipid‑based formulations further enhance lymphatic absorption. Custom processable permeation enhancers and specialty excipients ease raw-material processing hurdles. 

Overall, an integrated adaptive CMC [chemistry, manufacturing, and controls] framework aligns formulation, manufacturing, and clinical trials, enabling real-time formulation and process adjustments to accelerate oral peptide translational development.

Unique Analytical Challenges

TPN: Additionally, analytical testing for oral solid peptides is complex because degradation products can be subtle and easily masked by dense excipient matrices or PEs. How are analytical and stability testing workflows evolving to ensure precise quantitation during real-time release testing and long-term stability studies?

Zhang: That’s an excellent question. Analyzing oral solid peptide formulations poses unique analytical challenges: high concentrations of excipients and PEs tend to mask trace peptide degradation impurities. Today, analytical workflows are advancing significantly to deliver precise quantitative data that supports both real-time release testing and long-term stability programs.

Novel chromatography columns specially developed for peptide analysis enable efficient separation of impurities, guaranteeing robust method performance throughout the entire testing workflow and delivering consistent, reliable support for routine sample analysis.

Meanwhile, ‌UHPLC-HRAM MS (e.g., Orbitrap/Q-TOF)‌ is widely adopted to achieve baseline separation and structural confirmation of trace degradants (oxidation, deamidation, isomers) in complex matrices, with ppm-level sensitivity that effectively eliminates false negatives common in conventional UV detection.

Complementing this, ‌multi-dimensional chromatography (2D-LC) or HILIC-RP orthogonal separation modes‌ are introduced to drastically improve the resolution against interference from hydrophobic PE excipients.

Furthermore, comprehensive forced degradation studies are implemented at the method development stage to establish a true ‘stability-indicating’ method, ensuring better separation between all degradation peaks and excipient peaks — fully aligned with ICH Q2(R2) regulatory expectations.

Balancing Production and Performance

TPN: Looking ahead, converting a highly predictable, 100% bioavailable injectable peptide into a robust OSD form remains challenging. As the industry advances, should our primary benchmark for success be pushing the envelope to achieve higher absolute bioavailability, or should we accept low bioavailability and focus on engineering technologies that minimize patient variability instead?

Li: Oral peptide development forces a fundamental choice: push for higher bioavailability or focus on narrowing the gap between patients. High bioavailability is attractive — it improves pharmacological predictability and saves on expensive API — but the gut’s proteolytic and permeation barriers are formidable, even with SNAC or lipid vehicles. Pushing relentlessly for higher uptake only drives up formulation complexity, raises risks of gut mucosal irritation and inflates production costs.

Oral semaglutide (Rybelsus) serves as strong counterevidence: it delivers proven clinical and commercial value with roughly 1% bioavailability, showing steady therapeutic effect matters more than absorption magnitude. Regulators at the FDA and EMA have repeatedly highlighted that high inter‑patient variability in systemic exposure represents a greater developmental hurdle than moderately‑low average bioavailability.

Most industry teams therefore focus first on narrowing absorption variability. Tools including synchronized-release matrices, pH-specific enteric coatings, low-shear continuous production and standardized fasting dosing rules stabilize circulating drug levels for reliable patient outcomes. A realistic development workflow sets a minimal acceptable bioavailability floor, then refines formulations primarily to smooth out variable absorption, striking a workable balance between production feasibility and clinical performance.

About the Interviewees

Hong Li is Head of Formulation at BioDuro, bringing more than 20 years of experience across the full drug development lifecycle — from preformulation and feasibility through formulation and process development, clinical manufacturing, lifecycle management, and commercial production supporting global regulatory filings. She specializes in bioavailability enhancement solutions for complex small molecules and oral peptides.

Throughout her career, Hong has led teams delivering more than 100 innovator and generic drug development projects, translating scientific expertise into robust, regulatory-ready solutions.

Lixia Zhang is the Director of Analytical Service, CMC at BioDuro, bringing 20 years of pharmaceutical industry experience in analytical method development and validation, quality and stability studies, and specification establishment across early- to late-phase development programs. She has contributed to more than 10 NDA application projects and has in-depth knowledge of global pharmacopoeias and regulatory guidelines, including ICH, ChP, USP, EP, JP, NMPA, FDA, and EMA requirements.

Prior to joining BioDuro in July 2026, Lixia served as Associate Director at Shanghai SynTheAll Pharmaceutical Co., Ltd. She holds a Master’s degree in Organic Chemistry from Lanzhou University.

Image Credit: © Jackie Niam - stock.adobe.com