Breaking the Injection Barrier
For most of pharmaceutical history, peptide drugs meant one thing: needles. The delicate structure of peptides—easily destroyed by stomach acid and poorly absorbed through intestinal walls—seemed to make oral delivery impossible. That changed with the development of SNAC technology, culminating in the 2019 FDA approval of Rybelsus, the first oral GLP-1 receptor agonist.
The Challenge of Oral Peptide Delivery
Achieving therapeutic levels of orally administered peptides faces enormous obstacles:
Gastrointestinal Barriers
- Acid Degradation: Stomach pH (1.5-3.5) rapidly denatures most proteins and peptides
- Enzymatic Destruction: Pepsin and other proteases break peptide bonds
- Poor Permeability: The intestinal epithelium presents a formidable barrier to large molecules
- First-Pass Metabolism: Hepatic processing can eliminate peptides before they reach systemic circulation
These barriers explain why oral bioavailability of most peptides hovers near zero. Even with enhancement strategies, oral semaglutide achieves only about 1% bioavailability—yet this proves sufficient due to the peptide's remarkable potency.
What is SNAC?
SNAC (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate) is a small fatty acid derivative with a molecular weight of 279 daltons. Developed by Emisphere Technologies over more than 30 years, it represents the key enabling technology for oral semaglutide.
The approval of Rybelsus marked the culmination of this decades-long effort, proving that oral peptide delivery was not only possible but commercially viable.
How SNAC Works: A Multi-Mechanism Approach
SNAC enhances peptide absorption through several complementary mechanisms:
1. pH Buffering
As the tablet erodes in the stomach, SNAC creates a localized increase in pH around the peptide. This buffering action:
- Protects semaglutide from pepsin (which requires acidic pH)
- Reduces conversion of pepsinogen to active pepsin
- Creates a protective microenvironment for the peptide
2. Promoting Monomerization
GLP-1 peptides naturally form aggregates (oligomers) through hydrophobic interactions. SNAC disrupts these interactions by:
- Altering the polarity of the solution
- Weakening hydrophobic forces that cause aggregation
- Keeping semaglutide in its monomeric form, which absorbs more efficiently
3. Enhancing Membrane Permeability
SNAC increases transcellular permeability through:
- Increasing fluidity of cellular membranes
- Forming non-covalent complexes with the peptide
- Improving lipophilicity for better membrane diffusion
Importantly, research confirms that tight junctions are not involved in SNAC's mechanism—it works through transcellular transport rather than paracellular routes.
The Stomach as Absorption Site
One surprising discovery: unlike most oral medications absorbed in the small intestine, semaglutide with SNAC is absorbed primarily in the stomach.
Evidence for Gastric Absorption
- Scintigraphic Imaging: Studies show tablet erosion and absorption occurring in the stomach
- Pyloric Ligation Studies: Dogs with blocked pyloric sphincters showed similar semaglutide levels to normal dogs
- Pharmacokinetic Modeling: Data consistently points to gastric absorption
This unusual absorption site may actually be advantageous—the stomach's lower surface area means more concentrated local drug delivery and potentially more consistent absorption.
Why Semaglutide Was Ideal for SNAC
Not all peptides are good candidates for oral delivery. Semaglutide possessed several favorable properties:
| Property | Value | Why It Matters |
|---|---|---|
| Molecular Weight | 4,113.6 Da | Small enough for transcellular absorption |
| Half-Life | ~7 days (SC) | Long half-life compensates for low bioavailability |
| Potency | Very High | Effective at low absorbed amounts |
| Stability | Acyl chain stabilized | Resists rapid degradation |
The combination of high potency and long half-life means that even with ~1% bioavailability, therapeutic levels can be achieved with daily dosing.
Pharmacokinetics: Oral vs. Injectable
Absorption
- Oral semaglutide is absorbed faster but with lower overall bioavailability (0.8-1%)
- Food significantly reduces absorption—oral semaglutide must be taken fasting
Distribution and Elimination
Model-based analyses show that once absorbed, oral and subcutaneous semaglutide behave identically:
- Same two-compartment distribution
- Same first-order elimination
- Same metabolic pathways
SNAC Disposition
SNAC itself is rapidly absorbed and eliminated, with no accumulation after multiple daily doses. This favorable profile contributes to the overall safety of the formulation.
The December 2025 Milestone
In December 2025, the FDA approved oral semaglutide (now at 25 mg) for weight management—the first oral GLP-1 product for obesity. This higher dose delivers results comparable to the 2.4 mg injectable, representing a significant advance in patient convenience.
Emerging Technologies
SNAC's success has spurred development of alternative oral peptide delivery approaches:
Milk-Derived Extracellular Vesicles
Researchers have demonstrated oral delivery of both semaglutide and tirzepatide using milk-derived small extracellular vesicles (sEVs). Both peptides:
- Loaded efficiently onto sEVs in vitro
- Effectively reduced blood glucose in diabetic mice when administered orally
Oral Dissolvable Films
Companies like BioNxt are developing oral dissolvable film formulations for semaglutide, potentially offering even greater convenience than tablets.
Small Molecule GLP-1 Mimetics
The ultimate solution to oral delivery challenges may be small molecules that activate GLP-1 receptors. Eli Lilly's orforglipron, expected to receive FDA approval soon, is a non-peptide small molecule with superior oral absorption properties.
Implications for Peptide Therapeutics
The success of oral semaglutide has profound implications for the broader field:
Validated Proof of Concept
Rybelsus proves that peptide drugs can be successfully delivered orally at therapeutic levels—something many thought impossible.
Expanded Patient Access
Eliminating injection requirements removes a significant barrier for needle-averse patients, potentially expanding the treatable population.
Pipeline Opportunities
Numerous other peptides are now being evaluated for oral formulation using SNAC and similar technologies.
Manufacturing Considerations
Oral formulations require different manufacturing expertise than injectables, creating new industry capabilities.
Limitations and Considerations
Despite its success, oral semaglutide has practical limitations:
Dosing Constraints
- Must be taken on empty stomach
- Water only (≤4 oz) for swallowing
- 30-minute wait before eating or drinking
- Missing these requirements significantly reduces absorption
Bioavailability Ceiling
The ~1% bioavailability means oral doses must be much higher than injectable equivalents (25 mg oral vs. 2.4 mg injectable), potentially affecting cost and manufacturing.
Individual Variability
Gastric pH, emptying time, and other factors create more absorption variability than injectable administration.
Conclusion
The development of SNAC technology and its application to semaglutide represents a watershed moment in pharmaceutical science. By solving the "impossible" problem of oral peptide delivery, Emisphere and Novo Nordisk opened new therapeutic possibilities that will extend far beyond GLP-1 agonists.
As oral formulations of tirzepatide and other peptides move through development, and as alternative delivery technologies mature, we can expect the needle-free peptide revolution to accelerate. For patients and researchers alike, the message is clear: the future of peptide therapeutics is increasingly oral.
This article is for educational purposes only and does not constitute medical advice. All medication use should be supervised by qualified healthcare professionals.