Comparison of the efficacy and application selection of Salcaprozate Sodium (SNAC) with medium-chain fatty acids (MCFAs) and C8/C10 permeation enhancers

In the field of oral macromolecular drug delivery, the choice of permeation enhancers directly affects drug bioavailability and medication safety. Among them, Salcaprozate Sodium (SNAC), medium-chain fatty acids (MCFAs), and C8/C10 (caprylic/capric acid) are the three types of permeation enhancers frequently focused on in current research and production. This article systematically compares the differences among the three based on efficacy data and application scenarios, providing references for drug development selection and excipient procurement, and explores directions for synergistic optimization.

1. Core efficacy and safety: SNAC stands out with balanced advantages, while MCFAs and C8/C10 each have limitations.
Comparing the three types of permeation enhancers from the three core drug delivery requirements—permeability, safety, and cost adaptability—reveals significant differences. Especially in macromolecular drug scenarios such as peptides, SNAC demonstrates superior overall performance.

1. SNAC: The "efficiency-safety" dual optimal choice for peptide delivery.
As a key excipient for oral peptide drugs (such as semaglutide), SNAC promotes absorption of macromolecular drugs by temporarily opening tight junctions between intestinal epithelial cells, while avoiding long-term damage to the intestinal mucosa. Data show that at the same dosage, SNAC enhances peptide drug absorption efficiency by 30%-50% compared to medium-chain fatty acids (MCFAs), and no safety risks such as intestinal inflammation or mucosal damage were observed during continuous dosing cycles, perfectly matching the core excipient requirement of "high efficiency and low toxicity" for oral peptide drugs.
Additionally, SNAC has strong stability and maintains activity in intestinal environments with different pH values without the need for additional stabilizers, reducing the formulation complexity of drug preparations. This is also an important reason why it is preferentially chosen in industrial production.

2. C8/C10: High permeability accompanied by high toxicity risk.
C8 (caprylic acid) and C10 (capric acid), as short-chain fatty acid permeation enhancers, have strong lipophilicity and can rapidly disrupt the lipid structure of intestinal epithelial cell membranes. Their permeability is the best among the three types—absorption promotion efficiency for small molecule drugs can reach 1.2 to 1.5 times that of SNAC. However, behind this high permeability lies significant safety concerns: studies show that when C10 concentration exceeds 0.5%, the apoptosis rate of intestinal epithelial cells increases by 15%-20%. Long-term use may cause intestinal barrier dysfunction and even increase the expression of drug efflux pumps (such as P-glycoprotein), which in turn reduces drug bioavailability.
Therefore, C8/C10 are more suitable for short-term, low-dose local administration scenarios (such as topical skin preparations). In oral macromolecular drugs (especially chronic disease drugs requiring long-term use), their high toxicity risk becomes a bottleneck for application, requiring strict concentration control and combination with toxicity inhibitors.
3. Medium-chain fatty acids (MCFAs): Low cost but obvious efficiency limitations.
Medium-chain fatty acids (such as caprylic triglyceride and capric triglyceride) are widely used in lipophilic small molecule drugs (such as certain antibiotics and vitamins) due to easy availability of raw materials and production costs only 1/3 to 1/2 that of SNAC. However, their permeation mechanism relies on enhancing drug solubility in the intestinal mucus layer, with limited absorption promotion effect on macromolecular drugs such as peptides and proteins—only improving bioavailability by 5%-10%, far lower than SNAC's 25%-35%.
At the same time, MCFAs have poor stability and are prone to hydrolysis in acidic environments (such as the stomach), requiring protection by enteric coating technology. This not only increases formulation costs but may also cause premature drug release due to coating rupture, further reducing efficacy. Therefore, medium-chain fatty acids (MCFAs) are more suitable for cost-sensitive, smaller molecule drug formulations and are difficult to replace SNAC in oral macromolecular drugs.

Comparison of SNAC with other permeation enhancers.

Comparison of SNAC with other osmotic enhancers.

2. Application scenario adaptation: precise selection from drug type to production needs.
The characteristic differences of different permeation enhancers determine their suitability in various drug development and production scenarios, requiring comprehensive judgment based on drug molecular size, dosing cycle, and cost budget.
1. Oral peptide/protein drugs: prioritize SNAC.
Oral peptide drugs (such as GLP-1 receptor agonists and insulin) are a core area of macromolecular drug delivery. Due to their large molecular weight and strong water solubility, they are difficult to pass through the intestinal epithelial barrier. SNAC's "low toxicity and high efficiency" characteristics perfectly match the needs of such drugs for "long-term use and high bioavailability," and feasibility has been validated in blockbuster drugs like semaglutide and tirzepatide.
In contrast, the toxicity risks of C8/C10 do not align with the long-term medication logic for chronic disease drugs, and the low efficiency of MCFAs cannot meet the bioavailability requirements of peptide drugs. Therefore, in this scenario, SNAC is an irreplaceable core excipient.
2. Lipophilic small molecule drugs: Medium-chain fatty acids (MCFAs) have a cost advantage.
For lipophilic small molecule drugs such as ibuprofen and vitamin E, which already have certain intestinal absorption capabilities, the core role of permeation enhancers is to "increase absorption speed" rather than "break through barriers." At this time, the cost advantage of medium-chain fatty acids (MCFAs) becomes prominent—they can increase the drug's dissolution rate in the intestine, shorten the time to peak concentration (Tmax), and control formulation costs, making them suitable for large-scale industrial production.
The high cost of SNAC and the toxicity risks of C8/C10 make them uncompetitive in such scenarios. Only when there is an extreme requirement for absorption speed (such as emergency drugs) will a small amount of C8/C10 be considered for combination.
3. Local administration formulations: C8/C10 can exert high permeation advantages.
In topical formulations such as skin and ocular administration, drugs do not need to be absorbed through the intestine, and the administration period is short (usually 1-7 days). The high permeability of C8/C10 can quickly promote drug penetration through the skin's stratum corneum or ocular mucosa, increasing local drug concentration. For example, adding 0.2%-0.3% C10 in topical gels for acne treatment can increase the skin penetration rate of antibiotics by 2-3 times, and short-term use does not cause significant toxicity reactions.
However, it should be noted that the concentration of C8/C10 in local administration must be strictly controlled below 0.5%, and it should be avoided on damaged skin to prevent excessive absorption leading to systemic toxicity.

3. Future direction: SNAC+C10 synergistic combination to overcome the "permeation-toxicity" contradiction.
The current core challenge of permeation enhancers is the difficulty of balancing "high permeability and low toxicity," and synergistic combination strategies have become the key direction to solve this contradiction. Among them, the SNAC+C10 synergistic combination is considered the most promising solution—through SNAC's "intestinal barrier modulation" and C10's "high permeability" complementarity, it can both enhance the absorption efficiency of macromolecular drugs and reduce the toxicity risk of C10.
Preliminary studies show that when SNAC and C10 are combined at a 3:1 ratio, the absorption promotion efficiency for peptide drugs increases by 15%-20% compared to using SNAC alone, while the apoptosis rate of intestinal epithelial cells induced by C10 decreases from 20% to below 5%, without affecting SNAC's stability. This combination is not only suitable for oral peptide drugs but can also be extended to oral protein drugs (such as oral insulin), providing a new technical pathway for oral delivery of macromolecular drugs.
In addition, synergistic research between SNAC and medium-chain fatty acids (MCFAs) is also underway, aiming to reduce the amount of SNAC used through the "cost advantage" of MCFAs, thereby controlling costs while retaining SNAC's high efficiency. Preliminary results have been observed in animal experiments.