Semaglutide Spray

The nasal mucosa is rich in blood vessels and lymphatic vessels. Semaglutide spray can be rapidly absorbed through the nasal mucosa and enter the bloodstream, avoiding the first-pass effect of the liver and improving bioavailability. Nasal administration also has the advantages of simple operation and high patient compliance. For semaglutide, nasal mucosal delivery may be an effective alternative route of administration. Some studies have shown that nasal spray administration can achieve rapid absorption and effective delivery of drugs.

Moreover, nasal tissues possess relatively rigorous barrier characteristics. Tight junctions between epithelial cells obstruct the permeation of macromolecular polypeptides such as semaglutide. Local irritation induced by formulations is another hidden obstacle; irritating excipients may trigger nasal itching, congestion or sneezing, lowering patients' long-term adherence. To tackle these drawbacks, rational application of penetration enhancers, liposomal carriers and formulation optimization is required to prolong mucosal retention, resist enzymatic hydrolysis and boost transnasal absorption efficiency, so as to realize stable therapeutic concentrations of semaglutide via nasal spray.

As a non-invasive administration pathway, oral mucosal delivery effectively bypasses gastrointestinal digestion and hepatic first-pass metabolism, significantly elevating systemic bioavailability and reducing drug metabolism loss compared with conventional oral dosage forms. Furthermore, this delivery modality features convenient administration procedures, minimal operational complexity and favorable sensory tolerance, which greatly improves patient adherence and long-term medication compliance.

The oral cavity constitutes an intricate dynamic microenvironment with continuous saliva secretion, diverse oral flora and abundant hydrolytic enzymes. These endogenous factors may trigger structural degradation, conformational changes and metabolic inactivation of semaglutide molecules, undermining drug stability and reducing effective absorption dosage. In addition, compared with nasal mucosa, the oral epithelial barrier presents relatively lower overall permeability. The compact intercellular tight junctions greatly hinder the transmembrane transport of high-molecular polypeptide drugs.

As a crucial subdivision of oral mucosal tissues, the buccal mucosa possesses distinct histological and pharmacological advantages that render it superior to other mucosal delivery pathways. In comparison with nasal and sublingual mucosa, the buccal mucosa exhibits relatively elevated transmembrane permeability and stable tissue structure, coupled with exceptional patient compliance owing to its non-invasive, convenient and comfortable administration experience.

For semaglutide, a high-molecular-weight polypeptide drug with poor oral absorption characteristics, buccal mucosal delivery emerges as a highly potential alternative non-invasive administration route. Current pharmaceutical researches have focused on developing diversified buccal delivery devices, including microneedle patches, needle-free syringes and targeted jet injection systems. Each device adopts unique working mechanisms to break through mucosal absorption limitations, effectively promoting transbuccal drug penetration and further enhancing the bioavailability of semaglutide.

Furthermore, significant individual heterogeneity exists in buccal mucosal characteristics, including variations in epithelial thickness, tissue morphology, extracellular matrix composition and endogenous enzyme activity. Such individual differences lead to inconsistent drug absorption efficiency among different individuals, destabilizing in vivo drug exposure and therapeutic outcomes. These inherent defects greatly limit the repeatability and clinical popularization of buccal semaglutide delivery, necessitating targeted formulation modification and delivery system optimization to break through barrier restrictions.

Endogenous mucosal enzymes readily degrade polypeptide molecules before they enter the bloodstream. Meanwhile, restricted absorption surface area and tight epithelial junctions create low membrane permeability, further obstructing drug penetration. Collectively, these barriers drastically cut down the effective absorbed dose of semaglutide upon mucosal delivery. The resultant drop in bioavailability fails to achieve the required systemic drug concentration, ultimately weakening pharmacological activity and restricting the practical application of mucosal semaglutide preparations.

For instance, in the buccal mucosa, the epithelial layer is a non-keratinized layer with a thickness of 500-800 μm, composed of 40-50 layers of closely arranged squamous cells, forming a physical barrier. In addition, there are polar and non-polar lipids between the buccal mucosal epithelial cells. These lipids self-assemble into sheet-like structures and membrane-coated particles, forming a biochemical barrier. The oral microbiota and salivary enzymes, etc. may also have an impact on the stability and absorption of semaglutide.

To specify, nasal spray formulations frequently induce local mucosal irritation, accompanied by frequent sneezing, nasal dryness and slight itching, discouraging repeated daily administration. Drugs delivered via the oral mucosa often bring unpleasant bitter or strange tastes as well as persistent foreign body sensation in the mouth, exerting negative impacts on patients' daily life. Similarly, devices designed for buccal mucosal drug delivery may produce continuous pressure on local tissues, resulting in mild pain and irritation. Beyond physical discomfort, patients' health literacy and inherent perceptions of novel mucosal preparations cannot be overlooked.