Many drug candidates are poorly water-soluble. Microenvironmental pH (pH_M) modification in buccal/sublingual dosage forms has attracted increasing interest as a promising pharmaceutical strategy to enhance the oral mucosal absorption of drugs with pH-dependent solubility. Optimizing drug absorption at the oral mucosa using pH_M modification is considered to be a compromise between drug solubility and drug lipophilicity (Log D)/permeation. To create a desired pH_M around formulations during the dissolution process, a suitable amount of pH modifiers should be added in the formulations, and the appropriate methods of pH_M measurement are required. Despite pH_M modification having been demonstrated to be effective in enhancing the oral mucosal absorption of drugs, some potential risks, such as oral mucosal irritation and teeth erosion caused by the pH modifiers, should not been neglected during the formulation design process. This review aims to provide a short introduction to the pH_M modification concept in buccal/sublingual dosage forms, the properties of saliva related to pH_M modification, as well as suitable drug candidates and pH modifiers for pH_M modifying buccal/sublingual formulations. Additionally, the methods of pH_M measurement, pH_M modification methods and the corresponding challenges are summarized in the present review.

Buccal films containing a pH modifying excipient may be able to increase bioavailability of drugs with pH-dependent solubility such as saquinavir. Access to suitable in vitro drug release testing methods may facilitate buccal formulation development. This study aimed to explore two release testing methods for characterising buccal films and to elucidate the relationship between microenvironmental pH (pHM, i.e. the pH around the swelling films) and saquinavir release. The Franz diffusion cell method was applicable to investigate the effect of hydroxypropyl methylcellulose (HPMC) grade on saquinavir release. Films containing HPMC K3 LV had a faster saquinavir release than films containing HPMC K100 LV. A UV/Vis imaging method was developed to visualise saquinavir release and pHM changes during the initial dissolution. Within 5 min, the pHM decreased from 6.8 to around 5.4 for HPMC K100 LV-based films containing 11.1 % or 16.6 % (w/w) malic acid. Subsequently, the pHM increased due to increasing concentrations of saquinavir. An increase in malic acid content led to a faster saquinavir release. The combination of methods may be broadly applicable for excipient screening in development of buccal formulations. The imaging approach holds promise for characterizing other pH modifying formulation principles.

Oromucosal patches for drug delivery allow fast onset of action and ability to circumvent hepatic first pass metabolism of drugs. While conventional fabrication methods such as solvent casting or hot melt extrusion are ideal for scalable production of low-cost delivery patches, these methods chiefly allow for simple, homogenous patch designs. As alternative, a multi-material direct-ink-write 3D printing for rapid fabrication of complex oromucosal patches with unique design features was demonstrated in the present study. Specifically, three print-materials: an acidic saquinavir-loaded hydroxypropyl methylcellulose ink, an alkaline effervescent sodium carbonate-loaded ink, and a methyl cellulose backing material were combined in various designs. The CO₂ content and pH of the microenvironment were controlled by adjusting the number of alkaline layers in the patch. Additionally, the rigid and brittle patches were converted to compliant and stretchable patches by implementing mesh-like designs. Our results illustrate how 3D printing can be used for rapid design and fabrication of multifunctional or customized oromucosal patches with tailored dosages and changed drug permeation.