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Tacrine (THA), a centrally acting acetylcholine-esterase inhibitor, is presently administered perorally for the treatment of Alzheimer's disease (AD). However, its low bioavailablity (i.e., 17%) and short half-life (2-4 h) demand the search for alternative routes of administration. The primary objective of this study was to assess the potential of absorptive mucosae and skin as routes for improving the systemic delivery of THA. The Yucatan minipig, which has been used increasingly in biomedical research as a useful model for humans, and the domestic pig, which is available at low cost, were evaluated for their suitability as animal model. Permeation kinetics of THA across various absorptive mucosae (nasal, buccal, sublingual, and rectal) of both species of swine were studied in the hydrodynamically well-calibrated Valia-Chien permeation cells. For comparison, permeation through various intestinal segments (duodenum, jejunum, and ileum) was also measured. Results indicated that both species display similar permeation characteristics. However, the data obtained for the domestic pigs shows lower intra- and inter-animal variabilities than that of the Yucatan minipigs. The nasal mucosa was found to have the highest permeability, while the buccal mucosa had the lowest among the absorptive mucosae. The intrinsic permeabilities and diffusivity of THA across the four absorptive mucosae were not significantly different between species but lower than that for the intestinal segments for both species. Using dorsal skin as the model, the skin permeation of THA was also investigated and the results indicated that the domestic swine has a significantly higher skin permeability than the Yucatan minipig, with more than a 2-fold difference in intrinsic permeabilities. The intrinsic permeability, partition coefficient, and diffusivity for domestic pig skin are very similar to that for human cadaver skin. Considering the potential of bypassing the hepatic "first-pass" elimination, the absorptive mucosae may be useful routes for systemic delivery of THA to achieve improved bioavailability. With additional advantages of lower variability, ease of membrane excision, good accessibility, and lower cost, it is concluded that the domestic swine is a better animal model than the Yucatan minipig for preclinical studies on the systemic delivery of tacrine.

Introduction: Pilocarpine hydrochloride (pilo) ophthalmic solution has traditionally been used for the treatment of glaucoma, with opportunities to improve the tolerability profile experienced by patients. Pilocarpine hydrochloride ophthalmic solution 1.25% (Vuity TM , Allergan, an AbbVie company) was approved in late 2021 for the treatment of adults with presbyopia. This publication describes the properties of the optimized, proprietary vehicle of this new ophthalmic solution developed with the aim of improving tolerability upon instillation. Methods: An in vitro method determined the time required for the pH of pilo 1.25% in the proprietary vehicle (Optimized Formulation) and a commercially available 1% pilo ophthalmic solution (Generic Formulation) to equilibrate with the pH of simulated tear fluid (STF). In a pilot study, five of the six screened participants received one drop of the Optimized Formulation in one eye and Generic Formulation in the other. Ocular discomfort and vision blur were evaluated for each eye just prior to and at multiple times after drop instillation using visual analog scales (VAS), and adverse events were assessed. Results: The in vitro method showed that the Optimized Formulation achieved faster pH equilibration than the Generic Formulation. The pilot study revealed that the Optimized Formulation demonstrated less ocular discomfort, vision blur, and adverse events compared to the Generic. Conclusion:The in vitro and pilot study of the Optimized Formulation indicated that it rapidly equilibrates to the physiologic pH of the tear film, providing greater comfort and tolerability while also minimizing vision blur. Overall, the proprietary vehicle is expected to improve comfort, result in less vision blur, and provide a well-tolerated alternative method to deliver pilo for the treatment of presbyopia when compared to what is commercially available.

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