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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.

Chitosan is used in various drug delivery approaches as a pharmaceutical excipient. Although its potential as an immunomodulatory agent has been reported, its use in this capacity has not been fully explored. The efficacy of chitosan as an active pharmacological agent, particularly in anti-inflammatory therapy in inflammatory bowel diseases (IBD), was investigated in this study. The potential impact of the molecular weight (MW) and degree of deacetylation (DD) of chitosan was investigated together with 5-amino salicylic acid (5-ASA) for its efficacy in a combination anti-inflammatory therapy in murine experimental colitis. Such a combination would potentially be developed into novel dual strategies whereby chitosan acts as a mucoadhesive excipient as well as provide an additional anti-inflammatory benefit. Chitosan grades with different MW and DD were administered intrarectally alone or in combination with 5-ASA to colitis mice for 3 days. Myeloperoxidase (MPO) and alkaline phosphatase (ALP) activity and tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and nuclear factor kappa-B (NF-κB) levels were assessed from the colon. Intrarectal treatment of colitis with 30 mg/kg chitosan alone and with 30 mg/kg 5-ASA for 3 days led to a significant decrease in MPO, ALP, TNF-α, IL-6, IL-1β and NF-κB in colitis mice compared to untreated mice. Surprisingly, the efficacy of chitosan as an anti-inflammatory polymer was relatively independent from its structural properties, namely DD and MW. However, combinations of chitosan with 5-ASA showed a significant pharmacological improvement, whereby the additive anti-inflammatory efficacy observed shows the possibility of finetuning chitosan by combining it with anti-inflammatory agents to optimize its anti-inflammatory potential.

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