TY - JOUR
T1 - A potent and selective tacrine analog - Biomembrane permeation and physicochemical characterization
AU - Patani, George A.
AU - Yuan, Ping Pang
AU - Chien, Yie W.
N1 - Funding Information:
The authors are grateful to Dr. Lilan Chen and Dr. Senshang Lin for their helpful advice during this research. This research was supported in part by Johnson & Johnson Pre-doctoral Research Fellowship and Sintong Graduate Research Fellowship.
PY - 2005/11
Y1 - 2005/11
N2 - Cholinesterase inhibitors have been used for years in treatment of Alzheimer's disease (AD). Tacrine is the first acetylcholinesterase inhibitor approved for treating AD by the. regulatory agencies around the world. Unfortunately, a number of studies have shown tacrine to be associated with some severe side effects, including hepatotoxicity. These adverse effects may be attributed to its poor selectivity for acetylcholinesterase and have thus necessitated the research and development of more selective cholinesterase inhibitors with a greater specificity and higher potency. The heptylene-linked bis-tacrine analog (bis-THA) of Tacrine is a second-generation inhibitor of acetylcholinesterase, which has a potency that is 1000 times more potent than Tacrine in inhibition of the rat brain acetylcholinesterase and 10,000 times more selective for acetylcholinesterase over butyrylcholinesterase. A series of investigations have thus been initiated to characterize the physicochemical properties (e.g., pKa, partition coefficient, and stability) of this bis-THA analog as compared to its parent molecule (Tacrine). For AD treatment, the cholinesterase inhibitors need to be taken daily for long periods of time. Use of controlled-release dosage forms to deliver drugs for chronic administration, by taking advantage of their rate-controlling drug delivery features, has gained increasing popularity in recent years. On the other hand, the nasal route, which has been used to deliver drugs for achieving a direct delivery to the brain (via the olfactory pathway), could offer the benefits of brain targeting to the delivery of Tacrine and bis-THA. To investigate this feasibility, the permeation of Tacrine and bis-THA across the nasal mucosa was evaluated (in comparison with other absorptive mucosae). Studies of their permeation kinetics across the various absorptive mucosae, which were freshly excised from the domestic pig, indicated that the nasal mucosa could present a viable pathway for the systemic delivery of bis-THA. Delipidization studies suggested that the lipophilic components in the absorptive mucosae could play an important role in the permeation of bis-THA. The bis-THA has a pKa of ∼8 and its partition coefficient showed a sigmoidal pattern with solution pHs. It was found to be relatively stable at acidic pHs but subjected to a base-catalyzed degradation at the alkaline pHs (≥8) and at higher temperatures (≥50°C).
AB - Cholinesterase inhibitors have been used for years in treatment of Alzheimer's disease (AD). Tacrine is the first acetylcholinesterase inhibitor approved for treating AD by the. regulatory agencies around the world. Unfortunately, a number of studies have shown tacrine to be associated with some severe side effects, including hepatotoxicity. These adverse effects may be attributed to its poor selectivity for acetylcholinesterase and have thus necessitated the research and development of more selective cholinesterase inhibitors with a greater specificity and higher potency. The heptylene-linked bis-tacrine analog (bis-THA) of Tacrine is a second-generation inhibitor of acetylcholinesterase, which has a potency that is 1000 times more potent than Tacrine in inhibition of the rat brain acetylcholinesterase and 10,000 times more selective for acetylcholinesterase over butyrylcholinesterase. A series of investigations have thus been initiated to characterize the physicochemical properties (e.g., pKa, partition coefficient, and stability) of this bis-THA analog as compared to its parent molecule (Tacrine). For AD treatment, the cholinesterase inhibitors need to be taken daily for long periods of time. Use of controlled-release dosage forms to deliver drugs for chronic administration, by taking advantage of their rate-controlling drug delivery features, has gained increasing popularity in recent years. On the other hand, the nasal route, which has been used to deliver drugs for achieving a direct delivery to the brain (via the olfactory pathway), could offer the benefits of brain targeting to the delivery of Tacrine and bis-THA. To investigate this feasibility, the permeation of Tacrine and bis-THA across the nasal mucosa was evaluated (in comparison with other absorptive mucosae). Studies of their permeation kinetics across the various absorptive mucosae, which were freshly excised from the domestic pig, indicated that the nasal mucosa could present a viable pathway for the systemic delivery of bis-THA. Delipidization studies suggested that the lipophilic components in the absorptive mucosae could play an important role in the permeation of bis-THA. The bis-THA has a pKa of ∼8 and its partition coefficient showed a sigmoidal pattern with solution pHs. It was found to be relatively stable at acidic pHs but subjected to a base-catalyzed degradation at the alkaline pHs (≥8) and at higher temperatures (≥50°C).
KW - AD treatment
KW - Alzheimer's disease
KW - Biomembrane permeation
KW - Bis-tacrine analogs
KW - Brain-targeting delivery
KW - Cholinesterase inhibitors
KW - Mucosal permeability
KW - Physicochemical properties
KW - Tacrine analogs
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U2 - 10.1080/10837450500333179
DO - 10.1080/10837450500333179
M3 - Article
C2 - 16370182
AN - SCOPUS:28844453300
SN - 1083-7450
VL - 10
SP - 525
EP - 538
JO - Pharmaceutical Development and Technology
JF - Pharmaceutical Development and Technology
IS - 4
ER -