Patani George A, Pang Yuan Ping, Chien Yie W
Controlled Drug-Delivery Research Center, Rutgers University, Piscataway, New Jersey, USA.
Pharm Dev Technol. 2005;10(4):525-38. doi: 10.1080/10837450500333179.
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 approximately 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 (> or = 8) and at higher temperatures (> or = 50 degrees C).
多年来，胆碱酯酶抑制剂一直用于治疗阿尔茨海默病（AD）。他克林是首个获全球监管机构批准用于治疗AD的乙酰胆碱酯酶抑制剂。不幸的是，多项研究表明他克林与一些严重副作用相关，包括肝毒性。这些不良反应可能归因于其对乙酰胆碱酯酶的选择性较差，因此有必要研发更具选择性、特异性更高且效力更强的胆碱酯酶抑制剂。他克林的庚烯连接双他克林类似物（双THA）是第二代乙酰胆碱酯酶抑制剂，其抑制大鼠脑乙酰胆碱酯酶的效力比他克林高1000倍，对乙酰胆碱酯酶的选择性比对丁酰胆碱酯酶高10000倍。因此，已开展一系列研究来表征该双THA类似物与其母体分子（他克林）相比的物理化学性质（如pKa、分配系数和稳定性）。对于AD治疗，胆碱酯酶抑制剂需要长期每日服用。近年来，利用控释剂型的控释给药特性来递送用于慢性给药的药物越来越普遍。另一方面，已用于给药以实现直接递送至脑（通过嗅觉途径）的鼻腔途径，可为他克林和双THA的递送提供脑靶向益处。为研究这种可行性，评估了他克林和双THA透过鼻黏膜的情况（与其他吸收性黏膜进行比较）。对它们透过从家猪新鲜切取的各种吸收性黏膜的渗透动力学研究表明，鼻黏膜可为双THA的全身递送提供一条可行途径。脱脂研究表明，吸收性黏膜中的亲脂性成分在双THA的渗透中可能起重要作用。双THA的pKa约为8，其分配系数随溶液pH呈S形模式。发现它在酸性pH下相对稳定，但在碱性pH（≥8）和较高温度（≥50℃）下会发生碱催化降解。
