Intranasal CNS delivery of drugs against organophosphorous threat agents

描述（由申请人提供）：有机磷化学威胁剂（CTA）是军事和平民人口的主要风险。CTA通过抑制乙酰胆碱酯酶（AChE）发挥其毒性作用，导致乙酰胆碱在突触和神经肌肉接头处蓄积，导致急性CTA中毒症状，包括流涎、流泪、排便、肌肉抽搐、癫痫发作/癫痫持续状态，最终因呼吸衰竭而迅速死亡。急性CTA中毒的可用治疗包括以下组合：1）肟，以重新激活受抑制的AChE; 2）阿托品，以拮抗在毒蕈碱受体处形成的过量乙酰胆碱的作用; 3）地西泮或咪达唑仑，以变构方式增强抑制性神经递质-氨基丁酸（GABA）在GABAA受体处的作用。目前的治疗策略的两个主要局限性是：1）肟的血脑屏障（BBB）渗透性差和2）由于快速“老化”而对CTA抑制的AChE的再活化的抗性。肟类化合物快速输送到大脑对于重新激活大脑中快速老化的乙酰胆碱酯酶和保护大脑免受急性和随后的慢性损伤至关重要。非侵入性鼻内鼻-脑递送提供治疗剂更快地递送至大脑。该机制涉及可能的运输通过嗅上皮的神经上皮细胞以及通过三叉神经通路。这种方法的主要优点是，在生理条件下不能绕过BBB的带电分子或甚至高分子量药物可以成功地递送到大脑。鼻-脑递送的效率可以通过制备诸如药物的粘膜粘附纳米乳剂的制剂或通过将药物包封在可生物降解的纳米颗粒中来显著提高。我们的中心假设是，鼻内给药纳米乳剂形式的肟、阿托品和咪达唑仑的治疗制剂可以将这些药物快速递送至脑以及肺和血液循环，以在30分钟或更晚的时间点防止CTA。我们的长期目标是建立鼻内脑递送系统用于与化学威胁相关的治疗的功效，这在平民大规模伤亡情况下可以有巨大的用途。近期目标是为此目的开发粘膜粘附纳米乳液方法，并在临床前模型系统中测试其有效性。使用纳米乳液技术用于药物的鼻内脑递送是绕过BBB的高度创新的方法，并且沿着这些路线的努力正在许多实验室中进行。建议使用纳米乳液的鼻内脑递送技术需要研究以防止CTA或涉及平民大规模伤亡的任何其他情况。成功使用这种非侵入性技术对抗CTA的主要优点是：1）除了肺和血液之外，它还可以将肟（在生理条件下不能穿过BBB）快速递送到大脑以重新激活受抑制的AChE;以及2）它可以在暴露后立即自我施用以防止受抑制的AChE的“老化”及其对重新激活的抗性。成功使用鼻内脑递送技术对抗化学威胁剂将在临床医学和研究的许多其他领域开辟其更广泛的应用。

DESCRIPTION (provided by applicant): Organophosphorous Chemical Threat Agents (CTAs) are major risks for military and civilian population alike. CTAs exert their toxic effects by inhibiting acetylcholinesterase (AChE) leading to the accumulation of acetylcholine at synaptic and neuromuscular junctions leading to symptoms of acute CTA poisoning including salivation, lacrimation, defecation, muscular twitching, seizures/status epilepticus and ultimately rapid death due to respiratory failure. Available treatment for acute CTA poisoning includes combinations of: 1) oxime to reactivate the inhibited AChE; 2) atropine to antagonize the action of excess acetylcholine formed at muscarinic receptors and 3) diazepam or midazolam to allosterically potentiate the action of inhibitory neurotransmitter -amino butyric acid (GABA) at GABAA receptors. The two major limitations of the current therapeutic strategies are: 1) poor blood-brain barrier (BBB) permeability of oximes and 2) resistance for reactivation of the CTA-inhibited AChE due to rapid 'aging'. Quick delivery of oximes to the brain is critical to reactivat the rapidly 'aging' AChE in the brain and protect the brain from acute and subsequent chronic injuries. Non-invasive intranasal nose-to-brain delivery offers faster delivery of therapeutics to the brain. The mechanism involves possible transport through the neuroepithelial cells of olfactory epithelium as well as through trigeminal nerve pathways. The major advantage of this approach is that charged molecules or even high molecular weight drugs which cannot bypass the BBB under physiological conditions can be successfully delivered to the brain. Efficiency of nose-to- brain delivery can be significantly improved by either making formulations such as mucoadhesive nanoemulsions of the drugs or by encapsulating the drugs in biodegradable nanoparticles. Our central hypothesis is that intranasal administration of therapeutic formulations of oxime, atropine and midazolam in a nanoemulsion form can rapidly deliver these drugs to the brain in addition to lungs and blood circulation to protect against CTAs at 30 min or later time points. Our long term objective is to establish the efficacy of intranasal brain deliver systems for use with chemical threat- related therapeutics, which can be of tremendous use in civilian mass casualty situations. The immediate goal is to develop the mucoadhesive nanoemulsion approach for this purpose and test them for effectiveness in a preclinical model system. Use of nanoemulsion technology for intranasal brain delivery of drugs is a highly innovative approach to bypass BBB and efforts along these lines are underway in many laboratories. The proposed intranasal brain delivery technique using nanoemulsion needs to be investigated for protection against CTAs or any other situations involving civilian mass casualty. The major advantages of the successful use of this non-invasive technology against CTAs are: 1) it can rapidly deliver oximes (which cannot cross the BBB under physiological conditions) to the brain in addition to lungs and blood to reactivate the inhibited AChE; and 2) it can be self administered immediately after exposure to prevent 'aging' of the inhibited AChE and its resistance for reactivation. The successful use of an intranasal brain delivery technology against chemical threat agents will open up its wider application in numerous other areas of clinical medicine and research.