Nanocapsules as Carrier for Oral Delivery of Amifostine

氨磷汀(乙醇[R]，WR-2721)是一种细胞保护性药物，已被美国FDA批准用于接受放射治疗和某些形式的化疗的癌症患者的静脉给药。氨磷汀的化学防护和辐射防护作用仍然严重不足，这不是因为疗效有限，而主要是因为它的给药仅限于静脉和皮下给药。氨磷汀在口服时无效--这是最受欢迎的给药途径之一。三年前，我们开始努力克服这一限制，开发了一种配方，通过将氨磷汀结合到保护性聚合物基质中，防止了氨磷汀在胃肠道中的过早失活。这一努力的结果和其他人发表的工作清楚地表明，制定这样的提法确实是相当可行的。因此，在目前的应用中，我们建议在我们初步成功开发阿米福汀口服活性缓释制剂原型的基础上进行后续研究。虽然我们的原型公式清楚地建立了我们方法的科学有效性，但它在临床上的实际应用需要广泛的优化和严格的测试，我们在这一应用中建议将其作为我们当前工作的逻辑扩展。我们假设，在临床环境下，氨磷汀可以成功地配制成具有显著的化学和辐射防护作用的口服剂型。以下具体目标描述了逐步开发的方法：(I)优化氨磷汀的原型缓释纳米胶囊处方：使用喷雾干燥技术制备新的批次并优化工艺参数，以：a)获得所需的粒度分布和颗粒形态，b)最大限度地提高产率，c)最大限度地提高包封率，d)最大限度地减少残留溶剂的存在；(Ii)对氨磷汀的体外释放特性进行优化，以获得一个制剂，其初始释药量为20%-30%，然后持续释放3d，另一个制剂，其初始释药量为5%-10%，随后持续释放7d；(Ii)使用CD2F1雄性小鼠进行活体研究，以：a)评估氨磷汀的相对生物利用度，b)优化吸收和组织分布特征，以及c)评估和优化对急性全身伽玛照射(9.0GY)和分次全身伽马照射(连续三次治疗，每天3.0GY)的放射蛋白疗效。放射防护效果将使用以下参数进行评估：30天存活期、肠道通透性变化、空肠隐窝细胞存活率和骨髓造血祖细胞存活率(红系和红系)。 (4)评估两种最佳配方的长期(长达六个月)热稳定性。在小鼠成功地进行临床前评估后，这种新的给药系统将来可以用于狗的评估，随后进行人类临床试验。这种提法的发展将标志着在以下领域取得的重要进展 癌症治疗中的化学防护和放射防护。

Amifostine (Ethyol [R], WR-2721) is a cytoprotective drug that has been approved by the U.S. FDA for intravenous administration in cancer patients receiving radiation therapy and certain forms of chemotherapy. The chemoprotective and radioprotective benefits of amifostine remain grossly underutilized not because of limitations of efficacy but mainly because its administration is limited to intravenous and subcutaneous routes. Amifostine is not effective when administered orally - one of the most preferred routes of drug administration. Three years ago we began an effort to overcome this limitation by developing a formulation where amifostine's premature inactivation in the gastrointestinal tract was prevented due to its incorporation in a protective polymeric matrix. The results of this effort and published work by others clearly indicate that the development of such a formulation is indeed quite feasible. In the current application, we therefore propose to follow up on our initial success in developing a prototype of orally active sustained release formulation of amifostine. While our prototype formulation clearly establishes the scientific validity of our approach, its practical application in clinic demands extensive optimization and rigorous testing which we propose in this application as the logical extension of our current work. We hypothesize that amifostine can be successfully formulated to provide an oral dosage form with significant chemo-and radioprotection under clinical settings. The following specific aims delineate the step-wise approach towards such development: (I) Optimize the prototype sustained release nanoeapsule formulation of amifostine: Prepare new batches using the spray-drying technique and optimize processing parameters to: a) obtain desired particle size distribution and particle morphology, b) maximize the yield, c) maximize the efficiency of encapsulation, and d) minimize the presence of residual solvent; (II) Optimize for in vitro amifostine release characteristics to obtain one formulation with 20%-30% initial drug release followed by continued release for 3 days, and another formulation with 5%-10% initial drug release followed by continued release for 7 days; (lII) Conduct in viva studies using CD2F1 male mice to: a) Evaluate relative bioavailability of amifostine b) Optimize the absorption and tissue distribution characteristics and c) Evaluate and optimize for radioproteetive efficacy against both acute whole body gamma irradiation (9.0 GY) and fractionated whole body gamma irradiation (three consecutive treatments of 3.0 GY/day). The radioprotective efficacy will be measured using the following parameters: 30-day survival, changes in intestinal permeability, jejunal crypt cell survival, and bone marrow hemopoietic progenitor cell survival (erythroids and granulocytes/monocytes); and (IV) Evaluate the long-term (up to six months) thermal stability of the two best formulations. Following the successful preclinlcal evaluations in mice, this novel delivery system can be used, in the future, for evaluation in dogs followed by human clinical trials. Development of such a formulation will mark an important advancement in the field of chemoprotection and radioprotection during cancer therapy.