Nanocapsules as Carrier for Oral Delivery of Amifostine

Amifostine （Ethyol [R], WR-2721）是一种细胞保护药物，已被美国FDA批准用于接受放射治疗和某些形式化疗的癌症患者静脉注射。氨磷汀的化学保护和放射保护作用仍未得到充分利用，这不是由于其有效性的限制，而主要是因为其给药仅限于静脉注射和皮下注射。氨磷汀口服给药无效，而口服给药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，通过开发一种配方，其中氨磷汀在胃肠道中的过早失活是由其纳入保护性聚合物基质来防止的。这项工作的结果和其他人发表的工作清楚地表明，发展这样一种方案确实是相当可行的。因此，在目前的申请中，我们建议在开发氨磷汀口服活性缓释制剂原型的初步成功基础上进行后续研究。虽然我们的原型配方清楚地确立了我们方法的科学有效性，但其在临床中的实际应用需要广泛的优化和严格的测试，我们在此应用中提出将其作为我们当前工作的逻辑延伸。我们假设氨磷汀可以成功地配制成一种口服剂型，在临床环境下具有显著的化学和放射保护。以下具体目标描述了这种开发的分步方法：(1)优化氨磷汀缓释纳米胶囊的原型配方：使用喷雾干燥技术制备新批次并优化工艺参数，以获得所需的粒度分布和颗粒形态，b)最大化收率，c)最大化封装效率，d)最小化残留溶剂的存在；（二）优化氨磷汀体外释放特性，获得一种初释20% ~ 30%缓释3 d，另一种初释5% ~ 10%缓释7 d；（lII）利用CD2F1雄性小鼠进行体内研究：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性c)评估和优化急性全身γ照射（9.0 GY）和分段全身γ照射（连续三次3.0 GY/天）的放射防护效果。放射防护效果将通过以下参数来衡量：30天存活率、肠通透性变化、空肠隐窝细胞存活率和骨髓造血祖细胞存活率（红细胞和红细胞）

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.