Orally Active Formulations of DHA Dimers for the Treatment of Infectious Diseases

说明(申请人提供)：天然产物青蒿素是一种倍半萜内过氧物，具有已知的抗疟疾活性，对恶性疟原虫氯喹敏感和抗氯喹品系均有抗疟活性。除了抗疟疾活性外，青蒿素还被报道对几种不同的肿瘤细胞株具有细胞毒活性。最近，我们团队开展的青蒿素工作已经扩展到制备一系列双氢青蒿素二聚体(DHA二聚体)和测试这些二聚体对抗原虫感染的能力，以及与美国国家癌症研究所(NCI)和抗肿瘤筛查计划的合作。类似的DHA二聚体及其琥珀酸半酯(HS)在NCI筛查程序中显示出非常有希望的结果，在我们的初步体外和体内研究中显示了强大的抗疟疾活性。然而，口服抗疟药物的剂量大约是腹腔注射剂量的10倍。有几个因素可能导致观察到的口服吸收有限。这些可能包括药物/前体药物在胃肠道中的降解、在胃肠液中的溶解性较差、胃肠道壁渗透性有限或首次通过代谢。因此，这项建议的总体目标是阐明口服吸收受限的因素(S)，并通过克服口服吸收所面临的挑战的策略，开发具有高口服生物利用度的制剂(S)。这将通过一系列特定的目标来实现，其中包括：1：合成DHA二聚体肟和DHA二聚体肟半琥珀酸酯：这是两种被表征为口服生物利用度研究的先导二聚体的化合物。2：评估这些DHA二聚体的生物药学特性：这些研究将包括溶解度、logP、pH稳定性、在胃肠道和肝脏酶存在下的代谢稳定性以及化合物的体外渗透性。所获得的数据将有助于确定这些化合物在口服生物利用度方面的限制。3： 处方方法的发展：根据目标2的研究结果，将通过体外渗透性实验研究各种克服挑战的策略，包括增溶和稳定方法、渗透促进剂和纳米粒剂型的包合。4：大鼠口服生物利用度的描述：最后，有希望的配方将在体内进行测试。将口腔PK数据与腹膜内PK数据进行比较。血液样本将使用LC/MS/MS进行分析。预计至少有一种含有其中一种二聚体的配方将被确定为具有高口服生物利用度，并将在第二阶段进入开发研究。这项STTR应用是ElSohly实验室公司(ELI)和密西西比大学(UM)药剂学系之间的合作努力。

DESCRIPTION (provided by applicant): The natural product artemisinin is a sesquiterpene endoperoxide with known anti-malarial activity against both chloroquine-sensitive and chloroquine-resistant strains of the parasite Plasmodium falciparum. In addition to its anti-malarial activity, artemisinin was reported to have cytotoxic activity against several different tumor cell lines. Recently, artemisinin work conducted by our group has been extended to the preparation of a series of dihydroartemisinin dimers (DHA dimers) and the testing of these dimers against protozoal infections, as well as collaborative work with the National Cancer Institute (NCI) and the anti-tumor screening program. The analog DHA dimer oxime and its hemisuccinate ester (HS) have shown very promising results in the NCI screening program and strong activity against malaria in our initial in vitro and in vivo studies. However, the oral antimalarial dose needed was approximately 10-fold higher than the intraperitoneal dose. Several factors could be responsible for the observed limited oral absorption. These could include degradation of the drug/prodrug in the gastrointestinal tract, poor solubility in the gastrointestinal fluids, limited permeability across the gastro-intestinal walls or first-pass metabolism. Thus, the overall objective of this proposal is to elucidate the factor(s) behind the limited oral absorption and to develop formulation(s) that has high oral bioavailability, through strategies to overcome the challenges faced in oral absorption. This will be accomplished through a set of specific aims which include: 1: Synthesis of DHA dimer oxime and DHA dimer oxime hemisuccinate: These are the two compounds characterized as the lead dimers for oral bioavailability studies. 2: Evaluation of the biopharmaceutical characteristics of these DHA dimers: These studies will include solubility, logP, pH stability profile, metabolic stability in te presence of gastrointestinal and hepatic enzymes and in vitro permeability of the compounds. The data obtained will help identify the constraints in oral bioavailability of these compounds. 3: Development of formulation approaches: Based on the findings in Aim 2 various strategies to overcome the challenges including solubilization and stabilization approaches, inclusion of permeation enhancers and nanoparticle dosage forms will be investigated through in vitro permeability experiments. 4: Delineation of oral bioavailability in rats: Finally, promising formulations will be tested in vivo. The oral PK data will be compared to the intraperitoneal PK data. Blood samples will be analyzed using LC/MS/MS. It is anticipated that at least one formulation containing one of the dimers will be identified with high oral bioavailability and willbe progressed to developmental studies during phase II. This STTR application represents a collaborative effort between ElSohly Laboratories, Inc. (ELI), and the Department of Pharmaceutics at the University of Mississippi (UM).