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

描述（由申请人提供）：天然产物青蒿素是一种倍半萜内过氧化物，已知对氯喹敏感型和氯喹耐药型恶性疟原虫具有抗疟疾活性。除了抗疟疾活性外，据报道青蒿素对几种不同的肿瘤细胞系具有细胞毒活性。最近，我们小组开展的青蒿素工作已经扩展到一系列双氢青蒿素二聚体（DHA二聚体）的制备和这些二聚体对原生动物感染的检测，以及与美国国家癌症研究所（NCI）和抗肿瘤筛查项目的合作。类似物DHA二聚体肟及其半琥珀酸酯（HS）在NCI筛选程序中显示出非常有希望的结果，并在初步的体外和体内研究中显示出很强的抗疟疾活性。然而，所需的口服抗疟疾剂量比腹腔注射剂量大约高10倍。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/前药在胃肠道中的降解，在胃肠道液体中的溶解度差，通过胃肠道壁的渗透性有限或首次代谢。因此，本提案的总体目标是阐明有限口服吸收背后的因素，并通过克服口服吸收面临的挑战的策略开发具有高口服生物利用度的制剂。这将通过一系列具体目标来完成，其中包括：1：合成DHA二聚肟和DHA半旋二聚肟：这两种化合物被认为是口服生物利用度研究的主要二聚体。2：评价这些DHA二聚体的生物制药特性：这些研究将包括溶解度、logP、pH稳定性、胃肠道和肝酶存在下的代谢稳定性以及化合物的体外渗透性。获得的数据将有助于确定这些化合物口服生物利用度的限制。3：

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).