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

描述（由申请方提供）：天然产物青蒿素是一种倍半萜类内过氧化物，已知对氯喹敏感和氯喹抗性寄生虫恶性疟原虫株具有抗疟疾活性。除了其抗疟疾活性外，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，我们小组进行的青蒿素工作已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原生动物感染，以及与国家癌症研究所（NCI）和抗肿瘤筛选计划的合作。类似物DHA二聚体肟及其半琥珀酸酯（HS）在NCI筛选计划中显示出非常有希望的结果，并在我们最初的体外和体内研究中显示出对疟疾的强活性。然而，口服抗疟药所需的剂量大约是腹腔注射剂量的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、在胃肠液中的溶解度差、穿过胃肠壁的渗透性有限或首过代谢。因此，本提案的总体目标是阐明口服吸收受限背后的因素，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实现，包括：1：DHA二聚体肟和DHA二聚体肟半琥珀酸酯的合成：这是表征为用于口服生物利用度研究的主要二聚体的两种化合物。第二章：这些DHA二聚体的生物制药特性的评价：这些研究将包括溶解度、logP、pH稳定性曲线、在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的口服生物利用度的限制。第三章： 制剂方法的开发：基于目标2中的发现，将通过体外渗透性实验研究克服挑战的各种策略，包括增溶和稳定方法、渗透促进剂和纳米颗粒剂型的纳入。4：大鼠口服生物利用度的描述：最后，将在体内测试有前景的制剂。将口服PK数据与腹膜内PK数据进行比较。将使用LC/MS/MS分析血样。预计至少一种含有一种二聚体的制剂将被鉴定为具有高口服生物利用度，并将在II期进行开发研究。本STTR应用程序代表ElSohly Laboratories，Inc. (ELI)和密西西比大学（UM）的药剂学系。

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).