In vitro and in vivo efficacy of liposomal ciprofloxacin formulations against Myc

脂质体环丙沙星制剂抗 Myc 的体外和体内功效

• 批准号: 8520962
• 负责人: Luiz Eduardo Bermudez
• 金额: $ 27.78万
• 依托单位: ARADIGM CORPORATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520962
• 关键词: AIDS/HIV problem; Abscess; Acquired Immunodeficiency Syndrome; Amikacin; Animals; Antibiotics; Antimycobacterial Agents; Bacteria; Biological Assay; Breathing; Bronchiectasis; Cefoxitin; Chronic; Chronic lung disease; Ciprofloxacin; Clarithromycin; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Complication; Cyclic GMP; Cystic Fibrosis; Data; Diagnosis; Disease; Dose; Drug Formulations; Encapsulated; Ethambutol; FDA approved; Funding; Future; Genus Mycobacterium; Health; Human; Imipenem; Immunosuppression; In Vitro; Incidence; Individual; Infection; Liposomes; Liver; Lung; Lung diseases; Marketing; Measures; Microbial Biofilms; Modeling; Mus; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Nebulizer; Oral; Patients; Pharmaceutical Preparations; Phase; Program Development; Pseudomonas aeruginosa; Pulmonary Emphysema; Regimen; Research; Resistance; Resistance development; Safety; Site; Small Business Innovation Research Grant; Solutions; Spleen; System; Systemic Therapy; Testing; Treatment Efficacy; Vial device; base; chemotactic factor inactivator; commercial application; cystic fibrosis mouse; cystic fibrosis patients; efficacy testing; efficacy trial; in vitro Model; in vivo; in vivo Model; intraperitoneal; liquid formulation; macrophage; mouse model; mycobacterial; pathogen; patient population; programs; public health relevance

DESCRIPTION (provided by applicant): Lung infections by Mycobacterium avium and Mycobacterium abscessus are increasing in incidence. Diseases caused by both Mycobacteria are common in patients with chronic lung conditions, such as cystic fibrosis (CF), non-CF bronchiectasis and emphysema. In patients with AIDS, the M. avium infection is disseminated. The current clinical paradigm is to treat patients with M. avium or M. abscessus lung infections or M. avium disseminated infection with combination therapy given orally or by IV. Unfortunately, these therapies often fail. Thus, there is a need to develop new anti-mycobacterial therapies for both diseases. The overall objective of this project is test the efficacy of two new formulations of ciprofloxacin (Ciprofloxacin for Inhalation, CFI, Lipoquin(R); and Dual Release Ciprofloxacin for Inhalation, DRCFI, Pulmaquin(R)), developed recently specifically for inhalation a) alone and b) in combination with other anti- mycobacterial agents using in vitro and in vivo models of M. avium and M. abscessus lung infection and M. avium disseminated infection. The superior formulation(s) will then be taken into human clinical trials. Both formulations are comprised of ciprofloxacin encapsulated in liposomes, which provide sustained slow release of the ciprofloxacin from the liposome, allowing for once-daily dosing. The DRCFI formulation is a mixture of CFI and free ciprofloxacin, a non-liposomal solution. The rationale for developing DRCFI is to combine the advantages of an initial transient high concentration of free ciprofloxacin to increase maximum levels in the lung from the free ciprofloxacin component of DRCFI, followed by the slow release of ciprofloxacin from the CFI (liposomal component). Another advantage of these formulations is that the liposomes are avidly ingested by macrophages, bringing the ciprofloxacin into close proximity to the intracellular pathogens, thus further increasing anti-mycobacterial efficacy of the liposomal formulation compared to free ciprofloxacin alone. The specific aims are: 1) to test different concentrations of CFI and DRCFI in the macrophage test system: a) alone and in combination with clarithromycin, ethambutol, and amikacin against 3 clinical isolates of M. avium; b) alone and in combination with imipenem, cefoxitin, and amikacin against 3 clinical isolates of M. abscessus; 2) to test the same regimen of antibiotics against biofilms of M. abscess us and M. avium; 3) to test the in vivo efficacy of CFI and DRCFI in a mouse model of M. avium or M. abscess us lung infection; and 4) to test the same regimen as Aim 3 for M. avium in a mouse model of M. avium disseminated infection. If an efficacious treatment with CFI or DRCFI (alone or in combination with other drugs) is identified, we will progress into clinical studies in patiens with M. avium or M. abscessus lung infection or with M. avium disseminated infection, including those patients with HIV/AIDS. Aradigm already has sufficient safety data in humans and animals to support long-term clinical studies in patients with CFI and DRCFI as well as sufficient cGMP manufacturing in place to support large-scale clinical trials.

描述（由申请人提供）：由鸟分枝杆菌和脓肿分枝杆菌引起的肺部感染的发病率正在增加。由这两种分枝杆菌引起的疾病在慢性肺病患者中很常见，如囊性纤维化（CF）、非CF支气管扩张和肺气肿。在艾滋病患者中，鸟支原体感染是播散性的。目前的临床范例是口服或静脉注射联合治疗鸟分枝杆菌或脓肿分枝杆菌肺部感染或鸟分枝杆菌播散性感染的患者。不幸的是，这些治疗经常失败。因此，有必要为这两种疾病开发新的抗分枝杆菌疗法。该项目的总体目标是测试两种新配方环丙沙星的疗效(吸入用环丙沙星，CFI, Lipoquin(R)；和吸入用双释放环丙沙星，DRCFI, Pulmaquin(R))，最近专门用于吸入a)单独和b)与其他抗分枝杆菌药物联合使用，用于体外和体内模型的鸟支原体和脓肿支原体肺部感染和鸟支原体播散性感染。然后，优越的配方将被用于人体临床试验。这两种制剂均由包封在脂质体中的环丙沙星组成，提供环丙沙星从脂质体持续缓慢释放，允许每日一次给药。DRCFI制剂是CFI和游离环丙沙星（一种非脂质体溶液）的混合物。开发DRCFI的基本原理是结合初始瞬时高浓度游离环丙沙星的优势，通过DRCFI的游离环丙沙星成分增加肺中的最大水平，然后从CFI（脂质体成分）缓慢释放环丙沙星。这些制剂的另一个优点是脂质体被巨噬细胞大量摄取，使环丙沙星更接近细胞内病原体，从而与单独游离环丙沙星相比，进一步提高了脂质体制剂的抗分枝杆菌功效。具体目的是：1)在巨噬细胞试验系统中测试不同浓度的CFI和DRCFI: a)单独和联合克拉霉素、乙胺丁醇和阿米卡星对3种临床分离的鸟分枝杆菌的作用；b)单独或联合亚胺培南、头孢西丁和阿米卡星治疗3株临床分离的脓肿支原体；2)试验同一方案抗生素对脓肿支原体和鸟支原体生物膜的作用；3)检测CFI和DRCFI对鸟分枝杆菌或脓肿分枝杆菌肺部感染小鼠模型的体内疗效；4)在鸟分枝杆菌播散性感染小鼠模型中测试与Aim 3相同的方案。如果CFI或DRCFI（单独或与其他药物联合）的有效治疗被确定，我们将在鸟分枝杆菌或脓肿分枝杆菌肺部感染或鸟分枝杆菌播散性感染患者（包括艾滋病毒/艾滋病患者）中进行临床研究。Aradigm已经有足够的人类和动物安全性数据来支持CFI和DRCFI患者的长期临床研究，以及足够的cGMP生产来支持大规模临床试验。