Anti-PAH Drugs in Inhalable Nanoparticles for Sustained Pulmonary Vasodilation

可吸入纳米颗粒中的抗多环芳烃药物用于持续肺血管舒张

基本信息

批准号：
7936160
负责人：
Fakhrul Ahsan
金额：
$ 42.85万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2013-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7936160
关键词：
Address Affect Alprostadil Alveolar Macrophages Animal Model Antihypertensive Agents Biodistribution Blood Vessels Blood flow Breathing Bronchoalveolar Lavage Cardiovascular system Categories Catheters Cessation of life Chronic Disease Clinical Trials Continuous Infusion Data Development Disease Dose Drug Formulations Drug Kinetics Drug Stability Drug usage Effectiveness Encapsulated Epoprostenol Generations Glycolates Goals Half-Life Heart failure Human Human Volunteers Iloprost In Vitro Infection Infusion procedures Interruption Intravenous Investigational Drugs Laboratories Literature Lung Marketing Measurement Metabolic Mucociliary Clearance Particulate Patients Phagocytosis Pharmaceutical Preparations Pharmacologic Substance Powder dose form Property Prostaglandins I Pulmonary Circulation Pulmonary Hypertension Pulmonary artery structure Quality of life Rare Diseases Rho-associated kinase Risk Rodent Rodent Model Route Safety Site System Temperature Testing Therapeutic Therapeutic Agents Time Treprostinil United States Vasodilation aerosolized analog base comparative comparative efficacy controlled release drug efficacy fasudil healthy volunteer improved in vitro testing in vivo inhibitor/antagonist intravenous administration kinase inhibitor nano nanoparticle particle phosphodiesterase V pre-clinical pressure public health relevance pulmonary arterial hypertension receptor research study treatment duration

项目摘要

DESCRIPTION (provided by applicant): In this project, we propose to develop controlled release inhalable formulations of drugs used for the treatment of pulmonary arterial hypertension (PAH), a rare but debilitating and lethal disorder that affects around 50,000 to 100,000 people in the United States. Current therapy for PAH is challenging with regard to ease of administration, safety, efficacy and stability. Medications currently used to treat PAH include endothelial receptor antagonists, phosphodiesterase-5 inhibitors and prostacyclin analogues. Of these, prostacyclin analoguesgepoprostenol, treprostinil, and iloprostgare considered the first-line therapeutic agents. However, a major shortcoming of this class of drugs is their very short half-lives, which requires that they be administered by continuous infusion or multiple dosings per day. The risks associated with the use of a central catheter, infection at the site of administration, instability of the formulations at room temperature, and cardiovascular collapse due to interruption of infusion are the potentially serious complications of PAH therapy with epoprostenol and treprostinil. Although an inhaled prostacyclin analogue, iloprost, is currently available, this drug must be inhaled 9-12 times per day because of its short half-life of 20-30 minutes. Recently, fasudilgan investigational drug that belongs to a new class of anti-PAH drugsghas shown potential in reducing PAH in animal models. However, there is currently no data on the long-term safety and efficacy of the drug for the treatment of PAH. The challenges associated with current PAH therapy can be overcome by formulating them in inhalable controlled release polymeric and lipidic nano- or microparticles for selective and long-term pulmonary arterial activity. Thus, the hypothesis to be tested in this project is: Anti-PAH drugs encapsulated in long-acting inhalable particles are an efficacious and patient-compliant therapy for the long-term treatment of PAH. The objectives of this study will be accomplished by formulating iloprost, a commercially available inhalable prostacyclin analogue, and fasudil, a Rho-kinase inhibitor, in controlled release particulate carriers. The proposed formulations will initially be tested in vitro and in vivo for their suitability to be delivered via the pulmonary route. The efficacies of the formulations of the two drugs will be tested and cross-compared in PAH-induced rodent models. The safety will be investigated in three sets of experiments bronchoalveolar lavage, measurement of mucociliary transport rate, and assessment of the histopathological changes in the lungs. The long-term goal of this project is to generate preclinical data on the safety and efficacy of the proposed delivery system, so that further testing can be carried out in healthy volunteers and patients with PAH. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is a rare disease that restricts the flow of blood through the pulmonary arteries of the lungs, which leads to right heart failure and death. Epoprostenol, treprostinil, and iloprost are three important drugs that are currently used to treat PAH. Unfortunately, the first two drugs must be administered by using an intravenous catheter and the third one must be inhaled 6 to 12 times a day. These problems limit the effectiveness of these drugs in the treatment of PAH. In this project, we propose to develop a controlled release inhalable formulation of iloprost and an investigational drug fasudil and compare the efficacy of one drug with the other. If successful, identification of a long-lasting and efficacious inhalable formulation will eliminate the need for a catheter and multiple daily dosings. This will improve the quality of life and survival of patients with this devastating disease.

描述（由申请人提供）：在该项目中，我们建议开发用于治疗肺动脉高压（PAH）的药物的控释吸入制剂，这是一种罕见但使人衰弱和致命的疾病，影响着美国约 50,000 至 100,000 人国家。目前的 PAH 治疗在给药便利性、安全性、有效性和稳定性方面具有挑战性。目前用于治疗PAH的药物包括内皮受体拮抗剂、磷酸二酯酶5抑制剂和前列环素类似物。其中，前列环素类似物吉前列醇、曲前列环素和伊洛前列素被认为是一线治疗药物。然而，这类药物的一个主要缺点是它们的半衰期很短，这需要它们通过连续输注或每天多次给药的方式给药。与使用中心导管、给药部位感染、室温下制剂不稳定以及因输注中断导致的心血管衰竭相关的风险是依前列醇和曲前列环素治疗 PAH 的潜在严重并发症。虽然目前有吸入性前列环素类似物伊洛前列素，但由于该药物的半衰期较短，为 20-30 分钟，因此必须每天吸入 9-12 次。最近，属于新型抗多环芳烃药物的研究药物fasudilgan在动物模型中显示出减少多环芳烃的潜力。但目前尚无该药物治疗PAH的长期安全性和有效性的数据。与当前多环芳烃治疗相关的挑战可以通过将其配制为可吸入的控释聚合物和脂质纳米或微粒来克服，以实现选择性和长期的肺动脉活性。因此，本项目要测试的假设是：封装在长效可吸入颗粒中的抗PAH药物是长期治疗PAH的有效且患者依从的疗法。本研究的目标将通过在控释颗粒载体中配制伊洛前列素（一种市售的可吸入前列环素类似物）和法舒地尔（一种 Rho 激酶抑制剂）来实现。所提出的制剂最初将在体外和体内测试其是否适合通过肺部途径递送。两种药物制剂的功效将在多环芳烃诱导的啮齿动物模型中进行测试和交叉比较。安全性将通过三组实验进行研究：支气管肺泡灌洗、粘液纤毛转运率测量和肺部组织病理学变化评估。该项目的长期目标是生成有关所提出的输送系统的安全性和有效性的临床前数据，以便可以在健康志愿者和 PAH 患者中进行进一步的测试。公共卫生相关性：肺动脉高压 (PAH) 是一种罕见疾病，会限制肺部肺动脉的血液流动，导致右心衰竭和死亡。依前列醇、曲前列环素和伊洛前列素是目前用于治疗PAH的三种重要药物。不幸的是，前两种药物必须通过静脉导管给药，而第三种药物必须每天吸入 6 至 12 次。这些问题限制了这些药物治疗PAH的有效性。在该项目中，我们建议开发伊洛前列素和研究药物法舒地尔的控释吸入制剂，并比较一种药物与另一种药物的疗效。如果成功，找到一种持久有效的吸入制剂将消除对导管和每日多次给药的需要。这将改善患有这种毁灭性疾病的患者的生活质量和生存率。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Starch-coated magnetic liposomes as an inhalable carrier for accumulation of fasudil in the pulmonary vasculature.

DOI：
10.1016/j.ijpharm.2014.01.007
发表时间：
2014-04-10
期刊：
INTERNATIONAL JOURNAL OF PHARMACEUTICS
影响因子：
5.8
作者：
Nahar, Kamrun;Absar, Shahriar;Patel, Brijeshkumar;Ahsan, Fakhrul
通讯作者：
Ahsan, Fakhrul

Influence of PEI as a core modifying agent on PLGA microspheres of PGE₁, a pulmonary selective vasodilator.

DOI：
10.1016/j.ijpharm.2011.04.017
发表时间：
2011-07-15
期刊：
INTERNATIONAL JOURNAL OF PHARMACEUTICS
影响因子：
5.8
作者：
Gupta, Vivek;Ahsan, Fakhrul
通讯作者：
Ahsan, Fakhrul

Fasudil and SOD packaged in peptide-studded-liposomes: Properties, pharmacokinetics and ex-vivo targeting to isolated perfused rat lungs.

DOI：
10.1016/j.ijpharm.2015.04.031
发表时间：
2015-07-05
期刊：
INTERNATIONAL JOURNAL OF PHARMACEUTICS
影响因子：
5.8
作者：
Gupta, Nilesh;Al-Saikhan, Fahad I.;Patel, Brijeshkumar;Rashid, Jahidur;Ahsan, Fakhrul
通讯作者：
Ahsan, Fakhrul

Cell permeable peptide conjugated nanoerythrosomes of fasudil prolong pulmonary arterial vasodilation in PAH rats.