Anti-PAH Drugs in Inhalable Nanoparticles for Sustained Pulmonary Vasodilation

描述(申请人提供)：在这个项目中，我们建议开发用于治疗肺动脉高压(PAH)的药物的控释可吸入制剂。在美国，大约有50,000至10,000人受到这种罕见但令人衰弱和致命的疾病的影响。目前对PAH的治疗在易用性、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，前列环素类似物前列前列醇、曲普替尼和伊洛前列腺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半衰期非常短，这要求它们通过持续输液或每天多次给药。使用中心导尿管、给药部位感染、制剂在室温下不稳定以及因中断输液而导致的心血管衰竭等风险是使用环前列烯醇和曲普替尼治疗PAH的潜在严重并发症。虽然目前有吸入型前列环素类似物iloprost，但由于半衰期较短，每天必须吸入9-12次。近年来，一类新型的抗PAH药物法舒地甘在动物模型中显示出降低PAH的潜力。然而，目前还没有关于该药物治疗PAH的长期安全性和有效性的数据。目前与PAH治疗相关的挑战可以通过将其制成可吸入的、可控释的聚合物和脂类纳米或微粒来克服，以用于选择性和长期的肺动脉活动。因此，这个项目中要检验的假设是：长效可吸入颗粒中包裹的抗PAH药物是长期治疗PAH的有效和患者顺从的疗法。这项研究的目标将通过在控释微粒载体中配制可商业获得的可吸入前列环素类似物iloprost和Rho-Kinase抑制剂Fasudil来实现。建议的制剂最初将在体外和体内进行测试，以确定它们是否适合通过肺部途径给药。这两种药物配方的有效性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。安全性将在三组实验中进行调查，包括支气管肺泡灌洗、粘液纤毛传输速率的测量和肺组织病理学变化的评估。该项目的长期目标是生成有关拟议给药系统的安全性和有效性的临床前数据，以便在健康志愿者和PAH患者中进行进一步测试。 公共卫生相关性：肺动脉高压(PAH)是一种罕见的疾病，它限制血液通过肺的肺动脉流动，从而导致右心衰竭和死亡。埃前列烯醇、曲普替尼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，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。在这个项目中，我们建议开发一种伊洛前列素的控释吸入制剂和一种研究药物法舒地尔，并比较两种药物的疗效。如果成功，鉴定出一种持久有效的可吸入制剂将不再需要导管和每日多次给药。这将提高这种毁灭性疾病患者的生活质量和存活率。

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.