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

• 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
• 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

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）：在此项目中，我们建议开发用于治疗肺动脉高压（PAH）的药物的可控释放，这是一种罕见但具有衰老和致命的疾病，影响了美国约50,000至100,000人。当前对PAH的治疗方面的易于管理，安全性，有效性和稳定性。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，前列环蛋白类似物替代烯醇，曲霉素和伊洛普洛斯特策视为一线治疗剂。但是，这类药物的主要缺点是它们的半衰期很短，这要求它们通过连续输注或每天多种剂量来给药。与使用中央导管，在给药部位感染，室温下的不稳定性以及由于输注中断引起的心血管崩溃的风险是PAH治疗嗜积酚和treprostinil的可能严重并发症。尽管目前可以使用一种吸入的前列环蛋白类似物伊洛普罗斯（Iloprost），但由于其半衰期为20-30分钟，该药物每天必须每天吸入9-12次。最近，属于一种新的抗PAH药物的Fasudilgan研究药物在减少动物模型中的PAH方面具有潜力。但是，目前尚无有关该药物治疗PAH的长期安全性和功效的数据。与当前PAH治疗相关的挑战可以通过在可吸入的控制释放聚合物和脂质纳米或微粒中以选择性和长期肺动脉活性来克服它们。因此，在该项目中要检验的假设是：封装在长效吸入颗粒中的抗PAH药物是对PAH长期治疗的有效且符合患者的疗法。这项研究的目标将通过在受控的释放颗粒携带者中制定伊洛列前列素（一种可商购的可吸入的前列环素类似物和一种Rho-激酶抑制剂Fasudil）来实现。最初将在体外和体内测试所提出的配方，以通过肺途径递送其适合性。两种药物制剂的功效将在PAH诱导的啮齿动物模型中进行测试和交叉比较。将在三组实验支气管肺泡灌洗，测量粘膜纤毛运输速率以及评估肺部组织病理学变化的情况下研究安全性。该项目的长期目标是生成有关拟议交付系统的安全性和功效的临床前数据，以便可以在健康的志愿者和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）是一种罕见的疾病，它限制了血液通过肺部肺动脉的流动，从而导致正确的心力衰竭和死亡。嗜oprostenol，treprostinil和伊洛普罗斯特是目前用于治疗PAH的三种重要药物。不幸的是，必须使用静脉内导管来施用前两种药物，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在治疗PAH中的有效性。在这个项目中，我们建议开发一个可控的释放伊洛前列素和研究性药物的可吸收配方，并将一种药物与另一种药物的功效进行比较。如果成功，可以识别持久和有效的吸入配方，将消除对导管和多种每日剂量的需求。这将改善这种毁灭性疾病患者的生活质量和生存。

项目成果

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

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

• DOI: 10.1016/j.ejpb.2014.10.012
• 发表时间: 2014-11
• 期刊: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
• 作者: Gupta N;Patel B;Nahar K;Ahsan F
• 通讯作者: Ahsan F

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