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:
  • 金额:
    $ 42.85万
  • 依托单位:
  • 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

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,我们计划开发用于治疗肺动脉高压(PAH)的药物控释可吸入制剂,PAH是一种罕见但使人衰弱和致命的疾病,在美国影响约50,000至100,000人。PAH的当前治疗在给药难易性、安全性、疗效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,前列环素类似物吉泊前列醇、曲前列尼尔和伊洛前列素被认为是一线治疗药物。然而,这类药物的主要缺点是它们的半衰期非常短,这要求它们通过连续输注或每天多次给药来施用。与使用中心导管、给药部位感染、制剂在室温下不稳定以及因输注中断导致的心血管虚脱相关的风险是依前列醇和曲前列尼尔治疗PAH的潜在严重并发症。虽然目前有一种吸入性前列环素类似物伊洛前列素,但由于其半衰期短,仅为20-30分钟,因此必须每天吸入9-12次。最近,法舒地尔甘作为一类新的抗PAH药物,在动物模型中显示出降低PAH的潜力。然而,目前尚无关于该药物治疗PAH的长期安全性和有效性的数据。与当前PAH治疗相关的挑战可以通过将它们配制成可吸入控释聚合物和生物可降解纳米或微粒来克服,以用于选择性和长期的肺动脉活性。因此,本项目中要检验的假设是:封装在长效可吸入颗粒中的抗PAH药物是一种有效且患者依从性良好的治疗方法,可长期治疗PAH。本研究的目的将通过在控释颗粒载体中配制伊洛前列素(市售可吸入前列环素类似物)和法舒地尔(Rho激酶抑制剂)来实现。最初将在体外和体内测试拟定制剂通过肺部途径递送的适用性。将在PAH诱导的啮齿动物模型中检测和交叉比较两种药物制剂的疗效。将在三组实验(支气管肺泡灌洗、粘液纤毛转运率测量和肺组织病理学变化评估)中研究安全性。本项目的长期目标是生成关于拟定给药系统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,它限制了血液通过肺动脉的流动,导致右心衰竭和死亡。依前列醇、曲前列尼尔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,我们计划开发一种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。如果成功的话,确定一种持久有效的可吸入制剂将消除对导管和每日多次给药的需要。这将提高这种毁灭性疾病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:
  • 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.
PEI作为核心修饰剂对PGE₁的PLGA微球的影响,PGE₁是肺选择性血管扩张剂。
  • DOI:
    10.1016/j.ijpharm.2011.04.017
  • 发表时间:
    2011-07-15
  • 期刊:
  • 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:
  • 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
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Fakhrul Ahsan其他文献

Fakhrul Ahsan的其他文献

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{{ truncateString('Fakhrul Ahsan', 18)}}的其他基金

Inhaled Fasudil and DETA NONOate CAR-Targeted Liposomes for PAH
吸入法舒地尔和 DETA NONOate CAR 靶向脂质体治疗 PAH
  • 批准号:
    10478270
  • 财政年份:
    2021
  • 资助金额:
    $ 42.85万
  • 项目类别:
Inhaled Fasudil and DETA NONOate CAR-Targeted Liposomes for PAH
吸入法舒地尔和 DETA NONOate CAR 靶向脂质体治疗 PAH
  • 批准号:
    10274778
  • 财政年份:
    2021
  • 资助金额:
    $ 42.85万
  • 项目类别:
Inhaled Fasudil and DETA NONOate CAR-Targeted Liposomes for PAH
吸入法舒地尔和 DETA NONOate CAR 靶向脂质体治疗 PAH
  • 批准号:
    9907530
  • 财政年份:
    2020
  • 资助金额:
    $ 42.85万
  • 项目类别:
Recapitulation of sex- disparity in PAH on a microfluidic device and elucidation of the differences and similarities in the development, progression and therapy of PAH in male versus female patients
在微流体装置上重述 PAH 的性别差异,并阐明男性与女性患者在 PAH 的发生、进展和治疗方面的差异和相似之处
  • 批准号:
    10373119
  • 财政年份:
    2019
  • 资助金额:
    $ 42.85万
  • 项目类别:
Recapitulation of sex- disparity in PAH on a microfluidic device and elucidation of the differences and similarities in the development, progression and therapy of PAH in male versus female patients
在微流体装置上重述 PAH 的性别差异,并阐明男性与女性患者在 PAH 的发生、进展和治疗方面的差异和相似之处
  • 批准号:
    10307038
  • 财政年份:
    2019
  • 资助金额:
    $ 42.85万
  • 项目类别:
Targetable and Inhalable Nanoparticle Based Combination Therapy for PAH
基于靶向和可吸入纳米颗粒的 PAH 联合疗法
  • 批准号:
    9040247
  • 财政年份:
    2015
  • 资助金额:
    $ 42.85万
  • 项目类别:
Alkylglycoside Mediated Pulmonary Delivery of Heparins
烷基糖苷介导的肝素肺部输送
  • 批准号:
    6804856
  • 财政年份:
    2004
  • 资助金额:
    $ 42.85万
  • 项目类别:
Long Circulating Low Molecular Weight Heparins Pulmonary
长循环低分子肝素肺
  • 批准号:
    7127816
  • 财政年份:
    2004
  • 资助金额:
    $ 42.85万
  • 项目类别:

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