Calcium phosphate-interferon (CaP-IFN) particles for pulmonary delivery of IFN

用于肺部输送 IFN 的磷酸钙干扰素 (CaP-IFN) 颗粒

基本信息

批准号：
7539846
负责人：
TULIN MORCOL
金额：
$ 14.23万
依托单位：
BIOSANTE PHARMACEUTICALS, INC
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-11 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7539846
关键词：
Accounting Acute Adult Affect Agar Gel Electrophoresis Alpha Particles Alveolar Macrophages Animal Model Animals Antiviral Agents Anxiety Area Area Under Curve Biological Biological Assay Biological Availability Biological Preservation Blood Blood Circulation Blood specimen Breathing Caliber Cell Line Cells Cessation of life Characteristics Chronic Chronic Hepatitis B Clinical Complementary DNA Condition Consultations Cultured Cells Cytoplasmic Protein Data Deposition Developed Countries Development Dose Drug Delivery Systems Drug Formulations Drug Kinetics Enzyme-Linked Immunosorbent Assay Equation Europe Exubera Fluorescence Gastrointestinal tract structure Gene Expression Genes Goals Growth Hand Harvest Health Hepatitis B Hepatitis B Therapy Hepatitis B Virus Hepatitis C Hepatitis C virus Hour Housing Human Imaging Techniques In Vitro Individual Infection Inflammatory Response Infusion procedures Injection of therapeutic agent Insulin Interferon-alpha Interferon-beta Interferons Intramuscular Intramuscular Injections Investigation Janus kinase Knowledge Label Laser Scanning Confocal Microscopy Laser Scanning Microscopy Left Life Lung Marketing Mediating Methods Microscopic Molecular Monitor Morphology Mus Nanosphere Nature Nuclear Numbers Pain Particle Size Pathway interactions Patients Peripheral Blood Lymphocyte Pharmaceutical Preparations Phase Phosphorylation Placebos Play Pneumonia Polyethylene Glycols Polymerase Chain Reaction Polystyrenes Precipitation Primary carcinoma of the liver cells Process Property Proteins Protocols documentation Public Health Purpose RNA Radio Range Rate Rattus Relative (related person)Replicon Research Reverse Transcriptase Polymerase Chain Reaction Risk Role Route STAT protein Sampling Screening procedure Self-Administered Serum Signal Transduction Solutions Source Spectroscopy, Fourier Transform Infrared Spectrum Analysis Staging Stream Structural Protein Structure of parenchyma of lung Subcutaneous Injections Surface Suspension substance Suspensions Syringes System Technology Time Toxic effect Transcriptional Activation Treatment Protocols United States United States Food and Drug Administration United States National Institutes of Health Viral Physiology Virus Diseases Week World Health Organization absorption activating transcription factor base calcium phosphate cytokine design experience human disease improved in vivo insulin, polyethylene glycol(B1)-interferon therapy macrophage member nanocarrier nanoparticle particle pathogen preclinical study prevent research and development residence response size subcutaneous therapeutic protein time interval time use transmission process uptake

项目摘要

DESCRIPTION (provided by applicant): Chronic infections with hepatitis B or hepatitis C viruses are global health problems affecting hundreds of millions of people worldwide. Various commercial products of interferon alpha are approved in the United States for the treatment of adults with hepatitis B and hepatitis C. However, therapy with interferon involves multiple weekly injections via intramuscular or subcutaneous routes, which can be inconvenient, sometimes painful, and often anxiety producing. Because of its widespread and long-term use by the patients with chronic hepatitis B and hepatitis C, and because it is predominantly delivered by parenteral routes, interferon alpha is considered as one of the leading therapeutic protein candidates for delivery via alternative routes. With the approval of the first inhaled insulin product by the US FDA, pulmonary route has proved to be a viable alternative to injection in the treatment of acute human diseases. Thus, the development of an effective and convenient pulmonary administration methods for interferon alpha would be a significant improvement for the lives of patients who are currently receiving interferon therapy by injection. In this Phase I, we describe a method to develop interferon alpha formulations for pulmonary administration using our biodegradable and non-toxic calcium phosphate (CaP) particle technology. The design of the delivery system incorporates our knowledge, understanding, and previous experience in formulating protein drugs for pulmonary administration. The proposed formulation consists of IFN-incorporated CaP particles, which are manufactured in the presence of polyethylene glycol. The Phase I of the project includes formulation, physicochemical and biophysical characterization of the proposed IFN delivery system to assist us in formula optimization and process development. The biological viability of IFN, post formulation, will be judged, by evaluating its potential to activate IFN-induced cellular pathways in HepG2 cell cultures, and its anti-viral activity in a HCV replicon sytem. The potential of CaP-IFN particles to deliver IFN across the lungs into systemic circulation will be evaluated in normal rats using intratracheal administration approach. The clearance of CaP particles from the lungs following the intratracheal administration will be evaluated using fluorescence labeling and microscopic imaging techniques. The aims of Phase I are designed to guide us to identify the critical parameters of the proposed pulmonary delivery system for IFN for further investigation in Phase II. Public Health Relevance: In the current Phase I, feasibility of developing an interferon alpha formulation for pulmonary administration using BioSante's proprietary calcium phosphate (CaP) particle technology will be investigated. The proposed formulation for preliminary investigation will be developed by co-precipitation if IFN alpha with CaP particles in the presence of polyethylene glycol (PEG-3350). The components of CaP-PEG-IFN delivery system are all listed as `Generally Regarded as Safe', or GRAS, by the US FDA. Phase I of the project includes formulation and physicochemical characterization of the proposed IFN delivery system to assist us in formula optimization and process development. The retention of biological activity of IFN in the formulation will be evaluated in-vitro using a human hepatoma HepG2 cell line and by screening for the IFN-induced activation of 2',5' OAS genes by a R/T PCR method. The potential of CaP-IFN particles to deliver IFN across the lungs into the blood stream will be evaluated in normal rats using intratracheal administration approach. The clearance of CaP-IFN particles from the lungs following the intratracheal administration will be evaluated using fluorescence labeling and fluorescents imaging techniques. A decision whether to proceed into Phase II or not will be made based on the critical review of the findings by the members of the project team and based on consultations with NIH and other colleagues in the field.

描述（由申请人提供）：乙型肝炎或丙型肝炎病毒的慢性感染是影响全世界数亿人的全球健康问题。干扰素α的各种商业产品在美国被批准用于治疗患有乙型肝炎和丙型肝炎的成人。然而，干扰素治疗需要通过肌内或皮下途径每周多次注射，这可能不方便，有时痛苦，而且常常令人焦虑生产。由于慢性乙型肝炎和丙型肝炎患者广泛且长期使用，并且主要通过肠胃外途径递送，干扰素α被认为是通过替代途径递送的主要治疗性蛋白质候选者之一。随着第一个吸入胰岛素产品获得美国FDA的批准，肺途径已被证明是治疗人类急性疾病的注射胰岛素的可行替代方案。因此，开发一种有效且方便的干扰素α肺部给药方法将显着改善目前接受注射干扰素治疗的患者的生活。在第一阶段，我们描述了一种使用我们的可生物降解且无毒的磷酸钙 (CaP) 颗粒技术开发用于肺部给药的干扰素 α 制剂的方法。递送系统的设计结合了我们在配制用于肺部给药的蛋白质药物方面的知识、理解和先前经验。所提出的配方由掺有 IFN 的 CaP 颗粒组成，该颗粒是在聚乙二醇存在下制造的。该项目的第一阶段包括拟议的干扰素递送系统的配方、物理化学和生物物理表征，以帮助我们进行配方优化和工艺开发。通过评估其在 HepG2 细胞培养物中激活 IFN 诱导的细胞途径的潜力以及其在 HCV 复制子系统中的抗病毒活性，可以判断配制后 IFN 的生物活性。将使用气管内给药方法在正常大鼠中评估 CaP-IFN 颗粒将 IFN 穿过肺部递送至体循环的潜力。气管内给药后，CaP 颗粒从肺部的清除率将使用荧光标记和显微成像技术进行评估。第一阶段的目标旨在指导我们确定拟议的 IFN 肺部输送系统的关键参数，以便在第二阶段进行进一步研究。公共卫生相关性：在当前的第一阶段，将研究使用 BioSante 专有的磷酸钙 (CaP) 颗粒技术开发用于肺部给药的干扰素 α 制剂的可行性。拟议的初步研究配方将通过在聚乙二醇 (PEG-3350) 存在下将 IFN α 与 CaP 颗粒共沉淀来开发。 CaP-PEG-IFN 递送系统的成分均被美国 FDA 列为“普遍认为安全”（GRAS）。该项目的第一阶段包括拟议的干扰素递送系统的配方和理化表征，以帮助我们进行配方优化和工艺开发。将使用人肝癌HepG2细胞系并通过R/T PCR方法筛选IFN诱导的2',5'OAS基因的激活来体外评价制剂中IFN生物活性的保留。将使用气管内给药方法在正常大鼠中评估 CaP-IFN 颗粒将 IFN 穿过肺部输送到血流中的潜力。气管内给药后，CaP-IFN 颗粒从肺部的清除率将使用荧光标记和荧光成像技术进行评估。是否进入第二阶段的决定将基于项目团队成员对研究结果的严格审查以及与 NIH 和该领域其他同事的协商。