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

• 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
• 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

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(申请人提供)：慢性乙肝或丙型肝炎病毒感染是影响全球数亿人的全球性健康问题。各种商业产品的干扰素α在美国已被批准用于成人乙肝和丙型肝炎的治疗。然而，干扰素的治疗需要通过肌肉或皮下途径每周多次注射，这可能会带来不便，有时还会疼痛，而且经常会产生焦虑。由于干扰素被慢性乙型肝炎和丙型肝炎患者广泛和长期使用，并且主要通过非肠道途径传递，干扰素被认为是通过替代途径传递的主要治疗蛋白质之一。随着美国FDA批准了第一个吸入型胰岛素产品，肺途径已被证明是治疗急性人类疾病的一种可行的注射替代方案。因此，开发一种有效和方便的α干扰素肺部给药方法将显著改善目前正在接受干扰素注射治疗的患者的生活。在这一阶段，我们描述了一种使用我们的可生物降解和无毒的磷酸钙(CAP)颗粒技术开发用于肺部给药的干扰素α制剂的方法。给药系统的设计结合了我们在配制肺部给药蛋白药物方面的知识、理解和以前的经验。建议的配方由含有干扰素的帽状颗粒组成，这些颗粒是在聚乙二醇存在下制造的。该项目的第一阶段包括建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。将通过评估干扰素在HepG2细胞培养中激活干扰素诱导的细胞通路的潜力以及在丙型肝炎病毒复制子系统中的抗病毒活性来判断制剂后干扰素的生物学活性。将使用气管内给药方法在正常大鼠身上评估卡巴-干扰素颗粒将干扰素通过肺部输送到体循环的潜力。将使用荧光标记和显微成像技术评估气管内给药后帽子颗粒从肺中的清除情况。第一阶段的目的是指导我们确定建议的干扰素肺部给药系统的关键参数，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的专有磷酸钙(CAP)颗粒技术开发用于肺部给药的干扰素α配方的可行性。初步研究的拟议配方将通过在聚乙二醇存在下将干扰素α与帽颗粒(聚乙二醇3350)共沉淀来开发。卡普-聚乙二醇-干扰素递送系统的所有组件都被美国FDA列为“一般认为是安全的”或GRAS。该项目的第一阶段包括建议的干扰素递送系统的配方和物理化学特性，以帮助我们进行配方优化和工艺开发。干扰素在制剂中的生物活性将在体外使用人肝癌细胞株进行评估，并通过R/T聚合酶链式反应方法筛选干扰素诱导的2‘，5’OAS基因的激活。将使用气管内给药方法在正常大鼠身上评估卡巴-干扰素颗粒将干扰素通过肺部输送到血流中的潜力。在气管内给药后，将使用荧光标记和荧光成像技术评估卡巴-干扰素颗粒从肺中的清除情况。将根据项目小组成员对调查结果的认真审查，并根据与国家卫生研究院和外地其他同事的协商，决定是否进入第二阶段。