Myrdal Paul B, Karlage Kelly L, Stein Steve W, Brown Beth A, Haynes Alfred
College of Pharmacy, University of Arizona, 1703 East Mabel Street, Tucson, Arizona 85721, USA.
J Pharm Sci. 2004 Apr;93(4):1054-61. doi: 10.1002/jps.20025.
The goal of this study was to illustrate the potential to deliver relatively high doses of a therapeutic peptide using hydrofluoroalkane (HFA) metered dose inhaler (MDI) drug delivery systems. For the purposes of this study, cyclosporine was used as the model compound. Cyclosporine formulations, varying in peptide concentration, ethanol cosolvent concentration, and propellant type, were evaluated and optimized for product performance. As ethanol concentration was decreased from 10 to 3% by weight, fine particle fraction (the mass of cyclosporine which passes through a 4.7-micron cut point divided by the total mass of cyclosporine delivered ex-valve) increased from 34 to 68% for 227 and 33 to 52% for 134a formulations. Because of the excellent solubility properties of cyclosporine in HFA-based systems, minimal or no ethanol was needed as a cosolvent to achieve cyclosporine concentrations of 1.5% w/w. With these formulations, it was possible to obtain a fine particle mass (mass of particles <4.7 microns) greater than 500 microg per actuation. In addition, one formulation was chosen for stability analysis: 0.09% w/w cyclosporine, 10% w/w ethanol, 134a. Three different types of container closure systems (stainless steel, aluminum, and epoxy-coated canisters) and two storage configurations (upright and inverted) were evaluated. Cyclosporine was determined to be stable in HFA 134a-based MDI systems, regardless of container closure system and configuration, over a 2-year period. Cyclosporine represents a compelling example of how significant peptide doses are attainable through the use of solution-based MDIs. It has been shown that through formulation optimization, 2-3 mg of the peptide, cyclosporine, may be delivered in five actuations to the lung for local or systemic therapy.
本研究的目的是阐明使用氢氟烷烃（HFA）定量吸入器（MDI）给药系统递送相对高剂量治疗性肽的潜力。在本研究中，环孢素被用作模型化合物。对不同肽浓度、乙醇助溶剂浓度和推进剂类型的环孢素制剂进行了评估，并针对产品性能进行了优化。当乙醇浓度从10%（重量）降至3%时，227制剂的细颗粒分数（通过4.7微米切割点的环孢素质量除以阀后递送的环孢素总质量）从34%增加到68%，134a制剂从33%增加到52%。由于环孢素在基于HFA的系统中具有优异的溶解性，因此只需极少或无需乙醇作为助溶剂即可达到1.5%（w/w）的环孢素浓度。使用这些制剂，每次按压可获得大于500微克的细颗粒质量（颗粒<4.7微米的质量）。此外，选择了一种制剂进行稳定性分析：0.09%（w/w）环孢素、10%（w/w）乙醇、134a。评估了三种不同类型的容器封闭系统（不锈钢、铝和环氧涂层罐）和两种储存配置（直立和倒置）。结果表明，在两年时间内，无论容器封闭系统和配置如何，环孢素在基于HFA 134a的MDI系统中都是稳定的。环孢素是一个有说服力的例子，说明通过使用基于溶液的MDI可以实现显著的肽剂量。研究表明，通过制剂优化，2 - 3毫克的肽环孢素可在五次按压中递送至肺部用于局部或全身治疗。
