Non invasive methods to accelerate the development of injectable therapeutic depots

我们的愿景是创建一种低成本、非侵入性的仓库监控工具，可以实时提供有关注入仓库状态的关键信息。这种低成本的设备将应用于临床前研究和长效仓库开发的临床环境中，以加速这一过程。我们预计，该设备可以在家中开发，使患者受益，包括不同的肤色，作为一种评估和监测库性能的方式，使库剂量和未来的给药时间表能够个性化。我们的项目解决了目前制药行业对治疗药库的兴趣迅速增加的背景，并在此背景下是及时的，因为它是能够实现经典小分子药物和生物制剂的长期输送的药物，用于治疗包括癌症、艾滋病毒、神经疾病和精神病在内的疾病。长效库旨在几周或几个月的时间内控制患者的治疗；它消除了每天重复注射的必要性，以解决诸如血浆和组织药物水平的变化或长期患者治疗中的不依从性等问题。进一步推动需求的是，开发中需要长效注射技术的药物比例增加，特别是生物制品。目前，任何药物的长效注射库在其口服配方获得批准后，需要大约10年的开发时间才能推向市场。这是因为需要了解储存库在注射部位组织中的行为，以及对药物释放和治疗的生物利用度的关联影响。因此，为个别患者开发具有保证体内特定释药特征的长效库是极其困难的。此外，在药物开发或患者治疗期间，没有方法实时监测它们在临床前研究中的表现。我们的目标是基于光声原理开发一种低成本、非侵入性的可注射仓库表征工具的概念，该工具可以提供关于仓库特征和体内局部组织反应的信息。目标是：定义规范并建立原型光声仪器，该原型光声仪器将形成能够测量仓库行为关键参数的低成本设备的基础。设计、制造和优化原型光声仪器获取数据所需的长效仓库配方。这将包括选择储存库的组成成分和药物，以及选择合适的光声造影剂。使用(I)建立的体外组织模拟模型和(Ii)临床前、体内注射到大鼠皮下组织中的光声信号的采集。使用内部和广泛可用的代码对来自储存库的光声信号进行建模实时监测注射储存库的关键参数将提供了解储存库的行为所需的监视信息，并有助于预测药物释放和其生物利用度。我们建议使用光声监测和测量来以安全、非侵入性的方式收集这些信息，最初是在临床前，随后设想将其用于临床试验和治疗。这是解决这一问题的一种新颖而务实的方法，具有通向低成本实施的强大途径。

Our vision is to create a low-cost, non-invasive depot monitoring tool that can provide key information about the state of an injected depot in real time. This low-cost device will have applications in preclinical studies and in the clinical setting for long-acting depot development to accelerate the process. We envisage that the device could be developed to benefit patients, including different skin tones, at home as a way of assessing and monitoring depot performance, enabling personalisation of the depot dose and the administration schedule in the future.Our project addresses, and is timely in the context of, the current rapid increase in interest in therapeutic drug depots within the pharmaceutical industry as medicines capable of achieving long term delivery of classical small-molecule drugs and biologics for the treatment of diseases including, cancer, HIV, neurological disease and psychoses. A long-acting depot aims to control patient therapy over a period of weeks or months; it eliminates the necessity for repeated daily injections addressing issues such as variation in plasma and tissue drug levels or non-compliance in long term patient therapy. Demand is further driven by the increased proportion of drugs in development requiring long-acting injectable technologies, particularly biologicals. Currently, introduction to the market of a long-acting injectable depot of any drug takes ~10 years of development after approval of its oral formulation. This is due to the requirement to understand the depot's behaviour within the injection site tissue, and linked effects on release, and bioavailability of the drug for therapy. Consequently, it is extremely difficult to develop long-acting depots with a guaranteed specific release profile in-vivo for individual patients. Moreover, there is no method for real-time monitoring of their performance in preclinical studies during medicine development or during patient therapy.Our goal is to develop the concept of a low-cost, non-invasive injectable depot characterisation tool based on photoacoustic principles that can provide information on depot characteristics and in-vivo local tissue response.Objectives are:To define the specification and build prototype photoacoustic instrumentation that would form the basis of a low-cost device capable of measuring key parameters of the depot's behaviourDesign, fabrication and optimisation of a long-acting depot formulation required for data acquisition by the prototype photoacoustic instrumentation. This will include selection of depot constituent components and a drug, as well as a selection of appropriate photoacoustic contrast agents.Acquisition of photoacoustic signal in 'model' biological conditions using (i) established in-vitro tissue-mimicking phantoms and (ii) in preclinical, in-vivo injection into subcutaneous rat tissue.To model photoacoustic signals from the depot using in-house and widely available codeMonitoring key parameters of injected depot in real-time will provide surveillance information required to understand the depot's behaviour and aid in prediction of drug release and its bioavailability. We propose the use of photoacoustic monitoring and measurement to gather this information in a safe, non-invasive manner initially preclinically and subsequently envisage its use in clinical trials and therapy. This is a novel and pragmatic approach to the problem with a strong pathway to a low-cost implementation.