Engineering a topical hypobaric patch: A needle-free solution for biopharmaceutical drug administration into the skin

在过去的30年里，科学的进步导致了药物的开发和使用，这些药物可以纠正人体内非常特殊的功能障碍。然而，这些新药的活性成分现在通常比过去在药物中使用的要大得多。例如，20年前，药物中有效成分的一个常见例子是阿司匹林，其分子质量为180Da。相比之下，今天常用的新药，例如胰岛素和激素，其分子质量为Aprox。10,000 Da，即它们大100倍，而最复杂的试剂，如单抗，在145,000-160,000 Da的范围内，即1000倍。药物中这些新活性成分的高分子质量，通常被称为生物制药活性物质或先进疗法，给药物制造、质量控制和管理带来了挑战，这使得开发这种新型药物变得困难。在开发含有人体生物药物活性物质的药物时，最大的问题之一是它们不能作为简单的片剂给药。它们的复杂性意味着，如果它们简单地被一杯水吞下，就很容易被降解，而它们的大小意味着它们很难进入体内。因此，大多数生物药剂都是注射的。使用针头注射药物有许多缺点，包括但不限于针头刺伤、患者不想服药、针头恐惧症和疾病传播，特别是当针头重复使用和使用不当时。为了应对这些问题，科学家们一直在开发一些无针头的医疗设备，这些设备有可能将最新类型的药物输送到患者自己的家里。在这个项目中，一种设备将被开发出来，它可以在实验室中不使用针头的情况下将生物制药活性输送到皮肤中，从而可以在临床上与患者一起使用。该设备使用一个10便士大小的小腔来施加局部低压，这会使皮肤产生抛物线变形，从而使组织变薄，打开毛囊，增加腔下的皮肤血液流量。减压舱会自行密封在皮肤上，在30分钟的应用程序中它将保持密封性，这是无痛的，当它被移除时，皮肤不会受到损害。这种无针递送方式的优点是它不会破坏皮肤，它可以有效地递送带电分子和中性分子。给药过程被控制在30分钟内，因此对皮肤的主动渗透深度是一致的。为了促进设备的开发，该项目将系统地研究减压如何改变皮肤的特性，以及这些变化随后如何改变药物的给药。它将开发一个数学模型来描述从药物到皮肤的大型活性物质的输送，并使用这个数学模型来指导患者可以使用的减压装置的制造。它将在体外和体内测试和开发该设备，并将生成由商业合作伙伴提供的用于皮肤再生的新型活性物质的概念验证数据。

Scientific advances in the last 3 decades have resulted in the development and use of medicines that act to correct very specific malfunctions in the human body. However, the active component of these newer medicines is now typically much larger than those used in medicines in the past. For example, 20 years ago a common example of an active ingredient in a medicine was aspirin, with a molecular mass of 180 Da. In comparison, newer medicines which are commonly used today, for example, insulins and hormones have a molecular mass of aprox. 10,000 Da, i.e. they are 100 times larger, and the most complex agents e.g., monoclonal antibodies, are in the range of 145,000- 160,000 Da, i.e., 1000 times larger. The high molecular mass of these new active ingredients in medicines, often termed, biopharmaceutical actives or advanced therapies, has created medicine manufacture, quality control and administration challenges, which together make it difficult to develop this new type of medicines.One of the most problematic issues in developing medicines containing biopharmaceutical actives in humans is that they cannot be administered as a simple tablet. Their complexity means that they are easily degraded if they are simply swallowed with a glass of water and their size means that they find it difficult to pass into the body. As a consequence most biopharmaceutical agents are injected. Using needles to inject medicines has a number drawbacks including, but not limited to, needle stick injuries, patients not wanting to take the medicine, needle phobia and disease transmission, particularly when the needles are re-used and used incorrectly. In response to these issues scientists have been developing a number of 'needle-free' medical devices that have the potential to deliver the newest types of medicines to patients in their own homes.In this project a device, which has been shown capable of delivering biopharmaceutic actives into the skin without the use of needles in the laboratory, will developed to the point that it can be used in the clinical setting with patients. The device uses a small chamber (the size of a ten pence piece) to apply topical hypobaric pressure, which generates a parabolic deformation of the skin that thins the tissue, opens the hair follicles and increases the skin blood flow underneath the chamber. The hypobaric chamber self-seals onto the skin and it will remain airtight during a 30 min application protocol, which is painless and when it is removed the skin is not damaged. This needle-free approach to delivery has the advantages that it does not break the skin, it can deliver both charged and neutral molecules effectively. The delivery process is controlled over a 30 min period and hence active penetration depth into the skin is consistent.To facilitate the device development the project will systematically investigate how hypobaric pressure modifies the properties of the skin and how these changes subsequently alter drug delivery. It will develop a mathematical model to describe the delivery of large active agents from medicines into the skin and use this mathematical model to guide the fabrication hypobaric device that can be used by patients. It will test and develop the device both in-vitro and in-vivo and it will generate proof-of-concept data with a novel active for skin regeneration provided by a commercial partner.