Bremer U, Horres C R, Francoeur M L
Pharmetrix, Inc., Menlo Park, California 94025, USA.
Pharm Biotechnol. 1997;10:239-54. doi: 10.1007/0-306-46803-4_9.
When a therapeutic effect is optimized by precise control of specific temporal patterns of plasma levels, infusion offers distinct advantages over oral administration, bolus injection, or depot delivery of polypeptides. The limitations of oral delivery are well known, and although research is under way into development of carrier systems that prevent degradation of labile agents, it is unlikely that the variances in absorption will meet the need for precise control. Depot delivery from subcutaneous or intramuscular implants presents a difficult situation when local tissue reactions to the agent sometimes occur. Removal of a depot system in the event of adverse reactions presents additional difficulties. Bolus injections are unable to sustain constant plasma levels unless the drug half-life is long or the injections are frequently administered. Insulin injections, for example, would be required every 30-60 minutes to approximate the plasma levels provided by a continuous infusion; such frequent injections would not be practical on a 24-hour basis. For the developer of new polypeptides, parenteral administration offers the most direct route to the marketplace. The step from periodic injections to tightly controlled infusion is a logical progression as compared with modification of the molecules or vehicles to obtain equivalent profiles. In Table II several different types of devices that can be used for infusion of proteins are compared. Microelectronics have played a major role in the miniaturization of infusion devices and undoubtedly will continue to do so. Micromachining, a spin-off technology of integrated circuit manufacture, will also find application in small infusion devices. In the future, we will have cost-effective disposable devices (Saaman et al., 1994) built on this technology that are programmable and thus can be adapted to meet each individual therapeutic need (Horres, 1994). We can also expect to see more closed-loop drug delivery systems where biosensors and infusion devices are combined to optimize a particular therapy. Recent positive results obtained in diabetics by a decade on tight glucose control may forecast a resurgence of popularity of insulin pumps. At the other end of the spectrum, low-cost, small, and simple-to-use osmotically powered systems are close to being marketed; these systems will make infusion almost as convenient as transdermal patches. We will also see major advances in how drugs and devices are interfaced. Prefilled and ready-to-use drug cartridges have proven to be efficient in surgical and emergency medicine and can greatly improve most infusion applications. It is anticipated that coded, prefilled cartridges or pouches will be automatically, recognized by preprogrammed pumps to reduce operator labor and entry error.
当通过精确控制血浆水平的特定时间模式来优化治疗效果时，与口服给药、大剂量注射或多肽的长效释放相比，输注具有明显优势。口服给药的局限性众所周知，尽管目前正在研究开发能够防止不稳定药物降解的载体系统，但吸收的差异不太可能满足精确控制的需求。皮下或肌肉植入物的长效释放有时会引发局部组织对药物的反应，这带来了难题。出现不良反应时，移除长效释放系统更是难上加难。大剂量注射无法维持恒定的血浆水平，除非药物半衰期长或频繁注射。例如，胰岛素注射需要每30 - 60分钟进行一次，才能接近持续输注所提供的血浆水平；如此频繁的注射在24小时内是不切实际的。对于新型多肽的开发者而言，肠胃外给药是进入市场最直接的途径。与修饰分子或载体以获得等效的药代动力学曲线相比，从定期注射到严格控制的输注是一个合理的发展过程。表II比较了几种可用于蛋白质输注的不同类型的装置。微电子技术在输注装置的小型化过程中发挥了重要作用，而且无疑将继续发挥作用。微机械加工作为集成电路制造的衍生技术，也将在小型输注装置中得到应用。未来，我们将拥有基于该技术的具有成本效益的一次性装置（萨曼等人，1994年），这些装置可编程，因此能够根据个体治疗需求进行调整（霍雷斯，1994年）。我们还可以期待看到更多的闭环给药系统，其中生物传感器和输注装置相结合以优化特定治疗。糖尿病患者通过十年严格血糖控制所取得的近期积极成果，可能预示着胰岛素泵将再度流行。在另一端，低成本、小型且易于使用的渗透驱动系统即将上市；这些系统将使输注几乎与透皮贴剂一样方便。我们还将看到药物与装置连接方式的重大进展。预填充且即用型药筒已被证明在外科手术和急救医学中很有效，并且能够极大地改善大多数输注应用。预计编码的预填充药筒或药袋将被预编程的泵自动识别，以减少操作人员的工作量和输入错误。
