药片设计（Drug Tablet Design）应考虑哪些？FDA和EMA有规定

引言

仿制药应如何设计大小、片形、片重、包衣？
包衣片和非包衣片对患者有何临床意义？
什么是安全源于设计（SbD）？
老年人用药在处方设计时应做什么特殊考虑？
阅读本文后你将感受到FDA和EMA在这方面的关注，广大研发者在新药/仿制药申报、一致性评价研究中应关注这些问题，通过作者提供的参考文献链接可以直接下载原文。

Patients prefer tablet dosage forms because they look familiar, and tablets are usually coated, making them easy to recognize and simple to take. The disconcerting news, however, is that in asurvey of US adults, 4 in 10 reported difficulty in swallowing tablets, negatively affecting patient compliance. Of those 40% with difficulties, 14% delayed taking a dose, 8% skipped a dose, and 4% discontinued the medication altogether (1). Data like these have not escaped the attention of major regulatory agencies, including FDA and the European Medicines Agency (EMA).

患者喜欢片剂这一剂型，因为看起来很熟悉，而且药片通常是包衣的，对他们来讲容易识别和服用。然而，在美国一项成年人中的调查表明，有40%的人认为片剂吞咽困难，影响了患者的依从性。在这40%吞咽困难的人群中，14%的人延迟服药，8%的人会不按处方服药，还有4%的人中断治疗（1）。像这样的数据并没有逃过包括FDA和EMA在内的主要药品监管机构的注意。

Within the past three years, FDA issued two separate guidance documents that encourage drug formulators to design drug products with patient compliance and the reduction of medication errors in mind(2, 3). Commonly referred to in the United States as “safety by design” (SbD), the concepts outlined by FDA reference tablets that should be of an appropriate size, shape, and coating to enhance swallow ability and palatability of the drug.

在过去的三年里，FDA发布了两个指导原则来鼓励药品处方设计者考虑病人的依从性和减少用药错误（2, 3），在美国称之为“安全源于设计”（safety by design, SbD），FDA建议片剂应具有适当大小、形状、包衣，以提高吞咽性和口感。

In a guidance document, FDA noted that“coating can potentially affect the ease of swallowing tablets or capsules. Thelack of a film coating can decrease or prevent tablet mobility compared with acoated tablet of the same size and shape” (2). Logic dictates that if a dosage has the potential to be a choking hazard, then coating should be considered to aid the patient’s ability to swallow and avoid the risk of the patient nottaking their medication. This guidance from FDA was applicable to all new drug applications (NDAs) as well as abbreviated new drug applications (ANDA) and over-the-counter monograph drugs.

FDA在一个指导原则中指出，“包衣可能会影响药片或胶囊吞咽的方便性，与相同大小和形状的包衣片相比，不包衣可以降低或阻止片剂的流动性”（2）。如果一个药片有可能引起窒息的危险，那么应考虑采用包衣来帮助病人吞咽，并避免病人不服药的风险。FDA这个指导原则适用于所有新药申请（NDA）以及简略新药申请（ANDA）和非处方药（OTC）申请。

FDA suggested that generic-drug manufacturers should also ensure that the design of a generic version should not hinder patient compliance. Manufacturers should “consider the size, coating, and palatability of oral products. A drug product can become a choking hazard due to the size of the tablet or capsule. If the tablet or capsule coating is too sticky, it can become lodged in the patient’s throat or gastro intestinal tract” (3). The guidance also recommends more attention to dosage shape and size, encouraging manufacturers to reduce cross-sectional areas of larger tablets to improve swallowing. The guidance concludes that “tablet coating weight, surface area, disintegration time, palatability, and propensity for swelling should also be considered when designing oral products to avoid medication errors related to swallow ability and patient compliance” (3).

FDA建议仿制药生产商也应确保仿制药的设计不应妨碍患者的依从性。生产商应“考虑口服药品的大小、包衣和口感。由于片剂或胶囊的大小，药物可能会引起窒息危险。如果片剂或胶囊包衣过粘，可能会滞留在患者的咽喉或胃肠道中”（3）。该指导原则建议应更多地关注药品的形状和大小，鼓励生产商减少药片的截面积以改善吞咽。该指导认为“片剂的包衣、片重、表面积、崩解时限、口感和膨胀倾向应在研发时予以考虑，避免因患者的吞咽性和依从性导致用药错误”（3）。

Patient safety concerns are also being addressed by European regulators.  In November 2015, EMA issued a comprehensive guide on minimizing risk forpatients, which lists concerns for elderly patients who “may face physical and cognitive impairment, and hence, they may have difficulties in taking their medicines (e.g., swallowing tablets, opening packaging, or reading their user instruction and package leaflet). The pharmaceutical development of medicines for use by older patients should take such aspects into consideration” (4).

欧洲药品监管机构也在关注患者的安全性问题。在2015年11月，EMA发布了一个关于降低患者风险的指导原则，其中列出了老年患者可能面临的问题，如可能有身体和认知障碍，因此，他们可能在服药时会遇到困难（例如，在吞咽药片、打开包装、阅读患者指南或药品说明书时），在药物的研发中应考虑到老年患者这些方面的问题”（4）。

Focus on the elderly population continuesto be addressed with a reflection paper issued by EMA in 2017 on pharmaceutical development of medicines for use in the older population, especially to address tablet mobility (5). This paper discusses the particular problems that elderly populations face and cites that “elderly patients are more likely to experience conditions which lead to impaired swallowing, such as stroke or Parkinson’s disease. This can lead to accidental under dosing, which can be managed appropriately by the development and use of formulations which are easier for such patients to swallow” (5).

2017年底，EMA发表了一份关于老年人用药的特别文件，强调研发老年用药时，应考虑药片的流动性问题（5）。这份文件讨论了老年患者所面临的特殊问题“更容易出现吞咽障碍，如中风或帕金森病患者，这可能会导致意外的用药不足，在研发和使用药物时应进行适当的考虑，使这类病人更容易服用”（5）。

Tablets are now being presented asspecialized dosage forms: medicines that deliver complex treatments including drug combinations, layered tablets, and modified release forms, for which it iseven more important that the patient follows an exact dosing regimen. However,many of these newer dosage forms are presented as larger tablets, which reduces the frequency of dosing but may present issues with swallowing and tablet mobility. The importance of good tablet design to address patient acceptability and compliance is paramount, and addressing this need will help to satisfy regulatory concerns also. The fact that regulators and industry are now actively addressing this topic is goodnews for patients and caregivers.

片剂目前被列为特殊剂型：因为片剂可提供多种形式，如复方片、分层片、调释片。然而，这些新剂型中许多都是大药片，这虽然减少了用药次数，但可能会引起吞咽和药片流动性的问题。良好的片剂设计（good tablet design）对于解决患者的可接受性和依从性是至关重要的，解决这一问题也将有助于满足监管方的要求。监管机构和制药行业现在积极应对这一问题，这对患者和护理人员来说是个好消息！

谢分享。