Use of Additives in Oral Solid Dosage Forms to Inhibit Nitrosamine Formation

一些亚硝胺（如NDMA、NDEA）被归类为“关注队列”基因毒性杂质，在药品中需要控制到极低的限量。由于在几种上市药品中检测到某些亚硝胺超过可接受的每日摄入量，导致市场范围内的产品召回，最近监管部门将重点放在亚硝胺上。监管机构要求将没有安全数据或安全数据有限的新型亚硝胺视为致突变性，因此将其控制在非常低的可接受日摄入量，可低至纳克数量级。这对于含有易受亚硝化作用的胺官能团的药品来说是具有挑战性的。亚硝酸盐在辅料中以微量水平普遍存在，并可作为易损胺（通常是仲胺或活化叔胺）的亚硝化剂。需要制定策略来控制药品中亚硝胺的形成，例如添加一种化合物作为亚硝酸盐的清除剂或氧化剂（例如抗坏血酸/抗坏血酸钠），或使用添加剂来控制药品的pH值，使pH值不利于亚硝胺的形成。然而，这些方法在固相药物产品中抑制亚硝胺形成的工业经验很少。最具挑战性的方面之一仍然是确定和确保添加剂在每单位剂量内的充分分布，以防止亚硝胺的形成超过允许的限度。该项目将允许我们与葛兰素史克（化学工业）合作，在研究工业背景下使用不同可能的添加剂来研究亚硝胺形成的抑制作用。还可以研究其他参数，如利用pH值来抑制亚硝胺的形成。在第一年，我们首先对不同的亚硝胺进行分析和表征，特别是结构更复杂的亚硝胺（不是像NDMA这样的小结构，研究表明小的亚硝胺更容易致癌）。然后我们会找到任何模型胺，我们可以用来通过亚硝化形成亚硝胺。然后进行研究，寻找可能用于防止模型胺亚硝化的添加剂。明年，将进行配方化学，这些模型胺和添加剂将被制成片剂，并在大学实验室和葛兰素史克实验室测试亚硝胺的形成。在第三年，如果片剂结果是阳性的，那么将研究抑制剂（例如添加剂）的均匀性（包括抑制机制）和控制策略（看看它如何导致高质量的产品）。

Some nitrosamines (e.g. NDMA, NDEA) are classed as 'cohort of concern' genotoxic impurities and require control to extremely low limits in drug products. There has been a recent regulatory focus on nitrosamines due to detection of certain nitrosamines above the acceptable daily intake in several marketed drug products, leading to market-wide product recalls. Regulators require that novel nitrosamines, for which there is no or limited safety data, are regarded as mutagenic, and therefore controlled to very low acceptable daily intakes, which can be down to the order of nanograms. This can be challenging in drug products where the drug substance contains an amine functional group vulnerable to nitrosation. Nitrites are ubiquitous in excipients at trace levels and can act as nitrosating agents towards vulnerable amines (usually secondary or activated tertiary amines).There is a need for strategies to control the formation of nitrosamines in drug products such as the addition of a compound to act as a scavenging agent or oxidising agent towards nitrites (e.g. ascorbic acid/sodium ascorbate) or using an additive to control pH of the drug product, keeping the pH unfavourable for nitrosamine formation. However, there is very little industry experience with these approaches to inhibit nitrosamine formation in solid phase drug products. One of the most challenging aspects remains determining and ensuring sufficient distribution of the additive within each unit dose to prevent nitrosamine formation at levels above the permitted limit.This project will allow us to work with GSK (chemical industry) to investigate inhibition of nitrosamine formation using different possible additives within a research industry context. Other parameters could be investigated such as using pH to inhibit the formation of nitrosamine.In the first year, we would first conduct analysis of different nitrosamines and characterise them, in particular more complex structures of nitrosamines (not small structures such as NDMA as research shows that smaller nitrosamines are more likely to be carcinogenic). Then we would find any model amines that we can use to form nitrosamines through nitrosation. Then research would be conducted on finding possible additives that could be used to prevent nitrosation of the model amines. In the next year, formulation chemistry will then take place where these model amines and additives will be made into tablets and tested for nitrosamine formation both in the university labs as well as the GSK labs. In the third year, it the tablets results are positive, then the uniformity of the inhibitor (e.g. additives) will be investigated (including mechanism of inhibition) and control strategy would take place (to see how it would lead to a quality product).