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

在口服固体剂型中使用添加剂抑制亚硝胺形成

• 批准号: 2896874
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2896874
• 关键词: Use; Additives; Oral; Solid; Dosage

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).

一些亚硝胺（如NDMA、NDEA）被归类为“关注组群”遗传毒性杂质，需要在制剂中控制至极低限度。由于在几种市售药品中检测到某些亚硝胺超过可接受的每日摄入量，最近监管重点关注亚硝胺，导致市场范围内的产品召回。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诱变剂，因此将其控制在非常低的可接受每日摄入量，可低至纳克数量级。在原料药含有易发生亚硝化的胺官能团的制剂中，这可能具有挑战性。亚硝酸盐在辅料中普遍存在，含量极低，可以作为易受伤害的胺的亚硝化剂需要控制药物产品中亚硝胺的形成的策略，例如添加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物产品的pH，保持pH不利于亚硝胺形成。然而，这些方法抑制固相药物产品中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每个单位剂量内添加剂的充分分布，以防止超过允许限度的亚硝胺形成。该项目将使我们能够与GSK（化学工业）合作，在研究行业背景下使用不同的可能添加剂来研究亚硝胺形成的抑制作用。在第一年，我们会先分析不同的亚硝胺，特别是结构较复杂的亚硝胺（而不是像NDMA这样的小结构，因为研究显示较小的亚硝胺较可能致癌），并进行化学分析。然后，我们将找到任何模型胺，我们可以用来形成亚硝胺通过亚硝化。然后将进行研究，寻找可能的添加剂，可以用来防止模型胺的亚硝化。明年，将进行配方化学，将这些模型胺和添加剂制成片剂，并在大学实验室和GSK实验室进行亚硝胺形成测试。在第三年，如果片剂结果为阳性，则将研究抑制剂（例如添加剂）的均匀性（包括抑制机制），并采取控制策略（以了解如何获得优质产品）。