Kendall Richard, Lenoir Joke, Gerrard Stephen, Scheuerle Rebekah L, Slater Nigel K H, Tuleu Catherine
School of Pharmacy, University College London, London, UK.
Faculty of Pharmaceutical Sciences, University of Ghent, Ghent, Belgium.
Pharm Res. 2017 Apr;34(4):687-695. doi: 10.1007/s11095-016-1997-y. Epub 2017 Feb 13.
Neonates are particularly challenging to treat. A novel patented drug delivery device containing a rapidly disintegrating tablet held within a modified nipple shield (NSDS) was designed to deliver medication to infants during breastfeeding. However concerns exist around dermatological nipple tolerability with no pharmaceutical safety assessment guidance to study local tissue tolerance of the nipple and the areola. This is the first Slug Mucosal Irritation (SMI) study to evaluate irritancy potential of GRAS excipients commonly used to manufacture rapidly disintegrating immediate release solid oral dosage form METHODS: Zinc sulphate selected as the antidiarrheal model drug that reduces infant mortality, was blended with functional excipients at traditional levels [microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, magnesium stearate]. Slugs were exposed to blends slurried in human breast milk to assess their stinging, itching or burning potential, using objective values such as mucus production to categorize irritation potency RESULTS: Presently an in vivo assay, previously validated for prediction of ocular and nasal irritation, was used as an alternative to vertebrate models to anticipate the potential maternal dermatological tolerability issues to NSDS tablet components. The excipients did not elicit irritancy. However, mild irritancy was observed when zinc sulphate was present in blends.
These promising good tolerability results support the continued investigation of these excipients within NSDS rapidly disintegrating tablet formulations. Topical local tolerance effects being almost entirely limited to irritation, the slug assay potentially adds to the existing preformulation toolbox, and may sit in between the in vitro and existing in vivo assays.
新生儿治疗颇具挑战性。一种新型专利药物递送装置，其包含置于改良乳头罩（NSDS）内的速崩片，旨在在母乳喂养期间为婴儿给药。然而，对于乳头的皮肤耐受性存在担忧，且尚无药物安全性评估指南来研究乳头和乳晕的局部组织耐受性。这是第一项蛞蝓黏膜刺激性（SMI）研究，旨在评估常用于制造速崩即释固体口服剂型的GRAS辅料的刺激潜力。方法：选择硫酸锌作为降低婴儿死亡率的止泻模型药物，将其与传统水平的功能性辅料[微晶纤维素、淀粉乙醇酸钠、交联羧甲基纤维素钠、硬脂酸镁]混合。将药条暴露于用人母乳制成的混悬液中，以评估其刺痛、瘙痒或灼烧潜力，使用诸如黏液产生等客观值对刺激强度进行分类。结果：目前，一种先前已验证可预测眼鼻刺激的体内试验被用作脊椎动物模型的替代方法，以预测NSDS片剂成分对母体皮肤的潜在耐受性问题。辅料未引起刺激。然而，当混合物中存在硫酸锌时，观察到轻度刺激。结论：这些良好的耐受性结果支持在NSDS速崩片制剂中继续研究这些辅料。局部耐受性影响几乎完全限于刺激，蛞蝓试验可能会补充现有的处方前研究工具库，并且可能介于体外试验和现有的体内试验之间。
