title: Using the Slug Mucosal Irritation Assay to Investigate the Tolerability of Tablet Excipients on Human Skin in the Context of the Use of a Nipple Shield Delivery System.
abstract: 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.
authors.affiliation: School of Pharmacy, University College London, London, UK. richardakendall@gmail.com.
authors.forename: Richard
authors.initials: R
authors.lastname: Kendall
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Ghent, Ghent, Belgium.
authors.forename: Joke
authors.initials: J
authors.lastname: Lenoir
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gerrard
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
authors.forename: Rebekah L
authors.initials: RL
authors.lastname: Scheuerle
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK.
authors.forename: Nigel K H
authors.initials: NK
authors.lastname: Slater
authors.affiliation: School of Pharmacy, University College London, London, UK.
authors.forename: Catherine
authors.identifier: 0000-0001-8384-357X
authors.initials: C
authors.lastname: Tuleu
mesh_terms: D000818:Animals; D000930:Antidiarrheals / Q000633:toxicity; D001681:Biological Assay / Q000379:methods*; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems / Q000379:methods; D005079:Excipients / Q000633:toxicity*; D049851:Gastropoda / Q000187:drug effects*; D006801:Humans; D007223:Infant; D008895:Milk, Human; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism; D009093:Mucus / Q000378:metabolism; D009558:Nipples; D012867:Skin / Q000187:drug effects*; D023422:Skin Irritancy Tests / Q000379:methods; D013607:Tablets; D019287:Zinc Sulfate / Q000633:toxicity
chemical_list: D000930:Antidiarrheals; D005079:Excipients; D013607:Tablets; D019287:Zinc Sulfate
keywords: nipple shield delivery system; pediatric; skin tolerability; slug mucosal irritation assay; tablet excipients