Advanced Drug Delivery Reviews 73 (2014) 14–33 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Playing hide and seek with poorly tasting paediatric medicines: Do not forget the excipients☆ Jennifer Walsh a,⁎,AnneCramb,KatharinaWoertzc, Joerg Breitkreutz c, Gesine Winzenburg d, Roy Turner d, Catherine Tuleu e, On behalf of the European Formulation Initiative (EuPFI) a Jenny Walsh Consulting Ltd, BioCity Nottingham, Pennyfoot Street, Nottingham NG1 1GF, United Kingdom b Drug Product Development, Pfizer Ltd, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom c Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University Duesseldorf, Building 26.22, Universitaetsstrasse 1,40225 Duesseldorf, Germany d Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland e Centre for Paediatric Pharmacy Research, UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom article info abstract Available online 12 March 2014 The development of paediatric medicines can be challenging since this is a diverse patient population with specific needs. For example, the toxicity of excipients may differ in children compared to adults and children Keywords: have different taste preferences. Acceptable palatability of oral paediatric medicinal products is of great Paediatric importance to facilitate patient adherence. This has been recognised by regulatory authorities and so is becoming Taste masking a key aspect of paediatric pharmaceutical development studies. Many active pharmaceutical ingredients (APIs) Formulation have aversive taste characteristics and so it is necessary to utilise taste masking techniques to improve the Palatability palatability of paediatric oral formulations. The aim of this review is to provide an overview of different Dosage form Excipient approaches to taste masking APIs in paediatric oral dosage forms, with a focus on the tolerability of excipients used. In addition, where possible, the provision of examples of some marketed products is made. © 2014 Elsevier B.V. All rights reserved. Contents 1. Introduction...............................................................15 2. Bitter blockers and taste modifiers.....................................................16 2.1. Bitterreceptorantagonists.....................................................16 2.2. Tastetransductioncascadeblockers.................................................16 2.3. Gapsincurrentknowledgeandtechnologylimitations........................................16 3. Sweeteners and flavouringsystems.....................................................17 3.1. Sweeteners............................................................17 3.2. Flavours..............................................................19 3.3. Safety and toxicity of sweeteners and flavouringagents........................................20 4. ModificationofAPIsolubility.......................................................21 4.1. KeepingtheAPIunionised.....................................................21 4.2. Alternativesolidform.......................................................21 4.3. ChallengestoconsiderformodifyinganAPI.............................................22 5. Create a ‘molecular’ barrieraroundtheAPIbycomplexation.........................................23 5.1. Ion-exchangeresins........................................................23 5.1.1. Safetyandtoxicityofpharmaceuticalgradeionexchangeresins................................23 5.1.2. Formulationssuitableforthepaediatricpopulation......................................24 5.2. Cyclodextrins...........................................................24 5.2.1. Oralsafetyandtoxicityofcyclodextrins...........................................25 5.2.2. Formulationscontainingcyclodextrinsfortastemasking...................................25 ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "Drug delivery and the paediatric population: where are we at?". ⁎ Corresponding author. Tel.: +44 7757 948052. E-mail addresses: [email protected] (J. Walsh), anne.cram@pfizer.com (A. Cram), [email protected] (J. Breitkreutz), [email protected] (G. Winzenburg), [email protected] (R. Turner), [email protected] (C. Tuleu). http://dx.doi.org/10.1016/j.addr.2014.02.012 0169-409X/© 2014 Elsevier B.V. All rights reserved. J. Walsh et al. / Advanced Drug Delivery Reviews 73 (2014) 14–33 15 6. Apply a physical ‘barrier’ ontheAPIorthedosageform........................................... 26 6.1. Polymer film-coating....................................................... 26 6.1.1. Safetyandtoxicityofcoatingmaterials........................................... 27 6.1.2. Formulationssuitableforthepaediatricpopulation...................................... 28 6.2. Lipidicbarriersystem....................................................... 29 6.2.1. Commonlyusedlipidicexcipientsfortastemasking..................................... 29 6.2.2. Formulationscontaininglipidicexcipientsfortastemasking................................. 29 7. Summaryandconclusions........................................................ 30 References.................................................................. 31 1. Introduction Acceptability is driven by the characteristics of the user (age, ability, disease type and state) and by the characteristics of a medicinal product Acceptable palatability is paramount for paediatric formulations. such as: A survey of over 800 paediatricians showed that unpleasant taste of • palatability medication is a key barrier to compliance for 90.8% of patients with • swallowability (volume/size and shape, integrity of dosage form, acute illness and 83.9% of patients with chronic illness [1].Compliance e.g. functional coating) rates in children have been found to range from 11 to 93%, with major • complexity of manipulation if required factors attributed to formulation and palatability [2].Palatabilityis • the required dose e.g. the dosing volume, number of tablets etc. largely dictated by taste and this is a concern as a significant number • the required dosing frequency and duration treatment of active pharmaceutical ingredients (APIs) on the market and in devel- • the selected administration device opment have aversive taste. This is not considered to be a key issue • the primary and secondary container closure system when developing oral dose forms for adults who can swallow tablets • the actual mode of administration. since such products can be film or sugar-coated, thereby masking the taste of the API. In the paediatric population the issue is accentuated Palatability is one of the main elements of the patient acceptance of a by dysphagia, leading to an increased use of oral dosage forms such as medicinal product. It is defined as the overall appreciation of an (often liquids, (oro-) dispersible and chewable tablets where taste masking oral) medicine by organoleptic properties such as smell, taste, aftertaste becomes a greater challenge. In addition, differences in taste perception, and texture (i.e. mouthfeel), and possibly also vision and sound. It is de- sensitivity and tolerance between adults and children make taste termined by the characteristics of the components (API and excipients) assessment and development of palatable paediatric medications more and the way the API is formulated. Palatability is relevant for other complex. routes of administration e.g. buccal, nasal, inhalation. Thus not only The paediatric population represents a diverse group of patients, should a medicinal product not taste and smell (especially the aroma exhibiting differences in biological and physiological attributes com- on first opening and during consumption) unpleasant, it should have pared to adults. Indeed, children are not merely miniature adults because acceptable mouthfeel (viscosity, grittiness) and appearance (visual as- sensory systems mature postnatally and their responses to certain tastes pect, size and shape, packaging). Thus palatability and indeed accept- differ markedly from adults. Amongst these differences are heightened ability are key considerations when defining the target product profile. preferences for sweet-tasting and greater rejection of bitter-tasting The importance of acceptable palatability has been recognised by foods [3]. In addition, APIs and excipients are metabolized differently regulatory authorities, including the European Medicines Evaluation by children of different ages compared to adults [4]. Therefore the use Agency (EMA) [5]. The French regulatory authorities (Afssaps) launched of certain excipients may not be appropriate or the levels will be restrict- a study designed to determine the acceptability of oral liquid originator ed, which further complicates excipient selection. and generic antibiotics prescribed to ambulatory children [6]. The dis- Indeed, when designing an age-appropriate paediatric medicinal parity in the acceptability of the different antibiotics prescribed, even product, the excipients used should be selected using a benefitriskap- for the same drug has been confirmed by Wollner et al. [7]. proach, encompassing all aspects of the proposed excipients in parallel, Moreover within the requirements of the European Union's Paediat- including: ric Regulation [8], paediatric investigation plan (PIP) guidelines state that the proposed studies of particular relevance to the development • physico-chemical properties (stability, solubility,