View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Advanced Drug Delivery Reviews 73 (2014) 34–49 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Rectal route in the 21st Century to treat children☆ Vincent Jannin a,⁎,GillesLemagnenb,PascaleGueroultb, Denis Larrouture b, Catherine Tuleu c a Gattefossé S.A.S., 36 chemin de Genas, 69804 Saint-Priest cedex, France b Université Bordeaux Segalen, LTPIB UFR Pharmacie, 146 rue Leo Saignat, 33076 Bordeaux cedex, France c UCL School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom article info abstract Available online 25 May 2014 The rectal route can be considered a good alternative to the oral route for the paediatric population because these dosage forms are neither to be swallowed nor need to be taste-masked. Rectal forms can also be administered in Keywords: an emergency to unconscious or vomiting children. Their manufacturing cost is low with excipients generally Suppository regarded as safe. Some new formulation strategies, including mucoadhesive gels and suppositories, were intro- Paediatric duced to increase patient acceptability. Even if recent paediatric clinical studies have demonstrated the equiva- Patient-centred drug delivery lence of the rectal route with others, in order to enable the use of this promising route for the treatment of Hard fat children in the 21st Century, some effort should be focused on informing and educating parents and care givers. Malaria fi Market This review is the rst ever to address all the aforementioned items, and to list all drugs used in paediatric rectal forms in literature and marketed products in developed countries. © 2014 Elsevier B.V. All rights reserved. Contents 1. Introduction...............................................................35 2. Thechildandhumandimensions.....................................................35 2.1. Thechilddimension........................................................35 2.2. Thehumandimensions.......................................................36 2.2.1. Generalconsiderations...................................................36 2.2.2. Drugfactor........................................................37 2.2.3. Dosageformfactor....................................................37 2.2.4. Administrationdevicesandeaseofadministration......................................37 2.2.5. Patientbarriers......................................................37 3. Paediatric rectal dosage forms on the market and in the scientificliterature..................................39 3.1. RectaldosageformsinPharmacopoeias...............................................39 3.2. Paediatricrectaldosageformsonthemarket.............................................39 3.2.1. USA,Japanand5Europeancountries............................................39 3.2.2. CasestudyinFrance:evolutionofthemarketoverthelast20years..............................40 3.3. Paediatric rectal forms cited in the scientificliterature:ascopingexercise................................40 3.4. Suppositories:considerationsforpaediatricdosing..........................................41 3.4.1. Choiceoftheexcipient...................................................42 3.4.2. Manufacturability.....................................................42 3.4.3. Pharmacotechnicaltestingofsuppositories.........................................43 4. Paediatricclinicalstudies:a10-yearoverview................................................43 4.1. Analgesics,antipyreticsandNSAIDs.................................................43 4.2. Antiepileptics...........................................................43 4.3. Antimalarialdrugs.........................................................43 5. Thefuture................................................................44 5.1. Invitroandpreclinicalstudies....................................................44 5.1.1. Thermosensitiveand/ormucoadhesivegels.........................................44 ☆ 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 at: 36 chemin de Genas, 69804 Saint-Priest cedex, France. Tel.:+33 4 72 22 98 38; fax: +33 4 78 90 45 67. E-mail address: [email protected] (V. Jannin). http://dx.doi.org/10.1016/j.addr.2014.05.012 0169-409X/© 2014 Elsevier B.V. All rights reserved. V. Jannin et al. / Advanced Drug Delivery Reviews 73 (2014) 34–49 35 5.1.2. Suppositories....................................................... 44 5.1.3. Otherforms....................................................... 44 5.2. Vaccinationbytherectalroute................................................... 44 6. Conclusions............................................................... 45 References.................................................................. 45 1. Introduction of liquid is reported as relatively low (1–3 mL) and the pH neutral (pH 7–8) with low buffer capacity [4]. Its surface area is reported to be Rectal forms are one of the oldest pharmaceutical dosage forms as of about 200–400 cm2, without villi and microvilli, which is smaller their origin goes back to antiquity. The Old Testament refers to than the upper gastrointestinal tract, but larger than nasal and buccal ‘Magerarta’–suppository made of silver – and Hippocrates describes absorptive surfaces. However the epithelia in the rectum is made by a various compositions of acorns which were rectal dosage forms for single layer of columnar or cuboidal cells and goblet cells, histologically local effects. The first usage of the word suppository goes back to 1763 similar to the upper gastrointestinal tract, giving them comparable in the Universal Pharmacopoeia of Lemery. The term suppositorium abilities to absorb drugs [5]. comes from the Latin word supponere which means ‘substitute’ because Rectal dosage forms are also a good alternative to the peroral route this dosage form was introduced as a substitute to enema [1]. for certain groups of patients who cannot easily swallow tablets or At first rectal dosage forms were composed of solid supports im- capsules: this can be in the case of children and the elderly, as well as pregnated with medicinal substances. These supports were made of in the cases where patients may be unconscious or vomiting. baked honey, soap, tallow or even horn. These solid supports were Despite being one of the enteral routes, rectal drug delivery is not as substituted by cocoa butter in the late 18th Century. The first mention popular as the oral route for various obvious and less obvious reasons. of the addition of an active substance in the suppository mass was The aim of this review is to investigate these by looking at its applicabil- made by Henry and Guibourt in 1841 by the introduction of opium pel- ity in children, its applicability to treat various conditions (whether lets in the molten cocoa butter before moulding [2]. At that time the already implemented in practice or under research) and also the appli- classical weight of a suppository for adults was 5 g. In the following cen- cability of various traditional or more novel dosage forms, to assess if tury two alternative masses were proposed to cocoa butter: firstly a and when it could have the desirable attributes for paediatric drug mixture of gelatine, glycerine and water in 1897, and secondly, hard delivery. fat which was introduced after the Second World War due to shortage of cocoa butter. In the 20th Century, most of the rectal drug products 2. The child and human dimensions on the market were suppositories composed of fatty bases (hard fat), and are nowadays around 2 g for adults and 1 g for children. These rectal 2.1. The child dimension forms were particularly used in some European countries and in Japan where the use of suppositories is more accepted than in other territories Designing any formulation implies that patient factors are taken into like the United States of America or Laos for example. The first literature consideration. For paediatric subsets, extra challenges occur, the very cen- reference on the use of paediatric rectal dosage form (for premedication tral one being that children undergo physiological changes that could af- before anaesthesia) was reported in 1936 [3]. Even, if suppository was fect the pharmacokinetic/pharmacodynamic/pharmacogenomics. This is quite popular for adults during the 20th Century, the first market autho- why the International Conference on Harmonisation [6] has proposed a risation for a Paracetamol paediatric suppository in France was only subdivision for the purpose of paediatric medicines development to granted in 1981 (Doliprane, Sanofi). reflect biological ages. Administration of drug through the rectal route is amenable to both local and systemic drug delivery. It has been effectively used during the − Preterm newborn infants last centuries to treat local diseases of the anorectal area (for example − Term newborn infants (0 to 27 days) haemorrhoids) as well as to deliver drugs systemically as an alternative − Infants and toddlers (28 days to 23 months) to the oral route (including antipyretic and analgesic drugs such as Para- − Children (2 to 11 years) cetamol or Diclofenac) [4]. The latter case can be useful for drugs which: − Adolescents (12 to 16/18 years, dependent on region). - possess limited absorption in the upper gastrointestinal tract, The guideline on