Mini-Tablets: A Valid Strategy to Combine Efficacy and Safety in Pediatrics

In the treatment of pediatric diseases, mass-produced dosage forms are often not suitable for children. Commercially available medicines are commonly manipulated and mixed with food by caregivers at home, or extemporaneous medications are routinely compounded in the hospital pharmacies to treat hospitalized children. Despite considerable efforts by regulatory agencies, the pediatric population is still exposed to questionable and potentially harmful practices.

When designing medicines for children, the ability to fine-tune the dosage while ensuring the safety of the ingredients is of paramount importance. For these purposes solid formulations may represent a valid alternative to liquid formulations for their simpler formula and more stability, and, to overcome the problem of swelling ability, mini-tablets could be a practicable option.

This review deals with the different approaches that may be applied to develop mini-tablets intended for pediatrics with a focus on the safety of excipients. Alongside the conventional method of compression, 3D printing appeared particularly appealing, as it allows to reduce the number of ingredients and to avoid both the mixing of powders and intermediate steps such as granulation. Therefore, this technique could be well adaptable to the daily galenic preparations of a hospital pharmacy, thus leading to a reduction of the common practice of off-label preparations.

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About this article: Zuccari, G.; Alfei, S.; Marimpietri, D.; Iurilli, V.; Barabino, P.; Marchitto, L. Mini-Tablets: A Valid Strategy to Combine Efficacy and Safety in Pediatrics. Pharmaceuticals 2022, 15, 108. https://doi.org/10.3390/ph15010108

Excerpt on Excipients from the publication

Appropriate Excipients for Pediatrics
In principle, almost all drug formulations contain excipients that have been used for many years and are considered to have a generally regarded as safe (GRAS) status. They are described in monographs in various pharmacopeias and released with certificates of analyses, performed according to monograph test methods, that warrant their quality. In any case, the specifications embedded in the monographs are intended to cover use in adults and not in children. Consequently, although significant differences in pharmacokinetics and pharmacodynamics exist between the two patient populations, it is common practice to assume that excipients, which did not cause adverse reactions in adults, are safe also in neonates and/or children. In recent years, awareness that some excipients are less well tolerated in children, especially in neonates whose physiological systems are still undergoing development, has become known for the intervention of the regulatory authorities. In fact, some neonates may not be able to clear an excipient with the same rate as adults, as in cases of phenylketonuria. Therefore, not only the choice of the most suitable formulation but also the selection of excipients represent key factors in the development of adequate pediatric dosage forms. In the EMA guideline, it is stated how the selection of a safe excipient can be performed [9]. In projecting a new formulation, the EMA guideline suggests that a certain excipient should be chosen by drawing on the sources listed below in hierarchical order. Commission, ICH, and EMA guidelines

CHMP scientific opinions
Already authorized in pediatric medicines with known quantitative composition
Included in the European Food Legislation or Included in EFSA opinions
Other sources such as the expert committee on food additives (JECFA), indexed
Literature, or in-house scientific evidence

However, the opinions regarding food rarely comprise neonates, and if the information about safety is not available, additional costs to sustain animal and clinical toxicological studies are needed. As a result, the excipients used are not new in most cases. Moreover, the EMA guideline suggests that, despite the use of a novel excipient is important for pharmaceutical innovation, only a large-scale employment can provide more reliable data on its safety. Aiming at addressing some of the issues concerning the substances to be considered safe for developing pediatrics formulations, European and US Pediatric Formulations Initiatives (EU-US PFI) are working to collect from disparate resources available data, and to gather them under the umbrella of the Safety and Toxicity of Excipients for Pediatrics (STEP) database of practical use.

Among the largely employed substances in medicinal formulations, a particularly careful evaluation is needed in the choice of sweeteners, flavors, plasticizers, solvents, preservatives, and colorants. In neonates, substances such as benzyl alcohol and polysorbate 80 have been associated with increased mortality, parabens have been correlated to hyperbilirubinemia, while aspartame and acesulfame potassium are found to decrease sensibility to insulin. Both ethanol and propylene glycol can alter the central nervous system development and be metabolized by the same enzymatic pathway of many common drugs including paracetamol, they may increase the risk of reaching toxic API levels and API accumulation. Recently, it has been reported that the toxicity effects in neonates exposed to lopinavir/ritonavir oral solution (Kaletra^®), an antiviral drug combination for the treatment of HIV infection, were due mainly to excipient-excipient interaction. In fact, this solution contains relevant amounts of propylene glycol (152.7 mg/mL) and ethanol (356.3 mg/mL), which are both almost exclusively eliminated by metabolic clearance through alcohol dehydrogenase (ADH). More recently, it was speculated that the amount of ethanol present in the buprenorphine formulation (0.075 mg/mL, containing 30% ethanol, 0.016 mg/kg/day) could in part explain the differences in neonatal abstinence syndrome (NAS) symptoms observed in a clinical trial . In this regard, the U.S. Food and Drug Administration (FDA) recommends that medicines for children less than 6 years old should be alcohol free. In the European Union (EU), common drugs such as ranitidine, furosemide, mannitol, phenobarbital, cotrimoxazole, and paracetamol contain ethanol in their formulations. The revision of the annex to the EC guideline on “Excipients in the labeling and package leaflet of medicinal products for human use” recommends that ethanol should not be included in medicinal products unless its benefits far outweigh the risks associated with alcohol intake. In this context, the EMA proposed a limit of 1 mg/dL ethanol for a single dose of medication and a daily limit of ingestion of 6 mg/kg/day for children under 6 years.

Observations concerning the toxicity of excipients such as polysorbate, propylene glycol, benzyl alcohol, and benzalkonium chloride were already reported in the 1980s. Thrombocytopenia, renal dysfunction, hepatomegaly, and ascites were observed after the administration of a vitamin E supplement containing 9% polysorbate 80 and 1% polysorbate 20 to neonates. Furthermore, preterm neonates administered with parenteral nutrition formulations containing propylene glycol up to 3000 mg/day, underwent relevant side effects such as seizures or intracranial hemorrhage and other effects related to the chemical nature of the substance (hyperosmolarity, lactic acidosis, creatinine), due to their immature hepatic and renal clearance. While products containing high levels of propylene glycol should be avoided under the age of 4 years, as its accumulation may occur due to a higher half-life (e.g., 16.9 h in neonates vs. 5 h in adults), this solvent is worryingly present in intravenous preparations containing dexamethasone, diazepam, digoxin, lorazepam, nitroglycerin, or phenobarbital, thus exposing neonates to harmful concentrations . As reported in Table 1, the acceptable daily intake (ADI) for this solvent is equal to 1 mg/kg and 50 mg/kg for neonates up to 28 days and from 29 days up to 4 years, respectively. Continue reading here