Stability of Oral Liquid Dosage Forms in Pediatric Cardiology: A Prerequisite for Patient’s Safety—A Narrative Review

The lack of adequate pharmaceutical formulations for children leading to off-label use of drugs is a topic well-documented in the literature among healthcare specialists, regulators, and the academic community [1,2,3,4]. The importance of this topic can hardly be overestimated, but despite the efforts, there are some therapeutic areas, such as cardiovascular diseases in children, that are completely overlooked. Worldwide, initiatives are being taken in order to develop pediatric medicines, and the main regulators, namely, European Medicines Agency (EMA) and Food and Drug Administration (FDA) [5], have defined requirements and issued guidelines for the industry [6]. In the European Union (EU), the necessity of developing pediatric drugs has been regulated by the EMA through the Paediatric Regulation in 2007, whereas in the United States (US), pediatric drug development followed the Pediatric Research Equity Act (PREA) founded in 2003 and the Best Pharmaceuticals for Children Act (BPCA) founded in 2002, both regulated by the FDA.

A 10-year follow-up report of the Paediatric Regulation indicates a clear upwards trend, with 267 new medicines and 43 new pharmaceutical forms for children’s use [7]. The strong interest in this therapeutic area is also reflected in the number of Paediatric Investigation Plans (PIPs) submitted by pharmaceutical companies up until 2017 [8,9]. The World Health Organization (WHO) issues Model Lists of Essential Medicines for Children every two years in order to direct the research regarding certain drug substances that are considered essential for pediatric treatment. The eighth list from 2021 comprises enalapril, digoxin, furosemide, and dopamine [10]. The EMA also issued an inventory of pediatric therapeutic needs [11]. In the cardiovascular therapeutic area, several substances, such as clonidine, atenolol, bisoprolol, carvedilol, sotalol, amiodarone, flecainide, and nicardipine have been listed, with a particular focus on information required regarding safety and pharmacokinetics and the need for developing age-appropriate formulations [11,12,13]. Nonetheless, there are still few medications that have been approved for children’s use, especially regarding age-appropriate formulations. This aspect has also been emphasized by del Moral-Sanchez et al., whose findings indicate that for the cardiovascular therapeutic area, only 4.2% of oral dosage forms are available. Concerning all of the substances analyzed, it has been emphasized that despite overall high availability, few drug dosage formulations are age-appropriate [14]. It should, however, be noted that inconsistencies have also been identified, in the sense that some of the developed age-appropriate formulations are only developed to meet special pediatric requirements, e.g., an oral solution of propranolol for infantile hemangioma.

Based on the above considerations, it can be easily assumed that in the pediatric cardiology therapeutic area, the treatment is mostly constituted by off-label or even unlicensed practices, represented by the manipulation of the adult-approved dosage form. Current practices involve crushing the commercially available tablets or using the content of capsules and mixing them with a diluent in order to obtain a powder of a suitable dosage, which is then added to baby food or proper liquid for administration [15,16,17]. These practices are susceptible to dosing errors and can even disregard the existence of potentially harmful excipients that are inadequate for children’s use [16,18]. Another practice that involves diluting the commercially available injectable form for oral administration has also been mentioned in the literature [15,17,19].

There is an increasing interest in developing safe and effective pediatric formulations. Both solid and liquid oral dosage forms have been extensively studied in the literature [20,21,22,23,24], indicating suitable use in children. Several solid oral dosage forms have been studied to date, such as orodispersible tablets, mini-tablets, and chewable tablets [8,25,26,27]. While solid formulations demonstrated improved stability which supported longer shelf-lives, pediatric oral liquid dosage forms are dose-flexible and easy to swallow by the patients [20,28]. However, these solid oral dosage forms are not approved, and several extensive studies are required in order to establish their safe use in all age groups. According to EMA’s reflection paper on formulations of choice for the pediatric population, oral liquid dosage forms represent the form of choice for infants and toddlers (1 month–2 years) and young children (2–5 years) [29,30], especially in children less than 12 years old [18], and this is supported by current literature findings. The most common forms used are solutions, suspensions, and syrups. Solutions are preferred over suspensions due to better oral acceptance and the tendency of the latter to sediment, and also because insufficient redispersion makes them susceptible to dosing errors [30,31].

Some of the limitations of liquid dosage forms include the stability and the difficulty of obtaining controlled release formulations, which require multiple-day dosing, exposure to undesirable excipients, extra palatability, and higher costs [20,32]. The need for improving the liquid formulations and also the standardization of dosing devices in order to maintain dose flexibility and children’s acceptability have been emphasized [20,33,34]. Considering these aspects, pharmaceutical compounding of oral liquid dosage forms is challenging and can vary a lot in terms of provenance of Active Pharmaceutical Ingredient (API), excipients, preparation methods, and the dosage strength obtained. It is fairly stipulated in the literature that these compounded formulations are exempted from Good Manufacturing Practice (GMP), and the testing to assess product quality is inconsistent [35]. Therefore, rigorous stability studies should be conducted for every particular formulation, on a case-by-case basis.

In terms of opportunity, some Marketing Authorization Holders (MAHs) have already initiated actions towards pediatric drug administration by employing the so-called “industry-verified preparations”. This term refers to several well-defined and verified steps contained in the package leaflet in order to prepare an oral liquid from marketed tablets or capsules that can ensure the stability and dose uniformity of the preparation [9].

Many studies related to the stability of oral liquid dosage forms in the cardiovascular therapeutic area are present in the literature, which emphasize a continuous need for this formulation in order to cover the lack of approved medication. These findings are consistent with those of Belayneh and Tessema 2021, who conducted a systematic review of the stability of the extemporaneous pediatric oral formulations. Out of the 28 articles included in their study, 16 of them referred to one or many drug substances from the cardiovascular therapeutic area [21]. According to the literature, solid oral dosage forms are gaining popularity among children in terms of acceptability [36,37,38]. Regardless of the evident current shift towards the solid dosage forms, reflected also in the number of PIPs submitted [36], liquid oral dosage form still has the advantage of dose adaptation for different age categories and are still required for drug substances that are not approved in a solid oral dosage form.

Considering this knowledge gap and the evident need for improvement in this area, the purpose of this study is to provide a comprehensive overview of the stability of liquid oral dosage form used in pediatric cardiology, with a particular focus on the requirements, the compounding practices, and the study design.