Pediatric-friendly suspension for oral administration of pyrimethamine in congenital toxoplasmosis: Development and in use-stability study

Introduction

Toxoplasmosis is a disease caused by the intracellular parasite Toxoplasma gondii and is classified as a zoonosis since humans can participate in its life cycle [1,2]. This pathogen is distributed worldwide and can infect all warm-blooded animals; it is estimated that this infection affects one-third of the human population [3]. Human contagion occurs mainly through the ingestion of contaminated food or water; in addition, vertical transmission from infected mothers to fetuses can happen during pregnancy [1]. The parasite can pass through the placental barrier, causing serious effects, such as retinochoroiditis and central nervous system lesions; the disease also increases the morbidity and mortality of fetuses, neonates, and children. The severity of the consequences is related to the pregnancy stage, as the earlier the infection occurs, the worse is the fetal prognosis [1,4,5].

The objective of gestational treatment is to preserve fetal health [4]. When the chances of transplacental transmission are high, the usual therapy is the combination of sulfadiazine and pyrimethamine [1]. These drugs present a synergistic effect inhibiting the folic acid metabolism, which limits protozoan replication by affecting the purines and pyrimidines synthesis [[5], [6], [7]]. However, this treatment can present adverse effects, as pyrimethamine is not selective to the parasitic enzyme. To avoid them, the patient should receive folinic acid supplementation [6].
The treatment of congenital toxoplasmosis should continue throughout the first year of life to reduce disease severity, with the same drugs [3]. However, they are available only in solid dosage forms; commercially, PYM is only available as 25 mg tablets. The lack of oral liquid formulations can be a barrier to pediatric treatment, mainly due to the challenges associated with swallowing and the need to adjust the dose based on body weight. For example, the recommended PYM dosage is 1 mg/kg once a day, and the frequency may change as the treatment progresses [8].
Despite the advantages of liquid forms for pediatric patients, solid dosage forms remain as the most produced formulation. This is due to their low production cost, higher stability, and manufacturing flexibility, including the ability to film coat and control drug release [9].

In this scenario, extemporaneous liquid preparations represent an alternative to provide oral treatment for children and neonates. These formulations can be obtained from the active pharmaceutical ingredient (API) or by opening capsules and crushing tablets to solubilize or suspend the content in water, food, or other beverages [10,11]. Extemporaneous liquid form preparation can be challenging, since changing the pharmaceutical form involves some risks, such as calculation errors, possible toxicity or incompatibility of some pharmaceutical raw materials, problems with the formulation, microbiological contamination, and patient acceptability [11]. The toxicity of the excipients is a concern in the design of pediatric products because some compounds are not recommended for this age group. Therefore, they should be used just in sufficient quantities to improve the formulation and patient acceptance [12,13].

Several parameters must be considered when we are discussing the stability of compounding medicines, such as information about chemical, physical, and microbiologic stability to ensure the patient’s safety. There is no consensus in the literature regarding the Biopharmaceutics Classification System (BCS) for pyrimethamine, which is classified as either class II or IV [14,15]; therefore, the most likely liquid pharmaceutical form is a suspension. In this context, the literature reports studies that evaluated the stability of PYM in oral liquid form: Nahata et al. (1997) described the stability evaluation of a suspension prepared from crushed tablets; Lewis et al. (2017) prepared a suspension from the bulk powder; a solid dispersion of pyrimethamine was prepared and analyzed by Khatri et al. (2018) and the United States Pharmacopeia (2022) describes an oral suspension (2 mg/mL) prepared using the API diluted in a vehicle composed of a 1:1 mixture of methylcellulose 1 % and syrup [[16], [17], [18], [19]].

However, some of these formulations present commercial vehicles in their compositions, which can increase the formulation cost, promote exposure to undesirable excipients, and may not always be available [20]. The presence of ready-to-use syrups exposes the children to unnecessary excipients and to high concentrations of sugar that increase the chance of tooth caries and affect blood sugar levels [21]. In this context, this study proposes the development of PYM extemporaneous suspensions, using excipients carefully chosen to obtain safe products for the pediatric population, including neonates. As stabilizing agents, xanthan gum and carboxymethylcellulose were used, both well recognized for biocompatibility, non-toxic properties, and as rheology control agents for aqueous systems [22,23]. The formulation’s stability was evaluated by chemical, physical, and microbiological characteristics.