Evaluation of different techniques for wet granulation and pelletization processes using milk as innovative pharmaceutical excipient for pediatric use

Introduction

The development of medicines specifically designed for the pediatric population is still one of the biggest challenges in pharmaceutical research. The main problem underneath pediatric formulation design lies in the patients’ heterogeneity in this age range, which is reflected by the high variability in the pharmacokinetic and pharmacodynamic parameters between patients and within the same patient due to different physiological changes observed throughout growth. As a result, the safety and efficacy of medicines for children must be evaluated separately from those designed for adults. To overcome the small number of specifically designed medicines for children, many drugs must be used as “off-label” requiring the adjustment of the dose of the drug in the medicine designed for adults. Consequently, pediatric patients are likely to be exposed to wrong doses with occurrence of unexpected and undesirable adverse drug reactions (ADRs). Drugs that are most frequently prescribed off-label include analgesics, antibiotics, and bronchodilators (Choonara and Conroy, 2002, Malkawi et al., 2022). The “off-label” used medicines have not been specifically approved for use in the pediatric population due to the fact that they have never been adequately studied in well-designed clinical trials in children. This leads to a lack of both availability of medicines and data on the efficacy and safety of such medicines to be used in children. The lack of familiarity in dealing with children as patients is an ongoing area of concern in need of more research. Furthermore, to facilitate the development of pediatric-specific designed medicines, the European Medicines Agency (EMA) created the European Pediatric Regulation, a set of requirements and incentives to ensure quality and improve ethics in research and appropriate authorization to use medicines in children. According to this regulation, the Pediatric Committee (PDCO) was established, whose main role is to approve studies that every pharmaceutical company must carry out to evaluate the potential use of their pharmaceutical products in children, as part of a pediatric investigation plan (PIP) (Allen et al., 2018). The Pediatric Regulation highlights all troubles concerning the inappropriate handling of medicines for pediatric patients: administration through alternative routes, dose adjustment by non-qualified people (e.g. caregivers), manipulation (splitting or even crushing) of the dosage form and the adjustment of the dose only taking into consideration the age or the weight of the child, without considering the physiological maturity of the patient (Wang, 2015). All these inappropriate practices lead to poor accuracy and reproducibility of the new treatment and questionable stability of the drug and dosage form, compromising the quality, efficacy and safety.

The oral administration of drug products is considered the preferred way of delivering drugs for the treatment of many diseases. Delivering drug substances to the pediatric population is very challenging, since the acceptability of the pharmaceutical dosage form must be considered while designing and developing medicines for that target age group. Main troubles faced while delivering drug products to pediatric patients are related to unpalatable taste and smell of the drugs, color and texture, size and shape of the dosage form, which can be difficult to swell, decreasing patients’ compliance to therapy due to the rejection of the medicine. In the development of baby-sized medicines, emphasis is placed on solid dosage forms and the corresponding technologies aiming to improve formulations towards an easy administration, therapy adherence, and safety profile (Iurian et al., 2022, Mistry et al., 2017, Saito et al., 2022) In this perspective, the process of agglomeration shall be taken into account because multiple units are formed, easing the adjustment of the dose.

The size-enlargement of powdered raw materials requires techniques of combining fine particles or powder into larger and cohesive clusters or agglomerates, with enhanced packing and flow characteristics (Jannat et al., 2016, Macho et al., 2021, Parikh, 2005, Suresh et al., 2017). In the pharmaceutical field, agglomeration can be achieved through different techniques (wet shear granulation and pelletization by extrusion and spheronization), depending on the specific requirements of the desired product. From a mechanistic perspective, these techniques are based on the same mechanism, i.e., all require a binding liquid to bring single particles of powder together and create bonds between them to obtain larger dry agglomerates with new desirable properties, such as better flowability, increased density and reduced dust loss (Jang et al., 2020, Korakianiti et al., 2000, Lee and Yoo, 2022, Passerini et al., 2010, Politis and Rekkas, 2011, Rudić et al., 2019, Shanmugam, 2015).

The interest in using milk in the pharmaceutical field leads to identify the potential of using it as a binder. The Food and Agricultural Organization (FAO) suggests the use of milk in all the different stages of life since birth (Orubu et al., 2017). It is a universally consumed food with established safety for some of its components, which allows to include this product among the list of Generally Recognized As Safe (GRAS) substances of the Food and Drug Administration (FDA). The rational supporting the use of milk in pharmaceutical products comes mainly from its solubilizing, gastroprotective and taste-masking properties. Besides, its composition provides highly nutritive elements and immunological protection. Milk is a natural emulsifier as the drug can distribute either in the aqueous or in the lipophilic phases, increasing the solubilization of poorly water-soluble drugs (Charkoftaki et al., 2010, Kytariolos et al., 2013). The solubilizing effect of milk components must be mostly attributed to the fat and protein contents which offer a delivery system for hydrophobic or hydrophilic non dissolving drugs solving the problem of poor solubility when they are delivered orally. Moreover, the increasing interest in using milk in pediatrics must be related to its optimal taste-masking ability, mainly due to its ability to form oil in water emulsions with the active compound present in the lipid phase, reducing their concentration in the aqueous phase, thus decreasing the interaction with the sensory receptors responsible of transmitting the bitter taste (Bennett et al., 2012, Coupland and Hayes, 2014, Nese et al., 2020).
Paracetamol was selected as a model drug to challenge milk’s technological properties in the preparation of granules, for its broad use among the pediatric population as an analgesic and antipyretic drug to relieve mild-to-moderate pain and fever. Paracetamol is sparingly soluble in water (14.0 mg/mL at 25 °C) and presents a bitter taste, which might be masked when delivered with/in milk (Yalkowsky et al., 2016).

The aim of this work was to systematically analyze different techniques of agglomeration (low- and high-shear mixers and fluidized bed for granulation and extrusion and spheronization for pelletization), to gain a deep understanding of the processes, and to highlight the strengths and the weaknesses of each technique, using milk as a liquid binder to enable the formulator to choose the technique that will enable the manufacture of agglomerates presenting optimal properties. To reach the aim of the work, given the complexity of the processes studied, the work was conducted based on the Quality by Design (QbD) approach, following the ICH Q8 guideline on pharmaceutical development (ICH Q8 (R2). Pharmaceutical development, 2009, Ter Horst et al., 2014–2019), supported on a Design of Experiments (DoE) in which the multiple factors considered and their interactions led to the production of data that enabled the development of statistical models reflecting the relationships between the selected factors (formulation parameters and process conditions) and the responses (properties of the granules), contributing to maximize the quality of the granules obtained.

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Materials

Paracetamol (Paracetamol EP, C.F.M., Italy), lactose monohydrate (Lactochem Crystals, Zambon, Italy) or sorbitol (Sorbitol Powder, A.C.E.F., Italy), microcrystalline cellulose (MCC, Avicel® PH 101, FMC, Ireland), and liquid dairy milk with different fat contents (whole and skimmed UHT milk Esselunga, Italy) were considered in the project.

Martina E. Coldani, Luca Palugan, Anastasia Foppoli, Matteo Cerea, João F. Pinto, Evaluation of different techniques for wet granulation and pelletization processes using milk as innovative pharmaceutical excipient for pediatric use, International Journal of Pharmaceutics, 2024, 124836, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124836.

Read also our introduction article on Sorbitol here: