The effect of administration media on palatability and ease of swallowing of multiparticulate formulations

Multiparticulate formulations, in the form of pellets, granules or beads, offer a range of advantages over conventional tablets and capsules, such as ease of swallowing, flexible dose titration, and suitability for taste-masking and controlled-release (Lopez et al., 2015). They are considered a flexible solid dosage form for the delivery of drugs to a broad range of patients, including paediatrics, geriatrics and patients with swallowing difficulties. However, previous studies suggest that grittiness and rough mouthfeel perception might be a barrier to palatability and patient acceptability (Kimura et al., 2015, Lopez et al., 2018, Lopez et al., 2016). A potential solution to overcome palatability and acceptability issues could be co-administration with a suitable vehicle (i.e. sprinkle), which could help to conceal the presence of multiparticulates. Some drug products that contain multiparticulates within a capsule or sachet indicate in the labelling that the internal beads can be sprinkled on soft foods for their administration (FDA, 2012). Commercial examples include Depakote® sprinkle capsules (divalproex sodium), Creon® capsules (pancrelipase), Granupas® gastro-resistant granules in sachets (para-aminosalicylic acid) and Cipla’s lopinavir/ritonavir pellets in capsules (Hanning et al., 2016, Ternik et al., 2017). Typical vehicles recommended for products labelled for sprinkle include apple sauce and yogurt that provide both flavour and viscosity to facilitate administration and improve patient acceptability (Ternik et al., 2017).

Studies comparing sprinkle formulations to liquid dosage forms in children have commonly showed preference for the solid over the liquid form. A range of studies showed acceptance of iron supplement sprinkles and preference for these compared to oral drops in children with anaemia (Adu-Afarwuah et al., 2008, Geltman et al., 2009, Zlotkin et al., 2003). Likewise, studies involving children suffering from epilepsy consistently showed preference for sprinkle formulations over syrup (Cloyd et al., 1992, Motte et al., 2005, Verrotti et al., 2012). In a recent study, children showed preference for sprinkles over syrup after 12-week antiretroviral therapy; 72% of children below 12 months and 64% of children between 1 and 4 years preferred the multiparticulate dosage form. For those preferring syrups, key issues with sprinkles were problems masking the pellets with food and food refusal, and concerns about not giving the whole dose. However, multiparticulates overcome the storing and transporting issues of syrups (Kekitiinwa et al., 2016).

Medicines are known to be mixed with liquid and semi-solid foodstuff to allow administration in clinical practice (Akram and Mullen, 2015, Akram and Mullen, 2012). However, this is not without the risks that mixing medication with foodstuff could alter bioavailability and introduce poor control over dose intake (EMA, 2013). Therefore, when co-administration of medicines and foodstuff is recommended in the package leaflet, the potential impact on patient acceptability, dosing accuracy, compatibility and drug bioavailability of the proposed vehicle(s) must be investigated (EMA, 2013). This task becomes very impractical when medicines can be mixed with a range of foods with different composition and physical properties (e.g. rheology, pH, ionic strength) (Kersten et al., 2016). The development of a standard pharmaceutical vehicle, rationally designed and fit for purpose, could facilitate such investigations. This vehicle could be manufactured by industry and provided with the finished drug product (although this would increase the overall cost of the product) or it could be compounded in a pharmacy (Kluk and Sznitowska, 2014). Investigation into swallowing aids for the administration of oral solid formulations have been the focus of previous research, with some products already in the market in the form of sprays, pastes or jellies (Bunupuradah et al., 2006, Diamond and Lavallee, 2010, Yoshida et al., 2011).

The rheological properties of the administration media require special consideration. Thick fluids are known to exhibit prolonged oral transit times than thinner fluids, which can be used in the management of patient with dysphagia (Soares et al., 2015). Conversely, greater efforts are required to manipulate in the mouth and swallow thick fluids compared to thin ones (Ong et al., 2018, Steele et al., 2015). Consequently, overly thick liquids may increase the risk of post-swallow residue in the mouth and pharynx, especially for patients with reduced tongue or pharyngeal muscle strength (Steele et al., 2015). Newtonian fluids have also been reported to require greater effort in oral processing and swallowing than shear thinning fluids (Steele et al., 2015). In addition, the rheology of the vehicle also affects its palatability, with organoleptic attributes often reported to worsen as the consistency of the fluid increases (Garcia et al., 2005, Ong et al., 2018). Therefore, it is imperative that the rheological and sensory properties of the vehicle are adequately characterised.

The use of a suitable vehicle could facilitate administration of multiparticulates by preventing fast sedimentation, improving palatability and reducing the risk of aspiration or choking often associated with this dosage form design (Walsh et al., 2018). Development of media for the administration of multiparticulates and evaluation of its effect on palatability has been the focus of two recent studies (Kluk and Sznitowska, 2014, Lopez et al., 2016), both of which concluded that the use of polymeric hydrogels as administration media could help conceal the presence of particles, reducing oral grittiness perception. However, both studies focussed on a swirl and spit methodology, which overlooks other important sample attributes such as ease of swallowing. Moreover, neither of those studies investigated the palatability of the liquid vehicles alone, which limited their understanding on the effect of the palatability of the vehicle on the overall palatability and acceptability of the final formulations.

The aim of this work was to develop liquid vehicles for the administration of multiparticulates and to investigate the effect of the administration media properties on palatability and ease of swallowing of multiparticulate formulations. Administration media were developed using xanthan gum (XG) and carboxymethyl cellulose (CMC) as model hydrocolloids. The rheological properties of the hydrocolloids were characterised to investigate the effect of consistency and shear thinning behaviour on their performance as administration media. Palatability attributes and ease of swallowing of the vehicles alone and formulations containing model multiparticulates were evaluated in healthy volunteers.

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2. Materials and methods