Pediatric Orally Disintegrating Tablets (ODTs) with Enhanced Palatability Based on Propranolol HCl Coground with Hydroxypropyl-β-Cyclodextrin

Introduction

The development of age-appropriate formulations for children is the main issue of pediatric therapy to assure that all children, of different ages, as well as their caregivers, can easily access to safe and accurate dosage forms, as pointed out by the implementation of pediatric-specific guidelines provided by the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) [1].

Most drugs prescribed for the prevention or treatment of diseases in pediatrics are unlicensed or off-label from the point of view of formulation, therapeutic use, and/or route of administration, with the majority designed for and studied in adults [2].

The lack of suitable specific formulations often leads to a large use of extemporaneous preparations such as crushing of tablets dispensed as suspensions or dilution of existing liquid dosage forms. Such manipulations cause problems of loss of dosing accuracy, unknown bioavailability, and poor compliance for both young patients and their caregivers [3].
Some essential features are required by an optimal pediatric formulation to adequately improve drug acceptability, adherence, and more efficient therapy, such as ease of administration, appropriate dosage form for different pediatric age groups, low frequency of dosing, safety of excipients, palatability, and minimal discomfort or burden to minimize impact on lifestyle.

Among the different kinds of solid oral dosage forms, orally disintegrating tablets (ODTs) can represent a potential promising technological strategy for oral administration of drugs in pediatrics [4,5,6].

They combine all the advantages of solid dosage forms, such as accurate dosing, good stability and compliance of patients, easy manufacturing, and small packaging size with those of liquid formulations, including easier administration with no risks of choking. ODTs can be easily administered to children without requiring hospitalization or the support of medical professionals, and they have been shown to be well-tolerated and safe [7].

ODTs are able to quickly disintegrate inside the mouth, leading to partial drug absorption through the oral mucosa and thus allowing to partially avoid the first-pass metabolism and increase bioavailability [8,9]. On the other hand, their fast disintegration in the oral cavity leads to early contact of the drug with the taste buds, and therefore the palatability degree becomes critical for the patient acceptance [4,10,11].

Taste masking represents a very important property to be considered in the case of ODTs, since the bitter taste of a drug is one of the most significant drawbacks that can cause a reduction in drug adherence and then treatment failure [12]. Among the different possible taste-masking techniques, the use of cyclodextrins could represent an effective, safe, and low-cost strategy due to their capacity to form inclusion complexes with a wide variety of drugs, thus enabling not only the improvement of their physicochemical properties such as solubility and/or stability [13,14], but also to hide their unpleasant taste, as highlighted from a recent review [15]. The favorable effect of cyclodextrin complexation in hindering the bad, bitter taste sensation of the solubilized drugs has been shown, for example, in the case of cetirizine tablets [16], oral dispersible films and buccal films of indomethacin and furosemide [17], or phenylbutyrate ODTs [18,19]. Moreover, orally administered cyclodextrins have an outstanding safety profile, and may be considered safe and valuable excipients also in the pediatric field [20].

Among the different techniques proposed to prepare inclusion complexes with cyclodextrins in the solid state, mechanochemical activation by grinding seems to be a simple, fast, highly efficient, convenient, versatile, sustainable, eco-friendly, and solvent-free method [21].

Propranolol, largely prescribed in pediatrics as an antihypertensive and antiarrhythmic drug [22,23], is characterized by a bitter taste and an astringent aftertaste.

A previous study showed the effectiveness of complexation with hydroxypropyl-β-cyclodextrin in taste masking of liquid dosage forms of propranolol, making it possible to avoid the need to add potentially harmful excipients as sweeteners or flavoring agents and their solvents, commonly used to improve palatability [24].

Currently, there are no marketed solid dosage forms of propranolol specific for children, thus requiring crushing and dispersion in water of fractions of tablets for adults, with the consequent series of drawbacks as above described. Moreover, some excipients used in adult formulations could be potentially toxic for children [25,26,27].

On the basis of all these considerations, it was considered worthy of interest to investigate the feasibility of developing an oral propranolol-based solid dosage form specific for pediatric therapy, endowed with reliable dosing accuracy, high safety in use, good palatability, ease of swallowability, and ultimately better compliance by both pediatric patients and caregivers, by exploiting the approach of ODTs in combination with the use of drug–cyclodextrin complexation for achieving a safe taste masking.

This study, which represents a continuation of our previous one [24], is in line with the current trends in the pediatric field to switch from liquid to novel suitable solid oral dosage forms, mainly due to their easier transport, minor stability and storage issues, and greater accuracy in dosing [28].

Based on the results of our previous study, hydroxypropyl-β-cyclodextrin (HPβCD) was selected as a complexing agent for propranolol, and the equimolar drug:HPβCD coground system was used to prepare ODTs by direct compression. Different formulation variables, such as type and number of excipients, e.g., diluents and superdisintegrants (SDs), as well as process parameters, such as compression time, were investigated. The resulting tablets were characterized in terms of technological and morphological properties according to USP 43 and 11th Ph. Eur. official tests. Alternative tests to the USP and Ph. Eur. disintegration test specifically developed for ODTs, such as the simulated wetting test (SWT) and test on wire cloth [29,30,31], were also performed. Finally, the best ODT formulations were selected for dissolution studies through the flow-cell dissolution apparatus and for in vitro palatability evaluation by the electronic tongue, which emerged as a valid instrument for a rapid preliminary taste evaluation and screening of oral dosage forms [32,33] in comparison with analogous placebo and free-drug-loaded ODT formulations.

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Materials

Propranolol HCl was purchased from Fagron Italia Srl (Quarto Inferiore, Bologna, Italy), hydroxypropyl-β-cyclodextrin (HPβCD) (Cavasol W7 HP) was donated from Wacker Chemie AG (Munich, Germany), Pearlitol® Flash (co-processed mixture of D-mannitol-extra white maize starch) was kindly supplied by Roquette (Lestrem, France), as well as Ludiflash® (co-processed mixture of D-mannitol, crospovidone, polyvinylacetate, povidone) by BASF Pharma (Ludwigshafen, Germany), Pharmaburst® 500 (co-processed mixture of mannitol, silicon dioxide, sorbitol, crospovidone) by SPI Pharma (Wilmington, DE, USA), and Explotab® (sodium starch glycolate) by JRS Pharma, (Rosenberg, Germany). Sodium stearyl fumarate was kindly donated by Menarini Manufacturing (Florence, Italy). Simulated saliva (SS) fluid (8.00 g/L of NaCl, 0.19 g/L of KH2PO4, and 2.38 g/L of Na2HPO4) was prepared according to Late et al.

Cirri, M.; Mura, P.A.; Maestrelli, F.; Benedetti, S.; Buratti, S. Pediatric Orally Disintegrating Tablets (ODTs) with Enhanced Palatability Based on Propranolol HCl Coground with Hydroxypropyl-β-Cyclodextrin. Pharmaceutics 2024, 16, 1351. https://doi.org/10.3390/pharmaceutics16111351

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