*3.3. Minitablets*

Minitablets constitute a dosage form that ensures more dose flexibility and ease of drug administration in various children age groups than conventional tablets or capsules. Their main advantage is its small size ranging from 1 to 3 mm, with an average mass from 5 to 25 mg and possibility of adjusting single dose by counting the proper amount of minitablets. Minitablets are produced in the same way as conventional ones, by compression using tableting technology with single or multi-punch. They may appear as individual dosage form or could be delivered in capsules or sachets (Figure 9). The clinical researches have demonstrated that 2 mm tablets can be easily used in six-month old infants and 4 mm in children above one year of age, while orodispersible 2 mm tablets can be administered already for preterm neonates. Moreover, Klingmann et al. proved that children above six-months show greater acceptance of minitablets than syrups. Furthermore, they might provide combined release patterns [25,107–109]. Examples of commercially available MR minitablets are: Orfiril Long® and Pancrease MT® (Table 2). Orfiril Long® is provided in hard capsule or single sachet [89]. Pancrease MT® is also provided in minitablets form enclosed inside the capsule [90].

**Figure 9.** Scheme illustration of minitablets placed in capsule and sachet.

### *3.4. MR Orodispersible Formulations*

MR may be also ensured by rapidly disintegrating forms like orodispersible tablets and films. They constitute a relatively new and dynamically developing group of MR formulations. Preparing tablets with such a short disintegration time is a particularly beneficial feature, especially for young patients [110–112]. Prevacid® SoluTab™ is an instance of delayed release orally disintegrating tablet with compressed MR pellets containing lansoprazole (Table 2). An interesting example of immediate and extended release profiles combined in single dosage form are two commercially available medications namely Adzenys XR®-ODT with amphetamine (FDA approval in January 2016) and Cotempla® XR-ODT with methylphenidate group (approval in June 2017). They are indicated for ADHD treatment in children from 6 to 17 years of age. These formulations are available in wide range of doses: Adzenys ®—3.1 mg, 6.3 mg, 9.4 mg, 12.5 mg, 15.7 mg, 18.8 mg, and Cotempla ®—8.6 mg, 17.3 mg, and 25.9 mg allowing dosing in a wide age group. These products are obtained by XR-ODT (extended-release orally disintegrating tablet) technology and they dissolve quickly in the mouth (according to the FDA guidelines—up to 30 s or less) so that it can be easily swallowed. The technology utilized in the tablet uses two di fferent types of microparticles: immediately released in 25% (Cotempla ®) or 50% (Adzenys ®) and slowly released with the other 75% and 50%, respectively, throughout the day. Two di fferent polymers' coatings are applied to the XR microparticles: Interior polymer coating as di ffusion barrier (ethylcellulose) and exterior polymer coating being pH dependent (methacrylic acid). The technology allows for a drug to be incorporated into orodispersible dosage form using ion resin technology [72,73,77,78,113].

Orodispersible films are defined as thin polymeric films supposed to disintegrate in the oral cavity within seconds (there is no detailed monography in any Pharmacopoeia; FDA indicated 30 s or less as disintegration time). Their size and shape resemble postage stamp, with a thickness ranges from 12 to 100 μm and a surface from 2 cm<sup>2</sup> to 8 cm<sup>2</sup> (in the literature, the most frequently encountered dimension is 3 × 2 cm2, 2 × 2 cm2) [113–115]. They are usually manufactured by solvent casting, hot melt extrusion, semisolid casting method, rolling method or electrospinning. There are a number of preparations dedicated specifically for children in this form, but with immediate release, e.g., Pedia-Lax ® Quick Dissolve Strip, Orajel ™ Kids Sore Throat Relief Strips, IvyFilm Kiddies ® [116]. In contrast to fast dissolving films, MR release might be obtained by the mucoadhesive e ffect, which underlies buccal films preparation allowing for prolonged release at the application place. Buccal films are particularly addressed for pre-school and school children since they are thin, adaptable to the mucosal surface and able to o ffer an exact and flexible dose. Abruzzo et al. have designed buccal films for propranolol hydrochloride (β-blocker used in paediatric patients primarily for the treatment or prevention of cardiac arrhythmias and hypertension) administration. Polymeric layer was prepared by casting and drying of film-forming polymers' solutions (polyvinylpyrrolidone or polyvinylalcohol with addition of gelatin or chitosan). As a second layer applied onto the primary one in order to obtain prolonged drug delivery and mask its bitter taste, ethylcellulose was utilized. The formulation is intended for children ≥ 2 years of age and body weight around 12 kg [117].

### **4. Excipients Utilized in MR—Safety of Use in Children**

The safety of children's pharmacotherapy depends not only on the drug substance itself, but also on ingredients forming medicines (excipients). The choice of excipients is a crucial factor in the development of medicinal products for paediatric use. Excipient safely and commonly used in adults' therapy could be harmful for children, e.g., ethanol or propylene glycol cause neurotoxicity; some preservatives like benzyl alcohol, sodium benzoate may lead to allergic reactions. Additionally, a questionable issue is the utilization of parabens in the paediatric population. The most common polymers used for obtaining MR formulations are cellulose derivatives (especially hypromellose and ethylcellulose) utilized as coating polymers, taste masking agents, or e.g. a microparticles matrix (Table 3) [10,68,118–122]. Ethylcellulose as a biocompatible and gastro resistant polymer is used for preparaing sustained release syrup with hydrocodone and chlorpheniramine indicated for children above six-years (Tussionex ®, Table 1) [40]. Ethylcellulose (in aqueous suspension form) was also used for formulating MR microspheres with mirabegron by the spray drying technique, so oral sustained-release suspensions were obtained [51,52]. Emami et al. used hypromellose for formulating MR suspensions with theophylline [123]. Most cellulose derivatives are generally recognized as safe (GRAS) to use in children pharmacotherapy (Table 3). However, for most excipients used in pediatric formulations (e.g., ethylcellulose acetate, methacrylic acid copolymers, and lauryl sulfate), safety data are still limited. The EMA guidelines serve as a database for assessing the safety profile of excipients, so the presented data must be actualized, related to the age group, and relevant to the maximum daily exposure uptake [10,68,118].


**Table 3.** Safety data of excipients used in paediatric modified release preparation [10,68].

> NA: no data available.

\*

### **5. Novel Technologies 3D Printing for MR Formulations**

Pharmaceutical applications of 3D printing have increased over the past years. Printing technologies are cutting edge methods in tablets and films manufacturing. Inject printing is experimentally used for drug printing on different matrices, flexographic printing is employed to coat the drug loaded substrate with a polymeric film. An increasing number of researchers are employing 3D printing technologies to develop oral dosage forms with MR. There is a new approach using a non-contact printing system that incorporates both piezo-electric and solenoid valve-based inkjet printing technologies to deliver both drug and excipients onto the matrix. The main ideas of using this type of technology revolve around the fact that printing technologies would allow to develop pharmaceuticals in a tailored manner to meet some of the envisaged personalization needs of patients for potential use in the paediatric population [124,125]. Recently, 3D printing was utilized to create a multi-active solid dosage form, containing five different drugs within the same capsule, which were autonomously controlled with two separate release profiles, called Polypill® [126]. It would be especially useful for all patients who are taking medicines many times a day. The feasibility of 3D printing coupled with hot melt extrusion to prepare paediatric medicines that can be consumed easily by children from 2–11 years old was introduced. The medicines were designed in such a way to imitate 'candy-like' chewable tablets. For the purposes of the study, Starmix® (HARIBO PLC, UK) formulations were printed using indometacine as model drug and hypromellose acetate succinate as the polymeric excipient [127]. The culmination of 3D printing applications in oral dosage forms is the FDA approval (in August 2015) of 3D printed drug product called Spritam® (levetiracetam)—tablets for oral suspension manufactured by using the ZipDose® technology based on a powder bed (liquid 3D printing patented technology). Spritam® became the first 3D-printed drug approved by FDA as a prescription adjunctive therapy for treating patients with epilepsy for children from the age of four-years old (or 20 kg up). The technology enables immediate disintegration of the drug with a sip of water, making it easy for the patients to administer the drug, even in high doses. ZipDose® technology creates a porous formulation using 3D process that binds powders without compression. The method enables delivery of high drug doses of up to 1 g. Drugs formulated using ZipDose® technology are

specially designed for people with swallowing difficulties (drug dosage form disintegrate within approximately 11 s according to manufacturer) and those who skip regular drug doses, resulting in ineffective treatment outcomes—the children population perfectly fit in [128,129].
