**1. Introduction**

Creating an appropriate dosage form designed exactly for children still appears as an outgoing challenge for pharmaceutical technology and the distinction between adults and children pharmacokinetics should be considered. The statement that children can be treated as "small adults" is obviously incorrect, particularly in determining the therapeutic doses in individual age groups [1–4]. In paediatric pharmacotherapy, many factors regarding a convenient dosage form (e.g., age-suitable formulations in proper strength, off label use, and palatability) have to be included. Creating paediatric dosage forms is associated with many difficulties. Therefore, the main goal raised by regulations of European Medicines Agency (EMA) or paediatric scientific network groups is increasing the safety and efficiency of paediatric therapy by the enhancement the quality of clinical studies for children in various age groups (from birth to 18 years old) with better availability of pharmacokinetic data [5,6]. Scientific and governmental initiatives (The Best Pharmaceuticals for Children—BPCA, Paediatric Investigation Plan—PIP) are focused on the development of paediatric dosage forms adjusted to the child's age and as a consequence of enhancing the efficiency and safety of paediatric therapy [7,8]. The main directives implemented in the appropriate paediatric dosage forms development point basic difficulties connected with paediatric therapy. A special guideline concerning formulation and administration of suitable dosage forms and detailed information on how to use the medicines with regard to children was proposed (State of paediatric medicines in the European Union 10 report) [9]. Due to the special attention focused on the safety of excipients used in the paediatric formulations, the Step and Toxicity of Excipients for Paediatric Patients database has been created (STEP database) [10]. Additionally, EMA gave a support in providing clinical trials with children to promote and harmonize existing paediatric

guidelines [7,11–18]. As a result of these acts, the percentage of clinical trials included children (where only one participant was under 18 years at least) has increased from 8.3% in 2007 to 12.4% in 2016. Therefore, it still remains an outgoing problem as there is constantly not enough clinical trials with children compared to the numbers of clinical trials carried out in adults [9]. Challenges associated with conducting clinical trials in children include many childhood diseases, heterogeneity of the population and ethical problems [18]. Main problems related to paediatric therapy are presented in Figure 1.

**Figure 1.** Problems in paediatric pharmacotherapy practice [11,19,20].

Traditional dosage forms (e.g., tablets, capsules, and injections) are often not appropriate for children, hence cutting or crushing tablets, splitting capsule and then mixing with the food (solid or liquid) and dilution of injections are common practice [19–22]. Manipulation with dosage form may cause a risk of damage of formulation structure, hence side effects and changes in pharmacological effect might occur. Despite significant advances in the development of drug dosage forms dedicated especially for children, but unfortunately, unlicensed drugs are still used [1–4].

Oral route of administration is the most natural way of giving medicines for children. Regardless, child age is still the most popular liquid dosage forms. Their main advantages are safety and ease of swallowing, but the most important and most convenient factor is the possibility of drug administration in a wide group of children by volumetrically measuring a dose, precisely adjusted to a child's weight or age. Liquid dosage forms are preferred especially for newborns, infants, and smaller children, avoiding the risk of chocking and enhancing the probability of taking a full dose of the drug. For older children (above 6 years), despite liquid formulations, solid dosage forms (tablets, effervescent formulations, orodispersible tablets, films, pellets, or minitablets) could be safely administered. However, the individual swallowing abilities should be considered when administering oral solid forms for children. Nevertheless, numerous studies proved that pre-school (up to 6 years old) and even infants (6 months old) are able to safely swallow particles smaller than 3 mm (minitablets, pellets) [23–26]. While both liquid and solid forms are available in paediatric therapy, there are not many MR formulations dedicated for children. MR dosage forms ensure drug release in the entire gastrointestinal tract providing constant drug concentration and eliminating the necessity of taking several doses a day, hence improving pharmacotherapy effectiveness [19,27]. Additionally, it is worth emphasizing that utilizing MR technology creates a possibility of increasing drug stability. The most common example is formulating enteric pellets with proton pump inhibitors (omeprazole, pantoprazole), which are unstable in acidic pH. The main reason why MR paediatric forms are lacking includes the clinical aspects like a small range of strength suitable only for particular child's age. Changing clinical parameters in the chronic diseases requires frequent dose changes depending on the response to therapy, disease management, or age-related changes in strength dose, which requires the availability of a wide range of drug doses on the market. From a technological point of view, the production of various doses is simply unprofitable for pharmaceutical companies, considering that some of the MR technologies are rather expensive (Figure 2) [9,20]. The aim of the current article is to overview available paediatric MR oral liquid and solid formulations depending on the dosage forms and utilized technology, as well as to introduce new approaches and possibilities used in the children's pharmacotherapy.

**Figure 2.** Profits and limitations of use the modified release (MR) formulations in paediatric population.

### **2. MR Liquid Dosage Forms**

Oral liquid formulations (drops, solutions, suspensions, and syrups) are the most popular dosage forms indicated for children of all ages [6]. The main advantage of liquid forms is volumetric dosing, which gives an opportunity to precisely adjust the dose for the specific age groups by measuring an appropriate drug volume. Liquids are easy to swallow and can be administered by child caregivers, without any manipulation before administration, as in the case of tablets (crushing, mixing with food, or fluid). Nevertheless, the limiting factor of using liquids is their physicochemical and microbial instability in an aqueous environment, which entails the need to use preservatives or cosolvents. Additionally, dosing might be a hindering issue in connection with using a not calibrated spoon, oral syringes, or not properly measured drops. Limiting factor of using liquid forms in pediatric preparations is the drug taste as well. Therefore, common practice is to prepare suspensions rather than solutions. For this purpose, excipients such as natural or synthetic flavours or various technologies that minimize the unpleasant feeling of bitterness (e.g., dose sipping technology—straws with coated pellets) can be used [28–31]. Nonetheless, it is evident that conventional liquids are the most frequently chosen formulations, therefore MR oral liquid forms would be preferable for children to eliminate dosing several times per day, especially in chronic diseases. Not only reducing the frequent drug administration is important, but also providing a favorable pharmacokinetic profile of the drug with keeping drug concentration at a constant therapeutic level [32]. For comparison, in case of MR hard capsules, to achieve a prolonged action of the drug, it is possible to open the MR capsule and to administer the content (e.g., powder, pellets, and minitablets) after mixing with the fluid or food. However, this practice can result in dose errors or MR disturbance if the medication will be chewed not swallowed [19,33]. The following modifications are used for formulating prolonged drug release in liquid dosage forms: Drug/resin complexes, in situ gel formation, microencapsulation, and MR microparticles [34,35]. Despite liquid MR formulations seem to be suitable for applying to children, currently the number of MR liquid forms for children available in the market is limited. Table 1 presents an overview of MR oral liquid formulations with paediatric license and products with finished clinical trials being under the approval registration process by the Food and Drug Administration (FDA).



*Int. J. Mol. Sci.* **2019**, *20*, 3200

### *2.1. Drug-Resin Complexes*

Utilizing ion-exchange resins for getting a complex with drug is one of the techniques enabling modified drug release in oral liquids (Figure 3) [52]. Nowadays, the most often used resins are cationic exchange-resin with a free sulphuric acid group on the crosslinked polystyrene matrix (extended release utilized in liquids with, e.g., chlorpheniramine and dextromethorphan) and the anionic exchange-resin with amino groups, which are available in the market with paediatric licence (Table 1). Developed complexes are often incorporated into microcapsules (inside the particle or in the coat), lipospheres (lipid microspheres, size 0.01–100 μm), or directly suspended in suspending vehicles. Obtained suspensions are usually administered once (Dyanavel XR®, Quilivant XR®) or twice daily (Delsym®, MST® Continous®) [36,37,39]. Dyanavel XR® utilizes an ion exchange resin, where the amphetamine is bound to the sodium polystyrene sulfate resin through an ionic binding reaction. Dyanavel XR® contains immediate release and extended release components as complexes coated with pH independent polymers: Povidone and polyvinyl acetate [37]. Quillivant XR® is a powder forming an extended-release oral suspension after reconstitution with water. It contains approximately 20% immediate-release and 80% extended-release methylphenidate in drug-polistyrex complex form [39]. MST® Continous® is the example of syrup containing MR granules with morphine sulphate complexed with Dowex 50WX8 cationic exchange resin and suspended in a sugar free medium. It is recommended to take the suspension every 12 h [38].

**Figure 3.** Drug release modification utilizing drug-resin complexes.

### *2.2. Microparticles—Spray Drying Technique*

The other method of obtaining MR in oral liquids is the spray-drying technique. It creates the possibility of designing microparticles (microspheres, microcapsules) so that drug is incorporated or enclosed in a polymeric shell and then suspended in the liquid (Figure 4) [53,54]. This technique brings the grea<sup>t</sup> area on the achieving desired dissolution profile, improved drug stability, and also provides taste masking effect. Depending on the polymers used in the process, various sizes and properties of microparticles might be created. Spray drying is the process by which a dry powder product is formed from the starting solution or suspension [55–58]. Zmax® is an example of a single-dose, prolonged-release formulation of microspheres for oral suspension containing azithromycin (Table 1). Zmax® was approved as a one-dose-only treatment for mild-to-moderate acute bacterial sinusitis and community-acquired pneumonia. Azithromycin microspheres (50–300 μm) are produced with glyceryl behenate and poloxamer 407 utilization by a combining hot melt extrusion with spray congealing technology. Microspheres were formed by suspending azithromycin in a molten carrier matrix and spraying by a spinning-disk atomizer to form droplets, which congeal into solid microspheres upon cooling [41].

**Figure 4.** Drug release modification using spray-dried microparticles.

### *2.3. In situ Gel Formation*

Modified drug release in liquid formulations could be obtained by the in situ gel formation, which depends on temperature, pH, ions, or UV irradiation. Gel formation from liquid allows achieving a sustained or controlled release profile (Figure 5) [59–61]. Physicochemical characteristics like solubility or gelling properties of polymers are crucial for obtaining desired MR. Polymers used for in situ gel formation include gellan gum, xyloglucan, pluronics, tetronics, alginic acid, carbomer, hypromellose, pectins, chitosan, polycaprolactone or poly(DL-lactic acid), or poly(DL-lactide-co-glycolide) [62–64]. The in situ forming gel technique is used in SABER ™ technology (sucrose acetate isobutyrate extended release, SABER ™ Delivery System), where the biodegradable gel initially appears in low-viscosity fluid form. SABER ™ systems are dedicated as carriers for drugs in dosage forms administered orally (the clinical trials with SABER ™ delivery system for bupivacaine). After application, its viscosity increases, making an adhesive gel and MR of drug could be obtained. Orally administered drug di ffuses rapidly, leaving in situ drug depot [42,44]. Another system utilizing gel forming matrices is ORADUR ™. Gel matrices are able to accumulate high concentrations of drug, with the goal of once and twice-daily dosing. These are also designed to provide controlled long-term treatment preventing the abuse, e.g., the preparations with oxycodone (Remoxy ®) and methylphenidate [49–51]. Unfortunately, formulations based on ORADUR ™ and SABER ™ technologies despite completed clinical trials (phase 3) have still not been approved for marketing (Table 1).

**Figure 5.** In situ gel formation from liquid for obtaining sustained or controlled release profile of drug in liquid dosage form.

### **3. MR Solid Dosage Forms**

### *3.1. Matrix and Coated Tablets*

Traditional MR tablets are formulated by drug embedding in a hydrophilic (swelling), lipid, or insoluble matrix. A determinant factor for maintaining MR from all tablets types is obtained by incorporation to ensuring a sufficiently long way of drug diffusion. As hydrophilic carriers, water-soluble polymers are utilized: Cellulose derivatives (methylcellulose, hypromellose, and hydroxyprophylmethylcellulose) or sodium alginate. A common feature of these polymers is the formation

### *Int. J. Mol. Sci.* **2019**, *20*, 3200

of highly viscous gel in an aqueous environment hindering the drug diffusion. By suspending drug in the gastrointestinal insoluble carrier, shell tablets are obtained. Among excipients forming insoluble shell inorganic compounds (calcium sulphate, and di- and triphosphate) or organic (ethylcellulose, cellulose acetate) can be distinguished [65–68]. An interesting example of matrix tablet (intended for children ≥12 years) is Lamictal® XR (Table 2). The tablets are coated with an enteric layer ensuring MR. Simultaneously, there are apertures drilled from the core to the outer layer on both faces of the tablet's structure (DiffCORE™) to provide a controlled release of drug in the acidic environment of the stomach (Figure 6). Such a combination is designed to control the dissolution rate of lamotrigine over a period of approximately 12 to 15 h, leading to a gradual increase of lamotrigine level in serum [69].

**Figure 6.** Scheme illustration of DiffCORE™ system.



*Int. J. Mol. Sci.* **2019**, *20*, 3200 **Table 2.** *Cont.*


### *3.2. Multiparticulate MR Solid Dosage Forms (MultiP)*

Single-unit formulations contain drug in a single tablet or capsule form, whereas MultiP dosage forms comprise of quantity of particles combined into one dosage unit. They may exist as pellets, granules, minitablets, microparticles (microspheres, microcapsules), or nanoparticles with drugs being entrapped in or compacted in the matrix, as well as layered around cores and placed per se in sachets or capsules. MultiP provide many advantages over single-unit systems because of their small size and large surface, which allows leaving the stomach within a short period of time, which results in better distribution and bioavailability improvement. Another advantage of MultiP is the decreased risk of dose dumping due to damaged/broken coating, as well as reduced local irritation as MultiP are more uniformly dispersed in the gastrointestinal tract. Pellets reduce retention in a throat compared to the capsules or powders and improve physicochemical stability. MultiP dosage forms may o ffer a flexible dosing that allows covering a broad range of doses for di fferent age groups [98,99].

An example of such a system is Multi-Unit Pellet System (MUPS)—utilizing coated pellets for controlled release, usually filled into a capsule or compressed to a tablet form. MUPS technology has been adopted by the pharmaceutical industry as an alternative to conventional immediate or MR tablets. MUPS consisting of pellets ensures divisible dosage form without imparing the drug release characteristic of the individual units. In addition, compared to other carrier systems, MUPS preparations entail a lower risk of irritation and toxicity, dose stability, minimal fluctuations of drug concentration in plasma, and the ability to administer drugs with a narrow therapeutic index. Another advantage is the possibility of using di fferent taste masking techniques. The leading preparation being manufactured utilizing this technology is Losec MUPS with omeprazole for children (approved over 1 year of age and ≥ 10 kg) [85,100]. Formerly, attempts were made to obtain omeprazole as liquid form, however, due to its instability (rapid decomposition at wide range of pH), such a formulation could not be manufactured and launched in the market [101,102].

Another example of MultiP with paediatric licence is Moxatag ™—prolonged release pulsatile delivery technology (PULSYS ™) with multiple pellets inside. The typical PULSYS ™ drug delivery format is a tablet containing pellets with di fferent release profiles. The pellets with amoxicillin are formulated in a proportion that delivers optimal antibiotic levels. Manufacturers assume that this product can be presented in the future as sprinkle granules for the younges<sup>t</sup> patients [87,88]. Prevacid ® is an instance of delayed release capsules with pellets (also available as delayed release orally disintegrating tablet—Prevacid ® SoluTab ™) containing lansoprazole (Table 2). The pharmacokinetics of lansoprazole was studied in paediatric patients with gastroesophageal reflux disease (GERD) in two separate clinical studies (one children group aged from 1 to 11 years and the second from 12 to 17 years). Each capsule contains enteric-coated pellets consisting of methacrylic acid copolymer providing delayed release of lansoprazole [92,93].

The MR MultiP can also be used in the treatment of hypertension in children above 6 years. The combined (immediate and control) release profile (Coreg CR ®) or extended release (Toprol-XL ®) were designed for carvedilol and metoprolol, respectively (Table 2). Coreg CR ® is in hard gelatin capsules form filled with immediate or controlled release microparticles. Controlled release of carvedilol is ensured by coating multiparticles using methacrylic acid copolymer [76]. TOPROL-XL ® is available as extended release tablets and has been formulated to provide a controlled release of metoprolol for once-daily administration. The tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval [96,103].

The group of patients that requires special attention related to e ffective pharmacotherapy and has a particular need for taking MR formulations are children su ffering from ADHD. MR drug dosage forms allow for extended delivery with less variability throughout the day, improved tolerability and less frequent administration ensuring convenience and adherence, which is important in this patients' group therapy. Therefore, some pharmaceutical preparations utilizing MR have been introduced for treatment of children with ADHD (Table 2). An interesting example of multiparticulate drug delivery system is SODAS ® (Spheroidal Oral Drug Absorption System). Based on the production of controlled release beads, it is possible to provide a number of release profiles, including immediate and sustained release, giving rise to a fast onset of action, which is maintained for 24 h (Figure 7) [104]. Ritalin LA ® (methylphenidate hydrochloride) is an extended-release capsule with a bi-modal release profile based on SODAS ® system with paediatric license (Table 2). The preparation contains 50% of immediate release beads and 50% extended release beads covered by the polymer overcoat. The first peak in its bimodal profile occurs after 1 to 3 h and the second peak is approximately 6 h post dosage, therefore it is designed to be e ffective throughout the school day [94]. The second example bases on SODAS ® technology is Focalin ® XR (Table 2). Similar to the above description, each capsule contains 50% immediate release beads of methylphenidate and 50% extended release beads covered by a polymer, with the di fference that the beads can be sprinkled in food [81].

**Figure 7.** Scheme illustration of SODAS ® delivery system modified from Elan drug technologies [105].

The other example of MR formulation designed for children with ADHD is Adderall ® XR administered once daily (Table 2). Each capsule contains a 50:50 ratio of immediate and delayed-release beads. Di ffucaps system (utilized in Metadate CD ®) comprises both immediate release (30%) and extended release (70%) beads. Di ffucaps is multiparticulate system, where drug profiles are created by layering a drug onto a neutral core (e.g., sugar spheres, crystals, or granules) followed by the application of a rate-controlling, functional membrane (Figure 8). The physicochemical characteristics of coating materials (being water soluble/insoluble, pH dependent/independent) are conditional on individual drug features. Obtained beads are small in size, approximately 1 mm or less. By incorporating beads with di ffering drug release properties, combined release profiles can be achieved. Metadate CD ® designed to provide e fficacy throughout the school day is available in six capsule strengths (with possibility of sprinkle over food) [86].

**Figure 8.** Scheme illustration of Diffucaps® bead technology modified from Weil [106].
