Before Calpol, there was Paregoric. First concocted in the early 1700s as a palliative for asthma, its two
main ingredients were camphor and tincture of opium. Paregoric’s ability to soothe coughs quickly endeared it to worried parents and, well into the 20th century, it was also being used to treat children for toothache, diarrhoea and crying fits.

Its popularity would eventually wane after the emergence of prescription-drug laws. Although it is still available from some US pharmacies, it has been succeeded by a variety of medicinal syrups, largely down to the preference of parents and doctors alike to treat aches and pains in children with mild doses of paracetamol instead of hard opiates.

The fact that Paregoric was succeeded by the likes of Calpol and Nurofen is testament to an enduring partiality in paediatric pharmacology towards liquid formulations over pills, suspensions or powders. Despite the fact that some of these alternatives could prove more effective in delivering a cure to conditions that may merit more invasive treatments as time goes on, it is hard to persuade a child of that fact.

Oral solid formulations often have a sour or bitter taste and, to avoid the possibility of a remedy being spat out by the patient, the most efficient course of action in the short term is often to rely on a more appealing liquid substitute. But this, in turn, raises its own complications. The measurement of a single dose can prove to be a crude process: while specific guidance may be given on the label, overdosing is still a risk without the provision of an oral syringe, spoon or measuring cup.

Oral solid formulations can, of course, can be coated to mask their unpalatable flavour and ease swallowability, yet cases persist wherein granules and powders are administered along with food and drink to mask their poor mouthfeel – contrary to instruction on the packet that doing so will impair the product’s effectiveness. Meanwhile, immediate and modified-release tablets have tended not to be employed to treat illness in small children, given historic suspicions among medical practitioners that they are unable to swallow them whole.

An end to the research deficit

For these reasons, there has been a historical deficit of research into child-friendly pharmaceuticals. Since the mid-1990s, the passage of new laws and guidelines in the US and the EU has compelled pharmaceutical companies to produce drug formulations that are more appropriately suited for paediatric care. Nevertheless, disparity persists between the number of medicines tailor-made for adult use and those manufactured with children in mind.

According to Aditya Tatavarti, the principal scientist for oral-formulation science and technology at the Merck Research Laboratories, that might be about to change, with the rising popularity of a new form of pill that could act as an effective bridge between conventional liquid and solid oral formulations.

“Minitablets – sometimes referred to as microtablets – are small tablets, generally 1–3mm in diameter,” explains Tatavarti. “They’re generated on traditional pharmaceutical processing equipment with the use of specialised multi-tip tooling. As per US FDA guidance, they must be less than 2.5mm in diameter to qualify as oral granules and allow being sprinkled on soft food.

“These minitablets offer a unique and effective way of providing flexibility in dose adjustment, a consistent presentation of the required dose and a palatable form that can present a desired release date.”

Young worries

Tatavarti has spent almost two decades researching new methods of drug delivery. After completing his PhD in pharmaceutical sciences at the University of Maryland, he joined Merck in 2004 based on his research into controlled release systems. Since then, he has worked on perfecting drug delivery in a variety of areas, including in the treatment of cancer, diabetes and HIV.

“There continues to be a need to develop safer medications and enable high patient adherence – a critical issue that plagues chronic medications in the infectious-diseases area,” he says. “This is being achieved primarily through compact single-tablet regimens in the oral space, as well as in extended-duration therapies.”

Minitablets, in Tatavarti’s view, form a key component of this vision. “New regulations and innovative research across the industry and academia has resulted in advances that have created a paradigm shift in this area, with an increased focus on solid oral formulations such as multiparticulate systems,” he explains, of which the minitablet is but one. “They offer increased dose flexibility, ease of administration and superior taste.”

A study in 2015 assessing the appeal of minitablets among children aged between five and ten years at the Medical University of Gdansk found that 75% of surveyed two year olds willingly swallowed the drugs when suspended in fruit jelly on a serving spoon; that figure rose to 93% in three year olds. Over half of all the subjects were found to be “fully capable of swallowing all units without chewing”, the study found.

This followed a similar investigation conducted by the University of Dusseldorf three years earlier. In that case, researchers found that “the acceptability of uncoated minitablets was superior to syrup” among children aged between six months and five years. These results were also mirrored in the capability of the test subjects to swallow either formulation.

Tasty encapsulation

At Merck, Tatavarti and his fellow researchers have largely concentrated on this issue of palatability, masking the taste of active pharmaceutical ingredients in the minitablet through polymeric coatings. This has, however, raised new problems in how to tailor the effective release rate of the drug into the body, since a fine balance has to be struck between the availability of ‘pore formers’ – the parts of the minitablet that regulate drug release into the body – and the thickness of the polymeric coating that hosts them.

New regulations and innovative research across the industry and academia has resulted in advances that have created a paradigm shift in this area, with an increased focus on solid oral formulations such as multiparticulate systems.

In the area of encapsulation, there have been significant advances. “Bench-top encapsulators, for example, rely on laser counters to count and fill the precise number of minitablets into capsules,” Tatavarti says. “Recently, I travelled to an equipment-vendor facility in Italy, where we test ran some of our minitablets on the machines. It was shown to be a reliable way of encapsulating products where dose or count adjustment is key.”

Tatavarti is also particularly excited at the emergence of new microencapsulation techniques that may have a chance at superseding the traditional Wurster column-based-coating method, including pan coating through retrofitting, the use of continuous coaters and, most of all, those that employ coacervation or phase separation.

“These are highly effective in creating polymeric membranes of various degrees of porosity and thickness to completely encapsulate drug-containing particles, or even individual drug particles,” he says. “These coated particles can then be formulated into paediatric or adult orally dispersible tablets or minitablets. With technologies such as these, the process challenges associated with long coating runs can be avoided.”

Ultimately, Tatavarti is hopeful that minitablets will grow to be considered a reliable option for medical practitioners seeking a consistently precise unit dose in new treatment regimens: “Minitablets certainly offer a sustainable and long-term alternative to traditional solid or liquid dosage forms.”

What are minitablets?

Minitablets are tablets with a diameter equal to or less than 3mm, produced on conventional tablet presses equipped with multiple tooling. They are mainly developed as medication systems for paediatric and geriatric patients or for personalised medicine, as they offer easier swallowing and flexible dosing possibilities. They may also be used as multiple-unit modified-release systems, offering improved drug bioavailability compared with single-unit systems.

Minitablets offer a variety of benefits:

  • They do not require solvent for production, can be coated reproducibly and require less coating material.
  • There are many different types of minitablet available, including bio-adhesive, pH-responsive, gastro-retentive, paediatric and oral-disintegrating minitablets.
  • They offer better delivery of accurate doses in paediatrics and the possibility of dose flexibility with the administration of multiple minitablets.
  • They can be manufactured more easily than other tablets.
  • They have excellent size uniformity, with a regular shape and smooth surface.
  • They offer a substrate that is easy to coat with polymeric membranes for modified release.
  • They combine the advantages of multiple unit dosage forms with established manufacturing techniques and have fewer constraints compared with extrusion or spheronisation.
  • As several minitablets can be placed in each capsule, tablets with different combinations of drugs, doses and drug-release profiles can be included and patient compliance improved.
  • By combining different minitablets, incompatible drugs can be administered and concurrent diseases treated effectively.

Source: ‘Pharmaceutical mini tablets, its advantages and different enteric coating processes’, World Journal of Pharmacy and Pharmaceutical Science, Volume 4, Issue 8.