Pediatric Formulations – Are We Living in the Past?

• University of Copenhagen

Background

All else being equal, oral drug administration is the preferred option. Drugs, being poisons, taste like poison and evolution has equipped us with the means to detect and avoid them in time, i.e. the senses of taste and smell. Adult Humans differ from other animals in their ability to make the conscious decision to override the warnings reasoning that, in the long term, swallowing the bitter pill (pun intended) is for their own good.

It takes years of development for a child to gradually acquire this ability, and although children are generally healthier than adults, they still need to take medicines occasionally (and for a small group chronically), mostly and preferably through the oral route.

The pharmaceutical industry has largely neglected the pediatric segment, the syrup remaining the mainstay of the formulation arsenal. Fact: there are very few (if any at all) oral controlled-release products which are appropriate for children because it is difficult/impossible to design particles that are stable in syrup (see below). Contrary to the belief (read wishful thinking) of the industry, children are not fond of syrups [1]. Children do not like novelty in food; on the contrary, they are reticent to try new flavors and consistencies. It is largely assumed that children are unable to swallow solid objects. Thick, oversweet liquids with too much flavor are (thankfully) rarely a part of the diet of small children.

The FDA and the EMA now require Pediatric Investigational Protocols, PIPs, for all New Chemical Entities, including age-specific formulations, and the drying of the NCE-pipelines is forcing the industry to look at marginal areas, such as the pediatric population, for new opportunities.

Swallowing the Bitter Pill

Watching people eat can be a fascinating experience: the person visually evaluates and judges the food. Consider this: very few foods are colored blue and those that are will probably not be liked by children. “Good manners” have taught us not to, but we like to get information about the density, texture, consistency and smell of food, even before parting our lips. Children like to play with (read touch) their food.

Upon entering the mouth, the food is further analyzed for taste, “mouthfeel”, and an estimation of the number of chews needed to make it swallowable is made. This is the oral phase, defined as the phase encompassing all actions leading up to and including the act of swallowing an ingested bolus.

In the oral cavity, the food is sensed, wetted and masticated through a complex interaction of the many structures present; the lips, cheeks, alveolar ridge, hard and soft palates, teeth, floor of the mouth and tongue in the anterior region, and the soft palate, uvula, tonsillar pillars and the posterior section of the tongue in the posterior region. In addition, sensory nerves transmit the information needed to determine the chemical and physical acceptability of an ingested bolus for swallowing and to modulate the precise mechanics of the oral phase [2].

The above is reviewed in more detail in a recent article [3]. The oral phase is further divided into a preparatory phase and a transfer phase. In the former, the bolus is masticated, fractured and mixed with saliva (to change its consistency and lubrication), if necessary, until fit for the transfer phase where the bolus is positioned and transferred to the pharynx. Palatable liquids are swallowed right away, a piece of muffin requires about 4 seconds for the whole oral phase. A handful of peanuts might require 10 seconds for the preparatory phase [4].

At this point, let us consider our own experiences: some pliable objects can be swallowed right away: yogurt, crème caramel, oysters, noodles in soup, etc. They are soft, deform easily and, above all, are well lubricated. Consider the fact that evolution has developed a variety of objects meant to be swallowed easily, viz. seeds. Botanists have a name for the study of seed distribution through the digestive tract of animals, Endozoochory [5,6].

It’s the Flavor, Stupid!

Flavor, or flavour (UK) is defined as: “The sensory impression of a food or other substance, and is determined mainly by the chemical senses of taste and smell” (Wikipedia, July 2011). Flavor is decisive for a child to consider putting and keeping something in his/her mouth. Mennella and Beauchamp [7] have addressed in detail the challenges of developing products for children, with a focus on the challenges of taste masking.

Quoting Mary Poppins:

“A spoonful of sugar helps the medicine go down
The medicine go down-wown
The medicine go down
Just a spoonful of sugar helps the medicine go down
In a most delightful way”

Sounds good but, is it sound?

Maybe, but probably not. Flavor is the combination of smell and taste, not the taste alone or the smell alone. The taste and smell should be congruent [8] or it will be more difficult for a person to identify the flavor [9]. Also, certain tastes and smells can enhance or diminish the perceived sweetness [10]; for example, the same concentration of sucrose was perceived as being more or less sweet than the control depending on which flavor was added [11,12].

Different individuals can have widely different experiences when tasting the same product, genetics playing a significant role [13]. Taste in children is an even faster moving target because it develops as the child grows [14]. Children have a stronger liking for sweet [15] and salty tastes [16] than adults, but they seem to be more sensitive to bitter taste than adults [17,18]. Furthermore, the bitter, sweet [19] and possibly umani sensations are the result of ligands binding to proteins. Each ligand-protein binding has its own kinetics. The consequence is aftertaste.

Aftertaste is the taste intensity of a food or a drink that is perceived after that food or beverage is removed from the mouth. The aftertastes of different foods and beverages can vary by intensity and over time, but the unifying feature of aftertaste is that it is perceived after a food or beverage is either swallowed or spat out.

A combination of both receptor-dependent and receptor-independent processes might explain the signal transduction mechanisms for foods with distinct aftertastes, especially bitter foods. Chemicals in food interact with receptors on the taste receptor cells located on the tongue and the roof of the mouth. In the receptor-independent process, amphiphilic molecules such as quinine cross the taste receptor cell membranes. Once inside the taste receptor cell, these chemicals interact with intracellular G-proteins and then the signal is sent to the brain. Bitter compounds have to diffuse and therefore that pathway is delayed. This delay in the onset of intracellular signaling coupled to the extracellular receptor signaling might explain the lingering aftertaste of bitter foods [20]. The combination of both mechanisms results in an overall longer response to the bitter, and aftertaste perception subsequently occurs.

This section is not complete without mentioning that color can modify the perception of flavor, consider Figure 1. and of course, there is the blue food (or rather, there is not much blue food)…

Formulating for Children

Pediatric formulators often encounter claims such as “Medicine should NOT taste good, it should be for illness only” or “Teaching kids that medicine is yummy is risking they might find it and overdose.” Some believe that such statements are correct; others merely find them useful as they are relieved of the hassle of making a “better tasting” product. The present author feels it is futile to discuss the issue, since there are no “well tasting” products anyway. True, some vitamin products and some “generic” products (ibuprofen, acetaminophen, antitussives, etc.) may be accepted, even liked, by some children but certainly not by the majority of children.

In a globalization era, a Universal Taste, even better a Universal Flavor, accepted across geography and culture would be desirable, but this would be difficult to achieve, at best [6]. From the discussion of flavor, it follows that taste masking by “covering” the offending taste is very tricky, and that the smell should be addressed (harmonized) at the same time. There is the intriguing possibility of inhibiting the bitter receptors [21], but that possibility lies in the not-so-near future (toxicology and registration, among others).

Taste Masking vs. Taste Concealing

Here it might be advantageous to talk semantics. Taste masking, in the pharmaceutical industry, is a term used to describe any process where something is done about (unpleasant) taste, but this term can be somewhat confusing as the methods used can be very different. Many reviews are available on the subject, some of these recent, some much cited [22] and some in the present journal [23-25].

Here the author proposes using taste masking about a situation where chemicals are added to modify the taste, including addition of other flavors, sweeteners, pH modifiers (mostly to render the offending molecule insoluble/unavailable) etc.

On the other hand, the author proposes the term taste concealing for situations where the molecule is made unavailable to the receptors by “physical” means, such as entrapping the bad tasting substance by coating/encapsulation or in a matrix designed to retain the bad tasting substance, at least until it is swallowed thereby eliminating/limiting the exposure to the organs of smell and taste. Other “physical” methods include complexation with cyclodextrines, spheronization, liposomes, double emulsions, etc.

The pro-drug approach is not considered here because, by definition, the new chemical entity, would have eliminated the problem. Likewise, complexation with resins might also result in a structure regarded by the authorities as an NCE.

Vehicles

If a true solution of the drug can be taste masked, then a liquid vehicle may suffice and it might be possible to make it acceptable to children.

In cases where the drug is taste masked by insolubilization, it might be possible to formulate a suspension with the appropriate “caveat formulator”.

For the cases where drug is present as a particulate, the stability issues dominate. Is it possible, for example, to design a microencapsulation that will keep the drug entrapped for 2 years on the shelf and then release the same drug minutes after administration? The author believes that this is very difficult, if not impossible, the alternative being a powder for reconstitution where the dispensed product is water free but turns into something acceptable to children when mixed with water.

Finding Inspiration

There is too much stress upon Taste [26] and too little about the rest of the organoleptic properties. Innovation is being made but not enough and not fast enough [27]. The author is of the opinion that the “acceptable” formulation for the majority of young human beings (neonates, infants and children) is a semi-solid one (be it soft-ice, pudding, smoothie, etc.) and that inspiration can be found in nature, in the accumulated culinary wisdom and above all in the food industry.

Conclusion

Prediction is very difficult, especially about the future. (attributed to Niels Bohr). There are many uncertainties associated with pediatric formulations because of regulatory, technological, behavioral and even financial factors, but the author wagers that in the future, pediatric formulations will be very different from those currently available. Paraphrasing Allan Kay, the best way to predict the future is to formulate it.

Acknowledgements

The author would like to thank Niels Coley for proof-reading the manuscript.

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Author Biography

Daniel Bar-Shalom is, since 2009, an Associate Professor at The Department of Pharmaceutics and Analytical Chemistry Faculty of Pharmaceutical Sciences, University of Copenhagen. He also works for Bioneer a/s, a Danish non-for-profit organization consulting in the biotech field. He is one of the founders and the inventor of the technologies of Egalet a/s (including a pediatric formulation), a Danish Drug Delivery company where he was the Vice President for R&R until 2007. He is the inventor of numerous patents. He has degrees of Biology from Tel-Aviv University and Pharmacy from the Hebrew University of Jerusalem, both Israel. He has owned and worked at a pharmacy where he gained insight in the problems of real patients in real life situations.

This article was printed in the September/October 2011 issue of American Pharmaceutical Review - Volume 14, Issue 6. Copyright rests with the publisher. For more information about American Pharmaceutical Review and to read similar articles, visit www.americanpharmaceuticalreview.com and subscribe for free.