Around 50 years ago the Sabin vaccine was introduced in the UK to tackle polio, at the time a much-feared disease which killed hundreds of children every year in the UK alone and left thousands paralysed. Named after its discoverer, US medical researcher Albert Sabin, what made this vaccine different was its delivery method — drops of polio medicine on a cube of sugar, a more palatable alternative for its mostly young recipients than the more commonplace injection.
It is human nature to want to avoid injections when we can; 10% of the overall population is reported to have a needle phobia1 and in children they spark a particularly negative response. In fact, as many parents will testify, whether the mode of delivery is injection, tablet, syrup, liquid or other, giving simple, accurate and safe doses of medicine to sick children is often far from child’s play.
Sweetening the bitter pill
We have come a long way from the unregulated days of the early 1900s and medicines such as ‘Victor’s Infant’s Relief’. Marketed for the treatment of colic in children and containing an alarming list of ingredients, including cannabis and chloroform, it no doubt tasted as bad as it looked. However, despite current leaps and bounds in pharmaceutical medicine, children frequently refuse to take medication, either because they hate the taste, are feeling too belligerent or frightened, or are too unwell to cooperate.
Prescribing paediatric versions of drug formulations largely only tested in adult patients is something of a minefield as it is not always clear what constitutes an acceptable dose of the same medicine for a neonate, toddler or adolescent. Children are not simply ‘scaled-down adults’. There are physiological differences such as slower GI, but faster intramuscular absorption. Kidney function is not as mature in the very young, who also have a more permeable blood-brain barrier, less fat and a larger liver-to-body weight ratio. The common side effects of drugs are also not always predictably similar to those of adult patients. In the light of these differences, what constitutes an appropriate ‘child-sized’ medicine?
Getting the formula right is naturally a vital step, but once again, the combination of medicine and children is not always straightforward. For example, children are more sensitive or prone to allergic reaction to the excipients in a drug, added to increase shelf life, stabilise and improve the take-up of a medicine, or to enhance its texture, colour and taste.
A key stumbling block to administering medicine orally to children is ‘taste’, with over 90% of paediatricians reporting that a drug’s taste and palatability were the biggest barriers to completing treatment2. Drugs are by their nature bitter or unpleasantly metallic tasting, with children’s taste buds generally more bitter sensitive than those of adults. Bitterness is thought to have evolved as a natural deterrent against eating poisonous plants so evolution has programmed children to avoid bitter medicine. Adding sugars, salt, acids, and other substances to medicines to mask the bitterness is not always successful as the bitter taste can be caused by more than one compound in the medicine, each compound stimulating a different taste receptor3. Added to this, bitter tastes tend to linger long after the sweetness has gone.
Ways to mask bitter tastes are the subject of on-going research, such as that being jointly undertaken by the University of Bradford and Changzhou, China3, which is looking to develop technologies to make liquid formulations of children’s medicines more palatable. Researchers are looking at medicines such as the anti-inflammatory ibuprofen which in some formulations has a very strong aftertaste, and the traditional herbal medicine Shuang Huang Lian, used to treat flu and cold symptoms and renowned for its ghastly taste. Investigations focused on two methods for rendering a medicine ‘tasteless’: adding a ‘barrier’ to the medicine to prevent the molecules of the bitter compounds interacting with taste receptors; or using ‘neutralising’ compound molecules which bind to taste receptors, instead of the medicine, and prevent the underlying bitter taste being detected. Both approaches need to ensure the active medical ingredient remains potent and still able to be absorbed as normal by the body.
Tried and tested remedies?
As for adults, the guiding principle in paediatric pharmaceutical medicine is ‘balancing the benefits to the risks4. The heterogeneity of the paediatric group, ranging from new-born babies to adolescents, means there is no ‘onesize- fits-all’, and influencing factors can include the ability to swallow, treatment setting (hospital or home, developed or developing countries), dosing consistency, and whether the dosage form comes in a suitably paediatric dose-size.
In an ideal world, a single solid dose form exists which either can be swallowed whole, chewed, crushed and taken with food or dissolved in liquid such as juice. In practice, factors such as the ability to produce stable versions in liquid solution form, potential irritation of the GI tract, and the need to provide an accurate titration mean that a range of administration routes need to be considered.
Devices designed to help the medicine go down
A number of devices have been developed, or are in development, to make the task of giving medicines to children easier. One example, which tackles the thorny issue of receiving injections, is Buzzy®. Invented by paediatrician Amy Baxter, Buzzy is a reusable tool which works by ‘distracting’ the body’s nerves from the sharp pain of an injection needle. Attached close to the injection site, the brightly coloured device applies the Gate Control Theory technique — i.e. using a combination of vibration and coldness to dull or eliminate the sharp pain of the needle. Sending sensations other than pain down the same nerve pathway causes the brain to lessen or shut out the nerves which transmit pain. Phil Canner writes more about this in the context of hypodermic needle design on page 16 while Ben Wicks talks about the causes of pain on page 26.
A study of 81 children aged between 4 and 18 years looked at the effect of using Buzzy on pain levels and anxiety when receiving a venal injection, compared with standard treatment (mainly a coolant spray). The group using Buzzy reported significantly lower pain levels while signs of distress in the group of children not using Buzzy were more common5.
Most children who are old enough to choose prefer to take a medicine orally rather than have an injection. Unfortunately, many drugs, especially biologics (made from large proteins), cannot be produced in tablet-form and would anyway break down in the stomach before they could be absorbed. Researchers at MIT and the Massachusetts General Hospital have come up with a pot ential solution, an ingenious drug capsule coated with micro-needles which when swallowed can inject drugs directly into the lining of the stomach. When the capsule reaches the stomach, the PH-sensitive outer coating of the capsule is dissolved by the stomach acids and enzymes and the payload drug can be released through the micro-needles of the capsule6.
More conventional is the inspiration behind company Dose Sipping (DS) Technology’s XStraw, a specially modified drinking-straw which arrives pre-filled with medicinal pellets of exactly the right dosage, ready for use. Deployed with a child’s favourite drink, the XStraw contains a control filter which moves upwards whilst the patient is drinking, ensuring that the complete dose of medicine is taken and that there are no spills or losses7.
What if the issue is the delivery of vital medicine to very young patients, in places with very basic healthcare resources? More than seven million children under five years die each year in low-income countries mainly, from preventable conditions such as HIV, malaria and malnutrition. A significant number of these child-deaths are among babies in their first 28 days of life8. Drug delivery is difficult in developing countries; there is a lack of access to essential medicine in the right formulation, while medicines in liquid form are expensive and cumbersome to transport, require cold storage and have limited shelf life. Added stabilising ingredients and other excipients can be harmful to their young recipients, and soluble tablets or powders require a clea source of water — not guaranteed in some parts of the world — and a sterile means of administering the solution.
Not-for-profit organisation JustMilk has come up with a simple yet novel solution — the Nipple Shield Delivery System (NSDS)9. Constructed from low-cost silicone, the NSDS incorporates a rapidly dispersible tablet. With the NSDS in place, a mother is able to breastfeed in the normal way, and as milk passes through the shield, medicine or nutrients are picked up and passed to the infant. Avoiding aversion to breastfeeding by a child due to the introduction of unpleasant tasting medicine is one challenge that needs to be overcome. However, this accessible and low-cost device ensures reliable medicine delivery in the most basic of healthcare settings.
Are we there yet?
Although paediatric pharmaceutical medicine has come a long way, it remains a rapidly developing field and there are still many areas in which knowledge of the impact of medicines in children is limited. While we are not completely in the dark, there is more to learn about the potential side effects, safe excipients, or what constitutes a reliable ‘child-sized’ dose in a new drug.
More research and innovation is also needed to tackle issues such as better-tasting medicine, reformulation into child-friendly dose formats which do not require preparation before use, and medicine tailored to the target age group.
As more innovative drug delivery devices enter the market, it is worth bearing in mind that providing support to parents, caregivers and healthcare professionals who need to give medicines to children does not always require complex, high-value solutions. As XStraw, Buzzy and other devices show, sometimes, the best ideas are elegantly simple.
References
1. Hamilton, J.G. ‘Needle phobia: a neglected diagnosis’. Journal of Family Practice. 1995 Aug; 41(2):169 – 75.
2.Milne, C.P., Bruss, J.B., The economics of pediatric formulation development for offpatent drugs. Clinical Therapuetics 30(11), 2133 – 45 (2008).
3. Mennella, J.A. et al., The bad taste of medicines: Overview of basic research on bitter taste’. Clinical Therapuetics 35(8), 1225 – 1246 (2013).
4. World Health Organisation, ‘Development of paediatric medicines: Points to consider in formulation’. Draft Annex to 46th Report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations (2011).
5. Baxter, A.L. et al, ‘An integration of vibration and cold relieves venipuncture pain in a pediatric emergency department’. Pediatric Emergency Care 27(12), 1151 – 1156 (2011).
6. Trafton, A., New drug-delivery capsule may replace injections. MIT News, October 1, 2014.
7. DE Technology, ‘Drinking Straw Avoids Need to Swallow Bitter Pills’. February 6, 2014.
8. World Health Organisation. ‘Priority life-saving medicines for women and children 2021’. Essential Medicines for Children. https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2021.03.
9. Gerrard, S.E. et al, ’Modeling the physiological factors that affect drug delivery from a nipple shield delivery system to breastfeeding infants’ Journal of Pharmaceutical Sciences. https://www.academia.edu/4263236.
