formulations for children: problems and solutions

Formulations for children:problems and solutionsHannah K. Batchelor & John F. Marriott

Pharmacy, Pharmacology and Therapeutics, School of Clinical and Experimental Medicine, College of

Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

CorrespondenceDr Hannah Batchelor, Pharmacy,Pharmacology and Therapeutics Section,School of Clinical and ExperimentalMedicine, College of Medical and DentalSciences, Medical School Building,University of Birmingham, Birmingham,Edgbaston B15 2TT, UK.Tel.: +44 (0)121 414 3717Email: h.k.batchelor@bham.ac.uk-----------------------------------------------------------------------

Keywordsbioequivalence, biopharmaceutics, drugformulations, paediatric,pharmacokinetics-----------------------------------------------------------------------

Received7 August 2013

Accepted15 October 2013

Accepted ArticlePublished Online28 October 2013

Paediatric formulation design is complex as there is a need to understand the developmental physiological changes that occur duringchildhood and their impact on the absorption of drugs. Paediatric dose adjustments are usually based on achieving pharmacokineticor pharmacodynamic profiles equivalent to those achieved in adult populations. However, differences in the way in which childrenhandle adult products or the use of bespoke paediatric formulations can result in unexpected pharmacokinetic drug profiles withaltered clinical efficacy. Differences in drug formulations need to be understood by healthcare professionals involved in theprescribing, administration or dispensing of drugs to children such that appropriate advice is given to ensure that therapeuticoutcomes are achieved. This issue is not confined to oral medicines but is applicable for all routes of administration encountered inpaediatric therapy.

Introduction

Development of age appropriate medicines for childrenrequires not only an understanding of their preferences fordifferent formulations, flavours and textures of productsbut also an understanding of the physical and biochemicaldifferences between children and adults. The mostobvious difference between adult and paediatric drugtherapy is the complexity of dose adjustment and thealgorithms used to calculate dosages relevant to sub-populations within the overall paediatric population.There is much emphasis on the idiom that ‘children are notjust small adults’ in terms of drug therapy [1]. Indeed,growth and development are two major aspects of chil-dren not readily apparent in adults. The topic of humangrowth and development is extensive with many detaileddedicated reference works (e.g. [2, 3]).

There are several reviews that detail formulationoptions and their suitability for children across a range of

ages [4–8]. There is also regulatory guidance on formula-tion preference with age within a paediatric population[9–11]. However, there is a still a need for evidence basedinformation to guide the development of formulationsthat are appropriate and acceptable to children and youngpeople.

Owing to the wide age range of the paediatric popu-lation, it is unlikely that a single formulation will beappropriate across this range, necessitating multipleproduct variants. The design of an ideal paediatric formu-lation needs to consider the following factors: (i) pro-ducing minimal impact on the lifestyle of the child,manifesting as the lowest dosage frequency and apalatable product, (ii) provision of individualized dosingor dose banding appropriate for effective therapy,(iii) sufficient bioavailability, (iv) non-toxic excipientsin the formulation, (v) convenient and reliable adminis-tration and (vi) robust production process at minimalcost [12].

British Journal of ClinicalPharmacology

DOI:10.1111/bcp.12268

© 2013 The British Pharmacological Society Br J Clin Pharmacol / 79:3 / 405–418 / 405

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Barriers to using existingformulations

The use of unlicensed and off-label medicines for treatingchildren is widespread with associated risks as these prod-ucts have not been properly studied in paediatric popula-tions. Healthcare professionals and parents or caregiversare often required to manipulate an adult medicine toobtain an appropriate dose for a child, for example, bysplitting a tablet to provide a smaller dose or in morecomplex cases preparing a suspension from a crushedtablet. Such manipulations increase the variability in theproduct by inaccurate measurement, issues with stabilityor errors in instruction for manipulation [13]. There arecurrently regulatory and financial drivers to develop age-appropriate medicines for new drugs, yet there is a signifi-cant number of existing drugs where age-appropriateformulations are needed. There are priority lists for suchmedicines (e.g. [14, 15]).

Formulations and pharmacokinetics

Pharmaceutical formulation can affect the performance ofa drug, particularly with extemporaneously preparedproducts that are administered to children. One reportedcase study [16] described significant underdosing ofclobazam in a 3-year-old child with epilepsy. In this casethe extemporaneous preparation, although prepared asthe correct nominal concentration, was not fit for purposeas the active drug was not homogeneously suspended.The correct administered volume did not contain thecorrect dose resulting in sub-therapeutic treatment.

Ideally, any paediatric formulation should be bioe-quivalent to an adult product to minimize errors in pre-scribing and to enable simple switching of formulations atthe relevant age. Bioequivalence is usually assessed interms of peak plasma concentration (Cmax), time to Cmax

(tmax) and area under the absorption time curve (AUC) in aplot of plasma concentration against time. Differences inthe rate of absorption (faster or slower) will alter tmax yet areunlikely to affect Cmax or AUC. Differences in the extent ofabsorption will affect Cmax and AUC which typically havegreater clinical significance compared with changes in tmax.In terms of regulatory guidance, a significant difference isdefined as one where the 90% confidence interval fails tomeet the limits of 80–125% for either Cmax or AUC ofthe reference product’s profile [17]. Bioequivalence studiesare typically conducted in adult populations. A literaturesearch was conducted to identify bioequivalence studiesundertaken using paediatric formulations. The searchterms ‘pediatric’ OR ‘paediatric’ AND ‘bioequivalence’ OR‘bioavailability’ were used. The search was limited tothose where these terms appeared in the title, abstract orkeywords of articles within both Scopus (http://www.scopus.com) and Pubmed (http://www.pubmed.com)

databases up to January 2013. Table 1 reviews bio-equivalence studies reported in the literature and theresulting differences in pharmacokinetic profile comparedwith adults.

In total, 45 reports of bioequivalence studies of paedi-atric formulations were found. Of these 15 were con-ducted within a paediatric population, 29 within adultsand one in both paediatric and adults. The paediatric for-mulation was not equivalent to the reference adultproduct in 40% of cases included in this review. There were10 instances where the paediatric product showed higherbioavailability and 11 where the bioavailability wasreduced. These findings highlight the need to understandthe influence of formulation design on pharmacokineticperformance in paediatric populations. Typically liquidshave a rapid onset compared with tablets as there is nodisintegration step to retard absorption. Since paediatricproducts tend to be liquids it is unsurprising that thebioavailability is different in so many cases. Perhaps itis more surprising that there were 11 cases wherebioavailability was reduced in the paediatric formulation.However, as several formulations listed within Table 1were extemporaneously prepared rather than a bespokepaediatric formulation, it may be expected that these maynot perform in a similar way to the adult product.

Differences in paediatric physiology and anatomy canalso influence the absorption, distribution, metabolismand elimination of drugs. Therefore it is important tounderstand not only the formulation but how this mayinteract with the site of absorption to understand whetherdifferences in pharmacokinetics relate to formulation, ageor a combination of formulation and age for paediatricmedicines.

Routes of administration andformulation considerations relatingto pharmacology

There have been some excellent reviews on selection ofpaediatric formulations based on paediatric preferences(for example [4, 9, 64]) as well as reviews on physiologicaland anatomical differences in paediatric populations andthe consequences in drug therapy (e.g. [65, 66]). However,this review brings together these aspects to identifyissues in paediatric formulations for alternative routes ofadministration.

Oral drug delivery

Drugs given orally include liquid dosage forms (solutions,suspensions, syrups and emulsions) as well as solid dosageforms including tablets, capsules, granules/sprinkles,chewable tablets, orodispersible tablets and controlled

H. K. Batchelor & J. F. Marriott

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http://www.pubmed.com

Table 1Pharmacokinetic studies comparing paediatric formulations

Drug Test population Formulations evaluatedComparison of PK profile of the paediatricproduct compared with adult formulations Reference

Alisertib Adults Oral solution vs. powder in capsule Increased Cmax and AUC [18]Amlodipine Adults Suspension of a crushed tablet vs. an intact

tabletEquivalent Cmax and AUC [19]

Artemether-lumefantrine Children Dispersible vs. crushed conventional tablets Reduced Cmax and AUC for lumefantrineReduced Cmax and equivalent AUC for

artemether

[20]

Artemether-lumefantrine Adults Dispersible vs. conventional tablets Reduced Cmax and AUC for lumefantrineEquivalent Cmax and AUC for artemether

[21]

Artemether-lumefantrine Adults Dispersible vs. conventional tablets crushed Equivalent Cmax and AUC for lumefantrineIncreased Cmax and equivalent AUC for

artemether

[21]

Artesunate-mefloquine Children Granules vs. conventional tablet Equivalent Cmax and AUC [22]

Bosentan Adults Dispersible vs. conventional tablet Reduced Cmax and AUC [23]Candesartan cilexetil Adults Suspension vs. tablet Equivalent Cmax and AUC [24]

Cefteram pivoxil Adults Powder for oral suspension (pfos) vs. tablet Equivalent Cmax and AUC [25]Ciclosporin Adults Oral liquid (Neoral) vs. capsules (Neoimmun) Increased Cmax and equivalent AUC [26]Ciclosporin Children Oral cyclosporine dose incorporated into a

chocolate wafer or mixed with IsocalEquivalent Cmax and AUC [27]

Ciclosporin Children Microemulsified formulation compared withthe older oil-based formulation

Increased Cmax and AUC [28]

Ciclosporin Children Microemulsified formulation vs. lipidformulation

Increased Cmax and equivalent AUC [29]

Desmopressin Children Fast melt (120 μg) vs. conventional tablet(200 μg)

Equivalent Cmax and AUC (melt formulationhas greater availability on a dose matchedbasis)

[30]

Dexamethasone Adults Liquid vs. tablet Equivalent Cmax and AUC [31]Donepezil Adults Orally disintegrating tablet vs. conventional

tabletEquivalent Cmax and AUC [32]

Efavirenz Children Liquid vs. tablet or capsule Liquid showed reduced Cmax and AUCTablet and capsule had equivalent Cmax and

AUC

[33]

Eltrombopag Adults Powder for oral suspension (pfos) vs. tablet Increased Cmax and AUC [34]

Emtricitabine Children Oral solution vs. capsule Decreased Cmax and AUC [35]Everolimus Adults 6 × 0.25 mg dispersible tablet vs. 2 × 0.75 mg

conventionalDecreased Cmax and AUC [36]

Fixed dose combination oflamivudine, nevirapine andstavudine

Adults Reference oral liquid formulations vs. fixeddose combination tablet for suspension

Equivalent Cmax and AUC [37]

Fixed dose combination oflamivudine and stavudine

Adults Reference oral liquid formulations vs. fixeddose combination tablet for suspension


Flurbiprofen Adults Orally disintegrating tablet vs. conventionaltablet


Hydroxyurea Adults and children Coated breakable tablets and capsules Equivalent Cmax and AUC [40]

Magnesium valproate Adults Solution, suspension and enteric coatedtablets


Montelukast Adults Oral granules vs. chewable tablet Equivalent Cmax and AUC [42]

Mycophenolate mofetil Adults Dispersible tablets vs. capsule Equivalent Cmax and AUC [43]Nizatidine Adults Commercial oral syrup, an extemporaneous

solution in apple juice and anextemporaneous suspension in infantformula relative to the marketed capsuleformulation

Apple juice formulation reduced Cmax andAUC

All other formulations equivalent Cmax andAUC

[44]

Ondansetron Adults Orally disintegrating tablet vs. conventionaltablet


Prednisolone Adults Taste-masked oral prednisolone sodiumphosphate syrup, existing prednisolonesyrup and prednisolone sodium phosphatesolution


Propafenone Adults Suspension vs. commercial tablets Suspensions showed higher relativebioavailability

[47]

Formulations for children: problems and solutions

407Br J Clin Pharmacol / 79:3 /

release tablets. The oral route of administration is the pre-ferred route for patients of all ages for reasons of conveni-ence and stability.

Oral liquidsThe bitter taste associated with many drugs is thought tohave evolved as a deterrent against ingesting toxic sub-stances [67]. The major barrier in development of oralliquid formulations is taste-masking of drugs as more than90% of paediatricians in the US reported that a drug’s tasteand palatability were the greatest barriers to completingtreatment [68]. In some cases simple taste-masking isinsufficient and more complex formulations are requiredto encapsulate the drug providing taste-concealing pro-perties. The excipients used in the development of aproduct need to be safe and acceptable for use in children.Excipients are typically used to optimize the formulation ofthe medicine to improve palatability, shelf-life and/or

manufacturing processes. There are certain excipients thatshould not be used in childrens’ medicines as they canretard on-going organ development, for example, ethanol,propylene glycol, benzyl alcohol and parabens [65]. It isalso important to consider the electrolyte concentrationwhen developing medicines for neonates where renalfunction may be immature.

The maximum recommended single dosing volume is5 ml for children aged below 4 years and 10 ml for childrenaged between 4 and 12 years according to EMA draft guid-ance [11]. Oral liquid drops provide a mechanism to deliversmall volumes or low doses of a drug to children andare particularly useful in very young children. The use ofappropriate measuring devices with oral medicines isencouraged, particularly the use of oral syringes as theyhave superior accuracy compared with graduated pipettesor measuring spoons [9].

Liquids provide maximal dosing flexibility and it is pos-sible to use a single formulation over a wide age range

Table 1Continued

Drug Test population Formulations evaluatedComparison of PK profile of the paediatricproduct compared with adult formulations Reference

Risperidone Adults Oral dispersible tablet vs. conventional tablet Equivalent Cmax and AUC [48]

Rufinamide Adults Suspension vs. tablet Bioequivalence demonstrated [49]Salbutamol Adults Controlled release sprinkle dispersed in a

spoonful of jam vs. tabletReduced Cmax [50]

Sildenafil Adults Powder for oral suspension vs. tablet Equivalent Cmax and AUC [51]Somatropin Adults Powder for reconstitution vs. oral liquid Equivalent Cmax and AUC [52]

Stavudine Adults Open capsule dispersed in 5 ml water vs.intact capsules


Stavudine, lamivudine andnevirapine

Children Chewable tablet vs. oral liquid Equivalent Cmax and AUC for stavudine andneviapine

Increased bioavailability for lamivudine

[54]

Sunitinib Children Intact capsule vs. contents sprinkled on softfood (applesauce or yogurt)

Bioequivalence demonstrated [55]

Tacrolimus Children Prograf (normal release) and Advagraf(sustained release)

Advagraf showed reduced Cmax and AUC [56]

Topotecan Children Injectable formulation of topotecan givenorally vs. capsules

Injectable formulation given orally showedreduced bioavailability

[57]

Ursodeoxycholic acid Adults Suspension vs. capsules Equivalent Cmax and AUC [58]

Valganciclovir Adults Oral solution vs. tablet Equivalent Cmax and AUC [59]Valproate (VPA) Children Modified release granule to sprinkle vs.

solutionBlood concentrations were comparable [60]

Zidovudine and lamivudine Adults Fast disintegrating vs. conventional tablets Equivalent Cmax and AUC [61]Zidovudine, lamivudine

and nevirapineChildren Individual liquid formulations vs. fixed dose

combination tabletZidovudine liquid showed decreased Cmax and

equivalent AUCLamivudine liquid showed decreased Cmax and

AUCSsghjki]lklkliii4Nevirapine liquid showed increased Cmax and

AUC

[62]

Zidovudine, lamivudine, andabacavir

Children Oral solution vs. tablet Zidovudine liquid showed equivalent Cmax andAUC

Lamivudine liquid showed decreased Cmax andAUC

Abacavir liquid showed equivalent Cmax andAUC

[63]



(including neonates). However the volume used must beacceptable to the patient and the dosing device must be fitfor purpose.

Solids for reconstitutionThe use of dispersible tablets, powders, granules, pellets orsprinkles for reconstitution is a popular strategy in paedi-atric formulation development as the solid product typi-cally has better stability compared with a formulatedliquid. However, these reconstituted products also need tobe taste-masked. Reconstitution can occur either at thepoint of dispensing or at the point of administrationdepending on the product. The instructions for reconstitu-tion can be complicated for untrained individuals, yet it isimportant that the final product contains the correctdosage for the patient. If these solids for reconstitution areadministered in the absence of water they are only appro-priate for infants who are accepting solid food (typically >6months). For solids of a larger particle size the minimumage range may be higher owing to the risk of aspiration orchoking.

If dispersible products are not reconstituted in anappropriate volume of liquid then there is a risk of localtissue injury (similar to when tablets adhere to theoesophagus [69]) and a delay in the onset of action, sincethe solid material needs to dissolve prior to absorption.Therefore, it is important to consider the overall solubilityof any drug and how this may affect biopharmaceuticalperformance.

The volume of liquid used for administration of dispers-ible tablets is larger (up to 20 ml) than volumes typicallyused for conventional oral liquids, with volumes up to20 ml considered (by the EMA) to be appropriate for chil-dren below the age of 4 years and volumes of 50 ml forthose over 4 years old [11].

Oral solid dosage forms – conventional tabletsand capsulesConventional tablets are limited by their rigid dosecontent and the ability of the child to swallow a tablet. Thegeneral thinking is that children will accept tablets basedon size, where a smaller tablet is more likely to be accept-able. Tablets can be scored to allow splitting to reducetheir size yet this can result in inaccurate dosages withinthe fragmented tablets [70]. Draft EMA guidance proposedthat, ‘small tablets (i.e. tablets from 3 to 5 mm diameter,width or length whichever is the longest) will not be con-sidered acceptable for children below the age of 2 years,medium sized tablets (i.e. tablets from 5 to 10 mm) forchildren below the age 6 years, large tablets (i.e. tabletsfrom 10 to 15 mm) for children below the age of 12 yearsand very large tablets (i.e. tablets from 15 mm) for childrenbelow the age of 18 years’ [11], however, this recommen-dation was removed from the updated guidance docu-ment [7]. Studies that investigated the use of mini-tablets

(tablets ≤3 mm) found that mini-tablets were a potentialdosage form suitable for 2–6 year olds (based on placebotablets 3 mm in diameter) [71]. Additionally Spomer andco-workers found that very young children (6–12 months)were fully capable of swallowing mini-tablets of 2 mmdiameter, often accepting them in preference to sweetliquid formulations [72].

Standardized capsule sizes range from 11.1 mm (size 5)to 23.3 mm (size 00) in length. There are no data on accept-ability of capsule size in children although this should beconsidered to be equivalent to tablets. Capsules can beopened and the contents taken to improve acceptability inchildren. However this should only be undertaken whenjustified. However, the capsule contents may tasteunpleasant and the bioavailability of the opened capsulemay differ from that of the intact product.

In adults the recommended volume of water takenwith tablets and capsules is 250 ml based on clinical studyprotocol used during development of such products [73].The use of smaller volumes can delay onset of absorptionand reduce the overall bioavailability of a product, particu-larly drugs that are poorly water soluble [74, 75]. There areno literature reports that provide a similar volume of waterto be used in children. Therefore water ingestion mayincrease the variability in exposure observed followingtablet administration in children.

Chewable tablets and orodispersibleformulationsChewable tablets and orodispersible formulations need topossess good organoleptic properties including a goodmouth feel which is influenced by the drug’s crystallinestructure and solubility. The consequences of swallowingsuch tablets whole should be considered and it is prefer-able that their bioavailability is unaffected. WHO guidancesuggests that they should be developed such that thelabel can state, ‘tablets that may be chewed or swallowedwhole’ [9].

Orodispersible tablets, oral lyophilisates and oral filmsare solid products that are designed to dissolve within theoral cavity. These products dissolve and disperse withinthe saliva for absorption either directly from the oral cavityor for absorption from the gastrointestinal tract followingingestion. The ratio of absorption from each of these sitescan be important, particularly for drugs that show differ-ences in bioavailability from each route, for exampledesmopressin [76].

These products offer the level of pharmaceutical stabil-ity associated with solid dosage forms and are acceptableto even very young patients. However, they are limited bydose rigidity in the same way as conventional tablets. Theyare most suited to highly soluble drugs, although the solu-bility of the drug needs to be balanced with taste-maskingas highly soluble drugs will activate taste receptors on thetongue if they dissolve in saliva within the oral cavity [77].



The volume of liquid taken with such products should alsobe considered, particularly for poorly water soluble drugsas described previously.

Nasal drug delivery – formulationconsiderations

Intranasal drug administration is convenient with fastonsets of action approaching that of intravenous therapyand so nasal drug formulations are used within paediatricpopulations routinely. Intranasal medications can be deliv-ered using several methods. Drops can be instilled from asyringe or drugs can be nebulized or given through a pres-surized aerosol. All of these delivery methods have beendemonstrated to be effective [78]. While it is believed thatmetered-dose systems provide the greatest dose accuracyand reproducibility, their ease of use can vary significantly.There are no reports on the differences in nasal mucus,nasal pH or mucociliary clearance in paediatric patientscompared with adults. Therefore it is assumed that theseproperties remain the same in children as in adults. Thereare no reported paediatric specific nasal formulations thatdiffer from adult products. However, the similarities inanatomy and physiology ensure that products are likely toperform in the same way in adults compared with childrenwith few reported adverse effects following nasal drugdelivery.

Ocular drug delivery – formulationconsiderations

Many ocular medications, as drops, ointments, gels andinserts, are used in children to treat common bacterialand viral infections, inflammation and allergy, uveitis andglaucoma, as well as other conditions including myopia,amblyopia and strabismus. Eye conditions are prevalent inpaediatric populations. Within the United Kingdom morethan 5% of children have had at least one eye condition bythe age of 3 years [79].

The eye of the newborn is roughly two thirds of itsadult size, reaching an adult size around ages 3 to 4 years[80]. In the eye, membranes are thin in neonates andinfants, so drug absorption and corneal permeation maybe more rapid in these groups [81, 82]. The cornea of theneonate has 70% of the absorptive surface of the adultcornea, but the total intraocular volume is barely one thirdof the adult eye [83]. The area of contact between theposterior conjunctiva and the eye globe has been approxi-mated to 4 cm2 in adults [84]. This surface area would bereduced in children. Consequently, the ratio of surfacearea to internal volume could lead to drugs becomingsomewhat concentrated within the eye of paediatricpatients.

Basal tear volume increases with age. Typical volumesreported are 0.5 μl (range 0.6–2 μl) for neonates, 2.5 μl(range 1.4–7.75 μl) for infants (mean age 7 weeks) at anolder age, and 6 μl (range 2.73–12.75 μl) in adults [85]. Theage-related reduction in tear volume can lead to topicallyapplied medications becoming concentrated in youngerpatients.

Topical application of ocular drugs may cause seriousadverse ocular or systemic side effects. Children are atgreater risk of systemic side effects because ocular dosingis not weight-adjusted, and infants are especially vulner-able particularly in cases where drug metabolism isreduced in the young and/or an immature blood–brainbarrier [86].

There are examples where topical administration ofophthalmic medicines in children has led to elevated sys-temic drug concentrations or systemic side effects. Exam-ples include:

• elevated plasma concentrations of brimonidine1459 pg ml−1 and 700 pg ml−1 following instillation by eye(compared with reported adult studies that show amaximum concentration of 60 pg ml−1) leading to som-nolence or coma [86, 87].

• blood concentrations of timolol in five small childrenranged from 3.5 to 34 ng ml−1, in contrast to 2.45 ng ml−1

in adults following topical ocular administration [88].• systemic exposure of latanoprost ophthalmic solution

0.005% once daily was higher in a <3 year age group(166 pg ml−1) vs. other groups (49, 16 and 26 pg ml−1 forthe 3– <12 year, 12–<18 year, and ≥18 year age groups,respectively [89].

The increased systemic exposure observed in paediatricpatients has been attributed to absorption of eye dropsinto the systemic circulation where the reduced size of thepatient results in higher plasma concentrations of circulat-ing drug.

Calculating dosages for paediatric patients is complex.Body weight, surface area, development, metabolism,other medications taken and physiologic function can allaffect the dosage. Pharmacokinetic models that adjustdosage based on aqueous humour volume have previ-ously been proposed for topical pilocarpine [90]. It isestimated that a newborn requires only one half ofthe adult dosage of eyedrops to obtain an equivalentocular concentration; two thirds of the adult dosage isrequired at age 3 years and 90% of this dosage at age 6years [83]

Anatomical and physiological differences in the eyes ofneonates and infants leave them vulnerable to systemiceffects of topically administered ocular drugs. Furtherstudies are required to understand how formulationsbehave in a paediatric population. In addition, there maybe a need for a bespoke paediatric delivery device toprovide a smaller dose of topically applied medicines.



Otic drug delivery – formulationconsiderations

Drugs that act on the ear in paediatric populations includetherapies for otitis externa, otitis media and the removal ofear wax. These medicines are most frequently applied asear drops and sprays. A small volume is generally used asexcess will be lost out of the ear passage.

The outer ear in humans is not completely mature atbirth and various anatomical and physiological changesoccur with age. The external auditory canal (EAC) of aninfant is straighter, narrower and much shorter than in theadult. EAC volume increases with age from a mean value of0.56 ml [91] at 4–5 years of age up to 0.70–0.98 ml in adults[92]. Dosing devices allow smaller doses to be adminis-tered in paediatric patients and as there is no significantsystemic uptake from medicines administered aurallythere are little anticipated differences in treatments in pae-diatric patients compared with adults.

Otic drug formulations are used within paediatricpopulations routinely. There are no reported paediatricspecific formulations that differ from adult products.However, the similarities in anatomy and physiologyensure that products are likely to perform in the same wayin adults compared with children with few reportedadverse effects following otic drug delivery

Rectal drug delivery – formulationconsiderations

Rectal preparations are used to treat both local and sys-temic disorders in children. These are typically deliveredas creams, ointments, suppositories, foams, sprays andenemas. The rectal route of administration is particularlyuseful for infants and children who have difficulty in swal-lowing oral medicine. This route is also useful in cases ofnausea and vomiting or where upper intestinal disorderspresent may affect oral drug absorption.

The diameter, length and volume of the rectumchanges during development, with adult dimensionsbeing reached at about 10 years of age [93]. The rectallength increases with age from 4 cm as a neonate, 6 cm at1 year, 7 cm at 5 years, 9 cm at 10 years, 10 cm at 15 yearsand 10.5 cm as an adult [94]. The diameter of the rectum inchildren age 7 years was approximated as 21 mm byJoensson and co-workers [95].

Rectal delivery of paracetamol in pre-term infants wasinvestigated by van Lingen and co-workers. Their resultsshowed that there was rapid absorption with higher con-centrations attained in patients aged from 28–32 weekscompared with those over 32 weeks although the doseadministered was calculated on a mg kg−1 basis [96]. Thegreater absorption in the youngest patients may be afactor of both reduced thickness of the rectal wall akin toreduced thickness of external skin observed in preterm

infants. Increased plasma concentrations may also beinfluenced by the developmental immaturity of hepaticmetabolism in younger individuals [66].

Historically oral liquid preparations or injectablesolutions have been administered rectally when oraladministration was not appropriate and no specific rectalpreparation was available. The rectal delivery of oral liquidpreparations of antiepileptic agents was investigated byGraves & Kriel [97]. They found that most were well toler-ated and demonstrated clinical efficacy. A diazepam rectalsolution provided rapid systemic concentrations andimproved clinical outcomes compared with a diazepamsuppository in children [98].

Dose adjustments in paediatric patients are typicallymade based on weight, height or body surface area. Interms of rectal drug delivery for systemic effects, the rectalabsorptive surface area is an important factor to consider.Although dose adjustments are relatively simple for solu-tions and suspensions, the use of suppositories restrictssimple dose adjustment in many cases. Paediatric supposi-tories are typically manufactured as an appropriate size forchildren (1 g nominal weight). Where necessary, portionsof adult suppositories are used in paediatric patients as it isassumed that there is a uniform distribution of the activesubstance in the suppository matrix. However, there isunlikely to be any accuracy or stability data for such prac-tices and the resulting shape may not be optimal for rectalinsertion.

The formulation of paediatric dosage forms for rectaladministration follows the same principles as for adultproducts. Dosage adjustments in paediatric populationsneed to be considered carefully for systemically absorbedrectal products. The dimensions of paediatric supposito-ries should be considered to maximize patient and careracceptability.

Parenteral drug delivery

Intravenous injections are prepared using the same prin-ciples as for adult products, although there may be a needto consider the excipient load to ensure that this is appro-priate for children. The main drawback of intravenousadministration in the paediatric patient is associated withthe use of needles and the pain and fear associated withneedles.

Intramuscular injections can provide a depot of activedrug that reduces the frequency of injections although thelimited muscle mass in neonates and preterm neonatesrestricts wide use of this type of administration within thispopulation. However, in developing countries i.m. admin-istration is common owing to the difficulties associated inobtaining i.v. access and maintaining the i.v. line in chil-dren [99].

Neonates have reduced skeletal muscle blood flow andinefficient muscular contractions due to their limited



movements which may reduce the rate of absorptionof drugs following intramuscular administration [100].However, neonates and infants have a higher density ofskeletal muscle capillaries compared with older childrenwhich explains the greater efficiency in intramuscularabsorption observed for amikacin [101] and cephalothin[102] in younger paediatric populations.

The subcutaneous route is used routinely with childrento administer a wide variety of pharmacological prepara-tions including vaccinations, anticoagulants, analgesics,insulin, growth hormones and some anti-cancer agents[103]. Typical subcutaneous administration volumes arelimited to <2 ml in adults and <1 ml in children [104]. Analternative to subcutaneous injections includes the use ofneedle free injection devices such as jet injectors [105] thatdeliver drugs through the skin using high pressure orthrough the use of microneedles [106]. However, there arevery limited studies that report on the use of these tech-nologies in children. A commonly listed advantage lies inthe reduced pain offered by such devices yet no significantdifferences in pain between insulin administration byneedle and liquid-jet using the Vitajet II® device werereported in a study in patients aged 9–21 years [107].

For parenteral administration the dose volume needsto be considered to ensure that this can be accuratelymeasured, rather than relying on serial dilution whereerrors are more likely to occur with serious consequences[108].

Dermal and transdermal delivery

The skin undergoes many changes during development.This needs to be considered when paediatric formulationsare applied to the skin for both local and systemic action.The stratum corneum is intact shortly after birth (<1month), yet the way it stores and transports waterbecomes adult-like only after the first year of life [109]. Theratio of surface area to body weight is much higher in aneonate compared with an adult. Therefore the volume ofdistribution is lower per unit area of skin within the paedi-atric population [110].

Preparations for dermal (or cutaneous) administrationinclude liquid preparations (lotions and shampoos), semi-solid preparations (ointments and creams) and solidpreparations (powders). Although these products are typi-cally considered safe in terms of absorption, higher levelsmay be reached in paediatric patients or where skin isbroken.

Newborn infants are regularly exposed to a widevariety of topical agents, including treatments for rashes,antimicrobial agents, solvents and skin barriers or moistur-izers. The excipients used within such products needcareful consideration as transdermal absorption ofpropylene glycol from an antiseptic dressing used in a

preterm infant resulted in the infant going into a state ofcoma. Complete recovery occurred following cessation oftopical treatment [111].

Dose adjustments for children for topical products areusually relatively simple owing to the nature of theproduct that does not link to rigid dose units. However,establishing a dose unit can be difficult.

The paediatric population is an inviting target foreffective transdermal medication administration as theirskin is comparatively thin and well perfused. Transdermalpatches have been used to deliver drugs such as scopola-mine, fentanyl, oxybutynin and methylphenidate to chil-dren. Regulatory guidance states that, ‘the size and shapeof transdermal patches and medicated plasters should betailored to the size and shape of the child body andshould not interfere with daily routines’ [11]. Patches andplasters are usually developed for use as a single dose/strength. Although some patches can be cut for partialpatch administration, cutting others destroys the releaseof the medication.

The formulation used in transdermal patches can besimilar for adult and paediatric populations provided thatexcipient usage is appropriate for the youngest infants tobe treated.

Pulmonary drug delivery

Inhaled medications are commonly administered toinfants and small children with asthma and cystic fibrosis.Airway size, respiratory rate, inspiratory/expiratory flowrates and breathing patterns, as well as lung volumes andcapacities, change dramatically during the first monthsand years of life. For example, obligate nose breathing iscommon at birth and may persist to the age of 12 months,resulting in substantial differences in the route taken forinhaled material to reach the lungs [112].

Delivery devices used in paediatric populations are thesame as those used in adults although they are frequentlymodified by attaching a small infant or child sized mask.There is no clinical evidence demonstrating better clinicalresponse with or across interfaces (for example, mask vs.mouthpiece) [113, 114]. Therefore, selection of interfaces ismore dependent on age, tolerance of the device and pref-erence of the patient. Nebulized liquids are potentiallysuitable for young children who cannot use metered doseinhalers (MDIs) and dry powder inhalers (DPIs). MDIs maybe suitable for children from birth when combined with aspacer. The spacer eliminates the need for the patientto co-ordinate actuation with inhalation. A facemask isrequired until the child is able to manage with a mouth-piece. DPIs may be used for children from the age of 4–5years, as minimum inspiratory flow is required. DPIs andMDIs are preferred for older children because of their port-ability and convenience.



Dose adjustment for inhaled medications is typicallybased on body weight where extrapolation from adultdoses is acceptable for children from 3 to 12 years of age[112]. For inhaled medicines it is the delivery device thatcontrols the dosage and this is critical for paediatric popu-lations. However, the devices used are typically the sameas those used in adults, adapted to control the dosedelivered.

Conclusions

Paediatric formulations need to be appropriate for thechild in terms of dose, convenience and acceptability toensure compliance with the medication. There are differ-ences in paediatric anatomy and physiology that canimpact upon the performance of a drug that is differentfrom that observed in adults. The design of a paediatricformulation needs to take these differences in physiologyinto account to ensure that the pharmacokinetic profile ofthe drug is not compromised. This is of particular relevanceto neonates and infants who are furthest in developmentterms from an adult.

Formulation can lead to differences in pharmacokineticprofiles for a drug, highlighting the risks associated withusing off-label medicines that are manipulated to enableadministration to children. Prescribers need to be aware ofthe consequences of manipulating medicines formula-tions, particularly for drugs with a narrow therapeuticindex, even in extemporaneous compounding by a phar-macist where there is insufficient evidence on productquality. In addition, healthcare professionals should beaware that patients and their carers often further manipu-late medicines to aid in compliance, particularly within apaediatric population where 19% of all medicines admin-istered to children were manipulated [115].

The excipients used in paediatric formulations need tobe appropriate for the age group [116–118] to avoid theconsequences of excipient toxicity. Acceptability of medi-cines to paediatric patients is also of great importance inthe child receiving adequate therapy. Palatable formula-tions are known to achieve greater compliance. Thereforethis is critical in the design of a new paediatric formulation[119].

Competing Interests

Both authors have completed the Unified CompetingInterest form at http://www.icmje.org/coi_disclosure.pdf(available on request from the corresponding author) anddeclare HKB had support from National Institute for HealthResearch Medicines for Children Research Network for thesubmitted work, no financial relationships with any organi-zations that might have an interest in the submitted work

in the previous 3 years and no other relationships or activi-ties that could appear to have influenced the submittedwork.

The author (HB) would like to thank the National Institutefor Health Research Medicines for Children Research Networkfor their support for this research.

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formulations for children: problems and solutions

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