Pediatric formulations: Getting to the heart of the problem (página 2)

3.
Results

Table 1 lists oral cardiovascular drugs commonly used in
children for which a licensed liquid is available in UK. Table 2
lists the medicines for which there is no licensed liquid
available in UK. Fig. 1 summarises the options available to
administer oral medicines to children.

Table 1.

Commonly used cardiovascular drugs for which a licensed
liquid is available in UK

Table 2

Commonly used cardiovascular drugs for which no licensed
liquid is available in UK

The majority of medicines used for children, which act
on the cardiovascular system, were unlicensed. There was no
licensed liquid form for most medicines although
‘special’ preparations were available for almost all.
However, most ‘special’ liquids are expensive and
have short shelf-lives, which mean that extemporaneous production
still often occurs. A wide range of paediatric formulation
strengths were available, which adds to the complexity of
prescribing and administering the drugs.

4.
Discussion

There is evidence suggesting that adverse drug reactions
are more likely with UL/OL medicines (Turner et al., 1999 and
Choonara and Conroy, 2002). Dosing errors are thought to be a
major route by which children are exposed to medication errors
(Wong et al., 2004), and many of these could be linked to the use
of high-strength adult formulations.

4.1. What is wrong with the available liquid
formulations?

Licensed liquid formulations of drugs (Table 1) are, for
obvious reasons, the best option: their efficacy is supported by
clinical trial data, the dose is easy to adapt to weight or body
surface area, there are fewer problems with swallowing, and
prescribing information is easily available. Nevertheless, the
taste of the drug or the preparation itself is crucial to achieve
good compliance, especially in a field such as cardiology where
medicines are used to treat long-standing conditions.

Excipients are often required to modify the olfactive
properties of liquid preparations (colouring, sweetening and
flavouring agents). The choice of natural versus artificial
sweeteners (e.g. syrup versus sugar free SF preparations, Table
1) is polemical: the relevance of animal studies demonstrating
the carcinogenic potential of saccharin and cyclamate is unclear,
whereas monosaccharides (sorbitol, mannitol) may contribute to
osmotic diarrhoea. Some sweeteners may cause dental caries or
poor control of
diabetes mellitus
(sucrose, dextrose).

The use of excipients is also essential for ensuring
dose uniformity if the drug is in suspension, to promote chemical
stability, and prevent microbial growth during storage and use.
Formulating stable liquid medicines often requires substantially
more excipient content compared with solid dosage forms. Unlike
active ingredients, excipients are not well regulated in most
countries and some can be harmful to children (Bigeard, 2000,
Pawar and Kumar, 2002 and Rabiu et al., 2004). Propylene glycol
is considered less toxic than other glycols, but is estimated to
be one-third as intoxicating as ethanol. In the past, its
administration in significant volume was associated with adverse
effects on the central nervous system (Arulanantham and Genel,
1978), especially in neonates and children. Nevertheless,
licensed commercial preparations containing propylene glycol
(amiloride, propranolol, Table 1) and some also containing
ethanol (digoxin, furosemide, Table 1), and ethanol as a
solubilising agent, were still found.

The formulator is left with a difficult choice over
excipients, either those for which toxicity is known and
therefore predictable, or those with safety profiles which have
not been established in children.

Interestingly, although there is a licensed liquid
preparation of atenolol (Table 1), it is unlicensed in children.
This means that although it can be expected to be chemically
stable and bioavailable in adults, no evidence has been reviewed
by the MHRA to show whether it is safe, or indeed effective, when
used in children. This was the only example of a licensed liquid
formulation which is not recommended for children.

Both licensed and unlicensed preparations are often
produced in several different strengths. Furosemide is licensed
as 20 mg/5 mL, 40 mg/5 mL and 50 mg/5 mL. Some hospitals chose
just to stock the 50 mg/5 mL strength in order to reduce the risk
of medication errors, but this may mean that a small child of 3
kg will require a dose of 0.3 mL, which is difficult to measure
accurately. The range of strengths for ‘special’
products is also extremely diverse as manufacturers will produce
various strengths by request. An error where a child was given a
10-fold overdose of spironolactone (Table 2) was discovered
(Anonymous, 2003) when the hospital pharmacy supplied 1 mg/mL and
the community pharmacy supplied 10 mg/mL suspensions. Whilst the
availability of different strengths could be seen as an
opportunity to get the most appropriate dose, where there is a
10-fold difference in available strengths, confusion and serious
dosing errors can occur (Koren et al., 1986).

The use of ‘special’ liquids compared to
extemporaneous preparation, reduces the risk of production errors
and increases the quality of the medicine as manufacturers adhere
to quality assurance systems such as batch tracking, record
keeping, GMP, adverse reaction reporting, and inspections by
legal authorities at regular intervals, as for licensed liquids.
Despite this, there are a number of factors hindering the
wholesale adoption of specials. These include short shelf-life
(e.g. amiodarone has a 1 month shelf-life, captopril has to be
kept refrigerated for 1 month only, Table 2) leading to frequent
ordering, wastage and increased cost along with the lack of
immediate availability for rare products or for patients living
far away from the specialist centres. Yeung et al. (2004)
surveyed English specialist paediatric hospitals and showed that
more than 50% of the extemporaneous preparations made in UK were
available as specials. This also reflects on the lack of
standardisation in medicines management across UK due to a lack
of official guidance and information on ‘specials’
making supplies difficult, especially for non-specialist centres.
Difficulties arising from this lack of national guidance are
further amplified by the restrictions on advertising
‘specials’ making it difficult to find out whether a
product is available. Due to their legal status, manufacturers
are not allowed to promote their product in any way as
‘specials’ lack the regulatory approval from clinical
trials on dosing, efficacy and safety. The fact that the
pharmacokinetics and pharmacodynamics of ‘special’
products are rarely studied remains their largest disadvantage
compared with licensed products.

4.2. What is wrong with extemporaneous dispensing of
liquids?

In order to provide liquid formulations to administer
drugs with no liquid preparation available, or to overcome
‘special’ supply problems, extemporaneous
formulations are needed. They can be prepared by dilution of
existing liquid dosage forms (e.g. dilution of the injectable
form of clonidine, Table 2) if formulation parameters such as
excipients and pH are
suitable orally; they can be prepared directly from raw
materials/chemicals although there was no example in the
cardiovascular therapeutic area. The procedure of crushing
tablets and "dispensing/suspending" in water, food or beverages
prior to administration is associated with the highest risk of
errors in extemporaneous dispensing, mainly because they are
difficult to track as there is no record or control of
preparation.

Extemporaneous preparations tend to have little or no
compatibility study back up. Very few well-controlled stability
studies are published on in vitro compatibility issues between
manipulated solid dosage forms and food/beverages. Studies have
been undertaken with drugs for the gastrointestinal system
(Johnson et al., 2003 and Carrier et al., 2004), 5HT3 antagonist
drugs (Yamreudeewong et al., 1995) and labetalol for the
cardiovascular system (Nahata, 1991). Standardisation of
recommendations for suitable alimentary vehicles is highly
problematic. For example, a manufacturer may recommend that the
drug is stable when tablets are dissolved in apple juice
(Imatinib SPC, 2004), but surely it cannot be known whether the
drug is stable in any apple juice or other juices, whose pH and
ingredients may vary significantly between manufacturers and
countries.

There are few stability studies undertaken on
extemporaneous products. In the literature, shelf-life is
determined by chemical stability, mainly assessed by HPLC, for
specials or some extemporaneous preparations formulated in
pharmaceutical vehicles. Vehicles can be commercially available
(e.g. Ora®plus, Ora®sweet, Keltrol®) or prepared in
the dispensary (e.g. methylcellulose 1%, syrup NF). Mostly,
stability testing does not include physical and microbial
stability testing and does not mimic the ‘in-use’
stability when the preparation encounters variable temperatures
and frequent opening during the treatment course.

The bioavailability of extemporaneous products can be
unpredictable. A gross formulation obtained from crushed solid
dosage forms may not be bioequivalent with the dose form
swallowed whole. In the past, the priority has been to provide a
formulation that children can take rather than a formulation with
optimised bioavailability. Notterman et al. (1986) described an
example of inadequate isoniazid bioavailability of crushed
tablets and an extemporaneous preparation made from the
injection, compared with a licensed liquid.

As mentioned in Table 2, drug solubility is very
important to consider in extemporaneous preparation. If the
active is not soluble, it can lead to inaccuracy of dosing
through a lack of dose uniformity and reproducibility. This is a
major consideration when no suspending agents are used,
especially when the person administering the dose is
inexperienced and the dose is small (Tuleu et al., in
press).

Other problems with extemporaneous dispensing include
the expense of some drugs (bosentan, sildenafil, Table 2) and the
consequences of production errors, which can be fatal (Anonymous,
2000).

4.3. Is dosing accuracy a problem?

Where ‘special’ products are used, there is
some degree of certainty that the drug will be present in the
stated quantity within the expiry period. The main difference
between ‘specials’ and licensed liquids is that their
bioavailability usually remains untested. This means that the
bioavailability of ‘specials’ may depend on the
manufacturing technique used and may differ between
manufacturers. There is little incentive for
‘specials’ manufacturers to perform
bioavailability/bioequivalence studies as, without going to the
considerable expense of attempting to license the drug, dosing
recommendations based on such studies cannot be legally
made.

Extemporaneous preparation of doses by nurses or carers
is probably the least accurate method. The weight of a split
tablet can range from 50 to 150% of the actual half-tablet weight
(Teng et al., 2002) and accuracy does not seem to be improved by
using commercially available tablet cutters (Breitkreutz et al.,
1999). Insoluble drugs are often crushed and dispersed in water
to give a proportion of the dose. Without the use of suspending
agents, this method provides highly variable dosing especially if
the dose (volume) is small.

Although drug dosing in children is often based on body
weight, this can be a poor predictor of drug clearance (Anderson
et al., 1997). It is therefore questionable how much impact
inaccurate dosing will have on clinical outcomes, especially with
anti-hypertensive medications where dose is titrated to response.
The main problem will be with variability in dosing, which occurs
most frequently when solid doses are manipulated immediately
prior to administration.

Warfarin is available as a special but the expense and
short shelf-life along with the drug's water solubility means
that it is usually administered as tablets crushed and dispersed
in water. In a cohort study of paediatric patients receiving
warfarin therapy, children under 1 year took significantly longer
to achieve the target international normalised ratio (INR),
needed more INR tests per month and required more dose changes
per month compared with other age groups. Children under 6 years
were more likely to have INRs below the target range (Streif et
al., 1999). There are many factors which could explain these
differences but one which the authors did not explore was
formulation. Unfortunately, no details on the drug formulation
were given but it would seem most likely that crushed tablets
were used to administer the dose to younger age groups. Using an
inappropriate formulation leading to inaccurate dosing could have
been a factor in these patients requiring more blood tests
(potentially traumatic finger/heel pricks) and failing to reach
target INR values as quickly. This example highlights the
potential problems encountered when narrow therapeutic index
drugs are not available in liquid formulations showing that in
such situations, dosing accuracy is a problem.

4.4. Do children need access to
modified release products?

Nifedipine is unlicensed for use in children but is
often prescribed for hypertension secondary to renal failure. In
adults, short acting nifedipine is not recommended for use in
hypertension due to the rapid drops in blood pressure it causes,
leading to complications, such as reflex tachycardias (British
National Formulary, 2005). The usual recommendation is to give a
modified release (m/r) preparation to obviate large changes in
blood pressure. However, the only available m/r nifedipine
preparations are in tablet form, and many children are unable to
swallow whole tablets (Czyzewski et al., 2000). As a result,
children are prescribed short-acting nifedipine preparations,
which include withdrawing the dose from soft capsules, crushing
m/r tablets and using imported drops which have proved to give
variable dosing (Tuleu et al., in press). There is little
evidence for the safety of using short-acting nifedipine in
children, but a retrospective review did find it effective in
producing large reductions in mean arterial blood pressure,
albeit giving little information about how doses below 10 mg were
extracted from the capsules (Blaszak et al., 2001). Serious
adverse effects of large decreases in blood pressure in children
can include cerebral ischaemia (Sasaki et al., 1997),
particularly when the patient has long-standing hypertension.
This, along with a lack of prospectively collected safety data,
is the reason that some paediatricians advise against the use of
short-acting nifedipine outside the specialist hospital
environment (Flynn, 2002).

Nifedipine provides a prime example of the disparity
which exists between medicines for children and adults. Licensing
of nifedipine affords adults the benefit of once daily dosing,
decreased risk of adverse effects and formalised post-marketing
surveillance. Children, treated with the same drug, have to take
the dose three times a day, and are placed at potentially
increased risk of adverse effects because no m/r formulation is
available. So, in answer to the question: do children need
access to
modified release products, the answer is yes; the challenge being
to develop innovative drug delivery methods that children are
able to take. Such strategies may include: m/r small platforms
(minitablets, minicapsules), trans-dermal delivery (especially
for neonates), m/r liquids (nano or microparticles) with suitable
polymers.

4.5. Why have formulation issues not been addressed
in the past?

Drug formulation issues are frequently overlooked in the
reports of paediatric clinical trials. One of the core principles
in reporting scientific research is to give full details on how
the experiment was carried out so that it can be repeated.
Clinical trials involving medicines in children routinely fail to
do this by omitting information on the drug formulation and how
it was administered, impairing the reliability and validity of
results and hindering the transferability into clinical practice.
In the previous two sections, published trials on nifedipine
(Blaszak et al., 2001) and warfarin (Streif et al., 1999) have
been mentioned, neither of which gave full details of the
formulation used and how the drug was administered. A study on
the use of amlodipine in children with hypertension described how
they were administered a weight-specific dose using a powder
prepared from crushed tablets (Tallian et al., 1999). The report
did not specify how the powder was administered. It is unlikely
that each dose of powder was individually weighed out and as
amlodipine is only sparingly soluble in water, dispersing the
dose in water without using a suspending agent will lead to
variable dosing. Another study (Flynn et al., 2000) on amlodipine
in children recognised this problem by using a suspension
formulated in the hospital pharmacy.

These studies represent the variability of formulation
and administration information provided in published paediatric
clinical trials. The problem is not isolated to cardiology
medicines (Standing and Wong, 2004). A review of recent
paediatric clinical trials in high impact factor journals
(Standing et al., in press) found adequate formulation
information is provided in only 37% of reports. Adequate
formulation reporting was classified as providing sufficient
information for the study to be repeated (formulation and
manufacturer stated, where formulation was a tablet/capsule, an
account of whether children were able to swallow the dose whole
or how an aliquot of the dose was administered). Especially in
the case of ‘special’ or extemporaneous preparations,
it is vital that a reference on the medicine's formulation is
given, as unlike licensed products, unlicensed preparations may
not be bioequivalent between different manufacturers (or between
batches). This result suggests that many authors and journal
editors do not consider providing formulation information in
paediatric clinical trials to be important, when its potential
impact on the amount of drug received may have a profoundly
negative effect on the reproducibility (reliability) and to a
lesser extent validity of the results.

In addition to clinical trials frequently not providing
formulation information, therapeutic failure can often have a
number of explanations. For example, the failure of amiodarone to
control a patient's arrhythmia may be due to a dosing with a
proportion of a crushed tablet dispersed in water. Many drugs are
sparingly soluble such as amiodarone, nifedipine, in water, in
abscence of a suspending agent, most of the drug will be in the
solid form at the bottom of the measuring device. Unless the
mixture is thoroughly stirred immediately prior to giving the
dose, the amount of drug received by the patient is likely to be
very erratic (Tuleu et al., in
press). ‘Special’ and extemporaneous
products have almost never been tested for bioavailability and so
patients may be under or over dosed compared with a level
expected to be achieved by extrapolation data from licensed
formulations in adults. It is therefore possible that therapeutic
failure or adverse reactions due to overdose resulting from
inappropriate formulations go unrecognised by paediatricians and
pharmacists caring for the patient.

Another important reason for inadequate formulation
availability for children is a commercial one. At present in UK,
there is no financial incentive for pharmaceutical companies to
license paediatric medicines and develop suitable formulations
due to the relatively small market and high cost of developing
and producing them.

4.6. Will formulations improve in the
future?

In September 2004, the European Commission adopted a
legislative framework for regulation of medicinal products for
paediatric use in order to work towards an ethical, effective and
favourable environment for paediatric research and development
(Medicines for Children,
2004). These arrangements are similar to the one
established in USA during the late 1990s. The key objectives of
the EU proposed regulation are to increase the development and
authorisation of paediatric medicines while ensuring they are
subject to high quality research, but that no unnecessary
clinical trials are carried out. The proposal also aims to
improve the information available on medicines for children. Key
elements in the proposal are:

– A new expert committee within the European Medicines
Agency (EMEA) to assess and agree Paediatric Investigation Plans
(PIPs) presented by the pharmaceutical industry. A system of free
scientific advice will also be provided by the EMEA.

– A requirement at the time of marketing authorisation
application that data is presented on the drug's use in children.
A system of waivers and deferrals will ensure the requirements do
not delay the authorisation for medicines in adults.

– A reward for studying medicines for children of 6
months extension to the supplementary protection certificate; in
effect, 6-month patent extension for the product (including adult
use).

– For off-patent medicines, 8 plus 2 years of data
exclusivity on paediatric use of the product for new studies
awarded via a Paediatric Use Marketing Authorisation (PUMA).
These incentives are very similar to those in USA but the EU
proposal is more robust as it requires the sponsor to market the
paediatric medicine for the approved indication within 12 months,
speeding up the availability for patients. It does not
distinguish between studies required (with claimed benefit to
children) and those requested (with potential benefit to
children) as in USA.

– Increased safety monitoring for children's medicines
(pharmacovigilance).

– A compulsory submission by industry of existing
studies in children, an inventory of the EU therapeutic needs of
children and an EU network of investigators and trial centres to
conduct studies required. The EU proposes a transparent approach
to negative outcomes of the trials in children as any results
(positive or negative) will be included in a database of ongoing
or terminated studies; the results will also be incorporated on
the drug label, regardless of whether the indication is approved
or not.

This awaited legislation is likely to become effective
late 2006 and it is hoped that all future medicines for children
will have been investigated in children and, where there is an
appropriate indication, a licensed paediatric formulation will be
produced.

However, delays are anticipated as the Medicines
Investigation for the Children in Europe (MICE) fund, equivalent
to the National Institute of Health and FDA set up to support old
and commercially disregarded drugs in USA, has not yet been
sourced. This is a real issue as generics manufacturers do not
have substantial resources for research and development beyond
equivalence studies.

In the meantime, extemporaneous preparation, be it at
the bedside, by pharmacists or ‘special’
manufacturers will continue to be a major route by which
paediatric oral medicines are prepared. As a result of strong
national concern in UK (Safer and Better medicines for children,
2004 Safer and Better medicines for children, 2004. http://www.rcpch.ac.uk/publications/recent_publications/Safer_Better_Medicines.pdf,
last accessed on the 30th March 2005.Safer and Better medicines
for children, 2004 and National Service Framework (Standard 10),
2004), the first edition of the British National Formulary for
Children (BNF-C) is due to be published (British National
Formulary for children, 2005). It will provide a practical,
relevant, authoritative information source and guide prescribing,
dispensing and administration of medicines to children up to 18
years of age. By reflecting current evidence on efficacy and
safety of drugs within the limits of available clinical trial
data, BNF-C will provide practical guidance on the ‘off
label’ use of medicines.

In addition to legislative and formulary developments,
innovations in pharmaceutical formulations should improve the
ease in which children can access medicines. Innovative m/r
preparations have previously been mentioned, and the following
areas are also ripe for future developments and
research:

– New routes of administration such as oral-transmusosal
(buccal strips), intra-nasal and trans-dermal (for neonates
mainly).

– More research into alternative safe excipients for
children such as natural polymers (e.g. cyclodextrin to mask
taste of drugs, improve solubility or protect
drugs/patient).

– Children's ability to swallow and their preferences
need to be investigated. This will direct future formulation
research towards (mini) tablets, chewable tablets, dispersible
tablets or more oral liquids.

Although new and innovative formulations are urgently
needed, work on extemporaneous formulation should not be
disregarded.

Those findings reflect on numerous problems associated
with the lack of suitable formulations for children. This
emphasised the difficulty in prescribing and administering
cardiovascular drugs as a proof of concept, which can be extended
to many other therapeutic areas. In an era of evidence-based
medicine, it is unacceptable that drug formulations given to
children are not better designed to provide accurate and
reproducible dosing. With the expected new European regulations
and the obligation of clinical testing on the paediatric
population, it will be important that a strategy for paediatric
formulation research is put in place. The future of paediatric
drug formulations seems bright, but legislation must be supported
by innovative research on new and existing delivery
methods.

Acknowledgements

The Centre for Paediatric Pharmacy Research (CPPR) was
established in April 2002 as a collaboration between the School
of Pharmacy, the Institute of Child Health and Great Ormond
Street Hospital for Children. CPPR owes a large debt of gratitude
to Professor A.T. Florence, whose effort and commitment to
actively bridge research and practice has made a huge
contribution to its foundation and continuing success. Bonne
retraite! The authors would like to thank the pharmacists Jodi
New for collating audit data on ward-based extemporaneous
manipulations, and Judith Cope for helpful discussion on this
topic. We also thank Rosemont Pharmaceuticals for Joe Standing's
Ph.D. studentship and Pfizer for the educational grant funding
Dr. Tuleu's paediatric drug delivery lectureship. The authors
have received funding from different pharmaceutical manufacturers
in researching paediatric medications.

Enviado por:

Joseph F. Standinga, b and Catherine
Tuleub, c, l
,

aPharmacy Department, Great Ormond Street
Hospital for Children NHS Trust, Great Ormond Street, London WC1N
3JH, UK

bCentre for Paediatric Pharmacy Research, The
School of Pharmacy/Institute of Child Health, University of
London, 29–39 Brunswick Square, London WC1N 1AX,
UKcDepartment of Pharmaceutics, The School of
Pharmacy, University of London, 29–39 Brunswick Square,
London WC1N 1AX, UKReceived 6 April 2005; revised 11 May 2005;
accepted 16 May 2005.

Available online 24 June 2005.