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TABLE 8.2
paraben use in young children, the pharmaceutical sponsor changed the
composition and manufacturing procedure. Now it comes as a sterilized oral
liquid without preservation system, which is prefilled into an oral syringe for
single use and tightly sealed (see Table 8.1). The next two PUMA products
were oral liquid formulations: propranolol hydrochloride oral solution
without preservation system (Hemangiol), but high propylene glycol content
(2.60 mg per mL), and glycopyrronium bromide oral solution with sodium
benzoate as preservative (Sialanar). Sodium benzoate is considered a
relatively safe preservation agent at low doses. Propylene glycol has been
associated with serum hyperosmolality and also seizures
6,19,20
as it may pass
the blood–brain barrier in neonates and young infants, but not in adolescents
and adults.
The next PUMA products contain solid drug formulations. Dispersible
vigabatrin tablets (Kigabeq 100 and 500 mg) are dissolved in water on a
spoon in order to facilitate the drug administration. Alkindi contains smallsized pellets with hydrocortisone which are taste-masked by an ethyl
cellulose/hypromellose coating. By accumulating different counts of tastemasked pellets in hypromellose capsules, different dose strengths (0.5, 1.0,
2.0, and 5.0 mg) are obtained. The capsule is to be opened before use, and the
pellets can be sprinkled onto semisolid or liquid food. The newest PUMA
product, Slenyto, is a melatonin formulation with prolonged-release coated
mini-tablets which are filled into hard capsules at different quantities (1 and 5
mg dose strengths). Orodispersible mini-tablet formulations with 0.25 and
1.00 mg enalapril maleate are close to a PUMA filing.21 Orodispersible minitablets offer various beneficial features: precise dosing, high content
uniformity, good drug stability during storage as a solid dosage form, and safe
administration, resulting in a liquid dispersion in the saliva with ease of
swallowing.
22
Although the PUMA approach is not applicable in the United States, many
products with off-patent drug substances, but innovative drug dosage forms,
23
have been introduced to the market (Table 8.2). Many of these are available in
other countries outside the United States or EU, too.
24
Rece ntly Introduce d Me dicinal Products with Innovative Drug Dos age
Forms
a
Chewable tablets (e.g., Isentress) have been designed for school-aged
children and adolescents. Dispersible tablets for preparation of a solution or
suspension prior to administration are a good compromise between the
benefits of solid dosage forms in the package and liquid dosage forms at the
time point of administration. Advanced tablet geometries enable more flexible
dosing by splitting the dispersible tablets (e.g., Coartem, Tracleer, Carbaglu,
Siklos) before the liquid preparation. The remaining parts of the tablets
should not be reused as they lack primary packaging after breaking, which
may impact drug stability. Orodispersible films, for example, with
desloratadine or ondansetron, are sealed water-soluble polymeric films in
aluminum sachets for single use. These small thin strips immediately dissolve
on the tongue within a few seconds. Further, dose flexibility could be
increased by precise cutting or ad hoc preparation in hospital pharmacies in
general. However, these types of dose adjustments for pediatric use have not
been authorized yet.25 Spheronized granules (“pellets”) mini-tablets offer
multiple opportunities of modified drug release and sprinkling onto food
materials to facilitate swallowing.26 Mini-tablets are superior to pellets in the
precision of dosing, even at very small diameter like 1 or 2 mm, and,
therefore, qualify as a very flexible dosing system for pediatric use.
27–29
Some
pharmaceutical companies call mini-tablets in a primary package “granules,”
for example, for the product Kalydeco, because they are not monographed in
the pharmacopoeias and quality test specifications have not been authorized
so far. If flexible dosing is required because of a required dose titration step
or a narrow therapeutic window, a specific counting device may be required
to enable correct dosing.
MANIPULATING OR COMPOUNDING OF
DRUG PRODUCTS
The majority of commercially available drug products in the United States and
EU are not labeled for use in all subgroups of children.
When an appropriate drug product for the child is not available, the
options of the pediatrician include the following:
to refuse or delay the intended drug therapy
to change to another product/another drug substance even if the efficacy
and safety might be potentially inferior or unknown
to call the pharmaceutical manufacturer for scientific evidence on
manipulation or compounding of the authorized drug to make it more
child appropriate
to request the compounding of an extemporaneous drug formulation
based on different scientific evidence and quality levels.
Manipulation has been defined to happen close to the bedside, for
example, splitting or crushing a tablet before mixing with food. Compounding
means the preparation of a new drug formulation in advance, for example, in a
compounding center, a hospital, or a community pharmacy.30 It has to be
distinguished between authorized and nonauthorized manipulations or
compounding steps.
Authorized medicinal products have been approved by the competent
authorities after evaluation of all submitted data on quality, efficacy, and
safety. The Summary of Product Characteristics (SmPC) of the authorized
product reflects the approved practices for medical use. Further, the product
is subjected to a mandatory pharmacovigilance procedure after approval.
Authorized manipulations or compounding of the medicine include
reconstitution of a “dry syrup” (powder or granule) into a liquid formulation
or dissolution of a tablet for preparing a liquid for drug administration if these
procedures are described in the SmPC of the authorized medicinal product.
As the compounding is always performed by health care professionals in the
pharmacies, it can be assumed that the risk of failures is lower than the
manipulation procedures performed by naïve caregivers, such as parents or
grandparents (see Fig. 8.1).
Figure 8.1 Levels of evidence and quality of drug preparations for children. SmPC, Summary of
Product Characteristics.
If the SmPC comprises the required information, it can be assumed that the
quality of the resulting preparation has been tested and approved by the
competent authority. Splitting of tablets into pieces can only be accepted if the
breaking notches (scores) have been designed for dividing the tablet and if
there is evidence that this procedure reveals the intended doses. Splitting
devices as marketed in many variations usually do not improve the uniformity
of the resulting pieces.31 Crushing of tablets is unacceptable if a functional
coating (enteric or prolonged-release coating) is applied to the tablet core or
if there is a sophisticated technology for improving drug solubility or
dissolution in place, for example, by an amorphous solid dispersion. Crushing
would accelerate the forming of water-insoluble crystals by increased surface
and reduce the bioavailability by far as it has been demonstrated for lopinavir
and ritonavir with an exposure of less than 50% after crushing.32 Sprinkling
drug carriers onto food can be an issue if the food material interacts with the
drug product and impacts the stability or dosing accuracy. Instructions
provided in the SmPC should be strictly followed therefore. It has to be noted
that the pharmacovigilance program in place only covers authorized use of the
medicinal product.
If the SmPC does not include the required information (and this happens in
the majority of cases), the manipulation or compounding is called
“nonauthorized” use of approved medicines. Often, this has been called
“unlicensed use”; however, most national drug laws allow this
pharmaceutical practice in order to prepare child-appropriate drug
formulations and to bridge the gaps in pediatric health care. The quality of the
preparations obtained by nonauthorized manipulation or compounding is
generally inferior to the authorized variations as it always lacks official
approval and, in most cases, scientific evidence. Bioavailability is mostly
unknown when administering extemporaneous preparations.
If the composition and preparation procedure are monographed by a
pharmacopoeia, the higher quality can be assumed. The European Directorate
for the Quality of Medicines and Healthcare (EDQM) has launched a public
Pediatric Formulary in December 2019, which will be continuously enlarged
(paedform.edqm.eu). So far, it contains—beside some general provision and
texts—monographs on “hydrochlorothiazide 0.5 mg per mL oral solution” and
“sotalol 20 mg per mL oral solution.” Sources of these monographs are
compendial recipes. The composition of the drug formulation, according to
recent EMA guidelines, including the safety of excipients, the quality of the
drug substance, and the manufacturing procedure, has been evaluated by the
scientific committee, and the quality testing of the compounded preparations
has been performed by laboratory testing of competent authorities. The new
pediatric formulary will only contain monographs on drug substances for
which no authorized pediatric medicine is available within the member states
of the Council of Europe.
A major concern in compounding medicines is the quality of starting
materials. In the best case, pharmaceutical grades of the drug substance are
used, ideally indicated by a certificate of compliance from the authority.
However, costs are high for these qualities, and package sizes are often not
appropriate for a preparation in a hospital or community pharmacy. Therefore,
substances of questionable quality are often used, for example, by purchasing
from a catalog of chemicals. It should be noted that these qualities may not be
necessarily produced for pharmaceutical purposes, are not monitored by
pharmaceutical companies or authorities, and are often quality controlled in a
different way. In these cases and if the drug substance is not available at all,
the use of an authorized medicine, for example, a tablet or capsule, may be
superior. However, it should be noted that the actual drug content of the
products varies around the labeled claim and may be reduced already over
storage in an unknown magnitude. Impurities may be increased already, and
the compatibility of the excipients with the intended diluent is unproven (as
long as this is not described in the SmPC).
In order to facilitate the compounding, there are different commercial
diluents or dispersing agents available, for example, Ora Plus, Ora Sweet,
and SyrSpend. Stability studies for a number of drug preparations using these
standard materials are available in textbooks and scientific literature.
33,34
However, in some countries, the legal status of the suspending agents is
unclear, and their use is, therefore, not recommended or even illegal in those
countries. Further, some of them contain excipients, such as propyl paraben,
which are not recommended for young children. Included sweeteners like
sucrose and fructose increase blood sugar concentration and may cause
cariogenic effects. Sorbitol and xylitol may cause osmotic diarrhea. In total,
only a very limited number of these products matches the recommendations
for safe excipients of the EMA. The U.S. Pharmacopoeia has monographed a
number of these bases which can be prepared from pharmaceutical excipients,
mainly hypromellose and methylcellulose, but, in most cases significant, time
is just spent for the manufacturing of the diluents. Various recipes for different
pH values and preservative-free bases are available.
Intravenous medicinal products for adult patients are often too
concentrated for accurate dosing young children, in particular newborns.
Measurement of small volumes can be associated with inaccurate
administration of these drugs. In fact, intoxication has been reported in infants
with the use of concentrated digoxin and morphine.
35,36
When diluting
commercial intravenous products at the pharmacies, additional quality testing,
for example, on sterility and pyrogens, applies.
The need for extemporaneous formulations will continue despite recent
efforts to stimulate drug development and research for pediatric medicines.
There will be never a complete coverage of all the needs of pediatric patients
from different age groups. Compatibility and stability studies are still
required to improve the quality of extemporaneously prepared medicines.
Studies on the bioavailability, efficacy, and safety would be desirable, but are
scarce due to limited financial resources. The available information should be
made public as it has been started for the European Pediatric Formulary to
improve scientific evidence and knowledge on extemporaneous drug
formulations.
PALATABILITY OF MEDICINES
The child’s acceptance of a drug formulation is dependent on its
palatability.
37–39
Palatability includes the sensation of taste, flavor, and texture
(mouthfeel). Better tasting usually improves the ease of administration and the
loss of drug substance by spitting out. Liquid formulations often require the
addition of sweeteners and flavors in order to improve the taste or flavor of
the medicines. The risk–benefit balance between the toxicity of the added
pharmaceutical excipients and the improved taste perception has to be
carefully considered. In principle, different approaches for taste-masking are
feasible40:
Modify the pH of a liquid formulation
Add sweeteners and/or flavors in order to mimic another liquid
Increase the viscosity of the formulation to reduce drug diffusion to the
taste receptors
Add complexation agents (e.g., cyclodextrins or ion-exchange resins)
Add a pharmacologic taste blocker (e.g., adenosine monophosphate)
Introduce a barrier (e.g., using a polymer, wax, or fat coating)
Mix with food or beverage
Natural sweeteners may cause diarrhea and cariogenic effects. Chemical
sweeteners may show toxicity in children. Artificial or natural flavors
sometimes contain allergenic components that are often not fully disclosed by
the flavor manufacturer. Most cyclodextrins and ion-exchange resins display
low amounts for acceptable intake. A pharmacologically active taste blocker
has not been licensed for a pediatric product so far. Hence, in most cases, the
introduction of a diffusion barrier for the poorly tasting API is the last chance,
which automatically leads to a solid drug dosage form. Mixing or sprinkling
solid multiparticulates onto food usually results in short contact time and poor
diffusion of the unpleasant tasting API. If the stability or the bioavailability is
not impacted by using food as a vehicle, it can be an excellent choice for
improving the palatability and adherence. Just the texture of a multiparticulate
can be an issue as the child may perceive a “sandy” mouthfeel.41 Therefore,
palatability is another driving force for the shift of paradigm toward solid
drug formulations for children as these preparations offer more potential for
the pharmaceutical technologist to improve the palatability.
In pharmaceutical development of new medicines for children, a major
issue is how to predict the child’s aversion to an API or a drug formulation.
Taste panel results from adults usually cannot be extrapolated to children,
because children prefer more sweet and less bitter sensations of taste.
Pediatric taste data are only available in the clinical studies, usually obtained
in a hedonic scale approach,40 but then reformulation is hardly possible as it
would cause a loop in the drug development and some loss of time until the
authorization of the product. Predictive tools such as the Brief-Access Taste
Aversion (BATA) model42 and chemical taste sensing system (the so-called
“electronic tongues”)43 are very popular. They cannot replace taste results
from real pediatric patients, but enable better decision-making in the drug
development process.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
SUMMARY
Availability of a child-appropriate formulation is a limiting step for the
clinical use of medicines in newborn, infants, and children. New products
with advanced dosage forms, especially multiparticulate formulations as
pellets and mini-tablets, have appeared on the market. These new solid
dosage forms offer more opportunities in regard to taste-masking, safety of
used excipients, stability, dose uniformity, and flexibility than the previously
preferred liquid formulations. However, various gaps in pediatric medicines
are still existing. Therefore, manipulating authorized products or
compounding extemporaneous formulations is still common practice. In order
to further improve the quality, efficacy, and safety of compounded products,
more research is needed, and the results should be collected and published in
the public domain. Spontaneous “ad hoc” preparations without scientific
evidence should be abandoned unless there is not a single alternative for the
use in children.
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