Alternative Forms Of Oral Drug Delivery For Pediatric Patients

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PEDIATRIC PHARMACOTHERAPY
A Monthly Newsletter for Health Care Professionals from the
University of Virginia Children’s Hospital
Volume 19 Number 3 March 2013
Alternative Forms of Oral Drug Delivery for Pediatric Patients
Marcia L. Buck, Pharm.D., FCCP, FPPAG
he lack of an appropriate dosage form
limits the use of many medications that
may potentially benefit children. While this has
been a long-standing problem for pediatric
healthcare providers, little attention has been
paid to remedying it until recently. In 2005 the
Eunice Kennedy Shriver National Institute for
Child Health and Human Development, joined
by representatives from the Food and Drug
Administration (FDA), academic medicine, and
the pharmaceutical industry, formed the United
States (US) Pediatric Formulations Initiative in
an effort to stimulate research in pediatric
formulation technology.
1
Similar work by the
European Medication Agency (EMA) led to the
development of the European Pediatric
Formulation Initiative.
2
In addition, the World
Health Organization launched a global initiative
in 2007 entitled “Make Medicines Child Size” to
foster development of pediatric dosage
formulations.
3
These groups continue to guide
research in the field of pediatric drug delivery
and champion technologic advances.
Limitations with Current Products
One of the greatest challenges in pediatric
pharmacology has been optimization of oral drug
delivery. Although most children over 6 years
of age can be taught to swallow solid dosage
forms, many remain uncomfortable with it until
adolescence. In a recent study 54% of children
between 6 and 11 years told study investigators
that they were unable to easily swallow a tablet.
4
While altering oral tablets to create formulations
suitable for children has long been a part of
pediatric healthcare, it is clearly a less than ideal
option.
5
Crushing tablets to mix them with food or water
may change the rate or extent of drug absorption.
Best and colleagues recently found that crushing
lopinavir/ritonavir (Kaletra®) tablets, a common
practice for children with HIV-1 infection,
resulted in a significant change in drug
bioavailability.
6
The authors conducted a
pharmacokinetic study in 12 children between 10
and 16 years of age after administration of whole
and crushed tablets. The use of crushed tablets
resulted in a median decrease in the area under
the concentration versus time curve (AUC) of
45% for lopinavir and 47% for ritonavir (p =
0.003 and 0.006, respectively).
Cutting tablets, another common practice, may
be acceptable for some drugs, however this
practice can introduce considerable variability
between doses. In drugs with a narrow
therapeutic index, such as levothyroxine, this
variability may be enough to produce clinically
significant changes in clinical response.
7
When
cutting a tablet is necessary, family members
should receive specific instructions on the
process, including the proper use of a tablet
splitter. Family members involved in dose
preparation should also understand how to
dispose of unused drug and the need to avoid
repeated exposure to drugs that have
carcinogenic or teratogenic properties.
Having a pharmacist prepare an extemporaneous
oral suspension or solution can minimize these
issues, but even a relatively simple change in the
process, such as conversion to a sugar-free
suspending agent, addition of a flavoring, or use
of a different brand, may alter the stability of the
final product or the absorption characteristics of
the drug. While the availability of
extemporaneous formulations is widespread in
most developed countries, it may be limited in
parts of the world lacking necessary resources
such as a source of clean water.
5
Commercially available oral liquid medications
provide a more reliable, ready-to-use preparation
for infants and children, but bioequivalence with
solid oral dosage forms is still not assured. In
2012, Kasirye and colleagues published the
results of a pharmacokinetic study comparing
oral solutions and solid dosage forms of three
antiretrovirals in 19 children between 1 and 4
years of age.
8
Oral solutions of zidovudine and
abacavir produced similar AUC values to tablets,
but lamivudine AUC values were 45% lower
with the solution. The authors concluded that
administration of lamivudine solution based on
dosing guidelines developed for the tablets may
result in subtherapeutic serum concentrations.
T
A new oral liquid formulation of levothyroxine
available in Europe was recently shown to
produce lower rates of normalization of thyroid
function than a tablet given at the same dose.
9
Levothyroxine, digoxin, hydrocodone, and
phenobarbital are just a few examples of drugs
that cannot be easily formulated as liquids
because of their relative insolubility in water.
The traditional method of preparing liquid
formulations of these drugs has been as alcoholbased elixirs. The concentration of alcohol in
elixirs varies from 5% to as much as 40%. The
long-term effects of repeated exposure to the
alcohol in these products, particularly in infants
and toddlers, are not known.
The problems encountered with currently
available formulations highlight the need for the
development of new products that are both easy
to administer and capable of providing reliable
serum drug concentrations. Several alternatives
to traditional dosage formulations have been
introduced in the US over the past decade that
may fill this need. Extended release oral
suspensions, as well as orally disintegrating
tablets and films are ideally suited for children
unable to swallow tablets and capsules.
Extended Release Oral Liquids
One of the disadvantages of oral liquid
preparations has been the need to give multiple
doses throughout the day. Until recently,
extended release products have been available
only as tablets, capsules, or sprinkles. On June
10, 2005 the first extended release oral
suspension, Pfizer’s azithromycin product
(Zmax®), was approved by the FDA for the
treatment of community acquired pneumonia in
adults and children over 6 months of age and
acute bacterial sinusitis in adults.
10
It is
administered as a single 60 mg/kg dose (with an
adult dose of 2 grams).
On September 27, 2012, the FDA approved an
extended release oral suspension of
methylphenidate (Quillivant XRTM) developed by
NextWave Pharmaceuticals, a subsidiary of
Pfizer.
11
The suspension consists of cationic
polymer matrix particles that bind racemic
methylphenidate via ion exchange. Variation in
the thickness of the coating applied to the
particles results in 20% of the drug being
released immediately, with the remaining 80% of
the drug released over 12 hours. It is shipped as
a powder to be reconstituted with water prior to
dispensing to make a 5 mg/mL suspension.
In the February 2013 issue of the Journal of
Child and Adolescent Psychopharmacology,
Wigal and colleagues published the results of a
two-week double-blind, randomized, placebocontrolled trial of extended release
methylphenidate suspension in children with
attention-deficit/hyperactivity disorder
(ADHD).
12
Forty-five children between 6 and 12
years of age were enrolled. Following an openlabel dose optimization period, patients were
randomized to receive either active drug or
placebo for 1 week, followed by the alternative.
Use of the extended release methylphenidate
suspension resulted in improvement in scores on
ADHD rating scales and a standardized math test
similar to that reported with methylphenidate in
other studies. The new suspension has not yet
been evaluated in a comparison study with other
extended release methylphenidate dosage forms.
Orally Disintegrating Tablets
Orally disintegrating, or orodispersible, tablets
(ODTs) are designed to dissolve in the presence
of saliva within one minute. The primary
advantage of ODTs is that no external source of
liquid is needed for consumption.
13
For patients
with dysphagia or children too young to swallow
tablets or capsules, ODTs provide a useful
alternative. There are a variety of methods for
preparing ODTs, including freeze drying,
molding, compaction, granulation, spray drying,
flash heat processing, sublimation to increase
porosity, and direct compression. Disintegrating
aids, binding agents, and sweeteners are added to
the active drug moiety during production to
improve the feel of the product in the mouth,
making the dissolved drug smooth and creamy.
Several companies have patented technologies
for manufacturing ODTs, such as Zydis®
(Catalent, Inc.) Flashtab® (Prographarm),
Orasolv® (Cima), and Wowtab® (Yamanouchi
Pharma Technologies).
1,13
Although the development of ODTs began in the
1970s, the first product to reach the US market,
Claritin® Reditabs, was not approved by the FDA
until December 1996. Since that time the number
of ODT products has grown rapidly to include
more than two dozen prescription and nonprescription drugs (Table).
Table. Examples of Drugs Available as ODTs
Acetaminophen Loratadine
Alprazolam Metoclopramide
Aripiprazole Mirtazapine
Carbidopa-levodopa Olanzapine
Cetirizine Ondansetron
Citalopram Prednisolone
Clonazepam Risperidone
Clozapine Rizatriptan
Desloratadine Selegiline
Diphenhydramine Tramadol
Donepezil Vardenafil
Fexofenadine Zolmitriptan
Lansoprazole Zolpidem
Lamictal
While most currently available ODTs have been
designed for adolescents and adults, some have
been formulated specifically for younger
patients, such as Children’s Tylenol
Meltaways.
These grape punch or bubble gum flavored
tablets, designed for children 2-11 years of age,
contain 80 mg acetaminophen and may be
chewed or allowed to melt in the mouth.
An ODT formulation of prednisolone (Orapred
ODT®) has proven to be very useful in pediatric
patients with asthma or allergic conditions such
as atopic dermatitis.
14
Glucocorticoids are
extremely bitter and the taste is difficult to mask,
particularly in oral liquid products. The ODT
product uses a triple layer polymer formulation
to minimize the taste. Grape-flavored Orapred
ODT® is currently available in 10 mg, 15 mg,
and 30 mg strengths. In 2007, the manufacturer
conducted a survey of 973 children; 89%
reported a preference for the ODT product over
prednisolone oral liquid.
15
The primary
disadvantage of this product is the cost; at $6 to
$10 per tablet, it is considerably more expensive
than other prednisolone preparations.
Ondansetron ODT (Zofran ODT® and generics)
has been well accepted for the prevention or
treatment of nausea and vomiting in the pediatric
population.
16
As with standard oral tablets,
children 4-11 years of age may be given a 4 mg
ODT three times daily. The dose for older
children and adults is 8 mg taken three times
daily. In 2008, Davis and colleagues enrolled
221 children (5-16 years of age) into a
randomized, double-blind, placebo-controlled
trial of ondansetron ODT after tonsillectomy.
17
The incidence of emesis within the first 3 days
after surgery was significantly lower in the
ondansetron ODT group than in the placebo
group (14.6% versus 32%, p = 0.004).
In one of the few prospective randomized
pediatric studies to compare ODT products to
standard formulations, Çorapçioglu and Sarper
evaluated IV and ODT ondansetron products in
22 children (ages 3-17 years) with cancer.
18
The
children were randomized to receive either 5
mg/m
2
IV ondansetron or a 4 or 8 mg
ondansetron ODT 30 minutes before and 12
hours after chemotherapy. The percentage of
patients experiencing a complete treatment
response, defined as no nausea or vomiting, was
no different between the groups (82% of the IV
group and 85% of the ODT group, p= 0.981).
Response rates remained similar when a
subgroup of children receiving highly
emetogenic regimens was analyzed (75% of the
IV group and 80% of the ODT group, p = 0.931).
The ODT formulation is not without
disadvantages. Most products are available in a
single strength, often one that is too large for use
in younger children. Because of their fragility,
breaking, cutting, or splitting ODTs is not
recommended. For some drugs, the rapid
absorption from an ODT may result in a brief
exposure to very high, potentially toxic, drug
concentrations. New microencapsulation
techniques provide a slower, more controlled
release of drug from an ODT. Li and colleagues
at the Shanghai Eighth People’s Hospital have
developed a scopolamine ODT that contains
microparticles embedded with the drug.
19
It dissolves within 45 seconds, but the drug itself is
not completely absorbed into the bloodstream
until 90 minutes after administration.
Another important concern is the potential for
toxic ingestions of ODTs, particularly
acetaminophen. Without the need to swallow,
ODTs can be consumed in large numbers, even
by very young children. In 2011, Ceschi and
colleagues conducted a retrospective study of
acetaminophen ingestions in children < 6 years
of age reported to the Swiss Toxicological
Information Center between June 2003 and
August 2009.
20
The authors compared 187 tablet
ingestions and 16 cases involving The mean
ingested dose was 59% greater in the ODT group
(157.3 + 147.6 mg/kg compared to 98.7 + 77.7
mg/kg in the tablet group, p = 0.085). The
authors suggest that the rapid dissolution of the
ODT, as well as its sweet taste and candy-like
feel in the mouth may encourage children to
ingest more drug than what they would be able to
swallow if tablets were involved.
Orodispersible Films
Orodispersible films (ODFs) offer another option
for rapid drug delivery.
21
These thin films or
strips are often more acceptable to patients with
dysphagia or a fear of choking than solid dosage
forms or ODTs. Films consist of hydrophilic
polymers that dissolve in the mouth within
seconds. They may be placed on the tongue for
oral absorption, under the tongue for sublingual
absorption, or along the buccal surface for
transmucosal absorption directly into the
systemic circulation. The latter route bypasses
gut absorption and delivery into the hepatic
portal system, thus avoiding first pass
metabolism and increasing drug bioavailability.
The ODF formulation has already proven to be a
popular means of delivering over-the-counter
products such as breath fresheners (Listerine
Pocketpaks® Breath Strips), simethicone (Gas-X
Thin Strips®), and multivitamins. Several of the
first ODFs to reach the market (Benadryl®,
Children’s Triaminic®, and TheraFlu® thin strips),
however, have been subsequently discontinued.
The reasons for the removal appear to include
production issues as well as poor sales. The latter
may reflect the declining use of cough and cold
products in children over the past several years.
The first prescription ODF, a new formulation of
ondansetron (Zuplenz®), was approved by the
FDA on July 2, 2010.
22
It is available in both 4
mg and 8 mg strengths and is approved for use in
children 4 years of age and older. A month after
the release of this product, a buprenorphine ODF
(Suboxone® sublingual film) was approved for
the treatment of opioid dependence in adults.
Several ODFs are currently in development,
including films for levocetirizine, rizatriptan,
and rotavirus vaccine.
23
Summary
Many medications with the potential to benefit
children are not available in a formulation
appropriate for them. Innovations in drug
delivery technology are leading to new
alternatives better suited to the pediatric
population. The stability of ODTs and ODFs
and their ability to deliver drugs without a source
of clean water make these formulations ideal for
both developing and developed countries and
have made them a focus for the US and European
Pediatric Formulations Initiatives. As a result, it
can be expected that there will continue to be
considerable growth in this area in the future.
The editors would like to thank Drs. Alexis King
and Nancy McDaniel for serving as guest editors
for this issue.
References
1. Giacoia GP, Taylor-Zapata P, Zajicek A. Eunice Kennedy
Shriver National Institute of Child Health and Human
Development Pediatrics Formulation Initiative: proceedings
from the second workshop on pediatric formulations. Clin
Ther 2012;34(Suppl.):S1-S10.
2. Walsh J, Mills S. Formulating better medicines for
children: 4th European Paediatric Formulation Initiative
Conference. Ther Deliv 2013;4:21-5.
3. Sosnik A, Seremeta KP, Imperiale JC, et al. Novel
formulation and drug delivery strategies for the treatment of
pediatric poverty-related diseases. Expert Opin Drug Deliv
2012;9:303-23.
4. Meltzer EO, Welch MJ, Ostrom NK. Pill swallowing
ability and training in children 6 to 11 years of age. Clin
Pediatr 2006;45:725-33.
5. Tuleu C, Breitkreutz J. Educational paper: formulationrelated issues in pediatric clinical pharmacology. Eur J
Pediatr 2013;Epub ahead of print. DOI 10.1007/s00431-0121872-8.
6. Best BM, Capparelli EV, Diep H, et al. Pharmacokinetics
of lopinavir/ritonavir crushed versus whole tablets in
children. J Acquir Immune Defic Syndr 2011;58:385-91.
7. Shah RB, Collier JS, Sayeed VA, et al. Tablet splitting of
a narrow therapeutic index drug: a case with levothyroxine
sodium. AAPS Pharm Sci Tech 2010;11:1359-67.
8. Kasirye P, Kendall L, Adkison KK, et al.
Pharmacokinetics of antiretroviral drug varies with
formulation in the target population of children with HIV-1.
Clin Pharmacol Ther 2012;91:272-80.
9. Cassio A, Monti S, Rizzello A, et al. Comparison between
liquid and tablet formulations of levothyroxine in the initial
treatment of congenital hypothyroidism. J Pediatr 2013:Epub
ahead of print.
10. Zmax® prescribing information. Pfizer Inc., January
2013. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/0
50797s017lbl.pdf (accessed 3/6/13).
11. Quillivant XR prescribing information. NextWave
Pharmaceuticals, Inc., January 2013. Available at
http://www.quillivantxr.com/sites/default/files/quillivant-xrpi.pdf (accessed 3/7/13).
12. Wigal SB, Childress AC, Belden HW, et al. NWP06, an
extended-release oral suspension of methylphenidate,
improved attention-deficit/hyperactivity disorder symptoms
compared with placebo in a laboratory classroom study. J
Child Adolesc Psychopharmacol 2013;23:3-10.
13. Badgujar BP, Mundada AS. The technologies used for
developing orally disintegrating tablets: a review. Acta
Pharm 2011;61:117-39.
14. Orapred® ODT prescribing information. Shionogi Inc.,
December 2011. Available at http://www.orapredodt.com/
(accessed 3/4/13).
15. Kraun S. Orapred ODT tastes good: survey shows 89%
of patients prefer Orapred ODT over liquid. March 29, 2007.
Available at http://www.drugs.com/clinical_trials/orapredodt-tastes-good-449.html (accessed 3/4/13).
16. Zofran® ODT prescribing information. Glaxo Wellcome
Inc., December 2000. Available at
http://google2.fda.gov/search?q=zofran+odt&client=FDAgov
&site=FDAgov&lr=&proxystylesheet=FDAgov&output=xml
_no_dtd&getfields=* (accessed 3/4/13).
17. Davis JP, Fertal KM, Boretsky KR, et al. The effects of
oral ondansetron disintegrating tablets for prevention of athome emesis in pediatric patients after ear-nose-throat
surgery. Anesth Analg 2008;106:1117-21.
18. Çorapçioglu F, Sarper N. A prospective randomized trial
of the antiemetic efficacy and cost-effectiveness of
intravenous and orally disintegrating tablet of ondansetron in
children with cancer. Pediatr Hematol Oncol 2005;22:10314.
19. Li F, Yan C, Bi J, et al. A novel spray-dried
nanoparticles-in-microparticles system for formulating
scopolamine hydrobromide into orally disintegrating tablets.
Internat J Nanomed 2011;6:897-904.
20. Ceschi A, Hofer KE, Rauber-Lüthy C, et al. Paracetamol
orodispersible tablets: a risk for severe poisoning in children?
Eur J Clin Pharmacol 2011;67:97-9.
21. Nagaraju T, Gowthami R, Rajashekar M, et al.
Comprehensive review on oral disintegrating films. Curr
Drug Deliv 2012;Epub ahead of print.
22. Zuplenz® prescribing information. Par Pharmaceutical,
Inc., July 2010. Available at: http://zuplenz.com
/pdf/Zuplenz_PI_July-2010.pdf (accessed 3/7/13).
23. Patel JG, Modi AD. Formulation, optimization and
evaluation of levocetirizine dihydrochloride oral thin strip. J
Pharm Bioall Sci 2012;44:35-6.
Formulary Update
The following actions were taken at the February
meeting of the Pharmacy and Therapeutics
Committee:
1. the restrictions on prescribing of bosentan
(Tracleer®) were amended to include initiation of
therapy in the neonatal population.
Contributing Editor: Marcia Buck, Pharm.D.
Editorial Board: Kristi N. Hofer, Pharm.D.
Clara Jane Snipes, R.Ph.
Susan B. Cogut, Pharm.D.
If you have comments or suggestions for future
issues, please contact us at Box 800674, UVA
Health System, Charlottesville, VA 22908 or
by e-mail to mlb3u@virginia.edu. This
newsletter is also available at
http://www.medicine.virginia.edu/clinical/depar
tments/pediatrics/education/pharmnews

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