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Pediatric DrugsA Review of Commercially Available

Oral Formulations
ROBERT G. STRICKLEY, QUYNH IWATA, SYLVIA WU, TERRENCE C. DAHL
Formulation and Process Development, Gilead Sciences, Inc. 333 Lakeside Drive, Foster City, California 94404

Received 19 January 2007; accepted 22 May 2007


Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21101

ABSTRACT: Pediatric oral formulations can be quite scientifically challenging to develop


and the prerequisites for both a measurable dosage form to administer based upon bodyweight, and also taste-masking are two of the challenges unique for pediatric oral
formulations. The physicochemical and organoleptic properties of the active drug
substance such as solubility, chemical stability, and taste along with the intended dose
can determine which formulations are feasible to develop. Oral pediatric formulations are
available in 17 different varieties and can be either a ready-to-use formulation such as a
solution, syrup, suspension, tablet, scored tablet, chewable tablet, orally disintegrating
tablet, or thin strip, or can also be a formulation that requires manipulation such as a
powder for constitution to a suspension, tablet for constitution to a suspension, powder for
constitution to a solution, drops for reconstitution to a suspension, concentrated solution
for dilution, effervescent tablet, bulk oral granules, bulk oral powder, or solid in a capsule
to mix with food or drink. Recently there has been an increase in pediatric formulation
development inspired by increased regulatory incentives. The intent of this review is to
educate the reader on the various types of formulations administered orally to pediatrics,
the rationale in deciding which type of formulation to develop, the excipients used,
development challenges, the in-use handling of oral pediatric formulations, and
the regulatory incentives. 2007 Wiley-Liss, Inc. and the American Pharmacists Association
J Pharm Sci 97:17311774, 2008

Keywords: pediatric; formulation; suspensions; physical stability; oral drug delivery;


excipients; chemical stability; solid dosage form; solid-state stability; regulatory science

INTRODUCTION
Abbreviations: AUC, area-under-the-curve; BMS, Bristol
Myers Squibb Company; b.i.d., twice-a-day; Cmax, maximum
concentration; EDTA, ethylenediaminetetraacetic acid; EU,
European Union; FDA, Food and Drug Administration; GERD,
gastroesophageal reflux disease; HIV, human immunovirus;
HBV, hepatitis B virus; HPC, hydroxypropylcellulose; HPMC,
hydroxypropyl methylcellulose (hypromellose); ODT, orally
disintegrating tablet; PEG, polyethylene glycol; q.d., once-aday; q.i.d., four times-a-day; RT, room temperature; t.i.d.,
three times-a-day; TPGS, d-a-tocopheryl polyethylene glycol100 succinate; UK, United Kingdom; USA, United States of
America.
Correspondence to: Robert G. Strickley (Telephone: 650522-5580; Fax: 650-522-5875; E-mail: rstrickley@gilead.com)
Journal of Pharmaceutical Sciences, Vol. 97, 17311774 (2008)
2007 Wiley-Liss, Inc. and the American Pharmacists Association

Recently there has been an increase in pediatric


formulation development inspired by increased
regulatory incentives. Pediatric formulations can
be quite scientifically challenging to develop due
to unique requirements and limitations. Pediatric
formulations are delivered by many routes of
administration including oral, rectal, nasal, buccal/sublingual, topical/transdermal, injectable,
pulmonary, ocular, and ear drops. Pediatric
formulations are obviously designed to be administered to infants and children, but can also be
administered to adults who desire the ability to

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STRICKLEY ET AL.

adjust their dose, for ease of swallowing, or to


achieve a desired pharmacokinetic effect such as a
shorter onset of action or higher maximum
plasma concentration (Cmax) compared to the
conventional formulation such as a tablet.
This review focuses on commercially available
oral pediatric formulations1 and the challenges in
their development. Table 1 is a listing of excipients
used in commercially available pediatric oral
formulations. Tables 2 and 3 are selected lists of
commercially available pediatric oral formulations arranged by formulation type and then
alphabetically by the drugs generic name, which
is followed by the trade name. Oral pediatric
formulations are available in 17 different types of
formulation and can be a ready-to-use formulation
(Tab. 2) such as a solution, syrup, suspension,
tablet, scored tablet, chewable tablet, orally disintegrating tablet, or thin strip. An oral pediatric
formulation can also require manipulation such as
a powder for constitution to a suspension, tablet for
constitution to a suspension, powder for constitution to a solution, drops for reconstitution to a
suspension, concentrated solution for dilution,
effervescent tablet, bulk oral granules, bulk oral
powder, or solid in a capsule to mix with food or
drink (Tab. 3). Figure 1 is a bar chart showing the
occurrences, as identified in this review, of the 16
different types of prescription pediatric formulations. The intent of this review is to educate the
reader as the various types of formulations
administered orally to pediatrics, the rationale in
deciding which type of formulation to develop,
excipients used, development challenges, the inuse handling of oral pediatric formulations, and
regulatory incentives.

REGULATORY INCENTIVES
In December 1994 the Center for Drug Evaluation
at the Food and Drug Administration (FDA)
issued the first of what are commonly referred to
as The Pediatric Rules, as a response to the
observation that approximately 75% of prescription drugs in 1992 had inadequate pediatric use
information. Thus the FDA began to encourage
pharmaceutical companies to consider the pediatric population during two time periods: throughout a drugs development up to approval and
during marketing (www.fda.gov/cder/pediatric;
accessed May 21, 2007).
Since pediatric formulations may have low sales
volume, the Food and Drug Administration ModJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

ernization Act of 1997 and the Best Pharmaceuticals for Children Act of 2002 added an economic
incentive to industry. Specifically The Pediatric
Exclusivity Rule, also known as the Pediatric
Rule of 1998 grants the sponsor company an
additional 6 months of patent life on the active
moiety if a pediatric formulation is marketed or
pediatric dose information is provided. However,
the United States law granting pediatric exclusivity is scheduled to sunset in October of 2007. In
addition, under the Pediatric Research Equity Act
of 2003 the FDA can require pediatric studies of a
drug submitted in a new drug application if the
FDA determines the product is likely to be used in
a substantial number of pediatric patients. These
incentives seemed to have accomplished their
intended purpose since nearly 100 medicines for
sale in the United States of America (USA) have
received pediatric labeling since the late 1990s,
and 250 clinical studies have been conducted on
124 products as of July 2005.2 As of May 2007
the FDA has granted pediatric exclusivity to
136 approved drugs (www.fda.gov/cder/pediatric/
exgrant.htm; accessed May 21, 2007).
In Europe a legislative framework came into
force January 2007 by the European Commission
and was published in the Official Journal of
the European Union (EU) as regulation number 1901/2006 (http://ec.europa.eu/enterprise/
pharmaceuticals/eudralex/vol-1/reg_2006_1901/
reg_2006_1901_en.pdf; accessed May 21, 2007).
The European legislation is inspired by observations that Europe has 100 million children, which
is 20% of the total population, but there is a lack of
suitable pediatric formulations and dosing guidelines. European hospital dispensaries commonly
extemporaneously manipulate many adult drugs.
The European legislation also contains the incentive of 6-month patent extension, but is more
rigorous than the USA regulations in that the EU
proposal also requires that the sponsor at the time
of the marketing authorization application to
provide data on the use in children, and also to
market the pediatric formulation for the approved
indication within 12 months. The EU proposal also
provides incentives for off-patent medicines.

CLINICAL CHALLENGES
Clinical trials in pediatric patients are challenging due to pharmacokinetic variations with age,
potentially different doses for different age
groups, dose calculated based upon body-mass,
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Flavors
Sweeteners
Anise
Acesulfame potassium
Aspartame
Banana
High fructose corn syrup
Blackcurrant
Magnasweet
Bubble gum
Maltol
Cherry
Saccharin
Cotton candy
Saccharin sodium
Creamy caramel
Sucralose
Cre`me de vanilla
Aroma
Fruit punch
Grape
Menthol
Lemon cre`me
Yellow-plum-lemon
Mandarin orange
aroma
Mint
Mixed fruit
Orange
Peach
Peppermint
Strawberry and banana
Strawberry and cream
Strawberry and mint
Tutti-frutti
Vanilla

Taste and Sensory


Coatings
Solvents
Cellulose acetate
Castor oil
Dibutyl sebacate
Ethanol
Ethylcellulose
Glycerin
Stearic acid
Medium-chain triglyceride
Triethyl citrate
PEG 400
Copolymers
PEG 3350
Ammonium methacrylate
Propylene glycol
Butylated methacrylate
Vegetable oil
Carbomer 934P
Water
Polyacrylate methacrylate Surfactants
Lubricants
Docusate sodium
Magnesium stearate
Glycerol stearate
Stearic acid
Lecithin
Glidant
Poloxamer 188
Silicon dioxide
Poloxamer 331
Poloxamer 407
Polyoxyl 8 stearate
(Macrogol stearate)
Polyoxyl 35 castor oil
(Cremophor EL)
Polyoxyl 40 hydrogenated
castor oil (Cremophor
RH 40)
TPGS
Polysorbate 20
Polysorbate 80
Sodium lauryl sulfate

Solid Formulations
Bulk/diluter
Lactose
Maltodextrin
Mannitol
Microcrystalline cellulose
Sorbitol
Starch
Sucrose
Xylitol
Binder
Crospovidone
Povidone
Pregelatinized starch
Disintegrants
Croscarmellose
sodium
Sodium starch
glycolate

Table 1. Excipients Used in Pediatric Oral Formulations

Buffers/pH modifiers
Preservatives
Acetic acid
Benzoic acid
Ascorbic acid
Butylated hydroxy
Calcium carbonate
anisole
Calcium phosphate
Butylated hydroxy
Citric acid
toluene
Hydrochloric acid
Butylparaben
Magnesium carbonate
EDTA
Magnesium hydroxide
Methylparaben
Malic acid
Methylparaben
Potassium phosphate
sodium
Sodium bicarbonate
Potassium sorbate
Sodium citrate
Propylparaben
Sodium hydroxide
Propylparaben
Sodium phosphate
sodium
Succinic acid
Sodium benzoate
Suspending/dispersing
Sorbic acid
agents
Isotonicifier
Acacia
Sodium chloride
Guar gum
Mannitol
Carboxymethyl cellulose Antifoam
sodium
Simethicone
Crospovidone
Dimethicone
Hydroxypropyl cellulose
Hydroxypropyl
methylcellulose
Povidone
Propylene glycol alginate
Sodium alginate
Tragacanth
Xanthan Gum

Solution and Suspension


Formulations

PEDIATRIC ORAL FORMULATIONS

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Injection solution (for oral dosing)

Oral solution/room temperature

Oral solution/288C until expiration or 10 mg/mL


3 months at room temperature

Oral solution/room temperature

Dolasetron mesylate/Anzemet1

Efavirenz/Sustiva 30 mg/mL
Oral Solution

Emtricitabine/Emtriva1

Fluoxetine HCl/Prozac1

4 mg/mL

30 mg/mL

20 mg/mL

15 mg/mL

Oral solution/room temperature

Amprenavir/Agenerase1

20 mg/mL

Oral solution/room temperature

Abacavir sulfate/Ziagen1

Marketed Formulation/Storage

Active in
Formulation

Inactive in Formulation
(as Listed in Package
Insert or PDR)1

3 months to 16 years: 8 mg/kg Artificial strawberry and banana


up to 300 mg b.i.d.
flavor
Citric acid
Methylparaben
Propylparaben
Propylene glycol
Saccharin sodium
Sodium citrate
Sorbitol Solution
Water
412 years: 22.5 mg/kg b.i.d. Acesulfame potassium
or 17 mg/kg t.i.d. up to
Artificial grape bubblegum flavor
2800 mg per day
Citric acid
TPGS
Menthol
Natural peppermint flavor
PEG 400 (17%)
Propylene glycol (55%)
Saccharin sodium
Sodium chloride
Sodium citrate
216 years: 1.2 or 1.8 mg/kg Mannitol
up to 100 mg within 2 h Acetate buffer
prior to surgery or 1 h
Water
prior to chemotherapy
pH 3.23.8
270600 mg
Medium-chain triglycerides
Benzoic acid
Strawberry/mint flavor
6 mg/kg up to 240 mg
Cotton candy flavor
EDTA
Methylparaben
Propylparaben
Propylene glycol (2%)
Sodium phosphate
Water
Xylitol
HCl/NaOH to pH 7.2
1060 mg/day
Alcohol (0.23%)
Benzoic acid
Flavoring agent (mint)
Glycerin
Water
Sucrose

Dose

Selected Listing of Commercially Available Pediatric Oral FormulationsReady-to-Use

Drug Name/Marketed Name

Table 2.

GlaxoSmithKline/HIV

GlaxoSmithKline/HIV

Company/Indication

None

None

None

Eli Lilly/treatment of
depression and
obsessive compulsive
disorder ages 717

Gilead/HIV

BristolMyers
Squibb/HIV

Mix with apple or


Sanofi-Aventis/
apple-grape juice
antinauseant and
antiemetic

None

None

Preparation

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100 mg/mL

Oral solution/room temperature

Oral solution/room temperature

Lamivudine (3TC)/
(1) Epivir1
(2) Epivir-HBV1

Levetiracetam/Keppra1

Lopinavir and Ritonavir/


Kaletra1

(2) 5 mg/mL

Oral Solution/Room Temperature

Granisetron HCl/Kytril1

Oral Solution (fixed-dose combination)/ 80 mg/mL


room temperature until dispensed.
lopinavir and
For patient use store at 288C until
20 mg/mL
expiration or 2 months at room
ritonavir
temperature

(1) 10 mg/mL

0.2 mg free
base/mL

4 mg/mL

Oral solution/room temperature

Galantamine HBr/Reminyl1

50 mg/mL

Oral solution/288C

Gabapentin/Neurontin1
Glycerin
Xylitol
Artificial Cool Strawberry
Anise flavor
Methylparaben
Propylparaben
Sodium saccharin
Sodium Hydroxide
Water
Citric acid
None

None

None

FD&C Yellow No. 6


Orange flavor
Water
Sodium benzoate
Sorbitol
3 months to 16 years: 4 mg/kg (1) and (2) Artificial, strawberry,
None
up to 150 mg b.i.d.
and banana flavors
217 years: 3 mg/kg up
Citric acid
to 100 mg q.d.
Methylparaben
Propylparaben
Propylene glycol
Sodium citrate
Sucrose (200 mg/mL)
Water
2060 mg/kg b.i.d
Ammonium glycyrrhizinate
None
Citric acid
Glycerin
Maltitol solution
Methylparaben
Acesulfame potassium
Propylparaben
Water
Sodium citrate
Natural and artificial flavor (grape)
715 kg: 12/3 mg/kg,
Acesulfame potassium
None
1540 kg: 10/2.5 mg/kg
Alcohol (42.4% v/v)
up to 400/100 mg (5 mL) Artificial cotton candy
Citric acid
b.i.d.
Glycerin
High fructose corn syrup
Magnasweet-110
Menthol
Natural and artificial flavor
Peppermint oil
Polyoxyl 40 hydrogenated castor oil
Povidone
Propylene glycol (15% w/v)
Saccharin sodium
Sodium chloride
Sodium citrate
Water

1 mg b.i.d. or 2 mg Q.D.

1632 mg/day b.i.d.

1800 mg t.i.d.

(Continued)

Abbott/HIV

UCB/Antiepileptic

GlaxoSmithKline/HIV
hepatitis B

nausea and vomiting


associated with
chemotherapy

Roche/prevention of

Janssen/Alzheimer

ParkeDavis/Analgesic
for posttherapeutic
neuralgia

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Oral solution/room temperature

Oral solution/room temperature

Oral solution/room temperature

Oral solution/288C or at 258C

Oral solution/room temperature

Nizatidine/Axid1

Ondansetron HCl/Zofran1

Ribavirin/Rebetol1

Ritonavir/Norvir1

Marketed Formulation/Storage

Methylphenidate
HCL/Methylin1

Drug Name/Marketed Name

Table 2. (Continued)

80 mg/mL

40 mg/mL

1 mg/mL

15 mg/mL

1 or 2 mg/mL

Active in
Formulation
Citric acid
Water
Glycerin
Grape flavor
>12 years: 150 mg b.i.d up
Methylparaben
to 300 mg/day
Propylparaben
Glycerin
Sodium alginate
Water
Sodium chloride
Saccharin sodium
Sodium citrate
Citric acid
Sucrose
Bubble gum flavor
411 years: 4 mg t.i.d.
Citric acid
Water
Sodium benzoate
Sodium citrate
Sorbitol
Strawberry flavor
7.5 mg/kg up to 200 mg b.i.d. Sucrose
Glycerin
Sorbitol
Propylene glycol
Sodium citrate
Citric acid
Sodium benzoate
Natural and artificial flavor
Water
<600 mg b.i.d. or >1 month: Ethanol, 43%
Water, 15%
350400 mg/m2 up to
600 mg b.i.d (0.87.5 mL) Polyoxyl 35 castor oil
Propylene glycol
Citric acid
Saccharin sodium
Peppermint oil
Creamy caramel flavoring
FD&C Yellow No. 6

560 mg b.i.d.

Dose

Inactive in Formulation
(as Listed in Package
Insert or PDR)1

None

None

None

None

None

Preparation

Abbott/HIV

Schering/Hepatitis C

GlaxoSmithKline/
antiemetic

Braintree/treatment
of ulcers

Alliant Pharmaceuticals/
Attention-deficit,
hyperactivity disorder

Company/Indication

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Syrup/Room Temperature

Rimantadine HCl//Flumadine1

10 mg/mL

15 mg/mL

0.5 mg/mL

Syrup/4258C/4258C

Syrup

Desloratadine/Clarinex1

1 mg/mL

Ranitidine HCl/Zantac1

Syrup/room temperature

Cetirizine HCl/Zyrtec1

10 mg/mL

1 mg/mL
0.3 mg/mL

Syrup/room temperature

Amantadine HCl/Symmetrel1

500 mg/mL

Syrup/room temperature
Hydrocodone bitartrate
Homatropine methylbromide/
1
Antitussive Hycodan

Oral solution/room temperature

Sodium oxybate/Xyrem1

<10 years: 5 mg/kg up to


150 mg q.d. >10 years:
100 mg b.i.d

210 mg/kg up to 150 mg


b.i.d.

612 years of age:


2.5 mg hydrocodone
every 46 h up to a
maximum of 15 mg
per 24 h

611 months: 1.0 mg,


12 months5 years:
1.25 mg, 611 years:
2.5 mg >12 years: 5 mg
all q.d.

4.59.0 g/night divided into


two doses: at bedtime
and 2.54 h later
19 years of age: 24 mg/
pound/day (4.48.8 mg/
kg/day) up to 150 mg/day,
912 years of age:
100 mg b.i.d.
6 months 2 years:
2.55 mg per day,
25 years:
2.55 mg per day,
611 years:
510 mg per day

Malic acid
Water
pH 7.5
Flavors
Citric acid
Methylparaben
Propylparaben
Sorbitol
Acetic acid
Banana flavor
Glycerin
Grape flavor
Methylparaben
Propylene glycol
Propylparaben
Sodium acetate
Sugar syrup
Water (pH 45)
Propylene glycol
Sorbitol solution
Citric acid
Sodium citrate
Sodium benzoate
EDTA
Water
Sugar
Bubble gum flavor
Colors
Flavors
Methylparaben
Propylparaben
Sorbitol solution
Sucrose
Water
Alcohol (7.5%)
Butylparaben
Sodium phosphate
HPMC
Peppermint flavor
Potassium phosphate
Propylparaben
Water
Saccharin sodium
Sodium chloride
Sorbitol
Flavors
Citric acid
Methylparaben
Propylparaben
Saccharin sodium
Sorbitol
Water
None

None

None

None

None

None

None

(Continued)

Forrest/antiviral

GlaxoSmithKline/
treatment of ulcers,
and GERD

Endo/Antitussive,
symptomatic relief
of cough

Schering/antihistamine

Pfizer/Allergic rhinitis

Orphan medical/
cataplexy related
to narcolepsy
Endo/antiviral

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(Continued)

Syrup room temperature

Syrup/15258C

Suspension/room temperature

Suspension

Suspension/room temperature

Zidovudine (AZT)/Retrovir1

Acyclovir/Zovirax1

Carbamazepine/Tegretol1

Dextromethorphan Polistirex/
Delsym1 Over-the-counter

Marketed Formulation/Storage

Valproic acid/Depakene1

Drug Name/Marketed Name

Table 2.

Dose

Inactive in Formulation
(as Listed in Package
Insert or PDR)1

>10 years: 1060 mg/kg/day Dyes


Flavors
Glycerin
Methylparaben
Propylparaben
Sorbitol
Sucrose
Water
Sodium benzoate 0.2%
10 mg/mL
6 weeks12 years:
Citric acid
160 mg/m2 t.i.d. not
Flavors
to exceed 200 mg every
Glycerin
8 h, neonate: 2 mg/kg
Liquid sucrose
every 6 h
40 mg/mL
<40 kg: 20 mg/kg q.i.d.
Methylparaben
>40 kg: 800 mg
Propylparaben
(20 mL) q.i.d.
Carboxymethylcellulose sodium
Banana flavor
Glycerin
Microcrystalline cellulose
Sorbitol
Water
(1) Citric acid
20 mg/mL
<6 years: 1020 up to
Dyes
35 mg/kg/day, q.i.d.
Flavors
612 years: 50 mg
Potassium sorbate
(2.5 mL) q.i.d. up to
Propylene glycol
1000 mg daily
Sorbitol
Sucrose
Xanthan gum
Water
6 mg/mL
1223 months: 1.25 mL
Citric acid
(equivalents of
25 years: 2.5 mL
Dye
hydrobromide
612 years: 5 mL
EDTA
salt)
>12 years: 10 mL
Ethanol (0.26%)
Ethylcellulose
Flavors
High-fructose corn syrup
Methylparaben
Polyethylene glycol 3350
Polysorbate 80
Propylene glycol
Propylparaben
Sucrose
Tragacanth
Vegetable oil
Water
Xanthan gum

50 mg/mL

Active in
Formulation

Shake well before


using

Shake well before


using or
dispensing

Shake well before


using

None

None

Preparation

Celltech/cough
antitussive

Novartis/Antiseizure and
specific analgesic for
trigeminal neuralgia

GlaxoSmithKline/
antiviral (Herpes)

GlaxoSmithKline/HIV

Abbott/antiepileptic

Company/Indication

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Chewable tablet/room temperature

Amoxicillin/Amoxil1

Suspension//room temperature

Phenylephrine Tannate,
Pyrilamine Tannate,
Dextromethorphan Tannate/
Viravan1-DM

Suspension/room temperature

Suspension/15 308C

Nevirapine/Viramune1

Thiabendazole/Mintezol1

Suspension/use within 7 weeks of


first opening bottle

Oxcarbazepine/Trileptal1
Oral Suspension

200 or 400 mg

100 mg/mL

2.5, 6, 5 mg/mL

10 mg/mL

60 mg/mL
Maintenance:

2540 mg/kg/day up to
875 mg b.i.d., or
2040 mg/kg/day t.i.d.

30 lb: 250 mg b.i.d.

26 years: 2.5 mL
>12 years:
510 mL
612 years: 5 mL

4 mg/kg q.d. for the first


14 days followed by
47 mg/kg b.i.d.
thereafter. Maximum
daily dose 400 mg

Initial: 810 mg/kg b.i.d.


up to 1200 mg per day.
2029 kg:
900 mg/day,
2939 kg:
1200 mg/day,
>39 kg:
1800 mg/day

Ascorbic acid
Dispersible cellulose
Ethanol
Macrogol stearate
Methylparaben
Propylene glycol
Propylparaben
Sodium saccharin
Sorbic acid
Sorbitol
Yellow-plum-lemon aroma
Water
Carbomer 934P Methylparaben
Propylparaben
Sorbitol
Sucrose
Polysorbate 80
Sodium hydroxide
Water
Citric acid
Glycerin
Grape flavor
Magnesium aluminum silicate
Methylparaben
Sucralose
Ammonium glycyrrhizinate
Sodium benzoate
Sodium citrate
Sucrose
Xanthan gum
Water
Acacia
Calcium phosphate
Flavors
Lactose
Magnesium stearate
Mannitol
Methylcellulose
Sodium saccharin
Aspartame
Crospovidone
Magnesium stearate
Mannitol
Cherry-banana-peppermint
flavorings
Red 40 aluminum lake
None

Chew before
swallow

Shake well before


using

Shake well before


using, may be
mixed with
water.

(Continued)

GlaxoSmithKline/
antibiotic

Merck/Anthel-mintic
(expels intestinal
worms)

PediaMed
Pharmaceuticals/
antihistamine, nasal
decongestant,
antitussive

Boehringer Ingelheim/
HIV

Novartis/antiseizure

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Chewable tablets/room temperature

Chewable tablets/room temperature

Chewable tablet/room temperature

Chewable tablet/Room temperature

Lamotrigine/Lamictal1

Methylphenidate HCL/
Methylin1

Montelukast sodium/Singulair1

Chewable tablets, single-scored

Marketed Formulation/Storage

Cetirizine HCl/Zyrtec1

Carbamazepine/Tegretol

Drug Name/Marketed Name

Table 2. (Continued)

4 or 5 mg

2.5, 5, or 10 mg

2, 5, and 25 mg

5 and 10 mg

100 mg

Active in
Formulation
Silicon dioxide
Flavors
Gelatin
Glycerol
Magnesium stearate
Sodium starch glycolate
Starch
Stearic acid
Sucrose
25 years: 2.55 mg per day, Acesulfame potassium
611 years: 510 mg
Artificial grape flavor
per day
Colloidal silicon dioxide
Lactose monohydrate
Magnesium stearate
Mannitol
Microcrystalline cellulose
2, 5, or 25 mg
Blackcurrant flavor
Calcium carbonate
Low-substituted HPC
Magnesium aluminum silicate
Magnesium stearate
Povidone
Sodium saccharin
Sodium starch glycolate
560 mg b.i.d.
Aspartame
Maltose
Microcrystalline cellulose
Guar gum
Grape flavor
Pregelatined starch
Stearic acid
4 mg q.d.
Mannitol
Microcrystalline cellulose
HPC
Croscarmellose sodium
Cherry flavor
Aspartame
Magnesium stearate

<6 years: 1035 mg/kg/day


q.i.d.
612 years:
50 mg q.i.d.
up to 1000 mg
daily

Dose

Inactive in Formulation
(as Listed in Package
Insert or PDR)1

Pfizer/allergic rhinitis

Novartis/antiseizure and
specific analgesic for
trigeminal neuralgia

Company/Indication

None

None

Merck/asthma and
perennial allergic
rhinitis

Alliant Pharmaceuticals/
attention-deficit
hyperactivity disorder

SKB/antiseizure
Swallow whole,
chew, or mix with
water or diluted
fruit juice

None

None

Preparation

DOI 10.1002/jps

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

Orally disintegrating tablet


RediTabs1/room temperature

Desloratadine/Clarinex1

Delayed release orally disintegrating


tablet (SolutabTM)/room
temperature

Chewable tablet, single-scored/room


temperature

Thiabendazole/Mintezol1

Lansoprazole/PREVACID1/

Chewable tablet-scored/room
temperature

Phenylephrine Tannate,
Pyrilamine Tannate,
Dextromethorphan Tannate/
Viravan1-DM

15 or 30 mg

2.5 and 5 mg

500 mg

25, 30, 25 mg

<30 kg: 15 mg t.i.d.


>30 kg:
30 mg t.i.d.

611 years: 2.5 mg q.d.


>12 years:
5 mg q.d.

30 lb: 250 mg b.i.d.

26 years: tablet
612 years:
1 tablets
>12 years:
12 tablets

Citric acid
Calcium phosphate dibasic
Hypromellose
Grape flavor
Magnesium aluminum silicate
Magnesium stearate
Compressible sugar
Corn starch
Mannitol
Sucralose
Talc
Xanthan gum
Acacia
Calcium phosphate
Flavors
Lactose
Magnesium stearate
Mannitol
Methylcellulose
Sodium saccharin
Mannitol
Microcrystalline cellulose
Pregelatinized starch
Sodium starch glycolate
Magnesium stearate
Butylated methacrylate copolymer
Crospovidone
Aspartame
Citric acid
Sodium bicarbonate
Colloidal silicon dioxide
Ferric oxide
Tutti-frutti flavor
Lactose monohydrate
Microcrystalline cellulose
Magnesium carbonate
HPC
HPMC
Titanium dioxide
Talc
Mannitol
Methacrylic acid
Polyacrylate
PEG
Glyceryl monostearate
Polysorbate 80
Triethyl citrate
Ferric oxide
Citric acid
Crospovidone
Aspartame
Artificial strawberry flavor
Magnesium stearate

PediaMed
Pharmaceuticals/
antihistamine,
nasal decongestant,
antitussive

Place on tongue
and allow to
disintegrate
before
swallowing

Place on tongue
and allow to
disintegrate
before
swallowing

(Continued)

TAP/GERD or Erosive
esophagitis

Schering/antihistamine

Chew before swallow Merck/anthel-mintic


(expels intestinal
worms)

None

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

DOI 10.1002/jps

Lisdexamfetamine dimesylate/
VyvanseTM

Capsulehard gelatin/room
temperature
Capsule/room temperature

Atomoxetine HCl/Strattera1

10, 18, 25, 40,


and 60 mg
30, 50, 70 mg

(1) Orally disintegrating tablets


(1) 4 or 8 mg
(free base)
(2) 4, 8, or 24 mg
(2) Tablet (HCl salt)/room temperature

Ondansetron free base or HCl


salt/Zofran1

10 mg

Orally disintegrating tablet/room


temperature

Marketed Formulation/Storage

Active in
Formulation

Loratadine/
(1) Claritin1
(2) Triaminic1 Allerchews1
(3) Alavert1
Over-the-counter

Drug Name/Marketed Name

Table 2. (Continued)

0.51.2 mg/kg up to
100 mg q.d.
2070 mg/day q.d. in
the morning

411 years: 4 mg t.i.d.

>6 years: 10 mg q.d.

Dose

Preparation

(1) Citric acid


Place on tongue
Gelatin
and allow to
Mannitol
disintegrate
Mint flavor
before
1
(RediTabs )
swallowing
(2) Croscarmellose sodium
Crospovidone
Hypromellose
Magnesium stearate
Mannitol
Microcrystalline cellulose
(3) Flavor
Aspartame
Citric acid
Colloidal silicon dioxide
Corn syrup solids
Crospovidone
Magnesium stearate
Mannitol
Microcrystalline cellulose modified food starch
Sodium bicarbonate
(1) Place on tongue
(1) Aspartame
and allow to
Gelatin
disintegrate
Mannitol
before
Methylparaben sodium
swallowing
Propylparaben sodium
Strawberry flavor
(2) None
(2) Lactose
Microcrystalline cellulose
Pregelatinized starch
HPMC
Magnesium stearate
Pregelatinized starch
None
Dimethicone
Microcrystalline cellulose
None
Croscarmellose sodium
Magnesium stearate

Inactive in Formulation
(as Listed in Package
Insert or PDR)1

Lilly/attention-deficient
hyperactivity disorder
BristolMyers Squibb/
attention-deficient
hyperactivity disorder

GlaxoSmithKline/
antiemetic

(1) ScheringPlough
(2) Novartis consumer
(3) Wyeth/antihistamine

Company/Indication

DOI 10.1002/jps

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

2 mg

35 years: 2.5 mg/day,


5 mg (scored),
>6 years: 5 mg/day
10 mg (doublescored)

Tablet-scored/Room temperature

Tablet-scored and double scored/


Room temperature

Tablet/room temperature

Tablet/room temperature

Tablet/room temperature

Tablet/room temperature

Dextroamphetamine Sulfate/
Dextrostat1

Fexofenadine HCl/Allegra1

Irbesartan/Avapro1

Ivermectin/Stromectol1

Zafirlukast/Accolate1

10 mg b.i.d.

>15 kg: 200 mg/kg one


time dose

612 years: 75150 mg q.d.


1316 years:
150300 mg
q.d.

30 mg b.i.d.

q.d., once a day; b.i.d., twice a day; t.i.d., three times a day; q.i.d., four times a day.

10, 20 mg

3, 6 (scored) mg

75, 150 mg

30 mg

60 mg/kg q.d.

13 tablets q.d

Busulfan/Myleran1

Fixed-dose
combination
62.5 and 25 mg

Pediatric tablet/Room temperature

617 years: 2.55 mg


(amlodipine) q.d.

Atovaquone and Proguanil


HCl/Malarone1

Fixed-dose
combination
2.5/10, 2.5/20,
2.5/40, 5/10,
5/20, 5/40,
5/80 mg/mg

Tablet/room temperature

Amlodipine besylate and


Atorvastatin
calcium/Caduet1

Pfizer/hypertension,
angina

AstraZeneca/asthma

Merck/antiparasitic

BMS/antihypertension

Sanofi-Aventis/
antihistamine

Shire US/Narcolepsy

None or tablets may GlaxoSmithKline/


be crushed and
prevention and
mixed with
treatment of malaria
condensed
milk prior to
administration
None or break
GlaxoSmithKline/
tablets
treatment of leukemia

None

Lactose (anhydrous)
Magnesium stearate
Pregelatinized starch
None or break
Acacia
tablets
Corn starch
Lactose
Magnesium stearate
Sucrose
the 10 mg tablets contains Sodium
starch glycolate
Croscarmellose sodium
None
Magnesium stearate
Microcrystalline cellulose
Pregelatinized starch
Lactose
None
Microcrystalline cellulose
Pregelatinized starch
Croscarmellose sodium
Poloxamer 188
Silicon dioxide
Magnesium stearate
Microcrystalline cellulose
None or break the
Pregelatinized starch
6-mg tablet
Magnesium stearate
BHA
Citric acid
Croscarmellose sodium
None
Lactose
Magnesium stearate
Microcrystalline cellulose
Povidone
HPMC
Titanium dioxide

Calcium carbonate
Croscarmellose sodium
Microcrystalline cellulose
Pregelatinized starch
Polysorbate 80
HPC
Water
Colloidal silicon dioxide
Magnesium stearate
Hydroxypropyl cellulose
Magnesium stearate
Microcrystalline cellulose
Poloxamer 188
Povidone K30
Sodium starch glycolate
HPMC

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

DOI 10.1002/jps

Powder for constitution to a solution/ 1 mg/mL


powder at RT, Solution at 288C for
30 days

(1) Buffered powder for Oral Solution 100, 167, or


in single-dose packets/powder
250 mg
at RT, solution up to 4 h
(2) Pediatric Powder for Oral Solution 2 or 4 g
in 4- or 8-ounce bottles/powder
at RT, solution at 288C for 30 days

Stavudine/Zerit1

Didanosine/Videx1

50 mg/mL in
reconstituted
suspension

Drops for reconstitution to a


suspension/refrigeration
preferable, but not required.

Amoxicillin/Amoxil Pediatric
Drops for Oral Suspension

25 and 150 mg

20 mg/mL

Active in
Formulation

Effervescent tablet (EFFERdose1)/


4258C

Oral Concentrate (solution)/room


temperature

Marketed Formulation/Storage

Ranitidine HCl/Zantac1

Sertraline HCl/Zoloft

Drug Name/Marketed Name

<30 kg: 1 mg/kg b.i.d.


>60 kg: 40 mg
b.i.d.

2540 mg/kg/day up to
875 mg b.i.d., or
2040 mg/kg/day up
to 500 mg t.i.d.

210 mg/kg up to
150 mg b.i.d.

612 years: 25 mg q.d.


1317 years:
50 mg q.d.

Dose

Sodium citrate

FD & C Red No. 3


Bubble-gum flavorings
Silica gel
Sodium benzoate
Sodium citrate
Sucrose
Xanthan gum
Methylparaben
Propylparaben
Sodium carboxymethylcellulose
Sucrose
Antifoaming and flavoring agents
(1) Sodium phosphate dibasic

Aspartame
Monosodium citrate
Povidone
Sodium bicarbonate
Sodium benzoate

Glycerin
Alcohol (12%)
Menthol
BHT

Inactive in Formulation (as Listed


in Package Insert or PDR)

Table 3. Selected Listing of Commercially Available Pediatric Oral FormulationsManipulation Required


Company/Indication

BristolMyers Squibb/
HIV

(1) Add packet


BristolMyers Squibb/
contents to
HIV
4 ounces of water
Unstable at pH <3, do
(2) Add water to
not use fruit juice or
make 20 mg/mL,
acid-containing liquid
then further
dilute to
10 mg/mL with
an antacid
(Mylanta1,
Maalox1)

Constitute with
202 mL water

Pfizer/obsessiveUsing the supplied


compulsive disorder
dropper mix with
4 ounces (1/2 cup)
water, ginger ale,
lemon/lime soda,
lemonade or
orange juice
Dissolve one 25-mg GlaxoSmithKline/
tablet in at least
treatment of ulcers,
5 mL water, or
and GERD
one 150-mg
tablet in
68 ounces of
water, then
administer by
dropper, oral
syringe or drink
Reconstitute with
GlaxoSmithKline/
23 mL of water
antibiotic
to 50 mg/mL

Manipulation

DOI 10.1002/jps

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

Powder for constitution to a


suspension/powder at room
temperature, suspension
refrigerated for 10 days

Powder for constitution to a


suspension/refrigeration
preferable, but not required.

Powder for constitution to a


suspension/powder below
308C, suspension 58308C

Powder for constitution to a


suspension/powder at room
temperature, suspension
refrigerated

Powder for constitution to a


suspension/powder at room
temperature, suspension
refrigerated

Amoxicillin and Clavulanate


potassium/Augmentin1
(fixed-dose combination)

Amoxicillin/Amoxil1 for Oral


Suspension

Azithromycin/Zithromax1

Cefaclor/Ceclor1

Cefadroxil/Duricef1

(3) Chewable dispersible buffered


tablets/tablet at RT, solution up
to 1 h

120 mg/m2 b.i.d.

2540 mg/kg/day up to
875 mg b.i.d. or
2040 mg/kg/day up
to 500 mg t.i.d.
30 mg/kg single dose or
10 mg/kg q.d. for 3 days

Citric acid
Sucrose
(2) No mention
(3) Aspartame
Calcium carbonate
Microcrystalline cellulose
Magnesium hydroxide
Magnesium stearate
Crospovidone
Sorbitol
Mandarin-Orange flavor
Colloidal silicon dioxide
Flavorings
Succinic acid
Xanthan Gum
And one or more of:
Aspartame
HPMC
Mannitol
Silica gel
Silicon dioxide
Sodium saccharin
Not reported

Sucrose
Sodium phosphate tribasic
Hydroxypropyl cellulose
Xanthan gum
FD&C Red #40
Artificial cherry, cre`me de vanilla
and banana flavors
Suspension: 25,
20 mg/kg/day up to
Cellulose
37.4, 50, or
250 mg t.i.d.
Cornstarch
75 mg/mL
FD&C Red No. 40
Flavors
Silicone
Sodium lauryl sulfate
Sucrose
Xanthan gum
Suspension: 25,
15 mg/kg b.i.d., 30 mg/kg q.d. Polysorbate 80
50, 100 mg/mL
Sodium benzoate
Sucrose
Xanthan gum
Flavors
Yellow color

Suspension:
2040 mg/mL

Suspension: 125,
200, 250,
or 400 mg/mL

Powder:
2540 mg/kg/day up to
amoxicillin
875 mg b.i.d. or
1446%,
2040 mg/kg/day up
clavulanate
to 500 mg t.i.d.
3.87%,
(amoxicillin equivalent)
suspension:
amoxicillin
2580 mg/mL,
clavulanate
7.012 mg/mL

25, 50, 100, 150,


and 200 mg

Constitute with
water

Constitute with
water

Constitute with
water

Constitute with
water

Constitute with
water

(3) Two tablets in


1 ounce of water,
stir until uniform
dispersion,
consume as-is or
dilute with apple
juice (for flavor)

(Continued)

BristolMyers Squibb/
Antibiotic

Eli Lilly/antibiotic

Pfizer/antibiotic

GlaxoSmithKline/
antibiotic

GlaxoSmithKline
Beecham/antibiotic

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

DOI 10.1002/jps

Powder for constitution to a


suspension/room temperature

Powder for constitution to a


suspension/room temperature

Powder for constitution to a


suspension/powder at room
temperature, suspension 288C
(suspension  10 days)

Powder for constitution to a


suspension/powder 2258C,
suspension 288C (stable for
14 days)

Powder (coated microspheres) for


constitution to a suspension/
Powder at room temperature,
suspension 288C (suspension
10 days)

Cefixime/Suprax1

Cefprozil/Cefzil1

Ceftibuten/CeDax1

Cefuroxime axetil/Ceftin1

Marketed Formulation/Storage

Cefdinir/Omnicef1

Drug Name/Marketed Name

Table 3. (Continued )

10 kg 90 mg
20 kg 180 mg
40 kg 360 mg
>45 kg 400 mg
q.d.

7.515 mg/kg b.i.d. up to


500 mg/day

8 mg/kg/day (2.515 mL)

14 mg/kg/day (2.524 mL)

Dose

Suspension: 25 or 2030 mg/kg/day up to


50 mg/mL
a maximum of 500
1000 mg, divided b.i.d.

Suspension:
18 mg/mL

Suspension:
2550 mg/mL

Suspension:
20 mg/mL

Suspension:
25 mg/mL

Active in
Formulation

Constitute with
water

Constitute with
water

Constitute with
water

Constitute with
water

Manipulation

Sodium benzoate
Sucrose (200 mg/mL)
Titanium dioxide
Xanthan gum
Constitute with
Acesulfame potassium
water, must be
Aspartame
administered
Povidone K30
with food
Stearic acid
Sucrose
Tutti-frutti flavor
Xanthan gum
(SACA technologystearic
acid coatedfor taste-masking)

Sucrose
Citric acid
Sodium citrate
Sodium benzoate
Xanthan gum
Guar gum
Artificial strawberry and cream
flavor
Silicon dioxide
Magnesium stearate
Sucrose
Sodium benzoate
Xanthan gum
Strawberry and cream flavor
Silicon dioxide
Aspartame
Cellulose
Citric acid
Colloidal silicon dioxide
FD&C No. 3
Flavors (natural and artificial)
Glycine
Polysorbate 80
Simethicone
Sodium benzoate
Sodium CMC
Sodium chloride
Sucrose
Cherry flavor
Polysorbate 80
Silicon dioxide
Simethicone

Inactive in Formulation (as Listed


in Package Insert or PDR)

GlaxoSmithKline/
antibacterial

Biovail/antibiotic

BristolMyers Squibb/
antibiotic

Lupin/antibacterial

Abbott/antibiotic

Company/Indication

DOI 10.1002/jps

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

Powder for constitution to a


suspension/room temperature
(suspension for 30 days)

Famotidine/Pepcid1

Powder/granule for constitution to


a suspension/room temperature
(suspension for 21 days)

Powder (granules) for constitution to


a suspension/room temperature
(suspension for 14 days)

Clarithro-mycin/Biaxin1

Linezolid/Zyvox1

Microcapsules for constitution to


a suspension
Bottle (1) Solid microcapsules
(Bottle (2) Liquid diluent/Store below
308C but not frozen

Ciprofloxacin/Cipro1

Suspension:
20 mg/mL

Suspension:
8 mg/mL

Suspension: 25
or 50 mg/mL

Solid: 5% or 10%,
suspension:
50 or
100 mg/mL

15 mg/kg b.i.d., not to exceed Bottle (1) solid:


the adult dose of 500-mg Polyvinylpyrrolidone
Methacrylic acid copolymer
per dose
HPMC
Magnesium stearate
Polysorbate 20
Bottle (2) diluent:
Medium-chain triglycerides
Sucrose
Lecithin
Water
Strawberry flavor
7.5 mg/kg b.i.d. for 10 days
Carbomer
Castor oil
Citric acid
Hypromellose phthalate
Maltodextrin
Potassium sorbate
Povidone
Silicon dioxide
Sucrose
Xanthan gum
Titanium dioxide
Fruit punch flavor
<3 months: 0.5 mg/kg q.d.
Citric acid
3 months to
Flavors
1 year:
Microcrystalline cellulose
0.5 mg/kg b.i.d.
Carboxymethylcellulose sodium
116 years:
Sucrose
Xanthan gum
0.5 mg/kg/day
b.i.d. up to
Sodium benzoate 0.1%
40 mg/day
Sodium methylparaben 0.1%
Sodium propylparaben 0.02%
neonates (<7 days): 10 mg/kg Sucrose
b.i.d., <11 years:
Citric acid
10 mg/kg t.i.d.
Sodium citrate
Microcrystalline cellulose
Carboxymethylcellulose sodium
Aspartame
Xanthan gum
Mannitol
Sodium benzoate
Colloidal Silicon dioxide
Sodium chloride
Flavors
Merck/treatment of
ulcers

Abbott/antibiotic

(Continued)

Constitute with
Pharmacia & Upjohn/
123 mL of water
antibacterial
in two equal
portions, after
adding the first
60 mL shake
vigorously to wet
the powder, then
add the second
portion of water
and vigorously
shake to a
suspension

Constitute with
46 mL of water

Constitute with
27 mL or 55 mL
of water

Schering/antibiotic
Pour the solid
microcapsules
into the diluent,
shake for 15 s
Provided teaspoon
(5 mL) for dosing

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

DOI 10.1002/jps

Suspension:
1020 mg/mL

Vantin/Cefpodoxime Proxetil for


Oral Suspension

Granules for constitution to a


suspension/Granules at room
temperature, suspension 588C
for 14 days

Suspension:
12 mg/mL

Oseltamivir phosphate/Tamiflu1 Powder for constitution to a


suspension/room temperature

Powder for constitution to a


Suspension:
suspension/powder and suspension
20 mg/mL
15308C
Take suspension
with food

Nitazoxanide/Alinia1

Suspension:
200 mg/mL

Active in
Formulation

Powder for constitution to a


suspension/room temperature
(suspension for 60 days)

Marketed Formulation/Storage

Mycophenolate mofetil/
CellCept1

Drug Name/Marketed Name

Table 3. (Continued )

5200 mg/kg b.i.d

3075 mg b.i.d.

14 years: 100 mg b.i.d. for


3 days, 411 years:
200 mg b.i.d. for 3 days

600 mg/m b.i.d.

Dose
Aspartame
Citric acid
Colloidal silicon dioxide
Methylparaben
Mixed fruit flavor
Sodium citrate
Sorbitol
Soybean lecithin
Xanthan gum
Sodium benzoate
Sucrose
Xanthan gum
Microcrystalline cellulose
Carboxymethylcellulose sodium
Citric acid
Sodium citrate
Acacia gum
Sugar Syrup
FD&C Red #40
Natural strawberry flavor
Xanthan Gum
Monosodium citrate
Sodium benzoate
Sorbitol
Saccharin sodium
Titanium dioxide
Tutti-frutti flavoring
Lemon creme flavor
BHA
Sodium CMC
Microcrystalline cellulose
Carrageenan
Citric acid
Silicon dioxide
Croscarmellose sodium
Hydroxypropylcellulose
Lactose
Maltodextrin
Propylene glycol alginate
Sodium citrate
Sodium benzoate
Starch
Sucrose
Vegetable oil

Inactive in Formulation (as Listed


in Package Insert or PDR)

Roche/Antiviral for
influenza
(neuraminidase
inhibitor)

Romark/antiparasitic
(treatment of
diarrhea)

Roche/transplant
rejection

Company/Indication

Pharmacia & Upjohn/


Constitute with
Antibiotic
water: 29 mL in
50 mL bottle,
44 mL in 75 mL
bottle, 58 mL in
100 mL bottle,
Store constituted
suspension in the
refrigerator

Constitute with
52 mL water in
100 mL amber
glass bottle
to give 67 mL
suspension

Constitute with
water

Constitute with
94 mL water in
225 mL plastic
bottle to give
175 mL
suspension

Manipulation

DOI 10.1002/jps

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

50 mg/g powder
(1 scoopful
is 1 g)

5, 10, 20 mg

Oral Powder/room temperature

Sprinkle Powder in a
Capsule/room temperature

Extended release capsules/Room


temperature

Capsule/room temperature

Nelfinavir mesylate/Viracept1
Oral Powder

Dexmethyl-phenidate
HCl/FocalinTM XR

Methyl-phenidate
HCl/Ritalin LA1

Methyl-phenidate HCl/
Metadate1 CD 20 mg

5 mg/day up to 20 mg/day

4555 mg/kg b.i.d.,


or 2535 mg/kg t.i.d.

4 mg q.d.

100400 mg b.i.d.

10, 20, or 30 mg

2060 mg/day

10, 20, 30 or 40 mg >6 years: 1040 mg q.d.

0.8% w/w

Oral Granules/room temperature

Montelukast sodium/Singulair1
Oral Granules

Suspension:
40 mg/mL

Powder for constitution to a


suspension/Powder 288C for
18 months, suspension 5308C
for 14 days

Voriconazole/Vfend1

Sugar spheres
Povidone
HPMC
PEG
Ethylcellulose aqueous dispersion
Dibutyl sebacate
Titanium dioxide
FD&C Blue No. 2

Ammonium methacrylate
copolymer
Methacrylic acid copolymer
Sugar spheres
Triethyl citrate

Microcrystalline cellulose
Maltodextrin
Potassium phosphate dibasic
Crospovidone
Hydroxypropyl
Methylcellulose
Aspartame
Sucrose palmitate
Natural and artificial flavor
Ammonium methacrylate
copolymer
Methacrylic acid copolymer
PEG
Sugar spheres

Colloidal silicon dioxide


Titanium dioxide
Xanthan gum
Sodium citrate
Sodium benzoate
Citric acid
Natural orange flavor
Sucrose
Mannitol
HPC
Magnesium stearate
Directly in the
mouth, dissolved
in 5 mL baby
formula or breast
milk, mixed with
spoonful of
soft foods:
applesauce,
carrots, rice,
or ice cream
Solid powder is
mixed with
water, milk,
formula, soy
formula, soy milk
or dietary
supplement, and
then consumed
within 6 h
Open capsule and
sprinkle the
beads over a
spoonful of
applesauce,
consume
immediately
Open capsule and
sprinkle the
beads over
a spoonful of
applesauce,
consume
immediately
Open capsule and
sprinkle the solid
powder on food or
applesauce

(Continued)

UCB/attention-deficit
hyperactivity disorder

Novartis/attention-deficit
hyperactivity disorder

Novartis/Attention-deficit
hyperactivity disorder

Pfizer/HIV

Merck/asthma and
perennial allergic
rhinitis

Constitute with
Pfizer/antifungal
46 mL of water to
make 75 mL
(45 g of powder
in the bottle)

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

DOI 10.1002/jps

Sprinkle Capsules/room temperature

(1) Delayed release capsules

Topiramate/Topamax1

Lansoprazole/PREVACID1

(2) Delayed release for Oral


Suspension/Room temperature

Capsules/room temperature

Marketed Formulation/Storage

Succimer/Chemet1

Drug Name/Marketed Name

Table 3. (Continued )

15 or 30 mg

15 and 30 mg

100 mg

Active in
Formulation

>30 kg: 30 mg
t.i.d.

<30 kg: 15 mg t.i.d.

59 mg/kg/day starting
with 25 mg b.i.d.

10 mg/kg or 350 mg/m2


(15 capsules), t.i.d for
5 days, and b.i.d for
14 days

Dose

Manipulation

Company/Indication

Ovation/lead poisoning,
Open capsule and
heavy metal chelating
sprinkle the
agent
beads on a small
amount of soft
food, or swallow
the beads as-is
then follow with
fruit drink
Sugar spheres (sucrose and starch) Swallowed whole or Ortho-McNeil/
anticonvulsant,
carefully open
Povidone
epilepsy, migraine
capsule then
Cellulose acetate
headaches (adults)
sprinkle the
Gelatin
entire contents
Silicon dioxide
on a small
Sodium lauryl sulfate
amount of soft
food
(1) Open capsule and TAP/GERD or Erosive
sprinkle the
esophagitis
granules onto
applesauce,
ENSURE1
pudding, cottage
cheese, yogurt
or strained pears,
or juices (apple,
orange, or
tomato), swallow
immediately
(2) Open packet and
(1) Enteric-coated granules:
empty contents
HPC
into a container
Silicon dioxide
containing
Magnesium carbonate
2 tablespoons
Methacrylic acid copolymer
of water. Stir
Starch
well, drink
Talc
immediately.
Sugar
PEG
Polysorbate 80
Titanium Dioxide
Povidone
Sodium starch glycolate
Starch
Sucrose

Inactive in Formulation (as Listed


in Package Insert or PDR)

DOI 10.1002/jps

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

5, 10, 20, and


40 mg

Tablet to be constituted to a
suspension/tablets: room
temperature, constituted
suspension at 288C for up to
30 days

Tablet for Oral Suspension/room


temperature

Tablet to be constituted to a
suspension/Room temperature

Benazepril HCl/Lotensin1

Deferasirox/Exjade1

Imatinib mesylate Gleevec1

100, 400 mg

125, 250, and


500 mg

125 mg per
capsule

Valproic acid (sodium salt)/


Coated particles in hard gelatin
Depakote1 Sprinkle Capsules
capsules/room temperature
(Depakine1 Chronosphere1
in Europe)

Colloidal silicon dioxide


Crospovidone
HPMC
Magnesium stearate
Microcrystalline cellulose
Propylene glycol
Talc

>3 years: 260 mg/m2/day


up to 400 mg/day

20 mg/kg

Colloidal silicon dioxide


Crospovidone
Hydrogenated castor oil
HPMC
Lactose
Magnesium stearate
Microcrystalline cellulose
Polysorbate 80
Propylene glycol
Starch
Talc
Titanium dioxide
Lactose monohydrate
Crospovidone
Povidone
Sodium lauryl sulfate
Microcrystalline cellulose
Silicon dioxide
Magnesium stearate

0.10.6 mg/kg q.d. up


to 40 mg daily

(2) Enteric-coated granules:


Confectioners sugar
Mannitol
Docusate sodium
Ferric oxide
Silicon dioxide
Xanthan gum
Crospovidone
Citric acid
Sodium citrate
Magnesium stearate
Artificial Strawberry flavor
>10 years: 1060 mg/kg/day Cellulose polymers
D&C red # 28
FD&C #1
Gelatin
Iron oxide
Magnesium stearate
Silica gel
Titanium oxide
Triethyl citrate

(Continued)

Novartis/iron chelator
Tablets to be
(orphan drug status)
completely
dispersed in
water, orange
juice, or apple
juice to a fine
suspension, then
swallow
immediately
Place tablet in water Novartis/antineoplastic
or apple juice to
make 2 mg/mL,
stir with a spoon
to disperse,
consume
immediately

Open capsule and


Abbott (Sanofi-Aventis in
sprinkle the
Europe)/Antiseizure
entire contents
onto a small
amount of soft
food such as
applesauce or
pudding, swallow
the entire
contents without
chewing
Novartis/
Fifteen 20-mg
antihypertensive
tablets
constituted to a
2 mg/mL
suspension using
75 mL of
Ora-Plus1 and
75 mL of
Ora-Sweet1

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

DOI 10.1002/jps

Scored tablet to be crushed to


a suspension/Room temperature

Mefloquine HCl/Lariam1

>6 years: 0.07 mg/kg up


to 5 mg q.d.

Dose

250 mg

>3 months:
2025 mg/kg

25, 50, and 100 mg >6 years: 0.7 mg/kg up to


50 mg q.d.

5, 10, 20, and


40 mg

Active in
Formulation

q.d., once a day; b.i.d., twice a day; t.i.d., three times a day; q.i.d., four times a day.

Tablet to be constituted to a
suspension/tablets: room
temperature, constituted
suspension at 288C for up
to 4 weeks

Tablet to be constituted to a
suspension/tablets: room
temperature, constituted
suspension at 258C for up
to 4 weeks

Marketed Formulation/Storage

Losartan Potassium/Cozaar1

Lisinopril/Prinivil

Drug Name/Marketed Name

Table 3. (Continued )

Ammonium-calcium alginate
Corn starch
Crospovidone
Lactose
Magnesium stearate
Microcrystalline cellulose
Poloxamer 331
Talc

Microcrystalline cellulose
Lactose
Pregelatinized starch
Magnesium stearate
HPC
HPMC
Titanium dioxide

Calcium phosphate
Mannitol
Magnesium stearate
Starch

Inactive in Formulation (as Listed


in Package Insert or PDR)

Company/Indication

Ten 20-mg tablets


Merck/antihypertensive
constituted to a
1.0 mg/mL
suspension using
10 mL of water,
30 mL of Bicitra1
diluent, 160 mL
Ora-Sweet SF TM
Merck/antihypertensive
Ten 50-mg tablets
constituted to a
2.5 mg/mL
suspension using
10 mL of water
and 190 mL of a
1:1 mixture of
Ora-Plus1 and
Ora-Sweet SF1
Tablets may be
Roche/treatment or
crushed or
prophylaxis of
suspended in a
malaria
small amount of
water, milk, or
other beverage

Manipulation

PEDIATRIC ORAL FORMULATIONS

1753

Figure 1. Bar chart showing the occurrences, as identified in this review, of the 16
different types of prescription pediatric oral formulations, note that thin strips are
available only over-the-counter.

requirement of a measurable dosage form, taste


issues, and formulation preferences for different
age groups. Limited enrollment in clinical trials is
a serious issue that results in often not being able
to demonstrate efficacy and safety in all pediatric
groups and subpopulations. Pharmacokinetic
data in pediatrics may be used to extrapolate
efficacy and safety from data obtained in adults
and pediatrics of different age. However, extrapolating data from clinical trials in adults to the
pediatric population, and also assuming that a
preterm neonate handles drugs the same way as a
12-year-old child can lead to dangerous errors.3 In
the United Kingdom (UK) the Medicines for
Children initiative provided funding to set up
clinical trials infrastructure for proper pediatric
clinical trials.4 The UK also published in 2005
the first edition of a Paediatric British National
Formulary.5 The European Medicine Agency
in 2006 published two excellent documents
entitled Guideline on the Role of Pharmacokinetics in the Development of Medicinal Products
in the Paediatric Population (http://www.emea.
europa.eu/pdfs/human/ich/271199en.pdf; accessed
May 21, 2007), and Reflection Paper: Formulations of Choice for the Paediatric Population
(http://www.emea.europa.eu/pdfs/human/peg/
DOI 10.1002/jps

19481005en.pdf; accessed May 21, 2007). Below is


a summary of the key issues for consideration for
the development of a pediatric oral formulation,
based on this Reflection Paper.
Pediatrics are normally classified into categories according to age:
Preterm newborn infants.
Term newborn infants, neonates (027 days).
Infants and toddlers (28 days23 months).
Children (211 years).
Adolescents (1216 years).
Developmental Pharmacology
In the very young child organ function matures
rapidly effecting absorption, distribution, and
elimination. The most challenging age group is
<23 months, and the least predictable age group
is children 24 years, while adolescents are
similar to adults. Gastric pH is relatively high in
the neonatal period, gastric emptying increases,
gut motility matures during early infancy and
there are changes to splanchnic blood flow,
intestinal drug-metabolizing enzymes, microbial
flora and transporters. There are few published
bioavailability studies but in general, the rate of
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

1754

STRICKLEY ET AL.

absorption is slower in neonates and infants than


older pediatric patients. Distribution is effected
by a proportionally higher body water and lower
body fat in the first weeks, which reach normal
levels at approximately 1 year of age. The cytochrome (CYP) enzymes responsible for metabolism are immature at birth reaching maximum
function at approximately 2 years. In general,
clearance of drug molecules metabolized in the
liver is higher in children than adults, requiring
higher doses per body-mass.

Administration
The preferred means of administration is age
dependent with suppositories preferred for neonates; solution or syrups for infants; solutions,
syrups, suspensions, or effervescent dosage forms
for the 25 year age group; orally disintegrating
tablets, chewable tablets, or thin strips for ages
611 years; tablets, capsules, powders, orally
disintegrating tablets, chewable tablet, or thin
strips for adolescents. A major consideration with
any oral liquid formulation is the dosing volume,
which is recommended to be 5 mL for children
under the age of 5 years and 10 mL for children
over 5 years old. However, this can be increased
by having a more palatable formulation. To
simplify calculating the dose to be administered
the World Health Organization6 recommends to
dose on a mg/kg basis, because the calculation for
body surface area (BSA in m2) is rather complex
and involves both weight (W in kilograms) and
height (H in centimeters) as shown in Eq. (1). One
caution is to not overdose overweight children.
Another major consideration is at what age a child
can safely swallow a solid oral dosage such as a
tablet or capsule, which is generally considered
to be approximately 6 years. Another practical
concern is the convenience of the parent or care
giver, and not to burden the school with administering medicine to students.
BSAm2 Wkg0:425  Hcm0:725  0:007184
1
Taste, Smell, Color, and Texture
It is recommended to avoid unusual flavors and
complex taste mixtures, to increase the chance
that the formulation will be accepted by children.
Consideration of the target population will also
affect the flavor as cultural and social factors can
have strong effects on childrens attitudes and
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

preferences. Market research has demonstrated


that bubble gum and grape flavors are
preferred in the USA whereas citrus and red
berries is the European preference, and liquorice is a Scandinavian preference. The sweetness
of the formulation is also a key factor as children
are able to recognize sweetness from an early age.
Children prefer a higher level of sweetness than
adults thus intense sweeteners such as sodium
saccharin, aspartame or sucralose are sometimes
used. The most commonly used sweetener is
sucrose but it is recommended to be avoided in
preparations intended for long-term therapy and
should be replaced with sugar-free formulations
since sucrose causes dental issues. There are only
a few dyes that can be used in medicinal products
for humans from a regulatory perspective. However, color is an important factor to pediatric
medicines as children prefer brightly colored
preparations but at the same time, the use of
coloring agents should be limited due to their
association with hypersensitivity and other
adverse reactions. Smell is also a consideration
and many pediatric formulations include an
aroma excipient. Pediatric patients also prefer a
smooth texture, thus the viscosity can be modified
to an optimal level in solutions and suspensions,
and grittiness minimized in solid oral dosage
forms.

Dose Delivery Devices


Many pediatric formulations are measurable and
thereby a measuring device is required to aid in
the delivery of the formulation and should be
designed to allow accurate dose measurement
and a simple controlled administration. A custommade dose delivery device can be fabricated or
a commonly used household item can be recommended. Devices for oral pediatric formulations include household spoons, droppers,
measuring cups and spoons, cylindrical measuring scoops, graduated pipettes, and oral syringes.
The packaging configuration of the marketed
pediatric formulation must take into consideration the measuring device and the potential of
copackaging.

FORMULATION DEVELOPMENT
Technical complexities in pediatric formulation
development include dose modification, ease of
DOI 10.1002/jps

PEDIATRIC ORAL FORMULATIONS

administration/swallowing, taste-masking, chemical stability, physical stability, preservation,


considerations of a multi-phase and/or multi-use
product, packaging, providing/designing the
measuring device. Many pediatric formulations
require manipulation such as a solid that is
the manufactured commercial product used for
long-term storage and transportation, which is
constituted or reconstituted to a solution or a
suspension prior to administration (Tab. 3). In the
case of a manipulated formulation the technical
requirements include chemical stability, physical
stability, and antimicrobial preservation in both
the solid (long-term storage) and liquid phases
(in-use by patient). Since many pediatric formulations are packaged in multi-use containers a
preservative(s) may be required, but benzyl
alcohol must not be given to neonates due to their
immature metabolic function.
The first clinical trial of a newly developed
pediatric formulation can be a bioequivalence
study between the adult dosage form and the
new pediatric formulation in healthy adult volunteers. The dose given in the bioequivalence study

1755

is typically fixed at the usual adult dose, and is


usually considered the maximum dose of the
pediatric formulation that would be administered.
Bioequivalence of the pediatric formulation to the
adult formulation, such as a tablet or capsule, is
desirable but not required and is generally defined
as 80125% of the maximum plasma concentration (Cmax) and area-under-the-curve (AUC)
of plasma concentration versus time. The second
clinical trial of a newly developed pediatric
formulation can be an efficacy study in pediatric
patients in which the dose is adjusted based upon
body-mass or surface area.
One of the first issues for the formulation
scientist in developing a pediatric formulation is
which formulation to commercialize for ones
specific drug molecule. Figure 2 is a flow-chart of
the suggested decision-making in the choice of
which type of pediatric formulation to develop
depending on the need to develop a measurable
dosage, taste-masking, solubility, and chemical
stability. The formulation philosophy is from
simple to complex, meaning to minimize the
number of excipients and develop the simplest

Figure 2. Suggested decision-making flow-chart in the choice of a pediatric oral


formulation.
DOI 10.1002/jps

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1756

STRICKLEY ET AL.

possible formulation and manufacturing process.


A logical means to proceed is to begin with
preformulation data on chemical solubility and
stability. Solubility can determine the viability
of pursing a solution formulation, which can be
aqueous-based, mixed aqueous/organic, or entirely organic-based. The required solubility is such
that the upper dose is soluble in a convenient
volume preferably 10 mL, but can be as high as
tens of milliliters. Preformulation chemical stability data will allow for the generation of useful
simulations and the identification of formulations that have predicted or measured acceptable
chemical stability, and the elimination of unstable
formulations. These initial simulations or measurements are typically made with the free base or
free acid of the drug molecule, and thus do not take
into consideration different salt forms. The next
level of complexity would be to consider salts forms
and perturbations such as the common-ion effect
on solubility, or the effects of complexation on
solubility and/or stability.
The taste of measurable dosage forms is critically important to patient acceptability, particularly for children. Many drug substances are
extremely bitter or have other undesirable organoleptic properties that make the development of
palatable formulations a difficult challenge. A
sensory-directed formulation development process has been advanced from decades of experience
in the food industry where taste is paramount and
is being applied to the development of palatable
drug products.7 The process consists of three steps:
(a) taste assessment of the drug substance to
quantify the taste-masking challenge (b) base and
flavor system development to develop a palatable
formulation and (c) testing to verify patient
acceptability. Quantitative taste assessment by
trained evaluators is used throughout the process
to guide formulation development.
Formulation strategies to impart favorable
taste include adding sugars, sweeteners, and/or
flavors. Modifications to the active ingredient include a less soluble salt, polymorph, or prodrug. If
taste-masking is not successful, a tasteless formulation may be considered such as coated particles
surrounded by a water-soluble polymer. Since
taste (other factors being solubility, chemical and
physical stability, viscosity, preservation, along
with manufacturability) is one aspect of the overall
pediatric formulation, taste-masking should be
done within the constraints of the formulation
such as pH, organic solvents, and any other required excipients.89
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

TYPES OF PEDIATRIC FORMULATIONS


Ready-to-Use
Ready-to-use pediatric formulations are those
that do not require manipulation such as solutions, syrups, ready-to-use suspensions, chewable
tablets, or small tablets (Tab. 2). Many pediatric
formulations require manipulation such as a solid
that is constituted to a solution or suspension, a
solution that is constituted to a suspension, or an
oral powder that is sprinkled onto food or liquid
prior to administration (Tab. 3).

Solutions and Syrups


A solubilized formulation is one of the most
common types of pediatric formulations as at
least 24 commercially available solutions or
syrups were identified. Concentrations range
from 1 mg/mL to 500 mg/mL. Dose volumes range
from as low as 0.1 mL to as high as tens of mL,
with the ideal volume 5 mL. Solutions can be
aqueous-based, mixed aqueous/organic, or entirely organic-based. Most commercial oral solutions are stable at room temperature, but some
require refrigeration either during wholesale
storage (i.e., cold chain storage) and/or during
the patient in home usage. Most oral solutions
have flavors and preservatives, and some also
have colors. Thus oral solutions can be simple
formulations containing only one solvent and
one buffer, flavor, or preservative, but can also
be quite complex with multiple solvents, solubilizing excipients, buffers, sweeteners, flavor, preservatives, and dyes.
Aqueous-Based Oral Solutions
A drug molecule in which a measurable dosage
form is required, the taste can be masked, is
water-soluble, and chemically stable can be formulated as an aqueous-based oral solution or
syrup with no organic solvents or with a small
percentage (e.g., <5%) of organic solvent. The
challenges for a solution formulation include
solubility, chemical stability, taste-masking, and
preservation. For ionizable drugs a challenge can
be to identify a solution pH in which the drug is
both sufficiently soluble and chemically stable.
Aqueous-based oral solution formulations require
antimicrobial preservatives, and usually contain
flavors, sweeteners, colors, and dyes. Commercial
examples of aqueous-based oral solution formulaDOI 10.1002/jps

PEDIATRIC ORAL FORMULATIONS

1757

tions include prescription products Emtriva1


(emtricitabine), Ziagen1 (abacavir sulfate), Rebetol1 (Ribavirin/Schering, Kenilworth, NJ), and
Epivir1 (lamivudine).
Emtricitabine (Emtriva1/Gilead Sciences,
Foster City, CA) is a water-soluble nucleoside
analog reverse transcriptase inhibitor used in the
treatment of HIV infection and is available as
Emtriva1 capsules and oral solution, as a fixeddose double combination tablet with tenofovir DF
(Truvada1/Gilead Sciences), and a fixed-dose
triple combination tablet with tenofovir DF and
efavirenz (Atripla1/Gilead Sciences and Bristol
Myers Squibb, Foster City, CA). The adult dose of
emtricitabine is 200 mg once daily, but the relative
oral bioavailability of emtricitabine from the oral
solution is 80% compared to the capsule. The
pediatric dose of emtricitabine is 6 mg/kg up to
240 mg (24 mL) once daily for ages 3 months to
17 years. Emtriva1 oral solution has 10 mg/mL of
emtricitabine dissolved in water, propylene glycol,
EDTA, methylparaben, propylparaben, sodium
phosphate monobasic, xylitol, color, and cottoncandy flavor. Emtriva1 oral solution is to be
stored refrigerated or up to 3 months at room
temperature.
Abacavir sulfate (Ziagen1/GlaxoSmithKline,
Research Triangle Park, NC) is a water-soluble
carbocyclic nucleoside analog reverse transcriptase inhibitor used in the treatment of HIV
infection and is available as Ziagen1 tablets and
oral solution. The adult dose of abacavir sulfate is
either 300 mg twice daily or 600 mg once daily. The
oral bioavailability in adults of abacavir sulfate
from Ziagen1 tablets is 83% and the oral solution
is comparable to the tablets. The pediatric dose of
abacavir sulfate is 8 mg/kg up to 300 mg (15 mL)
twice daily for ages 3 months to 17 years, and at
this dose the pharmacokinetics are similar in
pediatrics (2 months to 13 years of age) and adults.
Ziagen1 oral solution contains abacavir sulfate
equivalent to 20 mg/mL of abacavir dissolved in
water, propylene glycol, citric acid, sodium citrate,
methylparaben, propylparaben, sodium saccharin, sorbitol solution, color and strawberry
and banana flavors.
Lamivudine (Epivir1/GlaxoSmithKline) is also
known as 3TC and is a water-soluble nucleoside
analog reverse transcriptase inhibitor used in the
treatment of HIV and hepatitis B virus (HBV)
infection and is available as Epivir1 and EpivirHBV1 tablets and oral solution. The oral bioavailability lamivudine is 86% in adults and is 66% in
pediatric patients 5 months to 16 years of age. The

systemic clearance of lamivudine decreases with


age from approximately 0.75 to 0.35 L/h  kg by
12 years of age, but is substantially reduced in
1-week-old neonates relative to pediatric patients.
For treatment of HIV the adult dose of lamivudine
is 300 mg daily and in pediatric patients 3 months
to 16 years of age is 4 mg/kg up to 150 mg twice
daily. For treatment of HBV the adult dose of
lamivudine is 100 mg daily and in pediatric
patients 217 years of age is 3 mg/kg up to
100 mg once daily. There was no significant
difference in the pharmacokinetics between Epivir1 tablets and oral solution. Epivir1 and EpivirHBV1 oral solution contains 10 and 5 mg/mL and
of lamivudine, respectively, dissolved in water,
propylene glycol, 200 mg/mL sucrose, methylparaben, propylparaben, citric acid, sodium citrate,
strawberry, and banana flavors.

DOI 10.1002/jps

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

Aqueous Oral Syrups


Water-soluble and chemically stable drugs, in
which the taste cannot be masked in an aqueousbased solution, can often be successfully formulated in an aqueous syrup formulation. A syrup
is a viscous solution usually containing a high
concentration of sugar or sugar substitute with or
without antimicrobial preservatives and flavorants.10 The characteristic body of a syrup is its
high viscosity, which is due the high concentration of sugar or a viscosity-modifying agent. The
high viscosity along with sweeteners and flavors
can mask the poor taste of some medicinal agents
since only a fraction of the drug makes contact
with the taste buds when a viscous syrup is
swallowed. The high concentration of a sugar
renders an oral syrup hypertonic and the lower
concentration of water makes syrups resistant to
microbial growth and thus no preservative is
required if the syrup is used soon after preparation, but in a multi-use product antimicrobial
preservation is required. The challenges for a
syrup formulation are similar to a solution
formulation and include solubility, chemical stability, compatibility with excipients, taste-masking, and the proper viscosity. Syrups are aqueousbased and at least one contains up to 7.5%
ethanol. Concentrations of active ingredient in
syrups range from 0.5 to 15 mg/mL, and dose
volumes range from as low as 0.13 mL/kg in
neonates to as high as 10 mL.
Eight commercially available pediatric formulations as syrups were identified. Commercial examples of aqueous-based oral syrup formulations

1758

STRICKLEY ET AL.

include Retrovir1 (zidovudine), Zyrtec1 (cetirizine), and Clarinex1 (desloratadine). Syrups OraPlus1 and/or Ora Sweet1 are also available as
nonmedicated vehicles that can be used in extemporaneous compounding (see Tablets for Constitution to a Suspension Section).
Zidovudine (Retrovir1/GlaxoSmithKline) also
known as azidothymidine (AZT) is a water-soluble
nucleoside analog reverse transcriptase inhibitor
used in the treatment of HIV infection and is
available as Retrovir1 tablets, capsules, syrup,
and an intravenous solution. Retrovir1 oral syrup
contains 10 mg/mL of zidovudine dissolved in
water; along with sucrose, glycerin, citric acid,
sodium benzoate, and flavors. The adult dose of
zidovudine is 600 mg daily, and the oral bioavailability zidovudine in adults and pediatric patients
greater than 14 days of age is 6164%, but is 89%
in neonates from birth to 14 days of age. The dose of
zidovudine in pediatric patients of 6 weeks to
12 years of age is 160 mg/m2 up to 200 mg every 8 h.
In neonates the dose of zidovudine is 2 mg/kg
(0.2 mL/kg) every 6 h.
Cetirizine (Zyrtec1/Pfizer, New York, NY) is a
water-soluble antihistamine that is a selective
H1-receptor antagonist indicated in the treatment
of allergies and is available as Zyrtec1 tablets,
chewable tablets (see Chewable Tablets Section)
and syrup. Zyrtec1 syrup contains 1 mg/mL of
cetirizine hydrochloride dissolved in water and
buffered with acetate to pH 45, sugar syrup,
propylene glycol, glycerin, methylparaben, propylparaben, and flavors. Zyrtec1 syrup is recommended for children under 2 years of age and the
dose of cetirizine hydrochloride in pediatric
patients 6 months to 2 years is 2.5 mg (2.5 mL)
once or twice a day. The recommended dose of
cetirizine hydrochloride in pediatrics 25 years of
age is up to 5 mg once a day either as 5 mL of
Zyrtec1 Syrup or one 5-mg chewable tablet. In
children greater than 6 years of age and adults the
recommended dose of cetirizine hydrochloride is
510 mg once a day either as 510 mL of Zyrtec1
Syrup or one 5- or 10-mg tablet.
Desloratadine (Clarinex1/Schering) is a longacting and slightly water-soluble tricyclic antihistamine that is a selective H1-receptor antagonist indicated in the treatment of allergies and is
available as Clarinex1 tablets, syrup, and RediTabs1 tablets (see Orally Disintegrating Tablets,
Fastmelt Dissolving Tablets Section). Desloratadine is metabolized to 3-hydroxydesloratadine, an
active metabolite, which is further glucuronidated. Desloratadine is a secondary cyclic amine

metabolite of loratadine (Claritin1/Schering),


which went off patent in 2003. Approximately 6%
of the population is poor metabolizers of desloratadine resulting in a sixfold higher exposure of
desloratadine, but there was no difference in the
prevalence of poor metabolizers across the age
range of 270 years. The elimination half-lives of
desloratadine and 3-hydroxydesloratadine are
both approximately 27 h. The syrup is bioequivalent to the tablets and no difference in clearance
was observed in pediatrics 611 years of age and
adults. Clarinex1 syrup contains 0.5 mg/mL of
desloratadine dissolved in water, sorbitol solution,
propylene glycol, sugar, EDTA, sodium benzoate,
flavors, and buffered with citrate. Clarinex1 syrup
is recommended for children under 5 years of age
and the dose of desloratadine in pediatric patients
611 months is 1.0 mg (2.0 mL) once a day, and is
1.25 mg (2.5 mL) once a day for patients 15 years
of age. The recommended dose of desloratadine in
pediatrics 611 years of age is 2.5 mg once a day
either as 5 mL of Clarinex1 syrup or one 2.5-mg
RediTabs1 tablet, and in patients greater than 12
years of age is 5 mg once a day either as 10 mL of
Clarinex1 syrup, or one 5-mg tablet.
Triaminic1 is a line of pediatric medications for
the treatment of pain, fever, colds, allergies,
coughs and are available in various formulations
including syrups, chewable tablets (Softchews1),
and Thin Strips1 (http://secure.novartisotc.com/
Triaminic/us_en/index.jsp; accessed May 21,
2007). There are seven Triaminic1 syrups containing the active ingredients dextromethorphan,
phenylephrine, diphenhydramine, acetaminophen, chlorpheniramine, and/or guaifenesin. The
inactive ingredients in Triaminic1 syrups include
the solvents water, propylene glycol, glycerin, and
PEG; the sweeteners acesulfame potassium, maltol, sorbitol, and sucrose; the pH-modifying buffers
citric acid, sodium citrate, and dibasic sodium
phosphate; the preservatives benzoic acid, sodium
benzoate, and EDTA; along with dyes and flavors.

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DOI 10.1002/jps

Organic Solvents in Oral Solutions


Organic solvents are used in oral solution and
elixir formulations when the aqueous solubility of
the active ingredient is low such that an impractically high dose volume would be required to
administer the intended dose. The challenges
for a developing an oral solution with organic
solvents include minimizing the amount of
organic solvent required to achieve the necessary
solubility, chemical stability, taste-masking, and

PEDIATRIC ORAL FORMULATIONS

1759

preservation. Many pediatric oral solutions contain small amounts of ethanol, propylene glycol or
PEGs, and four commercially available pediatric
oral solutions were identified with larger amounts
of organic solvent (ethanol, propylene glycol,
TPGS, PEG 400, or medium-chain triglycerides).
The highest percentage of solvent used is up to
100% medium-chain triglyceride, 55% propylene
glycol (the higher %s are contraindicated in
children younger than 4 years of age), 17% PEG
400, 12% D-a-tocopheryl polyethylene glycol-100
succinate (TPGS), and up to 42% ethanol.11 The
largest daily volume of a solvent administered by
the oral route occurs when consuming the full
adult dose and is 6 mL of ethanol when using
Norvir1 Oral Solution (ritonavir), 20 mL of
medium-chain triglyceride when using Sustiva1
Oral Solution (efavirenz), and when using
Agenerase1 Oral Solution (amprenavir) is 102 g
of propylene glycol, 32 g of PEG 400, and 22 g of
TPGS. Many over-the-counter oral solution formulations contain polyethylene glycol, propylene
glycol, glycerin, polysorbate 20, or poloxamer 407.
Ritonavir (Norvir1/Abbott, North Chicago, IL)
is solubilized to 80 mg/mL in a cosolvent mixture of
propylene glycol, 43% ethanol, 15% water
(unpublished data), the surfactant polyoxyethylene castor oil (Cremophor EL) and peppermint oil
in Norvir1 Oral Solution. Norvir1 Oral Solution is
dosed up to 7.5 mL twice daily, which is 3.1 mL of
ethanol representing the estimated maximum
amount of ethanol administered orally per dose.
A similar cosolvent mixture of propylene glycol,
42% ethanol, water, glycerin, Cremophor RH 40,
and peppermint oil is used to cosolubilize ritonavir
to 20 mg/mL and lopinavir, a nonionizable waterinsoluble HIV protease inhibitor, to 80 mg/mL in
the Kaletra1 oral solution. Kaletra Oral Solution
is dosed up to 5 mL twice daily, which is 2.1 mL of
ethanol per dose.
Amprenavir (Agenerase1/GlaxoSmithKline)
is solubilized to 15 mg/mL in a solvent system
composed (approximate percentages) of 12%
TPGS, 17% PEG 400, and 55% propylene glycol
and flavored with grape, bubblegum and peppermint. Due to the potential toxicity of administering
a large amount of propylene glycol Agenerase1
oral solution is contraindicated in infants and
children below the age of 4 years. The oral
bioavailability of amprenavir from the oral solution is 14% less than that from the capsule
formulation,1 thus the maximum dose of the oral
solution must be adjusted to 1400 mg, which is
approximately 92 mL, twice a day. The quantity of

excipients coadministered per 92 mL dose of


Amprenavir1 oral solution is 11 g of TPGS, 51 g
of propylene glycol, and 16 g of PEG 400,
representing the estimated highest amounts of
PEG 400, propylene glycol, and TPGS administered per dose that can be administered twice
daily. The recommended dose of amprenavir in
pediatrics 412 years of age is 22.5 mg/kg (1.5 mL/
kg) twice a day or 17 mg/kg (1.1 mL/kg) three times
a day.
Efavirenz (Sustiva1/BristolMyers Squibb) is
a water-insoluble nonnucleoside reverse transcriptase inhibitor (NNRTI) available in AtriplaTM
and Sustiva1 tablets and is used in the treatment
of HIV infection. Efavirenz is also available as an
oral solution where 30 mg/mL is dissolved in
medium-chain triglycerides along with benzoic
acid and strawberry/mint flavor. The daily dose of
efavirenz is 600 mg (20 mL) for adults and for
pediatrics is 270600 mg (920 mL) and these
dosing regimens deliver the maximum amount of
medium chain triglycerides per unit dose of any
currently marketed oral lipid-based formulation.

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Suspensions
A drug molecule in which a measurable dosage
form is required, the taste can be masked, is
chemically stable, but is not water-soluble can be
formulated as an oral suspension. A suspension is
a biphasic formulation and thus the challenges
involve both chemical and physical stability. The
challenges for a suspension formulation can be an
exercise in classical physical pharmacy including
include pH-dependent chemical stability and
solubility, rheology, particle settling, viscosity,
taste-masking, dose uniformity, and preservation.
The rate of degradation of a molecule in
suspension follows zero-order kinetics, in which
the rate of degradation is constant (kzero order), or in
other words the decrease in concentration, A(t), is a
linear function of time as shown in Eq. (2). The
zero-order rate constant is the product of the firstorder rate constant in solution (kfirst order), and the
concentration in solution (Asolution), Eq. (3). The
time for 90% remaining (t90, susp) can be defined as
the shelf-life, and its calculation is shown in
Eq. (4), where AT is the total combined concentration is solution and in suspension.
At A0  kzero order t

At A0  kfirst order Asolution t

1760

STRICKLEY ET AL.

Taste-masking is normally accomplished by


using sweeteners and flavors. Taste-masking
strategies can also involve minimizing the concentration of dissolved drug (i.e., in solution) by the
choice of the pH of minimum solubility, or the use
of a less soluble form of the drug.
Six commercially available prescription pediatric formulations as oral suspensions were identified. Commercial examples of aqueous-based
oral suspension formulations include Zovirax1
(acyclovir), Viramune1 (nevirapine), Viravan1
Suspension (phenylephrine tannate, pyrilamine
tannate, dextromethorphan tannate) and the

over-the-counter Delsym1 (dextromethorphan


polistirex).
Acyclovir (Zovirax1/GlaxoSmithKline) is a
nucleoside analog antiviral with activity against
herpes viruses and chickenpox, and is available as
a suspension, tablets, capsules, injection, cream,
and ointment. The recommended pediatric oral
formulation is the suspension, and the suspension
is bioequivalent to the capsules and tablets. The
pharmacokinetics of acyclovir are similar in
pediatric patients aged 7 months to 7 years and
in adults with a half-life of 2.5 h and an oral
bioavailability of 1020% with no food effect.
Acyclovir has two ionizable groups with a weak
acid pKa at 9.2, and a weak base pKa at 2.3 and thus
the water-solubility of acyclovir is pH-dependent
and is U-shaped. The minimum water solubility of
acyclovir is 2.5 mg/mL at physiological pH, but
increases upon ionization at pH values <2 and >10
to more than 100 mg/mL. Zovirax1 suspension
contains 40 mg/mL of acyclovir along with water,
glycerin, sorbitol, microcrystalline cellulose, carboxymethylcellulose sodium, methylparaben, propylparaben, and banana flavors. The dose of
acyclovir in children greater than 2 years of age
and under 40 kg is 20 mg/kg (0.5 mL/kg) four times
daily, and in children over 40 kg is the adult dose
of 800 mg (20 mL) four times daily. Zovirax1
suspension is to be stored at 15308C.
Nevirapine (Viramune1/Boehringer Ingelheim,
Ridge Field, CT) is an NNRTI with activity against
HIV-1, and is available as tablets and an oral
suspension. The minimum water solubility of
nevirapine is 0.1 mg/mL at physiological pH, but
is highly soluble at pH <3 due to protonation of its
weak basic functional group with a pKa of 2.8. The
oral bioavailability of nevirapine is 9095% and
the suspension is bioequivalent to the tablets.
Nevirapine is metabolized by cytochrome P450
oxidative enzymes to several hydroxylated and
subsequently glucuronidated metabolites that are
excreted in urine. Nevirapine is also an inducer of
CYP3A4 and CYP2B6 by 2025%, thus autoinduction of metabolism by nevirapine results in a 1.5- to
2-fold increase in the clearance of nevirapine from
the initial single dose to two-to-four weeks of
dosing at 200400 mg/day. The terminal halflife of nevirapine initially is 45 h at the start of
therapy to 2530 h following multiple doses, due
to metabolic autoinduction. The body-weight
adjusted clearance of nevirapine is at least
twofold higher in pediatrics younger than 8 years
compared to adults, and reached a maximum by
12 years and then decreased with increasing age.

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DOI 10.1002/jps

t90;susp

0:1AT
kfirst order Asolution

Therefore, the chemical stability in a suspension is determined by the amount of drug in


solution (Asolution), the rate of degradation in
solution (kfirst order), and the total concentration
of drug (AT). In more simple terms the shelf-life of a
suspension (t90, susp) is the shelf-life in solution (t90,
soln) divided by the fraction solubilized (fsol) as in
Eq. (5). Alternatively, the shelf-life of a suspension
(t90, susp) is the shelf-life in solution (t90, soln)
multiplied by the total concentration of drug (AT)
and divided by the drug solubility (Asolution) as in
Eq. (6)
t90;soln
fsol

t90;soln AT
Asolution

t90;susp

t90;susp

For ionizable drugs chemical stability of a suspension is a balance between pH-dependent solubility
and pH-dependent chemical stability and is
maximized when the fraction solubilized is minimized at the pH of maximum stability.
The rate of particle settling (n) in a suspension is
determined by the Stokes Eq. (7), where d is the
particle mean diameter, rs the particle density, ro
the density of the medium, g the acceleration due
to gravity, and Z the solution viscosity. The
parameters that can be controlled are the particle
size and the solution viscosity. Particle size can be
manipulated by process parameters such as
milling. Solution viscosity is easily modified by
adding suspending agents such as xanthan gum
and/or hydroxypropyl cellulose.
n

d2 rs  ro g
18h

PEDIATRIC ORAL FORMULATIONS

Viramune1 oral suspension contains 10 mg/mL of


nevirapine along with water, polysorbate 80,
sorbitol, sucrose, Carbomer 944P, methylparaben,
and propylparaben. The dose of nevirapine in
pediatric patients is 4 mg/kg once daily for the first
14 days, followed by 7 mg/kg twice daily thereafter
for patients 2 months to 8 years of age, and 4 mg/kg
twice daily for patients 8 years and older up to a
maximum of 400 mg per day for any patient.
Viramune1 oral suspension is to be stored at 15
308C.
Insoluble Salts in Suspension, Taste-Masking
One taste-masking strategy is to convert a watersoluble drug into a less soluble salt form.
PediaMedThe Pediatrics CompanyTM focuses
on developing medicines for children and one of
their technologies is the Tannate Conversion
Technology, a patented process that combines
active ingredients with tannic acid, which results
in a less soluble and taste-masked form of the
active drug substance, and a prolonged release of
the active ingredient. PediaMeds products
include Viravan1 Suspension and Chewable
Tablets (www.pediamedpharma.com; accessed
May 21, 2007). Viravan1 Suspension and Viravan1-DM Suspension use the tannate salts of
phenylephrine, pyrilamine, and dextromethorphan. Viravan1-DM Suspension is an antihistamine, nasal decongestant and antitussive
containing phenylephrine tannate, pyrilamine
tannate, and dextromethorphan tannate at 2.5,
6, and 5 mg/mL, respectively along with water,
glycerin, xanthan gum, sucralose, sucrose, magnesium aluminum silicate, methylparaben,
sodium benzoate, sodium citrate, ammonium
glycyrrhizinate, grape flavor, and dyes. The dose
volume of Viravan1-DM Suspension is 2.510 mL
depending on age and is given twice daily.

1761

drug because the ions in the digestive tract bind to


and displace the active drug from the resin. When
the Delsym1 arrives in the stomach, an amount of
dextromethorphan is directly released into the
blood stream while the rest slowly dissolves in
stomach acid. Delsym1 suspension is administered twice-a-day at a dose of 7.560 mg by using
1.25 mL for 12 year olds, 2.5 mL for 25 year
olds, 5 mL for 612 year olds, and 10 mL for
children greater than 95 pounds. Delsym1 suspension also contains the inactive ingredients
water, ethanol (0.26%), propylene glycol, PEG
3350, polysorbate 80, sucrose, fructose corn syrup,
citric acid, EDTA, methylparaben, propylparaben, ethylcellulose, vegetable oil, tragacanth,
xanthan gum, dye, and flavors.
Chewable Tablets

Dextromethorphan, available over-the-counter


as Delsym1 by Novartis Consumer Health and
Adams Respiratory Therapeutics, is the most
commonly recommended pediatric cough antitussive by a survey of pharmacists.12 Delsym1
suspension is a sustained release formulation
containing dextromethorphan polistirex, which is
a drug resin complex involving the anionic resin
sulfonated styrene-divinylbenzene, at a concentration of 6 mg/mL equivalents of the hydrobromide salt. In the gastrointestinal tract, a reverse
ion exchange reaction takes place to release the

Chewable tablets are growing in popularity and


the potential for this drug delivery system is
expanding. Though drug delivery by chewable
tablet would be highly advantageous in many
cases, usage has been limited as formulators have
encountered difficulties in achieving satisfactory
sensory characteristics. A drug molecule in which
a measurable dosage form is not required and the
taste can be masked can be formulated as a
chewable tablet. Some of the challenges to develop
a chewable tablet include taste-masking, mountfeel, grittiness, tooth picking, and manufacturing
issues. Packaging of chewable tablets can be a
critical aspect of the commercial product to
maintain the low moisture content in the chewable tablet during storage and thus blister
packaging is common practice with chewable
tablets.
Taste-masking in chewable tablets can be
achieved by using coated drug particles, insoluble
salts of the active ingredient(s), and the use of
flavor and/or sweeteners. To avoid excessive exposure of the drug in the mouth, chewable tablets
generally use coated drug particles.8 Therefore,
during manufacturing of chewable tablets that use
coated drug particles the compression force must
be less than in conventional tablets in order to not
break the coated surface of the drug particle that
provides the taste-masking property.
Mannitol is commonly used as an excipient in
the manufacture of chewable tablet formulations
because of its negative heat of solution, sweetness,
and mouth feel. Various grades of microcrystalline
cellulose are available such as Avicel CE-15 that
help provide a smoother mouth feel, eliminate

DOI 10.1002/jps

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Erodible Coating in Suspensions, Taste-Masking

1762

STRICKLEY ET AL.

grittiness, and reduce tooth packing. The texture


can be modified so the resulting chewable dose
form yields a creamy feeling dispersion. Avicel CE15 is designed to perform in direct compression
formulations, producing comparably softer tablets
that are less friable and disintegrate rapidly.
Eight chewable tablets as for pediatric administration were identified. Commercial examples of
chewable tablets are Singulair1 (montelukast
sodium), Videx1 (didanosine), Tegretol1 (carbamazepine), Mintezol1 (thiabendazole), Viravan1
(phenylephrine tannate, pyrilamine tannate, dextromethorphan tannate), and over-the-counter
Triaminic1.
Montelukast sodium (Singulair1/Merck, West
Point, PA) is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene (CysLT1) receptor and is indicated
for the treatment of asthma and allergies. Singulair1 Chewable Tablets and Singulair1 Oral
Granules (see Sprinkle Solids Section) are the
pediatric formulations of montelukast sodium.
The adult 10-mg tablet was introduced in 1998,
the chewable tablet in 2001, and the oral granules
in 2003.13 Singulair1 Chewable Tablets contain
4.2 or 5.2 mg of montelukast sodium along with
mannitol, microcrystalline cellulose, hydroxypropylcellulose (HPC), red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and
magnesium stearate. Montelukast sodium is
water-soluble and is rapidly absorbed after oral
administration. The oral bioavailability of montelukast from Singulair1 Chewable Tablets is 63
73%. The systemic exposure of montelukast was
higher in pediatrics compared to adults, with a
60% higher AUC and 89% higher Cmax for 611
months of age, and a 33% higher AUC and 60%
higher Cmax for 1223 months of age. The
recommended pediatric dose of Singulair1 Chewable Tablets is one 4-mg tablet daily for children
less than 5 years of age, and a 5-mg tablet daily for
children 614 years of age. Singulair1 Chewable
Tablets are packaged with a desiccant in a highdensity polyethylene bottle or in peelable foil
blister packs, and stored at room temperature.
Didanosine
(ddI,
Videx1/BristolMyers
Squibb) is a nucleoside HIV-1 reverse transcriptase inhibitor that is soluble in pH 6 water at 27
mg/mL, but chemically unstable in water at pH <3
with 10% decomposition to hypoxanthine in less
than 2 min at 378C.1 Didanosine is available in
three pediatric formulations: Videx1 Chewable/
Dispersible Buffered Tablets, Videx1 Buffered
Powder for Oral Solution, and Videx1 Pediatric

Powder for Oral Solution. The pediatric dose of ddI


is 120 mg/m2 up to the adult dose of 250 mg twice
daily. Videx1 Chewable/Dispersible Buffered
Tablets contain 25, 50, 100, 150, or 200 mg ddI in
a buffered formulation of calcium carbonate,
magnesium hydroxide, aspartame, sorbitol, microcrystalline cellulose, crospovidone, mandarinorange flavor, and magnesium stearate. To provide adequate buffering 24 tablets are thoroughly chewed or dispersed in at least 1 ounce of
water prior to consumption and the dispersion
consumed immediately. If additional flavoring is
desired dilute the dispersion with 1 ounce of apple
juice, which can be stored only up to 1 h at room
temperature.
Carbamazepine (Tegretol1/Novartis, East
Hanover, NJ, see Suspensions Section) chewable
tablets are single-scored and contain 100 mg of
carbamazepine along with sucrose, starch, sodium
starch glycolate, gelatin, glycerol, stearic acid,
magnesium stearate, silicon dioxide, and flavors.
The initial dose of carbamazepine chewable tablets
in children 612 years of age is 200 mg total daily
dose administered as one 100 mg of tablets twice
daily, then increase weekly by 100 mg/day until
the optimal response is obtained, which is up to a
typical dose of 400800 mg/day not to exceed
1000 mg/day. For children under 6 years of age the
initial dose is 1020 mg/day divided twice or four
time daily, then increase weekly to an ordinary
dose of 35 mg/day divided three or four time daily,
which for a 50-pound child would be 200450 mg
(2  4 chewable tablets) initially and up to
800 mg (7 chewable tablets) per day. Tegretol1
chewable tablets are packaged in either unit dose
blister packs or bottles, each with 100 chewable
tablets and are to be stored below 308C.
Thiabendazole
(Mintezol1/Merck)
singlescored chewable tablets contain 500 mg of thiabendazole along with methylcellulose, lactose,
mannitol, sodium saccharin, calcium phosphate,
magnesium stearate, acacia, and flavors. Thiabendazole is given twice daily at a dose of 250 mg
( chewable tablet) for a 30 kg patient, and 500 mg
(1 chewable tablet) for a 50 kg patient. Mintezol1
chewable tablets are packaged in unit doses of
36 individually sealed tablets that are to be stored
at 15308C.
PediaMeds chewable tablets include Viravan1
Chewable Tablets and Viravan1-DM Chewable
Tablets (www.pediamedpharma.com; accessed
May 21, 2007). Viravan1-DM chewable tablets
use the tannate salts of phenylephrine, pyrilamine, and dextromethorphan which have low

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

DOI 10.1002/jps

PEDIATRIC ORAL FORMULATIONS

water solubility and provide a taste-masking


aspect. Viravan1-DM chewable tablets contain
25 mg phenylephrine tannate, 30 mg pyrilamine
tannate, and 25 mg dextromethorphan tannate
along with compressible sugar, corn starch, mannitol, talc, xanthan gum, citric acid, calcium
phosphate dibasic, HPMC, magnesium aluminum
stearate, magnesium stearate, and grape flavor.
Viravan1-DM chewable tablets are scored and the
dose is to 2 tablets depending on age and is given
twice daily. Viravan1-DM chewable tablets are
package with 100 tablets per bottle and are to be
stored at room temperature and protected from
moisture.
Triaminic1 Softchews1 are available over-thecounter and are chewable tablets that contain
tasteless Microcaps1 by Eurand, which are drugcontaining granules that are coated with ethylcellulose and are further processed into flavored
chewable tablets. Triaminic1 Softchews1 Cough
and Runny Nose contain 1 mg of chlorpheniramine
maleate and 5 mg of dextromethorphan, while
Triaminic1 Softchews1 Cough & Sore Throat
contain 160 mg of acetaminophen and 5 mg of
dextromethorphan. Both Triaminic1 chewable
tablets also contain aspartame, citric acid, crospovidone, ethylcellulose, fractionated coconut oil
(medium-chain triglyceride), HPMC, magnesium
stearate, maltodextrin, mannitol, microcrystalline
cellulose, mono- and diglycerides, oleic acid,
povidone, silicon dioxide, sodium bicarbonate,
sodium chloride, sorbitol, starch, sucrose, and
triethyl citrate. Triaminic1 Softchews1 Cough
and Runny Nose is administered to children 6
12 years of age by using two tablets every 46 h.
Triaminic1 Softchews1 Cough & Sore Throat is
administered to children 26 years of age using
one tablet every 46 h, and 612 year olds using
two tablets every 46 h. Triaminic1 Softchews1
are scored and are package in unit dose blister
packs.

1763

In recent years, there has been considerable


growth in the number of orally dissolving and
chewable tablets on the market because of their
convenience and increase compliance among
pediatrics and geriatric patients. Orally dissolving tablets (ODTs) are also known as mouth
dissolving, orodisperse, fast dissolving, fast melt,
rapidly dissolving, quick dissolving, or disintegrating tablets. ODTs rapidly disintegrate on

contact with saliva, thus eliminating the need


for water and the difficulties some patients have
with swallowing tablets whole. ODTs rapidly
disintegrate in the mouth to small particles in
just a few seconds with small amounts of saliva, as
compared to tablets, lozenges, and buccal tablets
that require >1 min dissolve.14 ODTs release drug
in the mouth allowing the drug to be absorbed
in the mouth (buccal), pregastric, gastric and
throughout the gastrointestinal tract. The pharmacokinetic advantage of ODTs is quicker absorption and potential increased bioavailability, and
the administration advantages include ease of
swallowing.
A drug molecule in which a measurable dosage
form is not required, is a relatively low dose
(<20 mg), the taste can be masked, is watersoluble and permeable can be formulated as an
ODT. Taste is a critical component of ODTs since a
tablet disintegrates in the mouth, thus tastemasking features are often incorporated. Thus,
some of the challenges to develop an ODT
include taste-masking, rapid-dissolution mountfeel, manufacturing, tablet compression (hardness/friability) and packaging. ODTs are manufactured by three different processes: (1) freezedrying technologies, (2) direct compression, or (3)
molding or cotton-candy technologies.15 Packaging of ODTs can be a critical aspect of the
commercial product in order to maintain the low
moisture content in the chewable tablet during
storage and thus blister packaging is common
practice with chewable tablets. Some ODTs are
compressed into tablets and packaged bulk into
bottles, other ODTs are freeze-dried and are
blister packaged. ODTs that are compressed often
contain the disintegrant crospovidone, an anticaking agent such as silicon dioxide, filler such as
mannitol, and taste-masking agents such as
aspartame, and flavors.16
Of the more than 10 ODTs in the 2006 PDR at
least 3 are for pediatrics: Prevacid1 (lansoprazole), Zofran1 (ondansetron), and Clarinex1 RediTabs1 (desloratadine).
Lansoprazole (Prevacid1/TAP, Lake Forest, IL)
is a blockbuster antiulcerative drug used in the
treatment of gastroesophageal reflux disease
(GERD) with sales of over 3 billion US$ per year
and was the fourth best selling drug in 2005.
Lansoprazole is an antiulcerative belonging to a
class of antisecretory substituted benzimidazoles
that suppress gastric acid secretion by specific
inhibition of the (H, K)-ATPase enzyme system
at the secretory surface of the gastric parietal cell,

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Orally Disintegrating Tablets, Fastmelt


Dissolving Tablets

1764

STRICKLEY ET AL.

and thus has been characterized as a gastric acidpump inhibitor. Lansoprazole is moderately
unstable in acidic media with a half-life of 0.5 h
in pH 5.0, and of 18 h in pH 7 at 258C. Lansoprazole
is available in three enteric-coated oral solid
dosage forms: delayed-release granules in a capsule (see Sprinkle Solids Section), delayed release
granules for oral suspension (see Powder/Granules/Microcapsules/Microspheres for Constitution
to a Suspension Section), and delayed release
orally disintegrating tablets. Prevacid1 SolutabTM delayed release orally disintegrating tablets
contain 15 or 30 mg of lansoprazole in entericcoated microgranules along with lactose monohydrate, microcrystalline cellulose, magnesium carbonate, HPC, hydroxypropyl methylcellulose,
titanium dioxide, talc, mannitol, methacrylic acid,
polyacrylate, PEG, glyceryl monostearate, polysorbate 80, triethyl citrate, ferric oxide, citric acid,
crospovidone, aspartame, artificial strawberry
flavor, and magnesium stearate. Absorption of
lansoprazole is rapid with an oral bioavailability of
80% under fasted conditions. The pharmacokinetics of lansoprazole in pediatrics aged 1
17 years were similar to those observed in healthy
adults. The dose of lansoprazole is 15 and 30 mg
three times daily for children under 30 kg and over
30 kg, respectively. To administer Prevacid1
SolutabTM delayed release orally disintegrating
tablets place on the tongue and allow to disintegrate before swallowing (less than 1 min), do not
chew. Lansoprazole can also be administered
placing a 15 or 30 mg tablet in an oral syringe,
draw up 4 or 10 mL of water, gently shake,
administer via gavage or inject through a nanoscopic tube. Prevacid1 SolutabTM delayed release
orally disintegrating tablets are packaged in unit
dose packages of 30 tablets.
Ondansetron (Zofran1/GlaxoSmithKline) is an
antiemetic indicated in pediatrics for the prevention of nausea and vomiting associated with
moderately emetogenic cancer chemotherapy.
Ondansetron is available as the hydrochloride salt
in Zofran1 oral solution and tablet, and also as the
free base in Zofran1 orally disintegrating tablets.
Ondansetron is well absorbed with an oral bioavailability of 56% that increases slightly with
higher doses and with food. Ondansetron is
metabolized by human hepatic P450 enzymes
including CYPP1A2, CYP2D6, and CYP3A4.
Zofran1 orally disintegrating tablets are freezedried and contain 4 or 8 mg of ondansetron free
base along with aspartame, gelatin, mannitol,
methylparaben sodium, propylparaben sodium,

and strawberry flavor. The dose of ondansetron in


pediatrics 411 years of age is 4 mg given three
times daily, with the first dose 30 min before the
start of emetogenic chemotherapy, with subsequent doses 4 and 8 h after the first dose, and then
three times a day for the next 12 days. Zofran1
orally disintegrating tablets are package in peel
back foil blisters. Zofran1 orally disintegrating
tablets are to be removed from the packaging with
dry hands and immediately placed on the tongue
where it will dissolve in seconds, then swallow
with saliva.
Desloratadine (Clarinex1/Schering, see Solutions and Syrups Section) is widely used antihistamine available as Clarinex RediTabs1 tablets.
Clarinex RediTabs1 tablets are manufactured at
CIMA Labs, Inc. using their OraSolv1 orally
disintegrating drug delivery technology.17 Clarinex RediTabs1 tablets are effervescent and are
made by a direct compression process and contain
2.5 or 5 mg of desloratadine along with mannitol,
microcrystalline cellulose, pregelatinized starch,
sodium starch glycolate, magnesium stearate,
butylated methacrylate copolymer, crospovidone,
aspartame, citric acid, sodium bicarbonate, colloidal silicon dioxide, ferric oxide, and tutti-frutti
flavor. Clarinex RediTabs1 tablets are recommended for children over 6 years of age and the
dose of desloratadine in pediatric patients 611
years of age is 2.5 mg once a day either as one 2.5mg RediTabs1 tablet or 5 mL of Clarinex1 syrup,
and in patients greater than 12 years of age is 5 mg
once a day either as one 5-mg RediTabs1 tablet or
10 mL of Clarinex1 syrup. Clarinex1 RediTabs1
tablets are package in peel off foil blisters with
each tablet in its own cavity. Clarinex1 RediTabs1
tablets are to be placed on the tongue and allowed
to disintegrate before swallowing, and are taken
immediately after opening the blister.
Prednisolone phosphate (Orapred ODTTM/Alliant Pharmaceuticals, Alpharetta, GA) is a watersoluble phosphate ester prodrug of prednisolone
and is available in ODTs in strengths of 10, 15, and
30 mg (equivalents of prednisolone) that are also
manufactured by CIMA Labs, Inc. and are packaged in cards with six tablets per card. For doses
below 10 mg of prednisolone, an oral solution
(Pediapred1/UCB Pharma, Smyrna, GA) is also
available that contains 5 mg/mL equivalents of
prednisolone in a dye-free aqueous solution that
contains dibasic sodium phosphate, edetate disodium, methylparaben, sodium biphosphate, sorbitol, and bubblegum flavor. The oral solution
produces a 14% higher peak plasma level of

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

DOI 10.1002/jps

PEDIATRIC ORAL FORMULATIONS

prednisolone which occurs 20% faster than that


seen with tablets.
Childrens Benadryl1 Fastmelt ODTs are available over-the-counter and contain 19 mg of
diphenhydramine citrate using Eurands tasted
masked Microcaps1 along with the inactive
ingredients aspartame, citric acid, ethylcellulose,
lactitol monohydrate, magnesium stearate, mannitol, soy protein isolate, and stearic acid. Childrens Benadryl1 Fastmelt are taken every 46 h
and the dose for children 612 years of age is 12
tablets, and for adolescents 12 years of age and
over is 24 tablets. Each Childrens Benadryl1
Fastmelt is safety sealed and should be stored in a
dry place.
Loratadine is available over-the-counter as
Claritin1 RediTabs1, Alavert, and Triaminic1
AllerchewsTM orally disintegrating tablets. Loratadine was a blockbuster antihistamine for ScheringPlough that went off patent in 2003 and is now
available as Claritin1 tablets, syrup (see Solutions
and Syrups Section), and RediTabs1 orally disintegrating tablets. Claritin1 RediTabs1 uses
Cardinals Health Zydis fast-dissolving technology
and contain 10 mg of loratadine along with
mannitol, citric acid, gelatin and mint flavor. The
manufacturing process includes accurately filling
a suspension into a blister pocket, freezing and
lyophilization, and then the blisters are sealed
with aluminum foil paper laminate.15 Claritin1
RediTabs1 are recommended for children over 6
years of age and the dose of loratadine in pediatric
patients 611 years of age is 10 mg once a day as
one 10-mg Claritin1 RediTabs1 orally disintegrating tablet. Claritin1 RediTabs1 tablets are
package in peel back blister packs. Claritin1
RediTabs1 orally disintegrating tablet are to be
placed on the tongue and allowed to disintegrate
before swallowing, and are taken immediately
after opening the blister.
Tablets
A drug molecule, in which a measurable dosage
form is not required, can be formulated as a tablet
if the dose is low enough to make a small tablet
that can be easily swallowed. If taste is an issue
the tablet can be coated. For partial dose modification tablets for pediatric administration are
sometimes scored or even double scored, or are
taken as is, or crushed and mixed with drink or
food (see Tablets for Constitution to a Suspension
Section). Eight tablets with or without scoring
were identified for pediatric administration.
DOI 10.1002/jps

1765

Commercial examples of tablets are Dextrostat1


(dextroamphetamine sulfate), and the fixed-dose
combination tablets Malarone1 (atovaquone and
proguanil HCl), and Caduet1 (amlodipine besylate and atorvastin calcium).
Dextroamphetamine sulfate (Dextrostat1/
Shire US, Wayne, PA) is available as 5-mg scored
and 10-mg double-scored tablets for the treatment
of narcolepsy and attention-deficient/hyperactivity disorder. Dextrostat1 tablets contain acacia,
corn starch, lactose, magnesium stearate, sucrose,
and the 10 mg tablets also contain sodium starch
glycolate. The dose in pediatrics 35 years of age is
2.5 mg per day as one-half of a 5-mg tablet or a
quarter of a 10-mg tablet, and for pediatrics 6 years
of age and older is 540 mg per day.
Malarone1 (GlaxoSmithKline) pediatric tablets contain a fixed-dose combination of 62.5 mg
of atovaquone and 25 mg proguanil HCl for the
prevention and treatment of malaria. Malarone1
pediatric tablets contain hydroxypropyl cellulose,
magnesium stearate, microcrystalline cellulose,
poloxamer 188, povidone K30, and sodium starch
glycolate. The dose in patients 617 years of age is
13 tablets once a day, and the tablets may be
taken orally as-is or may be crushed and mixed
with condensed milk just prior to administration.
Caduet1 (Pfizer) is another fixed-dose combination tablet that can be administered to children 6
17 years of age. Caduet1 contains 2.510 mg of the
long-acting calcium channel blocker amlodipine
besylate and 1080 mg of the lipid-lowering agent
atorvastatin calcium in various combinations for
the treatment of hypertension/angina (amlodipine/Norvasc1) and also to reduce total cholesterol
and the prevention of cardiovascular disease
(atorvastatin/Lipitor1). Caduet1 tablets contain
calcium carbonate, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch, polysorbate 80, HPC, water, colloidal silicon dioxide,
and magnesium stearate, and the dose is one tablet
(2.5 or 5 mg of amlodipine) once daily.
Capsules
Atomoxetine (Strattera1/Lilly, Indianapolis, IN)
is prescribed for attention-deficient/hyperactivity
disorder and is available in 10, 18, 25, 40, and
60 mg in hard gelatin capsules along with
pregelatinized starch and dimethicone. Atomoxetine is rapidly absorbed with an oral bioavailability of 6394% and a half-life of 5 h. The
pharmacokinetics in children 6 years of age or
older is similar to adults. The dose of atomoxetine
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1766

STRICKLEY ET AL.

in children 6 years of age or older is initially


0.5 mg/kg for 3 days then increased to 1.2 mg/kg
up to 100 mg per day either as one dose in the
morning or divided into two daily doses. Strattera1 capsules are taken as is and without regard
to food.
Lisdexamfetamine dimesylate (VyvanseTM/
BristolMyers Squibb) is a lysine amide prodrug
of the primary amine dextroamphetamine that
was approved in 2007 for attention-deficient/
hyperactivity disorder in children 612 years of
age. Lisdexamfetamine is inactive and through
rate-limited hydrolysis in the body, L-lysine is
cleaved, gradually releasing the active dextroamphetamine with a tmax of 3.7 h,16 and thereby
providing the benefit of morning dosing before
school and eliminating school involvement in
administration and potential stigmatization by
teachers and students.17 VyvanseTM hard gelatin
capsules contain 30, 50, or 70 mg of lisdexamfetamine dimesylate along with microcrystalline cellulose, croscarmellose sodium, and magnesium
stearate. The dose of lisdexamfetamine dimesylate
is 3070 mg once a day in the morning.
Thin Strips
Thin strips are an exciting new formulation that
is a melt-in-your-mouth edible flavored film strip
first introduced over-the-counter by Pfizer in 2001
as Listerine PocketPaks. In 2004 Novartis Consumer Health, Inc. introduced Triaminic1 and
Theraflu1 Thin StripsTM, which was voted Product of the Year by Convenience Industry News
(www.businessweek.com/magazine/content/
06_31/b3995059.htm; accessed May 7, 2007). One
of the limitations in thin strips is that the amount
of active drug substance per strip is limited to
25 mg. A significant challenge is the packaging
of thin strips. Pfizer markets the over-the-counter
product Benadryl1 Allergy quick dissolve strips
that contain 25 mg of diphenhydramine along
with acesulfame potassium, carrageenan, glycerin, glyceryl oleate, locust bean gum, mediumchain triglycerides, polysorbate 80, povidone,
sodium polystyrene sulfonate, sucralose, xanthan
gum, dyes, and flavors. Each Benadryl1 Allergy
quick dissolve strips is individually wrapped in a
sealed pouch with 10 sealed pouches filled into a
hard plastic container and two containers per
package.
There are six Triaminic1 Thin StripsTM overthe-counter products (http://secure.novartisotc.
com/Triaminic/us_en/index.jsp; accessed May 21,
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

2007): (1) long acting cough suppressant contains


5.5 mg of dextromethorphan, (2) cough and runny
nose contains 12.5 mg of diphenhydramine HCl,
(3) cold and cough contains 3.67 mg of dextromethorphan and 12.5 mg of phenylephrine HCl,
(4) cold nasal decongestant contains 2.5 mg of
phenylephrine HCl, (5) decongestant contains
1.25 mg of phenylephrine HCl, and (6) decongestant plus cough contains 1.83 mg of dextromethorphan and 1.25 mg of phenylephrine HCl.
The inactive ingredients in Triaminic1 This
StripsTM include acetone, alcohol (less that 5%),
buffers, HPC, HPMC, maltodextrin, microcrystalline cellulose, PEG, pregelantized starch, propylene glycol, water, sorbitol, sucralose, dyes,
flavors, sodium polystyrene sulfonate, and/or
titanium dioxide. Each thin strip is individually
wrapped in a sealed packet with 16 strips per
package.

TYPES OF PEDIATRIC FORMULATIONS


Manipulation Required
Pediatric formulation that require manipulation
include a solid that is constituted to form a
solution or suspension, drops for reconstitution
to a suspension, an effervescent tablet, a dispersible tablet in water, an orally disintegrating
tablets in water, or an oral powder that is
sprinkled onto food or drink prior to administration (Tab. 3). Manipulated formulations require
that the chemical and physical stability be
considered before and after manipulation, and
that proper long-term storage, constitution procedures, and in-use handling instructions are
provided. Within this review all of the manipulated pediatric formulations are available only by
prescription, implying that no compounding
occurs by a nontrained professional. The availability of clean, filtered, or boiled water for
constitution or the availability/preference for
local food and drinks must also be considered.
Solid for Constitution to a Suspension
A solid that is constituted to a suspension appears
to be one of the most common types of commercially available pediatric oral formulations as
greater than 20 were identified: 15 powders,
6 tablets, 1 granular formulation, and 1 microcapsule formulation. The solid phase is a powder,
tablet, granules, or microcapsules that is the
DOI 10.1002/jps

PEDIATRIC ORAL FORMULATIONS

manufactured and packaged product for longterm storage and transportation, which is subsequently constituted to a suspension for the patient
in-use phase. Most solids for constitution are
constituted with water, but at least one is constituted with a diluent that is supplied in a
copackaged separate bottle.
A solid formulation for constitution must be
chemically stable both in the solid-state on the
shelf during prolonged storage for up to 2 years,
and also in the constituted suspension for the
duration of the in-use phase (days to weeks). The
formulation must also be physically stable both as
a solid that is easily constituted even after
prolonged storage, and as a suspension with no
foaming, minimal (slow) particle settling but
easily redispersed if the solid particles do settle,
and easily measurable. Thus at least four types of
stability are required in a solid for constitution to
an oral suspension:
. Solid-state chemical stability (extended storage).
. Solid-state physical stability (extended storage).
. Suspension chemical stability (in-use phase).
. Suspension physical stability (in-use phase).

1767

issues requiring the addition of a glidant such as


silicon dioxide. The physical stability of a suspension includes foaming and particle settling as
described previously by the Stokes Eq. (7). Foaming can be minimized by the addition of simethicone in the form of a powder. The ability to
accurately administer the suspension by is critical
and must be determined.
A drug molecule in which a measurable dosage
form is required and the taste can be masked, but is
neither water-soluble relative to the dose nor is
chemically stable for long-term storage can be
formulated as a solid that is constituted to a
suspension. Some of the challenges to develop a
solid for constitution to a suspension include tastemasking, solid-state chemical stability, solid-state
physical stability, packaging of the powder
sachets or bulk powder, ability to constitute the
powder to the suspension, particle size of the solid
and suspension, chemical stability of the suspension, physical stability of the suspension, preservation of the suspension, resuspendability of the
settled suspension, accurate dosing of the suspension using a syringe or other provided measuring
device, bioequivalence, availability of cold temperature storage and transportation (if necessary),
availability of clean water or boiled water, and the
potential need to copackage the diluent for constitution (if necessary).

Chemical stability is required for not only the


drug substance but also the other ingredients, and
both in the solid-state during shelf storage and in
the constituted suspension during the in-use
phase. The overall shelf-life of a solid for constitution to an oral suspension is determined by the
combined degradation in both solid-state and the
constituted suspension. Ideally the solid-state and
suspension will have sufficient stability to have
room temperature storage. However, chemical
instability may require special storage conditions
such as storage of the solid and/or constituted
suspension in at 288C in a refrigerator, or
desiccation of the solid.
The physical stability requirements of a solid for
constitution include ease of constitution and
favorable flow properties for ease of manufacturing and packaging. Solids may agglomerate over
time forming solid clumps or undesirable visible
chunks in the constituted suspension, and thus it
is common practice in both the food and pharmaceutical industries to add anticaking agents to
solids such as starch is added to powdered sucrose
to make confectionery sugar, or silica is added to
salt. Additionally, a solid must have favorable flow
properties for manufacturing and packaging

A powder or granules for constitution to an oral


suspension is a common pediatric formulation as
at least 18 products are commercially available
(see Tab. 3). The composition of a powder for
constitution to an oral suspension can have many
chemical components. These excipients include
sugars, sweeteners and flavors for favorable taste
properties, viscosity modifiers, dispersing agents
to assist in constitution, buffering agents, powderflow enhancers, and preservatives since the
suspension is a multi-use product. Commercial
examples of solid for constitution to a suspension
include Augmentin1 (amoxicillin/clavulanate),
Tamiflu1 (oseltamivir phosphate), CellCept1
(mycophenolate mofetil), Cipro1 (ciprofloxacin),
Ceftin1 (cefuroxime axetil), Biaxin1 (clarithromycin), and Prevacid1 (lansoprazole).
Augmentin1 (amoxicillin/clavulanate/GlaxoSmithKline) is a commonly prescribed antibacterial
consisting of the semisynthetic antibiotic amoxicillin and the b-lactamase inhibitor clavulanate

DOI 10.1002/jps

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Powder/Granules/Microcapsules/Microspheres for
Constitution to a Suspension

1768

STRICKLEY ET AL.

potassium, which are also available as chewable


tablets. Augmentin1 for Oral Suspension is available in four strengths and contains silicon dioxide,
flavorings (banana, orange, or orange-raspberry),
succinic acid, xanthan gum, and one or more
of: aspartame, HPMC, mannitol, silica gel, and
sodium saccharin. The powder is constituted with
water to amoxicillin/clavulanate concentrations of
25/6.25, 40/5.7, 50/12.5, or 80/11.4 mg/mL and is
administered at 2545 mg/kg/day divided into two
dose 12 h apart (40 or 80 mg/mL) or 2040 mg/kg/
day divided into three doses 8 h apart (25 or 50 mg/
mL). The constituted suspension can be stored
refrigerated for up to 10 days.
Oseltamivir phosphate (Tamiflu1/Roche, Nutley, NJ) is the ethyl ester prodrug of a neuraminidase inhibitor prescribed for the prophylaxis and
treatment of influenza. Tamiflu1 for Oral Suspension is available in one strength and contains
xanthan gum, monosodium citrate, sodium benzoate, sorbitol, saccharin sodium, titanium dioxide,
and tutti-frutti flavoring. The powder is constituted with 52 mL of water to make 67 mL of a
12 mg/mL (free base) suspension and is administered at 3075 mg twice-a-day.
Mycophenolate mofetil (CellCept1/Roche) is a
2-morpholinoethyl ester prodrug prescribed for
the prophylaxis of organ rejection within 24 h of
transplantation. CellCept1 for Oral Suspension is
available in one strength and contains aspartame,
citric acid, silicon dioxide, methylparaben, mixed
fruit flavor, sodium citrate, sorbitol, soybean
lecithin, and xanthan gum. The powder is constituted with 94 mL of water to make 175 mL of a
200 mg/mL suspension and is administered at
600 mg/m2 twice daily up to a maximum daily dose
of 2 g/10 mL.
Ciprofloxacin (Cipro1/Schering) is a synthetic
broad spectrum antimicrobial agent indicated in
the treatment of infections caused by susceptible
strains. Cipro1 for Oral Suspension is available in
two strengths 5% and 10% w/w and when constituted with the supplied diluent make 50 or
100 mg/mL suspensions, respectively. The solid is
microcapsules composed of ciprofloxacin, polyvinylpyrrolidone, methacrylic acid copolymer,
HPMC, magnesium stearate, and polysorbate 20.
The supplied diluent is medium-chain triglycerides, sucrose, lecithin, water, and strawberry
flavor. The microcapsules are poured into the
bottle of the supplied diluent. The dose is 15 mg/
kg twice daily up to 500 mg per dose. The dry
powder and constituted suspension are to be stored
below 308C but not frozen.

Cefuroxime axetil (Ceftin1/GlaxoSmithKline)


for oral suspension uses the SACA technology for
taste-maskingstearic acid coated microspheres.
Cefuroxime axetil has a strong bitter taste, which
may lead to low patient compliance. In this
formulation stearic acid is spray chilled with the
drug to form coated microspheres, resulting in a
taste-masking effect while also allowing release of
the drug in the lower gastrointestinal tract.18 The
oral suspension is almost bioequivalent to the
tablet with 91% AUC and 71% Cmax.
Clarithromycin (Biaxin1/Abbott Laboratories)
is a semi-synthetic macrolide antibiotic indicated
in the treatment of bacterial infections. Biaxin1
Granules for Oral Suspension is available at
strengths of 25 or 50 mg/mL and each in two sizes
of 50 or 100 mL of suspension after constitution
with 27 and 55 mL of water, respectively. The
granules are composed of clarithromycin, carbomer, castor oil, citric acid, hypromellose phthalate,
maltodextrin, potassium sorbate, povidone, silicon
dioxide, xanthan gum, titanium dioxide, and fruit
punch flavor. The dose is 7.5 mg/kg up to 500 mg
twice daily for 10 days. The dry granules and
constituted suspension are to be stored at 15
308C, with the suspension up to 14 days.
Lansoprazole (Prevacid1/TAP) is available in
enteric-coated delayed release granules for oral
suspension. Prevacid1 delayed release granules
for oral suspension contain 15 or 30 mg of lansoprazole in enteric-coated microgranules along
with confectioners sugar, mannitol, docusate
sodium, ferric oxide, silicon dioxide, xanthan
gum, crospovidone, citric acid, sodium citrate,
magnesium stearate, and artificial strawberry
flavor. The dose of lansoprazole is 15 and 30 mg
three times daily for children under 30 kg and over
30 kg, respectively. To administer Prevacid1
delayed release granules for oral suspension open
a packet and empty the contents into a container
containing two tablespoons of water, stir well, and
drink immediately. If any material remains, add
more water, stir, drink immediately. Prevacid1
delayed release granules for oral suspension are
packaged in unit dose packages of 30 packets.

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DOI 10.1002/jps

Tablets for Constitution to a Suspension


There are at least six commercially available
tablets that can be constituted to prepare an oral
suspension. The tablets are constituted with
either locally available water, apple juice, milk,
or other beverages, or with commercially available Ora-Sweet1 and/or Ora-Plus1 diluents, or

PEDIATRIC ORAL FORMULATIONS

1769

with a supplied diluent. Each product specifies


the handling of the suspension, and is either
consumed immediately or can be stored up to
4 weeks at room temperature or 288C. OraPlus1 contains carrageenan, calcium sulfate,
citric acid, methylparaben, microcrystalline cellulose, carboxymethylcellulose sodium, potassium
sorbate, simethicone, sodium phosphate, xanthan
gum, and water. Ora-Sweet1 contains citric acid,
berry citrus flavor, glycerin, methylparaben,
potassium sorbate, sodium phosphate, sorbitol,
sucrose, and water.
Deferasirox (Exjade1/Novartis) is an iron chelator prescribed for the treatment of chronic
overload due to blood transfusions in patients
2 years of age and older. Exjade1 Tablet for Oral
Suspension is available in 125, 250, and 500 mg
strengths, and the dose in both adults and
pediatric is 20 mg/kg calculated to the nearest
whole tablet. The tablet(s) is dispersed in water,
orange juice, or apple juice to a fine suspension
then swallowed immediately. Doses of less than 1 g
should be dispersed in 3.5 ounces of liquid and
doses of greater than 1 g in 7.0 ounces of liquid. In
adults the oral bioavailability is 70%, but the
systemic exposure of deferasirox is about 50%
lower for pediatrics. Exjade1 has orphan drug
status and is interesting in that the adult dose is on
a mg/kg basis thus necessitating flexibility in the
administered dose. The advantages in having the
same formulation for both adult and pediatric
indications are less expensive development and
manufacturing costs.
Imatinib mesylate (Gleevec1/Novartis) is a
protein-tyrosine kinase inhibitor antineoplastic
agent prescribed for the treatment of leukemia.
Gleevec1 film-coated tablets are available in
100 and 400 mg strengths, and administered to
pediatrics at a dose of 260340 mg/m2 or up to
400 mg. A tablet(s) is completely disintegrated in
water or apple juice to achieve a concentration of
2 mg/mL and swallowed immediately. The systemic exposure of imatinib is similar for pediatric
and adults, and in adults the oral bioavailability is
98%.
Losartan potassium (Cozaar1/Merck), benazepril hydrochloride (Lotensin1/Novartis), and lisinopril (Prinivil1/Merck) are ACE (angiotensinconverting enzyme) inhibitors used for the treatment of hypertension and the pediatric oral
formulations of all three are tablets that are
constituted with a diluent to a suspension. Losartan is orally active but most of the activity is due to
oxidation of the 5-hydroxymethyl on the imidazole

ring to the carboxylic acid metabolite during firstpass metabolism by CYP450 enzymes. The bioavailability of losartan is approximately 33%,
and about 14% of an orally administered dose is
converted to the active metabolite. Benazepril is
also a prodrug and hydrolysis of the ethyl ester
results in the active carboxylic acid metabolite,
and the extent of absorption of benazepril is 37%.
Losartan potassium is available in 25, 50, or
100 mg strength Cozaar1 tablets. Losartan has
been studied in patients greater than 6 years of
age, and the dose is 0.7 mg/kg up to 50 mg total
daily. To make a 2.5 mg/mL suspension, ten 50-mg
tablets are added to an 8 ounce (240 mL)
polyethylene terephthalate (PET) bottle containing ten milliliters of water and the contents shaken
for 2 min after which the concentrated suspension
is allowed to stand for 1 h, then shaken for 1 min,
then 190 mL of a 1:1 mixture of Ora-Plus1 and Ora
Sweet1 is added and the content shaken for 1 min.
The bioavailability of the suspension formulation
and tablet are similar with respect to both losartan
and its active metabolite. The pharmacokinetics of
losartan and its active metabolite were similar
across the age group studied of greater than 6
years of age. Benazepril hydrochloride is available
in 5, 10, 20, or 40 mg strength Lotensin1 tablets.
Benazepril has been studied in patients greater
than 7 years of age at dose of 0.10.6 mg/kg, and
the recommended starting dose is 0.2 mg/kg once
daily up to 40 mg total daily. To make a 2.0 mg/mL
suspension, fifteen 20-mg tablets are added to an
amber PET bottle containing 75 mL of Ora-Plus1
and the contents shaken for 2 min after which the
concentrated suspension is allowed to stand for
1 h, then shaken for 1 min, then 75 mL of OraSweet1 is added and the contents shaken. The
constituted suspensions of both Lotensin1 and
Cozaar1 can be stored for up to 30 days in a
refrigerator at 288C. Lisinopril is available in 5,
10, 20, or 40 mg strength Prinivil1 tablets.
Lisinopril has been studied in patients greater
than 6 years of age at dose of 0.10.2 mg/kg, and
the recommended starting dose is 0.07 mg/kg once
daily up to 5 mg total daily. To make a 1.0 mg/mL
suspension, ten 20-mg tablets are added to an
amber PET bottle containing 10 mL of water and
the contents shaken for a minute then 30 mL of
Bicitra1 and 160 mL of Ora-Sweet1 is added
and the contents shaken. The suspension can be
stored for up to 4 weeks in a refrigerator at or below
258C. The extent of absorption of lisinopril is
approximately 25% in both adults and pediatrics
patients.

DOI 10.1002/jps

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STRICKLEY ET AL.

As mentioned in the section on chewable tablets


Videx1 Chewable tablets can be dispersed in
water or apple juice and consumed within 1 h.
Also, as mentioned in the section on orally disintegrating tablets Prevacid1 SolutabTM tablets
can be dispersed in water and administered by oral
gavage or through a nanoscopic tube.
Solids for Constitution to a Solution
Three powders (two drugs) for constitution to a
solution appear to be commercially available:
Videx1 (didanosine, ddI) Pediatric Powder for
Oral Solution, Videx1 Buffered Powder for Oral
Solution, and Zerit1 (stavudine) for Oral Solution. Both drugs didanosine and stavudine are
water-soluble and used in the treatment of HIV.
Note the term constitution is used and not
reconstitution because the drug product is a
powder formulation that had not been previously
dissolved.
Videx1 Buffered Powder for Oral Solution is
available in single-dose child-resistant foil packets
containing 100, 167, or 250 mg of didanosine in a
buffered formulation of sodium phosphate dibasic,
sodium citrate, citric acid, and sucrose. Videx1
Buffered Powder for Oral Solution single-dose
packets are opened and the contents added to
water (do not use fruit juice or acid-containing
liquid) and stirred until complete dissolution and
the solution consumed immediately or stored up to
4 h at room temperature. Videx1 Pediatric Powder
for Oral Solution is available in 4- or 8-ounce glass
bottles containing 2000 or 4000 mg didanosine
with no other excipients (i.e., powder in a bottle).
Videx1 Pediatric Powder for Oral Solution is
constituted to 20 mg/mL with water, then to
10 mg/mL with an antacid Mylanta1 Double
Strength Liquid, Extra Strength Maalox1 Plus
Suspension, or Maalox1 TC Suspension, and can
then be stored up to 30 days at 288C.
Stavudine (Zerit1/BristolMyers Squibb) is a
nucleoside analog of thymidine and is HIV-1
reverse transcriptase inhibitor that is soluble in
water at 83 mg/mL, and is available in two
formulations Zerit1 Capsules and Zerit1 for Oral
Solution. The oral bioavailability of stavudine in
pediatrics (ages 5 weeks to 15 years, 243 kg) is
77 32% and in adults is 86 18%. The pediatric
dose of stavudine is 1 mg/kg up to the adult dose of
40 mg twice daily. Zerit1 for Oral Solution is
available in a dye-free fruit-flavored powder that is
constituted with 202 mL of water to make a
solution containing 1 mg/mL stavudine along with
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

the inactive ingredients methylparaben propylparaben, sodium carboxymethylcellulose, sucrose,


antifoaming agent, and flavoring agents. The
constituted solution can be stored at 288C for up
to 30 days.
Drops for Reconstitution to a Suspension
Only one suspension for reconstitution to a
suspension appears to be commercially available.
Amoxicillin is a semisynthetic antibiotic with a
broad spectrum of bactericidal activity and is
available as a monotherapy in Amoxicil1 capsules, tablets, chewable tablets, powder for oral
suspension, pediatric drops for oral suspension,
and in a fixed-dose combination with clavulanate
potassium in the popular Augmentin1. The dose
of amoxicillin is 2545 mg/kg/day in divided doses
every 12 h or 2040 mg/kg/day in divided doses
every 8 h, up to the adult dose regimens of 500
875 mg twice daily or 250500 mg three time
daily. The Amoxicil1 pediatric drops are pink
suspensions that are reconstituted by adding
23 mL of water to the 30-mL bottle and the
contents shaken vigorously to make a suspension
containing 50 mg/mL of amoxicillin along
with silica gel, sodium benzoate, sodium citrate,
sucrose, xanthan gum, dye, bubble-gum flavorings, and water. The pediatric drops for oral
suspension are stored at or below 20258C. The
reconstituted suspension can be placed directly on
the childs tongue for swallowing, or the suspension can be mixed with formula, milk, fruit juice,
water, ginger ale, or cold drinks and then consumed immediately. The reconstituted suspension is preferably stored refrigerated, and can be
stored for 14 days.
Concentrated Solution Diluted (Oral Concentrate)
Only two commercially available concentrated
solutions were identified that are diluted to a
solution and administered to pediatric patients. A
third oral concentrate was identified but is not
used in children, and is oxycodone hydrochloride
(Oxyfast1/Purdue Pharma, Stamford, CT), which
is an opium alkaloid formulated in an aqueous
solution with 20 mg/mL of oxycodone hydrochloride and supplied with a calibrated dropper from
which 0.251.0 mL is diluted with 30 mL of juice
or added to applesauce, pudding or other semisolid foods and consumed immediately.
Dolasetron mesylate (Anzemet1/Sanofi-Aventis, Bridgewater, NJ) is a water-soluble serotonin
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PEDIATRIC ORAL FORMULATIONS

subtype 3 (5-HT3) receptor antagonist used in the


prevention of chemotherapy-induced or postoperative nausea and/or vomiting and is available as
Anzemet1 tablets and injection. The injectable
formulation can be administered orally in pediatric patients 216 years of age after dilution with
apple or apple-grape juice and dosed at 1.2 mg/kg
up to 100 mg given within 2 h before surgery or
at 1.8 mg/kg up to 100 mg within 1 h before
chemotherapy. In pediatric patients the clearance
of dolasetron administered orally after dilution
with either apple or apple-grape juice was 34
300% greater and the half-life 21% shorter than in
healthy adults. Anzemet1 injection is 20 mg/mL of
dolasetron mesylate in water buffered at pH
3.23.8 (acetate) and isotonic with mannitol.
Anzemet1 injection is to be stored at room
temperature and the diluted product kept up to
2 h at room temperature.
Sertraline hydrochloride (Zoloft1/Pfizer) is a
slightly water-soluble selective serotonin reuptake inhibitor (SSRI) used in treatment of obsessive-compulsive and posttraumatic stress disorder
as is available as Zoloft1 scored tablets and an oral
concentrate. The dose of sertraline hydrochloride
is 25 mg once daily for children 612 years of age
and 50 mg for adolescents 1317 years of age.
Zoloft1scored tablets are available in strengths
of 25, 50, and 100 mg. Zoloft1 oral concentrate
contains 20 mg/mL of sertraline hydrochloride in
water with ethanol (12%), glycerin, menthol, and
BHT. Just prior to administration the required
volume is withdrawn from the bottle with the
supplied calibrated stopper and diluted into 4
ounces (1/2 cup) of either water, ginger ale, lemon/
lime soda, lemonade or orange juice and consumed
immediately.

1771

The administration procedure is to dissolve one


5-mg tablet in 5 mL water, or one 150-mg tablet in
68 ounces of water, then administer by dropper,
oral syringe, or drink. Do not chew, swallow
whole, or dissolve EFFERdose1 effervescent
tablets on the tongue. The taste of Zantac syrup
versus Zantac effervescent tablets was evaluated
and the conclusion is that the effervescent
formulation dissolved in water is preferred over
the ranitidine syrup. Better taste acceptance may
facilitate ease of administration and compliance
in pediatric patients.9 EFFERdose1 effervescent
tablets are to be stored at 4258C.
Sprinkle Solids

Effervescence is the release of carbon dioxide


when a solid containing sodium bicarbonate or
sodium carbonate and an acidic excipient such as
fumaric acid, citric acid, or monosodium citrate
is added to water. Ranitidine hydrochloride
(Zantac1/GlaxoSmithKline) is a water-soluble
antihistamine that is a selective H2-receptor
antagonist indicated in the treatment of ulcers
and GERD and is available as Zantac1 injection,
tablets, syrup, and effervescent tablets EFFERdose1. The EFFERdose1 effervescent tablets
contain 25 or 100 mg of ranitidine hydrochloride
along with aspartame, monosodium citrate, povidone, sodium bicarbonate, and sodium benzoate.

A drug molecule in which a measurable dosage


form is required but the taste cannot be easily
masked can be formulated as a tasteless oral
powder/granule that is sprinkled onto food immediately prior to administration. It is common
practice to either coat the active drug substance
to a tasteless solid, or to use sweeteners and
flavors to mask any poor taste. Challenges with
an oral powder/granule include taste-masking,
solid-state chemical stability, reproducible bulk
density, lack of static, manufacturing, packaging,
bioequivalence, and identifying acceptable foods
and/or drinks. Packaging is a critical component
of sprinkle solids and various configurations are
used such as a multi-use container with bulk
powder filled into a bottle and supplied with a
scoop; unit-dose filled into a sachet; or unit-dose
filled into a capsule that can be opened. At least
eight pediatric formulations were identified that
are solids sprinkled onto food or mixed with a
drink prior to administration. One is a bulk
powder in a bottle supplied with a scoop, whereas
the others are in capsules or sachets that are
opened and the solid contents emptied onto food.
Nelfinavir mesylate (Viracept1/Pfizer) is an
HIV protease inhibitor available as tablets and
an oral powder. Viracept1 Oral Powder contains
approximately 5% w/w nelfinavir mesylate (50 mg
nelfinavir free base/gram oral powder) along with
microcrystalline cellulose, maltodextrin, potassium phosphate dibasic, crospovidone, hypromellose, aspartame, sucrose palmitate, and natural
and artificial flavor. Viracept1 Oral Powder is
available in multi-use bottles with 144 g of powder
per bottle, and supplied with a tapered scoop that
delivers 1 g of powder per level scoop. The
recommended pediatric dose is 4555 mg/kg
(1015 g of powder) twice-a-day, or 2535 mg/kg

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Effervescent Tablets

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STRICKLEY ET AL.

(610 g of powder) three-times-a-day. Viracept1


Oral Powder may be mixed with a small amount of
water, milk, formula, soy formula, soy milk, or
dietary supplements, and once mixed, the entire
contents are consumed within 6 h. Viracept1 Oral
Powder administered as a 750 mg dose under fed
conditions was bioequivalent to three 250-mg
tablets. Food increases nelfinavir exposure and
decreases pharmacokinetic variability, which due
to inconsistent food intake in pediatric patients
can result in high variability in pediatric exposure.
Montelukast sodium (Singulair1/Merck) is
available as chewable tablets (see Chewable
Tablets Section) and oral granules and is approved
for children 6 months to 5 years. Singulair1 Oral
Granules contain 4.2 mg of montelukast sodium in
a net weight of 500 mg (0.8% w/w) of mannitol,
hydroxypropyl cellulose, and magnesium stearate,
and filled into a child-resistant foil packet. The
recommended pediatric dose of Singulair1 Oral
Granules is one packet of 4-mg oral granules daily.
Singulair1 Oral Granules may be administered
either directly in the mouth, dissolved in one
teaspoon (5 mL) of cold or room temperature baby
formula or breast milk, or mixed with a spoonful of
cold or room temperature soft foods limited to
applesauce, carrots, rice, or ice cream and consumed with 15 min (based upon stability studies).
The pharmacokinetics of montelukast is not
affected by food, and the oral bioavailability of
montelukast from Singulair1 Oral Granules is
approximately 70%. The systemic exposure of
montelukast was higher in pediatrics compared
to adults, with a 60% higher AUC and 89% higher
Cmax for 611 months of age, and a 33% higher
AUC and 60% higher Cmax for 1223 months of
age. Singulair1 Oral Granules are bioequivalent
to the 4-mg Singulair1 Chewable Tablet and are
recommended for children less than 5 years of age,
while the 5-mg Singulair1 Chewable Tablet are
recommended for patients 614 years of age, and
the 10-mg tablet for adults and adolescents
15 years of age and older. Singulair1 Oral
Granules are packaged in foil packets with 30
packets per carton.
Topiramate (Topamax1/Ortho-McNeil Neurologics, Titusville, NJ) is a bitter tasting sulfamatesubstituted monosaccharide used in the treatment
of epileptic convulsions and is available as capsules for adults and sprinkle capsules for pediatrics. Topamax1 Sprinkle Capsules contain 25 or
50 mg of topiramate layered onto small white to offwhite sugar spheres (nonpareils) composed of
sucrose and starch, which are filled into clear and

white hard gelatin capsules. The other inactive


ingredients are povidone, cellulose acetate, silicon
dioxide, and sodium lauryl sulfate. The recommended pediatric dose of Topamax1 Sprinkle
Capsules is 59 mg/kg/day twice-a-day beginning
with a 25 mg dose. Topamax1 Sprinkle Capsules
may be swallowed whole or administered by
carefully opening a capsule and then the entire
contents sprinkled on a small amount (teaspoon) of
soft food, then immediately swallowed without
chewing. Topamax1 Sprinkle Capsules are bioequivalent to the tablets and the pharmacokinetics
are not affected by food. Topiramate is extensively
metabolized and its clearance in pediatrics is
independent of dose of the range 19 mg/kg, but
the clearance in pediatrics is 50% higher than in
adults.
Valproic acid (Depakote1/Abbott) is available
as coated particles in hard gelatin capsules for
treatment of epileptic convulsions in pediatrics
10 years of age or older. Depakote1 sprinkle
capsules contain 125 mg of valproic acid per
capsule in coated particles of cellulose polymers.
Both Depakote1 sprinkle capsules and Depakene1 syrup (see Solutions and Syrups Section)
are recommended for patients greater than
10 years of age at a dose of 1060 mg/kg/day. To
administer Depakote1 sprinkle capsules, open the
capsule and sprinkle the entire contents onto a
small amount (1 tablespoon) of soft food such as
applesauce or pudding, and then swallow
the entire contents without chewing. Never store
the sprinkle/food mixture for future use.
Methylphenidate (Ritalin LA1/Novartis and
Metadate1 CD/UCB) and dexmethylphenidate
(FocalinTM XR/Novartis) are indicated in the
treatment of attention-deficient hyperactivity disorder and are available as extended-release (ER)
solids in capsules that are opened and the contents
sprinkled onto soft foods. The ER formulations
allow for both reduced side-effects due to a lower
dose and also negate the need for additional
daytime dosing. Metadate1 CD consists of beads
of <1.2 mm diameter coated with either an ER or
immediate-release (IR) methylphenidate formulation, and the commercial product contains 70% ER
and 30% IR, which showed better efficacy in 712
year old compared to a formulation of 60% ER and
40% IR.19 The pharmacokinetics of methylphenidate from Metadate1 CD has a biphasic absorption profile with tmax values of 1.5 and 4.5 h both
of which had similar Cmax values and an oral
bioavailability of 2831% with little food effect.
Metadate1 CD contains 10, 20, or 30 mg of

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PEDIATRIC ORAL FORMULATIONS

methylphenidate along with sugar spheres, povidone, HPMC, PEG, ethylcellulose, and dibutyl
sebacate. The dose of methylphenidate is initially
20 mg then titrated up to a maximum of 60 mg once
daily with breakfast. The capsules can be taken
whole or the capsule can be opened and the solid
powder sprinkled on soft food or applesauce.
Both Ritalin LA1 and FocalinTM XR ER capsules employ Elans proprietary SODAS1 (Spheroidal Oral Drug Absorption System) technology,
which contains half the dose as IR beads and half
the dose as enteric coated, delayed-release beads
(www.elan.com/EDT/drug_optimization/sodas.asp; accessed May 21, 2007). SODAS1 is based
on the production of uniform spherical beads of
12 mm in diameter containing drug plus excipients and coated with product specific controlled
release polymers. Each bead begins as an inert
core onto which drug is applied to manufacture the
IR beads, followed by a number of layers or
coatings of an appropriate mix of controlled release
polymers to manufacture the delayed-release
beads. These polymers (water-soluble and -insoluble, pH dependent/independent, etc.) form a
rate-controlling membrane around each bead.
Once produced, the beads are encapsulated into a
hard gelatin capsule. Combining a number of
different populations of beads with varying
degrees of controlled release gives rise to tailored
drug release profiles, making SODAS1 a highly
flexible and predictable oral drug delivery system.
Ritalin LA1 and FocalinTM XR ER capsules
contain sugar spheres, triethyl citrate, and copolymers of ammonium methacrylate and methacrylic acid that are filled into capsules, which
are opened and the beads sprinkled over a spoonful
of applesauce (not warm), swallow immediately in
its entirety. The Ritalin LA1 and FocalinTM XR
and applesauce mixture should not be stored for
future use.
Lansoprazole (Prevacid1/TAP) is available in
enteric-coated delayed-release granules in hard
gelatin capsules that can be swallowed whole or
can be opened and the granules sprinkled onto soft
foods. Prevacid1 delayed-release capsules contain
15 or 30 mg of lansoprazole in enteric-coated
granules along with HPC, silicon dioxide, magnesium carbonate, methacrylic acid copolymer,
starch, talc, sugar, PEG, polysorbate 80, and
titanium dioxide. The dose of lansoprazole is
15 and 30 mg three times daily for children under
30 kg and over 30 kg, respectively. To mix
Prevacid1 delayed release capsules with food,
open a capsule and sprinkle the granules onto
DOI 10.1002/jps

1773

applesauce, ENSURE1 pudding, cottage cheese,


yogurt, strained pears, or juices (apple, orange, or
tomato) and swallow immediately. Prevacid1
delayed release capsules are packaged in bottles
or unit dose packages of 30 capsules.
Succimer (Chemet1/Ovation, Deerfield, IL) is
an orally active heavy metal chelator indicated in
the treatment of lead poisoning in pediatric
patients with blood levels of lead above 45 mg/mL.
Succimer is a dithiol dicarboxylic acid (meso 2,3dimercaptosuccinic acid) that forms water-soluble
chelates with lead that are excreted in the urine.
Succimer has an unpleasant characteristic mercaptan odor and taste. Succimer is formulated in
Chemet1 as coated beads and filled into a hard
gelatin capsule. Each Chemet1 capsule contains
sucrose beads coated with 100 mg of succimer
along with povidone, sodium starch glycolate, and
starch. The dose of succimer is 10 mg/kg or 350 mg/
m2 (15 capsules) three times daily for the first
5 days and then twice daily for the next 14 days. In
young patients who cannot swallow capsules,
Chemet1 capsule can be administered by opening
the capsules and sprinkle the beads on a small
amount of food, or on a spoon and swallow as-is
followed with fruit drink.

CONCLUSION
Pediatric oral formulations are available in at
least 17 different formulations. Pediatric formulations can be scientifically challenging to
develop, and the choice of which formulation type
to develop is often dictated by the physicochemical
properties and the taste of the active drug
substance, along with the intended dose. In the
past 10 years has seen an increased attention in
the clinical development of pediatric formulations
and a ground swell is beginning to take shape
following U.S. legislation and now even pending
legislation resulting in the numerous pediatric
studies and drug label changes.20 Large pharmaceutical companies have devoted some resources
to pediatric drug development, but it is not a high
priority due to the smaller market size compared
to adult therapies. Thus there is a need for specialized pediatric pharmaceuticals companies such
as PediaMed-The Pediatrics Company (www.
pediamedpharma.com accessed May 21, 2007).

ACKNOWLEDGMENTS
The authors thank Phil Percel of Eurand in
Vandalia, Ohio and Jeff Worthington of Senopsys
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 5, MAY 2008

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1. Physicians Desk Reference1. 2007. 61st edition.


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6. UNICEF/WHO. Technical Consultation: Improving
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10. Allen LV Jr., Popovich NG, Ansel HC. 2005. Liquid


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LLC in Saugus, Massachusetts for helpful comments. The authors also thank Reza Oliyai of
Gilead Sciences in Foster City, CA for support and
encouragement.

REFERENCES