Beruflich Dokumente
Kultur Dokumente
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
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
1731
1732
STRICKLEY ET AL.
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,
DOI 10.1002/jps
DOI 10.1002/jps
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
Solid Formulations
Bulk/diluter
Lactose
Maltodextrin
Mannitol
Microcrystalline cellulose
Sorbitol
Starch
Sucrose
Xylitol
Binder
Crospovidone
Povidone
Pregelatinized starch
Disintegrants
Croscarmellose
sodium
Sodium starch
glycolate
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
1733
DOI 10.1002/jps
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
Amprenavir/Agenerase1
20 mg/mL
Abacavir sulfate/Ziagen1
Marketed Formulation/Storage
Active in
Formulation
Inactive in Formulation
(as Listed in Package
Insert or PDR)1
Dose
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
None
None
Preparation
DOI 10.1002/jps
100 mg/mL
Lamivudine (3TC)/
(1) Epivir1
(2) Epivir-HBV1
Levetiracetam/Keppra1
(2) 5 mg/mL
Granisetron HCl/Kytril1
(1) 10 mg/mL
0.2 mg free
base/mL
4 mg/mL
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
1 mg b.i.d. or 2 mg Q.D.
1800 mg t.i.d.
(Continued)
Abbott/HIV
UCB/Antiepileptic
GlaxoSmithKline/HIV
hepatitis B
Roche/prevention of
Janssen/Alzheimer
ParkeDavis/Analgesic
for posttherapeutic
neuralgia
DOI 10.1002/jps
Nizatidine/Axid1
Ondansetron HCl/Zofran1
Ribavirin/Rebetol1
Ritonavir/Norvir1
Marketed Formulation/Storage
Methylphenidate
HCL/Methylin1
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
DOI 10.1002/jps
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
Sodium oxybate/Xyrem1
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
DOI 10.1002/jps
(Continued)
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
Table 2.
Dose
Inactive in Formulation
(as Listed in Package
Insert or PDR)1
50 mg/mL
Active in
Formulation
None
None
Preparation
Celltech/cough
antitussive
Novartis/Antiseizure and
specific analgesic for
trigeminal neuralgia
GlaxoSmithKline/
antiviral (Herpes)
GlaxoSmithKline/HIV
Abbott/antiepileptic
Company/Indication
DOI 10.1002/jps
Amoxicillin/Amoxil1
Suspension//room temperature
Phenylephrine Tannate,
Pyrilamine Tannate,
Dextromethorphan Tannate/
Viravan1-DM
Suspension/room temperature
Suspension/15 308C
Nevirapine/Viramune1
Thiabendazole/Mintezol1
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.
26 years: 2.5 mL
>12 years:
510 mL
612 years: 5 mL
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
(Continued)
GlaxoSmithKline/
antibiotic
Merck/Anthel-mintic
(expels intestinal
worms)
PediaMed
Pharmaceuticals/
antihistamine, nasal
decongestant,
antitussive
Boehringer Ingelheim/
HIV
Novartis/antiseizure
DOI 10.1002/jps
Lamotrigine/Lamictal1
Methylphenidate HCL/
Methylin1
Montelukast sodium/Singulair1
Marketed Formulation/Storage
Cetirizine HCl/Zyrtec1
Carbamazepine/Tegretol
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
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
Desloratadine/Clarinex1
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
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
None
DOI 10.1002/jps
Lisdexamfetamine dimesylate/
VyvanseTM
Capsulehard gelatin/room
temperature
Capsule/room temperature
Atomoxetine HCl/Strattera1
10 mg
Marketed Formulation/Storage
Active in
Formulation
Loratadine/
(1) Claritin1
(2) Triaminic1 Allerchews1
(3) Alavert1
Over-the-counter
Table 2. (Continued)
0.51.2 mg/kg up to
100 mg q.d.
2070 mg/day q.d. in
the morning
Dose
Preparation
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
2 mg
Tablet-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.
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
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
Pfizer/hypertension,
angina
AstraZeneca/asthma
Merck/antiparasitic
BMS/antihypertension
Sanofi-Aventis/
antihistamine
Shire US/Narcolepsy
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
DOI 10.1002/jps
Stavudine/Zerit1
Didanosine/Videx1
50 mg/mL in
reconstituted
suspension
Amoxicillin/Amoxil Pediatric
Drops for Oral Suspension
25 and 150 mg
20 mg/mL
Active in
Formulation
Marketed Formulation/Storage
Ranitidine HCl/Zantac1
Sertraline HCl/Zoloft
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.
Dose
Sodium citrate
Aspartame
Monosodium citrate
Povidone
Sodium bicarbonate
Sodium benzoate
Glycerin
Alcohol (12%)
Menthol
BHT
BristolMyers Squibb/
HIV
Constitute with
202 mL water
Manipulation
DOI 10.1002/jps
Azithromycin/Zithromax1
Cefaclor/Ceclor1
Cefadroxil/Duricef1
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
Constitute with
water
Constitute with
water
Constitute with
water
Constitute with
water
Constitute with
water
(Continued)
BristolMyers Squibb/
Antibiotic
Eli Lilly/antibiotic
Pfizer/antibiotic
GlaxoSmithKline/
antibiotic
GlaxoSmithKline
Beecham/antibiotic
DOI 10.1002/jps
Cefixime/Suprax1
Cefprozil/Cefzil1
Ceftibuten/CeDax1
Cefuroxime axetil/Ceftin1
Marketed Formulation/Storage
Cefdinir/Omnicef1
Table 3. (Continued )
10 kg 90 mg
20 kg 180 mg
40 kg 360 mg
>45 kg 400 mg
q.d.
Dose
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
GlaxoSmithKline/
antibacterial
Biovail/antibiotic
BristolMyers Squibb/
antibiotic
Lupin/antibacterial
Abbott/antibiotic
Company/Indication
DOI 10.1002/jps
Famotidine/Pepcid1
Clarithro-mycin/Biaxin1
Linezolid/Zyvox1
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
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
DOI 10.1002/jps
Suspension:
1020 mg/mL
Suspension:
12 mg/mL
Nitazoxanide/Alinia1
Suspension:
200 mg/mL
Active in
Formulation
Marketed Formulation/Storage
Mycophenolate mofetil/
CellCept1
Table 3. (Continued )
3075 mg 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
Roche/Antiviral for
influenza
(neuraminidase
inhibitor)
Romark/antiparasitic
(treatment of
diarrhea)
Roche/transplant
rejection
Company/Indication
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
50 mg/g powder
(1 scoopful
is 1 g)
5, 10, 20 mg
Sprinkle Powder in a
Capsule/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
4 mg q.d.
100400 mg b.i.d.
10, 20, or 30 mg
2060 mg/day
0.8% w/w
Montelukast sodium/Singulair1
Oral Granules
Suspension:
40 mg/mL
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
(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)
DOI 10.1002/jps
Topiramate/Topamax1
Lansoprazole/PREVACID1
Capsules/room temperature
Marketed Formulation/Storage
Succimer/Chemet1
Table 3. (Continued )
15 or 30 mg
15 and 30 mg
100 mg
Active in
Formulation
>30 kg: 30 mg
t.i.d.
59 mg/kg/day starting
with 25 mg b.i.d.
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
DOI 10.1002/jps
Tablet to be constituted to a
suspension/tablets: room
temperature, constituted
suspension at 288C for up to
30 days
Tablet to be constituted to a
suspension/Room temperature
Benazepril HCl/Lotensin1
Deferasirox/Exjade1
100, 400 mg
125 mg per
capsule
20 mg/kg
(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
DOI 10.1002/jps
Mefloquine HCl/Lariam1
Dose
250 mg
>3 months:
2025 mg/kg
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
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
Company/Indication
Manipulation
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.
1754
STRICKLEY ET AL.
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
FORMULATION DEVELOPMENT
Technical complexities in pediatric formulation
development include dose modification, ease of
DOI 10.1002/jps
1755
1756
STRICKLEY ET AL.
1757
DOI 10.1002/jps
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
DOI 10.1002/jps
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
DOI 10.1002/jps
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
1760
STRICKLEY ET AL.
DOI 10.1002/jps
t90;susp
0:1AT
kfirst order Asolution
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
1761
DOI 10.1002/jps
1762
STRICKLEY ET AL.
DOI 10.1002/jps
1763
DOI 10.1002/jps
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,
DOI 10.1002/jps
1765
1766
STRICKLEY ET AL.
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
DOI 10.1002/jps
Powder/Granules/Microcapsules/Microspheres for
Constitution to a Suspension
1768
STRICKLEY ET AL.
DOI 10.1002/jps
1769
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
1770
STRICKLEY ET AL.
1771
DOI 10.1002/jps
Effervescent Tablets
1772
STRICKLEY ET AL.
DOI 10.1002/jps
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
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
1774
STRICKLEY ET AL.
DOI 10.1002/jps
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