Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/AJPS
Review
Sprinkle formulations—A review of commercially available products
Han Sol Lee a, Jeong-Jun Lee a, Myeong-Gyu Kim b, Ki-Taek Kim c, Cheong-Weon Cho a, ∗ Dae-Duk Kim d, Jae-Young Lee a, a College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea b Graduate School of Clinical Pharmacy, CHA University, Pocheon 11160, Republic of Korea c College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea d College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea a r t i c l e i n f o a b s t r a c t
Article history: Currently, sixty-five original sprinkle drug products are available in various dosage Received 19 November 2018 forms including tablets, powders, granules, immediate-release capsules, extended-release Revised 8 March 2019 capsules, delayed-release capsules, and multiparticulate drug delivery systems. By Accepted 12 May 2019 sprinkling on soft food vehicles, these products provide dosing flexibility and convenience Available online 8 July 2019 of administration, which potentially improve the compliance of patients with dysphagia. Due to these advantages, the growth of sprinkle products picked up since the 1990s, and
Keywords: several regulatory issues regarding this dosage form have been raised and documented.
Sprinkle formulation In this article, the types of sprinkle formulations were discussed by dividing them into
Soft food seven categories, and the commercial products were summarized in terms of the drug
Geriatric substance, pharmaceutical excipients, storage conditions and administration methods. In
Pediatric addition, several US Food and Drug Administration guidelines related to the regulatory
Dysphagia issues of sprinkle formulations were reviewed, which led to the conclusion that the future
Guidance for industry development of this promising dosage form demands integrated guidance for industry rather than scattered information in various documents. © 2019 Shenyang Pharmaceutical University. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )
tablets are preferred due to the dosing convenience, high
1. Introduction physicochemical stability, and cost-effectiveness [2,3] . However, the large size of solid formulations is challenging Oral delivery is regarded as the most desirable route for patients with dysphagia –often the elderly and children – of administration, given its non-invasiveness and high to swallow, which in turn promoted the development of patient acceptability [1] . Among the various types of novel oral formulations, including sprinkle formulations oral formulations, solid dosage forms like capsules and [1,4-6] .
∗ Corresponding author. College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea. Tel.: +82 42 821 5935 E-mail address: [email protected] (J.Y. Lee). Peer review under responsibility of Shenyang Pharmaceutical University. https://doi.org/10.1016/j.ajps.2019.05.003 1818-0876/© 2019 Shenyang Pharmaceutical University. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310 293
Fig. 1 – General administration methods for the sprinkle drug products in various dosage forms including tablets, powder, granules, immediate-release (IR) capsules, extended-release (ER) capsules, delayed-release (DR) capsules, and multiparticulate drug delivery system (MDDS).
Sprinkle formulations are drug-containing pellets accessdata.fda.gov/scripts/cder/daf/ ; last accessed October or granules that can be mixed with soft food before 2018). The product list was compiled based on the labeling administration ( Fig. 1 ). These formulations provide almost information of each product ( Tables 1–7 ). Unless otherwise the same dosing flexibility and ease of ingestion as liquid noted, the other information including generic name, drug formulations when sprinkled on liquid or semi-solid vehicles, substance, pharmaceutical ingredients, storage condition, and such as applesauce, pudding or yogurt [2,6] . The food taken administration method was also adapted from each product together with the drug can also mask the unpleasant taste labeling. and smell of the drug substance, which potentially improves patient compliance [7] . Moreover, sprinkle formulations are 2.2. Tablets available in tablet or capsule formulations for the convenience of handling and can be readily crushed or opened before being The labeling of tablet formulations usually carries a warning sprinkled on food, respectively [8] . Due to their solid state, that the product must not be crushed [10] . However, there sprinkle formulations guarantee the higher stability of loaded are more than nine crushable tablet products commercially drugs than liquid formulations during storage [9] . available. The administration of this sprinkle tablet is Since the first product was approved by the US Food performed by carefully crushing the tablet and immediately and Drug Administration (FDA) in the early 1940s, sixty-five original sprinkle formulations have been marketed in the US ( Fig. 2 ). The commercially available sprinkle formulations can be classified into seven formulation types, consisting of tablets, powder, granules, immediate-release (IR) capsules, extended-release (ER) capsules, delayed-release (DR) capsules, and multiparticulate drug delivery system (MDDS). Tables 1–7 show the formulation types arranged by the date of approval in the US. This review aims to provide the information of each sprinkle product regarding its drug substance, pharmaceutical ingredients, storage condition, and administration method. In addition, FDA guidance articles related to sprinkle formulations were introduced for the future development of this formulation.
2. Ty pe s of sprinkle formulations
2.1. Method of collecting information on sprinkle drug products Fig. 2 –The number of approved New Drug Applications (NDAs) for sprinkle drug products since 1941. A total of Sixty-five New Drug Applications (NDAs) for sprinkle drug sixty-five original sprinkle products are available on the US products were found in the FDA database ( https://www. pharmaceutical market. 294 Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310
US
2007 2017 1967 2011 2005 2011 2015 2017 2012 approval Initial
Squibb
Sankyo
Therapeutics
Mylan Novartis BioMarin Pharmaceutical Janssen Lundbeck Bristol-Myers Daiichi PTC Synergy Pharmaceuticals Company
of or kg,
the
of
10
must
mL
on on on on on on on
apple
small this as
water
240 a and and and and and and and and
than
of of of
Sprinkle
to in
syringe.
such spoonful water,
less a or mL
a min tablet tablet tablet tablet tablet tablet tablet tablet
120
5 in
fragments fragments fragments fragments fragments fragments fragments
30 on in in
pellets.
foods administer the the the the the the the the damage
juice, using
pudding.
or tablet tablet tablet tablet tablet tablet tablet
or
soft and weighing
dextrose within crush crush crush crush crush crush crush crush
of
apple powder orally the the the the the the the powder
applesauce.
crush 5% or
fragments
juice or
be infants
Carefully not delayed-release tablet applesauce. Carefully sprinkle applesauce. Dissolve water quantity applesauce Consume dissolution. For dissolve apple solution Carefully sprinkle applesauce. Carefully sprinkle applesauce. Carefully sprinkle water, juice, Carefully sprinkle applesauce. Carefully sprinkle applesauce. sprinkle applesauce. Carefully Manipulation
MCC; Talc; HPC;
Talc; MCC
starch;
Corn MCC; 188
coating
silicon
stearate dioxide;
sodium; sodium; fumarate corn
SLS
Magnesium Magnesium Magnesium
Talc chloride; Lactose Riboflavin;
stearate; stearate; stearate; stearate;
lactose; lactose;
polymer wax Pre-gelatinized
K30;
silicon Colloidal MCC; SD; acid;
Poloxamer phosphate; stearyl monohydrate; monohydrate;
Crospovidone; Crospovidone; Lactose
Crospovidone; starch;
Sodium Magnesium
-mannitol;
Lactose SLS; Anhydrous starch; Magnesium Cellulosic MCC; Povidone stearate; dioxide; Ascorbic Crospovidone;Dibasic calcium D Sodium Croscarmellose HPMC; monohydrate; stearate; Corn monohydrate; stearate; Anhydrous Croscarmellose SLS; Mannitol; starch; Magnesium Carnauba Colloidal Lactose Magnesium Pre-gelatinized Magnesium Excipients
tight
the
a
and in
in protect
and C C. C. C. C. C
C
room ° ° ° ° ° ° ° mg mg
C
° and
mg mg 25 25 25 25 25 25 or 25
36
moisture. moisture.
25 360 C
mg to to to to to to to 20 60 °
mg
mg
and
20 25 20 20 20 20 20 bottle 20 and 5
from from
200 20
and and
at below at at at at at at at 30, moisture.
light-resistant mg
– tablets. and
180, 15, 30,
and and
18, mg
50 Store and container. 90, Store protect 100 Store protect 10, Store temperature. Store 2.5 Store 15, Store 6, Store 3 Store original from Strength/Storage 10
products
iron
treatment treatment treatment prevention
chronic seizures Duchenne chronic
sprinkle infections
and and and
of of of of and
constipation
dystrophy
bacterial thromboembolism thromboembolism thromboembolism
available
Treatment of overload Tetrahydrobiopterin- responsive phenylketonuria of of of muscular Treatment idiopathic Treatment Prevention Prevention Treatment Treatment Prevention Indications
names
/plecanatide /deflazacort
/edoxaban R
/rivaroxaban – Commercially
/deferasirox /apixaban
R
/sapropterin
TM
/doxycycline R
R
R
1 R
R
/clobazam
R Brand/Generic Doryx hyclate Jadenu Kuvan dihydrochloride Xarelto Onfi Eliquis Savaysa Emflaza Trulance Table Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310 295
Approval
US
2007 2004 2001 2003 Initial
Squibb
Sciences
Gilead Bristol-Myers Shire BioMarin Pharmaceutical Company
the
mL
mL
such 5
a such
after
in
patient
240
in or
than
other liquid with
orally water). food of
to or
and
or months, or the
foods
or small food
less 6
food, a soft min
administered 120
powder mixed
soft juice, juice soft pudding. 30
consume in on on
. solution
water, than
be
and of yogurt) R baby
the
or
immediately
syringe. is
formula, and or with
this apple apple less weighing applesauce
within
food oral powder powder powder or or
of
should
syringe. food
Reyataz formula
infant quantity
an a dissolve vehicle
eat
powder
infants infants
applesauce, applesauce kg, water water
the
as yogurt. (applesauce (milk, If must taking For powder infant using Sprinkle amount similar immediately. Dissolve of small as Consume dissolution. For 10 of administer using Mix Sprinkle Manipulation
SD
dioxide;
EC;
Potassium Sucrose
Magnesium
HPC;
silicon acid;
Sucralose
-mannitol;
Mannitol; Aspartame; Colloidal Dextrates; stearate Ascorbic d citrate; Excipients
protect
and
the
C °
in and
powder mg moisture.
25 C C. C mg
g
° ° °
1 packet
1000 500 25 25 25 container.
from
per per –powder.
at at at below moisture.
and and
mg mg
40 Store original 50 Store 750 Store from 100 Store protect Strength/Storage products
renal
chronic patients HIV-1 HIV-1
serum
sprinkle in of of
of
and B
end-stage available Treatment infection hepatitis infection Reduction phosphate with disease Tetrahydrobiopterin- responsive phenylketonuria Treatment Indication
Name
fumarate /lanthanum
/atazanavir
R – Commercially
/tenofovir
R /sapropterin
R 2 R
Brand/Generic Viread disoproxil Reyataz Fosrenol carbonate Kuvan dihydrochloride Table 296 Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310
US
2012 2015 2015 2000 1998 2017 2005 approval Initial
Therapeutics Therapeutics
Merck Pfizer Novartis Vertex Pharmaceuticals Wellstat Corporation Wellstat Corporation Lupin Company
or or
or
or or
min.
any foods,
with
granules. granules. granules milk, 30 food food foods,
rice,
in
soft
formula
teaspoonful
mix the the the
applesauce. soft soft applesauce, applesauce, soft of a
pudding,
or without
breast within
in on on on on on on
applesauce. baby
foods. carrots,
granules.
or chew granules
administration. or
formula.
or dissolve
the
than yogurt, ingest for
crunching
spoonful
other
to
pudding
a
or
granules granules granules granules granules granules granules or
yogurt applesauce, formula infant and or
dissolve use crush chew try
liquid. milk
other
as as or applesauce,
with
cream. not not not not not
any baby
Dissolve of mix only ice Do liquid breast Sprinkle Do Do Sprinkle such Sprinkle liquid. pudding, milk such yogurt, Do Sprinkle yogurt, chewing Do in Sprinkle Sprinkle Manipulation
iron
SLS
Sugar 188 SLS;
silicon
dioxide;
sodium; Yellow Magnesium Povidone;
dioxide;
HPMC;
copolymer;
acid stearate; 80;
MCC;
PEG PEG
HPC; Sucralose; K30;Magnesium
Povidone; silicon Colloidal
Talc
Poloxamer
citrate; carbonate; monohydrate;
acetate-succinate;
Crospovidone; acrylate-methyl
Titanium
HPMC; HPMC;
Mannitol; stearate Crospovidone; Methacrylic copolymer; Polysorbate Sodium Talc; Triethyl oxide MCC; Povidone stearate; dioxide; Colloidal Croscarmellose HPMC Lactose Magnesium Mannitol; EC; EC; Ethyl methacrylate PEG4000; spheres; Excipients
and
the
in
and
C C. C C. C. and ° °
° °
°
mg
30 25 25 25 25
moisture moisture.
360 C. C.
° ° to to to to to
mg
15 20 20 20 25 25 20 package packet and
from from
75
packet packet
at at at at at at at
per
–granules. 180, per per and
mg g
mg g g
4 Store original protect light. 40 Store 90, Store protect 50 Store 2 Store 10 Store 2 Store Strength/Storage
products
of
iron
and
of
of
chronic
conditions
allergic erosive chronic hereditary cystic bacterial asthma,
and sprinkle or severe and
treatment
of of of of of of
of
or
reactions
aciduria prevention
Zollinger-Ellison
available
Prophylaxis treatment acute exercise-induced bronchoconstriction, alleviation rhinitis Treatment esophagitis pathological hypersecretory (e.g., syndrome) Treatment overload fibrosis Treatment orotic Emergency overdose adverse fluorouracil capecitabine vaginosis Treatment Treatment Indication
names
/uridine /ivacaftor /montelukast
/pantoprazole
/secnidazole R /uridine
R
R
– Commercially R R
TM
R
3
Brand/Generic Singulair sodium Protonix sodium Jadenu Sprinkle/deferasirox Kalydeco Xuriden triacetate Vistogard triacetate Solosec Table Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310 297
US
1992 2002 1995 1996 2007 2008 1998 1991 2000 approval Initial
Rare
Orphan
Pharms
Searle
Recordati Bristol-Myers Squibb Mylan Janssen GD Valeant Swedish Biovitrum Novartis Allergan Company
the be
to
spoon with without without
or use. choking. amount
can sprinkle mix sprinkle sprinkle sprinkle sprinkle sprinkle sprinkle
sprinkle
a
able
as six,
min.
in
min
and and and and and and and and of and not
15 5
yogurt. small formula.
before
drink. such a
prevent or
are age formula,
them
contents
mixture to on
food.
fruit immediately within the within immediately infant capsule capsule capsule capsule capsule capsule capsule capsule
food, capsule the
jelly,
who
the
soft applesauce. applesauce. water, applesauce. applesauce. food
the the the the the the the the the
putting soft with
with
(beads) on on on on on on on
under
grape foods,
or immediately
mixture mixture mixture mixture infants
open open open open open open open open with open
swallow
food the the the the solid
or
following contents contents contents contents contents contents contents
contents young children
soft
Carefully the of and Carefully contents applesauce, For ingest administered For carefully the Carefully the Ingest chewing. Carefully the Ingest water. Carefully the Chew immediately. Carefully the applesauce Carefully the Ingest Carefully the Ingest chewing. Manipulation
red
acid
citrate
aroma
starch
#10;FD&C stearate
188
acetate;SD
#2;FD&C
dioxide starch
iron
sodium;Gelatin dioxide
Trisodium blue
yellow
benzoate;Citric
silicon silicon silicon
#1;FD&C
-mannitol;Magnesium
Povidone;Sodium glycolate;Starch;Sucrose Lactose monohydrate;Magnesium stearate;SLS;Sodium glycolate Colloidal dioxide;Croscarmellose sodium;D&C blue #40;Gelatin;Magnesium stearate;MCC;Pharmaceutical glaze;Pregelatinized starch;SLS;Black oxide;Titanium Povidone;Cellulose SLS;Gelatin;Sorbitan monolaurate;Sugar spheres;Titanium Croscarmellose Lactose monohydrate;Magnesium stearate;Povidone;SLS Colloidal dioxide;Magnesium HPMC;Glycerol;Polysorbate 80;Sodium monohydrate dehydrate;Strawberry Colloidal dioxide;Crospovidone;Lactose monohydrate;Magnesium stearate;Poloxamer d stearate;Pre-gelatinized starch;SLS Excipients
and
to
days.
C 2
°
and
45
and
protect at
C. C C. C.
25
° ° ° ° to
room moisture. mg
25 25 25 25 and
light moisture. up
at
C. 20 mg mg
C. C
° to to to to mg mg below ° °
and
mg
200 200 15 25 20 or 20 20 25 25 capsules. and
from from mg 200 150 25
store
8 at at at at at at refrigerated at at
light
10, or and and
mg mg
–IR and and and C
5,
and
°
100 Store 50 Store 50 Store protect moisture. 15 Store protect 100 Store 750 Store 2, Store 8 temperature 150 Store 4 Store from Strength/Storage
products and
and
mercury,
1 signs
leukemia
primary
migraine benign positive nephropathic epilepsy ulcerative Philadelphia lead, HIV-1 osteoarthritis, the hereditary
sprinkle type arthritis, poisoning
and spondylitis, of of
of of of of of of of of of
hyperplasia
myeloid
pain,
arsenic available
and infection Treatment cystinosis Treatment prevention rheumatoid ankylosing acute dysmenorrhea Treatment colitis tyrosinemia chromosome chronic symptoms prostatic Treatment Treatment Treatment Treatment Treatment Treatment Indication
names
Sprinkle /cysteamine /celecoxib
/balsalazide
R R /succimer /nilotinib
/silodosin
R
/efavirenz
– Commercially
R
R R R
R
TM
4
Brand/Generic Chemet Sustiva Cystagon bitartrate Topamax Capsules/topiramate Celebrex Colazal disodium Orfadin Tasigna Rapaflo Table 298 Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310
)
US page
next
1950 1955 1975 1968 1977 1991 1992 1941 Approval 1995 Initial on
continued
(
Actavis Collegium Pharmaceutical Rhodes Pharmaceuticals Impax Laboratories Adamas Pharmaceuticals Teva Pharmaceuticals Recro Gainesville Sun Pharmaceutical GlaxoSmithKline Company
ice
min.
and and and and and and and and
60
and
yogurt.
warm. warm.
on on on on on on on on on yogurt, or
immediately immediately. immediately immediately capsule capsule capsule capsule capsule capsule capsule capsule within not not
foods. foods. granules. granules. capsule
is is
the a the the the the the the the
the the contents contents contents contents contents contents contents contents contents
pudding, pudding,
that that
other other
mixture mixture mixture mixture mixture
open open open open open open open open open jam.
the the the the the the the the the chewing. chewing. chewing.
use chew use chew or the the the the
the
not not not not
Carefully sprinkle applesauce. Do Do Carefully sprinkle applesauce, cream Carefully sprinkle applesauce. Ingest without Carefully sprinkle applesauce. Ingest Carefully sprinkle applesauce. Ingest without Carefully sprinkle applesauce. Do Do Carefully sprinkle applesauce Ingest without Carefully sprinkle applesauce, Ingest Carefully sprinkle applesauce Manipulation
iron
dioxide (20–25
vegetable starch
Clear acid;Ethyl
acid
citrate silicon acid
stearate
wax;Gelucire
silicon #40;Yellow oxide;Gelatin
chain
spheres dioxide
red copolymer;Triethyl
acid
Sugar
acid;Talc;Sugar acid;Yellow
oil;Hydrogenated
HPMC;EC;Methacrylic copolymer;PEG;DEP;Talc;Corn starch;Sucrose Myristic beeswax;Carnauba 50/13;Magnesium stearate;Colloidal Sugar spheres;HPMC;PEG;Ammonio methacrylate citrate;Talc;Colloidal dioxide;Titanium MCC;Mannitol;Tartaric cellulose;HPMC;Sodium glycolate;SLS;Povidone;Talc; Methacrylic copolymer;Triethyl citrate;Croscarmellose sodium;Magnesium Copovidone;EC;HPMC;Magnesium stearate;Medium triglycerides;MCC;Povidone;Talc DEP;EC;Gelatin;Opadry YS-1-7006 mesh);Titanium Fumaric spheres;Povidone;Shellac; Gelatin;FD&C oxide;Titanium dioxide;Methylparaben;Propylparaben; SD;SLS EC;HPMC;PEG400;PEG6000;Sugar spheres;Talc;Triethyl Crospovidone;Hydrogenated castor oil;Magnesium stearate;Methacrylic copolymer;MCC;Povidone Excipients
80,
and mg mg
mg
and 70,
mg and and
36 and protect protect protect protect 200 360
C C. C C. mg
50, 60,
° ° ° ° tight
200 moisture. moisture.
container. 80
and
25 25 25 25 and in and and and and and
carbidopa/mg 40, 50,
moisture. light
mg
C C C C C to to to to and ° ° ° ° °
and and 27,
and
and 30, 40,
mg
mg
36.25/145,
150, 240, 137
25 25 20 25 20 25 20 20 25
from from 18, 30
100, 40, 20, 30, capsules.
at at at at at at at at at
light light light. light.
and 130, 180,
50, 20, 15, 20, and
mg
13.5,
–ER
100, Store from Store light-resistant 60 Store protect 23.75/95, 48.75/195, 61.25/245 levodopa Store from 68.5 Store 15 Store from Store protect moisture. 25, Store 10, Store from 10, 120, 10, 9, Strength/Storage
in
pain pain
by products left
heart
to
or
and spasm severe severe therapy acute,
and
caused
failure, Parkinson’s
of of ADHD Parkinson’s dyskinesia hypertension hypertension, mild
intoxication dysfunction sprinkle with of of of of of of
and
myocardial
with muscle post-encephalitic
heart receiving
musculoskeletal
monoxide pectoris,
of available Management Management Treatment Treatment disease, parkinsonism, parkinsonism carbon manganese Treatment patients disease levodopa-based Relief associated painful conditions Treatment Treatment angina failure Treatment chronic ventricular following infarction, hypertension Indication
names /
Sprinkle/
TM
succinate
ER/
TM
sulfate phosphate
/
XR R /
/carbidopa – Commercially
/
/ R CR/
TM
R
5 R TM
R
levodopa
Brand/Generic Kadian morphine Xtampza oxycodone Aptensio methylphenidate hydrochloride Rytary and Gocovri amantadine Amrix cyclobenzaprine hydrochloride Verelan verapamil hydrochloride Kapspargo metoprolol Coreg carvedilol Table Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310 299
US
1996 1998 2009 2001 2003 1997 2014 Approval Initial
Upsher-Smith Laboratories Wyeth Upsher-Smith Laboratories Shire Forest Alpharma Pharmaceuticals Allergan Company
and and and and and and and
or
soft soft
on on on on on on on
crushing.
immediately immediately immediately immediately without capsule capsule capsule capsule capsule capsule capsule
or
foods. granules.
the the the the the the the
applesauce
the contents contents contents contents contents contents contents
as
other
mixture mixture mixture mixture mixture
open open open open open open open
the the the the the the the chewing chewing. chewing. chewing.
use chew the the the the the
such
not not
Carefully sprinkle food. Ingest without Carefully sprinkle applesauce. Ingest without sprinkle foods, pudding. Ingest without Carefully sprinkle applesauce. Ingest without Carefully sprinkle applesauce. Carefully sprinkle applesauce. Do Do Carefully sprinkle applesauce. Ingest chewing. Carefully Manipulation
iron
dioxide
chain acid
citrate
stearate triglycerides
beige;Sugar acid oxide;Red
oxide
silicon DEP;Magnesium dioxide
methacrylate
iron chain
iron
hydroxide;Oleic
2910;EC;DEP;Titanium
acid;Medium
copolymer
MCC;HPMC dioxide;Black oxide;Yellow Cellulose;EC;Gelatin;HPMC;Iron oxide;Titanium EC;Talc;Gelatin;Titanium HPMC;Methacrylic copolymer;Opadry spheres;Talc;Triethyl Sugar spheres;PVP;HPMC;Talc;PEG;EC; Ammonium acid;Medium Talc;Ammonio copolymer;Sugar spheres;EC;Sodium chloride;PEG;HPC;DBS;Methacrylic acid stearate;SLS;Ascorbic Sugar spheres;Povidone;Talc;HPMC;PEG; EC;Oleic triglycerides;Lactose monohydrate;MCC;Corn starch;Colloidal dioxide;Magnesium Excipients
mg
mg
200 30
and and
60/2.4,
and protect protect
mg C C. C
mg ° ° °
mg mg
and
and
50/2, 25 25 25 and and
28
moisture. light 150
mg hydrochloride/ 25,
C. C. C C
hydrochloride 100/4 to to to 150, ° ° ° °
sulfate/mg 28/10
and 20, and
750 20 20 20 25 25 25 25
from from
30/1.2, and 100,
and at at at at at at at 21, 15, light. light.
75,
and donepezil
50,
14, 10,
25, Store protect 37.5, Store 600 Store protect moisture. Store 7, Store 20/0.8, 80/3.2, morphine naltrexone Store from 14/10 memantine mg hydrochloride Store from 5, Strength/Storage
or
to to
disorder
the the
migraine
of of
syndrome
moderate epilepsy
of
anxiety
of prevention panic seizures major ADHD moderate moderate
type type anxiety
disorder, with of of or of of of
pain social and
dementia dementia
prevention
severe hypokalemia
Treatment associated Lennox-Gastaut and Treatment depressive generalized disorder, disorder, Treatment of Treatment Treatment severe Alzheimer’s Management to Treatment severe Alzheimer’s Indication
)
names sulfate and and
/ naltrexone
/memantine
R /morphine
R
XR/
R
R TM continued
XR
and
(
/memantine 5
/dextroamphetamine
R TM
Brand/Generic Qudexy topiramate Effexor venlafaxine Klor-Con Sprinkle/potassium chloride Adderall XR sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, amphetamine Namenda XR hydrochloride Embeda sulfate hydrochloride Namzaric hydrochloride donepezil hydrochloride Table 300 Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310
)
US page
next
1989 1989 1989 approval 1994 Initial on
continued
(
AbbVie R2 Pharma AstraZeneca Horizon Company
be
tested. foods, only
min
the
and and and
30
as soft applesauce. applesauce,
been
pudding. should
on on on juice.
not
or
immediately immediately immediately within capsule capsule capsule
juice.
has
the the the
fruit
applesauce,
contents contents contents contents
grapefruit or
mixture mixture mixture mixture
foods on
open open open
the the the chewing. chewing. chewing. chewing.
applesauce
use the the the the
soft jelly,
as
capsule
not
Carefully sprinkle such Ingest without The sprinkled other Ingest without Carefully sprinkle Ingest without Carefully sprinkle berry Do Ingest without Manipulation
d-55
acid stearate stearate 80 80
diglycerides 30
polymers
dioxide
L
carbonate monostearate
citrate citrate citrate citrate
spheres spheres and
gel
oxide
Cellulosic Iron Magnesium Silica Titanium Triethyl Calcium HPMC Methacrylic copolymer Mono Polysorbate Sugar Talc Triethyl Glyceryl 40–55 HPC HPMC Magnesium MCC Polysorbate Sugar Talc Triethyl MCC Eudragit HPMC Talc Triethyl SLS Excipients
20
at
after
light C.
and °
C. C ° and
°
25
8 25 from
respectively, C.
to °
mg mg to
20 25 2 before
40 75
C below at at at °
mg protect moisture. mg
and and 25
Store 49.3 Store 20 Store 25 Store to dispensing, and and 125 Strength/Storage capsules.
–DR
gastric
and
.
.
of eradication products
conditions,
pylori
epilepsy GERD, GERD nephropathic
hypersecretory
and pylori
(e.g.,
of of of of
pathological
and sprinkle
eradication
Helicobacter
Treatment Treatment ulcer, hypersecretory and Helicobacter Treatment pathological conditions Zollinger-Ellison syndrome), of Treatment cystinosis Indication available
names Strontium
Sprinkle
/cysteamine
R /esomeprazole
– Commercially R R
6
Brand/Generic Depakote Capsules/divalproex sodium Esomeprazole Delayed-Release Capsules/esomeprazole strontium Nexium magnesium Procysbi bitartrate Table Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310 301
)
US page
next
1995 1995 approval 1999 Initial on
continued
( Takeda Takeda Cerecor Company
food,
juice,
juice, min
and and and
15
cheese, baby applesauce. applesauce, applesauce,
juice. apple solution.
apple
on on on
immediately immediately. within capsule capsule capsule
cottage
pears, tomato
the the the
formula,
or
contents contents contents electrolyte
mixture mixture mixture
open open open
the the the chewing. chewing. vegetable-based
pudding,
strained infant juice,
the the the
or
pediatric
Carefully sprinkle Ingest without Carefully sprinkle Ensure, yogurt, orange Ingest Carefully sprinkle fruit- yogurt, or Ingest without Manipulation
dioxide dioxide dioxide
acid acid carbonate carbonate oxide stearate 80 80
chloride
dioxide dioxide dioxide silicon silicon silicon
citrate
2910
spheres sphere
8000
Sugar Magnesium Sucrose L-HPC Titanium HPC HPMC Talc Methacrylic copolymers PEG Triethyl Polysorbate Colloidal HPC L-HPC Colloidal Magnesium Methacrylic copolymer Starch Talc Sugar Sucrose PEG Polysorbate Titanium Colloidal Diacetylated monoglycerides EC HPC HPMCP Magnesium Magnesium Mannitol Talc Titanium Carrageenan Potassium Excipients
protect
C.
°
25 and
C. C to ° °
mg mg
mg
20 25 25
60 30
10 at at at
moisture.
and and
and
30 Store 15 Store Store from 5 Strength/Storage
ulcer,
.
GERD of
conditions,
esophagitis,
GERD erosive
and pylori
of of of
erosive
pathological eradication
esophagitis gastric/duodenal GERD, and hypersecretory and Helicobacter Treatment Treatment Treatment Indication
)
names
/rabeprazole
/dexlansoprazole /lansoprazole
R R R
TM continued
(
6
Brand/Generic Dexilant Prevacid Aciphex sprinkle sodium Table 302 Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310
)
US page
next
2009 2009 approval 2010 Initial on
continued
( AbbVie Forest Vivus Company
a a a
in in in
the the the breast breast breast
with with with or or or
pears.
capsule capsule capsule
applesauce, applesauce applesauce, or
carefully carefully carefully mixed mixed mixed
the the the
food food food
retained retained retained
as as as
sprinkle sprinkle sprinkle
be be be is is is
formula formula formula immediately immediately immediately soft soft soft
available
and and and
compromise
not not not adults, adults, adults, such such such
breast-feeding. breast-feeding. breast-feeding. bananas
drug drug drug
of
infant infant infant and and and acidic acidic acidic may
no no no less, less, less,
administer administer administer
mixture mixture mixture
should should should capsule capsule capsule or or or before on before on before on
chewing. chewing. chewing. temperature. temperature. into into into
this
that that that
the the the
4.5 4.5 4.5 the the the
as
commercially mouth. mouth. mouth.
infants, children infants, children infants, children of of of
room room
For contents Contents directly milk. For open contents pH at Ingest without Ensure the For contents Contents directly milk. For open contents pH and preparations Ingest without Ensure the For contents Contents directly milk efficacy. For open contents pH at Ingest without Ensure the Manipulation
oil
silica
dioxide
sodium
wax
castor
emulsion
acid-ethyl stearate stearate
silicon anhydrous
copolymer glycol citrate citrate citrate
alcohol
Cetyl Dimethicone HPMCP PEG Triethyl Colloidal Croscarmellose Hydrogenated HPMCP Magnesium MCC Talc Triethyl Cellulose; Colloidal Crospovidone Magnesium Methacrylic acrylate Montan Simethicone Talc Triethyl Excipients
units units
the
and
protect
USP
and in
12/38/60,
USP USP
10/32/42, 3
C C 3 3
° °
10 and
and
4.2/14.2/24.6,
moisture. moisture. 10 10
25 25 × C
× × °
and and
20/63/84,
6/19/30,
25 container 5/17/24,
from from
below at below of moisture.
lipase/protease
3/9.5/15, 24/76/120, 36/114/180 of lipase/protease/amylase Store protect 3/10/14, 15/47/63, 25/79/105, 40/126/168 of Store from 2.6/6.2/10.85, 10.5/35.5/61.5, 16.8/56.8/98.4 21/54.7/83.9 units lipase/protease/amylase Store original protect Strength/Storage
exocrine exocrine exocrine
insufficiency insufficiency insufficiency of of of
pancreatic pancreatic pancreatic Treatment Treatment Treatment Indication
)
names
/pancrelipase
R
/pancrelipase continued
R /pancrelipase
(
R
6
Brand/Generic Creon Zenpep Pancreaze Table Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310 303
US
2012 2012 approval Initial
Digestive Care Forest Company
a a
in in
the the breast breast
with with or or
capsule capsule efficacy.
applesauce, applesauce, efficacy.
carefully carefully
mixed mixed
the the
food food
retained retained
as as
sprinkle sprinkle
be be is is
formula formula immediately immediately soft soft
and and
diminish reduce not not
adults, adults, such such
breast-feeding. breast-feeding.
drug drug
infant infant and and acidic acidic may may
no no less, less,
administer administer
mixture mixture
should should capsule capsule or or before on before on
chewing. chewing. temperature. temperature. into into
this this
that that
the the
4.5 4.5 the the
as as
mouth. mouth. infants, children infants, children of of
room room
For contents Contents directly milk For open contents pH at Ingest without Ensure the For contents Contents directly milk For open contents pH at Ingest without Ensure the Manipulation
oil
dioxide
sodium
glycolate
castor
stearate
acetate
silicon
citrate bicarbonate carbonate starch
Sodium Sodium Cellulose phthalate Sodium DEP Ursodiol PVP Talc Colloidal Croscarmellose Hydrogenated HPMCP Magnesium MCC Talc Triethyl Excipients
and and units
USP
C C
° ° 3
and USP 10
and 25 25
moisture. moisture. 3
×
to to 10
×
20 20 lipase/protease
from from
13.8/27.6/27.6, at at of
4/14.375/15.125, 8/28.75/30.25, 16/57.5/60.5 units Store protect 4/8/8, 20.7/41.4/41.4, 23/46/46 of lipase/protease/amylase Store protect Strength/Storage
exocrine exocrine
insufficiency insufficiency of of
pancreatic pancreatic Treatment Treatment Indication
)
names
/pancrelipase
/pancrelipase continued
R (
TM
6
Brand/Generic Pertzye Ultresa Table 304 Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310
US
1955 1968 1998 2001 1998 2001 2002 2005 Approval Initial
Ironshore Pharmaceuticals Validus Pharmaceuticals Shire Recro Gainesville UCB Shire Novartis Novartis Company
on on on on on on on on
without capsule capsule capsule capsule capsule capsule capsule capsule
contents contents contents contents contents contents contents contents
the the the the the the the the
without without without the the the the the the the the
mixture mixture mixture mixture mixture mixture
open open open open open open open open
the the the the the the
sprinkle sprinkle sprinkle sprinkle sprinkle sprinkle sprinkle sprinkle
Carefully and applesauce. Ingest immediately. Carefully and applesauce. Ingest chewing. Carefully and applesauce. Carefully and applesauce. Ingest immediately chewing. Carefully and applesauce. Ingest immediately chewing. Carefully and applesauce. Carefully and applesauce. Ingest immediately chewing. Carefully and applesauce. Ingest immediately. Manipulation
(10
35,
and
25, and
citrate
oxide iron 30,
15, (10
mg
dioxide (5,
(10,
80;Talc
iron 40
dioxide;Triethyl and #2 Tan
acid Yellow spheres
beige;Sugar oxide
acid
citrate
acid
silicon silicon and
oxide acrylate;Methyl
Blue iron
35,
dioxide;Triethyl iron
30, spheres;Talc;Titanium citrate citrate
strengths);Sugar strengths); methacrylate methacrylate
15,
acid;Povidone;Shellac;SD;SLS;
mg mg
strengths);Gelatin;Methacrylic strengths) spheres;Povidone;HPMC;PEG; (10, acid;Colloidal acid;Colloidal
copolymer;PEG;Red 40 40
mg mg
DBS;EC;HPC;HPMC;Magnesium stearate;Methacrylic copolymer;MCC;Mono diglycerides;Polysorbate Citric dioxide;Lactose monohydrate;MCC;PEG;Povidone;SLS; Talc;Triethyl Citric dioxide;Lactose monohydrate;MCC;PEG;Povidone;SLS; Talc;Triethyl Fumaric Starch;Sugar dioxide Sugar EC;DBS;Gelatin;Titanium EC;HPMC;Methacrylic copolymer;Methyl methacrylate;Opadry spheres;Talc;Triethyl Ammonio copolymer;Black 40 acid and spheres;Talc;Titanium citrate;Yellow 40 Ammonio copolymer;FD&C and oxide strengths);Gelatin;Ink SW-8010;Methacrylic copolymer;PEG;Sugar Talc;Titanium Excipients
and
mg
mg
mg
and and 35,
protect protect protect 50 100
60
C C C
mg mg mg mg
° ° °
30,
moisture. moisture.
40
25 30 25 and and and
and and 300 300 300
moisture. moisture.
and
25, C C C C. C.
to to to ° ° ° ° °
and and 80, 40 and
and and and 20,
37.5,
20 25 25 25 15 20 25 25
from from
60, 30, 30,
at at at at at at at at 15, light light moisture.
25,
200, 200, 200,
40, 20, 20,
mg
10,
Store protect 100, Store from 100, Store from 100, Store from Store protect Store Store 40 Store 20, 10, 12.5, 10, 5, Strength/Storage – MDDS.
I
and
episodes products essential bipolar
epilepsy
associated of
ADHD ADHD ADHD ADHD ADHD acute pain
with with neuralgia of of of of of of of
and
mixed pain
or
sprinkle
trigeminal
Treatment manic associated disorder, with neuralgia, associated trigeminal epilepsy Management hypertension Treatment Treatment Treatment Treatment Treatment Treatment Indication
available
Names aspartate
and /methylphenidate
/carbamazepine
R /dextroamphetamine PM/verapamil
R /carbamazepine
– Commercially
R
R
R amphetamine dextroamphetamine
LA PM/methylphenidate 7
/methylphenidate /dexmethylphenidate
R R
Brand/Generic Jornay hydrochloride Equetro Carbatrol Verelan hydrochloride Metadate CD hydrochloride Mydayis sulfate, sulfate, saccharate, amphetamine monohydrate Ritalin hydrochloride Focalin XR hydrochloride Table Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310 305
sprinkling the fragments on soft food so that the patients can Viread R (tenofovir disoproxil fumarate; Gilead Sciences) is easily swallow them with food. a nucleotide analog that acts as reverse transcriptase inhibitor Doryx R (doxycycline hyclate; Mylan) is used to treat or for human immunodeficiency virus type 1 (HIV-1) and prevent infections that are caused by bacteria [11] . Doryx R hepatitis B virus. In a bioequivalence study conducted under tablets contain coated pellets of doxycycline hyclate in a DR non-fasting conditions, the average maximum plasma formulation. The tablet of 50/200 mg dose contains lactose, concentration (C max ) of tenofovir was 26.9% lower for the oral microcrystalline cellulose (MCC), povidone, starch wheat, powder compared with the tablet formulation. According to magnesium stearate, and cellulosic polymer coating. After the FDA review document, this difference can be attributed crushed, the obtained Doryx R pellets can be sprinkled on to the taste-masking technology used in Viread R [14] . applesauce and administered. The extent of absorption of However, the mean values of total area under the plasma doxycycline does not change with concomitant water, but the concentration-time curve (AUC) of tenofovir were similar absorption rate increases slightly. between the powder and the tablet. Jadenu R (deferasirox; Novartis) is an iron chelator agent Fosrenol R (lanthanum carbonate; Shire) is a phosphate indicated for the treatment of chronic iron overload caused binder for reducing serum phosphate level in patients by blood transfusions. Jadenu R includes 90, 180, and 360 mg with the end-stage renal disease. This product is available deferasirox. Inactive ingredients include MCC, crospovidone, in 750 or 1000 mg strength and contains colloidal silicon povidone K30, magnesium stearate, colloidal silicon dioxide dioxide, dextrates, and magnesium stearate as excipients. It and poloxamer 188. The instruction for manipulation is is recommended to sprinkle Fosrenol R on a small quantity to carefully crush the tablet and immediately sprinkle the of applesauce or other similar food, rather than to mix with contents on applesauce. Commercial grinders with serrated liquid vehicles due to its poor solubility. surfaces should be avoided when crushing the 90 mg tablet. Kuvan R (sapropterin dihydrochloride; BioMarin Sprinkled tablets should be consumed immediately and Pharmaceutical) can decrease blood phenylalanine levels. completely. Kuvan R is available in unit capacity packets of 100 or Xarelto R (rivaroxaban; Janssen) is an anticoagulant or 500 mg of sapropterin dihydrochloride. Each unit dose packet blood-thinner to reduce the risk of pulmonary embolism, contains ascorbic acid, d -mannitol, potassium citrate, and deep vein thrombosis, and stroke systemic embolism. sucralose. For infants weighing less than 10 kg, dissolve It is available in 10, 15, and 20 mg tablets, and contains powder in 5 ml of water or apple juice. Some of this solution croscarmellose sodium, hypromellose (HPMC), lactose can be administered orally via a syringe. Kuvan R powder monohydrate, magnesium stearate, MCC, and sodium lauryl is bioequivalent to the same dose of Kuvan R tablet. Before sulfate (SLS). Crushed Xarelto R is stable in applesauce and administration, the packet content needs to be dissolved in water for up to 4 h. A crushed Xarelto R tablet showed a 120–240 ml of water or apple juice; or sprinkled on a small comparable relative bioavailability compared with an intact amount of soft food such as applesauce or pudding. However, tablet [12] . administration with high-fat/high-calorie meal caused 1.84- R Savaysa (edoxaban; Daiichi Sankyo) is a factor Xa and 1.87-fold increase in the mean C max and AUC values of inhibitor to reduce the risk of systemic embolism and stroke sapropterin, respectively, with extensive individual variability. in patients with nonvalvular atrial fibrillation. The product comes in 15, 30, and 60 mg strengths, and contains mannitol, 2.4. Granules pregelatinized starch, crospovidone, hydroxypropyl cellulose (HPC), magnesium stearate, talc, and carnauba wax. The Granules are large and free-flowing particles, which are total systemic exposure of edoxaban is not affected by food. commonly prepared by the agglomeration of powder. There Administration of a crushed tablet mixed with soft food or are three types of granulations as dry granulation, wet suspended in water and given via a nasogastric tube showed granulation and fluid bed granulation. Dry granulation is similar absorption with the administration of an intact tablet. made by crushing large masses of powder mixture into small
Emflaza TM (deflazacort; PTC Therapeutics) is a pieces, and wet granules are made by adding a liquid binder corticosteroid used to treat Duchenne muscular dystrophy. or adhesive. Fluid bed granulation is made by spraying a It is available in 6, 18, 30, and 36 mg tablets, and contains granulating solution onto the particles [13] . Their size ranges colloidal silicon dioxide, lactose monohydrate, magnesium from 0.85 mm (sieve No. 20) to 4.75 mm (sieve No. 4). The stearate, and pre-gelatinized corn starch. Crushing and shape of granules is generally irregular [13] . There are more sprinkling of Emflaza TM on applesauce did not influence the than seven sprinkle granule products commercially available, bioavailability of deflazacort. which can be sprinkled on liquid or soft foods and swallowed without chewing. 2.3. Powders Singulair R (montelukast sodium; Merck) is a leukotriene receptor antagonist for prophylaxis and chronic treatment Powder is much easier to administer with food or drink of asthma, acute prevention of exercise-induced to elderly and pediatric patients compared with tablets or bronchoconstriction, and alleviation of allergic rhinitis. capsules. The powder formulations usually have fine bead- The product is available in 4 mg dose, and the inactive like morphology. The powder is typically 0.1 to 10 μm in ingredients include mannitol, HPC, and magnesium stearate. size [13] . Commercially, there are more than four products of Singulair R granules can be administered by dissolving in a sprinkle powder. teaspoonful of baby formula or breast milk or mixing with a 306 Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310
spoonful of soft food such as applesauce, carrots, rice or ice in adults and children. Topamax R sprinkle capsules include cream. 15 or 25 mg of topiramate-coated beads in a hard gelatin Jadenu R Sprinkle (deferasirox; Novartis) is used for capsule. Cellulose acetate, gelatin, povidone, SLS, sorbitan chronic iron overload caused by blood transfusion. Jadenu R monolaurate, sugar spheres, and titanium dioxide are added Sprinkle granules contain 90, 180, and 360 mg deferasirox. as excipients. Topamax R Sprinkle Capsules are bioequivalent MCC, povidone K30, magnesium stearate, colloidal silicon to the immediate-release tablet. Food does not affect the dioxide, and poloxamer 188 are included as excipients. bioavailability of topiramate.
The bioavailability (as AUC) of granules was 52% higher Colazal TM (balsalazide disodium; Valeant Pharms) is a than tablets, and the mean C max increased by 34% in the locally acting aminosalicylate to treat mild to active ulcerative fasted state, although the results were not clinically relevant. colitis. The 750 mg capsules have colloidal silicon dioxide and When sprinkle granules were taken with low-calorie food magnesium stearate as inactive ingredients. The systemic TM (approximately 450 calories with a fat content around 30% absorption of Colazal exhibited high variability in C max of total calories), AUC and C max were similar to those under and AUC values when administered as sprinkles and intact fasting condition. However, when administered with high- capsules. However, its ingestion with high-fat meal markedly calorie food (approximately 1000 calories with a fat content delayed the time to reach C max (T max ) compared with higher than 50% of total calories), AUC increased by 18% administration in the fasted state. R without changes in C max . Tasigna (nilotinib; Novartis) is a kinase inhibitor used Xuriden R (uridine triacetate; Wellstat Therapeutics Co.) to treat patients with Philadelphia chromosome-positive is a pyrimidine analog for the therapy of hereditary orotic chronic myeloid leukemia. Tasigna R contains 150 or 200 mg aciduria. Xuriden R 2 g packet contains ethylcellulose (EC), nilotinib with colloidal silicon dioxide, crospovidone, lactose HPMC, and polyethylene glycol (PEG) as inactive ingredients. monohydrate, magnesium stearate, and poloxamer 188. The granules can be sprinkled on applesauce, pudding, or Tasigna R sprinkled on applesauce and administered within yogurt; or may be mixed with milk or infant formula. The food 15 min is bioequivalent to the intact capsule. effect on uridine pharmacokinetics was negligible, showing no Rapaflo R (silodosin; Allergan) was developed for the difference in total urinary exposure and range. treatment of benign prostatic hyperplasia. Rapaflo R capsules
Solosec TM (secnidazole; Lupin) is a nitroimidazole include 4 or 8 mg of silodosin with D -mannitol, magnesium antimicrobial for the treatment of bacterial vaginosis in stearate, pre-gelatinized starch, and SLS. The bioequivalent adult women. Yellowish granules (4.8 g), which contain 2 g AUC and C max values were observed when the capsule was of secnidazole, are packed in a foil packet that is difficult administrated intact or with the capsule content sprinkled on for children to open. The other ingredients are ethyl applesauce. acrylate-methyl methacrylate copolymer, PEG4000, povidone, sugar spheres, and talc. Solosec TM exhibited no significant 2.6. Extended-release capsules difference in C max and AUC values when administered under fasting conditions (mixed with applesauce) or with high- ER drug products can reduce the frequency of dosing more calorie foods. Administration of Solosec TM with pudding or than two-fold compared with IR (conventional) products [15] . yogurt showed no difference either. ER dosage forms are divided into two types: sustained- release (SR) and controlled-release (CR) types. SR type releases 2.5. Immediate-release capsules cargo molecules over a sustained period, but not at a constant rate, whereas CR type releases the drug at a nearly Most oral formulations such as tablets, powder, granules, and constant rate [16] . More than twenty products are listed as capsules are designed to release the drug immediately after ER sprinkle capsules in the FDA database. The method of oral administration [15] . IR products generally provide fast administration of ER capsules is the same as that of IR absorption of the drug and consequent rapid onset of the capsules. pharmacokinetic effects. There are at least nine sprinkle IR Kadian R (morphine sulfate; Actavis) is an opioid agonist capsule products available commercially. Sprinkle IR capsules for the management of severe pain. Kadian R contains 10, 20, should be opened carefully, and the contents sprinkled on soft 30, 40, 50, 60, 70, 80, 100, 130, 150, or 200 mg of morphine foods need to be swallowed immediately without chewing. sulfate with HPMC, EC, methacrylic acid copolymer, PEG, DEP, Sustiva R (efavirenz; Bristol-Myers Squibb), a non- talc, corn starch, and sucrose. Capsule contents of Kadian R nucleoside reverse transcriptase inhibitor, is used in can be administered by sprinkling on applesauce, which is combination with other antiretroviral agents for the bioequivalent to the intact capsule. treatment of HIV-1 infection. Sustiva R contains 50 or 200 mg Rytary TM (carbidopa and levodopa; Impax Laboratories) is of efavirenz and lactose monohydrate, magnesium, stearate, indicated for the treatment of Parkinson’s disease. Rytary TM SLS, and sodium starch glycolate as inactive ingredients. comes in 23.75/95, 36.25/145, 48.75/195, and 61.25/245 mg This product should be administered orally once daily on strengths (carbidopa/levodopa). The inactive ingredients an empty stomach, preferably at bedtime. The AUC value are MCC, mannitol, tartaric acid, ethyl cellulose, HPMC, of Sustiva R sprinkled on applesauce was bioequivalent to sodium starch glycolate, SLS, povidone, talc, methacrylic that of the intact Sustiva R capsule when administered in the acid copolymer, triethyl citrate, croscarmellose sodium, and fasted state. magnesium stearate. Topamax R Sprinkle Capsules (topiramate; Janssen) are Gocovri TM (amantadine; Adamas Pharmaceuticals) is used for the treatment of epileptic convulsions and migraine used to treat dyskinesia in patients with Parkinson’s Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310 307
disease. Each amantadine capsule (68.5 or 137 mg dose) capsules. However, in most cases, DR and ER products are not contains copovidone, EC, HPMC, magnesium stearate, interchangeable due to the difference in release pattern. medium chain triglyceride, MCC, povidone, and talc as Depakote R sprinkle capsule (divalproex sodium; AbbVie) excipients. Administration of Gocovri TM as sprinkles on is used as monotherapy or adjuvant therapy for complex applesauce exerted no significant effect on the plasma partial seizures of adult and pediatric patients (ten years of pharmacokinetics of amantadine compared with the intact age and older) [17] . The coated beads of divalproex sodium are capsule administration. In addition, concomitant high-calorie contained in a hard gelatin capsule. Cellulosic polymers, iron food also did not affect the amantadine pharmacokinetics. oxide, magnesium stearate, silica gel, titanium dioxide, and Amrix R (cyclobenzaprine hydrochloride; Teva triethyl citrate are added as inactive ingredients. Depakote R Pharmaceuticals) is a muscle relaxant to be used as an sprinkle capsule should not be used as a substitute for adjunct to rest and physical therapy. Amrix R comes in 15 Depakote R ER tablet, as these products have different and 30 mg capsules, and the inactive ingredients include pharmacokinetic properties. diethyl phthalate(DEP), EC, gelatin, Opadry R Clear YS-1- Esomeprazole Strontium Delayed-Release Capsules 7006, sugar spheres NF (20–25 mesh), and titanium dioxide. (esomeprazole strontium; R2 Pharma) are used for Bioequivalence of Amrix R capsules administered as sprinkles gastroesophageal reflux disease (GERD), gastric and duodenal on applesauce compared with the intact capsule was proved. ulcer, and pathological hypersecretory conditions (e.g., Verelan R (verapamil hydrochloride; Recro Gainesville) Zollinger-Ellison syndrome) in adults. This product comes is used for the management of essential hypertension. in 49.3 mg dose and contains calcium carbonate, HPMC, This product contains 100, 200, or 300 mg of verapamil methacrylic acid copolymer, mono and diglycerides, hydrochloride and fumaric acid, povidone, shellac, SD, SLS, polysorbate 80, sugar spheres, talc, and triethyl citrate. starch, sugar spheres, talc, and titanium dioxide as inactive When administered after a high fat meal, AUC value was ingredients. When Verelan R capsule was administered by reduced by 52% compared with fasting condition. sprinkling on applesauce, the rate and extent of verapamil Aciphex R Sprinkle TM (rabeprazole sodium; FSC absorption were bioequivalent to those of the intact capsule Laboratories) is a proton-pump inhibitor (PPI) for GERD. This with the same dose. product contains granules of 5 or 10 mg of rabeprazole sodium Adderall XR R (dextroamphetamine sulfate; Shire) is used in a hard hypromellose capsule. The inactive ingredients for the treatment of attention deficit hyperactivity disorder are colloidal silicon dioxide, diacetylated monoglycerides, (ADHD). While the conventional Adderall tablets are designed EC, HPC, hypromellose phthalate (HPMCP), magnesium for IR type drug release, Adderall XR R capsules, which oxide, magnesium stearate, mannitol, talc, titanium dioxide, contains two types of drug-containing beads, provide double- carrageenan, and potassium chloride. Aciphex R administered pulsed delivery of amphetamine. The inactive ingredients with high-fat meal exhibited reduced C max and AUC (by 55% R in 5, 10, and 15 mg Adderall XR capsules include HPMC, and 33%, respectively) as well as delayed median T max (from methacrylic acid copolymer, Opadry R beige, sugar spheres, 2.5 to 4.5 h) compared with that with applesauce under fasted talc, and triethyl citrate. Adderall XR R capsules administered condition. The type of soft food (e.g., applesauce, yogurt and as an intact capsule and sprinkles on applesauce were liquid infant formula) did not significantly change T max , C max , bioequivalent in the fasted condition. Moreover, Adderall IR and AUC of rabeprazole. tablets (twice a day) can be replaced with the same dose of Adderall XR R capsules (once a day). 2.8. Multiparticulate drug delivery system (MDDS) Namzaric R ER capsules (memantine hydrochloride and donepezil hydrochloride; Allergan) are indicated for the The MDDS oral dosage form consists of small individual treatment of moderate to severe dementia of the Alzheimer subunits (e.g., beads or microencapsulated drugs) that exhibit type. Namzaric R contains 14/10 mg or 28/10 mg of memantine different properties [18] . These subunits can be compressed hydrochloride/donepezil hydrochloride in each capsule. into a tablet or packed into a capsule [19] . Most of the MDDS The other components are sugar spheres, povidone, talc, sprinkle products are designed based on the spheroidal oral HPMC, PEG, EC, oleic acid, medium chain triglycerides, drug absorption system (SODAS R ) or chronotherapeutic oral lactose monohydrate, MCC, corn starch, colloidal silicon drug absorption system (CODAS R ) technologies. R dioxide, and magnesium stearate. C max and AUC values of Metadate CD (methylphenidate hydrochloride; UCB) is Namzaric R in the fed and fasted conditions were similar. a central nervous system stimulant for the treatment of Moreover, no significant difference in the absorption of ADHD. Metadate CD R has a biphasic release pattern, which memantine hydrochloride was observed when the capsule is attributed from the IR (30% of dose) and ER (70% of dose) was administrated intact or with its contents sprinkled on beads included in the capsule. Metadate CD R contains 10, applesauce. 20, 30, 40, 50 or 60 mg of methylphenidate hydrochloride. The other components are sugar spheres, povidone, HPMC, PEG, 2.7. Delayed-release capsules EC aqueous dispersion, dibutyl sebacate (DBS), gelatin, and titanium dioxide. Metadate CD R administered as sprinkles In general, DR dosage forms refer to enteric-coated on applesauce showed bioequivalent systemic exposure (as formulations, of which drug release begins after a C max and AUC) of methylphenidate compared with the intact predetermined delay [13] . More than twelve products are capsule. listed as DR sprinkle capsules. The administration method Ritalin LA R (methylphenidate; Novartis) and Focalin TM of the DR capsule is the same as those of the IR and ER XR (dexmethylphenidate; Novartis) are also used to treat 308 Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310
(2) Modified-release products, of which drug release can be changed by splitting, should not be pre-scored. (3) The split tablet should be stable for 90 d under ambient condition. (4) The split tablet portions should meet the same criteria of finished-product testing as for a whole-tablet product of equivalent strength. However, this information is not directly applicable to sprinkle dosage forms. In May 2012, the US FDA released a brief guideline on the products labeled for sprinkle, where the following three recommendations are listed [24] . The first is the maximum bead size of sprinkle drug products. The agency recommends a target bead size up to 2.5 mm with less than 10% variation and a maximum size of 2.8 mm to avoid inadvertent chewing. The unintentional chewing of beads may compromise the safety and efficacy of the loaded drug. For example, a burst or an early release of the drug may occur for the ER or DR beads, respectively, and the unpleasant taste of released drug may lead to poor compliance with the oral Fig. 3 –Schematic illustration of SODAS R technology. The administration. Indeed, the labeling of most sprinkle beads spherical bead has a multilayered structure, of which the states that the contents should not be crushed, chewed, drug-containing core is coated with the layers of split, or dissolved. The second topic of the guidance is the release-controlling polymers. administration of the sprinkle products via the enteral feeding tube. According to these recommendations, the sprinkle drug products need to be delivered through an enteral feeding ADHD. Ritalin LA R and Focalin TM XR are designed based tube without loss of dose, crushing of beads, and tube on SODAS R technology, with which uniform spherical occlusions. Also, the manufacturer should display special beads of approximately 1 to 2 mm in diameter can be instructions on the product labeling regarding the information produced. The schematic illustration of SODAS R is shown on this alternative delivery method. The third part of guidance in Fig. 3 . The spherical bead has a multilayered structure contains the recommendations related to the bioequivalence of a drug/excipients core and release-controlling polymer and bioavailability studies. For the labeling to state that coatings [20,21] . The polymers in the coating layers can the drug product can be sprinkled, the information on the be water soluble, insoluble, or even pH-responsive. Their bioavailability or bioequivalence of the sprinkled formulation physicochemical properties directly affect the release pattern versus its intact form (for new drug applications, NDAs) or of the final product [2] . Additionally, by compounding beads reference listed drug (for abbreviated new drug applications, with different coatings, a customized drug-release profile ANDAs) should be included, respectively. Regarding the IR can be achieved, which makes SODAS R a versatile oral drug sprinkle products, the bioequivalence study is not necessary delivery system [2] . because their pharmacokinetic properties are expected to be Verelan R PM (verapamil hydrochloride; Schwarz Pharma) similar compared with the IR product of reference listed drug. is used for the management of essential hypertension. Recently in July 2018, the US FDA released a draft Verelan R PM administered at bedtime shows a 4 to 5 h of delay guidance on the use of liquids and/or soft foods as vehicles in drug release. This product contains DR beads of CODAS R , for drug administration [25] . This article encompasses not of which release-controlling polymer layer consists of both only general considerations for soft food vehicles but also water-soluble and insoluble polymers. When contacted with methodologies for assessing the impact of the vehicles on water in the gastrointestinal tract, the water-soluble polymer the drug product quality. The general considerations and in the coating gradually dissolves forming drug-releasing recommendations part focuses on the compatibility and pores. The water-insoluble polymer acts as a barrier to control suitability for selecting soft foods, possible impacts of vehicles the release of the drug [22] . The release rate of Verelan R on the drug product, and patient adherence and acceptance in PM is independent of pH and concomitant food. Moreover, terms of palatability and swallowability. According to this part, Verelan R PM administered as sprinkles on applesauce was the compatibility of commonly used soft foods with sprinkle bioequivalent to the intact capsule. formulations should be informed to ensure the efficacy and safety. Moreover, the product labeling needs to contain more than one example of soft food, because the limited 3. FDA guidance of sprinkle formulations types of food are inconvenient for patients with allergy or intolerance. A practical guidance that contains assessment criteria for When evaluating the compatibility and suitability, not only manufacturing and quality control of sprinkle formulations the properties of drug substance or drug product but also has been needed. The FDA guidance on tablet scoring is those of foods, such as acidity and drug-binding/chelating related to this issue to a certain degree [23] . (1) The split characteristics, should be taken into account. Approximate pH tablet portion should not have a lower amount of drug ranges of commonly used soft foods and liquids are provided than the minimum dose indicated on the approved labeling. in this guidance ( Fig. 4 ). In addition, the age of the target Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310 309
and consequently provide higher therapeutic benefit for patients.
Conflicts of interest
The authors declare that there is no conflicts of interest.
Acknowledgments
This work was supported by the National Research Foundation of Korea ( NRF) grant funded by the Ministry of Science and ICT (No. NRF-2018R1C1B6005379 ).
Supplementary material Fig. 4 – Approximate pH ranges of commonly used soft foods and liquids.(Adapted from Appendix A of Ref. [25] . Supplementary material associated with this article can be found, in the online version, at doi: 10.1016/j.ajps.2019.05.003 . population needs to be considered when selecting the flavor, references texture, and mouthfeel of the food vehicles, as the age-related responses to these properties are different. For example, some vehicles with grainy texture may cause inadvertent [1] Sastry SV , Nyshadham JR ,Fix JA . Recent technological chewing in young patients, and soft food vehicles are advances in oral drug delivery - a review. Pharm Sci Technol discouraged for infants who are able to ingest only the liquid Today 2000;3(4):138–45 . foods. [2] Strickley RG ,Iwata Q ,Wu S ,Dahl TC . Pediatric drugs-a
The guideline also provides methods for handling and review of commercially available oral formulations. J Pharm Sci 2008;97(5):1731–74 . dosing the mixture of the drug product and soft foods. The in [3] Tahaineh L , Wazaify M . Difficulties in swallowing oral vitro methods recommended for assessing impact of a vehicle medications in Jordan. Int J Clin Pharm 2017;39(2):373–9 . on product quality attributes part presents a standardized [4] Lau ETL , Steadman KJ ,Mak M ,Cichero JAY , Nissen LM . methodology for evaluating the integrity and dose uniformity Prevalence of swallowing difficulties and medication of drug products as well as the potency and stability of modification in customers of community pharmacists. J drug substance in the soft food vehicles. Moreover, this part Pharm Pract Res 2015;45(1):18–23. [5] Logrippo S , Ricci G , Sestili M ,Cespi M , Ferrara L , Palmieri GF , provides general recommendations for dissolution testing of et al. Oral drug therapy in elderly with dysphagia: between a the mixture of the drug product and soft food. rock and a hard place!. Clin Interv Aging 2017;12:241–51 . [6] Lopez FL ,Ernest TB ,Tuleu C ,Gul MO . Formulation approaches to pediatric oral drug delivery: benefits and 4. Conclusions limitations of current platforms. Expert Opin Drug Delivery 2015;12(11):1727–40 .
Sprinkle formulations can improve compliance of patients [7] Nunn T, Williams J. Formulation of medicines for children. Br J Clin Pharmacol 2005;59(6):674–6 . with dysphagia. Indeed, more than 75% and 93% of children [8] Sohi H , Sultana Y ,Khar RK . Taste masking technologies in preferred sprinkle dosage form to syrup and oral drops, oral pharmaceuticals: recent developments and approaches. respectively [26,27] . This preference spurred the growth of Drug Dev Ind Pharm 2004;30(5):429–48 . sprinkle products since the early 1990s as can be seen in [9] Nokhodchi A ,Javadzadeh Y . The effect of storage conditions Fig. 1 . However, the product number is still small; there on the physical stability of tablets. Pharm Technol Eur have been only sixty-five NDA approvals. The limited 2007;19(1):20–6 . kinds of sprinkle products compromise their flexibility and [10] Wright D. Swallowing difficulties protocol: medication administration. Nurs Stand 2002;17(14–15):43–5 . convenience of administration. In the complex medication [11] Phaechamud T , Praphanwittaya P , Laotaweesub K . Solvent regimen where both sprinkle and other dosage forms are effect on fluid characteristics of doxycycline hyclate-loaded mixed, patients would experience inconvenience due to bleached shellac in situ -forming gel and -microparticle the difference in administration methods. Considering formulations. J Pharm Investig 2018;48(3):409–19 . this unmet need and the market trend, it is expected [12] Moore KT , Krook MA , Vaidyanathan S , Sarich TC , that more and more sprinkle products will be launched Damaraju C, Fields LE. Rivaroxaban crushed tablet suspension characteristics and relative bioavailability in in the future. Nonetheless, this promising dosage form healthy adults when administered orally or via nasogastric does not have comprehensive guidance for industry. tube. Clin Pharmacol Drug Dev 2014;3(4):321–7 .
Compilation and reinforcement of scattered information [13] Kunii D ,Levenspiel O . Fluidization engineering. 2nd ed. New regarding sprinkle formulations in various regulatory York: John Wiley & Sons; 1991 . documents would further accelerate their development [14] US Department of Health and Human Services, Food and 310 Asian Journal of Pharmaceutical Sciences 15 (2020) 292–310
Drug Administration. Office of clinical pharmacology review [23] US Department of Health and Human Services, Food and of viread R . 2011. Available at: https://www.fda.gov/ Drug Administration. Guidance for Industry: tablet scoring: downloads/Drugs/DevelopmentApprovalProcess/ nomenclature, labeling, and data for evaluation. 2013. DevelopmentResources/UCM292364.pdf Available at: https: [15] Shargel L ,Andrew B ,Wu-Pong S . Applied biopharmaceutics //www.fda.gov/downloads/drugs/guidances/ucm269921.pdf & pharmacokinetics. 6th ed. New York: McGraw-Hill; 1999 . [24] US Department of Health and Human Services, Food and [16] Yvonne P ,Thomas R . Pharmaceutics–drug delivery and Drug Administration. Guidance for industry: size of beads in targeting. 2nd ed. London: Fastrack, Pharmaceutical Press; drug products labeled for sprinkle. 2012. Available at: 2010 . https://www.fda.gov/downloads/drugs/ [17] Feas DA , Igartúa DE , Calienni MN , Martinez CS ,Pifano M , guidancecomplianceregulatoryinformation/guidances/ Chiaramoni NS ,et al. Nutraceutical emulsion containing ucm240243.pdf valproic acid (NE-VPA): a drug delivery system for reversion [25] US Department of Health and Human Services, Food and of seizures in zebrafish larvae epilepsy model. J Pharm Drug Administration. Guidance for industry: use of liquids Investig 2017;47(5):429–37 . and/or soft foods as vehicles for drug administration: [18] Dey N , Majumdar S ,Rao M . Multiparticulate drug delivery general considerations for selection and in vitro methods for systems for controlled release. Trop J Pharm Res product quality assessments. 2018. Available at: 2008;7(3):1067–75 . https://www.fda.gov/downloads/Drugs/ [19] Patwekar SL , Baramade MK . Controlled release approach to GuidanceComplianceRegulatoryInformation/Guidances/ novel multiparticulate drug delivery system. Int J Pharm UCM614401.pdf Pharm Sci 2012;4(3):757–63 . [26] Cloyd JC , Kriel RL , Jones-Saete CM ,Ong BY ,Jancik JT , [20] Bodmeier R . Tableting of coated pellets. Eur J Pharm Remmel RP . Comparison of sprinkle versus syrup Biopharm 1997;43(1):1–8 . formulations of valproate for bioavailability, tolerance and [21] Devane J.G., Stark P., Fanning N.M. Multiparticulate modified preference. J Pediatr 1992;120(4):634–8 . release composition. US Patent No. 6228398B1. [27] Zlotkin S ,Antwi KY , Schauer C ,Yeung G . Use of [22] Youan BB . Chronopharmaceutics: gimmick or clinically microencapsulated iron (II) fumarate sprinkles to prevent relevant approach to drug delivery? J Control Rel recurrence of anaemia in infants and young children at high 2004;98(3):337–53 . risk. Bull World Health Organ 2003;81:108–15 .