Beruflich Dokumente
Kultur Dokumente
Review
a r t i c l e
i n f o
Article history:
Received 17 August 2013
Received in revised form
15 December 2013
Accepted 16 January 2014
Available online 6 February 2014
Keywords:
Human taste panel
UV spectroscopy
Electronic taste sensing system
Sample pretreatment
Sampling
Standardized protocols
a b s t r a c t
Approaches to improve the taste of oral dosage forms that contain unpleasant tasting drugs are versatile.
Likewise, the analytical in vitro and in vivo methods to assess taste-masking efcacy are diverse. Tastemasking has gained in importance since the EU legislation on medicines for children came into force in
2007, and taste-masking attributes are often required by regulatory authorities. However, standardized
guidance for the analytical evaluation is still poor. Published protocols rarely consider real conditions,
such as the volume of saliva or the residence time of solid oral dosage forms in the mouth. Methodological
limitations and problems regarding time point of evaluation, sampling or sample pretreatment are hardly
ever addressed. This critical review aims to evaluate and discuss published strategies in this context.
2014 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
In vivo evaluation of taste-masking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Panelists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Administration and inuence of pretreatment of drug formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
Time points of taste assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.
Taste assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
In vitro evaluation of taste-masking efcacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Determination of taste-masking properties by UV spectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.1.
Dissolution step . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2.
Sampling procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.3.
Analytical assessment and data evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Determination of taste-masking properties by electronic taste sensing systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1.
Commercially available electronic taste sensing systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2.
Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corresponding author. Tel.: +49 211 8114225; fax: +49 211 8114251.
E-mail addresses: Miriam.Pein@hhu.de (M. Pein), Maren.Preis@hhu.de (M. Preis), Carolin.Eckert@hhu.de (C. Eckert), Florian.Kiene@hhu.de (F.E. Kiene).
0378-5173/$ see front matter 2014 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.ijpharm.2014.01.036
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245
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4.
5.
3.2.3.
Dissolution step . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.4.
Sampling procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.5.
Analytical assessment and data evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Correlation of in vivo and in vitro taste assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
For drug therapy adherence and patient convenience, tastemasking of unpleasant tasting active pharmaceutical ingredients
(APIs) is desirable. Many research and developing groups spend
tremendous effort on developing taste-masked formulations,
whereof several approaches have been derived (Momin, 2012).
One taste-masking approach is to construct physical barriers as
realized in coated tablets or granules. As tablets are intended to
remain shortly in the oral cavity, a coating layer can shield the
unpleasant taste of the API from the taste buds in the oral cavity
until the tablet has been completely swallowed (Malik et al., 2011;
Nakano et al., 2013). Other common approaches are based on the
addition of sweeteners, ion exchange resins (Fu Lu et al., 1991) or
cyclodextrins (Mady et al., 2010; Preis et al., 2012; Suthar and Patel,
2011). As a substance needs to be dissolved for perception by the
receptors located in taste buds on the human tongue, a lower solubility is tantamount to a less bad taste. Therefore, pH modiers
converting a substance into its less soluble or even insoluble form
are also used to achieve taste-masking effects (Ogata et al., 2012).
With regard to the chemical stability of drug substances, consideration of the effects of mixing corresponding drug formulations
with food or beverages is important. For example, some antibiotics
are sensitive to a decreased pH (e.g. azithromycin) like present in
apple sauce, or to multivalent cations (e.g. tetracycline) present
in milk products. Nevertheless, this approach enables a simplied administration to children and elderly patients (Sadrieh et al.,
2005), because these groups often face problems in swallowing
solid dosage forms. Moreover, increased viscosity of a drug formulation might help to achieve a taste-masking effect by inhibiting
drug diffusion to the taste receptors.
Masking unpleasant tasting APIs is doubtlessly desirable, if they
are incorporated in solid oral dosage forms, which potentially
release the API within the oral cavity. This is even intended for
orodispersible solid dosage forms (European Pharmacopoeia, 2008;
Food and Drug Administration, 2008). Standardized testing protocols and specication limits are provided by the pharmacopoeia
such as adequate disintegration times (Ph. Eur.: 3 min European
Pharmacopoeia, 2008, FDA: 30 s (Food and Drug Administration,
2008)), but criteria for disintegration are not useful to judge about
the taste-masking efcacy. Drug release specications might be
feasibly adapted for the assessment of taste-masking effects. But
while, for example, immediate release dosage forms require a drug
release of 80% within the rst 45 min, such specications are not
provided for the drug release of orodispersible solid dosage forms.
Based on some taste-masking approaches, a delayed release behavior arises within the rst minutes of dissolution testing (Cerea et al.,
2004). According to a former FIP/AAPS guideline, a drug release
of 10% within the rst 5 min of dissolution indicates a successful taste-masking (Siewert et al., 2003). However, this arbitrary
threshold is highly dependent on the human perception threshold of each individual drug substance and dissolution methods as
such are not applicable to judge about taste-masking effects based
on the addition of sweeteners or avors.
So far, human taste panels are often used for the assessment
of taste-masking properties, e.g. in Refs. (Bhoyar et al., 2011b;
Cilurzo et al., 2011; Douroumis et al., 2011; Fukui-Soubou et al.,
250
251
251
252
252
252
2011; Kasliwal and Negi, 2011; Liew et al., 2012; Mady et al., 2010;
Makwana et al., 2010; Malik et al., 2011; Shah and Mashru, 2008a;
Sharma et al., 2012; Sharma and Chopra, 2012). But due to ethical and toxicological concerns, conducting human taste panels is
questionable, if the drugs of interest are still in the early stage of
development. On the contrary, analytical methods offer safe and
objective results. Thus, spectroscopic drug dissolution analysis and
electronic tongue measurements are often applied to assess the
efciency of taste-masking effects. Using UV spectroscopy, either
the dissolution prole of a sample is evaluated or the amount of
released drug after a predened dissolution time is determined. In
investigations with electronic taste sensing systems (e-tongues),
taste-masking effects are treated by univariate and/or multivariate
methods (Guhmann et al., 2012; Hoang Thi et al., 2012; Tokuyama
et al., 2009; Woertz et al., 2011b; Zheng and Keeney, 2006).
In contrast to the well-established pharmaceutical techniques
to obtain taste-masked formulations, taste assessment lacks precise description. This imbalance is due to the lacking denition of
taste-masking and missing standard evaluation tests and specications. Although some reviews have dealt with the assessment of
taste-masking effects in recent years (Anand et al., 2007; Datrange
et al., 2012; Sagar et al., 2012; Shet and Vaidya, 2013), the critical
aspects coming along with the according evaluation of solid oral
dosage forms are rarely discussed (Gittings et al., 2014; Woertz
et al., 2011a).
As the application of analytical methods for taste-masking
assessment gained importance, since the EU legislation on
medicines for children came into force in 2007 (Breitkreutz, 2008;
European Union, 2006), this review assembles and critically discusses recent approaches of assessing taste-masking properties
of solid oral dosage forms (granules, microspheres, pellets, tables
and lm formulations). Manuscripts have been considered, if the
assessment was performed with human taste panels (dened
as in vivo evaluation) and/or UV spectroscopy and/or electronic
tongue measurements (dened as in vitro measurements). UV
spectroscopy measurements comprise in this context on-line and
in-line UV-monitoring of the drug dissolution as well as off-line UV
detection or high performance liquid chromatography (HPLC) measurements after sampling. Electronic tongue measurements have
only been considered, if they were carried out with at least one of
the commercially available instruments (Insent or Astree).
2. In vivo evaluation of taste-masking
Although there are standardized protocols for taste evaluation (DIN10959, 1998; DIN10961, 1996; DIN10969, 2001; ISO3972,
1991), so far no standardized protocol exists for the evaluation of
taste-masking. Rather, the protocols described in literature differ
in their procedures, particularly with regard to the panelists, the
administration of the drug formulation and the time point(s) to
assess the taste-masking effects (Table 1).
2.1. Panelists
As summarized in Table 1, investigated studies have been conducted with 430 healthy adult human volunteers. If the ages of the
gender-mixed panelists were reported, they varied between 18 and
Table 1
In vivo evaluation of taste-masking (API: active pharmaceutical ingredient, CD: cyclodextrin, HPCD: hydroxpropyl--cyclodextrin, MDT: mouth dissolving tablets, No: number of panelists, n.s.: not specied, ODF: orodispersible
lm, ODT: orodispersible tablet, SRT: sustained release tablets, TM: taste-masking).
Dosage form
Taste-masking
strategy
Panelists
Perception
threshold
(mg/ml)
Panelist
training
Administration of
the solid oral
dosage form
Time point of
evaluation
Taste-masking
assessment procedure
(see also Tables 2 and 3)
Ref.
Aceclofenac
ODT
No.: 9
age: n.s.
sex: n.s.
n.s.
n.s.
100
Immediately after
administration
and at several
intervals for 5 min
(Kasliwal and
Negi, 2011)
Acetaminophen
Granules
HPCD:API
complexes including
neotame
(sweetener), orange
& peppermint avor
Application of
different granulation
processes
No.: 6
age: n.s.
sex: n.s.
1.08
Yes
22.5
<2
Yes
100
(Albertini et al.,
2004)
No.: 56
age: n.s.
sex: n.s.
As solution
(granules
dissolved over
3 min)
One tablet placed
onto the tongue
and chewed 10
times
No.: 20
age: n.s.
sex: n.s.
0.35
n.s.
268.3
n.s.
n.s.
(Sharma et al.,
2012)
No.: 4
age: n.s.
sex: n.s.
No.: 9
age: n.s.
sex: n.s.
n.s.
n.s.
510
n.s.
200
n.s.
(Bhasin and
Ghosh, 2012)
n.s.
No.: 10
age:
1825y
sex: n.s.
No.: 10
age: n.s.
sex: n.s.
n.s.
With
10 mg of
pure API
10
n.s.
Bitterness scores
(Douroumis
et al., 2011)
n.s.
n.s.
13.4
As aliquots of
0.50 L solution
After full
disintegration of
the tablet
10 s after
administration
(taste was also
evaluated at
1050 s after
rejecting the
tablet)
10 s, 1, 2, 5, 7,
10 min after
disintegration of
the tablet
15 s after
administration
Bitterness scores
(Cilurzo et al.,
2011)
No.: 16
age:
2223y
sex: 50:50
No.: 30 (20
for doxycycline)
age:
2029y
sex: 50:50
n.s.
n.s.
10
One lm placed
onto the tongue
After
disintegration of
the ODF
Bitterness scores
acceptability, aftertaste,
mouth feel, handling
(Liew et al.,
2012)
n.s.
n.s.
Doxy: 100
cipro: 500
KI: 130
As crushed tablet,
mixed with
masking agents
10 s after
administration
and 1 min after
swallowing (after
taste)
Palatability scores
(Sadrieh et al.,
2005)
Tablets
Granules,
ODT
Addition of Witepsol
H-15 or cacao, cocoa
butter, sucrose, cocoa
powder and
Benecoat BMI-40
Coating with
Eudragit EPO,
addition of mannitol,
aspartame, cocoa &
strawberry avor
Coating with
Eudragit EPO
Atorvastatin
calcium
ODT
Cefpodoxime
proxetil
SRT
Addition of
cation-exchange
resin tulsion-344
Cetirizine HCl
ODT
Coating with
Eudragit RL-30D
Diclofenac
sodium
ODF
Donezepil HCl
ODF
Doxycycline
(doxy),
ciprooxacin
HCl (cipro),
potassium
chloride (KI)
Tablets
Addition of sucralose,
saccharine, xylitol,
mint, licorice and
soft fruit avor
Addition of
aspartame, sucralose,
saccharine sodium,
pineapple avor
Mixing with masking
agents
10 s after the
repeated chewing
(Suzuki et al.,
2003)
(Bhoyar et al.,
2011a)
API
241
242
Table 1 (Continued)
Dosage form
Taste-masking
strategy
Panelists
Perception
threshold
(mg/ml)
Panelist
training
Administration of
the solid oral
dosage form
Time point of
evaluation
Taste-masking
assessment procedure
(see also Tables 2 and 3)
Ref.
Famotidine
ODT
Addition of
carboxymethyl--CD
and sulfobuthyether-CD
Addition of
sweetener
(aspartame), original
and generic products
Addition of
ion-exchange resin
tulsion-335
No.: 8
age:
2327y
sex: n.s.
No.: 11
age: n.s.
sex: n.s.
n.s.
Yes
20
After
disintegration of
the tablet
Bitterness scores
(Mady et al.,
2010)
n.s.
Yes
10
30 s after
administration
(Tokuyama
et al., 2009)
No.: 6
age: n.s.
sex: n.s.
n.s.
n.s.
10 s after
administration
Bitterness level:
++/
+++
(Sharma and
Chopra, 2012)
10 min (seconds?)
after
administration
(taste was also
evaluated at
1050 min
(seconds?) after
rejecting the
tablet)
n.s.
(Bhoyar et al.,
2011b)
Bitterness scores
(Malik et al.,
2011)
Y: recognition of bitter
taste
N: no perception of bitter
taste
Bitterness scores
(Bora et al.,
2008)
ODT
Levocetirizine
HCl
Granules,
MDT
Metformin HCl
SRT
Addition of
cation-exchange
resins indion 244,
254 and 264
No.: 9
age: n.s.
sex: n.s.
n.s.
n.s.
300
n.s.
Ooxacin
Microspheres
for ODT
Addition of Eudragit
E100
n.s.
n.s.
n.s.
n.s.
Ondansetron HCl
Microspheres
No.: 5
age: n.s.
sex: male
No.: 7
age:
2128y
sex: 4m/3f
No.: 10
age:
1822y
sex: n.s.
No.: 5
age: n.s.
sex: n.s.
0.075
n.s.
0.006
As solution (1 ml)
30 s after
administration of
the solutions
n.s.
n.s.
Granules placed
onto the tongue
n.s.
n.s.
Granules placed
onto the tongue
10 s after
administration
n.s.
(Prajapati et al.,
2010)
No.: 29
age:
22.3 0.9 y
sex:
13m/16f
No.: 18
age: n.s.
sex: 9m/9f
n.s.
n.s.
30
n.s.
Immediately after
administration
and after
disintegrating
(Nakano et al.,
2013)
n.s.
n.s.
30
As dispersion
(one tablet
dispersed in
10 ml water)
n.s.
10 s after
administration
Information on
acceptability, bitterness,
saltiness, sweetness
(Guffon et al.,
2012)
Taste-masking and
grittiness evaluation
(Singh et al.,
2012)
ODT
MDT
Piogliazone HCl
ODT
Pyridostigmine
bromide
Dispersible
tablet
Addition of
ion-exchange resin
indion 204,
sweetening agent
aspartame and
avoring agents
(peppermint, vanilla)
Coating of core
granules with
Eudragit EPO,
addition of
aspartame and NaCl
Addition of -CD and
avor
Sodium
phenylbutyrate
Granules
tablet
Coating,
composition: n.s.
No.: 13
age: n.s.
sex: n.s.
n.s.
n.s.
Tablet: 500
granules:
940
Sumatriptan
succinate
Granules
Addition of Eudragit
E100, -CD and
sweetener
No.: 12
age: n.s.
sex: n.s.
n.s.
n.s.
Drug content
varied depending
on TM strategy
Granules placed
on posterior
lobe of tongue
Immediately after
administration,
0.5 and 2 h after
ingestion
46 s after
administration
(Makwana
et al., 2010)
(Tan et al.,
2012)
API
Very good
Excellent
Highly
palatable
Good
Palatable
Fair
Tasteless
Poor
Aweful
Extremely
bitter
Very bitter
Intermediate
steps: 0.5, 1.5,
2.5, 3+
X = threshold
bitterness
Moderately
bitter
Intensely bitter
0.5 = threshold
Strong bitterness
Moderate
Moderate
bitter
Strong bitter
Slightly bitter
Moderately
bitter
Strongly bitter
Slightly
bitter
Bitter
Slightly
bitter
Bitter
Slightly
bitter/acceptable
Slightly
sweet/good
Very sweet/very
good
Moderately
bitter
Slightly bitter
Extremely
poor
Very poor
Strongly bitter
Bitter
Very bitter/poor
Bitter/poor
Palatable
Normal
Good
Tasteless
Tasteless
Slightly bitter
Pleasant
Tasteless
Tasteless
Slightly bitter
No bitterness
Slight
6
7
Additional
information
Moderately
bitter
Strongly bitter
4
No bitter taste
Acceptable
bitterness
Slightly bitter
0
1
(Makwana
et al., 2010)
(Douroumis et al.,
2011) (Kasliwal
and Negi, 2011)
(Cilurzo et al.,
2011)
(Bhoyar et al.,
2011b)
As described in Section 2.2, drug formulations have been administered with and without initial pretreatment for the taste-masking
evaluation. And as displayed in Fig. 1, the pretreatment time plays
Score
Table 2
Scoring systems for human taste panelslabeled with numbers from 07.
The most common way to administer drug formulations to panelists is the one that depicts reality most accurately: placing the
drug formulation directly onto the tongue (Table 1). In contrary,
some authors administered a prepared solution or suspension.
Administration of dissolved or dispersed drug formulations leads to
dened concentrations of unpleasant tasting API offered to the panelists. However, an increasing taste sensation over time is expected
when the drug formulation is placed directly onto the tongue. Pretreatment (dissolution/dispersion) times could offer safety margins
for evaluating taste-masking effects, if they were dened to be a little longer than the time needed to swallow a solid oral dosage form.
But on the contrary, the prognoses of the taste-masking efcacy
worsen, if the pretreatment times were too long.
Although the pretreatment (dissolution/dispersion) time obviously inuences the gustatoric sensation (especially of orodispersible drug formulations), detailed information was only given by
(Albertini et al., 2004) and (Shah and Mashru, 2008b): while Albertini et al. described a dissolution time over a period of 3 min (180 s)
followed by a ltration of the sample, Sha and Mashru administered 1 ml suspension prepared by dispersing equivalents of 1 g
primaquine for 15 s in water. For the taste-masking evaluation of
the four different drug formulations displayed in Fig. 1, these two
pretreatment procedures would cause signicant differences.
But although the pH and viscosity of the human saliva have a
great impact on the dissolution behavior and change with age and
food intake (Pfaffe et al., 2011), detailed information are lacking
concerning taste-masking evaluation in the perused literature.
(Malik et al.,
2011)
Palatable taste
Used, but not
dened
Used, but not
dened
Used, but not
dened
Worst taste
sensation
(Shah and
Mashru, 2008a)
(Sharma
et al., 2012)
(Suthar and
Patel, 2011)
(Mady et al.,
2010)
(Patel and
Vavia, 2008)
(Sadrieh
et al., 2005)
243
Not
palatable
Slightly
palatable
Average
244
Fig. 1. Schematic release behavior of four model drug formulations in the mouth. The pretreatment procedures of Shah and Mashru (2008b) and Albertini et al. (2004)) are
related to signicantly different drug releases.
an important role regarding the results. Thus, in the following, literature based time points are subdivided into those with and those
without pretreatment.
Where the drug formulation is directly placed onto the tongue
of the panelist, the rst time point of assessment was mostly set
immediately after administration (Bhoyar et al., 2011a,b; Guffon
et al., 2012) or at predened time points: 10 s (Kasliwal and Negi,
2011; Makwana et al., 2010; Sharma and Chopra, 2012; Singh et al.,
2012), 15 s (Cilurzo et al., 2011), 20 s (Sharma et al., 2012), or 30 s
(Tokuyama et al., 2009). Some authors predened the rst time
point of assessment after the disintegration of the tablet without giving any further information regarding the time (Bhasin and
Ghosh, 2012; Douroumis et al., 2011; Liew et al., 2012; Mady et al.,
2010). As this parameter is individually perceived by each panelist,
the results lack comparability. Suzuki et al. investigated the taste
of a chewable tablet 10 s after 10 chews (Suzuki et al., 2003).
Following Albertini et al., taste-masking effects were evaluated
after 3 min of dissolution. The resulting dispersion was ltered and
the corresponding solution assessed over 5 s by the volunteers.
The duration of the ltration was not specied. Sha and Mashru
evaluated the taste impression after 15 s of pre-dissolution and an
assessment by the volunteers after retaining the dispersion for 30 s
into their mouths. As no ltration step was described before the
administration, the dissolution process could be expected to proceed also after the 15 s of pre-dissolution. However, Fig. 2 displays
the concentrations that were expected after another 30 s of further
dissolution in the panelists mouth.
Table 3
Scoring systems for human taste panels using other score scales than numbers.
Scoring
++ Taste-masked with
bitter after taste
No taste-masking
0 slightly masked
Opportunity to
distinguish between no
bitterness, slight
bitterness (but
acceptable) and strong
bitterness
(unacceptable)
+++ Complete
taste-masking
+ Complete
taste-masked
Quinine HCl:
1: 0.0029 mM
2: 0.012 mM
3: 0.031 mM
4: 0.078 mM
5: 0.2 mM
Sucrose:
1: 29.24 mM
2: 97.72 mM
3: 187.1 mM
4: 409.4 mM
5: 994.1 mM
245
Fig. 2. Schematic release behavior of four model drug formulations in the mouth. The samples of Shah and Mashru (2008b) were dispersed over 15 s (dashed line) and
provided over 30 s as suspensions (indicated by the arrow, ending with the bold line). Albertini et al. provided ltered samples after a dissolution time of 3 min (Albertini
et al., 2004). The time, children with ADHD and AD could be taught to swallow a tablet was 30 s (Beck et al., 2005).
246
Table 4
In vitro evaluation of taste-masking (a.i.: additional information, API: active pharmaceutical ingredient, CD: cyclodextrin, IVIVC: correlation with human threshold data, n.s.: not specied, m: dissolution medium, ODF: orodispersible
lm, ODT: orodispersible tablet, SSF: simulated saliva uid, T: temperature in C, V: volume in ml).
Dosage form
Taste-masking
strategy
In vitro
assessment
tool
Calibration
procedure
Taste-masking
criteria
IVIVC
Dissolution
settings
Sample
(pre)treatment
Drug dose
Sampling
timepoint
Ref.
Acetaminophen
Granules
Application of
different
granulation
processes
UV
spectroscopy
(243 nm)
n.s.
Drug release of
pure API > tastemasked
formulation
n.s.
3 min
(Albertini
et al., 2004)
Wax matrix
containing
Eudragit EPO
UV
spectroscopy
(243 nm)
n.s.
Yes
200 mg
Each 5 min.
(Shiino et al.,
2010)
Powder
Addition of
caseinate and
lecithin
e-tongue
(Astree,
sensors JB, BA,
BB, HA, ZZ, CA,
GA)
n.s.
n.s.
n.s.
n.s.
(Hoang Thi
et al., 2012)
HPLC/UV
(243 nm)
n.s.
Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations
API released after
2 min < threshold
conc. according
to (Albertini
et al., 2004;
Shiino et al.,
2010)
Drug release of
the pure API is
compared to
drug release of
taste-masked
granules
Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations
Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations
Dissolution in
paddle apparatus
according to
USP24; on-line
sampling
(12.5 ml/min)
Dissolution in
paddle apparatus
according to
Japanese
Pharmacopoeia;
sample ltration
(0.45 m) before
off-line detection
n.s.
22.5 mg
Mold disks
V: 900
m: buffer
pH: 6.8
T: 37
a.i.: paddle
speed 50 rpm
V: 900
m:
phosphate
buffer
pH: 6.5
T: 37.0 0.5
a.i.: paddle
speed 50 rpm
V: n.s.
M: water
pH: n.s.
T: n.s.
Yes
V: 1 ml/min
m:
phosphate
buffer
pH: 7.4
T: 37
10 mg
2 min (4, 6, 8,
10, 15, 20, 25,
30 min)
n.s.
V: 10
m: SSF
pH: 6.8
T: n.s.
60 mg
5 min
(Huda and
Toshniwal,
2013)
n.s.
V: n.s.
m:
isopropylic
alcohol 80%
pH: n.s.
T: n.s.
Sample is placed in
a tube, dissolution
medium is
continuously
owing over the
sample, fractions
are kept
Dissolution of
granules; sample
ltration
(Whatman lter
paper) before
off-line detection
n.s.
n.s.
n.s.
(Bhasin and
Ghosh, 2012)
n.s.
V: n.s.
m: n.s.
pH: n.s.
T: n.s.
Dissolution of one
ODF
13.4 mg
After complete
dissolution
(Cilurzo et al.,
2011)
Atomoxetin
hydrochloride
Granules
Addition of
Eudragit EPO
and avors
HPLC/UV
(269 nm)
n.s.
Atorvastatin
ODT
Coating with
Eudragit EPO
e-tongue
(Astree,
sensors ZZ, AB,
GA, BB, CA, DA
and JE)
n.s.
Diclofenac
(sodium salt)
ODF
Addition of
sucralose,
saccharine,
xylitol, mint,
licorice and
soft fruit avor
e-tongue
(Insent SA402B,
bitterness
sensors C00,
AC0, AN0)
Yes
API
Diclofenac
sodium (DSS),
potassium
(DPS), free acid
(DFA)
ODTs, granules
Coating with
Eudragit EPO
In mg/100 ml
DFA: 0.55
DSS: 313
DPS: 1001000
Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations
n.s.
V: 100
m: puried
water
pH: n.s.
T: n.s.
HPLC/UV
(254 nm)
n.s.
Drug release
after 3 min of the
taste-masked
formulations < drug
release of nontaste-masked
drug
formulations
n.s.
V: 50
m: SSF
pH: 7.4
T: 37 0.5
a.i.: 50 rpm
paddle speed
Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations
Based on
Euclidean
distances for
released drug
amount after 30 s
+ correlation
with bitterness
score from
human panel
Released amount
of famotidine
after 30 s
yes
V: 100
m: masking
agent
pH: n.s.
T: RT
Yes
V: 100
m: water
pH: n.s.
T: 37 0.5
a.i.: 25 rpm
paddle speed
Doxycycline,
ciprooxacin
HCl, potassium
chloride
Tablets
Mixing with
masking agents
e-tongue
(Astree,
sensors JB, BA,
BB, HA, ZZ, CA,
GA)
n.s.
Famotidine
ODT
Addition of
sweetener
(aspartame),
original and
generic
products
e-tongue
(Astree,
sensors ZZ, BA,
BB, CA, GA, HA
and JB)
n.s.
HPLC/UV
(254 nm:
famotidine,
250 nm:
aspartame)
n.s.
e-tongue
(Insent, sensors
C00, AE1, AC0,
AN0).
n.s.
Nicotine
hydrogen
tartrate salt
ODF
Addition of
avors
Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations,
compared also
with standard
bitter substance
quinine
hydrochloride
Yes
n.s.
V: n.s.
m: water
pH: n.s.
T: n.s.
20 units of each
ODT were
dispersed in
100 mL of puried
water; sample
ltration (0.22 m
Whatman lter), if
necessary
Dissolution of
232.5 mg
diclofenac
(equivalent free
acid) in 50 mL of
SSF (comparable to
one dose per 5 mL);
sample ltration
(0.22 m Whatman
lter) before
off-line detection
Mixing of drug
(formulation) with
masking matrix
Dissolution of 10
ODTs (=100 mg
API); sample
ltration under low
pressure
Dissolution of 10
ODTs (=100 mg
API); sample
ltration (0.45 m
pore size
membrane) before
off-line detection
Dissolution of
0.15% (w/v) drug
equivalent
23.25 mg
3 min
(Guhmann
et al., 2012)
3 min
(Sampling at
0.55 min)
100 mg (doxy)
500 mg (cipro)
130 mg (KI)
n.s.
(Sadrieh
et al., 2005)
10 mg
10 s, 20 s, 30 s
and 60 s
(Tokuyama
et al., 2009)
1.5 mg
n.s.
(Cilurzo et al.,
2010)
e-tongue
(Insent
TS5000Z,
sensors AC0,
AN0, CT0, AE1,
C00, AAE, CA0)
247
248
Table 4 (Continued)
Dosage form
Taste-masking
strategy
In vitro
assessment
tool
Calibration
procedure
Taste-masking
criteria
IVIVC
Dissolution
settings
Sample
(pre)treatment
Drug dose
Sampling
timepoint
Ref.
NXP 1210
Lipid based
pellets
Lipids as
taste-masking
agents
UV
spectroscopy
(295 nm)
n.s.
n.s.
Dissolution in USP
33 paddle
apparatus 2
Drug release
after 2 min,
dissolution
measured
in-line
(Vaassen
et al., 2012)
Ooxacin
Microspheres
Addition of
Eudragit E100
UV
spectroscopy
(294 nm)
n.s.
n.s.
n.s.
Dissolution of
microspheres;
sample ltration
before off-line
detection
100 mg
5 min
(Malik et al.,
2011)
Ondansetron
HCl
Microspheres
UV
spectroscopy
(310 nm)
n.s.
Yes
Stirring and
dissolution under
stirring; ltration
before off-line
detection
8 mg
5 min
(Bora et al.,
2008)
Theophylline
Tablet
Spray drying
with Eudragit
E100, addition
of chitosan and
Methocel E15
LV
Coating with
Eudragit EPO
V: 900
m: KH2 PO4
buffer
pH: 7.5
T: 37
a.i.: 75 rpm
paddle speed
V: 25
m:
phosphate
buffer
pH: 6.8
T: n.s.
V: 25
m: buffer
pH: 6.8
T: n.s.
HPLC/UV
(291 nm)
1100 mg/L
(R2 = 0.998)
Onset of drug
release is delayed
n.s.
V: 900
m: buffer
pH: 5.5, 6
T: 37 0.5
a.i.: 50 rpm
paddle speed
n.s.
15 min
(Cerea et al.,
2004)
Quinine sulfate
Pellets
e-tongue
(Astree,
sensors BD, EB,
JA, JG, KA, OA,
OB), bitterness
score as a
function of
time
UV
spectroscopy
(235 nm)
n.s.
Bitterness
prediction
module
V: 100
m: water
pH: n.s.
T: n.s.
Dissolution in USP
26 paddle
apparatus 2;
sample ltration
(0.45 m nylon
lter) before
off-line detection
Dissolution;
sample ltration
100 mg
One
sample/min
over 5 min
bitterness
score as a
function of
time
(Kayumba
et al., 2007)
V: 900
m: water
pH: n.s.
T: 37 0.5
a.i.: 100 rpm,
rotation
speed of the
basket
V: n.s.
m: water
T: 37,
a.i.: 100 rpm
paddle speed
Sodium
phenylbutyrate
Granules
Coating with
Eudragit EPO
Coating,
composition:
n.s.
e-tongue
(Insent
TS5000Z,
sensors AC0,
AN0, CT0, AE1,
C00, AAE, CA0)
Fiber optical
UV probe
(Ocean optics)
n.s.
Drug
release < 9 mg/l
quinine (Suzuki
et al., 2003)
Yes
Log-linear
relation
between sensor
signal and drug
concentration
between
3001000 mg/ml
API
n.s.
Based on
Euclidean
distances of the
placebo
formulations to
the drug
formulations
n.s.
To provide a lag
time in the initial
dissolution phase
in contrast to the
licensed product
n.s.
V: n.s.
m: water
T: 37,
a.i.: 100 rpm
paddle speed
Dissolution
according to USP
Method 1applying
an automated
dissolution tester
Dissolution
according to
European
Pharmacopoeia
Dissolution
according to
European
Pharmacopoeia;
in-line detection
940 mg (per g
granules, if the
drug load is
comparable
with the drug
load of the
licensed
product)
Sampling after
2, 5, 30 min
(Guffon et al.,
2012)
API
249
(Shiino et al., 2010), but did not explain this choice. Apart from
this approach, which was in both cases only based on one concentration and time point, the success of a taste-masking has also
been discussed on the basis of the dissolution prole (Cerea et al.,
2004; Guffon et al., 2012). A delayed initial drug release was therein
dened as desirable lag-time or delayed onset. In this context, Guffon et al. reported about an initial lag-time of 10 s before the slow
progressive drug release started (Guffon et al., 2012).
Regarding the drug releases shown in Fig. 4, formulation 4 would
achieve a successful taste-masking for 8 s, while formulation 1
would be dened as taste-masked for 84 s, if the human perception
threshold concentration of the model drug were equivalent to a 10%
drug release according to (Siewert et al., 2003). None of the formulations would have been dened as taste-masked by Bora et al. or
Shiino et al., but evaluating the formulations by Guffon et al., initial
lag-times of >10 s could be proven for formulations 13. The availability of these data on the one hand and the comparability of the
threshold concentrations on the other hand are the main disadvantages of the method that compares the human perception threshold
with the released amount of drug. While for several drugs no perception threshold could be found in literature, for acetaminophen
(paracetamol) e.g., at least two different threshold concentrations
were described: 0.35 mg/ml in phosphate buffer pH 5.8 (Sharma
et al., 2012) and 1.08 mg/ml in water (Albertini et al., 2004).
250
Table 5
Realistic properties related to conditions in the human mouth.
Saliva
Tongue
Characteristics
Residual volume
Flow rate
Osmolality
Values
12 ml
0.51 ml/min
50100 mosmol/kg
Literature
(Lagerlf and
Dawes, 1984;
Zwier et al.,
2013)
pH depending
on age
5.77.5
Buffer capacity
Temperature
Force
6.1 mol/l
3536 C
(Hermes, 2012)
(Zwier et al.,
2013)
(Olsen, 2006)
0.135 N
(Hermes, 2012)
Fig. 3. Typical in vitro sampling frequencies indicated by the dashed lines (1, 2, 3 min) in comparison to the typical in vivo evaluation time of 30 s.
Fig. 4. In vitro dissolution proles of four model formulations combined with the in vivo human perception threshold.
251
Fig. 6. Schematic PCA map displaying sensor outputs of an electronic taste sensing
system in a two-dimensional graph; the information of the pure API are compared
with those of a drug-free formulation (placebo) and taste-masking approaches (formulation 1 and 2).
different formulations based on this complex information. A principal component analysis (PCA) aims to reduce the multidimensional
sensor information. The main information is then given in a two- or
three-dimensional graph, displaying the main discriminating factors as principal component 1 (PC1) on the x-axes, PC2 on the y-axes
and PC3 on the z-axes. In the schematic PCA map (Fig. 6), the API
represents the unpleasant taste, while the drug-free formulation
(placebo) displays the desired taste.
A pleasant taste for the drug formulation can be assumed, if
the distance to the placebo formulation is small or closely located.
Accordingly, an unsuccessful taste-masking approach is expected,
the closer the distance is towards the pure API. Euclidean distances
as the basis of each multivariate statistics can be calculated according to equation 2, where p and q represent the samples and n is the
number of variables used for the model in MVDA (Woertz et al.,
2010b).
d(p, q) =
n
i=1
(pi qi )2
252
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