Note: Descriptions are shown in the official language in which they were submitted.
~O 92/19209 2 ~ 9 PCr/US92/02692
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T~"TE-MASKED MEDICA~ENTS ANI~ T~EIR PREPARATION
This invention relates to tast~ -- ck; n~ of solid
medicaments, particularly by enveloping them in a taste-
masking polymer f ilm coati ng .
Therapeutic formulations designed for oral adminis-
tration often contain active ingredients which have an
unpleasant taste. For instance, many drugs produce a
bitter or acrid sensation when taken by mouth.
Various techniques are known for counteracting the
disagreeable taste of J~~;c-in~l products. Perhaps the
oldest dpp~ ~CI~ is to include a f lavoring agent in the
formulation t~ ~.veL~wi r the taste of the offend~ng cQm~-
ponent. Both solid and liquid --'i~ ts can be tas~e-
masked in this manner.
In the case of a solid medicament, taste-masking is
commonly effected by coating the medicament with a taste
blocking layer. This can be something as simple as a
sugar coating which dissolves to provide a pleasant
taste during the interval between ingestion and swallo~-
ing of the medicament. More recently, the pharmaceuti-
cal industry has focused its attention on coatings pro-
duced from film-forming polymers and considerable effort
has been devoted and continues to be devoted along this
line of approach for taste-masking of solid dosage
forms.
A new development in polymeric taste ~ k i n-J f ilms
is disclosed in U. S. Patent No. 4,851,226 to Julian et
al. These films are formed of a blend of a cellulose
ester and polyvinylpyrrolidone (PVP) applied to a me-
dicament such as acetyl-p-aminophenol (acetaminophen or
APAP) from an organic solvent solution of the polymers.
The purpose of the PVP, which is water soluble, is to
temper the hydrophobic character of the cellulose ester
and thereby control the drug release rate of the medi-
cation. According to the patent, a film coating may be
designed sQ that the medicine is released relatively
rapidly or in a sustained released mode. When rapid
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release is desired, the proportion of PVP in the film
coating is from about 12% to 20% by weight. If used
alone, however, the patentees found that the cellulose
ester coating would not provide adequate bioavailability
5 of the active ingredient at the specif ied coating levels
of 5% to 20% by weight. This is clearly evident from
Figure 1 of the patent depicting in graphic form the
diss~lution rate of APAP in simulated gastric fluid at a
cGating level of 17 . 5% by weight and which the percent
10 o~ PVP in the coating blend varied from 0% to 259~-by
weight. As will be noted, at 0% PVP in the film coating
drug release amounted to only 40% after 40 minutes.
The chief problem with the coatings of the Julian
et al. patent is that they are applied fron, an organic
15 solvent solution of the film-forming resin. Such sol-
vents tend to be toxic and/or flammable thereby posing a
hazard to personnel and operators. Also, organic sol-
vents are pollutants, necessitating the installation of
expensive and complex solvent ~c.,v~ systems to meet
20 environmental regulations. Furthermore, traces o~ re-
sidual soIvent may remain in the treated r-';rAr-nt
giving use to a potential health threat.
In accordance with the present invention solid
medicaments can be effectively taste ~k~d with a film
25 envelope consisting essentially of a cellulose ester
applied from a latex dispersion of the ester, while
maintaining rapid release of active ingredients. The
provision of such taste --~kPd medicaments constitutes
the main advantage and purpose of the invention. Other
3 0 advantages and purposes will become apparent in the
ensuing description.
The advantages and purposes aforesaid are realized
by employing as the source of the cellulose ester f ilm
envelope, an ultra-thin coating formed of the dried
35 residue of an a~ueous plasticized dispersion of the
cellulose ester. Remarkably, taste-masking of aspirin
tablets at coating levels significantly below about O . ~%
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have been realized while also exhibiting dissolution
profiles similar to uncoated controls.
Figure 1 is a graph of percent dissolution versus
time for aspirin tablets (acetylsalicylic acid - ASAJ
5 coated with the ultra-thin cellulose ester films made in
accordance with the invention and the uncoated core
control .
In Figure 1 the symbols have the following meaning:
o + Uncoated Cores
¢ CA Latex, 5 Min.
CA Latex, 10 Min.
Figure 2 is a graph o~ percent dissolution versus
time for ASA tablets coated with the ultra-thin cellu-
lose ester films of the invention, for ASA tablets simi-
larly coated with the cellulose ester/PVP blend of U. S.
Patent No. 4,851,226 to Julian et al., and for the~un-
coated core control.
In Figure 2 the symbols have the f ollowing meaning:
Uncoated Cores
~ CA/PVP Latex, S Min.
~ CA~VP Latex, 10 Min
The aqueous plasticized G~ l ose ester dispersion
used in the practice of the invention is a known chemi-
cal entity. Commonly referred to as a cellulose ester
latex, it is prepared by dissolving the polymer in a
suitable organic solvent, dispersing the resulting solu-
tion in an aqueous phase, homogenizing, and evaporating
the solvent. To the resulting latex is added an appro-
priate plasticizer.
Cellulose ester latex systems have previously been
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WO 92/19209 - PCI`/US92/026~j
investigated as a film coating material for controlled
release drug products . So f ar as is known, however,
there has been no recognltion or nppreciation by the
ph~ utlct:u~ical community that cellulose ester latex
5 dispersions would have application to tagte -s:k;n~
using the ultra-thin coating te~hniqlle as set forth
herein .
For a brief descrlption of cellulose ester latex
and its use in the fabrication of controlled drug de-
10 livery membranes, see B~n~c~hAe~ller et al. Proceed.
Intern. Symp. Control. Rel. Bioact.-Mater 12, (1985).
Illustrative of the cellulose ester latexes suita-
ble f or producing the ultra-thin coatings of the in-
vention are latexes made from cellulose acetate, cellu-
15 lose acetate butyrate and cellulose acetate phthalate.
~4~ ~ ~ 0 7 2 ~ ~
Cellulose ester polymers are manufactured and sold com-
mercially by a number of suppliers of industri21 chemi-
cals, f or example, the Eastman Kodak Company, Ringsport,
Tenn .
Examples of suitable plasticizers for cellulose
aqueous dispersions include triacetin, diacetin and
triethylcitrate .
As understood herein, ~ t. can be, for ex-
ample, granules, tablets including tablets of the com-
pressed coated grAnules o~ drugs such as Aspirin (ASA),
acet''m; nr~h~n, and ibuprofen.
The ultra-thin, t~ k;n~ films of the in-
vention are conveniently p.~ ce~ by coating the solid
4; ~~ substrate with an aqueous cellulose acetate
dispersion in which the preferred plasticizer is tri-
acetin. The triacetin is added to the dispersion and
the mixture thoroughly mixed. In general, the amount of
plastici2er ranges by weight from about 50~ to about
150%, preferably from about-ao% to 1209~, optimally about
100% of the solids content of the dispersion. A cellu-
lose acetate aqueous dispersion having a solids content
of by weight of rom about 28% to 32% is available from
the FMC Corporation under the designation CA398-10 latex
dispers ion .
The ultra-thin, taste ~-ckin~ cellulose films o~
the invention are applied to the solid m~; c~-nt in a
known manner and with standard pharmaceutical coating
equipment. Coating is normally carried out by spraying
in a pan or in a fluidized bed.
sOlids content of the aqueous cellulose ester coat-
ing formulation plus plasticizer is in the neighborhood
of from about by weight 10% to about 30%, preferably 15~
to 20%. In the final dried coating, the amount of plas-
ticizer present in the f ilm coating ranges by weight
from about 3096 to about 60%.
As previously pointed out, effective taste-masking
of standard p~armaceutical tablets such as an asplrin
* Trade-mark
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~0 92/19209 PCI/US92/026~
9 -5-
can be realized with the ultra-thin cellulose ester film
coatings of the invention at coating levels of about
. 4% by weight based on total solid dosage form weight.
Other types of solid dosage forms such as granules may
5 re~uire somewhat higher coating levels. So far as has
been detP~ni n~l, overall coating levels will vary from
about-0.3% to about 1.0% by weight for effective taste-
masking .
The amount of coating applied to the substrate can
10 be controlled in known manner such as solids content of
the coating dispersion and contact times.
The following examples, that is, p~c,ce-luL,=s and
test data tables illustrate the invention in further
detail. Throughout this specification and claims, all
15 parts and percentages are by weight unless otherwise
indicated .
COATING FORI~UI,ATIONS
Formula #1
Tn-lredientS % Wet* % ; n Drv Film
20Cellulose acetate lateX
(29 . 0% solids) ** 25. 86 50 . 0
Triacetin 7 . 50 50 . 0
Water 66 . 6~ ----
100 . 00 100. 0
25~ormula #2
Inqredients ~ Wet* 96 in Drv Film
Cellulose acetate latex ~ ~
(29.0% solids) 21.98 42.5
Triacetin 6 ~38 42.5
30Polyvinylpyrrolidone (PVP)*** 2.2~5 15.0
Water 69.39 ---- _
100. 00 100 . O
* 15 % solids concentration in coating fo~rmulation
35 ** CA398-10, FIIC Corporation
***golidonF~ 30, BASF
.. .. ..
-6- 2~ ~722~
COATING CONDITIoNs:
Constant Conditions:
The following conditions were held constant for both
batches .
5 Coating Equipment AccelaCota 24 inch pan
Batch Size 10 kg ASA cores
Inlet T~ UL~ Set 170 - 175F
Pump Type Peristaltic
Nozzle Size 1. 0 mm
Atomizing PL~DUL~: 25 psi
spray Rate 16 ~l/mi n/gun
Batch #1 (ASA 325 mg coated with coating solution itl: CA
latex)
Actual Inlet Temp. (C) 63 - 67
Exhaust Temp. (C) 37 - 43
Bed Temp. (C) 34 - 42
Batch #2 (ASA 325 mg coated with coating solution ~2: CA
latex with PVP
Actual Inlet Temp. (C) 62 - 66
Exhaust Temp. (C) 38 - 41
Bed Temp. (C) 36 - 42
Uncoated aspirin (ASA) cores and coated ASA tablet
physical properties data are presented in Table I. It
can be seen from the table that after five minutes of
coating, ASA tablets coated with CA latex without PVP
are exhibiting a 0 . 41% weight gain as compared to the
0 . 38% weight gain for the ASA tablets coated with CA
latex with PvP. No detectable film could be measured at
five minutes for coated ASA tablets without PVP, whereas
a film (thickness) of 0. 01 mm was measured for ASA tab-
lets coated with CA latex with PVP. When the coated
tablets were tasted after only five minutes coating, the
masking of the acid taste of Aspirin was clearly better
for the ASA tablets without PVP in the film relative to
* Trade-mark
~ ~722~ ~
the ASA tablets with PVP in the f ilm .
Julian et al. in U.5. Patent No. 4,851,226 state
that PVP, a water-soluble polymer, is required to pro-
vide release of the drug ace~Am;norh~ from granules/-
5 tablets coated with cellulose acetate applied from asolvent sy6tem. Dissolution analysis was performed on
the coated tablets of this invention to determine if PVP
was required to facilitate release of Aspirin from tab-
lets coat~d with cellulose acetate applied ~rom an aque-
1~ ous latex dispersion. The dissolution testing was per-
formed using USP Apparatus 1 (Basket) ~t 50 rpm with 500
ml of 0.05M acetate buffer, pH 4.5. The samples we~Q
analyzed on a Beckman DU-7 W/Vis :~ye~L~hotometer~
The dissolution analysis results are presented in Table
15 II and Figures 1 and 2.
Turning to the drawing, it can be seen from Figure
1 that the dissolution profile of ASA tablets coated
with ultra-thin CA latex are essentially identical to
the control ASA cores and that ASA release as depicted
20 in Figure 2 was faster than for tablets coated with the
Q latex/PVP blends of U.S. Patent 4,851,226 to Julian
et al. Moreover, it was found that ASA tablets coated
with Q latex without PVP exhibited superior taste-mask-
ing compared to tablets coated with CA latex/PVP blend
25 at approximately identical coating levels.
Clearly, there is no adYantage in using PVP to pro-
vide water solubility as claimed by Julian et al. since:
1. More effective taste-masking is realized at
lower coating levels using Q latex without PVP relative
3 0 to CA latex with PVP .
2. Dissolution analysis (ASA release) was more
rapid for Aspirin tablets coated solely with CA latex -
than with the CA latex/PVP blend.
* Trade-mark
~s 92/19209 2 ~ ~ 7 2 2 ~ P~/US92/02692
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\ 92/19209 ' 2 ~ ~ 7 2 2 ~ PCI/US92/02692
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TABLE I I
Dissolution Profile of Coated Aspirin Taklets -
Taste ~asking Study
~lean S Aspirin in Solution + S . D .
Cell~ll ose Acetate Latex Coatinc~ ~Batch 1)
5 ~in lO min
Time Cores CA Latex CA Latex
rmin~ (n-18) fns31 rn-~
5 21 + 5.2 22 + 6.4 39 1 ll.O
46 + 9 . 5 42 + 12 . 5 62 + 15 . 6
66 + lO . 7 61 + 14 . 2 78 + 14 . 2
30 94 + 5.7 91 + 12.1 96 + 5.0
Ce~lulose Acetate Latex With PVP rBatch 2 ~
CA Latex CA Latex
Time Cores w/ PVP w/ PVP
(min~ ~n=18~ rn=31 rn=3)
521 + 5.2 13 + 0.6 30 + 8.1
lO 46 + 9.5 27 + 3.2 55 + 6.1
15 66 + lO . 7 47 + 9 . o 77 + 4 . 7
3 o 94 T 5 . 7 74 + 10 . 5 lOo + 1 . 2
* ~Frade-mark
