DESCRIPTION
COATING AGENT FOR PHARMACEUTICAL SOLID PREPARATION,
PHARMACEUTICAL FILM FORMULATION, AND COATED
PHARMACEUTICAL SOLID PREPARATION
TECHNICAL FIELD
[0001]
The present invention relates to a coating agent for a pharmaceutical solid
preparation, a pharmaceutical film formulation and a coated pharmaceutical solid
preparation.
BACKGROUND ART
[0002]
A number of pharmaceuticals are not stable against oxygen and water vapor;
therefore, most of the commercially available pharmaceuticals, especially
pharmaceutical solid preparations, are packaged with a packaging material such as a
PTP (press through pack) sheet and protected from oxygen and water vapor.
[0003]
Meanwhile, at medical sites and dispensing pharmacies, in order to prevent
patients from forgetting to take their prescribed drugs and making mistakes in the
dosage thereof, it is widely practiced to use single-dose package that are prepared by
taking out a plurality of pharmaceuticals to be taken at once from the respective
packages of PTP sheet or the like and provide the pharmaceuticals altogether in one
bag. Furthermore, in western countries, patients often take out their
pharmaceuticals from the respective packages of PTP sheet or the like and place
them in separate pill cases or the like for storage; therefore, there has been a demand
for a method of improving the water vapor barrier property and oxygen barrier
property, that is, gas barrier properties, of a pharmaceutical solid preparation itself.
[0004]

As a method of improving the gas barrier properties of a pharmaceutical solid
preparation itself, methods of sugar-coating a pharmaceutical solid preparation and
methods of film-coating with a polymeric substance have been put into practice.
For instance, there have been developed a film coating agent in which stearic acid is
blended with aminoalkyl methacrylate copolymer E (Eudragit EPO (registered
trademark); Degussa Co.) (Patent Document 1); a resin composition obtained by
copolymerizing a polyvinyl alcohol with a polymerizable vinyl monomer (Patent
Document 2); a coating agent obtained by adding talc and a surfactant to a polyvinyl
alcohol (Patent Document 3); and a film coating agent in which bentonite is
uniformly dispersed in the form of a certain structure in PVA (Patent Document 4).
[0005]
Furthermore, the needs for a gas barrier film coating against those substances
other than oxygen and water vapor include the needs of preventing volatile
(subliminal) drugs or their decomposition products from being spread. When such
substances are spread, they may generate a bad odor and/or cause problems of, for
example, color change of other drugs when combined in a single-dose formulation.
For example, in olmesartan medoxomil preparations which are angiotensin II
receptor antagonists, it is known that the (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl
group released from olmesartan medoxomil is hydrolyzed into diacetyl to cause a
diacetyl-originated odor. Further, olmesartan medoxomil preparations are also
known to induce color change in a metformin hydrochloride preparation when placed
in a single-dose package with a metformin hydrochloride preparation and stored
under a high-temperature and high-humidity condition. This color change is caused
by a reaction between diacetyl originated from olmesartan medoxomil and the
guanidino group of metformin hydrochloride.
[0006]
As a method improving such odor and color change problems, there have

been reported a pharmaceutical package comprising a chemisorptive drying agent
(Patent Document 5), a film coating comprising carboxymethylcellulose (Patent
Document 6) and a coating comprising a polyvinyl alcohol copolymer (Patent
Document 7).
PRIOR ART DOCUMENTS
PATENT DOCUMENTS
[0007]
[Patent Document 1] Japanese Translated PCT Patent Application Laid-open
No. 2004-518750
[Patent Document 2] WO 2005/019286
[Patent Document 3] JP 2006-188490 A
[Patent Document 4] WO 2010/074223
[Patent Document 5] WO 2008/041663
[Patent Document 6] WO 2006/123765
[Patent Document 7] WO 2007/145191
SUMMARY OF THE INVENTION
PROBLEMS TO BE SOLVED BY THE INVENTION
[0008]
However, not only it requires a long time to sugar-coat a pharmaceutical solid
preparation for the purpose of attaining gas barrier properties, but also such sugar
coating has a large thickness and it thus enlarges the pharmaceutical solid
preparation itself, so that it may impose a burden upon patients for taking such a
large pharmaceutical solid preparation and may also extend the time required for the
drug effect to be expressed.
[0009]
Moreover, among those conventional methods of film-coating a
pharmaceutical solid preparation with a polymeric substance, only the film coating

agent of Patent Document 4 can attain excellent gas barrier properties that are
equivalent to a PTP sheet (water vapor permeability: less than 1.0 x 10-4
g-mm/cm -24 hr-atm, oxygen permeability coefficient: less than 1.0 x 10-4
cm3 mm/cm2-24 hr-atm) and those gas barrier properties that are obtained by other
methods are not comparable to those of a PTP sheet.
[0010]
Furthermore, with regard to the film coating agent of Patent Document 4,
since the disintegrating force of the resulting film itself is weak, it has been pointed
out not only that a delay in disintegration may occur to affect the drug effect when
the disintegration properties of a pharmaceutical solid preparation to be coated are
not sufficient, but also that the bioequivalence test associated with formulation
change may become more troublesome.
[0011]
Therefore, an object of the present invention is to provide a coating agent for
a pharmaceutical solid preparation, which imparts an unpackaged pharmaceutical
solid preparation with excellent barrier properties equivalent to those of a PTP sheet
without affecting the disintegration properties of the pharmaceutical solid preparation.
MEANS FOR SOLVING THE PROBLEMS
[0012]
The present inventors intensively studied in order to achieve the above-
described object and discovered that a coating agent in which a swelling clay is
uniformly dispersed in a polyethylene glycol is capable of imparting a
pharmaceutical solid preparation with gas barrier properties equivalent to those of a
PTP sheet and that a film formed by the coating agent has excellent disintegration
properties.
[0013]
That is, the present invention provides a coating agent for a pharmaceutical

solid preparation which comprises a polyethylene glycol having an average
molecular weight of 950 to 25,000 and a swelling clay, wherein the mass ratio of the
polyethylene glycol and the swelling clay is 2:8 to 6:4.
[0014]
By using the above-described film coating agent to form a thin film on the
surface of a pharmaceutical solid preparation so as to coat the pharmaceutical solid
preparation with the film layer, due to the effect of the mass ratio of the polyethylene
glycol and the swelling clay and the effect of the swelling clay being in a swollen
state, the swelling clay forms a labyrinth-like structure and exhibits an effect of
preventing the thus coated pharmaceutical solid preparation from coming into
contact with water vapor and oxygen (hereinafter, referred to as "labyrinth effect").
By this, even when the film layer is thin, the pharmaceutical solid preparation itself
can be imparted with excellent gas barrier properties that are equivalent to those of a
PTP sheet, so that the pharmaceutical solid preparation can be taken by patients
without any problem.
[0015]
It is preferred that the above-described swelling clay be bentonite or
magnesium aluminum silicate.
[0016]
By using bentonite or magnesium aluminum silicate, superior labyrinth effect
can be attained.
[0017]
It is preferred that the above-described coating agent contain a sugar alcohol
derivative-type surfactant in an amount of 0.5 to 30%.
[0018]
It is preferred that the above-described sugar alcohol derivative-type
surfactant be a sorbitan fatty acid ester.

[0019]
Further, the present invention provides a pharmaceutical film formulation
which is composed of the above-described coating agent and has a water vapor
permeability of less than 1.0 x 10-4 g-mm/cm2 24 hratm at a room temperature of
40°C and a relative humidity of 75%; and a coated pharmaceutical solid preparation
which is coated with the above-described coating agent and has a water vapor
permeability of less than 1.0 x 10-4 g-mm/cm2 24 hratm at a room temperature of
40°C and a relative humidity of 75%.
[0020]
Further, the present invention provides a pharmaceutical film formulation
which comprises a polyethylene glycol having an average molecular weight of 950 to
25,000 and a swelling clay, wherein the mass ratio of the above-described
polyethylene glycol and the above-described swelling clay is 2:8 to 6:4 and the water
vapor permeability at a room temperature of 40°C and a relative humidity of 75% is
less than 1.0 x 10-4 g-mm/cm2 24 hratm; and a coated pharmaceutical solid
preparation which has a coating layer comprising a polyethylene glycol having an
average molecular weight of 950 to 25,000 and a swelling clay, in which coating
layer the mass ratio of the above-described polyethylene glycol and the above-
described swelling clay is 2:8 to 6:4 and the water vapor permeability at a room
temperature of 40°C and a relative humidity of 75% is less than 1.0 × 10-4
g mm/cm2 24 hratm.
EFFECT OF THE INVENTION
[0021]
According to the present invention, since excellent gas barrier properties that
are equivalent to those of a PTP sheet can be imparted to a pharmaceutical solid
preparation itself even when it is in an unpackaged condition, deterioration of the
pharmaceutical solid preparation can be prevented and its medicinal component(s)

can be stably retained for a prolonged period of time. Further, according to the
present invention, since the formed film itself has excellent disintegration properties,
it can exhibit excellent gas barrier performance without affecting the disintegration
properties of the pharmaceutical solid preparation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022]
[Fig. 1] Fig. 1 shows the dissolution profiles of the tablets of Example 1 and
Comparative Example 4 and a commercially available tablet.
[Fig. 2-1] Fig. 2-1 shows the dissolution profiles of the tablets of Example 2
and Comparative Example 5 and a commercially available tablet.
[Fig. 2-2] Fig. 2-2 shows the dissolution profiles of the tablet of Example 2
before and after storage.
[Fig. 2-3] Fig. 2-3 shows the dissolution profiles of the tablet of Comparative
Example 5 before and after storage.
[Fig. 2-4] Fig. 2-4 shows the dissolution profiles of a commercially available
tablet before and after storage.
[Fig. 3] Fig. 3 is an image showing the film of Example 3, which was taken
under a focused ion beam transmission electron microscope.
[Fig. 4] Fig. 4 is an image showing the film of Example 4, which was taken
under a focused ion beam transmission electron microscope.
MODE FOR CARRYING OUT THE INVENTION
[0023]
Modes for carrying out the present invention will now be described; however,
the present invention is not restricted to the following modes. It is noted here that,
unless otherwise specified,"%" represents "% by mass (w/w%)".
[0024]
The coating agent for a pharmaceutical solid preparation according to the

present invention is characterized in that it comprises a polyethylene glycol having
an average molecular weight of 950 to 25,000 and a swelling clay and that the mass
ratio of the polyethylene glycol and the swelling clay is 2:8 to 6:4.
[0025]
The term "pharmaceutical solid preparation" used herein refers to a
pharmaceutical formulated in the form of a solid and examples thereof include
tablets (such as sublingual tablets and orally-disintegrating tablets), capsules (such as
soft capsules and microcapsules), granules, subtle granules, powders, pills, troches
and film formulations.
[0026]
The term "coating agent for a pharmaceutical solid preparation" used herein
refers to a composition which is capable of forming a thin film on the surface of a
pharmaceutical solid preparation to coat the pharmaceutical solid preparation with a
layer of the film. The above-described film imparts gas barrier properties to a
pharmaceutical solid preparation and plays a role in inhibiting, for example,
degradation of a medicinal component contained in the pharmaceutical solid
preparation by oxygen or water vapor, as well as color change or deterioration of the
pharmaceutical solid preparation.
[0027]
It is preferred that the mass of the film layer coating a pharmaceutical solid
preparation be 2 to 200% with respect to the mass of the pharmaceutical solid
preparation itself and, in cases where the pharmaceutical solid preparation is a tablet,
the mass of the film layer is preferably 3 to 70%, more preferably 3 to 20%, still
more preferably 3 to 15%.
[0028]
In order to form a thin film layer on the surface of a pharmaceutical solid
preparation using the coating agent for a pharmaceutical solid preparation according

to the present invention, the coating agent for a pharmaceutical solid preparation
according to the present invention may be, for example, sprayed or coated onto the
surface of the pharmaceutical solid preparation and the solvent contained in the
coating agent may then be removed by drying. More specifically, in cases where
the pharmaceutical solid preparation is in the form of a tablet, for example, a coating
pan or a tablet coating machine may be employed. Further, in cases where the
pharmaceutical solid preparation is in the form of granules or powder, for example, a
fluidized bed coating machine or a tumbling fluidized bed coating machine may be
employed.
[0029]
Examples of the solvent contained in the above-described coating agent
include water, C1 to C5 lower alcohols and mixed solvents thereof, and the above-
described solvent is preferably ethanol or water.
[0030]
Further, the coating agent for a pharmaceutical solid preparation according to
the present invention may not only be in a liquid state, but also in a solid state.
Examples of the coating agent in a solid state include those which are obtained by
spray-drying or freeze-drying a liquid coating agent and evaporating its solvent
component.
[0031]
Here, a film formulation can be obtained also by adding a medicinal
component to the coating agent for a pharmaceutical solid preparation according to
the present invention and then drying the resultant as is.
[0032]
The "medicinal component" contained in the pharmaceutical solid preparation
refers to one which is used in the treatment, prevention and/or diagnosis of a human
or animal disease and is not an equipment or an apparatus. Examples of such

medicinal component include chemotherapeutic agents, calcium antagonists,
antibiotics, respiratory stimulants, antitussive-expectorants, antineoplastic agents,
autonomic agents, psychotropic agents, local anesthetics, muscle relaxants, drugs for
digestive organs, antihistamines, toxicopetic agents, hypnosedatives, antiepileptics,
antipyretic agents, analgesic agents, anti-inflammatory agents, cardiac stimulants,
antiarrhythmic agents, diuretic agents, vasodilators, antilipemic agents, analeptic
modifying agents, vitamin preparations, anticoagulants, hepatic drugs, hypoglycemic
agents, hypotensive agents, colitis therapeutic agents, anti-asthmatic agents,
antianginal agents, antiemetic agents, glucocorticoids, therapeutic agents for
ulcerative colitis and Crohn's disease, antifungal agents, arteriolosclerosis therapeutic
agents, enzyme inhibitors, gout therapeutic agents, anti-Parkinson drugs, migraine
therapeutic agents, proteins and peptides. The excellent gas barrier properties that
are attained by the coating agent for a pharmaceutical solid preparation according to
the present invention sufficiently exhibit the effects thereof particularly in coating of
a pharmaceutical solid preparation containing a medicinal component having a
moisture-absorbing property, oxidative degradation property or odor property.
[0033]
The term "deterioration of a pharmaceutical solid preparation" used herein
refers to, for example, a change in the weight, hardness or shape of a pharmaceutical
solid preparation caused by oxygen or water vapor; a reduction or leakage of the
medicinal component content due to decomposition; cracking on the surface of a
pharmaceutical solid preparation; or a change in the outer appearance such as
coloration.
[0034]
The term "polyethylene glycol" (hereinafter, referred to as "PEG") used
herein refers to a polymeric compound (polyether) having a structure of polymerized
ethylene glycol and such a polymeric compound is referred to as "Macrogol" in the

Japanese and European Pharmacopoeias and "polyethylene glycol" in the U.S.
Pharmacopoeia (NF). Since the product number of each grade and its average
molecular weight are not uniformly defined among these three pharmacopeias, the
product name of a PEG is hereinafter indicated with the designation used by the
Japanese Pharmacopoeia. The PEG in the present invention is required to have an
average molecular weight of 950 to 25,000 (for example, Japanese Pharmacopoeia
Macrogol 1000, 4000, 6000 or 20000 (manufactured by NOF Corporation or Sanyo
Chemical Industries, Ltd.)) and in particular, the PEG is preferably one having an
average molecular weight of 7,000 to 9,300 (for example, Japanese Pharmacopoeia
Macrogol 6000). As long as the average molecular weight is in the above-described
range, a plurality of PEGs having different average molecular weights may be used
in combination as well.
[0035]
The term "swelling clay" used herein refers to a clay having a swelling
property. More specifically, the term refers to, among those fine powder substances
that exhibit viscosity and plasticity when containing an appropriate amount of water,
a substance having a swelling property.
[0036]
As the swelling clay, one which is negatively charged due to the composition
balance of the metal salt species is preferred, and examples of such negatively
charged swelling clay include smectites having a three-layer structure.
[0037]
The term "negatively charged" refers to a condition in which the.swelling
clay has a cation exchange capability and the amount of the change is expressed in
terms of the cation exchange capacity (CEC). Here, the unit of the cation exchange
capacity is milliequivalent/100 g (hereinafter, indicated as "meq/100 g") and
generally expressed in terms of the number of equivalents corresponding to the molar

concentration of monovalent ions.
[0038]
Examples of the smectites include beidellite, nontronite, saponite, hectorite,
sauconite, bentonite (hereinafter, referred to as "BT"), aluminum magnesium silicate
and mixtures thereof. Thereamong, BT and aluminum magnesium silicate are
preferred and BT is more preferred.
[0039]
It is preferred that the swelling clay be uniformly dispersed in a film formed
by the above-described coating agent for a pharmaceutical solid preparation. As an
"uniformly dispersed" condition, one in which the swelling clay is dispersed as a
single-layer belt-like structure is most preferred; however, it is difficult to exfoliate
the swelling clay down to single layer with a production equipment normally used in
the production of a pharmaceutical product. Practically, the swelling clay is
preferably in a condition where it is dispersed in the form of a belt-like laminated
structure having 10 to 100 layers of belt-like structures, and it is preferred that the
number of layers in the belt-like laminated structure be as small as possible. This is
because, in a film formed by the coating agent according present invention which
contains BT and a polymer in certain amounts, by allowing the swelling clay to be
uniformly dispersed in the form of a belt-like laminated structure having a small
number of layers, a superior labyrinth effect can be attained and the gas barrier
performance is consequently improved.
[0040]
In the cross-section of a film formed by the coating agent for a
pharmaceutical solid preparation according to the present invention in the thickness
direction, it is preferred that the above-described belt-like laminated structure be
dispersed in a mesh pattern and planarly oriented. The condition of the belt-like
laminated structure at the cross-section in the film thickness direction can be

observed under, for example, a transmission electron microscope (hereinafter,
referred to as "TEM").
[0041]
The term "mesh pattern" refers to a state in which the belt-like structure of the
swelling clay is literally forming a mesh when the dispersion state of the belt-like
laminated structure at the cross-section in the film thickness direction is expressed
two-dimensionally.
[0042]
The term "planarly oriented" refers to a state in which the belt-like structure
of the swelling clay is laminated in the film thickness direction.
[0043]
In order to allow the swelling clay to be dispersed as a belt-like laminated
structure in a film formed by the coating agent for a pharmaceutical solid preparation
according to the present invention, it is preferred that the swelling clay contained in
the coating agent be in a swollen state.
[0044]
The "swollen state" of the swelling clay refers to a state in which the swelling
clay contains a dispersion medium and is swollen. Examples of swelling clay in a
swollen state include a dispersion obtained by suspending a swelling clay in a
dispersion medium and stirring the resulting suspension using a homogenizer or the
like, and it is preferred that the swelling clay be dispersed in such a manner that all of
the swelling clay can pass through a filter paper when the dispersion is filtered.
Here, examples of the filter paper used in the above-described filtering operation
include a glass fiber filter paper GF/D (particle retention capacity: 2.7 µm;
manufactured by Whatman).
[0045]
Examples of the index for the degree of dispersion of the swelling clay

contained in the coating agent for a pharmaceutical solid preparation according to the
present invention as a belt-like laminated structure include haze value. A haze
value represents the turbidity of the coating agent and it becomes smaller as the
swelling clay is more uniformly dispersed and the coating agent becomes more
transparent. That is, a smaller haze value of the coating agent indicates a smaller
number of layers in the belt-like structure of the swelling clay. Here, as the
swelling clay contained in the coating agent for a pharmaceutical solid preparation
according to the present invention, a 3.5% aqueous solution containing only the
swelling clay whose haze value is not higher than 90% is preferred and one whose
haze value is not higher than 60% is more preferred.
[0046]
In the coating agent for a pharmaceutical solid preparation according to the
present invention, the mass ratio of the PEG and the swelling clay is required to be
2:8 to 6:4, and it is preferably 3:7.
[0047]
In cases where the mass of the swelling clay is less than 40% of the mass of
the PEG, the labyrinth effect provided by the swelling clay becomes small, so that
excellent gas barrier properties that are equivalent to those of a PTP sheet cannot be
attained. Meanwhile, in cases where the mass of the swelling clay is greater than 4
times the mass of the PEG, since the ratio of the swelling clay is excessively high,
the dispersion of the swelling clay as a belt-like laminated structure becomes
heterogeneous, so that excellent gas barrier properties that are equivalent to those of
a PTP sheet cannot be attained.
[0048]
Here, in order to sufficiently attain the labyrinth effect of the swelling clay, it
is preferred that the ratio of the swelling clay in a film formed by the above-
described coating agent for a pharmaceutical solid preparation be not less than 20%.

[0049]
The water vapor permeability of a film formed by the coating agent for a
pharmaceutical solid preparation according to the present invention is preferably 1.0
x 10-5 to 1.0 x 10-4 g-mm/cm2 24 hr-atm, which is equivalent to that of a PTP sheet,
more preferably 1.0 x 10-5 to 6.5 × 10-5 g-mm/cm2 24 hr-atm, still more preferably
1.0 x 10-5 to 3.0 x 10-5 g.mm/cm2 24 hr-atm.
[0050]
A film formed by the coating agent for a pharmaceutical solid preparation
according to the present invention exhibits excellent disintegration properties.
More specifically, in a dissolution test (37°C, paddle method, 50 rounds/min,
solvent: 900 ml of water) of a film formed in a size of 1 cm x 2 cm and a thickness of
60 urn, the film is disintegrated within 10 minutes to lose its shape.
[0051]
In order to allow the swelling clay to be uniformly dispersed in a film, it is
important to uniformly disperse the swelling clay in the coating agent solution. As
a dispersion apparatus therefor, an apparatus which has a stirring capability for
uniformly dispersing the swelling clay as a belt-like laminated structure is preferred
and, for example, a homogenizer (Polytron; Kinematica AG) or a thin-film spin
system high-speed mixer (FILMIX; PRJMIX Corporation) is suitably employed.
[0052]
The coating agent for a pharmaceutical solid preparation according to the
present invention may also contain a pharmaceutically acceptable additive(s) within
the range where the gas barrier properties of the coating agent are not impaired. For
example, in order to make the dispersion of the swelling clay as a belt-like laminated
structure more uniform, the coating agent may contain a surfactant as an additive.
In this case, the amount of the surfactant with respect to the total amount of the PEG
and the swelling clay is preferably 0.01 to 30 parts by mass, more preferably 1 to 20

parts by mass, still more preferably 5 to 15 parts by mass.
[0053]
As the above-described surfactant, a sugar alcohol derivative-type surfactant
is preferred. The term "sugar alcohol derivative-type surfactant" used herein refers
to a compound which has a sugar alcohol skeleton in the molecule and exhibits
surface-activating capability. Among such compounds, a sorbitan fatty acid ester is
preferred, and examples thereof include sorbitan monolaurates.
[0054]
In cases where a sugar alcohol derivative-type surfactant is used as an
additive, it is preferred that the coating agent for a pharmaceutical solid preparation
according to the present invention contain the sugar alcohol derivative-type
surfactant in an amount of 0.5 to 30%.
[0055]
The coating agent for a pharmaceutical solid preparation according to the
present invention may further contain additives which are commonly used in
coatings in the field of pharmaceuticals. Examples of such additive include
colorants that are masking agents, such as plant-extracted dyes; titanium oxide;
calcium carbonate; and silicon dioxide.
[0056]
A pharmaceutical solid preparation to be coated with a film layer formed by
the coating agent for a pharmaceutical solid preparation according to the present
invention may also be coated in advance with a film layer formed by other polymeric
substance or the like. In this case, it is preferred that the ratio of the swelling clay
with respect to the amount of the whole film layer of the pharmaceutical solid
preparation be not less than 5%.
EXAMPLES
[0057]

The present invention will now be concretely described by way of examples
thereof; however, the present invention is not restricted thereto.
[0058]
(Method of Measuring Water Vapor Permeability)
The water vapor permeability of a film formed by the coating agent for a
pharmaceutical solid preparation according to the present invention was measured in
accordance with JIS K8123 (1994) having minor modifications.
[0059]
Specifically, a film which was formed by a coating agent prepared as
appropriate was examined before the light and a portion of uniform thickness without
pinhole was selected and cut into a round shape of 3.5 cm in diameter to measure the
thickness of the film at 5 arbitrary spots. Then, 3 g of calcium chloride (850 to
2,000 urn in particle size) was placed in an aluminum cup (30 mm in diameter) and
the film cut into a round shape and a film fixation ring were sequentially placed on
the aluminum cup. A weight was placed on the ring to fix the ring, and in this
condition, molten paraffin wax was poured into the margin of the aluminum cup.
After the paraffin wax was solidified, the weight was removed and the mass of the
aluminum cup as a whole was measured to determine the initial mass. Thereafter,
the aluminum cup was placed in an incubator of 40°C and 75% RH and the
aluminum cup was taken out every 24 hours to measure the mass thereof. Then,
using the following equation, the water vapor permeability coefficient was calculated.
It is noted here that, in all of the below-described water vapor permeability
measurement tests, r = 1.5 cm, t = 24 hours and C = 1 atm.
Water vapor permeability (g.mm/cm2 24 hratm) = (W × A)/(B × t × C)
W: Increase in the mass in 24 hours (g)
A: Average film thickness at 5 spots (mm)
B: Permeation area, πr2 (cm2)

t: Elapsed time (hour)
C: Atmospheric pressure (atm)
[0060]
(Method of Measuring Haze Value)
Using an integrating sphere spectrophotometer (self-recording
spectrophotometer, Model UV-3101PC; Shimadzu Corporation), the total light
transmission spectrum and the diffusion-transmission spectrum were measured to
calculate the haze value.
[0061]
(Method of Measuring Oxygen Permeability Coefficient)
In accordance with JIS K7126-1 (2006) (Gas Permeability Test Method by
Gas Chromatography), the oxygen permeability coefficient of a film formed by the
coating agent for a pharmaceutical solid preparation according to the present
invention was measured at a temperature of 23 ± 2°C and a relative humidity of 90%
(90% RH) using an oxygen permeability coefficient measuring apparatus (GTR-
30XAD2G and 2700T.F; GTR Tec Corporation).
[0062]
(Dissolution Test of Sodium Valproate Preparation)
The dissolution test was performed in accordance with The Japanese
Pharmacopoeia, 15th Edition: "Dissolution Test" (2nd method). Using the Japanese
Pharmacopoeia 2nd solution for dissolution fluid for dissolution test as a test solution,
a tablet was loaded to 900 mL of the test solution and the eluted solution was
collected with time and quantified under the following HPLC conditions.
[0063]
«HPLC Conditions»
Mobile phase: 50 raM sodium dihydrogen phosphate/acetonitrile = 5/5 (v/v)
Column: Devolosil ODS-5 (4.6 x 150 mm)

Detection wavelength: 210 nm
[0064]
(Dissolution Test of Montelukast Sodium Preparation)
The dissolution test was performed in accordance with The Japanese
Pharmacopoeia, 15th Edition: "Dissolution Test" (2nd method). A tablet was
loaded to a test solution (900 mL) prepared by adding 0.5% polysorbate 80 to
distilled water and the eluted solution was collected with time and quantified under
the following HPLC conditions.
[0065]
«HPLC Conditions»
Mobile phase: acetate buffer (pH 3.5)/methanol = 15/85 (v/v)
Column: Hypersil ODS (4.6 x 250 mm)
Detection wavelength: 254 nm
[0066]
(Calculation Method of Increase in Mass due to Moisture Absorption by Tablet
(Increase in Moisture Absorption))
The mass of a tablet was measured before and after storage to calculate the
increase in moisture absorption using the following Equation 1.
Increase in moisture absorption (% by mass) = {(W - Ws)/Ws} x 100
Equation 1
W: Mass of tablet after storage (g)
Ws: Mass of tablet before storage (g)
[0067]
(Method of Evaluating Tablet Coloration)
Using a spectrocolorimeter (JP7100F/C; JUKI Corporation), L*, a* and b*
were measured, and the difference in the tablet color before and after storage (AE)
was calculated using the following Equation 2.


∆L: Difference in the brightness of tablet (L* axis) before and after storage
∆a: Difference in the value of red to green of tablet (a* axis) before and after
storage
∆b: Difference in the value of yellow to blue of tablet (b* axis) before and
after storage
[0068]
(Example 1)
To 445.1 parts by mass of water, 10.5 parts by mass of a PEG (Macrogol
6000 (average molecular weight: 7,300 to 9,300); NOF Corporation), 544.4 parts by
mass of 4.5% BT solution and 3.5 parts by mass of Span20 were added, and the
resultant was stirred using a homogenizer (Polytron (registered trademark) Model
KR) to obtain a coating agent (hereinafter, referred to as "the coating agent of
Example 1"). Here, as the 4.5% BT solution, a filtrate which was obtained by
adding 45 parts by mass of BT (Kunipia-F (cation exchange capacity: 115 meq/100
g); Kunimine Industries Co., Ltd.) to 955 parts by mass of stirred water, uniformly
dispersing the resulting solution using a homogenizer, and then centrifuging the
resultant and suction-filtering the thus obtained supernatant through a filter paper
was employed.
[0069]
To a coating pan (DRC-200; Powrex Corporation), 50 g of a sodium
valproate tablet (Depakene (registered trademark) tablet, 200 mg; Kyowa Hakko
Kirin Co., Ltd.) and 200 g of a placebo tablet (for bulking) were loaded, and the
sodium valproate tablet was coated with the coating agent of Example 1 to a film
thickness of 50 to 60 µm. The resulting coated sodium valproate tablet was stored
for 12 days at a temperature of 40°C and a relative humidity of 75% to examine the
change in the outer appearance and the dissolution profile before and after the

storage.
[0070]
Further, the coating agent of Example 1 was sprayed onto the back side of a
polypropylene balance tray and immediately dried with hot air using a dryer. After
repeating these operations several times, the resulting balance tray was placed in a
50°C oven and dried overnight and a film was then exfoliated from the balance tray
to measure its water vapor permeability.
[0071]
(Example 2)
To a coating pan (DRC-200; Powrex Corporation), 20 g of a montelukast
sodium tablet (Singulair (registered trademark) tablet, 10 mg; Banyu Pharmaceutical
Co., Ltd.) and 230 g of a placebo tablet (for bulking) were loaded, and the
montelukast sodium tablet was coated with the coating agent of Example 1 to a film
thickness of 60 to 80 urn. The resulting coated montelukast sodium tablet was
stored for one week at a temperature of 40°C and a relative humidity of 75% to
examine the dissolution profile and the increase in moisture absorption before and
after the storage.
[0072]
(Example 3)
To 111.95 parts by mass of water, 5.25 parts by mass of a PEG (Macrogol
6000; NOF Corporation) and 382.8 parts by mass of 3.2% BT solution were added,
and the resultant was stirred using a homogenizer to obtain a coating agent
(hereinafter, referred to as "the coating agent of Example 3"). Here, as the 3.2% BT
solution, a filtrate which was obtained by adding 32 parts by mass of BT (Kunipia-F;
Kunimine Industries Co., Ltd.) to 968 parts by mass of stirred water, uniformly
dispersing the resulting solution using a homogenizer, and then centrifuging the
resultant and suction-filtering the thus obtained supernatant through a filter paper

was employed.
[0073]
Thereafter, the coating agent of Example 3 was sprayed onto the back side of
a polypropylene balance tray and immediately dried with hot air using a dryer.
After repeating these operations several times, the resulting balance tray was placed
in a 50°C oven and dried overnight and a film was then exfoliated from the balance
tray to measure its water vapor permeability. Also, the haze value of the coating
agent of Example 3 was measured.
[0074]
(Example 4)
Using a coating agent obtained by adding 5.25 parts by mass of a PEG
(Macrogol 6000; NOF Corporation) and 272.2 parts by mass of 4.5% BT solution to
222.55 parts by mass of water and stirring the resultant using a homogenizer
(hereinafter referred to as "the coating agent of Example 4"), a film was formed in
the same manner as in Example 1 and its water vapor permeability and oxygen
permeability coefficient were measured. Also, the haze value of the coating agent
of Example 4 was measured.
[0075]
(Example 5)
Using a coating agent obtained by adding 5.25 parts by mass of a PEG
(Macrogol 1000 (average molecular weight 950 to 1,050); NOF Corporation) and
272.2 parts by mass of 4.5% BT solution to 222.55 parts by mass of water and
stirring the resultant using a homogenizer, a film was formed in the same manner as
in Example 1 and its water vapor permeability was measured.
[0076]
(Example 6)
Using a coating agent obtained by adding 5.25 parts by mass of a PEG

(Macrogol 4000 (average molecular weight: 2,600 to 3,800); NOF Corporation) and
272.2 parts by mass of 4.5% BT solution to 222.55 parts by mass of water and
stirring the resultant using a homogenizer, a film was formed in the same manner as
in Example 1 and its water vapor permeability was measured.
[0077]
(Example 7)
Using a coating agent obtained by adding 5.25 parts by mass of a PEG
(Macrogol 20000 (average molecular weight: 20,000 to 25,000); NOF Corporation)
and 272.2 parts by mass of 4.5% BT solution to 222.55 parts by mass of water and
stirring the resultant using a homogenizer, a film was formed in the same manner as
in Example 1 and its water vapor permeability was measured.
[0078]
(Example 8)
Using a coating agent obtained by adding 10.5 parts by mass of a PEG
(Macrogol 6000; NOF Corporation) and 155.56 parts by mass of 4.5% BT solution to
333.94 parts by mass of water and stirring the resultant using a homogenizer, a film
was formed in the same manner as in Example 1 and its water vapor permeability
was measured.
[0079]
(Example 9)
Using a coating agent obtained by adding 3.5 parts by mass of a PEG
(Macrogol 6000; NOF Corporation) and 437.5 parts by mass of 3.2% BT solution to
59.0 parts by mass of water and stirring the resultant using a homogenizer, a film was
formed in the same manner as in Example 1 and its water vapor permeability was
measured.
[0080]
(Example 10)

Using a coating agent obtained by adding 4.62 parts by mass of a PEG
(Macrogol 6000; NOF Corporation), 336.9 parts by mass of 3.2% BT solution and
2.1 parts by mass of Span80 to 156.38 parts by mass of water and stirring the
resultant using a homogenizer, a film was formed in the same manner as in Example
1 and its water vapor permeability was measured.
[0081]
(Example 11)
Using a coating agent obtained by adding 4.62 parts by mass of a PEG
(Macrogol 6000; NOF Corporation), 336.9 parts by mass of 3.2% BT solution and
2.1 parts by mass of Tween80 (Polysorbate 80) to 156.38 parts by mass of water and
stirring the resultant using a homogenizer, a film was formed in the same manner as
in Example 1 and its water vapor permeability was measured.
[0082]
(Example 12)
Using a coating agent obtained by adding 5.075 parts by mass of a PEG
(Macrogol 6000; NOF Corporation), 382.8 parts by mass of 3.2% BT solution and
0.175 parts by mass of liquid paraffin to 112.0 parts by mass of water and stirring the
resultant using a homogenizer, a film was formed in the same manner as in Example
1 and its water vapor permeability was measured.
[0083]
(Example 13)
To 544.4 parts by mass of 4.5% BT solution, 10.5 parts by mass of a PEG
(Macrogol 6000; NOF Corporation) was added, and the resultant was stirred using a
homogenizer. After adding thereto 3.5 parts by mass of Span20 and 531.15 parts by
mass of water, 450.45 parts by mass of ethanol was further added and the resultant
was stirred again using a homogenizer to obtain a coating agent (hereinafter, referred
to as "the coating agent of Example 13").

[0084]
Thereafter, 20 g of a montelukast sodium tablet (Singulair (registered
trademark) tablet, 10 mg; Banyu Pharmaceutical Co., Ltd.) and 230 g of a placebo
tablet (for bulking) were loaded to a coating pan (DRC-200; Powrex Corporation)
and the montelukast sodium tablet was coated with the coating agent of Example 13
to a film thickness of 60 to 80 µm. The resulting coated montelukast sodium tablet
was stored for one week at a temperature of 40°C and a relative humidity of 75% to
examine the increase in moisture absorption before and after the storage.
[0085]
Further, the coating agent of Example 13 was sprayed onto the back side of a
polypropylene balance tray and immediately dried with hot air using a dryer. After
repeating these operations several times, the resulting balance tray was placed in a
50°C oven and dried overnight and a film was then exfoliated from the balance tray
to measure its water vapor permeability.
[0086]
(Example 14)
To 127.4 parts by mass of 4.5% BT solution, 2.46 parts by mass of a PEG
(Macrogol 6000; NOF Corporation) was added, and the resultant was stirred. After
adding thereto 0.81 parts by mass of Span20 and 98.84 parts by mass of water,
225.55 parts by mass of ethanol was continuously added and the resultant was stirred
using a homogenizer to obtain a coating agent. Using the thus obtained coating
agent, a film was formed in the same manner as in Example 1 and its water vapor
permeability was measured.
[0087]
(Example 15)
To 76.23 parts by mass of 4.5% BT solution, 1.47 parts by mass of a PEG
(Macrogol 6000; NOF Corporation) was added, and the resultant was stirred. After

further adding thereto 2.10 parts by mass of Span20 and 120.2 parts by mass of water,
the resultant was stirred using a homogenizer to obtain a coating agent. Using the
thus obtained coating agent, a film was formed in the same manner as in Example 1
and its water vapor permeability was measured.
[0088]
(Example 16)
To a high-speed stirring apparatus (FILMIX Model 40-40; PRIMIX
Corporation) (hereinafter, referred to as "FILMIX"), 1.12 parts by mass of BT, 0.47
parts by mass of PEG 6000, 0.16 parts by mass of Span20 and 28.2 parts by mass of
water were loaded and mixed with stirring for 5 minutes. Then, 20.0 parts by mass
of water was continuously added thereto and the resultant was stirred using a stirrer
and suction-filtered through a filter paper to obtain a coating agent. Using the thus
obtained coating agent, a film was formed in the same manner as in Example 1 and
its water vapor permeability was measured.
[0089]
(Example 17)
Using FILMIX, 22.4 parts by mass of 5.0% BT solution and 0.47 parts by
mass of PEG 6000 were mixed with stirring for 5 minutes, and 0.16 parts by mass of
Span20 was added thereto and mixed with stirring for another 5 minutes. Then,
26.97 parts by mass of water was added and the resultant was stirred using a stirrer
and suction-filtered through a filter paper to obtain a coating agent. Using the thus
obtained coating agent, a film was formed in the same manner as in Example 1 and
its water vapor permeability was measured. Here, as the 5.0% BT solution, a
solution which was obtained by stirring 1.25 parts by mass of BT and 23.75 parts by
mass of water using FILMIX was employed.
[0090]
(Production of Olmesartan Medoxomil Core Tablet for Coating)

Since a commercially available tablet is a flat uncoated tablet and is thus not
suitable for film coating, the tablet was pulverized and re-tableted into an R tablet.
A commercially available olmesartan medoxomil-containing tablet (Olmetec tablet
(registered trademark), 20 mg; Daiichi Sankyo Co., Ltd.) was pulverized using a
mortar and the thus obtained pulverization product was re-tableted using a rotary
tableting machine to obtain an olmesartan medoxomil core tablet (7 mm in diameter,
10R).
[0091]
(Example 18)
The olmesartan medoxomil core tablet obtained by the above-described
production method was loaded to a coating pan (DRC-200; Powrex Corporation) and
coated with the coating agent of Example 1 to a film thickness of 60 to 80 µm. The
thus obtained coated olmesartan medoxomil tablet and a commercially available
metformin hydrochloride-containing tablet (Glycoran (registered trademark) tablet,
250 mg; Nippon Shinyaku Co., Ltd.) were placed in the same glass bottle. The
glass bottle was capped with a plastic cap and stored for one week at a temperature
of 40°C and a relative humidity of 75%. The change in color of the metformin
hydrochloride-containing tablet during the storage caused by diacetyl degraded and
released from olmesartan medoxomil was evaluated using a color difference meter.
[0092]
(Comparative Example 1)
Using a coating agent obtained by adding 12.25 parts by mass of a PEG
(Macrogol 6000; NOF Corporation) and 164.1 parts by mass of 3.2% BT solution to
323.65 parts by mass of water and stirring the resultant using a homogenizer, a film
was formed in the same manner as in Example 1 and its water vapor permeability
was measured.
[0093]

(Comparative Example 2)
Using a coating agent obtained by adding 1.75 parts by mass of a PEG
(Macrogol 6000; NOF Corporation) and 492.2 parts by mass of 3.2% BT solution to
6.05 parts by mass of water and stirring the resultant using a homogenizer, a film was
formed in the same manner as in Example 1 and its water vapor permeability was
measured.
[0094]
(Comparative Example 3)
Using a coating agent obtained by adding 5.25 parts by mass of a
polyethylene oxide (PolyOX80, Dow Corning; hereinafter, referred to as "PEO") and
382.8 parts by mass of 3.2% BT solution to 111.95 parts by mass of water and
stirring the resultant using a homogenizer, a film was formed in the same manner as
in Example 1 and its water vapor permeability was measured.
[0095]
(Comparative Example 4)
The gas-barrier coating agent according to Example 2 of Patent Document 4
was prepared. To 156.38 parts by mass of water, 4.62 parts by mass of polyvinyl
alcohol (Gohsenol EG-05, The Nippon Synthetic Chemical Industry Co., Ltd.;
hereinafter, referred to as "PVA"), 336.9 parts by mass of 3.2% BT solution and 2.1
parts by mass of Span20 (sorbitan monolaurate) were added, and the resultant was
stirred using a homogenizer to obtain a coating agent (hereinafter, referred to as "the
coating agent of Comparative Example 4").
[0096]
To a coating pan (DRC-200; Powrex Corporation), 25 g of a sodium
valproate tablet (Depakene (registered trademark) tablet, 200 mg; Kyowa Hakko
Kirin Co., Ltd.) and 225 g of a placebo tablet (for bulking) were loaded, and the
sodium valproate tablet was coated with the coating agent of Comparative Example 4

to a film thickness of 50 to 60 urn. The resulting coated sodium valproate tablet
was stored for 12 days at a temperature of 40°C and a relative humidity of 75% to
examine the change in the outer appearance and the dissolution profile before and
after the storage. Further, a film was formed in the same manner as in Example 1
and its water vapor permeability was measured.
[0097]
(Comparative Example 5)
To a coating pan (DRC-200; Powrex Corporation), 20 g of a montelukast
sodium tablet (Singulair (registered trademark) tablet, 10 mg; Banyu Pharmaceutical
Co., Ltd.) and 230 g of a placebo tablet (for bulking) were loaded, and the
montelukast sodium tablet was coated with the coating agent of Comparative
Example 4 to a film thickness of 50 to 60 µm. The resulting coated montelukast
sodium tablet was stored for one week at a temperature of 40°C and a relative
humidity of 75% to examine the dissolution profile before and after the storage.
[0098]
(Comparative Example 6)
Using a coating agent obtained by adding 1.37 parts by mass of polyethylene
glycol 400 (PEG 400; NOF Corporation) and 100.0 parts by mass of 3.2% BT
solution to 33.81 parts by mass of water and stirring the resultant using a
homogenizer, a film was formed in the same manner as in Example 1 and its water
vapor permeability was measured.
[0099]
(Comparative Example 7)
To 65.34 parts by mass of 4.5% BT solution, 1.26 parts by mass of a PEG
(Macrogol 6000; NOF Corporation) was added, and the resultant was stirred. After
adding thereto 2.80 parts by mass of Span20 and 130.6 parts by mass of water, the
resulting mixture was stirred using a homogenizer to obtain a coating agent. Using

the thus obtained coating agent, a film was formed in the same manner as in Example
1 and its water vapor permeability was measured.
[0100]
(Comparative Example 8)
The gas-barrier coating agent according to Example 2 of Patent Document 6
was prepared. To 1,200 parts by mass of water, 15.0 parts by mass of dextrose
(Japanese Pharmacopoeia dextrose, NG-TDA; San-ei Sucrochemical Co., Ltd.) and
35 parts by mass of sodium carboxymethylcellulose (T.P.T-JP 50; Gotoku Chemical
Co., Ltd.) were added and dissolved with stirring to obtain a coating agent
(hereinafter, referred to as "the coating agent of Comparative Example 8").
[0101]
An olmesartan medoxomil core tablet (7 mm in diameter, 10R) was loaded to
a coating pan (DRC-200; Powrex Corporation) and coated with the coating agent of
Comparative Example 8 to a film thickness of 60 to 80 µm. The thus obtained
coated olmesartan medoxomil tablet and a commercially available metformin
hydrochloride-containing tablet (Glycoran (registered trademark) tablet, 250 mg;
Nippon Shinyaku Co., Ltd.) were placed in the same glass bottle. The glass bottle
was capped with a plastic cap and stored for one week at a temperature of 40°C and a
relative humidity of 75%. The change in color of the metformin hydrochloride-
containing tablet during the storage caused by diacetyl degraded and released from
olmesartan medoxomil was evaluated using a color difference meter.
[0102]
(Reference Example 1)
A commercially available sodium valproate tablet (Depakene (registered
trademark) tablet, 200 mg; Kyowa Hakko Kirin Co., Ltd.) was stored for 12 days at a
temperature of 40°C and a relative humidity of 75% and the outer appearance thereof
was observed thereafter. Also, the dissolution profile, was examined before and

after the storage.
[0103]
(Reference Example 2)
For a commercially available montelukast sodium tablet (Singulair (registered
trademark) tablet, 10 mg; Banyu Pharmaceutical Co., Ltd.), the dissolution profile
was examined before and after one week of storage at a temperature of 40°C and a
relative humidity of 75%.
[0104]
(Reference Example 3)
For a commercially available montelukast sodium tablet (Singulair (registered
trademark) tablet, 10 mg; Banyu Pharmaceutical Co., Ltd.), the increase in moisture
absorption before and after one week of storage at a temperature of 40°C and a
relative humidity of 75% was calculated.
[0105]
(Reference Example 4)
A commercially available olmesartan medoxomil-containing tablet (Olmetec
tablet (registered trademark), 20 mg; Daiichi Sankyo Co., Ltd.) and a commercially
available metformin hydrochloride-containing tablet (Glycoran (registered
trademark) tablet, 250 mg; Nippon Shinyaku Co., Ltd.) were placed in the same glass
bottle. The glass bottle was capped with a plastic cap and stored for one week at a
temperature of 40°C and a relative humidity of 75%. The change in color of the
metformin hydrochloride-containing tablet during the storage caused by diacetyl
degraded and released from olmesartan medoxomil was evaluated using a color
difference meter.
[0106]
Table 1 shows the haze values of the coating agent of Example 3 and the
coating agent of Example 4.


Table 2 shows: the mass ratios of PEG, BT and the third component that were
contained in the respective coating agents prepared in Examples 1 and 3 to 12 and
Comparative Examples 1 to 4; the concentration of the respective BT solutions used
in preparation of the coating agents; and the water vapor permeabilities of the
respective films that were measured in Examples 1 and 3 to 12 and Comparative
Examples 1 to 4.
[0109]



From these results, it was revealed that the water vapor permeability is less
than 1.0 x 10-4 g-mm/cm2 24 hr-atm when the mass ratio of the PEG and the swelling
clay is in the range of 2:8 to 6:4, and those films formed by the coating agents of the
respective Examples were proven to have excellent gas barrier properties that are
equivalent to those of a PTP sheet. This means that, by forming a thin film layer on
the surface of a pharmaceutical solid preparation with the coating agent for a
pharmaceutical solid preparation according to the present invention to coat the
pharmaceutical solid preparation, excellent gas barrier properties that are equivalent
to those of a PTP sheet can be imparted to the pharmaceutical solid preparation itself.
[0111]
The film formed in Example 4 had an oxygen permeability coefficient of 1.4
x 10-5 cm3-mm/cm2-24 hr-atm, which was less than 1.0 x 10-4 cm3 -mm/cm2-24 hr-atm.
From this result, it was revealed that a film formed by the coating agent for a
pharmaceutical solid preparation according to the present invention has excellent gas
barrier properties that are equivalent to those of a PTP sheet not only for water vapor,
but also for oxygen.
[0112]
Table 3 shows the observation results of the outer appearances of the tablet of

Example 1, the tablet of Comparative Example 4 and a commercially available
sodium valproate tablet.
[0113]

According to the results, while a change in the outer appearance
(deliquescence) was observed for the commercially available sodium valproate tablet
after one day of storage, no change in the outer appearance was observed for those
sodium valproate tablets whose surface was coated with a thin film layer formed by
the coating agent for a pharmaceutical solid preparation according to the present
invention (the tablets of Example 1 and Comparative Example 4) even after 12 days
of storage. From these results, it was revealed that, by coating a pharmaceutical
solid preparation with the coating agent for a pharmaceutical solid preparation
according to the present invention in such a manner that a thin film layer is formed
on the surface, the pharmaceutical solid preparation is imparted with gas barrier
properties that are equivalent to those of a solid preparation coated with the gas
barrier coating agent of Patent Document 4.
[0115]
Next, the effect of a gas barrier film coating on the dissolution profile was
investigated. Fig. 1 shows the dissolution profiles of the tablets of Example 1 and
Comparative Example 4 and a commercially available sodium valproate tablet.
[0116]

According to the results shown in Fig. 1, while hardly any drug eluted from
the tablet of Comparative Example 4 even after 45 minutes, the tablet of Example 1
and the commercially available sodium valproate tablet both showed almost 100%
dissolution. From these results, it was revealed that there is absolutely no adverse
effect on the disintegration properties of a pharmaceutical solid preparation itself
even when it is coated with a film layer formed on the surface using the coating
agent for a pharmaceutical solid preparation according to the present invention. It
is noted here that, for the commercially available sodium valproate tablet after the
storage, the dissolution test could not be performed since sodium valproate
deliquesced during the storage.
[0117]
From the above-described results, as a pharmaceutical preparation, the tablet
of the present invention was proven to be superior to the tablet according to Patent
Document 4 since, although the tablet according to Patent Document 4 represented
by Comparative Example 4 exhibited gas barrier properties, it was observed with a
markedly delayed dissolution as compared to the tablet of the present invention
shown in Example 1.
[0118]
Fig. 2s (Figs. 2-1, 2-2, 2-3 and 2-4) show the dissolution profiles of the
tablets of Example 2 and Comparative Example 5 and a commercially available
montelukast sodium tablet.
[0119]
From the results shown in Fig. 2s, the commercially available montelukast
sodium tablet was confirmed to absorb moisture during storage and exhibit a
markedly delayed dissolution profile (Fig. 2-4). Meanwhile, there was no delay in
dissolution caused by storage was observed for the tablets of Example 2 and
Comparative Example 5 (Figs. 2-2 and 2-3). Furthermore, while dissolution of drug

from the tablet of Example 2 began about 15 minutes after the start of the test, in the
tablet of Comparative Example 5, dissolution began about 30 minutes after the start
of the test (Figs. 2-2 and 2-3). These results mean that those pharmaceutical solid
preparations whose surface was coated with a film layer formed by the coating agent
for a pharmaceutical solid preparation according to the present invention retained the
property of rapid drug dissolution because the film itself had disintegration properties.
[0120]
From the above-described results, as a pharmaceutical preparation, the tablet
of the present invention was proven to be superior to the tablet according to Patent
Document 4 since, although the tablet according to Patent Document 4 represented
by Comparative Example 5 exhibited gas barrier properties, it was observed with a
markedly delayed dissolution as compared to the tablet of the present invention
shown in Example 2.
[0121]
(TEM Measurement of Film)
Using a focused ion beam method, the cross-sections in the thickness
direction of the respective films formed in Examples 3 and 4 were observed under a
TEM. Fig 3 shows a micrograph of the film formed in Example 3 and Fig. 4 shows
a micrograph of the film formed in Example 4.
[0122]
From the results shown in Figs. 3 and 4, it was revealed that, in these films
formed by the coating agent for a pharmaceutical solid preparation according to the
present invention, the swelling clay was uniformly dispersed in the form of a belt-
like laminated structure.
[0123]
Table 4 shows the water vapor permeabilities of the films of Examples 13 and
14 where ethanol was used as a dissolution solvent of the coating agent. Table 5

shows the increase in moisture absorption by the coated montelukast sodium-
containing tablets of Examples 2 and 13 after being stored at 40°C and 75% RH.
[0124]

According to the results shown in Table 4, the films of Examples 13 and 14
where ethanol was used as a dissolution solvent had a water vapor permeability of
less than 1.0 x 10-4 cm3 -mm/cm2 24 hratm, so that it was revealed that excellent gas
barrier properties equivalent to those of a PTP sheet could be imparted to the
pharmaceutical solid preparations themselves in the same manner as in Example 1
where the dissolution solvent was water. In particular, the film of Example 13
where 30% ethanol was used as a dissolution solvent exhibited remarkable gas
barrier properties with a water vapor permeability of 8.6 × 10-6 g-mm/cm2-24 hratm.
Furthermore, according to the results shown in Table 5, while the commercially
available tablet, a reference example, showed an increase in moisture absorption by
3.9%, the coated montelukast sodium-containing tablet of Example 2 where water

was used as a coating solvent and the coated montelukast sodium-containing tablet of
Example 13 showed an increase in moisture absorption by 2.5% and 1.6%,
respectively; therefore, it was revealed that the coating agent according to the present
invention imparts high gas barrier performance to a pharmaceutical solid preparation.
[0127]
Table 6 shows the water vapor permeabilities of the film prepared with PEG
1000 (Example 5) and the film prepared with PEG 400 (Comparative Example 6).
[0128]

While the film of Comparative Example 6 where a PEG having a molecular
weight distribution of 380 to 420 was used had a water vapor permeability of not less
than 1.0 x 10-4 cm3-mm/cm2-24 hr.atm, the film of Example 5 where a PEG having a
molecular weight distribution of 950 to 1,050 was used had a water vapor
permeability of less than 1.0 x 10-4 cm3-mm/cm2-24 hratm. Therefore, it was
suggested that, in order to allow a pharmaceutical solid preparation to retain gas
barrier performance equivalent to that of a PTP packaging sheet, the PEG is required
to have a molecular weight distribution of not less than 950.
[0130]
Table 7 shows the water vapor permeabilities of the films having different
mass ratios of the third component in the respective coating agents.


While the film of Example 15 where the mass ratio of the third component
was 30% had a water vapor permeability of less than 1.0 x 10-4 cm3 -mm/cm2-24
hr-atm, the film of Comparative Example 7 where the mass ratio of the third
component was 40% had a water vapor permeability of not less than 1.0 x 10
cm3-mm/cm2-24 hr-atm. Therefore, it was suggested that, in order to allow a
pharmaceutical solid preparation to retain gas barrier performance equivalent to that
of a PTP packaging sheet, the mass ratio of the third component to be added to the
coating agent is required to be not higher than 30%.
[0133]
Table 8 shows the water vapor permeabilities of the films that were formed
by a coating agent prepared using FILMIX.
[0134]


[0135]
The films of Examples 16 and 17 that were prepared using FILMIX both had
a water vapor permeability of less than 1.0 × 10-4 cm3-mm/cm2-24 hr-atm.
Therefore, it was revealed that the stirring dispersion apparatus to be used in the
preparation of the coating agent is not restricted to a homogenizer (Polytron;
Kinematica AG) and that, as long as the apparatus is capable of dispersing the
components in such a manner that the resulting coating agent can be suction-filtered
through a filter paper, regardless of whether the components are added in the form of
a liquid or a solid such as powder, a coating agent which allows a pharmaceutical
solid preparation to retain gas barrier performance equivalent to that of a PTP
packaging sheet can be prepared.
[0136]
Table 9 shows the values of AE. The AE values were determined by placing
a set of the coated olmesartan medoxomil tablet of Example 18 and a commercially
available metformin hydrochloride-containing tablet, a set of the gas-barrier coating
agent of Comparative Example 8 and a commercially available metformin
hydrochloride-containing tablet or a set of the commercially available olmesartan
medoxomil-containing tablet of Reference Example 4 and a commercially available
metformin hydrochloride-containing tablet in the same bottle, storing the bottle for
one week at 40°C and 75% RH, and then evaluating the change in color of the
respective metformin hydrochloride-containing tablets before and after the storage
using a color difference meter.
[0137]


[0138]
As a result, the metformin hydrochloride tablet which was stored in the same
bottle as the coated olmesartan medoxomil tablet of Example 18 showed a AE value
clearly smaller than that of the metformin hydrochloride tablet stored in the same
bottle as the gas-barrier coating agent of Comparative Example 8. From this, it was
revealed that an olmesartan medoxomil tablet coated with the coating agent for a
pharmaceutical solid preparation according to the present invention inhibits color
change of a metformin hydrochloride-containing tablet during storage caused by
diacetyl degraded and released from olmesartan medoxomil. Furthermore, it was
suggested that the gas barrier effects of the coating agent for a pharmaceutical solid
preparation according to the present invention are superior as compared to the gas
barrier technology disclosed in Patent Document 6.
INDUSTRIAL APPLICABILITY
[0139]
In the field of pharmaceuticals, the coating agent for a pharmaceutical solid
preparation according to the present invention can be suitably used in the formation
of a film layer for coating a pharmaceutical solid preparation.

We claim:
1. A coating agent for a pharmaceutical solid preparation, which comprises a
polyethylene glycol having an average molecular weight of 950 to 25,000 and a
swelling clay,
wherein the mass ratio of said polyethylene glycol and said swelling clay is
2:8 to 6:4.
2. The coating agent according to claim 1, wherein said swelling clay is
bentonite or aluminum magnesium silicate.
3. The coating agent according to claim 1 or 2, which comprises a sugar alcohol
derivative-type surfactant in an amount of 0.5 to 30%.
4. The coating agent according to claim 3, wherein said sugar alcohol
derivative-type surfactant is a sorbitan fatty acid ester.
5. A pharmaceutical film formulation, which is composed of the coating agent
according to any one of claims 1 to 4 and has a water vapor permeability of less than
1.0 × 10-4 g∙mm/cm2∙24 hr∙atm at a room temperature of 40°C and a relative
humidity of 75%.
6. A coated pharmaceutical solid preparation, which is coated with the coating
agent according to any one of claims 1 to 4 and has a water vapor permeability of
less than 1.0 × 10-4 g∙mm/cm2∙24 hr∙atm at a room temperature of 40°C and a relative
humidity of 75%.
7. A pharmaceutical film formulation, which comprises a polyethylene glycol
having an average molecular weight of 950 to 25,000 and a swelling clay,
wherein the mass ratio of said polyethylene glycol and said swelling clay is
2:8 to 6:4 and
the water vapor permeability at a room temperature of 40°C and a relative
humidity of 75% is less than 1.0 × 10-4 g∙mm/cm2∙24 hr∙atm.
8. A coated pharmaceutical solid preparation, which comprises a coating layer,

said coating layer comprising a polyethylene glycol having an average
molecular weight of 950 to 25,000 and a swelling clay,
in which coating layer the mass ratio of said polyethylene glycol and said
swelling clay is 2:8 to 6:4 and
the water vapor permeability at a room temperature of 40°C and a relative
humidity of 75% is less than 1.0 × 10-4 g∙mm/cm2∙24 hr∙atm.