DESCRIPTION
TITLE OF THE INVENTION
Coating Material for Solid Medicine and Solid Medicine Formed with the
Same
TECHNICAL FIELD
The present invention relates to a coating material (coating agent) for a solid
formulation and a solid formulation using the same.
BACKGROUND ART
It is known that many pharmaceuticals are not stable against oxygen and
water vapor and that some change occurs in about 40% of pharmaceuticals when
they are left to stand in unpacked condition, thereby causing a fatal problem in the
pharmaceutical quality. Therefore, most of the commercially available
pharmaceuticals, especially solid formulations, are packaged with a packaging
material such as PTP (press through pack) sheet and protected from oxygen and
water vapor. In recent years, PTP sheets in which polyvinylidene chloride having
superior water vapor barrier property (moisture resistance) and oxygen barrier
property are laminated have been developed and put into practice.
As a method of improving the stability of a solid formulation against oxygen
and water vapor, methods of sugar-coating the solid formulation and methods of
film-coating the solid formulation with a macromolecular substance have been put
into practice. In the latter film-coating methods, polyvinyl alcohols and sodium
carboxymethyl cellulose are known as a macromolecular substance exhibiting

oxygen barrier property, and as a macromolecular substance exhibiting water vapor
barrier property, aminoalkyl methacrylate copolymer E (Eudragit EPO (registered
trademark); Degusssa Co.) is known.
Recently, as a macromolecular substance having an improved oxygen barrier
property, a resin composition obtained by copolymerizing a polyvinyl alcohol and a
polymerizable vinyl monomer (Patent Document 1) and a coating material obtained
by adding talc and a surfactant to a polyvinyl alcohol (Patent Document 2) have been
developed to try to improve the stability of solid formulations. In addition, in the
field of packaging films, as a method of improving gas barrier properties (oxygen
barrier property and water vapor barrier property) in high humidity, methods of
dispersing an intercalation compound in a polyvinyl alcohol have been proposed
(Patent Documents 3 and 4).
Meanwhile, at medical scenes and dispensing pharmacies, in order to prevent
patients from forgetting to take their prescribed drugs or making mistakes in the
dosage thereof, it is widely practiced to use single-dose formulation which is
prepared by taking a plurality of pharmaceuticals to be taken at once out of the
respective packaging material such as PTP sheet and provides them altogether in one
bag.
PRIOR ART DOCUMENTS
PATENT DOCUMENTS
[Patent Document 1] WO 05/019286
[Patent Document 2] JP 2006-188490 A
[Patent Document 3] JP 11-315222 A
[Patent Document 4] JP 9-150484 A

SUMMARY OF THE INVENTION
PROBLEMS TO BE SOLVED BY THE INVENTION
However, in those pharmaceuticals used in single-dose formulations,
although the stability against oxygen and water vapor is ensured by the packaging
material such as PTP sheet at the stage when the pharmaceuticals are put onto the
market, since they are stored in unpacked condition over a prolonged period at
medical scenes and the like, there is a risk of causing a deterioration in the quality of
the pharmaceuticals.
In order to avoid this risk, there is a method of sugar-coating a solid
formulation; however, sugar-coating of a solid formulation not only requires long
processing time, but also makes the resulting solid formulation excessively large,
rendering it difficult for patients to take. Consequently, there are currently limited
cases where this method is applicable. In addition, at present, the existing methods
of film-coating a solid formulation cannot allow the resulting solid formulation to
exhibit sufficient oxygen barrier property in high humidity, and even when the resin
composition according to Patent Document 1 is used, the resulting oxygen barrier
property falls short of that of a packaging material such as PTP sheet. In the field
of packaging films, there are coating materials having superior oxygen barrier
property; however, they cannot be applied to a solid formulation since they are
laminated films with a substrate film.
In view of the above, an object of the present invention is to provide a coating
material for a solid formulation which is capable of stably retaining the quality of the
effective ingredient in the solid formulation for a prolonged period even in unpacked
condition in such a manner that the solid formulation can be used in a single-dose

MEANS FOR SOLVING THE PROBLEMS
In order to achieve the above object, the present inventors intensively studied
to discover that a coating material in which a swelling clay forms specific laminated
structures in high hydrogen-bonding resin imparts gas barrier properties equivalent
or superior to those of a PTP sheet (oxygen permeability coefficient: less than 1x10-
4 cm3-mm/cm2-24hratm; water vapor permeability: less than 1 x 10-4
g-mm/cm2-24hratm) to a solid formulation.
That is, the present invention provides a coating material for a solid
formulation which comprises a high hydrogen-bonding resin and a swelling clay.
When this coating material is applied (coated) on a solid formulation and dried, a
coating film in which the laminated structures of the aforementioned swelling clay
are oriented planarly and dispersed in a network fashion is formed, so that the gas
barrier properties of the coating material can be improved to a level equivalent or
superior to those of a PTP packaging material. In addition, since the formed
coating film is thinner than a sugar coat, the taking of the formulation by patients is
not adversely affected as well.
In the aforementioned coating material, it is preferred that the ratio of the area
occupied by the aforementioned planarly-oriented laminated structures be not less
than 30% with respect to the area of the longitudinal section of the aforementioned
coating film, and it is more preferred that the mass ratio of the high hydrogen-
bonding resin and the swelling clay be 4:6 to 6:4. In this case, since the laminated
structures of the swelling clay become likely to intertwine with each other, the gas
barrier properties of the resulting coating film can be further improved.

Further, it is preferred that the aforementioned coating material comprise a
sugar alcohol derivative-type surfactant. In this case, it is preferred that the mass
ratio of the aforementioned high hydrogen-bonding resin and the aforementioned
swelling clay be 2:8 to 5:5 and that the content of the aforementioned sugar alcohol
derivative-type surfactant be 7 to 35%. When the aforementioned coating material
comprises a sugar alcohol derivative-type surfactant, since the oxygen permeability
coefficient and water vapor permeability of the formed coating film can be further
decreased, the stability of the effective ingredient in the solid formulation against
oxygen and water vapor can be further improved.
It is preferred that the aforementioned high hydrogen-bonding resin be a
polyvinyl alcohol and that the aforementioned swelling clay be a bentonite. The
polyvinyl alcohol improves the oxygen barrier property in low humidity and the
bentonite is oriented planarly in parallel to the surface direction of the high
hydrogen-bonding resin layer to produce path effect, so that the gas barrier properties
in high humidity can be improved.
It is preferred that the aforementioned sugar alcohol derivative-type surfactant
be a sorbitan fatty acid ester. When the aforementioned coating material comprises
a sorbitan fatty acid ester, since the dispersion of the swelling clay is improved, the
gas barrier properties can be improved.
Further, the present invention provides a solid formulation coated with the
aforementioned coating material. This solid formulation can retain the stability of
the effective ingredient therein for a prolonged period even in unpacked condition in
such a manner that the solid formulation can be used in a single-dose formulation.

EFFECTS OF THE INVENTION
According to the present invention, a solid formulation can be coated with a
thin coating film in such a manner that the taking thereof is not adversely affected,
and gas barrier properties equivalent or superior to those of a packaging material
such as PTP sheet can be imparted. Therefore, the solid formulation coated with
the aforementioned coating material can retain the stability of the effective ingredient
in the solid formulation for a prolonged period even in unpacked condition, so that
the solid formulation can be used in single-dose formulation without causing a
deterioration in the quality of the pharmaceutical.
Further, since the coating material according to the present invention has
excellent moisture resistance and excellent disintegration property at the same time,
it may be applied in coating not only sustained release formulations, but also
immediate release formulations. In addition, since the coating material according to
the present invention can be produced using a coating machine commonly used by
those skilled in the art such as a continuous aeration coating machine, fluidized bed
coating machine or pan coater, the coating material according to the present
invention may be widely used and the coating operation thereof on a solid
formulation can be easily carried out.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows a focused ion beam-transmission electron micrograph of the
coating film of Example 1.
Fig. 2 shows a focused ion beam-transmission electron micrograph of the
coating film of Example 2.
Fig. 3 shows a focused ion beam-transmission electron micrograph of the

coating film of Example 3.
Fig. 4 shows a focused ion beam-transmission electron micrograph of the
coating film of Comparative Example 4.
Fig. 5 shows a focused ion beam-transmission electron micrograph of the
coating film of Comparative Example 5.
Fig. 6 is a graph showing the changes with time in the drug residual ratio of
the ascorbic acid tablet.
Fig. 7 is a graph showing the changes with time in the drug residual ratio of
the propantheline bromide tablet.
MODE FOR CARRYING OUT THE INVENTION
The preferred embodiments for carrying out the present invention will now be
described. However, the present invention is not restricted to the following
embodiments, and unless otherwise specified, the unit "%" represents "mass-to-mass
percentage (w/w%)".
The coating material according to the present invention is characterized by
comprising a high hydrogen-bonding resin and a swelling clay. When the coating
material is coated on a solid formulation and dried, since a coating film in which the
laminated structures of the aforementioned swelling clay are oriented planarly and
dispersed in a network fashion is formed, the gas barrier properties of the coating
material can be improved to a level equivalent or superior to those of a PTP
packaging material.
The term "coating material " refers to a composition which forms a thin
coating film when coated on a solid formulation, thereby preventing the effective
ingredient contained in the solid formulation from being degraded or the like by

oxygen, water, light or the like. The aforementioned coating material can be
prepared by dispersing it in an appropriate solvent in accordance with the intended
use and utilized to coat a solid formulation and produce a coating film or film
formulation. Here, a coating film can be obtained by drying the solvent (water and
the like) from the coating material or a solution containing the coating material, and a
film formulation can be obtained by adding an effective ingredient to the coating
material and subsequently drying in the same manner as in the case of the coating
film production.
Examples of the aforementioned solvent include water, chain having 1 to not
more than 5 carbon atoms (lower alcohols) and mixed solvents thereof, and water is
particularly preferred.
The term "high hydrogen-bonding resin" refers to a resin having a high
content of hydrogen-bonding group, and examples thereof include high hydrogen-
bonding resins which satisfy a ratio of 5 to 60% in terms of the mass of the
hydrogen-bonding group per unit resin mass. Examples of the hydrogen-bonding
group include hydroxyl group, amino group, thiol group, carboxyl group, sulfonic
acid group and phosphate group. As the high hydrogen-bonding resin used in the
aforementioned coating material, a resin having a high content of hydroxyl group is
more suitable. Examples of the aforementioned high hydrogen-bonding resin
include polyvinyl alcohols and polysaccharides, and the high hydrogen-bonding resin
is preferably a polyvinyl alcohol or sodium carboxymethyl cellulose, more preferably
a polyvinyl alcohol. The polyvinyl alcohol may contain a derivative thereof. It is
noted here that the aforementioned high hydrogen-bonding resin may be used in
combination as long as the amount thereof is within the range which does not impair
the gas barrier properties.

The aforementioned polyvinyl alcohol refers to one which is generally
obtained by saponification of polyvinyl acetate and it encompasses partially
saponified polyvinyl alcohols in which the acetate group remains in an amount of
several 10%, as well as completely saponified polyvinyl alcohols in which the
acetate group remains in an amount of only a few %. The saponification degree of
the polyvinyl alcohol is preferably 70 to 97 mol%. The average polymerization
degree is preferably 200 to 3,000, more preferably 600 to 2,400. Here, as the
aforementioned polyvinyl alcohol, two or more polyvinyl alcohols having different
saponification degrees and average polymerization degrees may be used in
combination. For mixing of two or more polyvinyl alcohols, for example, there is a
method in which a polyvinyl alcohol having a low polymerization grade is added and
then a polyvinyl alcohol having a high polymerization grade is mixed. Examples of
the polyvinyl alcohol include various types of Poval (Kuraray Co., Ltd.) and
Gohsenol (Nippon Synthetic Chemical Industry Co., Ltd.).
The term "swelling clay" refers to a clay having a swelling property. More
particularly, 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.
As the swelling clay, one which is negatively charged due to the composition
balance of the metal salt species is preferred, and examples thereof include smectites
such as hydrated aluminum silicate having three-layer structure.
The term "negatively charged" refers to a condition in which the swelling
clay has a cation exchange property, and the amount of the charge is expressed in the

cation exchange capacity (CEC). Here, the unit of cation exchange capacity is
milligram equivalent/100 g (normally, expressed as "meq/100 g") and generally
expressed in the number of equivalents corresponding to the molarity of monovalent
ions.
Examples of the smectites include beidellite, nontronite, saponite, hectorite,
sauconite, bentonite and aluminum magnesium silicate, and these may be used
individually or two or more thereof may be used in combination as appropriate.
Among such smectites, aluminum magnesium silicate and a bentonite are preferred,
and a bentonite is more preferred. It is noted here that the aforementioned swelling
clay may be used in combination as long as the amount thereof is within the range
which does not impair the gas barrier properties.
The term "solid formulation" refers to a formulation in a solid form, and
examples thereof include tablets (including sublingual tablets and orally-
disintegrating tablets), capsules (including soft capsules and microcapsules), granules,
subtle granules, powders, balls, troches and films.
Examples of the method of coating the solid formulation include, in cases
where the solid formulation is in the form of a tablet, those coating methods using a
coating pan or tablet coating machine; and in cases where the solid formulation is in
the form of granules or powder, those methods using a fluidized bed coating machine
or tumbling fluidized coating machine.
The term "laminated structure" refers to a structure in which a plurality of
layered structures are laminated, and the term "orient planarly" means to arrange in
parallel to the reference plane. That is, the term "a coating film in which the

laminated structures of the swelling clay are oriented planarly and dispersed in a
network fashion" refers to a coating film in which the bands of the swelling clay are
laminated in 10 to 100 layers to form laminated structures which are arranged in
almost parallel to the transverse section of the coating film (cross-section parallel to
the coating film surface) and the bands are dispersed in a network fashion in the
coating film. In this case, not only the bands are oriented completely in parallel, but
also they may be oriented with undulations or in such a manner that the bands runs
near or far from other bands running in all directions.
Since the aforementioned coating material for a solid formulation can form a
thin coating film which prevents permeation of oxygen and water vapor on the
surface of the solid formulation, the coating material can impart gas barrier
properties equivalent or superior to those of a packaging material such as PTP sheet
(oxygen permeability coefficient: less than 1 x 10-4 cm3-mm/cm2-24hratm; water
vapor permeability: less than 1 x 10-4 g-mm/cm2-24hratm) to the solid formulation.
In the aforementioned coating material, the ratio of the area occupied by the
aforementioned planarly-oriented laminated structures is, with respect to the area of
the longitudinal section (cross-section perpendicular to the coating film surface) of
the aforementioned coating film, preferably not less than 30%, more preferably not
less than 35%, still more preferably not less than 42%.
Further, in the aforementioned coating material, it is preferred that the mass
ratio of the high hydrogen-bonding resin and the swelling clay be 4:6 to 6:4. When
the mass ratio of the high hydrogen-bonding resin and the swelling clay is not higher
than 3:7, the coating material becomes highly viscous, so that spraying thereof may
become difficult. In this case, spraying may become possible by lowering the

concentration of the coating material; however, there may arise another problem such
as prolonged production time. Further, when the mass ratio of the high hydrogen-
bonding resin and the swelling clay is not less than 7:3, gas barrier properties
equivalent or superior to those of a packaging material such as PTP sheet may not be
attained.
The term "sugar alcohol derivative-type surfactant" refers to a surfactant
having a sugar alcohol skeleton in the molecule. Examples of the type of the sugar
alcohol include mannitol, xylitol, maltitol, trehalose, inositol and sorbitol.
Examples of surfactant having a structure in which a hydrophobic group is bound to
the sugar alcohol via an ester bond include sorbitan fatty acid esters, polyoxyalkylene
sorbitan fatty acid esters, sucrose fatty acid esters, sorbit fatty acid esters,
polyoxyalkylene sorbit fatty acid esters, polyglycerols, polyglycerol fatty acid esters,
glycerol fatty acid esters and polyoxyalkylene glycerol fatty acid esters.
As the sugar alcohol derivative-type surfactant used in the aforementioned
coating material, a sorbitan fatty acid ester and a sucrose fatty acid ester are preferred,
and a sorbitan fatty acid ester is more preferred. Further, among sorbitan fatty acid
esters, those having a high ratio of monoester are preferred, and those having a HLB
(Hydrophilic Lipophilic Balance) in the range of 4 to 10 are preferred. In addition,
the acyl group constituting the hydrophobic group may be any of the saturated,
unsaturated, straight or branched acyl groups, and it is preferred that the acyl group
have 12 to 18 carbon atoms. Examples of such sorbitan fatty acid esters include
sorbitan monolaurate, sorbitan monopalmitate and sorbitan monoleate, and these may
be suitably used in the aforementioned coating material. It is noted here that the
aforementioned sugar alcohol derivative-type surfactant may be used in combination
as long as the amount thereof is within the range which does not impair the gas

barrier properties.
When the aforementioned coating material comprises the sugar alcohol
derivative-type surfactant, the mass ratio of the high hydrogen-bonding resin and the
swelling clay is preferably 2:8 to 5:5, more preferably 2:8 to 4:6, still more
preferably 2:8 to 3:7. When the mass ratio of the high hydrogen-bonding resin and
the swelling clay is not higher than 1:9, the coating material becomes highly viscous,
making the coating operation difficult. In this case, coating may become possible
by lowering the concentration of the coating material with an addition of a solvent;
however, there may arise another problem such as prolonged production time.
Further, when the mass ratio of the high hydrogen-bonding resin and the swelling
clay becomes not less than 6:4, gas barrier properties equivalent or superior to those
of a packaging material such as PTP sheet may not be attained.
Although the content of the aforementioned sugar alcohol derivative-type
surfactant varies depending on the ratio of the aforementioned high hydrogen-
bonding resin and the aforementioned swelling clay, it is preferably 7 to 35%, more
preferably 10 to 30%, still more preferably 12 to 24%. Here, the term "the content
of the sugar alcohol derivative-type surfactant" refers to a ratio (%) of the sugar
alcohol derivative-type surfactant with respect to the entire mixture obtained by
adding the sugar alcohol derivative-type surfactant to the high hydrogen-bonding
resin and the swelling clay. By adding such sugar alcohol derivative-type surfactant,
coating of the solid formulation becomes easy and the gas barrier properties of the
resulting coating film are improved; however, depending on the mass ratio of the
high hydrogen-bonding resin and the swelling clay, when the content of the sugar
alcohol derivative-type surfactant becomes not higher than 6% or not less than 36%,
gas barrier properties equivalent or superior to those of a packaging material such as

PTP sheet may not be attained.
In the aforementioned coating material, a pharmacologically acceptable
additive may be added as long as the amount thereof is within the range which does
not impair the gas barrier properties. For example, by adding a sugar or sugar
alcohol such as maltose, maltitol, sorbitol, xylitol, fructose, glucose, lactitol,
isomaltose, lactose, erythritol, mannitol, trehalose or sucrose, croscarmellose sodium
or low-substituted hydroxypropyl cellulose as a swelling property-disintegrating
agent, the disintegration property of the coating film can be improved, and by adding
triethyl citrate, polyethylene glycol or glycerin as a plasticizer, the strength of the
coating film can be improved.
Also, an additive which is conventionally used in film-coating by those
skilled in the art may be further added to the aforementioned coating material.
Examples of such additive include coloring agents such as plant-extract dyes and
masking agents such as titanium oxide, calcium carbonate and silicon dioxide.
The solid formulation according to the present invention is characterized by
being coated with the aforementioned coating material.
Examples of the aforementioned solid formulation include tablets (including
sublingual tablets and orally-disintegrating tablets), capsules (including soft capsules
and microcapsules), granules, subtle granules, powders, balls, troches and films.
The aforementioned solid formulation may be one which has a coating film of
the aforementioned coating material on the surface thereof having another coating
film made of a gastric-soluble or enteric-soluble macromolecular substance or the

like, or one which has another coating film made of a gastric-soluble or enteric-
soluble macromolecular substance or the like on the surface thereof having a coating
film of the aforementioned coating material.
EXAMPLES
The present invention will now be concretely described by way of examples
thereof; however, the present invention is not restricted thereto.
The dispersion condition of the swelling clay, oxygen permeability
coefficient and water vapor permeability were measured by using a coating film
(film) obtained from the coating material.
(Method of evaluating the dispersion condition of the swelling clay)
In accordance with a focused ion beam method, the coating film was made
thin by a gadolinium ion beam (FB-2000A; Hitachi High-Tech Manufacturing &
Service Corporation). The thus obtained thin coating film was observed under a
transmission electron microscope (H-9000UHR; Hitachi High-Tech Manufacturing
& Service Corporation) to visually measure the number of laminated layers of the
swelling clay.
When the swelling clay is oriented planarly to the transverse section of the
coating film (cross-section parallel to the coating film surface), a focused and clear
micrograph is obtained, so that a single layer of the swelling clay (thickness of about
1 nm) and a laminated structure thereof can be observed. On the other hand, when
the swelling clay is not oriented planarly, an unfocused and fuzzy micrograph is
obtained. Therefore, the ratio of the laminated structure of the swelling clay
oriented planarly to the transverse section of the coating film was calculated by

dividing the area of the focused micrograph of the laminated structure by the area of
the observation region (2.5µm x 2.5 µm square). The area was expressed in a
numerical value by performing image analysis with NIHimage.
(Method of measuring the oxygen permeability coefficient)
In accordance with a standard specification in the art, JIS K7126-1 (2006)
(Gas Permeability Test Method by Gas Chromatography), the oxygen permeability
coefficient was measured at a temperature of 23 ± 2°C in relative humidities of 0%
(0% RH) and 90% (90% RH) by using an oxygen permeability coefficient measuring
apparatus (GTR-30XAD2 and G2700T-F; GTR Tec Corporation). Hereinafter,
relative humidity is abbreviated as "RH".
(Method of measuring the water vapor permeability)
A standard specification in the art, JIS K8123 (1994), was partially modified
to measure the water vapor permeability. First, a coating film prepared by the
method described below was held up to the light and a circular piece having a
diameter of 3.5 cm was excised from a portion of the coating film having no pinhole
and uniform thickness. The thickness of the coating film was measured at 5
arbitrary spots. Next, 3 g of calcium chloride (particle size of 850 to 2,000 µm) was
placed in an aluminum cup (diameter of 30 mm), and the thus excised circular
coating film and a film-fixing ring were placed in the order mentioned onto the
aluminum cup. The ring was fixed by placing a weight thereon. 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 entire
aluminum cup was measured as the initial mass. Then, the aluminum cup was
placed in a thermostat bath at 40°C and 75% RH. The aluminum cup was removed
every 24 hours to measure the mass thereof, and the water vapor permeability was

calculated using the following equation. It should be noted here that, in all of the
below-described tests for measuring the water vapor permeability, the following
applied: r = 1.5 cm, t = 24 hours and C = 1 atm.
Water vapor permeability P (gmm/cm -24hr-atm) = WA/BtC
W: Increased mass in 24 hours (g)
A: Average thickness of the coating film at 5 spots (mm)
B: Permeation area πr2 (cm2)
t: Elapsed time (hr)
C: Atmospheric pressure (atm)
(Reference Example 1) Preparation of a polyvinyl alcohol-based coating film
To 42.5 parts by mass of water, 7.5 parts by mass of OPADRY II HP
(registered trademark) (Colorcon Japan) was added, and the resulting mixture was
stirred to obtain a dispersion. Then, the thus obtained dispersion was poured into a
polypropylene tray having a flat bottom and dried overnight in a 50°C oven in a
leveled condition to obtain a coating film. This coating film was a polyvinyl
alcohol (PVA)-based coating film. Hereinafter, polyvinyl alcohol is abbreviated as
"PVA".
(Reference Example 2) Preparation of a modified PVA-based coating film
To 45.0 parts by mass of water, 3.5 parts by mass of POVACOAT (registered
trademark) (Nisshin Kasei Co., Ltd.), 1.0 parts by mass of titanium oxide and 0.5
parts by mass of talc were added, and the resulting mixture was stirred to obtain a
dispersion. A coating film was then obtained in the same manner as in Reference
Example 1. This coating film was a modified PVA-based coating film.

(Reference Example 3) Preparation of a sodium carboxymethyl cellulose-based
coating film
To 46.5 parts by mass of water, 3.5 parts by mass of OPAGLOS2 (registered
trademark) (Colorcon Japan) was added, and the resulting mixture was stirred to
obtain a dispersion. A coating film was obtained in the same manner as in
Reference Example 1. This coating film was a sodium carboxymethyl cellulose
(CMC)-based coating film. Hereinafter, sodium carboxymethyl cellulose is
abbreviated as "CMC".
Table 1 shows the results of the measurements of the oxygen permeability
coefficient and the water vapor permeability of the coating films of Reference
Examples 1 to 3 used for coating solid formulations.

From Table 1, it became apparent that only the PTP packaging material had
both the oxygen permeability coefficient and the water vapor permeability at less
than 1 x 10-4 and that the gas barrier properties of the coating films of Reference
Examples 1 to 3 used for coating solid formulations were markedly inferior
compared to those of the PTP packaging material.

(Example 1)
To 42.55 parts by mass of water, 1.2 parts by mass of PVA (EG-05; Nippon
Synthetic Chemical Industry Co., Ltd.) and 56.25 parts by mass of 3.2% bentonite
solution were added, and the resulting mixture was stirred using a homogenizer
(Polytron Model KR) to obtain a dispersion. The 3.2% bentonite solution was
prepared by adding 32 parts by mass of bentonite (Kunipia-F; Kunimine Industries
Co., Ltd.) (cation exchange capacity: 115 meq/100 g) to 968 parts by mass of stirred
water; uniformly dispersing the resulting mixture using a homogenizer; and then
suction-filtrating the resultant through a filter paper. Hereinafter, bentonite is
abbreviated as "BT".
The thus obtained dispersion was sprayed onto the back side of the
polypropylene balance tray and immediately dried with hot air using a dryer. After
repeating several rounds of the spraying and dryer drying, the balance tray was
altogether placed in a 50°C oven and dried overnight. Subsequently, a coating film
was separated from the balance tray to obtain the coating film of Example 1.
(Example 2)
To 137.0 parts by mass of water, 2.64 parts by mass of PVA (EG-05; Nippon
Synthetic Chemical Industry Co., Ltd.), 192.5 parts by mass of 3.2% BT solution and
1.2 parts by mass of sorbitan monolaurate (Span20; Wako Pure Chemical Industries,
Ltd.) were added, and the resulting mixture was stirred using the homogenizer
(Polytron Model KR) to obtain a dispersion. From this dispersion, the coating film
of Example 2 was obtained in accordance with the method of Example 1.
(Comparative Example 1)
To 42.55 parts by mass of water, 1.2 parts by mass of hydroxypropylmethyl

cellulose (TC-5W; Shin-Etsu Chemical Co., Ltd.) and 56.25 parts by mass of 3.2%
BT solution were added, and the resulting mixture was stirred using the homogenizer
(Polytron Model KR) to obtain a dispersion. From this dispersion, the coating film
of Comparative Example 1 was obtained in accordance with the method of Example
1. Hereinafter, hydroxypropylmethyl cellulose is abbreviated as "HPMC".
(Comparative Example 2)
To 96.4 parts by mass of water, 10.0 parts by mass of PVA was added, and
the resulting mixture was stirred using a stirrer to obtain a dispersion. From this
dispersion, the coating film of Comparative Example 2 was obtained in accordance
with the method of Example 1.
(Comparative Example 3)
To 56.7 parts by mass of water, 2.64 parts by mass of PVA, 6.16 parts by
mass of talc and 1.2 parts by mass of sorbitan monolaurate were added, and the
resulting mixture was stirred using the homogenizer to obtain a dispersion. From
this dispersion, the coating film of Comparative Example 3 was obtained in
accordance with the method of Example 1.
Table 2 shows the results of the measurements of the oxygen permeability
coefficient and the water vapor permeability of the coating films obtained in
Examples 1 and 2 and Comparative Examples 1 to 3.


As a result, it was revealed that, compared to HPMC, PVA, that is, a high
hydrogen-bonding resin, exhibited more prominent effect to decrease the oxygen
permeability coefficient and the water vapor permeability of the coating film
(comparison between Example 1 and Comparative Example 1). In addition, when
BT, that is, a swelling clay, was contained in the coating film, the oxygen
permeability coefficient and the water vapor permeability of the coating film were
both markedly decreased (comparison between Example 1 and Comparative
Example 2), and this effect was more prominent compared to the case in which talc
was used in place of BT (comparison between Example 2 and Comparative Example
3). From these results, it was revealed that the coating film of Example 1
comprising PVA and BT at a particular ratio and the coating film of Example 2
comprising PVA, BT and sorbitan monolaurate at a particular ratio had both the
oxygen permeability coefficient and the water vapor permeability at less than 1x10-
4 and that, therefore, these coating films had gas barrier properties equivalent or
superior to those of the PTP packaging material.
(Measurement of the coating films under a transmission electron microscope)
Using a focused ion beam method, the longitudinal section of the coating
films of Examples 1 and 2 were observed under a transmission electron microscope.

Figs. 1 and 2 show micrographs of Examples 1 and 2, respectively.
(Example 3)
To 51.6 parts by mass of water, 1.5 parts by mass of PVA and 46.9 parts by
mass of 3.2% BT solution were added, and the coating film of Example 3 was
obtained in accordance with the method of Example 1. Using a focused ion beam
method, the longitudinal section of the coating film of Example 3 was observed
under a transmission electron microscope. The micrograph thereof is shown in Fig.
3.
(Comparative Example 4)
To 33.5 parts by mass of water, 0.9 parts by mass of PVA and 65.6 parts by
mass of 3.2% BT solution were added, and the coating film of Comparative Example
4 was obtained in accordance with the method of Example 1. The cross-section of
the coating film was observed in accordance with the method of Example 3. The
micrograph thereof is shown in Fig. 4.
(Comparative Example 5)
To 89.9 parts by mass of water, 2.25 parts by mass of PVA and 7.8 parts by
mass of 3.2% BT solution were added, and the coating film of Comparative Example
5 was obtained in accordance with the method of Example 1. The cross-section of
me coating film was observed in accordance with the method of Example 3. The
micrograph thereof is shown in Fig. 5.
Table 3 shows the dispersion condition of BT, as well as the oxygen
permeability coefficient and the water vapor permeability of the coating films
obtained in Examples 1 to 3 and Comparative Examples 4 and 5.


As a result, it was revealed that gas barrier properties equivalent or superior
to those of the PTP packaging material can be attained when the ratio of the BT
laminated structures oriented planarly to the transverse section of the coating film is
not less than 30%.
(Example 4)
Following the constitution shown in Table 4, water, PVA and BT solution
were mixed, and a coating film was obtained in accordance with the method of
Example 1. The oxygen permeability coefficient (23°C, 90% RH) and the water
vapor permeability (40°C, 75% RH) were measured.
(Comparative Example 6)
Following the constitution shown in Table 4, water, PVA and BT solution
were mixed, and a dispersion was obtained in accordance with the method of
Example 1. A coating film was then obtained by the method of Example 1, and the
oxygen permeability coefficient (23°C, 90% RH) and the water vapor permeability
(40°C, 75% RH) were measured.

Table 4 shows the effects of the mass ratio of PVA and BT (PVA/BT) on the
oxygen permeability coefficient and the water vapor permeability.

As a result, it was revealed that, when the mass ratio of PVA and BT
(PVA/BT) is 4:6 to 6:4 (4/6 to 6/4), the oxygen permeability coefficient and the
water vapor permeability both becomes less than 1 x 10-4 and that, therefore, gas
barrier properties equivalent or superior to those of the PTP packaging material can
be attained.
(Examples 5 to 7 and Comparative Examples 7 to 9)
Water, PVA, BT solution and respective surfactant were mixed and a
dispersion was obtained in accordance with the method of Example 2. A coating
film was then obtained by the method of Example 1, and the oxygen permeability
coefficient (23°C, 90% RH) and the water vapor permeability (40°C, 75% RH) were
measured.
Table 5 shows the effects of the type of the surfactant on the oxygen
permeability coefficient and the water vapor permeability. The evaluations were
carried out by fixing the mass ratio of PVA, BT and the respective surfactant at
26.4:61.6:12(26.4/61.6/12).


As a result, it was revealed that, in addition to the addition of sorbitan
monolaurate, the addition of sorbitan monopalmitate, sorbitan monooleate or sucrose
stearate makes both of the oxygen permeability coefficient and the water vapor
permeability to become less than 1 x 10-4 and that, therefore, gas barrier properties
equivalent or superior to those of the PTP packaging material can be attained. This
suggests that the sugar alcohol derivative-type surfactants contribute to an
improvement of gas barrier properties.
(Examples 8 to 10)
Following the constitution shown in Table 6, water, PVA, BT solution and
sorbitan monolaurate were mixed, and a dispersion was obtained in accordance with
the method of Example 1. A coating film was then obtained by the method of
Example 1, and the oxygen permeability coefficient (23°C, 90% RH) and the water
vapor permeability (40°C, 75% RH) were measured.
(Comparative Examples 10 and 11)
Following the constitution shown in Table 6, water, PVA, BT solution and

sorbitan monolaurate were mixed, and a dispersion was obtained in accordance with
the method of Example 2. A coating film was then obtained by the method of
Example 1, and the oxygen permeability coefficient (23°C, 90% RH) and the water
vapor permeability (40°C, 75% RH) were measured.
Table 6 shows the effects of the mass ratio of PVA and BT (PVA/BT) on the
oxygen permeability coefficient and the water vapor permeability. Here, the
content of sorbitan monolaurate was set at 12% in all of the cases.

As a result, it was revealed that, when the mass ratio of PVA and BT
(PVA/BT) is 2:8 to 5:5 (2/8 to 5/5), the addition of sorbitan monolaurate makes both
of the oxygen permeability coefficient and the water vapor permeability to become
less than 1 x 10-4 and that, therefore, gas barrier properties equivalent or superior to
those of the PTP packaging material can be attained.
(Examples 11 and 12 and Comparative Example 12)
Following the constitution shown in Table 7, water, PVA, BT solution and
sorbitan monolaurate were mixed, and a dispersion was obtained in accordance with
the method of Example 2. A coating film was then obtained by the method of
Example 1, and the oxygen permeability coefficient (23 °C, 90% RH) and the water

vapor permeability (40°C, 75% RH) were measured.
Table 7 shows the effects of the sorbitan monolaurate content on the oxygen
permeability coefficient and the water vapor permeability. Here, the evaluations
were carried out by fixing the mass ratio of PVA and BT (PVA/BT) at 5:5 (5/5).

As a result, it was revealed that, when PVA/BT = 5/5, the sorbitan
monolaurate content in the range of 0 to 24% makes both of the oxygen permeability
coefficient and the water vapor permeability to be less than 1 x 10-4 and that,
therefore, gas barrier properties equivalent or superior to those of the PTP packaging
material can be attained.
(Examples 13 and 14 and Comparative Examples 13 and 14)
Following the constitution shown in Table 8, water, PVA, BT solution and
sorbitan monolaurate were mixed, and a dispersion was obtained in accordance with
the method of Example 2. A coating film was then obtained by the method of
Example 1, and the oxygen permeability coefficient (23 °C, 90% RH) and the water
vapor permeability (40°C, 75% RH) were measured.
Table 8 shows the effects of the sorbitan monolaurate content on the oxygen

permeability coefficient and the water vapor permeability. Here, the evaluations
were carried out by fixing the mass ratio of PVA and BT (PVA/BT) at 2:8 (2/8).

As a result, it was revealed that, when PVA/BT = 2/8, the sorbitan
monolaurate content in the range of 12 to 36% makes both of the oxygen
permeability coefficient and the water vapor permeability to be less than 1 x 10-4 and
that, therefore, gas barrier properties equivalent or superior to those of the PTP
packaging material can be attained.
(Comparative Example 15)
(Production of an ascorbic acid-containing tablet)
In order to evaluate the barrier properties against oxygen and water vapor, an
ascorbic acid-containing tablet which is unstable against oxygen and water vapor was
produced.
First, lactose, crystalline cellulose and hydroxypropyl cellulose-SL were
loaded into a vertical granulator and granulated with water in which cupric sulfate
pentahydrate had been dissolved. The thus obtained granules were dried overnight
at 50°C and pulverized using a comil to obtain granules A. Then, the granules A
and ascorbic acid were loaded into a vertical granulator and after granulation with

ethanol, the resultant was dried at 50°C for 2 hours and pulverized using a comil to
obtain granules B. Subsequently, the granules B, a low-substituted hydroxypropyl
cellulose, croscarmellose sodium and magnesium stearate were mixed, and the
resultant was tableted using a rotary tableting machine (Kikusui Chemical Industries
Co., Ltd.) to obtain an ascorbic acid-containing tablet (diameter of 8 mm, 12R).
The thus obtained ascorbic acid-containing tablet not coated with a coating material
was used as Comparative Example 15.
(Example 15)
(Production of an ascorbic acid-containing coated tablet coated with the dispersion of
Example 2)
To a coating pan (Hi-Coater mini; Freund Corporation), 400 g of the ascorbic
acid tablet of Comparative Example 15 was loaded, and the dispersion prepared in
Example 2 was used as the coating material to coat the ascorbic acid-containing
tablet. The coating with the coating material was performed to a coating thickness
of 60 µm to obtain an ascorbic acid-containing coated tablet. The thus obtained
ascorbic acid-containing coated tablet coated with the dispersion of Example 2 was
used as Example 15.
(Comparative Example 16)
(Production of an ascorbic acid-containing coated tablet coated with the dispersion of
Reference Example 3)
To the coating pan (Hi-Coater mini; Freund Corporation), 400 g of the
ascorbic acid tablet of Comparative Example 15 was loaded, and the dispersion
prepared in Reference Example 3 was used as the coating material to coat the tablet.
The coating with the coating material was performed to a coating thickness of 60 µm.
The thus obtained ascorbic acid-containing coated tablet coated with the dispersion

of Reference Example 3 was used as Comparative Example 16.
(The disintegration property of the ascorbic acid-containing coated tablet)
The disintegration property of the ascorbic acid-containing coated tablet of
Example 15 was evaluated using an elution tester. That is, one ascorbic acid-
containing coated tablet was placed in 900 mL of water which had been heated to
37°C, and the time required for the coating film to start to detach from the tablet
surface was measured. As the result, the time required for the coating film to start
to detach from the tablet surface was about 2 minutes. Consequently, it was
revealed that the ascorbic acid-containing coated tablet of Example 15 has excellent
disintegration property, and it was suggested that the dispersion of Example 2 may
be applied in coating not only sustained release formulations, but also immediate
release formulations.
(The storage stability of the ascorbic acid-containing coated tablets)
The ascorbic acid-containing tablet of Comparative Example 15 and the
ascorbic acid-containing coated tablets of Example 15 and Comparative Example 16
were stored for 4 weeks in an open condition or an airtight condition in a desiccator
at 25°C and 95% RH to evaluate the residual ratio of ascorbic acid (drug residual
ratio) with time. The term "in an open condition" means to place each tablet as is in
the desiccator, and the term "in an airtight condition" means to put each tablet into a
glass bottle having a plastic inner lid and outer lid, which bottle is then sealed, and
place the glass bottle in the desiccator while maintaining the sealed condition.
Fig. 6 is a graph showing the changes with time in the drug residual ratio. In
Fig. 6, the open triangle (Δ), filled triangle (Δ), open square (), filled square (■),

open circle (o) and filled circle (•) represent the results of: the ascorbic acid-
containing coated tablet of Example 15 placed in an airtight condition; the ascorbic
acid-containing coated tablet of Example 15 in an open condition; the ascorbic acid-
containing coated tablet of Comparative Example 16 placed in an airtight condition;
the ascorbic acid-containing coated tablet of Comparative Example 16 placed in an
open condition; the ascorbic acid-containing tablet of Comparative Example 15
placed in an airtight condition; and the ascorbic acid-containing tablet of
Comparative Example 15 placed in an open condition, respectively. In addition, the
ordinate and the abscissa indicate the drug residual ratio (%) and the storage period
(W), respectively, and the W means weeks.
In the ascorbic acid-containing tablet of Comparative Example 15 and the
ascorbic acid-containing coated tablet of Comparative Example 16 in an open
condition, the drug residual ratio decreased with time; however, in the ascorbic acid-
containing coated tablet of Example 15 in an open condition, degradation of the drug
was not observed even after the 4-week storage and the stability was maintained at a
level equivalent to the case where the tablet was placed in an airtight condition.
Accordingly, it was revealed that the ascorbic acid-containing coated tablet of
Example 15 has high barrier properties against oxygen and water vapor.
(Comparative Example 17)
(Production of a propantheline bromide-containing tablet)
In order to evaluate gas barrier properties, a propantheline bromide-
containing tablet known to be extremely unstable in unpacked condition was
produced. A propantheline bromide-containing tablet (Methaphyllin (registered
trademark); Eisai Co., Ltd.) was pulverized using a mortar in a dry box to prevent

moisture absorption, and the thus obtained granules of the pulverized tablet were
again tableted using a rotary tableting machine (Kikusui Chemical Industries Co.,
Ltd.) to obtain a propantheline bromide-containing tablet (diameter of 8 mm, 12R).
The thus obtained propantheline bromide-containing tablet not coated with a coating
material was used as Comparative Example 17.
(Example 16)
(Production of a propantheline bromide-containing coated tablet coated with the
dispersion of Example 2)
To the coating pan (Hi-Coater mini; Freund Corporation), 400 g of the
propantheline bromide-containing tablet of Comparative Example 17 was loaded,
and the dispersion prepared in Example 2 was used as the coating material to coat the
propantheline bromide-containing tablet. The coating with the coating material was
performed to a coating thickness of 60 fun to obtain a propantheline bromide-
containing coated tablet. The thus obtained propantheline bromide-containing
coated tablet was used as Example 16.
(Comparative Example 18)
(Production of a propantheline bromide-containing coated tablet coated with a
commercially-available general-purpose coating formulation solution)
To distilled water, a mixture of hydroxypropylmethyl cellulose 2910, titanium
oxide and Macrogol 400 (Opadry OY-7300(registered trademark); Colorcon Japan)
was added and dissolved to obtain a commercially-available general-purpose coating
formulation solution. To the coating pan (Hi-Coater mini; Freund Corporation),
400 g of the propantheline bromide-containing tablet of Comparative Example 17
was loaded, and the commercially-available general-purpose coating formulation
solution was used as the coating material to coat the tablet. The coating with the

coating material was performed to a coating thickness of 60 µm. The thus obtained
propantheline bromide-containing coated tablet was used as Comparative Example
18.
(Comparative Example 19)
(Production of a propantheline bromide-containing coated tablet coated with a
commercially-available moisture-resistant formulation solution)
Sodium lauryl sulfate (15 g) was added to distilled water (875 g) and the
resultant was stirred until the sodium lauryl sulfate was completely dissolved. Next,
aminoalkyl methacrylate copolymer E (Eudragit EPO (registered trademark);
Degusssa Co.) (100 g) was added and stirred, and when it was uniformly dispersed,
stearic acid (10 g) was added. The resultant was further stirred to obtain a
commercially-available moisture-resistant formulation solution. To the coating pan
(Hi-Coater mini; Freund Corporation), 400 g of the propantheline bromide-
containing tablet of Comparative Example 17 was loaded, and the commercially-
available moisture-resistant coating formulation solution was used as the coating
material to coat the tablet. The coating with the coating material was performed to
a coating thickness of 60 µm. The thus obtained propantheline bromide-containing
coated tablet was used as Comparative Example 19.
(Comparative Example 20)
(Propantheline bromide sugar-coated tablet)
A propantheline bromide tablet (Pro-Banthine (registered trademark); Pfizer
Inc.) as is, was used as the propantheline bromide sugar-coated tablet of Comparative
Example 20.
(The storage stability of the propantheline bromide-containing coated tablets and the

propantheline bromide sugar-coated tablet)
The propantheline bromide-containing tablet of Comparative Example 17, the
propantheline bromide-containing coated tablets of Example 16 and Comparative
Examples 18 and 19, and the propantheline bromide sugar-coated tablet of
Comparative Example 20 were each stored for 2 months in an open condition in a
desiccator at 30°C and 75% RH to evaluate the residual ratio of propantheline
bromide (drug residual ratio) with time. Here, the term "in an open condition"
means to put each tablet in a glass bottle and place the glass bottle as is without any
covering in the desiccator.
Fig. 7 is a graph showing the changes with time in the residual ratio of
propantheline bromide (drug residual ratio). In Fig. 7, the open circle (o), filled
circle (•), filled square (■), filled triangle (A) and open triangle (A) represent the
results of: the propantheline bromide-containing coated tablet of Example 16; the
propantheline bromide-containing tablet of Comparative Example 17; the
propantheline bromide-containing coated tablet of Comparative Example 18; the
propantheline bromide-containing coated tablet of Comparative Example 19; and the
propantheline bromide sugar-coated tablet of Comparative Example 20, respectively.
In addition, the ordinate and the abscissa indicate the drug residual ratio (%) and the
storage period (W), respectively, and the W means weeks.
As a result, in the propantheline bromide-containing tablet of Comparative
Example 17, as well as in the propantheline bromide-containing coated tablets of
Comparative Example 18 and Comparative Example 19, the drug residual ratio
markedly decreased during the 4-week storage in an open condition; however, in the
propantheline bromide-containing coated tablet of Example 16 and the propantheline

bromide sugar-coated tablet of Comparative Example 20, degradation of the drug
was not observed even after the 4-week storage in an open condition.
In addition, in the propantheline bromide-containing coated tablet of Example
16 and the propantheline bromide sugar-coated tablet of Comparative Example 20,
when they were stored in an open condition for 8 weeks, a minor decrease in their
drug residual ratio was observed; however, there was no significant difference in
their drug residual ratios. Therefore, it was revealed that the propantheline
bromide-containing coated tablet of Example 16 has high barrier properties at a level
equivalent to the propantheline bromide sugar-coated tablet.
Furthermore, in the propantheline bromide sugar-coated tablet of
Comparative Example 20, when it was stored in an open condition for 8 weeks, there
was confirmed an adhesion to the wall of the glass bottle and between the
propantheline bromide sugar-coated tablets caused by melting of the sugar coat and a
deterioration in the quality was observed; however, in the propantheline bromide-
containing coated tablets of Example 16, such an adhesion to the wall of the glass
bottle and between the propantheline bromide-containing coated tablet was not
observed at all. Therefore, it was revealed that the propantheline bromide-
containing coated tablet of Example 16, in an open condition at 30°C and 75% RH,
has a superior apparent stability compared to the propantheline bromide sugar-coated
tablet of Comparative Example 20.
From the above Examples, it was demonstrated that the gas barrier coating
material according to the present invention is useful as a versatile coating material
for solid formulations, especially as a coating film of solid formulations which
contain a drug unstable against oxygen and/or water vapor.

INDUSTRIAL APPLICABILITY
The coating material according to the present invention is useful as a coating
material for solid formulations, especially as a coating film of solid formulations
which contain a drug unstable against oxygen and/or water vapor.

we claim:
1. A coating material for a solid formulation, comprising a high hydrogen-
bonding resin and a swelling clay.
2. The coating material according to claim 1, which forms, when coated on a
solid formulation and dried, a coating film in which laminated structures of said
swelling clay are oriented planarly and dispersed in a network fashion.
3. The coating material according to claim 2, wherein the ratio of the area
occupied by said planarly-oriented laminated structures is not less than 30% with
respect to the area of the longitudinal section of said coating film.
4. The coating material according to any one of claims 1 to 3, wherein the mass
ratio of said high hydrogen-bonding resin and said swelling clay is 4:6 to 6:4.
5. The coating material according to any one of claims 1 to 3, wherein said
coating material comprises a sugar alcohol derivative-type surfactant.
6. The coating material according to claim 5, wherein the mass ratio of said high
hydrogen-bonding resin and said swelling clay is 2:8 to 5:5.
7. The coating material according to claim 5 or 6, wherein the content of said
sugar alcohol derivative-type surfactant is 7 to 35%.
8. The coating material according to any one of claims 1 to 7, wherein said high
hydrogen-bonding resin is a polyvinyl alcohol.
9. The coating material according to any one of claims 1 to 8, wherein said
swelling clay is a bentonite.
10. The coating material according to any one of claims 4 to 9, wherein said
sugar alcohol derivative-type surfactant is a sorbitan fatty acid ester.
11. A solid formulation coated with the coating material according to any one of
claims 1 to 10.

An object of the present invention is to provide a coating material for a solid
formulation which is capable of stably retaining the effective ingredient in the solid
formulation for a prolonged period even in unpacked condition in such a manner that
the solid formulation can be used in a single-dose formulation. The present
invention provides a coating material for a solid formulation which comprises a high
hydrogen-bonding resin and a swelling clay and, when coated on a solid formulation
and dried, forms a coating film in which the laminated structures of the
aforementioned swelling clay are oriented planarly and dispersed in a network
fashion.