DESCRIPTION
TITLE OF THE INVENTION
Coated Solid Preparation
TECHNICAL FIELD
[0001]
The present invention relates to a coated solid preparation.
BACKGROUND ART
[0002]
Leukotriene is a lipid mediator produced from arachidonic acid by 5-
lipoxygenase and involved in inflammation and contraction of airway muscle and
decrease/accumulation of the fluid amount in lung. Leukotriene C4, D4, and E4,
which contain cysteine in their molecules, are called cysteinyl leukotriene, and
cysteinyl leukotriene 1 (hereinafter referred to as "CysLT1") receptor and cysteinyl
leukotriene 2 (hereinafter referred to as "CysLT2") receptor are known as a receptor
thereof. CysLT1 receptors and CysLT2 receptors, both of which are expressed in
mastocytes, eosinophils, and endothelial cells, induce inflammation in endothelial
cells under the stimulus of cysteinyl leukotriene, provide stimulation of chemokine
production by mast cells, and are responsible for causing bronchial asthma and
inflammatory disease.
[0003]
Montelukast is an orally-active leukotriene receptor antagonist that
selectively inhibits CysLT1 receptors. Sodium salts of montelukast (hereinafter
referred to as "montelukast sodium") have been used as a useful therapeutic agent for
respiratory disease, asthma, and allergic rhinitis. However, montelukast sodium has
very high hygroscopicity, and it has been reported that Singulair (registered
trademark) tablets and Kipres (registered trademark) tablets, which are commercially
available as a pharmaceutical, have a problem in that they cause delayed
disintegration and delayed dissolution due to moisture absorption upon storage for 4
weeks under conditions of 25°C and a relative humidity of 85% (hereinafter referred
to as "85% RH") (Non-patent Document 1).
[0004]
As a method of improving the hygroscopicity of montelukast sodium, using
montelukast sodium after converting it into free acid has been reported (Patent
Document 1). However, a method of improving the hygroscopicity of montelukast
sodium using a formulation approach has not been reported yet.
[0005]
In general, as a method of improving hygroscopic stability of a solid
preparation, sugar-coating of a solid preparation and film-coating of a solid
preparation with a macromolecular substance have been put to practical use. For
the latter film-coating, an aminoalkyl methacrylate copolymer E (Eudragit EPO
(registered trademark); Degussa) is known as a macromolecular substance that
exhibits moisture barrier properties, and a film coating agent having an improved
moisture barrier performance by adding stearic acid to an aminoalkyl methacrylate
copolymer E (Patent Document 2) have been developed.
[0006]
Even in the case where a solid preparation is not coated directly with a film,
there is the case where hygroscopic stability is secured by packaging with packaging
materials having high water vapor barrier properties. Examples of such a case
include the case where a solid preparation is indirectly protected from moisture by
placing the solid preparation in a PTP (press through pack) sheet laminated with
polyvinylidene chloride and sealing the sheet.
[0007]
On the other hand, from the standpoint of preventing forgetting to take
prescribed drugs or taking a wrong dose, one-dose packages have been widely used
at clinical sites and dispensing pharmacies recently. One-dose packages are
provided to patients in such a manner that a pharmacist takes out a plurality of solid
preparations to be taken in one dose from a packaging material such as a PTP sheet
and puts them in one package for each patient. In addition, in western countries,
patients often subdivide a pharmaceutical taken out from a package such as a PTP
sheet for storage in a pill case or the like, and therefore methods for improving the
water vapor barrier properties of a solid preparation itself have been demanded.
PRIOR ART DOCUMENTS
PATENT DOCUMENTS
[0008]
Patent Document 1: JP 2007-508271 W
Patent Document 2: JP 2004-518750 W
NON-PATENT DOCUMENTS
[0009]
Non-patent Document 1: "Information on the stability of tablets and capsules
in unpacked condition" (6th revised edition), Nishioka et al., Iyaku (Medicine and
Drug) Journal Co., Ltd., 2009, p.237
SUMMARY OF THE INVENTION
PROBLEMS TO BE SOLVED BY THE INVENTION
[0010]
However, in one-dose packaging, since each solid preparation will be stored
for a long period of time in an automatic packing machine in a naked state as taken
out in advance from a packaging material such as a PTP sheet, the protective effect
of the packaging material against humidity wears off, and particularly for a solid
preparation containing montelukast sodium which has high hygroscopicity as an
active ingredient, it is extremely difficult at present to formulate in a one-dose
package because of being susceptible to humidity during storage. In other words,
patients who receive a preparation containing montelukast sodium as an active
ingredient have not gained the advantage of one-dose package that it improves drug
compliance to enhance a therapeutic effect, and therefore there is a need to develop,
using a formulation approach, a preparation adaptable to one-dose package
containing montelukast sodium as an active ingredient.
[0011]
Thus, an object of the present invention is to provide a montelukast-
containing coated solid preparation that can be applied to one-dose package, wherein
the humidity stability of montelukast or a pharmacologically acceptable salt thereof
contained therein is maintained even when the preparation is unpacked.
MEANS FOR SOLVING THE PROBLEMS
[0012]
To achieve the above object, the present inventors intensively studied to
discover that a coated solid preparation with significantly improved stability to
humidity can be obtained by coating a solid preparation containing as an active
ingredient montelukast or a pharmacologically acceptable salt thereof with a coating
agent containing a particular component in a particular state without increasing the
size of the coated solid preparation (without posing any problem in patients' taking
the coated solid preparation).
[0013]
Thus, the present invention provides a coated solid preparation containing as
an active ingredient montelukast or a pharmacologically acceptable salt thereof and
being coated with a coating layer comprising polyvinyl alcohol and swelling clay,
wherein the mass ratio of the above-described polyvinyl alcohol to the above-
described swelling clay in the above-described coating layer is 8:2 to 3:7.
[0014]
In the coating layer of the coated solid preparation described above, the
swelling clay has a labyrinth-like structure to exert the effect of preventing the
contact of the solid preparation with water vapor (hereinafter referred to as "labyrinth
effect") under the influence of the mass ratio of polyvinyl alcohol to swelling clay
and the swollen state of swelling clay. Therefore, the humidity stability of the
coated solid preparation and of the medicinal ingredient montelukast can be
improved, and the delayed disintegration and delayed dissolution of the coated solid
preparation caused by moisture absorption can also be prevented. Further, the
above-described coated solid preparation exerts a sufficient labyrinth effect even
when the coating layer is in the state of a thin film, and therefore there is no problem
in patients' taking the coated solid preparation.
[0015]
In the above-described coated solid preparation, the above-described swelling
clay is preferably dispersed as a laminated structure, and the increase in moisture
absorption of the coated solid preparation at 40°C and a relative humidity of 75% is
preferably not more than 3% by mass.
[0016]
In the coating layer of the coated solid preparation described above, if the
swelling clay is dispersed as a laminated structure, the labyrinth effect is strongly
exerted, and the humidity stability of the coated solid preparation and of the
medicinal ingredient montelukast can be further improved. Further, when the
increase in moisture absorption of the above-described coated solid preparation
under the environment of room temperature 40°C and a relative humidity of 75% is
not more than 3% by mass, such a quality stability that there is no problem in
handling under a normal room-temperature environment can be maintained for a long
period of time, and the delayed disintegration and delayed dissolution can also be
stably prevented.
[0017]
In the above-described coated solid preparation, the above-described swelling
clay is preferably bentonite or magnesium aluminum silicate.
[0018]
Bentonite and magnesium aluminum silicate are able to further improve the
humidity stability of the coated solid preparation because they produce a larger
labyrinth effect in the coating layer formed on the surface of the solid preparation.
EFFECTS OF THE INVENTION
[0019]
According to the present invention, the humidity stability of the coated solid
preparation and of montelukast or a pharmacologically acceptable salt thereof
contained in the coated solid preparation can be maintained even when the
preparation is unpacked. In addition, the present invention provides a montelukast-
containing coated solid preparation that can be applied to one-dose package even
when the preparation is unpacked, and the present invention contributes to improving
the drug compliance of patients who receive the coated solid preparation to enhance
a therapeutic effect. Further, the coated solid preparation of the present invention is
applicable not only to tablets but also granule preparations.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020]
Figure 1 is a release profile of Reference Example;
Figure 2 is a focused ion beam transmission electron micrograph of the film
of Example 1;
Figure 3 is a focused ion beam transmission electron micrograph of the film
of Example 2;
Figure 4 is a focused ion beam transmission electron micrograph of the film
of Example 3;
Figure 5 is a focused ion beam transmission electron micrograph of the film
of Comparative Example 3; and
Figure 6 is a focused ion beam transmission electron micrograph of the film
of Comparative Example 4.
BEST MODE FOR CARRYING OUT THE INVENTION
[0021]
Preferred embodiments for carrying out the present invention will now be
described. It should be understood, however, that the present invention is not
limited to the following embodiments, and unless otherwise specified, "%" means "%
by mass (w/w%)".
[0022]
The coated solid preparation of the present invention is characterized by
containing as an active ingredient montelukast or a pharmacologically acceptable salt
thereof and being coated with a coating layer comprising polyvinyl alcohol and
swelling clay, wherein the mass ratio of the above-described polyvinyl alcohol to the
above-described swelling clay in the above-described coating layer is 8:2 to 3:7.
[0023]
"Solid preparation" refers to a pharmaceutical formulated to be a solid,
examples of which include tablets (including sublingual tablets and orally
disintegrating tablets), capsules (including soft capsules and microcapsules), granules,
fine granules, powders, balls, troches, or filming agents.
[0024]
"Coated solid preparation" refers to a preparation in which a coating layer is
formed to prevent the pharmacologically active components from, for example,
being decomposed by oxygen, water vapor, light, and the like by coating the surface
of the above-described solid preparation with a coating agent.
[0025]
Examples of "montelukast or a pharmacologically acceptable salt thereof
include, for example, montelukast or montelukast sodium. Examples of
commercially available preparations of montelukast sodium include, for example,
Singulair tablets 10 mg (Banyu Pharmaceutical Co., Ltd.), Singulair chewable tablets
(Banyu Pharmaceutical Co., Ltd.), Singulair fine granules 4 mg (Banyu
Pharmaceutical Co., Ltd.), Kipres tablets (KYORIN Pharmaceutical Co., Ltd.),
Kipres chewable tablets (KYORIN Pharmaceutical Co., Ltd.), or Kipres fine
granules 4 mg (KYORIN Pharmaceutical Co., Ltd.).
[0026]
"Polyvinyl alcohol" (hereinafter referred to as "PVA") refers to an alcohol
obtained by saponifying polyvinyl acetate, including from partially saponificated
PVA having several ten percent of residual acetic acid groups to completely
saponificated PVA having only a few percent of residual acetic acid groups.
[0027]
The saponification degree of PVA is preferably 70 to 97 mol%. The
average degree of polymerization of PVA is preferably 200 to 3000 and more
preferably 600 to 2400.
[0028]
The above-described PVA may be used by mixing two or more PVAs having
different saponification degree and different average degree of polymerization.
When mixing two or more PVAs, for example, it is preferable to add a PVA of high
polymerization grade to a PVA of low polymerization grade and mix them.
[0029]
Examples of PVAs include, for example, various types of Poval (Kuraray Co.,
Ltd.) or Gohsenol (Nippon Synthetic Chemical Industry Co., Ltd.).
[0030]
"Swelling clay" refers to clay having swelling properties, and particularly to a
substance having swelling properties among finely-powdered substances that exhibit
viscosity and plasticity when containing an appropriate amount of water.
[0031]
As the swelling clay, those that are negatively charged because of the
compositional balance of the metal salt species are preferred, examples of which
include smectites such as hydrated aluminum silicate having a three-layer structure.
[0032]
"Negatively charged" refers to the state of the swelling clay's having cation
exchange capability, and the amount of charge is expressed as Cation Exchange
Capacity (CEC). The unit of cation exchange capacity is milliequivalent/100 grams
(hereinafter referred to as "meq/100 g") and generally expressed as the number of
equivalents which corresponds to the molar concentration of monovalent ions.
[0033]
Examples of the above-described smectite include, for example, beidellite,
nontronite, saponite, hectorite, sauconite, bentonite (hereinafter referred to as "BT "),
magnesium aluminum silicate, or mixtures thereof. BT or magnesium aluminum
silicate is preferred, and BT is more preferred.
[0034]
The above-described swelling clay is preferably dispersed as a laminated
structure. "Laminated structure" refers to a laminated structure formed by stacking
of a plurality of layer-shaped structures, particularly to a structure in which 10 to 100
layers of the strips of swelling clay are stacked. For dispersing the swelling clay as
a laminated structure, it is preferable to coat the surface of the solid preparation with
a coating agent containing swelling clay in a swollen state.
[0035]
In the cross section in the thickness direction of the film formed from a
coating agent containing swelling clay, strips of the swelling clay is preferably
dispersed in a mesh pattern and planarly oriented. The state of the strips of the
swelling clay in the cross section in the thickness direction of the film can be
observed by using, for example, a transmission electron microscope (TEM).
[0036]
"In a mesh pattern" refers to the situation where strips of the swelling clay are
forming literally a mesh when the dispersion state of the strips of the swelling clay in
the cross section in the thickness direction of the film is expressed two-dimensionally.
[0037]
"Planarly oriented" refers to the situation where the strips of the swelling clay
are laminated in the thickness direction of the film.
[0038]
"Swollen state of swelling clay" refers to the state in which the swelling clay
is swollen by containing a dispersion medium. Examples of the swelling clay in a
swollen state include, for example, a dispersion obtained by suspending swelling clay
in a dispersion medium and stirring the suspension, for example, with a homogenizer,
and it is preferable to be dispersed to the extent that all the swelling clay is able to
pass through a filter paper when the dispersion is filtered. Examples of the filter
paper used in the above-described filtering operation include, for example, No.5B
quantitative filter paper (ADVANTEC) and a glass fiber filter paper GF/D (particle
holding capacity; 2.7 urn, Whatman).
[0039]
Examples of dispersion media for a coating agent containing swelling clay,
i.e., solvents used in preparation of a coating agent include, for example, water,
organic solvents such as lower alcohols having 5 or less carbon atoms, or mixed
solvents thereof, among which water is preferred.
[0040]
To the above-described coating agent, pharmaceutically acceptable additives
may be added; for improving the dispersibility of the swelling clay, surfactants can
be added, and for improving the disintegration properties of the coated solid
preparation, for example, saccharides and sugar alcohols, such as maltose, maltitol,
sorbitol, xylitol, fructose, glucose, lactitol, isomaltose, lactose, erythritol, mannitol,
trehalose, or sucrose; croscarmellose sodium; or low-substituted
hydroxypropylcellulose can be added.
[0041]
To the above-described coating agent, additives generally used for coating in
the pharmaceutical field may be further added, and examples of such additives
include, for example, coloring agents such as dyes extracted from plants, titanium
oxide, calcium carbonate, or silicon dioxide, which serve as a masking agent.
[0042]
"Coating layer" refers to a layer of a film formed by coating a solid
preparation with a coating agent. The coating layer of the present invention
contains PVA and swelling clay, and the mass ratio of the PVA to the swelling clay
is 8:2 to 3:7 and preferably 6: 4 to 3:7.
[0043]
The reason is that, when the mass of swelling clay is less than one fourth of
the mass of PVA, the labyrinth effect of swelling clay is reduced, so that the
humidity stability of montelukast or a pharmacologically acceptable salt thereof
cannot be sufficiently obtained, and when the mass of swelling clay is above 2.3
times the mass of PVA, the laminated structure of the coating layer becomes non-
uniform because of the too high ratio of swelling clay, so that the humidity stability
of montelukast or a pharmacologically acceptable salt thereof cannot be sufficiently
obtained again. The percentage of swelling clay in the above-described coating
layer is preferably 5% or more based on the total coating layer.
[0044]
The increase in moisture absorption of tablets after the above-described
coated solid preparation has been stored under the environment of 40°C and a
relative humidity of 75% for 1 week is preferably 3% or less and more preferably 2%
or less.
[0045]
The water vapor transmission of the above-described coating layer is
preferably 1.0 x 10"5 to 1.0 x 10"4 g-mm/cm2-24 hratm, more preferably 1.0 x 10"5 to
6.0 x 10"5 g-rnm/cm2-24 hr-atm, and still more preferably 1.0 x 10'5 to 3.5 x 10"5
g-mm/cm -24 hr-atm.
[0046]
The above-described coating layer preferably covers the solid preparation at a
mass percentage of 2 to 200% based on the solid preparation, and when the solid
preparation is tablets, the mass percentage is preferably 3 to 30%, more preferably 3
to 20%, and still more preferably 3 to 15%.
[0047]
Examples of the method for coating the surface of the solid preparation with a
coating agent include, for example, the use of a coating pan or a coating machine for
tablets in the case where the solid preparation is in the form of tablets, and, for
example, the use of a fluidized-bed coating machine or a rolling fluidized-bed
coating machine in the case where the solid preparation is in the form of granules or
powders.
[0048]
The above-described coated solid preparation may be further coated with a
functional film, for example, of gastric-soluble or enteric-soluble macromolecular
substances. Further, the inner side of the coating layer containing PVA and
swelling clay according to the present invention may be coated in advance with a
functional film, for example, of gastric-soluble or enteric-soluble macromolecular
substances.
EXAMPLES
[0049]
The present invention will now be specifically described by way of examples,
but the present invention is not limited thereto.
[0050]
(Reference Example)
For the tablets obtained by storing montelukast sodium tablets (Singulair
tablets 10 mg; Banyu Pharmaceutical Co., Ltd.) for 1 week under conditions of 40°C
and a relative humidity of 75% (hereinafter referred to as "1-week stored tablets at
40°C and 75% RH"), dissolution tests and measurements of disintegration time were
performed. The dissolution tests were carried out in accordance with the Japanese
Pharmacopoeia, 15th Edition, Dissolution Test, Second Method; the tablets were
placed into a 900 mL of a test solution obtained by adding polysorbate 80 of 0.5%
concentration to distilled water, and dissolved solutions were collected over time for
a quantitative determination under the HPLC conditions below. The release profile
is shown in Figure 1.
[0051]
(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
[0052]
From the release profile shown in Figure 1, it is clear that the 1 -week stored
tablets at 40°C and 75% RH exhibit significantly delayed dissolution compared to
montelukast sodium tablets before storage (hereinafter referred to as "pre-storage
tablets"). Also for disintegration time, the disintegration time of the pre-storage
tablets is within 10 minutes, whereas the disintegration time of the 1-week stored
tablets at 40°C and 75% RH reached as long as 40 minutes. The conditions of
storage at 40°C and a relative humidity of 75% for 1 week can be considered as
further accelerated conditions of the conditions of storage at 85% RH for 4 weeks
reported in the prior art reference (Non-patent Document 1). Thus, as described
below, the tablets after storage at 40°C and a relative humidity of 75% for 1 week
were evaluated for increase in moisture absorption and disintegration delay time to
thereby confirm the excellent effect of the present invention.
[0053]
(Method for calculating increase in moisture absorption)
The mass of the pre-storage tablets and the post-storage tablets were
measured, and the increase in moisture absorption was calculated by Equation 1
below.
Increase in moisture absorption (% by mass) = ((W - Ws) / Ws) x 100
Equation 1
W: Mass of post-storage tablets (g)
Ws: Mass of pre-storage tablets (g)
[0054]
(Method of measuring disintegration time)
Disintegration tests were performed in accordance with Japanese
Pharmacopoeia, 15th Edition, Disintegration Test, to measure disintegration time.
Specifically, using distilled water as a test solution, the time until tablets lose their
shape under conditions of a stroke of 30 times/min was taken as the disintegration
time.
[0055]
(Method for calculating disintegration delay time)
The disintegration time of the pre-storage tablets and post-storage tablets
were measured, and the disintegration delay time was calculated by Equation 2
below.
Disintegration delay time (min) = T - Ts Equation 2
T: Disintegration time of post-storage tablets (min)
Ts: Disintegration time of pre-storage tablets (min)
[0056]
(Method of measuring water vapor transmission)
The measurement of the water vapor transmission of the coating layer
constituting the coated solid preparation of the present invention was performed in
accordance with JIS K 8123 (1994) with minor modifications.
[0057]
Specifically, a film of a coating layer formed with a coating agent prepared as
appropriate was cut, with light passing therethrough, selectively at a portion of
uniform thickness without a pinhole into a circle with a diameter of 3.5 cm, and the
thickness of the film was measured at arbitrary five points.
[0058]
Next, 3 g of calcium chloride (particle size: 850 to 2000 urn) was placed in an
aluminum cup (diameter: 30 mm), and the film of a coating layer cut into a circle and
a ring for fixing the film were sequentially placed on the aluminum cup. The ring
was fixed by placing a weight on the ring, and in this state, molten paraffin wax was
poured into the edge of the aluminum cup. After the paraffin wax was solidified,
the weight was removed, and the mass of the whole aluminum cup was measured to
determine the initial mass. Then, the aluminum cup was placed in a thermostat bath
at 40°C and 75% RH. The aluminum cup was taken out every 24 hours for
measuring the mass to calculate the water vapor transmission coefficient by using
Equation 3 below. In all of the tests for measuring the water vapor transmission
described below, r = 1.5 cm; t = 24 hours; and C = 1 atm.
Water vapor transmission P (g-mm/cm2-24 hr-atm) = WxA/BxtxC
Equation 3
W: Mass increased in 24 hours (g)
A: Average value of film thickness at five points (mm)
B: Transmission area 7tr (cm )
t: Elapsed time (hr)
C: Atmospheric pressure (atm)
[0059]
(Example 1)
To 234.6 parts by mass of water, added were 6.9 parts by mass of PVA (EG-
05; Nippon Synthetic Chemical Industry Co., Ltd.), 505.3 parts by mass of a 3.2%
BT solution, and 3.2 parts by mass of sorbitan monolaurate (hereinafter referred to as
"Span 20"), and the resulting mixture was stirred with a homogenizer (Polytron
Model KR) to obtain a coating agent (hereinafter referred to as "Example 1 coating
agent"). As a 3.2% BT solution, used was a filtrate obtained by adding 32 parts by
mass of BT (Kunipia-F; KUN1MINE INDUSTRIES CO., LTD., cation exchange
capability: 115 meq/100 g) to 968 parts by mass of stirred water, stirring the resulting
mixture with the homogenizer for uniform dispersion, and then suction-filtering the
resultant through a filter paper.
[0060]
Twenty grams of montelukast sodium tablets (Singulair tablets 10 mg; Banyu
Pharmaceutical Co., Ltd.) and 280 g of placebo tablets were placed in a coating pan
(HI-COATER MINI; Freund Industrial Co., Ltd.), and Example 1 coating agent was
applied to the tablets until the thickness of the coating layer reached 50 to 60 µm.
For the coated montelukast sodium tablets obtained, the increase in moisture
absorption and the disintegration delay time after storage for 1 week under
conditions of 40°C and a relative humidity of 75% were calculated.
[0061]
Example 1 coating agent was sprayed onto the back of a polypropylene
balance tray, and immediately dried with hot air from a dryer. After repeating these
operations several times, the balance tray was allowed to stand in an oven at 50°C
and dried overnight, and a film was separated from the balance tray to measure the
water vapor transmission.
[0062]
(Example 2)
From a coating agent obtained by adding 14.0 parts by mass of PVA and
656.2 parts by mass of a 3.2% BT solution to 329.8 parts by mass of water and
stirring the resulting mixture with a homogenizer, a film was produced in the same
manner as in Example 1, and the water vapor transmission was measured.
[0063]
(Example 3)
Using a coating agent obtained by adding 20.0 parts by mass of PVA and
625.0 parts by mass of a 3.2% BT solution to 355.0 parts by mass of water and
stirring the resulting mixture with a homogenizer, coated montelukast sodium tablets
was obtained in the same manner as in Example 1, and the increase in moisture
absorption after storage for 1 week under conditions of 40°C and a relative humidity
of 75% RH was calculated. Further, a film was produced from the coating agent in
the same manner as in Example 1, and the water vapor transmission was measured.
[0064]
(Example 4)
Using a coating agent obtained by adding 21.0 parts by mass of PVA and
437.5 parts by mass of a 3.2% BT solution to 541.5 parts by mass of water and
stirring the resulting mixture with a homogenizer, coated montelukast sodium tablets
was obtained in the same manner as in Example 1, and the increase in moisture
absorption after storage for 1 week under conditions of 40°C and a relative humidity
of 75% RH was calculated. Further, a film was produced from the coating agent in
the same manner as in Example 1, and the water vapor transmission was measured.
[0065]
(Example 5)
Using a coating agent obtained by adding 32.0 parts by mass of PVA and
250.0 parts by mass of a 3.2%BT solution to 718.0 parts by mass of water and
stirring the resulting mixture with a homogenizer, coated montelukast sodium tablets
was obtained in the same manner as in Example 1, and the increase in moisture
absorption after storage for 1 week under conditions of 40°C and a relative humidity
of 75% RH was calculated. Further, a film was produced in the same manner as in
Example 1, and the water vapor transmission was measured.
[0066]
(Example 6)
To 234.6 parts by mass of water, added were 6.9 parts by mass of PVA, 505.3
parts by mass of a 3.2% magnesium aluminum silicate solution, and 3.2 parts by
mass of Span 20, and the resulting mixture was stirred with a homogenizer to prepare
a coating agent. A film was produced in the same manner as in Example 1, and the
water vapor transmission was measured. As a 3.2% magnesium aluminum silicate
solution, used was a filtrate obtained by adding 32 parts by mass of magnesium
aluminum silicate (Veegum-HV; R.T. Vanderbilt Company, Inc.) to 968 parts by
mass of stirred water, stirring the resulting mixture with the homogenizer for uniform
dispersion, and then suction-filtering the resultant through a filter paper.
[0067]
(Comparative Example 1)
The increase in moisture absorption and the disintegration delay time after
montelukast sodium tablets (Singulair tablets 10 mg; Banyu Pharmaceutical Co.,
Ltd.) have been stored for 1 week under conditions of 40°C and a relative humidity
of 75% were calculated.
[0068]
(Comparative Example 2)
Using a coating agent obtained by adding 7.0 parts by mass of PVA and
875.0 parts by mass of a 3.2% BT solution to 118.0 parts by mass of water and
stirring the resulting mixture with a homogenizer, coated montelukast sodium tablets
was obtained in the same manner as in Example 1, and the increase in moisture
absorption after storage for 1 week under conditions of 40°C and a relative humidity
of 75% was calculated. Further, a film was produced from the coating agent
obtained in the same manner as in Example 1, and the water vapor transmission was
measured.
[0069]
(Comparative Example 3)
Using a coating agent obtained by adding 36.0 parts by mass of PVA and
125.0 parts by mass of a 3.2% BT solution to 839.0 parts by mass of water and
stirring the resulting mixture with a homogenizer, coated montelukast sodium tablets
was obtained in the same manner as in Example 1, and the increase in moisture
absorption after storage for 1 week under conditions of 40°C and a relative humidity
of 75% was calculated. Further, a film was produced from the coating agent
obtained in the same manner as in Example 1, and the water vapor transmission was
measured.
[0070]
(Comparative Example 4)
From a coating agent obtained by adding 3.0 parts by mass of PVA and 843.8
parts by mass of a 3.2% BT solution to 153.2 parts by mass of water and stirring the
resulting mixture with a homogenizer, a film was produced in the same manner as in
Example 1, and the water vapor transmission was measured.
[0071]
The mass ratio of PVA to BT to the third component contained in each
coating agent of Examples 1 to 6 and Comparative Examples 1 to 4, the increase in
moisture absorption calculated in Examples 1, 3 to 5 and Comparative Examples 1 to
3, and the water vapor transmission measured in Examples 1 to 6 and Comparative
Examples 2 to 4 are shown in Table 1.
[0072]

[0073]
From the results in Table 1, it is clear that when the mass ratio of PVA to
swelling clay is in the range of 8:2 to 3:7, the increase in moisture absorption of the
montelukast sodium tablets is not more than 3.0% by mass, and the water vapor
transmission of the film is not more than 1.0 x 10-4; therefore, the coated solid
preparation of the present invention is very stable to humidity.
[0074]
Further, the disintegration delay time in Comparative Example 1 is 30
minutes, whereas the disintegration delay time in Example 1 is 4 minutes. Also
from these results, it is clear that the disintegration delay time of the coated solid
preparation of the present invention is significantly short, and the disintegration
performance can be maintained even if the preparation has been stored under a high
humidity environment.
[0075]
(Measurement of films under transmission electron microscope)
Using the focused ion beam technique, the longitudinal section of each film
obtained in Examples 1 to 3 and Comparative Examples 3 and 4 was observed under
a transmission electron microscope. The micrograph of Example 1, the micrograph
of Example 2, the micrograph of Example 3, the micrograph of Comparative
Example 3, and the micrograph of Comparative Example 4 are shown in Figure 1,
Figure 2, Figure 3, Figure 4, and Figure 5, respectively.
[0076]
In the micrographs of Figures 2 to 4, BT was uniformly dispersed as a
laminated structure in the film, but in Figure 5, BT formed little or no laminated
structure. Also in Figure 6, areas where BT is not planarly oriented are found here
and there. From the observations above, it is presumed that the uniform dispersion
of the laminated structure of BT significantly contributes to the water vapor
transmission of the film and the humidity stability of solid preparations such as
montelukast sodium tablets.
[0077]
(Comparative Example 5)
From a coating agent obtained by adding 16.0 parts by mass of PVA and 4.0
parts by mass of BT to 480.0 parts by mass of water and stirring the resulting mixture
with a magnetic stirrer for 15 minutes, a film was produced in the same manner as in
Example 1, and the water vapor transmission was measured.
[0078]
(Example 7)
Using a coating agent obtained by adding 6.9 parts by mass of PVA, 505.3
parts by mass of a 3.2% BT solution, 3.2 parts by mass of Span 20, and 3.94 parts by
mass of maltitol to 343.5 parts by mass of water and stirring the resulting mixture
with a homogenizer, coated montelukast sodium tablets was obtained in the same
manner as in Example 1, and the increase in moisture absorption after storage for 1
week under conditions of 40°C and a relative humidity of 75% was calculated.
Further, a film was produced in the same manner as in Example 1, and the water
vapor transmission was measured.
[0079]
The increase in moisture absorption and the water vapor transmission
measured and calculated in Examples 1 and 7 and Comparative Example 5 are shown
in Table 2.
[0080]
The results in Table 2 show that, in both the case where a nonionic surfactant
was added to PVA and BT (Example 1) and the case where sugar alcohol was further
added (Example 7), the increase in moisture absorption was not more than 3% by
mass, and the water vapor transmission of the film was not more than 1.0 x 10-4.
[0082]
The comparison of Example 5 and Comparative Example 5 showed that BT is
preferably added not as a powder but in a swollen state.
INDUSTRIAL APPLICABILITY
[0083]
The coated solid preparation of the present invention can be suitably used as a
pharmaceutical applicable to one-dose package.
We Claim:
1. A coated solid preparation containing as an active ingredient montelukast or a
pharmacologically acceptable salt thereof and being coated with a coating layer
comprising polyvinyl alcohol and swelling clay, wherein the mass ratio of said
polyvinyl alcohol to said swelling clay in said coating layer is 8:2 to 3:7 and said
swelling clay is dispersed as a laminated structure.
2. The coated solid preparation according to claim 1, wherein the increase in
moisture absorption of the coated solid preparation at 40°C and a relative humidity of
75% is not more than 3% by mass.
3. The coated solid preparation according to claim 1 or 2, wherein said swelling
clay is bentonite or magnesium aluminum silicate.

ABSTRACT

An object of the present invention is to provide a montelukast-containing
coated solid preparation that can be applied to one-dose package, wherein the
humidity stability of montelukast or a pharmacologically acceptable salt thereof
contained therein is maintained even when the preparation is unpacked. The
present invention provides a coated solid preparation containing as an active
ingredient montelukast or a pharmacologically acceptable salt thereof and being
coated with a coating layer comprising polyvinyl alcohol and swelling clay, wherein
the mass ratio of the above-described polyvinyl alcohol to the above-described
swelling clay in the above-described coating layer is 8:2 to 3:7.