Note: Descriptions are shown in the official language in which they were submitted.
CA 02619367 2008-01-29
DESCRIPTION
GEL PREPARATION FOR ORAL ADMINISTRATION
Technical Field
[0001]
The present invention relates to a gel preparation
comprising an HMG-CoA reductase inhibitor, intended for
administration to patients with hyperlipemia or
hypercholesterolemia in need for oral administration of
an HMG-CoA reductase inhibitor.
Background Art
[0002]
Gel preparations for oral administration are suitable
for patients having difficulty in swallowing compared
with conventional solid preparations such as tablets and
capsules. Additionally, these gel preparations are
advantageous over liquid preparations in that the risk
for aspiration is minimal, and that the bad tastes, such
as bitter tastes and harsh tastes, of pharmacologically
active ingredients thereof are mitigated.
[0003]
Currently commercially available dosage forms for drugs
belonging to the HMG-CoA reductase inhibitor family
include, for example, tablets, capsules, fine granules,
oral liquids and the like. These drugs are frequently
administered to elderly, bedridden or tube feeding
patients. The patients suffer age-related impairments in
their ability to swallow, which tend to be accompanied
by symptoms such as dry mouth. Generally, solid
preparations are relatively difficult to swallow,
whereas liquid preparations pose problems associated
with aspiration and choking during swallowing. Because
the recipient of an HMG-CoA reductase inhibitor used to
treat hyperlipemia, a lifestyle-related disease, over
several months to several years, or even longer times is
often a bedridden patient, a patient with dysphagia, or
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CA 02619367 2008-01-29
an tube feeding patient, there is a demand for a gel
preparation having physical properties such as
viscoelasticity and liquid thickness in a dosage form
that does not clog the throat, does not induce reflex
s vomiting, is easily swallowable, and permits painless
ingestion by the patient. However, no research has been
conducted into a gel preparation for oral administration
comprising an HMG-CoA reductase inhibitor.
Disclosure of the Invention
io [0004]
Compounds belonging to the HMG-CoA reductase inhibitor
family are generically called statin-series compounds,
most of which are unstable in acidic aqueous solutions
and suspensions, and hence must be prepared at pH levels
15 of 7 or higher. On the other hand, because alkaline
preparations at pH levels of 11 or higher are likely to
cause adverse reactions such as stomatitis in taking, a
gel preparation of an HMG-CoA reductase inhibitor for
oral administration must be prepared at pH levels
2o between 7 and 10. Hence, a gel preparation comprising an
HMG-CoA reductase inhibitor, and adjusted to a pH levels
between 7 and 10, was investigated. When agar or K
carrageenan, both commonly used pharmaceutical additives,
was used as the gelling agent, the gel preparation
25 obtained exhibited unstable physical properties such as
considerable syneresis. On the other hand, if xanthan
gum or L carrageenan is added for suppressing syneresis
with reducing the content ratio of agar or K carrageenan,
the gel preparation obtained lacks gel strength and
3o exhibits poor form retention; the preparation collapses
in the oral cavity at the time of removal from its
containers and during ingestion, the bad tastes, such as
bitter tastes and harsh tastes, of the HMG-CoA reductase
inhibitor are intensely perceived, these preparations
35 are not suitable for taking orally.
2
CA 02619367 2008-01-29
[0005]
Amid this situation, the present inventors diligently
investigated to obtain a gel preparation for oral
administration comprising an HMG-CoA reductase inhibitor
as the primary ingredient, wherein gel formation during
manufacturing is not interfered with, syneresis during
storage is less likely, form retention is good, collapse
in the oral cavity is unlikely, bad tastes such as
bitter tastes and harsh tastes are suppressed, throat
io passage is good, and swallowing is easy, and which is
suitable for routine ingestion. As a result, the
inventors found that a gel preparation for oral
administration having a pH level between 7 and 10,
wherein syneresis is unlikely, storage stability is good,
and bad tastes such as bitter tastes and harsh tastes
are suppressed, can be obtained by blending a
combination of L carrageenan and locust bean gum as a
gelling agent, in combination with one or more
substances selected from agar, polysaccharides having a
sulfuric acid group and/or a carboxyl group, cellulose
derivatives, mannans, polysaccharides having an amino
group, and starch derivatives, blending as required, one
or more substances selected from cellulose derivatives,
polyvinyl-series compounds, polysaccharides, starch
derivatives, macrogol, alginic acid and derivatives
thereof, as a polymer compound, and blending a salt of
an organic and/or an inorganic acid and a cation and/or
a hydroxide thereof as a buffering agent. And they
developed the present invention.
3o [0006]
Accordingly, the present invention relates to a gel
preparation for oral administration comprising an HMG-
CoA reductase inhibitor, a gelling agent, a polymer
compound, a salt of an acid and a cation and/or a
hydroxide thereof, a base, a sweetening agent, an
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CA 02619367 2008-01-29
antiseptic, and water, and having a pH level between 7
and 10.
Best Mode for Carrying out the Invention
[0007]
The HMG-CoA reductase inhibitor contained as an active
ingredient of the gel preparation for oral
administration of the present invention is administered
as a therapeutic agent for hyperlipemia, and may be
derived from any of microbially-derived natural
io substances, semi-synthetic derivatives and totally
synthetic compounds; examples include the statin-series
compounds described in patent documents 1 to 8,
preferably pravastatin, lovastatin, simvastatin,
fluvastatin, livastatin, atorvastatin, rosvastatin or
pitavastatin, more preferably pravastatin, lovastatin,
simvastatin, fluvastatin, atorvastatin, rosvastatin or
pitavastatin, still more preferably pravastatin,
atorvastatin, fluvastatin or pitavastatin, and/or a
pharmacologically acceptable salt thereof (suitably
sodium salt or calcium salt and the like). Each HMG-CoA
reductase inhibitor involves geometrical isomers, or, if
containing asymmetric carbons, stereoisomers; these
isomers can exist as hydrated form; all of these isomers
and mixtures thereof are encompassed in the present
invention.
[Patent document 1] JP-A-SHO-57-2240 (USP4346227)
[Patent document 2] JP-A-SHO-57-163374 (USP4231938)
[Patent document 3] JP-A-SHO-56-122375 (USP444784)
[Patent document 4] JP-T-SHO-60-500015 (USP4739073)
[Patent document 5] JP-A-HEI-1-216974 (USP5006530)
[Patent document 6] JP-A-HEI-1-279866 (USP5854259 and
USP5856336)
[Patent document 7] JP-A-HEI-3-58967 (USP5273995)
[Patent document 8] JP-A-HEI-5-178841 (USP5260440)
[0008]
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CA 02619367 2008-01-29
In Japan, the usual dosage of an HMG-CoA reductase
inhibitor in the gel preparation for oral administration
of the present invention is about 1 to about 30 mg per
administration, depending on the choice of HMG-CoA
reductase inhibitor; for example, 5 to 10 mg for
pravastatin sodium, 5 to 20 mg for simvastatin, 10 mg
for atorvastatin, 10 to 30 mg for fluvastatin, and 1 to
2 mg for pitavastatin calcium. The weight of an easily
ingestible (for example, ingestible at a mouthful) jelly
io of the present invention is usually about 0.4 to about
g. Hence, the content ratio of HMG-CoA reductase
inhibitor is preferably 0.001 to 50% by mass, more
preferably 0.01 to 40% by mass, still more preferably
0.05 to 20% by mass, relative to the total amount of the
Zs entire composition.
[0009]
In the gel preparation for oral administration of the
present invention, agar, pectin, sodium alginate,
carrageenan, locust bean gum, xanthan gum, and guar gum
can serve as gelling agents showing good gelling
performance at pH levels between 7 and 10 and in the
presence of an HMG-CoA reductase inhibitor during
manufacturing of the preparation. However, if a gelling
agent showing strong gelling power, such as agar or K
carrageenan, is used alone, syneresis during storage of
the preparation is likely to occur, although the
moldability is good. On the other hand, if a gelling
agent showing weak or almost no gelling power, such as L
carrageenan, locust bean gum, or xanthan gum, is used
3o alone, the moldability is poor, although the syneresis
is very unlikely to occur. In both cases, the
preparations are not suitable for taking orally. These
shortcomings have been effectively improved by using in
combination two or more gelling agents selected from
agar, non-ionic polysaccharides, polysaccharides having
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CA 02619367 2008-01-29
a sulfuric acid group and/or a carboxyl group,
aminopolysaccharides, cellulose derivatives and proteins.
More specifically, such combinations of gelling agents
include combinations of two or more substances selected
from gelatin, milk casein, mannans, carrageenan, starch,
gelatinized starch, tragacanth gum, tamarind seed
polysaccharide, gellan gum, karaya gum, cassia gum, tara
gum, chitosan, psyllium seed gum, ghatti gum and the
like, exemplified by a combination of agar, i
carrageenan, xanthan gum and locust bean gum, a
combination of K carrageenan, locust bean gum, guar gum
and pectin, a combination of L carrageenan, K
carrageenan, locust bean gum and guar gum, and a
combination of alginic acid sodium, pectin, xanthan gum
and agar. The amount of these gelling agents added is
preferably 0.05 to 15% by mass, more preferably 0.2 to
10% by mass, still more preferably 0.5 to 5% by mass,
relative to the total amount of the entire gel
preparation.
[0010]
Adding a polymer compound to increase the gel form
retenting capability of the gelling agent contained in
the gel preparation of the present invention is
effective to decrease syneresis and leads to mitigate
the bitter and harsh tastes of the HMG-CoA reductase
inhibitor to improve the sensory property by enhancing
the gel form retention in the oral cavity at the time of
ingestion. The polymer compound added to provide this
function is selected from cellulose derivatives,
polyvinyl-series compounds, polysaccharides, starch
derivatives, macrogol, alginic acid and derivatives
thereof, hydroxypropylcellulose,
hydroxyethylmethylcellulose, methylcellulose and the
like, and these can be used singly or in combination.
The amount of these polymers added is preferably 0.05 to
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CA 02619367 2008-01-29
15% by mass, more preferably 0.2 to 10% by mass, still
more preferably 0.5 to 5% by mass, relative to the total
amount of the entire gel preparation.
[0011]
Buffering agents that are effective in keeping the gel
preparation for oral administration of the present
invention at a pH between 7 and 10, and that produce a
gel showing almost no syneresis, include salts of
organic acids such as lactic acid, citric acid, tartaric
io acid, malic acid, and adipic acid and/or inorganic acids
such as phosphoric acid, and metal ions such as
potassium ion, sodium ion, calcium ion and magnesium ion
and/or hydroxides of these metal ions. The amount of
buffering agent added is not subject to limitation, and
is preferably not less than 0.001% by mass and not more
than 15% by mass, relative to the total amount of the
entire gel preparation.
[0012]
The gel preparation for oral administration of the
present invention may contain preservative agents.
Examples of the preservative agents include isobutyl
para-oxybenzoate, isopropyl para-oxybenzoate, ethyl
para-oxybenzoate, propyl para-oxybenzoate, methyl para-
oxybenzoate, benzoic acid, sodium edetate, calcium
disodium edetate, salicylic acid, sorbic acid,
dehydroacetic acid and salts thereof, chlorobutanol,
benzyl alcohol, phenylethyl alcohol, phenoxyethanol, 1-
menthol, dl-camphor, cetylpyridinium chloride,
benzethonium chloride, benzalkonium chloride and the
like; the amount of antiseptic added is not subject to
limitation.
[0013]
The base contained in the gel preparation for oral
administration of the present invention is exemplified
by polyhydric alcohol glycerols, propylene glycol, D-
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CA 02619367 2008-01-29
sorbitol, xylitol, mannitol, erythritol, maltitol, and
saccharides such as trehalose, raffinose, sucrose,
fructose, glucose, and lactose; and the amount of
substrate added is not subject to limitation.
[0014]
The sweetening agent contained in the gel preparation
for oral administration of the present invention is
exemplified by saccharin sodium, aspartame, stevia,
glycyrrhizinic acid, derivatives thereof, and mixtures
io thereof; these sweetening agents are particularly used
to mitigate the bitter tastes and harsh tastes of HMG-
CoA reductase inhibitor adjusted to a pH levels between
7 and 10; the ratio by weight of the HMG-CoA reductase
inhibitor to the sweetening agent is 1:0.001 to 1:40.
Furthermore, appropriate amounts of fructose, purified
white soft sugar, palatinose, trehalose,
oligosaccharides, isomerized sugars, muscovado,
hydrangea macrophyla powder, glycyrrhiza extract,
sucralose, thaumatin, glucose, starch syrup, reducing
maltose starch syrup and the like may be used to improve
the taste of the gel preparation.
[0015]
The gel preparation for oral administration of the
present invention can be prepared in the same manner as
the method for preparing a commonly known gel
composition except that the above-described ingredients
may be blended. More specifically, an HMG-CoA reductase
inhibitor and other ingredients are added to an
appropriate amount of water or warm water, this mixture
is uniformly stirred and homogenized optionally with
heating using a mechanical stirrer equipped with an
appropriate mechanism for heating and cooling; the
resulting homogenate is filled and cooled to solidify in
an optionally chosen container, whereby the gel
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CA 02619367 2008-01-29
preparation for oral administration of the present
invention can be prepared.
[0016]
Although the gelling time varies depending on the amount
of drug liquid filled, the drug liquid usually gels to
yield a gel composition of the present invention when
allowed to stand at normal temperature for 1 to 2 hours,
or at 10 C or lower for 1 hour.
[0017]
io Although the manufacturing process comprises the
following steps, the individual raw materials may not
always be added in the order indicated, and the order
can be changed as appropriate. The HMG-CoA reductase
inhibitor used in step (2) is exemplified by pravastatin
sodium, fluvastatin sodium, atorvastatin calcium hydrate,
pitavastatin calcium, simvastatin and the like.
(1) Weigh out water and a buffering agent, place in the
preparation chamber, and the mixture is stirred and
dissolved at room temperature or under appropriate
2o heating.
(2) Add an HMG-CoA reductase inhibitor.
(3) Add a gelling agent and a polymer compound, and the
mixture is stirred and dissolved with heating at 75 to
95 C.
(4) Add a preservative agent, a flavoring agent, a
sweetening agent and the like, and thereafter adjust the
pH levels to 7 to 10, and perform thermal sterilization.
(5) While maintaining an appropriate temperature,
dispense the drug liquid from the preparation chamber to
3o an optionally chosen container.
(6) Cool the drug liquid to solidify using an
appropriate cooling apparatus or method, and package to
obtain a finished product.
Effect of the Invention
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[0018]
As is evident from the results of the evaluations of the
formulations shown in Examples 1 to 8 and Comparative
Examples 1 to 8, gel preparations for oral
administration comprising a gelling agent, a polymer
compound, a buffering agent, a sweetening agent, a
preservative agent, a base water and a coupound
belonging to the HMG-CoA reductase inhibitor having a pH
levels between 7 and 10 were found to exhibit good gel
io form retention, to be unlikely to undergo syneresis, to
have excellent storage stability, and to have suppressed
bad tastes such as bitter tastes and harsh tastes.
[0019]
The present invention is described in more detail by
means of the following examples, which, however, are not
to be construed as limiting the scope of the present
invention.
Examples
[0020]
2o Gel preparations for oral administration were prepared
as described in Example 1, using the formulations shown
in Examples 1 to 8 and Comparative Examples 1 to 8 (e.g.,
10.53 to 31.59 mg of fluvastatin sodium, 1 to 2 mg of
pitavastatin, and 5 to 10 mg of pravastatin sodium were
given each time).
[0021]
All example formulations for gel preparations for oral
administration comprising an HMG-CoA reductase inhibitor
as the pharmacologically active ingredient, are shown in
3o Tables 1 to 4. Each formulation was filled up to a
container with a capacity of 1 to 10 mL, and the
container was closed and cooled to yield a gel
preparation for oral administration. The gel
preparations for oral administration thus obtained had a
pH levels between 7 and 10.
CA 02619367 2008-01-29
[0 022]
[Table 1]
Example formulations by mass)
Example 1 Example 2 Comp. Comp.
Example 1 Example 2
Fluvastatin sodium 0.7 0.7 0.7 0.7
Pectin 0.1 0 0 0
Locust bean 0.3 0.2 0 0.3
gum
anthan gum 0.1 0 0 0
K 0.2 0.1 0 0
carrageenan
L 0.4 0.6 0 0.4
carrageenan
gar powder 0 0.3 0.8 0
icrocrys-
talline 0 0 0 0
cellulose
D-sorbitol 20.0 20.0 20.0 20.0
ase/addit Glycerol 10.0 10.0 10.0 10.0
ives Saccharin 0.1 0.1 0.1 0.1
sodium
Sodium 1.0 0 0 1.0
citrate
Citric acid 0.001 0.5 0.5 0.001
Sodium 0 0.3 0.3 0
hydroxide
Ethyl 0.04 0.04 0.04 0.04
araben
Propyl 0.02 0.02 0.02 0.02
araben
Strawberry 0.05 0.05 0.05 0.05
essence
Purified Remainder Remainder Remainder Remainder
water
Total 100 100 100 100
H 8.3 9.2 8.9 8.4
Gel form Good Good Good Poor
retention
Syneresis
during lmost no lmost no lmost no
storage at syneresis syneresis Intensified syneresis
room observed observed over time observed
temperature
Easy to Easy to Large
Ease of remove, and remove, Liquid amount of
removal small and small spills and liquid
from amount of amount of difficult remaining
and
Evaluation container liquid liquid to remove
difficult
remaining remaining
to remove
Uncomfort- Uncomfort-
No bad No bad able able
tastes tastes
tastes such such as such as tastes
Tastes upon as bitter itter itter such as
tastes and itter
ingestion harsh tastes and tastes and tastes and
tastes harsh harsh harsh
tastes tastes
perceived erceived erceived tastes
slightly erceived
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CA 02619367 2008-01-29
[0023]
[Table 2]
Example formulations (% by mass)
Example 3 Example 4 Comp. Comp.
xample 3 Example 4
Pitavastatin calcium 0.05 0.05 0.05 0.05
Pectin 0 0.1 0 0
Locust bean 0.3 0.25 0 0
gum
anthan gum 0.4 0 0.5 0
K carrageenan 0 0.2 0 0.6
i carrageenan 0.6 0.55 0 0
gar powder 0.1 0 0 0
icrocrys-
talline 0.2 0.3 0.2 0.4
cellulose
D-sorbitol 10.0 10.0 10.0 10.0
Erythritol 15.0 15.0 15.0 15.0
Glycerol 5.0 5.0 5.0 5.0
ase/addit Saccharin 0.1 0.1 0.1 0.1
ives sodium
Disodium
hydrogen 1.0 0.8 0
hosphate
Phosphoric 0.01 0.6 0.005 0.5
acid
Sodium 0 0.5 0 0.4
ydroxide
Ethyl paraben 0 0.02 0.02 0.04
Propyl 0.04 0.02 0.02 0.04
araben
1-menthol 0.04 0.04 0.04 0.04
Purified Remainder Remainder Remainder Remainder
ater
Total 100 100 100 100
H 8.0 9.0 7.8 8.7
Gel form Good Good Poor Good
retention
Syneresis lmost no lmost no lmost no
during storage Intensified
syneresis syneresis syneresis
at room over time
temperature observed observed observed
Easy to Easy to Large
Ease of remove, remove, amount of Liquid
removal from and small and small liquid spills and
container amount of amount of remaining difficult
Evaluation liquid liquid and to remove
remaining remaining difficult
No bad o bad Bad tastes Bad tastes
tastes tastes such as such as
such as such as itter itter
Tastes upon bitter itter tastes and tastes and
ingestion tastes and tastes and harsh harsh
harsh harsh tastes tastes
tastes tastes erceived erceived
erceived erceived slightly slightly
12
CA 02619367 2008-01-29
[0024]
[Table 3]
Example formulations (% by mass)
Example 5 Example 6 Comp. Comp.
Example 5 Example 6
Pravastatin sodium 0.25 0.25 0.25 0.25
Pectin 0.2 0 0 0
Locust bean 0.2 0.2 0.2 0
gum
anthan gum 0.4 0.1 0 0
x carrageenan 0 0.1 0 0
L carrageenan 0.5 0.6 0.5 0.5
gar powder 0 0.1 0 0.5
icrocrys-
talline 0 0 0 0
cellulose
Powdered
reducing 15.0 10.0 10.0 10.0
altose
ase/addit starch syrup
Erythritol 0 10.0 10.0 0
ives Glycerol 15.0 10.0 10.0 15.0
Saccharin 0.2 0.15 0.15 0.2
sodium
Sodium 0.8 0.8 0 0.8
citrate
alic acid 0.01 0.01 0.5 0
Sodium 0 0 0.4 0
ydroxide
Ethyl paraben 0.02 0.02 0.02 0.02
Propyl 0.02 0.02 0.02 0.02
araben
1-menthol 0.08 0.05 0.05 0.08
Purified Remainder Remainder Remainder Remainder
ater
Total 100 100 100 100
H 8.3 8.3 9.2 8.4
Gel form Good Good Poor Good
retention
Syneresis lmost no lmost no lmost no
during storage Intensified
syneresis syneresis syneresis
at room over time
temperature observed observed observed
Easy to Easy to Large
amount of
Ease of remove, remove, liquid Liquid
removal from and small and small remaining spills and
container amount of amount of and difficult
Evaluation liquid liquid to remove
remaining remaining difficult
to remove
o bad No bad Bad tastes Bad tastes
tastes tastes such as such as
such as such as itter itter
Tastes upon itter itter tastes and tastes and
ingestion tastes and tastes and arsh harsh
arsh harsh tastes tastes
tastes tastes
erceived erceived perceived erceived
13
CA 02619367 2008-01-29
[0025]
[Table 4]
Example formulations (% by mass)
Example 7 Example 8 Comp. Comp.
xample 7 Example 8
torvastatin calcium 0.36 0.36 0.36 0.36
hydrate
Pectin 0 0.2 0.4 0
Locust bean 0.2 0.2 0 0
gum
anthan gum 0.2 0.3 0 0
K 0 0.15 0 0.4
carrageenan
L 0.6 0.6 0.4 0
carrageenan
gar powder 0.2 0 0 0.4
icrocrys-
talline 0.5 0.8 0.8 0.5
cellulose
Trehalose 15.0 10.0 15.0 10.0
ylitol 15.0 10.0 15.0 10.0
ase/addit Glycerol 0 10.0 0 10.0
ives Saccharin 0.1 0.1 0.1 0.1
sodium
Sodium 1.2 0 0 0.8
citrate
Citric acid 0.01 0.6 0.5 0
Sodium 0 0.5 0.4 0
hydroxide
Ethyl 0.03 0.04 0.04 0.03
araben
Propyl 0.03 0.02 0.02 0.03
araben
Lemon 0.04 0.04 0.04 0.04
essence
Purified Remainder Remainder Remainder Remainder
ater
Total 100 100 100 100
H 7.8 9.2 8.6 8.3
Gel form Good Good Poor Good
retention
Syneresis
during lmost no lmost no lmost no
storage at syneresis syneresis syneresis Intensified
room observed observed observed over time
temperature
Easy to Easy to Large
Ease of remove, and remove, amount of Liquid
removal small and small liquid spills and
Evaluation from amount of amount of remaining difficult
container liquid liquid and to remove
difficult
remaining remaining
to remove
No bad No bad Bad tastes Bad tastes
tastes such tastes such as such as
as bitter such as itter itter
Tastes upon bitter tastes and tastes and
ingestion tastes and tastes and harsh harsh
harsh harsh tastes tastes
tastes tastes erceived erceived
erceived erceived slightly slightly
14
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Industrial Applicability
[0026]
A gel preparation for oral administration that is easily
swallowable and eliminates the bad tastes such as bitter
s tastes and harsh tastes of the HMG-CoA reductase
inhibitor contained therein can be provided for patients
with hyperlipemia or hypercholesterolemia in need of
oral administration of an HMG-CoA reductase inhibitor by
enclosing or packaging the gel preparation in containers
io that are easily handleable at the time of ingestion,
whereby the drug compliance of patients with these
diseases, including those with difficulty in taking
conventional preparations, are significantly improved.
