U.S. patent application number 15/355357 was filed with the patent office on 2017-03-09 for orally dispersible tablet.
This patent application is currently assigned to Takeda Pharmaceutical Company Limited. The applicant listed for this patent is Takeda Pharmaceutical Company Limited. Invention is credited to Tetsuya Matsuura, Naoki Nagahara, Yutaka Tanoue, Yutaka Yamagata.
Application Number | 20170065553 15/355357 |
Document ID | / |
Family ID | 45567081 |
Filed Date | 2017-03-09 |
United States Patent
Application |
20170065553 |
Kind Code |
A1 |
Tanoue; Yutaka ; et
al. |
March 9, 2017 |
ORALLY DISPERSIBLE TABLET
Abstract
The present invention provides a preparation with improved
disintegration property, a preparation showing improved
bioavailability of a medicament, production methods thereof and the
like. A rapidly disintegrating preparation comprising granules
comprising a medicament coated with a coating layer containing
sugar or sugar alcohol; and a disintegrant. A production method of
a rapidly disintegrating preparation including a step of producing
granules comprising a medicament, a step of forming a coating layer
containing sugar or sugar alcohol on the obtained granules and a
step of mixing the coated granules with a disintegrant and molding
the mixture.
Inventors: |
Tanoue; Yutaka; (Osaka,
JP) ; Matsuura; Tetsuya; (Osaka, JP) ;
Yamagata; Yutaka; (Osaka, JP) ; Nagahara; Naoki;
(Osaka, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Takeda Pharmaceutical Company Limited |
Osaka |
|
JP |
|
|
Assignee: |
Takeda Pharmaceutical Company
Limited
Osaka
JP
|
Family ID: |
45567081 |
Appl. No.: |
15/355357 |
Filed: |
November 18, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13261266 |
Jul 10, 2012 |
|
|
|
PCT/JP2012/051279 |
Jan 16, 2012 |
|
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15355357 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2095 20130101;
C07D 307/81 20130101; A61K 9/2081 20130101; A61P 25/00 20180101;
A61P 25/18 20180101; A61P 25/24 20180101; A61K 31/343 20130101;
A61K 9/2059 20130101; A61K 9/2027 20130101; A61K 9/2018 20130101;
A61K 9/2054 20130101; A61K 9/2031 20130101; A61K 9/2013 20130101;
A61K 9/0056 20130101; A61K 9/2063 20130101; A61K 9/006 20130101;
A61K 9/205 20130101 |
International
Class: |
A61K 31/343 20060101
A61K031/343; A61K 9/20 20060101 A61K009/20; A61K 9/00 20060101
A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 17, 2011 |
JP |
2011-007371 |
Oct 14, 2011 |
JP |
2011-227333 |
Claims
1. A rapidly disintegrating preparation comprising granules
comprising a medicament coated with a coating layer containing
sugar or sugar alcohol; and a disintegrant.
2. The rapidly disintegrating preparation according to claim 1,
wherein the granules comprising a medicament further contains a
binder.
3. The rapidly disintegrating preparation according to claim 1,
wherein the granules comprising a medicament further contains a
masking agent.
4. The rapidly disintegrating preparation according to claim 1,
wherein the granules comprising a medicament further contains a
solubilizer.
5. The preparation according to claim 1, which is for oral-mucosal
absorption.
6. The preparation according to claim 5, wherein the medicament is
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de.
7. The preparation according to claim 5, which is a tablet.
8. A method of producing a rapidly disintegrating preparation,
comprising a step of producing granules comprising a medicament, a
step of forming a coating layer containing sugar or sugar alcohol
on the obtained granules, and a step of mixing the coated granules
with a disintegrant and molding the mixture.
9.-33. (canceled)
Description
TECHNICAL FIELD
[0001] The present invention relates to a preparation with improved
disintegration property, a preparation with improved
bioavailability of medicament, production methods thereof and the
like.
BACKGROUND OF THE INVENTION
[0002] Patent document 1 discloses a tablet containing sugar
alcohol or saccharide having an average particle size of 30 .mu.m
or below, an active ingredient and a disintegrant, and a production
method of a tablet comprising compression molding a mixture
containing sugar alcohol or sugar having an average particle size
of 30 .mu.m or below, an active ingredient and a disintegrant.
[0003] Patent document 2 discloses an orally dispersible solid
pharmaceutical composition of agomelatine, which contains
agomelatine and granules of simultaneously-dried lactose and
starch.
[0004] Patent document 3 discloses an orally dispersible, coated
solid pharmaceutical composition of agomelatine, which contains a
central core or a central layer comprising agomelatine and
excipients allowing an orally dispersible formulation to be
obtained, and an orally dispersible coating.
[0005] However, patent documents 1-3 do not disclose improvement of
preparation characteristics such as disintegration property and the
like by enclosing components such as masking agent, binder and the
like that prevent disintegration in granules.
DOCUMENT LIST
Patent Documents
[0006] patent document 1: WO1997/047287 patent document 2:
JP-A-2005-523253 patent document 3: JP-A-2007-182440
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0007] An object of the present invention is to provide a novel
formulation technique capable of improving disintegration property.
In addition, another object of the present invention is to provide
a preparation useful as an orally rapidly disintegrating
preparation. Moreover, an object of the present invention is to
provide a preparation capable of promoting medicament absorption
from the oral mucosa by rapid disintegration after sublingual
administration, and improving the medicament bioavailability.
Means of Solving the Problems
[0008] The present inventors have conducted intensive studies in an
attempt to solve the aforementioned problems and found that the
disintegration property of a medicament can be improved and the
bioavailability thereof can also be improved by containing a
component that prevents disintegration (masking agent, binder and
the like) as a granulation component in granules, and formulating
the preparation after coating a surface of the granule with sugar
or sugar alcohol, which resulted in the completion of the present
invention.
[0009] Accordingly, the present invention provides the
following.
[1] A rapidly disintegrating preparation comprising granules
comprising a medicament coated with a coating layer containing
sugar or sugar alcohol; and a disintegrant (hereinafter sometimes
to be abbreviated as preparation [1], the same for the following
[2] to [18]). [2] The rapidly disintegrating preparation of the
above-mentioned [1], wherein the granules comprising a medicament
further contains a binder. [3] The rapidly disintegrating
preparation of the above-mentioned [1], wherein the granules
comprising a medicament further contains a masking agent. [4] The
rapidly disintegrating preparation of the above-mentioned [1],
wherein the granules comprising a medicament further contains a
solubilizer. [4-1] The rapidly disintegrating preparation of any of
the above-mentioned [1]-[4], wherein the disintegration time is not
more than 30 sec. [4-2] The rapidly disintegrating preparation of
any of the above-mentioned [1]-[4], wherein the disintegration time
is not more than 30 sec and the absolute hardness is not less than
1.0 N/mm.sup.2.
[0010] The "rapidly disintegrating preparation" of the present
invention is also superior as a preparation for allowing absorption
of a medicament from the oral mucosa. Specifically, it is as
described below.
[5] The preparation of any of the above-mentioned [1]-[4], which is
for oral-mucosal absorption. [6] The preparation of the
above-mentioned [5], wherein the medicament is
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de (general name ramelteon; hereinafter sometimes to be abbreviated
as compound A). [7] The preparation of the above-mentioned [5] or
[6], which is a tablet. [8] A method of producing a rapidly
disintegrating preparation, comprising a step of producing granules
comprising a medicament, a step of forming a coating layer
containing sugar or sugar alcohol on the obtained granules, and a
step of mixing the coated granules with a disintegrant and molding
the mixture.
[0011] In addition to the above-mentioned preparation [6], the
present inventors have conducted intensive studies of a preparation
superior in the absorption of compound A from the oral mucosa, and
showing improved bioavailability thereof, and complete the
following invention.
[9] A preparation for oral-mucosal absorption comprising
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de as a medicament; which shows a higher ratio of the medicament in
an unchanged form and a metabolite of the medicament (i.e.,
medicament in unchanged form/metabolite of the medicament) after
transfer into blood than that by oral administration. [10] A
preparation for oral-mucosal absorption comprising
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de as a medicament; which shows a higher ratio of the medicament in
an unchanged form and a metabolite of the medicament after transfer
into blood than that by oral administration, and a disintegration
time of not more than 30 sec. [11] A preparation for oral-mucosal
absorption comprising
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de as a medicament; which shows a higher ratio of the medicament in
an unchanged form and a metabolite of the medicament after transfer
into blood than that by oral administration, a disintegration time
of not more than 30 sec, and absolute hardness of not less than 1.0
N/mm.sup.2. [12] A preparation for oral-mucosal absorption
comprising
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de and a masking agent; which shows not less than about 10-fold
improved bioavailability of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de, as compared to that by oral administration. [13] A preparation
for oral-mucosal absorption comprising
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de and a masking agent; which shows not less than about 10-fold
improved bioavailability of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de, as compared to that by oral administration, and a
disintegration time of not more than 30 sec. [14] A preparation for
oral-mucosal absorption comprising
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de and a masking agent; which shows not less than about 10-fold
improved bioavailability of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de, as compared to that by oral administration, a disintegration
time of not more than 30 sec, and absolute hardness of not less
than 1.0 N/mm.sup.2. [15] A preparation for oral-mucosal absorption
comprising
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de, sugar or sugar alcohol, and a disintegrant; which shows not
less than about 10-fold improved bioavailability of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de, as compared to that by oral administration, and a
disintegration time of not more than 30 sec. [16] A preparation for
oral-mucosal absorption comprising
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de, sugar or sugar alcohol, and a disintegrant; which shows not
less than about 10-fold improved bioavailability of
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de, as compared to that by oral administration, a disintegration
time of not more than 30 sec, and absolute hardness of not less
than 1.0 N/mm.sup.2. [17] The preparation of any of the
above-mentioned [9]-[16], which is a tablet. [18] The preparation
of the above-mentioned [9] or [12], which is in the form of a film,
troche, solution, suspension, freeze-dried preparation, chewing gum
or spray. [19] A method for the prophylaxis and/or treatment of a
bipolar disorder comprising administering
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de oral-mucosally to a human. [20] The method of the
above-mentioned [19], wherein the oral-mucosal administration is
sublingual administration or buccal administration (more preferably
sublingual administration). [21] The method of the above-mentioned
[19], wherein
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de is administered in 0.05-1.0 mg per day. [22] The method of the
above-mentioned [19], wherein the bipolar disorder is bipolar
disorder I. [23] The method of the above-mentioned [19], wherein
the prophylaxis and/or treatment of a bipolar disorder is a
treatment of a depression symptom associated with the bipolar
disorder or maintenance of a remission phase of the bipolar
disorder. [24] A drug for the prophylaxis and/or treatment of a
bipolar disorder, which comprises, as an active ingredient,
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de to be oral-mucosally administered to a human. [25] The drug of
the above-mentioned [24], wherein the oral-mucosal administration
is sublingual administration or buccal administration (more
preferably sublingual administration). [26] The drug of the
above-mentioned [24], wherein
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]pr-
opionamide is administered in 0.05-1.0 mg per day. [27] The drug of
the above-mentioned [24], wherein the bipolar disorder is bipolar
disorder I. [28] The method of the above-mentioned [24], wherein
the prophylaxis and/or treatment of a bipolar disorder is a
treatment of a depression symptom associated with the bipolar
disorder or maintenance of a remission phase of the bipolar
disorder. [29]
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de for the prophylaxis and/or treatment of a bipolar disorder by
oral-mucosal administration to a human. [30] The
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de of the above-mentioned [29], wherein the oral-mucosal
administration is sublingual administration or buccal
administration (more preferably sublingual administration). [31]
The
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de of the above-mentioned [29], which is administered in 0.05-1.0
mg per day. [32] The
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de of the above-mentioned [29], wherein the bipolar disorder is
bipolar disorder I. [33] The
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de of the above-mentioned [29], wherein the prophylaxis and/or
treatment of the bipolar disorder is a treatment of a depression
symptom associated with the bipolar disorder or maintenance of a
remission phase of the bipolar disorder. [34] The method of the
above-mentioned [19]-[23], wherein
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]pr-
opionamide is administered as the preparation of the
above-mentioned [5]-[7], or [9]-[18]. [35] The drug of the
above-mentioned [24]-[28], wherein
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]pr-
opionamide is administered as the preparation of the
above-mentioned [5]-[7], or [9]-[18]. [36] The
(S)--N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionami-
de of the above-mentioned [29]-[33], which is administered as the
preparation of the above-mentioned [5]-[7], or [9]-[18].
Effect of the Invention
[0012] According to the present invention, a rapidly disintegrating
preparation superior in the disintegration property, a preparation
with improved medicament bioavailability and production methods
thereof and the like can be provided.
[0013] The rapidly disintegrating preparations [1] to [7] of the
present invention contain a medicament in granules, and a
disintegrant as an extragranule component. Even when a medicament
(e.g., compound A etc.) with poor compatibility with the
disintegrant is to be used, therefore, an influence of the
disintegrant on the medicament can be reduced, thus improving the
stability of the medicament.
[0014] The rapidly disintegrating preparation of the present
invention can improve disintegration property by enclosing a
component that prevents disintegration (e.g., masking agent, binder
etc.) in granules. In addition, it can achieve high disintegration
property by ensuring the invasion route of water into the
preparation by coating the component that prevents disintegration
with sugar or sugar alcohol. Moreover, in the rapidly
disintegrating preparation of the present invention, a medicament
is coated with sugar or sugar alcohol. Therefore, the dissolution
property of the medicament from the preparation can be improved
even when the medicament has high surface hydrophobicity, by
altering the surface to be hydrophilic.
[0015] The rapidly disintegrating preparation of the present
invention can achieve both the good disintegration property and the
good preparation hardness.
[0016] Among the rapidly disintegrating preparations [1] to [7] of
the present invention, the rapidly disintegrating preparations [5]
to [7] for oral-mucosal absorption of the present invention are
expected to provide an immediate effect by absorption of the
medicament from the oral mucosa. The rapidly disintegrating
preparation for oral-mucosal absorption of the present invention
can improve bioavailability by increasing the blood concentration
of a medicament (e.g., compound A etc.) susceptible to a first pass
effect by oral administration. In addition, the rapidly
disintegrating preparation for oral-mucosal absorption of the
present invention can suppress inconsistent absorption of such
medicaments, and further, inconsistent effectiveness as
medicaments. Moreover, the rapidly disintegrating preparation for
oral-mucosal absorption of the present invention can afford a low
dose medicament and a compact preparation based on the improved
medicament bioavailability.
[0017] According to the production method of the present invention,
the rapidly disintegrating preparations [1] to [7] of the present
invention having the above-mentioned effects can be produced.
DESCRIPTION OF EMBODIMENTS
[0018] The rapidly disintegrating preparation of the present
invention is explained in detail in the following.
[0019] The rapidly disintegrating preparation of the present
invention contains granules comprising a medicament coated with a
coating layer containing sugar or sugar alcohol, and a
disintegrant.
[0020] While the medicament to be used in the present invention is
not particularly limited, for example, antipyretic analgesic
antiphlogistic drugs, antipsychotic drugs, antianxiety drugs,
antidepressant drugs, sedative-hypnotic drugs, gastrointestinal
drugs, antacid drugs, antitussive expectorant drugs,
antihypertensive agents, drugs for diabetes, drugs for
osteoporosis, skeleton muscle relaxants, anti-cancer agents and the
like can be recited.
[0021] In the rapidly disintegrating preparation of the present
invention, the content of the medicament is generally 0.03-50 wt %,
preferably 0.03-20 wt %, more preferably 0.03-3 wt %, relative to
the total weight of the preparation.
[0022] The rapidly disintegrating preparation of the present
invention contains a disintegrant as an extragranule component, and
therefore, an influence of the disintegrant on the medicament can
be reduced even when a medicament having poor compatibility with
the disintegrant is used, and the medicament stability can be
improved. Thus, the present invention is particularly effective
when a medicament having poor compatibility with the disintegrant
(e.g. compound A, etc) is used as a medicament.
[0023] Compound A is a known therapeutic agent for sleep disorders,
which is disclosed in U.S. Pat. No. 6,034,239 and the like, and can
be produced by a known method such as the method described in this
document and the like.
[0024] In the rapidly disintegrating preparation of the present
invention, an excipient is contained in granules comprising a
medicament coated with a coating layer containing sugar or sugar
alcohol.
[0025] Examples of the excipient include starches such as corn
starch and the like; sugar or sugar alcohols such as lactose,
fructose, glucose, mannitol (e.g., D-mannitol), sorbitol (e.g.,
D-sorbitol), erythritol (e.g., D-erythritol), sucrose and the like:
anhydrous calcium phosphate, microcrystalline cellulose,
micromicrocrystalline cellulose, powdered glycyrrhiza, sodium
hydrogen carbonate, calcium phosphate, calcium sulfate, calcium
carbonate, precipitated calcium carbonate, calcium silicate and the
like, and corn starch, D-mannitol and microcrystalline cellulose
are preferable.
[0026] The content of the excipient is generally 13-94 wt %,
preferably 54-94 wt %, more preferably 81-93 wt %, relative to the
total weight of the preparation.
[0027] The rapidly disintegrating preparation of the present
invention may further contain an additive, where necessary, in the
granules comprising a medicament.
[0028] Examples of the additive optionally contained in the
granules comprising a medicament include binder, masking agent,
solubilizer and the like, which may be used in combination where
necessary.
[0029] Examples of the binder include starches such as potato
starch, wheat starch, rice starch, partly pregelatinized starch,
pregelatinized starch, porous starch and the like,
hydroxypropylcellulose, hydroxypropylmethylcellulose,
polyvinylpyrrolidone, gelatin, starch, gum arabic powder,
tragacanth, carmellose, sodium alginate, pullulan, glycerol and the
like, and partly pregelatinized starch, hydroxypropylcellulose and
pregelatinized starch are preferable.
[0030] The content of the binder is generally 0.5-20 wt %,
preferably 0.5-15 wt %, more preferably 1-10 wt %, relative to the
total weight of the preparation.
[0031] Examples of the masking agent include various flavoring
agents (thaumatin, sucralose, saccharin, aspartame, xylitol, citric
acid, L-sodium glutamate etc.), various receptor antagonists
(BENECOAT, sodium chloride etc.), various cation channel
antagonists (L-arginine etc.), various clathration agents
(.alpha.-cyclodextrin, .beta.-cyclodextrin etc.), various flavors
(strawberry flavor, mint flavor, orange flavor, vanillin etc.) and
the like. Two or more thereof may be used in combination where
necessary.
[0032] The content of the masking agent is generally 0.01-10 wt %,
preferably 0.01-5 wt %, more preferably 0.01-1 wt %, relative to
the total weight of the preparation.
[0033] Examples of the solubilizer include various aqueous solvents
(polyethylene glycol, propylene glycol, glycerol etc.), various
clathration agents (.alpha.-cyclodextrin, .beta.-cyclodextrin
etc.), various surfactants (sodium lauryl sulfate, polysorbate 80,
polyoxyethylene(160)polyoxypropylene(30)glycol etc.) and the like.
Two or more thereof may be used in combination where necessary.
[0034] The content of the solubilizer is generally not more than 20
wt %, preferably not more than 15 wt %, more preferably not more
than 10 wt %, relative to the total weight of the preparation.
[0035] In the rapidly disintegrating preparation of the present
invention, disintegration property can be improved by including a
component that prevents disintegration (e.g., masking agent,
binder, solubilizer etc.) in granules. In addition, as mentioned
below, the preparation can achieve high disintegration property by
ensuring the invasion route of water into the preparation by
coating the component that prevents disintegration with sugar or
sugar alcohol.
[0036] The rapidly disintegrating preparation of the present
invention contains sugar or sugar alcohol in a coating layer formed
on the granules comprising a medicament.
[0037] Examples of the sugar or sugar alcohol include lactose,
fructose, glucose, mannitol (e.g., D-mannitol), sorbitol (e.g.,
D-sorbitol), erythritol (e.g., D-erythritol), sucrose and the like,
and D-mannitol is preferable.
[0038] The preparation can achieve high disintegration property by
ensuring the invasion route of water into the preparation by
coating the granules comprising a medicament with sugar or sugar
alcohol. In addition, the dissolution property of the medicament
from the preparation can be improved.
[0039] The content of the sugar contained in the coating layer is
generally 5-20 wt %, preferably 5-15 wt %, more preferably 5-10 wt
%, relative to the total weight of the preparation.
[0040] The content of the sugar alcohol contained in the coating
layer is generally 5-20 wt %, preferably 5-15 wt %, more preferably
5-10 wt %, relative to the total weight of the preparation.
[0041] The content of the sugar and sugar alcohol contained in the
coating layer is generally 5-20 wt %, preferably 5-15 wt %, more
preferably 5-10 wt %, relative to the total weight of the
preparation.
[0042] The rapidly disintegrating preparation of the present
invention may further contain an additive in the coating layer as
necessary.
[0043] Examples of the additive optionally contained in the coating
layer include excipient, disintegrant and the like, which may be
used in combination as necessary.
[0044] Examples of the excipient include starches such as corn
starch and the like; anhydrous calcium phosphate, microcrystalline
cellulose, micromicrocrystalline cellulose, powdered glycyrrhiza,
sodium hydrogen carbonate, calcium phosphate, calcium sulfate,
calcium carbonate, precipitated calcium carbonate, calcium silicate
and the like, and corn starch and microcrystalline cellulose are
preferable.
[0045] Examples of the disintegrant include amino acid, starch,
corn starch, carmellose, carmellose sodium, carmellose calcium,
croscarmellose sodium, crospovidone, low-substituted
hydroxypropylcellulose, hydroxypropyl starch, sodium carboxymethyl
starch and the like, and crospovidone and carmellose are
preferable.
[0046] In the rapidly disintegrating preparation of the present
invention, the average particle size of the "granules comprising a
medicament coated with a coating layer containing sugar or sugar
alcohol" is generally 50 .mu.m-500 .mu.m, preferably 50 .mu.m-355
.mu.m, more preferably 50 .mu.m-150 .mu.m. In the present
specification, the average particle size is a value measured by a
laser diffraction particle size analyzer, SYMPATEC: HELOS&RODOS
and the like.
[0047] In the rapidly disintegrating preparation of the present
invention, examples of the disintegrant contained as an
extragranule component include amino acid, starch, corn starch,
carmellose, carmellose sodium, carmellose calcium, croscarmellose
sodium, crospovidone, low-substituted hydroxypropylcellulose,
hydroxypropyl starch, sodium carboxymethyl starch and the like, and
crospovidone and carmellose are preferable.
[0048] The content of the disintegrant is generally 0.5-15 wt %,
preferably 1-10 wt %, more preferably 2-5 wt %, relative to the
total weight of the preparation.
[0049] In the rapidly disintegrating preparation of the present
invention, examples of the lubricant optionally contained as an
extragranule component include magnesium stearate, stearic acid,
calcium stearate, talc (purified talc), sucrose esters of fatty
acid, sodium stearyl fumarate and the like, and sodium stearyl
fumarate is preferable.
[0050] The content of the lubricant is generally 0.5-2 wt %,
preferably 0.5-1.5 wt %, more preferably 0.5-1 wt %, relative to
the total weight of the preparation.
[0051] The rapidly disintegrating preparation of the present
invention may further contain an additive as an extragranule
component where necessary.
[0052] Examples of the additive include masking agent, solubilizer
and the like, explained above, which may be used in combination
where necessary.
[0053] The rapidly disintegrating preparation of the present
invention is not only useful as a so-called "orally disintegratable
preparation" aiming at oral administration of a medicament, but
also preferable as a preparation for oral-mucosal absorption
(particularly, sublingual preparation, buccal preparation).
[0054] The rapidly disintegrating preparation for oral-mucosal
absorption of the present invention can be expected to show
immediate effect by absorption from the oral mucosa. The rapidly
disintegrating preparation for oral-mucosal absorption of the
present invention is particularly effective when a medicament
(e.g., compound A etc.) susceptible to a first pass effect by oral
administration is used. The rapidly disintegrating preparation for
oral-mucosal absorption of the present invention can improve
bioavailability by increasing the blood concentration of such
medicament. In addition, the rapidly disintegrating preparation for
oral-mucosal absorption of the present invention can suppress
inconsistent absorption of such medicaments, and further,
inconsistent effectiveness as medicaments. Moreover, the rapidly
disintegrating preparation for oral-mucosal absorption of the
present invention can afford a low dose medicament and a compact
preparation based on the improved medicament bioavailability.
[0055] When compound A is particularly used as a medicament, the
rapidly disintegrating preparation for oral-mucosal absorption of
the present invention shows an effect in that the ratio of the
medicament in an unchanged form and a metabolite of the medicament
after transfer into blood is higher than that by oral
administration. In addition, the rapidly disintegrating preparation
for oral-mucosal absorption of the present invention shows not less
than about 10-fold improved bioavailability of compound A, as
compared to that by oral administration.
[0056] While the dosage form of the rapidly disintegrating
preparation of the present invention is not particularly limited,
it is preferably a tablet.
[0057] When the rapidly disintegrating preparation of the present
invention is a tablet, the weight of the preparation is preferably
about 20-200 mg.
[0058] When the rapidly disintegrating preparation of the present
invention is a tablet, the absolute hardness is generally not less
than 1.0 N/mm.sup.2, preferably not less than 1.5 N/mm.sup.2, more
preferably not less than 2.0 N/mm.sup.2. When the rapidly
disintegrating preparation of the present invention is a tablet,
the absolute hardness is generally not more than 5.0
N/mm.sup.2.
[0059] When the rapidly disintegrating preparation of the present
invention is a tablet, the disintegration time is generally not
more than 30 sec, preferably not more than 15 sec, more preferably
not more than 10 sec. When the rapidly disintegrating preparation
of the present invention is a tablet, the disintegration time is
generally not less than 1 sec.
[0060] In the rapidly disintegrating preparation of the present
invention, the disintegration property can be improved by
including, in granules, a component that prevents disintegration,
as described above. In addition, it can achieve high disintegration
property by ensuring the invasion route of water into the
preparation by coating the component that prevents disintegration
with sugar or sugar alcohol. Therefore, even when the rapidly
disintegrating preparation of the present invention is molded to
have the above-mentioned high absolute hardness, it shows good
disintegration property. Thus, the rapidly disintegrating
preparation of the present invention can achieve both the good
disintegration property and the good preparation hardness.
[0061] The rapidly disintegrating preparation of the present
invention preferably shows a disintegration time of not more than
30 sec, and absolute hardness of not less than 1.0 N/mm.sup.2.
[0062] The rapidly disintegrating preparation of the present
invention can be produced by a method conventionally used in the
pharmaceutical-technical field. For example, the preparation can be
produced by the following production method of the rapidly
disintegrating preparation of the present invention.
[0063] The production method of the rapidly disintegrating
preparation of the present invention includes
step (1): producing granules comprising a medicament, step (2):
forming a coating layer containing sugar or sugar alcohol on the
obtained granules, and step (3): mixing the coated granules with a
disintegrant and molding the mixture.
[0064] In steps (1)-(3), an additive may be further added as
necessary. As the kind and amount of the "medicament", "sugar",
"sugar alcohol", "disintegrant" and "additive" to be used in steps
(1)-(3), those exemplified for the above-mentioned rapidly
disintegrating preparation can be mentioned. As the particle size
of the coated granules obtained in step (2), the range exemplified
as the particle size of the "granules comprising a medicament
coated with a coating layer containing sugar or sugar alcohol" of
the above-mentioned rapidly disintegrating preparation can be
mentioned
[0065] The production of the granule in step (1) and formation of
the coating layer in step (2) can also be carried out
simultaneously.
[0066] For example, the preparation can be specifically produced as
follows.
[0067] Sugar or sugar alcohol (e.g., D-mannitol etc.) is dissolved
in a suitable solvent (e.g., water etc.) to give a coating
solution.
[0068] A medicament (e.g., compound A etc.) and any additive (e.g.,
excipient such as D-mannitol, microcrystalline cellulose and the
like, binder such as partly pregelatinized starch and the like
etc.) are mixed to give a mixture. The obtained mixture is
granulated while spraying the coating solution thereon, and dried
to give a granulated powder (coated granules). The obtained
granulated powder (coated granules) may be sieved as necessary.
[0069] The obtained coated granules, a disintegrant (e.g.,
crospovidone etc.) and any additive (e.g., lubricant such as sodium
stearyl fumarate etc., and the like) are mixed to give a mixed
powder. The obtained mixed powder is compression-molded to give a
tablet.
[0070] Here, the mixing (including granulation, drying, sieving and
the like) is carried out by using a preparation machine, for
example, V-type mixer, tumbler mixer (TM-30, TM-15S; SHOWA KAGAKU
KIKAI CO., LTD.: TM20-0-0; Suehiro Kakoki Co., Ltd.), high speed
mixer granulator (FM-VG-10; POWREX CORPORATION), universal kneader
(HATA IRON WORKS CO., LTD.), fluid bed dryer granulator (LAB-1,
FD-3S, FD-3SN, FD-5S; POWREX CORPORATION), box type vacuum dryer
(Kusuki Kikai Seisakusho), power mill grinding machine (P-3, SHOWA
KAGAKU KIKAI CO., LTD.), centrifugation rolling granulator
(CF-mini, CF-260, CF-360; Freund Corporation), dry type granulator,
spray-drying granulator, rolling granulator (MP-10; POWREX
CORPORATION) and the like.
[0071] Coating is carried out by using, for example, a preparation
machine, for example, centrifugation rolling granulator (CF-mini,
CF-260, CF-360; Freund Corporation), rolling granulator (MP-10;
POWREX CORPORATION), general fluidized bed coater, wurster-type
coater and the like.
[0072] Compression molding is carried out by using, for example,
single punch tableting machine (Kikusui Seisakusho Ltd.), rotary
tableting machine (AQUARIUS 36K, AQUARIUS 2L; Kikusui Seisakusho
Ltd.), AUTOGRAPH (AG-5000B, SHIMADZU Corporation) and the like, and
by punching generally at a pressure of 1-30 kN.
[0073] In addition to the application of the above-mentioned
"rapidly disintegrating preparation of the present invention" to
compound A, the present inventors have intensively studied a
preparation superior in the absorption of compound A from the oral
mucosa and having improved bioavailability of compound A, and
completed the following invention.
[0074] That is, the present invention also relates to a preparation
for oral-mucosal absorption containing compound A as a medicament;
which shows a higher ratio of the medicament in an unchanged form
and a metabolite of the medicament after transfer into blood than
that by oral administration (preparations [9] to [11], [17] and
[18]) (hereinafter sometimes to be abbreviated as preparation (A)
of the present invention).
[0075] When the dosage form of preparation (A) is a tablet, the
disintegration time is preferably not more than 30 sec. When the
dosage form in preparation (A) is a tablet, more preferably, the
disintegration time is not more than 30 sec, and the absolute
hardness is not less than 1.0 N/mm.sup.2.
[0076] The aforementioned preparations [5] to [7] are also
encompassed in the "preparation (A)".
[0077] The present invention also relates to a preparation for
oral-mucosal absorption, which contains compound A, and shows not
less than about 10-fold improved bioavailability of compound A, as
compared to that by oral administration (preparations [12] to [18])
(hereinafter sometimes to be abbreviated as preparation (B) of the
present invention). Here, "about" means 5% error range. The
bioavailability is generally improved within the range of not more
than about 30-fold, more specifically not more than about
20-fold.
[0078] When the dosage form of preparation (B) is a tablet,
preferably, the disintegration time is not more than 30 sec. When
the dosage form in preparation (B) is a tablet, more preferably,
the disintegration time is not more than 30 sec, and the absolute
hardness is not less than 1.0 N/mm.sup.2.
[0079] The aforementioned preparations [5] to [7] are also
encompassed in the "preparation (B)".
[0080] Here, whether or not "bioavailability of compound A is
improved not less than about 10-fold as compared to oral
administration" is evaluated as follows.
[0081] Each preparation is administered intravenously, orally or
oral-mucosally, the plasma concentration after lapse of each time
period is measured, and the area under the plasma concentration
time curve (AUC) is calculated according to the trapezoidal rule.
In addition, bioavailability (BA) is calculated according to the
following formula.
BA (%)=(oral or oral-mucosal administration AUC/intravenous
administration AUC).times.100.
[0082] The ratio of the calculated BA by oral-mucosal
administration relative to the calculated BA by oral administration
(that is, BA by oral-mucosal administration/BA by oral
administration) is calculated.
[0083] In this case, when the "ratio of the BA by oral-mucosal
administration relative to the BA by oral administration" is not
less than 10, the preparation is evaluated to show "not less than
about 10-fold improved bioavailability of compound A as compared to
that by oral administration".
[0084] As for the specific preparations to be subjected to a test
and test methods, the below-mentioned Experimental Example 3 can be
referred to. However, when a substantially similar evaluation is
possible, the method is not limited to that of Experimental Example
3.
[0085] The present invention also relates to a preparation for
oral-mucosal absorption, which contains compound A and shows a
higher ratio of a medicament in an unchanged form and a metabolite
of the medicament after transfer into blood than that by oral
administration (preparations [9] to [11]) (hereinafter sometimes to
be abbreviated as preparation (C) of the present invention).
[0086] The "greater than the ratio" specifically means not less
than about 5-fold, preferably not less than about 10-fold. It is
generally not more than about 30-fold, more specifically not more
than about 20-fold. Here, "about" means 5% error range.
[0087] When the dosage form of preparation (C) is a tablet,
preferably, the disintegration time is not more than 30 sec. When
the dosage form of preparation (C) is a tablet, more preferably,
disintegration time is not more than 30 sec, and the absolute
hardness is not less than 1.0 N/mm.sup.2.
[0088] The aforementioned preparations [5] to [7] are also
encompassed in the "preparation (C)".
[0089] Here, whether or not the "ratio of the medicament in an
unchanged form and a metabolite of the medicament after transfer
into blood is higher than that by oral administration" is evaluated
as follows.
[0090] Each preparation is administered orally or oral-mucosally,
the plasma concentration of both the unchanged form and metabolite
after lapse of each time period is measured, and the area under the
plasma concentration time curve (AUC) of the both is calculated
according to the trapezoidal rule. The ratio of the unchanged form
and metabolite (i.e., AUC of unchanged form/AUC of metabolite) in
each preparation is calculated.
[0091] In this case, when the ratio by oral-mucosal administration
is higher than that by oral administration, it is evaluated "the
ratio of a medicament in an unchanged form and a metabolite of the
medicament after transfer into blood is higher than that by oral
administration".
[0092] As for the specific preparations to be subjected to a test
and test methods, the below-mentioned Experimental Example 4 can be
referred to. However, when a substantially similar evaluation is
possible, the method is not limited to that of Experimental Example
4.
[0093] While the dosage forms of preparation (A), preparation (B)
and preparation (C) are not particularly limited as long as they
can be administered from the oral mucosa. For example, tablet
(e.g., sublingual tablet, buccal tablet), film, troche, solution,
suspension, freeze-dried preparation, chewing gum, spray and the
like can be mentioned. Among these, tablet is preferable.
[0094] As the kind and amount of "compound A", "masking agent",
"sugar", "sugar alcohol" and "disintegrant" to be used for
preparation (A), preparation (B) or preparation (C), those
exemplified for the above-mentioned rapidly disintegrating
preparation can be mentioned.
[0095] In the present specification, the absolute hardness is
hardness per unit area, and is defined according to the following
formula.
absolute hardness (N/mm.sup.2)=hardness (N)/(thickness
(mm).times.diameter (mm))
[0096] In the present invention, the tablet hardness can be
measured by a tablet hardness tester (TH-303MP, Toyama Sangyo CO.,
LTD.).
[0097] In the present specification, the disintegration time is a
value measured by a disintegration tester (ODT-101, Toyama Sangyo
CO., LTD.) for orally rapidly disintegrating tablet.
[0098] Preparations (A)-(C) can be produced, for example, according
to the production method explained for "the rapidly disintegrating
preparation of the present invention". Particularly, when the
dosage form of preparations (A)-(C) is tablet, such production
method is preferable. It is also possible to apply other techniques
for orally disintegrating preparations.
[0099] When the dosage form of preparations (A)-(C) is film, the
preparations can be produced according to a conventional method as
follows. For example, the preparation can be produced by applying
or spraying a coating solution (solution or suspension, solvent is,
for example, purified water) containing a medicament, a film
carrier, other film carriers used as necessary and the like to the
surface of a support medium, and drying same (JP-B-3460538).
[0100] When the dosage form of preparations (A)-(C) is freeze-dried
preparation, the preparation can be produced according to a
conventional method as follows. For example, the preparation can be
produced by mixing a medicament, a polymer, sugars and the like,
and dissolving and lyophilizing them (Manufacturing Chemist,
February 36 (1990)).
[0101] When the dosage form of preparations (A)-(C) is chewing gum,
the preparation can be produced according to a conventional method
as follows. For example, the preparation can be produced by adding
a medicament, additive such as sweetener, flavor, colorant,
softening agent, flavoring substance and the like to a gum base
containing a resin for a gum base as a main component, wax, an
emulsifier and a filler, uniformly kneading them in a kneader, and
processing them into a plate form, a block form and the like
(JP-A-2009-136240).
[0102] When the dosage form of preparations (A)-(C) is troche, the
preparation can be produced according to a general production
method of tablets.
[0103] When the dosage form of preparations (A)-(C) is solution or
suspension, the preparation can be produced according to a general
production method of liquids.
[0104] When the dosage form of preparations (A)-(C) is spray, the
preparation can be produced according to a general production
method of spray.
[0105] The preparation of the present invention can be safely
administered to a mammal (e.g., human, mouse, rat, rabbit, dog,
cat, bovine, horse, swine, monkey), particularly human.
[0106] The dose of the preparation of the present invention varies
depending on the subject of administration, administration route,
disease and the like. For example, when a preparation for
oral-mucosal absorption containing compound A as a medicament is
administered to an adult, the dose of compound A is about
0.0002-about 0.02 mg/kg body weight, preferably about 0.0002-about
0.01 mg/kg body weight, more preferably about 0.0002-about 0.005
mg/kg body weight, most preferably about 0.0002-about 0.004 mg/kg
body weight, which can be administered in one to several portions a
day.
[0107] It is known that melatonin secretion decreases to cause
disorders in the circadian rhythm in patients with bipolar
disorders. Compound A is a superior melatonin receptor agonist, and
considered to be effective for the prophylaxis or treatment of
diseases possibly influenced by melatonin. In fact, compound A is
suggested to be effective for the treatment of bipolar disorders
(particularly maintenance of remission phase) in the clinical
evaluation by oral administration.
[0108] As mentioned above, the present invention provides a
preparation showing superior absorption of compound A from the oral
mucosa and improved bioavailability thereof. Hence, a more
effective method for the prophylaxis and/or treatment of bipolar
disorders, and a more effective drug for the prophylaxis and/or
treatment of bipolar disorders are provided. To be precise, by
oral-mucosal administration of compound
[0109] A to patients affected with bipolar disorders, the bipolar
disorders can be prevented and/or treated. Specifically, such
prophylaxis and/or treatment can be performed by appropriately
administering the preparation of the present invention to
humans.
[0110] Here, the administration route of compound A is preferably
sublingual administration or buccal administration, and sublingual
administration is particularly preferable.
[0111] While the dose of compound A is as mentioned above, for
administration as a sublingual tablet or a buccal tablet, for
example, a tablet containing 0.05-1.5 mg (preferably, 0.05-1.0 mg,
more preferably, 0.1-1.0 mg, and most preferably, 0.1 mg, 0.4 mg
and 0.8 mg) of compound A per tablet is preferably administered to
patients in one to three portions (preferably once) per day.
[0112] As the target disease, it is particularly effective for
bipolar disorder I. Specifically, it is effective for the
"treatment of depression symptoms (particularly, acute depression
symptoms) associated with bipolar disorder" and "maintenance of
remission phase of bipolar disorder".
[0113] For the "prophylaxis and/or treatment of bipolar disorders
by oral-mucosal administration of compound A", other medicaments
for the prophylaxis and/or treatment of bipolar disorders may be
used in combination. Such other medicaments for the prophylaxis
and/or treatment of bipolar disorders to be used in combination
with "compound A" (hereinafter referred to as "combination
medicament") may include mood stabilizer (e.g. lithium, valproic
acid, carbamazepine, lamotrigine, etc) and antipsychotics (e.g.
quetiapine, olanzapine, etc), and a combination of one or more
medicaments selected from them. In addition thereto, one or more
SSRI (selective serotonin reuptake inhibitors) (e.g. fluvoxamine,
paroxetine, escitalopram, fluoxetine, citalopram, etc) may also be
administered in combination with "compound A" and the
aforementioned "combination medicament".
[0114] The administration mode of the "combination medicament" is
not particularly restricted, and it is sufficient that "compound A"
and "combination medicament" be combined in administration.
Examples of such administration mode include the following:
(1) administration of a single preparation obtained by
simultaneously processing "compound A" and "combination
medicament", (2) simultaneous administration of two kinds of
preparations of "compound A" and "combination medicament", which
have been separately produced, by the same administration route,
(3) administration of two kinds of preparations of "compound A" and
"combination medicament", which have been separately produced, by
the same administration route in a staggered manner, (4)
simultaneous administration of two kinds of preparations of
"compound A" and "combination medicament", which have been
separately produced, by different administration routes, (5)
administration of two kinds of preparations of "compound A" and
"combination medicament", which have been separately produced, by
different administration routes in a staggered manner (e.g.,
administration in the order of "compound A" and "combination
medicament", or in the reverse order) and the like.
[0115] The dosage of the "combination medicament" may be determined
according to the dose clinically used, and can be appropriately
selected depending on an administration subject, administration
route, seriousness of the disease, combination, and the like.
[0116] The "combination medicament" can be administered in the same
dosage form as clinically used or in a different dosage form
suitable for this combination therapy.
[0117] When compound A is administered oral-mucosally to a human
subject, the blood kinetic of it is quite similar to that of the
endogenous melatonin, and therefore compound A can regulate
circadian rhythm, which is thought to be disturbed in bipolar
patients, better than existing drugs and even melatonin/other
melatonin agonists. Thus, compound A is expected to show superior
effect on bipolar disease to existing drugs. In addition, this
circadian rhythm regulating effect can also translate into better
normalizing circadian rhythm and/or sleep/awake cycle in bipolar
patients.
EXAMPLES
[0118] The present invention is explained in more detail in the
following by referring to Examples, which are not to be construed
as limitative. The preparation additives (e.g., D-mannitol,
microcrystalline cellulose, and the like) used in the following
Examples and Comparative Examples were the Japanese Pharmacopoeia
15th Edition or Japanese Pharmaceutical Excipients 2003 compatible
products.
Example 1
[0119] (1) D-Mannitol (PEARLITOL 50C, Roquette) (450.0 g) was
dissolved in purified water (2550 g) to give a coating solution.
Compound A (150.5 g), D-mannitol (3068 g), microcrystalline
cellulose (CEOLUS PH-101, Asahi Kasei Corporation) (112.5 g), and
partly pregelatinized starch (PCS, Asahi Kasei Corporation) (450.0
g) were uniformly mixed in a fluid bed dryer granulator (FD-5S,
POWREX CORPORATION), granulated while spraying the coating solution
(3000 g), and dried to give a granulated powder. A part of the
obtained granulated powder was ground in a power mill grinding
machine (P-3, SHOWA KAGAKU KIKAI CO., LTD.) using a 1.5 mm.phi.
punching screen to give a sieved powder. (2) To the obtained sieved
powder (1692 g) were added crospovidone (Kollidon CL-F, BASF) (90
g) and sodium stearyl fumarate (PRUV, JRS PHARMA) (18 g), and the
mixture was mixed in a tumbler mixer (TM-30, SHOWA KAGAKU KIKAI
CO., LTD.) to give a mixed powder. (3) The mixed powder was
tableted by a rotary tableting machine (AQUA 08242L2JI, Kikusui
Seisakusho Ltd.) using a 4 mm.phi. punch (tableting pressure: 4 kN,
weight per tablet: 30 mg) to give a tablet.
Composition of Preparation (30 mg)
TABLE-US-00001 [0120] compound A 1.0 mg D-mannitol (in granules)
20.45 mg D-mannitol (in coating layer) 3.0 mg microcrystalline
cellulose 0.75 mg partly pregelatinized starch 3.0 mg crospovidone
1.5 mg sodium stearyl fumarate 0.3 mg total 30 mg
Comparative Example 1
[0121] Polyethylene glycol 400 (PEG400) (Wako Pure Chemical
Industries, Ltd.) (15 g) was dissolved in purified water (35 g) to
give PEG400 solution. Compound A (12.5 mg) was added to PEG400
solution (50 ml), and the mixture was stirred and insonated, and
filtered using a hydrophilic filter (0.45 .mu.m). The obtained
compound A solution was divided into small portions (1 ml
each).
Composition of Preparation (1 ml)
TABLE-US-00002 [0122] compound A 0.25 mg PEG400 300.0 mg purified
water 700.0 mg total 1000.25 mg
Comparative Example 2
[0123] (1) Hydroxypropylcellulose (HPC-L, NIPPON SODA CO., LTD.)
(40 g) was dissolved in purified water (627 g) to give a binding
solution. Compound A (2.5 g), lactose (DMV INTERNATIONAL) (1053.5
g), and corn starch (Japan Corn Starch Co., Ltd.) (160 g) were
uniformly mixed in a fluid bed dryer granulator (MP-01, POWREX
CORPORATION), granulated while spraying the binding solution (667
g), and dried to give a granulated powder. The obtained granules
were sieved through a 16 mesh (aperture 1.0 mm) sieve to give a
sieved powder. (2) Corn starch (17 g) and magnesium stearate (5 g)
were added to the obtained sieved powder (628 g) and mixed in a bag
to give a mixed powder. (3) The mixed powder was tableted by a
rotary tableting machine (compact tableting machine, Kikusui
Seisakusho Ltd.) by using a 4 mm.phi. punch (tableting pressure: 7
kN, weight per tablet: 130 mg) to give a tablet (core tablet). (4)
Hydroxypropylmethylcellulose (TC-5R) (22.44 g) and Copovidone (4.5
g) were dissolved in purified water (198 g) and dispersed therein
to give dispersion I. Titanium oxide (25 g) and yellow ferric oxide
(0.5 g) were dispersed in purified water (450 g) to give dispersion
II. Dispersion II was added to dispersion I, and the mixture was
stirred to give a coating solution. The coating solution was
sprayed on the core tablet obtained in (3) until the weight of the
core tablet increased by 5 mg per tablet by using a coater (High
Coater HC-LABO, Freund Corporation) to give a film-coated tablet
having the following composition.
Composition of Preparation (135 mg)
TABLE-US-00003 [0124] compound A 0.25 mg lactose 105.35 mg corn
starch 19.4 mg hydroxypropylcellulose 4.0 mg magnesium stearate 1.0
mg hydroxypropylmethylcellulose 3.74 mg Copovidone 0.75 mg titanium
oxide 0.5 mg yellow ferric oxide 0.01 mg total 135 mg
Example 2
[0125] (1) D-Mannitol (PEARITOL 50C, Roquette) (120 g) was
dissolved in purified water (680 g) to give a coating solution.
Compound A (10 g), D-mannitol (848 g), microcrystalline cellulose
(CEOLUS PH-101, Asahi Kasei Corporation) (30 g), and partly
pregelatinized starch (PCS, Asahi Kasei Corporation) (120 g) were
uniformly mixed in a fluid bed dryer granulator (MP-01, POWREX
CORPORATION), granulated while spraying a coating solution (800 g),
and dried to give a granulated powder. The obtained granules were
sieved through a 16 mesh (aperture 1.0 mm) sieve to give a sieved
powder. (2) The obtained sieved powder (28.2 g), crospovidone
(Kollidon CL-F, BASF) (1.5 g) and sodium stearyl fumarate (0.3 g)
were mixed in a glass bottle. The obtained mixture was tableted
(tableting pressure: 3 KN/punch, tablet weight per tablet: 30 mg)
by an AUTOGRAPH (AG-5000B, SHIMADZU Corporation) using a 4 mm.phi.
punch to give a core tablet with the following composition.
[0049]
Composition of Preparation (30 mg)
TABLE-US-00004 [0126] compound A 0.25 mg D-mannitol (in granules)
21.2 mg D-mannitol (in coating layer) 3.0 mg microcrystalline
cellulose 0.75 mg partly pregelatinized starch 3.0 mg crospovidone
1.5 mg sodium stearyl fumarate 0.3 mg total 30 mg
Comparative Example 3
[0127] PEG400 (Wako Pure Chemical Industries, Ltd.) (60 g) was
dissolved in purified water (110 g) to give PEG400 solution.
Compound A (100.0 mg) was added to the PEG400 solution (100 ml),
and the mixture was stirred and insonated, and filtered using a
hydrophilic filter (0.45 .mu.m). The obtained compound A solution
was divided into small portions (1 ml each).
Composition of Preparation (1 ml)
TABLE-US-00005 [0128] compound A 1.0 mg PEG400 352.9 mg purified
water 647.1 mg total 1001 mg
Comparative Example 4
[0129] (1) Hydroxypropylcellulose (HPC-L, NIPPON SODA CO., LTD.)
(660 g) was dissolved in purified water (10230 g) to give a binding
solution. Compound A (165.3 g), lactose (DMV INTERNATIONAL) (17260
g), and corn starch (Japan Corn Starch Co., Ltd.) (2640 g) were
uniformly mixed in a fluid bed dryer granulator (FD-S2, POWREX
CORPORATION), granulated while spraying a binding solution (10890
g), and dried to give a granulated powder. This granulation step
was performed twice. A part of the obtained granulated powder was
ground by a power mill grinding machine (P-3, SHOWA KAGAKU KIKAI
CO., LTD.) using a 1.5 mm.phi. punching screen to give a sieved
powder. (2) Corn starch (1013 g) and magnesium stearate (298 g)
were added to the obtained sieved powder (37430 g), and the mixture
was mixed in a tumbler mixer (TM20-0-0, Suehiro Kakoki Co., Ltd.)
to give a mixed powder. (3) The mixed powder was tableted by a
rotary tableting machine (AQUARIUS 36K, Kikusui Seisakusho Ltd.) by
using a 7 mm.phi. punch (tableting pressure: 7 kN, weight per
tablet: 130 mg) to give a tablet (core tablet). (4)
Hydroxypropylmethylcellulose (TC-5R, Shin-Etsu Chemical Co., Ltd.)
(1548 g) and Copovidone (310.5 g) were dissolved in purified water
(16150 g) and dispersed therein to give dispersion I. Titanium
oxide (207 g) and yellow ferric oxide (4.14 g) were dispersed in
purified water (1822 g) to give dispersion II. Dispersion II was
added to dispersion I, and the mixture was stirred to give a
coating solution. Using a coater (High Coater HCF-100N, Freund
Corporation), the coating solution was sprayed on the core tablet
obtained in (3) until the weight of the core tablet increased by 5
mg per tablet to give a film-coated tablet having the following
composition.
Composition of Preparation (135 mg)
TABLE-US-00006 [0130] compound A 1.0 mg lactose 104.6 mg corn
starch 19.4 mg hydroxypropylcellulose 4.0 mg magnesium stearate 1.0
mg hydroxypropylmethylcellulose 3.74 mg Copovidone 0.75 mg titanium
oxide 0.5 mg yellow ferric oxide 0.01 mg total 135 mg
Example 3
[0131] (1) D-mannitol (PEARLITOL 50C, Roquette) (120 g) was
dissolved in purified water (680 g) to give a coating solution.
Compound A (40 g), D-mannitol (818 g), microcrystalline cellulose
(CEOLUS PH-101, Asahi Kasei Corporation) (30 g), and partly
pregelatinized starch (PCS, Asahi Kasei Corporation) (120 g) were
uniformly mixed in a fluid bed dryer granulator (MP-01, POWREX
CORPORATION), granulated while spraying the coating solution (800
g), and dried to give a granulated powder. The obtained granules
were sieved through a 16 mesh (aperture 1.0 mm) sieve to give a
sieved powder. (2) The obtained sieved powder (28.2 g),
crospovidone (Kollidon CL-F, BASF) (1.5 g) and sodium stearyl
fumarate (0.3 g) were mixed in a glass bottle. The obtained mixture
was tableted (tableting pressure: 3 KN/punch, tablet weight per
tablet: 30 mg) by an AUTOGRAPH (AG-5000B, SHIMADZU Corporation) by
using a 4 mm.phi. punch to give a core tablet with the following
composition.
Composition of Preparation (30 mg)
TABLE-US-00007 [0132] compound A 1.0 mg D-mannitol (in granules)
20.45 mg D-mannitol (in coating layer) 3.0 mg microcrystalline
cellulose 0.75 mg partly pregelatinized starch 3.0 mg crospovidone
1.5 mg sodium stearyl fumarate 0.3 mg total 30 mg
Example 4
[0133] Compound A (5 g) and CMEC (20 g) were dissolved in
acetone:ethanol=3:2 mixed solution (500 ml), and spray-dried by a
spray dryer (Pulvis Mini Spray, YAMATO SCIENTIFIC CO., LTD.). The
obtained solid dispersion powder was dried in vacuo at 40.degree.
C. for 16 hr. To the solid dispersion powder (0.5 g) was added
D-mannitol (PEARLITOL 100SD, Roquette) (11.5 g) and mixed in a
bottle. The obtained mixed powder was divided into small portions
(120 mg each).
Composition of Preparation (120 mg)
TABLE-US-00008 [0134] compound A 1.0 mg CMEC 4.0 mg D-mannitol
115.0 mg total 120 mg
Example 5
[0135] Hydroxypropyl-.beta.-cyclodextrin (hereinafter sometimes
referred to as HP-.beta.-CyD) (KLEPTOSE HPB, Roquette) (75 g) was
dissolved in purified water (422.5 g). Compound A (2.5 g) was
dissolved in the obtained HP-.beta.-CyD aqueous solution to give a
coating solution. D-Mannitol (PEARLITOL 50C, Roquette) (200 g) and
microcrystalline cellulose (CEOLUS PH-101, Asahi Kasei Corporation)
(7.5 g) were uniformly mixed in a fluid bed dryer granulator
(MP-01, POWREX CORPORATION), granulated while spraying the coating
solution (500 g), and dried to give a granulated powder. The
obtained granules were sieved through a 16 mesh (aperture 1.0 mm)
sieve to give a sieved powder. The obtained sieved powder was
divided into small portions (114 mg each).
Composition of Preparation (114 mg)
TABLE-US-00009 [0136] compound A 1.0 mg HP-.beta.-CyD 30.0 mg
D-mannitol 80.0 mg microcrystalline cellulose 3.0 mg total 114
mg
Example 6
[0137] (1) D-Mannitol (PEARLITOL 50C, Roquette) (450 g) was
dissolved in purified water (2550 g) to give a coating solution.
Compound A (37.6 g), D-mannitol (3180 g), microcrystalline
cellulose (CEOLUS PH-101, Asahi Kasei Corporation) (112.5 g), and
partly pregelatinized starch (PCS, Asahi Kasei Corporation) (450 g)
were uniformly mixed in a fluid bed dryer granulator (FD-5S, POWREX
CORPORATION), granulated while spraying the coating solution (3000
g), and dried to give a granulated powder. A part of the obtained
granulated powder was ground by a power mill grinding machine (P-3,
SHOWA KAGAKU KIKAI CO., LTD.) using a 1.5 mm.phi. punching screen
to give a sieved powder. (2) Crospovidone (Kollidon CL-F, BASF) (90
g) and sodium stearyl fumarate (18 g) were added to the obtained
sieved powder (1692 g), and the mixture was mixed in a tumbler
mixer (TM-15S, SHOWA KAGAKU KIKAI CO., LTD.) to give a mixed
powder. (3) The mixed powder was tableted by a rotary tableting
machine (AQUARIUS 2L, Kikusui Seisakusho Ltd.) by using a 4 mm.phi.
punch (tableting pressure: 4 kN, weight per tablet: 30 mg) to give
a core tablet with the following composition.
Composition of Preparation (30 mg)
TABLE-US-00010 [0138] compound A 0.25 mg D-mannitol (in granules)
21.2 mg D-mannitol (in coating layer) 3.0 mg microcrystalline
cellulose 0.75 mg partly pregelatinized starch 3.0 mg crospovidone
1.5 mg sodium stearyl fumarate 0.3 mg total 30 mg
Example 7
[0139] (1) D-mannitol (PEARLITOL 50C, Roquette) (450 g) was
dissolved in purified water (2550 g) to give a coating solution.
Compound A (150.5 g), D-mannitol (3068 g), microcrystalline
cellulose (CEOLUS PH-101, Asahi Kasei Corporation) (112.5 g), and
partly pregelatinized starch (PCS, Asahi Kasei Corporation) (450 g)
were uniformly mixed in a fluid bed dryer granulator (FD-5S, POWREX
CORPORATION), granulated while spraying the coating solution (3000
g), and dried to give a granulated powder. A part of the obtained
granulated powder was ground by a power mill grinding machine (P-3,
SHOWA KAGAKU KIKAI CO., LTD.) using a 1.5 mm.phi. punching screen
to give a sieved powder. (2) Crospovidone (Kollidon CL-F, BASF) (90
g) and sodium stearyl fumarate (18 g) were added to the obtained
sieved powder (1692 g), and the mixture was mixed in a tumbler
mixer (TM-15S, SHOWA KAGAKU KIKAI CO., LTD.) to give a mixed
powder. (3) The mixed powder was tableted by a rotary tableting
machine (AQUARIUS 2L, Kikusui Seisakusho Ltd.) by using a 4 mm.phi.
punch (tableting pressure: 4 kN, weight per tablet: 30 mg) to give
a core tablet with the following composition.
Composition of Preparation (30 mg)
TABLE-US-00011 [0140] compound A 1.0 mg D-mannitol (in granules)
20.45 mg D-mannitol (in coating layer) 3.0 mg microcrystalline
cellulose 0.75 mg partly pregelatinized starch 3.0 mg crospovidone
1.5 mg sodium stearyl fumarate 0.3 mg total 30 mg
(1) Hydroxypropylcellulose (HPC-L, NIPPON SODA CO., LTD.) (660 g)
was dissolved in purified water (10230 g) to give a binding
solution. Compound A (1320 g), lactose (DMV INTERNATIONAL) (16104
g), and corn starch (Japan Corn Starch Co., Ltd.) (2640 g) were
uniformly mixed in a fluid bed dryer granulator (FD-S2, POWREX
CORPORATION), granulated while spraying the binding solution (10890
g), and dried to give a granulated powder. This granulation step
was performed twice. A part of the obtained granulated powder was
ground by a power mill grinding machine (P-3, SHOWA KAGAKU KIKAI
CO., LTD.) using a 1.5 mm.phi. punching screen to give a sieved
powder. (2) Corn starch (1013 g) and magnesium stearate (298 g)
were added to the obtained sieved powder (37430 g), and the mixture
was mixed in a tumbler mixer (TM20-0-0, Suehiro Kakoki Co., Ltd.)
to give a mixed powder. (3) The mixed powder was tableted by a
rotary tableting machine (AQUARIUS 36K, Kikusui Seisakusho Ltd.) by
using a 7 mm.phi. punch (tableting pressure: 7 kN, weight per
tablet: 130 mg) to give a tablet (core tablet). (4)
Hydroxypropylmethylcellulose (TC-5R, Shin-Etsu Chemical Co., Ltd.)
(1548 g) and Copovidone (310.5 g) were dissolved and dispersed in
purified water (16150 g) to give dispersion I. Titanium oxide (207
g) and yellow ferric oxide (4.14 g) were dispersed in purified
water (1822 g) to give dispersion II. Dispersion II was added to
dispersion I, and the mixture was stirred to give a coating
solution. Using a coater (High Coater HCF-100N, Freund
Corporation), the coating solution was sprayed on the core tablet
obtained in (3) until the weight of the core tablet increased by 5
mg per tablet to give a film-coated tablet having the following
composition.
Composition of Preparation (135 mg)
TABLE-US-00012 [0141] compound A 8.0 mg lactose 97.6 mg corn starch
19.4 mg hydroxypropylcellulose 4.0 mg magnesium stearate 1.0 mg
hydroxypropylmethylcellulose 3.74 mg Copovidone 0.75 mg titanium
oxide 0.5 mg yellow ferric oxide 0.01 mg total 135 mg
Example 8
[0142] (1) D-Mannitol (PEARLITOL 50C, Roquette) (510 g) was
dissolved in purified water (2890 g) to give a coating solution.
Compound A (17.05 g), D-mannitol (3114 g), microcrystalline
cellulose (CEOLUS PH-101, Asahi Kasei Corporation) (127.5 g), and
partly pregelatinized starch (PCS, Asahi Kasei Corporation) (510 g)
were uniformly mixed in a fluid bed dryer granulator (FD-5S, POWREX
CORPORATION), granulated while spraying the coating solution (3400
g), and dried to give a granulated powder. A part of the obtained
granulated powder was sieved using a round sieve (mesh size 1.0
mm.phi.) to give sieved powder A. (2) The same step as (1) was
performed to give sieved powder B. (3) To the obtained sieved
powder A (3146.5 g) and sieved powder B (3146.5 g) were added
crospovidone (Kollidon CL-F, BASF) (375.0 g), aspartame (750 g),
vanillin (7.5 g) and sodium stearyl fumarate (75 g), and the
mixture was mixed in a tumbler mixer (TM-60S, SHOWA KAGAKU KIKAI
CO., LTD.) to give a mixed powder. (4) The mixed powder was
tableted by a rotary tableting machine (AQUARIUS 2L, Kikusui
Seisakusho Ltd.) using a 4 mm.phi. punch (tableting pressure: 4 kN,
weight per tablet: 30 mg) to give a core tablet with the following
composition.
Composition of Preparation (30 mg)
TABLE-US-00013 [0143] compound A 0.1 mg D-mannitol (in granules)
18.32 mg D-mannitol (in coating layer) 3.0 mg microcrystalline
cellulose 0.75 mg partly pregelatinized starch 3.0 mg crospovidone
1.5 mg sodium stearyl fumarate 0.3 mg aspartame 3.0 mg vanillin
0.03 mg total 30 mg
Example 9
[0144] (1) D-Mannitol (PEARLITOL 50C, Roquette) (510 g) was
dissolved in purified water (2890 g) to give a coating solution.
Compound A (68.20 g), D-mannitol (3063 g), microcrystalline
cellulose (CEOLUS PH-101, Asahi Kasei Corporation) (127.5 g), and
partly pregelatinized starch (PCS, Asahi Kasei Corporation) (510 g)
were uniformly mixed in a fluid bed dryer granulator (FD-5S, POWREX
CORPORATION), granulated while spraying the coating solution (3400
g), and dried to give a granulated powder. A part of the obtained
granulated powder was sieved by using a round sieve (mesh size 1.0
mm.phi.) to give sieved powder A. (2) The same step as (1) was
performed to give sieved powder B. (3) To the obtained sieved
powder A (3146.5 g) and sieved powder B (3146.5 g) were added
crospovidone (Kollidon CL-F, BASF) (375.0 g), aspartame (750 g),
vanillin (7.5 g) and sodium stearyl fumarate (75 g), and the
mixture was mixed in a tumbler mixer (TM-60S, SHOWA KAGAKU KIKAI
CO., LTD.) to give a mixed powder. (4) The mixed powder was
tableted by a rotary tableting machine (AQUARIUS 2L, Kikusui
Seisakusho Ltd.) using a 4 mm.phi. punch (tableting pressure: 4 kN,
weight per tablet: 30 mg) to give a core tablet with the following
composition.
Composition of Preparation (30 mg)
TABLE-US-00014 [0145] compound A 0.4 mg D-mannitol (in granules)
18.02 mg D-mannitol (in coating layer) 3.0 mg microcrystalline
cellulose 0.75 mg partly pregelatinized starch 3.0 mg crospovidone
1.5 mg sodium stearyl fumarate 0.3 mg aspartame 3.0 mg vanillin
0.03 mg total 30 mg
Example 10
[0146] (1) D-Mannitol (PEARLITOL 50C, Roquette) (510 g) was
dissolved in purified water (2890 g) to give a coating solution.
Compound A (136.4 g), D-mannitol (2995 g), microcrystalline
cellulose (CEOLUS PH-101, Asahi Kasei Corporation) (127.5 g), and
partly pregelatinized starch (PCS, Asahi Kasei Corporation) (510 g)
were uniformly mixed in a fluid bed dryer granulator (FD-5S, POWREX
CORPORATION), granulated while spraying the coating solution (3400
g), and dried to give a granulated powder. A part of the obtained
granulated powder was sieved by using a round sieve (mesh size 1.0
mm.phi.) to give sieved powder A. (2) The same step as (1) was
performed to give sieved powder B. (3) To the obtained sieved
powder A (3146.5 g) and sieved powder B (3146.5 g) were added
crospovidone (Kollidon CL-F, BASF) (375.0 g), aspartame (750 g),
vanillin (7.5 g) and sodium stearyl fumarate (75 g), and the
mixture was mixed in a tumbler mixer (TM-60S, SHOWA KAGAKU KIKAI
CO., LTD.) to give a mixed powder. (4) The mixed powder was
tableted by a rotary tableting machine (AQUARIUS 2L, Kikusui
Seisakusho Ltd.) using a 4 mm.phi. punch (tableting pressure: 4 kN,
weight per tablet: 30 mg) to give a core tablet with the following
composition.
Composition of Preparation (30 mg)
TABLE-US-00015 [0147] compound A 0.8 mg D-mannitol (in granules)
17.62 mg D-mannitol (in coating layer) 3.0 mg microcrystalline
cellulose 0.75 mg partly pregelatinized starch 3.0 mg crospovidone
1.5 mg sodium stearyl fumarate 0.3 mg aspartame 3.0 mg vanillin
0.03 mg total 30 mg
Experimental Example 1
[0148] The tablet obtained in Example 1 was measured for the tablet
hardness and disintegration time. The tablet hardness was measured
by a tablet hardness tester (TH-303MP, Toyama Sangyo CO., LTD.)
(n=10). The disintegration time was measured by a disintegration
tester (ODT-101, Toyama Sangyo CO., LTD.) (n=6). The results are
shown in Table 1.
disintegration tester conditions rotation number: 50 rpm plummet:
15 mm.phi., (10 g)
TABLE-US-00016 TABLE 1 hardness 21 N absolute hardness 2.73
N/mm.sup.2 disintegration 5.24 sec
Experimental Example 2
[0149] The mixed powder obtained in Example 1 was measured for the
dissolution property. The mixed powder (15 g) (corresponding to 500
mg of compound A) was placed in the Japanese Pharmacopoeia 2nd
fluid (500 ml), and the dissolution property was evaluated by the
Paddle Method, rotation number 25 rpm, 37.degree. C. After adding
the sample, the eluate was sampled with time (0.25 min, 0.5 min,
0.75 min, 1 min, 5 min, 15 min, 30 min), filtered by using a
hydrophilic filter (0.45 .mu.m), dissolved by 10-fold diluting with
the extract (water/acetonitrile mixed solution (1:1)), and
quantified by high performance liquid column chromatography (HPLC)
under the following conditions to calculate the solubility. The
results are shown in Table 2.
HPLC Conditions
[0150] detector: ultraviolet ray absorption spectrophotometer
measurement wavelength: 240 nm column: YMC-Pack ODS-AM AM-307, 5
.mu.m, inner diameter: 4.6 mm length: 75 mm column temperature:
25.degree. C. mobile phase: 0.01 mol/L phosphate
buffer/acetonitrile mixed solution (5:3) flow: 1.2 ml/min
TABLE-US-00017 TABLE 2 time (min) compound A concentration (mg/ml)
0 0 0.25 0.103 0.5 0.218 0.75 0.225 1 0.237 5 0.273 15 0.279 30
0.280
Experimental Example 3
[0151] The injections obtained in Comparative Examples 1, 3, oral
tablets obtained in Comparative Examples 2, 4 and preparations for
oral-mucosal absorption obtained in Examples 2-5 were measured for
blood kinetics after intravenous injection, oral, sublingual and
buccal administrations in Macaca fascicularis under fasting
conditions. The plasma concentration before administration, and 5
min, 10 min, 20 min, 30 min, 60 min, 120 min, 240 min and 360 min
after administration was measured, and the area under the plasma
concentration time curve (AUC) was calculated according to the
trapezoidal rule. In addition, bioavailability (BA) was determined
by calculating the ratio of AUC by oral, sublingual or buccal
administration to AUC by intravenous injection. The results are
shown in Table 3.
TABLE-US-00018 TABLE 3 administration dose (mg) route preparation
T.sub.max (min) C.sub.max (ng/ml) AUC (ng min/ml) BA (%) 0.25
intravenous Comparative 9.0 .+-. 6.5 63.4 .+-. 14.1 2933.8 .+-.
578.5 -- injection Example 1 oral Comparative 132.0 .+-. 130.1 0.4
.+-. 0.1 54.4 .+-. 22.6 1.9 Example 2 sublingual Example 2 34.0
.+-. 15.2 12.5 .+-. 5.9 1218.0 .+-. 655.8 41.5 buccal Example 6
36.0 .+-. 18.0 22.7 .+-. 12.3 1656.0 .+-. 726.0 56.4 1 intravenous
Comparative 3.2 .+-. 1.6 509.7 .+-. 248.9 16889.5 .+-. 2057.2 --
injection Example 3 oral Comparative 8.0 .+-. 13.0 0.8 .+-. 1.2
21.3 .+-. 35.8 0.1 Example 4 sublingual Example 3 28.0 .+-. 4.5
38.5 .+-. 12.8 3062.4 .+-. 1129.9 18.1 Example 4 42.0 .+-. 16.0
31.4 .+-. 8.6 3206.9 .+-. 809.9 19.0 Example 5 48.0 .+-. 16.0 46.6
.+-. 13.8 4568.4 .+-. 1286.3 27.0 buccal Example 7 36.0 .+-. 12.0
87.1 .+-. 21.2 5862.0 .+-. 1038.0 34.7
Experimental Example 4
[0152] Oral preparation and preparation for oral-mucosal absorption
were measured for blood kinetics of unchanged form and activity
metabolite M-II after oral or sublingual administration to human.
The plasma concentration before administration, and 5 min, 10 min,
15 min, 20 min, 30 min, 45 min, 60 min, 90 min, 120 min, 180 min,
240 min, 360 min, 480 min, 600 min, 720 min and 1440 min after
administration was measured, and the area under the plasma
concentration time curve (AUC) was calculated according to the
trapezoidal rule. The results are shown in Table 4.
TABLE-US-00019 TABLE 4 measurement dose administration T.sub.max
C.sub.max AUC(0-tlqc) AUC(0-inf ) substance (mg) route preparation
(min) (ng/ml) (ng min/ml) (ng min/ml) unchanged 8 oral Comparative
45.0 (19.8-120.0) 4.76 .+-. 5.19 364.8 .+-. 383.0 334.2 .+-. 347.6
form Example 8 0.5 sublingual Example 6 15.0 (9.0-30.0) 4.74 .+-.
1.52 215.4 .+-. 64.6 223.8 .+-. 67.1 active 8 oral Comparative 60.0
(30.0-180.0) 68.1 .+-. 23.2 12495.0 .+-. 4998.0 12747.0 .+-. 5098.8
metabolite Example 8 M-II 0.5 sublingual Example 6 45.0 (15.0-60.0)
4.18 .+-. 1.26 596.4 .+-. 280.3 730.8 .+-. 285.0
Example 10
[0153] A methylcellulose powder (0.5 g) was dissolved in water
(99.5 g) under ice-cooling, and compound A (100 mg) was added to
the obtained solution (10 ml), stirred and uniformly dispersed
therein. The obtained suspension was filled in a spray device
(spray amount: 100 .mu.L/time) to give an oral spray
preparation.
Example 11
[0154] Hydroxypropyl-.beta.-cyclodextrin (HP-.beta.-CyD) (40 g) was
dissolved in water (60 g), and compound A (100 mg) was added to the
obtained solution (10 ml), stirred and dissolved therein. The
obtained solution was filled in a spray device (spray amount: 100
.mu.L/time) to give an oral spray preparation.
Example 12
[0155] Compound A (100 mg), polyvinylpyrrolidone (1 g) and
hydroxypropylcellulose (18 g) were added to ethanol (100 ml) and
dissolved by stirring. The obtained solution (1 ml) was spread flat
on a plastic sheet and dried to give an orally rapidly dissolving
film preparation.
Example 13
[0156] Compound A (100 mg), D-mannitol (5 g) and
hydroxypropylcellulose (100 mg) were added to a mixed solution (100
ml) of water and ethanol (4:1) and dissolved by stirring. The
obtained solution (1 ml) was dispensed to a pocket of a blister
pack with vinyl chloride resin as an inner film, frozen at
-30.degree. C., and dried by a vacuum dryer to give an orally
rapidly dissolving freeze-dried preparation.
INDUSTRIAL APPLICABILITY
[0157] The present invention can provide a novel preparation
showing improved bioavailability of a medicament and a production
method thereof and the like.
[0158] When compound A is administered nasally (through nasal
mucosa) to a human subject, it is expected to be effective on
prophylaxis and/or treatment of bipolar disease as administered
oral-mucosally as disclosed above. Compound A can be administered,
for example, in the form of the formulation as disclosed in WO
01/15735.
[0159] When compound A is administered to a human subject, it can
be also administered in the dosage forms suitable for inhalation
(e.g. nebulizer, etc) in order to prevent and/or treat bipolar
disease. The dosage forms can be produced according to a general
production method in this art. The dose of compound A can be
decided referring to, for example, the preparations (A) to (C) in
the present application.
[0160] This application is based on patent application Nos.
2011-007371 and 2011-227333 filed in Japan, the contents of which
are incorporated in full herein.
* * * * *