U.S. patent application number 10/407226 was filed with the patent office on 2003-10-30 for pharmaceutical composition reduced in bitter taste and the like.
This patent application is currently assigned to Eisai Co., Ltd.. Invention is credited to Harada, Tsutomu, Ukai, Koji.
Application Number | 20030203007 10/407226 |
Document ID | / |
Family ID | 17097365 |
Filed Date | 2003-10-30 |
United States Patent
Application |
20030203007 |
Kind Code |
A1 |
Ukai, Koji ; et al. |
October 30, 2003 |
Pharmaceutical composition reduced in bitter taste and the like
Abstract
The present invention provides a composition alleviated in a
bitter taste or the like of a medicament. The present invention
relates to a composition comprising a basic medicament having an
unpleasant taste and polyvinylpyrrolidone and/or copolyvidone; or a
method for alleviating an unpleasant taste of a basic medicament
having the unpleasant taste by adding polyvinylpyrrolidone and/or
copolyvidone. The present invention further provides a composition
comprising (1) a basic medicament, (2) polyvinylpyrrolidone and/or
copolyvidone, and (3) propylene glycol and/or D-sorbitol; a
composition comprising (1) a basic medicament, (2)
polyvinylpyrrolidone and/or copolyvidone, and (4) an antioxidant;
and a composition comprising (1) a basic medicament, (2)
polyvinylpyrrolidone and/or copolyvidone, and (5) a colorant or
flavor containing a sulfuric acid or sulfurous acid group.
Inventors: |
Ukai, Koji; (Gifu, JP)
; Harada, Tsutomu; (Aichi, JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
Eisai Co., Ltd.
|
Family ID: |
17097365 |
Appl. No.: |
10/407226 |
Filed: |
April 7, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10407226 |
Apr 7, 2003 |
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09530391 |
Apr 28, 2000 |
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6576677 |
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09530391 |
Apr 28, 2000 |
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PCT/JP99/04616 |
Aug 26, 1999 |
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Current U.S.
Class: |
424/439 ;
424/486; 514/150 |
Current CPC
Class: |
Y10S 514/963 20130101;
A61K 9/0095 20130101; A61K 47/32 20130101 |
Class at
Publication: |
424/439 ;
424/486; 514/150 |
International
Class: |
A61K 031/655; A61K
009/14; A61K 047/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 28, 1998 |
JP |
10-242997 |
Claims
1. A pharmaceutical composition comprising a basic medicament
characterized by having a proton existing as a positive charge
under acidic conditions and at least one component selected from
the group consisting of polyvinylpyrrolidone and copolyvidone, said
composition comprising 5 to 200 parts by weight of
polyvinylpyrrolidone and/or copolyvidone per 1 part by weight of
the medicament.
2. The composition as claimed in claim 1, which is in the form of
syrups, jellies, dry syrups, liquids, effervescent preparations,
lemonades, elixirs, liniments or fine granules.
3. A method for alleviating an unpleasant taste of a basic
medicament characterized by having a proton existing as a positive
charge under acidic conditions comprising adding thereto at least
one component selected from the group consisting of
polyvinylpyrrolidone and copolyvidone in an amount of from 5 to 200
parts by weight of polyvinylpyrrolidone and/or copolyvidone per 1
part by weight of the medicament.
4. A composition comprising a basic medicament characterized by
having a proton existing as a positive charge under acidic
conditions, at least one component selected from the group
consisting of polyvinylpyrrolidone and copolyvidone and at least
one component selected from the group consisting of propylene
glycol and D-sorbitol, said composition comprising 5 to 200 parts
by weight of polyvinylpyrrolidone and/or copolyvidone per 1 part by
weight of the medicament.
5. A method for suppressing the formation of analogues of a basic
medicament characterized by having a proton existing as a positive
charge under acidic conditions caused by the addition of
polyvinylpyrrolidone or copolyvidone thereto, comprising further
adding at least one component selected from propylene glycol and
D-sorbitol, said polyvinylpyrrolidone and/or copolyvidone being
added in an amount of from 5 to 200 parts by weight per 1 part by
weight of the medicament.
6. The method of claim 5, wherein said medicament is in the form of
syrups, jellies, dry syrups, liquids, effervescent preparations,
lemonades, elixirs, liniments or fine granules.
7. A composition comprising a basic medicament characterized by
having a proton existing as a positive charge under acidic
conditions, at least one component selected from the group
consisting of polyvinylpyrrolidone and copolyvidone, and an
antioxidant, said composition comprising 5 to 200 parts by weight
of polyvinylpyrrolidone and/or copolyvidone per 1 part by weight of
the medicament.
8. The composition as claimed in claim 7, wherein the antioxidant
is selected from the group consisting of sodium bisulfite, sodium
sulfite, sodium pyrosulfite, cysteine, citric acid, sodium edetate,
ascorbic acid and erythorbic acid.
9. A method for suppressing the formation of analogues of a basic
medicament characterized by having a proton existing as a positive
charge under acidic conditions caused by the addition of
polyvinylpyrrolidone or copolyvidone thereto, comprising further
adding an antioxidant, said polyvinylpyrrolidone and/or
copolyvidone being added in an amount of from 5 to 200 parts by
weight per 1 part by weight of the medicament.
10. The method of claim 9, wherein said medicament is in the form
of syrups, jellies, dry syrups, liquids, effervescent preparations,
lemonades, elixirs, liniments or fine granules.
11. The method of claim 9, wherein said antioxidant is selected
from the group consisting of sodium bisulfite, sodium sulfite,
sodium pyrosulfite, cysteine, citric acid, sodium edetate, ascorbic
acid and erythorbic acid.
12. A composition comprising a basic medicament characterized by
having a proton existing as a positive charge under acidic
conditions, at least one component selected from the group
consisting of polyvinylpyrrolidone and copolyvidone, and a colorant
or flavor containing a sulfuric acid or sulfurous acid group, said
composition comprising 5 to 200 parts by weight of
polyvinylpyrrolidone and/or copolyvidone per 1 part by weight of
the medicament.
13. The composition as claimed in claim 12, wherein the colorant or
flavor containing a sulfuric acid or sulfurous acid group is
selected from the group consisting of trisodium
2-hydroxyazonaphthalene-4',6,8-trisulfonate- ,
2',4',5',7'-tetraiodofluorescein disodium salt, trisodium
2-hydroxyazonahthalene-3,4',6-trisulfonate, disodium
3-[N-ethyl-N-[4-[[-N-ethyl-N-(3-sulfonatobenzyl)amino]phenyl](2-sulfonato-
phenyl)methylene]-2,5-cyclohexadienyliden]ammoniomethyl]benzenesulfonate,
disodium
2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)-2,3-dihydro-3-o-
xo-1H-indole-5-sulfonate, disodium
N-ethyl-N-[4-[[ethyl[(3-sulfophenyl)met-
hyl]amino]phenyl](4-hydroxyl-2-sulfophenyl)methylene)-2,5-cyclohexadien-1--
ylidene]-3-sulfobenzenemethaneaminiumhydroxide, trisodium
3-carbonato-5-hydroxy-1-(4-sulfonatophenyl)-1H-pyrazol-4-azo-4'-(benzenes-
ulfonate) and disodium
2-hydroxy-6-sulfonatonaphthalen-1-azo-(4'-benzenesu- lfonate).
14. A method for suppressing the formation of an insoluble
precipitate of a basic medicament characterized by having a proton
existing as a positive charge under acidic conditions caused by the
addition of a colorant or flavor containing a sulfuric acid or
sulfurous acid group thereto, comprising adding at least one
component selected from the group consisting of
polyvinylpyrrolidone and copolyvidone in an amount of from 5 to 200
parts by weight per 1 part by weight of the medicament.
15. The method of claim 14, wherein said medicament is in the form
of syrups, jellies, dry syrups, liquids, effervescent preparations,
lemonades, elixirs, liniments or fine granules.
16. The method of claim 14, wherein said colorant is selected from
the group consisting of trisodium
2-hydroxyazonaphthalene-4',6,8-trisulfonate- ,
2',4',5',7'-tetraiodofluorescein disodium salt, trisodium
2-hydroxyazonahthalene-3,4',6-trisulfonate, disodium
3-[N-ethyl-N-[4-[[-N-ethyl-N-(3-sulfonatobenzyl)amino]phenyl](2-sulfonato-
phenyl)methylene]-2,5-cyclohexadienyliden]ammoniomethyl]benzenesulfonate,
disodium
2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)-2,3-dihydro-3-o-
xo-1H-indole-5-sulfonate, disodium
N-ethyl-N-[4-[[ethyl[(3-sulfophenyl)met-
hyl]amino]phenyl](4-hydroxyl-2-sulfophenyl)methylene)-2,5-cyclohexadien-1--
ylidene]-3-sulfobenzenemethaneaminiumhydroxide, trisodium
3-carbonato-5-hydroxy-1-(4-sulfonatophenyl)-1H-pyrazol-4-azo-4'-(benzenes-
ulfonate) and disodium
2-hydroxy-6-sulfonatonaphthalen-1-azo-(4'-benzenesu- lfonate).
17. The method as claimed in claim 14, further comprising adding at
least one component selected from propylene glycol and
D-sorbitol.
18. The method as claimed in claim 14, further comprising adding a
colorant or flavor containing a sulfuric acid or sulfurous acid
group.
19. The method as claimed in claim 14, further comprising adding an
antioxidant.
20. A method for alleviating an unpleasant taste of a basic
medicament characterized by having a proton existing as a positive
charge under acidic conditions comprising adding thereto at least
one component selected from the group consisting of
polyvinylpyrrolidone and copolyvidone, said composition being in
the form of syrups, jellies, dry syrups, liquids, effervescent
preparations, lemonades, elixirs, liniments or fine granules, said
polyvinylpyrrolidone and/or copolyvidone being added in an amount
of from 5 to 200 parts by weight per 1 part by weight of the
medicament.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a composition or a method
for reducing an unpleasant taste of a basic medicament having the
unpleasant taste. In addition, the present invention relates to a
composition alleviated in the defect of a composition containing a
basic medicament, or a method for alleviating the defect.
PRIOR ART
[0002] Since oral administration of a medicament having an
unpleasant taste such as bitter taste or numbness puts a burden on
a patient and lowers compliance, various devices have been made to
improve the taste of the medicament. When the medicament is solid
such as tablets or granules, a bitter taste or the like can be
masked in a relatively easy manner, for example, by coating or
incorporation of the medicament in the matrix. For liquids, it is
the common practice to conceal a taste of the medicament under a
sweet taste substance such as sucrose, which is however only a
camouflage. A technique for essentially masking a bitter taste or
the like is hardly known. Polyvinylpyrrolidone is known as a binder
used for the preparation of tablets or the like. In JP-A 3-287535
and JP-A 4-18015, it is disclosed that a clear and stable aqueous
solution is available by the addition of polyvinylpyrrolidone to a
medicament sparingly soluble in water.
[0003] An object of the present invention is to alleviate an
unpleasant taste of an oral medicament and moreover, to suppress
the formation of a precipitate or decomposition product.
DISCLOSURE OF THE INVENTION
[0004] The present invention is directed to a composition
comprising a basic medicament having an unpleasant taste and
polyvinylpyrrolidone and/or copolyvidone. In addition, it is also
directed to a method for alleviating an unpleasant taste of a basic
medicament having the unpleasant taste by adding
polyvinylpyrrolidone and/or copolyvidone thereto.
[0005] In a further aspect of the present invention, there is also
provided a composition comprising (1) a basic medicament, (2)
polyvinylpyrrolidone and/or copolyvidone, and (3) propylene glycol
and/or D-sorbitol.
[0006] In a still further aspect of the present invention, there is
also provided a composition comprising (1) a basic medicament, (2)
polyvinylpyrrolidone and/or copolyvidone, and (4) an
antioxidant.
[0007] In a still further aspect of the present invention, there is
also provided a composition comprising (1) a basic medicament, (2)
polyvinylpyrrolidone and/or copolyvidone, and (5) a colorant or
flavor containing a sulfuric acid or sulfurous acid group.
[0008] The present invention makes it possible to reduce an
unpleasant taste of a basic medicament having the unpleasant taste
and this is the first object of the present invention.
[0009] Addition of polyvinylpyrrolidone and/or copolyvidone
increases analogues to the basic medicament with the passage of
time. The second object of the present invention is to suppress
this increase of analogues.
[0010] Addition of a colorant or flavor having a sulfuric acid or
sulfurous acid group happens to form an insoluble precipitate of
the basic medicament. To suppress the formation of this precipitate
is also an object of the present invention.
[0011] The basic medicament having an unpleasant taste in the
present invention means a medicament in which a proton exists as a
positive charge under acidic conditions and which has an unpleasant
taste. Examples include ticlopidine hydrochloride, azelastine
hydrochloride, etilefrine hydrochloride, diltiazem hydrochloride,
propranolol hydrochloride, indeloxazine hydrochloride,
aminoguanidine hydrochloride and donepezil hydrochloride. Among
these, effects are particularly remarkable when donepezil
hydrochloride is used. Donepezil hydrochloride is chemically named
(1-benzyl-4-(5,6-dimethoxyindanon-2-yl)methylpiperidi- ne
hydrochloride, and it is a remedy for Alzheimer's disease of a
slight to a medium degree. The aqueous solution thereof has a sharp
bitterness and numbness.
[0012] In the present invention, polyvinylpyrrolidone and/or the
like reduces an unpleasant taste. Described specifically, a basic
medicament having an unpleasant taste, which the medicament has
been positively charged by a proton bound thereto in a solution, is
trapped by two pyrrolidone groups, whereby contact of the basic
medicament with a taste bud is sterically hindered.
[0013] In the present invention, polyvinylpyrrolidone is a linear
polymer of 1-vinyl-2-pyrrolidone and that having an average
molecular weight ranging from several thousand to several million
can be used, with that having an average molecular weight of about
10000 to 2000000 is preferable.
[0014] In the Japanese Pharmacopoeia, polyvinylpyrrolidones having
an average molecular weight of 25000, 40000 and 1200000 are
described as polyvinylpyrrolidone K25, polyvinylpyrrolidone K30 and
polyvinylpyrrolidone K90, respectively. They are easily available
as Kollidon, the trade name. In the codices of Japan, USA and
England, it is officially described as povidone, while in the codex
of Europe, it is officially described as polyvidone. Both are
embraced in the present invention.
[0015] In the present invention, copolyvidone is a (6:4) copolymer
of a chain-structured vinyl pyrrolidone and vinyl acetate and for
example, it is officially described in the codex of Europe as
copolyvidone. In the present invention, polyvinylpyrrolidone and
copolyvidone may be used either singly or in combination.
[0016] In the present invention, a ratio of a basic medicament
having an unpleasant taste to polyvinylpyrrolidone and/or
copolyvidone differs depending on the molecular weight or the like
and cannot be determined in the wholesale manner.
Polyvinylpyrrolidone having an average molecular weight of 40000 is
usually added in an amount of 5 to 200 parts by weight, preferably
20 to 200 parts by weight or 100 to 200 parts by weight, more
preferably 140 to 200 parts by weight, each based on 1 part by
weight of the basic medicament such as donepezil hydrochloride. It
is added in an amount of 5 to 100 parts by weight for the
solubilization of an insoluble substance, and 50 to 200 parts by
weight for masking of a bitter taste. The larger the molecular
weight of polyvinylpyrrolidone, the less the amount of it to be
added, while the smaller, the more the amount to be added.
[0017] Specific examples of the formulated preparation usable in
the present invention include water-soluble liquids, syrups,
elixirs, jellies, dry syrups, effervescent preparations, lemonades,
aerosols, ophthalmic solutions, nasal drops, suppositories,
cataplasmas, liniments, lotions and fine granules. Among these,
syrups and jellies are particularly preferable. Syrups are each
available by adding a sweetener such as sucrose, glucose, mannitol,
xylitol, aspartame, saccharin or sorbitol and optionally a taste
and smell corrigent. Jellies are usually available by adding, to
the composition of the present invention, a gum and then a
sweetener such as sucrose, glucose, mannitol, xylitol, aspartame,
saccharin or sorbitol and optionally a taste and smell corrigent.
The pH of the preparation is usually in the range of from 3 to
7.
[0018] The composition of the present invention in the form of an
aqueous solution can be produced by weighing necessary amounts of a
medicament and polyvinylpyrrolidone and/or copolyvidone, adding a
sweetener, flavor or the like as needed and then dissolving the
resulting mixture in water. When the medicament is donepezil
hydrochloride, the dose is usually 1 to 20 mg/once.
[0019] The present invention provides a composition containing a
basic medicament. The basic medicament includes the above-mentioned
basic medicament having an unpleasant taste and the other basic
medicaments. Examples thereof include acebutolol hydrochloride,
aprindine hydrochloride, alprenolol hydrochloride, ambroxol
hydrochloride, isoprenaline hydrochloride, imipramine
hydrochloride, diphenidol hydrochloride, diltiazem hydrochloride,
thiamine hydrochloride, trazodone hydrochloride, bunazosin
hydrochloride, bunitrolol hydrochloride, ranitidine hydrochloride
and midodrine hydrochloride.
[0020] In addition, the present invention provides a composition
comprising (1) a basic medicament, (2) polyvinylpyrrolidone and/or
copolyvidone, and (3) propylene glycol and/or D-sorbitol, or a
composition comprising (1) a basic medicament, (2)
polyvinylpyrrolidone and/or copolyvidone, and (4) an antioxidant.
When the basic medicament and polyvinylpyrrolidone and/or
copolyvidone are mixed, an amount of analogues of the basic
medicament happens to increase upon storage. Addition of propylene
glycol and/or D-sorbitol, or an antioxidant, however, can markedly
suppress the increase of the analogues. Accordingly, the present
invention also provides a method for suppressing the formation of
analogues by the addition of such substances. Examples of the
antioxidant usable in the present invention include sodium
bisulfite, sodium sulfite, sodium pyrosulfite, cysteine, citric
acid, sodium edetate, ascorbic acid and erythorbic acid. They may
be used either singly or in combination.
[0021] The present invention further provides a composition
comprising (1) a basic medicament, (2) polyvinylpyrrolidone and/or
copolyvidone, and (5) a colorant or flavor containing a sulfuric
acid or sulfurous acid group. Although the addition, to a basic
medicament, of a colorant or flavor containing a sulfuric acid or
sulfurous acid group happens to form an insoluble precipitate, the
addition of polyvinylpyrrolidone and/or copolyvidone can remarkably
suppress the formation of the insoluble precipitate. Accordingly,
the present invention also provides a method for suppressing the
formation of an insoluble precipitate of the basic medicament
caused by the addition of a colorant or flavor containing a
sulfuric acid or sulfurous acid group, by the addition of
polyvinylpyrrolidone and/or copolyvidone. Examples of the colorant
or flavor containing a sulfuric acid or sulfurous acid group
include Food Red No. 102 (trisodium
2-hydroxyazonaphthalene-4',6,8-trisulfonate), Food Red No. 40, Food
Red No. 3 (2',4',5',7'-tetraiodofluorescein disodium salt), Food
Red No. 2 (trisodium 2-hydroxyazonaphthalene-3,4',6-trisulfon-
ate), Food Blue No. 1 (disodium
3-[N-ethyl-N-[4-[[-N-ethyl-N-(3-sulfonatob- enzyl)amino]phenyl]
(2-sulfonatophenyl)methylene]-2,5-cyclohexadienyliden]-
ammoniomethyl]benzenesulfonate), Food Blue No. 2 (Acid Blue 74,
disodium
2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)-2,3-dihydro-3-oxo-1H-ind-
ole-5-sulfonate), Food Green No. 3 (disodium
N-ethyl-N-[4-[[ethyl[(3-sulfo- phenyl)methyllamino]phenyl]
(4-hydroxy-2-sulfophenyl)methylene]-2,5-cycloh-
exadien-1-ylidene]-3-sulfobenzenemethaneaminiumhydroxide), Food
Yellow No. 4 (trisodium
3-carbonato-5-hydroxy-1-(4-sulfonatophenyl)-1H-pyrazol-4-azo-
-4'-(benzenesulfonate)) and Food Yellow No. 5 (disodium
2-hydroxy-6-sulfonatonaphthalen-1-azo-(4'-benzenesulfonate)). They
may be used either singly or in combination.
[0022] The composition according to the present invention has
remarkable effects for alleviating an unpleasant taste of a
medicament and it is particularly useful when formulated into an
orally administered liquid or jelly. It can remarkably suppress an
increase, during storage, in the amount of the analogues of the
basic medicament caused by the addition of polyvinylpyrrolidone
and/or copolyvidone Moreover, it can prevent the formation of an
insoluble precipitate of the basic medicament caused by the
sulfuric acid or sulfurous acid group existing in the colorant or
flavor.
[0023] The above-described effects will be described more
specifically by Tests given below.
[0024] Test 1
[0025] Examinees A and B held in their mouths Test solution 1
having, dissolved therein, 5 mg of donepezil hydrochloride and 700
mg of polyvinylpyrrolidone (average molecular weight: about 40000)
per 5 g of the solution and Control solution 1 having, dissolved
therein, 5 mg of donepezil hydrochloride per 5 g of the solution,
and then evaluated the degree of a bitter taste and numbness. The
results are shown in Table 1. It is apparent from Table 1 that the
composition according to the present invention remarkably
alleviates an unpleasant taste of the medicament.
1 TABLE 1 A B Examinee Bitterness Numbness Bitterness Numbness
Control solution 1 + + + + + + + + + + + + Test just after .+-.
.+-. .+-. .+-. solu- the administration tion 1 30 mm after .+-. +
.+-. + the administration
[0026] Test 2
[0027] Seven healthy examinees held in their mouths test solutions
(Test solution 2, 3 and 4) having, dissolved therein, 5 mg of
donepezil hydrochloride and each of 700 mg, 500 mg and 100 mg of
polyvinylpyrrolidone (average molecular weight: 40000) per 5 g of
the solution and Control solution 2 having, dissolved therein, 5 mg
of donepezil hydrochloride and 3 g of sorbitol per 5 g of the
solution. Five seconds later, they disgorged each of the solutions,
rinsed their mouths with tap water and evaluated the degree of a
bitter taste and numbness. Evaluation was conducted when they took
the solution (when the test solution or control solution was held
in the mouth), just after disgorging (before rinsing with water)
and 5 minutes after disgorging (after rinsing with water). The
evaluation standards and results are shown in Table 2. From Table
2, it is evident that the more the amount of polyvinylpyrrolidone
added, the scores relating to the bitter taste and numbness
increased, that is, the effects for masking an unpleasant taste
heightened. The effects for alleviating the numbness are
particularly remarkable compared with the control solution having
sorbitol incorporated therein, suggesting that the effects of the
present invention are not brought by false impression due to a
sweet taste.
2TABLE 2 Evaluation standards Evaluation scores Bitterness Numbness
5 No feeling No feeling 4 Dim feeling Dim feeling 3 Slightly bitter
Slightly numb 2 Bitter Numb 1 Very bitter Very numb Bitterness Test
Test Test Control Examinee solution 2 solution 3 solution 4
solution 2 K. U. 5 4 2 4 H. A. 1 2 1 5 T. H. 3 2 2 5 M. K. 3 2 2 4
S. I. 3 2 2 3 K. K. 4 4 5 5 Y. I. 4 4 2 4 Avg 3.3 2.9 2.3 4.3
Numbness (when took the solution) Test Test Test Control Examinee
solution 2 solution 3 solution 4 solution 2 K. U. 5 4 3 3 H. A. 5 5
4 5 T. H. 3 2 1 4 M. K. 5 3 3 3 S. I. 5 5 5 3 K. K. 5 5 5 5 Y. I. 5
4 3 4 Avg 4.7 4.0 3.4 3.9 Numbness (just after disgorging) Test
Test Test Control Examinee solution 2 solution 3 solution 4
solution 2 K. U. 5 4 3 2 H. A. 5 5 3 5 T. H. 3 2 1 3 M. K. 5 5 4 2
S. I. 4 5 5 3 K. K. 5 5 5 5 Y. I. 4 3 3 4 Avg 4.4 4.1 3.4 3.4
Numbness (5 mm after disgorging) Test Test Test Control Examinee
solution 2 solution 3 solution 4 solution 2 K. U. 4 3 2 2 H. A. 5 4
2 5 T. H. 4 2 1 2 M. K. 5 5 4 3 S. I. 3 4 4 3 K. K. 5 5 4 5 Y. I. 4
3 3 4 Avg 4.3 3.7 2.9 3.4
[0028] Test 3
[0029] Samples obtained by incorporating 20% by weight of
D-sorbitol into an aqueous solution containing 0.1%. by weight of
donepezil hydrochloride, obtained by incorporating 6% by weight of
propylene glycol in the same aqueous solution and obtained by
incorporating 5% by weight of polyvinylpyrrolidone to each of the
above samples were stored at 60.degree. C. for 2 weeks or 1 month
and the amount of analogues to donepezil hydrochloride was
measured. The results are shown in Table 3.
[0030] It is apparent from Table 3 that the formation of the
analogues is remarkably suppressed by incorporating D-sorbitol or
propylene glycol.
3TABLE 3 Relationship between the amount of analogue and stabilizer
term of storage not incorporated D-sorbitol propylene glycol
60.degree. C. (%) 20% incorporated (%) 6% incorporated (%) E2020
0.1% 2 W 0.00 0.00 0.00 1 M 0.03 0.00 0.00 E2020 0.1% + PVP 5% 2W
0.36 0.10 0.00 1M 0.61 0.27 0.19
[0031] Test 4
[0032] Storage test was conducted by storing a preparation, which
had been formulated as shown in Table 4, at 60.degree. C. for 2
weeks or at 45.degree. C. for 1 month. As a result, no analogues to
donepezil hydrochloride was detected from the sample added with
sodium bisulfite.
4 TABLE 4 Control Test sample Fillers mg/5 ml mg/5 ml Donepezil
hydrochloride 5 5 Sodium bisulfite 1 70% D-sorbitol 1785 1785
Povidone K30 250 250 Citric acid 10 10 Sodium citrate proper amount
proper amount Sodium benzoate 5 5 Food Red No. 40 0.05 0.05
Strawberry flavor 15 15 Purified water proper amount proper amount
Total 5 ml 5 ml Total amount of analoges 0.60% 0% (60.degree. C./2
W) Total amount of analoges 0.46% 0% (45.degree. C./1 M)
[0033] Test 5
[0034] From the formulation similar to that shown in Table 5 except
that povidone is not added, a precipitate appeared under the
storage conditions at a room temperature or in a cool place
(4.degree. C.).
5 TABLE 5 Prescription 1 Prescription 2 Fillers mg/5 ml mg/5 ml
Donepezil hydrochloride 5 5 70% D-sorbitol 1785 1785 Povidone K30
250 250 Citric acid 10 10 Sodium citrate proper amount proper
amount Sodium benzoate 5 5 Food Red No. 40 0.05 0 Sunset Yellow 0
0.02 Strawberry flavor 15 0 Orange flavor 0 15 Purified water
proper amount proper amount Total 5 ml 5 ml
EXAMPLES
[0035] The present invention will hereinafter be described more in
detail in accordance with Examples, but the present invention
should not be limited by them.
Example 1
[0036] A composition of the present invention was obtained by
dissolving 50 mg of donepezil hydrochloride and 7.00 g of
polyvinylpyrrolidone in 42.95 g of water.
Example 2
[0037] In 400 g of purified water were dissolved 500 mg of
donepezil hydrochloride, 70 g of polyvinylpyrrolidone (average
molecular weight: about 40000), 100 g of sorbitol, 1 g of saccharin
sodium, 1 g of sodium citrate and 1.5 g of sodium benzoate,
followed by the addition of citric acid to adjust the pH of the
resulting solution to 5.0. The total volume of the solution was
adjusted to 500ml, and 5 g portions of the solution were put into
vials.
Example 3
[0038] Povidone (2.5 g, trade name: Kollidon 30) was added to
purified water in portions to dissolve. A 70% D-sorbitol solution
(17.9 g), 100 mg of citric acid (100 mg) and benzoic acid (50 mg)
were added to the resulting solution to dissolve. Donepezil
hydrochloride (50 mg) was then added to the resulting solution to
dissolve, followed by the addition of sodium citrate to adjust the
pH of the resulting solution to 3.9. To the resulting solution were
further added 0.5 mg of Food Red No. 40 and 150 mg of strawberry
flavor. Purified water was added to give a total volume of 50 ml.
Into vials were pipetted 5 ml portions of the resulting
solution.
Example 4
[0039] Povidone (2.5 g, trade name: Kollidon 30) was added to
purified water in portions to dissolve. A 70% D-sorbitol solution
(17.9 g), 100 mg of citric acid (100 mg) and benzoic acid (50 mg)
were added to the resulting solution to dissolve. Donepezil
hydrochloride (50 mg) was then added to the resulting solution to
dissolve, followed by the addition of sodium citrate to adjust the
pH of the resulting solution to 3.9. To the resulting solution were
further added 0.2 mg of Sunset Yellow and 150 mg of orange flavor,
followed by the addition of purified water to give a total amount
of 50 ml. Into vials were pipetted 5 ml portions of the resulting
solution.
Example 5
[0040] Purified water was added to 50 mg of donepezil
hydrochloride, 2.5 g of polyvinylpyrrolidone and 10 g of D-sorbitol
to dissolve and the total volume was adjusted to 50 ml.
Example 6
[0041] Purified water was added to 50 mg of donepezil
hydrochloride, 2.5 g of polyvinylpyrrolidone and 3 g of propylene
glycol to dissolve and the total volume was adjusted to 50 ml.
Example 7
[0042] Povidone (2.5 g, trade name: Kollidon 30) was added to
purified water in portions to dissolve. In the resulting solution,
A 70% D-sorbitol solution (17.9 g), citric acid (100 mg), sodium
benzoate (50 mg) and sodium bisulfite (10 mg) were added to the
resulting solution to dissolve. Donepezil hydrochloride (5 mg) was
added to the resulting solution to dissolve, followed by the
addition of sodium citrate to adjust its pH to 3.9. To the
resulting solution were further added Food Red No. 40 (0.5 mg) and
150 mg of strawberry flavor, followed by the addition of purified
water to give a total amount of 50 ml. Into vials were pipetted 5
ml portions of the resulting solution.
Example 8
[0043] Povidone (2000 g, trade name: Kollidon 30) was added in
portions to 15L of purified water to dissolve. To the resulting
solution was added 13280 g of a 70% D-sorbitol solution, followed
by stirring for 30 minutes. After the complete dissolution of
copolydone was confirmed, 400 g of a 20% citric acid solution and
400 g of a 10% sodium benzoate solution were added to the reaction
mixture to dissolve. A solution of donepezil hydrochloride (40 g)
dissolved in 1000 g of a 70% D-sorbitol solution was added thereto,
followed by stirring. A solution of methylparaben (40 g) dissolved
in 2400 g of propylene glycol was further added thereto, followed
by stirring. A 10% sodium citrate solution was added to the
resulting mixture to adjust the pH thereof to 3.9. To the resulting
solution were further added a 0.2% solution (200 g) of Food Red No.
40 and 120 g of strawberry flavor, followed by the addition of
purified water to give a total amount of 40 L. The resulting
mixture was stirred. The resulting solution was filtered through a
0.22 .mu.m filter and 5 ml portions were pipetted into aluminum
stick packages.
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