U.S. patent application number 11/498147 was filed with the patent office on 2006-11-30 for fast-dissolving pharmaceutical composition.
Invention is credited to Hiroshi Fujioka, Kazuyoshi Ogasawara, Mamoru Ohashi, Yoshimi Shirai.
Application Number | 20060269599 11/498147 |
Document ID | / |
Family ID | 17959478 |
Filed Date | 2006-11-30 |
United States Patent
Application |
20060269599 |
Kind Code |
A1 |
Ohashi; Mamoru ; et
al. |
November 30, 2006 |
Fast-dissolving pharmaceutical composition
Abstract
A fast-dissolving pharmaceutical composition comprising
micronized
(R)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-
-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (hereinafter, referred to
as AS-3201). The present pharmaceutical composition has improved
dissolution characteristics as well as a good bioavailability.
Inventors: |
Ohashi; Mamoru;
(Amagasaki-shi, JP) ; Ogasawara; Kazuyoshi;
(Kitakatsuragi-gun, JP) ; Shirai; Yoshimi;
(Suita-shi, JP) ; Fujioka; Hiroshi; (Ibaraki-shi,
JP) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
2033 K STREET N. W.
SUITE 800
WASHINGTON
DC
20006-1021
US
|
Family ID: |
17959478 |
Appl. No.: |
11/498147 |
Filed: |
August 3, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09529715 |
Apr 19, 2000 |
|
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PCT/JP98/04658 |
Oct 15, 1998 |
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11498147 |
Aug 3, 2006 |
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Current U.S.
Class: |
424/464 ;
514/250 |
Current CPC
Class: |
Y10S 514/96 20130101;
A61K 47/02 20130101; A61K 9/2013 20130101; A61K 31/499 20130101;
A61K 9/2054 20130101; A61K 47/12 20130101; A61P 3/10 20180101; Y10S
514/951 20130101 |
Class at
Publication: |
424/464 ;
514/250 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/498 20060101 A61K031/498 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 20, 1997 |
JP |
306635/1997 |
Claims
1-12. (canceled)
13. A fast-dissolving pharmaceutical composition comprising
micronized (R)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo
[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone
(hereinafter, referred to as "AS-3201").
14. The fast-dissolving pharmaceutical composition according to
claim 13, wherein the mean particle size of the micronized AS-3201
is less than about 10 .mu.m.
15. The fast-dissolving pharmaceutical composition according to
claim 13, wherein the mean particle size of the micronized AS-3201
is less than about 5 .mu.m.
16. The fast-dissolving pharmaceutical composition according to
claim 13, wherein the mean particle size of the micronized AS-3201
is in the range of about 0.5 .mu.m-about 3 .mu.m.
17. The fast-dissolving pharmaceutical composition according to any
one of claims 13 to 16, which has a dissolution percentage of the
active substance 50% or more for 15 minutes after the start of the
dissolution test.
18. The fast-dissolving pharmaceutical composition according to
claim 17, which has a dissolution percentage of the active
substance 80% or more for 15 minutes after the start of the
dissolution test.
Description
TECHNICAL FIELD
[0001] The present invention relates to a fast-dissolving
pharmaceutical composition of
(R)-2-(4-bromo-2-fluoro-benzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine--
4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (hereinafter, referred to
as "AS-3201") having a potent aldose reductase inhibitory
activity.
BACKGROUND ART
[0002] AS-3201 is the compound of the following formula. Said
compound is described in Example 22 of Japanese Patent No. 2516147
(U.S. Pat. No. 5,258,382), Reference Example 12 of JP-A-6-192222
(Chem. Abstr., 122, 9860 (1995)), and Experiment of JP-A-8-176105
(Chem. Abstr., 125, 221569 (1996)), and its potent aldose reductase
inhibitory activities are disclosed therein. ##STR1##
[0003] Example 28 of Japanese Patent No. 2516147 (U.S. Pat. No.
5,258,382) describes a method for preparing specific tablets of
AS-3201. That is, it is described therein that AS-3201 (1 g), corn
starch (25 g), lactose (58 g), crystalline cellulose (11 g),
hydroxypropylcellulose (3 g), light anhydrous silicic acid (1 g)
and magnesium stearate (1 g) are blended, granulated and made into
1,000 tablets each weighing 100 mg by a conventional method.
[0004] During the studies on methods for preparing
AS-3201-containing pharmaceutical compositions having an excellent
bioavailability, the present inventors have found that the
water-solubility of said substance is extremely low in the range of
low pH to the extent of several .mu.g/ml, and therefore, the plasma
concentration of AS-3201 varies widely among the individuals to be
administered.
[0005] Under such circumstances, the present inventors have further
intensively studied, and have found that by using micronized
AS-3201 in a composition, the dissolution characteristics of said
substance from the composition are remarkably improved, and as a
result, an AS-3201-containing fast-dissolving pharmaceutical
composition having a good bioavailability can be obtained, and
finally have accomplished the present invention.
DISCLOSURE OF INVENTION
[0006] The present invention provides a fast-dissolving
pharmaceutical composition comprising micronized AS-3201.
[0007] The terms used in the present specification are explained
below.
[0008] The "micronized AS-3201" means powders of AS-3201 having a
mean particle size of less than about 20 .mu.m. The "mean particle
size" means a particle size of being at 50% in cumulative particle
distribution on weight or volume basis (ref., HA Lieberman et al.,
"Pharmaceutical Dosage Forms: Tablets", Marcel Dekker, Inc., New
York, 1990, vol. 2, 174-186; Kouichi IINOYA (edit.) "Handbook of
Powder and Particle Measurement (in Japanese)", The NIKKAN KOGYO
SHINBUN LTD., 1981, 29-36). The "dissolution test" means a test in
which the dissolution of AS-3201 from test pharmaceutical
compositions in an amount corresponding to 20 mg of AS-3201 is
evaluated according to Paddle method (50 rpm) specified in the
Twelfth Edition of the Pharmacopoeia of Japan, using a 0.2 M
phosphate buffer (pH 6.5, 900 ml) as a test solution, and assaying
AS-3201 by spectrophotometry at 300 nm. The "pK.sup.a1" means an
acid dissociation exponent of an acidic substance at 25.degree. C.
in an infinitely diluted solution thereof. When an acidic substance
is a polybasic acid, it means an acid dissociation exponent at the
first step of dissociation. The "water-solubility" means a maximum
amount of a solute being dissolved in 100 ml of water. The term
"about" is used with the intention of including values following
said term.
[0009] The mean particle size of the micronized AS-3201 is
preferably less than about 10 .mu.m, more preferably less than
about 5 .mu.m, and most preferably in the range of about 0.5 .mu.m
to about 3 .mu.m.
[0010] According to the method disclosed in Japanese Patent No.
2516147 (U.S. Pat. No. 5,258,382), crystals of AS-3201 having a
mean particle size of about 60 .mu.m to about 120 .mu.m can usually
be obtained. The micronization of AS-3201 crystals is carried out
using a mill that is conventionally used in the pharmaceutical
field. Mills are, for example, a fluid energy mill such as Jet Mill
(manufactured by SEISHIN ENTERPRISE Co., LTD., Japan), a high speed
rotative impact mill such as Sample Mill (manufactured by Hosokawa
Micron Corporation, Japan), Pin Mill (manufactured by ALPINE,
Germany), or Angmill (manufactured by Hosokawa Micron Corporation,
Japan), a wet form high speed tumbling trituration mill such as
MICROS (manufactured by Nara Machinery Co., Ltd., Japan), and a
tumbling mill such as a ball mill. In order to obtain micronized
powders having a mean particle size of less than about 5 .mu.m, a
fluid energy mill is preferably used. The micronization can be
carried out on AS-3201 crystals alone, or on a mixture of AS-3201
crystals and a part or whole of pharmaceutical excipients or
carriers, which are used in the preparation of pharmaceutical
compositions.
[0011] The AS-3201-containing fast-dissolving pharmaceutical
composition of the present invention may be solid dosage forms, and
includes, for example, tablets, capsules, granules, powders, etc.
These pharmaceutical compositions can be prepared by mixing
micronized AS-3201 with pharmaceutical excipients or carriers such
as diluents, disintegrators, binders and lubricants by a
conventional method. For example, the mixture is granulated by
wet-granulation such as high-shear granulation, fluid bed
granulation, agitation fluid bed granulation, centrifugal fluid bed
granulation, or extrusion granulation, or by dry-granulation such
as roller compaction or slugging, and then the resulting granules
are put into capsules for capsule preparations, or compressed for
tablet preparations. Alternatively, a mixture of micronized AS-3201
and pharmaceutical excipients or carriers. can directly be put into
capsules for capsule preparations, or compressed for tablet
preparations. These pharmaceutical compositions may optionally be
coated, or may additionally contain stabilizers, surfactants,
coloring agents, flavoring agents, etc.
[0012] The pharmaceutical excipients or carriers may be any ones
except for ones showing a bad compatibility with AS-3201. The
diluents include, for example, lactose, starch, crystalline
cellulose, D-mannitol, sucrose, glucose, erythritol, xylitol,
D-sorbitol, anhydrous dibasic calcium phosphate, and calcium
sulfate. The disintegrators are, for example, starch, crystalline
cellulose, low substituted hydroxypropylcellulose, carmellose,
carmellose calcium, sodium carboxymethyl starch, croscarmellose
sodium, partly pregelatinized starch, and hydroxypropyl starch. The
binders are, for example, acacia, starch, hydroxypropylcellulose,
hydroxypropylmethylcellulose, polyvinyl alcohol, pullulan, gelatin,
ethylcellulose, methylcellulose, carmellose sodium, and dextrin.
The lubricants are, for example, magnesium stearate, calcium
stearate, stearic acid, sucrose esters of fatty acids, light
anhydrous silicic acid, talc, hydrogenated oil, and macrogol.
[0013] The stabilizer may be any pharmaceutically acceptable acidic
substances having an acidity more potent than that of AS-3201,
i.e., pK.sub.a=5.6-5.8, and preferable acidic substances are ones
having a pK.sub.a1 of less than about 4.5 and a water-solubility of
larger than about 10 g/100 ml at 15.degree. C.-25.degree. C. More
preferable acidic substances are ones having a pK.sub.a1 of less
than about 3.3 and a water-solubility of larger than about 50 g/100
ml at 15.degree. C.-25.degree. C. Especially preferable acidic
substances are, for example, citric acid, tartaric acid, maleic
acid, and phosphoric acid. Among these acidic substances, tartaric
acid is most preferable. The content of the acidic substance is
preferably in the range of about 0.5% by weight to about 2.5% by
weight. It is preferable to add a stabilizer in the case of
preparing a pharmaceutical composition containing AS-3201 in a
ratio of less than about 5% by weight.
[0014] The surfactants to be used in the present pharmaceutical
composition are, for example, sorbitan fatty acid esters and
polysorbates. The coloring agents are, for example, tar color,
caramel, and red iron oxide. The flavoring agents are, for example,
sweeteners and perfumes.
[0015] The dissolution characteristics of the active substance from
the composition can be remarkably improved by using micronized
AS-3201, and by further controlling the combination ratio of
pharmaceutical excipients or carriers, AS-3201-containing
fast-dissolving pharmaceutical compositions having more improved
dissolution characteristics as well as good bioavailability can be
obtained. The combination ratio of the pharmaceutical excipients or
carriers may vary depending on the content of AS-3201. The content
of AS-3201 in the present fast-dissolving pharmaceutical
composition is usually in the range of about 0.5% by weight to
about 25% by weight, to the total weight of the pharmaceutical
composition. When the content of AS-3201 is in the range of about
0.5% by weight to 5% by weight to the total weight of the
pharmaceutical composition, then the pharmaceutical composition
usually comprises a diluent in a ratio of about 51% by
weight--about 93.8% by weight, a disintegrator in a ratio of about
5% by weight--about 35% by weight, a binder in a ratio of about
0.5% by weight--about 5% by weight, and a lubricant in a ratio of
about 0.2% by weight--about 4% by weight. More preferably, the
pharmaceutical composition comprises a diluent in a ratio of about
59% by weight--about 88% by weight, a disintegrator in a ratio of
about 10% by weight--about 30% by weight, a binder in a ratio of
about 1% by weight--about 3% by weight, and a lubricant in a ratio
of about 0.5% by weight--about 3% by weight. When the content of
AS-3201 is more than 5% by weight and less than about 25% by weight
to the total weight of the pharmaceutical composition, then the
present composition usually comprises .a diluent in a ratio of
about 16% by weight--about 84.3% by weight, a disintegrator in a
ratio of about 10% by weight--about 50% by weight, a binder in a
ratio of about 0.5% by weight--about 5% by weight, and a lubricant
in a ratio of about 0.2% by weight--about 4% by weight, and more
preferably, a diluent in a ratio of about 29% by weight--about
73.5% by weight, a disintegrator in a ratio of about 20% by
weight--about 40% by weight, a binder in a ratio of about 1% by
weight--about 3% by weight, and a lubricant in a ratio of about
0.5% by weight--about 3% by weight.
[0016] Since AS-3201 has an extremely low water-solubility to the
extent of several ug/ml in the range of low pH, there is
a-correlation between the initial dissolution rate and the
bioavailability of AS-3201-containing pharmaceutical compositions,
and compositions having a better initial dissolution rate can show
a better bioavailability. From the viewpoint of the above,
preferable compositions are ones having a dissolution percentage of
the active substance of 50% or more for 15 minutes after the start
of the dissolution test, and more preferable pharmaceutical
compositions are ones having a dissolution percentage of the active
substance of 80% or more for 15 minutes after the start of the
dissolution test.
[0017] The AS-3201-containing fast-dissolving pharmaceutical
composition of the present invention may be packed in a bottle
using materials of low moisture-permeability or in damp-proof
packages such as heat-sealed packages, if necessary.
BRIEF DESCRIPTION OF DRAWINGS
[0018] FIG. 1 is a graph showing a dissolution pattern of the
tablets of Examples 1 and 2, and Comparative Example 1.
BEST MODE FOR CARRYING OUT THE INVENTION
[0019] The present invention is illustrated in more detail by
Examples and Comparative Example, but the present invention should
not be construed to be limited thereto. The mean particle size was
measured using a laser diffraction particle size distribution
analyzer (HELOS & RODOS (trademark), manufactured by SYMPATEC
GmbH, Germany), and calculated from cumulative particle
distribution on volume basis by dry air dispersion method
(dispersion air pressure: 0.5 atm).
EXAMPLE 1
[0020] TABLE-US-00001 Preparation of tablets: AS-3201 160 g
Tartaric acid 8 g Lactose 492 g Low substituted
hydroxypropylcellulose 300 g Hydroxypropylcellulose 20 g Magnesium
stearate 20 g Total 1000 g
[0021] AS-3201 crystals were micronized using Single Truck Jet Mill
(manufactured by SEISHIN ENTERPRISE CO., LTD., hereinafter
abbreviated as "Jet Mill") with compression air pressure of 6
kgf/cm.sup.2 to give powders having a mean particle size of about
1.5 .mu.m. The micronized AS-3201 powders thus obtained, lactose,
and low substituted hydroxypropylcellulose were charged into a
fluid bed granulator and drier, and then the mixture was granulated
by spraying thereto a solution of tartaric acid in a 5% aqueous
hydroxypropylcellulose solution. The granules were dried, and
thereto was added magnesium stearate, and the mixture was blended
in a V-blender. The resultant was compressed on a rotary tableting
machine to give tablets weighing 125 mg and containing 20 mg of
AS-3201 each.
EXAMPLE 2
Preparation of Tablets:
[0022] AS-3201 crystals were micronized by Sample Mill
(manufactured by Hosokawa Micron Corporation) to give powders
having a mean particle size of about 10 .mu.m. The micronized
AS-3201 powders thus obtained were granulated, dried and compressed
in the same manner as in Example 1, to give tablets weighing 125 mg
and containing 20 mg of AS-3201 each.
Comparative Example 1
Preparation of Tablets:
[0023] Non-micronized AS-3201 crystals having. a mean particle size
of about 87 .mu.m were granulated, dried and compressed in the same
manner as in Example 1, to give tablets weighing 125 mg and
containing 20 mg of AS-3201 each.
Experiment 1
Dissolution Test:
[0024] The dissolution of the active substance from the tablets
obtained in Examples 1 and 2 and Comparative Example 1 was
evaluated according to Paddle method (50 rpm) specified in the
Twelfth Edition of the Pharmacopoeia of Japan, using a 0.2 M
phosphate buffer (pH 6.5, 900 ml) as a test solution. The
quantitative assay of AS-3201 was carried out by spectrophotometry
at 300 nm.
[0025] The results are shown in FIG. 1. Each point of FIG. 1 shows
the mean value of the results in three repeats of the experiments
on each tablet of Example 1, Example 2 and Comparative Example
1.
[0026] As is shown in FIG. 1, the tablets of Example 1 and Example
2 show remarkably improved dissolution characteristics, as compared
with the tablets of Comparative Example 1.
EXAMPLE 3
[0027] TABLE-US-00002 Preparation of tablets: AS-3201 160 g
Tartaric acid 10 g Lactose 600 g Low substituted
hydroxypropylcellulose 200 g Hydroxypropylcellulose 20 g Magnesium
stearate 10 g Total 1000 g
[0028] The above components were treated in the same manner as in
Example 1, and compressed to give tablets weighing 125 mg and
containing 20 mg of AS-3201 each. The dissolution percentage of the
active substance from the tablets thus obtained for 15 minutes
after the start of the dissolution test was 72.6%.
EXAMPLE 4
[0029] TABLE-US-00003 Preparation of tablets: AS-3201 20 g Tartaric
acid 8 g Lactose 732 g Low substituted hydroxypropylcellulose 200 g
Hydroxypropylcel lulose 20 g Magnesium stearate 20 g Total 1000
g
[0030] AS-3201 crystals were micronized using Jet Mill with
compression air pressure of 6 kgf/cm.sup.2, and the resultant was
charged into a fluid bed granulator and drier together with lactose
and low substituted hydroxypropylcellulose, and then, the resultant
was granulated by spraying thereto a solution of tartaric acid in a
5% aqueous hydroxypropylcellulose solution. The granules were
dried, and thereto was added magnesium stearate, and the mixture
was blended in a V-blender. The resultant was compressed on a
rotary tableting machine to give tablets weighing 125 mg and
containing 2.5 mg of AS-3201 each.
[0031] The dissolution percentage of the active substance from the
tablets thus obtained for 15 minutes after the start of the
dissolution test was 93.0%.
EXAMPLE 5
[0032] TABLE-US-00004 Preparation of tablets: AS-3201 80 g Tartaric
acid 4 g Lactose 246 g Low substituted hydroxypropylcellulose 150 g
Hydroxypropylcellulose 10 g Magnesium stearate 10 g Total 500 g
[0033] AS-3201 crystals were micronized using Jet Mill with
compression air pressure of 6 kgf/cm.sup.2, and thereto were added
lactose and low substituted hydroxypropylcellulose, and then, the
resulting mixture was blended in a Versatile Mixer for 5 minutes.
To the mixture was added a solution of tartaric acid in a 4%
aqueous hydroxypropylcellulose solution, and the mixture was
further kneaded for 10 minutes. The mixture was dried, and thereto
was added magnesium stearate, and the resulting mixture was
compressed on a single-punch tableting machine to give tablets
weighing 125 mg and containing 20 mg of AS-3201 each.
[0034] The dissolution percentage of the active substance from the
tablets thus obtained for 15 minutes after the start of the
dissolution test was 93.2%.
EXAMPLE 6
[0035] TABLE-US-00005 Preparation of tablets: AS-3201 144 g Lactose
549 g Low substituted hydroxypropylcellulose 180 g Hydroxypropylcel
lulose 18 g Magnesium stearate 9 g Total 900 g
[0036] AS-3201 crystals were micronized using Jet Mill with
compression air pressure of 6 kgf/cm.sup.2, and the resultant was
put into a fluid bed granulator and drier together with lactose and
low substituted hydroxypropylcellulose, and then, the mixture was
granulated by spraying thereto a 5% aqueous hydroxypropylcellulose
solution. After drying, to the granules was added magnesium
stearate, and the mixture was blended in a V-blender. The resultant
was compressed on a rotary tableting machine to give tablets
weighing 125 mg and containing 20 mg of AS-3201 each.
[0037] The dissolution percentage of the active substance from the
tablets thus obtained for 15 minutes after the start of the
dissolution test was 92.0%.
EXAMPLES 7-9
[0038] TABLE-US-00006 Preparation of tablets: Ex. 7 Ex. 8 Ex. 9
AS-3201 40 g 40 g 40 g Tartaric acid 8 g 8 g 8 g Lactose 712 g 672
g 632 g Low substituted hydroxy- 200 g 240 g 280 g propylcellulose
Hydroxypropylcellulose 20 g 20 g 20 g Magnesium stearate 20 g 20 g
20 g Total 1000 g 1000 g 1000 g
[0039] AS-3201 micronized using Jet Mill was granulated, dried and
compressed in the same manner as in Example 1 to give tablets
weighing 125 mg and containing 5 mg of AS-3201 each.
[0040] The dissolution percentages of the active substance from the
tablets of Examples 7, 8 and 9 for 15 minutes after the start of
the dissolution test were 91.0%, 94.5% and 92.7%, respectively.
Examples 10-12
[0041] TABLE-US-00007 Preparation of tablets: Ex. 10 Ex. 11 Ex. 12
AS-32O1 80 g 80 g 80 g Tartaric acid 8 g 8 g 8 g Lactose 672 g 632
g 592 g Low substituted hydroxy- 200 g 240 g 280 g propylcellulose
Hydroxypropylcellulose 20 g 20 g 20 g Magnesium stearate 20 g 20 g
20 g Total 1000 g 1000 g 1000 g
[0042] AS-3201 micronized using Jet Mill was granulated, dried and
compressed in the same manner as in Example 1 to give tablets
weighing 125 mg and containing 10 mg of AS-3201 each.
[0043] The dissolution percentages of the active substance from the
tablets of Examples 10, 11 and 12 for 15 minutes after the start of
the dissolution test were 89.4%, 91.6% and 92.2%, respectively.
INDUSTRIAL APPLICABILITY
[0044] As explained above, the AS-3201-containing fast-dissolving
pharmaceutical composition of the present invention has improved
dissolution characteristics as well as a good bioavailability.
* * * * *