Note: Descriptions are shown in the official language in which they were submitted.
CA 02547939 2003-12-24
Specification
Pharmaceutical Composition for Controlled Release of Active Substances and
The Manufacturing Method Thereof
Field of the Invention
The present invention pertains to a pharmaceutical composition for controlled
release, which comprises a drug, polyethylene oxide with a molecular weight of
2,000,000 or higher, and a specific size controlling agent for the above-
mentioned
polyethylene oxide and wherein the above-mentioned drug and above-mentioned
specific
size controlling agent are uniformly dispersed in the above-mentioned
polyethylene oxide.
Moreover, the present invention pertains to a method of manufacturing this
controlled-
release pharmaceutical composition as well as a controlled-release
pharmaceutical
preparation comprising particles of this controlled-release pharmaceutical
composition.
Background of the Invention
Sustained-release pharmaceutical preparations are developed for the purpose of
improving compliance as a result of reducing the number of times they are
administered
or preventing adverse reaction by making the blood concentration fluctuations
(peakltrough) smaller and thereby realizing stable therapeutic results, and
various
pharmaceutical preparations have been developed in recent years. Various
sustained-
release pharmaceutical preparations have been created by the present applicant
as well.
Of these, hydrogel sustained-release pharmaceutical preparations comprising a
hydrophilic base (also gelation enhancer hereafter) and hydrogel-forming
polymer can be
easily manufactured because the composition and components are simple. This
sustained-release pharmaceutical preparation can release a drug in the upper
digestive
tract, including the stomach and the small intestine, as well as the lower
digestive tract,
including the colon. In other words, the entire digestive tract can be used as
the site of
absorption. Therefore, it is highly practical and very useful as a
pharmaceutical
CA 02547939 2003-12-24
preparation with small inter-subject variation in terms of drug absorption in
humans (for
instance, refer to Patent Reference 1: International Publication Pamphlet No.
94/06414).
The inventors of inventions relating to the above-mentioned sustained-release
pharmaceutical preparations proposed various polymers as hydrogel-forming
polymers,
but of these, polyethylene oxide is capable of imparting particularly good
controlled-
release performance to the pharmaceutical preparation and therefore,
polyethylene oxide
is usually selected as the polymer of first choice for the hydrogel-forming
polymer.
However, polyethylene oxide is a water-soluble thermoplastic resin in the form
of a white
powder or granules whose molecular weight reaches several 100,000 to several
1,000,000
that is obtained by polymerization of ethylene oxide, and polyethylene oxide
with a
molecular weight of 2,000,000 or higher becomes very sticky when exposed to
moisture.
Therefore, when water is added to polyethylene oxide or polyethylene oxide is
handled
under high humidity, it shows a very high viscosity, and polyethylene oxide
can therefore
be perceived as a substance that is difficult to handle during each process of
pulverization, granulation, tableting, and the like, particularly during
granulation.
Therefore, methods have been presented in the past, including wet granulation,
whereby
for example, a chloride solvent such as dichloromethane or carbon
tetrachloride or an
alcohol solvent such as methanol, ethanol, or propanol is used alone or as a
mixture with
water direct tableting, and dry granulation when sustained-release
pharmaceutical
preparations that use polyethylene oxide, particularly matrix-type controlled-
release
pharmaceutical preparations that contain polyethylene oxide as the controlled-
release
base, contain a high concentration of polyethylene oxide with a high
viscosity, (for
instance, refer to Patent Reference 1: International Publication Pamphlet No.
94/06414,
Patent Reference 2: International Publication Pamphlet No. 01/10466, Patent
Reference
3: Specification of US Patent No. 5273758). .
In addition, there is also a method of producing a pharmaceutical preparation
by
spray granulation of tablet starting materials comprising polyethylene oxide
with a
molecular weight of 100,000 using an aqueous hydroxypropylmethyl cellulose
solution
(Patent Reference 4: Specification of US Patent No. 4662880, Patent Reference
5:
Specification of US Patent No. 4810502 (corresponds to Japanese Kokai Patent
No. Hei
7-215869)). Although the conditions of wet granulation, and the like, are not
entered to
2
CA 02547939 2003-12-24
-. -a
such an extent that granulation can be conducted by persons in the field,
polyethylene
oxide with a molecular weight of 2,000,000 or higher has a viscosity of 2,000
mPa~s or
higher (millipascal second: aqueous 2% w/v solution, 25°C) and this
viscosity is
dramatically higher than the viscosity of polyethylene oxide with a molecular
weight of
100,000 of 30 to 50 mPa~s (aqueous 5% w/v solution, 25°C). Therefore,
it appears that
when the same wet granulation method is used, granulation proceeds too far or
a powder
the particles of which become thread-like in appearance is produced and a
powder that is
appropriate for tableting cannot be made in that powder particles with poor
fluidity are
produced, and the like.
Furthermore, it goes without saying that when a controlled-release
pharmaceutical
preparation containing a low dose of drug is made, it must be made so that the
active
ingredient is contained uniformly per unit of the pharmaceutical preparation.
Nevertheless, there are also problems with direct tableting and dry
granulation in that the
drug is scattered and the drug content is reduced, or uniformity of drug
content is
diminished, and further, productivity is poor because the
granulation/pulverization
process is repeated, and the like.
Furthermore, a variety of problems are indicated with wet granulation using an
organic solvent, including environmental pollution, safety during manufacture
(risk of
explosion, and the~like), expenditure on manufacturing facilities (explosion-
proof
equipment, use of organic solvents, and recovery facilities), and the like
(for instance,
refer to Patent Reference 3).
Patent Reference 1:
International Publication Pamphlet No. 94/06414
Patent Reference 2:
Internaitonal Publication Pamphlet No. 01/10466
Patent Reference 3:
Specification of US Patent No. 5,273,758
Patent Reference 4:
CA 02547939 2003-12-24
-..
Specification of US Patent No. 4,662,880
Patent Reference 5:
Specificaton of US Patent No. 4,810,502 (corresponds to Japanese Kokai Patent
No. Hei 7(1995]-215869)
Consequently, there is the need today for the presentation of a powder that is
appropriate for tableting in order to manufacture a pharmaceutical composition
for
controlled release of active substances containing polyethylene oxide with a
molecular
weight of 2,000,000 or higher and having good uniformity of drug content, the
presentation of a controlled-release pharmaceutical composition containing
this powder,
and the presentation of a method of manufacturing this powder or a controlled-
release
pharmaceutical composition containing this powder.
Disclosure of the Invention
The present inventors knew that many problems are encountered and
realistically,
manufacture is difficult during manufacturing a powder for controlled-release
by aqueous
system by using polyethylene oxide particles when the wet granulation method
using a
conventional binder is employed. That is, for instance, a powder that is
appropriate for
tableting cannot be manufactured because various diverse problems are
encountered. For
instance, when a binder that has binding force but shows poor plasticity, such
as PVP, is
used, granulation proceeds too_ far and powder particles with a high specific
volume and
poor fluidity are obtained, when a saccharide that has viscosity increasing
power and
binding force but becomes thread-like during spray drying, such as sorbitol,
or a
surfactant that has plasticity but shows poor binding force, such as
polysorbate, is used, a
powder with a small particle diameter is produced (the powder further breaks
down into
very fine particles) and becomes a powder that has a strong tendency toward
being
scattered and therefore, tableting is obstructed, and the like.
Therefore, the, present inventors discovered that when a portion of the
polyethylene glycol (also PEG hereafter) that is used as a gelation enhancer
(hydrophilic
base) of the components of the above-mentioned hydrogel-forming sustained
release
pharmaceutical preparation is added to a suspension of the drug and this
suspension is
4
CA 02547939 2003-12-24
sprayed on the polyethylene oxide, polyethylene oxide with a high viscosity
does not
become thread-like and can be sized into powder that has properties (specific
volume,
and the like) suitable for tableting. Surprisingly, the inventors discovered
that even if a
suspension containing a low dose of the drug is sprayed, the controlled-
release
pharmaceutical preparation consisting of this spray-dried product is a
pharmaceutical
preparation with superior uniformity of content.
As a result of further intense studies focusing on polyethylene oxide, the
inventors
discovered that when polyethylene oxide of a high viscosity and PEG in solid
form are
used for the fluidized bed granulator and an aqueous solution of the drug is
sprayed on
this, a polyethylene oxide sized product showing properties suitable for
tableting can be
produced, as with the above-mentioned method, and that superior uniformity of
content is
displayed by the controlled-release pharmaceutical preparation obtained by
tableting this
sized product.
Furthermore, the inventors also discovered that powder particles with
polyethylene oxide properties that are appropriate for tableting, and a
controlled-release
pharmaceutical preparation with excellent uniformity of content that is
obtained by
tableting these polyethylene oxide powder particles are obtained when
hydroxypropylmethyl cellulose (also HPMC hereafter), hydroxypropyl cellulose
(also
HPC hereafter) or methyl cellulose (also.MC hereafter) of a specific viscosity
glade is
used as with PEG.
The details of this mechanism are still unclear. The polyethylene oxide
product
itself is a powder that is an aggregate of very fine particles and when water
is used, this is
broken down into fine particles, or on the other hand, marked granulation will
proceed.
However, it is hypothesized that by selecting and using a specific substance
with the
appropriate plasticity and binding force, the polyethylene oxide particles
themselves will
rebind with the polyethylene oxide powder particles that have properties
appropriate for
tableting and thereby be sized. The polyethylene oxide powder of the present
invention
is also referred to hereafter as the polyethylene oxide sized product or
simply the sized
product.
The present invention is based on this series of discoveries, presenting
CA 02547939 2003-12-24
1. a pharmaceutical composition for controlled release comprising a sized
product, which comprises (a) a drug, (b) polyethylene oxide with a viscosity-
average
molecular weight of 2,000,000 or more, and (c) a size controlling agent for
(b)
polyethylene oxide and wherein of said three components, at least size
controlling agent
(c) is uniformly dispersed in polyethylene oxide (b),
2. a pharmaceutical composition for controlled release according to above-
mentioned 1, wherein (c) size controlling agent for (b) polyethylene oxide is
one or two
or more selected from the group consisting of polyethylene glycol that is
solid at ordinary
temperature, hydroxypropylmethyl cellulose of 2 to 15 mPa~s (2% w/v),
hydroxypropylmethyl cellulose of 2 to 10 mPa~s (2% w/v), and methyl cellulose
of 2 to
15 mPa~s (2% w/v),
3. a pharmaceutical composition for controlled release according to above-
mentioned 1, wherein the amount of (c) size controlling agent for (b)
polyethylene oxide
is 0.5 to 60 wt% per polyethylene oxide (b),
4. a pharmaceutical composition for controlled release according to above-
mentioned 1, wherein when polyethylene glycol is selected as (c) size
controlling agent
for (b) polyethylene oxide; the amount is 0.5 to 60 wt% per unit of the
pharmaceutical
preparation,
5. a pharmaceutical composition for controlled release according to above-
mentioned 1, wherein the amount of polyethylene oxide (b) is 10 to 95 wt% per
unit of
the pharmaceutical preparation,
6. a pharmaceutical composition for controlled release according to above-
mentioned 1, wherein the amount of polyethylene oxide (b) added is at least 70
mg per
unit of the pharmaceutical preparation,
7. a pharmaceutical composition for controlled release according to above-
mentioned 1, wherein viscosity-average molecular weight of polyethylene oxide
(b) is
5,000,000 or higher,
8. a pharmaceutical composition for controlled release according to above-
mentioned 1, which further comprises a hydrophilic base,
6
CA 02547939 2003-12-24
9. a pharmaceutical composition for controlled release according to above-
mentioned 8, wherein the amount of water required to dissolve 1 g of the above-
mentioned base is 5 ml or less (20 ~ S°C),
10. a pharmaceutical composition for controlled release according to above-
mentioned 9, wherein the hydrophilic base is polyethylene glycol, sucrose, or
polyvinyl
pyrrolidone,
11. a pharmaceutical composition for controlled release according to above-
mentioned 8, wherein the amount of hydrophilic base is 5 to 80 wt% per unit of
the
pharmaceutical preparation,
12. a pharmaceutical composition for controlled release according to above-
mentioned 1 or 8, which further comprises yellow ferric oxide and/or red
ferric oxide,
13. a pharmaceutical composition for controlled release according to above-
mentioned 12, wherein the amount of yellow ferric oxide and/or ferric oxide is
0.3 to 20
wt% per polyethylene oxide,
14. a pharmaceutical composition for controlled release according to above-
mentioned 1, wherein the amount of drug is 85 wt% or less per unit of the
pharmaceutical
preparation,
15. a pharmaceutical composition for controlled release according to above-
mentioned 14, wherein the amount of drug is 10 wt% or less per unit of the
pharmaceutical preparation,
16. a pharmaceutical composition for controlled release according to any one
of above-mentioned 1 through 15, wherein the drug is tamsulosin hydrochloride,
17. a pharmaceutical composition for controlled release according to above-
mentioned 1, which comprises essentially no organic solvent, and
18. a polyethylene oxide-containing powder for controlled-release
pharmaceutical compositions, which contains polyethylene oxide (b) with a
viscosity-
average molecular weight of 2,000,000 or higher and (c) a size controlling
agent for (b)
polyethylene oxide and wherein at least size controlling agent (c) is
uniformly dispersed
in polyethylene oxide (b).
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CA 02547939 2003-12-24
19. a sized product according to claim 18, wherein (c) a size controlling
agent
for (b) polyethylene oxide is one or two or more selected from the group
consisting of
polyethylene glycol that is solid at ordinary temperature, hydroxypropylmethyl
cellulose
of 2 to 15 mPa~s (2% w/v), hydroxypropylmethyl cellulose of 2 to 10 mPa~s (2%
w/v),
and methyl cellulose of 2 to 15 mPa~s (2% w/v),
20. a sized product according to claim 18, wherein the amount of (c) a size
controlling agent for (b) polyethylene oxide is 0.5 to 60 wt% per polyethylene
oxide (b),
21. a sized product according to claim 18, wherein when polyethylene glycol
is selected as (c) a size controlling agent for (b) polyethylene oxide, the
amount is 0.5 to
60 wt% per unit of the pharmaceutical preparation,
22. a sized product according to claim 18, wherein the amount of polyethylene
oxide (b) is 10 to 95 wt% per unit of the pharmaceutical preparation,
23. a sized product according to claim 18, wherein the amount of polyethylene
oxide (b) added is at least 70 mg per unit of the pharmaceutical preparation,
24. a sized product according to claim 18, wherein viscosity-average
molecular weight of polyethylene oxide (b).is 5,000,000 or higher,
25. a sized product according to claim 18, which further comprises a
hydrophilic base,
26. a sized product according to claim 25, wherein the amount of water
required to dissolve 1 g of said base is 5 ml or less (20 ~ 5°C),
27. a sized product according to claim 26, wherein the hydrophilic base is
polyethylene glycol, sucrose, or polyvinyl pyrrolidone,
28. a sized product according to claim 25, wherein the amount of hydrophilic
base is 5 to 80 wt% per unit of the pharmaceutical preparation,
29. a sized product according to any one of claims 18 to 25, which further
comprises yellow ferric oxide andlor red ferric oxide,
30. a sized product according to claim 29, wherein the amount of yellow ferric
oxide and/or ferric oxide is 0.3 to 20 wt% per polyethylene oxide,
8
CA 02547939 2003-12-24
31. a sized product according to claim 18, which further comprises a drug,
32. a sized product according to claim 18 or 31, wherein the amount of drug is
85 wt% or less per unit of the pharmaceutical preparation,
33. a sized product according to claim 32, wherein the amount of drug is 10
wt% or less per unit of the pharmaceutical preparation,
34. a sized product according to any one of claims 18 through 33, wherein the
drug is tamsulosin hydrochloride,
35. a sized product according to claim 18, which comprises essentially no
organic solvent,
36. a use of a sized product according to any one of claims 18 through 35 as a
base for controlled-release. preparation.
International Publication Pamphlet No. 92/10169 (corresponding to Japanese
Patent No. 3239319) describes that the invention relating to a manufacturing
method for a
sustained-release dosage form for oral use, utilizing hydrophilic matrix gel
component as
a base, performing by using aqueous solution containing 20 - SO % solute,
which is
selected one or more from a poly-alcohol or polyvinylpyrrolidone, which is
capable of
becoming gel when, administering orally to a mammal such as human, wherein gel-
forming component is hydroxypropylmethylcellulose having various kinds of
viscosity
grade, wherein manufacturing wet-granules is preventing gelation of
hydroxypropylmethylcellulose during granulation process. Said pamphlet also
describes
that wet-granulation by utilizing granulation in order to make granules
obtained by .
granulation crushable as a granulation method for HPMC. However, the present
invention is not a technology relating to method of wet-granulation, but
discloses a
method for re-sizing granulation by re-binding microscopic particles of
polyethylenoxide
which is broken up by spraying water, which becomes highly thread-like in
appearance.
The "sizing" in the present Specification is different from the unit operation
of
"granulation" that is normally conducted by persons in this field, and it is
also different
from the process whereby a portion of a specific size is extracted by a
sifting operation,
and the like.
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CA 02547939 2003-12-24
The "granulation" in the present Specification means a series of unit
operations by
which a granulated product of good uniformity is manufactured by binding
particles to
one another in order to improve adhesion and scattering of fine powder. In
particular,
when a pharmaceutical preparation with a low drug dose and good uniformity of
content
is to be manufactured, the drug is separately pulverized by itself, or
pulverized after
mixing with some of the additives to make fine particles in order to guarantee
uniformity
of content. Then a granulation process is generally conducted using a
fluidized bed
granulator. Consequently, growth of the particles is promoted by "granulation"
and
therefore, a powder with a large particle diameter and large specific volume
is
manufactured.
In contrast to this, "sizing" is a series of unit procedures whereby water is
sprayed
onto the polyethylene oxide (Also PEO hereafter) powder with a high viscosity
(commercial product) that is used in the present invention to manufacture
powder
particles (sized product) having a pre-determined particle diameter and a pre-
determined
specific volume. In detail, "polyethylene oxide sized products (Also PEO sized
products
hereafter)", for instance, in contrast to the case that part or all of
particle breaks down
into very fine particle when water is sprayed onto a PEO powder (commercial
products)
used in the present invention and become powder products being bound
irregularly after
drying, the case using the polyethylene oxide sizing agent used in the present
invention,
the PEO powder is sized to the powder particle which shows specific range of
particle.
size and specific range of specific volume as a result of keeping the PEO
powder from
breaking down into very fine particles and/or as a result of re-binding into
spherical shape
during drying, and the like, are contained. That is, the "sizing" in the
present
specification means a series of single operations, not by which the PEO
particles grow,
but by which very fine particles of PEO that have been broken down by spraying
with
water re-bind during drying and re-form a powder of a size and specific volume
appropriate for tableting.
The "particle diameter" in the present specification is represented by the
average
particle diameter defined as the cumulative 50% average particle diameter of
the powder
(,um) and the amount of fine powder (%) of 75 ~m or smaller. Specific volume
is
represented by the volume per unit weight of the powder (ml/g).
CA 02547939 2003-12-24
r._ 1
"Comprises essentially no organic solvent." or "uses essentially no organic
solvent" in the present specification means in addition to the fact that water
only is
always used as the solvent, organic solvent remains and/or is used within a
range that is
pharmaceutically acceptable, or organic solvent remains andlor is used within
the range
of environmental standards. To this extent, it does not exclude compositions
that
comprise organic solvent within a range that is pharmaceutically acceptable or
within a
range that does not exceed environmental standards.
The controlled-release pharmaceutical composition or the sized product of the
present invention will now be described in detail:
There are no particular restrictions to the drug used in the present invention
as
long as it is an active ingredient that is effective in terms of treatment or
in terms of
prevention. Examples of this drug are anti-inflammatory, antipyretics,
anticonvulsants,
or analgesics such as indomethacin, diclofenac, diclofenac sodium, codeine,
ibuprofen,
phenylbutazone, oxyphenbutazone, mepyrizole, aspirin, etenzamide,
acetaminophen,
aminopyrine, phenacetin, butyl bromide scopolamine, morphine, ethomidrin,
pentazocin,
fenoprofen calcium, naproxen, celecoxib, valdecoxib, and tramadol, anti-
rheumatic drugs
'such as etodolac, anti-tuberculosis drugs such as isoniazide, and ethambutol
hydrochloride, drugs_for treatment of circulatory disorders such as isosorbide
nitrate,
nitroglycerin, riifedipine, barnidepine hydrochloride, nicardipine
hydrochloride,
dipyridamol, amrinone, indenolol hydrochloride, hydralazine hydrochloride,
methyl
dopa, furosemide, spironolactone, guanetidine nitrate, reserpine, amothrolol
hydrochloride, lisinopril, methoprolol, pyrocarbine, and talsaltan,
neuroleptics.such as
chloropromazine hydrochloride, amitripityline hydrochloride, nemonapride,
haloperidol,
moperon hydrochloride, perfenazine, diazepam, lorazepam, chlordiazepoxide,
azinazolam, alprazolam, methylphenidate, milnasipran, peroxetin, risperidone,
and
sodium valproate, antiemetics such as metoclopramide, ramosetron
hydrochloride,
granisetron hydrochloride, ondansetron hydrochloride, and azasetron
hydrochloride,
antihistamines such as chlorpheniramine maleate and diphenhydramine
hydrochloride,
vitamins such as thiamine nitrate, tocopherol acetate, cycothiamine, pyridoxal
phosphate,
cobamamide, ascorbic acid, and nicotinamide, drugs for gout~such as
allopurinol,
colchicine, and probenecid, drugs for Parkinson's disease such as levodopa and
selegiline,
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CA 02547939 2003-12-24
_ _ _ ,
hypnotic sedatives such as amobarbitol, bromovaleryl urea, midazolam, and
chloral
hydrate, anti-malignant tumor drugs such as fluorouracil, carmofur,
acralvidine
hydrochloride, cyclophosphamide, and thiodepa, anti-allergy drugs such as
pseudoephedrin and terfenadine, drugs used to treat decongestant such as
phenylpropanolamine and ephedrines, drugs used for diabetes such as
acetohexamide,
insulin, torbutamide, desmopressin, and glypizine, diuretics such as
hydrochlorothiazide,
polythiazide, and triamuteren, bronchodilators such as aminophylline,
formoterol
furmate, and theophylline, antitussives such as codeine phosphate, noscapine,
dimemorphan phosphate, and dextromethorphan, anti-arrhythmia drugs such as
quinidine
nitrate, digitoxin, propaphenone hydrochloride, and procainamide, topical
anesthetics
such as ethyl aminobenzoate, lidocaine, and dibucaine hydrochloride, anti-
epilepsy drugs
such as phenytoin, ethosuximide, and primidone, synthetic corticosteroids such
as
hydrocortisone, prednisolone, triamcinolone, and betamethazone, drugs for the
digestive
tract such as famotidine, ranitidine hydrochloride, cimetidine, sucralfate,
sulphide,
tepreson, pravatol, 5-aminosalicylic acid, sulfathalazin, omeprazol, and
lansoprazole,
drugs for the central nervous system such as indeloxazine, id~penon, thiaprid
hydrochloride, biphemelan hydrochloride, and calcium homopantothenate, drugs
for
treatment of hyperlipidemia such as pravastatin sodium, simvastatin,
lovastatin, and
atorvastatin, antibiotics such as ampicillin hydrochloride phthalidyl,
cefotetan, and
josamycin, BPH drugs such as tamsulosin, doxazosin mesylate, and terazosin
hydrochloride, anti-asthma drugs such as pranlukast, zafirlukast, albuterol,
ambroxol,
budesonide, and reperbutenol, drugs used to improve peripheral circulation of
prostaglandin I derivatives such as beraprost sodium, anticoagulants,
hypotensive drugs,
drugs used to treat heart failure, drugs used to treat the various
complications of diabetes,
drugs used to treat gastric ulcers, drugs used to treat skin ulcers, drugs
used to treat
hyperlipidemia, anti-asthma drugs, and the like. The drug can be used in free
form or as
a salt that is pharmaceutically acceptable. Moreover, one or a combination of
two or
more drugs can be used. Furthermore, even better results are obtained fiom the
present
invention when a very small amount of active ingredient that is effective in
terms of
treatment or prevention or a drug that is effective in low doses and is
slightly water
12
CA 02547939 2003-12-24
soluble is used as the drug in the present invention. Of the above-mentioned
drugs,
tamsulosin is particularly preferred as the drug.
The chemical name for tamsulosin is (R)(-)-S-(2-((2-(0-
ethoxyphenoxy)ethyl)amino)propyl)-2-methoxybenzenesulfonamide and it is
represented
by the following structural formula. It was first disclosed together with its
pharmaceutically acceptable salts in Japanese Kokai Patent No. Sho 56(1981)-
110665.
CH3
CH30 ~ , CHZ C-NHCHZCHzO
HzN02S H 0-CH2CH3
It is known that tamsulosin and its salts have adrenalin a1A receptor-blocking
activity, in other words, the same hydrochloride (tamsulosin hydrochloride)
has the
ability to block the al receptor of the urethra and prostate and therefore is
a popular drug
for reducing pressure applied to the prostate along the pressure curvature
inside the
urethra and for improvement of the dysuria that accompanies prostatomegaly.
Tamsulosin hydrochloride is also a drug that is clinically very useful in that
it has been
recognized as clinically effective for the treatment of lower urinary tract
disorders.
Tamsulosin and its pharmaceutically acceptable salts can be easily procured by
the manufacturing method entered in Japanese Kokai Patents No. Sho 56-110665
and No.
Sho 62-114952, or by manufacturing in accordance with this method.
Tamsulosin can form a pharmaceutically acceptable acid or a base addition salt
with a wide variety of inorganic and organic salts and bases. Such salts are
also a part of
the present invention. Examples are salts of inorganic acids, such as
hydrochloric acid,
sulfuric acid, and phosphoric acid, salts of organic acids, such as fumaric
acid, malic
acid, citric acid, and succinic acid, salts of alkali metals, such as sodium
and potassium,
and salts of alkali earth metals, such as calcium and magnesium.
Hydrochlorides are
most preferred in the present invention and these salts can be manufactured by
conventional methods.
13
CA 02547939 2003-12-24
1
'The amount of drug that is added is usually selected as needed and. used as
needed
based on the type of drug and medical use (indications), and there are no
special
restrictions as long as it is the amount that is effective in terms of
treatment or prevention.
A drug that is effective in very small doses (low-dose drug) is particularly
preferred
because the desired effects of the present invention are even better. However,
it can be
easily assumed that uniformity of content can even be accomplished with drugs
that are
effective in high doses (high-dose drugs), and therefore, there are no
particular
restrictions to the amount of drug that is added. This amount that is added is
illustrated
later using a hydrogel sustained-release pharmaceutical preparation. However,
it is
preferably 85 wt% or less, more preferab1y.80 wt% or less, further preferably
50 wt%,
and more further preferably 10 wt% or less, of the total pharmaceutical
preparation. It is
1 wt% or less when the drug is tamsulosin. The dose of tamsulosin or its
pharmaceutically acceptable salt is determined as needed in accordance with
the
individual case taking into consideration the route of administration, the
symptoms of the
illness, the age and sex of the administration subject, and the like. The dose
of
tamsulosin hydrochloride is normally approximatelyØ1 mg to 1.6 mg/day of
active
ingredient to one adult by oral administration and this is administered orally
once a day.
There are no special restrictions to the polyethylene oxide (Also PEO
hereafter)
that is used in the present invention as long as it is one with which release
of drug from
the controlled-release pharmaceutical preparation containing PEO as the
sustained release
base can be controlled. Examples of this PEO are POLYOX~ WSR-303 (viscosity-
average molecular weight of 7,000,000, viscosity of 7,500 to 10,000 mPa~s
(millipascal
second: in an aqueous 1% W/V solution at 25°C), POLYOX~ WSR Coagulant
(viscosity-
average molecular weight of 5,000,000, viscosity of 5,500 to 7,500 mPa~s (in
an aqueous
1% W/V solution at 25°C)), POLYOX~ WSR-301 (viscosity-average molecular
weight
of 4,000,000, viscosity of 1,650 to 5,500 mPa~s (in an aqueous 1% W/V solution
at
25°C)), and POLYOX~ WSR N-60K (viscosity-average molecular weight of
2,000,000,
viscosity of 2,000 to 4,000 mPa~s (in an aqueous 2% W/V solution at
25°C) (all
manufactured by The Dow Chemical Company), ALKOX~ E-75 (viscosity-average
molecular weight of 2,000,000 to 2,500,000, viscosity of 40 to 70 mPa~s (in an
aqueous
0.5% W/V solution at 25°C)), ALKOX~ E-100 (viscosity-average molecular
weight of
14
CA 02547939 2003-12-24
2,500,000 to 3,000,000, viscosity of 90 to 110 mPa~s (in an aqueous 0.5% W/V
solution
at 2S°C)), ALKOX~ E-130 (viscosity-average molecular weight of
3,000,000 to
3,500,000, viscosity of 130 to 140 mPa~s (in an aqueous O.S% W/V solution at
25°C)),
ALKOX~ E-160 (viscosity-average molecular weight of 3,600,000 to 4,000,000,
viscosity of 150 to 160 mPa~s (in an aqueous O.S% W/V solution at
2S°C)), and
ALKOX~ E-240 (viscosity-average molecular weight of 4,000,000 to 5,000,000,
viscosity of 200 to 240 mPa~s (in an aqueous O.S% W/V solution at 2S°C)
(all
manufactured by Meisei Chemical Works, Ltd.), and PEO-8 (viscosity-average
molecular
weight of 1,700,000 to 2,200,000, viscosity of 20 to 70 mPa~s (in an aqueous
O.S% W/V
solution at 25°C)), PEO-15 viscosity-average molecular weight of
3,300,000 to
3,800,000, viscosity of I30 to 250 mPa~s (in an aqueous Q.5% W/V solution at
25°C)),
and PEO-18 (viscosity-average molecular weight of 4,300,000 to 4,800,000,
viscosity of
250 to 480 mPa~s (in an aqueous 0.5% W/V solution at 25°C)) (all
manufactured by
Sumitomo Seika Chemicals Co., Ltd.). Of these, PEO with a high viscosity at
the time of
gelling or with a high viscosity-average molecular weight is preferred. PEO
with a
viscosity of 2,000 mPa~s or higher in an aqueous 2% solution (25°C) or
with a viscosity-
average molecular weight of 2,000,000 to 10,000,000.is preferred. PEO with a
viscosity-
average molecular weight of 4,000,000 to 10,000,000 is further preferred and
that with a
viscosity-average molecular weight of 5,000,000 to 10,000,000 is more further
preferred.
PEO with a viscosity-average molecular weight of 7,000,000 (for instance,
POLYOX~
WSR-303) is optimah One or a combination of two or more PEO of different
molecular
weights, grades, and the like can be used.
There are no special restrictions to the amount of polyethylene oxide added as
long as it is the amount with which release of the drug from the hydrogel-
forming
sustained-release pharmaceutical preparation can usually be controlled.
However, it is
preferred that it be 10 to 95 wt% per the total pharmaceutical preparation,
and 15 to 90
wt% per the total pharmaceutical preparation is further preferred. Moreover,
the amount.
of PEO that is added is preferably 70 mg or more, further preferably 100 mg or
more,
more further preferably 150 mg or more, per 1 unit of the pharmaceutical
preparation. If
the drug is tamsulosin hydrochloride, the amount of PEO added is preferably
100 mg to
300 mg, further preferably 150 mg to 250 mg, more further preferably 200 mg. A
CA 02547939 2003-12-24
controlled-release pharmaceutical preparation (tablet) that is manufactured
using this
amount of PEO with a viscosity-average molecular weight of 7,000,000 (for
instance,
PEO with the brand name POLYOX WSR-303) from among the above-mentioned types
of PEO will provide marked effects as a controlled-release pharmaceutical
preparation.
There are no special restrictions to the size controlling agent for
polyethylene
oxide that is used in the present invention as long as it is powder particles
that are
suitable .for tableting PEO of a high viscosity with an aqueous system. This
size
controlling agent is a substance having the appropriate plasticity and binding
ability.
Solid polyethylene glycol (PEG hereafter), low viscosity grades of
hydroxypropylmethyl
cellulose (HPMC hereafter), hydroxypropyl cellulose (HPC hereafter), and
methyl .
cellulose (MC hereafter), and the like are given as this sine controlling
agent. This size
controlling agent can be used dissolved and/or suspended in water. Moreover,
because
the above-mentioned effects can be realized with PEG by dissolving part of the
PEG in
solid form with high water solubility using sprayed water, it can be used as
the PEO size
controlling agent of the present invention, even if it is added in solid form.
PEG that is solid at ordinary temperature (PEG4000, PEG6000, PEG8000) is
preferred as the PEG. Macrogol 4000 (Japanese Pharmacopoiea, molecular weight
of
2,600 to 3,800, brand name: Macrogol 4000/Sanyo Chemical Industries, Ltd., NOF
Corporation, Lion Corporation, and the like), Macrogol 6000 (Japan
Pharmaceopoiea,
molecular weight of 7,300 to 9,300, brand name: Macrogol 6000/Sanyo Chemical
Industries, Ltd., NOF Corporation, Lion Corporation, and the like), Macrogol
20000
(Japan Pharmacopoeia, molecular weight of 15,000 to 25,000, brand name:
Macrogol
20000 (Sanyo Chemical Industries, Ltd., NOF Corporation, Lion Corporation, and
the
like), polyethylene glycol 8000 (IJSP/NF, molecular weight of 7,000 to 9,000,
brand
name: Polyethylene glycol 8000/The Dow Chemical Company, and the like), and
the
like are specifically given. Low-viscosity grades of HPCM (viscosity of 2 to
15 mPa~s,
aqueous 2% W/V solution, 20 °C) are preferred. The brand names of TC-SE
(viscosity of
3 mPa~s, aqueous 2% W/V solution, 20°C, Shin-Etsu Chemical Co., Ltd.),
TC-SR
(viscosity of 6 mPa~s, aqueous 2% W/V solution, 20°C, Shin-Etsu
Chemical Co., Ltd.),
TC-SS (viscosity of 15 mPa~s, aqueous 2% WN solution, 20°C, Shin-Etsu
Chemical Co.,
16
CA 02547939 2003-12-24
Ltd.), Methocel E3 (viscosity of 3 mPa~s, aqueous 2% W/V solution,
20°C, The Dow
Chemical Company), Methocel ES (viscosity of 5 mPa~s, aqueous 2% W/V solution,
20°C, The Dow Chemical Company), Methocel E15 (viscosity of 15 mPa~s,
aqueous 2%
W/V solution, 20°C, The Dow Chemical Company), and the like are
specifically given.
Low viscosity grades (viscosity of 2 to 10 mPa~s, aqueous 2% W/V solution,
20°C) are
preferred as the HPC. The brand names of HPC-SSL (viscosity of 3.0 to 5.9
mPa~s,
aqueous 2%W/V solution, 20°C, Nippon Soda Co., Ltd.), HPC-SL (viscosity
of 2.0 to 2.9
mPa~s, aqueous 2% WN solutoin, 20°C, Nippon Soda Co., Ltd.), HPC-L
(viscosity of
6.0 to 10.0 mPa~s, aqueous 2% W/V solution, 20°C, Nippon Soda Co.,
Ltd.), and the like
are specifically given. Low viscosity grades (viscosity of 2 to 15 mPa~s,
aqueous 2%
W/V solution, 20°C) are preferred as the MC. The brand name of Methocel
A15-LV
(viscosity of 15 mPa~s, aqueous 2% W/V solution, 20°C, The Dow Chemical
Company),
Metolose SM4 (viscosity of 4 mPa~s, aqueous 2% W/V solution, 20°C,
Shin-Etsu
Chemical Co., Ltd.), Metolose SM15 (viscosity of 15 mPa~s, aqueous 2% W/V
soluition,
20°C, Shin-Etsu Chemical Co., Ltd.), and the like are specifically
given.
' PEG and/or HPMC are further preferred as the size controlling agent for
polyethylene oxide, and PEG is the ideal size controlling agent of the present
invention,
even if added in powder form. One or a combination of two or more size
controlling
agents of the present'invention can be used. The method whereby water or an
aqueous
solution containing a binder is sprayed after physical mixing, the method
whereby an
aqueous solution containing a size controlling agent is sprayed, and the like
are given as
the state in which the size controlling agent is used.
There are no special restrictions to the amount of size controlling agent for
polyethylene oxide that is used as long as it is the amount that can size PEO
with an
aqueous system. It is usually 0.5 to 60 wt% per unit of pharmaceutical
preparation.
When PEG as the size controlling agent of the present invention' is sprayed in
the form of
an aqueous solution, the amount is preferably 0.5 to 3 wt%, further preferably
1 to 2 wt%,
per unit of pharmaceutical preparation. When a substance other than PEG as the
size
controlling agent of the present invention is sprayed in the form of an
aqueous solution,
the amount is preferably 0.5 to 3 wt%, further preferably 1 to 2 wt%, per unit
of
1?
CA 02547939 2003-12-24
pharmaceutical preparation. Moreover, when PEG is used as a solid size
controlling
agent, the amount is preferably 5 to 60 wt%, further preferably 10 to 30 wt%.
The amount of substance other than PEG as the size controlling agent that is
used
in the form of an aqueous solution is small when compared to the amount that
is usually
used as a binder (3 to 5 wt%). 1f less than 0.5 wt% is used, there will be
problems in that
the desired sizing will not be performed and there will be a large amount of
fine powder,
there will be a reduction in uniformity of drug content, a powder of poor
fluidity will
further be produced, and the like. If the amount is more than 3 wt%,
granulation will
proceed to too great an extent and as a result, fluidity of the powder will
decrease, the
powder will be too large, re-pulverizing after drying will be necessary, and
the like and as
a result, there is concern that problems will remain with uniformity of drug
content.
There are no special restrictions to the controlled-release pharmaceutical
composition of the present invention as long as it is a pharmaceutical
composition,
particularly a pharmaceutical preparation, with which release of the drug is
controlled.
The hydrogel sustained-release pharmaceutical preparation in International
Publication
Pamphlet No. 94/06414 is an example of this controlled-release pharmaceutical
composition (particularly a controlled-release pharmaceutical. preparation).
The above-
mentioned hydrogel, sustained-release pharmaceutical preparation consists of a
drug, a
gelation enhancer with a specific solubility (hydrophilic base), and PEO of a
specific
molecular weight as the basic structural components. Moreover, when PEO is
used as the
controlled-release pharmaceutical preparation, yellow ferric oxide and/or red
ferric oxide
are added as PEO stabilizers, as entered in International Publication Pamphlet
No.
01/10466. The mechanism of drug release is as entered in International
Publication
Pamphlet No. 94/06414 with any pharmaceutical preparation. That is, the
controlled-
release pharmaceutical preparation absorbs water during its stay in the upper
digestive
tract to undergo substantially complete gelation (70% or higher, preferably
80% or
higher) and then it moves to the lower digestive tract as the surface of the
pharmaceutical
preparation is eroded and drug continues to be released with erosion.
Therefore, good
and continuous release and absorption of the drug are performed, even in the
colon with a
small water content. The controlled-release pharmaceutical composition or
hydrogel
18
CA 02547939 2003-12-24
_.
sustained-release pharmaceutical preparation can also contain pharmaceutical
fillers as
needed.
When the controlled-release pharmaceutical preparation of the present
invention
further contains a hydrophilic base, there are no special restrictions to the
hydrophilic
base (gelation enhancer) required in the present invention as long as it can
be dissolved
before the PEO that is required in the present invention gels. The amount of
water
needed to dissolve 1 g of this hydrophilic base is preferably S ml or less (20
~ 5°C),
further preferably 4 ml or less (same temperature). Hydrophilic polymers such
as
polyethylene glycol (for instance, Macrogol 400, Macrogol 1500, Macrogol 4000,
Macrogol 6000, and Macrogol 20000 (all manufactured by NOF Corporation)) and
polyvinyl pyrrolidone (for instance, PVP~ K30 (BASF); sugar alcohols such as D-
sorbitol and xylitol, saccharides such as sucrose, maltose, lactulose, D-
fructose, dextran
(for instance, Dextran 40), and glucose, surfactants such as polyoxyethylene-
hydrogenated castor oil (for instance, Cremophor~ RH40 (BASF, HCO-40, HCO-60
(Nikko Chemicals), polyoxyethylene polyoxypropylene glycol (for instance;
Pluronic~
F68 (Asahi Denka Co., Ltd.) and polyoxyethylene sorbitan higher fatty acid
esters (for
instance, Tween 80 (Kanto Kagaku Co., Ltd.), salts such as sodium chloride and
magnesium chloride, organic acids such as citric acid and tartaric acid, amino
acids such
as glycine, ~-alanine, and lysine hydrochloride, and aminosaccharides such as
meglumine
are given as examples of the hydrophilic base. Polyethylene glycol, sucrose,
and
polyvinyl pyrrolidone are preferred and polyethylene glycol (particularly
Macrogol 6000
and Macrogol 8000) are further preferred. One or a combination of two or more
hydrophilic bases can be used iwthe present invention.
The amount of hydrophilic base (gelation enhancer) that is used is preferably
5 to
80 wt% per total pharmaceutical preparation, further preferably 5 to 60 wt%
per total
pharmaceutical preparation. Furthermore, when the gelation enhancer serves as
what is
called a size controlling agent in the present invention, the amount of
gelation enhancer is
calculated as the combined amount.
It is preferred that yellow ferric oxide and/or red ferric oxide is added as
the PEO
stabilizer to the controlled-release pharmaceutical preparation of the present
invention
19
CA 02547939 2003-12-24
CUSPS No. 9,629,405 (refer to corresponding International Patent Publication
Pamphlet
No. 01/10466)). The amount of this stabilizer is preferably 1 to 20 wt%,
further
preferably 3 to 15 wt%, per total mount of pharmaceutical preparation when it
is a
physical mixture in a matrix. For instance, the amount of red ferric oxide is
preferably 5
to 20 wt%, further preferably 10 to 15 wt%, per total amount of pharmaceutical
preparation. The amount of yellow ferric oxide is preferably 1 to 20 wt%,
further
preferably 3 to 10 wt%. When added with a film coating, the amount is
preferably 0.3 to
2%, further preferably 0.5 to 1.5%, per tablet weight. The concentration of
yellow ferric
oxide or red ferric oxide that is present in the film in this case is
preferably 5 to 50%,
further preferably 10 to 20%. The "physical mixture in a matrix" used here is
defined as
a means with which, for instance, drug, polyethylene oxide and the above-
mentioned
ferric oxide are uniformly dispersed so that the drug and the above-mentioned
ferric
oxide are uniforriily dispersed in the PEO that becomes the main base of the
controlled-
release pharmaceutical preparation. Moreover, the "film coating" here is
defined as for
instance, dissolution or suspension of the above-mentioned ferric oxide in a
water-soluble
polymer solution such as hydroxypropyl methyl cellulose and coating tablets
that have
been separately prepared with this in the form of a thin film. The yellow
ferric oxide
and/or red ferric oxide of the present invention can usually be found anywhere
in the
pharmaceutical preparation. For instance, the yellow ferric oxide and/or red
ferric oxide
can be present in the film of film coating, in the granulation product of
granulation, or in
the matrix (for instance, near the polyethylene oxide).
A variety of pharmaceutical fillers are further used as needed with the
controlled-
release pharmaceutical composition of the present invention to make a
pharmaceutical
preparation. There are no special restrictions to these drug fillers as long
as they are
pharmaceutically and pharmacologically acceptable. For instance, binders,
disintegrating
agents, sour flavorings, foaming agents, artificial sweeteners, fragrances,
lubricants,
coloring agents, stabilizers, buffer agents, and antioxidants are used.
Hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol,
methyl
cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methyl cellulose, and
gum arabic
are examples of binders. Corn starch, starches, carmellose calcium, carmellose
sodium,
and hydroxypropyl cellulose with a low degree of substitution are examples of
the
CA 02547939 2003-12-24
disintegrating agent. Citric acid, tartaric acid, and malic acid are examples
of the sour
flavoring. Sodium bicarbonate is an example of the foaming agent. Saccharin
sodium,
dispotassium glycyrrhizinate, aspartame, stevia, and somatin are examples of
artificial
sweeteners. Lemon, lemon lime, orange, and menthol are examples of fragrances.
Magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene
glycol, talc,
and stearic acid are examples of lubricants. Yellow ferric oxide, red ferric
oxide, yellow
food colorings No. 4 and No. 5, red food colorings No. 3 and No. 102, and blue
food
coloring No. 3 are examples of coloring agents. It is confirmed that yellow
ferric oxide
and red ferric oxide have a particularly marked photostabilizing effect on
tamsulosin
hydrochloride when used in controlled-release pharmaceutical preparations to
which
tamsulosin hydrochloride have been added, and these coloring agents are also
given as
photostabilizers. The amount of coloring agent is usually a trace (a trace to
0.1 wt%).
However, when added as the stabilizer, there are no special restrictions to
the amount as
long as it usually provides stabilizing effects as a photostabilizer, but it
is normally 0.1 to
2 wt%, preferably 0.5 to 1 wt%. Citric acid, succinic acid, fumaric acid,
tartaric acid,
ascorbic acid and their salts, glutamic acid, glutamine, glycine, aspartic
acid, alanine,
arginine, and their salts, magnesium oxide, zinc oxide, magnesium hydroxide,
phosphoric
acid, boric acid and their salts, and the like are given as buffer agents.
Ascorbic acid,
dibutyl hydroxytolu~eme and propyl gallate are given as examples of
antioxidants.
Appropriate amounts of one or a combinate of two or more pharmaceutical
fillers can be
added as needed
The method of manufacturing the controlled-release pharmaceutical composition
or the sized product of the present invention will now be described in detail:
The processes involved in the manufacture of the controlled-release
pharmaceutical composition of the present invention are essentially as follow:
(1) Process of pulverization and mixing of components,
(2) Process of suspending and/or dissolving PEO size controlling agent
(process of preparation of size controlling agent solution)
(3) Process of sizing and drying whereby the size controlling agent solution
that was prepared in above-mentioned process (2) is sprayed onto PEO of a high
viscosity
21
CA 02547939 2003-12-24
with a molecular weight of 2,000,000 or higher (process of preparing P)r0
sizing product
(powder particles)
(4) Process of uniformly mixing PEO sizing product obtained by above-
mentioned process (3) and a pharmaceutically acceptable filler
(5) Process of molding
(1) Process of pulverization and mixing of components
There are no special restrictions to the equipment and means of this process
as
long as it is a method whereby usually pulverization is pharmaceutically
possible. There
are no special restrictions to the equipment or means of the process of mixing
of each
component that follows pulverization as long as it is a method by which
usually each
component can be uniformly mixed pharmaceutically.
A hammer mill, ball mill, jet pulverization device, and colloid mill are
examples
of the pulverization device. There are no special restrictions to the
pulverization
conditions as long as they are selected as needed. For instance, in the case
of the hammer
mill, punch diameter of the screen is usually 0.5 to 5 mm, preferably 0.8 to 2
mm. The
powder feed speed is usually SO to 500 g/minute, preferably 100 to 200
g/minute. A V-
type mixer, ribbon mixer, container mixer, and high-shear agitating mixer are
examples
of the mixing device. There are no special restrictions to the mixing
conditions as long as
they are selected as needed. For instance, in the case of a container mixer
with a capacity
of 20 L, the rotating speed is usually 10 to 40 rpm, preferably 20 to 30 rpm,
It is
preferred that each component is pre-mixed using a sieve of, for instance, 42
mesh
(opening of 355 ~cm) for pulverization pre-treatment of each component.
(2) Process of suspending and/or dissolving the PEO size controlling agent
(process of preparation of size controlling agent solution)
There are no particular restrictions to the equipment or means of this process
as
long as it is a method whereby the size controlling agent can be uniformly
dissolved
and/orsuspended.
The magnetic stirrer and propeller mixer are examples of the suspending
(dissolving) device. There are no special restrictions to the conditions for
preparing the
22
CA 02547939 2003-12-24
size controlling agent solution as long as they are selected as needed. There
are no
special restrictions to the concentration of the size controlling agent
solution as long as it
is the concentration of size controlling agent that is sprayed by fluidized
bed granulation.
This concentration is usually l to 50% W/W, preferably 2 to 30% W/W. With PEG
it is
1 to SO% W/W, preferably S to 30% W/W. With HPMC, it is 1 to 20% W/W,
preferably
2 to 10% W/W. With HPC it is 1 to 20% W/W, preferably 2 to 10% W/W. With MC it
is 1 to 20% W/W, preferably 2 to 10% W/W.
(3) Process of sizing and drying whereby the size controlling agent solution
that was prepared in above-mentioned process (2) is sprayed onto PEO of a high
viscosity
with a molecular weight of 2,000,000 or higher (process of preparing PEO sized
product
(powder particles)
There are no special restrictions to the equipment or means of this process as
long
as it is a method by which PEO with a high viscosity can be wet sized using an
aqueous
solution of a PEO size controlling agent.
Examples of the spraying device (method) are the high-shear agitation
granulation
method, crushing (pulverization) granulation method, fluidized bed granulation
method,
extrusion granulation method, tumbling granulation method, and spray
granulation
method, or device for by using its method thereof. The fluidized bed
granulation method
or device is preferred and the tumbling fluidized bed granulation or device is
particularly
preferred because it is possible to easily and uniformly mix a low-dose drug
and
hydrophilic base with PEO of a high viscosity.
Examples of the sizing device are the fluidized bed granulator (for instance,
the
flow water, Freund Industry Co., Ltd., the GPCG, Glatt Co., Ltd.), a
granulation and
coating device equipped with a horizontal rotating disc having a flat powder
contact part
(for instance, a centrifugal fluidization and granulator (for instance, the CF
granulator of
Freund Industry Co., Ltd.), and a granulation and coating device having an
aeration part
and wherein a rotating disk with a flat surface is placed at the bottom of the
fluidized bed
(for instance, the spiral flow or flow water with rotor container, both made
by Freund
Industry Co., Ltd.).
23
CA 02547939 2003-12-24
There are no special restrictions to the amount of water during sizing as long
as it
is the amount with which size controlling agent (and preferably drug) can be
uniformly
dissolved and/or suspended (dispersed). When PEG is used in solid form, there
are no
special restrictions as long as it is the amount that can size the PEO.
When used in liquid form, it is usually 10 wt% or less, preferably 8 wt% or
less,
further preferably 5 wt% or less, per PEO. There are no special restrictions
to the method
of adding water during sizing as long as it is a method by which a nonuinform
product
consisting of mass of powder aggregate and untreated powder is not usually
produced.
Examples are the continuous spraying method whereby water is continuously
added and
the intermittent spraying method whereby a drying process and further, a
shaking process
are set up somewhere in the granulation process.
There are no special restrictions to the speed with which water is added
during
granulation as long as it is a speed with which a nonuniform product
consisting of masses
of powder aggregate and untreated powder is not usually produced. For
instance, it is
usually 0.1 to 1 wt%/inin, preferably 0.2 to 0.8 wt%/min, further preferably
0.4 to 0.6
wt%/min, per PEO in the case of fluidized bed granulation.
There are no special restrictions to the temperature of the powder during
sizing as
long as it is a temperature that will not induce thermal denaturation of the
PEO. For
instance, it is 20°C to the melting point of PEO (62 to 67°C),
preferably 20°C to SO°C,
further preferably 20°C to 35°C, ideally 25°C to
30°C.
There are no special restrictions to the equipment and means of the drying
process
as long as it is a method whereby the sized product is dried. Examples of the
drying
device are the fluidized bed granulator (for instance, the flow coater, Freund
Industry
Co., Ltd., the GPCG, Glatt Co., Ltd.), a granulation and coating device
equipped with a
horizontal rotating disc having a flat powder contact part (for instance, a
centrifugal
fluidization and granulator (for instance, the CF granulator of Freund
Industry Co., .Ltd.),
and a granulation and coating device having an aeration part and wherein a
rotating disk
with a flat surface is placed at the bottom of the fluidized bed (for
instance, the spiral
flow or flow water with rotor container, both made by Freund Industry Co.,
Ltd.). There
are no special restrictions to the drying conditions as long as they are
conditions under
24
CA 02547939 2003-12-24
which a sized article will usually dry in the fluidized bed. For instance,
when drying inlet
temperature is set at 50° and drying is performed until the sized
article temperature
becomes 40°C, drying of the sized article is almost complete. The
aeration drying
method and reduced pressure drying method can also be used as the drying
method.
The powder particles (sized product) that are obtained can be evaluated by the
following methods:
(Average particle diameter
The "average particle diameter" means the cumulative 50% average particle
diameter. The average particle diameter can be determined with an automatic
particle
diameter distribution determination device (brand name: Robot Sifter, Seishin
Enterprise
Co., Ltd.), and the like. Usually it is approximately 50 to 500 Vim,
preferably
approximately 60 to 300,um, further preferably 80 to 200 hem.
(Amount of very fine powder]
The "amount of very fine powder" means the amount of particles that are ?5,uzn
or smaller. Particle size can be determined with an automatic particle
diameter
distribution determination device (brand name: Robot Sifter, Seishin
Enterprise Co.,
Ltd.), and the like. As an evaluation criterion, the amount of particles. that
are ?5 ~m or
smaller is preferably 20% or less, further preferably 15% or less.
(Specific Volume]
Using a powder property determination device (Powder Tester PT-D, Hosokawa
Micron Corporation), a specific amount of sample is placed on a 20 mesh sieve
and
continuously allowed to fall naturally through a funnel into a receptacle with
an inner
capacity of 100 ml while being vibrated. After the pile of sample is scraped
off of the
receptacle with a flat metal plate, the mass of the receptacle into which the
sample has
been introduced is weighed and specific volume is calculated. It is preferably
1.5 to 3.5
mLJg, further preferably 2.0 to 3.0 m)<.Jg.
(Angle of repose)
Using a powder property determination device (Powder Tester PT-D, Hosokawa
Micron Corporation), the "angle of repose" is found by allowing a specific
amount of
CA 02547939 2003-12-24
sample to continuously fall onto a disc-shaped determination table as it is
vibrated until
the sample begins to spill from the edge of the table, forming a cone-shaped
pile, and
reading the angle of inclination of this pile with a protractor. As an
evaluation criterion,
the angle of repose is preferably 45° or smaller, further preferably
42° or smaller.
(Fluidity) (degree of compression)
Using a powder property determination device (Powder Tester PT-D, Hosokawa
Micron Corporation), a specific amount of sample is placed on a 20 mesh sieve
and
continuously allowed to fall naturally through a funnel into a receptacle with
an inner
capacity of 100 ml while being vibrated. After the pile of sample is scraped
off of the
receptacle with a flat metal plate, the mass of the receptacle into which the
sample has
been introduced is weighed and minimum apparent density is calculated. A top
vessel is
further attached and excess powder is added and tapped with a vibrator. The
top vessel is
removed and the pile of sample is scraped off of the receptacle with a flat
metal plate.
Then the mass of the receptacle into which the sample has been introduced is
weighed
and tapped apparent density is determined. The degree of compression of the
powder is
calculated from the minimum density and the tapped density using the following
formula.
It is preferably 15% or less, further preferably 10% or less.
Degree of compression (%) _ (T-M)/T x 100
T: Tapped density
M: Minimum density
(4) Process of uniformly mixing PEO sizing product obtained by above-
mentioned process (3) and a pharmaceutically acceptable filler
There are no special restrictions to the equipment or means of this process as
long
as it is a method whereby the PEO sized product obtained by above-mentioned
process
(3) and pharmaceutically acceptable filler are uniformly mixed. The method
whereby
they are uniformly mixed in one or two processes selected from the group
consisting of
(1) the process of dissolving and/or suspending in the spraying liquid, (2)
the process
whereby the powder particles are prepared, and (3) the process of being
uniformly mixed
with a pharmaceutically acceptable filler is an example.
26
CA 02547939 2003-12-24
(5) Process of molding
There are no special restrictions to the equipment or means of this process as
long
as it is a method with which a pharmaceutical compression molded article
(preferably
tablets) is usually made.
Examples of the tableting device are rotary tablet machine, (for instance HT P-
22,
Hata Iron Works, Ltd.) and a single tablet machine (for instance, KM-2, Okada
Seiko
Co., Ltd.). Examples of the tableting conditions are 20 to 30 rpm as the
number of
rotations of the turn table and a tableting pressure of 200 to 600 kgf/punch.
The sized product itself, or tablets, fine particles, granules, capsules of
sized
product packed in, for instance, gelatin hard capsules, that are made by
conventional
methods, and the like are given as the pharmaceutical composition
(pharmaceutical
preparation). There are no special restrictions to the method of manufacturing
the
controlled-release pharmaceutical composition of the prsent invention or its
pharmaceutical preparation as long as it is a method whereby the desired
pharmaceutical
preparation is manufactured using combinations of the above-mentioned methods
or
conventional methods as needed.
Preferred Embodiments of the Invention
The present invention will now be explained in further detail with comparative
examples, examples, and experiments, but this does not mean that the present
invention is
limited to these examples and experiments.
Furthermore, although the examples of the present~invention include an example
in which the composition does not comprise a drug, this example is one where a
very
small dose of drug is used in the pharmaceutical preparation of the present
invention, that
is, a trace of drug (a trace dose that is effective in terms of treating or
preventing disease)
that is so small that it will not affect the properties of the PEO sized
product is used in the
pharmaceutical preparation of the present invention.
(Example 1]
Four parts of Macrogol 6000 were dissolved in 36 parts of water while being
mixed with a magnetic stirrer to prepare the spraying liquid (concentration of
10% W/V).
2?
CA 02547939 2003-12-24
Next, 400 parts PEO (POLYOX~' WSR-303,1'he Dow Chemical Company) were
introduced to a fluid bed granulator (Flow Coater, Freund Industry Co., Ltd.)
and sized
by spraying the above-mentioned spraying liquid with an inlet temperature of
30°C,
spraying speed of 5 g/minute, and spraying/drying/shaking cycle of 20
seconds/30
seconds/10 seconds. After granulation, the sized product was dried for 30
minutes at an
inlet temperature of 40°C to obtain the sized product of the present
invention.
[Example 2J
The sized product of the present invention was obtained by the method in
Example 1 using 2 parts of Macrogol 60000 and 38 parts of water.
(Example 3)
The sized product of the present invention was obtained by the same
manufacturing method as in Example 1 with the PEG being changed to HPMC (6
mPa~s)
as the binder.
[Reference 1, Comparative Examples 1 through 4J .
The powder properties of commercial PEO (powder properties of unsized
product: Reference) will serve as Reference 1.
A comparative example sized product was obtained by the same method as in
Example 1 using water (Comparative Example 1), PVP (Comparative Example 2),
sorbitol (Comparative Example 3), and Tween 80 (Comparative Example 4) as the
size
controlling agent. The properties of the sized products are shown in Table 1.
Table 1
ExampleExampleExampleCoraparativeComparativeComparativeComparativeReference
1 2 3 Example Example Example Example 1
1 2 3 4
Size PEG PEG HPMC None PVP Sorbitol Tween80 Commer-
controlling (water) cial
agent unsized
Weight 1.0 0.5 1.0 None 1.0 1.0 1.0 product
ratio
(9'0)
to PEO
Liquid 10 5 10 10 10 10. 10
concentration .
(
28
CA 02547939 2003-12-24
Average 136 142 134 176 201. 110 114 122
particle
diameter
(%)
Amount 13.3 11.2 14.6 2.8 0.2 37.7 26.6 21.0
of
fine powder
(%) (<
75
hem)
Specific 2.72 2.92 2.75 3.42 3.19 2.42 2.26 2,27
~~
volume
(mug)
Angle 40 39 37 40 42 39 38 39
of
repose
()
Degree 8.0 12.5 10.6 20.2 15.2 7.0 10.5 11.4
of
compression .
(%)
<Results and Discussion>
The effects of each type of size controlling agent during aqueous sizing of
PEO
were studied.
When the commercial PEO product was observed with an electron microscope,
the fine particles of about 10 ~m had' aggregated to form aggregated particles
of 50 to
200,um. When powder properties were determined, specific volume was 2.3 mLJg,
there
was approximately 21% fine powder of 75,u or smaller, and the degree of
compression,
which is an indicator of fluidity, was 11.4%.
When the PEO was sized by being sprayed with water only without using any size
controlling agent whatsoever, granulation proceeded and the amount of fine
powder of 75
gum or smaller decreased to approximately 3%. However, the product was bulky
(specific
volume of 3.4 ml/g) and fluidity was poor with the degree of compression being
20.2%.
Electron micrographs revealed particles that had bound together without being
broken
down into fine particles of uniform size (electron micrographs were not
appended).
When PVP was used as the size controlling agent, the particles grew
(granulation
proceeded) more than when only water was used and as a result, the amount of
fine
powder of 75 /Cm or smaller was approximately 0%, specific volume was 3.2
ml/g, and
fluidity was poor with the degree of compression being 15.2%. A granulation
product
was observed in electron micrographs wherein particles that had been broken
down were
of a uniform size (electron micrographs were not appended).
29
CA 02547939 2003-12-24
The amount of fine powder of 75 fem or smaller increased to 38% and 27% with
aqueous sorbitol and aqueous polysorbate solutions, respectively. Particles
that had been
broken down into fine particles were observed in the electron micrographs
(electron
micrographs were not appended).
Fine powder of the appropriate size that contained 13% and 15% of fine powder
of 75;um or smaller was granulated using aqueous solutions of PEG and HPMC,
respectively, without increasing the average particle diameter. Fluidity was
also
improved over that of the original PEO particles with the degree of
compression being
7.7% and 10.6%, respectively. A reduction in fine particles and the formation
of particles
with a smooth surface of 100 to 200 ~m was observed in electron micrographs
(electron
micrographs were not appended).
<Evaluations>
Granulation usually means a series of unit processes by which particle growth
is
promoted and decreases fine powder in order to eliminate the problems of
adhesion to the
punch and scattering of powder during tableting.
When sorbitol and polysorbate are used as the PEO size controlling agent,
there is
a large amount of fine powder and therefore, these substances are not
appropriate.
Sorbitol and polysorbate have a high plasticity and poor binding force and
therefore, when they are used as a PEO size controlling agent, it is thought
that the PEO
particles that have been broken down by spraying with an aqueous solution do
not re-bind
during drying and cannot be sized.
When PVP is used as the PEO size controlling agent, there is a reduction in
fine
powder, but a powder of high specific volume and poor fluidity is produced and
there are
problems in terms of the above-mentioned tableting osbstruction and weight
uniformity.
Therefore, PVP is undesirable.
PVP has poor plasticity and strong binding force and therefore, when used as a
PEO size controlling agent, it is thought the PEO particles that have been
broken down
into fine particles dry, and granulation to larger particles proceeds.
CA 02547939 2003-12-24
When PEG or HPMC is used as the PEO size controlling agent, there is a
reduction in the amount of fine powder and a sized product of good fluidity is
obtained.
PEG and HPMC have the appropriate plasticity and binding force and therefore,
it
appears that when they are used as a PEO size controlling agent, it is
possible that fine
PEO particles that have been broken down re-bind and dry in a state of good
fluidity and
with a smooth surface.
(Example 4)
First, 4.8 parts of Macrogol 6000 were mixed and dissolved in 14.4 parts of
water
using a magnetic stirrer. Then 0.8 part of tamsulosin hydrochloride that had
been pre-
pulverized with a hammer mill (Sample Mill AP-S, using 1 mm screen, Hosokawa
Micron Corporation) was suspended (partially dissolved) in this liquid while
mixing with
a magnetic stirrer to prepare the spraying liquid. Next, 75.2 parts of
Macrogol 6000 and
400 parts of PEO (POLYOX~ WSR-303, The Dow Chemical Company) were introduced
to a fluidized bed granulator (FLOW COATER, Freund Industry Co., Ltd.) and
sizing
was performed by spraying the above-mentioned spraying liquid at an inlet
temperature
of 25°C, spraying speed of 5 g/minute and spray/dry cycle of 20
seconds/40 seconds.
After sizing, the sized product was dried for 30 minutes at an inlet
temperature of 40°C to
obtain the sized product of the present invention. The sized product had an
average
particle diameter of 94 ~Cm, a specific volume of 2.27 mL/g, and angle of
repose of 39°.
Blending uniformity of the drug in the sized product was good with drug
content being
97.3% at a standard deviation of 1.2%. After adding and mixing 2.4 parts of
magnesium
stearate with 480.8 parts of this dry sized product, this mixture was made
tableted at a
tablet weight of 241.6 mg under a tableting pressure of 400 kgf/punch from a 9
mm ~
punch using a rotary tablet machine (HT P-22, Hata Iron Works, Ltd.) to obtain
the
controlled-release pharmaceutical preparation (tablets) of the present
invention. The
tablets that were obtained had few variations with standard deviation of
weight being
0.2%.
(Example 5]
First, 4.8 parts of Macrogol 6000 were mixed and dissolved in 14.2 parts of
water
using a magnetic stirrer. Then 1.0 part of tamsulosin hydrochloride that had
been pre-
31
CA 02547939 2003-12-24
pulverized with a hammer mill (Sample Mill AP-S, using 1 mm screen, Hosokawa
Micron Corporation) was suspended (partially dissolved) in this liquid while
mixing with
a magnetic stirrer to prepare the spraying liquid. Next, 70.2 parts of
Macrogol 6000 and
375 parts of PEO (POLYOX~ WSR-303, The Dow Chemical Company) were introduced
to a fluidized bed granulator (FLOW COATER, Freund Industry Co., Ltd.) and
sizing
was performed by spraying the above-mentioned spraying liquid at an inlet
temperature
of 25°C, spraying speed of 5 g/minute and spray/dry cycle of 20
seconds/40 seconds.
After sizing, the sized product was dried for 30 minutes at an inlet
temperature of 40°C to
obtain the sized product of the present invention. The sized product had an
average
particle diameter of 93 Vim, a specific volume of 2.22 mh/g, and angle of
repose of 39°.
Blending uniformity of the drug in the sized product was. good with drug
content being
97.7% at a standard deviation of 0.7%. After adding and mixing 2.25 parts of
magnesium stearate with 451 parts of this dry sized product, this mixture was
made
tableted at a tablet weight of 181.3 mg under a tableting pressure of 400
kgf/punch from a
7.5 mm c~ punch using a rotary tablet machine (HT P-22, Hata Iron Works, Ltd.)
to obtain
the controlled-release pharmaceutical preparation (tablets) of the present
invention. The
tablets that were obtained had few variations with standard deviation of
weight being
0.4%.
(Example 6]
First, 3.84 parts of Macrogol 6000 were mixed and dissolved in 9.76 parts of
water using a magnetic stirrer. Then 2.4 parts of tamsulosin hydrochloride
that had been
pre-pulverized with a hammer mill (Sample Mill AP-S, using 1 mm screen,
Hosokawa
Micron Corporation) were suspended in this liquid while mixing with a magnetic
stirrer
to prepare the spraying liquid. Next, 76.16 parts of Macrogol 6000 and 400
parts of PEO
(POLYOX~ WSR-303, The Dow Chemical Company) were introduced to a fluidized bed
granulator (FLOW COATER, Freund Industry Co., Ltd.) and sizing was performed
by
spraying the above-mentioned spraying liquid at an inlet temperature of
25°C, spraying
speed of 5 g/minute and spray/dry cycle of 20 secondsl40 seconds. After
sizing, the sized
product was dried for 30 minutes at an inlet temperature of 40°C to
obtain the sized
product. of the present invention. The sized product had an average particle
diameter of
32
CA 02547939 2003-12-24
100 /.cm, a specific volume of 2.38 mL/g, and angle of repose of 3S°.
After adding and
mixing 2.4 parts of magnesium stearate with 452.4 parts of this dry sized
product, this
mixture was made tableted at a tablet weight of 242.4 mg under a tableting
pressure of
400 kgf/punch from a 9 mm ~ punch using a rotary tablet machine (HT P-22, Hata
Iron
Works, Ltd.) to obtain the controlled-release pharmaceutical preparation
(tablets) of the
present invention. The tablets that were obtained had few variations with
standard
deviation of weight being 0.6%, and uniformity of content was also good at a
standard
deviation of 1.0%.
(Example 7J
First, 4.8 parts of Macrogol 6000 were mixed and dissolved in 14.4 parts of
water
using a magnetic stirrer. Then 0.8 part of tamsulosin hydrochloride that had
been pre-
pulverized with a hammer mill (Sample Mill AP-S, using 1 mm screen, Hosokawa
Micron Corporation) was suspended in this liquid while mixing with a magnetic
stirrer to
prepare the spraying liquid. Next, 75.2 parts of Macrogol 6000 and 400 parts
of PEO
(POLYOX~ WSR-303, The Dow Chemical Company) were introduced to a fluidized bed
granulator (FLOW COATER, Freund Industry Co., Ltd.) and sizing was performed
by
spraying the above-mentioned spraying liquid at an inlet temperature of
30°C, spraying
speed of 5 g/minute and spray/dry cycle of 20 seconds/40 seconds. After
sizing, the sized
product was dried for 30 minutes at an inlet temperature of 40°C to
obtain the sized
product of the present invention. The sized product had an average particle
diameter of
106,um, a specific volume of 2.33 mug, and angle of repose of 36°.
After adding and
mixing 2.4 parts of magnesium stearate with 480.8 parts of this dry sized
product, this
mixture was made tableted at a tablet weight of 241.6 mg under a tableting
pressure of
400 kgf/punch from a 9 mm ~ punch using a-rotary tablet machine (HT P-22, Hata
Iron
Works, Ltd.). The tablets that were obtained had few variations. with standard
deviation
of weight being 0.5%. The tablets were further spray coated with a liquid in
which 5.04
parts of hydroxypropylmethyl cellulose (TC-SR, Shin-Etsu Chemical Co., Ltd.),
0.95 part
of Macrogol 6000, and 1.26 parts of yellow ferric oxide had been
dissolved/dispersed at
an inlet temperature of 60°C, pan rotating speed of 13 rpm, and coating
liquid feed speed
of 5 g/minute using an aeration-type coating device (Hi-Coater HCT-30, Freund
Industry
33
CA 02547939 2003-12-24
Co., Ltd.) until the coating component was 3% of the tablet weight to obtain
the
controlled-release pharmaceutical preparation (film-coated tablets) of the
present
invention. When the film-coated tablets that were obtained were observed
microscopically, there was uniform distribution of the coloring matter and the
surface
was smooth and gelation of the PEO was not seen.
[Example 8)
First, 1.2 parts of tamsulosin hydrochloride were dissolved in 148.8 parts of
water
to prepare the spraying liquid. Next, 60 parts of Macrogol 6000 and 300 parts
of PEO
(POLYOX~-WSR, The Dow Chemical Company) were introduced to a fluidized bed
granulator (FLOW COATER, Freund Industry Co., Ltd.) and sizing was performed
by
spraying the above-mentioned spraying liquid at an inlettemperature of
30°C, spraying
speed of 5 g/minute and spray/dry cycle of 20 seconds/40 seconds. After
sizing, the sized
product was dried for 30 minutes at an inlet temperature of 40°C to
obtain the sized
product of the present invention. The sized product had an average particle
diameter of
108,um, a specific volume of 2.66 mLJg, and angle of repose of 40°.
After adding and
mixing 1.8 parts of magnesium stearate with this dry sized product, this
mixture was
made tableted at a tablet weight of 121 mg under a tableting pressure of 400
kgf/punch
from a 7.0 mm ~ punch using a rotary tablet machine (HT P-22, Hata Iron Works,
Ltd.)
to obtain the controlled-release pharmaceutical preparation (tablets) of the
present
invention. The tablets that were obtained had few variations with standard
deviation of
weight being 0.6%. Moreover, the drug content of the tablets was 97.8% and
uniformity
of content was good at a standard deviation of 1.4%.
[Example 9]
First, 2.0 parts of hydroxypropylmethyl cellulose (6 mPa~s) were mixed and
dissolved in 18.0 parts of water using a magnetic stirrer. Then 0.8 part of
tamsulosin
hydrochloride that had been pre-pulverized with a hammer mill (Sample Mill AP-
S,
using 1 mm screen, Hosokawa Micron Corporation) was suspended (partially
dissolved)
in this liquid while mixing with a magnetic stirrer to prepare the spraying
liquid. Next,
78.0 parts of Macrogol 6000 and 400 parts of PEO (POLYOX~ WSR-303, The Dow
Chemical Company) were introduced to a fluidized bed granulator (FLOW COATER,
34
CA 02547939 2003-12-24
Freund Industry Co., Ltd.) and sizing was performed by spraying the above-
mentioned
spraying liquid at an inlet temperature of 30°C, spraying speed of 5
g/minute and
spray/dry cycle of 20 seconds/40 seconds. After sizing, the sized product was
dried for
30 minutes at an inlet temperature of 40°C to obtain the sized product
of the present
invention. The sized product had an average particle diameter of 95 Vim, a
specific
volume of 2.53 mL,/g, and angle of repose of 36°. Blending uniformity
of the drug in the
sized product was good with drug content being 101.6% at a standard deviation
of 1.4%.
(Example 10]
First, 3.84 parts of Macrogol 6000 were mixed and dissolved in 10.56 parts of
water using a magnetic stirrer. Then 1.6 parts of tamsulosin hydrochloride
that had been
pre-pulverized with a hammer mill (Sample Mill AP-S, using 1 mm screen,
Hosokawa
Micron Corporation) were suspended in this liquid while being mixed with a
magnetic
stirrer to prepare the spraying liquid. Next, 76.16 parts of Macrogol 6000 and
400 parts
of PEO (POLYOX~ WSR-303, The Dow Chemical Company) were introduced to a
fluidized bed granulator (FLOW COATER, Freund Industry Co., Ltd.) and sizing
was
performed by spraying the above-mentioned spraying liquid at an inlet
temperature of
25°C, spraying speed of 5 g/minute and spray/dry cycle of 20 seconds/40
seconds. After
sizing, the sized product was dried for 30 minutes at an inlet temperature of
40°C to
obtain the sized product of the present invention. The sized product had an
average
particle diameter of 96 ~cm, a specific volume of 2.27 mL/g, and angle of
repose of 37°.
After adding and mixing 2.4 parts of magnesium stearate with 481.6 parts of
this dry
sized product, this mixture was made tableted at a tablet weight of 242 mg
under a
tableting pressure of 400 kgf/punch from a 9 mm ~ punch using a rotary tablet
machine
(HT P-22, Hata Iron Works, Ltd.) to obtain the controlled-release
pharmaceutical
preparation (tablets) of the present invention. The tablets that were obtained
had few
variations with standard deviation of weight being 0.6%, and uniformity of
content was
also good at a standard deviation of 1.8%.
(Comparative Example 5]
After coarse mixing of 10 parts of tamsulosin hydrochloride and 190 parts of
Macrogol 6000 with a poly bag, the mixture was pulverized with a hammer mill
(Sample
CA 02547939 2003-12-24
Mill AP-S, using 1 mm screen, Hosokawa Micron Corporation). Then 84.8 parts of
Macrogol 6000 and S00 parts of PEO (POLYOX~ WSR-303, The Dow Chemical
Company) were added to 16 parts of the mixed and pulverized product and this
was
mixed for 10 minutes at 25 rpm using a double cone-type mixer (5 L-type,
Tokuju
Corporation). Then 3.0 parts of magnesium stearate were further added and
mixed to
obtain a comparative pharmaceutical preparation of the present invention. When
uniformity of drug content of the mixed product that was obtained was
confirmed, there
was a reduction in drug content at 91.5% and a standard deviation of 1.4%.
[Comparative Example 6]
First, 3.84 parts of sorbitol were dissolved in 11.36 parts of water while
mixing
with a magnetic stirrer. Then 0.8 part of tamsulosin hydrochloride that had
been pre-
pulverized with a hammer mill (Sample Mill AP-S, using 1 mm screen, Hosokawa
Micron Corporation) were suspended in this liquid while being mixed with a
magnetic
stirrer to prepare the spraying liquid. Next, 76.16 parts of sorbitol and 400
parts of PEO
(POLYOX~ WSR-303, The Dow Chemical Company) were introduced to a fluidized bed
granulator (FLOW COATER, Freund Industry Co., Ltd.) and sizing was performed
by
spraying the above-mentioned spraying liquid at an inlet temperature of
30°C, spraying
speed of 5 g/minute, and spray/dry cycle of 20 seconds/40 seconds. After
sizing, the sized
product was dried for 30 minutes at an inlet temperature of 40°C to
obtain the sized
product of the present invention. The sized product had an average particle
diameter of
110 Vim, a specific volume of 2.04 mI,/g, and angle of repose of 38°.
Blending
uniformity of the drug in the sized product revealed a reduced uniformity of
content at a
drug content of 98.2% and standard deviation of 5.4%.
Industrial Applicability
The present invention presents a controlled-release pharmaceutical composition
containing a sized product, which contains a drug, polyethylene oxide of high
viscosity
and specific PEO size controlling agent and wherein of these three components,
at least
the size controlling agent is uniformly dispersed in the polyethylene oxide.
By means of the present invention, it is possible to present a controlled-
release
pharmaceutical composition for oral use with good uniformity of content,
particularly for
36
CA 02547939 2003-12-24
low-dose drugs, and therefore, it can be used as useful pharmaceutical
preparation
technology that is extremely popular, particularly for controlled-release
pharmaceutical
compositions comprising polyethylene oxide of a high viscosity as the
controlled-release
base.
37
