Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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DESCRIPTION
SOLID PHARMACEUTICAL PREPARATION
This is a divisional application of Canadian Patent
Application No. 2,286,753 filed May 26, 1998.
mE:~HNTCAL FIELD
The present invention relates to a solid
preparation,. especially a preparation capable of buccal
disintegration or dissolution, having characteristics
of fast disintegration or dissolution in the oral
cavity even without water.
BACKGR UND ART
There has been a demand for development of a
pharmaceutical.preparation capable of buccal
disintegration or dissolution, which can be, if
necessary, administered readily even without water, by
aged people and children anywhere or anytime. Examples
of prior art references disclosing such preparation are
shown below.
JP-A H9(1997)-48726 discloses rapid buccal
dissolution type preparations comprising a drug and a
material wetting in a mouldable way on humidifying and
retaining a shape after moulding and drying. Such
material is exemplified by sugars, sugar alcohols, and
water-soluble polymers.
JP-A H5(1993)-271054 (EP-A 553777) discloses a
method of producing a rapid buccal dissolution type
tablets comprising a pharmacologically active
ingredient and sugars.
JP-A 89(1997)-71523 discloses tablets with rapid
disintegration in the oral cavity which comprise a
drug, crystalline cellulose, low-substituted
hydroxypropylcellulose and a lubricant.
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However, these prior art references nowhere
disclose a solid preparation comprising (1) a
pharmaceutically active ingredient, (2) one or more
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water-soluble sugar alcohol selected from the group
consisting of sorbitol, maltitol, reduced starch
saccharide, xylitol, reduced paratinose and erythritol,
and (3) low-substituted hydroxypropylcellulose having
hydroxypropoxyl group contents of 7.0 to 9.9 percent by
weight.
There has been a demand for development of a solid
preparation which exhibits excellent buccal
disintegration and dissolution and also an appropriate
strength (hardness) such that the solid preparation
never disintegrates or suffers damage in the course of
the production steps or distribution stages.
DISCLOSURE OF INVENTION
The present invention relates to a solid
preparation comprising (1) a pharmaceutically active
ingredient, (2) one or more water-soluble sugar alcohol
selected from the.group consisting of sorbitol,
maititol, reduced starch saccharide, xylitol, reduced
paratinose and erythritol (hereafter also referred to
as a water-soluble sugar alcohol), and (3)
low-substituted hydroxypropylcellulose having
hydroxypropoxyl group contents of 7.0 to 9.9 percent by
weight.
The present invention further relates to use of
low-substituted hydroxypropylcellulose having
hydroxypropoxyl group contents of 7.0 to 9.9 percent by
weight for the manufacture of a pharmaceutical
preparation capable of buccal disintegration or
dissolution.
The present invention further relates to method of
improving buccal 3isintegration or dissolution of a
solid pharmaceutical preparation characterized by using
low-substituted hydroxypropylcellulose having
hydroxypropoxyl group contents of 7.0 to 9.9 percent by
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weight.
The pharmaceutically active ingredient to be used
in the present invention may be in any optional form,
for example, a solid, powder or granular, crystalline,
oily or solution form.
As the pharmaceutically active ingredient, for
instance, there may be mentioned one or more
ingredients selected from the group consisting of
nourishing and health-promoting agents,
antipyretic-analgesic-antiinflammatory agents,
antipsychotic drugs, antianxiety drugs,
antidepressants, hypnotic-sedatives, spasmolytics,
central nervous system affecting drugs, cerebral
metabolism ameliolators, antiepileptics,
sympathomimetic agents, gastrointestinal function
conditioning agents, antacids, antiulcer agents,
antitussive-expectorants, antiemetics, respiratory
stimulants, bronchodilators, antiallergic agents,
dental buccal drugs, antihistamines, cardiotonics,
antiarrhythmic agents, diuretics, hypotensive agents,
vasoconstrictors, coronary vasodilators, peripheral
vasodilators, antihyperlipidemic agents, cholagogues,
antibiotics, chemotherapeutic agents, antidiabetic
agents, drugs for osteoporosis, skeletal muscle
relaxants, antidinics, hormones, alkaloid narcotics,
sulfa drugs, antipodagrics, anticoagulants,
anti-malignant tumor agents, agents for alzheimer's
disease, etc.
Examples of the nourishing and health-promoting
agents include vitamins such as vitamin A, vitamin D,
vitamin E (d-a-tocopherol acetate, etc.), vitamin B1
(dibenzoylthiamine, fursultiamine hydrochloride, etc.),
vitamin BZ (riboflavin butyrate, etc.), vitamin B6
(pyridoxine hydrochloride, etc.), vitamin C (ascorbic
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acid, sodium L-ascorbate, etc.), vitamin B1z
(hydroxocobalamin acetate, etc.), etc.; minerals such
as calcium, magnesium and iron; proteins, amino acids,
oligosaccharides, crude drugs, etc.
Examples of the
antipyretic-analgesic-antiinflammatory agents include
aspirin, acetaminophen, ethenzamide, ibuprofen,
diphenhydramine hydrochloride, dl-chlorpheniramine
maleate, dihydrocodeine phosphate, noscapine;
methylephedrine hydrochloride, phenylpropanolamine
hydrochloride; caffeine, anhydrous caffeine,
serratiopeptidase, lysozyme chloride, tolfenamic acid,
mefenamic acid, diclofenac sodium, flufenamic acid,
salicylamide, aminopyrine, ketoprofen, indomethacin,
bucolome, pentazocine, etc.
Examples of the antipsychotic drugs include
chlorpromazine, reserpine, etc.
Examples of the antianxiety drugs include
alprazolam, chlordiazepoxide, diazepam, etc.
Examples of the antidepressants include
imipramine, maprotiline, amphetamine, etc.
Examples of the hypnotic-sedatives include
estazolam, nitrazepam, diazepam, perlapine,
phenobarbital sodium, etc.
Examples of the spasmolytics include scopolamine
hydrobromide, diphenhydramine hydrochloride, papaverine
hydrochloride, etc.
Examples of the central nervous system affecting
drugs include citicoline, rotirenine; etc.
Examples of the cerebral metabolism ameliolators
include vinpocetine, meclofenoxate hydrochloride, etc.
Examples of the antiepileptics include phenytoin,
carbamazepine, etc.
Examples of the sympathomimetic agents include
isoproterenol hydrochloride, etc.
Examples of the gastrointestinal function
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conditioning agents include stomachic-digestives such
as diastase, saccharated pepsin, scopolia extract,
cellulase AP3, lipase AP, cinnamon oil, etc.;
intestinal function controlling drugs such as perperine
5 hydrochloride, resistant lactic acid bacterium,
Lactobacillus bifidus, etc.
Examples of the antacids include magnesium
carbonate, sodium hydrogen carbonate, magnesium
aluminometasilicate, synthetic hydrotalcite,
precipitated calcium carbonate, magnesium oxide, etc.
Examples of the antiulcer agents include
lansoprazole, omeprazole, rabeprazole, pantoprazole,
famotidine, cimetidine, ranitidine hydrochloride, etc.
Examples of the antitussive-expectorants include
chloperastine hydrochloride, dextromethorphan
hydrobromide, theophylline, potassium
guaiacolsulfonate, guaifenesin, codeine phosphate, etc.
Examples of the antiemetics include diphenidol
hydrochloride, metoclopramide, etc.
Examples of the respiratory stimulants include
levallorphan tatrate, etc.
Examples of the bronchodilators include
theophylline, salbutamol sulfate, etc.
Examples of the antiallergic agents include
amlexanox, seratrodast, etc.
Examples of the dental buccal drugs include
oxytetracycline, triamcinolone acetonide, chlorhexidine
hydrochloride, lidocaine, etc.
Examples of the antihistamines include
diphenhydramine hydrochloride, promethazine,
isothipendyl hydrochloride, dl-chlorpheniramine
maleate, etc.
Examples of the cardiotonics include caffeine,
digoxin, etc.
Examples of the antiarryhythmic agents include
procainamide hydrochloride, propranolol hydrochloride,
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pindolol, etc.
Examples of the diuretics include isosorbide,
furosemide, etc.
Examples of the hypotensive agents include
delapril hydrochloride, captopril, hexamethonium
bromide, hydralazine hydrochloride, labetalol
hydrochloride, manidipine hydrochloride, candesartan
cilexetil, methyldopa, losartan,- valsartan, eprosartan,
irbesartan, tasosartan, telmisartan, pomisartan,
ripisartan, forasartan, etc.
Examples of the vasoconstrictors include
phenylephrine hydrochloride, etc.
Examples of the coronary vasodilators include
carbocromen hydrochloride, molsidomine, verapamil
hydrochloride, etc.
Examples of the peripheral vasodilators include
cinnarizine, etc.
Examples of the antihyperlipidemic agents include
cerivastatin sodium, simvastatin, pravastatin sodium,
etc.
Examples of the cholagogues include dehydrocholic
acid, trepibutone, etc.
Examples of the antibiotics include cephem
antibiotics such as cefalexin, amoxicillin,
.pivmecillinam hydrochloride, cefotiam dihydrochloride,
cefozopran hydrochloride, cefmenoxime hydrochloride,
cefsluodin sodium, etc.; synthetic antibacterials such
as ampicillin, cyclacillin, sulbenicillin sodium,
nalidixic acid, enoxacin, etc.; monobactam antibiotics
such as carumonam sodium; penem antibiotics, carbapenem
antibiotics, etc.
Examples of the chemotherapeutic agents include
sulfamethizole hydrochloride, thiazosulfone, etc.
Examples of the antidiabetic agents include
tolbutamide, voglibose, pioglitazone (hydrochloride),
troglitazone,
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5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]
-2,4-thiazolidinedione (BRL-49653), acarbose, miglitol,
emiglitate, etc.
Examples of the drugs for osteoporosis include
ipriflavone, etc.
Examples of the skeletal muscle relaxants include
methocarbamol, etc.
Examples of the antidinics include meclizine
hydrochloride, dimenhydrinate, etc.
Examples of the hormones include riothyroinine
sodium, dexamethasone sodium phosphate, prednisolone,
oxendolone, leupororelin acetate, etc.
Examples of the alkaloid narcotics include opium,
morphine hydrochloride, ipecac, oxycodone
hydrochloride, opium alkaloids hydrochlorides, cocaine
hydrochloride, etc.
Examples of the sulfa drugs include sulfanilamide,
sufamethizole, etc.
Examples of the antipodagrics include allopurinol,
colchicine, etc.
Examples of the anticoagulants include dicoumarol,
etc.
Examples of the anti-malignant tumor agents
include 5-fluorouracil, uracil, mitomycin, etc.
Examples of the agents for alzheimer's disease
include idebenone, vinpocetine, etc.
The pharmaceutically active ingredients may be
coated, by the per se known method, for masking the
taste and odor or for enteric dissolution or sustained
release. The coating material that can be employed
includes, for instance, enteric coating polymers such
as cellulose acetate phthalate, methacrylic acid
copolymer L, methacrylic acid copolymer LD, methacrylic
acid copolymer S, hydroxypropylmethylcellulose
phthalate, hydroxypropylmethylcellulose acetate
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succinate, carboxymethylethylcellulose, etc.; gastric
coating polymers such as polyvinylacetal
diethylaminoacetate, aminoalkyl methacrylate copolymer,
etc.; water-soluble polymers such as
hydroxypropylcellulose, hydroxypropylmethylcellulose,
etc.; water-insoluble polymers such as ethylcellulose,
aminoalkyl methacrylate copolymer RS, ethylacrylate
methylmethacrylate copolymer, etc.; wax, etc.
The above pharmaceutically active ingredients are
used, for instance, in an amount of 0.01 to 70 weight
parts, preferably 0.02 to 50 weight parts, more
preferably 0.05 to 30 weight parts, per 100 weight
parts of a solid preparation.
Among the above pharmaceutically active
ingredients, nourishing and health-promoting agents,
antipyretic-analgesic-antiinflammatory agents,
hypnotic-sedatives, central nervous system affecting
drugs, gastrointestinal function conditioning agents,
antiulcer agents, antitussive-expectorants,
antiallergic agents, antiarrhythmic agents, diuretics,
hypotensive agents, vasoconstrictors, coronary
vasodilators, antihyperlipidemic agents, antidiabetic
agents, drugs for osteoporosis, skeletal muscle
relaxants and antidinics are preferably employed.
The pharmaceutically active ingredients especially
preferably employed in the present invention are
lansoprazole, voglibose and candesartan cilexetil.
In the present invention, a water-soluble sugar
alcohol~means a water-soluble sugar alcohol which needs
water in an amount of less than 30 ml when 1 g of a
water-soluble sugar alcohol is added to water and
dissolved within about 30 minutes at 20 °C by strongly
shaking every 5 minutes for 30 seconds.
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As the water-soluble sugar alcohol, sorbitol,
maltitol, reduced starch saccharide, xylitol, reduced
paratinose or erythritol is employed. Two or more of
these water-soluble sugar alcohols can be used as a
mixture in a given ratio.
The water-soluble sugar alcohol is preferably
xylitol or erythritol, especially preferably
erythritol. As erythritol, one that is produced by
fermentation with yeasts using glucose as the starting
material, and that has a particle size of at most 50
mesh is used. Such erythritol is available as a
product on the market such as a product manufactured by
Nikken Chemical Co., Ltd.(Japan), etc.
The water-soluble sugar alcohol is used, for
instance, in an amount of 5 to 97 weight parts,
preferably 10 to 90 weight parts, per 100 weight parts
of a solid preparation. If the amount of the
water-soluble sugar alcohol to be used is too much
compared with such ranges, sufficient strength of a
preparation can not be obtained. On the contrary, the
amount of the water-soluble sugar alcohol to be used is
too small, sufficient buccal disintegration or
dissolution can not be obtained. Both of these are not
preferable.
The hydroxypropoxyl group contents of a
low-substituted hydroxypropylcellulose employed in the
present invention range from 7.0 to 9.9 percent by
weight.
Examples of the low-substituted
hydroxypropylcellulose having hydroxypropoxyl group
contents of 7.0 to 9.9 percent by weight include LH-22,
LH-32, and mixtures thereof. These are available as a
product on the market such as a product manufactured by
Shin-Etsu Chemical Co., Ltd.(Japan).
The low-substituted hydroxypropylcellulose having
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hydroxypropoxyl group contents of 7.0 to 9.9 percent by
weight is used in an amount of 3 to 50 weight parts,
preferably 5 to 40 weight parts, per 100 weight parts
of a solid preparation. If the amount of the
5 low-substituted hydroxypropylcellulose to be used is
too much compared with such ranges, sufficient buccal
disintegration or dissolution can not be obtained. On
the contrary, the amount of the low-substituted
hydroxypropylcellulose to be used is too small,
10 sufficient strength of a preparation can not be
obtained. Both of these are not preferable.
Thus, buccal disintegration or dissolution in a
solid preparation can be improved by using
low-substituted hydroxypropylcellulose having
hydroxypropoxyl group contents of 7.0 to 9.9 percent by
weight.
The solid preparation of the present invention is
useful especially as a preparation which is capable of
buccal disintegration or dissolution, and administered
without water or together with water.
The dosage forms of a solid preparation of the
present invention includes tablets, granules, fine
granules, etc., with preference given to tablets.
Unless buccal disintegration or dissolution, or
strength of a preparation is interfered with, a solid
preparation of the present invention may further
contain a variety of additives which are commonly
employed in the manufacture of preparations in general
dosage forms. The amount of such additives to be used
is one commonly employed in the manufacture of
preparations in general dosage forms.
Such additives include, for instance, binders,
acids, foaming agents, artificial sweeteners,
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flavorants, lubricants, colorants, stabilizers,
disintegrators, etc.
Examples of the binders include
hydroxypropylcellulose, hydroxypropylmethylcellulose,
crystalline cellulose, pregelatinized starch,
polyvinylpyrrolidone, gum arabic powder, gelatin,
pullulan, etc. The use of crystalline cellulose as the
binders provides a solid preparation which exhibits
more excellent strength of a preparation while
retaining excellent buccal disintegration and
dissolution. Such crystalline cellulose includes one
that is called microcrystalline cellulose. Examples of
the crystalline cellulose include CEOLUS*KG801, Avicel*
PH101, Avicel*pH102, Avicel* PH301, Avicel*PH302, Avicel*
RC-A591NF (crystalline cellulose carmellose sodium),
etc. Among these, preferably employed is CEOLUS*KG801
which is also called crystalline.cellulose of high
compressibility. Two or more of the crystalline .
cellulose can be used as a mixture in a given ratio.
Such crystalline cellulose is available as a product on
the market such as a product manufactured by Asahi
Chemical Co., Ltd.(Japan). Crystalline cellulose is
used, for instance, in an amount of about 3 to 50
weight parts, preferably about 5 to 40 weight parts,
more preferably about 5 to ZO weight parts, per 100
weight parts of a solid preparation.
Examples of the acids include citric acid,
tartaric acid, malic acid, etc.
Examples of the foaming agents include sodium
hydrogen carbonate, etc.
Examples of the artificial sweeteners include
saccharin sodium, dipotassium glycyrrhizinate,
aspartame, stevia, thaumatin, etc.
Examples of the flavorants include lemon, lemon
Lime, orange, menthol, etc.
Examples of the lubricants include magnesium
*Trade-mark
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stearate, sucrose fatty acid ester, polyethyleneglycol;
talc, stearic acid, etc. The use of polyethyleneglycol
as the lubricants provides a stable solid preparation
in which decomposition of-a pharmaceutically active
ingredient with the Lapse of day is suppressed. In
this case, polyethyleneglycol is used, for instance, in
an amount of 0.01 to 10 weight parts, preferably 0.1 to
5 weight parts, per 100 weight parts of a solid
preparation.
Examples of the colorants include various food
colorants (e. g. Food Yellow No. 5, Food RED No.2, Food
Blue No.2, etc.), food lakes, red iron oxide, etc.
Examples of the stabilizers include a basic
substance in the case of a basic pharmaceutically
active ingredient, and an acidic substance in the case
of an acidic pharmaceutically active ingredient.
Examples of the disintegrators include those
called super disintegrators and exemplified by
crospovidone [manufactured by ISP Inc. (U.S.A.), BASF
(Germany)], croscarmellose sodium [FMC-Asahi Chemical
Co., Ltd. (Japan)], carmellose calcium [Gotoku
Chemical(Yakuhin), (Japan)]; hydroxypropylcellulose;
carboxymethylstarch sodium [Matsutani Chemical Co.,
Ltd. (Japan)]; corn starch, etc., with preference given
to crospovidone. Two or more of these disintegrators
can be used as a mixture in a given ratio.
As crospovidone, any cross-linked homopolymer
called 1-ethenyl-2-pyrrolidinone homopolymer may be
used, and usually crospovidone having a molecular
weight of at least 1,000,000 is used. Specific
examples of crospovidone available as a product on the
market include Cross-linked povidone, Kollidon*CL
[manufactured by BASF (Germany)], Polyplasdone* XL,
Polyplasdone*XL-10, INF-ZO [manufactured by ISP Inc.
(U.S.A.)], polyvinylpolypyrrolidone, PVPP and
1-vinyl-2-pyrrolidinone homopolymer.
*Trade-mark
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The disintegrator is used, for instance, in an
amount of 0.1 to 20 weight parts, preferably 1 to 10
weight parts, per 100 weight parts of a solid
preparation.
When a pharmaceutically active ingredient is one
that is unstable to an acid, such as lansoprazole,
omeprazole, rabeprazole, pantoprazole, etc., an basic
inorganic salt is preferably incorporated for the
purpose of stabilizing the pharmaceutically active
ingredient in a solid preparation. Examples of the
basic inorganic salt include basic inorganic salts of
sodium, potassium, magnesium and/or calcium. Two or
more of these basic inorganic salts can be used as a
mixture in a given ratio.
Examples of the basic inorganic salts of sodium
include sodium carbonate, sodium hydrogen carbonate,
etc.
Examples of the basic inorganic salts of potassium
include potassium carbonate, potassium hydrogen
carbonate, sodium potassium carbonate, etc.
Examples of the basic inorganic salts of magnesium
include heavy magnesium carbonate, magnesium carbonate,
magnesium oxide, magnesium hydroxide, magnesium
metasilicate aluminate, magnesium silicate aluminate,
magnesium silicate, magnesium aluminate, synthetic
hydrotalcite [ Mg6A12 ( OH ) 16 . C03 . 4H20 ] and aluminum
magnesium hydroxide [2.5MgO.A1z03.xHz0], with preference
given to heavy magnesium carbonate, magnesium
carbonate, magnesium oxide, magnesium hydroxide, etc.
Examples of the basic inorganic salts of calcium
include precipitated calcium carbonate, calcium
hydroxide, etc.
The basic inorganic salt is preferably, a basic
inorganic salt of magnesium, more preferably heavy
magnesium carbonate, magnesium carbonate, magnesium
oxide, magnesium hydroxide.
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The amount of the basic inorganic salt to be used
is appropriately selected depending on kinds of the
basic inorganic salt and is, for instance, about 0.3 to
200 percents by weight, preferably about 1 to 100
percents by weight, more preferably about 10 to 50
percents by weight, especially preferably about 20 to
40 percents by weight, based on a pharmaceutically
active ingredient.
The solid preparation of the present invention can
be produced in accordance with a conventional method in
the fields of pharmaceutics. Such methods include, for
instance, a method which comprises blending, if
necessary after addition of water, a pharmaceutically
active ingredient, a water-soluble sugar alcohol and
low-substituted hydroxypropylcellulose having
hydroxypropoxyl group contents of 7.0 to 9.9 percent by
weight, and molding, if necessary followed by drying.
Here, the solid preparation of the present invention
can be produced without using water.
The blending procedure can be carried out by any
of the conventional blending techniques such as
admixing, kneading, granulating, etc. The blending
procedure is carried out, for instance, by using an
apparatus such as Vertical Granulator GV10
[manufactured by Powrex Corp. (U.S.A.)], Universal
Kneader [manufactured by Hata Iron Works Co., Ltd.
(Japan)] and fluidized bed granulator LAB-1 and FD-3S
[manufactured by Powrex Corp. (U.S.A.)].
The molding procedure can be carried out, for
instance, by tabletting with a pressure of 0.5 to 3
ton/cmZ.by using a single-punch tabletting machine
[Kikusui Seisakusho (Japan)] or a rotary type
tabletting machine [Kikusui Seisakusho (Japan)] when a
solid preparation is a tablet.
The drying procedure can be carried out by any of
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the techniques used commonly in the art, such. as vacuum
drying, fluidized-bed drying, etc.
The solid preparation of the present invention
5 thus obtained exhibits fast disintegrability or
dissolubility in the buccal cavity, and also an
appropriate strength of preparation.
The buccal dissolution time of the solid
preparation of the present invention (the time for
10 healthy male or female adults to complete
disintegration of a solid preparation by buccal saliva)
is usually about 5 to about 50 seconds, preferably
about 5 to about 40 seconds, more preferably about 5 to
about 30 seconds.
15 The strength of the solid preparation of the
present invention (measurement with a tablet hardness
tester) is usually about 2 to about 20 kg, preferably
about 4 to about 15 kg.
The solid preparation of the present invention can
be safely administered orally to mammals such as mice,
rats, rabbits, cats, dogs, bovines, horses, monkeys,
humans, etc.
While the dosage varies depending on kinds of a
pharmaceutically active ingredient, a subject,
diseases, etc., the dosage can be selected so that the
dosage of the pharmaceutically active ingredient is an
effective amount.
For instance, when lansoprazole is employed as a
pharmaceutically active ingredient, the solid
preparation of the present invention is useful for
treatment and prophylaxis of digestive ulcer (e. g.,
gastric ulcer, duodenal ulcer, anastomotic ulcer,
Zollinger-Ellison syndrome, etc), gastritis, reflux
esophagitis, etc.; eradication of H. pyroli;
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suppression of gastrointestinal bleeding caused by
digestive ulcer, acute stress ulcer and hemorrhagic
gastritis; suppression of gastrointestinal bleeding
caused by invasive stress (e.g., stress caused by
cerebrovascular disease, head injury, failure of many
organs, burn injury of a wide range, which necessitate
a large-scale operation necessitating the following
intensive management, or intensive care); treatment and
prophylaxis of ulcer caused by non-steroidal
anti-inflammatory agent; treatment and prophylaxis of
.gastric hyperacidity and ulcer caused by postoperative
stress; administration before anesthesia, etc., and the
dosage thereof per an adult (body weight: 60 kg) is 0.5
to 1500 mg/day, preferably 5 to 150 mg/day, as
lansoprazole.
When voglibose is employed as a pharmaceutically
active ingredient, the solid preparation of the present
invention is useful for treatment and prophylaxis of
obesity, adiposity, hyperlipemia, diabetes, etc., and
the dosage thereof per an adult (body weight: 60 kg) is
0.01 to 30 mg/day, preferably 0.1 to 3 mg/day, as
voglibose. This solid preparation can be administered
once a day, or two or three times separately a day.
Further, when candesartan cilexetil is employed as
a pharmaceutically active ingredient, the solid
preparation of the present invention is useful for
treatment and prophylaxis of hypertension, cardiac
diseases, cerebral apoplexy, renal diseases, etc., and
the dosage thereof per an adult (body weight: 60 kg) is
1 to 50 mg/day, preferably 2 to 30 mg/day, as
candesartan cilexetil.
~T MODE FOR CARRYING OUT THE INVENTION
The following Working Examples and Comparative
Examples are further illustrative but by no means
limitative of the present invention.
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The physical properties of the tablets prepared in
Working Examples and Comparative Examples were
determined by the following test methods.
(1) Hardness test
Determination was carried out with a tablet
hardness tester [manufactured by Toyama Sangyo, Co.
Ltd. (Japan)]. The test was performed in 10 runs and
mean values were shown.
(2) Huccal disintegration time
Time for complete disintegration or dissolution
only by saliva in the buccal cavity was determined.
Working Example 1
A fluidized bed granulator [manufactured by Powrex
Corp. (U.S.A.), LAB-1] was charged with 0.8 g of
voglibose, 636.8 g of erythritol [manufactured by
Nikken Chemical Co., Ltd. (Japan)] and 160.0 g of
low-substituted hydroxypropylcellulose LH-32
[hydroxypropoxyl group contents of 8.8 ~ by weight,
manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)];
and granulation was carried out while spraying
distilled water. The granules were dried and then 2.4
g of magnesium stearate was added. The mixture was
tabletted using a rotary type tabletting machine with a
punch having a beveled edge, 10 mm in diameter, at a
tabletting pressure of 1.5 ton/cm2, to provide tablets
each weighing 400 mg.
The hardness and buccal disintegration time of
each tablet thus obtained were 6.1 kg and 27 seconds
respectively.
Working Example 2
A fluidized bed granulator [manufactured by Powrex
Corp. (U.S.A.), LAB-1] was charged with 32.0 g of
candesartan cilexetil, 862.8 g of erythritol
[manufactured by Nikken Chemical Co., Ltd. (Japan)],
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240.0 g of low-substituted hydroxypropylcellulose LH-32
[hydroxypropoxyl group contents of 8.8 % by weight,
manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)],
1.6 g of polyethylene glycol [manufactured by Sanyo
Kasei Kogyo Co., Ltd. (Japan)] and 60.0 g of
crospovidone, and granulation was carried out while
spraying distilled water. The granules were dried and
then 3.6 g of magnesium stearate was added. The
mixture was tabletted using a rotary type tablettincj
machine with a punch having a beveled edge, l0 mm in
diameter, at a tabletting pressure of 1.0 ton/cm2, to
provide tablets each weighing 300 mg.
The hardness and buccal disintegration time of
each tablet thus obtained were 6.1 kg and 21 seconds
respectively.
Working Example 3
A fluidized bed granulator [manufactured by Powrex
Corp. (U.S.A.), FD-3SN] was charged with 32.0 g of
candesartan cilexetil, 922.8 g of erythritol
[manufactured by Nikken Chemical Co., Ltd. (Japan)],
240.0 g of low-substituted hydroxypropylcellulose LH-32
(hydroxypropoxyl group contents of 8.8 % by weight,
manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)]
and 1.6 g of polyethylene glycol [manufactured by Sanyo
Rasei Kogyo Co., Ltd. (Japan)], and granulation was
carried out while spraying distilled water. The
granules were dried and then 3.6 g of. magnesium
stearate was added. The mixture was tabletted using a
rotary type tabletting machine with a punch having a
beveled edge, 10 mm in diameter, at a tabletting
pressure of 1.0 ton/cm2, to provide tablets each
weighing 300 mg.
The hardness and buccal disintegration time of
each tablet thus obtained were 7.1 kg and 22 seconds
respectively.
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19
Working Example 4
A fluidized bed granulator [manufactured by Powrex
Corp. (U.S.A.), FD-3SN] was charged with 32.0 g of
candesartan cilexetil, 924.4 g of erythritol
[manufactured by Nikken Chemical Co., Ltd. (Japan)] and
240.0 g of low-substituted hydroxypropylcellulose LH-32
[hydroxypropoxyl group contents of 8.8 ~ by weight,
manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)],
and granulation was carried ou.t while spraying
distilled water. The granules were dried and then 3.6
g of magnesium stearate was added. The mixture was
tabletted using a rotary type tabletting machine with a
punch having a beveled edge, 10 mm in diameter, at a
tabletting pressure of 1.0 ton/cmZ, to provide tablets
each weighing 300 mg.
The hardness and buccal disintegration time of
each tablet thus obtained were 8.5 kg and 22 seconds
respectively.
Working Example 5
(1) Production of powders having a core
A centrifugal fluidized coating granulator
[manufactured by Powrex Corp. (U.S.A.), MP-lOJ was
charged with 300 g of Nonpareil*105 (partilcle diameter
of 100 to 200 Vim). While the inlet air temperature and
the temperature of the loading being controlled at 85
°C and about 28 °C respectively, the Nonpareil*was
coated by spraying a bulk liquid of the following
composition prepared in advance in accordance with the
tangiantial spray method at a spray rate of 20 g /min.
The spraying operation was stopped when the specified
amount of the bulk liquid had been sprayed, and then
drying was carried out in the granulator for ? minutes.
The resulting granules were sieved through a #60
circular sieve (250 Vim) and a #100 circular sieve (150
Vim) to provide ?50 g of powders having a core.
*Trade-mark
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(Bulk liquid]
Lansoprazole 300 g
Magnesium carbonate 100 g
Low-substituted hydroxypropylcellulose 50 g
5 LH-32
Hydroxypropylcellulose (Type SSL) 100 g
Water 1650 g
(2) Production of film-undercoated powders having a
10 core
A centrifugal fluidized coating granulator
[manufactured by Powrex Corp. (U.S.A.), MP-10] was
charged with 680 g of the above gowders having a core.
While the inlet air temperature and the temperature of
15 the loading being controlled at 70 °C and about 36 °C
respectively, an undercoating liquid of the following
composition prepared in advance was sprayed in
accordance with the tangiantial spray method at a spray
rate of 10 g /min. to provide 650 g of a
20 film-undercoated powders having a core.
[Undercoating liquid]
Hydroxypropylmethylcellulose 32 g
(Type 2910, viscosity of 3 centistokes}
Talc 8 g
Water 760 g
(3) Production of enteric-coated powders having a core
A centrifugal fluidized coating granulator
[manufactured by Powrex Corp. (U.S.A.), MP-10] was
charged with 450 g of the above film-undercoated
powders having a core. While the inlet air temperature
and the temperature of the loading being controlled at
65 °C and about 36 °C respectively, an enteric film
coating liquid of the following composition prepared in
advance was sprayed in accordance with the tangiantial
spray method at .a spray rate of 17 g /min. The coated
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21
powders were dried in vacuum at 40 °C for 16 hours, and
sieved through a #42 circular sieve (355 um) and a #80
circular sieve (177 Vim) to provide 950 g of
enteric-coated powders having a core.
[Enteric film coating liquid]
Eudragit* L30D-55 1078.3 g
Eudragit* NE30D 138.5 g
Triethyl citrate 46.0 g
Glyceryl monostearate 23.1 g
Talc 16.0 g
Polysorbate 80 9.0 mg
Yellow iron oxide 0.5 g
Water 2038.5 g
(4) Production of granulated powders
A fluidized bed granulator [manufactured by Powrex
Corp. (U.S.A.), LAB-1] was charged with 1321.2 g of
erythritol [manufactured by Nikken Chemical Co., Ltd.
(Japan)], 360.0 g of low-substituted
hydroxypropylcellulose LH-32 [hydroxypropoxyl group
contents of 8.8 ~ by weight, manufactured by Shin-Etsu
Chemical Co., Ltd. (Japan)], 18.0 g of anhydrous citric
acid, and 1.8 g of aspartame, and granulation was
carried out while .spraying a solution which was
prepared by dissolving 3.6 g of polyethylene glycol
(PEG-6000) in 896.4 m1 of distilled water. The
granules were dried to provide granulated powders. To
the granulated powders were added 90.0 g of
crospovidone and 5.4 g of magnesium stearate, which was
admixed in a bag to give mixed powders,
(5) Production of tablets capable of buccal
disintegration or dissolution
200.0 g of the above enteric-coated powders having
a core and 300.0 g of the above mixed powders were
tabletted using an autograph with a punch having a
*Trade-mark
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22
beveled edge, 11 mm in diameter, at a tabletting
pressure of 1.0 ton/cmZ, to provide tablets each
weighing 500 mg.
The hardness and buccal disintegration time of
each tablet thus obtained were 4.2 kg and 27 seconds
respectively:
Working Example 6
A fluidized bed granulator [manufactured by Powrex
Corp. (U.S.A.), LAB-1] was charged with 0.8 g of
voglibose, 895.6 8 of erythritol [manufactured by
Nikken Chemical Co., Ltd. (Japan)], 240.0 g of
low-substituted hydroxypropylcellulose LH-32
[hydroxypropoxyl group contents of 8.8 $ by weight,
manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)]
and 60.0 g of crospovidone, and granulation was carried
out while spraying distilled water . The granules were
dried and then 3.6 g of magnesium stearate was added.
The mixture was tabletted using a rotary type
tabletting machine with a punch having a beveled edge,
10 mm in diameter, at a tabletting pressure of 1.0
ton/cmz, to provide tablets each weighing 300 mg.
The hardness and buccal disintegration time of
each tablet thus obtained were 7.0 kg and 17 seconds
respectively.
Working Example 7
A fluidized bed granulator [manufactured by Powrex
Corp. (U.S.A.), LAB-1] was charged with 0.8 g of
voglibose, 871.6 g of erythritol [manufactured by
Nikken Chemical Co., Ltd. (Japan)], 240.0 g of
low-substituted hydroxypropylcellulose LH-32
(hydroxypropoxyl group contents of 8.8 ~ by weight,
manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)],
24.0 g of crospovidone and 60:0 g of CEOLUS KG 801
[manufactured by Asahi Chemical Co., Ltd. (Japan)], and
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23
granulation was carried out while spraying distilled
water. The granules were dried and then 3.6 g of
magnesium stearate was added. The mixture was
tabletted using a rotary type tabletting machine with a
punch having a beveled edge, 10 mm in diameter, at a
tabletting pressure of 1.0 ton/cmZ, to provide tablets
each weighing 300 mg.
The hardness and buccal disintegration time of
each tablet thus obtained were 10.4 kg and 24 seconds
respectively.
Comparative Example 1
Tablets were produced in the same manner as in
Working Example 1 except that low-substituted
hydroxypropylcellulose LH-32 was replaced by
low-substituted hydroxypropylcellulose LH-31
[hydroxypropoxyl group contents of 11.0 ~ by weight,
manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)].
The hardness and buccal disintegration time of
each tablet thus obtained were 8.4 kg and 77 seconds
respectively.
Comparative Example 2
Tablets were produced in the same manner as in
Working Example 1 except that low-substituted
hydroxypropylcellulose LH-32 was replaced by
low-substituted hydroxypropylcellulose LH-30
[hydroxypropoxyl group contents of 14.6 ~ by weight,
manufactured by Shin-Etsu Chemical Co., Ltd. (Japan)].
The hardness and buccal disintegration time of
each tablet thus obtained were 6.B kg and 5l seconds
respectively.
Industrial Applicability
The solid preparation of the present invention
possesses excellent disintegrability or dissolubility,
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24
and is used for treatment or prophylaxis of various
diseases as a preparation capable of buccal
disintegration or dissolution which can be administered
without water by aged people and children anywhere or
anytime,
Further, the solid preparation also possesses an
appropriate strength of preparation, and is excellent
in long-term storage stability.
