Note: Descriptions are shown in the official language in which they were submitted.
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DESCRIPTION
PHARMACEUTICAL COMPOSITION HAVING IMPROVED TASTE
Technical Field
The present invention relates to a pharmaceutical
composition for internal use, wherein an unpleasant taste
of a drug having an unpleasant taste such as bitter
taste, puckery taste, acid taste, etc. is reduced and its
ease of taking is improved. The pharmaceutical
composition has such a characteristic that the unpleasant
taste is significantly inhibited and reduced on taking it
and control of the dose is simple and, therefore, it is a
pharmaceutical. composition suited particularly for a
child drug dosage form.
Prior Art
Among dosage forms of drugs, a dry syrup prepared
by adding water on taking is effective for manufacturing
a preparation by using drugs which are unstable in water.
Furthermore, the dry syrup is often used as a child
dosage form because of its flexibility of the dose and
good ease of taking.
The dry syrup includes, for example, those
converted into a solution and those converted into a
suspension, when adding water. When manufacturing the
preparation, the form is selected according to physical
properties such as solubility of the drug, and purpose in
the preparation effect such as sustained release. In the
case where the drug has an unpleasant taste such as
bitter taste, there can be employed the form of a
suspending syrup obtained by forming the drug into solid
particles wherein the taste of the drug is masked out by
any method, and dispersing the solid particles.
As the method of reducing the bitter taste of the
drug in the suspending dry syrup, there have hitherto
been developed a method of changing a salt of original
drug (Japanese Unexamined Patent Publication Nos.
295422/1992, 327526/1992 and 139996/1993), a method of
using a derivative (W092/06991) and a method of
inhibiting dissolution by containing a drug in an
insoluble base (Japanese Unexamined Patent Publication
Nos. 95719/1979, 303928/1988, 187629/1992, 288821/1990,
327528/1992 and 501027/1994). EP-A-0826376 discloses the
preparation for masking the bitter taste comprising an
unpleasantly tasting drug, high polymers soluble in the
stomach and monoglycerides in the ~3 crystal form, , and
further discloses that the preparation is formulated in
dry syrups. In all techniques, there was a problem that,
when inhibition degree of dissolution is too large,
release in the gastrointestinal tract is not quickly
conducted and the bioavailability of the drug is lowered.
It is an important object to reconcile conflicting
:~ conditions such as masking of the bitter taste and good
release in the gastrointestinal tract in good balance in
the development of the dosage form of drugs. Recently,
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there has been suggested a technique capable of masking
the taste for several hours to several days after
suspending the drug in water without deteriorating the
bioavailability of the drug (Japanese Unexamined Patent
Publication No. 76517/1995).
However, according to these prior arts developed on
the assumption that the bioavailability of the drug is
obtained persistently, it is impossible to completely
inhibit the dissolution of the drug, which occurs until
the drug is taken after suspending particles containing
the drug. Therefore, these prior arts are effective for
a drug having low water solubility and a drug having high
threshold value of bitter taste because patients do not
feel the bitter taste even if a small amount of the drug
is dissolved. However, in the case of a drug having high
water solubility and low threshold value of bitter taste,
the bitter taste is caused by this dissolution of a trace
amount of the drug. The suspending syrup has a drawback
that particles are remained in the mouth, thereby causing
an unexpected bitter taste, sometimes.
Thus, in the case of the drug which is freely
soluble in water and has strong bitter taste, it is
difficult to prepare an oral solid medicine having both
two conditions such as masking of the taste and good
release in the gastrointestinal tract, or a dry syrup
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based on the dry medicine, by using the prior art at
present.
Disclosure of the Invention
In light of such problems of the prior art, the
S present invention has been developed.
Thus an object of the present invention is to
provide a pharmaceutical composition, which can be easily
taken without feeling an unpleasant taste of a drug by
adding water to the drug having the unpleasant feel such
as bitter taste before use, and which is superior in
dissolution in the gastrointestinal tract.
The present inventors have intensively studied
constantly to attain the above object, and found that, by
taking drug-containing particles wherein the taste of the
drug is masked out in a state of being dispersed and
included in a jelly, it is possible to take even a drug,
which is freely soluble in water and has a comparatively
strong bitter taste, in a state where the bitter taste is
sufficiently masked out without feeling the bitter taste.
On the basis of such a knowledge, the present inventors
have further studied and confirmed that a pharmaceutical
composition suiting the above object can be prepared by
combining a drug, wherein its unpleasant taste is masked
out to such a degree that intrinsic bioavailability of
the drug is not adversely affected, with a gelling agent
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capable of being converted rapidly into a form of agar
(jelly) when adding water.
That is, the present invention is a pharmaceutical
composition comprising a drug-containing substance
5 wherein an unpleasant taste of the drug is masked out,
and a gelling agent. The pharmaceutical composition is
converted into a jelly-like preparation containing the
above drug-containing substance when being added to
water.
Accordingly, the pharmaceutical composition of the
present invention can be taken as a jelly-like
preparation by adding water before use. That is, the
present invention makes it possible to conduct masking of
a drug having particularly strong bitter taste, which
could not be sufficiently attained by the form of a
suspending syrup according to the prior art, by taking,
as a form on taking, the form of jelly wherein the drug
whose unpleasant taste is masked out are dispersed and
included. That is, according to the pharmaceutical
preparation of the present invention, even if masking of
the drug-containing substance is insufficient for
securing the bioavailability thereby to cause leakage of
the drug in the mouth on taking, diffusion of the drug is
inhibited because a medium is in the form of jelly and,
furthermore, the drug-containing substance is taken in a
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state of being surrounded by a jelly and is hardly
remained in the mouth. Therefore, appearance of the
bitter taste derived from the drug is prevented. Since
the jelly component is quickly diluted after transferring
to the gastrointestinal tract, an influence is not
exerted on the dissolution of the drug from the drug-
containing substance and the release characteristics as a
drug-containing substance unit are maintained, thereby to
ensure the bioavailability of the drug.
Furthermore, since the pharmaceutical composition
of the present invention is a preparation prepared before
use, which is used in combination with water in a proper
amount before use, unlike a coated drug such as
conventional sugar-coated tablet, film-coated tablet,
etc., it is possible to control the dose and is optimum
for application to a child drug. Furthermore, the form
of a jelly is easily taken and is also useful as an oral
dosage form to infants, patients suffering from
dysphagia, and aged persons.
Brief Description of Drawings
Fig. 1 shows the solution out curve of the jelly
composition of Example 11.
Fig. 2 shows the solution out curve of the jelly
composition of Example 14.
Mode for Carrying out the Invention
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The pharmaceutical composition of the present
invention will be described hereinafter. In the present
specification, the particle diameter or particle size
distribution of the drug show a value measured by the
sieving method employed in Japanese Pharmacopoeia unless
otherwise stated.
The drug to be used in the pharmaceutical
composition according to the present invention is not
specifically limited, but examples thereof include
preferably drug which affords an unpleasant taste such as
bitter taste, puckery taste, acid taste, etc., to the
subject, and more preferably water-freely soluble drug
which is easily dissolved in the mouth.
According to the present invention, the unpleasant
taste of the drug is masked out to some extent by the
prior art and the remaining unpleasant taste of the drug,
which can not be completely masked out, is covered by
taking the form of a jelly. Therefore, the present
invention is particularly useful for a drug which is not
sufficiently masked out by the prior art because of
strong unpleasant taste and/or high water solubility.
More specifically, the drug includes, for example,
antimicrobial drug which is generally considered to be
bitter (e. g. pyridonecarboxylic acid synthetic
antimicrobial drug, etc.); antibiotic which is generally
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considered to be bitter [for example, penicillin
antibiotic (e. g. bacampicillin, etc.), cephem antibiotic
(e. g. cepaclor, cefotiam hexetil hydrochloride, cefteram
pivoxil, etc.), macrolide antibiotic (e. g. erythromycin,
clarithromycin, josamycin, etc.).and other antibiotic
(e. g. tetracycline, chloramphenicol, etc.) (including
embodiments of salts thereof); antitussive/expectorant
(e. g. tipepidine hibenzate, guaifenesin, diphenhydramine
hydrochloride, promethazine hydrochloride,
chlorpheniramine maleate, methylephedrine hydrochloride,
dihydrocodeine phosphate, caffeine, anhydrous caffeine,
etc.); tegafur, alacepril, sodium valproate,
meclofenoxate hydrochloride, aminophylline, calcium
hopatenate, calcium pantothenate, phenobarbital,
cimetidine, etilefrine hydrochloride, pirenzepine
hydrochloride, diltiazem hydrochloride, piromidic acid
hydrate, propranolol hydrochloride, flufenamic acid,
chlorpromazine, digitoxin, promethazine hydrochloride,
metoclopramide hydrochloride, acetaminophen, aspirin,
ibuprofen, benzydamine hydrochloride, alprenolol
hydrochloride, bifemelane hydrochloride, lidocaine,
tolmetin sodium, nortripyline hydrochloride, loperamide
hydrochloride, etc.
The pyridonecarboxylic acid synthetic antimicrobial
drug is particularly preferred. The pyridonecarboxylic
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acid antimicrobial drug is generally referred to as
newquinolone and examples thereof include synthetic
antimicrobial drugs such as enoxacin, norfloxacin,
ofloxacin, levofloxacin, cyprofloxacin, lomefloxacin,
tosufloxacin, nadifloxacin, grepafloxacin, trovafloxacin
and acid addition salts thereof. The acid addition salt
include, for example, inorganic salt such as
hydrochloride, nitrate, etc. and organic acid salt such
as salts of citric acid, salicylic acid, tosylic acid,
mesylic acid, etc. These drugs may also be an anhydrate
or a hydrate.
Generally, the above drugs are freely soluble in
water and have strong bitter taste. Among them,
grepafloxacin had such a problem that masking is not
easily conducted by a conventional method and is
insufficient because of low threshold value of bitter
taste, such as 1 Ng/ml, and high water solubility.
Therefore, the drug used in the present invention is
preferably a drug which is insufficiently masked out by
the conventional method because the threshold value of
bitter taste is low (ranging from several to several tens
~rg/ml) and the drug is freely soluble in water. The drug
is preferably grepafloxacin described above, more
preferably grepafloxacin hydrochloride, and particularly
preferably grepafloxacin hydrate.
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The term "threshold value of bitter taste" used
herein means a minimum concentration (w/v) of the drug
wherein human generally feels bitter. For example, it
can be determined from a minimum drug concentration of a
5 test solution wherein at least one of subjects felt
bitter after the subjects contain each of aqueous
solutions (10 ml) of various drug concentrations in the
mouth for 10 seconds.
It is possible to mask out the unpleasant taste of
10 these drugs by using the masking method used usually in
the medical field, thereby making it possible to prepare
a drug-containing substance (see "Taste Masking in Oral
Pharmaceuticals", Glenn M. Roy; Pharmaceutical
Technology, APRIL, 1994, PP. 84-99).
More specifically, the masking method include the
following method:
(1) a method of granulating so as to disperse a drug in a
matrix such as hydrogel or waxes;
(2) a method of adsorbing a drug to a porous polymer or
an ion exchange resin;
(3) a method of masking by further granulating those
obtained by the methods (1) and (2);
(4) a method of film coating, for example,
(i) film-coating those obtained by granulating a drug,
together with an excipient such as lactose, sucrose,
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mannitol, cornstarch, etc. and a disintegrator such as
croscarmellose sodium, etc., using a binder such as
hydroxypropyl cellulose,
(ii) film-coating those obtained by the methods (1) and
(2), and
(iii) film-coating those obtained by the method (3); and
(5) a method of encapsulating by using a method of drying
in liquid, a coacervation method, etc.
The hydrogel matrix base used herein includes, for
example, gelatinized starch, partially gelatinized
starch, gelatin, powdered acacia, methylcellulose,
carmellose (carboxymethylcellulose), carmellose sodium
(carboxymethylcellulose sodium), hydroxypropylcellulose,
hydroxypropylmethylcellulose, polyvinyl pyrrolidone, low
substituted hydroxypropylcellulose, sodium alginate,
pullulan, dextrin, starch, pectin, carmellose calcium
(carboxymethylcelllose calcium) or the like. The wax
matrix base includes, for example, hydrogenated castor
oil, hydrogenated soybean oil, glycerin fatty esters,
sorbitan fatty esters or the like.
The porous polymer includes, for example, nonionic
synthetic absorbent such as polystyrene, porous silica or
the like. The ion exchange resin includes, for example,
cation exchanger such as styrenesulfonic acid strong
acidic cation exchange resin, acrylic weak-acidic cation
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exchange resin, methacrylic cation exchange resin,
methacrylic acid copolymer (e. g. Eudragit L, etc.),
carboxyvinyl polymer, zeolites, synthetic zeolite,
Permtite, etc.; anion exchager such as styrenic strong-
basic ion exchange resin, acrylic acid weak-basic ion
exchange resin, hydrated iron oxide gel, etc.
The film-coating base and encapsulating base
include, for example, polymers such as water-soluble
polymer, water-insoluble polymer, acid-soluble polymer,
enteric polymer, etc.
The water-soluble polymer includes, for example,
powdered acacia, gelatin, sodium alginate,
methylcellulose, carmellose, carmellose sodium,
hydroxypropylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose, polyvinyl pyrrolidone, etc.
The water-insoluble polymer includes, for example,
ethylcellulose, purified shellac, waxes, etc.
The acid-soluble polymer includes, for example,
aminoalkyl Methacrylate Copolymer E, polyvinyl acetal
diethylaminoacetate, etc.
The enteric polymer includes, for example,
carboxymethylethylcellulose, hydroxypropylmethylcellulose
phthalate, hydroxypropylmethylcellulose acetate
succinate, methacrylic acid copolymer, cellulose acetate
phthalate, etc.
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The drug-containing substance wherein the
unpleasant taste of the drug is masked out, which is
obtained by the method described above, preferably has a
granular form such as powder, fine granule, granule, etc.
As the method of granulating such a drug-containing
substance, any of per se known method can be used, and
examples thereof include extrusion granulating method,
crush granulating method, fluidized bed granulating
method, centrifugal granulating method, rolling
granulating method, high-speed stir granulating method,
etc. In the flowing method, fluidized bed, centrifugal
flow, air-permeable coating pan, high-speed stirring or a
combination type equipment thereof can be used and a
suitable equipment can be selected according to the
shape, size and production method.
The particle diameter of the drug-containing
substance can be appropriately set according to the
unpleasant taste (e.g. bitter taste, etc.y of the drug or
the degree of masking. Since the drug-containing
substance is finally taken in a state of being surrounded
by a jelly, it is not necessary to pursue refining of
particles for the purpose of improving the dispersion of
the particles and avoiding foreigners, like the case of
the dosage form of syrup. It is possible to use the
drug-containing substance having a particle diameter of
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up to about 2 mm and the particle diameter is not
specifically limited, but is usually from 50 to 1800 um,
preferably from 75 to 1500 arm, and more preferably from
100 to 1000 arm.
According to the desired particle diameter of the
drug-containing substance, the masking method can be
appropriately selected.
In the case where the drug-containing substance in
the form of fine particles having a particle diameter of
up to 300 arm (usually from 75 to 300 Nm, and preferably
from 100 to 250 arm) is prepared, there can be preferably
employed a method of preparing wax matrix type fine
particles using a method of dispersing a drug in a fatty
acid ester of glycerol base. If necessary, the resulting
fine particles can also be film-coated by using a water-
insoluble coating agent such as pH-depending dissolution
type polymer.
The fatty acid ester of glycerol base includes, for
example, glyceryl monostearate, citric acid and fatty
acid esters of glycerol, glyceryl monobehenate, etc. The
water-soluble coating agent such as pH-depending
dissolution type polymer includes, for example,
aminoalkyl Methacrylate Copolymer E, Methacrylic acid
Copolymer L, Methacrylic acid Copolymer LD,
hydroxypropylmethylcellulose phthalate,
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hydroxymethylcellulose acetate succinate, etc.
In this case, the mixing ratio of the drug to fatty
acid ester of glycerol in the fine particles, and the
amount of the coating agent vary depending on the kind of
5 the drug, i.e. degree of the bitter taste of the drug and
its release characteristics and, therefore, they are
appropriately selected according to them. In the case of
a drug having high water solubility and low threshold
value of bitter taste (about several Ng/mL), the amount
10 of the fatty acid ester of glycerol to be mixed with 1
part by weight of the drug contained in the fine
particles is not less than 1.5 parts by weight,
preferably not less than 2.5 parts by weight, and more
preferably not less than 4 parts by weight. The upper
15 limit of the amount of the fatty acid ester of glycerol
in such a case is about 15 parts by weight.
The proportion of the coating film component based
on 100% by weight of the core particles is usually from
10 to 100% by weight, preferably from 10 to 80% by
weight, and more preferably from 10 to 60% by weight.
The above drug-containing substance can be prepared
by the following method. First, the drug is molten or
dispersed in a molten fatty acid ester of glycerol.
Then, this melt is dropped on a disc rotating at high
speed, using a proper liquid delivery pump. The dropped
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melt is splashed by a centrifugal force of the disc and
then solidified with cooling during the dropping to
obtain microspherical particles. Then, a solution
containing a coating film component is sprayed from a
spray gun with allowing to flow the resulting
microspherical particles in a fluidized bed granulator to
form microspherical coated particles.
In the case where a comparative large drug-
containing substance having a particle diameter of larger
than 500 pm is prepared, there can be preferably used a
masking method of including a drug in gel beads such as
water-insoluble alginate beads. In this case, the
content of the drug can be usually set within a range
from 10 to 90% by weight based on 100% by weight of the
drug-containing substance, optionally. When the content
is too small, penetration of water into beads is
accelerated and release of the drug is promoted.
Therefore, in the case of the drug which is freely
soluble in water, the content is not less than 20% by
weight, preferably from 20 to 90% by weight, and more
preferably from 30 to 80% by weight.
The above drug-containing substance can be
prepared, for example, by the following method. First, a
drug is dispersed in an aqueous solution of sodium
alginate. Then, the resulting suspension is added
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dropwise in an aqueous solution containing a calcium salt
such as calcium chloride. The added liquid droplets are
immediately solidified by the reaction between alginic
acid and calcium ions, thereby to form beads including
S the drug therein. The resulting beads are collected,
washed and then dried to obtain masked particles (drug-
containing substancey.
Furthermore, the resulting masked particles may
also be coated with the above proper coating agent, if
I0 necessary. In the case of coating with the water-soluble
polymer such as gelatin, acacia, etc., it is possible to
form a coating film by using the coacervation method
before collecting the beads. That is, a polymer film
made of gelatin is formed simultaneously with formation
15 of alginic acid beads by previously mixing a polymer with
an aqueous solution containing a calcium salt, adding
dropwise an aqueous sodium alginate solution wherein a
drug is suspended, and adding a coacervation inducer such
as alcohol.
20 It is possible to mix various excipients,
disintegrants, lubricants and other additives, which are
usually used in the production of the drug, with the
drug-containing substance, in addition to the drug and
masking agent.
25 On the other hand, as the gelling agent used in the
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pharmaceutical composition of the present invention,
those requiring any treatment such as heating, cooling,
etc. in the case of gelation are not suitable, but those
having a property capable of gelling quickly at normal
S temperature when adding water are desirable. The gelling
agent having such physical properties is preferably a
polymer capable of causing crosslinking gelation in the
presence of polyvalent metallic ions. The term "gelling
agent" used in the present invention includes not only
those composed of a single component, but also those
capable of causing gelation by using two or more
components in combination. The polymer capable of
causing crosslinking gelation by an action of the
polyvalent metallic ions includes, for example, alginate,
pectic acid salt, etc. Among them, an alginate is
preferred. The salt of the alginic acid and pectic acid
includes, for example, salt of alkali metal such as
sodium, potassium, etc.; salt of alkali earth metal such
as calcium, etc.; or partially esterified one thereof.
Among them, a sodium salt of alginic acid or pectic acid,
particularly sodium alginate has great value in use
because it is widely used as a viscous agent or a gelling
agent in the field of foods and those having different
molecular weights are commercially available.
Regarding almost all of commercially available
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sodium alginates, the viscosity in the form of an aqueous
solution is defined. The viscosity of sodium alginate
used in the present invention is from 20 to 1000 cP,
preferably from 50 to 800 cP, and more preferably from 80
to 800 cP, in terms of the viscosity of an aqueous 1%
solution at 20~ (using a rotary viscometer at 30 rpm).
Regarding sodium alginate, a product having ultra-
low viscosity defined as a viscosity of an aqueous 10%
solution is commercially available. In the case of those
having too low viscosity, it is difficult to obtain
strong gel intensity. On the other hand, in the case of
those having high viscosity, it becomes difficult to
dissolve when adding water. In both cases, it becomes
disadvantageous for masking of the drug.
In addition, sodium alginate is classified into
various grades according to a composition ratio of
mannuronic acid to guluronic acid as a constituent unit
of the polymer, that is ratio M/G. Since the gelation of
alginic acid due to metallic ions is based on chelete
crosslinking in the guluronic acid moiety, the ratio M/G
is large. That is, in the case of those containing a
large amount of mannuronic acid, a soft gel is liable to
be obtained and the ratio M/G is small. That is, in the
case of those containing a small amount of mannuronic
acid, a hard gel is liable to be obtained. The ratio M/G
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of commercially available sodium alginate is from 0.3 to
2.5. In the present invention, a jelly having desired
hardness can be prepared even when using any sodium
alginate having the hardness within this range. It is
5 possible to prepare a jelly having a desired strength by
appropriately selecting the ratio M/G within a range from
preferably 0.5 to 2, and more preferably from 1 to 2.
The ratio M/G can be determined according to the method
of Haug et al. (A. Haug et al., Carbohydrate Research 32,
10 (1974) 217-225).
Examples of the polyvalent metallic ion include
ions of salt of alkali earth metal such as magnesium,
calcium, etc.; and ions of salt of divalent /trivalent
metal such as aluminum, iron, copper, zinc, etc. Among
15 them, calcium ion is preferred as an additive of the
medicine.
Examples of the supply component of the calcium ion
include calcium salt of inorganic acid, such as calcium
chloride, calcium sulfate, calcium monohydrogenphosphate,
20 calcium carbonate, etc.; and calcium salt of organic
acid, such as calcium lactate, calcium gluconate, calcium
citrate, etc. When using a salt, which is neutral and
insoluble in water, such as calcium sulfate, calcium
citrate, monohydrogenphosphate, calcium carbonate, etc.
among them, since ions are not emitted only by adding
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water, it becomes necessary to add an acid for dissolving
the salt. Therefore, in the present invention, it is
also possible to add an organic acid such as citric acid,
adipic acid, glucono-b-lactone acid, etc.
It is very important for the gelling agent to form
a homogeneous jelly as fast as possible when adding
water. Since the gelation in the case of using sodium
alginate and a calcium salt as the gelling agent occurs
in the following two stages, that is (i) hydration of
sodium alginate and (ii) formation of a salt with calcium
ions, partial gelation of alginic acid occurs in the case
where sodium alginate has high viscosity and a long time
is required for hydration or dissociation of the calcium
salt occurs too fast, resulting in heterogeneous jelly.
Particularly, when using a salt, which is neutral and
soluble in water, such as calcium chloride, calcium
lactate, etc., calcium ions are emitted fast but partial
gelation of alginic acid is intensively conducted.
Therefore, the resultant is composed of two phases, i.e.
hard gel and a liquid portion and dissolution of the drug
is sometimes accelerated. To overcome such a
disadvantage, the gelation reaction can be delayed by
adding sodium citrate or sodium pyrophosphate which has
an chelete action to calcium ions.
The hardness of the jelly to be formed when water
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is mixed with the pharmaceutical composition comprising a
drug-containing substance wherein an unpleasant taste of
the drug is masked out, and a gelling agent according to
the present invention is not specifically limited. In
view of the feel on taking and dispersed state of drug
particles, the jelly preferably has a hardness enough to
endure elasticity for shape retention. Such a hardness
of the jelly can be controlled by appropriately
selecting/controlling the kind and amount of the gelling
agent, as a principal factor, as well as amount of water
to be added on taking.
For example, when using sodium alginate and a
calcium salt as the gelling agent, it is a mixing ratio
of sodium alginate to water that decides the hardness of
the jelly. The amount of sodium alginate to be mixed
with water so as to obtain a jelly having a proper
hardness varies depending on the specification viscosity
and ratio M/G, but is from about 0.2 to 5% by weight,
preferably from about 0.5 to 3% by weight, and more
preferably from about 0.5 to 2% by weight. The hardness
of the jelly includes, for example, hardness of the jelly
thus prepared.
Since the pharmaceutical composition of the present
invention is provided in a solid state and water is added
by users, the dose is set by previously defining the
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amount of water to be added on taking in the
manufacturing of the preparation.
When the amount of the calcium salt to be mixed
with the gelling agent is too small, the gelation becomes
insufficient. On the other hand, even if the amount is
too large, excess calcium salt causes a change in taste.
The proper amount of the calcium salt is from 0.1 to 1.5
mol, preferably from 0.1 to 1 mol, and more preferably
from 0.2 to 0.7 mol, per mol (molecular weight per
carboxyl group: 198) of sodium alginate. In the case of
a water-insoluble calcium salt, it is necessary to select
an organic acid required for dissociation of it and to
set the amount of the organic acid, carefully, because
not only control of the gelation rate but also the taste
of the jelly are influenced by them.
The gelling agent in the present invention
preferably contains the sodium alginate and calcium salt
describe above as a principal component, and may also
contain organic acids, chelating agents, sweeteners (e. g.
purified sucrose, saccharin sodium, thaumatin, aspartame,
etc.) and flavors (e. g. cherry flavor, strawberry flavor,
orange flavor, etc.).
In the pharmaceutical composition of the present
invention, the mixing ratio of the drug-containing
substance to the gelling agent is set by generally
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evaluating in view of the feel on taking, bitter taste,
etc., considering the volume of the jelly formed by
adding water on taking, and the amount of the drug-
containing substance dispersed therein. When the amount
of the drug-containing substance (drug particles) is too
large, since the resulting jelly has rough feel to the
tongue and the particles are often made contacted with
the tongue, there is a possibility of the appearance of
the bitter taste, unfavorably, which is not preferred.
To the contrary, when the amount of the gelling agent is
too large, the requisite amount of water increases and it
becomes difficult to take.
In the case of preparing by adding 2 to 20 mL of
water to the pharmaceutical composition of the present
invention in the dose per time on taking (e. g. 50 to 1000
mg of the drug-containing substance is contained), proper
weight ratio of the drug-containing substance to the
gelling agent is from 1:0.01 to 1:2, preferably from
1:0.025 to 1:1.2, and more preferably from 1:0.025 to
1:O.B, in terms of the amount of sodium alginate
contained in the gelling agent.
As described above, the pharmaceutical composition
of the present invention is basically composed of two
components, i.e. a drug-containing substance wherein the
bitter taste of the drug is masked out, and a gelling
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agent, and these components may be separately packaged
and mixed before use. In the manufacturing of the
preparation, these components may be mixed after
preparing separately. Alternatively, a preparation can
5 be manufactured by mixing the drug-containing substance
with the gelling agent component and granulating the
mixture, or coating the drug-containing substance (in the
granular form) with the gelling agent component. The
pharmaceutical composition of the present invention
10 includes any of these embodiments.
The present invention further includes the
following embodiments.
(1) A pharmaceutical composition comprising a drug-
containing substance wherein an unpleasant taste of the
15 drug is masked out, and a gelling agent.
(2) The pharmaceutical composition according to (1),
which is added to water before taking and.is taken as a
jelly-like preparation.
(3) The pharmaceutical composition according to (1),
20 wherein the drug-containing substance has a powdered or
granular form.
(4) The pharmaceutical composition according to (3),
wherein the drug-containing substance has a form of fine
particles obtained by dispersing the drug in a fatty acid
25 ester of glycerol base and said fine particles may be
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26
coated with a coating agent of one or more of a water-
soluble polymer, a water-insoluble polymer, an acid-
soluble polymer and an enteric polymer.
(5) The pharmaceutical composition according to (4),
S wherein the drug-containing substance contains a fatty
acid ester of glycerol in an amount of 1.5 to 15 parts by
weight based on 1 part of the drug.
(6) The pharmaceutical composition according to (4},
wherein a proportion of the coating agent for coating the
drug-containing substance is from 10 to 100% by weight
based on 100% by weight of the non-coated drug-containing
substance.
(7) The pharmaceutical composition according to (3),
wherein the drug-containing substance in which the
unpleasant taste of the drug is masked out is a substance
in the form of fine particles obtained by including the
drug in alginate beads.
(8) The pharmaceutical composition according to (7),
which contains the drug in the proportion of 10 to 90% by
weight based on 100% by weight of the drug-containing
substance.
(9) The pharmaceutical composition according to (2),
wherein the gelling agent is in a powdered or granular
form.
(10} The pharmaceutical composition according to (3),
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wherein the gelling agent is contained in the embodiment
of coating the surface of the powdered or granular drug-
containing substance.
(11) The pharmaceutical composition according to (1),
wherein the gelling agent contains a polymer capable of
gelling by a bridge action of polyvalent metallic ion as
the gelling agent.
(12) The pharmaceutical composition according to (11),
which contains sodium alginate and a calcium salt as the
gelling agent.
(13) The pharmaceutical composition according to (12),
wherein the gelling agent contains the calcium salt in a
proportion of 0.1 to 1.5 mol based on 1 mol of sodium
alginate.
(14) The pharmaceutical composition according to (12),
wherein a mixing ratio by weight of the drug-containing
substance to the gelling agent is from 1:0.01 to 1:2 in
terms of a proportion of sodium alginate contained in the
gelling agent.
(15) The pharmaceutical composition according to (1),
wherein the drug is an antimicrobial drug or antibiotic
having a bitter taste.
(16) The pharmaceutical composition according to (15),
wherein the drug is a pyridonecarboxylic acid synthetic
antimicrobial drug.
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(17) The pharmaceutical composition according to (16),
wherein the drug is a pyridonecarboxylic acid synthetic
antimicrobial drug selected from the group consisting of
enoxacin, norfloxacin, ofloxacin, levofloxacin,
cyprofloxacin, lomefloxacin, tosufloxacin, nadifloxacin,
grepafloxacin, trovafloxacin and acid addition salts
thereof.
(18) The pharmaceutical composition according to (2),
wherein the drug is grepafloxacin or an acid addition
salt thereof
(19) The pharmaceutical composition according to (4) or
(7), wherein the gelling agent contains a polymer capable
of gelling by abridge action of polyvalentmetallic ion
as the gelling agent.
(20) A method of producing a pharmaceutical composition
wherein unpleasant taste of the drug is masked out, which
comprises (1) preparing a drug-containing substance in
which the unpleasant taste is masked out, (2) preparing a
gelling agent capable of gelling at normal temperature
when added to water, and (3) mixing the drug-containing
substance and the gelling agent.
(21) A method of administering a drug having unpleasant
taste to humans, which comprises mixing a drug-containing
substance in which the unpleasant taste is masked out and
a gelling agent capable of gelling at normal temperature
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29
when added to water, adding the mixture to water under
stirring and taking the resulting composition orally.
Examples
The following Examples further illustrate the
pharmaceutical composition of the present invention in
detail, but the present invention is not limited by these
Examples.
Example 1
(A) Drug-containing substance
After 90g of fatty acid ester of glycerol was
molten at about 100 °C, 10 g of grepafloxacin
hydrochloride was added and dispersed therein by using a
homogenizer after sufficiently compatibilizing. The
resultant was granulated with cooling on a rotary table
under the conditions of a revolving speed of 2000 rpm to
obtain 100 g of homogeneous microspherical particles
(average particle diameter: about 150 ~.m).
(B) Gelling agent
8 g of sodium alginate, 1.6 g of sodium citrate,
0.8 g of calcium lactate, 8 g of adipic acid and 183.6 g
of powdered sucrose were mixed to obtain 202 g of a
gelling agent powder.
100 g of the drug-containing particles and 202 g of
the powder of the gelling agent, thus obtained, were
mixed to obtain a powdered composition of the present
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invention. To 1.5 g of the composition was added 5 ml of
water with a few minutes of stirring to obtain a jelly-
like composition wherein the drug-containing particles
are dispersed.
5 Example 2
(A) Drug-containing substance
After 84 g of fatty acid ester of glycerol was
molten at about 100 °C, 15 g of grepafloxacin
hydrochloride and 1 g of calcium monohydrogen phosphate
10 were added and dispersed therein by using a homogenizer
after sufficiently compatibilizing. The resultant was
granulated with cooling on a rotary table under the
conditions of a revolving speed of 2000 rpm to obtain 100
g of homogeneous microspherical particles (average
15 particle diameter: about 150 ~,m).
(B) Gelling agent
8 g of sodium alginate, 1.6 g of sodium citrate,
0.8 g of calcium monohydrogen phosphate, 8 g of adipic
acid and 183.6 g of powdered sucrose were mixed to obtain
20 202 g of a gelling agent powder.
100 g of the drug-containing particles and 202 g of
the powder of the gelling agent, thus obtained, were
mixed to obtain a powdered composition of the present
invention. To 1.5 g of the composition was added 5 ml Of
25 water with a few minutes of stirring to obtain a jelly-
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like composition wherein the drug-containing particles
are dispersed.
Example 3
(A) Drug-containing substance
After 9 kg of fatty acid ester of glycerol was
molten at about 100 °C, 1 kg of grepafloxacin
hydrochloride was dispersed therein and the resultant was
granulated with spray cooling by using a spray drying
equipment under the conditions of an inlet-air
temperature of 50 ~ and an atomizer revolving speed of
10000 rpm. As a result, 10 kg of a 10% grepafloxacin
hydrochloride pharmaceutical composition (average
particle diameter: about 150 Vim) was obtained.
(8) Gelling agent
800 g of sodium alginate, 80 g of calcium
gluconate, 80 g of citric acid and 18.3 kg of powdered
sucrose were mixed and then granulated by.rotary
fluidized bed granulator (New Marumerizer, manufactured
by Fuji Paudal Co.,Ltd.) to obtain 19.26 kg of a
granulated powder (average particle diameter: about 20
N,m) of a gelling agent.
10 kg of the drug-containing particles and 19.26 kg
of the granulated powder of the gelling agent, thus
obtained, were mixed to obtain 29.26 kg of a granulated
powdered composition for jelly preparation of the present
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invention. To 1.5 g of the granulated powdered
composition was added 5 ml of water with a few minutes of
stirring to obtain a jelly-like composition wherein the
drug-containing particles are dispersed.
Example 4
(A) Drug-containing substance
After 500 g of the microspherical particles
obtained in. Example 3 were charged in a rotary fluidized
bed granulation coating equipment (NQ-125, manufactured
by Fuji Paudal Co., Ltd.) and the inlet-air temperature
and product temperature were controlled to 60 °C and 30-
40 °C, respectively, 1500 g of 25 % Methacrylic acid
Copolymer LD suspension [containing 1000 g of Eudragit
L30D55, (manufactured by Rohm Pharma Co., Ltd.), 30 g of
triehyl citrate and 290 g of purified water] was sprayed
on the microspherical particles, and then dried to obtain
a coated powder (average particle diameter: about 200 to
250 Vim).
(B) Gelling agent
400 g of sodium alginate, 40 g of calcium
monohydrogenphosphate, 80 g of sodium citrate, 260 g of
adipic acid, 20 g of a flavor, 2 g of a colorant Food Red
No. 2, 100 g of aspartame and 9000 g of powdered sucrose
were mixed to obtain a gelling agent powder.
850 g of the drug-containing particles and 9000 g
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33
of the gelling agent powder, thus obtained, were mixed to
obtain a powdered composition for jelly preparation of
the present invention. To 5 g of the powdered
composition was added 10 ml of water with a few minutes
of stirring to obtain a jelly-like composition wherein
the drug-containing particles are dispersed.
Example 5
(A) Drug-containing substance
After 500 g of the microspherical particles
obtained in Example 3 were charged in a rotary fluidized
bed granulation coating equipment (NQ-125, manufactured
by Fuji Paudal Co., Ltd.) and the inlet-air temperature
and product temperature were controlled to 60 °C and 35-
40 ~, respectively, ethylcellulose (Aquacoat made of
FMC: manufactured by Asahi Chemical Industry Co., Ltd.)
was sprayed on the microspherical particles in the
proportion of 25 to 100% to obtain a coated powder
(average particle diameter: about 200 to 250 um).
(B) Gelling agent
400 g of sodium alginate, 20 g of calcium
carbonate, 200 g of adipic acid, 20 g of a flavor, 2 g of
a colorant Food Red No. 2 and 11650 g of purified sucrose
were mixed to obtain a gelling agent powder.
500 g of the drug-containing particles and 10000 g
of the gelling agent powder, thus obtained, were mixed to
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34
obtain a powdered composition for jelly preparation of
the present invention. To 4 g of the powdered
composition was added 10 ml of water with a few minutes
of~stirring to obtain a jelly-like composition wherein
the drug-containing particles are dispersed.
Example 6
(A) Drug-containing substance
After 500 g of the microspherical particles
obtained in Example 3 were charged in a rotary fluidized
bed granulation coating equipment (NQ-125, manufactured
by Fuji Paudal Co., Ltd.) and the inlet-air temperature
and product temperature were controlled to 60 ~ and 35-
40 ~, respectively, a mixed film of ethylcellulose
(Aquacoat made of FMC: manufactured by Asahi Chemical
Industry Co., Ltd.) and hydroxypropylmethylcellulose (TC-
5E, manufactured by Shin-Etsu Chemical Co., Ltd.) was
sprayed on the microspherical particles in the proportion
of 25 to 100% to obtain a coated powder (average particle
diameter: about 200 to 250 Vim).
(B) Gelling agent
400 g of sodium alginate, 40 g of calcium
monohydrogenphosphate, 200 g of adipic acid, 20 g of a
flavor, 2 g of a colorant Food Red No. 2 and 11650 g of
purified sucrose were mixed to obtain a gelling agent
powder .
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500 g of the drug-containing particles and 10000 g
of the gelling agent powder, thus obtained, were mixed to
obtain a powdered composition for jelly preparation of
the present invention. To 5 g of the powdered
5 composition was added 10 ml of water with a few minutes
of stirring to obtain a jelly-like composition wherein
the drug-containing particles are dispersed.
Example 7
(A) Drug-containing substance
10 After 500 g of the microspherical particles
obtained in Example 3 were charged in a rotary fluidized
bed granulation coating equipment (NQ-125, manufactured
by Fuji Paudal Co., Ltd.) and the inlet-air temperature
and product temperature were controlled to 60~ and 35-40
15 °C, respectively, a mixed film of Aquacoat made of FMC
(manufactured by Asahi Chemical Industry Co., Ltd.) and
mannitol (manufactured by Kyowa Hakko Kogyo Co., Ltd.)
was sprayed on the microspherical particles in the
proportion of 25 to 100% to obtain a coated powder
20 (average particle diameter: about 200 to 250 Vim).
(B) Gelling agent
400 g of sodium alginate, 40 g of calcium
monohydrogenphosphate, 200 g of adipic acid, 20 g of a
flavor, 2 g of a colorant Food Red No. 2 and 11650 g of
25 powdered sucrose were mixed to obtain a gelling agent
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36
powder.
500 g of the drug-containing particles and 10000 g
of the gelling agent powder, thus obtained, were mixed to
obtain a powdered composition for jelly preparation of
S the present invention. To 5 g of the powdered
composition was added 10 ml of water with a few minutes
of stirring to obtain a jelly-like composition wherein
the drug-containing particles are dispersed.
Example 8
In addition to 100 g of the microspherical
particles (drug-containing substance) obtained in Example
3, 8 g of sodium alginate, 0.8 g of calcium sulfate, 8 g
of citric acid, 0.2 g of a strawberry flavor, 0.02 g of a
colorant Food Red No. 2 and 183 g of powdered sucrose
were charged in a rotary fluidized bed granulator (MP-O1,
manufactured by Powrex Co., Ltd.) and the inlet-air
temperature and product temperature were controlled to 60
and 35-40 ~, respectively, the mixture was granulated
and dried using a 5% solution of hydroxypropyl cellulose
(HPC-L) as a binder to obtain a powdered composition for
jelly (average particle diameter: about 250 Vim) according
to the present invention. To 1 g of the powdered
composition was added 2 ml of water with a few minutes of
stirring to obtain a jelly-like composition wherein the
drug-containing particles are dispersed.
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Example 9
In addition to 100 g of the microspherical
particles (drug-containing substance) obtained in Example
3, 8 g of sodium alginate, 0.8 g of calcium citrate, 8 g
of citric acid, 0.2 g of a strawberry flavor, 0.02 g of a
colorant Food Red No. 2 and 183 g of powdered sucrose
were charged in a flow granulating equipment (MP-O1) and
the inlet-air temperature and product temperature were
controlled to 60 ~ and 35-40 ~, respectively, the
mixture was granulated and dried using a 5% solution of
hydroxypropylmethylcellulose (HPMC) as a binder to obtain
a powdered composition for preparation of jelly (average
particle diameter: about 250 um) according to the present
invention. To 1 g of the powdered composition was added
2 ml of water with a few minutes of stirring to obtain a
jelly-like composition wherein the drug-containing
particles are dispersed.
Example 10
After 500 g of the microspherical particles (drug-
containing substance) obtained in Example 3 were charged
in a centrifugal coating granulator (CF-360, manufactured
by Freund Industry Co.,Ltd.), the particles were
granulated with scattering a mixed powder containing 40 g
of sodium alginate, 4 g of calcium citrate, 40 g of
citric acid, l g of a strawberry flavor, 0.1 g of a
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38
colorant Food Red No. 2 and 915 g of powdered sucrose
using 150 g of purified water, and then dried to obtain a
granulated composition for preparation of jelly according
to the present invention. To 2 g of the granulated
composition was added 4 ml of water with a few minutes of
stirring to obtain a jelly-like composition wherein the
drug-containing particles are dispersed.
Example 11
In addition to 255 g of the microspherical
particles (drug-containing substance) obtained in Example
4, a gelling agent component containing 12 g of sodium
alginate, 1.2 g of calcium monohydrogen phosphate, 7.5 g
of citric acid, 2.4 g of sodium citrate, 0.6 g of a
strawberry flavor, 0.06 g of a colorant Food Red No. 2, 3
g of a thaumatin, 2.25 g of a a-cyclodextrine and 270 g
of powdered sucrose were charged in a rotary fluidized
bed granulator (MP-Ol,manufactued by Powrex Co., Ltd.)
and the inlet-air temperature and product temperature
were controlled to 60 °C and 35-40 ~, respectively, the
mixture was granulated by using a 5% solution of
hydroxypropyl cellulose (HPC-L) as a binder, and dried to
obtain a powdered composition for preparation of jelly
(average particle diameter: about 250 arm) according to
the present invention.
To, 2 g of the powdered composition was added, 4 ml
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39
of water with a few minutes of stirring to obtain a .
jelly-like composition wherein the drug-containing
particles are dispersed.
Example 12
(A) Drug-containing substance
To 300 mL of an aqueous 2 w/v% solution of sodium
alginate, 10 g of grepafloxacin hydrochloride and an
equimolar amount of sodium hydroxide were added and
suspended. The resulting suspension was added dropwise
in 3L of an aqueous calcium chloride solution (1 w/v%)
via a nozzle having an inner diameter of 0.5 mm to form
gel beads. The resulting beads were allowed to stand in
an aqueous calcium chloride solution for 2 hours,
collected and then washed with water and acetone. The
beads were air-dried for 12 hours and then vacuum-dried
at room temperature for 2 hours to obtain 10 g of drug
particles wherein the content of the drug is 60 w/w% and
the diameter is 0.8 mm.
(B) Gelling agent
4 g of sodium alginate, 0.4 g of calcium
monohydrogenphosphate, 0.8 g of sodium citrate, 2.6 g of
adipic acid, 0.2 g of a strawberry flavor, 0.02 g of a
colorant Food Red No. 2, 1 g of aspartame and 90 g of
purified sucrose were mixed to obtain a gelling agent
powder .
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10 g of the drug-containing particles and 90 g of
the gelling agent powder, thus obtained, were mixed to
obtain a composition for jelly preparation of the present
invention.
5 To 1 g of the powdered composition was added 3 mL
of water with a few minutes of stirring to obtain a
jelly-like composition wherein the drug-containing
particles are dispersed.
Example 13
10 After 395 g of the drug-containing particle
obtained by a similar method to Example 12 were charged
in a centrifugal coating granulator (CF-360, manufactured
by Freund Industry Co., Ltd.), 1690 g of an aminoalkyl
Methacrylate Copolymer E solution (7%) containing 140 g
15 of aminoalkyl Methacrylate Copolymer E (Eudragit E100)
and 60 g of talc in a mixture solution of ethanol (1400g)
and purified water (400g) was sprayed on the above
particles to obtain a coated particle (drug-containing
substance).
20 After 200 g of the coated granules were charged in
a centrifugal coating granulator (CF-360, Freund Industry
Co., Ltd.), the particles were granulated with scattering
a gelling agent component containing 80 g of sodium
alginate, 8 g of calcium monohydrogen phosphate, 16 g of
25 citric acid, 50 g of adipic acid, 4 g of strawberry
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41
flavor, 0.4 g of a colorant Food Red No. 2 and 1840 g of
powdered sucrose to obtain a gelling agent composition
(granule diameter; 1000 to 2500 Vim) of the present
invention.
To 1.3 g of the composition was added 4 mL of
water with a few minutes of stirring to obtain a jelly-
like composition wherein the drug-containing particles
are dispersed.
Example 14
After 400 g of the drug-containing particles
obtained by a similar method to Example 12 were charged
in a flow granulating equipment (NQ-125, manufactured by
Fuji Paudal Co., Ltd.), and the inlet-air temperature and
product temperature were controlled to 60 °C and 30 to 40
°C, respectively, 80 g of a methacrylic acid copolymer LD
solution (25 %) [a mixed suspension containing 1000 g of
Eudragit L30D55 (manufactured by Rohm Pharma Co., Ltd.),
30 g of triethyl citrate and 290 g of purified water] was
sprayed on the particles to obtain a coated particle
(drug-containing substance).
After 200 g of the coated granules were charged in
a centrifugal coating granulator (CF-360 manufactured by
Freund Industry Co. Ltd.), the particules were granulated
with scattering a gelling component containing 80 g of
sodium alginate, 8 g of calcium monohydrogen phosphate,
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16 g of sodium citrate, 50 g of adipic acid, 4 g of a
strawberry flavor, 0.4 g of a colorant Food Red No. 2 and
1840 g of powdered sucrose to obtain a gelling agent
composition (granule diameter; 850 to 2000 arm) of the
present invention.
To 1 g of the composition was added 3 mL of water
with a few minutes of stirring to obtain a jelly-like
composition wherein the drug-containing particles are
dispersed.
Example 15
(A) Drug-containing substance
After 400 g of purified sucrose was charged in a
centrifugal coating granulator (CF-360, manufactured by
Freund Industry Co. Ltd.), a granulate was obtained by
IS using 130 g of purified water with scattering a mixture
of 120 g of grepafloxacin hydrochloride, 200 g of
purified sucrose and 280 g of corn starch. Subsequently,
the resulting granule was coated with
hydroxypropylmethylcellulose phthalate and an
ethylcellulose solution (containing 150 g of
hydroxypropylmethylcellulose phthalate (HPMCP HP-55S,
manufactured by Shin-Etsu Chemical Co., Ltd.), 120 g of
ethylcellulose "ETHOCEL STD lOCPS" (manufactured by Dow
Chemical Co.) and 1.5 g of fatty acid ester of glycerol
("Myvacet 9-40T", manufactured by Koyo Shokai Co.) as a
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plasticizer in 2500 g of ethanol and 2500 g of
dichloromethane) using the spray system, dried at 60 °C
and adjusted to obtain spherical masked particles having
a particle diameter of 0.25 to 1 mm.
(B) Gelling agent
120 g of sodium alginate, 20 g of calcium lactate,
24 g of sodium citrate, 6 g of a flavor, 0.6 g of a
colorant Food Red No. 2 and 1128 g of purified sucrose
were mixed to obtain a gelling agent powdered
composition.
1000 g of the drug-containing particles and 1000 g
of the gelling agent powder, thus obtained, were mixed to
obtain a composition for jelly preparation of the present
invention. To 0.5 g of the composition was added 3 ml of
water with a few minutes of stirring to obtain a jelly-
like composition wherein the drug-containing particles
are dispersed.
Example 16
(A) Drug-containing substance
After 1080 g of purified sucrose was charged in a
centrifugal coating granulator (CF-360, manufactured by
Freund Industry Co., Ltd.), a granulate was obtained by
using 250 g of purified water with scattering a mixture
of 1350 g of grepafloxacin hydrochloride and 400 g of
2S lactose. The resulting granule was dried at 50 °C and
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sieved to obtain spherical particles having a particle
diameter of 0.25 to 2 mm. Subsequently, 2800 g of the
resulting particles were coated with
hydroxypropylmethylcellulose and an ethylcellulose
solution (containing 52 g of hydroxypropylmethylcellulose
(HPMC TC-5R, manufactured by Shin-Etsu Chemical Co.,
Ltd.), 139 g of ethylcellulose "ETHOCEL STD lOCPS"
(manufactured by Dow Chemical Co.), 19 g of fatty acid
ester of glycerol ("Myvacet 9-40T", manufactured by Koyo
IO Shokai Co.) as a plasticizer in 3093 g of ethanol and 515
g of purified water) using the spray system, dried at 40
and sieved to obtain spherical masked particles having
a particle diameter of 0.25 to 2 mm.
(B) Gelling agent
360 g of sodium alginate,' 35 g of calcium sulphate,
150 g of gluconodeltalactone, 18 g of a flavor, 1.8 g of
a colorant Food Red No. 2 and 3400 g of purified sucrose
were charged in a spiler flow (model FLO-5 manufactured
by Fleund Industry Co., Ltd.) and granulated using 2000 g
of a 5% HPC-L solution (average particle diameter: 75 to
1000 ~,m) .
3000 g of the drug-containing particles and 4000 g
of the gelling agent powder, thus obtained, were mixed to
obtain a powdered composition for jelly preparation of
the present invention. To 0.6 g of the powdered
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composition was added 5 ml of water with a few minutes of
stirring to obtain a jelly-like composition wherein the
drug-containing particles are dispersed.
Example 17
5 (A) Drug-containing substance
After 500 g of purified sucrose were charged in a
centrifugal flow type coating granulator (CF-360
manufactured by Freund Industry Co. Ltd.), a granulate
was obtained by scattering a mixture of 297 g of
10 grepafloxacin hydrochloride and 300 g of powdered sucrose
with a 145 g of 3 % solution of hydropropylcellose (HPC-
L) as a binder. The resulting granule was dried at 50 RC
for 12 hours to obtain a granular particle having a
particle diameter of 355 to 850 pm. Subsequently, after
15 500 g of the resulting particles were charged in a
centrifugal flow type coating granular (CF-360
manufactured by Freund Industry Co. Ltd.), a granulate
was obtained by using 110 g of hydroxypropylcelullose (3
%) with scattering 500 g of powdered sucrose and dried at
20 50 °C for 12 hours to obtain a granular particle having
diameter of 500 to 1000 um.
900 g of the resulting granular particles were
charged in a centrifugal flow type coating granular, and
a hydroxypropylmethylcelullose solution (5%) containing
25 50 g of hydroxypropylmethylcelullose (TC-5R, manufactured
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46
by Shin-Etsu Chemical Co., Ltd. ) in 47S g of ethanol and
475 g of purified water was sprayed on the particles, and
dried at 60 ~ and sieved to obtain a spherical particle
having a particle diameter of 500 to 1000 Vim.
S Subsequently, 400 g of the resulting spherical
particle were charged in a rotary fluidized bed
granulator (NQ-125, manufactured by Fuji Paudal Co.,
Ltd.), a methacrylic acid copolymer LD solution
[containing 30 g of triethyl citrate, 1000 g of
methacrylic acid copolymer LD (Eudragit L30D55,
manufactured by Rohm Pharma Co., Ltd.)] and 290 g of
purified water was sprayed on the particles in the
proportion of 10 to 50 % to obtain a coated particle.
Further, an aminaalkyl Methacrylate Copolymer E solution
containing 20 g of talc and 80 g of aminoalkyl
Methacrylate Copolymer E (Eudragit E 100, manufactured by
Rhom Pharma Co., Ltd.) in 810 g of ethanol and 90 g of
purified water was coated on the resulted particles in
the proportion of 5 to 50 % to obtain a double coated
particle. The resulted particles were dried at 40 °C and
sieved to obtain drug-containing particles having a
particle diameter of 500 to 2000 Vim.
(B) Gelling agent
400 g of purified sucrose were charged in a
centrifugal coating granular (CF-360, manufactured by
CA 02338996 2001-O1-29
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47
Freund Industry Co., Ltd.) and granulated with scattering
a powder mixture of 40 g sodium alginate, 4 g of calcium
monohydrogenphosphate, 8 g of sodium citrate, 25 g of
adipic acid, 2 g of a strawberry flavor, 0.2 g of a
S colorant Food Red No.2 and 520 g of powdered sucrose by
using purified water as a binder to obtain a gelling
agent particle having a particle diameter of 1000 to 2000
um. 200 g of the drug-containing particles and 400 g of
the gelling agent particles, thus obtained, were mixed to
obtain a jelly preparation of the present invention.
To 1.5 g of the resulted composition were added 3 ml
of water with a few minutes of stirring to obtain a
jelly-like composition wherein the drug-containing
particles are dispersed.
Example 18
500 g of the drug-containing particles obtained
by a similar method to Example 17 were charged in a
centrifugal coating granular (CF-360, manufactured by
Freund Industry Co., Ltd.) and granulated with scattering
a gelling agent component containing 80 g of sodium
alginate, 8 g of calcium monohydrogenphosphate, 16 g of
sodium citrate, 50 g of citric acid, 4 g of a strawberry
flavor, 0.4 g of a colorant Food Red No.3 and 1840 g of
powdered sucrose by using purified water as a binder to
obtain a gelling agent composition having a particle
CA 02338996 2001-O1-29
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48
diameter 1000 to 2500 Nm according to the present
invention.
To 1.5 g of the resulted composition were added 3 ml
of water with a few minutes of stirring to obtain a
jelly-like composition wherein the drug-containing
particles are dispersed.
Examples 19 to 21
In the same manner as in Examples 1, except for
using ofloxacin, cyprofloxacin hydrochloride and
lomefloxacin hydrochloride in place of grepafloxacin
hydrochloride, the pharmaceutical compositions of the
present invention can be prepared.
Experiment Example 1
With respect to the powdered compositions for jelly
prepared in Example 4 and Example 12, the bitter taste
was evaluated by an organoleptic test due to eleven
subjects.
Specifically, in the case of the powdered
composition for jelly of Example 4, a jelly-like sample
was prepared by mixing 5 g of the powdered composition
with 10 ml of water (at normal temperature of 15 to 25
°C), followed by stirring. In the case of the powdered
composition for jelly of Example 12, a jelly-like sample
was prepared by mixing 1 g of the powdered composition
with 3 ml of water (at normal temperature of 15 to 25
CA 02338996 2001-O1-29
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49
°C), followed by stirring. The resulting jelly-like
samples were orally administered to the respective
subjects. A syrup, which is prepared by suspending each
of drug-containing substances obtained in the respective
Examples in a 30% sucrose solution containing 0.7%
carboxymethylcellulose sodium (CMC~Na), not in the
gelleing agent, was orally administered to the respective
subjects in the same manner as described above, as a
control test. The results are shown in Table 1.
CA 02338996 2001-O1-29
WO 00/06122 PCf/JP99/04046
m
ro~
0
N N V~ N .-1
N
H
G
?i
O
tn
U
N
~i d
O
ro
o
x w
~,~,
~
O CD M O O O
f..
i-1
9,
N
O
~
m
a~
r-~
N
'J
N
f-I
C',
h
C1~
rl
m
b
O
N M N O
N
O
?~
O
O ~
U
'.r w
+~
O
O
O
d
x m
O
ro
~ t~ M .-I O O
~r
G~,
~
wi
N
r~
~
~,'~
N
.~
.
O
h
+~
r1
m ro m m m m
x >., o~
a a a a a w
ro N o ~
o ~ o o o o cu
a~ ro 0 m
m ro m m m m 5
3 G ~ ro
v s~ s~ s~ s~
~ .N .v
N w a~ a7 N v
b m
w wro u.~ w wro
~
,~, a~ o a~ a~
a~ a~ ro
~
w ~ w w w w
m m m m ~'
~' ro
o ro o o o~ro o
ro ro ~
.o
a-'
iI ~-I ~-1 ~I f.1
W 'H ~ t~,
i-1 i-I f-1 1~
'
N N dl N N O
~ N N w O
dl
i7 .C7 .Ll ~ .L~
+~ +~ ~ ~ O
O .1~ ~ ~ ~ ~ O
O O O N
.L.~ ,1~ .1-i
'.1 ''.1 ",~ "~' '~
.L".. .C: .~' .r .Li
r1 ri rl ''1 j.1
z a z z z z a
.~ a a 3 m
.a .~ .o
CA 02338996 2001-O1-29
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51
As is shown in Table 1, it became apparent that the
pharmaceutical composition (formed into a ferry
preparation before use) of the present invention
effectively inhibit a bitter taste which appears when
S forming into a syrup.
Experimental Example 2
Jelly compositions prepared in Example 11 and
Example 14 were subjected to a dissolution out test
according to a dissolution test method, the second method
(paddle method) of the Japanese Pharmacopoeia.
Specifically, 2 g (50 mg as the drug) of the
composition for jelly of Example 11 was jelled by adding
4 mL of water. The jelled product was added to 500 mL of
the second solution for the disintegration test according
to the Japanese Pharmacopoeia, and the drug solution rate
was measured every predetermined time under the condition
of a temperature of 37 °C, the paddle rotation of 100rpm.
Similarly, 1 g (50 mg as the drug) of the composition for
jell of Example 14 was jelled by adding 3 mL of water and
subjected to the same test.
The respective control samples, which contain the
drug-containing substance only (50 mg as the drug)
without containing the gelling agent in the respective
compositions of Example 11 and 14, were subjected to the
same dissolution test. Namely, the control sample for
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52
the composition of Example 11 corresponds to the drug-
containing substance obtained in Example 4, and the
control sample for the composition of Example 14
corresponds to the coated product obtained by coating
methacrylic acid copolymer LD on the drug-containing
substance prepared in Example 12.
The results are shown in Figs. 1 and 2.
From the results, it was proved that the solution rate of
the drug-containing substance only is not almost affected
by the jelly composition. The results show that the
pharmaceutical composition of the present invention is
useful for masking the drug flavor under the condition
that the absorption of the drug is not almost affected.
Industrial Applicability
The present invention makes it possible to conduct
masking of a drug having unpleasant taste by taking, as a
form on taking, the form of jelly wherein the drug whose
unpleasant taste is masked out are dispersed and
included. Even if masking of the drug-containing
substance is insufficient for securing the
bioavailability thereby to cause leakage of the drug in
the mouth on taking, diffusion of the drug is inhibited
because a medium is in the form of jelly and,
furthermore, the drug-containing substance is taken in a
state of being surrounded by a jelly and is hardly
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53
remained in the mouth.
The composition of the present invention is used in
combination with water in a proper amount when
administered, unlike a coated drug such as conventional
sugar-coated tablet, film-coated tablet, etc., it is
possible to control the dose and is optimum for
application to a child drug. Furthermore, the form of a
jelly is easily taken and is also useful as an oral
dosage form to infants, patients suffering from
dysphagia, and aged persons.
The disclosure of Japanese Patent Application
Serial No.lO-217517, filed on July 31, 1998, is
incorporated herein by reference.
