Note: Descriptions are shown in the official language in which they were submitted.
CA 02328100 2000-10-10
SPECIFICATION
Tablet Production Method and Tablet
Technical Field
The present invention relates to a tablet production method,
particularly a method wherein a tablet can be immediately
disintegrated at an objective part, a method wherein a tablet
with an engraved mark or a dividing line or an anomalous tablet
can be produced without causing sticking and so on, and a method
wherein a tablet including granule covered with film ( so called
multiple unit tablet) can be easily manufactured without
damaging function of the granule.
The present invention also relates to a tablet which can
be rapidly disintegrated at a target region of a living body
such as oral cavity, a tablet wherein function of the contained
granule isn't damaged, and a tablet added with function such
as sustained release which isn't damaged when divided.
Background Art
A tablet and a capsule are very useful pharmaceuticals for
carrying and dosing and a tablet is easy to be taken for elder
person or a patient because it doesn't float on the water when
dos ing with water . Furt:her, it has many advantages such that
production cost can be held down. Therefore, it is a most
multipurpose dosage form for oral administration and
CA 02328100 2000-10-10
- 2 -
intrabuccal administration.
In these years, a tablet which is formed anomalous other
than circular in order to distinguish the product at a glance,
a tablet provided with an engraved mark such as a company name
or a chemical code, and a tablet with a dividing line which
can be divided along the dividing line in order to administer
most suitable amount of drug depending on the age and weight
of a patient have been rapidly come into wide use.
There are several kinds of tablets such as an uncoated
tablets made by compressing powder or granule, a coating tablet
covered with a film on the tablet body for the purpose of
prolongation,sustained release,rapid release,highsolubility
in stomach, high solubility in intestine, prevention of bitter
taste, and so on, a matrix type tablet (single unit tablet)
tabletted by dispersing active substance in a base matrix of
release inhibition material with hydrophobic property or
hydrophilic property, and a tablet (multiple unit tablet) 101
including granule produced by tabletting molding material in
which granule 102 containing active substance, diluting agent
103 , and lubricant 104 are uniformly mixed liken in Fig . 2 0 ( a ) .
As granule 102 containing active substance included in the
tablet ( multiple unit tablet ) 1 O1 , in order that a f fixed amount
of active substance is continuously released for a fixed time
by one dosage of the tablet 101 or the granule 102 is dissolved
at an objective region such as intestine, there are granule
CA 02328100 2000-10-10
- 3 -
of which part 102a containing active substance is covered with
a film 102b having sustained release or high solubility in
intestine as shown in Fig. 20 ( b ) or granule wherein the active
substance 102c is dispersed in a base insoluble in water such
as fat, wax, and Vaseline or in the base matrix 102d of hydrophobic
high molecular material such as silicon rubber, and plastic
and an interface of the base matrix 102d is retreated accompanied
with release of the active substance 102c from the base matrix
102d so that the active substance 102c is continuously leased
as shown in Fig.20(c).
Conventionally such a tablet with an engraved mark or a
dividing line, an anomalous tablet, and a tablet including
granule (multiple unit tablet) has been manufactured by an
internal lubricant method and an external lubricant spraying
method.
According to an internal lubricant method, lubricant such
as magnesium stearate, lauryl sodium sulphate, and talc are
mixed in a molding material other than active substance and
diluting agent in order to execute smooth tabletting by
preventing adhering of molding material on punches and dies
and priding between the punches and the dies at the time of
producing tablets by compressing molding material by means of
the punches and the dies, and for the purpose of preventing
defective tablets causing sticking (phenomenon causing hurt
on a tablet surface when molding material is adhered on the
CA 02328100 2000-10-10
- 4 -
punch surface ) , capping ( phenomenon showing peeling of the top
of tablet like a cap) , laminating (phenomenon showing peeling
of the tablet like a layer), and binding (phenomenon causing
lengthwise hurt on the tablet surface when a tablet is discharged
from the die).
As an external tablet spraying method, a production method
has been already supposed in JP-B-41-11273 and JP-A-56-14098.
Fig.21 shows a production method disclosed in
JP-B-41-11273.
According to the method comprised of charging a fixed amount
of material to be tabletted in a die, tabletting the charged
material in the die by means of a pair of an upper and a lower
punches, and discharging the tablet, as a procedure before
molding material is charged in the die 151 as shown in Fig. 21 ( a ) ,
a spray nozzle 159 for spraying lubricant L is provided above
the die 151 and lubricant L is applied on a surface 153s ( lower
surface ) of the upper punch 153 and a surface 154s ( upper surface )
of the lower punch 154, both of which are provided for the die
151 which comes to a place where the spray nozzle 159 is placed.
Then molding material is charged in the die 151 as shown in
Fig.21(b), and the charged material m is compressed by means
of the upper punch 153 on which lower surface 153s is applied
with lubricant L and the lower punch 154 of which upper surface
154s is applied with lubricant as shown in Fig.21(c).
The member indicated by the numeral 152 in Fig.21 shows
CA 02328100 2000-10-10
- 5 -
a rotary table provided with the die 151 ( The same numeral is
used in Fig.22.).
Fig.22 shows a tablet production method described in
JP-A-56-14098.
According to this method, before molding material is charged
in a die 151, a spray 15E> for spraying lubricant L and a nozzle
159 for spraying air are provided above the die 151 . Lubricant
L is sprayed in the spray 156 when the die 151 comes where the
spray 156 is provided as shown in Fig. 22 ( a ) , lubricant is applied
on a surface 154s ( upper surface ) of a lower punch 154 provided
for the die 151 as shown in Fig.22(b). As shown in Fig.22(c),
compressed air is sprayed on the lower punch 154 at a position
where the nozzle 159 is provided, lubricant L applied on the
upper surface 154s of the lower punch 154 is blown upwardly
to be dispersed, then the dispersed lubricant L is attached
on an inner wall 151s of the die 151 and a surface 153s (lower
surface) of an upper punch 153. Thereafter, molding material
m is compressed to produce a tablet by means of lubricated inner
wall 151s of the die 151, lubricated lower surface 153s of the
upper punch 153, and lubricated upper surface 154s of the lower
punch 154.
However, a tablet produced by an internal lubricant method
includes lubricant therein and has a problem wherein
disintegrating time of a tablet is delayed because of water
repellency of lubricant so that it becomes hard to produce a
CA 02328100 2000-10-10
- 6 -
tablet which is required to be rapidly disintegrated at a target
region like an intrabuccally rapidly disintegrable tablet.
Moreover, when a tablet with an engraved mark, a tablet
with a dividing line or an anomalous tablet with different shape
are produced according to prior internal lubricant method or
external lubricant spraying method, the produced tablet is apt
to cause sticking, capping, laminating and binding.
According to an internal lubricant method, high tabletting
pressure is required ( generally 1 ton/c m - 2 ton/c m ) in order
to obtain practical hardness. Therefore, when a tablet
containing granule (multiple unit tablet) 101 is produced
according to this method, the film 102b formed on the surface
of the granule 102 contained in the tablet 101 is damaged when
tabletted, or the granule 102 is plastically deformed or
destroyed when unreasonable force is applied to the granule
102 so that functions of the granule 102 contained in the tablet
101 such as rapid release, sustained release, prolongation of
mode of action, or function of dissolving at an objective region
can't be obtained.
Conventionally as a method to prevent the film 102b formed
on the surface of the granule 102 from being damaged while
tabletting, there has been disclosed multiple granule in
JP-A-62-103012, a chewable drug tablet containing gustation
shielding agent in JP-A-2-106, and a rapid release microcapsule
in JP-A-57-150612. However, they are produced by
CA 02328100 2000-10-10
pharmaceutically devising the construction and material of the
film 102b. According to such a method, material and
construction to be selected are limited and a film usually used
for the purpose of prolongation of mode of action, sustained
release, rapid release, high solubility in stomach, high
solubility in intestine, and prevention of bitter taste can't
be used.
Further, as a method to keep the function of the film by
restraining breakage of the film of granule, there is a method
wherein practical hardness of a tablet is obtained by tabletting
while dispersing granule in a large amount of diluting agent.
According to such a method, there is a problem that a tablet
containing a large amount of granule therein can't be produced.
From the above-mentioned problems, application of a tablet
containing granule (multiple unit tablet) is limited and
pharmaceuticals containing granule, so called microcapsule are
not launched on the marked as a formulation such as tablet which
is easily taken by a patient or patients but as formulations
such as capsule or granule which are not easily taken by a patient
or patients.
A single unit type tablet which is coated with such as film
or sugar on the surface of the tabletted uncoated tablet is
popular as a tablet having the functions such as prolongation
of made of action, sustained release, rapid release, high
solubility in stomach, high solubility in intestine or
CA 02328100 2000-10-10
_ $ _
prevention of bitter taste. However, in case that such a single
unit type tablet is formed as a dividable tablet having a dividing
line on the surface, the film is destroyed and the function
added to the tablet is lostwhen the tablet is divided. Therefore,
it can't meet the requirement of physician or pharmacist of
a hospital or a clinic to launch on the market a dividable tablet
with prolongation of mode of action, sustained release, rapid
release, high solubility in stomach, high solubility in
intestine or prevention of bitter taste which can minutely
prepare an appropriate amount in conformity to each patient.
The present invention is proposed to solve the
above-mentioned problems. The first object of the present
invention is to provide a production method of a tablet which
is required to be immediately disintegrated at an objective
region like an intrabuccally rapidly disintegrable tablet.
The second object of the present invention is to provide
a production method of a tablet with an engraved mark or a dividing
line or an anomalous tablet without causing sticking, capping,
laminating and binding.
The third object of the present invention is to provide
a tablet production method wherein a tablet containing granule
(multiple unit tablet) can be produced without damaging the
function of the granule ( which may be called as a microcapsule )
contained therein, to provide a tablet containing granule
(multiple unit tablet) which can be immediately dissolved at
CA 02328100 2000-10-10
- 9 -
an objective region, a tablet containing granule (multiple unit
tablet) of which function isn't damaged without specially
devising the construction and the material of the film formed
on the granule. Moreover, the object of the present invention
is to provide a dividable tablet with a dividing line which
has prolongation of mode of action, sustained release, rapid
release, high solubility in stomach, high solubility in
intestine, prevention of bitter taste, and such functions aren' t
damaged when the tablet is divided.
Disclosure of the Invention
The inventors of the present invention have done research
on a tablet production method for a long time and found by
experiments that when punches and a die of a tabletting machine
are housed in a spraying chamber, pulsating vibration air is
generated in the spraying chamber, lubricant is applied on the
surfaces of the punches and the die, and molding material is
tabletted by means of the lubricated punches and die to produce
a tablet with an engraved mark or a dividing line or an anomalous
tablet, such tablets haven't caused sticking, capping,
laminating and binding. After hard endeavor, they have
completed the present invention.
Further the inventors have already proposed a tablet
production method in JP-A-7-124231 wherein molding material
is prevented from adhering on the punches and the dies so that
CA 02328100 2000-10-10
molding material can be continuously tabletted smoothly and
stably for a long time and moreover a tablet can be produced
without adhering molding material on the punches and the dies
even if the amount of used lubricant is remarkably reduced.
The inventors have thought that when this method is used, a
tablet which has enough practical hardness and further its
disintegrant time isn't delayed can be produced even if
tabletting pressure is low. After hard endeavor, they have
completed the present invention.
According to the tablet production method as set forth in
claim 1, a tablet including at least active substance is produced
by means of a die and a pair of punches. The method is comprised
of preparing molding material including active substance;
housing the pair of punches and the die in a spraying chamber;
generating pulsating vibration air andsprayinglubricant mixed
in air in the spraying chamber; applying lubricant on the surfaces
of the pair of punches and the die housed in the spraying chamber
while the lubricant sprayed in the spraying chamber is mixed
with the pulsating vibration air, and tabletting the molding
material by means of the pair of punches and the die on which
surfaces the lubricant is applied.
Several kinds of lubricant can be used for the tablet
production method of the present invention. Lubricant isn't
specifically limited, for example, there are stearate acid metal
salt (magnesium stearate, calcium stearate and so on), stearic
CA 02328100 2000-10-10
- 11 -
acid, sodium lauryl sulfate, sodium lauryl magnesium, powdered
gum arabic, carnauba wax, anhydrous silicic acid, magnesium
oxide, silic acid hydrate, boric acid, fatty acid sodium salt,
leucine, and so on which have been commonly used. One of them
may be used solely or more than two of them may be combined.
According to the tablet production method of the present
invention, diluting agent is added in molding material for
forming the shape of a tablet other than active substance.
As for diluting agent, there are several kinds, such as
saccharides (lactose, sucrose, glucose, mannitol, and so on),
starch ( for example, potato, wheat, corn and so on ) , inorganic
substance (calcium carbonate, calcium sulfate, sodium
bicarbonate,sodium chloride,andso on),crystalline cellulose,
powdered plant (powdered glycyrrhiza, powdered gentian, and
so on).
Molding material containing active substance may include
binder, supplement such as solution adjuvant, solubilizer, or
disintegrant, corrigent, colorant, adjuvant for
pharmaceiticals,antioxidant,preservative,opacifying agent,
antistatic agent, aroma, sweetening agent, fluidizing agent,
flavoring agent, and so on if required other than active substance
and diluting agent. However, molding material is powdered or
granular material which doesn't include lubricant.
"Pulsating vibration air" in the present invention means
a wave of air of which air pressure is changed. Positive or
CA 02328100 2000-10-10
- 12 -
negative pulsating vibration air may be used and of which
amplitude, wave length, wave shape, frequency, and period may
not be limited if it can generate air vibration all over the
spraying chamber and forcibly diffuse the particle of lubricant
sprayed therein.
"Positive pulsating vibration air" used in this invention
includes both positive pulsating vibration air of which peak
and valley are positive and positive pulsating vibration air
of which peak is higher than atmospheric pressure and valley
is almost the same as atmospheric pressure.
"Negative pulsating vibration air" used in this invention
includes both pulsating vibration air of which peak and valley
are negative and pulsating vibration air of which peak is almost
the same as atmospheric pressure and valley is negative.
Conditions of pulsating vibration air depend on size and
shape of punches and dies of a tabletting machine, size and
shape of a spraying chamber, how a lubricant spraying means
is provided, and description of active substance. Therefore,
conditions can't be simply defined, however it is easily defined
based on experiments.
According to this tablet production method, pulsating
vibration air is generated and lubricant is sprayed in the
spraying chamber. As a :result, the sprayed lubricant is mixed
with pulsating vibration air.
Further according to this method, lubricant is applied on
CA 02328100 2000-10-10
- 13 -
the surfaces of the die and the pair of punches under a condition
wherein lubricant is mixed with pulsating vibration air, namely
a condition wherein lubricant is hardly attached on the surfaces
of the punches and the die.
When lubricant is designed to be applied on the surfaces
of the punches and the die under such a hard condition, lubricant
can be uniformly applied thereon. This fact has been confirmed
by an experiment by the present inventors.
Consequently, molding material is prevented from adhering
on the pair of punches and the die while tabletted so that sticking
is hardly caused.
Moreover, as the result that lubricant is uniformly applied
on the surface of the pair of punches and the die, the produced
tablet doesn' t cause sticking even if the amount of used lubricant
per a tablet is remarkably reduced comparing with the prior
internal lubricant method and the prior external lubricant
spraying method.
Therefore, a tablet: of which surface a minute amount of
lubricant is attached can be produced. Such a tablet doesn't
happen that disintegrant time doesn't delay because of water
repellency of lubricant.
According to the production method, a tablet which can be
rapidly disintegrated at. an object region such as target region
of living body can be produced.
Further according to the production method, because
CA 02328100 2000-10-10
- 14 -
lubricant isn't included in molding material, a tablet with
practical hardness can be produced even if tabletting pressure
is lower than that of prior art when molding material is tabletted
by means of a pair of punches and a die.
Hence, when a tablet including granule having f ilm on the
surface is produced, the film isn't destroyed.
Also when a tablet including granule containing active
substance in a base matrix is produced, the function of the
contained matrix isn't damaged.
According to the tablet production method as set forth in
claim 2, a tablet including at least active substance is produced
by means of a die and a pair of punches . The method is comprised
of the steps of; preparing molding material including active
substance; housing the pair of punches and the dies in a spraying
chamber; spraying lubricant mixed in pulsating vibration air
in the spraying chamber; applying lubricant on the surfaces
of the pair of punches and the die housed in the spraying chamber;
and tabletting the molding material by means of the pair of
punches and the die on which surfaces the lubricant is applied.
According to thistablet production method, lubricant mixed
with pulsating vibration air is designed to be sprayed in the
spraying chamber.
Further according to this method, lubricant is applied on
the surfaces of the die and the pair of punches under a condition
wherein lubricant is mixed with pulsating vibration air, namely
CA 02328100 2000-10-10
- 15 -
a condition wherein lubricant is hardly attached on the surfaces
of the punches and the die.
When lubricant is designed to be applied on the surfaces
of the punches and the die under such a hard condition, lubricant
can be uniformly applied thereon.
Consequently, molding material is prevented from adhering
on the pair of punches and the die while tabletted so that sticking
is hardly caused.
Moreover, as the result that lubricant is uniformly applied
on the surfaces of the pair of punches and the die, the produced
tablet doesn' t cause sticking even if the amount of used lubricant
per a tablet is remarkably reduced comparing with the prior
internal lubricant method and the prior external lubricant
spraying method.
Therefore, a tablet: of which surface a minute amount of
lubricant is attached can be produced. Such a tablet doesn' t
happen that disintegrant time delays because of water repellency
of lubricant.
According to the production method, a tablet which can be
rapidly disintegrated at. an object region such as target region
of living body can be produced.
Further according to the production method, because
lubricant isn't included in molding material, a tablet with
practical hardness can be produced even if tabletting pressure
is lower than that of prior art when molding material is tabletted
CA 02328100 2000-10-10
- 16 -
by means of a pair of punches and a die.
Hence, when a tablet including filmed granule on the surface
is produced, the film isn't destroyed.
Also when a tablet including granule containing active
substance in a base matrix is produced, the function of the
contained matrix isn't damaged.
The tablet production method as set forth in claim 3 is
characterized in that pulsating vibration air used in the method
of claim 2 is positive pulsating vibration air.
According to this method, a spraying means for spraying
lubricant mixed with positive pulsating vibration air is
required to be provided so that the system can be simplified.
Further the inventors have paid attention in JP-A-7-124231
that when material is tabletted at a remarkably low pressure,
the produced tablet has enough practical hardness. They have
thought that a tablet including granule can be produced by this
method without damaging t:he coated film of the granule, so called
microcapsule, damaging the contained granule, nor deforming
plasticity. After hard endeavor, they have completed the
present invention.
According to the tablet production method as set forth in
claim 4, a tablet including granule containing at least active
substance is produced by means of a die and a pair of punches .
The method is comprised of the steps of ; mixing granule containing
active substance and diluting agent uniformly and preparing
CA 02328100 2000-10-10
molding materialincluding granule containing activesubstance;
housing the pair of punches and the dies in a spraying chamber;
generating pulsating vibration air andspraying lubricant mixed
in air in the spraying chamber; applying lubricant on the surfaces
of the pair of punches and the dies housed in the spraying chamber
while the lubricant sprayed in the spraying chamber is mixed
with the pulsating vibration air; and tabletting the molding
material including granule containing the active substance by
means of the pair of punches and the die on which surfaces the
lubricant is applied.
"A tablet including granule containing at least active
compound" includes a tablet produced by tabletting only granule
containing active substance and a tablet produced by tabletting
molding material in which granule containing at least active
substance, diluent, bulking agent, filler, and other diluting
agent such as excipient are uniformly mixed. Further molding
material may include supplement such as solution adjuvant,
solubilizer, and disintegrant, antioxidant, preservative,
opacifying agent, antistatic agent, aroma, sweetening agent,
fluidizing agent, flavoring agent, colorant and so on.
"Granule including active substance" includes granule
which is provided with film on the part including at least active
substance (therapeutic main ingredient) for the purpose of
prolongation of mode of action, sustained release, rapid release,
high solubility in stomach, high solubility in intestine,
CA 02328100 2000-10-10
- 18 -
prevention of bitter taste, and granule in which active substance
is dispersed in a base matrix.
Coating material for the film covering the surface of the
part including active substance (therapeutic main ingredient)
isn't required to be special. It may be generally used film
coating agent such as sugar coating, ethylcellulose (EC),
hydroxypropylsellulose (HPC), hydroxypropylmethylcellulose
phthalate (HPMC), carboxymethylcellulose, and cellulose group
such as hydroxypropylmethylcellulose, acetate succinate
(HPMCAS), carboxymethylethylcellulose (CMEC), and cellulose
acetate phthalate ( CAP ) , acrylic acid group such as methaacrylic
acid copolymer, enteric coating agent such as natural product
like shellac, sustained release coating agent such as
ethylcellulose (EC), sucrose ester, aminoalkylmetaacrilate
copolymer, copolymer of. ethylacrylate - methylmethacrylate,
and several kinds of material such as coating material disclosed
in JP-A-57-150612, JP-A-62-103012, and JP-A-2-106.
According to this method, a tablet with practical hardness
can be produced at low tabletting pressure because lubricant
isn't included in molding material. Therefore, a tablet can
be produced without breaking film and granule and without causing
plastic deformation even if the construction and material of
the film provided for the purpose of prolongation of mode of
action, sustained release, rapid release, high solubility in
stomach, high solubility in intestine, prevention of bitter
CA 02328100 2000-10-10
- 19 -
taste and the base matrix aren't devised.
The production method of a tablet including granule
containing at least active substance by means of a die and a
pair of punches as set forth in claim 5 is comprised of the
steps of; mixing granule containing active substance and
diluting agent uniformly and preparing molding material
including granule containing active substance; housing the
pair of punches and the die in a spraying chamber; spraying
lubricant mixed in pulsating vibration air in the spraying
chamber; applying lubricant on the surfaces of the pair of punches
and the die housed in the spraying chamber; and tabletting
the molding material including granule containing the active
substance by means of the pair of punches and the die on which
surfaces the lubricant is applied.
According to this method, a tablet with practical hardness
can be produced at low tabletting pressure because lubricant
isn't included in molding material. Therefore, a tablet can
be produced without breaking film and granule and without causing
plastic deformation even if the construction and material of
the film provided for the purpose of prolongation of mode of
action, sustained release, rapid release, high solubility in
stomach, high solubility in intestine, prevention of bitter
taste and the base matrix aren't devised.
The tablet production method as set forth in claim 6 is
characterized in that the pulsating vibration air used in the
CA 02328100 2000-10-10
- 20 -
tablet production methad in claim 5 is a positive pulsating
vibration air.
According to this method, a spraying means for spraying
lubricant mixed with positive pulsating vibration air is
required to be provided so that the system can be simplified.
The tablet production method as set forth in claim 7 proposes
a preferable embodiment of granule containing active substance
(so called microcapsule) to be included in molding material
and defies granule containing active substance described in
any one of claims 4 - 6 is granule containing active substance
and diluting agent.
According to this method, granule containing active
substance and diluting agent is used as granule containing active
substance ( so called microcapsule ) so that the particle diameter
and particle size of the granule containing active substance
can be easily changed by the diluting agent.
Therefore, a tablet can be easily produced by controlling
the diameter and the size of granule containing active substance
so as to facilitate coating a film on the surface.
Further, the diameter and the size of granule containing
active substance can be made so as to derive the function of
granule to the full extent.
The tablet production method as set forth in claim 8 proposes
another preferable emba diment of granule containing active
substance (so called microcapsule) to be included in molding
CA 02328100 2000-10-10
- 21 -
material and defies granule containing active substance used
in the method as set forth in any one of claims 4 - 6 is granule
containing active substance in base matrix.
"Granule containing active substance in base matrix" means
granule wherein active substance (powder) is uniformly
dispersed in a base insoluble in water such as fat, wax, and
Vaseline or in a base matrix of hydrophobic high molecular
material such as silicon rubber, and plastic.
According to this production method, because tablet can
be produced at low tabletting pressure, a tabletting can be
executed without destroying the function of base matrix even
if granule contained in the tablet includes active substance
in the base matrix.
The tablet production method as set forth in claim 9 proposes
further preferable embodiment of granule containing active
substance (so called microcapsule) to be included in molding
material and defies granule containing active substance used
in the method as set forth in any one of claims 4 - 8 is granule
of which part containing active substance is coated with film.
According to this production method, because tablet can
be produced at low tabletting pressure, a tabletting can be
executed without destroying the coating film even if granule
contained in the tablet is coated with a film.
A coating method such as well known fluidized bed coating
may be used as a method for coating granule with a film.
CA 02328100 2000-10-10
- 22 -
According to the tablet production method as set forth in
claim 10, the following steps as set forth in claim 1 or 4 are
continuously executed; housing the pair of punches and the die
in the spraying chamber; generating pulsating vibration air,
spraying lubricant mixed in air in the spraying chamber; and
applying the lubricant on the surfaces of the pair of punches
and the die while the lubricant sprayed in the spraying chamber
is mixed with pulsating vibration air; and tabletting the molding
material by means of the pair of punches and the die on which
surfaces the lubricant is applied.
According to this method, tabletting is continuously
executed utilizing the fact that molding material isn't adhered
on the punches and the die so that sticking isn't caused. A
tablet including active substance and a tablet including granule
containing active substance can be produced at industrial
production base.
The tablet production method as set forth in claim 11 is
characterized in that the following steps in claim 2 or 5 are
continuously executed; housing the pair of punches and the die
in the spraying chamber; spraying lubricant mixed in positive
pulsating vibration air in the spraying chamber, and applying
the lubricant on the surfaces of the pair of punches and the
die; and tabletting the molding material by means of the pair
of punches and the die onwhich surfaces the lubricant is applied.
According to this method, tabletting is continuously
CA 02328100 2000-10-10
- 23 -
executed utilizing the fact that molding material isn't adhered
on the punches and the die so that sticking isn't caused. A
tablet including active substance and a tablet including granule
containing active substance can be produced at industrial
production base.
The tablet production method as set forth in claim 12 is
characterized in that in the method of any one of claims 1 -
11 punches and a die construct a female mold of a tablet having
an engraved mark or a dividing line and an anomalous tablet.
"Anomalous tablet" in this specification means a tablet
with a shape except for round, for example, track ( capsule ) ,
rugby ball, polygon such as triangle, rectangle, pentagon, and
so on, diamond, almond, bombshell, half moon, heart, star, and
so on.
According to this method, because lubricant is applied on
the surface of the punches and the die constructing a female
mold for a tablet with an engraved mark or a dividing line and
for an anomalous tablet in the spraying chamber in which pulsating
vibration air is generated, lubricant can be applied uniformly
comparing with the prior external lubricant spraying method .
As a result, molding material is hardly attached on the surface
of the punches and the die while compressing a tablet with an
engraved mark or a dividing line or an anomalous tablet so that
sticking, capping, and laminating of such a tablet are prevented.
The tablet production method as set forth in claim 13 is
CA 02328100 2000-10-10
- 24 -
characterized in that in the production method in any one of
claims 1 - 12 tabletting pressure of the step for tabletting
the molding material by means of the lubricated pair of punches
and die is low.
"Low pressure" in this specification means that tabletting
pressure is lower comparing with the prior internal lubricant
method and the prior external lubricant spraying method. More
concretely explained,thistablet production method can produce
a tablet having enough practical level hardness even if its
tabletting pressure is less than or equal to 1 ton/c m.
According to this tablet production method, as tabletting
pressure for compressing molding material is low, tabletting
can be executed without destroying a film even if granule
contained in the tablet is covered with a film. Further, if
granule contained in a tablet includes active substance in a
base matrix, tabletting can be executed without destroying the
function of the base matrix.
The tablet production method as set forth in claim 14 is
characterized in that in the production method in any one of
claims 1 - 13 the amount of lubricant sprayed in the spraying
chamber is greater than or equal to 0.0001 weight percent and
less than or equal to 0.2 weight percent per a tablet.
It is preferable to reduce the amount of lubricant as far
as possible in order to prevent extension of disintegration
time of a tablet and lowering of hardness. It is preferable
CA 02328100 2000-10-10
- 25 -
to set the amount of lubricant used for a tablet to be compressed
is greater than or equal to 0.0001 weight percent and less than
or equal to 0.2 weight percent per a tablet.
Depending on an experiment, it was found that a tablet didn' t
cause tabletting problems such as sticking and could be produced
continuously even if the amount of lubricant was greater than
0. 0001 weight percent and less than or equal to 0 . 1 weight percent
per a tablet.
According to this method, lubricant is applied on the
surface (inner wall) of the die, the surface (lower surface)
of the upper punch, and the surface ( upper surface ) of the lower
punch, all of which are housed in the spraying chamber, by means
of pulsating vibration air. Namely lubricant is applied on
the surfaces under a condition where lubricant is hardly attached
on the surfaces . Therefore, a minute amount of lubricant can
be applied on the surface ( inner wall ) of the die, the surface
(lower surface) of the upper punch, and the surface (upper
surface) of the lower punch. As a result, even if the amount
of lubricant sprayed in the spraying chamber is only minute
despite of kinds of active substance, diluting agent and
lubricant, molding material can be prevented from sticking on
the punches and the die of the tabletting machine. Consequently
the amount of lubricant sprayed for tabletting at one time can
be remarkably reduced.
In accordance with this method, the produced tablet doesn't
CA 02328100 2000-10-10
- 26 -
include lubricant therein and minute amount of lubricant is
attached on the surface so that disintegration time isn't
delayed.
Therefore, if the tablet produced by this method is used
as an uncoated, it becames rapidly disintegrable tablet and
a tablet which is required to be immediately disintegrated at
an objective regionlike an intrabuccally rapidly disintegrable
tablet can be easily produced. Further if a film coat which
can be dissolved at an objective region is executed on the surface
of a tablet, the tablet itself is immediately dissolved at a
desired region when a film coat is dissolved, so that a tablet
which can be dissolved at an objective region can be produced.
Further according to this method, tablet can be produced
at a low tabletting pressure. When a tablet including granule
containing active substance is produced, the granule is hardly
damaged or plastic deformation is hardly caused when tabletting .
Therefore, the function of the granule containing active
substance in the tablet isn't apt to be damaged.
Therefore, according to the production method, if the
produced tablet including granule containing active substance
is used as an uncoated tablet, it becomes rapidly disintegrable
tablet and a tablet which is required to be immediately
disintegrated at an objective region and the granule containing
active substance can be dissolved while showing its function
like an intrabuccally rapidly disintegrable tablet can be easily
CA 02328100 2000-10-10
- 27 -
produced. Further if a film coat which can be dissolved at
an objective region is executed on the surface of a tablet,
the tablet which is required that it is immediately dissolved
at a desired region when a film coat is dissolved can be produced.
The tablet as set forth in claim 15 is provided with lubricant
only on the surface of a tablet including granule containing
active substance in diluting agent and the amount of lubricant
is greater than or equal to 0.0001 weight percent and less than
or equal to 0.2 weight percent per a tablet.
It is preferable to reduce the amount of lubricant as far
as possible in order to prevent extension of disintegration
time of a tablet and lowering of hardness. It is preferable
to set the amount of lubricant used for a tablet to be compressed
is greater than or equal to 0.0001 weight percent and less than
or equal to 0.2 weight percent per a tablet.
Depending on an experiment, it was found that a tablet didn' t
cause tabletting problems such as sticking and could be produced
continuously even if the amount of lubricant was greater than
or equal to 0.0001 weight percent and less than or equal to
0.1 weight percent per a tablet.
According to the tablet, as lubricant isn' t included therein
and a minute amount is attached on the surface, there is no
problem such that disintegration time of the tablet delays
because of water repellency of lubricant.
Therefore, if the tablet is used as an uncoated tablet,
CA 02328100 2000-10-10
- 28 -
it becomes a rapidly disintegrable tablet and the tablet is
immediately disintegrated at an objective region like an
intrabuccally rapidly disintegrable tablet and activesubstance
contained in the tablet is immediately released.
Moreover, if a film coat which can be dissolved at an
objective region is executed on the surface of the tablet, the
tablet itself can be dissolved at the objective region when
the film coat is dissolved, so that active substance contained
in the tablet is immediately released.
The tablet as set forth in claim 16 has lubricant only on
the surface of the tablet including granule containing active
substance in diluting agent.
According to the tablet, as lubricant isn' t included therein
and a minute amount is attached on the surface, there is no
problem such that disintegration time of the tablet delays
because of water repellency of lubricant.
Therefore, if the tablet is used as an uncoated tablet,
it becomes a rapidly di.sintegrable tablet and the tablet is
immediately disintegrated at an objective region like an
intrabuccally rapidly disintegrable tablet and granule
containing active substance (so called microcapsule) included
in the tablet is immediately released.
Moreover, if a film coat which can be dissolved at an
objective region is executed on the surface of the tablet, the
tablet itself can be dissolved at the objective region when
CA 02328100 2000-10-10
- 29 -
the film coat is dissolved, so that granule containing active
substance (so called microcapsule) included in the tablet is
immediately released.
The tablet as set forth in claim 17 - 19 defines preferable
construction of the granule containing active substance of the
tablet as set forth in claim 16.
According to the tablet as set forth in claim 17, the tablet
as set forth in claim 16 is characterized in that the granule
containing active substance is granule containing active
substance and diluting agent.
According to such a tablet, as granule containing active
substance and diluting agent is used as granule containing active
substance (so called microcapsule), the particle diameter and
size of the granule can be easily modified by diluting agent.
Therefore, a tablet production can be easily executed by
controlling the particle diameter and size of the granule so
as to be easily coated with a film on the surface of the tablet.
Further, the diameter and the size of granule containing
active substance can be made so as to derive the function of
granule to the full extent.
According to the tablet as set forth in claim 18, the tablet
in claim 16 is characterized in that the granule containing
active substance is granule including active substance in base
matrix.
According to such a tablet, as diluting agent used as bulking
CA 02328100 2000-10-10
- 30 -
agent doesn' t include lubricant, there is no problem such that
disintegration time of the tablet delays because of water
repellency of lubricant..
Further, as the tablet includes granule containing active
substance in the base matrix, the base matrix can achieve its
desired objective function.
For example, if the base matrix aims at prolongation of
mode of action, the tablet also becomes to have a function of
sustained release by the base matrix.
Therefore, if unfilmed granule containing active substance
and granule containing active substance in base matrix are mixed
in a tablet, they are immediately released from the tablet when
the tablet is dissolved. The active substance contained in
the unfilmed granule is immediately absorbed in a body when
the tablet isdisintegrated. Therefore, the tablet hassuperior
rapid onset of action.
As for the granule containing active substance in the base
matrix, for example, if the base matrix aims at prolongation
of mode of action, the tablet also becomes to have a function
of prolongation of mode of action by the base matrix.
Namely, the tablet yields both rapid onset of action and
prolongation of mode of action.
If the active substance is analgesic, anti-inflammatory
agent, or antidote, unfilmed granule containing such agent and
granule containing such agent in the base matrix are mixed.
CA 02328100 2000-10-10
- 31 -
Thereby, a new tablet such as a once daily tablet, namely a
quick & slow release tablet, by which pain, inflammation or
fever of a patient is immediately remedied and analgesic action,
anti-inflammatory action, or antidote action is kept long when
a patient takes this medicine can be obtained.
The tablet as set forth in claim 19 is characterized in
that the granule containing active substance of the tablet of
any .one of claims 16 - 18 is granule of which part containing
active substance is covered with film.
According to such a tablet, as diluting agent used as bulking
agent doesn' t include lubricant, there is no problem such that
disintegration time of the tablet delays because of water
repellency of lubricant.
Further, as the tablet includes granule containing active
substance, a film coated on the surface of the granule containing
active substance brings out a desired objective function.
For example, the f ilm coated on the granule containing active
substance aims at prolongation of mode of action, the tablet
also yields prolongation of mode of action because of the film.
Therefore, if unfilmed granule containing active substance
and filmed granule containing active substance are mixed in
a tablet, they are released from the tablet when the tablet
is dissolved. The active substance contained in the unfilmed
granule is immediately absorbed in a body when the tablet is
disintegrated. Therefore, the tablet has superior rapid onset
CA 02328100 2000-10-10
- 32 -
of action.
As for the filmed granule containing active substance, for
example, if the film aims at prolongation of mode of action,
the tablet also becomes to have prolongation of mode of action
because of the function of the film. Namely, the tablet has
both rapid onset of action and prolongation of mode of action.
If the active substance is analgesic, anti-inflammatory
agent, or antidote, unfilmed granule containing such agent and
filmed granule containing such agent are mixed. Thereby, a
new tablet such as a once daily tablet, namely a quick & slow
release tablet, by which pain, inflammation or fever of a patient
is immediately remedied and analgesic action, anti-inflammatory
action, or antidote action is kept long when a patient takes
this medicine can be obtained.
According to the tablet as set forth in claim 20, the amount
of lubricant used in the tablet described in any one of claims
16 - 19 is greater than or equal to 0.0001 weight ~ and less
than or equal to 0.2 weight percent per a tablet.
It is preferable to reduce the amount of lubricant as far
as possible, preferably greater than or equal to 0.0001 weight
percent and less than or equal to 0 . 1 weight percent per a tablet.
Because the tablet is provided with a minute amount of
lubricant on the surface, its disintegration time doesn' t delay.
According to the tablet as set forth in claim 21, the tablet
described in any one of c7_aims 15 - 20 is provided with a dividing
CA 02328100 2000-10-10
- 33 -
line on the surface thereof.
Because the tablet has a dividing line, it can be easily
divided along the line. Therefore, appropriate amount of drug
depending on the weight or age of a patient can be taken by
a patient.
The tablet as set forth in claim 22 is characterized in
that the shape of the tablet described in any one of claims
15 - 21 is anomalous.
Because the tablet has anomalous shape, drugs can be easily
distinguished by its shape. Therefore, medication error is
hardly happened.
The tablet as set forth in claim 23 is characterized in
that the standard deviation of disintegration time of the tablet
or elution time of the active substance described any one of
claims 15 - 22 is less than or equal to 15 percent of average
disintegrating time or average elution time.
The fact that the standard deviation of disintegration time
of the tablet or elution time of the active substance can be
less than or equal to 15 percent of average disintegrating time
or average elution time is an effect of the experiment done
by the present inventors.
Further according t:o the experiment done by the present
inventors, it was found that the standard deviation of
disintegration time of the tablet or elution time of the active
substance could be less than or equal to 10.0 percent of average
CA 02328100 2000-10-10
- 34 -
disintegrating time of the tablet or average elution time fo
the active substance. Further it was also found that the
standard deviation of disintegrating time of the tablet or
elution time of the active substance could be less than or equal
to 7 .5 percent of average disintegrating time or average elution
time, further less than or equal to 7.0 percent.
Because lubricant i.s uniformly applied on the surface of
the tablet (uncoated tablet), there is no wide variation of
disintegration time of the tablet and elution time of the active
substance. Therefore, the tablet of which standard deviation
of disintegrating time of the tablet or elution time of the
active substance is less than or equal to 15 . 0 percent of average
disintegrating time or average elution time can be easily
produced.
Further, the tablet of which standard deviation of
disintegrating time of the tablet or elution time of the active
substance is less than or equal to 10.0 percent of average
disintegrating time or average elution time, which has been
considered to be difficult in the prior art, can be easily
produced.
Moreover, the tablet of which standard deviation of
disintegrating time of the tablet or elution time of the active
substance is less than or equal to 7.5 percent, further 7.0
percent, of average disintegrating time or average elution time,
which has been impossible to produce in the prior art as far
CA 02328100 2000-10-10
- 35 -
as the inventors know, can be produced.
Because lubricant is uniformly applied on the surface of
the tablet (uncoated tablet), there is no wide variation of
disintegration time of the tablet and elution time of the active
substance.
Hence, there is no variation of the time before appearing
the effect of drugs between tablets.
The tablet as set forth in claim 24 is characterized in
that the lubricant of the tablet described in any one of claims
15 - 23 is magnesium stearate.
When magnesium stearate is used as lubricant, the amount
of lubricant contained in the tablet can be easily measured
by atomic absorption spectrometry.
Brief Description of Drawings
Fig.l shows a schematic construction of an enlarged view
around a rotary table of a rotary type tabletting machine used
for executing the present invention.
Fig.2 shows a schematic section of the enlarged view around
the rotary table of the rotary type tabletting machine shown
in Fig. 1.
Fig . 3 is a schematic view around a spraying chamber, Fig. 3 ( a )
schematically shows a construction of the spraying chamber,
and Fig.3 (b) schematically shows a construction of a pulsating
vibration air generation means.
CA 02328100 2000-10-10
- 36 -
Fig.4 explains a concrete example of pulsating vibration
air, Fig.4(a) and Fig.4(b) show negative pulsating vibration
air respectively.
Fig . 5 is a schematic view around a spraying chamber, Fig. 5 ( a )
schematically shows a construction of the spraying chamber,
and Fig.5(b) schematica:Lly shows a construction of a pulsating
vibration air generation means.
Fig.6 explains a concrete example of pulsating vibration
air, Fig.6(a) and Fig.6(b) show positive pulsating vibration
air respectively.
Fig.7schematically explainsmany kindsof tabletsproduced
in experiments . A schematic plane view of each tablet is shown
at left and its schematic side view is shown at right.
Fig.Bschematically explainsmany kindsof tabletsproduced
in experiments . A schematic plane view of each tablet is shown
at left and its schematic side view is shown at right.
Fig.9schematically explainsmany kindsof tabletsproduced
in experiments . A schematic plane view of each tablet is shown
at left and its schematic side view is shown at right.
Fig.lO schematically explains many kinds of tablets
produced in experiments . A schematic plane view of each tablet
is shown at left and its schematic side view is shown at right.
Fig.ll schematically explains many kinds of tablets
produced in experiments . A schematic plane view of each tablet
is shown at left and its schematic side view is shown at right.
CA 02328100 2000-10-10
- 37 -
Fig. l2 is a graph showing cross relationship between
tabletting pressure and hardness of produced tablet.
Fig.l3 is a graph showing cross relationship between time
and dissolution rate.
Fig.l4 is a graph showing cross relationship between time
and dissolution rate.
Fig.lS schematically shows a sectional view of means
(metering feeder) for quantitatively supplying lubricant
contained in a hopper into a conduit.
Fig. l6 is a schematic plane view showing one embodiment
of an elastic membrane used for the means (metering feeder)
in Fig. l5.
Fig. l7 schematically shows operations of the means
(metering feeder) shown in Fig. l5.
Fig.l8 is a schematic plane view showing another embodiment
of an elastic membrane used for the means (metering feeder)
in Fig. l5.
Fig. l9 is a schematic sectional view showing another
embodiment of pulsating vibration air generation means.
Fig.20 schematically explains a construction of a tablet,
Fig. 20 ( a ) explains a multiple unit type tablet, Fig. 20 ( b ) and
Fig.20 ( c ) explain the canstruction of the granule included in
the multiple unit type 'tablet.
Fig.21 schematically shows the tablet production method
described in JP-B-41-11273.
CA 02328100 2000-10-10
- 38 -
Fig.22 schematically shows the tablet production method
described in JP-A-56-14098.
Disclosure of the Invention
The present invention will be detailed hereinafter
referring to the attached drawings.
(Embodiment of the Invention 1)
In this embodiment t:he production method of a tablet which
is immediately disintegrated at an objective region will be
explained referring to the attached drawings.
Here the present invention will be explained by an example
using a rotary type tabletting machine.
Fig.l shows schematic construction by enlarging one
part around a rotary table of a rotary type tabletting machine
used for executing the present invention.
Fig.2 is a schematic section when one part of Fig.l around
the rotary table is enlarged.
As shown in Fig.l and Fig.2, the rotary type tabletting
machine A is comprised of a rotatably provided rotary table
2having pluraldiesl,w in circumferentialdirection, plural
upper punches 3, w and plural lower punches 4, w provided so
as to correspond to each dies 1, -~ . A spraying chamber 8 is
provided at P1 which is before a point P2 where molding material
is charged in the die 1. A pulsating vibration air generation
means 7 is connected to the spraying chamber 8 and a spray nozzle
CA 02328100 2000-10-10
- 39 -
9 for spraying lubricant L is provided in the spraying chamber
8. In this embodiment, an air source 10 such as a cylinder
charging compressed air is connected to the spray nozzle 9 and
lubricant L is designed to be sprayed from the spray nozzle
9 by the air generated from the source 10.
Next, tablet production procedure using this machine Awill
be explained.
The rotary table 2 is rotated at a fixed speed, pulsating
vibration air is generated in the spraying chamber 8 by driving
the pulsating vibration air generation means 7 when the die
1 comes to the point P1 where the spraying chamber 8 is provided
according to rotation of the rotary table 2, lubricant L is
simultaneously sprayed from the spray nozzle 9, and lubricant
L is applied on a surface (inner wall) is of the die 1, a surface
( lower surface ) 3s of the upper punch 3 , and a surface ( upper
surface) 4s of the lower punch 4.
Then, molding material m is charged in the die 1 which comes
to the point P2 for charging molding material m in the die 1
accompanied with rotation of the rotary table 2 and extra molding
material m is scraped. Thereafter, when the die 1 charged with
molding material m comes to a point P3 for compressing molding
material m, molding material m in the die 1 is compressed to
produce a tablet by means of the upper punch 3 of which surface
(lower surface) 3s is applied with lubricant L and the lower
punch 4 of which surface (upper surface) 4s is applied with
CA 02328100 2000-10-10
- 40 -
lubricant L. Further, when the die 1 comes to a point P4, a
tablet T is discharged from the die 1 so that the tablet T is
produced.
Fig.3(a) shows schematic construction around the spraying
chamber 8 and Fig. 3 ( b ) illustrates construction by an example
of pulsating vibration air generation means 7.
In this example, the pulsating vibration air generation
means 7 is connected to the spraying chamber 8 via a conduit
13.
In Fig.3(b) the numeral 71 shows a blower, 72 shows a
cylindrical tube, 73 shows a valve element provided rotatably
around a rotary axis 74 so as to divide inside of the tube 72
into two parts. The conduit 13 and a conduit 14 coupled to
the blower 71 are connected at a given place of the side of
the tube 72. The valve element 73 is designed to be rotated
at a desired rotational velocity by means of a valve rotation
control means (not shown).
When the blower 71 is rotated at a given rotation number
and the valve element 73 is also rotated at a given rotational
speed, the spraying chamber 8 and the blower 71 are connected
as the valve element 73 is positioned at a place shown by a
solid line in the figure. When the valve element 73 is positioned
at a place shown by a dotted line, the spraying chamber 8 and
the blower 71 are blocked off by the valve element 73.
Accordingly, pulsating vibration air with its peak at
CA 02328100 2000-10-10
- 41 -
atmospheric pressure and its valley at negative pressure shown
in Fig. 4 ( a ) or pulsating vibration air with its peak and valley
at negative pressure shown in Fig.4 (b) can be produced in the
spraying chamber 8.
Here "negative pressure" means that the pressure in the
spraying chamber 8 is lower than outside pressure ( atmospheric
pressure).
When lubricant L is sprayed from the spray nozzle 9 while
generating pulsating vibration air shown in Fig. 4 ( a ) or Fig. 4 ( b ) ,
sprayed lubricant L is diffused by the pulsating vibration air
and is uniformly applied on the surface ( inner wall ) is of the
die 1, the surface (lower surface) 3s of the upper punch 3 and
the surface (upper surface) 4s of the lower punch 4 both of
which are provided so as to correspond to the die 1 housed in
the spraying chamber 8.
According to this tablet production method, as lubricant
L can be uniformly app lied on the surface (inner wall) is of
the die 1, the surface {lower surface) 3s of the upper punch
3, and the surface (upper surface) 4s of the lower punch 4,
molding material m can be prevented from adhering on the die
1, the upper punch 3, and the lower punch 4 of the tabletting
machine A even if the amount of lubricant L sprayed in the spraying
chamber 8 is only a little regardless of the kinds of active
substance, diluting agent, and lubricant.
This method is characterized in that the amount of lubricant
CA 02328100 2000-10-10
- 42 -
sprayed in the spraying chamber is remarkably reduced utilizing
this effect. The spray amount of lubricant L to be sprayed
in the spraying chamber 8 is controlled to be greater than or
equal to 0.0001 weight ~ and less than or equal to 0.2 weight ~
per the weight of tablet . Further it may be controlled greater
than or equal to 0.0001 weight ~ and less than or equal to 0.1
weight
According to this method, only a part of lubricant L applied
on the surface ( inner wall ) is of the die 1 , the surface ( lower
surface) 3s of the upper punch 3, and the surface (upper surface)
4s of the lower punch 4 exists on the surface of the tablet
and the tablet doesn't include lubricant L therein. Therefore,
the used amount of lubricant L for the tablet T is remarkably
small comparing with the tablet produced by the prior production
method. Hence, a problem, which has been found in the prior
tablet, wherein disintegration time of tablet delays because
of water repellency of lubricant L is never happened.
Further, because lubricant L isn' t included in the molding
material m, produced tablet can obtain practical hardness even
if tabletting pressure .is low (practically less than 1 ton/c
m ) comparing with the case that molding material m including
lubricant L is tabletted.
Accordingly, if the tablet T produced by the production
method is used as an uncoated tablet, it becomes a rapidly
disintegrable tablet and is suitable as a tablet which is required
CA 02328100 2000-10-10
- 43 -
to be disintegrated at an objective region like an intrabuccally
rapidly disintegrable tablet.
If a film coat which can be dissolved at an objective region
is executed on the surface of the tablet T, the tablet itself
can be immediately dissolved at the objective region so that
a tablet which can be dissolved at an objective region can be
produced.
Further, when granule of which surface of a part containing
active substance is filmed is included in a tablet as granule
containing active substance, the film coated on the surface
isn't destroyed at the time of compression (tabletting) because
the tablet T can be compressed (tabletted) at low pressure.
Accordingly, the film coated on the granule containing active
substance can bring out a desired objective function.
For example, the film coated on the granule containing active
substance aims at prolongation of mode of action, the tablet
also has sustained release because of the film.
Therefore, if unfilmed granule containing active substance
and filmed granule containing active substance are mixed in
the tablet T, they are immediately released from the tablet
T when the tablet T is disintegrated. The active substance
contained in the unfilmed granule is immediately absorbed in
a body when the tablet is disintegrated. Therefore, the tablet
has superior rapid onset of action.
As for the filmed granule containing active substance, for
CA 02328100 2000-10-10
- 44 -
example, if the film aims at prolongation of mode of action,
the tablet also becomes to have prolongation of mode of action
because of the function of the film.
Namely, the tablet has both rapid onset of action and
prolongation of mode of action.
If the active substance is analgesic (morphine
hydrochloride and so on ) , anti-inflammatory agent ( indometacin,
diclofenac sodium and so on), or antidote(sulphyrine and so
on), unfilmed granule containing such agent and filmed granule
containing such agent are mixed in the tablet T. Thereby, a
new tablet such as a once daily tablet, namely a quick & slow
release tablet, by which pain, inflammation or fever of a patient
is immediately remedied and analgesic action, anti-inflammatory
action, or antidote action is kept long and also has rapid onset
of action when a patient: takes this medicine can be obtained.
Moreover, when granule containing active substance in a
base matrix is included in the tablet T as granule containing
active substance, the function of the base matrix isn' t destroyed
at the time of compress ion ( tabletting ) because the tablet T
can be compressed (tabletted) at low pressure. Accordingly,
the base matrix can bring out a desired objective function.
Therefore, if unfilmed granule containing activesubstance
and granule containing active substance in the base matrix are
mixed in the tablet T, they are immediately released from the
tablet T when the tablet T is disintegrated. The active
CA 02328100 2000-10-10
- 45 -
substance contained in the unfilmed granule is immediately
absorbed in a body when the tablet T is disintegrated. Therefore,
the tablet has superior rapid onset of action.
As for the granule containing active substance in the base
matrix, for example, if the base matrix aims at prolongation
of mode of action, the tablet T also becomes to have prolongation
of mode of action because of the function of the base matrix.
Namely, the tablet T has both rapid onset of action and
prolongation of mode of action.
If the active substance is analgesic (morphine
hydrochloride and so on ) , anti-inflammatory agent ( indometacin,
diclofenac sodium and so on), or antidote(sulphyrine and so
on), unfilmed granule containing such agent and granule
containing such agent in the base matrix are mixed in the tablet
T. Thereby, a new tablet such as a once daily tablet, namely
a quick & slow release tablet, by which pain, inflammation or
fever of a patient is immediately remedied and analgesic action,
anti-inflammatory action, or antidote action is kept long and
also has rapid onset of action when a patient takes this medicine
can be obtained.
It is preferable to reduce the amount of lubricant L sprayed
in the spraying chamber 8 as far as sticking of molding material
m to the die 1, the upper punch 3, and the lower punch 4 of
the tabletting machine A is prevented. In order to prevent
that the disintegration time of the produced tablet is extended
CA 02328100 2000-10-10
- 46 -
and the hardness is lowered, it is preferably greater than or
equal to 0.0001 weight percent and less than or equal to 0.2
weight percent per a tablet, although it depends on the nature
of the molding material. According to an experiment, when the
amount of lubricant L was greater than or equal to 0.001 weight
percent and less than or equal to 0 . 1 weight percent per a tablet,
it was found that problems such as sticking weren't caused and
continuous tabletting could be executed.
Because lubricant L is uniformly applied on the surface
of the tablet T ( uncoated tablet ) , there is no wide variation
of disintegration time of the tablet and elution time of the
active substance.
Hence, there is no variation of the time before appearing
the effect of drugs between tablets.
Next, the present invention will be explained based on
concrete experimental data.
(Experiment 1)
According to normal fluid-bed granulation method,
polyvinyl alcohol was sprayed on the powder of which prescription
was shown in the following table 1, particle was grown, and
granulated material with prescribed size was manufactured.
Then, the obtained granule was sized by means of a No.28 mesh.
Next, it was tabletted to produce a 130mg tablet at a speed
of rotating a rotary table 2 at 30 times per a minute by means
of the tabletting machine A with 7mm diameter punch and die
CA 02328100 2000-10-10
- 47 -
set.
When tabletting, magnesium stearate was used as lubricant.
The amount of air sprayed from the nozzle 9 shown in Fig. 3 ( a ) ,
rotation number and suction amount of the pulsating vibration
air generation means 7 were controlled in such a manner that
the amount of the magnesium stearate sprayed in the spraying
chamber 8 was adjusted such that weight ~ of lubricant L included
in one produced tablet became 0.03 weight ~ for the entire amount
of the tablet.
More concretely, pulsating vibration air of which period
was more than or equal t:o 1Hz and less than or equal to lOHz,
its valley was about 10~ - 5~ lower than atmospheric pressure,
and its peak was almost equal to or a litter lower than atmospheric
pressure was used in this experiment.
WSG-type 15 by Glatt Co., Ltd. was used as a fluid-bed
granulator and RATA HT-X20 by Hata Seisakusho Co., Ltd. was
used as a main body of a tabletting machine.
CA 02328100 2000-10-10
- 48 -
Table 1
combined ingredient weight $
Levodopa 9.p
(Japanese Pharmacopoeia)
Lactose 57.5
Cornstarch 28.5
Polyvinyl alcohol 5.0
Total 100.0
(Comparison 1)
Magnesium stearate was added as lubricant for the granule
produced like the experiment 1 in a ratio of 0.03 weight o for
the entire amount of a tablet. After they were well mixed by
a V type mixer, they were continuously tabletted by an internal
lubricant method at a speed of rotating the rotary table at
30 times per minute by means of a set of 7mm punch and die so
as to produce the material into a 130mg tablet. However, tablet
wasn't continuously produced because molding material adhered
on the punches and the dies.
Then in order to solve this, magnesium stearate was added
as lubricant for the granule used in the experiment 1 in a ratio
of 0.8 weight o for the entire amount of a tablet. After they
were well mixed by a V type mixer, they were continuously
tabletted by an internal :lubricant method at a speed of rotating
the rotary table at 30 times per minute by means of a set of
CA 02328100 2000-10-10
- 49 -
7mm punch and die so as to produce the material into a 130mg
tablet.
However, it was hard to continuously produce a tablet because
molding material adhered on the punches and the dies.
HATA HT-X20 by Hata Seisakusho Co., Ltd. was used as the
tabletting machine A.
(Comparison 2)
The granule produced like the experiment 1 was tabletted
by means of a set of 7mm punch and die so as to produce a 130mg
tablet. Stearate magnesium was applied on the surfaces 3s,
4s of the punches 3, 4 and the surface is of the die 1 according
to the method described in JP-B-41-11273 so that the weight ~
of lubricant became 0.03 weight $ per a produced tablet. Then
the material was continuously tabletted at a speed of rotating
the rotary table at 30 times per minute.
HATA HT-X20 by Hata Seisakusho Co., Ltd. was used as the
tabletting machine A.
Next, disintegration test according to ,Tapanese
Pharmacopoeia was executed for three kinds of tablets produced
according to the experiment l, the comparison 1, and the
comparison 2 at a given test number (N=5).
The result is shown in Table 2.
CA 02328100 2000-10-10
- 50 -
Table 2
Tabletting hardness Disintegration time (min)
Pressure (kg) (n = 5)
(ton/c m) Average measurement
(standard variation)
experiment
1 0.7 9 6.0
(0.2)
comparison 0.7 6 10.2
1 (-!-0.9)
comparison 0.7 9 g.0
2 (--0.6)
According to the table 2 , it was found that the experiment
1 had high hardness comparing with the comparison 1 and had
short disintegration time comparing with the comparisons 1 and
2. And also its disintegration time doesn't widely vary.
Also it was found that in the experiment 1 had the same
hardness as the comparison 2, however, disintegration time was
CA 02328100 2000-10-10
- 51 -
short and variation of disintegration time was small.
When the rotary type tabletting machine A provided with
the pulsating vibration air generation means 7 shown in Fig.l
was used, it was found that the produced tablet has practical
hardness at a tabletting pressure of 0.7 ton/c m.
As the result, it was also found that in the experiment
1 lubricant was uniformly applied on the surface of the tablet .
The standard deviation of the disintegration time of the
tablet in the experiment 1 was 0.2 and the disintegration time
of each tablet was less than or equal to 7~ . From the above
experiment, it was found that the standard deviation of the
disintegration time of the tablet or the diluting time of active
substance could easily become less than or equal to 15~ of the
average dis integration time of the tablet or the average diluting
time of active substance.
Moreover according to the above experiment, it was found
that the standard deviation of the disintegration time of the
tablet or the diluting time of active substance could easily
become less than or equal to 10% of the average disintegration
time of the tablet or the average diluting time of active
substance. Furthermore, it was also found that the standard
deviation of the dis integration time of the tablet or the diluting
time of active substance could easily become less than or equal
to 7.0~ of the average disintegration time of the tablet or
the average diluting time of active substance.
CA 02328100 2000-10-10
- 52 -
Therefore, it was cleared that a tablet without having
variation of disintegration time and diluting time of active
substance could be easily produced.
In this embodiment, the system shown in Fig.3 (b) was used
as a pulsating vibration air generation means 7. However, it
is only an example and any kinds of system can be used as the
pulsating vibration air generation means 7. For example, the
blower 71 may be connected to the end of the conduit 13, a solenoid
valve may be provided in the middle of the conduit 13 for opening
and closing the conduit 13, the blower 71 may be rotated at
a given rotation number so as to suck air in the spraying chamber
8, and the conduit 13 may be opened or closed at a prescribed
period by the solenoid valve. Otherwise the blower 71 may be
connected to the end of the conduit 13, the blower 71 may be
rotated fast or slowly at a given period, and air in the spraying
chamber 8 may be sucked strongly and weakly.
Also in the above-mentioned embodiment, the pulsating
vibration air shown in Fig . 4 ( a ) or Fig . 4 ( b ) was generated . The
system shown in Fig.5 may be constructed and the pulsating
vibration air shown in Fig.6(a) or Fig.6(b) may be generated
in the spraying chamber 8. Namely, in the embodiment shown
in Fig.5, a pulsating vibration air generation means 7A is
connected to the end of the conduit 13, a hopper 15 storing
lubricant L is connected in midstream of the conduit 13, and
a compressed air generation means 16 such as a cylinder charging
CA 02328100 2000-10-10
- 53 -
compressed air is connected to the hopper 15 as shown in Fig. 5 ( a ) .
The numeral 17 in Fig . 5 ( a ) shows a blower provided if required .
When the blower 17 is driven, air in the spraying chamber 8
is sucked and pulsating vibration air supplied in the spraying
chamber 8 and lubricant L are induced to be discharged from
the spraying chamber 8.
The system shown in Fig.5 is provided with the nozzle means
for spraying lubricant mixed with positive pulsating vibration
air so that the construction of the spraying chamber 8 can be
simplified.
As shown in Fig. 5 ( b ) , the pulsating vibration air generation
means 7A is provided with the blower 71, the cylindrical tube
72 connected to the conduit 13 between the blower 71 and the
hopper 15, and the valve element 73 which is rotatable around
the rotary axis 74 in the tube 72 and is designed to divide
the inside of the tube 72 into two parts. The conduit 13 and
the conduit 14 coupled to the blower 71 are connected to the
side of the tube 72. The valve element 73 is constructed so
as to be rotated at a desired rotational velocity by means of
a valve rotation control means (not shown).
When the blower 71 .is rotated at a given rotation number
to send air to the spraying chamber 8 and the valve element
73 is also rotated at a given rotational velocity, the spraying
chamber 8 and the blower '71 are connected when the valve element
73 is located at the place shown as a slid line in the figure.
CA 02328100 2000-10-10
- 54 -
When the valve element 73 is located at a dotted line, the spraying
chamber 8 and the blower 71 are blocked of f by the valve element
73. Accordingly pulsating vibration air with its peak at
positive pressure and its valley at atmospheric pressure as
shown in Fig . 6 ( a ) is generated in the spraying chamber 8 .
Otherwise, pulsating vibration air with its peak and valley
at positive pressure as shown in Fig.6(b) may be generated in
the spraying chamber 8. While keeping this condition, the
compres sed air generation means 16 may be driven to feed lubricant
L contained in the hopper 15 to the conduit 13 and a fixed amount
of lubricant L may be supplied in the spraying chamber 8 together
with the current of pulsating vibration air.
Here positive pressure means that the pressure in the
spraying chamber 8 is higher than the pressure outside of the
spraying chamber 8.
Otherwise, the blower 71 may be provided at the end of the
conduit 13 , the solenoid valve for opening and clos ing the conduit
13 may be provided in the midstream of the conduit 13 , the blower
71 may be rotated at a given rotation number to feed air in
the spraying chamber 8, the conduit 13 may be opened and closed
periodically by the solenoid valve, then pulsating vibration
air may be generated in the spraying chamber 8 and the conduit
13. While keeping such a condition, the compression air
generation means 16 may be driven to feed lubricant L contained
in the hopper 15 to the conduit 13 and a fixed amount of lubricant
CA 02328100 2000-10-10
- 55 -
L is supplied in the spraying chamber 8 together with the current
of pulsating vibration air. On the other hand, the blower 71
may be connected at the end of the conduit 13, the blower 71
may be rotated fast or slowly at a given period so as to feed
air strongly or weekly in the spraying chamber 8, and pulsating
vibration air may be generated in the spraying chamber 8 and
the conduit 13. While keeping this condition, the compression
air generation means 16 may be driven so as to feed lubricant
L contained in the hopper 15 to the conduit 13 and a fixed amount
of lubricant L may be supplied in the spraying chamber 8 together
with the current of pulsating vibration air.
When pulsating vibration air shown in Fig.6(a) or Fig.6(b)
is used wherein its period is more than or equal to 1Hz and
less than or equal to lOHz, its peak is about 10$ - 5~ higher
than atmospheric pressure, and its valley is almost equal to
or a litter higher than atmospheric pressure, the effect same
as the experiment 1 can be obtained ( same as following embodiment
2 and 3).
(Embodiment of the Invention 2)
Here, an example of producing several shapes of tablets
by means of punches and a die for constructing a female mold
of a tablet with an engraved mark or a dividing line, or an
anomalous tablet as the die 1, the upper punch 3, and the lower
punch 4 of the rotary type tabletting machine A.
(Experiment 2)
CA 02328100 2000-10-10
- 56 -
Several anomalous tablets having the shape shown in Fig.7
- 11 were produced using a female mold for constructing a tablet
shown in Fig . 7 - Fig . 11 as the die 1 , the upper punch 3 , and
the lower punch 4 of the rotary type tabletting machine A.
More concretely explained, according to normal fluid-bed
granulation method, glybuzole and mannitol were mixed at a ratio
of 7 . 3, polyvinyl alcohol was sprayed, granule having a
prescribed particle size and prescribed particle size
distribution was manufactured, and the obtained granule was
sized by means of a No.28 mesh.
The punches 3, 4 and the die 1 for constructing a female
mold of the tablets shown in Fig.7 - Fig.ll were housed in the
spraying chamber 8, pulsating vibration air shown in Fig.4(a)
was generated, magnesium stearate was applied as lubricant L
on the surface 3s, 4s of the punches 3, 4 and the surface is
of the die 1, and granule was continuously tabletted at a speed
of rotating the rotary table 1 at 30 times per a minute by means
of the lubricated punches 3, 4 and the die 1.
When tabletting, magnesium stearate was used as lubricant.
The amount of air sprayed from the nozzle 9 shown in Fig.3(a),
rotation number and suction amount of the pulsating vibration
air generation means 7 were controlled in such a manner that
the amount of the magnesium stearate sprayed in the spraying
chamber 8 was adjusted such that weight ~ of lubricant L included
in one produced tablet became 0 . 03 weight ~ for the entire amount
CA 02328100 2000-10-10
- 57 -
of the tablet.
More concretely, pulsating vibration air of which period
was more than or equal to 1Hz and less than or equal to lOHz,
its valley was about 10~ - 5~ lower than atmospheric pressure,
and its peak was almost equal to or a litter higher than
atmospheric pressure was used in this experiment.
WSG-type 15 by Glatt Co., Ltd. was used as a fluid-bed
granulator and HATA HT-X20 by Hata Seisakusho Co., Ltd. was
used as a main body of a tabletting machine.
The tablet in Fig.7(a) shows a circular tablet generally
called flat plain, the tablet in Fig.7 (b) shows a circular tablet
generally called shallow concave plain, the tablet in Fig. 7 (c )
shows a circular tablet generally called normal concave plain,
the tablet in Fig. 7 ( d) shows a circular tablet generally called
deep concave plain, tablet in Fig. 7 ( a ) shows a circular tablet
generally called ball or pill, tablet in Fig . 7 ( f ) shows a circular
tablet generally called flat beveled edge.
The tablet in Fig . 8 ( a ) shows a circular tablet generally
called double radius, the tablet in Fig.8(b) shows a circular
tablet generally called bevel and concave, the tablet in Fig . 8 ( c )
shows a circular tablet generally called dimple, the tablet
in Fig.8(d) shows a circular tablet called ring, the tablet
in Fig.8(e) shows a a circular tablet generally called rim,
and the tablet in Fig. 8 ( f ) shows a capsule type tablet generally
called capsule.
CA 02328100 2000-10-10
- 58 -
The tablet in Fig . 9 ( a ) shows an oval tablet generally called
oval, the tablet in Fig. 9 (b ) shows an elliptical tablet generally
called ellipse, the tablet in Fig . 9 ( c ) shows a rectangular tablet
generally called square, the tablet in Fig.9(d) shows a
triangular tablet generally called triangle, the tablet in
Fig.9(e) shows a pentangular tablet generally called pentagon,
and the tablet in Fig. 9 ( f ) shows a hexagonal tablet generally
called hexagon.
The tablet in Fig. 10 ( a ) shows a heptagonal tablet generally
called heptagon, the tablet in Fig.lO(b) shows an octagonal
tablet generally called octagon, the tablet in Fig . 10 ( c ) shows
a diamond-shaped tablet generally called diamond, the tablet
in Fig.lO(d) shows a pillow-shaped tablet generally called
pillow or ballel, the tablet in Fig. 10 ( a ) shows a rectangular
tablet generally called rectangle, and the tablet in Fig. lOf )
shows an almond-shaped tablet generally called almond.
The tablet in Fig.l:1(a) shows a sagittal tablet generally
called arrow head, the tablet in Fig. 11 (b ) shows a bullet-shaped
tablet generally called bullet, the tablet in Fig . 11 ( c ) shows
a semilunar tablet generally called half moon, the tablet shown
in Fig.ll(d) shows a shell-shaped tablet generally called
shelled, the tablet in Fig.ll(e) shows a heart-shaped tablet
generally called heart, and the tablet in Fig.ll(f) shows a
star-shaped tablet generally called star.
(Comparison 3)
CA 02328100 2000-10-10
- 59 -
Magnesium stearate was added as lubricant for the granule
produced like the experiment 2 in a ratio of 1.0 weight ~ for
the entire amount of a tablet. After they were well mixed by
a V type mixer, they were continuously tabletted by means of
the punches 3, 4 and the die 1 used in the experiment 1 according
to an internal lubricant method at a speed of rotating the rotary
table at 30 times per minute.
WSG-type 15 by Glatt Co., Ltd. was used as a fluid-bed
granulator and RATA HT-X20 by Hata Seisakusho Co., Ltd. was
used as a main body of a tabletting machine.
For each experiment: 2 and comparison 3, material was
continuously tabletted for 5 hours by means of punches and a
die constructing a female mold shown in Fig. 7 Fig. 11 and produced
tablet was sampled with t:ime. Time which didn't cause sticking
was measured by smoothness of produced tablet surface. In the
experiment2,sticking wasn't happened afters hours. However,
in the comparison 3 sticking was happened after 1 hour and
inferior goods were produced.
From the above-mentioned results, it became apparent that
the tablet production method of the present invention could
be preferably used for producing a tablet with an engraved mark
or a dividing line, or an anomalous tablet.
The same experiments as the experiment 2 and the comparison
3 were executed for a tablet with an engraved mark or a dividing
line. The punches 3, 4 and the die 1 of the external lubricant
CA 02328100 2000-10-10
- 60 -
spraying type tabletting machine A were housed in the spraying
chamber 8, pulsating vibration air shown in Fig.4(a) was
generated, magnesium stearate was applied as lubricant L on
the surface 3s, 4s of the punches 3, 4 and the surface is of
the die 1, and granule was continuously tabletted by means of
the lubricated punches 3, 4 and the die 1. It was found that
sticking was hardly caused for the tablet with an engraved mark
or a dividing line in this case comparing with an internal
lubricant method wherein materialmixed with magnesiumstearate
as lubricant L was continuously tabletted.
(Embodiment of the Invention 3)
Here an example for produc ing a tablet ( multiple unit tablet )
including granule containing active substance (so called
microcapsule) by means of the rotary type tabletting machine
A shown in the embodiment of the invention 1 will be explained.
(Production of Granule on which Surface is Film Coated)
1) Reference 1 (production of sustained release
microcapsule granule containing theophylline as active
substance)
While a mixture of 50g of theophyline, 25g of cornstarch,
25g of powder sugar was added to 900g of circular granule
crystalline cellulose (brand name . CELFIA, Asahi Chemical
Industry Co. , Ltd. ) as nuclear particle by a quantitative feeder
at a rate of lOg/min mass flow rate, 1008 of ethanol losution
in which 5g of hydroxypropylcellulose (brand name : HPC-L, Nippon
CA 02328100 2000-10-10
- 61 -
Soda Co. , Ltd. ) was dissolved was sprayed at a rate of 5g/min.
mass flow rate , and the mixture was kneaded and granulated,
using a centrifugal fluid coating means (CF-360 type, Freund
Industrial Co., Ltd.). Then granule was taken out, left at
rest for drying at 60°C for one hour, and uncoated granule was
obtained.
l.Okg of the obtained uncoated granule was fed in the
centrifugal fluid coating means, 2000g of ethanol solution in
which 100g of aminoalkylmetaacrilatecopolymer (brand name .
EudragitRS, RohmPharma Co. , Ltd. ) was dissolved was spray coated,
dried through circulation at 60°C for twelve hours, then
sustained release microcapsule granule was obtained (such
obtained sustained release microcapsule granule is called
reference 1).
2) Reference 2 (production of microcapsule formed with
enteric coating)
l.Okg of the uncoat:ed granule obtained in the reference
1 was fed in the centrifugal fluid coating means (CF-360 type,
Freund Industrial Co., Ltd.), 1500m1 of water dispersions
comprising 1808 of am:inoalkylmetaacrilatecopolymer (brand
name : EudragitRS, Rohm Pharma Co. , Ltd ) , 18g of triacetin ( Yuki
Gosei Kogyo Co., Ltd.), 90g of talc as a dry solid standard
was sprayed on 3008 of 50 mesh lactose (brand name : DMV-50M,
Pharmatose Co., Ltd.) at a rate of 6m1 per minute, after the
film was produced 60$, dried through circulation at 60°C for
CA 02328100 2000-10-10
- 62 -
twelve hours, then enteric coating microcapsule was obtained
(such obtained enteric coating microcapsule granule is called
reference 2).
(Experiment 3)
7008 of lactose for direct tabletting ( brand name : tabletose,
Taiyo Kagaku Co. , Ltd. ) and 300g of crystalline cellulose (brand
name . Avice1PH101, Asa hi Chemical Industry Co., Ltd.) were
mixed with lkg of the sustained release microcapsule granule
of the reference 1 and granule for tabletting was obtained.
Magnesium stearate (SakaiChemical Industry Co., Ltd.) was
uniformly sprayed as lubricant L as dry type on the surface
( inner wall ) is of the die 1, the surface ( lower surface) 3s
of the upper punch 3, and the surface (lower surface) 4s of
the lower punch 4 while pulsating vibration air is generated
in the spraying chamber 8. The granule was tabletted at a
tabletting pressure of 500kg/punch, 1000kg/punch, and
1500kg/punch by means c>f a flat punch with a dividing line.
Then sustained release microcapsule tablet (multiple unit
tablet) with a dividing line was obtained.
The amount of magnesium stearate contained in the obtained
sustained release microcapsule tablet (multiple unit tablet)
was measured. It was 0.07 weight o.
In this experiment, pulsating vibration air of which period
was more than or equal t:o 1Hz and less than or equal to lOHz,
its valley was about 10~ - 5~ lower than atmospheric pressure,
CA 02328100 2000-10-10
- 63 -
and its peakwas almost equal to or a litter lower than atmospheric
pressure was used in this experiment.
(Experiment 4)
350g of lactose for direct tabletting and 1508 of crystalline
cellulose were mixed with 5008 of enteric microcapsule of the
reference 2 and granule for tabletting was obtained.
Magnesium stearate (Sakai Chemical Industry Co., Ltd.) was
uniformly sprayed as lubricant L as dry type on the surface
(inner wall) is of the die 1, the surface (lower surface) 3s
of the upper punch 3, and the surface (lower surface) 4s of
the lower punch 4 while pulsating vibration air is generated
in the spraying chamber 8. The granule was tabletted at a
tabletting pressure of 500kg/punch, 1000kg/punch, and
1500kg/punch by means of a flat punch with a dividing line as
the punch 3 of the rotary type tabletting machine A shown in
the embodiment of the invention 1. Then enteric microcapsule
tablet (multiple unit tablet ) with a dividing line was obtained.
In this experiment, :pulsating vibration air of which period
was more than or equal t:o 1Hz and less than or equal to lOHz,
its valley was about 10~ - 5~ lower than atmospheric pressure,
and its peak was almost equal to or a litter lower than atmospheric
pressure was used in this experiment.
The comparisons 4 and 5 show examples when sustained release
microcapsule tablet (multiple unit tablet) with a dividing line
is produced according to the prior internal lubricant method .
CA 02328100 2000-10-10
- 64 -
(Comparison 4)
7008 of lactose for direct tabletting, 2808 of crystalline
cellulose, and 20g of magnesium stearate as lubricant were mixed
with lkg of sustained release microcapsule granule of the
reference 1 and granule for tabletting was obtained.
Then the granule was tabletted at a tabletting pressure
of 500kg/punch, 1000kg/'punch, and 1500kg/punch by means of a
flat punch with a dividing line and sustained release
microcapsule tablet (multiple unit tablet ) with a dividing line
was obtained.
(Comparison 5)
7008 of lactose for direct tabletting, 2808 of crystalline
cellulose, and 20g of magnesium stearate as lubricant were mixed
with lkg of enteric microcapsule granule of the reference 2
and granule for tabletting was obtained.
Then the granule was tabletted at a tabletting pressure
of 500kg/punch, 1000kg/punch, and 1500kg/punch by means of a
flat punch with a dividing line and enteric microcapsule tablet
(multiple unit tablet) with a dividing line was obtained.
(Comparison 6)
In thiscomparison, sustained release microcapsule tablet
( s ingle unit tablet ) was produced according to the prior internal
lubricant method.
25g of theophylline, 7008 of lactose for direct tabletting,
2658 of crystalline cellulose, and lOg of magnesium stearate
CA 02328100 2000-10-10
- 65 -
as lubricant were mixed and granule for tabletting was obtained.
Then the granule was tabletted at a tabletting pressure
of 500kg/punch, 1000kg/punch, and 1500kg/punch by means of a
flat punch with a dividing line and uncoated tablet with a
dividing line was obtained.
Then 20008 of ethanol dispersing liquid in which 1008 of
ethyl cellulose (brand name : ETHOCEL, DowChem. Co., Ltd. ) was
dispersed was sprayed to the obtained uncoated tablet and
sustained release single unit tablet with a dividing line was
obtained.
Next, relationship of tabletting pressure and hardness of
tablet was examined for each experiment 3, 4, and comparison
4, 5.
(relation of tabletting pressure and hardness of tablet)
Mechanical strength ( hardness ) of the tablet obtained in
the experiment 3, 4 and comparison 4, 5 was measured by means
of tablet hardness measurement means (name : TH203CP, Toyama
Sangyo Co., Ltd.).
The result is shown in table 3 and Fig. l2.
CA 02328100 2000-10-10
- 66 -
Table 3
tabletting Hardness
pressure
(k / unch Ex eriment Ex eriment Com arison Com arison
3 4 4 5
500 5.0 5.5 2.0 2.0
1000 10.0 11.0 4.5 5.0
1500 14.0 15.0 9.0 9.5
According to the result of the table 3 and Fig.l2, a
tabletting pressure over 1000kg/punch was required to obtain
practical hardness ( generally hardness to be destroyed at 3 . 7kg
- 7 . Okg is required ) in the comparisons 4 and 5 . However, it
was found that adequate hardness was obtained at a tabletting
pressure of 500kg/punch in the experiments 3 and 4.
From these results, it became clear that tablet with
practical hardness could be produced at lower tabletting
pressure than the prior art according to the present invention.
(Dissolution Test)
The tablet produced at a tabletting pressure of 500kg/punch
in the experiments 3 and 4 (hereinafter called experiment 5
and experiment 6 respectively) and the tablet produced at a
tabletting pressure of 1000kg/punch in the comparisons 4 and
(hereinafter called comparison 7 and comparison 8
respectively) were used as specimen of dissolution test.
In the dissolution test, dissolution rate was measured by
a first liquid by Japanese Pharmacopoeia the 11'h edition for
first two hours, the specimen was pulled up after two hours
CA 02328100 2000-10-10
- 67 -
and transferred to a second liquid to obtain dissolution rate
again according to a rotary basket method described in
dissolution test of ,Tapanese Pharmacopoeia the llt" edition.
The result is shown in the following table 4 and Fig. l3.
Table 4
DissolutionExperimentComparisonReferenceExperimentComparisonReference
Time (hour)5 7 1 6 8 2
0 0 0 0 0 0 0
0.25 5 15 5 0 30 0
0.50 12 40 10 0 70 0
0.75 15 65 15 0 95 0
1.00 22 80 20 0 100 0
1.50 30 95 30 0 100 0
2.00 41 100 40 2 100 1
2.50 51 100 50 55 100 60
3.00 61 100 60 100 100 100
4.00 82 100 80 100 100 100
5.00 100 100 100 100 100 100
From the above-mentioned results of table 4 and Fig. l3,
it was found that each tablet in the experiment 5 and the
experiments 6 showed similar dissolution behavior as the
sustained release microcapsule granule (reference 1) and the
enteric microcapsule granule (reference 2) respectively.
According to the above-mentioned relation of the tabletting
pressure and the tablet hardness, and the result of this
experiment, it became apparent6 that the film coated on the
surface of the microcapsule granule didn't cause damage while
CA 02328100 2000-10-10
- 68 -
tabletting because it could be tabletted at low pressure. On
the other hand, it was faund that each tablet in the comparisons
7 and 8 lost sustained release function and enteric function
respectively.
(Dissolution Test of Dividable Tablet)
Next, equally divided tablet of the experiments 5 and 6
and equally divided tablet of the comparison 6 were used as
specimen of dissolution test and dissolution rate was obtained
according to the same method of the above-mentioned dissolution
test.
The result is shown in the following table 5 and Fig. l4.
Table 5
DissolutionExperimentExperimentExperimentExperimentComparisoncomparison
Time (hour)5 5 (divided)6 6 (divided6 6 (divided)
0 0 0 0 0 0 0
0.25 5 7 0 0 5 40
0.50 12 13 0 0 10 75
0.75 15 16 0 0 15 90
1.00 22 23 0 0 20 100
1.50 30 41 0 1 30 100
2.00 41 52 2 3 40 100
2.50 51 64 55 60 50 100
3.00 61 83 100 100 60 100
4.00 82 100 100 100 80 100
5.00 100 100 100 100 100 100
From the above-mentioned results of table 5 and Fig. l4,
it was found that the tablets in the experiment 5 and the
CA 02328100 2000-10-10
- 69 -
experiments 6 showed similar dissolution behavior as the
sustained release microcapsule granule (reference 1) and the
enteric microcapsule granule (reference 2) respectively and
showed sustained release function and enteric function even
if they were divided. However, the tablet in the comparison
6 lost sustained release function and enteric function when
divided.
From the above results, it became apparent that the tablet
(multiple unit tablet) in the present invention didn't lost
sustained release function and enteric function even if they
were divided.
In the embodiment of the invention 3 the multiple unit tablet
of which granule surface was film coated was used. However,
it is only an example. As a tablet having practical hardness
can be produced at a low tabletting pressure according to the
tablet production method of the present invention, a multiple
unit tablet including active substance in a base matrix can
be produced without destroying or plastically deforming the
granule contained in the tablet.
When the amount of lubricant sprayed in the spraying chamber
8 is remarkably reduced like the embodiment of the invention
1, a tablet which doesn't contain lubricant therein and is
provided with a minute amount of lubricant thereon can be produced,
so that disintegration time of the tablet doesn't delay.
Therefore, if the tablet :is used as an uncoated tablet, it becomes
CA 02328100 2000-10-10
- 70 -
a rapidly disintegrable tablet and it is suitable as a tablet
which is required to be immediately disintegrated at an objective
region like an intrabuccally rapidly disintegrable tablet.
Further, if a film which can be dissolved at an objective region
is coated on the surface, the tablet can be dissolved at the
objective region when thefilm coat is dissolved. Accordingly,
it is suitably used as a tablet which is required to be dissolved
at the objective region.
The inventors of the present invention measured the
disintegration time of the tablet and the dissolution time of
active substance produced in the experiments 1 - 4. They found
that the standard deviation thereof was within 10~ of the average
disintegration time of 'the tablet and the average dissolution
time of active substance.
This embodiment showed an example in which a centrifugal
fluid coating machine was used to produce granule to be contained
in the tablet. However, warm air which is strengthened or
weakened at a prescribed period may generated in a warm air
conduit at a procedure of pelletizing the granule with a desired
particle size, the granule may be pelletized in such a manner
that a part of powder to be granulated and material under
granulated always falls to be piled on a screen while pelletiz ing,
and a film may be formed on the granulated material by spraying
coating liquid on the granulated material. It is because that
when material is granulated while warm air which is strengthened
CA 02328100 2000-10-10
- 71 -
or weakened at a prescribed period may generated in the warm
air conduit at a procedure of pelletizing the granule with a
desired particle size, the granule may be pelletized in such
a manner that a part of powder to be granulated and material
under granulated always falls to be piled on a screen while
pelletizing, granulated material with small specific volume
can be produced comparing with the granulated material which
is produced by fluidizing powder to be granulated and material
under granulated by means of steady flow warm air. The
granulated material becomes hard so as to be scarcely damaged
at the time of tabletting, therefore, a film coated on the
granulated material becomes hardly damaged.
The process for coating a film on the granulated material
isn't limited to the above-mentioned fluid-bed coating method.
It may be executed according to a Pan coating method or a
compression coating method.
Examples of using a rotary type tabletting machine are
explained in the embodiments of the invention 1 - 3, however,
they are only examples and the present invention can be executed
by using a single-shot tabletting machine such as an eccentric
type tabletting machine other than the rotary type tabletting
machine.
In the above mentioned embodiments of the invention, a system
wherein a hopper 15 is connected in midstream of the conduit
13 and the compression air generation means 16 such as an air
CA 02328100 2000-10-10
- 72 -
cylinder charged with compressed air is connected to the hopper
15 is explained. However, a system for discharging lubricant
L stored in the hopper 15 isn't limited to such a system.
Fig.l5 schematically shows a construction of such a system.
According to this system, a pulsating vibration air
generation means 7A is connected to one end 13a of the conduit
13, a discharge port 15a of the hopper 15 is connected in midway
of the conduit 13 , and an elastic membrane 18 having an aperture
( a slit in this example ) 18a is provided for the discharge port
15a so as to become a bottom of the hopper 15 (see Fig.l6).
The elastic membrane 18 is made of rubber such as a silicon
rubber.
The member shown as 15b in Fig.l5 is a lid and is provided
for the hopper 15 removably and airtightly.
Next, operations of the system will be explained.
Fig. l7 is an explanatory figure schematically showing
operation of the system.
For using the system, the lid 15b is airtightly attached
on the hopper 15 after lubricant L is contained in the hopper
15.
Then, when the pulsating vibration air generation means
7A is driven to supply positive pulsating vibration air to the
conduit 13, the air pressure in the conduit 13 becomes higher
than that in the hopper 15 while positive pulsating vibration
air is at peak side. As shown in Fig. 17 ( a ) , the elastic membrane
CA 02328100 2000-10-10
- 73 -
18 is deformed with its center curved upwardly in such a manner
that the center becomes an antinode and the circumferential
edge becomes a node.
In this case, the section of the aperture (slit in this
example) 18a becomes V-shaped with its upper end opened. A
part of lubricant L stored in the hopper 15 drops in the V-shaped
aperture (slit in this example) 18a.
As positive pulsating vibration air changes from peak to
valley, the air pressure in the conduit 13 is generally lowered
so as to be the same as that in the hopper 15. The elastic
membrane 18 is going to get back to its original shape because
of its resilience as shown in Fig. 17 (b) . The lubricant L dropped
in the V-shaped aperture (slit in this example) 18a is caught
in the aperture 18a.
When the positive pulsating vibration air supplied in the
conduit 13 is at its valley, the air pressure in the conduit
13 becomes lower than that in the hopper 15 and the elastic
membrane 18 is deformed with its center curved downwardly in
such a manner that the center is antinode and the circumferential
edge is node as shown i.n Fgi.l7(c).
In this case, the section of the aperture (slit in this
example ) 18a becomes reverse V-shaped with its lower end opened.
The lubricant L caught in the aperture 18a is discharged to
the conduit 13.
Then the lubricant L discharged in the conduit 13 is
CA 02328100 2000-10-10
- 74 -
immediately mixed with positive pulsating vibration air
supplied in the conduit 13 to be dispersed therein and is
pneumatically transported to a spraying chamber ( refer to the
spraying chamber 8 in Fig. S).
The elastic membrane 18 repeats up and down vibration as
shown in Fig. 17 ( a ) - Fig. 17 ( c ) according to vibration amplitude,
wave length, wave shape, and vibration frequency of positive
pulsating vibration air.
Therefore, as long as vibration amplitude, wave length,
wave shape, and vibration frequency of positive pulsating
vibration air supplied in the conduit 13 are fixed, the elastic
membrane 18 vibrates up and down at a fixed vibration amplitude
andfrequency. Accordingly the amount oflubricant L discharged
in the conduit 13 via the aperture (slit in this sample) 18a
is constant.
Further according to this system, because positive
pulsating vibration air is supplied in the conduit 13, there
are no phenomenon such as adhesion of powdered material on the
inner wall of the conduit 13 and blowing-out of powdered material
in the conduit 13 which :have been seen in the case that steady
air pressure is used for pneumatically transporting powdered
material.
Therefore, according to this system, lubricant L is
discharged from the other end 13b of the conduit 13 at the same
density as the lubricant L discharged to the conduit 13.
CA 02328100 2000-10-10
- 75 -
In other words this system can be functioned as a metering
feeder .
Therefore, when the other end 13b of the conduit 13 is
connected to the spraying chamber (refer to spraying chamber
8 in Fig. 5 ) , as long as the size of the aperture ( slit in this
example) 18a is fixed, and vibration amplitude, wave length,
wave shape, and vibration frequency of positive pulsating
vibration air supplied in the conduit 13 are fixed, lubricant
L with constant density can be always supplied in the spraying
chamber (refer to spraying chamber 8 in Fig.5).
Further, a media fo:r pneumatically transporting lubricant
L is air even if it is a positive pulsating vibration air so
that the amount of lubricant L mixed with positive pulsating
vibration air can be extremely minimized.
Accordingly, because a minute amount of lubricant L can
be always sprayed in stable condition in the spraying chamber
( refer to spraying chamber 8 in Fig . 5 ) , minute amount of lubricant
L can be applied on the surfaces of the punches(the surface
(lower surface) 3s of the upper punch and the surface (upper
surface) 4s of the lower punch 4 as shown in Fig.2) and the
surface (inner wall) is of the die 1.
In Fig.l6, the elastic membrane has a slit 18a, however,
this is only a preferable example. The aperture provided for
the elastic membrane isn't limited to the slit 18a and the
aperture may be small ones or the number isn't limited to one.
CA 02328100 2000-10-10
- 76 -
For example, an elastic membrane with plural small apertures
18b may be used as shown in Fig. l8.
When the size and the number of the aperture or conditions
(vibration amplitude, wave length, wave shape, and vibration
frequency) of positive pulsating vibration air supplied in the
conduit 13 are varied, the density of lubricant L supplied in
the spraying chamber (refer to the spraying chamber 8 in Fig.5)
can be changed diversely.
In this embodiment, a rotary type pulsating vibration air
generation means 7A shown in Fig. 3 ( b ) and Fig. 5 ( b ) wherein the
valve element 73 is provided rotatably around the rotary axis
74 so as to divide inside of the tube 72 into two parts is explained
as a pulsating vibration air generation means. However, it
isn't limited to such means 7A.
Fig. l9 shows a section of other embodiment of pulsating
vibration air generation means.
The high pressure pulsating vibration air generation means
7B is provided with a valve chamber 94 having a valve seat 9.
between an input port 91 and an output port 92 and a valve plug
96 which is opened and closed by a cam mechanism 95.
The cam mechanism 95 is provided with a rotary cam 97
rotatable by a driving means such as a motor (not shown) and
a roller 98 attached at the lower end of the valve plug 96.
The valve seat 93 is formed with a hole narrowing into the
output port 92 and the valve plug 96 is formed like a reverse
CA 02328100 2000-10-10
- 77 _
mortar so as to conform to the shape of the valve seat 93 and
designed to airtightly close the valve seat 93.
Further in this embodiment, an axis 96a of the valve plug
96 is provided in an axis hole 99h of a case 99 so as not to
leak air and so as to be movably up and down.
The roller 98 is rotatably pinched by the rotary cam 97
and moves up and down according to a concavo-convex pattern
on the rotary cam 97 while rotating.
More detailed, the rotary cam 97 is provided with an inner
rotary cam 97a and an outside rotary cam 97b.
Concavo-convex pattern is provided for the inner rotary
cam 97a and the outside rotary cam 97b respectively so as to
keep distance of the roller 98 and to keep in line each other.
The roller 98 is pinched between the inner rotary cam 97a
and the outside rotary cam 97b and is moved up and down while
rotating according to the concavo-convex pattern provided for
the inner rotary cam 97a and the outside rotary cam 97b by rotating
the rotary cam 97 without causing jumping of the valve plug
96.
The convavo-convex pattern provided for the rotary cam 97
is selected according to physical property of lubricant L stored
in the hopper 15.
In this embodiment, a flow rate control means 102 is provided
for the input port 91 and compressed air which is generated
by an air source 71 and of which flow rate is adjusted properly
CA 02328100 2000-10-10
_ 7g
by the flow rate control means 102 is supplied in the input
port 91.
Further, one end of a conduit (the conduit 13 shown in Fig.3
or Fig.5) is connected to the output port 92.
The numeral 100 in Fig. l9 shows a flow rate control port
provided if required. An output control valve 101 for adjusting
pressure of pulsating vibration air generated from the output
port 92 is provided so as to be adjustable at a desired condition
from full communication to atmospheric air and shut down from
atmospheric air.
Next, operational procedure for generating positive
pulsating vibration air having a desired period, vibration
amplitude, and wave shape by means of the high pressure pulsating
vibration air generation means 7B will be explained.
The rotary cam 97 which is easy to mix lubricant L with
air according to physical property of lubricant L stored in
the hopper 15 is attached to a rotary axis Ma of a driving means
(not shown) of the high pressure pulsating vibration air
generation means 7B.
Then the air source 71 is driven and a fixed amount of
compressed air is supplied to the input port 92 by adjusting
the flow rate control means 102.
Further, the rotary cam 97 is rotated at a fixed rotational
velocity by actuating the driving means (not shown).
The pressure of pulsating vibration air discharged from
CA 02328100 2000-10-10
_ 79 -
the output port 92 is controlled by adjusting the output control
valve 101, if required.
When the rotary cam 97 is rotated at a fixed rotational
velocity, the valve plug 96 moves up and down according to the
concavo-convex pattern of the rotary cam 97. Therefore, when
the valve seat 93 is controlled at full closed, half opened,
or full opened according to the concavo-convex pattern of the
rotary cam 97, pulsating vibration air with a desired wave shape
can be outputted from t:he output port 92.
According to the high pressure pulsating vibration air
generation means 7B, rotational velocity of the rotary cam 97
may be changed by controlling the driving means (not shown)
in order to obtain a desired period of pulsating vibration air
discharged from the output port 92. Further, the air source
71, the flow rate control means 102, and/or the output control
valve 101 may be appropriately controlled in order to obtain
a desired vibration amplitude of pulsating vibration air
discharged from the output port 92.
Industrial Applicability
As mentioned above, according to the tablet production
method in claim 1 , lubricant is sprayed at the same time pulsating
vibration air is generated in the spraying chamber. When
lubricant is sprayed in the spraying chamber while pulsating
vibration air is generated, lubricant is mixed with pulsating
CA 02328100 2000-10-10
- 80 -
vibration air.
Further according to this method, lubricant is applied on
the surfaces of a pair of punches and a die while lubricant
is mixed with pulsating vibration air, namely under difficult
condition to apply lubricant on the surfaces thereof.
When lubricant is going to be applied on the surfaces under
such a difficult condition, it can be uniformly applied on the
surfaces of the pair of punches and the die.
Accordingly, as molding material is hardly adhered on the
pair of punches and the die, sticking and so on aren' t apt to
be caused on the produced tablet in this tablet production method .
Moreover, as the result that lubricant is uniformly applied
on the surfaces of the pair of punches and the die, the produced
tablet hardly causes sticking and so on comparing with the prior
internal lubricant method and the prior external lubricant
spraying method eve if the amount of lubricant used for a tablet
is remarkably reduced.
Herewith, as a tablet on which surface minute amount of
lubricant is attached can be produced, the tablet produced by
this method doesn't happen disintegration time delay because
of water repellency of lubricant.
Therefore according to this tablet production method, a
tablet which can be disintegrated at an objective region such
as target region of living body can be produced.
Moreover according to the method, because molding material
CA 02328100 2000-10-10
- 81 -
doesn't include lubricant therein, a tablet having practical
hardness can be produced even if its tabletting pressure is
lower than that of prior art when molding material is tabletted
with the die and the pair of punches.
Hence, when a tablet including granule on which surface
a film is coated is produced, the film formed on the surface
of the granule isn't destroyed.
And when a tablet including granule containing active
substance in the base matrix is produced, the function of the
matrix contained in the tablet isn't damaged.
According to the tablet production method in claim 2,
lubricant mixed with pulsating vibration air is designed to
be sprayed in the spraying chamber.
Further according to this method, lubricant is applied on
the surfaces of a pair of punches and a die while lubricant
is mixed with pulsating vibration air, namely under difficult
condition to apply lubricant on the surfaces thereof.
When lubricant is going to be applied on the surfaces under
such a difficult condition, it can be uniformly applied on the
surfaces.
Accordingly, as molding material is hardly adhered on the
pair of punches and the die, sticking and so on aren' t apt to
be caus ed on the produced tablet in this tablet production method .
Moreover, as the result that lubricant is uniformly applied
on the surfaces of the pair of punches and the die, the produced
CA 02328100 2000-10-10
- 82 -
tablet hardly causes sticking and so on comparing with the prior
internal lubricant method and the prior external lubricant
spraying method eve if the amount of lubricant used for a tablet
is remarkably reduced.
Herewith, as a tablet on which surface minute amount of
lubricant is attached can be produced, the tablet produced by
this method doesn't happen disintegration time delay because
of water repellency of lubricant.
Therefore according to this tablet production method, a
tablet which can be rapidly disintegrated at an objective region
such as target region of living body can be produced.
Moreover according to the method, because molding material
doesn't include lubricant therein, a tablet having practical
hardness can be produced even if its tabletting pressure is
lower than that of prior art when molding material is tabletted
with the die and the pair of punches.
Hence, when a tablet including granule on which surface
a film is coated is produced, the film formed on the surface
of the granule isn't destroyed.
And when a tablet including granule containing active
substance in a base matrix is produced, the function of the
matrix contained in the tablet isn't damaged.
According to the tablet production method in claim 3, a
spraying means for spraying lubricant mixed with positive
pulsating vibration air is provided in the spraying chamber,
CA 02328100 2000-10-10
- 83 -
so the production system can be simplified.
According to this method, a tablet with practical hardness
can be produced at low tabletting pressure because lubricant
isn't included in molding material. Therefore, a tablet can
be produced without breaking film and granule and without causing
plastic deformation even if the construction and material of
the film and the base matrix aren't devised for the purpose
of prolongation of mode of action, sustained release, rapid
release, high solubility in stomach, high solubility in
intestine, prevention of bitter taste.
According to the tablet production method in claim 5, a
tablet with practical hardness can be produced at low tabletting
pressure because lubricant isn't included in molding material.
Therefore, a tablet can be produced without breaking film and
granule and without causing plastic deformation even if the
construction and material of the film and the base matrix aren't
devised for the purpose of prolongation of mode of action,
sustained release, rapid release, high solubility in stomach,
high solubility in intestine, prevention of bitter taste.
According to the tablet production method in claim 6, a
spraying means for spraying lubricant mixed with positive
pulsating vibration air is required to be provided so that the
system can be simplified.
According to the tablet production method in claim 7 , granule
containing active substance and diluting agent is used as granule
CA 02328100 2000-10-10
- 84 -
containing active substance (so called microcapsule) so that
the particle diameter and particle size containing active
substance can be easily changed.
Therefore, a tablet can be easily produced by controlling
the diameter and the size of granule containing active substance
so as to facilitate coating on the surface.
Further, the diameter and the size of granule containing
active substance can be made so as to derive the function of
granule to the full extent.
According to the production method in claim 8 , because tablet
can be produced at low tabletting pressure, a tabletting can
be executed without destroying the function of a base matrix
even if granule contained in the tablet includes active substance
in the base matrix.
According to the production method in claim 9 , because tablet
can be produced at low tabletting pressure, a tabletting can
be executed without destroying the coating film even if granule
contained in the tablet is coated with a film.
According to the tablet production method in claim 10,
tabletting is continuously executed utilizing the fact that
molding material isn' t adhered on the punches and the dies so
thatsticking isn't caused. A tablet including activesubstance
and a tablet including granule containing active substance can
be produced at industrial production base.
According to the tablet production method in claim 11,
CA 02328100 2000-10-10
- 85 -
tabletting is continuously executed utilizing the fact that
molding material isn' t adhered on the punches and the dies so
thatsticking isn't caused. A tablet including activesubstance
and a tablet including granule containing active substance can
be produced at industrial production base.
According to the tablet production method in claim 12,
because lubricant is applied on the surface of the punches and
the dies constructing a female mold for a tablet with an engraved
mark or a dividing line and for an anomalous tablet in the spraying
chamber in which pulsating vibration air is generated, lubricant
can be applied uniformly comparing with the prior external
lubricant spraying method. As a result, molding material is
hardly attached on the surfaces of the punches and the dies
while compressing a tablet with an engraved mark or a dividing
line or an anomalous tablet so that sticking, capping, and
laminating of such a tablet are prevented.
According to the tablet production method in claim 13 , as
tabletting pressure for compressing molding material is low,
tabletting can be executed without destroying a film even if
granule contained in the tablet is covered with a film. Further,
if granule contained in a tablet includes active substance in
a base matrix, tabletting can be executed without destroying
the function of the base matrix.
According to the tablet production method in claim 14,
even if the amount of lubricant sprayed at one tabletting is
CA 02328100 2000-10-10
- 86 -
remarkably reduced, a tablet can be produced without causing
sticking and so on. Consequently the produced tablet doesn't
include lubricant therein and minute amount of lubricant is
attached on the surface so that disintegration time isn't
delayed.
Further according to this method, tablet can be produced
at a low tabletting pressure, and the granule is hardly destroyed
or plastic deformation is caused, so that the function of the
granule containing active substance in the tablet isn't apt
to be damaged.
Therefore, according to the production method, if the
produced tablet is used as an uncoated tablet, it becomes a
rapidly disintegrable tablet and a tablet which is required
to be immediately disintegrated at an objective region like
an intrabuccally rapid:Ly disintegrable tablet can be easily
produced. Further if a film coat which can be dissolved at
an objective region is executed on the surface of a tablet,
the tablet itself is immediately dissolved at a desired region
when a film coat is dissolved, so that a tablet which can be
dissolved at an objective region can be produced.
According to the tablet in claim 15, as lubricant isn't
included therein and a minute amount is attached on the surface,
there is no problem such that disintegrant time of the tablet
delays because of water repellency of lubricant.
Therefore, if the tablet is used as an uncoated tablet,
CA 02328100 2000-10-10
_ $~
it becomes a rapidly disintegrable tablet and the tablet is
immediately disintegrated at an objective region like an
intrabuccally rapidly disintegrable tablet and activesubstance
f
contained in the tablet is immediately released.
Moreover, if a film coat which can be dissolved at an
objective region is executed on the surface of the tablet, the
tablet itself can be dissolved at an objective region when the
film coat is dissolved, so that active substance contained in
the tablet is immediately released.
According to the tablet in claim 16, as lubricant isn't
included therein and a minute amount is attached on the surface,
there is no problem such that disintegrant time of the tablet
delays because of water repellency of lubricant.
Therefore, if the tablet is used as an uncoated tablet,
it becomes a rapidly disintegrable tablet and the tablet is
immediately disintegrated at an objective region like an
intrabuccally rapidly disintegrable tablet and granule
containing activesubstance(so called microcapsule)contained
in the tablet is immediately released.
Moreover, if a film coat which can be dissolved at an
objective region is executed on the surface of the tablet, the
tablet itself can be dissolved at an objective region when the
film coat is dissolved, so that granule containing active
substance ( so called microcapsule ) contained in the tablet is
immediately released.
CA 02328100 2000-10-10
_ 88 _
According to the tablet in claim 17 , as granule containing
active substance and diluting agent is used as granule containing
active substance (so called microcapsule), the particle
diameter and size of the granule can be easily modified by
diluting agent.
Therefore, a tablet production can be easily executed by
controlling the particle diameter and size of the granule
containing active substance so as to coat a film on the surface
of the tablet.
Further, the diameter and the size of granule containing
active substance can be made so as to derive the function of
granule to the full extent.
According to the tablet in claim 18, as diluting agent used
as bulking agent doesn't include lubricant, there is no problem
such that disintegration time of the tablet delays because of
water repellency of lubricant.
Further, as the tablet includes granule containing active
substance in the base matrix, the base matrix can achieve its
desired objective function.
For example, if the base matrix aims at prolongation of
mode of action, the tablet also becomes to have a function of
sustained release by the base matrix.
Therefore, if unfilmed granule containing activesubstance
and granule containing active substance in base matrix are mixed
in a tablet, they are immediately released from the tablet when
CA 02328100 2000-10-10
_ 89 _
the tablet is dissolved. The active substance contained in
the unfilmed granule is immediately absorbed in a body when
the tablet isdisintegrated. Therefore, the tablet hassuperior
rapid onset of action.
As for the granule containing active substance in the base
matrix, for example, if the base matrix aims at prolongation
of mode of action, the tablet also becomes to have a function
of prolongation of mode of action by the base matrix.
Namely, the tablet has both rapid onset of action and
prolongation of mode of action.
If the active substance is analgesic, anti-inflammatory
agent, or antidote, unfilmed granule containing such agent and
granule containing such agent in the base matrix are mixed.
Thereby, a new tablet such as a once daily tablet, namely a
quick & slow release tablet, by which pain, inflammation or
fever of a patient is immediately remedied and analgesic action,
anti-inflammatory action, or antidote action is kept long when
a patient takes this medicine can be obtained.
According to the tablet in claim 19, as diluting agent used
as bulking agent doesn't include lubricant, there is no problem
such that disintegration time of the tablet delays because of
water repellency of lubricant.
Further, as the tab:Let includes granule containing active
substance, a film coated on the surface of the granule containing
active substance brings out a desired objective function.
CA 02328100 2000-10-10
- 90 -
For example, the film coated on the granule containing active
substance aims at prolongation of mode of action, the tablet
also has prolongation of mode of action because of the film.
Therefore, if unfilmed granule containing activesubstance
and filmed granule containing active substance are mixed in
a tablet, they are immediately released from the tablet when
the tablet is dissolved. The active substance contained in
the unfilmed granule is immediately absorbed in a body when
the tablet isdisintegrated. Therefore, the tablet hassuperior
rapid onset of action.
As for the filmed granule containing active substance, for
example, if the film aims at prolongation of mode of action,
the tablet also becomes to have prolongation of mode of action
because of the function of the film.
Namely, the tablet has both rapid onset of action and
prolongation of mode of action.
If the active substance is analgesic, anti-inflammatory
agent, or antidote, unfilmed granule containing such agent and
filmed granule containing such agent are mixed. Thereby, a
new tablet such as a once daily tablet, namely a quick & slow
release tablet, by which pain, inflammation or fever of a patient
is immediately remedied and analgesic action, anti-inflammatory
action, or antidote action is kept long when a patient takes
this medicine can be obtained.
Because the tablet in claim 20 is provided with a minute
CA 02328100 2000-10-10
- 91 -
amount of lubricant on the surface, its disintegration time
doesn't delay.
As the tablet in claim 21 has a dividing line, it can be
easily divided along the line. Therefore, appropriate amount
of drug depending on the weight or age of a patient can be taken
by a patient.
Because the tablet in claim 22 has anomalous shape, drugs
can be easily distinguished by itsshape. Therefore, medication
error is hardly happened.
According to the tablet in claim 23, because lubricant is
uniformly applied on the surface of the tablet ( uncoated tablet ) ,
there is no wide variation of disintegration time of the tablet
and elution time of the active substance. Therefore, the tablet
of which standard deviation of disintegrating time of the tablet
or elution time of the active substance is less than 15.0 percent
of average disintegrating time or average elution time can be
easily produced.
Further, the tablet of which standard deviation of
disintegrating time of the tablet or elution time of the active
substance is less than 10.0 percent of average disintegrating
time or average elution time, which has been considered to be
difficult in the prior art, can be easily produced.
Moreover, the tablet of which standard deviation of
disintegrating time of the tablet or elution time of the active
substance is less than 7.5 percent of average disintegrating
CA 02328100 2000-10-10
- 92 -
time or average elution time, which has been imposs ible to produce
in the prior art as far as the inventors know, can be produced.
Because lubricant :is uniformly applied on the surface of
the tablet (uncoated tablet), there is no wide variation of
disintegration time of the tablet and elution time of the active
substance.
Hence, there is no variation of the time before appearing
the effect of drugs between tablets.
According to the tablet in claim 24, as magnesium stearate
is used as lubricant, the amount of lubricant contained in the
tablet can be easily measured.
