U.S. patent number 3,725,556 [Application Number 05/089,120] was granted by the patent office on 1973-04-03 for method of manufacturing rapidly disintegrating pharmaceutical tablets.
Invention is credited to Dieter Hanssen, Adolf Knecht.
United States Patent |
3,725,556 |
Hanssen , et al. |
April 3, 1973 |
**Please see images for:
( Certificate of Correction ) ** |
METHOD OF MANUFACTURING RAPIDLY DISINTEGRATING PHARMACEUTICAL
TABLETS
Abstract
A method of compounding the inert pharmaceutical carrier
ingredients and active drug ingredient of a pharmaceutical tablet
composition, which circumvents the conventional granulation step
prior to compression in the manufacture of pharmaceutical tablets
and results in very rapidly disintegrating tablets; the method
consists of 1. spray-drying, after inert gas foaming, a suspension
of A. 1 - 20 percent by weight of very finely divided silicon
dioxide or aluminum oxide and B. 60 - 98 percent by weight of at
least one fine-grained, inert filler material chosen from the group
consisting of selected from the group consisting of substantially
water-insoluble rice starch and corn starch and alkaline earth
metal phosphates, in an aqueous solution of C. 1 - 20 percent of a
water-soluble binder, 2. adding the active drug ingredient to the
resulting spray-dried, ungranulated tablet pre-mix, and 3.
compressing the resulting composition together with the active
agent and a tablet lubricant, into pharmaceutical tablets.
Inventors: |
Hanssen; Dieter (Ingelheim/am
Rhine, DT), Knecht; Adolf (Munzingen, DT) |
Family
ID: |
22215802 |
Appl.
No.: |
05/089,120 |
Filed: |
November 12, 1970 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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779269 |
Nov 26, 1968 |
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Current U.S.
Class: |
514/770; 514/778;
514/960 |
Current CPC
Class: |
A61K
9/2004 (20130101); Y10S 514/96 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); A01n 009/00 () |
Field of
Search: |
;264/117,121-123
;424/357-366 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Raff et al. J. Pharm. Sci. 50; 76-79 (1961) .
Scott et al. J. Pharm. Sci. 53; 670-675 (1964) .
Kornblum J. Pharm. Sci. 58: 125-127 (1969).
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Primary Examiner: Rose; Shep K.
Parent Case Text
This is a continuation-in-part of copending application Ser. No.
779,269, filed Nov. 26, 1968, now abandoned.
Claims
We claim:
1. The method of manufacturing pharmaceutical tablets which
spontaneously and completely disintegrate in water or in a potable
aqueous liquid within 2 or 3 minutes by a process wherein the
conventional granulation step prior to the compression in the
manufacture of pharmaceutical tablets is circumvented or displaced
by subjecting the inert ingredients or a mixture thereof with one
or more active ingredients to a spray-drying treatment, said
process consisting of the steps of
a. spraying-drying, after inert gas foaming, in a conventional
spray-drying tower (A) as hereinafter defined and (B) as
hereinafter defined in an aqueous solution of (C) as hereinafter
defined, and then
b. compressing the resulting composition, together with the active
agent and a tablet lubricant, in a conventional tablet-making
machine, into a quickly-disintegrating pharmaceutical compressed
tablet consisting essentially of one or more active ingredients
added prior to compression of the tablet, without granulation, to
an ungranulated tablet pre-mix consisting essentially of
(A) 1 - 20 percent by weight of finely divided silicon dioxide or
aluminum oxide,
(B) 60 - 90 percent by weight of at least one fine-grained inert
filler material selected from the group consisting of substantially
water-insoluble rice starch or corn starch and alkaline earth metal
phosphates, and
(C) 1 - 20 percent by weight of a water-soluble binder selected
from the group consisting of hydroxyethyl cellulose, carboxymethyl
cellulose, water-soluble starch, gum arabic, tragacanth, alginates,
gelatin and polyvinylpyrrolidone.
2. The method according to claim 1, wherein component (A) has a
particle size of 10 - 100 m.mu. and a surface area of 10 - 500
m.sup.2 /gm.
3. The method according to claim 1, wherein said component (A) is
colloidal silicic acid.
4. The method according to claim 1, wherein said component (C) is
substantially water-insoluble rice starch.
5. The method according to claim 1, wherein said binder (C) is a
water-soluble cellulose derivative, a water-soluble starch, a
water-soluble plant gum or a mixture of two or more of these.
Description
This invention relates to a novel method of compounding the inert
pharmaceutical carrier ingredients and active drug ingredients of a
pharmaceutical tablet composition, which circumvents the
conventional grnulation step prior to compression in the
manufacture of pharmaceutical tablets and results in very rapidly
disintegrating tablets exhibiting very desirable properties,
especially with respect to oral administration of drugs to infants
and small children.
BACKGROUND OF THE INVENTION AND STATE OF THE ART
Pharmaceutical tablets are usually prepared from a mixture which,
in addition to one or more active drug ingredients, contains a
number of therapeutically inert, physiologically compatible carrier
components which serve as diluents, adsorbents, agglutinants,
disintegration promoters, lubricants and the like. These
ingredients are generally first intimately admixed with each other,
the mixture is granulated, and the granulate is then compressed
into tablets with the aid of a conventional tablet-making
machine.
It is also known that the granulating step can be circumvented by
subjecting the inert ingredients or a mixture thereof and the
active ingredient to a spray-drying treatment [see Raff et al., J.
Pharm. Sci. 50 (1961), 76; Gunsel and Lachmann, ibid. 52 (1963),
178; and U.S. Pat. No. 3,293,132]. However, since spray-drying is a
relatively expensive procedure, this method has until now not
displaced the conventional granulating step in the manufacture of
pharmaceutical tablets.
THE INVENTION
We have discovered that by applying the spray-drying procedure to a
very particular combination of inert pharmaceutical carrier
ingredients it is not only possible to avoid the granulation step
but also to produce pharmaceutical tablets having such uncommonly
favorable properties that the application of this more costly
procedure becomes justifiable for certain particular cases.
In heretofore conventional pharmaceutical tablet compositions the
achievement of a satisfactory disintegration rate of the tablet is
often predicated upon the incorporation of disintegration promoters
which, upon coming in contact with water or aqueous liquids,
channel the water as rapidly as possible into the center of the
compressed tablet and then undergo swelling with the water and thus
cause a bursting of the compacted bond of the tablet. However, due
to the nature of the active ingredient, a satisfactory and rapid
disintegration is sometimes difficult to achieve or not achievable
at all; in some instances disintegration periods of up to half an
hour or more must be accepted.
In accordance with the present invention we provide a
pharmaceutical tablet composition which, when compressed into
pharmaceutical tablets in conventional manner in a tablet-making
machine, is capable of channeling the water toward the center of
the tablet very rapidly and, in addition, producing extraordinarily
good disintegration within a very short period of time. The
disintegration periods achieved thereby are generally less than one
minute and in every case do not exceed the span of 2 or 3
minutes.
The method according to the present invention has the further
advantage that it may be employed for the manufacture of rectal
tablets and of tablets which, upon addition of a small amount of
water, rapidly form a smooth and homogeneous slurry or, upon
addition of somewhat larger amounts of water, rapidly form a
potable suspension. The employment of a tablet containing an exact
dose of an active ingredient as a means which immediately yields a
slurry that is tolerated by infants and small children upon being
admixed with a small amount of water or a potable suspension upon
being stirred with somewhat more water, represents a substantial
broadening of the spectrum of application of drugs. Thus, a
so-called slurry-tablet must fulfill the following
requirements:
1. It must, upon being brought in contact with a small amount of
water (about twice the volume of the tablet), spontaneously and
promptly disintegrate, i.e., within a few seconds or no more than a
minute.
2. The slurry must be uniform, easily spreadable and
smooth-tasting.
3. Upon further dilution with a little more water, so that the
total volume does not exceed a few child's swallows, the slurry
must be capable of being stirred into a substantially homogeneous
and free-flowing suspension.
4. In place of with water, the slurry should also be dilutable or
freely miscible with fruit juice, milk, baby cereal, cream of wheat
or the like.
The above requirements are fully met by pharmaceutical tablets
manufactured by the method according to the present invention.
More particularly, the method of making pharmaceutical tablets
pursuant to the present invention consists of
1. spray-drying, after inert gas foaming, a suspension of
A. 1 - 20 percent by weight of very finely divided silicon dioxide
or aluminum oxide and
B. 60 - 98 percent by weight of at least one fine-grained, inert
filler material chosen from the group consisting of starches
selected from the group consisting of substantially water-insoluble
rice starch and corn starch, and alkaline earth metal phosphates,
in an aqueous solution of
C. 1 - 20 percent of a water-soluble binder,
2. adding the active ingredient to the resulting spray-dried,
ungranulated tablet pre-mix, and
3. compressing the resulting composition, together with the active
agent and a tablet lubricant, into pharmaceutical tablets.
The disintegration properties of pharmaceutical tablets prepared by
the method according to the present invention may be further
improved by employing the spray-dried three-component mixture
described in the preceding paragraph in combination with a
spray-dried two-component mixture obtained by spray-drying a
suspension of component (A) in an aqueous solution of component
(C). The quantity of the spray-dried two-component mixture may
amount to between 5 and 50 percent by weight, based on the total
weight of the finished pharmaceutical tablet inclusive of the
active ingredient.
The silicon dioxide or aluminum oxide used as component (A) in the
spray-drying step of the method according to the present invention
should be provided in highly dispersed to colloidal form with a
particle size of 10 - 100 m.mu. or a surface area of about 10 to
500 m.sup.2 /gm. Colloidal silicic acid sold under the name
"Aerosil" is a particularly suitable example.
Component (B) is preferably provided in fine-grained form with a
particle size between 10 and 20 .mu..
Examples of water-soluble binders suitable for use as component (C)
are water-soluble cellulose derivatives, such as
hydroxyethylcellulose or carboxymethylcellulose, water-soluble
starches such as amylum pectinum solubile, water-soluble plant gums
such as gum arabic or tragacanth, alginates, gelatin and
polyvinylpyrrolidone.
Of course, all of the components of the spray-dried tablet pre-mix
must be chemically inert with respect to each other and
therapeutically inert as well as physiologically compatible.
The size of the individual particles obtained from the spray-drying
procedure lies generally between 10 and 70 .mu.. The spray-dried,
ungranulated tablet pre-mix according to the present invention is
admixed with one or more active ingredients as well as with other
optional adjuvents, and the mixture is then pressed into
pharmaceutical tablets in conventional fashion. If the spray-dried
tablet pre-mix composition according to the present invention is
used as the disintegration-promoting component in pharmaceutical
tablets, the composition should advantageously constitute about 10
to 70 percent by weight of the finished tablet. In the case of
so-called slurry-tablets the spray-dried three-component tablet
pre-mix composition, possibly in combination with the spray-dried
two-component composition previously referred to, forms the major
constituent of the tablet composition to which, in most cases, only
the active ingredient needs to be added prior to making the
tablet.
The preparation of the tablet pre-mix composition according to the
present invention is, as indicated above, effected by subjecting a
suspension of components (A) and (B) in an aqueous solution of
component (C) to spray-drying. The water-soluble binder (C) should
preferably be soluble in cold water and capable of swelling;
particularly suitable is soluble starch (amylum pectinum solubile).
In accordance with an illustrative embodiment of the process, the
suspension of (A) and (B) in an aqueous solution of (C) is adjusted
to a suitable viscosity, then foamed with an inert gas such as
carbondioxide, and then spray-dried. The spray-drying may be
effected in conventional spray-drying towers. The solids content of
the suspension to be spray-dried lies advantageously between 15 and
50 percent by weight, and if the suspension is foamed with the
inert gas the solids content is preferably from 15 to 30 percent by
weight.
A preferred tablet pre-mix composition according to the present
invention contains, for example, 12 - 18 percent by weight of
colloidal silicic acid, 3 - 15 percent by weight of water-soluble
binder, and 67 - 85 percent by weight of water-insoluble rice
starch or corn starch.
Analogous to the above-described process, a two-component
spray-dried composition, which is advantageously added to the
three-component spray-dried composition for the manufacture of
slurry-tablets, is obtained by suspending finely dispersed silicon
dioxide or aluminum oxide in an aqueous solution of a swellable,
water-soluble binder, such as a hydrophilic cellulose derivative,
and thereafter spray-drying the suspension. A preferred
two-component spray-dried composition consists, for example, of 90
percent by weight of colloidal silicic acid and 10 percent by
weight of water-soluble binder.
The combination of the three-component spray-dried composition with
the two-component spray-dried composition produces a particularly
advantageous tablet pre-mix composition for inclusion in
pharmaceutical slurry-tablets.
The following examples further illustrate the present invention and
will enable others skilled in the art to understand it more
completely. It should be understood, however, that the invention is
not limited solely to the particular examples given below. The
parts are parts by weight.
EXAMPLE 1
Rapidly disintegrating pharmaceutical tablets were prepared from
the following ingredients:
Parts Penicillin V potassium 145 Sulfadimethoxine 150 Spray-dried
composition I 558 Talcum 40 Colloidal silicic acid 20 Magnesium
stearate 12 conventional 925
The spray-dried composition I was prepared in the following manner
from the following ingredients:
Parts Substantially water-insoluble rice starch 70 Colloidal
silicic acid 15 Soluble starch 15 Total 100
The soluble starch was dissolved in hot water, the resulting
solution was cooled to about 40.degree. C., and then the silicic
acid and the rice starch were stirred in. The suspension thus
obtained was spray-dried in a convespray-drying tower with an
entrance temperature of about 200.degree. C. and an exit
temperature of about 75.degree. C.
The tablets were made in the following manner:
The penicillin V potassium and the sulfadimethoxine were passed
through a fine screen, thoroughly admixed with the other
ingredients, and the resulting mixture was pressed into 925 mgm
tablets with a diameter of 15 mm with the aid of a conventional
tablet making machine. Each tablet contained 145 mgm of penicillin
V potassium and 150 mgm of sulfadimethoxine and completely
disintegrated within 2 to 3 minutes after coming in contact with
water or an aqueous liquid.
EXAMPLE 2
Slurry-tablets were prepared from the following ingredients:
Parts Aspirin 300.0 Spray-dried composition I 88.0 Spray-dried
composition II 10.0 Magnesium stearate 1.0 Cyclamate 0.6 Saccharin
0.4 Total 400.0
Spray-dried composition I was the same as that in Example 1.
Spray-dried composition II was obtained from 90 parts of colloidal
silicic acid and 10 parts of hydroxyethyl cellulose by dissolving
the hydroxyethyl cellulose in water at about 50.degree. C.,
accompanied by vigorous stirring, incorporating into the solution
the colloidal silicic acid by stirring, and spray-drying the
resulting suspension in a spray-drying tower having an entrance
temperature of about 220.degree. C. and an exit temperature of
about 80.degree. - 100.degree. C.
The two spray-dried compositions were thoroughly admixed with each
other as well as with the other tablet ingredients, and the mixture
was pressed into 400 mgm-tablets. Each tablet contained 300 mgm of
aspirin and, in contact with about twice its volume of water,
disintegrated within less than a minute to form a smooth aqueous
slurry.
EXAMPLE 3
Antibiotic slurry-tablets were prepared from the following
ingredients:
Parts Spray-dried composition I 1193.0 Spray-dried composition II
150.0 Penicillin V potassium 133.0 Magnesium stearate 15.0
Cyclamate/saccharin (2:1) 10.0 Total 1500.0
The spray-dried compositions I and II were the same as those in
Examples 1 and 2, respectively. The ingredients were thoroughly
admixed with each other, and the mixture was pressed into 1,500
mgm-tablets. Each tablet contained 132 mgm of penicillin V
potassium and, in contact with about twice its volume of water,
disintegrated within less than a minute to form a smooth aqueous
slurry.
EXAMPLE 4
The same results were obtained as in Examples 1, 2 and 3 when the
spray-dried composition I therein was replaced by one prepared from
the following ingredients:
Parts Substantially water-insoluble rice starch 74 Colloidal
silicic acid 15 Soluble starch 10 Tragacanth 1 Total 100
The tragacanth and the soluble starch were dissolved in water and,
while stirring, the colloidal silicic acid and the rice starch were
incorporated into the solution. The resulting suspension was
spray-dried in a conventional spray-drying tower having an entrance
temperature of about 180.degree. - 200.degree. C. and an exit
temperature of about 70.degree. - 80.degree. C.
EXAMPLE 5
The same results were obtained as in Examples 1, 2 and 3 when the
spray-dried composition I therein was replaced by one prepared
according to Example 4 from the following ingredients:
Parts Corn starch 73.5 Colloidal silicic acid 15.0 Soluble starch
10.0 Gum arabic 1.5 Total 100.0
EXAMPLE 6
The same results were obtained as in Examples 1, 2 and 3 when the
spray-dried composition I therein was replaced by one prepared from
the following ingredients:
Parts Calcium hydrogen phosphate, fine 85 Colloidal silicic acid 10
Carboxymethyl cellulose 5 Total 100
The carboxymethyl cellulose was dissolved in warm water, while
vigorously stirring. After the carboxymethyl cellulose was
thoroughly wetted throughout, the colloidal silicic acid and the
finely divided calcium phosphate were stirred in, and the resulting
aqueous suspension was spray-dried in customary fashion.
It should be understood that the physical properties of the active
drug ingredient have no bearing upon the operativeness of the
present invention. Thus, it is immaterial, for example, whether the
active ingredient is water-soluble or not; the only criterion is
that it must lend itself to incorporation into a pharmaceutical
tablet. In other words, any active ingredient which is normally
administered in tablet form may be combined with the spray-dried,
ungranulated tablet pre-mix composition according to the present
invention.
While the present invention has been illustrated with the aid of
certain specific embodiments thereof, it will be readily apparent
to others skilled in the art that the invention is not limited to
these particular embodiments, and that various changes and
modifications may be made without departing from the spirit of the
invention or the scope of the appended claims.
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