U.S. patent number 3,639,168 [Application Number 04/820,283] was granted by the patent office on 1972-02-01 for direct compression vehicles.
This patent grant is currently assigned to SuCrest Corporation. Invention is credited to Charles B. Broeg, Anthony Monti, John P. Troy.
United States Patent |
3,639,168 |
Monti , et al. |
February 1, 1972 |
DIRECT COMPRESSION VEHICLES
Abstract
Direct compression vehicle useful for preparation of tablets by
the direct compression technique is obtained by dispersing a
diluent such as sugar, in a fully hydrated hydratable polymer, such
as starch, drying the resulting dispersion, and reducing the dried
product to particles of the desired size. The vehicle can be
admixed with the active material and, if desired, a lubricant, and
the resulting mixture compressed without prior granulation or
slugging to form a tablet.
Inventors: |
Monti; Anthony (Irvington,
NY), Troy; John P. (Hicksville, NY), Broeg; Charles
B. (Short Hills, NJ) |
Assignee: |
SuCrest Corporation (NY,
NY)
|
Family
ID: |
25230380 |
Appl.
No.: |
04/820,283 |
Filed: |
April 29, 1969 |
Current U.S.
Class: |
127/29; 127/63;
424/606; 8/526; 264/122; 424/686; 424/687; 424/690; 424/695;
424/720; 424/722; 424/723; 426/650; 514/769; 514/777 |
Current CPC
Class: |
A61K
9/2059 (20130101); A61K 9/2018 (20130101); A61K
9/205 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); C13f 003/00 () |
Field of
Search: |
;127/29,30,63
;99/134R |
Other References
A Little and K. A. Mitchell, "Tablet Making," Second Edition,
44-53, The Northern Publishing Co., Ltd. Liverpool, 1963..
|
Primary Examiner: Wolk; Morris O.
Assistant Examiner: Morantz; Sidney
Claims
What is claimed is:
1. In a method for producing a tablet by the direct compression of
a mixture including an active material and a direct compression
vehicle, the improvement of employing a dry granular direct
compression vehicle comprising an inert, edible diluent dispersed
throughout a matrix of a hydratable polymer prepared by mixing said
diluent and said polymer with water in proportions sufficient to
provide a substantially fluid mixture of an aqueous solution or
dispersion of diluent dispersed throughout swollen, hydrated
polymer, and thereafter drying said mixture, and forming particles
therefrom.
2. A method according to claim 1 wherein said diluent is selected
from the group consisting of a monosaccharide, a disaccharide, a
polyol of the formula HOCH.sub.2 (CHOH).sub.x CH.sub.2 OH wherein x
is 1 to 4, sodium chloride, sodium citrate, calcium carbonate,
calcium sulfate or tricalcium phosphate.
3. A method according to claim 1 wherein said hydratable polymer is
selected from the group consisting of starch, agar, locust bean
gum, carrageen, dextrin or cereal flour.
4. A method according to claim 1 wherein the ratio of diluent to
polymer is from about 0.25 to about 250 parts by weight diluent per
part of polymer.
5. The tablet produced by the process of claim 1.
6. A dry, granular direct compression vehicle comprising an inert,
edible diluent dispersed throughout a matrix of starch prepared by
mixing said diluent and starch with water in proportions sufficient
to provide a substantially fluid mixture of an aqueous solution or
dispersion of diluent dispersed throughout swollen, hydrated
starch, and thereafter drying said mixture and forming particles
therefrom.
7. A vehicle according to claim 6 wherein said diluent is selected
from the group consisting of a monosaccharide, a disaccharide, a
polyol of the formula HOCH.sub.2 (CHOH).sub.x CH.sub.2 OH wherein x
is 1 to 4, sodium chloride, sodium citrate, calcium carbonate,
calcium sulfate or tricalcium phosphate.
8. A vehicle according to claim 6 wherein said diluent is present
in an amount of from about 0.25 to about 250 parts per part of
starch.
9. A vehicle according to claim 8 wherein said diluent is selected
from the group consisting of a monosaccharide or a
disaccharide.
10. A vehicle according to claim 8 wherein said diluent is selected
from the group consisting of sucrose or invert sugar.
Description
This invention relates to direct compression vehicles. More
particularly, this invention relates to a particulate composition
which can be admixed with an active and optionally, a lubricant,
and the resulting mixture directly compressed into a tablet without
the necessity of granulation or slugging of the mixture.
There are two general methods for forming tablets, i.e.,
compression of a dry particulate material and trituration, or
molding of a moist material, of which the first technique is by far
the most frequently employed. The compression technique may be
further subdivided into three major categories, viz direct
compression, wet granulation and dry granulation. The direct
compression technique is the most desirable, in that it employs the
fewest steps and, in the case of the production of tablets
containing sensitive or unstable actives, such as certain
pharmaceuticals, minimizes the exposure to water or other
conditions tending to adversely affect stability of the active.
Unfortunately, however, it has been found that the direct
compression technique is of limited applicability.
First, most active materials possess poor compression properties,
and thus are unsuitable for this technique. In addition, many
actives are required in such small amounts per unit dosage form
that direct compression of the active alone is impractical, if not
impossible. As a result, the active must be admixed with a direct
compression vehicle, i.e., an inert composition which is compatible
with the active and has good compressibility. In addition, the
direct compression vehicle should have good flowability, good
stability under normal ambient conditions, no adverse effect on
tablet disintegration time, the ability to produce good table
surfaces, and low cost.
To date, however, no material has been found which satisfies all of
these criteria. For example, of the most popular of such
compression vehicles, spray-dried lactose possesses poor stability
and discolors on storing, dicalcium phosphate provides tablets
having poor strength, and microcrystalline cellulose is
expensive.
It is an object of the present invention to provide a new direct
compression vehicle.
It is a further object of this invention to provide a
multicomponent compression vehicle which may be combined with an
active and, if desired, a lubricant, and the resulting dry mixture
subjected to direct compression.
The direct compression vehicles of the present invention comprise
minute particles of a dispersion of certain water-soluble or
dispersible inert diluents in a matrix of a hydratable high
polymer.
The diluent can be any normally solid material, i.e., any material
which is solid under conditions of normal atmospheric pressures and
temperatures, provided it is inert, edible and permissable in the
table formed from the direct compression vehicle. Thus, it can be
water-soluble or insoluble in water. If insoluble, however, it must
be capable of reduction to a size which is useful in the direct
compression vehicle of this invention, i.e., a size below about 200
mesh, and preferably below about 10 microns.
Preferred diluents include normally saccharine materials, i.e., a
mono or disaccharide such as glucose, mannose, galactose, fructose,
arabinose, xylose, sucrose, maltose and lactose; as well as certain
polyols of the formula HOCH.sub.2 (CHOH).sub.x CH.sub.2 OH wherein
x is 1-4, such as glycerol, erythritol, arabitol, xylitol,
adonitol, mannitol, dulcitol and sorbitol. In addition, certain
salts may be employed, including sodium chloride, sodium citrate,
calcium carbonate, calcium sulfate and tricalcium phosphate. The
diluent may be one or a mixture of two or more of the aforesaid
substances. In the event the diluent is a sugar, it may be of
synthetic or natural origin, and may be supplied to the mixing step
in the form of a solution or syrup, such as molasses, affination
syrup, invert syrup and the like.
The hydrated polymer includes hydrophilic polysaccharides,
hydrocolloids or proteinaceous materials which, although not
soluble in water, are hydrated upon admixture with water, and when
substantially fully hydrated form a clear aqueous sol of swollen
polymer and water. Illustrative examples of these high polymers
include starch, agar, locust bean gum, carrageen, dextrin, cereal
flour and the like.
The polymer, diluent and water are admixed in any convenient manner
and in proportions such that there is obtained a substantially
clear fluid mixture comprising an aqueous solution or dispersion of
diluent dispersed throughout the swollen hydrated polymer. The
precise conditions and proportions will vary widely, depending upon
the polymer employed, and the amount of and additive employed.
The amount of water necessary to hydrate the hydrophilic polymer is
either known or is readily determined by the simple experiment of
adding water in known amount to a known amount of dry polymer until
a clear sol is obtained. In general, at least about 8 parts of
water are required per part of starch or dextrin, at least about 25
parts of water are required per part of locust bean gum, and at
least about 33 of water are required per part of agar and
carrageen. The foregoing amounts of water provide tablets of
optimum strength, but lesser amounts of water, for example as low
as 50 percent or more of the above values, can be employed and
still obtain a useful tablet.
When the diluent is insoluble in water, no additional water is
required. When, however, the diluent is water-soluble, enough
additional water must be employed to dissolve the additive. For
example, if sucrose is added to a clear, fully hydrated starch the
resulting mixture becomes more fluid because the sucrose has a
greater affinity for water than starch, and thus removes some of
the water of hydration. If, however, in addition to the 8 parts
water per part starch necessary for fully hydration, there is added
at least 0.5 part water per part sucrose to ensure solution of the
sucrose, the starch remains hydrated. Although greater quantities
of water can be employed if desired, they are unnecessary and, in
fact, are disadvantageous in increasing the heat load for drying
and may preclude the use of certain drying techniques, such as drum
drying, which require a relatively viscous liquid.
The ratio of water-soluble additive to hydratable polymer can vary
widely, depending upon the particular materials employed and the
characteristics desired in the product direct compression vehicle.
In general, however, ratios of from about 0.25 to about 250 parts
of additive per part of polymer, preferably from about 2 to about
50 parts additive per part of polymer, are useful. Ratios of from
about 20 to about 30 parts additive per part of polymer are most
preferred.
Drying of the resulting dispersion may be effected by a variety of
techniques, such as spray drying, tray drying, drum drying and the
like. In a preferred technique, the dispersion is dried by
deposition on a heated surface to effect evaporation and convert
the dispersion into a dry, hot, plastic film, removing the film
from the heated surface and attenuating the film while
simultaneously cooling it, to convert the plastic film to a brittle
or frangible condition. After the film has been thus cooled, it is
fragmented and ground to a desired particle size and the ground
product is employed. In this technique, the mixture of hydratable
polymer and diluent should, of course, have the property of being
plastic when in a hot, dry state.
A preferred way to practice the method of this invention is through
the use of a heated drum dryer and a cooled rotary takeoff reel
located a slight distance therefrom with a current of cooling air
passing therefrom.
In such a process the dispersion of the aqueous solution of a
saccharine material and the high polymer is prepared and introduced
into the nip between a pair of steam-heated oppositely rotating
drums at a rate to effect rapid evaporation of the water, but
without permitting the resultant dehydrated product, which contains
not more than 4 percent moisture, and which forms a relatively
thick plastic film on the surfaces of the drums, to reach a
temperature at which destructive decomposition would begin. Thus,
the temperature of the dehydrated material should not exceed about
350.degree. F. and the operating conditions of the drums should be
adjusted accordingly. At the line of transfer to the reel, which is
rotating with a peripheral speed greater than that of the drum, the
hot dehydrated film is removed by a doctor blade from its
associated drum and transferred to the reel across a current of
cooling air, having a 60.degree. -80.degree. F. temperature, which
effects an initial cooling of the dehydrated material to near room
temperature. This cooling effect is enhanced by the thinning or
drawing down of the film as a consequence of having the reel
operate at the greater peripheral speed. Since the reel is also
cooled by 60.degree.-80.degree. F. air, the thin film is further
cooled to a room temperature of about 70.degree. F. to about
95.degree. F. and the cooling air at the line of removal of the
film from the reel aids both its removal therefrom and a final
cooling to a brittle or frangible state. The frangible film then
drops away from the reel as a brittle sheet or fragments onto a
conveyor for transport to a storage bin or to a comminuting device
for reduction to the desired particle size for direct
tabletting.
If only one takeoff reel is used, it will, of course, be necessary
to provide a scraper or other means on the opposite drum to prevent
passage of the hot dehydrated film therearound and force it over
onto the other drum.
Although in the foregoing description of the method mention has
been made of a two-drum dryer with either a single or two takeoff
reels, it will be appreciated that a single drum dryer with a
single takeoff reel can be used with equal effectiveness.
The dried product is broken up into particles having the desired
dimensions and, if necessary, screened to achieve the proper size
range and distribution. The resulting particulate product comprises
minute particles of the water-soluble additive dispersed throughout
the high-polymer matrix, and is substantially different in
appearance and properties from mixtures of the same dry materials
which are obtained by dry blending, or even wet granulation
techniques. The reason for the difference is that none of the
heretofore known techniques for preparing tabletting materials or
blends employ sufficient water to both hydrate the polymer and
dissolve the additive. On the other hand, U.S. Pat. No. 2,963,373
to Monti et al. discloses an icing percursor comprising agar or
carrageen and starch and/or sugar which is prepared according to
the foregoing technique, and it has been found that the resulting
product is an excellent direct compression vehicle in accordance
with this invention. Other previously known products which may be
employed as directly compressible vehicles are the modified
polysaccharide gums of Monti et al. disclosed in U.S. Pat. No.
3,042,668.
The granular direct compression vehicle of this invention is
admixed with the active which it is desired to incorporate into
tablet form and, if necessary, a lubricant, and the mixture
tabletted by known direct compression procedures. The proportions
of vehicle, active and lubricant are not critical, and obviously
depend upon the active and the unit dose desired in the tablet. In
general, however, the direct compression vehicle will comprise at
least 10 percent of the tabletting mixture, and thus the resulting
tablet, although amounts within the range of from about 70 percent
to about 95 percent are most common.
By the term "active material" is meant any material intended for
ingestion having a beneficial or desirable effect on the user.
Suitable active materials include therapeutic materials, such as
anesthetics, antibiotics, antitussives, vitamins, aspirin,
antacids, and the like; foodstuffs such as cocoa, dried oats, fruit
flakes and the like; edible dyes and other food additives; and so
on. The vehicle is a free-flowing granular material and imparts
improved flow characteristics to the active material and other
components of the blend, thereby assuring ease of tabletting.
The blend of direct compression vehicle, active material and other
additives is mixed and directly compressed to form a tablet
employing conventional techniques and apparatus.
The following examples are illustrative. Unless otherwise
specified, all parts and percentages are by weight.
EXAMPLE 1
A mixture of 182 pounds of sucrose, 35 pounds of tapioca flour, 300
pounds of starch and 400 gallons of water was heated to 180.degree.
F., and 714 pounds of a 70 percent invert syrup was added. The
resulting mixture was drum dried to a moisture content of about
2.13 percent, and then broken up into flakes of about one half an
inch. The resulting particulate flake material was admixed with
calcium stearate in a ratio of 99 parts to 1 part and after
pulverization to yield a product having a particle size of below
about 200 mesh (95 percent through 200 mesh), compressed to form
13/32-inch, 0.5-gram tablets at 1,000 and 3,000. The resulting
tablets had Stokes hardnesses of 3.25 and 4.1 kilograms,
respectively, and evidenced no capping.
EXAMPLE 2
Employing procedures similar to those described in example 1, a
flake product containing about 46 parts invert sugar, 25 parts
starch, 28 parts sucrose and 1 percent water was produced and
admixed with Cab-O-Sil brand silica gel to provide a mixture
containing 98 parts flake and 2 parts silica gel. The resulting
mixture, after pulverizing, was tabletted at 3,000 and 9,000 p.s.i.
The tablets produced at 3,000 p.s.i. were ejected at a pressure of
100 p.s.i., evidenced only slight capping and had a hardness of
19.5. At 9,000 p.s.i. and ejection pressure of 350 p.s.i. no
capping was observed and tablet hardness was in excess of 45
kg.
In a second run equal parts of the flake and sucrose were mixed and
pulverized, and then magnesium stearate was blended in to provide
49 parts each of flake and sucrose and 2 parts magnesium stearate.
Tablets compressed at 3,000 p.s.i. and ejected at 60 p.s.i. had a
hardness of 20.75 and evidenced no capping, and those compressed at
9,000 p.s.i. and ejected at 95 p.s.i. had a hardness of 37.5 kg.
and evidenced no capping.
EXAMPLE 3
Employing procedures similar to those described in example 1, a
mixture of 350 pounds of starch and 284 pounds sucrose in 450
gallons of water and 571 pounds of 70 percent invert sugar was drum
dried to about 2 percent moisture and crushed to form flakes having
a size of about one-half an inch. The resulting product, after
further pulverizing to below about 200 mesh, was compressed at
3,000 and 9,000 p.s.i. and 35 p.s.i. ejection pressure to form
13/32-inch tablets weighing 0.5 grams. Tablet hardness was 38.5 and
greater than 45, respectively, and no capping was observed.
The flake product was admixed with sucrose and calcium stearate to
provide a mixture containing 60 parts flake, 39 parts sucrose and 1
part stearate, and the resulting mixture tabletted. At 3,000 p.s.i.
the ejection pressure was 50 p.s.i. and tablet hardness was 13.5.
At 9,000 p.s.i. the ejection pressure was 45 p.s.i. and tablet
hardness was 22. No capping was observed at either pressure.
EXAMPLE 4
Employing procedures similar to those described in example 1, a
flake product containing 22.5 percent invert sugar, 42.4 percent
sucrose, 32.1 percent starch and 3 percent moisture was blended to
form a mixture of 66.6 parts flake, 32.35 parts sucrose and 1.0
parts calcium stearate. Tablets pressed at 1,000, 3,000 and 9,000
p.s.i. had hardnesses of 6.5, 14.5 and 23.0, respectively.
EXAMPLE 5
Employing procedures similar to those described in example 1, a
mixture of 1 part locust bean gum, 25 parts sugar and 100 parts
water was heated to 180.degree. F. and drum dried to less than 1
percent moisture and reduced to 1/2-inch flakes. The resulting
product, after pulverization to a product of less than about 200
mesh, was compressed at 4,500 p.s.i. to form a tablet having a
hardness of greater than 42 kg.
EXAMPLE 6
Employing procedures similar to those described in example 1, a
mixture of 4 parts of agar, 70 parts sucrose and 200 parts water
was boiled and then drum dried and flaked. After pulverizing, the
product was compressed at 4,500 p.s.i. to form a tablet having a
hardness of greater than 42 kg.
EXAMPLE 7
Employing procedures similar to those described in example 1, a
mixture of 4 parts carrageen, 70 parts sucrose and 200 parts water
was drum dried and flaked. The flake product, after pulverizing,
was compressed at 4,500 p.s.i. to form a tablet having a hardness
of greater than 42 kg.
Each of the direct compression vehicles of the foregoing examples
can be blended in accordance with the following recipes and
compressed to form tablets or wafers.
---------------------------------------------------------------------------
CONFECTIONERY TABLETS OR WAFERS
1. lemon-flavored confectionery tablet: 100.0 pt. direct
compression vehicle 1.0 pt. citric acid, dry 0.25 pt. encapsulated
lemon flavor 0.10 pt. yellow color No. 5 1.0 pt. magnesium
stearate
2. Grape-flavored confectionery tablet: 50.0 pt. direct compression
vehicle 50.0 pt. 6.times. powdered sugar 2.0 pt. tartaric acid 0.25
pt. grape flavor 0.05 pt. grape color 0.5 pt. calcium stearate
3. Cherry-flavored confectionery tablet: 100.0 pt. direct
compression vehicle 2.0 pt. fumaric acid 0.2 pt. cherry flavor 0.1
pt. red color 1.0 pt. magnesium stearate
__________________________________________________________________________
---------------------------------------------------------------------------
B. PHARMACEUTICAL FORMULATIONS
1. 50.0 pt. direct compression vehicle 37.5 pt. aluminum hydroxide
1.0 pt. magnesium stearate
2. 100.0 pt. direct compression vehicle 25.0 pt. calcium carbonate
5.0 pt. magnesium carbonate 1 drop peppermint oil 2.0 pt. magnesium
stearate
3. 100.0 pt. direct compression vehicle 25.0 pt. acetyl salicylic
acid 15.0 pt. corn starch 2.0 pt. magnesium stearate
4. 90.0 pt. direct compression vehicle 10.0 pt. vitamin C in dry
form 2.0 pt. magnesium stearate
__________________________________________________________________________
Other active ingredients of use in blends with the direct
compression vehicle are: sodium bicarbonate, acetanilid,
phenacetin, and magnesium trisilicate.
---------------------------------------------------------------------------
C. SPECIALTY PRODUCTS
1. Invertase sugar tablet 96.4 pt. direct compression vehicle 3.6
pt. liquid triple strength invertase (K=0.9) 1.0 pt. magnesium
stearate
2. Cocoa-sugar tablet 90.0 pt. direct compression vehicle 10.0 pt.
high fat cocoa 0.2 pt. dendritic salt 1.0 pt. magnesium stearate
After blending, the mixture is tabletted to form a cocoa-sugar
tablet.
3. Sugar-synthetic sweetener tablet 450.0 pt. direct compression
vehicle 7.16 pt. calcium cyclamate 0.8 pt. sodium saccharin 5.0 pt.
calcium stearate
4. Highly concentrated color tablet 90.0 pt. direct compression
vehicle 10.0 pt. dried yellow FD&C No. 6 10.0 pt. sodium
benzoate
5. Yeast Food Tablet 34.0 pt. calcium sulfate (2H.sub.2 0) 23.0 pt.
flour 9.0 pt. ammonium chloride 0.25 pt. potassium bromate 17.75
pt. sodium dihydrogen phosphate 16.0 pt. salt 900.0 pt. direct
compression vehicle 10.0 pt. magnesium stearate
* * * * *