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Патент USA US3096261

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July 2, 1963
H. s. RUDZKI
3,096,248
METHOD OF MAKING AN ENCAPSULATED TABLET
Filed April 6, 1959
INVENTOR
HENRYK S. RUDZKI
BY
mmgq “0:”;
ATTORNEY
3,096,248
United States Patent 0 ” 1C6
Patented July 2, 1963
2
i
tablet containing such vitamins as B1, B12, C and others,
and particularly if the tablet core is a multivitamin prod
uct. The moisture may trigger chemical reactions be
tween the difierent components, resulting in a substantial
3,096,248
METHOD OF MAKTNG AN ENCAPSULATED
TABLET
Henryk S. Rudzki, West Los Angeles, Calif., assignor to
loss of potency. Other common drugs which are sensi
tive to moisture are aspirin, ferrous sulfate, iodoforrn,
Rexall Drug & Chemical Company, Los Angeles, Calif.,
a corporation of Delaware
Filed Apr. 6, 1959, Ser. No. 804,489
1 Claim. (til. 167-82)
etc.
It vhas also been found that when plastic materials are
applied in solution by panicoating, the coating upon
compressed tablets having a coating of protective material 10 evaporation of the solvent becomes tacky, causing the
This invention relates to tablets and particularly to
tablet cores to stick to each other.
and to the methods of making same. ' The invention in its
To overcome this a
“duster” has been used, for example: talc, magnesium
carbonate, calcium carbonate, etc. This procedure suifers
from the disadvantage that the solid particles of the
broadest sense embraces such tablets applicable in ‘any
?eld in which their advantageous characteristics can be
bene?cially employed; ‘for example human or veterinary
15 “duster” cause the ?lm deposited to be dis-continuous,
medicine, human or animal food products.
tending to permit the ingress of moisture at these particles.
However, their main application at present is in the pro
In addition to the di?iculties in controlling the pan
vision of pharmaceutical tablets coated with a moisture
coating procedure to achieve a good appearance of the
and odor-resistant layer, this layer being soluble or partly
tablet, a continuous even ?lm, even distribution of color,
soluble in body ?uids and capable, if desired, of acting
as a means of delaying or prolonging the therapeutic ac 20 etc, the use of organic solvents has the disadvantage of
requiring special additional equipment to exhaust and re
tion of the therapeutically active ingredient.
cover the vapors. The use of such solvents also involves
In the past pharmaceutical tablets have been mostly
hazards such as danger of explosion, toxicity of vapors,
sugar-coated. This process is a long and tedious one, re
and costliness. Also, it is possible for toxic traces to be
quiring considerable skill and experience on the part of
the operator to achieve a satisfactory product. Even with 25 left in the ?lm coating of the tablet. Such traces of solvent
trapped in the ?lm coating may also evaporate subse
experienced operators the process requires about three
quently leaving pinholes in the ?lm, enabling moisture
days {for completion, varying somewhat according to the
or other deleterious ‘factors to affect the tablet core.
size, shape and nature of the tablet and of the coating,
Another drawback to the pan-coating procedure resides
color and composition.
The purpose of tablet coatings is several fold. Coat 30 in the fact that only‘ about 100,000 tablets can be coated
ings are used to provide an elegant appearance to the
tablet, to protect the tablet ingredients fro-m deterioration
and destruction by moisture, light, lair, etc., to delay. or
prolong the dissolution of the active ingredients of the
35
tablet in the body ?uids.
Sugar-coatings possess various disadvantages.
They
in one pan so that a battery of such pans is required to
achieve a useful production output. In the case of sugar
coating, a substantial amount of dust is produced by the
tumbling of the tablets in the rotating pans, requiring an
adequate air exhaust system. Cold and warm air inputs
are necessary and the shape of the coating pan makes it
are hard, brittle and are easily scratched. They do not
difficult to remove the moisture or solvent from its con
provide effective protection against moisture, air, etc.,
tents.
and are too soluble to provide an eifective delayed or
prolonged-action tablet.
“Carbowax 6000,” a polyethylene glycol polymer, has
40 been used to replace sugar for tablet coatings in the pan
coating procedure to provide a protective, delayed or pro
longed action coating, but has been found to require a
Prior tablet-coating processes have depended upon the
use of the process known as pan-coating.
This process
gradual build-up on the tablet of a dozen or more coat
comprises placing tablet cores containing the active in—
ings, and the ?nished tablet coating has been found to be
gredients in a revolving pan and applying a coating solu
tion to the tumbling tablets in small amounts and then 45 too brittle and consequently tends to detach from the
tablet.
'
drying them with the ‘aid of warm vair or direct heat.
It ‘is auobject of the present invention to provide
Only ‘after one application of the coating solution ‘has been
tablets whereby the active ingredients are protected from
totally dried can another portion of solution be ‘applied;
the ingress of air and moisture by a continuous protective
and these steps have to be repeated a sufficient number
of times to build the tablet to the required size, shape and 50 coating.
It is another object of this invention to provide a medic
color. This accounts for the time-consuming nature of
inal tablet coated with a plastic material which is soluble
the process.
in body ?uids whereby the medicament is released after
It is also known to use in place of sugar and/or sugar
a time delay and/ or for a prolonged period.
'
solutions, other materials such as plastics or resinous sub
stances, for instance: hydroxyethyl cellulose, ethyl cellu 55 Another object of this invention is to provide an im
proved method of making coated tablets.
lose, carboxymethyl cellulose, polyvinylpyrollidone, etc.
Another object of this invention is to provide a method
of making coated tablets which are of improved appear
ance, texture and taste, having improved resistance to
ing time is achieved. To protect the ingredients of the 60 external factors such as moisture and air, and having a
controlled medicament release pattern when exposed to
tablet core from moisture, resinous materials such as
By reason of the fact that such materials are applied in
solutions in alcohols or other organic solvents which are
of higher volatility than water, a shortening of the coat
shellac, zein, cellulose acetate-phthalate, etc, have been
applied prior to applying the sugar-coating by‘ pan-coat
ing. However, unless the resinous-coating is applied in
thick layers, it still permits the ingress of moisture, espe
cially when using the pan-coating procedure as it is diffi
the body ?uids.
'
‘
Further objects and features of advantage will be recog
nized by one skilled in the art from the following detailed
65
description.
~
1
The concept of this invention resides in a compressed
tablet comprising a core hermetically enclosed in a coat
cult thereby to produce a uniform ‘and continuous ?lm
ing of protective material, said coating being of contin
on the tablet core; “pin-holes” are quite often present,
uous character as a result of fusion under compression.
allowing the moisture from the sugar solutions to pene
trate into the tablet core. This moisture penetration has 70 According to the invention, a compressed tablet hermeti
cally sealed in a coating of protective material is pre
a most damaging effect on the stability of the ingredients
pared by providing a core, containing the desired active
in the tablet core in many instances, for example: in a
3,096,248
3
ingredients, and then forming by fusion under compres
sion upon the core a continuous coating of protective ma
terial. This process may be described as “compression
encapsulation.” It may be carried out in machines of
the type described in U.S. Patent No. 2,700,938. Various
other machines currently available for compression-coat
4
shows the recession of the lower punch, the bottom ?ll
and the core tablet into the die and the introduction of
coating granules 6 called the “top ?ll” for the top coating
of the tablet. FIGURE 4 shows the positions of the
punches during the compression step which causes fusion
and flow of the bottom ?ll and top ?ll around the tablet
core to form a'continuous coating 7 which hermetically
seals the core 5. FIGURE 5 shows the positions of the
punches during the ejection of the coated tablet 8 from
tablets should be relatively non-toxic even on chronic
administration, preferably white or colorless, stable and 10 the die.
In the embodiment shown in FIGURE 7, the core ma’
solid at normal temperatures, and resistant to air, mois
terial is in granular form 9 hermetically enclosed in the:
ture, light and heat, chemically and pharmaceutically
plastic material 10.
compatible with or inert towards the other ingredients
The embodiment illustrated in FIGURE 8 comprises?
of the tablet, palatable or practically odorless and taste
less and soluble in body ?uids in greater or less degree. 15 a compressed core tablet or granular core 11, enclosed
in an opaque plastic coating 12, having a window 13 of;
Such substances may be waxes, resins, polymers or co
transparent plastic.
polymers or plastics such as cellulose derivatives. These
The coating thickness at the sides of the tablet is con
may be natural or synthetic, and may be thermoplastic
trolled by the di?erence between the core tablet diameter
or thermosetting materials.
Among the materials which We have found suitable are 20 and the size of the coating die. The thicknesses of the
ing may be used for compression encapsulation.
Coating materials which may be used for medicinal
polyethylene glycols of high molecular weight, ranging
coating, top and bottom, are independently adjustable
and can be controlled more or less as desired by varying
in average molecular weight from about 4,000 to about
the shape of the die, the nature of the coating material
20,000 (“Carbowax”), or their modi?cations such as
and/or the amounts of the bottom ?ll and the top ?ll.
fatty acid mono- or di-esters or others, higher condensates
Some coating materials suffer from the drawback of
of polyethylene oxide known as “Polyox” resins which 25
tending to stick to the punches or die cavities. In such
range in average molecular weight from about 200,000
cases this dif?culty may be overcome by the use of lubri
to 5,500,000, vinyl polymers such as “Carbopol” (high
cants such as metallic stearates, talc, starches, oils and
molecular Weight), polyvinyl alcohol, polyvinyl acetate
and polyvinyl chloride, polyvinyl pyrrollidone, polyethyl
ene and polystyrene; acrylic resins such as polymethyl 30
waxes.
The coating material may be colored with suitable
methacrylate and polyacrylamides; cellulose derivatives
colors such as the FD & C colors and/ or D & C and/or
such as cellulose ethers and esters, for example: ethyl and
pigments. The dry plastic coating material should be
reduced to a suitable mesh size and be free-?owing. If
desired, the tablet can be polished by the usual methods.
cellulose, cellulose acetate and cellulose acetate-phthalate;
modi?ed starches and copolymers of such materials; and 35 The coating formed around the core tablets in this man
ner is a continuous integral ?lm. If excipients or func
mixtures thereof. Thermosetting materials may also be
tional ?llers are included in the coating material the proc
used, for example: urea-formaldehyde or melamine
ess causes these to be enmeshed in a matrix which re
formaldehyde resins. When using a thermosetting resin
mains as a continuous integral ?lm coating around the
it is advantageous to use it in an incompletely cured state;
it is then possible during, or immediately after, the sub 40 tablet core.
The compression step causes the coating material to
sequent compression encapsulation step to subject it to
methyl cellulose, carboxymethyl cellulose, hydroxyethyl
moderate heat treatment, thereby curing and hardening
fuse and flow around the core tablet to form a continuous
coating with no bubbles or voids. If desired, this process
the resin and rendering it insoluble to the desired degree.
may be assisted by raising the temperature of the die.
In carrying out the present invention, the coating ma
terial in granular form is ?rst fed into the die of a tablet 45 When thermosetting materials are used as coatings the
extent of curing is controlled to produce a ?lm which
compressing machine. The core tablet is then placed
has the requisite swelling, solubility or dispersability char
on top of the coating granules and more coating granules
acteristics.
are fed into the die cavity on top of the core tablet. The
It is also possible by the process of this invention to
contents of the die cavity are subjected to compression
and the coating granules are caused to fuse. The fused 50 combine two incompatible drugs; one is incorporated in a
core tablet and the other in the coating material. By
coating flows around the tablet core, forming thereon a
repeating the press-coating process ‘layer separation of
continuous coating which hermetically seals the core.
successive ingredients may be effected for instance for
These operations are best carried out under conditions
multi-vitamin mineral tablets. Such conotrl in pan-coat
of controlled temperature and humidity.
The successive stages in the process and the products 55 ing is di?icult and time-consuming. Tablet cores may be
‘formulated for rapid ‘disintegration and compressed to a
thereof are illustrated in the accompanying drawings, in
which:
lesser degree.
punches during the introduction of coating granules 4
to diabetics and others who should restrict the use of
‘called the “bottom ?ll” for the bottom coating of the
sugar. Also when used for prolonged action or time-de
lay tablets prolonged time diffusion may be obtained
By means of the process of this invention the disin
FIGURES l to 5 represent vertical mid-sections
tegration time of the tablet may be made independent of
through the'punches and die of a tablet compressing ma
60 the pH of the body ?uid environment, and made a func
chine at successive stages of the process.
tion only of time, by controlling the thickness or char
FIGURE‘ 6 is an enlarged vertical cross-sectional view
acter of the applied coating material. For example: a
of a'?nished tablet in accord with my invention.
methyl cellulose ?lm coating of thickness from about
FIGURE 7 is an enlarged vertical cross-sectional vview
0.28 to 0.70 mm. will dissolve in the stomach before
of a ?nished tablet in accord with a modi?ed form of my 65 the gastric contents are discharged into the intestinal tract.
' invention.
However, if the thickness of the coat is increased to 2
FIGURE 8 is an enlarged vertical cross-sectional view
mm. then the coating will provide enteric protection be
of a ?nished tablet in accord with a further modi?ed form
cause it does not entirely dissolve before the tablet is
of my invention.
passed into the intestinal tract.
‘In the drawings 1 represents the upper and 2 the lower 70
Additional advantages of this invention are that tablets
vpunch in a die 3. FIGURE 1 shows the positions of the
with sugarless coatings thus produced are of special value
tablet. ‘FIGURE 2 shows the placing of the‘core tablet
Scentered and bedded on the bottom ?ll; FIGURE 3 75 rather than a mere delayed disintegration as with prior
3,096,248
6
5
EXAMPLE 4
art types. It is also possible to use an opaque coating
material for the bottom and side surfaces of the tablet
Cellulose Acetate-Phthalate
and apply granules of transparent coating material for the
One thousand grams of cellulose acetate-phthalate were
top surface of the tablet so as to create a “windowed”
passed through a No. 30 mesh screen. The tablet cores
used were ‘compressed with a No. 5 oval punch. These
tablet cores and the granular coating material were fed
tablet, by feeding the bottom and top coating granules
from two hoppers.
When preparing medicinal tablets we have found it pos
into a Manesty DryCota machine, and the coating com
pressed on the cores, using a special oval punch No. 6.
sible to use a size of coating granule from about num
ber 14 to number 200 mesh; however, depending upon the
These operations were carried out at a relative humidity
speci?c flow characteristics of the material used, a mesh 10 of 30% and at a temperature of 75 ° F.
.
size of from about 16 to 60 mesh is ‘generally preferable.
The tablets produced had a hard glossy surface; there
We have found that the coating pressure may be be
was no evidence of sticking or capping.
tween about 1,000 and about 75,000 pounds per square
When a pressure of 27,000 p.s.i. was employed in the
inch. It is generally preferred to use between about 2,000
compression encapsulation step, a ?lm thickness of 1 mm.
and 35,00 pounds per square inch.
15 was produced on the tablet, whereas at 40,000 p.s.i. the
It is also possible by the use of a tableting machine with
thickness was 0.3 mm. The coating had the following
suitable hoppers to use a loose granulation or powder as
a core and to surround it with a coating granulation, then
compress both core and coating into a tablet in one oper
characteristics :
27,000 p.s.i.
ation.
The ‘following non-limiting examples illustrate various
Gloss
embodiments of the present invention:
EXAMPLE 1
____ __d
Gms.
Moderate _____ __
High.
Fragility
N one
None.
Negligible.
25
Disintegration 1(gastric
(intestinal
juice)
juice)____
______ __ 122hour
min ________
undis- __ 41
1 hr. mm.
“Silene E.F.” (calcium silicate) _______________ __ 100
Acacia
Semi-lustre.
None.
Elasticity _________________________ _.
Permeability______________________ -_ Law (under
Core Granulation
-
N one
Transparency
40,000 p.s.i.
solved.
20
Mix well, and adsorb on to mix vitamin E _______ __ 100
undissolved.
lDisintegra-tion test according to U.S.P. XVI_, using the
(Then granulate with water q.s. to achieve a doughy
prescribed apparatus and technique, was used in this and
30 the following examples.
paste. Granulate thru No. 16 screen if required,
dry at 120° F. to 0.25% moisture. Pass thru No.
EXAMPLE 5
20 mesh screen.)
Methyl Cellulose Coated Tablet
EXAMPLE 2
Five
hundred
grams of “'Methocel,” (grade 2602 of 50
Core Tablet
35 cps. viscosity) and having a No. 60 mesh size, produced
Parts
Salicylamide, powd
40
Acetphenetidin, U.S.P ________________________ .__
70
by an intermediate compacting step (slugging) with sub
sequent regrinding and separation of the 60 mesh fraction,
Hesperidin, puri?ed, powd ____________________ __
Sugar, powd. --3 percent corn starch ___________ __
9
7
compression encapsulation was carried out using a special
oval punch No. 6 at an ambient temperature of 78° F. and
was compressed on tablet cores of the following formula,
Caffeine alkaloid, anhydrous U.S.P _____________ __ 8.5
Pyrilamine maleate, U.S.P ____________________ __ 20 4.0 which had been performed with a No. 5 oval punch. The
relative humidity of 26%.
Mix well. Granulate thin No. 8 screen, using a
solution of:
Parts
Acid, ascorbic U.S.P., powd. No. 200 _________ __
“Methocel” (50 cps. viscosity) ___________ __
1
45 Granulate through No. 14 screen, using a 7% gela
Alcohol, S.D. 3A (95 percent) ____________ __ 20
tin solution:
Dry at 140° F., and screen thru No. 20 mesh.
Add and mix well magnesium stearate
Dry at 130° F. Pass dried granulation through No.
10 screen. Add and mix well with following gran
ulation:
Corn starch _____________________________ __
7
Talc, powd
7
____
Acid, ascorbic U.S.P _____________________ __
24
Pass thru .a No. 20 screen.
(Compress tablets, using 15/32" deep cup punch. Each
' tablet weighs 9.7 grains.)
EXAMPLE 3
Polyvinyl Alcohol Coating
U.S.P ____________________________ __
0.12
Nicotinamide U.S.P., powd ______________ __
Riboavin U.S.P., powd __________________ __
Calcium pantothenate (dextro.) U.S.P _____ __
4
0.45
1.5
0.42
50 Mix the following:
Granulate thru No. 14 screen with following solution:
Gelatin U.S.P
0.5
vWater
30 55
Dry at 140° F.
17.7
60
Pyridoxine hydrochloride U.S.P. powd ____ __
Sugar, milk U.S.P., powd ________________ __
4.6
'(Granulate through No. 14 screen, using a 2% 50
cps. Methocel in alcohol (95 percent) SD3A so
lution. Dry at 140° F.)
Pass through No. 16 screen and add, mix well:
Magnesium stearate U.S.P _______________ __
01
One hundred grams of polyvinyl alcohol (Alvanol
grade 50-42), was passed through a comminutor with
Mix the following:
Vitamin A & D “Crystalets” (500,000 units A
a N0. 30 mesh screen. It Was then passed through a No.
40 screen to remove the bigger particles, and mixed well.
and 50,000 D/gram) _________________ __
3.8
Thiamine hydrochloride U.S.P. ?ne crystals__
10.9
Acid, tartaric, N.F., powd _______________ __
0.4
Five grams of titanium dioxide N.F. were added and then 65
mixed well in; then 0.5 gram of magnesium stearate were
Vitamin B12, oral-1000 mcgm./ gm. activity__ 0.51
Acid, folic U.S.P., powd. (adjust if neces
mixed well.
This coating granulation was fed into a machine of the
sary) ______________ __‘ _____________ __ 0.015
Manesty DryCota type, and compressed upon a tablet
Now, add and mix well:
core made with 7A6 inch size deep cup punches, using a 70
Magnesium stearate U.S.P _______________ __ 0.01
1/2 inch extra deep cup punch.
Combine above 4 mixtures and compress, using a
The tablets were prepared at a room temperature of
No. 3 oval punch.
75° F. and relatively humidity of 30%. No sticking to
(Each tablet core=3.4 grains.)
the punches was observed and the coated tablet produced
The tablets produced had a continuous surfaces ?lm
75
had a closely ?tting continuous plastic ?lm-like coating.
3,096,248
"5'
a
,
8
which was slightly transparent, cream colored and of hard
larger refractory particles. Nine hundred grams of the
surface texture.
screened material (approximately 20 mesh size) were
mixed with 200 grams of Dry Ice fragments of a size be
Using a compression encapsulating pressure of 27,000
p.s.i. the ?lm coating had a thickness of 0.7 mm., whereas
tween one and two inches and 1allowed to stand ‘one-half
at 40,000 p.s.i. the ?lm thickness was 0.28 mm. The coat- 5 hour. The mixture was then passed slowly through a
ings had the following characteristics:
27,000 psi
Fitz comminutor four times, with the hammer ends posi
tioned forward and with the continuous addition of 300
40,000 psi
grams of Dry Ice, using a No. 20 screen. The commi
nuted material was then passed through a No. 20 mesh
Fragimy __________________________ __ Moderate ____ __ Practicauy
Gloss
None
Tran§parency
SP0“
Elasticity ____ __
Fair _______ __~___
Permeability 1__
D
.
Fair (under
. .
1S rntegmmnume (gas t new i Ce)
20
v. '
mmu t es --___
10 screen and the retained material discarded (21%).
Home
lustre_
Sen.“Fairly good.
None detectei
a7
then used for compression encapsulating on /16 1nch
.
15 tablet cores, using
extra deep. cup 1/2 inch die and
punches.
.
.
. .
mm ut 65 .
These operations were carried out at a relative humidity
‘
l Permeability tested by moisture pickup of core determined by weight
v
O
of 40% and .a' temperature of 25
increase after 24 hours exposure at 94% relative humidity.
C' .
.
.
The resulting tablets showed no sticking to the die or
EMIMPLE6
_
From
the remaining material (approximately
79%) 6% of the
.
?nes (over 60 mesh) were discarded.
This now free-?owing . granular coating
material
was
.
7
.
Moderate
the punches.
.
The characteristics of the coated tablet
20 were found to vary according to the pressure used in the
Sodlum cm‘boxymefhylcfllulose Coated Tablets
compression encapsulating step, and were considered ex
Eight hundred grams of sodium carboxymethylcellu-
cellent above 36,000 p.s.i.
10,000 p.s.i.
Film thickness _________________ ..
Fragi1ityofcoat__
Gloss ________ __
1 mm _________ ..
27,000 p.s.i.
46,000 p.s.i.
Over 60,000 p.s.i.
0.25 mm _______ __
0 10 mm. ________ __
Extremely thin,
_. High (poor)__... Low (good)____. None ____________ __ None.
Low (lustre)-__- Moderate__
High (true gloss)
g .
Transparency
Elasticity___
Low __________ _.
Low __________ __
Permeability.__._
Moderate
_
Fair ___________ _.
High.
._ Poor (over 2%).. Fair (about 1%).
Disintegration (gastricjuice)-._._
10min ________ __
> None detected.
18 min ________ __
lose between 40 and 60 mesh were used for coating tablet
35 min.
EXAMPLE 9
cores ‘of the same formula as in Example No. 5, and com
Polyacrylamide Coated Tablets
pressed with a No. 5 oval punch. The compression en- 35
capsulating was carried out using a special No. 6 oval
One thousand grams of polyacrylamide No. 100 were
sieved to remove all particles greater than No. 40 mesh.
The coated tablets produced showed no evidence of
Of the ?nes constituting 41%, 11% were removed and
sticking or lamination; their surface was hard with a ?lm~
800 grams of the-remaining material were mixed well
like appearance. The compression pressure used was 40 with-8 grams vof cetyl alcohol NF. as a plasticizer. Tablet
27,000 p.s.i., resulting in a coating ?lm thickness of 0.7
cores of 7/16'inch were compression-encapsulated with the
punch.
mm., of low gloss and high elasticity. Compression was
‘above mixture in '1/2 inch deep cup die punches.
carried out at a room temperature of 78° F. and relative
These operations were carried out at a relative humidity
humidity of 26%. The U.S.P. XVI disintegration time
45 of 30% and room temperature of 76° F.
(gastric) was 28 minutes.
The coated tablets produced showed no evidence of
EXAMPLE 7
sticking or capping. The coating ?lm characteristics at
Carboxymethylcellulose Coated Tablets
Carboxymethylcellulose (type 70-8), extra ?ne grind,
various compression pressures were considered very good
and are tabulated below:
18,000 p.s.i.
36,000 p.s.i.
45,000 p.s.i.
Over 68,000 p.s.i.
0.4 mm-_____
0.075 mm ____ __
Extremely thin.
Moderat
Fa1r.__..
Moderat
Transparency- _
Elasticity _____ __
_
_ . _ _ __
Permeability___. _______ -.
Disintegration:
_
Gastric juice. ______ _-
Intestine-L . .
__
_______ __
Faun".
one
High.
High.
_.
Good.
Fair (l%)___
None detected;
18m1n______
min____.__
25min.
12min.
minimum 60 mesh granules, was used as a coating material
on tablet cores ‘as described in Example No. 5. The op
Three-eighths inch tablet cores of this material were
also coated in % inch deep cup ‘die punches and the re
erations were carried out at a room temperature of 80° F .
sults were similar.
and relative humidity of 26%. The compression encap
sulation was carried out a pressure between 27,000 and
32,000 p.s.i.
EXAMPLE 1O
“Carbowax” Coated Tablets
One hundred and ?fty grams of “Carbowax 6000,”
The resulting tablets were coated with a hard, continu
micronized, were mixed thoroughly with 136 grams of
ous, very strong ?lm with high elasticity and of 0.6 mm.
thickness.
70 powdered Italian talc and 15 grams of titanium dioxide.
EXAMPLE 8
“P0lyox" Resin (WSR-SOJ) Coated Tablets
The mixture was passed through a No. 30 mesh screen
and then granulated through a No. 14 mesh screen with
aqueous alcohol (alcohol 75%, water 25%). The gran—
ulate was dried in an oven at 120° F. and then passed
through a No. 16 mesh screen. To the product, 1% of
One thousand grams of “Polyox” resin WSR-301 were
screened through a No. 16 mesh screen to remove the 75 magnesium stearate (Plymouth) (3 grams’), was added.
3,096,248
10
well with 100 grams of Italian talc and 10 grams of ti
Tablet cores of the formula in Example No. 2, were
compressed with an oval punch No. 5 and were compres~
sion-cncapsulated with the above coating material in a
special oval No. 6 punch. These operations were carried
tanium dioxide. The mixture was granulated with ether,
using a 20 mesh screen, and the product was placed in
an oven at 40° C. to evaporate the ether completely. One
gram of magnesium stearate was added and the mixture
was used to compression encapsulate 756 inch tablet cores,
out at a room temperature of 72° F. ‘and relative hu
midity of 27%. Compression pressure was between
using 1A2 inch special deep cup punches.
22,000 and 27,000 p.s.i.
The coated tablets produced exhibited a continuous
The coated tablets produced showed no evidence of
glossy ?lm-like coating, and were found to be satisfactory
capping, sticking or of lamination. The ?lm thickness
of the coating was 0.5 mm. and the coating possessed the 10 with compression pressures from 9,050 pounds to 45,000
pounds. The data obtained showed that the degree of
following characteristics:
core shrinkage was less than 4% . Cores used were made
of soft ‘aspirin compound (5 grain, 7A6 inch) prepared as
Fragility _______________________ __ None.
Gloss
High (excellent).
follows.
Transparency ___________________ __ Moderate.
15 5 gr. aspirin tablets, USP:
Parts
Actyl salicylic acid, USP ______________ __ 250.00
Elasticity ______ __‘__, _______________ _. Low.
Permeability ____________________ _- Low.
Corn starch _________________________ __
Potato starch"; _____________________ __
Disintegration (gastric juice) ______ _- 4 min.
18.75
6.25
EXAMPLE 11
275.00
20
The procedure ‘described in Example 10 above was fol
Mix thoroughly and compress only in relative humidity
lowed, but with the addition of a small quantity of tar
of less than 25% to a hardness of 3 to 4 kilograms as
trazine yellow No. 5, FD & C, to the aqueous alcohol
measured on the Monsanto Hardness Tester that tablets
granulating solution.
The compression encapsulated tablets produced were
will disintegrate in one minute.
25
The test results are tabulated below:
evenly colored and possessed a glossy surface texture.
The coating was found to be uniform and continuous, had
Coating: Carbopol 940 (Goodrich).
Core: Aspirin 5 gr. 716 inch.
a thickness of 0.55 mm. and otherwise possessed the same
U.S.P. disintegraCore
Test N0.
,
Core
weight,
Coating, weight]
mg.
thickness
Core
Est.
_
thickness, shrink- coating
before/
age,
pressure,
after, in. percent p.s.i.
Permeability
tion time
Coating
stnppabihty
_ ‘
Gastric‘ Enteric,
'
24 hr.—94=° RH.
48 hr.—64° RE.
H1111
'
350
360
60 rug/.012” (.3 mm.)__
55 nag/.008" (.2 mm.)__
174/174
178/178
None
None
13, 500
13, 500
Coat strips
leaving
55 min. _
25 min..
5
5
360
90 rug/.02" (.5 mm.)--
175/170
2.9
13, 500
got? in-
2 hrs____
10
Under 1% wt. inc. None.
App. 2% wt. inc--.
Do.
Not detected ____ __ Not detected.
ac .
characteristics as the samples made in Example No. 10,
although disintegration time was slightly longer, 4.5 min.
(gastric).
EXAMPLE 14
The procedure described in Example 13 was followed,
using “Carbopol 934” (Goodrich Chemical) in place of
“Carbopol 940.”
~
The compressed coated’ tablets produced were satis
factory up through compression pressures of 31,680 p.s.i.,
and similar in all respects to samples made in Example 13.
EXAMPLE 12
The procedure described in Example -10 was followed
except that half the quantity of “Carbowax 6000” was
EXAMPLE
used (75 grams), together with an equal quantity of
15
‘
'
“Carbowax compound 20- ” (75 grams). The coated 50 Coating: Polyvinyl alcohol, processed as in Example 3.
Cores: Aspirin 5 grain V16 inch 5 kg. Strong Cobb
tablets produced at various compression pressures showed
_' hardness.
, 1 f
the characteristics tabulated below:
18,000 psi.
45,000 p.s.i.
36,000 p.s.i.
63,000 p.s.l.
0.100 mm____ Extremely thin.
Elasticity.
_____________________ __
....
None.
High ______ -.
High.
Moderate__ _ None notice
Transparency ____________________________ __
- Permeability _______________ _.
Disintegration (gastric juice). _ _
None ______ ..
a
Fair ___________ __
Fair _______ ._
High (over 5%)
Fair (1%) __
25 min ________ _.
15 min ____ _.
EXAMPLE 13
Two hundred . grams ‘of “Carbopol 940” were mixed
Test No.
Coat each side, weight]
thickness
Punch: 1/2 inch extra deep cup.
The test results were as follows:
Core
Core
Est.
thickness, shrink- coating
before/
age pressure,1
after, in.
p.s.i.
"
375
200 111g./.059” (1.5 111111.)--- . 177/. 177
150 rug/.045” ____ __
385
120 mg./.035”__._
. 182/. 181+ Nil
None
27,000
do
22, 500
18, 000
360
100 rug/.030" __________ --
.172/. 172
18 000
None
Coat
U.S.P. disintegra-
strips
and
core
tion time
intact
Gastric
Enteric,
min.
380
180]. 180
None.
11 min.
'
Core
weight,
mg.
e.
High.
.
Permeability
24 hr;-94° RH.
48 hr.—64° R.H.
12
11
10.5 kg. hardness (Strong Cobb). Samples A, B,
C, D, E.
EXAMPLE 16
Coating: Cellulose Acetate-phthalate, processed as in
Example 4.
Cores: Thiourea 8 gr. 7/56 inch med. hard 7 kg. (Strong 5
(b) Thiourea 7/16 inch 8 gr. med. hard 8 kg. (8.0.).
Samples F, G.
(c) Aspirin compound A.P.C. 7A6 inch 5 gr. soft
Cobb).
5 kg. Samples H, I, J.
Punch: 1/2 inch extra deep cup.
The test results were as follows:
U.S.P. disintegra-
Core
Sample
Weight,
Coat each side,
No.
mg.
weight/thickness
Core
Core
before/after,
in.
age
Est.
thickness, shrink-
Coat
eating
Permeability
tion time
strips
pressure, and core
p.s.i.
intact
Gastric,
Enteric,
min.
min.
24 hr.—94° RH.
48 11r.—64° R.H.
510
150 lug/.045” (.11 mm.)
17
15
500
500
150 mg./.040” (30x)
150 mg./.043” (30X)__
17
16 _____d0 ___________ __
__
510
200 ling/057” (40x)._
22
20
520
525
180 ling/055” (40X)__
150 mg./.038” (30x)__
20
18
19 ____.d0 ______ __
12 _
540
375
385
150 mg./.039” (30x)__
200 mg./. 064” (40x)._
200 mg./.061” (40X)__
15
20
24
13 _
18 _
23 _
370
200 lug/.064” (60X) ____ __
25
24
0 ‘
Test not suitable“ Soft coat.
.
1App.
Do.
Test not suitable. Soft OK.
___
_
Do.
Soft.
_
D0.
_ Soft coat.
_ Soft OK.
_____do ___________ __
OK.
.
The test results were as follows:
Test No.
Gore
weight,
Gore
Est.
thickness, Gore coating
before]
shrink- pressure,
Goat each side, weight]
thickness
‘mg.
A ______ ._
after, in.
. 174/.17-1
age
Coat
strips
and
p.s.i.
U.S.P. disintegration Time
core
'
Permeability
Emma
intact
Gastric
Yes-__-_
min ’
24 biz-94° RH.
48 him-64° RH.
None.
525
150 mg./.043” __________ __
None .
27, 000
Overl hr__
40
None _________ __
540
120 rug/04” (1 mm).
_
.176/.175+ Ni1____
127,000
Yes"-.. Over1hr__
22
None _________ __ None.
530
100 mg./.028” __________ __
. 172/.171-l- Nil____
22, 500
Yes-.-“ 50 min____
15
Under 1% _____ __ Traces.
1 Mod
EXAMPLE 17
Coating: Modi?ed starch.
EXAMPLE 19‘
Preparation, wet granulate
Coating: Carboxymethyl-cellulose (type 708). Prepara~
with 1% FDC Red No. 1 using 95% alcohol through
(a) 30 mesh; (b) 60 mesh; (c) 200 mesh.
Cores: Ferrous sulfate compound 7A6 inch 8 grain, med.
tion, slug then grind to 40 mesh.
Core: “Ferrous sulfate compound 7/16 inch” 8 grain me
dium hardness (7 kg.).
hardness (7 kg).
Test results were as follows:
Test
Core
weight,
Coat each side,
No.
mg.
weight/thickness
Core
thickness,
Core
ShI'lJlk-
Est.
Coating
pres-
before/
age
sure,1
and core
p.s.i.
intact
after, in.
Coat
U.S.P.
Permeability
strip- disintegration time
pability
Gastric,
Enteric,
min.
min.
24 Ina-94° RH.
48 hr.~64° R.'H.
520
540
250 mg./.08” (2 mm.)___200 mg./.07”__
.170/.169+
.170/.169+
22,000
31, 700
40
30
30 None __________ __ None.
25 ____-d0___
_
0.
550
150 mg./.06”-
.176/.176
31, 700
25
15
Under 1%
None found.
1 Abt.
The test results were as follows:
Test No.
Core
weight,
_
_
Core
Coat each slde, weight]
thickness
thickness
before]
mg_
after, in.
Est.
Core coating
shrink- pressure,
age
p.s.i.
Coat
strippability
530
200 0rang/.067” (.17 mm.)
B ______ -_
550
200 nag/.065” (60x) ______ __
O________
570
150 mg./.049" (60x)-
D ______ __
530
Permeability
tion time
and core
into
A ______ __
U. 8.1’. disintegra7
Gastric
Enteric
24 him-94° R.H.
48 hr.—64° RH.
. 169/. 163+ Nil_.-_
18, 000
. 171/.171
None _
27, 000
Yes_ ____
30 min __ ___._do ________ __
Do.
-
.177/. 177
-._do-_
36, 000
Yes_____ 1 hour___ 20 min __ __-__do ________ __
Do.
150 mg./.05” (60x) _______ __
. 171/.171
_._do__
31, 700
Yes_____
Do.
X
.
Yes_____ 110 mi_n_ 40 min __ None _________ __ None.
.
90 min __
45 min __
18 min __
Under 1% _____ __
EXAMPLE 20
EXAMPLE 18
~ 70 Coating:
Coating: “Carbowax 6000” microm'zed.
in Example No.10.
Preparation as
Punches: 1/2 inch special deep.
Cores:
(a) Ammonium chloride-bromide 7A6 inch 71/2 grns.
Polyacrylamide grade 100 resin, plasticized as fol
lows:
In testA polyoxyethylene stearate and cetyl al
cohol. In tests B, C and D polyoxyethylene
stearate alone.
3,096,248
13
Test
No.
Core
Weight,
mg.
lubricant as needed.
Est.
Core
Core coating
Coat each side,
thickness, shrink- presweight/thickness before/after,
age
sure,1
in.
p.s.i.
Coat
strippability
and core
intact
.170/.170
14
phthalate while tumbling in a coating pan and dust with
Cores: Iron sulfate compound. Aver. size 8 gr. 7/16 inch
medium hardness.
U. S. P.
disintegration time
Gastric
Enteric
Permeability
24 hr.—
94° RH.
48 hr.
64° 13.11.
A ______ __
520
2012 rug/.074"
None__
18,000
Yes.____ No over 2 hrs.. Yes 15 min__ Not detected--- Not detected.
B ______ __
520
200 mg./.070”____
.171—/.170+ ___do___
18,000
1.8 In
Yes.--" No over 2 hrs__ Yes 20 min__ _-___do _________ __
Do.
0 ______ __
555
150 rug/.054’ ____
.176-|-/.177
___do___
18, 000
Yes“---
No _____________ __do _________ __
Do.
D ______ __
545
100 mg./.030"____
.17l—/.l70+ “.110---
18, 000
Yes_____ Yes 25 min
No
Do.
Yes 1 hour____
_____do
1 App.
EXAMPLE ‘21
EXAMPLE 24
Compression Encapsulation of Coated Pellets
Compression Encapsulation "Wind0w” Coatings
Coating: Opaque portion, “Carbowax 6000” micronized 20 The process of Example 23 was used except that coated
pellets with varying disintegration times were used as the
colored with FDC Red No. 2 prepared as in Example
core material.
No. 10 or sodium carboxymethyl cellulose prepared as
in Example No. 6. Transparent or translucent win
The coated pellets are made as follows:
dow: Polyvinyl alcohol prepared as in Example No. 3
Per tablet, mg.
or uncolored “Carbowax 6000” as in Example No. 10.
25 d-Amphetamine sulfate _______________________ __ l0
Core: Ammonium chloride 7/16 inch, 8 grain.
Stearic acid
_ 15
Punch: 1/2 inch extra deep cup.
25
The table cores were compression encapsulated on a
“Manesty DryCota” machine ‘by feeding a 200 mg. bottom
Melt the stearic acid and disperse the d-amphetamine sul
?ll of opaque colored Carbowax or carboxymethyl ce1— 30 'fate therein. While pasty force through a No. 30 screen.
l-ulose, superimposing the core and then feeding the 120
Roll into uniform free ?owing spheres in a pan.
mg. top ?ll of. uncolored polyvinyl alcohol or “Carbo
25 mg. ‘were fed into the die between two 120 mg.
Wax 6000,” followed by compression at 27,000 p.s.i.
charges of coating granulation.
The product was a uniformly colored high gloss coat
I claim:
on the tablets which was fused to and framed a transparent 35
A method of making ‘an oral dosage tablet form which
colorless uniformly shaped window across one entire face
comprises: compressing ‘a ?rst ?nely-divided medicinal
of each tablet. The coat was uniform in thickness and
ingredient-containing portion to form a compressed tablet
hermetically sealed the core but could be stripped from
core having smaller dimensions than the desired ?nished
the core without damaging the latter.
'
EXAMPLE 22
tablet form; positioning the preformed compressed tablet
40 core in contact with a coating material containing a second
?nely'divided medicinal ingredient portion; compressing
Compression Encapsulation of Powders
said second portion, at a pressure between about 1000 and
about 75,000 pounds per square inch, about said com
Coating material: “Carbowax 6000” prepared as in Ex
pressed tablet core until it fuses to form a continuous in
ample No. 10.
45 tegral ?lm coating which hermetically seals the core.
Punch: 1/2 inch extra deep cup and regular types.
Core: consists of free ?owing powders of which the fol
References Cited in the ?le of this patent
lowing is an example: Vitamin A Orystallets, mixed
UNITED STATES PATENTS
gently With 1% magnesium stearate.
1,087,843
Smith ________________ __ Feb. 17, 1914
Procedure: 120 mg. of “Carbowax” coating granula
1,289,873
1,502,006
1,593,907
tion was bottom ?lled into the die of a Manesty DryCota
machine. Next 25 mg. of the lubricated Vitamin A Crys
tallets are fed onto the center of the bottom till. 120 mg.
of “Carbowax” are now top ?lled and a pressure of ap
proximately 36,000 to 45,000 p.s.i. is applied (high).
55
The product was a highly glossy, smooth, uniform, hard,
very durable and resistant tablet bearing the crystallets
enmeshed in the center as a “core.”
This example was successfully repeated with car-boxy
methyl cellulose, polyacrylamide, polyvinyl alcohol, modi
60
?ed ‘starch, Canbopol and other plastics.
EXAMPLE 23
Compression Encapsulation of Granules
The process of Example 22 was used with a phenobar 65
bital granulation and “Carbowax 6000” micronized as
coating material prepared in Example No. 10. The re
quisite dose of prepared granulation was thereby enmeshed
within the center of the tablets to ‘form a “core.”
70
The phenobarbital granulation is made as follows:
Phenobarbital, 50 grams. Prepare a dough with soya
flour and water; knead; mix in the phenobarbital to yield
a concentration of 1%; grain medicament per 50 mg. of dry
granulation. Granulate through a No. 30 mesh and dry.
Spray the granulation with shellac or cellulose acetate 76
Murakami ____________ __ Dec. 31, 1918
Alvord _______________ __ July 22, 1924
Madan _______________ __ July 27, 1926
2,155,444
Pittenger et a1. _____ __‘___ Apr. 25, 1939
2,155,445
2,219,578
Pittenger et al _________ __ Apr. 25, 1939
Pittenger et‘al __________ __ Oct. 29, 1940
2,540,253
2,656,298
2,685,517
2,700,938
2,757,124
Gakenheimer __________ __ Feb. 6,
Loewe ________________ __ Oct. 20‘,
Dunmire ______________ __ Aug. 3,
Wolif et al _____________ __ Feb. 1,
Wolif ________________ __ July 31,
195.1
1953
1954
1955
1956
2,784,100
2,798,838
2,809,917
2,849,965
2,857,313
2,879,724
2,887,436
2,887,438
2,888,382
2,953,497
2,957,804
2,987,445
2,991,226
Endicott et al. _________ __ Mar. 5,
Robinson et a1 __________ __ July 9,
,Hermelin _____________ __ Oct. 15,
Stott _________________ __ Sept. 2,
Cooper et al ___________ __ Oct. 21,
Wyatt et val ____________ __ Mar. 31,
Klioze et al ___________ __ May 19,
Cooper et al ___________ __ May 19,
Pleyte et a1 ____________ __ May 26,
Press ________________ __ Sept. 20,
Shuyler ______________ __ Oct. 25,
Levesque ______________ __ June 6,
Millar et a1 _____________ __ July 4,
1957
1957
1957
1958
1958
1959
1959
1959
1959
1960
1960
1961
1961
(Other references on following page)
3,096,248
15
2,996,431
3,019,169
3,039,933
3,048,526
Barry _______________ __ Aug. 15,
Klumpp et al ___________ __ Jan. 30,
Goldman ____________ __ June 19,
Boswell _______________ __ Aug. 7,
1961
1962
1962
1962
OTHER REFERENCES
Mitchell: “Coating Tablets by Compression,” Mfg.
Chem. 26(3) March 1955, pp. 107-111.
Robinson (II): “Coating Tablets by Compression,” in
Mfg. Chem., 26(4), April 1955, pp‘. 164-5.
The Pharmaceutical J. (Br.) I, “The Coating of Tablets
Strickland et al.: I. A. Ph. A., sci. ed.,.vol. 45, No. 7,
July 1956, pp. 482-486.
Cooper et al. (III): “Tablet Coating Wet and Dry,”
Drug and Cosmetic Industry, 79(2), pp. 188, 277-280,
August 1956.
Windheuser et al.: I. A. Ph. A., sci. ed., vol. 95, No. 8,
August 1956, pp. 542-545.
~ Chapman et. al.: “Physiological Availability of Drugs in
Tablets,” Canad. Med. Assn. 1., vol. 76, pp. 102-106,
January 15, 1957.
Dragstedt: “Oral Medication with Preparations for Pro
longed Action,” I.A.M.A., vol. 168, No. 12, pp. 1652
1655, November 22, 1958.
aments with Predictable Retarded Effect,” (in Italian) in
The Pharm. 1.: vol. 181, No. 4960, pp 398-9, Novem
Bolletino Chimico Farmaceutico (Milan), 99, pp. 485 15 ber 22, 1958.
‘Lazarus et al.: “Oral Prolonged Action Medicaments:
493, 1955.
Tsevdos: “Press-Coated and Multi-Layered Tablets,”
Their Pharmaceutical Control and Therapeutic Aspects,”
Drug and Cosmetic Industry, 78(1), pp. 38-40, 113-4,
J. of Pharm. & Pharmacol, vol. 11, No. 5, pp. 257-290
January 1956.
'
(pp. 266-271, 277-279, and 285-288 are especially perti
Cooper et a1. (11): “Tablet Coating Wet and Dry,” 20 nent to in vitro tablet availability of drugs), May 1959.
Drug and Cosmetic Industry 79(1), pp. 38-9, 108, 118,
Campbell et al.: “OralProlonged Action Medication,”
12041, 124, July 1956.
Practitioner, vol. 183, pp. 758-765, December 1959.
by Compression,” vol. 174, May 7, 1955, pp. 362-3.
Miccicche: “Preparation of Orally Administered Medic
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