>1 ited States atent

ll
No US. Gerald CONTROLLED Jersey & 586,623, 1966. and Drawing. Cl. (30., Wayne
)P. This 424-49 lint. Polli, Inc, Oct. Continuation-impart application M. Cl.
14, Rahway, Norristown, Grim, A6137 RELEASE 1966, 3/00, 3,538,214
Cilalfont, Apr. and N.J., 3/10; Clyde 22, MEDICINAL S
er. a P
an, o f 1969, No.
corporation A61k applications E. assignors 597,861, S hoop, S er. 9 /00
No. TABLETS Lansrlalc, to 3 Nov. of Ser. 818,395 Claims Merck New No. 30,
10
ABSTRACT OF THE DISCLOSURE A tablet c ore containing a
medicinal a gent is coated with a
?lm made up of a W ater-insoluble p lastic and p ar
15 ticles of a material which is chosen for its selective solu bility or digestibility
in gastro or intestinal ?uids. The removal of the latter material by the intended
gastro or intestinal through which ?uids results the medicinal in a membranous agent
slowly or leaches dialytic ?lm out.
20
RELATED CASES This is a continuation-in-part of U.S. patent application
25 now Ser. application abandoned.
No. 586,623, Ser. No. ?led 597,861 Oct. 14, ?led 1966, Nov. and 30, US. 1966
patent both
PRIOR ART and See This particularly related invention cases.
to relates tablet to preparations pharmaceutical which c ompositions upon in gestion
are capable of controlling the release of the con tained medicine or drug over
extended periods of time. pharmaceutical This invention also tablets.
involves a process for making these
This controlled release of a medicine or drug is im provide tablet with portant
thereby a at medicine for the eliminates frequent several body requires intervals.
with the reasons. need medication a fairly The In for the treatment constant
swallowing ?rst over place a high long of an any it blood time serves ordinary disease
titre and to
ise the e
of w liminated medicine. quickly If the medicine from the is body metabolized
it w ould be o r neces other
of sary tain at considerably this the to i
nvention swallow desired less blood an makes
frequent ordinary level. it possible The i ntervals.
tablet controlled to quite swallow often release the to main tablet tablet
Some medicines have such a narrow t
herapeutic ratio therapeutic an that ordinary
slightly effect, tablet moreof is w ill taken, it cause than the adverse is rapid
necessary release t oxic of symptoms. to its achieve medical If a
50
content may cause such a high blood level that undesir able side reactions will occur.
The controlled release tablet of toxic amount this symptoms.
invention of medicine prevents and thereby the sudden prevents release the of onset a
large of
tary Some m
ucosa medicines and their a re rapid inherently release irritating
from the t o ordinary the alimen tab the let may medicine. cause The damage
tablet a t of the the present loci o f invention concentrations prevents of
the build-up o
f such a troublesome c
oncentration. not trol Tablets been the release
entirely have b een of s atisfactory. t he prepared contained in Some the medicine past
of them which but have they will have been con
too expensive to make either because of the expensive ingredients or the complicated
apparatus or process to make them or they have been too large because of the necessary
tablets have additives been unsatisfactory to obtain the because delayed they release.
have lacked Other
70 a uniform release time although made in
exactly the

3,538,214. Patented Nov. 3, 1970

2 same way. The tablets of the present invention employ in
expensive tableting material and achieve an exceptionally uniform release of
the medicine. These tablets can be made of relatively small size. Furthermore
the total elapsed drug release time can be varied and established by the
practice of this invention.
Another important consideration is that the material which causes the controlled
drug release must be physio logically acceptable. It must have no or a negligible
toxic effect upon the person. It must be completely eliminated so that even during
prolonged use it does not accumulate in a persons tissues.
In accordance with the invention, a tablet containing the drug is made in a
conventional manner and to it is applied a coating composition which will form a mem
branous ?lm through which the drug slowly will be leached out. This slow leaching
action will occur because gastro-intestinal ?uids can but slowly pass through the
coating ?lm to reach the drug in the tablet core and the drug which then becomes
dissolved in the gastro-intestinal ?uids can but slowly pass out through the coating
?lm and into the stomach and/or intestines. As the ?lm remains substantially intact
throughout the time that all the drug is being leached out the escape of the drug is
prolonged and the rate of drug administration remains about uni form.
The coating composition is made up of a plastic hav ing a low water vapor
permeability such as cellulose ace tate, a ?lm modifying agent hereinafter to be
described, a solvent such as acetone and, if desired, a plasticizer and/ or a coloring
material. The plastic should be insoluble in gastro-intestinal ?uids. Suitable
plastics in addition to cellulose acetate are ethylcellulose, cellulose nitrate, low
water soluble polyvinyl alcohols and the other plastic pharmaceutical coatings. '
The ?lm modifying agent mentioned above should beamaterialwhichischosensothat
it will be selectively but readily soluble or digestible in either the stomach ?uids
or in the intestinal ?uids so that when it is partially or fully removed from the
coating ?lm the plastic which remains is of a membranous or dialyticnature.Ifitis
intended that the medicament be released in the stomach, the ?lm modifyingagentmust
be one that will beremovedbytheacidconditionsofthestomach.Ontheotherhand,
if it is intended that the medicament be released in the intestines (i.e. the tablet
is to pass through the stomach substantially intact). The ?lm modifying agentmustbe
one that will be removed by the alkaline conditions of the intestines.
For removal in the stomach, suitable ?lm modifying agents are calcium
carbonate, calcium phosphates (mono, di, tri), magnesium citrate, magnesium
oxide, sodium bi carbonate, potassium bicarbonate, tetraethanolamine, lac
tose, polyvinyl pyrrolidone and solid polyethylene gly cols; they are
hereinafter referred to as Table 1 agents. Satisfactory results have been
obtained when from about 0.1 to about 30 parts by weight of the plastic
substance has been combined with one part by weight of modifying agent. Most
satisfactory results have been obtained when from 1 part to 3 parts by weight
of the plastic substances have been combined with one part of the modifying
agent. For removal in the intestines, suitable ?lm modifying agents are
benzoic acid, propionic acid, sorbic acid, sali cyclic acid and cellulose
acetate phthalate; they are here inafter referred to as Table 2 agents. These
agents are used in the same relative amounts set forth above for the other ?lm
modifying agents.
In addition to acetone, conventionalsolvents,suchasmethanol,ethanoland
chloroform may be used. The plasticizer may be the conventional ones such as
diethyl phthalate, caster oil, propyelne glycol or glycerol, added

3,538,214 to the ?lm forming composition 3
to make it less fragile if this The is desired.
?lm forming composition i s applied as a coating to medicinal being the dependent
tablet agent cores, upon of t he the the tablet. amount desired In and rate practice,
coating of release it has thickness of been the
found that s
atisfactory results may be obtained when an average pharmaceutical tablet
is coated w ith from about tion, 5 to about although 100 mg. the amounts of the novel
of composition the composition of this involved inven
ployed the may To practitioner be apply and varied the this in amount hereof.
ccordance of composition, control with of the conventional release medicament
coating a
desired t ablet em
by
coating practices are used. This may use a tumbling bar rel into which the coating
composition is sprayed or it may coating use composition the ?uidized is column
sprayed technique upwardly in through which the the bed. inducing coating type
Heretofore, coating resists passage to it pharmaceutical disintegration has through
been the the practice stomach. by tablets stomach to to This apply insure ?uids
enteric-type an nonlesion
enteric
but is vention fully entering disintegrated obviates and going the or through
necessity dissolved the for by intestine. the any intestinal such The
enteric-type present ?uids in
on
This ing c
oating ?lm i s u pon because modifying either this the agent novel stomach
membrane ? lm resists o r t he of disintegration intestine this invention. dissolv
tomach ?uids and prevents or delays release of the medic inal agent in the stomach
by s
according to the selected intent. It allows slow release of the medicinal agent from
the tablet into either the stomach or the intestines depending on the chosen intent,
and does not permit a rapid release. This is because, as stated above, the continuous
dialytic ?lm of this invention serves as a membrane to selectively let gastro or
intestinal ?uids through to reach the tablet core to dissolve the medicinal agent
contained therein and to let the dissolved medicinal agent slowly leach out ward
through this continuous dialytic ?lm and into the gastro or intestinal tract. The
dialytic ?lm not only re stricts the access of the gastro-intestinal ?uids to the
medicinal agent of the matrix core, but it moreover serves to position or space the
medicinal agent itself away from the gastro-intestinal mucosa so that a large
concentration thereof is not permitted to reach a compartively small area of the
gastro-intestinal mucosa.
In the practice of this invention, it is possible to pro vide a ?nal overcoating to
improve the appearance, taste or stability of the tablet. This may contain sugar, or a
?lm former in combination with dyes or pigments, or even other medicaments. This
latter medicament may for example, be one which is to be administered with the drug in
the tablet core but which should not be in con tact with each other in the complete
tablet. This may be because of the incompatibility of the two or because it is rapidly
desired The following that and the that medicine the examples drug in in the are the
 outer illustrative core coating be released of be composi released slowly.
tions of the present invention and are not to be construed in having as
tablets in the limiting. the intestines having stomach. coatings Examples
coatings after which Examples passing 1 will which to 11 become 12 intact will
inclusive to 21 become through a inclusive membranous described membranous the
stomach. describe tablets ?lm
EXAMPLE 1 Ingredients for the tablet core: Per tablet, mg. Potassium chloride
(granular) ___________ __ 572 Glyoxalated gelatin _____________________ __ 572 Stearic
acid ___________________________ __ 6 gelatin ,The amounts set forth of above
potassium are intimately chloride mixed. and glyoxalated A portion 18 removed and
mixed with the stearic acid. This is then
4 passed remaining through potassium a n
umber chloride 12 glyoxalated sieve
and gelatin added m ixture. to the
The resultant mixture is then slugged, and the slugs are crushed and fed through a
Fitzmill ?tted with a 2A screen, tablets having and the the resulting desired granules
weight are of compressed potassium chloride. to form
Ingredients for the membranous coating: Percent
Nitrocellulose __________________________ __ 3.0 Calcium c
arbonate
______________________ _ _ 1.0 10
Castor oil _____________________________ __ 1.0 Propylene glycol
________________________ __ 1.0 Acetone to 100.0%. The nitrocellulose is ?rst wetted
with a small amount of cellulose acetone, is dispersed. and the mixture The calcium
agitated carbonate until all of is the dispersed nitro
20
persion glycol nozzle reduced in product glycol some in dispersion clogging
the through signi?cantly.
of the the calcium remaining acetone, in an is the homogenizer added carbonate,
acetone. subsequent and with the castor To caster stirring. or spraying the mill, oil
oil nitrocellulose the By and and operation incidence passing propylene propylene
dis
the of is
25
workers continuous The ?lm in the spraying c
oating art. Eight is operation applied (8)
milligrams to Well the known t ablet of dry cores to coating skilled by a
are applied to each matrix tablet.
EXAMPLE 2
30
Other examples of the invention involve the substitution for the potassium chloride in
Example 1 of other drugs which require a prolonged administration. Potassium chlo ride
is one example of an irritating drug which should slowly be released and other
examples such as aspirin 35
are apparent. An example ofadrugwhichshouldbereleasedoveraprolongedperiodto
maintain a blood level foranextendedperiodisanantihistaminesuchasneoantergan.
Other drugs, such as hypotensive, tran
40
quilizers, Furthermore, etc., are instead obvious.
of the tablet forming materials
methods. named other conventional in Example materials 1, the core and tablets be
shaped may be by made known of
EXAMPLE 3 Following the procedure set forth in Example 1 but substituting
an equivalent a
mount of ethyl cellulose or cellulose acetate for the nitro cellulose,
equivalent re s ults are obtained.
EXAMPLE 4
prepared Tablets as containing described in 572 Example mg. potassium 1.
chloride are
A ?lm forming composition of the formula:
Nitrocellulose ____________________________ __ 4.0% Polyethylene glycol 400
____________________ __ 1.2% Acetone q.s., 100.0%. is prepared in accordance with the
general procedures set 60
forth interchanged i n Example ingredients 1, with hereof. the substitution The
resultant of t he ?lm different coat is tion applied as in Example to the
tablets 1. F ive by (5) a continuous milligrams spraying of dry coating
opera
are applied to each matrix tablet. 65
EXAMPLE 5 pared Tablets as described containing in Example 572 mg.
potassium 1.
chloride are pre
70
A coating solution of the formula:
Percent Nitrocellulose ______________________________ __ 3.0 Castor oil
__________________________________ __ 1.0 Propylene glycol
____________________________ __ 1.0 75
Lactose Acetone q.s., ___________________________________ 100.0%.
__ 1.0

3,538,214
is prepared according to the method described in Example applied spraying 1.
This to solution operation. each matrix is applied Fifteen tablet.
to (15) the milligrams tablets by of a coating continuous are
EXAMPLE 6 prepared Tablets A coating as containing described
composition in 572 Example of the mg. formula:
potassium 1.
chloride are
Percent Nitrocellulose ______________________________ __ 3.0 Castor oil
_________________________________ __ 1.0 Propylene glycol ___________________________
__ 1.0 Magnesium oxide ___________________________ __ 1.0 Acetone q.s., 100.0% . is 5,
prepared except that according magnesium to the oxide method is substituted described
in for Example lactose. applied This spraying solution to operation. each is matrix
applied Twenty tablet.
to the milligrams tablets by of a coating continuous are
EXAMPLE 7 Tablets containing 572 mg. potassium chloride are pre pared as
described in Example 1.
- A coating solution of the formula:
Percent Nitrocellulose ______________________________ __ 1.5 Castor oil
_________________________________ __ 0.5 Propylene glycol ____________________________
__ 0.5 Magnesium oxide ___________________________ __ 0.5 Acetone q.s., 100.0% . is
prepared according to the method described in Ex tinuous ample 5. spraying This
solution operation. is applied Twenty to the (20) tablets milligrams by a con of
coating are applied to each tablet core.
EXAMPLE 8
Ingredients for the tablet core: Per tablet, mg. Potassium c hloride (granular)
____________ __ 572 Stearic acid ___________________________ __ 3 The mixture is
mixed, granulated and tableted as in conventional any of the preceding practices
examples.
and the tablet core is coated as in
EXAMPLE 9 Other examples of the invention involve substitution of one or
more of the Table 1 agents mentioned above, for the calcium carbonate or magnesium
oxide in the above examples. '
EXAMPLE 10
' To any one of the preceding coated tablets is added as without is an the
overcoating, following:
a dye or a a pigment. conventional A representative sugar coating overcoating with or
coating Place pan t
he and tablets apply which 2 charges have of been a gelatin-acacia
undercoated solu i n a
nd dust with kaolin. Then apply 7 charges of 17 lb. cut contains syrup titanium
tion a
and then dioxide. apply 14 Over charges this is of applied white syrup 12 charges
which
of dried, glaze 17 trayed lb. after cut up which syrup. and they again The are
air tablets dried.
glazed are with trayed pharmaceutical up and air
EXAMPLE 1 1 tionally The overcoating includes a medicament. of E
xample For 10
example, is applied with b ut potas addi
sium could chloride contain in hydrochlorothiazide the internal matrix in core, the
the amount overcoating of 25 mg. or 50 mg. per tablet. The hydrochlorothiazide is
mixed and milled with cut syrup and it is applied onto the tablets charges which
containing have the been titanium undercoated, dioxide.
just prior to the
6 plemented pharmaceutically The The titanium tablets with
ioxide any acceptable.
prepared d
n c
other i an accordance be pigment replaced with or with dye the or teachings
which b e s up
is
of gastric Example ?uid a
nd 1 were simulated tested intestinal for effectiveness baths
and in t he s imulated results obtained are tabulated below in Table I.
TABLE I
10
Test. -
Percent time, drug hrs.
released
?uid 1 1 2 3
so. 0 1663 1 A=Simulated gastric ?uid; B=Sin1u1ated
intestinal ?uid.
Tablets prepared according to Example 4 tested in the
20
same manner gave the following data:
TABLE II
Test -~_ Percent time, drug hrs.
released
?uid 1 1 2 3 4 25
Wt. of coating, mg.:
5 _________________________________ __ A
25.0 ________________ _ 5
_________________________________ __ B 9 0.0 ________________ __
1 A=Simulated gastric ?uid; B=Simulated intestinal ?uid. tablets The following having
coatings Examples which 12 will to 21 pass inclusive intact illustrate through the
testines.
stomach and become a membranous ?lm in the in
EXAMPLE 12
35
Ingredients Potassium for the chloride tablet (granular) core: Per tablet, mg.
____________ __. 572 Glyoxalated gelatin ______________________ __ 572 Stearic acid
____ 6 gelatin The amounts set forth of above potassium are intimately chloride mixed.
and glyoxalated A portion is removed and mixed with the stearic acid. This is then
maining passed through potassium a number chloride 12 glyoxalated sieve and added
gelatin to mixture. the re
The resultant mixture is then slugged, and the slugs are 45
having crushed and the the and resulting desired fed through granules weight a
Fitzmill of are potassium compressed litted chloride.
with to a form 2A screen, tablets
50
Ingredients I for the membranous coating Amount per Percent tablet, mg.
Cellulose acetate- _ __________________ _ _ 2. 0 6. 67 Cellulose acetate phthalate . .
Diethyl phthalate _____ . _ Acetone to- _ _________________ __
The cellulose acetate is ?rst wetted with a small amount cellulose of acetone, acetate
and the is mixture dispersed. agitated The cellulose until all acetate of the
60
phthalate l ose d iethyl a cetate phthalate is dispersion dispersed in the the in
remaining s ome d iethyl o f phthalate acetone. the acetone, To solution the and
cellu and t he
the stirring. c
ellulose By passing acetate the phthalate product solution through are
a homogenizer a dded with
65

or quent m
ill, spraying the incidence operation of is nozzle reduced
clogging s igni?cantly.
in the subse~
70
continuous workers coating The ?lm are in t
he applied spraying coating art.
Twenty to is operation each applied seven m atrix to well (27) the tablet.
known tablet milligrams cores to EXAMPLE 13
of skilled by dry a
for Other t he potassium examples of chloride the invention in Example involve
12 the of o ther substitution drugs
75
chloride which require is o
ne a example prolonged of administration. an
irritating drug Potassium w hich

3,538,214
should slowly be released and other examples such as aspirin are apparent. An example
of a drug which should be released over a prolonged period to maintain a blood level
neoantergan. for an extended Other durgs, period such is an as antihistamine
hypotensive, tranquil such as
other izers, named Furthermore, etc. conventional in are Example obvious.
instead materials 12, the of core the and tablet tablets be shaped forming may
be by materials made known of
methods.
EXAMPLE 14 substituting Following an the equivalent procedure a mount set f
orth of in
ethyl Example cellulose 12 but for the cellulose acetate, equivalent results are
obtained.
EXAMPLE 15 Tablets containing 572 mg. p
otassium chloride are prepared A
?lm as forming described composition in Example of t he 12.
formula:
Percent
Nitrocellulose _______ ___i _____________________ __ 1.5 Castor oil
__________________________________ __ 0.5 Propylene glycol _____ a
_____________________ __ 0.5 Benzoic acid _______________________________ __ 0.5
Acetone q.s., 100.0%. is prepared in accordance with the general procedures set ferent
forth interchanged in Example ingredients 12, with the hereof. substitution The
resultant of the ?lm
dif
coat operation is a
pplied as in to Example the tablets 12. Thirty-three by a
continuous milligrams spraying of dry coating are applied to each matrix tablet.
6 Tablets containing 572 mg. potassium chloride are pre pared A
EXAMPLE 1
coating as described s olution in of Example the formula:
12.
Percent
Nitrocellulose _____ ___. ______________________ .. 3.0 Castor oil
______________________________ __,____ 1.0 Propylene glycol ______ __.
____________________ __ 1.0 Benzoic acid _____________________________ __.\_... 1.0
Acetone q.s., 100.0% . is prepared according to the method described in Ex ample
continuous 12. This spraying solution operation. is applied Twenty-seven to the
tablets (27) milli by a
grams of coating are applied to each matrix tablet.
7 Tablets containing 572 m
EXAMPLE 1 g. p otassium chloride are pre pared A
coating as d
escribed c omposition in Example of t he 1 2.
formula:
Percent
Nitrocellulose _______ _. __________ _
_. _ _________ __ 3.0 Castor oil
__________________________________ __ 1 .0 P ropylene glycol _____ .___l
____________________ __ 1.0 Cellulose acetate phthalate ______ __\ ____________ __'l.0
Acetone q.s., 100.0%. is ample prepared 16, except according that cellulose to the
method acetate described phthalate in is sub Ex
tablets stituted by for a benzoic continuous acid. spraying This solution
operation. is applied Twenty to milli
the
grams of coating are applied to each matrix tablet.
EXAMPLE 1 8 prepared A Tablets coating as containing described solution
of in 572 the Example mg. formula:
potassium 12.
chloride are
Percent
Nitrocellulose ________ __, ______________________ __ 1.5 Castor oil
___________________________________ __ 0.5 Propylene glycol ______ __.
____________________ __ 0.5 Cellulose acetate phthalate ___________________ __ 0.5
Acetone q.s., 100.0%.
is prepared according to the 8 method described in Ex-v .
ample continuous 16. This s
praying solution operation. is applied Twenty to
the milligrams tablets by o f a
coating are applied to each tablet core.
5 EXAMPLE 19 _
Ingredients for the tablet c ore: Per tablet, mg. Potassium chloride (granular)
__________ __.__ 572 Stearic acid ___________________________ __ 3 10 This mixture is
mixed, granulated and tableted as in
conventional in any of the practices preceding and examples.
the tablet core is coated as
EXAMPLE 20 15
Other e xamples of the invention involve s ubstitution. of one or more of the
Table 2 a gents mentioned above, for above t he examples.
benzoic acid or cellulose acetate phthalate in the
EXAMPLE 21 To any o
ne of the preceding c
oated t ablets of Examples 12 to
s added as an overcoating, a
20 i conventional sugar t ative c oating, overcoating with
or w ithout is the following:
a dye or a pigment. A represen
coating Place pan t
he and tablets apply which 2 charges have been of a undercoated
gelatin-acacia in s o
a
lution and dust with kaolin. Then apply 7 charges of 17' lb. cut syrup and then apply
14 charges of white syrup which contains titanium dioxide. Over this is applied 12 30
charges and ceutical air dried, of glaze, 17 after trayed lb. cut which up syrup. and
they again The are tablets glazed air dried.
are with trayed pharmai up
EXAMPLE 22
35
The overcoating of Example 21 is applied but it ad ditionally includes a
medicament.Forexample,withpotassiumcoatingcouldchloridecontaininthe
hydrochlorothiazide internal matrix core, in the the amount
over
of 25 mg. or 50 mg. per tablet. The hydrochlorothiazide 40
is mixed and milled with cut syrup and it is applied o
nto the the charges tablets
which containing have the been titanium undercoated, d ioxide.
just prior to
plemented maceutically The titanium with acceptable.
any dioxide other can pigment be replaced or dye with which or is be phar sup
The t ablets prepared i
n accordance with the teachings gastric of Example ?uid and 12
were simulated tested intestinal for effectiveness baths and in the simulated results
obtained are tabulated below in Table III.
50
TABLE III
Percent time, drug hrs.
released
s 1 A=Sin1ulated gastric ?uid; B=Simulated intestinal ?uid. Tablets prepared
l a
according to Example 19 tested in 60 the same manner gave the following data:
TABLE IV
Percent time, drug hrs.
released
Test - --~ 65 ?uidl 1 2 3 4
Wt. of coating mg.:
16 ______ __ ________________________ __ A 0
.5 1 .0 __________ __ ' 16
________________________________ _- B 0.0 2.0 9 .3 2 6.4
1 A=Simulated gastric ?uid; B=Simulated intestinal ?uid.
What 1. A pharmaceutical is claimed is:
tablet consisting of (a) an internal matrix core comprising potassium chlo ride to
soluble be or capable in other gastro-intestinal irritating of producing active ?uids
lesions medicament and of which the gastro-in is which known is

 3,538,214 9 10 testinal mucosa in passing through the stomach and 2. A tablet
according to claim 1 in which said coating intestines, thereof is permitted
particularly to when reach a a comparatively large concentration small part is l to
?lm 3 parts modifying by weight agent.
of said plastic substance and 1
(b) area m
ate a coating of mixture the gastro-intestinal on of said from core 0.1
which to m ucosa; 30 parts comprises and by weight an inti of
3. A tablet according to claim 1 in which hydrochloro
a modifying plastic substance agent, and one part by weight of a ?lm
References Cited (i) vapor said
permeability plastic substance and being which one remains of low substan~ water 10
UNITED S TATES PATENTS thiazide is incorporated in the coating and potassium
ide is in t
chlo r he internal matrix core.
low is lose tlally . selected water acetate mtact . soluble from 1n . ethylcellulose
gastro-lntestrnal the ol group . vin,l . cellulose consisting alcohols ?uids . nitrate
and of whlch cellu
and . 2,881,085 2,887,440 4/1959 5/1959 Endicott Greminger et et al. a1 ____ _____
424-35 __ 424_35 XR
2928770 2921883 3 /1960 1/1960 B ardam Reese e-t """"" a]! """" 424_35 424*35 XR
XR (ii) said ?lm m odifying P Y a gent Y being one that will 15 2,971,889 3 030 273
2/1961 4/1962
Swintosky _________ __ 424_31
be ing readily selected soluble from the in the group stomach consisting fluids of and
mag- be- > 3079303 3 039 933 6/1962 2/1963 zglgggg Raff et a1 '"
424_35 XR nesium oxide, magnesium citrate, sodium bicar- 3096248 7/1963 Rudzki """"
" 424_35 XR bonate, potassium bicarbonate, tetraethanol- 3112220 11/1963 Heiser
ez'e'l'l """ 424_35 XR amine and lactose in the case of coatings to 20 3247O66
4/1966 Milosovich """ '" 424_35 XR form a membranous ?lm in the stomach,
and nal one ?uids that and will be being readily selected soluble from in the the
intesti- group SHEP K_ ROSE
Primary Examiner
intestines. the s
tomach consisting case of and o f coatings p ropionic form a to
membranous acid p ass and intact sorbic through ? lm acid in t he the in 25
Us CL X_R.
424-20 21 22 32 33 35 153 246