Note: Descriptions are shown in the official language in which they were submitted.
106Z613
1528
SUM~ARY AND DETAILED DISCRIPTION~
The present invention relates to enteric capsules.
More particularly, the invention relates to pharmaceutical
capsules having enteric properties and comprising
(1) gelatin or hydroxypropyl methylcellulose and
(2) an ammonium salt o~ either a) cellulose acetate
phthalate, b~ hydroxypropyl methylcellulose phthalate,
or c) a copolymer o~ methacrylic acid and methacrylic ~ci~
alkyl ester; optionally in combination with other
i~gredients, and to methods for the production of such
pharmaceutical capsules.
As used herein, the te~m "enteric properties"
means the properties of being soluble in or disintegrated
by the alkaline intestinal secretions but being subs~antially
insoluble or resistant to solution in the acid secretions
of the stomach. The term "enteric capsules" means capsules
having enteric properties. Hydroxypropyl methylcellulose
(National Formulary XIII) and cellulose acetate phthalate -
~U.S.P. XVIII) are sometimes referred to herein as HPMC
and CAP, respectively. The term "hydroxypropyl methyl-
cellulose phthalate" means a cellulose derivative which,
like cellulose itself, is a polymeric, high molecular
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weight substance; and which has the following ~structural
unit
H OR CH20R
~ ~ H H /r-~ \ O
H~o ~ o R ~ H
CH20R H OR
where R represents variously hydrogen, methyl, hydroxy-
propyl having the formula
CH3- CH -CH2-
OH
carboxybenzoyl having the formula
~-0
=o
OH
or 2-carboxybenzoyloxypropyl having the formula
CH3 - CH - CH2-
~, 1-0
,~ Ir
~L7-o
OH
Hydroxypropyl methylcellulose phthalate is sometimes ~,
referred to herein as HPMCP.
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1~6Z613 ~`
For use in the invention, HPMCP typically has
approximately 15-30% methoxyl content~ 4-15% hydroxy-
propoxyl content, and 15-40% carboxybenzoyl content.
HPMCP can be prepared according to any of a
number of methods. At the presen~ time, at least two
grades or types of HPMCP are commercially available from
the Shinetsu Chemical Company of Tokyo, Japan. These
grades or types are known as HP-50 and HP-55~ HP-50 is
stated to have 20-25% methoxyl content, 8-12% hydroxy-
propoxyl content, and 20-27% car~oxybenzoyl content.
HP-55 is stated to have 18-22~/o methoxyl content9 6-10~/o .
hydroxylpropoxyl content, and 27-35~/o carboxybenzoyl content.
Both HP-50 and HP-55 are soluble in water by the addition -~
of base. HP-50 is stated to dissolve above pH 5~ HP-55
is stated to dissolve above pH 5. 5
The copolymer of methacrylic acid and methacrylic
acid alkyl ester, sometimes referred to herein as -
MA acid/ester copolymer, has the following structural unit:
ICH3 ICH3 ICH3
--C CH2 C CH2 ~C--CH2--
C-O C=O C=O
OH O.R OH
where R is a lower alkyl group, in particular9 a methyl or
ethyl group.
MA acid/ester copolymer can be prepared according
to any of a number of methods. At least two grades or
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types of MA acid/ester copolymer are commercially
available from Rohm & Haas Company of Tokyo, Japan.
These grades or types are known as EUD-L and EUD-S. The acid
value (amount of mg. of caustic potash needed to neutralize
1 gram of the dried substance~ is stated as 292 for EUD-L
and 178 for EUD-S. Both EUD-L and E~D-S are soluble in
water when base is added. EUD-L is stated to dissolve
above pH 6 and EUD-S above pH 7.
Ordinary pharmaceutical capsules made of gelatin
do not have enteric properties and therefore when ingested
do not reach the intestine while intact but instead rapidly
dissolve or disintegrate in the acid secretions of the
stomach. There is, however, a need for pharmaceutical
capsules having enteric properties. In many cases,
medicinal substances are more readily utilized ahd are
of greater therapeutic value if they are absorbed from
the upper portion of the intestine. Medikal science has
long sought ~o provide efficient means for rendering such
substances available for absorption from the intestinal
tract. This problem arises from the fact that many medicinals
are either not absorbed from the stomach or rapidly destroyed
on contact with the acid present in the stomach. Some
examples of mediçinals of this type are gland products
and penicillin. Many medicinals, such as hog bile,
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quinacrine, sulfa dr~gs, and the like, also are very
unpleasant to take and cause severe gastric disturbances
which may be coupled with very unpleasant regurgitation
of the drug. Another use for enteric capsules is to
prevent the breakdown or dilution of drugs which are
used for their effect in the intestinal tract, such as
intestinal antiseptics or anthelmintics. It is obvious
that there is a great need for a practical method of -
administering medicinals of the above types in a form
,o having enteric properties. `
Many attémpts have been made heretofore to obtain ;
suitable enteric capsules. In general, methods of
manufacture for enteric capsules fall into one of two `~
classes~
(I) Those comprising treating the exterior of the
assembled filled capsule, for example with formalin to
decrease the solubility of the capsule wall, or with a
coating of an enteric substance; -
(II) and those comprising forming the capsule parts by the
dip-molding technique using a dipping solution which itself
after drying possesses enteric properties.
The method according to the present invention
falls under category II. Of the methods of this type,
the use of CAP and of alkali metal salt of HPMCP is known
in the art.
~06Z6~3
However, it has been found that capsules made
using the dip-molding technique employing the known
enteric dipping solutions often lack the elastic properties
of gelatin and in some cases after aging lose their enteric
properties.
It is an object of the present invention to
provide improved enteric capsules.
It is also an object of the invention to provide
enteric capsules having improved elasticity, i.e., freedom
,D from brittleness.
It is a further object of the invention to
provide enteric capsules having improved re~ention of
enteric properties when subjected to prolonged storage.
It is still a further object of the in~ention ~o
provide methods for manufacturing such improved enteric
capsules.
The enteric capsules of the present invention,
which advantageously meet these objects, are formed or -~
dip-molded from a homogeneous film-forming mixture
comprising 1) gelatin or hydroxylpropyl methylcelluiose
and 2) an ammonil~m salt of a polymer of the group
consisting of CAP, HPMCP, and MA acid/ester copolymer;
optionally in combination with additional ingredients
10626~3 ~:
such as plasticizer and/or coloring agent.
In manufacturing enteric capsules in a series
of steps according to the invention, CAP, HPMCP or ;
MA acid/ester copolymer is first dissolved in a dilute
aqueous solution of ammonium hydroxide. Sufficient
ammonium hydroxide is used to effect complete solution;
any excess is removed subsequently as described below.
Gelatin or HPMC is then added to the resulting aqueous -
solution of the ammonium salt (of CAP, HPMCP or
MA acid/ester copolymer~ and is dissolved in any suitable
way, optionally with heating, for a time sufficient to
allow complete solution. The ratio of ammonium salt to
gelatin or HPMC can be varied and is preferably 5 parts of
ammonium salt by weight, measured as free acid form, to
1 to 5 parts by weight of gelatin or HPMC. Sufficient
ammonium salt must be present in the finished capsule to :
render it insoluble in the s~omach acid but the quantity
must not be so great as to prevent the rapid dissolution
of the capsule when it comes in contact with the alkaline
contents of the intestine. The resulting solution, if
necessary after heating to obtain the desired viscosity,
is suitable far the production of capsule parts by the dip-
molding procedure If the solution contains excess ammonia
or has foam, the same can be removed by heating the
solution under slightly reduced pressure. The pH of the
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1~;)6Z613
defoamed solution is about 6.4 to 7.8. For capsule
production, suitable metal mold pins are dipped into
the solution (free of foam) and the wet film thus formed
on the pins upon lifting from the solution is dried
gradually at 40 C. in the conventional way to obtain
the desired hard shell capsule parts. The wall thickness
of capsules produced by the dip-molding depends on the
viscosity of the dipping solution. If a thin-walled
capsule is desired more water is used, whereas if a
thick-walled capsule is desired a more concentrated or
viscous solution is used.
The wall thickness of the capsule is also dependent
upon the temperature of the dipping solution. This factor, ~ i
however, is maintained fairly constant since an appreciable
change in temperature is necessary in order to produce a
small change in wall thickness and it is undesirable from
a practical standpoint to vary the temperature over large
ranges. Therefore, the solution in the dipping pan is
kept at a fairly constant temperature between about 32
and 49 5. and preferably in the neighborhood of about
35-37 C.
If desired, a colorin~ agent or a plasticizer may ~
be added to our new enteric capsules without destroying
or substantially altering their valuable chemical and
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physical properties. The same kinds of coloring agents
as used in the usual hard shell capsules are suitable.
Up to 5~/0 (by weight of the dry gelatin or HPMC) of a
plasticizer, such as glycerine or propylene glycol, may
be added if desired.
The new enteric capsules can be produced in any ~-
of the customary forms for pharmaceutical capsules.
However, we prefer to make our new capsules in the form
of conventional, hard shell gelatin capsules comprising ~ -
telescopically engaged body and cap portions, and having
in addition vne or more locking features.
The new enteric capsules of the invention have
excellent enteric properties and pharmaceutical ac-
ceptability. They are chemically and physically stable
and do not develop significantly increased acidity during
storage and use. In addition, they have a uniform wall
thickness and a low percentage of manufacturing defects.
Although it is known in the prior art that the
mentioned polymers have enteric properties and can be
used for the surface coating of pharmaceutical formulations
such as tablets and granules, it is surprising that
satisfactory pharmaceutical capsules can be manufactured
by incorporating the polymer throughout the capsule wall
itself. This is because the commercial manufacture of
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` 106Z613
pharmaceu~ical capsules is such a sensitive operation
that it is adversely affected by almost any change in
the conventional ingredients or operating conditions.
The invention is illustrated by the following
examples.
Example 1
Aqueous ammonium hydroxide (10%~ 42 ml ) is diluted
with 300 ml. of water and, with stirring, 85 g. of HPMCP
~grade HP-55) is added and dissolved. Gelatin (40 g.) is
,~ added to the resulting homogeneous solution and the mixture is
allowed to stand to permit hydration and complete solution of
the gelatin. The latter solution is heated to 60 C. and left
standing overnight at room temperature. Then it is heated
under a slightly reduced pressure to eliminate excess
ammonia and to defoam the solution. In a typical procedure,
the pH of the obtained solution was 7.4. For the formation
of capsule halves by the dip-molding technique the ;
homogeneous solution is placed in separate dipping pans
(cap and body pans) maintained at respective temperatures
~0 of 36.7 C. and 34.4 C. Previously lubricated metallic
cap and body mold pins;are dipped into the dipping solutions
thus obtained and are withdrawn and lifted slowly in -
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106Z613 .~ ~
conventional fashion to provide for even distribution `
of the liquid film layer over the effective area of
each mold pin. The coated pins are then kept stationary
for a sufficient period to gellify the film layer on
the pin. The capsule halves thus formed are dried by
blowing with dehumidified air at 15-16 C., and are
removed from the pins, trimmed and joined together with
the other halves of the capsule to provide the finished
enteric hard shell capsules ready for filling.
,0 As a demonstration that the capsules have the
desired enteric properties, the same are subjected to a
standard dissolution test of the type described in the
Japanése Pharmacopeia, 8th Ed., 855-859, simulating -
conditions of the human body. To simulate the acid
~-;
conditions in the stomach, an artificial gastric juice is
used having a pH of about 1.2. It contains 2.0 g. of
sodium chloride and 24.0 ml. of dilute hydrochIoric acid
diluted with water to a total volume of 1,000 ml. The
alkaline conditions of the intestine are simulated by
L use of an artificial intestinal juice having a pH of
about 7.5. It contains 35.8 g. of disodium hydrogen
phosphate and 6.0 mlO of dilute hydrochloric acid diluted
with water to a total volume of 1,000 ml. Both the acid
and alkaline tests are carried out at 37+2 C.
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,
106Z613
The empty gelatin/HPMCP ammonium salt capsules obtained
according to the invention are filled with No. 2 Red
lactose powder and banded with an enteric seal, i.e.,
a material which is insoluble in artificial gastric
juice and insoluble artificial intestinal juice.
In a typical procedure when the resulting filled
capsules were subjected to this dissolution test, they
were found uniformly unchanged after 120 minutes in the
first solution (artificial gastric juice~, and when
,~ transferred to the second solution (artificial intestinal
juice), the capsules completely disintegrated and
dissolved within 5 to 10 minutes so that the capsule ;
contents were thereby released exclusively in the
alkaline environment.
Cellulose acetate phthalate (CAP~ 50 g.) is
dissolved in 220 ml. of 1.5% aqueous ammonium hydroxide
and 50 g. of hydroxypropyl methylcellulose is added thereto.
The mixture is heated to provide complete solution, and
L O the resulting solution is heated under reduced pressure
by the above-described method to remove excess ammonia;
final pH, 6.6. Capsules are then prepared from the
resulting HPMC/CAP ammonium salt enteric dipping solution
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~ 06Z6~3
by the above-described method and are fllled and
tested by the same method, typically with the same
result~ i.e., no dissolution when sub~ec~ed to
artificial gastric juice but complete dissolution and
content release in the alkaline environment within a
short exposure period.
Example 3: ;
Methacrylic acid/methacrylic acid ethyl
ester copolymer (EUD-S, 96 g.) is dissolved in 400 ml.
,~ of 2% aqueous ammonium hydroxide and 27 g. of gelatin
is added thereto. The mixture is allowed to stand to ;
accomplish hydration of the gelatin and the resulting
solution is heated to 60 C. and left standing overnight
at room temperature. The foam and excess ammonia are
removed by heating the solution under reduced pressure; ~ ; -
final pH of the solution was 7.6. Capsules are prepared
from this solution using the method described in
Example 1. The empty capsules are filled and sealed
in the same way and tested for enteric properties by the -
~o dissolution test as described. These MA acid/ester
copolymer capsules typically meet the requirements of
insolubility in gastric fluid and prompt solubility
in intestinal fluid.
';
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1062613
In other tests designed to show the enteric
characteristics on aging, it was found that the capsules
of ~he invention using ammonium salt as exemplified,
unlike prior art enteric capsules, all pass the
described enteric dissolution test. Thus, in the aging
test simulating one year aging after manufacture (storage
for 4 weeks at 40 C. under 40~/0 relative humidity), the
capsules of the present invention did not dissolve in
gastric fluid but dissolved promptly in intestinal
,o fluid. Also, these càpsules when produced with coloring
~gents in the dipping solution did not undergo adverse
color change under aging conditions. Moreover, the
capsules had excellent retention of elasticity, -`
transparency and lustre under aging. Significantly,
the capsules were free of any tendency to generate any
odor of ammonia undFr aging-
.,
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