Note: Descriptions are shown in the official language in which they were submitted.
CA 02769046 2012-01-24
Coating agent for the dip coating of capsule halves
Field of the invention
According to the claims, the invention relates to a
coating composition for the enteric coating of capsule
halves made of water-soluble or water-swellable polymer
material in the dipping process.
Prior art
Huyghebaert et al., European Journal of Pharmaceutical
Sciences 21 (2004) 617-623, describe an alternative
method for the enteric coating of capsules made of
hydroxypropylmethylcellulose (HPMC) in which ready-to-
use enteric capsule parts are obtained.
In the introductory section, it is reported that
enteric coated HPMC capsules have for a long time been
used in the dietetic food supplement industry as
vegetarian alternatives to gelatine. It is also
mentioned that although the enteric coating of hard
gelatine capsules made of organic solutions is
possible, it is difficult to execute and may lead to
embrittlement of the capsules, which can result in poor
adhesion of the coating. This can be overcome by
applying an intermediate layer, although this is
lengthy and complicated. Moreover, coating processes
from aqueous preparations have the advantage over
coating processes from organic solutions on account of
the toxicological and safety aspects. The coating of
gelatine capsules from aqueous preparations, however,
is very demanding and requires long processing times on
account of the solubility of the gelatine in water,
which overall leads to high costs.
It is furthermore reported that, in, contrast to
gelatine capsules, HPMC capsules can be enteric coated
relatively easily from aqueous preparations. However,
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it is necessary to additionally apply a sealing between
the capsule halves, e.g. through a gelatine solution to
be applied manually, in order to avoid an untightness
of the capsule and an uncontrolled escape of the
contents in the stomach. Another technique is to apply
water/ethanol mixtures between the capsule halves and
to weld the parts together at 40-60 C.
Using aqueous preparations (EUDRAGIT FS 30 D,
EUDRAGIT L 30 D-55, Aquoat AS-HF or Sureteric ) based
on (meth)acrylate copolymers or polyvinyl acetate
phthalate, plasticizers such as triethyl citrate and
further auxiliaries, such as, for example, talc, it is
possible to provide HPMC capsules with an enteric film.
A separate sealing step can be dispensed with in the
case of this coating technology. In particular, HPMC
capsules which have been coated with (meth)acrylate
copolymers are depicted as particularly advantageous in
the sum of their properties.
It is furthermore mentioned that the dipping process
for the enteric coating of capsules is very time-
consuming and can bring with it a multitude of
practical problems. In particular, the problems consist
in an uneven coating and unsatisfactory enteric
properties.
Problem and solution
Capsules filled with active ingredients or food
constituents, in particular made of gelatine or
hydroxypropylmethylcellulose, have been used for a long
time in the fields of pharmacy, food supplements and
cosmetics. Active ingredients are to be understood as
meaning in particular pharmaceutical active
ingredients, food supplements or active ingredients
with an assumed cosmetic effect, so-called
cosmeceuticals. Enteric coatings which are intended to
prevent the capsule contents from being released in the
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stomach have likewise been known for a long time.
Whereas capsule halves e.g. made of gelatine are
produced with high precision in the dipping process,
the enteric coatings for such capsules are produced
almost exclusively in the spraying process. Attempts to
apply enteric coatings in the dipping process have
hitherto proven unsatisfactory.
It was seen as an object to provide a coating
composition for the enteric coating of capsule halves
which can be applied in the dipping process.
Furthermore, the coating composition should comprise no
organic solvents. The coating composition should ensure
the tightness of the closed capsules in the gastric
juice without the capsules having to be provided to
this end with an additional sealing. The coating
composition should have adequate flowability in order
to be able to be applied in the dipping process, but at
the same time permit short drying times. The dried
coating should be sufficiently elastic and have a
uniform coating thickness. In the milieu of the
intestine, rapid dissolution of the capsules should
take place.
The object is achieved by a
coating composition for the enteric coating of capsule
halves made of water-soluble or water-swellable polymer
material in the dipping process, in the form of an
aqueous dispersion or solution, comprising a polymer
mixture of at least one first (meth)acrylate copolymer,
which is enteric, and at least one further
(meth)acrylate copolymer which is enteric or water-
insoluble, and also auxiliaries which influence the
viscosity of the dispersion and the elasticity of the
dried polymer film, characterized in that the solids
content of the dispersion or solution is more than 25%
by weight and the viscosity is 150 to 1500 mPa=s, where
a dried film produced from the dispersion or solution
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has an elongation at break of at least 200% and a
capsule composed of two capsule halves coated with the
dispersion or solution in the dipping process does not
dissolve in 0.1 N HC1 at pH 1.2 after two hours, but
then dissolves completely in buffer at pH 6.8 in less
than 30 minutes.
Explanation of the invention
According to the claims, the invention relates to a
coating composition for the enteric coating of capsule
halves made of water-soluble or water-swellable polymer
material in the dipping process.
Capsule halves and capsules
Capsule halves may be upper or lower parts of a
capsule. Upper and lower part fit together such that
they can be engaged in one another in a locking manner
and form a closed capsule. A capsule thus consists of
an upper and a lower half which can be filled as
required as a container with an active ingredient and
then is firmly closed by engaging with the upper part.
Filled capsules are provided in particular for oral
application. Capsules e.g. made of gelatine without an
enteric coating dissolve in the stomach.
Capsule halves, upper or lower parts, consist in
particular of a water-soluble or water-swellable
polymer material. Both capsule halves preferably
consist of gelatine or of hydroxypropylmethylcellulose.
Preference is given to gelatine. Less customary, but
also possible material for capsule halves are polymers
such as, for example, starch, pectin or agar.
As a rule, a capsule consists of a uniform, in
particular of the same or identical material.
Consequently, preferably both capsule halves, upper and
lower halves, consist e.g. uniformly of gelatine, in
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particular of the same or identical gelatine.
Capsules and capsule halves made of water-soluble or
water-swellable polymer material are used widely for
5 administering pharmaceutical active ingredients or food
supplements. In particular, mention may be made of the
fields of pharmacy and food supplements
(nutraceuticals), where the field of cosmetics, as far
as food supplements or potential active ingredients
(cosmeceuticals) are concerned, may be included.
The capsule halves are enteric coated. "Enteric coated"
means that the capsule halves have been enteric coated
on their exterior. A closed capsule is therefore
protected externally from dissolution in gastric juice,
pH 1 to about 5. The enteric coating rapidly dissolves
in the area of the intestinal fluid, above pH 5,
meaning that the underlying capsule material likewise
dissolves and releases the contents.
A capsule composed of two capsule halves enteric coated
with the dispersion or solution in the dipping process
does not dissolve in 0.1 N HC1 (artificial gastric
fluid according to USP without the addition of enzyme)
at pH 1.2 after 2 hours, then dissolve completely in
buffer at pH 6.8 according to USP, either after
rebuffering the pH 1.2 medium to pH 6.8 or by
transferring the capsule to the pH 6.8 buffer. Suitable
testing methods are known to the person skilled in the
art and can be found, for example, in USP 32. The
capsules are held under the surface of the liquid using
sinkers.
Dimension of capsules
Within the context of the invention, a closed capsule
can have a total length in the range from about 5 to
50 mm. The diameter of the upper part can be in the
range from about 4 to 12 mm. The diameter of the lower
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part can be in the range from about 2 to 10 mm. The
length of the upper part can be in the range from about
4 to 20 mm and that of the lower part in the range from
8 to 30 mm. The fill volume can be between about 0.1
and 2 ml.
Capsules can be divided, for example, into standardized
sizes from 000 to 5 (see in this context e.g.:
Fahrig W. and Hofer U. (1983): Die Kapsel, Grundlagen,
Technologie and Biopharmazie einer modernen Arzneiform
[Capsules, Principles, Technology and Biopharmacy of a
Modern Drug Form], Wissenschaftliche
Verlagsgesellschaft mbH Stuttgart).
A closed capsule of size 000 has, for example, a total
length of about 28 mm for a diameter of the upper part
of about 9.9 mm and a diameter of the lower part of
about 9.5 mm. The length of the upper part is about
14 mm, that of the lower part 22 mm. The fill volume is
about 1.4 ml.
A closed capsule of size 5 has, for example, a total
length of about 10 mm for a diameter of the upper part
of about 4.8 mm and a diameter of the lower part of
about 4.6 mm. The length of the upper part is about
5.6 mm, that of the lower part 9.4 mm. The fill volume
is about 0.13 ml.
Layer thicknesses
The coating composition according to the invention is
preferably adjusted so that, in the dried state,
coating films with layer thicknesses in the range from
20 to 100, in particular 40 to 80 pm, are produced. In
this connection, the capsule halves can already be
produced such that the wall thicknesses on the outside
are in each case reduced by the layer thickness of the
enteric coating to be expected, such that standard wall
thicknesses arise again following the dip coating. If,
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for example, a customary standard capsule upper part
and lower part made of gelatine has a wall thickness of
100 pm, then the wall thicknesses for enteric coated
capsules are reduced in the preparation to e.g. ca.
60 gm. Then, in the dipping process, an enteric coating
with a layer thickness in the dried state of ca. 40 pm
is applied. The resulting upper and lower parts then
again have wall thicknesses of 100 m and can be
further processed in the same way as standard capsules
without altering the machine settings.
Sealing function of the enteric coating
As a result of the preparation in dipping processes,
the lower capsule half, the lower part, receives a
continuous enteric coating which, in the closed state,
is partly overlapped by the upper part. Favoured by the
elasticity of the film and its uniformity, the
overlapped part of the enteric coating assumes here a
sealing function which effectively prevents the
penetration of gastric fluid through a possible gap
between the lower part and the upper part. The dipping
process thus offers an advantage over the coating of
closed capsules in a spraying process in which no
overlapping occurs, as a result of which the abutment
point on the edge of the upper part always brings with
it the potential risk of untightness. In many cases,
therefore, prior to the enteric coating of closed
capsules in a spraying process, a sealing band is
applied or another measure is undertaken for sealing
the abutment point. Measures of this kind can be
dispensed with when applying the coating composition
according to the invention in the dipping process,
which represents a further advantage.
The tightness of the capsule material can be
demonstrated, for example, by pouring a marker, e.g. a
dye or an active ingredient that is easy to detect and
readily soluble in water, into the coated capsule
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halves or into the capsule and observing its escape
into the medium or its retention in the capsule during
the incubation for 2 hours in 0.1 N HCl or in
artificial gastric fluid pH 1.2 in accordance with USP.
Here, no or only a very small part of the marker should
be detectable in the medium, less than 10%.
Aqueous dispersion or solution
The coating composition according to the invention is
in the form of an aqueous dispersion or solution. The
term "aqueous dispersion or solution" is understood in
the broad sense and is intended to include all
transition states, in particular also so-called
polymer/colloidal solutions. The aqueous dispersion
consists of a solid phase and a liquid phase. The
solids phase and the liquid phase add up to 100% by
weight.
The liquid phase of the aqueous dispersion or solution
is based essentially or completely on the dispersant or
solvent water. The liquid phase thus consists of at
least 95% by weight, preferably at least 98% by weight,
in particular 100% by weight, of water. Organic
solvents, such as, for example, ethanol, isopropanol or
acetone, may be present up to 5% by weight, preferably
up to 2% by weight. This may be of use in individual
cases for lowering the surface tension or for
preventing microbiological contamination. Preferably,
however, no organic solvents are present.
The term "dispersion or solution" refers to the fact
that the substances present can in their totality be
present either in dispersed form, dissolved form or
else partly dispersed or dissolved in an intermediate
state. The aqueous dispersion or solution preferably
has a pH of from 6.0 to 10.0, in particular from 6.5 to
9Ø In this pH range, the (meth)acrylate copolymers
present are predominantly in dispersed or at least
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partly dissolved form. Plasticizers are generally
present in dissolved form. Other additives or
auxiliaries, such as, for example, talc, may be present
in dispersed form.
Solids content
The solids content of the aqueous dispersion or
solution is more than 25% by weight, preferably more
than 30% by weight, in particular 32 - 36% by weight.
For comparison, the solids contents of dispersions or
solutions which are used in spraying processes are
generally only around 20% by weight.
The solids content is used in particular together with
the viscosity for controlling the balance between good
wettability of the as yet uncoated capsule halves in
the dipping process and acceptable drying time of the
coated capsule halves after the dipping process. If the
solids content is too low, the drying times become too
long, and, moreover, as a rule no adequate viscosity
can be built up. If the solids content is too high,
this may lead to drop formations on the dipsticks and
to overall uneven coatings. Consequently, no exact
adjustment of the layer thickness is possible.
Viscosity
The viscosity of the aqueous dispersion or solution is
150 to 1500, preferably 180 to 1000, in particular 200
to 350 mPa=s. The viscosity can be determined, for
example, using a Brookfield rotary viscometer. The
determination method is known to the person skilled in
the art (see e.g. ISO 3219:1993).
Elongation at break
The elasticity of the dried polymer film can
essentially be characterized by its elongation at
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break. A dried film produced from the dispersion or
solution according to the invention, e.g. by pouring,
has an elongation at break of at least 200, preferably
at least 250%. The elongation at break in [%] can be
determined on sample films in accordance with
DIN 53 455.
(Meth)acrylate copolymers
The aqueous dispersion or solution comprises a polymer
mixture of at least one first (meth)acrylate copolymer,
which is enteric, and at least one further
(meth)acrylate copolymer, which is enteric or water-
insoluble.
At least one first (meth)acrylate copolymer means one
or more first (meth)acrylate copolymers.
At least one further (meth)acrylate copolymer means one
or more further (meth)acrylate copolymers.
The polymer mixture comprises or consists of at least
two (meth)acrylate copolymers. Preferably, the polymer
mixture comprises or consists of two (meth)acrylate
copolymers.
The first (meth)acrylate copolymer, which is enteric,
and the further (meth)acrylate copolymer, which is
enteric or water-insoluble, are preferably present in a
ratio of from 2:1 to 1:2.
The first (meth)acrylate copolymer, which is enteric,
and the further (meth)acrylate copolymer, which is
enteric or water-insoluble, constitute preferably at
least 45% by weight, particularly preferably at least
60% by weight, in particular at least 70% by weight, of
the solid present in the dispersion.
An enteric (meth)acrylate copolymer is understood as
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meaning those (meth)acrylate copolymers which are
insoluble in the pH range of gastric fluid, pH 1.0 to
5.0, but dissolve in the pH range of the intestinal
fluid, above pH 5.0, in particular pH 5.5 to 8Ø In
particular, enteric coated drug forms in 0.1 N HC1
release at most 10% of the active ingredient present
over the course of 2 hours. Enteric (meth)acrylate
copolymers are synonymous with (meth)acrylate
copolymers which are composed of C1- to C4-alkyl esters
of acrylic acid or methacrylic acid and have at least
5%, preferably 5 to 70%, in particular 8 to 60%, of
monomer radicals with anionic groups, as a rule
methacrylic acid radicals. Cl- to C4-alkyl esters of
acrylic acid or methacrylic acid are in particular
methyl methacrylate, ethyl methacrylate, butyl
methacrylate, methyl acrylate, ethyl acrylate and butyl
acrylate.
First enteric (meth)acrylate copolymer
Preferably, the first enteric (meth)acrylate copolymer
is an anionic (meth)acrylate copolymer. Preferably, the
glass transition temperature of the first
(meth)acrylate copolymer in accordance with
ISO 11357-2, point 3.3.3, is more than 70 C.
Preferably, the first enteric (meth)acrylate copolymer
is a polymer of 40 to 60% by weight of methacrylic acid
and 60 to 40% by weight of methyl methacrylate or 60 to
40% by weight of ethyl acrylate (grade EUDRAGIT L100
or EUDRAGIT L100-55).
Of suitability in particular is EUDRAGIT L100-55,
which is a copolymer of 50% by weight of ethyl acrylate
and 50% by weight of methacrylic acid.
Likewise suitable are anionic (meth)acrylate copolymers
of 20 to 40% by weight of methacrylic acid and 80 to
60% by weight of methyl methacrylate (grade
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EUDRAGIT S).
Further (meth)acrylate copolymer
The further (meth)acrylate copolymer may be enteric or
water-insoluble. If the further (meth)acrylate
copolymer is an enteric polymer, it is different from
the first enteric (meth)acrylate copolymer.
Further anionic (meth)acrylate copolymer
Preferably, the further (meth)acrylate copolymer may be
an enteric, anionic polymer which is different from the
first enteric (meth)acrylate copolymer. Preferably, the
glass transition temperature of the further
(meth)acrylate copolymer in accordance with
ISO 11357-2, point 3.3.3, is at most 70, preferably at
most 60, in particular at most 50 C, e.g. 40 to 60 C.
Of particular suitability is, for example, a polymer of
10 to 30% by weight of methyl methacrylate, 50 to 70%
by weight of methyl acrylate and 5 to 15% by weight of
methacrylic acid (grade EUDRAGIT FS).
Specifically, for example EUDRAGIT FS, which is a
copolymer of 25% by weight of methyl methacrylate, 65%
by weight of methyl acrylate and 10% by weight of
methacrylic acid, is suitable. EUDRAGIT FS 30 D is a
dispersion comprising 30% by weight of EUDRAGIT FS.
Also suitable for the purposes of the invention is a
(meth)acrylate copolymer (see WO 2003/072087), which is
composed of
20 to 34% by weight of methacrylic acid and/or
acrylic acid,
20 to 69% by weight of methyl acrylate and
0 to 40% by weight of ethyl acrylate and/or
optionally
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0 to 10% by weight of further vinylically
copolymerizable monomers,
with the proviso that the glass transition temperature
of the (meth)acrylate copolymer in accordance with
ISO 11357-2, point 3.3.3, is at most 60 C. This
(meth)acrylate copolymer has in particular very good
elongation at break properties.
The copolymer is composed in particular of radically
polymerized units of
to 34, preferably 25 to 33, particularly preferably
28 to 32% by weight of methacrylic acid or acrylic
15 acid, preferably methacrylic acid,
20 to 69, preferably 35 to 65, particularly preferably
35 to 55% by weight of methyl acrylate and optionally
20 0 to 40, preferably 5 to 35, particularly preferably 15
to 35% by weight of ethyl acrylate, with the proviso
that the glass transition temperature of the copolymer
(measurement without the addition of plasticizer at a
residual monomer content (REMO) of less than 100 ppm,
heating rate 10 C/min, nitrogen atmosphere) in
accordance with ISO 11357-2, point 3.3.3 (Tmg), is at
most 60, preferably 40 to 60, particularly preferably
45 to 55 C.
The copolymer preferably consists essentially to
exclusively of the monomers methacrylic acid, methyl
acrylate and ethyl acrylate in the quantitative
fractions given above.
However, it is additionally possible, without leading
to an impairment of the essential properties, for small
amounts in the range from 0 to 10, e.g. 1 to 5% by
weight of further vinylically copolymerizable monomers,
such as, for example, methyl methacrylate, butyl
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methacrylate, butyl acrylate or hydroxyethyl
methacrylate, to be present.
Glass transition temperature here is to be understood
in particular as meaning the midpoint temperature Tmg in
accordance with ISO 11357-2, point 3.3.3. Measurement
takes place without the addition of plasticizer, at
residual monomer contents (REMO) of less than 100 ppm,
at a heating rate of 10 C/min and under a nitrogen
atmosphere.
Also suitable for the purposes of the invention are
(meth)acrylate copolymers (see WO 2004/096185)
comprising
20 to 33% by weight of methacrylic acid and/or
acrylic acid,
5 to 30% by weight of methyl acrylate and
to 40% by weight of ethyl acrylate and
20 greater than 10 to 30% by weight of butyl
methacrylate and
optionally
0 to 10% by weight of further vinylically
copolymerizable monomers, where the fractions of
the monomers add up to 100% by weight,
with the proviso that the glass transition temperature
of the copolymer in accordance with ISO 11357-2, point
3.3.3 (midpoint temperature Tmg) is 55 to 70 C. On
account of their good mechanical properties, copolymers
of this type are particularly suitable for compressing
pellets to give tablets.
The aforementioned copolymer is composed in particular
of radically polymerized units of
20 to 33% by weight, preferably 25 to 32% by
weight, particularly preferably 28 to 31% by
weight, of methacrylic acid or acrylic acid,
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preferably methacrylic acid,
to 30% by weight, preferably 10 to 28% by
weight, particularly preferably 15 to 25% by
5 weight, of methyl acrylate,
20 to 40% by weight, preferably 25 to 35% by
weight, particularly preferably 28 to 32% by
weight, of ethyl acrylate, and
greater than 10 to 30% by weight, preferably 15 to
25% by weight, particularly preferably 18 to 22%
by weight, of butyl methacrylate,
where the monomer composition is selected so that the
glass transition temperature of the copolymer is 55 to
70 C, preferably 59 to 66 C, particularly preferably 60
to 65 C.
The copolymer preferably consists essentially to
exclusively, to 90, 95 or 99 to 100% by weight, of the
monomers methacrylic acid, methyl acrylate, ethyl
acrylate and butyl methacrylate in the quantitative
ranges stated above.
However, it is also possible, without having to lead to
an impairment of the essential properties, for small
amounts in the range from 0 to 10, e.g. 1 to 53 by
weight of further vinylically copolymerizable monomers,
such as, for example, methyl methacrylate, butyl
acrylate, hydroxyethyl methacrylate, vinylpyrrolidone,
vinylmalonic acid, styrene, vinyl alcohol, vinyl
acetate and/or derivatives thereof, to be present.
Water-insoluble (meth)acrylate copolymers
Within the context of the invention, a water-insoluble
(meth)acrylate copolymer is to be understood as meaning
those (meth)acrylate copolymers which are water-
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insoluble or merely water-swellable over the entire pH
range from 1 to 14. These are preferably "neutral"
(meth)acrylate copolymers. Neutral is understood as
meaning that the (meth)acrylate copolymers are composed
predominantly or completely of neutral monomers, e.g.
to more than 95% by weight, to more than 98% by weight,
to more than 99% by weight or to 100% by weight.
Accordingly, the term "neutral" does not entirely rule
out the presence of ionic groups in the polymer.
(Meth)acrylate copolymers with a content of less than
5% by weight, preferably less than 2% by weight,
preferably less than 1% by weight, of ionic, in
particular anionic groups, are referred to as "neutral"
within the context of the invention or as "essentially
neutral". These neutral or essentially neutral, or
optionally only to a small extent, ionic polymers are
water-insoluble or merely water-swellable and have no
enteric properties.
The further (meth)acrylate copolymer may preferably be
a water-insoluble polymer which is a polymer of 20 to
40% by weight of ethyl acrylate, 60 to 80% by weight of
methyl methacrylate and less than 5% by weight,
preferably less than 2% by weight, preferably less than
1% by weight, of methacrylic acid (grade EUDRAGIT NE
or EUDRAGIT NM).
For example, EUDRAGIT NE, which is a copolymer of 30%
by weight of ethyl acrylate and 70% by weight of methyl
methacrylate, is suitable.
Auxiliaries which influence the viscosity of the
dispersion or solution and the elasticity of the dried
polymer film
The viscosity of the dispersion and the elasticity or
the elongation at break of the dried polymer film can
usually not be brought into the required ranges by the
polymer mixture alone. Consequently, the aqueous
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dispersion or solution additionally comprises
auxiliaries which, together with the polymer mixture,
influence or increase and steer into the required
ranges the viscosity of the dispersion and the
elasticity of the dried polymer film.
A comparatively strong influencing of said parameters
can be achieved in particular through the addition of
plasticizers or basic substances. These auxiliaries
preferably constitute at most 30% by weight, in
particular at most 20% by weight, of the solid present
in the dispersion. The content of these auxiliaries can
be, for example, 5 to 30% by weight, preferably 10 to
20% by weight, of the solid present in the dispersion.
Plasticizers
Plasticizers can contribute to influencing and/or
increasing the viscosity of the dispersion and the
elasticity of the dried polymer film.
Substances suitable as plasticizers generally have a
molecular weight (MW) between 100 and 20 000 and
contain one or more hydrophilic groups in the molecule,
e.g. hydroxyl, ester or amino groups. Citrates,
phthalates, sebacates, castor oil are suitable.
Examples of suitable plasticizers are alkyl esters of
citric acid, propylene glycol, glycerol esters, alkyl
esters of phthalic acid, alkyl esters of sebacic acid,
sucrose esters, sorbitan esters, diethyl sebacate,
dibutyl sebacate and polyethylene glycol 300 to 35 000.
Preferred plasticizers are tributyl citrate, triethyl
citrate, acetyltriethyl citrate, dibutyl sebacate and
diethyl sebacate. The use amounts of plasticizers may
be in the range from 1 to 30, preferably 5 to 25% by
weight, based on the polymer mixture. Preference is
given to polyethylene glycols with a high molecular
weight, in particular polyethylene glycol 20 000 or
polyethylene glycol 35 000, which can greatly increase
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the viscosity of the dispersion or solution.
Preferably, the use amounts for polyethylene glycol
20 000 or polyethylene glycol 35 000 are 5 to 25, in
particular 10 to 20% by weight, based on the polymer
mixture. Additionally, other plasticizers, such as, for
example, triethyl citrate, in amounts of from 5 to 15%
by weight based on the polymer mixture, can be combined
with polyethylene glycol 20 000 or polyethylene glycol
35 000.
Basic substances
Basic substances can contribute to influencing or
increasing the viscosity of the dispersion and the
elasticity of the dried polymer film.
In order to prepare an aqueous solution of the enteric
(meth)acrylate copolymer, a partial or complete
neutralization of the acid groups is generally
necessary. The first or optionally also a further
enteric (meth)acrylate copolymer can, for example, be
gradually stirred into water and in so doing be
partially or completely neutralized by adding a basic
substance, such as, for example, NaOH, KOH, ammonium
hydroxide or organic bases, such as, for example,
triethanolamine. It is also possible to use a powder of
the copolymer to which a base, e.g. NaOH, has already
been added during its preparation for the purpose of
(partial) neutralization, meaning that the powder is an
already (partially) neutralized polymer. Particular
preference is given to sodium hydroxide solution or
NaOH.
Further suitable basic substances are, for example:
sodium carbonate, potassium carbonate, sodium
bicarbonate, trisodium phosphate, trisodium citrate or
ammonia or physiologically compatible amines, such as
triethanolamine or tris(hydroxymethyl)aminomethane, the
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cationic, basic amino acids histidine, arginine and/or
lysine, natural or synthetic oligomers or polymers,
e.g. of 3 to 100, preferably 5 to 25, units, of
histidine, arginine or lysine, polyhistidines,
polyarginines, polylysines, cationic or zwitterionic
phospholipids, such as, for example,
phosphatidylcholine, ribonucleosides, condensation
products of the hydroxyl function on carbon atom 1 of
ribose with the heterocyclic amino function of the
bases adenine, guanine, cytosine, thymine or uracil,
corresponding to the occurrence in RNA, or
deoxyribonucleosides, condensation products of the
hydroxyl function on carbon atom 1 of deoxyribose with
the heterocyclic amino function of the bases adenine,
guanine, cytosine, thymine or uracil, corresponding to
the occurrence in DNA.
Preference is given to a degree of neutralization of
from 3 to 12 mol% of the anionic groups at least of the
(meth)acrylate copolymer. Preferably, the
neutralization takes place with sodium hydroxide in the
form of 1.5 to 2 normal sodium hydroxide solution. The
relatively high concentration of the sodium hydroxide
solution prevents too great a reduction in the solids
content. The partial neutralization is accompanied by a
thickening of the dispersion or solution, i.e. an
increase in the viscosity.
The quantitative fraction of basic substances of the
total content of the auxiliaries which influence or
increase the viscosity of the dispersion and the
elasticity of the dried polymer film is more likely to
be low compared to plasticizers. The influence of the
basic substances in particular on the viscosity,
however, is relatively great, meaning that even these
comparatively small amounts bring about significant
effects. Preference is given to using a combination of
plasticizers and basic substances.
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Further pharmaceutically customary auxiliaries which
are not plasticizers or bases
If appropriate, further pharmaceutically customary
auxiliaries, which are not plasticizers or bases, but
which are also used in the fields of food supplements
and cosmetics, may be present in amounts of, for
example, at most 25% by weight, at most 10% by weight,
or at most 5% by weight, based on the total solids
content of the dispersion or solution. Compared to the
plasticizers or the bases, these further
pharmaceutically customary auxiliaries only influence
the viscosity of the dispersion or solution and the
elasticity of the dried polymer film to a low degree,
if at all.
Here, mention is to be made, for example, of
antioxidants, dyes, flavourings, lustre agents,
lubricants, such as, for example, talc, wetting agents,
pigments, stabilizers, sweeteners etc. These serve
primarily as processing auxiliaries and are intended
primarily to ensure, for example, a safe and
reproducible production process, good long-term storage
stabilities, a pleasant appearance or the
identifiability.
In particular, pigments require particular mention. In
order to be covering, pigments have to be added, for
example, in relatively high concentrations, for example
in amounts of from 10 to 25% by weight, based on the
total solids content of the dispersion or solution. In
this large amount and depending on the pigment used, an
at least slight, measurable influence on the viscosity
of the dispersion or the elasticity of the dried
polymer film is usually observed. When adding large
amounts, of pigments, the viscosity will possibly
increase whereas the elasticity of the dried polymer
film generally ought to decrease. However, this can be
compensated through a slight shift in the type and
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quantitative ratios of the other components which, for
their part, have a relatively great influence on the
viscosity of the dispersion or the elasticity of the
dried polymer film, the polymer mixture, and, if
appropriate, plasticizers or bases.
Further auxiliaries which are not plasticizers or bases
and which are also not pigments are, if present at all,
generally present in much lower concentrations, e.g.
less than 10% by weight, less than 5% by weight or less
than 2% by weight, based on the total solids content of
the dispersion or solution. Consequently, these further
auxiliaries merely influence the viscosity of the
dispersion or the elasticity of the dried polymer film
in a negligible manner or only to a very slight extent.
Preferably, only plasticizers and/or bases and also
optionally pigments are present as auxiliaries.
Dipping process
The dipping processes or dip coating processes for
producing capsule halves and for the enteric coating of
capsule halves are known to the person skilled in the
art (see in this regard e.g.: Fahrig W. and Hofer U.
(1983): Die Kapsel, Grundlagen, Technologie and
Biopharmazie einer modernen Arzneiform [Capsules,
Principles, Technology and Biopharmacy of a Modern Drug
Form], Wissenschaftliche Verlagsgesellschaft mbH
Stuttgart).
Capsule halves are produced by dipping sticks into
viscous solutions, e.g. gelatine solutions. The sticks
are then removed from the viscous solution. The viscous
solution dries on the sticks. The capsule halves are
cut off straight from the sticks using a cutting tool
and then removed from the sticks. Since matching upper
and lower parts of capsules have different sizes and
geometries, they are produced separately.
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The process for the enteric coating of capsule halves
can be integrated into the dipping process for
producing capsule halves by, in an additional step,
dipping the capsule halves dried on the dipsticks into
the coating composition according to the invention. In
an analogous manner, the enteric coated capsule halves
are cut off straight from the sticks using a cutting
tool and are then removed from the sticks.
Process
The invention furthermore relates to a
process for producing enteric coated capsule halves in
the dipping process by means of the steps:
= Dipping uncoated capsule halves on dipsticks into
a coating composition according to one or more of
Claims 1 to 10,
= Removing the sticks with the enteric coated
capsule halves,
= Drying the coating composition,
= Cutting off the coated capsule halves on the
sticks by means of a cutting tool and
= Removing the enteric coated capsule halves from
the sticks.
Use
The invention relates to the use of a coating
composition according to the invention for the enteric
coating of capsule halves in the dipping process. The
enteric coated capsule halves can be used for producing
capsules filled with active ingredients or food
supplements for oral applications in the fields of
pharmacy, food supplements or cosmetics.
Examples
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First (meth)acrylate copolymer:
EUDRAGIT L100-55 is a copolymer of 50% by weight
of ethyl acrylate and 50% by weight of methacrylic
acid.
Further (meth)acrylate copolymers
EUDRAGIT FS is a copolymer of 25% by weight of
methyl methacrylate, 65% by weight of methyl
acrylate and 10% by weight of methacrylic acid.
EUDRAGIT FS 30 D is a dispersion comprising 30%
by weight of EUDRAGIT FS.
EUDRAGIT NE is a copolymer of 30% by weight of
ethyl acrylate and 70% by weight of methyl
methacrylate.
Auxiliaries which influence the viscosity of the
dispersion and the elasticity of the dried polymer
film:
Polyethylene glycol 35 000 (PEG 35 000) and
triethyl citrate (TEC), and NaOH (for the partial
neutralization of EUDRAGIT L100-55 / EUDRAGIT
L 30 D55).
Formulations:
A partially neutralized redispersion of
EUDRAGIT L 100 - 55 served as the basis for all
examples and as comparative examples. This has the
purpose of achieving a somewhat higher solids
concentration than with standard commercial
EUDRAGIT L 30 D - 55.
For this, 300 g of EUDRAGIT L 100 - 55 were
incorporated into 650 g of demineralized water through
slow addition by means of a propeller stirrer. After
stirring for 30 minutes, 50 g of 2 N NaOH solution were
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then slowly added in order to produce a dispersion with
a solids content of 30.4%. The degree of partial
neutralization corresponds to about 6 mol% of the
anionic groups present in the copolymer. The following
final mixtures were prepared using this base
formulation. Standard commercial hard gelatine capsule
shells were coated therewith by dipping with subsequent
drying.
The results of Examples 1 to 3 and Comparative Examples
C4 to C7 are summarized in the table below.
Table
Example 1 2 3 C4 C5 C6 C7
EUDRAGIT
L 100-55 100 100 100 100 100 / /
dispersion
with 30.4%
solids
EUDRAGIT / 100 100 / / 100 100
FS 30 D
EUDRAGIT 100 / / / / / /
NE 30 D
PEG 35 000 15 15 15 / 30 / /
(% of polymer)
PEG 20 000 / / / 20 / / /
(% of polymer)
TEC (% of / 5 10 / / 10 20
polymer)
Viscosity 801 316 290 70 8700 70 70
[mPa=s ]
Elongation at
break [%] 430 261 398 34 225 394 1236
Dissolution of 25-30 15-20 15-20 15-20 15-20 > 60 > 60
sample capsule min min min min min min min
at pH 6.8
ISolids content 33.2 34.2 35.1 34.3 36.1 32.0 34.0
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[% by wt.)
Brittleness of +++ + ++ --- - ++ +++
the sample
capsule
of polymer = o by weight, based on the polymer or
polymers
+++ = ideal, ++ = good, + = just acceptable,
- = too thick and nonuniform, --- = very brittle
