U.S. patent application number 09/766859 was filed with the patent office on 2001-09-20 for acrylic enteric coating compositions.
Invention is credited to Chittamuru, Ramireddy, Farrell, Thomas P., Lehmann, Klaus, Mehra, Dev K., Petereit, Hans-Ulrich, Reyes, George, Vesey, Charles F..
Application Number | 20010022972 09/766859 |
Document ID | / |
Family ID | 23995328 |
Filed Date | 2001-09-20 |
United States Patent
Application |
20010022972 |
Kind Code |
A1 |
Chittamuru, Ramireddy ; et
al. |
September 20, 2001 |
Acrylic enteric coating compositions
Abstract
A non-toxic, edible, enteric film coating, dry powder
composition for use in making an aqueous enteric suspension which
may be used in coating pharmaceutical tablets comprises a) an
acrylic resin, said resin comprising i) from 20 to 85 percent by
weight of at least one alkyl acrylate or alkyl methacrylate moiety,
ii) from 80 to 15 percent by weight of at least one vinyl or
vinylidene moiety having a carboxylic acid group capable of salt
formation, and iii) from 0 to 30 percent by weight of at least one
other vinyl or vinylidene moiety copolymerizable with i) and ii),
b) an alkalizing agent capable of reacting with the acrylic resin
such that, after reaction, 0.1 to 10 mole percent of the acidic
groups in 1a-ii) are present in the salt form, and c) a
detacktifier.
Inventors: |
Chittamuru, Ramireddy;
(Lansdale, PA) ; Reyes, George; (Perkiomenville,
PA) ; Farrell, Thomas P.; (Warrington, PA) ;
Vesey, Charles F.; (Hatfield, PA) ; Mehra, Dev
K.; (Furlong, PA) ; Petereit, Hans-Ulrich;
(Darmstadt, DE) ; Lehmann, Klaus; (Rossdorf,
DE) |
Correspondence
Address: |
ROBERTS & MERCANTI, LLP
ENTERPRISE DEVELOPMENT CENTER II
105 LOCK STREET
NEWARK
NJ
07103
US
|
Family ID: |
23995328 |
Appl. No.: |
09/766859 |
Filed: |
January 19, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09766859 |
Jan 19, 2001 |
|
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09501866 |
Feb 10, 2000 |
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Current U.S.
Class: |
424/439 ;
424/440; 424/476; 424/479; 424/480; 424/481; 424/482; 424/490;
424/493; 424/494; 424/496; 424/497; 424/498; 427/2.21; 524/297;
524/89 |
Current CPC
Class: |
A61K 9/2813 20130101;
A61K 9/2846 20130101; A61K 9/2893 20130101; A61K 47/02
20130101 |
Class at
Publication: |
424/439 ;
427/2.21; 424/440; 424/476; 424/479; 424/480; 424/481; 424/482;
424/490; 424/493; 424/494; 424/496; 424/497; 424/498; 524/89;
524/297 |
International
Class: |
A61K 047/00 |
Claims
1. A non-toxic, edible, enteric film coating, dry powder
composition for use in making an aqueous enteric suspension which
may be used in coating pharmaceutical tablets comprising a) an
acrylic resin, said resin comprising i) from 20 to 85 percent by
weight of at least one alkyl acrylate or alkyl methacrylate moiety,
ii) from 80 to 15 percent by weight of at least one vinyl or
vinylidene moiety having a carboxylic acid group capable of salt
formation, and iii) from 0 to 30 percent by weight of at least one
other vinyl or vinylidene moiety copolymerizable with i) and ii),
b) an alkalizing agent capable of reacting with the acrylic resin
such that, after reaction, 0.1 to 10 mole percent of the acidic
groups in 1a-ii) are present in the salt form, and c) a
detackifier.
2. The enteric film coating dry powder composition of claim 1,
further including a plasticizer.
3. The enteric film coating dry powder composition of claim 1,
further including a pigment.
4. The enteric film coating dry powder composition of claim 1,
further including a flow aid.
5. The enteric film coating dry powder composition of claim 1,
further including a surfactant.
6. The enteric film coating dry powder composition of claim 1,
further including an anti-agglomerating agent.
7. The enteric film coating dry powder composition of claim 1,
further including a secondary film former.
8. The enteric film coating dry powder composition of claim 1,
further including a secondary detackifier.
9. The enteric film coating dry powder composition of claim 1, the
alkyl acrylate being ethyl acrylate and the vinyl or vinylidene
moiety having a carboxylic acid group capable of salt formation
being methacrylic acid.
10. The enteric film coating dry powder composition of claim 1, the
alkalizing agent (b) being a bicarbonate, a carbonate, a phosphate,
or a hydroxide of sodium or potassium, magnesium carbonate,
magnesium hydroxide, ammonium carbonate, ammonium bicarbonate,
magnesium oxide, calcium hydroxide, or mixtures thereof.
11. The enteric film coating dry powder composition of claim 1, the
detackifier being talc, aluminum hydrate, glyceryl monostearate,
kaolin, or mixtures thereof.
12. The enteric film coating dry powder composition of claim 2, the
plasticizer being triethylcitrate, glyceryltriacetate,
acetyltriethylcitrate, dibutyl sebacate, diethylphthalate,
polyethylene glycol having a molecular weight in the range of 200
to 8000, glycerol, castor oil, copolymers of propylene oxide and
ethylene oxide, or mixtures thereof.
13. The enteric film coating dry powder composition of claim 3, the
pigment being FD&C and D&C lakes, titanium dioxide,
magnesium carbonate, talc, pyrogenic silica, iron oxides, channel
black, riboflavin, carmine 40, curcumin, annatto, insoluble dyes,
pearlescent pigments based on mica and/or titanium dioxide or
mixtures thereof.
14. The enteric film coating dry powder composition of claim 4, the
flow aid being silica.
15. The enteric film coating dry powder composition of claim 5, the
surfactant being sodium lauryl sulfate, dioctyl sodium
sulfosuccinate, polysorbate 80, Tween 80 or mixtures thereof.
16. The enteric film coating dry powder composition of claim 6, the
anti-agglomerating agent being kaolin.
17. The enteric film coating dry powder composition of claim 7, the
secondary film former being xanthan gum, sodium alginate, propylene
glycol alginate, hydroxypropylmethylcellulose (HPMC),
hydroxyethylecellulose (HEC), sodium carboxymethylcellulose (sodium
CMC), polyvinylpyrrolidone (PVP), Konjac flour, carrageenan, other
film-forming polymer or mixtures thereof.
18. The enteric film coating dry powder composition of claim 8, the
secondary detackifier being sodium sulfate, calcium sulfate,
calcium chloride, other inorganic or organic water-sequestering
agents or mixtures thereof.
19. The enteric film coating dry powder composition of claim 9,
further including a plasticizer, a pigment, a flow aid, a
surfactant, an anti-agglomerating agent, a secondary film former,
and a secondary detackifier, the acrylic resin being in a range of
about 20 to about 80 percent by weight of the composition, the
alkalizing agent being a bicarbonate, a carbonate, a phosphate, or
a hydroxide of sodium or potassium, magnesium carbonate, magnesium
hydroxide, ammonium carbonate, ammonium bicarbonate, magnesium
oxide, calcium hydroxide, or mixtures thereof the detackifier being
talc, aluminum hydrate, glyceryl monostearate, kaolin, or mixtures
thereof, the detackifier being in the range of about 5% to about
40% by weight of the composition, the plasticizer being
triethylcitrate, glyceryltriacetate, acetyltriethylcitrate, dibutyl
sebacate, diethylphthalate, polyethylene glycol leaving a molecular
weight in the range of 200 to 8000, glycerol, castor oil,
copolymers of propylene oxide and ethylene oxide, or mixtures
thereof, the plasticizer being in the range of about 2% to about
20% by weight of the composition, the pigment being FD&C and
D&C lakes, titanium dioxide, magnesium carbonate, talc,
pyrogenic silica, iron oxides, channel black, riboflavin, carmine
40, curcumin, annatto, insoluble dyes, pearlescent pigments based
on mica and/or titanium dioxide or mixtures thereof, the pigment
being in the range of greater than 0% to about 50% by weight of the
composition, the flow aid being silica, the flow aid being in the
range of greater than 0% to about 3% by weight of the composition,
the surfactant being sodium lauryl sulfate, dioctyl sodium
sulfosuccinate, polysorbate 80, Tween 80 or mixtures thereof, the
surfactant being in the range of greater than 0% to about 5% by
weight of the composition, the anti-agglomerating agent being
kaolin, the anti-agglomerating agent being present in the range of
greater than 0% to about 40% by weight of the composition, the
secondary film former being xanthan gum, sodium alginate, propylene
glycol alginate (PGA), hydroxypropylmethylcellulose (HPMC),
hydroxyethylecellulose (HEC), sodium carboxymethylcellulose (sodium
CMC), polyvinylpyrrolidone (PVP), Konjac flour, carrageenan, other
film-forming polymer or mixtures thereof, the secondary film former
being present in the amount of greater than 0% to about 5% by
weight of the composition, the secondary detackifier being sodium
sulfate, calcium sulfate, calcium chloride, other inorganic or
organic water-sequestering agents or mixtures thereof, and the
secondary detackifier being present in the amount of greater than
0% to about 5% by weight of the composition.
20. A non-toxic, edible, enteric film coating, dry powder
composition for use in making an aqueous enteric suspension which
may be used in coating pharmaceutical tablets comprising a) an
acrylic resin, said resin comprising i) from 15 to 80 percent by
weight of at least one vinyl or vinylidene moiety having a
carboxylic acid group capable of salt formation, and ii) from 20 to
85 percent by weight of at least one other vinyl or vinylidene
moiety copolymerizable with i), b) an alkalizing agent capable of
reacting with the acrylic resin such that, after reaction, 0.1 to
10 mole percent of the acidic groups in 1a-i) are present in the
salt form, and c) a detackifier.
21. The composition of claim 20, further including, a plasticizer,
a pigment, a flow aid, a surfactant, and anti-agglomerating agent,
a secondary film former, a secondary detacktifier, or a combination
thereof.
22. A non-toxic, edible, enteric film coating, dry powder
composition for use in making an aqueous enteric suspension which
may be used in coating pharmaceutical tablets comprising a) an
acrylic resin comprising at least one vinyl or vinylidene moiety
having a carboxylic acid group capable of salt formation, b) an
alkalizing agent capable of reacting with the acrylic resin such
that, after reaction, 0.1 to 10 mole percent of the acidic groups
of the vinyl or vinylidene moiety are present in the salt form, and
c) a detackifier.
23. The composition of claim 22, further including a plasticizer, a
pigment, a flow aid, a surfactant, and anti-agglomerating agent, a
secondary film former, a secondary detacktifier, or a combination
thereof.
24. A method of making an aqueous coating dispersion for use in
pharmaceuticals, confectionery and food, comprising the steps of
(a) dry blending an acrylic resin, an alkalizing agent, and a
detackifier to form a non-toxic, edible, enteric film coating, dry
powder composition using a "V-blender," food processor or similar
apparatus, (b) adding blended composition to water, and (c)
stirring said composition in water using a high-shear mixer or
similar apparatus to form an aqueous coating suspension.
25. The method of claim 24, further including mixing a plasticizer,
a pigment, a flow aid, a surfactant, and anti-agglomerating agent,
a secondary film former, a secondary detacktifier, or a combination
thereof with the acrylic resin, the alkalizing agent, and the
detacktifier to form the non-toxic, edible, enteric film coating,
dry powder composition.
26. The method of coating substrates such as pharmaceutical tablets
and the like with a film coating comprising the steps of mixing an
acrylic resin, an alkalizing agent, and a detacktifier together to
form a non-toxic, edible, enteric film coating, dry powder
composition, mixing the composition into water to form an aqueous
coating suspension, applying an effective amount of said coating
suspension onto said substrates to form a film coating on said
substrates, and drying the film coating on said substrates.
27. The method of claim 26, further including mixing a plasticizer,
a pigment, a flow aid, a surfactant, and anti-agglomerating agent,
a secondary film former, a secondary detacktifier, or a combination
thereof with the acrylic resin, the alkalizing agent, and the
detacktifier to form the non-toxic, edible, enteric film coating,
dry powder composition.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to the field of aqueous enteric film
coating of pharmaceutical tablets and the like for preventing
release of the ingredients of the coated tablet in the gastric
juices of the stomach and for releasing the ingredients of the
tablets in the intestines, and more particularly concerns providing
a fully-formulated, non-toxic, edible, enteric, film-coating, dry
powder composition based on an acrylic resin for use in making an
aqueous enteric coating suspension that may be used in coating
pharmaceuticals with an intestinally soluble coating that is
insoluble in gastric juices of the stomach.
[0003] 2. Description of the Prior Art
[0004] Several aqueous enteric film-coating systems are known.
These include the AQUATERIC system, based on cellulose acetate
phthalate, the SURETERIC system, based on polyvinylacetate
phthalate (PVAP), and the EUDRAGIT system, based on copolymers of
acrylic acid esters and methacrylic acid. Both the AQUATERIC and
EUDRAGIT systems require at least three processing steps to form
the enteric coating suspension. With the AQUATERIC system, the
AQUATERIC powder is dispersed in water followed by stepwise
addition of plasticizer Tween 80 and optional pigments to form the
AQUATERIC suspension. The EUDRAGIT L system is available as a
powder (L100-55) or as an aqueous dispersion (L30-D). The "EUDRAGIT
L Technical Application Pamphlet (Info LD-13/e)" published by Rohm
Pharma GmbH specifics a step-wise procedure to prepare an aqueous
enteric dispersion which includes: 1) addition of the EUDRAGIT
L100-55 powder to water; 2) dropwise addition of a pre-calculated
amount of aqueous sodium hydroxide solution; 3) stirring of the
dispersion for 30 minutes using a simple stirrer running at a
medium and controllable speed; 4) filtration of the suspension; 5)
subsequent addition of an aqueous solution of plasticizer (at a
recommended use level of 10% by weight with respect to the EUDRAGIT
L100-55 powder), "separating agent", and anti-foam to the filtered
suspension; 6) further stirring; and 7) final filtration. Special
precautions noted in this pamphlet include the warning that
coagulation of the EUDRAGIT L aqueous dispersion may occur as a
result of the presence of electrolytes, foam formation, exposure to
heat and frost, the presence of finely divided pigments and
exposure to high shear gradients when using fast-running stirrers
and mills. Special attention is also drawn to the requirement to
observe the specified formulation ratios, as a deviation could
result in the formation of coagulum, which as set out in the
pamphlet is "impossible" to redisperse rendering the entire aqueous
dispersion "unusable."
[0005] The EUDRAGIT L30-D suspension is a dispersion of ethyl
acrylate/methacrylic acid copolymer, 30% by weight in water. The
"EUDRAGIT L Technical Application Pamphlet (Info LD-11/e)"
published by Rohm Pharma GmbH specifies a multi-step process for
forming a complete aqueous dispersion system based on EUDRAGIT
L30-D suspension that includes: 1) addition of plasticizer, 2)
addition of a "separating agent"; 3) addition of an anti-foam; 4)
optional addition of pigments; 5) stirring; and 6) final
filtration. Special precautions, identical to those described for
EUDRAGIT L100-55 powder, are also indicated in the EUDRAGIT L30-D
suspension pamphlet.
[0006] The SURETERIC composition, which is described in Colorcon
U.S. Pat. No. 5,733,575. which is incorporated herein by reference,
advanced the art in the field by teaching the complete formulation
of an enteric film coating pre-mix, which may be dispersed readily
in water along with an anti-foam in two steps. The SURETERIC system
requires the addition of a viscosity modifier to prevent settling
of the suspended solids in the resulting aqueous dispersion during
coating.
[0007] Lehmann et al. U.S. Pat. No. 4,520,172, which is
incorporated herein by reference, discloses a binary mixture of
EUDRAGIT L copolymer and a suitable alkalizing agent or
"salt-forming agent." However, there are no known enteric
film-coating systems based on the copolymer of ethyl acrylate and
methacrylic acid of the EUDRAGIT L system that are analogous to the
SURETERIC system. Further, given the precautions cited in the Rohm
Pharma literature and the chemical differences between PVAP and the
methacrylic acid/ethyl acrylate copolymers, it would be surprising
and unexpected if the Lehmann et al. binary system could be
expanded into a fully-formulated solid composition which could then
be dispersed readily in water for use in providing an enteric film
coating.
SUMMARY OF THE INVENTION
[0008] It is an object of this invention to provide a
fully-formulated, enteric film coating composition based on
EUDRAGIT L copolymers that may be readily dispersed in water and
applied to pharmaceutical tablets and the like.
[0009] Another object of this invention is to provide a fully
formulated, enteric film coating composition based on EUDRAGIT L
copolymers which does not cake upon preparation.
[0010] Another object of this invention is to provide a fully
formulated, enteric film coating composition based on EUDRAGIT L
copolymers which does not form agglomerates upon storage at
elevated temperature and humidity.
[0011] Another object of this invention is to provide a
fully-formulated, enteric film coating composition based on
EUDRAGIT L copolymers which may be dispersed readily into water to
form a coating dispersion that when applied to pharmaceutical
tablets produces a tack-free coating.
[0012] Another object of this invention is to provide a fully
formulated, enteric film coating composition, containing lake
pigment and neutralizing agent, said lake pigment being stable upon
dispersion in water.
[0013] Another object of this invention is to provide a
fully-formulated, enteric film coating composition based on
EUDRAGIT L copolymers which may be dispersed readily into water to
form a coating dispersion that when applied to pharmaceutical
tablets produces a film coating having an exceptional degree of
film strength. This exceptional film strength is manifested by
excellent performance in a "stressed disintegration test."
[0014] Another object of this invention is to provide a fully
formulated, enteric film coating composition based on EUDRAGIT L
copolymers that disperses in water without the formation of
coagulum.
[0015] Another object of this invention is to reduce the number of
steps in the preparation of aqueous film coating dispersions based
on EUDRAGIT L copolymers from six (6) or more to two (2), thereby
achieving the beneficial result of reducing the overall preparation
time for preparing aqueous film coating dispersions from about 90
minutes to about 20 minutes.
[0016] These and other objects of the invention are accomplished by
our invention, which is described below.
DETAILED DESCRIPTION OF THE INVENTION
[0017] In accordance with the invention, our non-toxic, edible,
enteric film coating, dry powder composition for use in making an
aqueous enteric suspension which may be used in coating
pharmaceutical tablets comprises an acrylic resin (e.g., EUDRAGIT L
copolymers), an alkalizing agent, and a detackifier. Optionally but
advantageously, our dry powder composition may also include one or
more of the following additives: a plasticizer; a pigment; a flow
aid; a surfactant; an anti-agglomerating agent; a secondary film
former; and a secondary detackifier. In a particularly preferred
embodiment of this invention, the inventive dry powder composition
contains an acrylic resin, an alkalizing agent, a detackifier, a
plasticizer, a pigment, a flow aid, a surfactant, an
anti-agglomerating agent, a secondary film-former and a secondary
detackifier.
[0018] A method of making the inventive dry powder composition
comprises the steps of mixing an acrylic resin with an alkalizing
agent, detackifier, and optionally with one or more of the
following additives: a plasticizer; a pigment; a flow aid; a
surfactant; an anti-agglomerating agent; a secondary film former;
and a secondary detackifier. The resulting enteric film coating dry
powder composition and a separately-added anti-foam is readily
dispersed in water, preferably deionized water, using a high shear
mixer and is ready to use in 15-30 minutes. A high shear mixer is
used rather than a slower stirrer to eliminate the formation of
coagulum.
[0019] In accordance with the invention, a method of coating
substrates, such as pharmaceutical tablets and the like, comprises
mixing sequentially anti-foam and the inventive dry composition
into water to form a coating suspension, applying the coating
suspension onto the substrate to be coated to form a film coating
oil the substrates, and drying the film coating on the
substrates.
[0020] The enteric polymer is an acrylic resin which comprises at
least one vinyl or vinylidene moiety having a carboxylic acid group
capable of salt formation. The acrylic resin may comprise of at
least one vinyl or vinylidene moiety having a carboxylic acid group
capable of salt formation and at least one alkyl acrylate or alkyl
methacrylate moiety. The acrylic resin also may comprise of at
least one vinyl or vinylidene moiety having a carboxylic acid group
capable of salt formation, at least one alkyl acrylate or alkyl
methacrylate moiety, and at least one other vinyl or vinylidene
moiety copolymerizable with a) the alkyl acrylate or alkyl
methacrylate moiety and b) the vinyl or vinylidene moiety having a
carboxylic acid group capable of salt formation. Further, the
acrylic resin may comprise of at least one vinyl or vinylidene
moiety having a carboxylic acid group capable of salt formation and
at least one other vinyl or vinylidene moiety copolymerizable with
the vinyl or vinylidene moiety having a carboxylic acid group
capable of salt formation.
[0021] Preferably, the enteric polymer is an acrylic resin which is
comprised of: (1) from 20 to 85 percent by weight of at least one
alkyl acrylate or alkyl methacrylate moiety; (2) from 80 to 15
percent by weight of at least one vinyl or vinylidene moiety having
a carboxylic acid group capable of salt formation; and (3) from 0
to 30 percent by weight of at least one other vinyl or vinylidene
moiety copolymerizable with (1) and (2). In a particularly
preferred embodiment of this invention, the alkyl acrylate (1) is
ethyl acrylate, and the vinyl moiety (2) is methacrylic acid.
EUDRAGIT L100-55 powder is one example of a copolymer system
meeting this definition.
[0022] Preferably, the acrylic resin comprises about 20% to about
80% by weight of the dry coating composition of the invention.
[0023] The alkalizing agent may be a bicarbonate, a carbonate, a
phosphate, or a hydroxide of sodium or potassium, magnesium
carbonate, magnesium hydroxide, ammonium carbonate, ammonium
bicarbonate, magnesium oxide, calcium hydroxide, or mixtures
thereof. The quantity of alkalizing agent used is directly
dependent on the amount of carboxylic acid-bearing vinyl or
vinylidene moiety present in the acrylic resin. Specifically, said
alkalizing agent is added in a quantity such that, after reaction
with the acrylic resin, 0.1 to 10 mole percent of the acidic groups
are present in the salt form.
[0024] The detackifer may be talc, aluminum hydrate, glyceryl
monostearate, kaolin, or mixtures thereof and is used principally
to reduce the incidence of tablet-to-tablet sticking that can occur
during the film coating of pharmaceutical tablets and the like
using aqueous dispersions based on the inventive compositions.
Preferably, the detackifier comprises about 5% to about 40% by
weight of the dry coating composition of the invention.
[0025] The plasticizer may be triethylcitrate, glyceryltriacetate,
acetyltriethylcitrate, dibutyl sebacate, diethylphthalate,
polyethylene glycol having a molecular weight in the range of 200
to 8000, glycerol, castor oil, copolymers of propylene oxide and
ethylene oxide, or mixtures thereof. When no plasticizer is
included in the dry powder composition of the invention, the
plasticizer is mixed separately into the coating suspension of the
invention. Preferably, the plasticizer comprises 0% to about 20% by
weight of the coating composition of the invention, and more
preferably, the plasticizer comprises about 2% to about 20% by
weight of the dry coating composition of the invention.
[0026] The pigment may be an FD&C or a D&C lake, titanium
dioxide, magnesium carbonate, talc, pyrogenic silica, iron oxides,
channel black, riboflavin, carmine 40, curcumin, annatto, insoluble
dyes, pearlescent pigments based on mica and/or titanium dioxide or
mixtures thereof. Other examples of suitable pigments are listed in
Jeffries U.S. Pat. No. 3,149,040; Butler, et. al. U.S. Pat. No.
3,297,535; and Colorcon U.S. Pat. No. 3,981,984; all of which are
incorporated herein by reference. The pigment may also include lake
blends which contain a plasticizer and OPADRY pigmented coating
compositions, some of which are disclosed in Colorcon U.S. Pat. No.
4,543,370 , which is incorporated herein by reference. Preferably,
the pigment comprises 0% to about 50% by weight of the inventive
dry coating composition.
[0027] The flow aid may be silica such as fumed silica, supplied
under the tradename Cab-O-Sil by Cabot, Inc. The flow aid imparts
flowability to the powdered composition during dry blending and
subsequent transferring from the blender to a storage container.
Preferably, the flow aid comprises 0% to about 3% by weight of the
inventive dry coating composition.
[0028] The surfactant may be sodium lauryl sulfate, dioctyl sodium
sulfosuccinate, polysorbate 80, Tween 80, or mixtures thereof.
Preferably, the surfactant comprises 0% to about 5% by weight of
the inventive dry composition.
[0029] The anti-agglomerating agent may be kaolin. The quantity of
anti-agglomerating agent in the inventive dry coating composition
ranges from 0% to about 40% by weight of the inventive dry coating
composition. Surprisingly, it has been found that relatively low
levels of kaolin prevent clumping during preparation of the
powdered composition and during storage of the final composition at
elevated temperature and humidity. Preferably, kaolin is used at
levels from greater than 0 percent to about 40% by weight of the
composition. It has unexpectedly been found that a given level of
kaolin imparts a much greater level of anti-agglomerating effect
than the same amount of talc or silica, which are also known to be
anti-agglomerating agents. Beneficially, kaolin serves both as an
anti-agglomerating agent and a detackifier.
[0030] The secondary film former may be xanthan gum, sodium
alginate, propylene glycol alginate, hydroxypropylmethylcellulose
(HPMC), hydroxyethylecellulose (HEC), sodium carboxymethylcellulose
(sodium CMC), polyvinylpyrrolidone (PVP), Konjac flour,
carrageenan, other film-forming polymer or mixtures thereof.
Preferably, the amount of secondary film former in the coating
composition ranges from 0% to about 5% by weight of the dry coating
composition of the invention. Use of the secondary film former
improves the film strength of the inventive composition.
Surprisingly, very low levels of a secondary film former can
improve film strength as demonstrated by coating performance in the
"stressed enteric test" developed by Colorcon. In a preferred
embodiment of this invention, the incorporation of xanthan gum at a
level of 0.5% by weight of the inventive composition resulted in
superior stressed enteric test results when compared to a
composition without xanthan gum.
[0031] The secondary detackifier may be sodium sulfate, calcium
sulfate, calcium chloride, other inorganic or organic
water-sequestering agents or mixtures thereof Preferably, the
amount of secondary detackifier in the coating composition ranges
from 0% to about 5% by weight of the inventive dry coating
composition of the invention. Surprisingly, incorporation of very
low levels (greater than 0 to 5% by weight) of a secondary
detackifier results in a dramatic reduction of tablet tackiness,
after being film-coated using the inventive aqueous dispersions in
the most tack-prone formulations. In a preferred embodiment of this
invention, incorporation of calcium sulfate, at a level of only
0.15% by weight of the composition, results in the formation of
tack-free tablets when coated with the inventive aqueous
dispersions.
[0032] Surprisingly, a given level of calcium sulfate or similar
water-sequestering compound is much more effective in reducing
coated tablet tack than identical levels of other known
detackifiers such as talc and glyceryl monostearate. It is
postulated that the secondary detackifer is functioning as a
water-sequestering agent and binds free water on the tablet
surface, preventing interaction of the water with the coalescing
polymer, thereby effectively increasing the polymer glass
transition temperature (Tg) and its resistance to further softening
and attendant sticking to like tablets.
[0033] It is particularly advantageous to incorporate as many of
the benefit-imparting additives of the inventive compositions into
one formulation as possible. Therefore, a particularly preferred
embodiment of this invention is the composition comprising: 1) an
acrylic resin, preferably about 20 to about 80% by weight of the
composition; 2) an alkalizing agent, present in an amount such that
between about 0.1 to 10 mol % of the carboxylic acid groups on the
acrylic resin will be neutralized; 3) a detackifier, preferably in
the range of about 5% to about 40% by weight of the composition; 4)
a plasticizer, preferably in the range of about 2% to about 20% by
weight of the composition; 5) a pigment, preferably in the range of
greater than 0% to about 50% by weight of the composition; 6) a
flow aid, preferably in the range of greater than 0% to about 3% by
weight of the composition; 7) a surfactant, preferably in the range
of greater than 0% to about 5% by weight of the composition; 8) an
anti-agglomerating agent, preferably in the range of greater than
0% to 40% by weight of the composition; 9) a secondary film former,
preferably in the amount of greater than 0% to about 5% by weight
of the composition; and 10) a secondary detackifier, preferably in
the amount of greater than 0% to about 5% by weight of the
composition.
[0034] It has been unexpectedly found that when said
fully-formulated composition, containing lake pigments, is
dispersed in water, the lake pigment is completely stable. That is
no color bleeding is observed. This is particularly surprising in
light of current industry art which dictates that colorants be
added to the dispersion only after the neutralization step (acrylic
polymer reacted with neutralizing agent) is complete in order to
avoid "color bleeding."
[0035] A preferred method of preparing the inventive compositions
is by conventional dry-blending using a "V-blender", food processor
or similar device. Inventive compositions prepared by these
conventional blending technologies are dispersed in aqueous
solution prior to film-coating substrates, such as pharmaceutical
tablets and the like, with the aid of a high shear mixer. Use of a
high shear mixer allows the formation of a homogeneous aqueous
dispersion without the formation of problematic coagulum. The
following examples further illustrate the invention.
EXAMPLE 1
[0036] Aspirin cores (2.5 Kg total charge; 325 mg aspirin per
tablet) were coated sequentially with a sub-coating dispersion made
from a white Opadry.RTM. II coating composition (formula #574-39)
and an enteric coating suspension prepared from the inventive
composition. First, the Opadry II sub-coating dispersion was
prepared by adding the dry Opadry II formula (50 grams) to
deionized water (250 grams) and stirring this combination with a
propeller mixer for 30 minutes. A homogeneous dispersion was thus
obtained.
[0037] The inventive enteric, dry powder composition of this
Example 1 was prepared by thoroughly mixing Eudragit.RTM. L100-55
powder (120.3 grams; 48.13 wt %), sodium bicarbonate (3.6 grams;
1.44 wt %), talc (57.3 grams; 22.93 wt %), Yellow#6 lake pigment
(9.5 grams; 3.8 wt %), titanium dioxide (14.3 grams; 5.7 wt %),
fumed silica (3.3 grams; 1.25 wt %), sodium lauryl sulfate (1.25
,grams; 0.5 wt %), kaolin (12.5 grams; 5 wt %) and xanthan gum
(0.625 grams; 0.25 wt %) in a food processor for five minutes. To
this solid mixture was added triethylcitrate (27.5 grams; 11 wt %).
After an additional two minutes of mixing, a homogeneous,
free-flowing powder with no visible agglomerates was obtained.
[0038] The inventive enteric suspension was then prepared by first
mixing Anti-foam FG-10 (1 gram) into deionized water (1.25 Kg)
using a Silverson high-shear mixer (Model L-4RT-A) equipped with a
general purpose dispersion head (i.e., GPDH ring) and operating at
1,500-2,000 RPM, with the stator placed in the center of vessel,
for two minutes. The mixer stir rate was increased to 10,000 RPM,
and the inventive enteric dry powder composition (250 grams) was
added gradually to the vortex at a rate slow enough to avoid
clumping (about one minute). After the addition was complete, the
stator was placed off-center in the vessel to minimize air
entrainment, and the suspension was further mixed at 10,000 RPM for
an additional ten (10) minutes to yield a homogeneous, suspension
with no visible agglomerates and no observable pigment degradation
nor color bleeding.
[0039] To a 15 inch diameter O'Hara LabCoat 1 coating pan equipped
with a Cole-Parmer Masterflex pump with one pump head,
platinum-cured silicone tubing (size 15) and one Spraying Systems
spray gun (1/8" VAU SS; fluid nozzle-VF60100-SS; air
cap-VA1282125-60-SS), were added aspirin cores (2.5 Kg total
charge; 325 mg of aspirin per tablet). The tablets were
sequentially coated with the Opadry II sub-coating dispersion and
the inventive, enteric coating suspension under the following
process conditions:
1 Coating Process Parameters (15" O'Hara LabCoat 1) Subcoat Enteric
Coat Fluid Delivery Rate (g/min) 30 20 Atomizing Air Pressure (psi)
20 20 Pattern Air Pressure (psi) 30 30 Tablet Bed Temperature
(.degree. C.) 43 30 Pan Speed (RPM) 15 17
[0040] No tackiness or tablet-to-tablet sticking was observed
during the coating run.
[0041] The final coated tablets were evaluated using USP
Dissolution Method <711> according to the "delayed-release"
aspirin monograph. As prescribed by this method, six tablets coated
as described in Example 1 were placed in 0.1 N HCl for two hours at
37.degree. C. The release in the acid phase of the test after two
hours was 0.1%, as compared with the upper limit of 10%. The six
tablets were then placed in phosphate buffer (pH=6.8), and the
amount of aspirin released after 90 minutes was greater than 80% in
35 minutes, as compared to the compendial requirement of not less
than 80% released after 90 minutes.
[0042] The final coated tablets were also evaluated using a
modified version of USP Disintegration Method <701>. Fifty
tablets prepared as described in Example 1 were stressed for 100
revolutions in a friabilator. Then, the 50 stressed tablets were
placed in a basket assembly and immersed for one hour in simulated
gastric fluid (0.1 N HCl). The basket was moved up and down in the
simulated gastric fluid at a rate of about 28-32 cycles/minute.
Fifty unstressed tablets were also placed in a basket assembly and
immersed for one hour in simulated gastric fluid. The basket was
moved up and down at a rate of about 28-32 cycles/min. The
integrity of the tablets was evaluated after removal from the
simulated gastric fluid. In both cases (stressed and unstressed),
none of the tablets exhibited signs of bloating, cracks or
fissures. The final coated tablets were also examined
qualitatively. The resulting orange coating was smooth and uniform
and showed no evidence of chipping, peeling or color
non-uniformity.
EXAMPLES 2-5
[0043] Examples 2-5 are inventive compositions and inventive
suspensions prepared in a manner analogous to the method described
in Example 1 with slight adjustments to the composition as detailed
in the following table. In all Examples 2-5, inventive compositions
were free-flowing powders with no agglomerates, which when
suspended in water, yielded suspensions with no visible coagulum
and no observable pigment degradation or color bleeding. In all
Examples 2-5, no tackiness was observed during the tablet-coating
step. All tablets appeared smooth and uniform in both texture and
color. Differences were noted in dissolution test performance as a
function of xanthan gum content. The presence of xanthan gum in the
formulas resulted in improved stressed dissolution test
performance, which strongly suggests the film strength and
imperviousness significantly increased when only very small
quantities of xanthan gum were added.
2 Comparative Data Table - Examples 2-5 Wt % in 250 Grams
Components Example 2 Example 3 Example 4 Example 5 Eudragit .RTM.
L100-55 55.0 55.0 55.0 55.0 Sodium bicarbonate 1.65 1.65 1.65 1.65
Talc 20.1 20.6 24.6 16.0 Kaolin 5.0 5.0 5.0 5.0 Titanium dioxide
3.0 3.0 3.0 S.4 Yellow #6 lake pigment 2.0 2.0 2.0 5.6 Sodium
lauryl sulfate 0.5 0.5 0.5 0.5 Fumed Silica 1.25 1.25 1.25 1.25
Triethylcitrate 11.0 11.0 6.5 6.5 Xanthan Gum 0.5 0.0 0.5 0.0 100%
100% 100% 100% % Passed Standard Disintegration 100 100 100 100
Test Stressed Disintegration 98 90 84 28 Test
EXAMPLES 6-9
[0044] Examples 6-9 are inventive compositions and inventive
suspensions prepared in a manner analogous to the method described
in Example 1 with slight adjustments to the composition as detailed
in the following table. In Examples 6-9, inventive compositions
were free-flowing powders with no agglomerates, which when
suspended in water, yielded suspensions with no visible coagulum
and no observable pigment degradation or color bleeding. During the
tablet coating step of Examples 6-9, the tablet bed temperature was
32-35.degree. C., in contrast to the bed temperature of 30.degree.
C. maintained in Examples 1-5. Generally, propensity toward
tackiness increases with increasing bed temperature. In Example 6,
some tackiness and tablet-to-tablet sticking was observed in the
tablet coating step. In Examples 7-9, no tackiness was observed
during the tablet coating step. The propensity towards tackiness at
elevated bed temperature was offset by the addition of very small
quantities of a secondary detackifier (sodium sulfate, calcium
sulfate dihydrate or calcium chloride). Upon completion of the
coating runs, all tablets appeared smooth and uniform in both
texture and color.
3 8/25 (Comparative Data Table - ExampIes 6-9 Wt % in 250 Grams
Components Example 6 Example 7 Example 8 Example 9 Eudragit .RTM.
L100-55 49.0 49.0 49.0 49.0 Sodium bicarbonate 1.45 1.47 1.47 1.47
Talc 25.45 25.3 25.3 25.3 Kaolin 5.0 5.0 5.0 5.0 Titanium dioxide
5.82 5.82 5.82 5.82 Yellow #6 lake pigment 3.88 3.88 3.88 3.88
Sodium lauryl sulfate 0.5 0.5 0.5 0.5 Fumed Silica 1.30 1.28 1.28
1.28 Triethylcitrate 7.6 7.6 7.6 7.6 Sodium sulfate 0.0 0.15 0.0
0.0 Calcium sulfate dihydrate 0.0 0.0 0. 15 0.0 Calcium chloride
0.0 0.0 0.0 0.15 100% 100% 100% 100% Tackiness during Coating YES
NO NO NO % Passed Std Dissolution 100 100 100 100 Test
EXAMPLES 10 & 11
[0045] Examples 10 and 11 are inventive compositions and inventive
suspensions prepared in a manner analogous to the method described
in Example 1 except iron oxide-based colorants were used. In
Examples 10 and 11, inventive compositions were free-flowing
powders with no agglomerates, which when suspended in water,
yielded suspensions with no visible coagulum and no observable
color bleeding. In Examples 10 and 11, no tackiness was observed
during the tablet-coating step. All tablets appeared smooth and
uniform in both texture and color.
4 Comparative Data Table - Examples 10 and 11 Wt % in 250 Grams
Components Example 10 Example 11 Eudragit .RTM. L100-55 50.0 50.0
Sodium bicarbonate 1.50 1.50 Talc 26.25 26.25 Kaolin 5.0 5.0
Titanium dioxide 5.1 5.1 Red iron oxide 3.4 0.0 Yellow iron oxide
0.0 3.4 Sodium lauryl sulfate 0.5 0.5 Fumed Silica 1.25 1.25
Triethylcitrate 7.0 7.0 100% 100% Tablet Color Red Yellow Standard
Disintegration Test 98 100 (% Passed)
EXAMPLES 12-15
[0046] Examples 12-15 are inventive compositions and inventive
suspensions prepared in a manner analogous to the method described
in Example 1 with some changes to the formula as detailed in the
following table. When kaolin was included in the formula, there was
no evidence of caking or agglomerate formation in the powder. In
contrast, formulas, which contained talc but no kaolin, did show
significant caking and agglomerate formation in the powder. The
formulations or Examples 12 to 15 were tested for color bleeding,
and the test results showed no evidence of color bleeding in the
aqueous suspensions prepared from the inventive compositions both
at "time zero" and after storage of the powder compositions for one
month at 40.degree. C. and 75% relative humidity. All tablets
appeared smooth and uniform in both texture and color.
5 Comparative Data Table - Examples 12-15 Wt % in 250 Grams Example
Example Example Example Components 12 13 14 15 Eudragit .RTM.
L100-55 55.0 55.0 49.0 49.0 Sodium bicarbonate 1.76 1.76 1.57 1.57
Talc 30.0 0.0 27.0 0.0 Kaolin 0.0 30.0 0.0 27.0 Titanium dioxide
0.0 0.0 5.82 5.82 Yellow #6 Lake Pigment 0.0 0.0 3.88 3.88 Sodium
lauryl sulfate 0.5 0.5 0.5 0.5 Glyceryl monostearate 1 .6 1 .6 1 .5
1 .5 Tween .RTM. 80 2.2 2.2 2.0 2.0 Fumed Silica 0.94 0.94 0.73
0.73 Triethylcitrate 8.0 8.0 8.0 8.0 100% 100% 100% 100%
Agglomerate Formation Upon powder preparation YES NO YES NO After
powder storage for YES NO YES NO 1 month at 40.degree. C./ 75% RH
Tablet Color White White Orange Orange Standard Disintegration 96
100 98 94 Test (% Passed)
EXAMPLES 16-18
[0047] Examples 16-18 are inventive compositions and inventive
suspensions prepared in a manner analogous to the method described
in Example 1 with sonic changes to the formula as detailed in the
following table. When kaolin was included in the formula, there was
no evidence of caking or agglomerate formation in the powder. In
contrast, formulas, which contained talc but no kaolin, did show
significant caking and agglomerate formation in the powder. There
was no evidence of color bleeding in the aqueous suspensions
prepared from the inventive compositions both at "time zero" and
after storage of the powder compositions for one month at
40.degree. C. and 75% relative humidity. All tablets appeared
smooth and uniform in both texture and color. In Example 18,
elimination of glyceryl monostearate, sodium lauryl sulfate and
Tween 80 from the formula resulted in the production of coated
tablets that had much less gloss or sheen than those of Examples 16
and 17.
6 Comparative Data Table - Examples 16-18 Wt % in 250 Grams
Components Example 16 Example 17 Example 18 Eudragit .RTM. L100-55
49.0 49.0 49.0 Sodium diphosphate 1.65 1.65 1.65 (anhydrous) Talc
27.0 0.0 0.0 Kaolin 0.0 27.0 31.9 Titanium dioxide 5.82 5.82 5.82
Yellow #6 Lake Pigment 3.88 3.88 3.88 Sodium lauryl sulfate 0.5 0.5
0.0 Glyceryl monostearate 1.5 1.5 0.0 Tween .RTM. 80 2.0 2.0 0.0
Fumed Silica 0.9 0.9 0.0 Triethylcitrate 7.75 7.75 7.75 100% 100%
100% Agglomerate Formation Upon powder preparation YES NO NO After
powder storage for YES NO N/A 1 month at 40.degree. C./ 75% RH
Tablet Color/Appearance Orange/Shiny Orange/Shiny Orange/Dull
Standard Disintegration 94 98 92 Test (% Passed)
EXAMPLES 19-26
[0048] Examples 19-26 are inventive compositions and inventive
suspensions prepared in a manner analogous to the method described
in Example 1 except that significant adjustments were made to the
formulation, and the powder preparation (100 grams), suspension
preparation (500 grams) and coating process (12" diameter pan; 1 Kg
charge of aspirin cores) were scaled down.
7 Comparative Data Table - Examples 19-22 Wt % in 100 Grams
Components Example 19 Example 20 Example 21 Example 22 Eudragit
.RTM. L100-55 60.0 60.0 60.0 60.0 Sodium bicarbonate 1.8 1.8 1.8
1.8 Talc 38 2 31.0 28.5 36.9 Kaolin 0.0 0.0 0.0 0.0 Titanium
dioxide 0.0 0.0 5.82 0.0 Yellow #6 lake pigment 0.0 0.0 3.88 0.0
Sodium lauryl sulfate 0.0 0.0 0.0 0.0 Fumed Silica 0.0 0.0 0.0 1.3
Triethylcitrate 0.0 7.2 0.0 0.0 Calcium sulfate dihydrate 0.0 0.0
0.0 0.0 Xanthan Gum 0.0 0.0 0.0 0.0 100% 100% 100% 100% % Passed
Standard Disintegration 98 100 2 98 Test Stressed Disintegration 0
2 0 0 Test Tablet Color/Appearance White/Dull White/Shiny
Orange/Dull White/Dull
[0049]
8 Comparative Data Table - Examples 23-26 Wt % in 100 Grams
Components Example 23 Example 24 Example 25 Example 26 Eudragit
.RTM. L100-55 60.0 60.0 60.0 60.0 Sodium bicarbonate 1.8 1.8 1.8
1.8 Talc 37.7 33.2 37.7 38.05 Kaolin 0.0 5.0 0.0 0.0 Titanium
dioxide 0.0 0.0 0.0 0.0 Yellow #6 lake pigment 0.0 0.0 0.0 0.0
Sodium lauryl sulfate 0.5 0.0 0.0 0.0 Fumed Silica 0.0 0.0 0.0 0.0
Triethylcitrate 0.0 0.0 0.0 0.0 Calcium sulfate dihydrate 0.0 0.0
0.0 0.15 Xanthan Gum 0.0 0.0 0.5 0.0 100% 100% 100% 100% % Passed
Standard Disintegration 98 96 94 100 Test Stressed Disintegration 0
0 2 0 Test Tablet Color/Appearance White/Dull White/Dull White/Dull
White/Dull
* * * * *