U.S. patent number RE35,200 [Application Number 08/122,759] was granted by the patent office on 1996-04-02 for coating for pharmaceutical dosage forms.
This patent grant is currently assigned to Rohm GmbH. Invention is credited to Dieter Dreher, Harry Goetz, Klaus Lehmann.
United States Patent |
RE35,200 |
Lehmann , et al. |
April 2, 1996 |
Coating for pharmaceutical dosage forms
Abstract
Coated pharmaceutical dosage forms which are resistant to
gastric juice and release their active ingredient rapidly at a
predetermined pH value in the range from pH 5 to pH 8 are obtained
in accordance with the invention by coating pharmaceutical dosage
forms with an aqueous dispersion containing dispersed latex
particles of a first polymer which contains carboxyl groups and is
water soluble between pH 5 and pH 8 and of a second water insoluble
film forming polymer, in a weight ratio between 60:40 and 5:95.
Inventors: |
Lehmann; Klaus (Rossdorf,
DE), Dreher; Dieter (Darmstadt, DE), Goetz;
Harry (Alsbach-Haehnlein, DE) |
Assignee: |
Rohm GmbH (Darmstadt,
DE)
|
Family
ID: |
6227795 |
Appl.
No.: |
08/122,759 |
Filed: |
September 16, 1993 |
Related U.S. Patent Documents
|
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
Reissue of: |
697288 |
Feb 1, 1985 |
04644031 |
Feb 17, 1987 |
|
|
Foreign Application Priority Data
|
|
|
|
|
Feb 15, 1984 [DE] |
|
|
34 05 378.6 |
|
Current U.S.
Class: |
524/501; 424/463;
424/462; 427/2.19; 524/523; 424/490; 424/482; 524/522; 427/2.16;
424/459; 424/474; 424/497; 424/458; 424/475 |
Current CPC
Class: |
C09D
133/08 (20130101); A61K 9/2846 (20130101); A61K
9/5026 (20130101); C09D 133/064 (20130101); C09D
133/064 (20130101); C08L 2666/04 (20130101); C09D
133/08 (20130101); C08L 2666/04 (20130101); C08L
33/064 (20130101); C08L 33/08 (20130101) |
Current International
Class: |
A61K
9/50 (20060101); C09D 133/06 (20060101); C09D
133/08 (20060101); A61K 9/28 (20060101); C08L
33/00 (20060101); C08L 33/08 (20060101); C08L
33/06 (20060101); C08J 003/02 (); C08K 003/20 ();
A61K 009/32 (); A01N 025/10 (); C08L 033/00 () |
Field of
Search: |
;524/501,522,523
;427/3,2.16,2.19 ;424/458,459,462,463,474,475,482,490,497 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
52075 |
|
May 1982 |
|
EP |
|
1467855 |
|
Feb 1968 |
|
DE |
|
1617351 |
|
Jan 1972 |
|
DE |
|
2135073 |
|
Dec 1973 |
|
DE |
|
3127237 |
|
Jan 1983 |
|
DE |
|
3134222 |
|
Mar 1983 |
|
DE |
|
1393374 |
|
May 1975 |
|
GB |
|
Other References
Gove et al., Webster's Third New International Dictionary of the
English Language Unabridged, published by G. & C. Merriam
Company, Springfield, Massachusetts, U.S.A., 1965, p. 23..
|
Primary Examiner: Griffin; Ronald W.
Claims
What is claimed is:
1. An aqueous dispersion adaptable to use for coating
pharmaceutical dosage forms, said dispersion having a pH below 6
and comprising
(A) dispersed latex particles of a polymer containing carboxyl
groups which is water insoluble at a pH below 6 but become water
soluble at least in a portion of the pH range between pH 5 and pH
8, and
(B) dispersed latex particles of a water insoluble film forming
polymer.Iadd.,
wherein the weight ratio of the particles (A) and (B) is between
60.40 and 5:95.Iaddend..
2. An aqueous dispersion as in claim 1 wherein said polymers (A)
and (B) are emulsion polymers of vinyl and/or vinylidene
monomers.
3. An aqueous dispersion as in claim 2 wherein said polymer
containing carboxyl groups contains from 10 to 70 weight percent of
at least one of acrylic acid and methacrylic acid.
4. An aqueous dispersion as in claim 2 wherein said polymers (A)
and (B) comprise alkyl esters of acrylic acid and/or methacrylic
acid.
5. An aqueous dispersion as in claim 2 having a combined content of
said polymers (A) and (B) from 10 to 40 percent by weight.
6. An aqueous dispersion as in claim 1 wherein said film forming
polymer has a dynamic glass transition temperature between
10.degree. C. and 60.degree. C.
7. A method for making a coated pharmaceutical dosage form
resistant to gastric juice which comprises coating a medicament
core with an aqueous dispersion of a coating composition as in
claim 1 and drying said coated core.
8. A method as in claim 7 wherein the coated pharmaceutical dosage
form is dried with air at a temperature below 60.degree. C.
9. A pharmaceutical dosage form resistant to gastric juice
comprising a medicament core having thereover a coating
comprising
(A) a polymer containing carboxyl groups which is water insoluble
at a pH below 5 but becomes water soluble at least in a portion of
the pH range between pH 5 and pH 8, and
(B) a water insoluble film forming polymer, in a weight ratio
between 60:40 and 5:95.
10. A pharmaceutical dosage form as in claim 9 wherein said coating
has a thickness between 10 and 50 microns.
11. A pharmaceutical dosage form as in claim 9 in the form of small
particles wherein the weight of said coating is between 10 and 20
percent by weight of the coated core.
12. A pharmaceutical dosage form as in claim 9 in the form of
tablets, dragees, or capsules wherein the weight of said coating is
between 3 and 5 percent by weight of the coated core.
Description
The present invention relates to a an aqueous dispersion of a
synthetic resin having carboxyl groups and of a film forming
synthetic resin, said dispersion being adaptable to use as a
coating composition for pharmaceutical dosage forms and to
pharmaceutical dosage forms coated therewith.
Coating compositions for medicinal tablets containing a water
soluble, film forming synthetic resin in the form of an aqueous
dispersion and a water soluble or alkali soluble substance are
known from German patent publication No. 16 17 351. For coatings
which are to be resistant to gastric juice, an alkali soluble
substance is used concurrently therewith, which substance is
dissolved out of the tablet coating in an alkaline environment and
leaves pores through which the active ingredient can then diffuse.
Fatty acids, for example, are proposed as alkali soluble
substances. The release of active ingredient begins when the tablet
enters an aqueous medium having a pH value at which the alkali
soluble substance dissolves.
From the same publication it is further known incorporate into the
coating macromolecular water soluble substances, such as
polyethylene glycols, which are soluble regardless of the pH value
of the medium. The use of alkali soluble macromolecular substances
had not been known up to that time; however, it was to be expected
that, like low molecular weight alkali soluable substances, they
would render the coating diffusion permeable at a pH value at which
they are soluble.
The combination of a dispersed acrylate polymer with a water
insoluble cellulose ether is known from European patent publication
No. 52 075. It results in coatings for pharmaceutical dosage forms
which produce a delayed release of the active ingredient.
According to German patent publication No. 31 27 237, an aqueous
dispersion of a coating composition resistant to gastric juice is
combined with polyethylene glycol and polyvinyl pyrrolidone to
produce dosage form coatings which rapidly decompose in intestinal
juice.
Thiele and Pflegel reported in "Pharmazie", 1981, 858-859, and
1983, 43-45, on tablet coatings of aqueous dispersions containing
from 98 to 99 weight percent of a hydrophobic acrylate/methacrylate
polymer incorporating a small number of carboxyl groups and from 1
to 2 weight percent of a hydrophilic copolymer of acrylic or
methacrylic acid and acrylate or methacrylate alkyl esters, both
percentages being based on the total polymer content. While the
addition of the last-mentioned polymeric material enhances the
diffusion permeability, it does not result in rapid release of the
active ingredient in the alkaline range. With additions of more
than 2 weight percent of the hydrophilic polymer, the coating was
found to be unstable. A dependence of the permeability on the pH
value was not observed. The release of the active ingredient takes
place solely by diffusion through the nonporous membrane, largely
independently of pH.
Disperions of polymers which contain from 10 to 55 weight percent
of monomeric units carrying carboxyl groups are known for coating
dosage forms from German patent publication No. 21 35 073. These
give coatings on pharmaceutical dosage forms which dissolve even in
the weakly alkaline medium of the upper portions of the intestine,
rapidly with a high content of carboxyl groups, more slowly with a
low content of carboxyl groups.
There has been a need for supplementing the range of pharmaceutical
dosage form coatings in the form of aqueous dispersions with
compositions which are film forming at moderately high temperature
and which give coatings that are resistant to gastric juice and
which release the active ingredient only, but rapidly, in the more
alkaline intestinal juice.
Coating compositions are available, dissolved in organic solvents,
which result in fast or slow delivery of the active ingredient at
any desired pH value in the physiological range. The release
characteristics can be controlled over a wide range through the
content of carboxyl groups of the polymer. However, this principle
cannot be translated to aqueous coating dispersions. Rapid release
of the active ingredient is obtained at pH 5.5 with a dispersion of
a copolymer of equal parts of ethyl acrylate and methacrylic acid.
However, when the acid content is reduced to 30 weight percent, the
active ingredient is released much more slowly, although at the
same pH value. A shifting of the fast release to a higher pH range
also could not be obtained by using a harder polymer formulation,
such as one involving partial replacement of the acrylate component
with methacrylate. This would merely result in loss of film forming
capacity.
Surprisingly, it has now been found that the release range of
coatings resistant to gastric juice can be shifted to higher pH
values if the pharmaceutical dosage forms are coated with an
aqueous coating dispersion which contains, as a coating composition
or binder, dispersed latex particles of
(A) a polymer containing carboxyl groups which is water soluble
between pH 5 and pH 8, and
(B) a water insoluble film forming polymer, the ratio of the total
weights of the latex particles (A) and (B) being between 60:40 and
5:95.
The release characteristics of the coatings produced in accordance
with the invention as compared to other coatings are readily
apparent from the accompanying Figure. The latter illustrates the
release of the active ingredient coated with different coatings I
to VII and which are exposed to a medium the pH value of which is
increased stepwise at regular time intervals. This simulates
passage through the intestinal tract.
In the tabulation which follows, the following abbreviations are
used for the constituents of the copolymers:
EA=Ethyl acrylate
MMA=Methyl methacrylate
MA=Methacrylic acid
The percentages given are weight percent.
The following emulsion polymers were investigated and, unless
otherwise stated, were used as a dispersion or mixture of
dispersions for film formation (parts and percentages are by
weight):
I--50% EA, 50% MA
II--70% EA, 30% MA
III--70% EA, 30% MA; film formation from organic solution
IV--3 parts 50% EA, 50% MA and 7 parts 50% EA, 50% MMA
V--3 parts 50% MMA, 50% MA and 7 parts 50% EA, 50% MMA VI--3 parts
60% MMA, 40% MA and 7 parts 50% EA, 50% MMA
VII--3 parts 70% MMA, 30% MA and 7 parts 50% EA, 50% MMA
What is desired is as steep a slope of the release curve as
possible from a value as close as possible to the zero line to a
value as high as possible. The requirement for resistance to
gastric juice may be regarded as satisfied when release of the
active ingredient at pH values below pH 4 remains less than 5
percent of the enclosed amount of active ingredient for one hour.
As is apparent from the graph in the FIGURE, this behavior is
obtained with the coating compositions of the invention at all pH
values above pH 5.5, found in the intestinal tract.
Release can be made to occur at any desired pH value by variation
of that component of the coating composition which contains the
carboxyl groups, whereas in obtaining the data for the FIGURE the
film forming component remained unchanged with respect to its
nature and amount. It has been found that film formation is not
impaired by component (A), which becomes progressively harder from
IV to VII. Component (B) can therefore be selected solely on the
basis of the requirements of the film forming process.
Remarkably, the release characteristics of the inventive coatings
differ considerably from the findings obtained by Thiele and
Pflegel on membranes made from 98 to 99 percent of hydrophobic
polymers and from 1 to 2 percent of hydrophilic polymers containing
carboxyl groups which had been produced from dispersions. While
these membranes remained free of pores, examination of the coatings
of the invention under an electron microscope has shown that,
starting at a certain pH value, the polymer component (A)
containing carboxyl groups is dissolved out of the coating with
formation of pores. As a result, the rate of release suddenly
increases. This behavior was quite unexpected, especially since
Thiele and Pflegel had observed no pH dependence of the release
characteristics.
Aqueous dispersions of the coating composition are suitable for the
manufacture of pharmaceutical dosage forms which are to pass
through the stomach unaltered and are to release their active
ingredient quickly in a narrowly limited portion of the intestine
characterized by its pH value.
The polymer containing carboxyl groups is present in the form of
latex particles dispersed in an aqueous phase. The preparation of
such latices is described in German patent publication Nos. 21 35
073 and 31 34 222, for example. However, the dispersion of this
polymer need not itself be film forming. Hardening monomers such as
lower methacrylate esters may therefore form a higher proportion of
the polymer than if the dispersion were used alone as coating
composition.
The polymer containing carboxyl groups must be water soluble at
least in a portion of the pH range between pH 5 and pH 8 but may be
water insoluble in the lower portion of that range. To be
dispersible in water, it must be water insoluble at least below pH
5. Above pH 8, it will usually be water soluble; however, this
property is immaterial for the purposes of the invention. The
aqueous dispersion of the latex particles (A) and (B) has in all
cases a pH value at which the polymer containing carboxyl groups is
not dissolved. (Polymers, unlike other solutes, do not have
saturation concentrations. They are either water soluble or water
insoluble. If soluble, one can prepare, for example, a 1 percent
solution of the polymer).
As a rule, the polymer is produced by free radical emulsion
polymerization of vinyl or vinylidene monomers in an aqueous phase.
A portion, preferably from 10 to 70 weight percent, and more
particularly from 25 to 55 weight percent, of the monomers contains
at least one carboxyl group. Preferred vinyl and vinylidene
toohomers of this type are acrylic acid and methacrylic acid.
However, maleic, fumaric, crotonic and itaconic acid are also
usable. The remaining portion of the vinyl monomers is free of
carboxyl groups and may consist of esters of the carboxylic acids
named, and particularly of alkyl esters having from 1 to 8 carbon
atoms in the alkyl radical, acrylonitrile or methacrylonitrile,
styrene, alpha-methylstyrene, vinyltoluene, vinyl chloride or vinyl
esters of fatty acids, for example vinyl acetate. Hydrophilizing
neutral comonomers such as acrylamide, methacrylamide or
vinylpyrrolidone, or hydroxyalkyl esters of acrylic acid or of
methacrylic acid, may go into the composition of the emulsion
polymers in limited amounts. They will produce some diffusion
permeability of the coating even at low pH values, which is
desirable only in special cases.
The amount of the monomers containing carboxyl groups should in
each case be such that the polymer is water soluble in the range
from pH 5 to pH 8 and that the active ingredient is released at the
desired pH value. When the polymer (A) is investigated by itself,
it is found that its rate of dissolution is dependent on the
carboxyl group content. Hydrophilic monomers will increase the
dissolution rate, while hydrophobic monomers will decrease it. For
the purposes of the invention, water soluble polymers are polymers
which, in the form of films having a thickness ranging from 10 to
20 microns, dissolve in artificial intestinal juice of pH 7.5
within not more than 60 minutes with moderate agitation. In the
inventive coatings, delayed water solubility has the effect of
shifting the point of release to higher pH values.
The rate of dissolution depends also on the molecular weight. The
weight average molecular weight generally should not be over
500,000 and preferably ranges from 50,000 to 300,000.
Preferred polymers containing carboxyl groups comprise (A) 10 to
70, preferably 25 to 55, percent by weight of acrylic acid or
methacrylic acid, (B) 90-30, preferably 75 to 25, percent by weight
of an unsaturated ester monomer, and (C) up to 20 percent by weight
of other unsaturated monomers copolymerizable with monomers (A) and
(B), with monomers (A) and (B) together being at least 80 percent
by weight of the total monomers. The unsaturated ester monomers
include the alkyl esters of unsaturated carboxylic acids,
particularly those esters of alkanols having 1 to 8 carbon atoms
and vinyl esters of saturated fatty acids, such as vinyl acetate or
propionate. The unsaturated ester monomers preferably contain a
total of 4 to 12 carbon atoms.
An especially preferred group of copolymers comprise (A) 10 to 70,
preferably 25 to 55, percent by weight of acrylic acid or
methacrylic acid and (B) 90 to 30, preferably 75 to 45, percent by
weight of a C.sub.1 -C.sub.8 -alkyl ester, preferably a C.sub.1
-C.sub.4 -ester, of acrylic acid or of methacrylic acid.
The film forming polymer is also present in the form of latex
particles dispersed in an aqueous phase and preferably is also
produced by free radical emulsion polymerization of suitable vinyl
or vinylidene monomers. A large number of film-forming aqueous
polymer dispersions is on the market, and their preparation is
generally known from numerous publications.
Emulsion polymers are termed "film forming" when, under the usual
conditions of application of aqueous pharmaceutical dosage form
coating dispersions, they result in a continuous film which firmly
adheres to the coated core. As a rule, such film formation takes
place even at room temperature; however, a higher drying
temperature may be used. The film forming polymer is usually
selected so that in the form of an aqueous latex it has a minimum
film forming temperature in conformity with DIN 53787 of not over
60.degree. C., and preferably not over 40.degree. C. This condition
is usually satisfied when the dynamic glass-transition temperature
(the T.sub..lambda.max value in conformity with DIN 53445) is not
over 80.degree. C., and preferably not over 60.degree. C.
The emulsion polymers may be composed of the same vinyl monomers as
the polymers containing carboxyl groups. However, the proportion of
monomers containing carboxyl groups should be considerably smaller,
if not zero. Hydrophilic comonomers, too, should go into the
composition of the polymer only in so limited an amount that the
polymer is not water soluble in the physiological pH range of the
gastrointestinal tract i.e. from pH 1 to pH 8. If the polymer is
water soluble only above pH 8, it is still usable.
For the polymer to have film forming capacity, its composition must
include a sufficient proportion of "soft" monomers. These are those
vinyl monomers the homopolymers of which have a dynamic glass
transition temperature, T.sub..lambda.max, below 10.degree. C.
Among these are, in the first place, the alkyl esters of acrylic
acid. As a rule, they should represent from 40 to 80 weight percent
of the polymer. However, their proportion should not be so high
that the dynamic glass transition temperature is below 0.degree.
C., as otherwise the coatings made from them will be too soft or
even tacky. Commercial pharmaceutical dosage form coating
dispersions for the production of insoluble coating dispersions for
diffusion tablets meet these requirements and are well suited for
the purposes of the invention.
The balance of the film forming polymers comprises "hard" vinyl
monomers, i.e. those forming homopolymers having a dynamic glass
transition temperature above 10.degree. C. These monomers are as a
rule present in an amount from 20 to 60 percent, of which up to 5
percent may be unsaturated carboxylic acids. Preferred copolymers
comprise from 40 to 80 percent by weight of those alkyl esters of
acrylic acid or of methacrylic acid which form a homopolymer having
a T.sub..lambda.max less than 10.degree. C., particularly acrylates
of C.sub.1 -C.sub.8 -alkanols; 60 to 20 percent by weight of
methacrylate esters forming homopolymers with a T.sub..lambda.max
greater than 10.degree. C.; and 0 to 5 percent by weight of acrylic
acid or methacrylic acids.
The coating composition is advantageously prepared by mixing the
lattices of the types (A) and (B) in a weight ratio of the two
polymer types between 60:40 and 5:95, and preferably between 50:50
and 30:70. Of course, the dispersions to be mixed must be
compatible with each other. For example, they must not contain
oppositely charged emulsifiers if this would result in
coagulation.
The minimum film forming temperature of the coating composition is
affected by the mixing ratio. It should be between the minimum film
forming temperatures of the starting lattices of the polymers (A)
and (B). If it is undesirably high, it can be reduced by the
addition of film forming aids which either remain in the film as
plasticizers or evaporate as volatile solvents during drying.
Examples of such film forming aids are ethylene glycol or propylene
glycol, glycerine, esters of citric acid, and polyethylene
glycols.
As the amount of polymer (A) is increased in relation to that of
polymer (B), the rate of release of the active ingredient enclosed
in the coated dosage form increases above the pH value at which
permeability to the active ingredient sets in. While with low
polymer (A) contents the coating membrane becomes permeable but
remains intact, with higher polymer (A) levels it disintegrates
soon after the pH value at which it becomes permeable is reached,
especially when the coated core develops a shattering action by
swelling.
As a rule, the polymers (A) and (B) will represent from 10 to 40
weight percent of the aqueous coating composition. The rest will be
water, emulsifiers dissolved therein, and optional additives.
In addition to the polymers (A) and (B), the coating composition
may contain commonly used dissolved or suspended auxiliary
substances and additives. Apart from the film forming aids
mentioned, possible additives are preservatives, thickeners,
lustering agents, dyes and pigments, for example.
The viscosity of the liquid coating composition advantageously
ranges from 10 to 100 centipoises. Its pH value should be below 6
and usually is between 2 and 5. The size of the latex particles
therein is not critical and the sizes are in the usual range from
0.01 to 1 micron.
All pharmaceutical dosage forms which must be resistant to gastric
juice and which must release the enclosed active ingredient in the
intestinal tract at a predetermined pH value relatively quickly can
be coated in accordance with the invention. As a rule, at least 80
percent of the active ingredient is released within 60 minutes.
Tablets, dragee cores, pills, granules, crystals and powders, and
even gelatin capsules can be coated. Granules or pellets can also
be manufactured by conventional granulating methods using the
compositions of the invention. The granules in turn may be coated
or compacted into tablets.
The coating methods correspond to those used with conventional
dispersions for coating pharmaceutical dosage forms. Pan coating
methods in which the coating is poured or sprayed onto the rotating
dosage forms either in portions or continuously are preferred.
Usually warm air is then blown onto them to dry them. Fluidized bed
coating is also advantageous and is preferably carried out at an
air temperature between 40.degree. C. and 60.degree. C.
Although the coating thickness may be as much as 50 microns, the
pH-dependent release characteristics are especially apparent with
coating thicknesses between 10 and 30 microns. This corresponds to
a coating weight between 10 and 20 weight percent, based on the
weight of the coated core, in the coating of granules, particles,
and crystals, and between 3 and 5 weight percent in the case of
tablets, dragees, or capsules. Below this range release is likely
to be increasingly time-dependent rather than pH-dependent, and
above this range, an increasingly delayed release at the pH value
of the dissolution range can be expected.
A better understanding of the present invention and of its many
advantages will be had by referring to the following specific
examples given by way of illustration.
EXAMPLE 1
141 g of a 30 percent dispersion of a copolymer of equal parts of
methacrylic acid and ethyl acrylate (42 g of solids) were mixed
with 328 g of a 30 percent dispersion of film forming copolymer of
ethyl acrylate and methyl methacrylate in a ratio of 2:1 (98 g of
solids). A suspension of 70 g of talc in 514 g of water was then
added. The mixture had a pH of 5.7. (The film forming copolymer has
a T.sub..lambda.max of 29.degree. C. The minimum film forming
temperature of the aqueous dispersion is 8.degree. C.).
3 kg of quinine sulfate tablets (each weighing 206.5 mg and having
a diameter of 8 mm and a height of 3.7 mm) were preheated to about
32.degree. C. in a coating pan with a diameter of 35 cm rotating at
40 rpm by blowing in warm air at 65.degree. C. to 70.degree. C. and
were then continuously sprayed with the aqueous polymer dispersion
while warm air continued to be blown in. An air pressure spray gun
having a nozzle diameter of 1.0 mm and a spraying pressure of 0.8
bar was used for this purpose. The polymer emulsion was delivered
to the spray gun through a hose pump and the spray rate was thus
set at about 9 grams/minute. Total spraying time was 2 hours. The
coated tablets were then dried further for 2 hours at 40.degree. C.
in a circulating air drying cabinet. The coating was 50 microns
thick.
When tested in a USP disintegration tester, the tablets were
initially resistant to gastric juice at pH 1.3 for 60 minutes.
Neither disintegration nor release of the active ingredient
occurred even after another 30 minutes in a buffer solution of pH
5.5. Rapid release of active ingredient first occurred in a buffer
solution of pH 6.0 (see curve IV) and all tablets disintegrated
within 12 to 16 minutes.
EXAMPLE 2
141 g of a 30 percent dispersion of a copolymer of equal parts of
methacrylic acid and methyl methacrylate (42 g of solids) were
mixed with 328 g of a 30 percent dispersion of a copolymer of ethyl
acrylate and methyl methacrylate in the ratio of 2:1 (98 g of
solids). A suspension of 70 g of talc in 514 g of water was then
added. The pH value was 6.0.
3 kg of quinine sulfate tablets were then coated as in Example 1.
The coating was 50 microns thick.
When the coated tablets were tested in the USP disintegration
tester, they, too, were found to be resistant to gastric juice for
60 minutes. Even after another 30 minutes in a test solution of pH
5.5 and a further 30 minutes in a test solution of pH 6.0, there
was no disintegration and no release of active ingredient. Only
when a buffer solution of pH 6.5 was then introduced did the
tablets disintegrate, within 2 to 11 minutes and with fast release
of active ingredient. (See curve V.)
EXAMPLE 3
141 g of a 30 percent dispersion of a copolymer of methacrylic acid
and methyl methacrylate in a ratio of 1:2 (42 g of solids) were
mixed with 328 g of a 30 percent dispersion of a copolymer of ethyl
acrylate and methyl methacrylate in a ratio of 2:1 (98 g of
solids). A suspension of 70 g of talc in 514 g of water Was then
added. The pH value was 6.6.
3 kg of quinine sulfate tablets were coated as in Example 1. The
coating was 50 microns thick.
In the USP disintegration tester, the coated tablets were resistant
to gastric juice for 60 minutes, and neither disintegration nor
appreciable release of active ingredient was observed when they
were stirred in test solutions at pH 5.5., 6.0, 6.5 and 7.0,
respectively, for 30 minutes each. Only at pH 7.5 did the tablets
disintegrate, within 11 to 16 minutes and with rapid release of
active ingredient. (Curve VII.)
EXAMPLE 4
1000 g of a 30 percent emulsion polymer of ethyl acrylate and
methyl methacrylate in a ratio of 2:1 (300 g of solids) were mixed
with a solution of 10 g of polyoxyethylene sorbitan monooleate
("Tween 80") in 20 g of water. To this there were added 1000 g of
30 percent emulsion polymer of equal parts of methacrylic acid and
ethyl acrylate (300 g of solids), and then a suspension of 151 g of
talc in 582 g water, 1 g of a silicone defoaming emulsion being
further admixed. The mixture had a pH of 5.6.
1 kg of theophylline granules of a particle size ranging from 0.3
to 0.8 mm were suspended in a stream of warm air in a fluidized bed
apparatus, preheated to about 40.degree. C., and sprayed through a
nozzle projecting into the fluidized bed while a stream of hot air
of 40.degree. C. was maintained. The nozzle aperture was 1.2 mm;
the spraying pressure was 1.8 bars. The spray rate, which was
regulated through a hose pump, was 11 grams/minute: the total
spraying time was 131 minutes. The total amount of coating applied
corresponded to an increase in 20 percent in the weight of the
granules and was 25 microns thick. Samples were taken also after 10
and 15 percent of the coating had been applied (respective: coating
thicknesses of 9 and 19 microns). A significant delay in the
dissolution of the active ingredient in the gastric juice was
observable even after just 10 percent of the coating had been
applied.
The granules coated with 15 percent of the coating mixture were
found. to be resistant to gastric juice for 120 minutes in the USP
paddle apparatus, that is to say the release of active ingredient
was less than 5 percent. Rapid release of active ingredient then
set in already at pH 5.5.
The granules coated with 20 percent of the coating mixture also
proved resistant to gastric juice. At pH 5.5., an initially slow
release of active ingredient was observable which sharply increased
at pH 6.5.
EXAMPLE 5
1000 g of a 30 percent emulsion polymer of ethyl acrylate and
methyl methacrylate in a ratio of 2:1 (300 g of solids) were mixed,
after the addition of 10 g of polyoxyethylene sorbitan monoleate in
20 g of water, with 100 g of a 30 percent emulsion polymer of equal
parts methacrylic acid and ethyl acrylate (30 g of solids). A spray
formulation was prepared from 685 g of this mixture with a
suspension of 150 g of talc in 600 g of water. When the
constitutents were stirred together, 1 g of a silicone defoaming
emulsion was added to suppress foaming. The suspension had a pH of
6.8.
This spray formulation was sprayed onto 1 kg of theophylline
granules as described in Example 4. With an application of 5 to 15
percent, the release curves show an approximately linear release of
active ingredient in the pH region above 5.5.
* * * * *