Note: Descriptions are shown in the official language in which they were submitted.
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Case 4-1314 _
Quick-disinte~ra~L~ E~essed shapes containing
pharmaceutical active substances
The invention relates to quick-disintegrating pressed
shapes containing pharmaceutical active substances in a
granular delayed-release formA
lt is kllown that pharmaceutical active substances can
be mixed together and coated with coating substances
retarding the release of the active substances, the
mixture then being processed into the form of granules,
which can either be administered directly in this form,
or be administered after being filled into capsules or
after further processing into tablet form. Granular
delayed release forms of pharmaceutical active substances
known hitherto have various disadvantages. There are
difficulties in connection with their production: the mode
of production is complicated, or the use of organic
solvents is necessary, or the auxiliaries used are not
ideal with regard to the effect aimed at, namely, the
correctly delayed release of active substances. Problems
arise also with respect to the external properties of these
granules, for example unsatisfactory free flowability or
sensitivity to moisture, disadvantages which become
unpleasantly evident either with the direct administration,
that is to say, with dosing and possibly with the
simultaneous taking of food or stimulants, or with the
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filling of the capsules. FurthermoreJ individual doses of above 600 mg packed
in capsu~sare not suitable since the capsules are too large to be swallowed.
The qui.ck-dis;.ntegrating pressed shapes according to the invention
are characteri~ed in that they consist essen~ially of a compressed mixture of
(a) an effective amount of a pharmaceutical active substance in
granular form coated with an amount effective to retard the release of a
mixture consisting essentially of poly (H + meth)-acrylic acid-~methyl, ethyl)
esters insoluble but dispersible in water and ethyl cellulose insoluble but
dispersible in water wherein the weight ratio of acrylic acid esters and ethyl
cellulose is 2.5:1 to S:l;
(b) a disintegrating agent having a high di.sintegrating capaci.ty as
well as good binding propertles.
Pharmaceutical preparations in a granular delayed-release form are
known, particularly as coated granules or ;n matrix form, th~.t i.s, for example,
also ahsorbed on ion-exchangers. Particularly suitable for the present
: invention are however granules coated with coating materials retarding the
release of the active substances, and especi.ally of which the coating consists
essentially of a homogeneous mlxture of a polyacrylate insoluble but dispersible
in water and a cellulose ether:insoluble but dispersible in water.
~ 20 The two coat mg materials preferably used according to the i.nvention
; are known i.ndividually as coating materials. Each applied on its own is not
however suitable for the purpose of the present invention. The first-mentioned
is very thermoplastic and coated granules produced therewith tend to stick
together, and the second-mentionedJ when used in customary amounts and in normal
processing, gives in the case of the present mode of application a coating which
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has an insufficient retarding effect. It was therefore not possible to
anticipate that the combination of the coati.ng materials, individually ~msuitable
for the present purpose, would give an excellent result iJI every respect.
The pharmaceutical active substance granules produced
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according to the invention are hence free-flowing,
insensitive to moisture and neutral in taste, and they
produce the desired delayed release of active substance
with great uniformity. A microscopic examination has
moreover shown that the individual active-substance
granule is very evenly coated, so that it substantially
retains its original shape. It is thus possible with a
homogeneous starting material to easily obtain a homogeneous
end product.
Suitable active substances for the granular delayed-
release form of pharmaceutical active substances according
to the invention are in particular granular or crystalline
substances. Especially suitable are solid gran~lles or
monocrystals within the range of size of 0.3 - 2 mm
(diameter), whlch have a certain mechanicaL strength, a
property which is of special importance when the coated
granules are subsequently to be processed lnto pressed
shapes .
Suitable as coating materials are on the one hand
in particular polyacrylates of the formula
R R
I
CH - C - CH - C - - -
C = O C = O
I
ORI OR'
R = H, CH3
R' = CH3 ~ C2H5
Substances of this type are obtained by emulsion poly-
merisation, and they contain the copolymer having a
molecular weight of some 100,000 in the form of latex
particles with a diameter of around or below l~m. A
corresponding product which is particularly suitable is
sold by Rohm Pharma GmbH, Darmstadt (Fed. Rep. of Germany)
under the name of Euclragit ~ ~30D, this is in the form of an aqueous
dispersion, and is an ethyl acrylate/methyl methacrylate 70:30 copolymer having
a molecular weight of 800,000.
And on the other hand the coating material used is preferably
ethyl cellulose. A particularly suitable product is that sol~ by F~C Corporation,
Philadelphia, ~Pennsylvania, USA) under the name of Aquacoat ~ ECD-30, this
being in the form of a 30% aqueous polymeric dispersion having a low particle
size (latex form) and a narrow particle-size distribution.
The above two coating materials (poly ~H + meth)-acrylic acid-
(methyl + ethyl) ester and ethyl cellulose) are preferably used in the weight
ratio of 2.5 : 1 to 5: l. and preferably in the ratio of 3 : l.
It is advantageous to mix together with the granules coated accordin~
to the invention small amounts, for example 0.5 to 1% of colloidal silicon
dioxide, for example Aerosil ~ , which is marketecl by Degussa~ Frankurt ~Fed.
Rep. of Germany). Tho Eree ~lowability of the granules is improved by this
addition. There can naturally be added to the coating-material mixture
also other auxiliaries in small amounts, for example dyestuffs or flavouring
agents.
The pharmaceutical active-substance granules used according to
the invention can be produced in a manner known per se. This applies also
in the case of the coated granules. These are produced in the fluidised-
bed spraying apparatus known for this purpose, or in coating pans. The coating-
material mixture is fed in as an aqueous dispersion at room temperature, and
spraying is best performed with air at a temperature of 25 to 30. The
individual granules are readily obtained in this manner, that is to say no
undesirable agglomeration of granules
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occurs.
Surprisingly, the pharmaceutical active-substance
granules used according to the invention can readily be
pressed together with a disintegrating agent having a high
disintegrating capacity and good binding properties, and
with the customary auxiliaries otherwise used for forming
tablets, within a wide dosage range into moulded shapes,
for example tablets or capsule- or rod-shaped compressed
products. The formed shapes thus obtained have the property
of rapidly disintegrating into separate granules in the
stomach of the person being treated and hence becoming
well dispersed. A localised overconcentration of the
active substance in the digestive tract is in this way
prevented, and a uniform, slowly occurring release of
active substance dispersed over a large resorptlon area is
ensured. It has been verified by microscopic examination
that the individual granules have scarcely been damaged
as a result of compression, so that on release of the active
substance from the granules, the active substance is able to
bring into effect its original advantageous properties
virtually completely. When a formed or moulded shape has
to be produced with two or more active substances, the
individually dyed pharmaceutical active-substance granules
can be prepared separately, a factor which facilitates
identification, and which renders the patient aware of the
fact that the preparation being taken contains two or more
active substances.
Suitable as disintegrating agents having a high
disintegrating capacity and good binding properties for
the formed shapes obtainable according to the invention
are in particular crosslinked pol~vinylpolypyrrolidone
(PVPP), for example Polyplasdone~XL marketed by the GAF
Corporation, New York, N.Y. (USA), or Kollidon ~ CL (BASF,
LudwigshafenlRhein, Fed. Rep. of ~ermany), or sodium
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carboxymethyl starches, for example Primojel ~ marketed by
W.A. Scholten's Chemische Fabriken N.V. Foxhol (NL), or
Explotab ~ marketed by E. Mendell Co. Inc., New York (USA).
In the case of the auxiliaries otherwise customarily
used for tabLetting, these are in particular binders,
lubricants and antisticking agents.
The usual tablet-compressing machines can be used
for producing the formed shapes obtainable according to
the invention.
Since the mechanical strength of the formed shapes is
surprisingly good, it is possible to produce all the
desired customary forms, Eor example tablets and capsules
or rod-shaped moulded products, with or without breaking
grooves. These pressed products can be provided if
desired witll a protecti~e coat of lacquer known ~or
this purpose.
All pharmaceutical active substances which can be used
for peroral administration and for which a delayed release
in the gastro-intestinal tract is desired are essentially
suitable, in the form of granules or crystals o~ an
appropriate size, for being processed according to the
invention. The present invention is however particularly
advantageous with respect to the use of active substances
which, when used at a fairly high concentration, can cause
local irritation of the mucous lining of the gastro-
intestinal tract, and which are administered in large
single doses. This applied for example in the case of
potassium chloride administered in the treatment of
hypopotassaemia, or in the case of lithium salts in
psychotherapy.
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Example 1
Com~osition
per dose ~er batch
potassium chloride
crystals having a
particle size of
0.5 - 1.2 mm 1000.0 mg 5000.0 g
Eudragit ~ E30D solid 180.0 mg 900.0 g
Aquacoat ~ ECD solid 55.0 mg 275.0 g
Aerosil 200 4.0 mg 20.0 g
Aerosil ~ 200 6.0 mg 30.0 g
Polyplasdone XL 150.0 mg 750.0 g
magnesium stearate 5.0 m~ 25.0 ~
1400.0 mg 7000.0 g
Production
A) Coated ~ranules
1. starting material: potassium chloride;
2. Eudragit ~ E30D and Aquacoat ~ ECD are mixed together
with slight stirring;
3. 1. sprayed with 2. in a fluidised-bed granulator
(fluidised-bed granulator Aeromatik ST 7):
- sprayed according to co-current principle,
- the mixture of the dispersions is stirred during
the spraying operation,
- inlet-air temperature 28C,
- throughput about ~0 g/minute;
4. drying at 28C inlet-air temperature (fluidised-bed
dryer Aeromatik ST 7) for about 10 minutes;
5. dry coated granules are mixed with Aerosil ~ 200 for
10 minutes;
6. mixture 5. is sieved, sieve size 1.5 - 2.0 mm.
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Properties:
free-flowing, tasteless,
release properties for potassium chloride (Van der Kamp
disintegration tester, in water at 37C):
after 1 hourabout 2~ %
after 2 hoursabout 45 %
after 4 hoursabout 81 %
after 6 hoursabout 96 % .
B) Pressed shapes
Coated granules, Aerosil ~200, Polyplasdone~XL
and magnesium stearate are mixed together for 15 minutes.
The mixture is subsequently compressed, on a commercial
tablet-compressing machine, into the form of rodlets
(or example Korsch EK0); punch size 20.7 x 8.6 mm.
Properties:
decomposition in water at 37C ~ 5 minutes 9
release properties for potassium chloride (Van der Kamp
dislntegration tester, in water at 37G):
after 1 hourabout 30 %
after 2 hoursabout 50 %
after 4 hoursabout 80 %
after 6 hoursabout 98 % .
E-xample 2
Composition per dose per batch
potassium chloride
crystals having a
particle si~e of
0.3 - 0.8 mm 600.0 mg 900.0 g
Eudragit ~ E30D solid 115.0 mg 172.5 g
Aquacoat ~ ECD solid 35.0 mg 52.5 g
Aerosil ~ 200 5.0 mg 7.5 g
Polyplasdone ~ XL 92.0 mg 138.0 g
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magnesium stearate 3.0 mg 4.5 g
850.0 mg 1275~0 g
Production
A) Coated ~ranules:
l. starting material: potassiurn chloride;
2. Eudragit ~ ~30D and Aquacoat ~ ECD 30 are mixed together
with slight stirring;
3. 1. sprayed with 2. in a fluidised-bed granulator
(fluidised-bed granulator Aeromatik Strea 1):
- sprayed according to co-current principle,
- the mixture o~ the dispersions is stirred durillg the
spraying operation,
- air-inlet temperat-lre 28C,
~ throughput about 8 g/minute;
4. drying at 28C air-inlet temperature (fluidised-bed
dryer Aeromatik ST 7) ~or about 10 minutes;
5. dried coated granules are mixed with Aerosil ~ 200 for
10 minutes;
6. mixture 5. is sieved, sieve size 1.5 - 2.0 mm.
Properties:
free-~lowing, tasteless,
release properties for potassium chloride (Van der Kamp
disintegration tester, in water at 37C):
after 1 hour about 38 %
after 2 hours about 74 %
after 3 hours about 96 % .
_) Pressed shapes
Coated granules, cross-linked polyvinylpolypyrrolidone
and magnesium stearate are mixed together for 15 minutes.
The mixture is subsequently compressed, on a commercial
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tablet-compressing machine, into the form of rodlets
(for example Korsch EK0); punch size 20.7 x 8.6 mm.
Properties
decomposition in water at 37C ~ 5 minu~es,
release properties for potassium chl.oride (Van der Kamp
disintegration tester, in water at 37C):
after 1 hour about 42 %
after 2 hours about 70 %
after 3 hours about 90 %
Example 3
Composition dose m~/batch g
pirprofen crystals (0.5 mm)600.0 mg/g
Eudragit ~ E30D (solid)24.0 mg/g (80 g of
~ dispersion)
Aquacoat~ECD 30 (solid)6.0 mgtg (20 g of
dispersion)
Aerosil ~ 200 5.0 mg/g
Polyplasdone ~ XL lS0.0 mg/g
cottonseed oil (hydr.~5.0 mg/g -
Production
1. starting material: pirprofen,
2. Eudragit ~ E30D and Aquacoat ~ ECD30 are mixed together
with slight stirring;
3. 1. sprayed with 2. in a fl.uidised~bed granulator
Aeromatik Strea 1:
- sprayed according to co~current principle,
- dispersion is stirred,
- air-inlet temperature 35C,
- throughput about 8 g/minute;
4. drying at 35C air-inlet temperature (fluidised-bed
dryer Strea 1) for about 10 minutes;
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5. dry coated granules are mixed with Aerosil ~ 200 for
about lO minutes,
6. mixture 5. sieved through sieve-size l.S - 2.0 mm.
B) Pressed_shapes
- 5. mixed with Polyplasdone ~ XL and hydrogenated cotton-
seed oil for 15 minutes in a tumbler mixer, type Turbula
- homogeneous mixture 6. compressed, on a tablet press EK0,
into the form of rod-shaped tablets, 16.4 x 8.6 mm.
Test data
disintegration in water at 37OCl into 30 sec.
disintegration in gastric juice~ panrdtiiVideusal 1 min.
Exam~le 4
~ dose mg/batch
Zerolit ~ 225 4% crosslinked
(particLe siæe 0.1 - 0.3 mm)
200 mg/g coated with 100 mg/g
of Pirprofen, total weight 300 mg/g
Polyplasdone ~ XL 150 mg/g
Avicel ~ PH 102 150 mg/g
600 mg/g
Production
Zerolit ~ 225 (cationic ion-exchanger, Dia-proxim Ltd.,
England~, Polyplasdone ~ XL and Avicel ~ PH 102 (granulated
microcrystalline cellulose, FMC, USA) are sieved through
sieve having a mesh size of 0.8 mm. The sieved components
are mixed for 10 minutes in a Turbula ~ m~xer~The homogeneous
mixture is compressed, in a tablet-compressing machine, for
example Korsch EK0, to form round tablets.
Properties: diameter of tablets 9.0 mm,
hardness of tablets about 80 Newton,
disintegration (water at 37C) about 15 sec.
