MELANGE D'ALGINATES ET DE POLYACRYLATES; SON UTILISATION

MIXTURE OF ALGINATES AND POLYACRYLATES AND ITS USE

Abrégé français

Un mélange d'un alginate et d'un polyacrylate dans un rapport compris entre 15:1 et 1:2 sert à préparer des formes médicamenteuses de stockage.

Abrégé anglais

A mixture of an alginate and
a polyacrylate in a ratio of from 15 : 1 to 1 : 2 is
suitable for the preparation of depot drug forms.

Revendications

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined as
follows:
1. A tablet for sustained release of a drug
selected from the group consisting of propafenone,
barucainide, nesapidil, gallopamil and biperiden, said
tablet being composed of a blend of a unit dosage of said
drug with a mixture of an alginate with a polyacrylate in
a ratio of 15 : 1 to 1 : 2, wherein said polyacrylate is
the formula:
<IMG>
where R1 is C1-C4-alkyl, R2 is hydrogen or C1-C4-alkyl, R3 is
hydrogen, C1-C4-alkyl or a radical -(CH2)n-NR5R6 or -(CH2)
n-N~R5R6R7 Cl~, where n is from 1 to 4 and R5, R6 and R7 are
each hydrogen or C1-C4-alkyl, R4 is hydrogen or C1-C4-alkyl
and m is from 500 to 1,500.
2. The tablet of claim 1, wherein the drug is
gallopamil and the ratio of alginate to polyacrylate is
ranging from 15 : 1 to 2 : 1.
3. The tablet of claim 1, wherein the drug is
propafenone and the ratio of alginate to polyacrylate is
ranging from 15 : 1 to 2 : 1.
4. The tablet claim 1, 2 or 3, wherein said
polyacrylate is the one commercially available under the
trade mark EUDRAGIT R RS.
5. The tablet of claim 1, 2 or 3, wherein the
ratio of alginate to polyacrylate is ranging from 9 : 1 to

2 : 1.
6. The tablet of claim 5, wherein the alginate
is selected from the group consisting of propylene glycol
alginates and alkali and alkaline earth metal alginates.
7. The tablet of claim 5, wherein said
polyacrylate is the one commercially available under the
trade mark EUDRAGIT R RS.
8. The tablet of claim 6, wherein said
polyacrylate is the one commercially available under the
trade mark EUDRAGIT R RS.

Description

133919~
Mixture of alqinates and polyacrylates and its use
The present invention relates to a mixture of
alginates and polyacrylates and its use in the preparation
5 of depot drugs.
It is known that alginates can be used for the
preparation of depot drugs (Pharm, Ind. 33 (1971), 296).
However, the use of alginates for this purpose often
presents difficulties. For example, the formulations
10 frequently do not achieve sufficient hardness when
tableted. Their abrasion is therefore very high, which
presents problems during subsequent film coating.
Insufficient hardness leads to breaking during filling on
filling machines. Furthermore, alginates readily absorb
15 water, which leads to swelling of the tablets or, in the
case of film tablets, to cracking of the films, unless
complete protection from moisture is ensured by
complicated and expensive packaging.
Conventional alginate-based sustained-release
20 tablets show no plasma level having a pronounced plateau
character, despite zero order in vitro release, and still
show a pronounced and not always desirable plasma peak
despite a substantial delay in the time of maximum plasma
concentration compared with drug forms which release the
25 active compound rapidly.
It has now been found that these difficulties
can be avoided if polyacrylates or polymethacrylates are
mixed with alginates.
More particularly, the present invention as
30 broadly disclosed hereinafter relates to the use of a
mixture of an alginate and a polymethacrylate or copolymer
of acrylic and methacrylic acid in a ratio of from 15 :
1 to 1 : 2, preferably 9 : 1 to 2 : 1, for the
preparation of depot drugs.
B

1339194
However, the invention as claimed is restricted
to a tablet for sustained release of a drug selected from
the group consisting of propafenone, barucainide,
nesapidil, gallopamil and biperiden, said tablet being
5 composed of a blend of a unit dosage of said drug with a
mixture of an alginate with a polyacrylate in a ratio of
: 1 to 1 : 2, wherein said polyacrylate is the
formula:
Rl R2
--CH2--f--CH2--1--
fo fo
~13 (i~ 4
-- m
15 where R1 is C1-C4-alkyl, R2 is hydrogen or C1-C4-alkyl, R3 is
hydrogen, C1-C4-alkyl or a radical -(CH2)n-NR5R6 or -(CH2) n~
N~R5R6R7 Cle, where n is from 1 to 4 and R5, R6 and R7 are
each hydrogen or C1-C4-alkyl, R4 is hydrogen or C1-C4-alkyl
and m is from 500 to 1,500.
Particularly suitable alginates that can be used
herein are propylene glycol alginates and alkali and
alkaline earth metal alginates, in particular the sodium,
potassium, ammonium and calcium alginates. These
alginates are described for example, in the book by Roy L.
z5 Whistler, Industrial Gums, New York, 1973, in the
subsection by McNeely and Pettitt on alginates. They are
mainly used as gel formers or thickeners in food
technology, in the printing, textile and paper industries
and in welding electrodes.
30As aforesaid, particularly suitable
polyacrylates are those of the formula:
I t R 2
--CH 2 - f - cH 2--f--
CO CO
351 0
R3 14
-- m

1339194
where R1 is C1-C4-alkyl, RZ is hydrogen or C1-C4-alkyl,
R3 is hydrogen, C1-C4-alkyl or a radical -(CH2)n-NR5R6 or
-~CH2)n-N~R5R6R7 Cle, where n is from 1 to 4 and R5, R6 and
R7 are each hydrogen or C1-C4-alkyl, R~ is hydrogen or
5 C1-C4-alkyl and m is from 500 to 1,500.
If the polyacrylate is used in the form of the
ammonium salt (R3 = -(CH2)n-N~R5R6R7 Cl~), m is preferably
from 7,000 to 11,000, in particular from 8,000 to 10,000.
In the other cases, m is preferably from 700 to 1,000.
Such methacrylates and copolymers are described
in, for example, Houben-Weyl, Methoden der organischen
Chemie, Thieme-Verlag, Stuttgart, 1961. Products which
are commercially available under the trade mark EUDRAGIT~
are particularly suitable. The EUDRAGIT~ products include
15 different species respectively called EUDRAGIT~ E, L/S,
RS, RL/RS, NED, LD in the advertising brochure of their
manufacture, Rohm Pharma GmbH, Darmstadt.
In accordance with a particularly preferred
embodiment of the invention, use is made of the EUDRAGIT~
20 RS product.
The novel mixture of alginate and polyacrylate
is particularly suitable for the preparation of oral depot
forms (viz. tablets) of propafenone, barucainide,
nesapidil, gallopamil and biperiden.
The use of this novel mixture has the following
advantages:
1. The release of the active compound from the drug
forms is substantially linear.
2. The tablet cores are very hard and abrasion-
resistant, so that they can be further processed
without difficulties.

13391~9
3a
3.The hygroscopicity of the alginates is no longer
disadvantageous during tablet preparation. The tablet-
ing mixtures can be pressed directly without granula-
tion, and the expensive and complicated wet granulationcan be avoided. Film tablets no longer require any
special protection from moisture and no longer crack
during open storage for a short time.
4.After administration of the novel drug forms, the
plasma level of active compound has a pronounced
plateau character and a substantially flatter curve
than after administration of drug forms which are only
based on alginates.
The Examples which follow illustrate the invention.
EXAMPLE 1
Tablets having the following composition (in mg)
were prepared in a conventional manner:
A B C D E F
Gallopamil.HCl 100 100 100 100 100 100
Na alginate 300 240 200 166 132 332
~udragit E 32 92 132 166 200 0
PVP 13 13 13 13 13 13
Mg stearate 4 4 4 4 4 4
Cellulose powder31 31 31 31 31 31
For this purpose, gallopamil.HCl, Na alginate and
~udragit E are dry-blended in a mixer, moistened with an
aqueous solution of PVP or PVP/PVA copolymers ~ ollidon
30, ~ollidon 25 or @kollidon VA 64) while stirring,
forced through a sieve and dried in a fluidized-bed
drier, passed again through a ~ieve and mixed with Mg
stearate and cellulose powder. The mixtures were pressed
to give tablets weighing 480 mg.
Barucainide was processed similarly.
The hardness of the tablets was determined using

1339194
-- 4 --
the ~harmatest hardness tester and their abrasion was
measured with the~Pharmatest friabilator (400 revolutions
in 13 minutes).
The following results were obtained:
Tablets A B C D E F
Hardness (N) 104 122 137 103 84 61
Abrasion (%) 0.1 0.1 0.1 1.0 1.0 3.8
Similar values were obtained when gallopamil was
replaced with another active compound, eg. barucainide,
or another ~Eudragit (eg. 6~udragit RS) was used instead
- of ~Eudragit E.
EXAMPLE 2
If the mixtures A to F of Example 1 are pressed
directly without granulation to give tablets, the result-
ing tablets have a hardness of from 70 to 110 N. Mixture
F, however, gives unusable tablets having a hardness of
- only 10 N.
EXAMPLE 3
Tablets having the following composition (in mg)
20 were prepared similarly to Example 1:
G H
Gallopamil 100 100
Na alginate 267 267
~Eudragit RS 67
PVP 13 13
Mg stearate 4 4
Cellulose powder 29 29
Tablets G had a hardness of 120 N and tablets H
had a hardness of 78 N. The corresponding values for the
friability were 0.05% and 2.1%, respectively.
If the tablets are produced by direct compres-
sion, ie. without granulation, tablets having a hardness
of 100 N tG) or 13 N (H) are obtained. -
Testing the tablets
Test persons each received 1 tablet G or H (cf.Example 3). Blood samples were then taken at certain

133~1 9~
time intervals and the content of gallopamil therein was
det~ ined:
Time (h) 0.5 1 2 3 4 6 8 10 12
G (ng/ml of
plasma) 0.7 0.94.6 6.8 10 9.0 8.9 8.2 5.9
H (ng/ml of
plasma) 3.8 10 29 33 36 17 10 6.4 6.9
In contrast to H, G has a substantially flatter
plasma level curve.
_~, . 10 EXAMPLE 4
Tablets having the following composition (in mg)
were prepared:
J R
Propafenone.HCl 600 600
Na alginate 253 253
@Eudragit RS 53
Cellulose 11 11
PVP 20 20
Mg stearate 3 3
The preparation was carried out by moist granu-
lation of a mixture of propafenone and alginate (in case
- J also with ~udragit) with an aqueous PVP solution and
subsequent addition of cellulose and Mg stearate to the
- 25 dried granules. The granules were converted into tablets
-~ similarly to Example 1.
In case J, the tablets obtained had a hardness of
165 N and their friability was virtually impossible to
measure. In case R, the tablets obtained were unusable
and did not withstand subsequent film coating without
giving a fairly large amount of fragments. The applica-
tion of a rapidly dissolving film is absolutely essential
for masking the extremely bitter flavor of propafenone.