MEDICAMENT FORMS HAVING CONTROLLED RELEASE AND CONTAINING ACTIVE SUBSTANCES WHICH EASILY DISSOLVE IN WATER

FORMES GALENIQUES A LIBERATION COMMANDEE CONTENANT DES PRINCIPES ACTIFS A BONNE SOLUBILITE DANS L'EAU

English Abstract

The invention relates to a medicament form containing an active substance with
a water-solubility, according to USP, ranging from 23 to 30 in a matrix that
is based on acrylate polymers, whereby the medicament form can be obtained by
melt extrusion.

French Abstract

L'invention concerne une forme galénique contenant un principe actif dont la solubilité dans l'eau selon la norme US, est comprise entre 23 et 30, dans une matrice à base de polymères acryliques. Ladite forme galénique s'obtient par extrusion par fusion.

Claims

We claim:
1. A drug form comprising an active ingredient with a water
solubility as defined in USP 23 of up to 30 in a matrix based
on acrylate polymers, the drug form being obtained by melt
extrusion.
2. A drug form as claimed in claim 1, in which the active
ingredient is in amorphous form.
3. A drug form as claimed in claim 1 or 2, comprising a
methacrylic acid copolymer as matrix polymer.
4. A drug form as claimed in any of claims 1 to 3, comprising a
methacrylic ester copolymer as matrix polymer.
5. A drug form as claimed in any of claims 1 to 4, comprising a
combination of a methacrylic acid copolymer and a methacrylic
ester copolymer.
6. A drug form as claimed in any of claims 1 to 5, comprising:
metoprolol tartrate as active ingredient.
7. A process for producing a drug form as claimed in any of
claims 1 to 6, which comprises a mixture of active ingredient
and matrix polymer being subjected to melt extrusion and
shaping.
8. A process as claimed in claim 7, wherein the shaping takes
place by calendering.

Description

CA 02359381 2001-07-13
1
MEDICAMENT FORMS HAVING CONTROLLED RELEASE AND CONTAINING
ACTIVE SUBSTANCES WHICH EASILY DISSOLVE IN WATER
The present invention relates to drug forms with controlled
release comprising active ingredients with a water solubility as
defined in USP of up to 30 in a matrix based on acrylate
polymers, which are obtained by melt extrusion.
It is generally known that controlled release, in particular slow
linear release, is problematic in the case of active ingredients
with good water solubility. In particular, slow release of
metoprolol tartrate is difficult by conventional means.
EP-A 240 904 discloses that it is possible to produce drug forms
by melt extrusion.
It is an object of the present invention to find drug forms which
make controlled release possible for active ingredients with good
water solubility.
We have found that this object is achieved by tie drug forms
defined at the outset.
Active ingredients with good water solubility-according to the
invention are those having a water solubility as defined in USP
23 of from l to 10 (freely soluble) -or 10 to 30.-(soluble),
preferably less than 1 (very soluble). Th~2 numbers relate to the
number of parts of solvent required per part of substance to be
dissolved.
Preferred active ingredients are metoprolol and its salts;
particularly preferably metoprolol tartrate.
The active ingredients are homogeneously dispersed or dissolved
in the form pf a solid solution in a matrix based on acrylate
polymers during the melt extrusion. The active ingredient is
preferably present in the matrix in X-ray amorphous form. It is
particularly' preferred for solid solutions of the active
ingredient to be obtained.
Particularly suitable acrylate polymers are swellable polymers of

CA 02359381 2001-07-13
la
the Eudragit~ type. Examples of suitable polymers are methacrylic
acid copolymers (Eudragit L types) such as 1:1 methacrylic
acid/ethyl acrylate copolymers M 250,000, 1:1 methacrylic
acid/methyl methacrylate copolymers M 135,000, 1:2 methacrylic
acid/methyl methacrylate copolymers M 135,000 or

Knoll AG 990049 O.Z. 0480/01206 D8
2
dimethylaminoethyl methacrylate copolymers (Eudragit E) such as
poly(1:2 butyl methacrylate/2-dimethylaminoethyl methacrylate) Mt
150,000. The methacrylic ester copolymers which swell
pH-independently (Eudragit NE) are preferred, such as 2:1 ethyl
acrylate/methyl methacrylate copolymer M 800,000, particularly
preferably 2:1 methyl methacrylate/ethyl acrylate copolymer with
5 or 10% trimethylammoniomethyl methacrylate chloride (Eudragit
RS and RL types)M 150,000.
It is also possible to use mixtures of said polymers.
The amounts of active ingredient and acrylate polymers are chosen
so that the drug forms comprise from 1 to 50% by weight,
preferably 10 to 30% by weight, of active ingredient.
Particularly suitable formulations are those comprising from 1 to
80, preferably 10 to 40, % by weight of Eudragit RL and from 1 to
50, preferably 5 to 20, % by weight of Eudragit RS.
The matrix may additionally comprise further polymers, for w
a0 example homo- or copolymers of N=yinylpyrrolidone such as .... ,
povidone or copovidone 6:4 or, preferably, cellulose ethers such
as hydroxypropylmethylcellulose, ethylcellulose or . .
hydroxypropylcellulose.
Tt is also possible to add other conventional pharmaceutical
ancillary substances for additional slowing of release. These
include, in particular, water-repellent ancillary substances such
'as lipids or salts thereof, for e:eample stearic acid, palmitic
acid, hydrogenated ricinoleic acid or the like, preferably
magnesium stearate.
The preparations may additionally contain other conventional
pharmaceutical ancillary substances in the amounts customary for
this purpose, for example stabilizers, antioxidants, colorings,
flavorings or bulking agents, such as highly disperse silica, or
lubricants.
The preparations according to the invention are produced by
mixing the components with use of shear forces and input of
thermal energy. The mixing preferably takes place in a single
screw or multiscrew extruder, particularly preferably a twin
screw extruder. Input of thermal energy produces a melt of the
components of the mixture. This normally takes place by heating
the extruder jacket to temperatures in the range from 50 to 180,
preferably 80 to 130°C. The active ingredient can be mixed with
the other components before or after the melting of the polymeric
CA 02359381 2001-07-13

Knoll AG 990049 O.Z. 0480/01206 D8
3
binder. The melts are solvent-free. This means that no water or
organic solvent is added.
The molten mixture of the components is conveyed by the screw
movement toward the extruder outlet, which preferably consists of
a die. After extrusion through the die, the still plastic
composition is shaped to suitable drug forms.
Suitable drug forms are preferably tablets, in particular bolus
tablets, lenticular tablets or oblong tablets.
Tablets are preferably produced by the process described in
EP-A 240 906, by passing the still plastic extrudate between two
rolls driven in opposite directions with mutually opposing
depressions in the surface of the rolls. It is also possible, by
appropriate choice of the shape of these depressions, to obtain
tablets with scores. Granules or pellets can be obtained by cold
cut or, preferably, by hot cut.
The drug forms can additionally be provided with coatings.~known
per se and having no effect on the release characteristics.
It is surprisingly possible by the combination according to .the
invention of melt extrusion with an appropriate formulation based
on acrylate polymers to produce drug forms with controlled
release even for active ingredients with good water solubility.
It was. in particular not to be expected that-siow-release
metoprolol tartrate preparations which, in terms of their
release, are bioequivalent to the metoprolol succinate-containing
marketed product Beloc-ZOK~ can be obtained in a simple manner by
melt extrusion with an appropriate formula..
Examples
The tablets were produced by extruding the mixtures listed in the
following table in a corotating twin screw extruder of the Werner
& Pfleiderer ZKS-40 type and subsequent calendering to oblong
tablets weighing 500 mg by the process described in EP-A 240 906.
Extruder temperature profile:
Feed section: 20 to 25~C, section 1: 80~C, section 2: 110~C,
section 3: 110~C, section 4: 130~C, die: 130~C. The speed of
rotation was 110 rpm; the output was 15 kg/h. The tablets were
then coated with an amount of 15 mg per tablet. Composition of
the coating:
CA 02359381 2001-07-13

,,
Kaoll AG 990049 O.Z. 0480/01206 D~
4
Hydroxypropylmethylcellulose 2920 6cp 58.04
Talc 4.10
Polyethylene glycol 400 9.00
Titanium dioxide 15.43
Hydroxypropylmethylcellulose l5cp 5.76
Hydroxypropylcellulose 5.76
Polyethylene glycol 6000 1.61
Highly disperse silica 0.15
Sodium docusate 0.15
The in vitro release was determined in accordance with USP 23 in
a paddle apparatus at 100 rpm in simulated intestinal fluid at pH
6.8, no-change, 24 h.
ao : ...:
a5
35
45
CA 02359381 2001-07-13

CA 02359381 2001-07-13
. Kaoll AG 990049 O.Z. 0480/01206 DE
M O O ~ O
* lp O O M O
M W O v-I tf1tn
e~rl d~ N rl
tp O O O O
* d~ O O O O N
N 00 C1 O rl O
e-1M rl d~ d~
O O OO O
O M e-110O N
'~O O O00
N M eiM
t0 d~ O O O
O d~ 111 O O O O
00 N O rI G~
M M N
d~ O O O
eh u1 O O O M
OD N O rl OD
M M N
l0 d~ O O O
cW I1 O O O
W
CO N O .-I 0~
M M N
10 ~ D O
eIW I1 O O
W
00 O O
M d~ N
W O t0OD O
w ~ d~ M rl O
00 O O r1
M erN
10 cp O
~ ll1 O ~W
O
~
OD O rl N
M tD N
M O O O l~ ~
10 O O O M W
d,.. . . . . ~w
. lfl O rl 1t1
OD
~ rl d~ N
M CD01O O
l0 N OO O O\
M
W O OO ~-!
M ~~ p
M ~ o 0
m M o 0
o
N . . . . O
-1
ri d~ W r~
W M O O O L~
~ 10 O O O M MO
~ ~
J~t .-1 r1 d~ N
N
dP ~
, J-1~ ~i
r1 ~ iJ U1 ''I
~ .~m ~ s o w
.~ ~,
s
~ ~x a N 0 U
l 1 O W~"
l
r U W ~ r , U O
r 1
N
0-II~r1~iro U01 ? ~-IU ~
Ql ~ C
r -r T ~ ~ r ~ f-~ U
0 ~
N U ' ~ U
rtt tTb~ ?t -II ~ rlrou
b ~C !
r
L~ cdIdO r-I O ~ 'dO ~dW x .Y.,
i-l U ~ ~ '
O 1-i11~..,~ ~1 ~ ,?~riO 00U!
~ rl r-I
~ roro~ ~~ ro ~a .~ro~ -~~
~
~ a ~a~-~ ~, o ~ o -~~ a~
-~, v o
~ w w;~x x w w ~nA H x*
~n U ro
~ N

Kaoll AG 990049 O.Z. 0480/01206 DE
6
Figure 1 shows the in vitro release from a tablet of Example 11
(n=6) compared with the marketed product Beloc-ZOK Retard (95 mg
of metoprolol succinate).
A tablet of Example 11 was administered as a single dose to eight
healthy male volunteers in the fasting state. Beloc-ZOR (with the
same amount of free metoprolol base) was administered as
reference substance under the same conditions. Figure 2 shows the
geometric mean plasma concentration. The squares indicate the
extrudate form according to the invention, and the diamonds
indicate the reference substance.
ao
30
40
CA 02359381 2001-07-13