Note: Descriptions are shown in the official language in which they were submitted.
' , WO 02/064124 CA 02434976 2003-07-15 PCT/EP01/01374
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77036pct.208
Medical Formulation containing a Muscarinic Agonist
The invention relates to a new pharmaceutical formulation containing the
muscarinic
agonist talsaclidine and processes for preparing it.
Background to the invention
Talsaclidine (Wa12014), being a muscarinic agonist, is a pharmacologically
valuable
compound. Muscarinic agonists may be of great therapeutic benefit in the
treatment
of Alzheimer's disease, for example. Talsaclidine 1' has the following
chemical
structure:
O ~~
H
1'
The aim of the present invention is to develop a pharmaceutical formulation
for oral
administration which releases the active substance talsaclidine relatively
rapidly and
~5 completely. A further aim of the present invention is to provide a
formulation which is
characterised by ease of handling during the preparation process and can
therefore
be reproducibly manufactured on an industrial scale while maintaining a high
quality.
Detailed description of the invention
2o The above objectives can be achieved by the formulation described in detail
hereinafter.
The present invention relates to a tablet containing talsaclidine 1',
characterised in
that it consists of a core containing the active substance talsaclidine and a
film
25 coating enclosing this core. The tablet according to the invention may also
be termed
a film-coated tablet within the scope of the present invention.
The active substance talsaclidine is preferably present in the formulation
according
to the invention in the form of a physiologically acceptable acid addition
salt 1. The
3o term physiologically acceptable acid addition salts according to the
invention denotes
pharmaceutically acceptable salts selected from among the salts of
hydrochloric
acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic
acid,
acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric
acid and
malefic acid. If desired, mixtures of the above acids may also be used to
prepare the
35 salts. According to the invention the preferred salts of talsaclidine are
selected from
among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate and
CA 02434976 2003-07-15
2
methanesulphonate. Most preferably, the salts are selected from among the
hydrochloride, hydrobromide and fumarate, while talsaclidine fumarate is most
important according to the invention. The active substance may optionally be
in the
form of a hydrate. Preferably, however, according to the invention, the
talsaclidine is
added in an anhydrous form. The active substance is preferably used in
crystalline,
unground form or after being ground in a pinned disc mill, but preferably in
unground
form. More preferably, the active substance is used in unground form with a
particle
size distribution within the following limits: D,o <_ 20Nm, Dso 10-80Nm, Duo
<_ 300pm.
Most preferably, the particle size distribution of the active substance used
in the
1o formulation according to the invention is in the following ranges: D,o <_ 5
- 15Nm, Duo
25 - 75 Nm, D9o <_ 275Nm. The numerical values given above for D,o, Dso and
Duo in
Nm (microns) are the particle size ranges within which a through total of 10
vol.%,
50 vol.-% or 90 vol.% of the measured particles (cumulative volume
distribution) is
achieved. These values were determined by the laser diffractometry method, in
the
95 present instance particularly using a so-called dry dispersion at a 2 bar
dispersion
pressure and a focal length f = 500 mm, e.g. using a SympatecIRODOS apparatus.
This method is known in the prior art.
Where reference is made to salts of talsaclidine within the scope of the
present
20 _invention, this is indicated by the numeral 1. Any explicit reference to
the base
talsaclidine, on the other hand, is indicated by the use of the numeral 1'.
Based on the total mass of the core of the film-coated tablets according to
the
invention talsaclidine 1' is present according to the invention in amounts of
0.5 to 25
25 wt.%, preferably 0.7 to 20 wt.%, particularly preferably about 0.9 to 15
wt.%.
Particularly preferably, the proportion of 1' is between 9 and 14 wt.% based
on the
total mass of the core. If talsaclidine is used for example in the form of the
preferred
salt _1 talsaclidine fumarate according to the invention in the formulation
according to
the invention, the proportion of 1 based on the total mass of the core of the
film-
3o coated tablets according to the invention is between about 0.85 and 43
wt.%,
preferably between about 1.2 and 34 wt.%, particularly preferably between
about 1.5
and 26 wt.%. Particularly preferably the proportion of 1 in the case of
talsaclidine
fumarate is between about 15 and 24 wt.% based on the total mass of the core.
s5 The core of the pharmaceutical formulation according to the invention
contains, in
addition to the active substance, at least one excipient as filler/dry binder.
Within the scope of the present invention modified lactose, particularly spray-
dried
lactose is of particular importance as the excipient. This excipient has
proved
particularly advantageous in the formulation according to the invention. A
preferred
CA 02434976 2003-07-15
3
aspect of the present invention thus relates to a film-coated tablet
containing
talsaclidine which contains in its core, in addition to the active substance,
modified
lactose, particularly spray-dried lactose, particularly preferably spray-dried
lactose
monohydrate as excipient.
By spray-dried lactose is meant lactose produced by spray agglomeration when
spray-drying a suspension of a-lactose monohydrate crystals in an aqueous
lactose
solution. The spray-drying process results in a free flowing powder with a
granulometry suitable for direct tabletting (for example 80-100% < 250Nm) and
an
~o amorphous content of for example 5 - 25%, which is responsible for the high
binding
power of spray-dried lactose.
According to the invention the weight ratio between the components contained
in the
core of the film-coated tablet, namely modified lactose, preferably spray-
dried
~5 lactose, to active substance 1' is in the range from about 1:1 to about
70:1.
Preferably, the ratio of modified, preferably spray-dried lactose to 1' is in
the range
from about 1.5:1 to about 35:1, particularly preferably in a range from about
2:1 to
about 8:1. Preferably, the proportion by weight of modified, preferably spray-
dried
lactose based on the total mass of the core of the film-coated tablet
according to the
2o invention is in a range from about 20 - 70 wt.%, preferably between about
30 - 60
wt. %.
The core of the film-coated tablet according to the invention may also
contain, in
addition to modified, preferably spray-dried lactose and active substance,
other
25 excipients or fillers. According to the invention it is preferable to use
those
compounds which can act as dry binders. Preferred dry binders according to the
invention are selected from among powdered cellulose, microcrystalline
cellulose,
starch, povidone, cellulose derivatives and mixtures of these compounds.
Preferred
binders are powdered cellulose and /or microcrystalline cellulose,
particularly
so preferably microcrystalline cellulose. If one of the abovementioned binders
is added
to the formulation according to the invention, the weight ratio of modified,
preferably
spray-dried lactose to binder is preferably about 5:1 to about 1:4, preferably
about
4:1 to about 1:3, particularly preferably about 3:1 to 1:2. It is particularly
preferable
according to the invention if the weight ratio of spray-dried lactose to
binder is in the
35 range from about 2:1 to about 1:1.
The core of the film-coated tablet according to the invention may also contain
disintegrants in addition to the ingredients mentioned above. Within the scope
of the
present invention these disintegrants may optionally also be known as
breakdown
CA 02434976 2003-07-15
4
agents. These are preferably selected according to the invention from among
sodium starch glycolate, crospovidone, croscarmellose, sodium-
carboxymethylcellulose, dried corn starch and mixtures thereof. Particularly
preferably, within the scope of the present invention, sodium starch
glycolate,
crospovidone and croscarmellose, preferably sodium starch glycolate, are used.
If
the abovementioned disintegrants are used, the amount by weight used based on
the total mass of the core of the film-coated tablet according to the
invention is
preferably in a range from about 1 -10 wt.%, particularly preferably about 3 -
8
wt. % .
The core of the film-coated tablet according to the invention may also contain
flow
regulators as additional ingredients. Flow regulators within the scope of the
present
invention include, for example, silicon dioxide, talc and magnesium stearate.
According to the invention silicon dioxide is preferably used, particularly
preferably in
~5 colloidal, highly dispersed form. If the abovementioned flow regulators are
used, the
amount by weight thereof based on the total mass of the core of the film-
coated
tablet according to the invention is preferably in a range from about 0.1 - 5
wt.%,
preferably about 0.3 - 2 wt.%, particularly preferably between 0.4 and 1.5
wt.%.
2o The core of the film-coated tablet according to the invention may also
contain flow
agents, lubricants and mould release agents as further ingredients. These
include,
for example, within the scope of the present invention, stearic acid,
magnesium
stearate, sodium stearyl fumarate, glycerol tribehenate and mixtures thereof.
According to the invention, stearic acid and magnesium stearate are preferably
used.
25 The amount by weight based on the total mass of the core of the film-coated
tablet
according to the invention is preferably in a range from about 0.1 - 5 wt.%,
preferably about 0.5 - 3 wt.%, particularly preferably about 1 - 2 wt.%.
Particularly
good release from the mould in the production of the film-coated tablets
according to
the invention is achieved when magnesium stearate is used in an amount of at
least
30 1.0 wt.%, preferably about 1.5 wt.%.
The film or film coating enveloping the core of the film-coated tablets
according to
the invention contains as essential ingredient a film forming agent selected
from
among hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose,
35 hydroxymethylcellulose, hydroxyethylcellulose and poly(ethylacrylate)
methylmethacrylate, the latter in the form of Eudragit NE 30 D, for example.
Alternatively, Eudragit RL 30 D or Eudragit E 12.5 may be used, for example.
The
above ingredients may optionally also be used in the form of mixtures thereof.
Preferred film-forming agents are hydroxypropylmethylcellulose,
CA 02434976 2003-07-15
hydroxypropylcellulose, hydroxymethylcellulose and hydroxyethylcellulose, of
which
hydroxypropylmethylcellulose and hydroxypropylcellulose are particularly
preferred
as film-forming agents according to the invention. The abovementioned film-
forming
agents may be used on their own or in the form of the mixtures thereof. If
only one of
the abovementioned film-forming agents is used, hydroxypropylmethylcellulose
is of
particular importance in this context within the scope of the present
invention. The
amount by weight of film-forming agents based on the total mass of the film
coating
of the film-coated tablet according to the invention is preferably in a range
from
about 20 - 95 wt.%, preferably 30 - 90 wt.%.
~o
The film coating may contain, as further ingredients, emulsifiers and
plasticisers such
as, for example, polyethyleneglycol, glycerol and propyleneglycol, optionally
in the
form of the mixtures thereof. Preferably, polyethyleneglycols are used as
plasticisers.
Without restricting the subject matter of the invention thereto,
polyethyleneglycol 400
~s and polyethyleneglycol 6000 are examples of particularly preferred
polyethyleneglycols. The amount of plasticiser by weight based on the total
mass of
the film coating of the film-coated tablet according to the invention is
preferably in a
range from about 1 - 30 wt.%, preferably 3 - 25 wt.%, particularly preferably
5 -15
wt. %.
The film coating of the film-coated tablet according to the invention may also
contain
coloured pigments and pigmenting excipients. Iron oxide, titanium dioxide,
talc and
mixtures thereof may be mentioned by way of example.
The following procedure may be used, for example, to prepare the film-coated
tablet
according to the invention.
In a suitable free-fall mixer the excipient spray-dried lactose is mixed with
the active
substance _1. The active substance premix obtained therefrom is then mixed in
a
suitable screening machine. This reduces the proportion of coarser particles
of active
3o substance which may possibly go into the manufacturing process. Depending
on the
particle size of the compound 1 used, the preparation of this premix with the
subsequent screening process may also be avoided.
In another step of the process, more excipient is added to this active
substance
premix. As well as spray-dried lactose one or more other excipients may also
be
added. Moreover, during this step of the process, other ingredients of the
formulation
such as disintegrants and flow regulators may optionally also be added. After
the
mixing process has finished the mixture obtained is screened again. This
intermediate screening is the essential step for obtaining a uniformity of the
contents
CA 02434976 2003-07-15
6
of the mixture in conformity with the Pharmacopoeia. The flow agent, lubricant
and
mould release agent are then added to this screened active substance mixture.
The mixture of active substance and excipient thus obtained is then compressed
in a
suitable tablet press to form the film-coated tablet cores according to the
invention.
The compressing force should be kept within a range from 5 - 15 kN, preferably
8 -
12 kN, for example, in the case of tablet cores which contain 36 mg of
talsaclidine 1'.
Higher compressing forces may lead to tablets with a delayed release of active
substance. Lower compressing forces may lead to tablets which are mechanically
unstable.
The tablet cores may take various forms, of which round biplanar or biconvex
and
oval or oblong shapes are preferred.
In order to prepare the film coating suspension the essential and optional
ingredients
~5 of the film coating are taken up in a suitable solvent. According to the
invention water
is preferably used as the solvent. When water is used as solvent, the
ingredients of
the film coating are partly in dispersed form.
After the coating suspension is finished the tablet cores obtained previously
are
2o coated with the desired film in a suitable coating apparatus analogously to
coating
methods known in the art.
CA 02434976 2003-07-15
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The Examples that follow serve to illustrate some formulations according to
the
invention. They are intended solely as possible methods given by way of
example,
without restricting the invention to their content.
Example 1:
Core
talsaclidine fumarate: 61.287 mg
lactose monohydrate (spray-dried): 99.363 mg
1o microcrystalline cellulose: 90.450 mg
sodium starch glycolate: 13.500 mg
highly dispersed silicon dioxide: 1.350 mg
magnesium stearate: 4.050 mg
Total (core): 270.00 mg
Film coating
hydroxypropylmethylcellulose: 3.500 mg
polyethyleneglycol 400 0.350 mg
titanium dioxide: 1.750 mg
2o talc: 1.358 mg
iron oxide (yellow): 0.042 mg
Total (coating): 7.000 mg
Total (film-coated tablet): 277.000 mg
Example 2:
Core
so talsaclidine fumarate: 5.11 mg
lactose monohydrate (spray-dried): 209.09 mg
microcrystalline cellulose: 102.00 mg
sodium starch glycolate: 17.00 mg
highly dispersed silicon dioxide: 3.40 mg
a5 stearic acid' 3.40 mg
Total (core): 340.00 mg
CA 02434976 2003-07-15
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Film coating
hydroxypropylmethylcellulose: 1.1416 mg
polyethyleneglycol 6000 1.4269 mg
titanium dioxide: 1.5696 mg
talc: 4.5662 mg
methacrylic acid copolymer Eudrac~it: 1.2843 mg
Total (coating): 10.000 mg
Total (film-coated tablet): 350.000 mg
Example 3:
Core
~5 talsaclidine fumarate: 10.21 mg
lactose monohydrate (spray-dried): 203.99 mg
microcrystalline cellulose: 102.00 mg
sodium starch glycolate: 17.00 mg
highly dispersed silicon dioxide: 3.40 mg
2o stearic acid: 3.40 mg
Total (core): 340.00 mg
Film coating: analogously to Example 2
25 Total (film-coated tablet): 350.000 mg
Example 4:
30 Core
talsaclidine fumarate: 20.43 mg
lactose monohydrate (spray-dried): 193.77 mg
microcrystalline cellulose: 102.00 mg
sodium starch glycolate: 17.00 mg
35 highly dispersed silicon dioxide:3.40 mg
stearic acid' 3.40 mg
Total (core): 340.00 mg
CA 02434976 2003-07-15
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Film coatincl: analogously to Example 2
Total (film-coated tablet): 350.000 mg
Example 5:
Core
talsaclidine fumarate: 40.86 mg
90 lactose monohydrate (spray-dried):173.34 mg
microcrystalline cellulose: 102.00 mg
sodium starch glycolate: 17.00 mg
highly dispersed silicon dioxide: 3.40 mg
stearic acid: 3.40 mg
95 Total (core): 340.00 mg
film coating: analogously to Example 2
Total (film-coated tablet): 350.000 mg
Example 6:
Core
talsaclidine fumarate: 51.07 mg
lactose monohydrate (spray-dried): 163.13 mg
microcrystalline cellulose: 102.00 mg
sodium starch glycolate: 17.00 mg
highly dispersed silicon dioxide: 3.40 mg
so stearic acid' 3.40 mq
Total (core): 340.00 mg
film coating: analogously to Example 2
Total (film-coated tablet): 350.000 mg
CA 02434976 2003-07-15
Example 7:
core
talsaclidine fumarate: 61.29 mg
5 lactose monohydrate (spray-dried):152.91 mg
microcrystalline cellulose: 102.00 mg
sodium starch glycolate: 17.00 mg
highly dispersed silicon dioxide: 3.40 mg
stearic acid: 3.40 mg
9o Total (core): 340.00 mg
film coating: analogously to Example 2
Total (film-coated tablet): 350.000 mg
Example 8:
Core
2o talsaclidine fumarate: 81.72 mg
lactose monohydrate (spray-dried): 132.48 mg
microcrystalline cellulose: 102.00 mg
sodium starch glycolate: 17.00 mg
highly dispersed silicon dioxide: 3.40 mg
25 stearic acid: 3.40 mg
Total (core): 340.00 mg
Film coating: analogously to Example 2
so Total (film-coated tablet): 350.000 mg
CA 02434976 2003-07-15
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Example 9:
Core
talsaclidine fumarate: 40.86 mg
lactose monohydrate (spray-dried):66.24 mg
microcrystalline cellulose: 60.30 mg
sodium starch glycolate: 9.00 mg
highly dispersed silicon dioxide: 0.90 mg
stearic acid: 2.70 mA
~o Total (core): 180.00
mg
Film coating: analogously to Example 1
Total (film-coated tablet): 185.000 mg
