Note: Descriptions are shown in the official language in which they were submitted.
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219211Q~
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Active substance carrier for the controlled release of active sub-
stances in the gastrointestinal tract with a delayed pylorus pas-
sage
The present invention relates to the use of a web-shaped, sheet-
like substrate provided with openings and loaded with active sub-
stance.
Active substance carriers and administration forms having a pro-
longed retention time in the stomach are used to make possible a
local therapy of stomach diseases. In addition, they permit the re-
lease of active substances over a period which altogether is longer
than that of conventional peroral administration forms so that the
frequency of intake can be reduced.
A prolonged residence time in the stomach is provided by admini-
stration forms which either have a particularly low density and
float on the gastric juice or cannot pass the pylorus owing to their
size or bulkiness.
For example, floating administration forms are those having a large
portion of lipophilic, low-density substances (DE 26 11 041 ). In
addition, there are descriptions how a delayed-action tablet or
capsule can be caused to float by means of a plurality of air inclu-
sions (EP-A 0 297 978, DE-A 38 03 482). Finally, gas-producing
substances or mixtures, for example, C03 producing effervescent
mixtures, can be incorporated into an enclosed administration
form; this at the same time results in an expansion of such a de-
vice after application (US 4 996 058).
A great disadvantage of the floating administration forms is their
unreliable gastro-retentivity. As long as their passage through the
,
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2
pylorus is not additionally impeded by their size (EP-A 0 308 9041,
flotation takes place only in persons sitting or standing upright. In
case of lying persons the pylorus is likely to come into contact
with the surface of the gastric juice, with the floating administra-
tion form being preferentially transported into the small intestine
(A.J. Moes, Crit. Rev. Therap. Drug Carrier Syst. 10, 143, 1993).
Additionally, flotation of such devices requires the presence of a
minimum amount of gastric juice; this, however, cannot always be
supposed in patients.
Administration forms retained in the stomach because of their size
or bulkiness have also been known for a long time now. Since the
administration form is to be swallowed and must~therefore not~ex-
ceed a certain maximum dimension, different mechanisms used to
enlarge the device in the stomach after application have been de-
scribed. For example, this can be achieved by providing a gas
phase in the device after contact with aqueous liquid (US 4 996
058), or by swelling of hydrophilic components in the gastric juice
(EP 0 425 154, US 5 147 646, EP 0 310 326, US 4 207 890, US
4 434 153). The disadvantage of these administration forms pri- ,
marify lies in the fact that they either have an insufficient stability
to resist the contractile forces produced by the musculature of the
stomach wall or - in case they have this strength - involve the risk
of resulting in an undesired and probably dangerous pylorus ob-
struction which prevents the further transport of the remaining
gastric contents.
Also, differently shaped, bulky active substance-carrying devices
are known which, for application purposes, are present in a com-
pressed or contracted form first. In this connection, the com-
pressed or contracted state is generally fixed by means of enclo-
sures, such as capsules, until these disintegrate in the gastric
juice. After disintegration of the enclosure, recovery forces or the
swelling pressure of hydrophilic components cause the bulky
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3
structures to revert to their original shape (US 4 735 804, EP 0
202 159, US 5 002 772, EPA 0 415 671 ~.
As long as their mechanical stability is sufficient to resist the gas-
tric contraction, they might be best suitable as gastro-retentive
administration forms because the pylorus passage is prevented
reliably and emptying the remaining stomach contents is not im-
peded.
In contrast to construction features'of various gastro-retentive
systems, aspects with respect to.production.engineering are:only -
scarcely described in the art. Owing to the complex shaping ofrthe
knowngastro-retentive administration forms;~the industrial series
production of such systems involves considerable effort and capi-
tal cost. Continuous processes~have not been described as yet.
Gastro-retentive administration forms-frequently comprise different
components serving either the conservation of the shape or the
active substance release. Also, there are no pharmaceutical test
methods ensuring the quality of these administration forms during
production. Large and unwieldy structures having a high mechani-
cal stability are difficult to manufacture; in addition, it is disadvan-
tageous that they may cause stomach irritations.
It is the object of the present invention to provide an active sub-
stance carrier for the controlled release of active substances in the
gastrointestinal tract with a delayed pylorus passage, which
avoids or even overcomes the above-mentioned disadvantages and
difficulties, permits a considerably prolonged retention time in the
stomach under release of active substances during a local therapy
of the stomach or the gastric mucous membrane, facilitates the
oral application to a very high degree, and is suitable for an eco-
nomically efficient series production.
To solve this object, the present invention proposes the use of an
active substance carrier in web form provided with openings and a
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4
substrate charged with active substance as starting material for
the production of an active substance carrier for the controlled
release of active substances in the gastrointestinal tract and which
exhibits a delayed pylorus passage.
The material of the active substance carrier is very advantageous
in many respects. It permits an economic production by using
known, continuous processes for processing web-shaped, sheet-
like material, such as winding up and off,~coating'and punching,
as well as encasing with a material.promoting the coherence. The
gastro-retentive embodiments which can be produced thereby
have additional advantageous properties. Foninstance, owing to
the sheet-like design of the active-substance carrier,-irritations~of ..
the gastric mucosa are not - or only to a very slight degree - to be
expected; these occur when the known three-dimensional bulky
structures are used which are retained in the stomach because of
their size or bulkiness. In particular when the device which unfolds
in the gastric juice after erosion of the casing has a sufficient me-
chanical stability, a high reliability with respect to the gastro-re-
tentivity is to be expected. At an obtainable minimum expansion
of 5 cm', the active substance carrier is greater than the opening
of the human pylorus, with the maximum expansion to up to 8
cm' providing an even greater certainty of preventing the pylorus
passage. As compared with most of the previous systems,
wherein the passage through the pylorus takes place as soon as
the stomach musculature succeeds in reducing the device to a
sufficient extent,' better adjustment.of the intended residence time
of the active substance carrier in the stomach is achieved. Since
the degree of stomach contractions depends on a great variety of
factors which can hardly be controlled in practice, for example,
the activity state of the autonomic nervous system, in particular
that of the parasympathetic nervous system, the retention time of
the administration forms proposed so far may well be subject to a
high degree of individual variability when in use. In contrast to
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2192110
this, the retention time of the active substance carrier according to
the present invention can be adjusted with a considerably higher
reliability by means of the galenic formulation: the composition
determines the rate at which the device in the gastric juice -
mainly by means of erosion - loses the properties causing its re-
tention.
The fact that the active substance ca«ier is provided with aper-
tures counteracts the danger of an unintentional pylorus obstruc-
tion. As a rule, the pylorus allows the passage of liquid material
having a low to medium viscosity and of particulate material hav-
ing a particle size of up to about 2 mm. If, for example, the active
substahce carrier has openings of 3 mm or more in diameter, it is
ensured that an undesired pylorus obstruction.cannot.take place:- .
Even in case the device should lie down over the pylorus opening,
it would merely cause a screening effect.
According to one embodiment of the present invention, the active
substance carrier comprises at least one active substance develop-
ing a local effect in the stomach. This may be an active substance
which is preferably absorbed by the gastric mucosa. However, it,
may also be an active substance for which an absorption window
exists in the upper portion of the small intestine. Thus, the subject
matter of the present invention is also suitable for the administra-
tion of active substances developing their effect in the upper por-
tion of the small intestine. So far, conventional peroral depot
forms have not been suitable for this purpose, since they release
most of the dose not until having left the upper region of the small
intestine. The active substance carrier according to the present
invention can ensure that released active substance in dissolved
form is supplied to the upper small intestine in an even manner
over a prolonged period of time.
The present invention has several therapeutic advantages. On the
one hand, it permits a considerably improved local treatment of
2192110
6
stomach diseases, as compared with conventional administration
forms. These particularly include the hyperacidity, microbial infec-
tions, the gastritis, and the ulcer. Efficacious drugs are available
for the treatment of these and other stomach diseases; their ef-
fectiveness and therapeutic index, respectively, is increased by the
fact that they are administered by means of the active substance
carrier according to the present invention. Thereby a particularly
large portion of the applied active substance dose is brought into
immediate contact with the affected tissue: The period of local
exposure to effective drug concentrations is increased. Examples
of such active substances include mineral antacids, HZ receptor
blockers, such as cimetidine, ranitidine, famotidine, nizatidine,
roxatidine, and their salts; muscarine receptor.blockers; such as
pirenzipine; so-called protowpumps, such as omeprazol and miso-
prostol; drugs which are effective against heliobacter pylorii and
other microbial noxae, such as proglumide and carbenoxolone.
According to an embodiment, the active substance carrier addi-
tionally comprises gaseous substances, gas-producing substances
and mixtures, or liquid and solid substances and/or their mixtures
having a relative density of < 1. This supports the retention of the
active substance carrier in the stomach by the fact that - in addi-
tion to the size of its area - it becomes a floating device.
According to the present invention, the active substance carrier
consists of or comprises a material which is erodable in biological
liquids. The composition of the material that is used substantially
determines the retention time of the gastro-retentive device in the
stomach. It is preferred that it consist of one or several physio-
logically acceptable polymers and further pharmaceutical adju-
vants, for example, softening agents, wetting agents, hydrophiliz-_
ing agents, stabilizers, dyes, release agents, buffer salts, and the
like. Examples of the polymers to be used include polysaccharides,
such as gums, starch or cellulose derivatives; polyacrylates and
i , 21921.0
polymethacrylates; polylactides, polyglycolides, poly(oxyethylenes)
and polyoxypropylenes; proteins, polyvinyl alcohop, polyvinyl
acetate), polyvinyl chloride), or polyvinyl pyrrolidone); silicone
elastomers, and copolymers. By using suitable mixtures an erosion
rate can be adjusted which achieves the intended retention time in
the stomach. At the end of this period, a device manufactured ac-
cording to the present invention has lost its mechanical stability to
a degree that allows its size reduction by the gastric contraction
and thus its passage through the pylorus. At the end of this pe-
riod, an active substance carrier produced according to the pres-
ent invention has lost its mechanical stability to a degree that al-
lows its size reduction by gastric 'contractions and thus its passage
through the pylorus.
The dimensions of active substance carriers that can be manufac-
tured according to the present invention are changed by means of
rolling or folding them in such a manner that they are rendered
suitable for a peroral application. This implies that the sheet-like
material be flexible and not brittle. After rolling up or folding, the
devices are preferably provided with a suitable enclosure which ,
keeps them in this state until application. A hard gelatin capsule,
for example, is such a casing; however, any other envelope is
suitable which holds the device in its rolled or folded state, disin-
tegrates in the gastric juice, and is pysiologically acceptable.
As a whole the active substance carrier is superior to the state of
the art by a great variety of advantages. These include the fact
that the active substance carrier makes it possible in a long-term
therapy to reduce the frequency of taking to an extent by far ex-
ceeding that of conventional sustained-release forms. In general,
depot drugs are useful in the long-term therapy if the active sub-
stance is eliminated from the body very quickly, i.e., at an
elimination half-life of less than about 10-20 h. In case the intake
frequency can be reduced by means of sustained-release forms,
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extreme variations of the blood level and with that undesired side
effects can be avoided and the patient compliance be improved.
When the active substance carrier according to the present inven-
tion is used, the intake frequency of many active substances can
be reduced to a once-a-day dose which represents another prog-
ress in the therapeutic safety.
