Note: Descriptions are shown in the official language in which they were submitted.
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'E
r
Active substance carrier for the release of apomorphine in
the oral cavity
The present invention relates to a pharmaceutical prepa-
ration for application of active substances in the region
of the oral cavity or oral mucosa. In particular, it
relates to a preparation which is adapted to be flat and in
the form of a foil-, paper- or wafer-shaped administration
form.
Flat active substance carriers have already been developed
and produced, for various purposes. DE-OS 27 46 414 can be
regarded as fundamental to this administration form, said
document describing a foil-type tape of active substance,
binder and further active substances, with a direct
relation existing, by reason of the homogeneous thickness
and density, between a unit of length of the tape and the
dose of active substance contained therein. The advantages
of the continuous dosage property have been recognized also
by other applicants and have been described in specific
individual variants. Thus, DE-PS 36 30 603 claims a flat-
shaped carrier material, for example in the form of a
separating layer, having an active substance-containing
coating, the latter having to be peeled off the carrier
material after having been previously separated into dosage
units.
The practicality of the flat format in general as well as
the advantages afforded by the production of this
administration form and by the dosage employing said
administration form have been recognized a.n the prior art.
Further advantages can be derived such as the fact that,
relative to the weight of the administration form, a
relatively large surface may be printed on the said
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administration form, thus increasing intake safety as wall
as affording the possibility of discrete intake without any
liguid being available.
If an active substance is to be applied that can be brought
to absorption via the oral mucosa, a flat, film- or paper-
like active substance carrier enables a more rapid onset of
action than in the case of application of conventional
administration forms, such as tablets. Tablets are
typically adapted for active substance release in the
gastrointestinal tract after swallowing. Usual, rapidly
disintegrating tablets release active substance in the
stomach, with the disintegration of the administration form
being a precondition for the active substance release.
Freguently, the disintegration of a tablet in the liquids
contained in the gastrointestinal tract is a mufti-stage
process. If the tablet has a coat, this must first
disintegrate in order to expose the pressed piece. This is
followed by so-called primary disintegration, during which
the tablet disintegrates into small fragments, e.g. into
the granules from which it was pressed, said fragments in
turn disintegrating during the so-called secondary
disintegration into the powders they are composed of.
Whereas the primary disintegration is macroscopically
visible, and according to the pharmacopoeia is tested
employing a special apparatus, secondary disintegration is
hardly perceptible or measurable, although it is a direct
prerequisite of the dissolution of active ingredient. It
follows that even if usual tablets are retained in the
mouth until they are macroscopically disintegrated, this
does not necessarily mean that they have already released
the active substances contained therein, whereas flat,
film- or paper-like active substance carriers are capable
of doing so within a few seconds, up to minutes, after
application thereof. Insofar, the latter are better
suitable than tablets for introducing active substances
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more quickly into the organism, and they can be
advantageously used where a rapid onset of action is
required or desirable, thus, for example, in the
administration of analgesics, antiallergics, antitussives,
antiemetiCS, active substances against angina pectoris,
migraine, hypotension or hypotonia, etc.
Despite these obvious advantages, such flat administration
forms have hitherto hardly been successful. Obviously, the
advantage as compared to conventional administration forms
does not suffice for many manufacturers of pharmaceutics to
develop products of this type comprising the usual active
ingredients and to pursue the legal drug approval thereof,
which involves considerable effort and high costs.
Moreover, existing production machinery and existing know-
how cannot be used for these novel products; this means
that the necessity of large investments would arise.
Despite the above-described advantages of flat; film- or
paper-like administration forms, the therapeutic and/or
economic advantage over conventional tablets in adminis-
tration of common active substances which are also
perorally applicable is not great enough to justify the
costs of switching over to these administration forms.
It is thus the object of the present invention to create a
pharmaceutical preparation on the basis of, and having the
general advantages of, flat, film- or paper-like active
substance carriers, which pharmaceutical preparation,
however, affords, apart from the above advantages,
additional economical and/or therapeutical advantages over
pharmaceutical preparations of the same active substance
which are based on conventional administration forms such
as tablets, due to the combination with a special active
substance.
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The object is solved in accordance with Claim 1 by
providing a pharmaceutical preparation on the basis of a
flat, foil-, paper- or wafer-like active substance carrier
and containing as active substance apomorphine or one of
its therapeutically acceptable salts.
As Will be explained in the following, an administration
form according to Claim 1 is by far superior to a
conventional oral administration form for administeriag
apomorphine - both from the econamical as well as the
therapeutical point of view; it is especially suitable for
the therapy of Parkinson's disease.
Part of the symptoms and signs of Parkinson's disease is
fluctuating dyskinesia, which is hardly accessible to
pharmacotherapy and which is known under the term of
"on-off phenomenon". This is the sudden change between good
ability and akinesia. The active agent apomorphine, a
potent dopamiae agonist, is suitable for acute therapy of
the "off phases". However, for this purpose, apomorphine
must be injected subcutaneously since it is hardly
bioavailable after peroral administration, that is it
appears in the blood circulation only to the very small
extent of a few percent of the dose taken. Presumably, the
reason for the lack in bioavailability lies in the
extensive decomposition of the substance during the first
liver passage following gastrointestinal absorption
("first-pass effect").
A possibility of avoiding the first-pass effect in oral
administration is to bring the active substance to
absorption already on the oral mucosa. In order to enter
the central systemic circulation, an active substance which
enters into the blood via the oral mucosa does not have to
first pass the portal system and thus, in concentrated
form, the liver, which metabolizes the active substance. A
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prerequisite for buccal or sublingual application, however,
is a sufficient permeability of the oral mucosa to the
active substance, taking into consideration the required
dose. Permeability in turn depends to a large extent on the
physicochemical properties of the active substance. Buccal
or sublingual administration of apomorphine appears to be
very much desirable, due to the fact that injections of the
patient are thereby avoided.
In recent years several research groups have therefore
attempted to apply apomorphine via the oral mucosa. In
fact, it has been possible to detect a relevant absolute
bioavailability after sublingual administration in several
e~eriments carried out independently from each other, as,
for example, by Gancher et al. (Movement Disorders 6
[1991], pages 212-215), who found values of bioavailability
between 10 and 22%. Montastruc et al. (Clin.Neuropharmacol.
14 [1991], pages 432 - 437) showed the equivalents of 30 mg
of apomorphine sublingually, to 3 mg of the active
substance subcutaneously. Similar results are found in
Hughes et al. (Clin.Neuropharmacol. 14 [1991], pages 556-
561), Durif et al. (Eur.J.Clin.Pharmaco1.41 [1991], pages
493 - 494), and others.
It is to be criticized, however, that nowhere in the
methodic portion of the publications of these studies have
the parameters of the sublingual application themselves
been defined. The only indications a.n this respect are made
by Gancher et al., who instruct the test persons to keep
the apomorphine tablets of 6 mg each under their tongue
until they are dissolved. Where the tablets had not
disintegrated after 5 minutes, the test persons were
allowed to take a small drink of water, but not to swallow
this. In the other applications it was obviously riot
ensured at all that either a portion of the active
substance dose that was as great as possible or at least a
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portion that came as near to being equally large as
possible was available to the oral mucosa for absorption
from the administration form. At least the duration of
action, however, should be selected so as to be sufficient
and constant, and swallowing of saliva should be eliminated
over a constant period of time in order to methodically
limit sublingual application against a peroral one.
Moreover, the administration form administered is all of
the above mentioned cases, gamely a peroral tablet, is to
be regarded, as has already been stated, as totally
unsuitable for sublingual application. Presumably, it was
precisely this problem which caused the high variability
observed in the above mentioned studies.
This is completely different for the application of apo-
morphine by-means of an administration form according to
Claim 1. This administration form can be brought into
direct contact with the oral mucosa. Due to the flat shape,
immediately after application about half of the surface of
the administration form, which is large any way, is located
directly on the mucosa. The apomorphine released thus
encounters two factors particularly favourable for entry
into the body, namely a short diffusion path and a large
diffusion area. This dianinishes the portion of apomorphine
that is swallowed, which in the case of other active agents
would not be a particular problem. However, with apo-
morphine, swallowing of the active substance should be
avoided if possible, or to be reduced since for the above
mentioned reasons swallowed apomorphine is ineffective.
Even in the case of the most simple embodiment as a rapidly
disintegrating administration form according to the
invention, i.e. having a disintegration time of up to 15
min following application or following introduction into
aqueous media, it emerged in the case of one test parson
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that an apomorphine-containing film is superior to an
apomorphine-containing tablet.
An improved contact of the pharmaceutical preparation with
the oral mucosa can be achieved through selecting the
auxiliary substances. It is known of certain orally
applicable auXlllary agents which are frequently used in
pharmaceutics that they have mucoadhesive properties.
Exam4ples for such mucoadhesive substances are polyacrylic
acid,-carboxymethylcellulose, tragacanth, alginic acid,
gelatin, hydroxymethylcellulose, methylcellulose and gum
arabic. In addition, it is known of various non-
mucoadhesive substances that in certain mixing ratios they
also develop mucoadhesive properties. An example for such a
mixture is glycerol monooleate/water in a ratio of 84:16
(Engstrom et al., Pharm. Tech. Eur. 7 [1995, No. 2, pages
14-17).
Tahere mucoadhesive auxiliary substances are used, it is
preferable for the administration form of the pharma-
ceutical preparation according to the invention to have a
two-layer or multi-layer structure, whereby only that layer
which upon application is to come into contact with the
mucosa should be equipped with mucoadhesive properties.
This prevents the preparation from conglutinating various
parts of the mucosa with each other, which would lead to
sensations of considerable discomfort during application.
Good adhesion of the administration form leads to the
active substance being optimally available for absorption.
In addition, it is the prerequisite for a further,
preferred embodiment of the invention, namely a controlled-
release preparation. In the preparation according to the
invention, the active substance amount, respectively the
portion of the active substance dose administered, that is
absorbed is dependent not only on the contact surface and
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the permeability of the mucosa, but also on the duration of
contact. =n order to allow a larger amount of active
ingredient to enter the body via the relatively small
surface of the oral mucosa, it may be necessary to permit a
long duration of contact; this, however requires that the
preparation does not disintegrate too rapidly, but, through
the addition of auxiliary substances that are slightly or
slowly soluble in saliva, releases the active substance for
the desired duration of time. Suitable auxiliary substances
may be, for exaiqple, film-forming polymers having poor
water-solubility, such as ethylcellulose, cellulose
acetate, highly hydrolized polyvinyl alcohol and many more.
Administration of apomorphine typically results in unwanted
side effects. In the first place, nausea, vomiting and
decrease in blood pressure are to be mentioned. These side
affects must be regarded as being serious and as imposing
limits on therapy. However, it is known that through
simultaneous administration of antiemetically effective
dopamine antagonists such as metoclopramide, but especially
domperidone, the occurrence of side effects can be
eliminated or alleviated without the amorphine losing its
anti-Parkinson action.
A further preferred embodiment of the present invention
therefore contains as active substances apomorphine in
combination with a dopamine antagonist in a combination.
=n the following, preparation examples will be given of the
pharmaceutical preparation according to the invention:
Example 1:
7 g 8s0
3
.
8
g TiOz
.
5
18.4 g polyvinyl pyrrolidone
18.9,g potato starch
23.3 g ethanol
9
4.0 g~~H2O
16.6 g~~apomorphine HCI
1.8 g~~aroma
1.2 g~~sweetener
3.0 g~~acidifying agent
H2O is placed in a heatable, mixing vessel which can be
evacuated. Polyvinylpyrrolidone is dispersed therein and
allowed to swell. TiO2 is dispersed in this mass. To
accelerate the swelling process of the polivinyl-pyrrolidone,
the mass be heated. At room temperature,
potato starch is despersed in the homogeneous mass.
Ethanol, residual H2O and apomorphine HCI are added while
stirring. The mass is heated to 100°C while stirring. After
cooling to room temperature, aroma, sweetener and
acidifying agent are added, and the mass is degasified
under vacuum. The mass is spread onto a suitable carrier
material using a doctor knife, and is dried for 30 minutes
at 80°C. Dosage units are punched out with a wad punch.
Example 2:
135.8 g~~H2O
35.7 g~~polyvinyl alcohol
9.9 g~~TiO2
46.5 g~~SiO2
20.0 g~~glycerol (85%)
50.0 g~~apomorphine HCI
4.8 g~~aroma
3.2 g~~sweetener
8.0 g~~acidifying agent
H2O is placed in a heatable mixing vessel which can be
evacuated, and TiO2 is dispersed therein. Polyvinyl alcohol
and apomorphine HCI are powdered thereto, and are
homogenized while heating to about 80°C. The mass is
degasified under vacuum. After cooling to room temperature,
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SiOs, glycerol, aroma, sweetener and acidifying agent are
added and homogenized. The mass is degasified under vacuum.
The mass is spread onto a suitable carrier material using a
doctor knife, and is dried for 30 minutes at 80~C. Dosage
units are punched out with a wad punch.
