Indian Patents
Title of Invention

A PROCESS FOR THE PRODUCTION OF A TABLET
Abstract The invention relates to a form of administration comprising a physiologically effective substance (A); one or several optional physiologically acceptable adjuvants (B); a synthetic or natural polymer (C); and an optional natural, semisynthetic, or synthetic wax (D). Said form of administration is provided with a minimum breaking strength of 400 N while releasing the physiologically effective substance (A) at least partly in a delayed manner in physiological conditions.
Full Text PCT application WO 2006/082099 A
Break-resistant delayed release forms of administration
The present invention relates to a form of administration for administering a physiologically
active substance (A), wherein the form of administration is mechanically stabilised, so that it
cannot be comminuted with conventional methods, such as pounding, crushing, grinding in a
mortar, etc, or at least can only be comminuted with great difficulty. The substance (A) is
released from the form of administration according to the invention under physiological
conditions with an at least partially delayed profile.
Numerous physiologically active substances, such as nutritional supplements, therapeutic
agents, etc are produced as delayed-release formulations, ie, unlike the case with conventional
formulations (eg so-called "immediate release" formulations), the release of the substances
from these formulations into the organism is delayed for a comparatively long period, often
amounting to several hours. The release of the substance from the form of administration on
the one hand and metabolisation or excretion by the organism on the other, ensure a relatively
uniform blood plasma level for the administered substance. As a consequence of this, it is
frequently possible to reduce the number of dose units to be taken per day by patients, often,
intake is only required once or twice a day.
In certain cases, delayed-release formulations may also reduce the extent of the side effects of
the substance. For example, some therapeutic agents result in intensified side effects if a
specific concentration limit of the therapeutic agent is exceeded, at least transiently. Such
therapeutic agents are, therefore, to a large extent, unsuitable for "immediate release"
formulations, in particular if administration only two or three times daily is desirable.
Medicinal agents of this kind therefore are usually administered as delayed-release
formulations, whereby the continuous release of the active substance is ensured and the short-
term occurrence of elevated concentrations is avoided.
In the case of delayed-release formulations, the physiologically active substance is usually
either embedded in a matrix that controls release, and/or the form of administration is coated
with a film that controls release.
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PCT application WO 2006/082099 A
However, elderly patients in particular frequently have difficulties taking solid forms of
administration, such as tablets, gelatin capsules, etc. They choke on them and sometimes
develop pronounced aversions to such forms of administration.
To counter this, various types of apparatus have been developed by means of which solid
forms of administration can be comminuted or pulverised ("tablet crusher"). This type of
apparatus is used, for example, by the care staff in old people's homes. The forms of
administration are then given to the people requiring care not as tablets etc, but as powder, in
order, for example, to avoid the problems with swallowing tablets.
However, the comminution of forms of administration with apparatus of this type is
problematic if the forms of administration are delayed-release formulations. To be precise,
comminution generally results in the destruction of the inner structure of the form of
administration, which is responsible for the delayed release, thus cancelling out the delayed-
release action. As a result of the comminution, the diffusion paths of the constituent
physiologically active substances are shortened and/or the diffusion barriers removed. For
example, after comminution, a delayed-release formulation in which the delayed release is to
be achieved by means of a film coating only retains the film coating on a small percentage of
its solid surface. As a consequence of this, after administration, frequently the entire amount
of the physiologically active substance originally contained in the form of administration is
released in a relatively short time, whereby a comparatively very high plasma concentration
of the substance is achieved for a relatively short time. In this way, the original delayed-
release formulations become "immediate release" formulations.
However, depending upon the physiological effectiveness of the substance, this may cause
considerable side effects, in extreme cases even the death of the patient. Examples of
substances with a hazard potential of this type include anti-parkinson drugs, antiepileptics,
antidiabetics, antihypertensive agents, antiarrhythmics, etc.
As a rule, the people who comminute the forms of administration for themselves or for others
are not aware of these risks. Deaths of patients are known which are probably attributable to
the pulverisation of delayed-release formulations by nurses or carers. For further details,
reference is made for example to JE Mitchell, Oral Dosage Forms That Should Not Be
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PCT application WO 2006/082099 A
Crushed: 2000 Update. Hospital Pharmacy, 2000; H Miller et al., To Crush or Not to Crush,
Nursing 2000; R Grittith et al., Tablet Crushing and the law: the implications for nursing;
Prof Nurse 2003; JG Schier et al, Fatality from administration of labetalol and crushed
extended-release nifedipine, Ann Pharmacotherapy 2003; A James, The legal and clinical
implications of crushing tablet medication, Nurse Times 2005, 100(50), 28-9; and P Cornish,
"Avoid the Crush": hazards of medication administration in patients with dysphagia or a
feeding tube, CMAJ 2005, 172(7), 871-2.
Delayed-release formulations can also create problems with small children. For example,
children are often unable to distinguish solid forms of administration from sweets. If children
find such forms of administration, for example because their parents have carelessly left them
lying around in the home, there is a risk that the children may think the forms of
administration are sweets, put them in their mouths and chew them. If this involves delayed-
release formulations containing a therapeutic agent in a dose intended for adults, in such a
case, the child is already at risk of an overdose due to the larger content of therapeutic agent.
Chewing the form of administration and the associated cancellation of the delayed-release
action intensifies this risk still further, since the already excessive dose is also released in a
greatly reduced period of time, which would entail considerable risks even for an adult but
could have consequences that are even more drastic for a child.
Chewing delayed-release formulations can also lead to an overdose of the substance contained
therein in adults. For example, adults sometimes chew the forms of administration quite
deliberately, since, often in ignorance of the type and purpose of a delayed-release
formulation, they hope this will achieve a quicker effect.
A known possibility for reducing the risks resulting from the comminution of delayed-release
formulations is to add antagonists, ie antidotes or compounds which produce physiological
defence reactions, to the form of administration, wherein the physiological action of these
additives is, if possible, only activated if the form of administration has been comminuted
before administration. However, this method has the drawback that the physiologically active
substance is nonetheless administered in non-delayed form and that the organism is
additionally exposed to another physiologically active substance, for example an antidote, or
that a defence reaction, such as vomiting, for example, is triggered.
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PCT application WO 2006/082099 A
There is, therefore, a requirement for pharmaceutical forms of administration with delayed
release that reduce the risk of overdose so that there is no need for antidotes, etc.
The invention is based on the object of providing a form of administration having advantages
over the forms of administration in the prior art. The form of administration should release a
physiologically active substance with delayed release but reduce the risk of overdose, in
particular as the consequence of improper handling of the form of administration, such as
chewing, crushing, grinding in a mortar, etc.
It was surprisingly found that this object is achieved by a form of administration comprising
a physiologically active substance (A) (= component (A))
optionally one or a plurality of physiologically compatible excipients (B) (= component
(B)),
a synthetic or natural polymer (C) (= component (C)) and
optionally a natural, semi-synthetic or synthetic wax (D) (= component (D)),
wherein the form of administration has a resistance to breaking of at least 400 N, preferably at
least 420 N, more preferably at least 440 N, still more preferably at least 460 N, most
preferably at least 480 N and in particular at least 500 N and, under physiological conditions,
the physiologically active substance (A) is at least partially delayed. Consequently, the form
of administration according to the invention comprises a physiologically active substance (A)
with at least partially delayed release.
The form of administration according to the invention exhibits mechanical strength over a
wide temperature range, in addition to the resistance to breaking, optionally also sufficient
hardness and impact strength, so that it is virtually impossible for it to be comminuted or
pulverised by chewing, grinding in a mortar, pounding, etc. and also by means of
commercially available apparatus for the pulverisation of conventional forms of
administration. In this regard, this is not necessarily achieved by the hardness of the form of
administration. For example, in particular its impact strength may have the result that,
although it may be deformed due to an external mechanical action, for example by means of a
hammer, it does not disintegrate into numerous fragments. Comminution is not even
successful if the form of administration is first chilled to increase its brittleness, for example
to temperatures below -25°C, -40°C or even in liquid nitrogen.
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PCT application WO 2006/082099 A
As a consequence of this, delayed release is retained and an overdose due to incorrect
handling of the form of administration is effectively prevented.
The advantageous properties of the forms of administration according to the invention, in
particular also their mechanical properties, cannot be automatically achieved by processing
the components (A), (C), optionally (B) and optionally (D) by means of any conventional
methods for the production of forms of administration. Instead, it is usually necessary to
select suitable types of apparatus for production and set suitable parameters, in particular
pressure/force, temperature and time. It is only when the components are exposed to a
sufficient pressure at a sufficient temperature for a sufficient period during production that
forms of administration with the desired properties are obtained. Therefore, even if
conventional types of apparatus are used, it is usually necessary to adapt the production
protocols in order to meet the required criteria.
Delayed release according to the invention should preferably be understood to mean a release
profile in which the physiologically active substance is released over a lengthy period with a
reduced intake frequency with the object of an extended therapeutic action. In particular, this
is achieved with peroral administration. The expression "with at least partially delayed
release" covers according to the invention all forms of administration which ensure modified
release of the physiologically active substances contained therein. The forms of
administration are preferably coated or uncoated forms of administration that are produced
with special excipients, with particular methods or by a combination of both options in order
purposefully to change the release rate or the location of the release.
The time profile of the release with the forms of administration according to the invention
includes the following types: extended release, delayed release, repeat action release,
prolonged release and sustained release.
For the purposes of the description, "delayed release" preferably means the delayed release of
the physiologically active substance for a defined finite time (lag time) after which release
takes place unhindered. "Repeat action release" preferably defines the initial release of a first
portion of the physiologically active substance followed by at least one further portion that is
released following this. "Prolonged release" preferably defines release at a reduced rate in
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PCT application WO 2006/082099 A
order to maintain therapeutic efficacy, reduce toxic effects or for other therapeutic reasons.
"Sustained prolonged release" preferably defines a continuous release over a relatively long
period in order to reduce the frequency of administration. For further details, reference is
made for example, to KH Bauer, Lehrbuch der Pharmazeutischen Technologie, 6th Edition,
WVG Stuttgart, 1999 and the European Pharmacopoeia.
In a preferred embodiment, under physiological conditions, after 5 hours, the form of
administration according to the invention has released at the most 99%, more preferably at the
most 90%, more preferably at the most 75%, still more preferably at the most 50%, most
preferably at the most 40% and in particular at the most 30% of the substance (A). In this
regard, it is particularly preferable for the form of administration in this case to contain
neither tramadol hydrochloride, nor oxycodone hydrochloride, more preferably no opioid
[N02A] (for the meaning of "N02A" see below). The release is in this regard preferably
determined using the standardised method in the European Pharmacopoeia, preferably under
the conditions described in example 1.
Preferably, under physiological conditions, the form of administration according to the
invention releases the physiologically active substance (A) as follows: 0.1 to 75 % by weight
after 30 minutes, 0.5 to 95 % by weight after 240 minutes, 1.0 to 100 % by weight after 480
minutes and 2.5 to 100 % by weight after 720 minutes.
Further preferred release profiles 1 to 5 are summarised in the following table [data in % by
weight of released component (A)]:

Time[h] Nol No 2 No 3 No 4 No 5
1 0-30 0-50 0-50 15-25 20-50
2 0-40 0-75 0-75 25-35 40-75
4 3-55 3-95 10-95 30-45 60-95
8 10-65 10-100 35-100 40-60 80-100
12 20-75 20-100 55-100 55-70 90-100
16 30-88 30-100 70-100 60-75
24 50-100 50-100 >90
36 >80 >80
Preferably, the release behaviour of the form of administration according to the invention is
largely independent of the pH value of the release medium, that is, the release profile in
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PCT application WO 2006/082099 A
artificial intestinal juice preferably corresponds substantially to the release profile in artificial
gastric juice. Preferably, at any time during the measurement, the deviation of the two release
profiles from each other is at the most 20%, more preferably at the most 15%, still more
preferably at the most 10%, still more preferably at the most 7.5%, most preferably at the
most 5.0% and in particular at the most 2.5%.
Preferably, the form of administration according to the invention has uniform release
behaviour. In this regard, preferably, the release behaviour of the physiologically active
substance (A) is interindividually uniform (that is compared to the forms of administration
produced using the same method) and/or uniform within a single form of administration (that
is compared to partial segments of the same form of administration). Preferably, in a
comparison of this kind of two samples each with a mass of preferably 500 mg, at any time of
the measurement, the total amounts of the released active substance deviate from each other
by at the most 20%, more preferably at the most 15%, still more preferably at the most 10%,
still more preferably by at the most 7.5%, most preferably at the most 5.0% and in particular
by at the most 2.5%.
Preferably, the release profile of the form of administration according to the invention is
stable in storage, preferably in storage at a high temperature, eg at 37°C, for 3 months in
sealed containers. In this context, "stable in storage" means that, in a comparison of the initial
release profile with the release profile after storage, the two release profiles deviated from
each other by at the most 20%, more preferably by at the most 15%, still more preferably by
at the most 10%, still more preferably by at the most 7.5%, most preferably by at the most
5.0% and in particular by at the most 2.5%.
By the use of certain polymers, in suitable quantities and under suitable conditions it is
achieved according to the invention that the form of administration has a resistance to
breaking of at least 400 N, preferably at least 420 N, more preferably at least 440 N, still more
preferably at least 460 N, most preferably 480 N and in particular at least 500 N (measured as
specified in the description; the preferred method for the determination of the resistance to
breaking according to the invention is a modification of the method "Resistance to Crushing
of Tablets" described in the European Pharmacopoeia 5,0 on page 235, 2.9.8). This enables
comminution, eg pulverisation of the form of administration with conventional means, to be
effectively prevented.
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PCT application WO 2006/082099 A
According to the invention, comminution should be understood to mean the pulverisation of
the form of administration under the application of force with conventional means, such as,
for example, a mortar and pestle, hammer, mallet or other usual means for pulverisation, in
particular also devices specially developed for this purpose (tablet crushers), wherein any
fines that may occur (particle size equal to or smaller than 0.3 mm) must not exceed 5 % by
weight.
The form of administration according to the invention is therefore suitable for preventing an
overdose of physiologically active substances, in particular of nutritional supplements and
therapeutic agents, which are provided in delayed-release formulations. In this regard, it is
possible to dispense with antidotes, irritants, etc. In addition to preventing overdoses and the
accompanying risks for patients, the forms of administration according to the invention also
ensure that the other advantages of the delayed-release formulation, such as for example
uniform release over a lengthy period are retained and cannot be easily cancelled out.
To achieve the necessary resistance to breaking of the form of administration according to the
invention, at least one synthetic or natural polymer (C) is used, which contributes
considerably to the increased resistance to breaking of the form of administration. The
resistance to breaking of the form of administration is at least 400 N, preferably at least 420
N, more preferably at least 440 N, still more preferably at least 460 N, most preferably at least
480 N and in particular at least 500 N, wherein the resistance to breaking is determined
according to method specified in the description. In a preferred embodiment, the resistance to
breaking of the form of administration is at least 500 N, more preferably at least 600 N, more
preferably at least 700 N, still more preferably at least 800 N, still more preferably at least
900 N, most preferably at least 1000 N and in particular at least 1100 N.
In addition to its resistance to breaking, the form of administration according to the invention
is preferably also characterised by further mechanical properties, for example its hardness,
impact resistance, impact elasticity and/or its modulus of elasticity, optionally also at low
temperatures (eg below -24°C, below -40°C or in liquid nitrogen).
In a preferred embodiment, the form of administration according to the invention has a
density of at least 0,80 or at least 0.85 g/cm3, more preferably at least 0.90 or at least 0.95
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PCT application WO 2006/082099 A
g/cm3, still more preferably at least 1.00, at least 1.05 or at least 1.10 g/cm3, most preferably
in the region of 0.80 to 1.35 g/cm3 and in particular in the region of 0.95 to 1.25 g/cm3.
The form of administration according to the invention is characterised by a comparatively
homogeneous distribution of density. Preferably, the densities of two partial segments of the
form of administration each with a volume of 1.0 mm3 deviate from each other by at the most
±10%, more preferably by at the most ±7.5%, still more preferably by at the most ±5.0%,
most preferably by at the most ±2.5% and in particular by at the most ±1.0%.
The form of administration according to the invention is characterised by a comparatively
homogeneous distribution of the physiologically active substance (A). Preferably, the content
of component (A) in two partial segments of the form of administration each with a volume
1.0 mm3 deviate from each other by at the most ±10%, more preferably by at the most ±7.5%,
still more preferably by at the most ±5.0%, most preferably by at the most ±2.5% and in
particular by at the most ± 1.0%.
The total weight of the form of administration according to the invention is preferably in
region of 0.01 g to 1.5 g, more preferably of 0.05 g to 1.2 g, more preferably of 0.1 g to 1.0 g,
most preferably of 0.2 g to 0.9 g and in particular of 0.25 g to 0.8 g.
Preferably, the form of administration according to the invention comprises at least one
polymer (C) selected from the group consisting of polyalkylene oxide, preferably
polymethylene oxide, polyethylene oxide, polypropylene oxide; polyethylene, polypropylene,
polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, poly(hydroxy fatty acids), such
as, for example, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol®),
poly(hydroxyvaleric acid), polycaprolactone, polyvinyl alcohol, polyesteramide, polyethylene
succinate, polylactone, polyglycolide, polyurethane, polyvinylpyrrolidone, polyamide,
polylactide, polyacetal (for example polysaccharides optionally with modified side chains),
polylactid/glycolide, polylactone, polyglycolide, polyorthoester, polyanhydride, block
polymers of polyethylene glycol and polybutylene terephthalate (Polyactive®), polyanhydride
(Polifeprosan), the copolymers thereof and mixtures of at least two of the polymers named.
High-molecular, thermoplastic polyalkylene oxides, in particular polyethylene oxide,
polypropylene oxide or (block) copolymers thereof are preferred. Particularly preferred are
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PCT application WO 2006/082099 A
high-molecular polyalkylene oxides, in particular polyethylene oxides, with a preferably
weight average molecular weight (Mw) or viscosity average molecular weight (M ) of at least
0.5 106 g/mol, preferably at least 1.0 106 g/mol, more preferably at least 2.5 106 g/mol, still
more preferably at least 5.0 106 g/mol, most preferably at least 7.5 105 g/mol or 7.5 10 g/mol
and in particular at least 10 106 g/mol, preferably 1.0 106 to 15 106 g/mol. The person skilled
in the art knows suitable methods for the determination of Mw or M . Preferably, M is
determined by rheological measurements and Mw is determined by gel permeation
chromatography (GPC) on suitable phases.
The polymers (C) preferably have a viscosity at 25 °C of 4,500 to 17,600 mPa/s (cP),
measured in a 5 % by weight aqueous solution using a Brookfield viscosimeter, Model RVF
(spindle No 2 / rotational speed 2 rpm), of 400 to 4,000 mPa/s (cP), measured on a 2 % by
weight aqueous solution using said viscosimeter (spindle No 1 or 3 / rotational speed 10 rpm)
or of 1,650 to 10,000 mPa/s (cP), measured on a 1 % by weight aqueous solution using said
viscosimeter (spindle No 2 / rotational speed 2 rpm).
The polymer (C) is preferably used as a powder. It may be soluble in water.
Preferably, the polymer (C) is used in a quantity of at least 20 % by weight, more preferably
at least 30 % by weight, still more preferably at least 40 % by weight, most preferably at least
50 % by weight, and in particular at least 60 % by weight, based on the total weight of the
form of administration. In a preferred embodiment, the quantity is in the region 20 to 49 % by
weight, based on the total weight of the form of administration.
The form of administration according to the invention is suitable for the administration of a
plurality of physiologically active substances (A) in one form of administration. Preferably,
the form of administration contains only one specific physiologically active substance (A),
preferably a nutritional supplement or a therapeutic agent (= active pharmaceutical
ingredient).
The percentage by weight of the physiologically active substance (A) based on the total
weight of the form of administration according to the invention is preferably in the region of
0.01 to 95 % by weight, more preferably 0.5 to 80 % by weight, still more preferably 1.0 to 70
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PCT application WO 2006/082099 A
% by weight, most preferably 5.0 to 60 % by weight and in particular 10 to 50 % by weight.
In a preferred embodiment, the percentage by weight is more than 20 % by weight.
In a preferred embodiment of the form of administration according to the invention, it does
not contain any psychotropically active substance. The person skilled in the art knows which
substances have a psychotropic action. Substances that influence psychological processes
commonly have a psychotropic action, ie a specific action on psychological functions. Thus,
substances with a psychotropic action can influence moods, either raising them or lowering
them. For the purposes of the description, substances with a psychotropic action include in
particular opioids, stimulants, tranquillisers (barbiturates and benzodiazepines) and further
narcotics. Preferably, substances with a psychotropic action are substances which, in
particular when improperly administered (in particular with the intention of abuse) cause an
accelerated increase in active ingredient levels compared to proper oral administration giving
the abuser the desired effect, namely the "kick". This kick can be achieved for example if the
powdered form of administration is administered nasally, ie sniffed. Preferably, substances
with a psychotropic action are substances which (in the appropriate dose, form of
administration and type of administration) influence human mental activity and/or sensory
perception in such a way that they are in principle suitable for abuse.
The following opiates, opioids, tranquillisers or other narcotics are substances with a
psychotropic action and according to the invention therefore are preferably not contained in
the form of administration: alfentanil, allobarbital, allylprodine, alphaprodine, alprazolam,
amfepramone, amphetamine, amphetaminil, amobarbital, anileridine, apocodeine, barbital,
bemidone, benzylmorphine, bezitramide, bromazepam, brotizolam, buprenorphine,
butobarbital, butorphanol, camazepam, carfentanil, cathine/ D-norpseudoephedrine,
chlordiazepoxide, clobazam, clofedanol, clonazepam, clonitazene, clorazepate, clotiazepam,
cloxazolam, cocaine, codeine, cyclobarbital, cyclorphan, cyprenorphine, delorazepam,
desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone,
diazepam, dihydrocodeine, dihydromorphine, dihydromorphone, dimenoxadol,
dimephetamol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, dronabinol,
eptazocine, estazolam, ethoheptazine, ethylmethylthiambutene, ethyl loflazepate,
ethylmorphine, etonitazene, etorphine, fencamfamine, fenethylline, fenpipramide,
fenproporex, ^entanyl, fludiazepam, flunitrazepam, flurazepam, halazepam, haloxazolam,
heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, hydroxymethyl-
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PCT application WO 2006/082099 A
morphinan, ketazolam, ketobemidone, levacetylmethadol (LAAM), levomethadone,
levorphanol, levophenacylmorphane, levoxemacin, lofentanil, loprazolam, lorazepam,
lormetazepam, mazindol, medazepam, mefenorex, meperidine, meprobamate, metapon,
meptazinol, metazocine, methylmorphine, metamphetamine, methadone, methaqualone, 3-
methylfentanyl, 4-methylfentanyl, methylphenidate, methylphenobarbital, methyprylon,
metopon, midazolam, modafinil, morphine, myrophine, nabilone, nalbuphene, nalorphine,
narceine, nicomorphine, nimetazepam, nitrazepam, nordazepam, norlevorphanol,
normethadone, normorphine, norpipanone, opium, oxazepam, oxazolam, oxycodone,
oxymorphone, Papaver somniferum, Papaveretum, pernoline, pentazocine, pentobarbital,
pethidine, phenadoxone, phenomorphane, phenazocine, phenoperidine, piminodine,
pholcodeine, phenmetrazine, phenobarbital, phentermine, pinazepam, pipradrol, piritramide,
prazepam, profadol, proheptazine, promedol, properidine, propoxyphene, remifentanil,
secbutabarbital, secobarbital, sufentanil, temazepam, tetrazepam, tilidine (cis and trans),
tramadol, triazolam, binylbital, N-(l-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide,
(lR,2R)-3-(3-dimethylamino-l-ethyl-2-methyl-propyl)-phenol, (1R, 2R, 4S)-2-
(dimethylamino)methyl-4-(p-fluorbenzyloxy)-1 -(m-methoxyphenyl)cyclohexanol, (1R, 2R)-
3-(2-dimethylaminomethyl-cyclohexyl)-phenol, (IS, 2S)-3(3-dimethylamino-1 -ethyl-2-
methyl-propyl)-phenol, (2R, 3R)-l-dimethylamino-3(3-methoxy-phenyl)-2-methyl-pentan-3-
ol, (IRS, 3RS, 6RS)-6-dimethylaminomethyl-l-(3-methoxy-phenyl)-cyclohexane-l,3-diol,
preferably as racemate, 3-(2-dimethylaminomethyl-l-hydroxy-cyclohexyl)-phenyl 2-(4-
isobutyl-phenyl)-propionate, 3-(2-dimethylaminomethyl-1 -hydroxy-cyclohexyl)phenyl 2-(6-
methoxy-naphthalen-2-yl)-propionate, 3-(2-dimethylaminomethyl-cyclohex-1 -enyl)-phenyl 2-
(4-isobutyl-phenyl)-propionate, 3-(2-Dimethylaminomethyl-cyclohex-1 -enyl)-phenyl 2-(6-
methoxy-naphthalen-2-yl)-propionate, (RR-SS)-2-acetoxy-4-trifluoromethyl-benzoic acid 3-
(2-dimethylaminomethyl-1 -hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-
trifluoromethyl-benzoic acid 3-(2-dimethylaminomethyl-l-hydroxy-cyclohexyl)-phenyl ester,
(RR-SS)-4-chloro-2-hydroxy-benzoic acid 3-(2-dimethylaminomethyl- 1-hydroxy-
cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-methyl-benzoic acid 3-(2-
dimethylaminomethyl-l-hydroxy-cyclohexyl)-phenyl ester, (RR-SS)-2-hydroxy-4-methoxy-
benzoic acid 3-(2-dimethylaminomethyl-l-hydroxy-cyclohexyl)-phenyl-ester, (RR-SS)-2-
hydroxy-5-nitro-benzoic acid 3-(2-dimethylaminomethyl-l-hydroxy-cyclohexyl)-phenyl
ester, (RR-SS)-2',4'-difluoro-3-hydroxy-biphenyl-4-carboxylic acid 3-(2-
dimethylaminomethyl-l-hydroxy-cyclohexyl)-phenyl ester and corresponding stereoisomeric
compounds, in each case the corresponding derivatives thereof, physiologically compatible
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PCT application WO 2006/082099 A
enantiomers, stereoisomers, diastereomers and racemates and the physiologically compatible
derivatives thereof, for example ethers, esters or amides, and in each case the physiologically
compatible compounds thereof, in particular the salts and solvates thereof, for example
hydrochloride.
In particular, the form of administration according to the invention preferably does not
contain any substance selected from the group consisting of opioids [A07DA, N01AH, N02A,
R05DA, R05FA,], barbiturates [N01AF, N01AG, N03AA], benzodiazepine derivatives
[N03AE], agents for the treatment of opiate dependence [N07BC], anxiolytics [N05B],
hypnotics and sedatives [N05C], psychostimulants, agents for the treatment of attention
deficit/hyperactivity disorder (ADHD) and nootropics [N06B], antiemetics [A04A],
antiobesity preparations excluding diet products [A08A], centrally acting muscle relaxants
[M03B] and antidotes [V03AB]. The references in brackets hereby correspond to the ATC
Index, as used by the WHO for the classification of therapeutic agents (preferred version:
January 2005 or 2006). With regard to further information on the ATC Index, reference is
made for example to U Fricke, J Giinther, Anatomisch-therapeutisch-chemische
Klassifikation mit Tagesdosen fur den deutschen Arzneimittelmarkt: Methodik der ATC-
Klassifikation und DDD-Festlegung. ATC-Index mit DDD-Angaben, Wissenschaftliches
Institut der AOK and Swiss Pharmaceutical Society, Index Nominum: International Drug
Directory, CRC Press; 18th edition (January 31, 2004).
In a preferred embodiment, the form of administration according to the invention does not
contain any compound selected from the group consisting of
(1) analgesics, such as, for example, aspirin, acetaminophen, deflunisal, etc,
(2) anaesthetics, such as, for example, lidocaine, procaine, benzocaine, xylocaine, etc,
(3) antiarthritiics and anti-inflammatory agents, such as, for example, phenylbutazone,
indomethacin, sulindac, dexamethasone, ibuprofen, allopurinol, oxyphenbutazone
probenecid, cortisone, hydrocortisone, betamethasone, dexamethasone, fluocortolone,
prednisolone, triamcinolone, indomethacin, sulindac and the salts thereof and
corresponding sulfides, etc,
(4) antiasthma drugs, such as, for example, theophylline, ephedrine, beclomethasone
dipropionate, epinephrine, etc,
(5) urinary tract disinfectives, such as, for example, sulfarmethoxazole, trimethoprim,
nitrofurantoin, norfloxicin, etc,
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PCT application WO 2006/082099 A
(6) anticoagulants, such as, for example, heparin, bishydroxy coumarin, warfarin, etc,
(7) anticonvulsants, such as, for example, diphenylhydantoin, diazepam, etc,
(8) antidepressants, such as, for example, amitriptyline, chlordiazepoxide, perphenazine,
protriptyline, imipramine, doxepin, etc,
(9) substances suitable for the treatment of diabetes and for the regulation of blood sugar,
such as, for example, insulin, tolbutamide, tolazamide, somatotropin, acetohexamide,
chlorpropamide, etc,
(10) antineoplastics, such as, for example, adriamycin, fluouracil, methotrexate,
asparaginase, etc,
(11) antipsychotics, such as, for example, prochlorperazine, lithium carbonate, lithium
citrate, thioridazine, molindone, fluphenazine, trifluoperazine, perphenazine,
amitriptyline, triflupromazine, etc,
(12) antihypertensives, such as, for example, spironolactone, methyldopa, hydralazine,
clonidine, chlorothiazide, deserpidine, timolol, propanolol, metaprotol, prazosin
hydrochloride, reserpine, etc,
(13) muscle relaxants, such as, for example, mephalan, danbrolene, cyclobenzaprine,
methocarbarnol, diazepam, succinoyl chloride, etc,
(14) antiprotozoals, such as, for example, chloramphenicol, chloroquine, trimethoprim and
sulfamethoxazole,
(15) spermicidals, such as, for example, nonoxynol,
(16) antibacterial substances, such as, for example, beta-lactam antibiotics, tetracyclines,
chloramphenicol, neomycin, cefoxitin, thienamycin, gramicidin, bacitracin,
sulfonamides, aminoglycoside antibiotics, tobramycin, nitrofurazone, nalidixic acid
and analogues and the antimicrobial combination of fludalanine/pentizidone,
(17) antihistamines and decongestants, such as, for example, perilamine, chlorpheniramine
(eg chlorpheniramine maleate), tetrahydrozoline and antazoline,
(18) antiparasitic substances, such as, for example, ivermectin,
(19) antiviral substances, such as, for example, acyclovir and interferon,
(20) antifungal, amoebicidal, trichomonacidal agents or antiprotozoals, such as, for
example, polyoxyethylene nonylphenol, alkylaryl sulfonate, oxyquinoline sulfate,
miconazole nitrate, sulfanil amide, candicidin, sulfisoxazole, nysatidin, clotrimazole,
metronidazol, etc, and
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PCT application WO 2006/082099 A
(21) losoxanthrone, theophylline or B-hydroxyethyl-theophylline (etophylline),
diphenhydramine or the hydrochloride thereof, diltiazem or the hydrochloride thereof
and diphenylethyl(adenosine).
In a preferred embodiment, the form of administration according to the invention does not
contain any substances which irritate the nasal passages and/or pharynx, that is substances
which, when administered via the nasal passages and/or pharynx, bring about a physical
reaction which is either so unpleasant for the patient that he/she is unwilling or unable to
continue the administration, for example burning, or in a physiological way prevents the
intake of the active ingredient, for example due to increased nasal secretion or sneezing.
Further examples of substances which irritate the nasal passages and/or pharynx are
substances which cause burning, itching, an urge to sneeze, increased secretions or a
combination of at least two of these irritations. Corresponding substances and the
conventionally used quantities thereof are known to the person skilled in the art. For example,
some of the substances which irritate the nasal passages/or pharynx are based on one or more
ingredients or one or more plant parts of a hot substance drug. Corresponding hot substance
drugs are known per se to the person skilled in the art and are described, for example, in
"Pharmazeutische Biologie - Drogen und ihre Inhaltsstoffe" by Prof Dr Hildebert Wagner,
2nd revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982, pages 82 et seq. The
corresponding description is hereby introduced as a reference and is deemed to be part of the
disclosure.
The form of administration according to the invention furthermore preferably does not contain
any antagonists for the physiologically active substance (A), preferably no antagonists against
psychotropic substances, in particular no antagonists against opioids. Suitable antagonists for
a given physiologically active substance (A) are known to the person skilled in the art and can
be present as such or in the form of corresponding derivatives thereof, in particular esters or
ethers, or in each case in the form of corresponding physiologically compatible compounds,
in particular in the form of the salts or solvates thereof. Preferably, the form of administration
according to the invention does not contain any antagonists selected from the group
comprising naloxone, naltrexone, nalmefene, nalide, nalmexone, nalorphine or naluphine, in
each case optionally in the form of a corresponding physiologically compatible compound, in
particular in the form of a base, a salt or solvates and no neuroleptics, eg a compound selected
from the group comprising aloperidol, promethacine, fluphenazine (fluophenozine),
15

PCT application WO 2006/082099 A
perphenazine, levomepromazine, thioridazine, perazine, chlorpromazine, chlorprothixine
(chlorprotheaxine), zuclopentixol (zuclopantexol), flupentixol (flupentexol), prothipendyl
(prithipendyl), zotepine, benperidol (penperidol), pipamperone (piparmerone), melperone
(melperol) and bromperidol.
The form of administration according to the invention furthermore preferably does not contain
any emetics. Emetics are known to the person skilled in the art and can be present as such or
in the form of corresponding derivatives, in particular esters or ethers, or in each case in the
form of corresponding physiologically compatible compounds, in particular in the form of the
salts or solvates thereof. Preferably, the form of administration according to the invention
does not contain any emetics based on one or more ingredients of ipecacuanhae root (ipecac),
eg based on the ingredient emetine, such as are described, for example, in "Pharmazeutische
Biologie - Drogen und ihre Inhaltsstoffe" by Prof Dr Hildebert Wagner, 2nd, revised edition,
Gustav Fischer Verlag, Stuttgart, New York 1982. The corresponding literature description is
hereby introduced as a reference and is deemed to be part of the disclosure. Preferably, the
form of administration according to the invention also does not contain any apomorphine as
an emetic.
Finally, the form of administration according to the invention preferably also does not contain
any bitter substances. Bitter substances and the quantities effective for use may be found in
US- 2003/0064099 Al, the corresponding disclosure of which should be deemed to be a
disclosure of the present invention and is hereby introduced as a reference. Examples of bitter
substances include aromatic oils, such as peppermint oil, eucalyptus oil, bitter almond oil,
menthol, fruit aroma substances, aromatic substances from lemons, oranges, limes, grapefruit
or mixtures thereof, and/or denatonium benzoate.
Therefore, the form of administration according to the invention preferably does not contain
any substances with a psychotropic action, nor substances that irritate the nasal passages
and/or pharynx, nor antagonists for the physiologically active substance (A), nor emetic nor
bitter substances.
In a preferred embodiment the form of administration according to the invention contains as
the physiologically active substance (A) a nutritional supplement. Nutritional supplements
preferably contain one or more nutrients in a concentrated, measured form that is atypical of
16

PCT application WO 2006/082099 A
foodstuffs. They are intended to supplement the daily diet in cases in which the diet is
insufficient or a supplementation is desired. Preferably, the nutritional supplement is selected
from the group consisting of vitamins, mineral supplements, trace elements, enzymes, fatty
acids, amino acids, and antioxidants. Particularly preferred nutritional supplements are
vitamins, provitamins and the derivatives thereof, in particular retinol, calcitriol, tocopherol,
phylloquinone, thiamine, riboflavine, folic acid, niacin (in particular nicotinamide),
pantothenic acid, pyridoxal, cobalamin, L-ascorbic acid, biocytin, biotin and carotenoids.
In a preferred embodiment, the form of administration according to the invention contains as
the physiologically active substance (A) a therapeutic agent (= active pharmaceutical
ingredient) justifying the use of the form of administration as medicinal product and being
responsible for the efficacy thereof. Suitable therapeutic agents in the form of administration
according to the invention are in principle all known therapeutic agents, wherein the
therapeutic agents as such can be present in the form of administration according to the
invention in the form of the derivatives thereof, in particular esters or ethers, or in each case in
the form of corresponding physiologically compatible compounds, in particular in the form of
the corresponding salts or solvates thereof, as racemates or in the enriched form of one or
more stereoisomers (enantiomers or diastereomers).
Particularly preferably, the form of administration according to the invention contains one
substance (A) or a plurality of substances (A) selected from the group consisting of
- agents for the treatment and prevention of diseases of the alimentary system and
metabolism [A], in particular stomatological preparations [A01], agents for the treatment
and prevention of acid-related disorders [A02], agents for the treatment and prevention of
functional gastrointestinal disorders [A03], serotonin 5HT3 antagonists [A04AA],
antihistamines preparations [A04AB], agents for bile and liver therapy [A05], laxatives
[A06], intestinal anti-infectives [A07A], intestinal adsorbents [A07B], electrolytes with
carbohydrates [A07C], intestinal anti-inflammatory agents [A07E], antidiarrhoeal
microorganisms [A07F], digestives including enzymes [A09], drugs used in diabetes
[A 10], vitamins [Al 1], mineral supplements [A 12], anabolic agents for systemic use [A 14]
and appetite stimulants [A 15];
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PCT application WO 2006/082099 A
- agents for the treatment and prevention of diseases of the blood and the blood-forming
organs [B], in particular antithrombotic agents [B01], antihaemorrhagics [B02],
antianaemic agents [B03] and other haematological agents [B06],
- agents for the treatment and prevention of diseases of the cardiovascular system [C], in
particular agents for cardiac therapy [C01], antihypertensives [C02], diuretics [C03],
peripheral vasodilators [C04], vasoprotectives [C05], antihypotensive agents [C06A], B-
adrenoceptor antagonists [C07], calcium channel blockers [C08], agents acting on the
renin-angiotensin system [C09] and lipid-lowering agents [CIO]
- dermatologicals [D], in particular antifungals for systemic use [DOIB], antipsoriatics for
systemic use [D05B], anti-acne preparations for systemic use [D10B]
- agents for the treatment and prevention of diseases of the urogenital system and sex
hormones [G], in particular gynaecological antiinfectives and antiseptics [G01], oxytocics
[G02A], sympathomimetic labour suppressants [G02CA], prolactine inhibitors [G02CB],
hormonal contraceptives for systemic use [G03] and urologicals [G04]
- systemic hormone preparations excluding sex hormones and insulins [H], in particular
pituitary and hypothalamic hormones and analogues [HOI], corticosteroids for systemic
use [H02], thyroid preparations [H03], pancreatic hormones [H04] and agents for the
regulation of the calcium homeostasis [H05],
- antiinfectives for systemic use [J], in particular antibiotics for systemic use [J01],
antimycotics for systemic use [J02], antimycobacterials [J04], antivirals for systemic use
[J05], immune sera and immunglobulins [J06] and vaccines [J07],
- antineoplastic and immunmodulating agents [L], in particular antineoplastic agents [L01],
agents for endocrine therapy [L02], immunostimulants [L03] and immunosuppressive
agents [L04];
- agents for the treatment and prevention of diseases of the musculo-skeletal system [M], in
particular anti-inflammatory and antirheumatic products [M01], peripherally acting muscle
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PCT application WO 2006/082099 A
relaxants [M03A], directly acting muscle relaxants [M03C], antigout preparations [M04]
and agents for the treatment of bone diseases [M05];
- agents for the treatment and prevention of diseases of the nervous system [N], in particular
salicylic acid and derivatives thereof [N02BA], pyrazolones [N02BB], anilides [N02BE],
ergot alkaloids [N02CA], corticosteroids derivates [N02CB], selective serotonin 5HTi
agonists [N02CC], hydantoin derivates [N03AB], oxazolidine derivates [N03AC],
succinimide derivates [N03AD], carboxamide derivatives [N03AF], fatty acid derivatives
[N03AG], antiparkinson drugs [N04]), antipsychotics [N05A], antidepressants [N06A],
anti-dementia drugs [N06D], parasympathomimetics [N07A] and antivertigo preparations
[N07C],
- antiparasitic products, insecticides and repellents [P], in particular antiprotozoals [P01],
antihelmintics [P02] and ectoparasiticides including scabicides, insecticides and repellents
[P03],
- agents for the treatment and prevention of diseases of the respiratory system [R], in
particular nasal preparations [R01], throat preparations [R02], drugs for obstructive airway
diseases [R03], expectorants excluding combinations with cough suppressants [R05C] and
antihistamines for systemic use [R06],
- agents for the treatment and prevention of diseases of the sensory organs [S], in particular
otologicals [S02];
- general nutrients [V06] and therapeutic radiopharmaceuticals [V10],
wherein once again the references in square brackets correspond to the ATC index as used by
the WHO for the classification of therapeutic agents (preferred version: January 2005 or
2006).
Preferably the form of administration according to the invention contains one substance (A)
or a plurality of substances (A) selected from the group consisting of 4-aminomethylbenzoic
acid, abacavir, abamectin, abciximab, abibendan, abrin, acamprosat, acarbose, acebutolol,
aceclidine, aceclofenac, acediasulfone, acemetacin, acenocoumarol, acetazolamide,
19

PCT application WO 2006/082099 A
acetoacetic acid, acetyldigoxin, acetylandromedol, acetylcysteine, B-acetyldigoxin,
acetylhistamine, acetylsalicylic acid, acetylthiocholine, aciclovir, acipimox, acitretin,
aclarubicin, aconitine, acriflavinium chloride, acrivastine, actinoquinol, acylaminopenicillin,
adalimumab, adapalene, adefovir, adefovir dipivoxil, adenosine, adenosine phosphate,
adenosine triphosphate, adipiodone, adrenalin, aescin, agalsidase alfa, agalsidase beta,
agaricic acid, ajmaline, alanine, albendazole, alcuronium, aldesleukin, aldosterone,
alemtuzumab, alendronic acid, alfacalcidol, alfuzosin, algeldrate F, alitretinoin, alizapride,
allantoin F, allopurinol, allyl isorhodanate, almasilate F, almotriptan, a-acetyldigoxin,
alprenolol, alprostadil, alteplase, aluminium glycinate F, aluminium hydroxide F, aluminium
phosphate F, aluminium triformate, amantadine, ambazone, ambroxol, ambutonium bromide,
formic acid, amicacin, amidephrine, amidotrizoic acid, amifostine, amikacin, amiloride,
aminoacetic acid, aminoglutethimide, aminophylline, aminoquinuride, amiodarone,
amisulpride, amitriptyline, amitryptiline, amlodipine, amorolfine, amoxicillin, amphotericin
B, ampicillin, amprenavir, amylmetacresol, amyl nitrite, anagrelide, anakinra, anastrozole,
ancrod, anistreplase, antazoline, antithrombin III, apomorphine, apraclonidine, aprepitant,
aprindine, aprotinin, arcitumomab, arginine, aripiprazole, arsenic trioxide, artemether,
articaine, ascorbic acid, asparagine, L-asparaginase, aspartic acid, atazanavir, atenolol,
atomoxetine, atorvastatin, atosiban, atovaquone, atracurium, atracurium besylate, atropine,
auranofin, azapropazone, azathioprine, azelaic acid, azelastine, azidothymidine, azithromycin,
azlocillin, aztreonam, N2 alanyl levoglutamide, p-aminosalicylic acid,
bacampicillin, bacitracin, baclofen, balsalazide, bambuterol, bamethan, bamipine,
barbexaclone, barium sulfate F, barnidipine, basiliximab, batroxobin, becaplermin,
beclomethasone, bendamustine (bedamustine), befunolol, bemiparin, benactyzine, benazepril,
bencyclane, bendazac, bendroflumethiazide, benperidol (penperidol), benproperine,
benserazide, benzaseride, benzathine, benzatropine, benzbromarone, benzocaine, benzoyl
peroxide, benzyclane, benzydamine, benzylpenicillin, benzylphenyl glycolate, betacarotene,
betahistidine, betahistine, betamethasone, betanechol, betaxolol, bethanechol chloride,
betiatide, bevacizumab, bexarotene, bezafibrate, bibenzonium bromide, bicalutamide,
bicisate, bifonazole, bimatoprost, biperiden, bisoprolol, bivalirudin, bleomycin, blood clotting
factor VII, VIII, IX, X, XIII, bornapine, bornaprine, bortezomib, bosentan, botulinum toxin
type B, brimonidine, brinzolamide, brivudin, bromhexine, bromocriptine, bromperidol,
brompheniramine, brotizolam, budesonide, budipine, bufexamac, buflomedil, bumetanide,
20

PCT application WO 2006/082099 A
bunazosin, buphenine, bupivacaine, bupranolol, bupropion, buserelin, buspirone, busulfan,
butalamine, butanilicaine, butenafine, butethamate, butinoline, butizide, butylscopolaminium,
5-chlorcarvacrol, Cl esterase inhibitor, cabergoline, cadexomer iodine, cafedrine, calcipotriol,
calcitonin, calcitriol, camylofine, candesartan cilexetil, canrenoic acid, capecitabine,
capreomycin, capsaicin, captopril, carazolol, carbaldrate F, carbamazepine, carbasalate
calcium, carbenoxolone, carbidopa, carbimazole, carbinoxamine, carboplatin, carglumic acid,
carmustine, caroverine, carteolol, carvedilol, caspofungin, cefaclor, cefadroxil, cefalexin,
cefaloridine, cefamandole, cefazolin, cefdinir, cefepime, cefetamet-pivotil, cefixime,
cefodizime, cefoperazone, cefotaxime, cefotiam, cefoxitin, cefpirome, cefpodoxime,
cefpodoxime-proxetil, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone,
cefuroxime, celecoxib, celiprolol, certoparin, cetirizine, cetrimide, cetrimonium bromide,
cetrorelix, cetuximab, cetylpiridinium, chenodeoxycholsaure, quinidine, quinine, quinine iron
citrate F, quinine tannate F, chlorambucil, chloramphenicol, chlorbutynol, chlorhexidine,
chlormidazole, chlorobutanol, chloroquine, chloroxylenol, chlorphenamine, chlorphenesin,
chlorphenoxamine, chlorpromazine, chlorprothixene (chlorprotheaxine), chlortalidone,
chlortetracycline, chlorzoxazone, choline, chondroitin sulfate, choriogonadotropin alfa,
chorionic gonadotropin, chrysarobin, chymotrypsin, ciclesonide, cicletanine, ciclopirox,
ciclosporin, cidofovir, cilastatin, cilazapril, cimetidine, cinacalcet, cinchocaine, cinnarizine,
cinolazepam, ciprofloxacin, cisapride, cisatracurium besylate, cisplatin, citalopram, citicoline,
cladribine, clarithromycin, clavulanic acid, clemastine, clenbuterol, clindamycin, clioquinol,
clobetasol, clobetasone, clobutinol, clocortolone, clodronic acid, clofibrate, clomifene,
clomipramine, clonazepam, clonidine, clopamide, clopidogrel, clostebol acetate, clostridium
botulinum, clotrimazole, cloxiquine, clozapine, cocarboxylase, colchicine, colecalciferol,
colesevelam, colestipol, colestyramine, colfosceril palmitate, colistin, zinc eyewash F,
corticorelin, corticotrophin, cortisone, cresol, croconazole, cromoglicic acid, crotamiton,
cryofluorane, cumarin, cyanamide, cyanocobalamin, cyclizine, cyclobutyrol, cyclopentolate,
cyclophosphamide, cycloserine, cyproheptadine, cyproterone, cysteine, cytarabin, cytarabine,
2,4-dichlorobenzyl alcohol, 2-diethylaminoethanol, dacarbazine, daclizumab, dactinomycin,
dalfopristin, dalteparin, danaparoid, danazol, dantrolene, dapiprazole, dapsone, darbepoetin
alfa, darifenacin, daunorubicin, deamol, deanol (deanolace), decarbazine, dectaflur F,
deferiprone, deferoxamine, delapril, demeclocycline, denaverine, depreotide, dequalinium,
desflurane, desipramine, desirudin, deslanoside, desloratadine, desmeninol, desmopressin,
21

PCT application WO 2006/082099 A
desogestrel, desoximetasone, desoxyribonuclease, detajmium, dexamethasone,
dexchlorpheniramine, dexibuprofen, dexketoprofen, dexrazoxane, dextran, dextromethorphan,
diacerein, diacetyl morphine, dibenzepin, dibotermin alfa, diclofenac, diclofenamide,
didanosine, dienestrol, dienogest, diethylstilbestrol, difloxacin, diflucortolone, diflunisal,
digitoxin, digoxin, dihydralazine, dihydroergocornine, dihydroergocristine,
dihydroergocryptine, dihydroergotamine, dihydroergotoxine, dihydrotachysterol,
diisopropylamine, dikalium clorazepate, diltiazem, dimenhydrinate, dimepranol, dimercaprol,
dimethyl sulfoxide, dimethindene, dinatriumselenit, dinoprost, dinoproston, diosmin,
diphenhydramine, diphenoxylate, diphenylpyraline, dipivefrine, diprophylline, dipyridamole,
disopyramide, dinitrogen monoxide, distigmine, disulfiram, dithranol, dixyrazine, D-
norpseudoephedrine, dobesilate calcium, dobutamine, docetaxel, dofetilide, dolasetron,
domperidone, donepezil, dopamine, dopexamine, dornase alfa, dorzolamide, dosulepin,
doxapram, doxazosin, doxepin, doxorubicin, doxycycline, doxylamine, drofenine, droperidol,
drospirenone, drotrecogin alfa, duloxetine, dutasteride, dydrogesterone, N,N'-
dihydroxymethyl urea,
ebastine, econazole, ecothiopate iodide, efalizumab, efavirenz, eflornithine, iron (III)
ammonium citrate F, superparamagnetic iron oxide, elcatonin, eletriptan, emedastine,
emepronium, emepronium carrageenate, emetine, emtricitabine, enalapril, enalaprilat,
enflurane, enfuvirtide, enoxacin, enoxaparin, entacapone, ephedrine, ephedrine racephedrine,
epinastine, epinephrine, epirubicin, eplerenone, epoetin alfa, epoetin beta, epoetin delta,
epoprostenol, eprazinone, eprosartan, eptacog alfa, eptifibatide, eptotermin alfa, erdosteine,
ergocalciferol, ergometrine, ergotamide, ertapenem, erythromycin, escitalopram, esmolol,
esomeprazole, estradiol, estramustine, estriol, estrone, etacrynic acid, etamivan, etanercept,
ethacridine, ethambutol, ethaverine, ethinylestradiol, ethisterone, ethosuximide, etidronic
acid, etilefrine, etodolac, etofenamate, etofibrate, etofylline, etomidate, etonogestrel,
etoposide, etoricoxib, everolimus, exametazimus, exemestane, ezetimibe,
3-fluortyrosine, famciclovir, famotidine, felbamate, felbinac, felodipine, fenbufene, fendiline,
fenofibrate, fenoterol, fenticonazole, fexofenadine, fibrinogen, fibrinolysin, filgrastim,
finasteride, flavoxate, flecainide, flucloxacillin, fluconazole, fludarabine, fludeoxyglucose
[ F], fludrocortisone, flufenamic acid, flumazenil, flumetasone, flunarizine, flunisolide,
fluocinolone acetonide, fluocinonide, fluocortolone, fluphenazine (fluophenozine),
fluorescein dilaurate, fluorescein sodium, fluorometholone, fluorouracil, fluorphosphoric acid,
22

PCT application WO 2006/082099 A
fluorsilane, fluoxetil, fluoxetine, flupentixol, fluphenazine, flupirtine, fluprednidene,
flurbiprofen, flutamide, fluticasone, flutrimazole, fluvastatin, fluvoxamine, folinic acid,
follitropin alfa, follitropin beta, folic acid, fomepizole, fomivirsen, fondaparinux, formestane,
formoterol, fosamprenavir, foscarnet, fosfestrol, fosfomycin, fosinopril, fosphenytoin,
fotemustine, framycetin, framycetin, frovatriptan, fulvestrant, furosemide, fusafungine,
fusidic acid, fytic acid,
gabapentin, gadobenic acid, gadobutrol, gadodiamide, gadopentetic acid, gadoteridol,
gadoteric acid, gadoteric acid -meglumine, gadoxetic acid, galantamine, gallopamil,
ganciclovir, ganirelix, gatifloxacin, gemcitabine, gemfibrozil, gentamicin, gepefrine,
gestodene, glatiramer, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide,
gliquidone, glisoxepide, glucagon, glutamine, glutamic acid, glycopyrronium,
glycopyrronium bromide, glycyrrhetinic acid, gonadorelin, goserelin, gramicidin, granisetron,
grepafloxacin, griseofulvin, g-strophanthin, guajacol, guanethidine, guanfacine,
13C urea, 4-hydroxybutyric acid, halcinonide, halofantrine, halometasone, haloperidol,
halothane, haem, haematoporphyrin, heparin, hepatitis B vaccine, heptaminol, hexobarbital,
hexobendine, hexoprenaline, histamine, histidine, homatropine, homofenazine, human
albumin, hyaluronidase, hydralazine, hydrastinine, hydroquinone, hydrochlorothiazide,
hydrocortisone, hydrotalcite F, hydroxocobalamin, hydroxycarbamide, hydroxychloroquine,
hydroxycine, hydroxylamine, hydroxyprogesterone, hydroxyzine, hymecromone,
ibandronic acid, ibopamine, ibritumomab tiuxetan, ibuprofen, ibutilide, idarubicin,
ifosfamide, iloprost, imatinib, imatinib mesylate, imidapril, imiglucerase, imipenem,
imipramine, imiquimod, immunocyanin, indanazoline, indapamide, indinavir, indium chloride
[luIn], indobufen, indometacin, indoramin, infliximab, inosine, insulin, insulin aspart, insulin
detemir, insulin glargine, insulin glulisine, insulin lispro, interferon alfa, interferon alfa-2b,
interferon alfacon-1, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma,
iobitridol, iodine, iodamide, iodixanol, ioflupane [1231], iohexol, iomeprol, iopamidol,
iopentol, iopromide, iosarcol, iotrolan, iotroxic acid, ioversol, ioxaglic acid, ioxitalamic acid,
ipatropium, irbesartan, irinotecan, irinotecan, isepamicin, isoaminile, isoconazole, isoflurane,
isoleucine, isoniazid, isonicotinic acid, isoprenaline, isosorbide, isospaglumic acid,
isotretinoin, isoxsuprine, isradipine, itraconazole,
23

PCT application WO 2006/082099 A
josamycin,
potassium permanganate, kallidinogenase, kanamycin, kawain, kebuzone, ketamine,
ketoconazole, ketoprofen, ketorolac, ketotifen, collagenase, creosote,
labetalol, lacidipine, lactitol, lamivudine, lamotrigine, lanreotide, lansoprazole, laronidase,
latanoprost, leflunomide, lenograstim, lepirudin, lercanidipine, letrozole, leucine, leuprorelin,
levallorphan, levamisole, levetiracetam, levobunolol, levobupivacaine, levocabastine,
levocetirizine, levodopa, levofloxacin, levofolinate calcium, levomepromazine, levomethadyl,
levonorgestrel, levopropylhexedrine, levosimendan, levothyroxine, lidocaine, lincomycin,
lindane, linezolid, liothyronine, lisinopril, lisuride, lobeline, lodoxamide, lofepramine,
lomefloxacin, lomustine, lonazolac, loperamide, lopinavir, loratadine, lorazepam oxide,
lornoxicam, losartan, loteprednole, lovastatin, lumefantrine, lutropin alfa, lymecycline,
lynestrenol, lypressin, lysine,
magaldrat F, magnesium pidolate, magnesium-L-aspartate, mangafodipir, manidipine,
maprotiline, mebendazole, mebeverine, meclofenoxate, mecloxamine, meclozine,
medrogestone, medroxyprogesterone, mefenaminic acid, mefloquine, megestrol, melagatrane,
melitracen, melperone (melperol), melphalan, memantine, menadione, mepacrine,
mepartricin, mephenytoin, mepindolol, mepivacaine, mepyramine, mequinol, mercaptamine,
mercaptopurine, meropenem, mesalazine, mesna, mesterolone, mesuximide, metaclazepam,
metamizole, metamphetamine, metenolone, metenolone acetate, metformin, methanthelinium,
methazolamide, methenamine, methionine, methohexital, methotrexate, 5-methoxypsoralen,
8-methoxypsoralen, methyl 5-aminolevulinate, methylbenactyzium bromide, methyldopa,
methylergometrine, methylprednisolone, methylrosanilinium, methyltestosterone,
methylthionium chloride, methysergide, metildigoxin, metipranolol, metoclopramide,
metoprolol, methixene (metrixene), metronidazole, mexiletine, mezlocillin, mianserine,
miconazole, midodrine, mifepristone, miglitol, miglustat, milnacipran, milrinone, miltefosine,
minocycline, minoxidil, mirtazapine, misoprostol, mitobronitol, mitomycin, mitotane,
mitoxantrone, mivacurium chloride, mivacuronium, mizolastine, moclobemide, moexipril,
molgramostim, molsidomine, mometasone, monochloroacetic acid, montelukast, moroctocog
alfa, moxaverine, moxifloxacin, moxonidine, mupirocin, mycophenolate mofetil,
24

PCT application WO 2006/082099 A
nadifloxacin, nadrolon decanonate, nadroparin calcium, naftidrofuryl, naftifine, nalbuphine,
nalide, nalmefene, nalmexone, naloxone, naltrexone, naluphine, naphazoline, 2-naphthol,
naproxen, naratriptan, naratriptan, nateglinide, sodim aurothiomalate, sodium phenylbutyrate,
sodium fluoride, sodium hyaluronate, sodium iodide [131I], sodium molybdate [99Mo], sodium
phenylbutyrate, n-butyl-p-aminobenzoate, n-butylscopolaminium bromide, nebivolol,
nedocromil, nefazodone, nefopam, nelfinavir, neomycin, neostigmine, neostigmine
methylsulfate, netilmicin, nevirapine, n-heptyl-2-phenyl glycinate, nicardipine, nicergoline,
nicethamide, niclosamine, nicoboxil, nicorandil, nicotine, nicotine aldehyde, nicotinamide,
nicotin resinate, nicotinic acid, nicotinic acid ester, nicotinyl alcohol, nifedipine, niflumic
acid, nifuratel, nilvadipine, nimesulide, nimodipine, nimorazole, nimustine (nimustatine),
nisoldipine, nitisinone, nitrendipine, nitric oxide, nitrofurantoin, nitroglycerine, nizatidine, N-
methylephedrine, nonacog alfa, nonivamide, noradrenalin, norelgestromin, norepinephrine,
norethisterone, norfenefrine, norfloxacin, norgestimate, norgestrel, nortriptyline, noscapine,
nystatin,
obidoxime chloride, octafluoropropane, octocog alfa, octodrine, octreotide, odansetron,
ofloxacin, olaflur F, olanzapine, olmesartan medoxomil, olopatadine, olsalazine, omeprazole,
omoconazole, ondansetron, opipramol, oral cholera vaccine, orciprenaline, orlistat,
ornipressin, orphenadrine, oseltamivir, osteogenic protein-1 (BMP-7), oxaprozin, oxatomide,
oxcarbazepine, oxedrine tartrate, oxetacaine, oxiconazole, oxilofrine, oxitropium, 2-oxo-3-
methylbutytric acid, 2-oxo-3-methylvaleric acid, 2-oxo-3-phenylpropionic acid, 2-oxo-4-
methylvaleric acid, oxprenolol, oxybuprocaine, oxybuprocaine, oxybutynin, oxybutynin,
oxyfedrine, oxymetazoline, oxytetracycline, oxytocin,
paclitaxel, palinavir, palivizumab, palonosetrone, pamidronic acid, pancuronium
(pancurmium), pantoprazole, papaverine, paracetamol, paraldehyde, parecoxib, paricalcitol,
parnaparin, paromomycin, paroxetine, pefloxacin, pegfilgrastim, peginterferon alfa,
pegvisomant, pemetrexed, penbutolol, penciclovir, penfluridol, penicillamine, pentaerithrityl
tetranitrate, pentamidine, pentetrazol, pentetreotide, pentosan polysulfate sodium,
pentoxifylline, pentoxyverine, perazine, perchloric acid, perflenapent, perflisopent, perflutren,
pergolide, perindopril, perphenazine, phenacetin, phenamazid, phenazone, phenazopyridine,
pheniramine, phenol, phenolphthalein, phenoxybenzamine, phenoxymethylpenicillin,
phenprocoumon, phentolamine, phenylalanine, phenylbutazone, phenylephrine,
phenylpropanolamine, phenyltoloxamine, phenytoin, phloroglucinol, pholedrine,
25

PCT application WO 2006/082099 A
phthalylsulfathiazole, physostigmine, phytomenadione, phytosterin, picric acid, pilocarpine,
pimecrolimus, pimozide, pinaverium bromide, pindolol, pioglitazone, pipamperone,
pipazetate, pipecuronium bromide, pipemidic acid, pipenzolate, piperacillin, piprinhydrinate,
piracetam, pirarubicin, pirbuterol, pirenzepine, piritramide, piroxicam, pivmecillinam,
pizotifen, podophyllotoxin, polidocanol, polycarbophil, polyestradiol phosphate, polymyxin
B, polymyxin-B, polystyrenesulfonic acid, porfimer, prajmaline, prajmalium bitartrate,
pramipexole, pranoprofen, prasterone, pravastatin, prazepam, prazosin, prednicarbate,
prednisolone, prednisone, pregabalin, proglumetacin (preglumetacin), pridinol, prilocaine,
primaquine, primidone, procaine, procainamide, procarbazil, procarbazine, procyclidin,
progesterone, proglumetacin, proglumide, proguanil, proline, promethazine, propacetamol,
propafenon, propanolol, propicillin, propiverine, propofol, propranolol, propylthiouracil,
propyphenazone, protamine, protamine sulfate, protein C, prothipendyl (prithipendyl),
prothrombin, protionamide, protirelin, proxymetacaine, proxyphylline, pseudoephedrine,
pulmonal, pyrantel, pyrazinamide, pyridostigmine, pyridostigmine bromide, pyridoxine, 3-
pyridylmethanol, pyrimethamine, pyrithione zinc, pyritinol, pyrogallol, pyrvinium, pyrvinium
embonate,
mercury amide chloride, quetiapine, quinagolide, quinapril, quinupristin,
rabeprazole, racecadotrile, racephedrine, raloxifene, raltitrexed, ramipril, ranitidine,
rasagiline, rasburicase, raubasine, reboxetine, repaglinide, reproterol, reserpine, resorcinol,
reteplase, retinol, reviparin, ribavirin, riboflavin, rifabutin, rifampicin, rifamycin, rifaximin,
rilmenidine, riluzol, rimexolone, risedronic acid, risperidone, ritonavir, rituximab,
rivastigmine, rizatriptan, rocuronium bromide, rofecoxib, ropinirole, ropivacaine, ropivacaine,
rosiglitazone, red mercuric sulfide F, roxatidine, roxithromycin,
salbutamol, salicylic acid, salmeterol, nitric acid, nitrous acid, salverine, samarium [153Sm]
lexidronam, saquinavir, sulfur hexafluoride, scopolamine, selegiline, selenium sulfide, serine,
sermorelin, sertaconazole, sertindole, sertraline, sevelamer, sevoflurane, sibutramine, silver
chloride F, sildenafil, silibinin, simvastatin, sirolimus, solifenacin, formaldehyde solution,
somatostatin, somatropin, sotalol, spaglumic acid, sparteine, spectinomycin, spiramycin,
spirapril, spironolactone, stavudine, streptodornase, streptokinase, streptomycin, strontium
ranelate, strontium chloride, strychnine, sucralfate F, sulbactam, sulesomab, sulfacetamide,
sulfadiazine, sulfadimethoxine, sulfaguanidin, sulfamerazine, sulfamethoxazole,
26

PCT application WO 2006/082099 A
sulfamethoxydiazine, sulfametrole, sulfanilamide, sulfasalazine, sulfathiazole, sulfisomidine,
sulindac, sulodexide, sulfur hexafluoride, sulpiride, sulprostone, sultamicillin, sultiame,
sumatriptan, suxamethonium,
tacalcitol, tacrolimus, tadalafil, tamoxifen, tamsulosin, tasonermin, taurolidine, tazarotene,
tazobactam, tegafur, teicoplanin, telithromycin, telmisartan, temoporfin, temozolomide,
tenecteplase, teniposide, tenofovir, tenofovir disoproxil, tenoxicam, terazosin, terbinafme,
terbutaline, terfenadine, teriparatide, terizidone, terlipressin, testosterone, testosterone
propionate, testosterone undecanonate, tetracaine, tetracosactide, tetracycline,
tetrafluoroborat-l+, tetrofosmin, tetryzoline, thallium chloride [201Tl], theobromine,
theodrenaline, theodrenaline, theophylline, thiamazole, thiamine, thiethylperazine,
thiocolchicoside, thiopental, thioridazine, thiotepa, threonine, thrombin, thrombokinase,
thymol, thyrotropin alfa, tiagabine, tianeptine, tiapride, tibolone, ticlopidine, tiludronic acid,
timolol, tinzaparin, tioconazole, tioguanine, tiotropium bromide, tirilazad, tirofiban,
tisopurine, tizamidine, tizanidine, tobramycin, tocainide, tolazoline, tolbutamide, tolcapone,
tolfenaminic acid, tolmetin, tolperisone, tolterodine, topiramate, topotecan, torasemide,
toremifene, tramazoline, trandolapril, tranexamic acid, tranylcypromine, trapidil, trastuzumab,
travoprost, trazodone, tretinoin, triamcinolone, triamcinolone acetonide, triamterene,
trichloroacetic acid, triethylperazine, trifluoperazine, triflupromazine, trihexyphenidyl,
trimebutine, trimecaine, trimegestone, trimetazidine, trimethoprim, trimipramine,
tripelenamine, triprolidine, triptorelin, tritoqualine, trofosfamide, tromantadine, trometamol,
tropicamide, tropisetron, trospium, tryptophan, tubocurarine chloride, tulobuterol, tyloxapol,
tyrosine, tyrothricin,
unoprostone, urapid, urapidil, urokinase, ursodeoxycholic acid,
valaciclovir, valdecoxib, valganciclovir, valinr, valproic acid, valsartan, vancomycin,
vardenafil, vecuronium (vecurmium), vecuronium bromide, venlafaxin, verapamil,
verteporfin, vigabatrin, viloxacine, vinblastine, vincamine, vincristine, vindesine, vinorelbine,
vinpocetine, viquidil, voriconazole, votumumab,
hydrogen peroxide,
xantinol nicotinate, ximelagatrane, xipamide, xylometazoline,
27

PCT application WO 2006/082099 A
yohimbine, yttrium Y chloride,
zalcitabine, zaleplon, zanamivir, zidovudine, zinc acetate dihydrate, zinc chloride, zinc citrate,
zinc sulfate, ziprasidone, zofenopril, zoledronic acid, zolmitriptan, zolpidem, zolpidem
tartrate, zonisamide, zopiclone, zotepine and zuclopenthixol (zucklopantexol).
The aforementioned compounds are primarily referred to by their International
Nonproprietary Names (INN) known to the person skilled in the art. Further details may be
found, for example, in International Nonproprietary Names (INN) for Pharmaceutical
Substances, World Health Organisation (WHO).
In a preferred embodiment, the form of administration according to the invention contains one
substance (A) or a plurality of substances (A) selected from the group consisting of 1,1-(3-
dimethylamino-3-phenylpentamethylen)-6-fluor-l,3,4,9-tetrahydropyrano[3,4-b]indole, in
particular its hemicitrate, l,l-[3-dimethylamino-3-(2-thienyl)pentamethylen]-l,3,4,9-
tetrahydropyrano[3,4-b]indole, in particular its citrate and l,l-[3-dimethylamino-3-(2-
thienyl)pentamethylen]-l,3,4,9-tetrahydropyrano[3,4-b]-6-fluoro-indole, in particular its
hemicitrate. The aforementioned substances are known in the prior art (see WO 2004/043967,
WO 2005/066183).
Furthermore, in addition to the achievement of the necessary resistance to breaking of the
form of administration according to the invention, at least one natural, semi-synthetic or
synthetic wax (D) can be used (= component (D)). Preferably, waxes with a softening point of
at least 50°C, more preferably at least 55°C, still more preferably at least 60°C, most
preferably at least 65°C and in particular at least 70°C. Particularly preferable are carnauba
wax and beeswax. Quite particularly preferable is carnauba wax. Carnauba wax is a natural
wax obtained from the leaves of the carnauba palm and has a softening point of at least 80°C.
With the additional use of the wax component, it is used together with at least one polymer
(C) in such quantities that the form of administration has a resistance to breaking of at least
400 N, preferably at least 500 N.
Suitable for use as excipients (B) are the usual known excipients for the formulation of solid
forms of administration. Preferably, these are plasticisers, such as triacetin and polyethylene
28

PCT application WO 2006/082099 A
glycol, preferably a low-molecular polyethylene glycol, excipients, influencing the release of
the active ingredient, preferably hydrophobic or hydrophilic, preferably hydrophilic polymers,
quite particularly preferably hydroxypropylmethylcellulose and/or antioxidants. Preferably
used as hydrophilic matrix materials are polymers, particularly preferably cellulose ethers,
cellulose esters and/or acrylic resins. Quite particularly preferable used as matrix materials are
ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,
hydroxymethylcellulose, poly(meth)acryl acid and/or the derivatives thereof, such as the salts,
amides or esters thereof.
Suitable antioxidants are ascorbic acid, butylhydroxyanisole (BHA), butylhydroxytoluene
(BHT), salts of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C, vitamin E and
the derivatives thereof, sodium bisulfite, particularly preferably butylhydroxytoluene or
butylhydroxyanisole and a-tocopherol.
The antioxidant is preferably in quantities of 0.01 to 10 % by weight, preferably 0.03 to 5 %
by weight, based on the total weight of the form of administration.
The forms of administration according to the invention are characterised by the fact that due
to their resistance to breaking, they cannot be pulverised by means of the usual comminution
means, such as a mortar and pestle. This means an overdose is virtually impossible. However,
in order further to increase the resistance to breaking of the form of administration, the forms
of administration according to the invention can contain further means for enhancing
resistance to breaking as excipients (B).
The form of administration according to the invention is preferably solid and is suitable for
oral, vaginal or rectal, preferably oral administration. It is preferably not in film form. In a
further preferred embodiment, the form of administration according to the invention is present
in the form of a tablet, a capsule or in the form of an oral osmotic therapeutic system (OROS).
In a preferred embodiment, the form of administration according to the invention is present as
a tablet.
The form of administration according to the invention can be present in multiparticulate form,
preferably in the form of microtablets, microcapsules, micropellets, granules, spheroids, beads
29

PCT application WO 2006/082099 A
or pellets, optionally packaged into capsules or press into tablets, preferably for oral
administration. Hereby, preferably the individual particles as such have a resistance to
breaking of at least 400 N, optionally also a tablet produced therefrom.
Preferably, the multiparticulate forms have a size or size distribution in the region of 0.1 to 3
mm, in particular preferably in the region of 0.5 to 2 mm. Depending upon the desired form of
administration, the usual excipients (B) are optionally also used for the formulation of the
form of administration.
The form of administration according to the invention can be produced by different methods,
which are explained in greater detail below; the invention also relates to forms of
administration obtainable by any of these methods:
The method to produce of the form of administration according to the invention preferably
comprises the following steps:
(a) mixing of component (A), optionally (B), (C), optionally (D),
(b) optionally preforming the mixture obtained from step (a) mixture, preferably by
applying heat and/or force to the mixture obtained from (a), wherein the quantity of heat
supplied is preferably not sufficient to heat component (C) to its softening point,
(c) hardening of the mixture by applying heat and force, wherein the supply of heat can
take place during and/or before the application of force and quantity of heat supplied is
sufficient to heat the component (C) at least to its softening point,
(d) optionally singulating the hardened mixture,
(e) optionally shaping the form of administration and
(f) optionally coating with a film coating.
The heat can be supplied directly or by means of ultrasound. The application of force and/or
the shaping of the form of administration can take place, for example, by direct tabletting or
30

PCT application WO 2006/082099 A
by means of suitable extruders, in particular with twin-screw extruders (roller die extruders)
or planetary gear extruders.
The following method variants are particularly preferable:
Method variant 1:
In this embodiment, the form of administration according to the invention is preferably
produced without the use of an extruder, wherein preferably components (A), optionally (B),
(C) and the optionally present component (D) are mixed and the resulting mixture, optionally
after granulation, is shaped into the form of administration with the preceding or simultaneous
application of heat.
This heating and application of force to produce the form of administration is performed
without the use of an extruder.
The mixing of the components (A), optionally (B), (C) and optionally (D) is performed in a
mixer known to the person skilled in the art. The mixer can be for example a roll mixer,
shaking mixer, shear mixer or compulsory mixer.
The resultant mixture is preferably shaped directly into the form of administration according
to the invention by the application of force with the preceding or simultaneous application of
heat. For example, the mixture can be shaped into tablets by direct tabletting. With direct
tabletting with the simultaneous application of heat, the tabletting tool, ie the lower punch,
upper punch and the die, is used to heat mixture to be pressed to at least the softening point of
the polymer component (C) and then pressed. With direct tabletting with the preceding
application of heat, the material to be pressed is heated immediately prior to tabletting to at
least the softening point of the component (C) and then pressed by means of the tabletting
tool.
So, for example, a tabletting tool with upper punch, lower punch and die for tablets with a 10
mm diameter and a radius of curvature of 8 mm can be used to press 300 mg of powder
mixture at a temperature of 80°C, wherein the pressure resulting from application of a force of
for example 2 kN or 4 kN can be maintained for 15 s, for example.
31

PCT application WO 2006/082099 A
The resultant mixture of the components (A), optionally (B), (C) and optionally component
(D) can also be first granulated and then be shaped into the form of administration according
to the invention under the application of force with the preceding or simultaneous application
of heat.
Each time force is applied, this is continued until the form of administration has achieved a
breaking resistance of at least 400 N, 420 N, 440 N, 460 N, 480 N, preferably at least 500 N.
The granulation can be performed in known granulators by moist granulation or melt
granulation.
Each of the known method steps, in particular the heating and simultaneous or subsequent
application of force to produce of the form of administration according to the invention is
performed without the use of an extruder.
Method variant 2:
In this method variant, the form of administration according to the invention is produced by
thermoforming by means of an extruder without thereby any discoloration of the extrudate
being observed.
To investigate the degree of discoloration caused by this thermoforming, the colour of the
mixture of the starting components of which the form of administration consists is first
determined without the addition of a colour-imparting component, such as, for example, a
coloured pigment or a coloured component (eg oc-tocopherol). This composition is then
thermoformed according to the invention, wherein all method steps including the cooling of
the extrudate are performed under an inert gas atmosphere. By way of comparison to this, the
same composition is produced using the same method but without an inert gas atmosphere.
The coloration is determined of the form of administration produced according to the
invention from the starting composition and the form of administration produced for purposes
of comparison. The determination is performed with the assistance of "Munsell Book of
Colour" from Munsell Colour Company Baltimore, Maryland, USA, 1966 edition. If the
coloration of the form of administration thermoformed according to the invention has a
32

PCT application WO 2006/082099 A
coloration with the identification No N 9.5/ but at the most a coloration with the identification
No 5Y 9/1, the thermoforming is classed as being "without discoloration". If the form of
administration has a coloration with the identification No 5Y 9/2 or more, determined in
accordance with the Munsell Book of Colour, the thermoforming is classed as being "with
discoloration".
Surprisingly, the forms of administration according to the invention exhibit no discoloration
that can be classified in accordance with the above classification if the entire production
method is performed under an inert gas atmosphere, preferably under a nitrogen atmosphere
by means of an extruder for thermoforming.
This variant according to the invention for the production of the forms of administration
according to the invention is characterised by the fact that
z) components (A), optionally (B), (C) and the optionally present component (D) are mixed,
y) the resultant mixture is heated in the extruder to at least the softening point of component
(C) and extruded by the application of force through the outlet orifice of the extruder,
x) the still plastic extrudate is singulated and shaped into the form of administration or
w) the cooled and optionally reheated singulated extrudate is shaped into the form of
administration,
wherein the method steps y) and x) and optionally the method steps z) and w) are performed
under an inert gas atmosphere, preferably a nitrogen atmosphere.
The mixing of the components according to method step z) can also take place in the extruder.
The mixture of components (A), optionally (B), (C) and optionally (D) can also be performed
in a mixer known to the person skilled in the art. The mixer can be for example a roll mixer,
shaking mixer, shear mixer or compulsory mixer.
33

PCT application WO 2006/082099 A
Before mixing with the further components, component (C) and the optionally present
component (D) according to the invention is preferably provided with an antioxidant. This can
take place by mixing the two components (C) with the antioxidant, preferably by dissolving
or suspending the antioxidant in a highly volatile solvent and homogeneously mixing this
solution or suspension with component (C) and the optionally present component (D) and
removing the solvent by drying, preferably under an inert gas atmosphere.
The, preferably molten, mixture which has been heated in the extruder to at least the softening
point of component (C) is extruded from the extruder through a die with at least one bore.
The performance of the method process according to the invention requires the use of suitable
extruders, preferably screw extruders (roller die extruders), wherein extruders which are
equipped with two screws (rollers) are particularly preferred.
The extrusion is preferably performed so that the expansion of the extruded strand is
preferably at the most 50%, ie, that when using an extrusion die with a diameter of 6 mm for
example, the extruded strand should have a diameter of at the most 9 mm. More preferably,
the expansion of the strand is at the most 40%, still more preferably at the most 35%, most
preferably at the most 30% and in particular at the most 25%. It has surprisingly been found
that if the extruded material in the extruder is exposed to a severe mechanical stress, a
significant expansion of the strand occurs thereby resulting in undesirable irregularities of the
properties, in particular the mechanical properties, of the extruded strand.
Preferably, the extruder comprises at least two temperature zones, wherein in the first zone,
which is downstream from a feed zone and optionally a mixing zone, the heating of the
mixture takes place up to at least the softening point of component (C). The throughput of the
mixture is preferably from 2.0 kg to 8.0 kg/hour.
After heating to at least the softening point of component (C), the molten mixture is conveyed
by means of screws, further homogenised, compressed or compacted, so that, immediately
before emerging from the extruder die, it has a minimum pressure of 5 bar, preferably of at
least 10 bar, and is extruded through the die as an extruded strand or extruded strands,
depending on the number of bores which the die comprises. The die geometry or the geometry
of the bores is freely selectable. For example, the die or the bores can have a round, oblong or
34

PCT application WO 2006/082099 A
oval cross section, wherein the round cross section preferably has a diameter of 0.1 mm to 15
mm and the oblong cross section preferably has a maximum lengthwise extension of 21 mm
and a crosswise extension of 10 mm. Preferably, the die or the bores have a round cross
section. The casing of the extruder used according to the invention can be heated or cooled.
The corresponding temperature control, ie heating or cooling, is arranged so that the mixture
to be extruded has at least an average temperature (product temperature) corresponding to the
softening point of component (C) and does not rise above a temperature at which the
physiologically active substance (A) to be processed may be damaged. Preferably, the
temperature of the mixture to be extruded is adjusted to below 180°C, preferably below
150°C, but at least to the softening temperature of component (C).
After the extrusion of the molten mixture and, optionally, cooling of the extruded strand or
the extruded strands, the extrudates are preferably singulated. This singulation can preferably
be performed by cutting up the extrudates by means of revolving or rotating knives, water jet
cutters, wires, blades or by means of laser cutters.
An inert gas atmosphere is not necessary for the intermediate or final storage of the optionally
singulated extrudate or the final shape of the form of administration according to the
invention.
The singulated extrudate may be pelletised with conventional methods or be pressed into
tablets in order to impart the final shape to the form of administration. It is, however, also
possible not to singulate the extruded strands and, and by means of contrarotating calender
rolls comprising opposing recesses in their outer sleeve, to form them into the final shape,
preferably a tablet, and to singulate these by conventional methods
If the optionally singulated extrudate is not immediately to be shaped into the final shape, but
instead cooled for storage, after the period of storage, an inert gas atmosphere, preferably a
nitrogen atmosphere, should be provided and must be maintained during heating of the stored
extrudate up until plasticisation and final shaping into the form of administration.
The application of force in the extruder onto the at least plasticised mixture is adjusted by
controlling the rotational speed of the conveying device in the extruder and the geometry
thereof and by dimensioning the outlet orifice in such a manner that the pressure necessary for
35

PCT application WO 2006/082099 A
extruding the plasticised mixture is built up in the extruder, preferably immediately prior to
extrusion. The extrusion parameters necessary for each particular composition to produce a
form of administration with a resistance to breaking of at least 400 N, preferably of at least
500 N, can be established by simple preliminary testing.
Suitable for extrusion is, for example, a twin-screw-extruder made by the Leistritz,
(Nuremberg) of the type Micro 27 GL 40 D, screw diameter 18 mm. Screws having eccentric
screw tips may be used. A round-section die with a diameter of 8 mm can be used as a die.
The entire extrusion method should be performed under a N2 atmosphere. The extrusion
parameters can be adjusted, for example, to the following values: screw speed: 100 rpm,
throughput: 4 kg/h; product temperature: 125°C; and casing temperature: 120°C.
Method variant 3:
With this method variant to produce the form of administration according to the invention,
heat is supplied by means of ultrasound.
To this end, first of all a homogeneous mixture of at least component (A) and component (C)
(= binder) is produced. Further excipients, such as for example fillers, plasticisers, lubricants
or dyes, may also be incorporated into this mixture. A low molecular weight polyethylene
glycol is preferably used as a plasticiser.
Mixing may be performed by means of conventional mixers. Examples of suitable mixers are
roll mixers, which are also known as tumbler, drum or rotary mixers, container mixers, barrel
mixers (drum hoop mixers or tumbling mixers) or shaking mixers, shear mixers, compulsory
mixers, plough bar mixers, planetary kneader-mixers, Z kneaders, sigma kneaders, fluid
mixers or high-intensity mixers.
The selection of the suitable mixer is determined inter alia by the free-flowing properties and
cohesive strength of the material to be mixed.
The mixture is then subjected to shaping. The mixture is preferably shaped during or after the
application of ultrasonication, preferably by compaction.
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PCT application WO 2006/082099 A
During the ultrasonication, it is particularly preferable that there is direct contact between the
mixture and the sonotrode of the ultrasound device. An ultrasound device as shown in Figure
1 is preferably used in the method according to the invention
In this Figure 1,(1) denotes the press, with which the necessary force is applied, (2) the
converter, (3) the booster, (4) the sonotrode, (5) the shaping die, (6) the lower punch, (7) the
base plate, (8) and (9) the ultrasound generator and device controller. The reference numbers
used relate solely to Figure 1.
During the ultrasonication, a frequency of 1 kHz to 2 MHz, preferably of 15 to 40 kHz,
should be maintained. The ultrasonication should be performed until softening of the polymer
(C) is achieved. This is preferably achieved within a few seconds, particularly preferably
within 0.1 to 5 seconds, preferably 0.5 to 3 seconds.
The ultrasonication and the application of force ensure uniform energy transfer thus achieving
the rapid and homogeneous sintering of the mixture. This produces forms of administration
with a resistance to breaking of at least 400 N, preferably of at least 500 N, which hence
cannot be pulverised.
Before shaping is performed, the mixture may be granulated after the mixing operation, after
which the resultant granules are shaped into the form of administration, such as tablets, by
ultrasonication and the application of force.
Granulation may be performed in machinery and apparatus known to the person skilled in the
art.
If granulation is performed as wet granulation, water or aqueous solutions, such as for
example ethanol/water or isopropanol/water, may be used as the granulation liquid.
The mixture or the granules produced therefrom may also be subjected to melt extrusion for
further shaping, wherein the mixture is converted into a melt by ultrasonication and the
application of force and then extruded through dies. The strands or strand obtained in this
manner may be singulated to the desired length using known devices. The shaped articles
singulated in this manner may optionally furthermore be converted into the final shape with
ultrasonication and application of force.
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PCT application WO 2006/082099 A
The final shaping to the form of administration is preferably performed by the application of
force in appropriate moulds.
The above-described formed articles may also be produced according to a calendering process
by initially plasticising the mixture or the granules produced therefrom by means of
ultrasonication and the application of force and extruding through a suitable die. These
extrudates are then shaped into the final shape between two contrarotating shaping rolls,
preferably under the application of force.
As already mentioned, shaping to produce the final shape of the form of administration by
using a mixture of substance (A) and the polymer (C) with a resistance to breaking of at least
400 N, preferably of at least 500 N, is preferably performed in powder form by direct
compression with the application of force, wherein ultrasonication of this mixture is provided
before or during the application of force. The force is at most the force that is conventionally
used for shaping forms of administration such as tablets, or for pressing granules into the
corresponding final shape.
The tablets produced according to the invention may also be multilayer tablets.
In the case of multilayer tablets, at least the layer that contains substance (A) should be
exposed to ultrasound and the application of force.
The corresponding necessary application of force may also be applied to the mixture by
means of extruder rolls or calender rolls. Preferably, the shaping of the forms of
administration is performed by the direct pressing of a powdered mixture of the components
of the form of administration or corresponding granules formed therefrom, wherein
ultrasonication is preferably performed during or before shaping. Such exposure is continued
until the polymer (C) has softened, which is conventionally achieved in less than 1 second to
at most 5 seconds.
Suitable as a press is, for example, a Branson WPS, 94-003-A, Pneumatic (Branson
Ultraschall, Dietzenbach, Germany) with a plain press surface. A suitable generator (2000 W)
is, for example, a Branson PG-220A, 94-001-A analogue (Branson Ultraschall) with a
38

PCT application WO 2006/082099 A
sonotrode diameter of 12 mm. A die with a diameter of 12 mm can be used, whereby the
bottom of the die is formed by a lower punch with a plain press-surface and a diameter of 12
mm. Suitable parameters for plastification are frequency: 20 kHz; amplitude: 50%; force: 250
N. The ultrasonication and the application force by means of the sonotrode may be
maintained for 0.5 seconds, for example, wherein the ultrasonication and application of force
preferably take place simultaneously.
Method variant 4:
With this method variant to produce the form of administration according to the invention,
components (A), (C) and optionally (D) and optionally present excipients (B), such as
antioxidants, plasticisers and/or release-delaying excipients are processed by means of a
planetary-gear extruder to produce the form of administration according to the invention.
Planetary-gear extruders are known and described inter alia in detail in the Handbuch der
Kunststoff-Extrusionstechnik I (1989) "Grundlagen" in Chapter 1.2 "Klassifizierung von
Extrudern", pages 4 to 6. The corresponding description is hereby introduced as a reference
and is deemed to be part of the disclosure.
The following explains the use of a planetary-gear extruder in the method according to the
invention with reference to Figures 2 and 3. These explanations are given merely by way of
example and do not restrict the general concept of the invention
Figure 2 shows a section through a planetary gear extruder and
Figure 3 shows the mode of operation of the planetary gear extruders.
Figure 2 shows a planetary-gear extruder that may be used in the method according to the
invention. This extruder substantially comprises a shaft 1, which, relative to the direction of
transport of the mixture of the components listed above to be extruded, is initially constructed
as a feed screw 5 and subsequently as the central spindle 3 of the planetary-gear extruder.
Around the central spindle 3, there are preferably arranged three to seven planetary spindles 4,
which are in turn surrounded by a casing in the form of a housing 6.
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PCT application WO 2006/082099 A
In the planetary-gear extruder, the extrusion of the composition used in the method according
to the invention for the production of a form of administration preferably proceeds as follows,
with reference to Figure 2. As shown by the arrow 2, the components to be extruded are
apportioned by the apportioning unit 7 in the area of the feed screw 5 and conveyed by the
rotation thereof (drive not shown) in the direction of the central spindle 3. The person skilled
in the art will understand that it is possible to mix the starting materials (components) in the
area of the feed screw. However, it is also possible to premix the components of the form of
administration and to apportion this mixture via the apportioning unit 7 in the area of the feed
screw 5. The mixture is conveyed into the feed zone of the planetary-gear extruder. By
heating to at least the softening point of component (C), the mixture is melted and the molten
mixture is conveyed into the area of the central spindle, ie the extrusion zone, by the
interaction of the central spindle 3 and the planetary spindles 4, further homogenised,
compressed or compacted and extruded through the die 8 as an extruded strand or extruded
strands, depending on how many bores the die comprises. The die geometry or the geometry
of the bores is freely selectable. Thus, the die or the bores may exhibit a round, oblong or oval
cross-section, wherein the round cross-section preferably has a diameter of 0.1 mm to 15 mm
and the oblong cross-section preferably has a maximum lengthwise extension of 21 mm and a
crosswise extension of 10 mm. The extrusion die may also take the form of a slot die.
Preferably, the die or the bores have a round, oval or oblong cross-section. Both the casing 6
of the planetary-gear extruder used according to the invention and the central spindle may be
heated or cooled. The corresponding temperature control, i.e. heating or cooling, is so
arranged that the mixture to be extruded exhibits an average temperature corresponding to the
softening point of component (C) and does not rise above a temperature at which the
substance (A) to be processed may be damaged. Preferably, the temperature of the mixture to
be extruded is adjusted to below 180°C, preferably below 150°C, but at least to the softening
point of component (C). The reference numbers used relate solely to Figures 2 and 3.
Following the extrusion of the molten mixture and, optionally, cooling of the extruded strand
or extruded strands, the extrudates are singulated (not shown in Figure 2). This singulation
can preferably be performed by cutting up the extrudates by means of revolving or rotating
knives, water jet cutters, wires, blades or with the assistance of laser cutters.
40

PCT application WO 2006/082099 A
Optionally after further cooling of the singulated extrudates, which are preferably present in
the form of disks, they are optionally re-shaped into the final shape of the form of
administration, wherein they can be exposed to heat again if necessary.
This shaping, for example into tablets, may proceed in that the plastic extrudate is shaped
with press-forming with the assistance of two contrarotating rolls preferably with mutually
opposing recesses for plastification in the roll sleeve, with the design of the recesses
determining the tablet shape.
However, it is also possible to form the tablets from the singulated extrudates in each case
with the assistance of an optionally heated die and at least one shaping punch. To this end, the
cylindrical granules obtained after singulation of the extruded strand can preferably be used.
Apart from being pressed into tablets, these granules or other multiparticulate shapes
obtained, such as pellets or spheroids, can also be packaged into capsules in order to be used
as a form of administration produced according to the invention.
In a further preferred embodiment, the extruded strands extruded through a plurality of bores
in the extrusion die can, after cooling thereof, optionally be brought together by interlacing or
wrapping in the manner of rope production to produce a thicker strand than the individual
extruded strands. This strand can optionally be further processed by partially dissolving with a
suitable solvent or by heating to the softening point of the polymer (C) and optionally
removing the solvent in accordance with the above-stated singulation and shaping of an
individual strand.
Figure 3 shows a cross-section through the planetary-gear extruder. Around the rotating
central spindle 3 there are arranged at least three, in the case illustrated 6, planetary spindles
4, the flanks 41 of which interact on the one hand with the flank 31 of the central spindle 4
and on the other hand with the flanks 61 of the casing 6 of the planetary-gear extruder. The
rotation of the central spindle 3 and the rolling of the respective flanks over one another cause
the planetary spindles 4 each to rotate around their own axis, as shown by arrow 42, and
around the central spindle 4, as shown by arrow 43. In this way, the compression or
compaction sought according to the invention of the component mixture used according to the
invention of the forms of administration produced according to the invention is achieved. The
reference numbers used relate solely to Figures 2 and 3.
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PCT application WO 2006/082099 A
If necessary, the planetary-gear extruder used can comprise not only an extrusion zone but
also at least one further zone, in order that the mixture to be extruded can also optionally be
degassed.
The process according to the invention can be performed discontinuously or continuously,
preferably continuously.
A suitable extruder is, for example, a planetary gear extruder with four planetary spindles of
the type BCG 10 (LBB Bohle, Ennigerloh, Germany) with an extrusion die with a diameter of
8 mm. A gravimetrical dosing of 3.0 kg/h is suitable. The extrusion can be performed, for
example, with a rotational speed of 28.6 rpm and a product temperature of about 88°C.
Method variant 5:
This variant for the production of the form of administration according to the invention is
performed by processing at least the components (A), (C) and optionally (D) and optionally
present excipients (B), such as antioxidants, plasticisers and/or release-delaying excipients,
with the addition of a solvent for component (C), ie for the polymer or polymers (C), to
produce the form of administration.
To this end, components (A), optionally (B), (C) and the optionally present component (D)
are mixed and, after addition of the solvent and optionally after granulation, the resultant
formulation mixture is shaped to produce the form of administration.
The mixing of components (A), optionally (B), C and optionally (D) is performed in a mixer
known to the person skilled in the art. The mixer can be, for example, a roll mixer, shaking
mixer, shear mixer or compulsory mixer.
The solvent for the polymer (C) is added at least in such quantities that the formulation
mixture is uniformly moistened
Suitable solvents for the polymer (C) are preferably aqueous solvents, such as water, mixtures
of water and aliphatic alcohols, preferably Cl to C6 alcohols, esters, ethers, hydrocarbons,
42

PCT application WO 2006/082099 A
particularly preferably distilled water, short-chain alcohols, such as methanol, ethanol,
isopropanol, butanol or aqueous alcohol solutions.
The solvent is preferably added under agitation. The uniformly moistened composition is then
dried. Drying preferably proceeds by the application of heat at temperatures at which it is
possible to rule out any discoloration of the composition. This temperature can be established
by simple preliminary testing.
Before or after the drying, the composition can be divided into sub-portions that preferably in
each case correspond to the mass of a unit of the form of administration. The corresponding
dried portions are then shaped to produce the form of administration.
This is preferably performed by using tablet presses.
It is also possible to moisten the formulation mixture that, before addition of the solvent, the
•formulation mixture is divided, preferably in moulds, into sub-portions, dispersed in a liquid
dispersant with stirring and then the solvent is added. Component (C) is not soluble in the
dispersant, which must be miscible with the solvent.
Suitable dispersants are preferably hydrophilic solvents, such as aliphatic alcohols, ketones,
esters. Short-chain alcohols are preferably used.
Alternatively, the formulation mixture can also be moistened in such a manner that the
solvent is incorporated into the formulation mixture as a foam. Such a foam of the solvent is
preferably produced with the means of a high-speed mixer, preferably with the addition of
conventional foam stabilisers. Suitable stabilisers are, for example, hydrophilic polymers such
as for example hydroxypropylmethylcellulose.
Preferably, the foam is also incorporated into the formulation mixture under agitation which
preferably results in a granulated composition.
Before or after being divided into sub-portions, which preferably correspond to the mass of a
unit of the form of administration, the granulated composition is dried and then shaped into
the form of administration.
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PCT application WO 2006/082099 A
Drying and shaping can preferably proceed as described above. The method according to the
invention can also be performed in such a manner that solvent is added to the formulation
mixture in such a quantity that a shapeable paste is obtained.
Before or after being dried, which may be performed as explained above, a paste of this kind
can be divided into sub-portions and the dried portions, after further division in each case into
a portion corresponding to the mass of a unit of the form of administration, are shaped or
converted to yield the form of administration.
It is possible int his regard to form the sub-portions in the form of strands, which may be
produced by means of a screen or a strand former. The dried strands are preferably singulated
and shaped to produce the form of administration. This shaping is preferably performed by
means of a tablet press, using shaping rollers or shaping belts equipped with rollers.
It is also possible to convert the paste into a planar structure and to stamp the form of
administration out of the dried structure.
Advantageously, the paste is processed by means of an extruder, wherein, depending on the
type of the extrusion, strands or planar structures are produced, which are singulated by
chopping, cutting or stamping. The singulated sub-portions may be shaped, formed or
stamped as described above to produce the form of administration. Corresponding devices are
known to the person skilled in the art
In this regard, the method according to the invention may here be performed continuously or
discontinuously.
It is also possible to add solvent to the formulation mixture in such a quantity that at least the
polymer component (C) is dissolved. A solution or dispersion/suspension of this kind is
preferably converted into a planar structure, wherein preferably an extruder with a flat die is
used or the solution is cast onto a planar support.
As described above, after drying, the forms of administration can be obtained from the planar
structures by stamping or calendering. It is also possible, as described above, to convert the
44

PCT application WO 2006/082099 A
solution into strands and to singulate these, preferably after they have been dried, and shape
them to produce the form of administration.
Alternatively, the solution can also be divided into portions such that, after drying, they each
correspond to the mass of a unit of the form of administration, wherein with moulds which
already correspond to the shape of the unit of the form of administration are preferably used
for this purpose.
If the solution is divided into any desired portions, after drying, the portions can optionally be
combined again and be shaped to obtain the form of administration, such as, for example,
packaged in a capsule or pressed to form a tablet.
Preferably, the formulation mixtures combined with solvent are processed at temperatures of
20°C to 40°C, wherein, apart from during drying to remove the solvent and the optionally
present dispersant, no higher temperatures are used. The drying temperature must be selected
below the decomposition temperature of the components. Optionally, after shaping to obtain
the form of administration, further drying corresponding to the above-described drying may
be performed.
Combinations of individual steps of the above method variants are also possible in order to
produce the form of administration according to the invention.
The above-described method variants 2 and 4 comprise the extrusion of a composition
comprising components (A), (C), optionally (B) and optionally (D). Preferably, extrusion is
performed by means of twin-screw-extruders or planetary-gear-extruders, wherein twin-screw
extruders are particularly preferred.
It has surprisingly been found that extrudates exhibiting an advantageous morphology are
obtainable by means of planetary-gear-extruders and twin-screw-extruders. For example, it
has been found that under suitable conditions the extrudate is surrounded by a shell that may
be denoted as "extrusion skin". Said extrusion skin can be regarded as a sleeve-like or tubular
structure forming a circumferential section of the extrudate about its longitudinal extrusion
axis so that the outer surface of said sleeve-like or tubular structure forms the closed shell of
45

PCT application WO 2006/082099 A
the extrudate. Usually, only the front faces of the extrudate are not covered by the extrusion
skin.
The extrusion skin differs in its morphology from the core of the extrudate, which it surrounds
in a sleeve-like manner and is connected thereto preferably in a seamless manner. Usually, the
extrusion skin is visible with the naked eye in the cross section of the extrudate, optionally by
means of a microscope, since due to the different morphology of the material forming the core
and that forming the extrusion skin, their optical properties also differ. It appears that due to
the extrusion process, the material forming the extrusion skin is exposed to mechanical and
thermal conditions differing from the conditions to which the material forming the core of the
extrudate is exposed, the consequence of which is that a heterogeneous morphology of the
extruded strand is obtained, with, for example, a radial symmetry when an extrusion die with
circular shape is used. Hereby, the material forming the extrusion skin and the material
forming the core are usually distinguished by their morphology, preferably, however, not by
their composition, in particular not by the relative content of components (A), (C), optionally
(B) and optionally (D).
The extrusion skin usually covers the entire shell of the extrudate in the sense of a one-piece
tubular sleeve, independently of the geometry chosen for the extrusion die. Therefore, the
extrudate can have circular, elliptic or even other cross sections.
The extrusion skin preferably has a uniform thickness. Preferably, the layer thickness of the
extrusion skin is within the range from 0.1 to 4.0 mm, more preferably 0.15 to 3.5 mm, still
more preferably 0.2 to 3.0 mm, most preferably 0.2 to 2.5 mm and in particular 0.2 to 2.0 mm.
In a preferred embodiment the sum total of the thickness of the extrusion skin over both
opposing sides amounts to 0.5 to 50%, more preferably 1.0 to 40%, still more preferably 1.5
to 35%, most preferably 2.0 to 30% and in particular 2.5 to 25% of the diameter of the
extrudate.
Figure 4 shows a schematic view of extrudate (71) with a sleeve-like extrusion skin (72)
entirely surrounding the core (73) about the longitudinal extrusion axis (74). The outer surface
of extrusion skin (72) forms the shell (75) of the extrudate (71).
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PCT application WO 2006/082099 A
It has surprisingly been found that extrudates with an extrusion skin of this kind have
beneficial mechanical properties. They are particularly suitable as intermediates in the
production of the forms of administration according to the invention, because they may be
advantageously processed, in particular by singulating and/or shaping.
If the forms of administration according to the invention are produced by means of extrusion
processes in which the above-described extrudate with an extrusion skin is obtained as an
intermediate, the forms of administration obtained therefrom are preferably also characterised
by a particular morphology.
In a preferred embodiment, those regions, which have formed the extrusion skin in the
extruded intermediate, are still visible with the naked eye, optionally by means of a
microscope, in the cross section of the form of administration. This is due to the fact that
usually the further processing, in particular the singulating and/or shaping of the extrudate
causes the different nature and thereby also the different optical properties of the material
forming the extrusion skin and the material forming the core to be maintained. In the
following, that region of the form of administration that has emerged from the extrusion skin
in the course of further processing of the extrudate (intermediate) into the form of
administration, will be referred to as the "sleeve-shaped region".
Preferably, the form of administration according to the invention comprises a sleeve-shaped
region and a core located therein. In this regard, the sleeve-shaped region is preferably
connected to the core in a seamless manner. Preferably both the sleeve-shaped region and the
core have substantially the same chemical composition, ie substantially the same relative
content of components (A), (C), optionally (B) and optionally (D). In this regard, the material
forming the sleeve-shaped region has a morphology differing from the material forming the
core. Usually, this different morphology is also expressed in terms of different optical
properties, so that the sleeve-shaped region and the core are visible with the naked eye in the
cross-section of the form of administration.
If the form of administration according to the invention is coated, for example with a film
coating, the sleeve-shaped region is arranged between the film coating and the core.
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PCT application WO 2006/082099 A
Since the extrudate containing the extrusion skin (intermediate) can be processed in different
ways to obtain the form of administration according to the invention, the sleeve-shaped
domain can adopt different arrangements and extensions within the form of administration
according to the invention. However, common to all arrangements is the fact that the sleeve-
shaped region partially covers the surface of the core, but usually not its entire surface.
Preferably, two opposite surfaces of the core are not covered, or at least not fully covered by
the sleeve-shaped region. In other words, preferably the sleeve-shaped region has two
openings/recesses on opposing sides.
The sleeve-shaped region can have a uniform layer thickness. It is also possible, however, that
during the processing, the shaping (eg press-forming) of the extrudate can cause different
regions of the extrusion skin to be compressed or extended to different degrees so that the
layer thickness of the sleeve-shaped region within the form of administration can vary.
Preferably the layer thickness of the sleeve-shaped region is within the range from 0.1 to 4.0
mm, more preferably 0.15 to 3.5 mm, still more preferably 0.2 to 3.0 mm, most preferably 0.2
to 2.5 mm and in particular 0.2 to 2.0 mm
Figures 5A and 5B are two schematic views of preferred arrangements of the sleeve-shaped
region within the form of administration according to the invention. In this regard, the forms
of administration (81) comprise a sleeve-shaped region (82) partially surrounding the core
(83). The opposing surfaces (84a) and (84b) of the core (83), however, are not covered by the
sleeve-shaped region (82).
The method for the production of the form of administration according to the invention is
preferably performed continuously. Preferably, the method involves the extrusion of a
homogeneous mixture of components (A), (C), optionally (B) and optionally (D). In this
regard, it is particularly advantageous for the intermediate obtained, eg the strand obtained by
extrusion, to have uniform properties. Particularly desirable are uniform density, uniform
distribution of the active substance, uniform mechanical properties, uniform porosity, uniform
surface finish, etc. Only under these circumstances can the uniformity of the pharmacological
properties, such as the stability of the release profile, be ensured and the amount of rejects
kept low.
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PCT application WO 2006/082099 A
Preferably, the method according to the present invention may be performed in such a way
that the quantity of rejects is less than 25%, more preferably less than 20%, most preferably
less than 15% and in particular less than 10%, wherein the rejection criteria are the FDA
standards regarding the intervariability of the content of component (A), its release profile
and/or the density of the form of administration when comparing two forms of administration,
preferably taken from the same batch.
It has surprisingly been found that the above properties may be obtained by means of twin-
screw-extruders and planetary-gear-extruders, wherein twin-screw-extruders are particularly
preferred.
The method according to the invention preferably involves the extrusion of a mixture of
components (A), (C), optionally (B) and optionally (D), preferably by means of a planetary-
gear-extruder or a twin-screw-extruder. After extrusion, the extrudate is preferably singulated,
shaped and optionally coated in order to obtain the final form of administration.
In a preferred embodiment of the method according to the invention, shaping is performed
with the mixture of components (A), (C), optionally (B) and optionally (D) in plasticised
state. It has surprisingly been found that the extrusion of certain polymers (C), particularly of
high molecular weight polyethylene oxides, produces intermediates exhibiting a certain
memory effect, ie a certain recovery capacity: if the singulated extrudates are shaped at
ambient temperature, eg by press-forming, forms of administration are obtained which tend to
regain their original outer shape due to storage under conditions of stress, ie they return to the
shaped form they had prior to shaping.
The shape of the form of administration during storage under conditions of stress, e.g. at
40°C/75% RH, may also be unstable for other reasons.
The memory effect significantly impairs the storage stability of the form of administration,
since by regaining its outer shape, numerous properties of the form of administration are
changed. The same applies to any changes to the outer shape due to other reasons.
It has been found that, for example, depending on the extrusion conditions, a significant
expansion of the strand may occur thereby resulting in an increase in the volume of the
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PCT application WO 2006/082099 A
extrudate, ie a decrease in its density. This expansion can be compensated by subsequently
press-forming the singulated extrudate at a sufficient pressure, since, under these conditions,
the expansion of the material may be reversed.
If, however, the press-forming was performed at ambient temperature, the memory effect of
the compressed extrudate causes it to swell and expand resulting in a significant increase in
the volume of the form of administration.
It has surprisingly been found that a memory effect of this kind may be suppressed if shaping
of the singulated extrudate is performed at an increased temperature, ie in the plasticised state
of the mixture of components (A), (C), optionally (B) and optionally (D). Preferably, the
shaping is performed at a pressure of at least 1 kN, more preferably within the range from 2
kN to 50 kN, eg by means of a tablet press. Preferably, shaping is performed at a temperature
which is about 40°C, more preferably about 30°C and in particular about 25°C below the
melting range of the mixture of components (A), (C), optionally (B) and optionally (D). The
melting range of a given mixture may be determined by conventional methods, preferably by
DSC (eg with a DSC model 2920 (TA Instruments, New Castle) and ultrahigh pure nitrogen
as purge gas at a flow rate of 150 ml/min; approximate sample weight of 10-20 mg, sealed in
nonhermetic aluminium pans; temperature gradient 10°C/min).
In a preferred embodiment, the outer shape of the form of administration according to the
invention does not substantially change when stored for at least 12 h, preferably for at least 24
h, at 40°C and 75% RH, preferably in an open container.
In a preferred embodiment, when stored for at least 12 h, preferably for at least 24 h, at a
temperature of 20°C below the melting range of the mixture of components (A), (C),
optionally (B) and optionally (D), optionally at a temperature of 40°C and 75% RH, the
volume of the form of administration according to the invention increases by not more than
20% or 17.5%, more preferably not more than 15% or 12.5%, still more preferably not more
than 10% or 7.5%, most preferably not more than 6.0%, 5.0% or 4.0% and in particular not
more than 3.0%, 2.0% or 1.0%
The form of administration according to the invention exhibits controlled release of the active
ingredient. It is in this regard preferably suitable for twice daily administration to patients.
50

PCT application WO 2006/082099 A
The form of administration according to the invention can comprise one or more substances
(A) at least partially in a further delayed-release form, wherein delayed release may be
achieved by means of conventional materials and methods known to the person skilled in the
art, for example by embedding the substance in a release-delaying matrix or by applying one
or more release-delaying coatings. The release of the substance must, however, be controlled
such that the addition of release-delaying materials does not impair the necessary hardness.
Controlled release from the form of administration according to the invention is preferably
achieved by embedding the substance in a matrix. The excipients acting as matrix materials
control the release. Matrix materials may, for example, be hydrophilic, gel-forming materials,
from which release proceeds mainly by diffusion, or hydrophobic materials, from which
release proceeds mainly by diffusion from the pores in the matrix.
Physiologically compatible, hydrophilic materials, which are known to the person skilled in
the art, may be used as matrix materials. Polymers, particularly preferably cellulose ethers,
cellulose esters and/or acrylic resins are preferably used as hydrophilic matrix materials.
Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,
hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivatives thereof, such as the
salts, amides or esters thereof are quite particularly preferably used as matrix materials.
Also preferred are matrix materials produced from hydrophobic materials, such as
hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding
esters or ethers or mixtures thereof. Mono- or diglycerides of C12-C30 fatty acids and/or
C12-C30 fatty alcohols and/or waxes or mixtures thereof are particularly preferably used as
hydrophobic materials
It is also possible to use mixtures of the above-stated hydrophilic and hydrophobic materials
as matrix materials.
In addition, components (C) and the optionally present component (D), which serve to
achieve the resistance to breaking of at least 400 N, which is necessary according to the
invention, may furthermore themselves serve as additional matrix materials.
51

PCT application WO 2006/082099 A
If the form of administration according to the invention is intended for oral administration, it
may also preferably comprise a coating that is resistant to gastric juices and dissolves as a
function of the pH value of the release environment. By means of this coating, it is possible to
ensure that the form of administration according to the invention passes through the stomach
undissolved and the active ingredient is only released in the intestines. The coating that is
resistant to gastric juices preferably dissolves at a pH value of between 5 and 7.5.
Corresponding materials and methods for the delayed release of active ingredients and for the
application of coatings that are resistant to gastric juices are known to the person skilled in the
art, for example from "Coated Pharmaceutical Dosage Forms - Fundamentals, Manufacturing
Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials" by Kurt H Bauer,
K Lehmann, Hermann P Osterwald, Rothgang, Gerhart, 1st edition, 1998, Medpharm
Scientific Publishers. The corresponding literature description is hereby introduced as a
reference and is deemed to be part of the disclosure.
One object of the invention relates to the use of a physiologically active substance (A) as
described above and/or a synthetic or natural polymer (C) as described above to produce of
the form of administration according to the invention for the prevention and/or treatment of a
disease with the prevention of an overdose of the physiologically active substance (A), in
particular as the result of the comminution of the form of administration by exposure to
mechanical action.
The invention also relates to the use of a physiologically active substance (A) as described
above and/or a synthetic or natural polymer (C) as described above to produce the form of
administration according to the invention to prevent an unintentional disruption, in particular
cancellation, of the delayed release of the physiologically active substance (A) as the result of
the comminution of the form of administration by exposure to mechanical action.
The invention further relates to the use of a form of administration according to the invention
to produce a medicine for the prevention and/or treatment of a disease with the prevention of
an overdose of the physiologically active substance (A), in particular as the result of the
comminution of the medicine by exposure to mechanical action.
52

PCT application WO 2006/082099 A
Finally, the invention relates to the use of the form of administration according to the
invention to produce a medicine for the prevention and/or treatment of the disease with the
prevention of an unintentional disruption, in particular cancellation of the delayed release of
the physiologically active substance (A) as the result of the comminution of the medicine by
exposure to mechanical action.
In this regard, said mechanical action is preferably selected from the group consisting of
chewing, grinding in a mortar, pounding and the use of apparatus for the pulverisation of
conventional forms of administration.
The resistance to breaking of the forms of administration according to the invention is
determined according to the stated measurement method, wherein forms of administration
other than tablets are also tested.
To determine the resistance to breaking of the form of administration according to the
invention, forms of administration, preferably tablets, with a diameter of 10 mm and a height
of 5 mm are produced.
With these forms of administration, preferably tablets, the resistance to breaking of the form
of administration is determined in accordance with the method for determining the resistance
to breaking of tablets published in the European Pharmacopoeia 1997, page 143, 144, method
No 2.9.8. using the apparatus described below. The apparatus used for the measurement is a
"Zwick Z 2.5" materials tester, Fmax = 2.5 kN with a maximum draw of 1150 mm, which
should be set up with one column and one spindle, a clearance behind of 100 mm and a test
speed adjustable between 0.1 and 800 mm/min together with testControl software.
Measurement is performed using a pressure piston with screw-in inserts and a cylinder
(diameter 10 mm), a force transducer, Fmax. 1 kN, diameter = 8 mm, class 0.5 from 10 N,
class 1 from 2 N to ISO 7500-1, with manufacturer's test certificate M according to DIN
55350-18 (Zwick gross force Fmax = 1.45 kN) (all apparatus from Zwick GmbH & Co. KG,
Ulm, Germany) with Order No BTC-FR 2.5 TH. D09 for the tester, Order No BTC-LC
0050N. P01 for the force transducer, Order No BO 70000 S06 for the centring device.
Figure 6 shows the measurement of the resistance to breaking of a tablet, in particular the
adjustment device (6) for the tablet (4) used for this purpose before and during the
53

PCT application WO 2006/082099 A
measurement. To this end, the tablet (4) is held between the upper pressure plate (1) and the
lower pressure plate (3) of the force application apparatus (not shown) with the assistance of
two 2-part clamping devices, which are in each case firmly attached (not shown) to the upper
and lower pressure plate once the spacing (5) necessary for accommodating and centring the
tablet to be measured has been established. The spacing (5) may be established by moving the
2-part clamping devices horizontally outwards or inwards in each case on the pressure plate
on which they are mounted. The reference numbers used relate solely to Figure 6.
If the form of administration according to the invention is in multiparticulate form, the
resistance to breaking may alternatively be determined by means of two pressure plates, such
as depicted for example in Figure 7.
Figure 7 shows an upper pressure plate (10) and a lower pressure plate (11), between which
the probe (12), for example a pellet, is introduced. The two pressure plates are used to apply
force to the probe. The evaluation of the result of the measurement is performed in the same
way as in the method described above in relation to Figure 6.
The tablets deemed resistant to breaking under a specific load include not only those that have
not broken but also those that may have suffered plastic deformation under the action of the
force.
The invention is explained below with reference to examples. These explanations are given
merely by way of example and do not restrict the general concept of the invention.
In a first series of examples diltiazem hydrochloride, verapamil hydrochloride and
carbamazepine were used as the active ingredients (substance (A)).
Example 1:

Components Per tablet Complete batch
Diltiazem HC1 90.0 mg 720 mg
Polyethylene oxide(Polyox WSR 303, , NF, MW 7 000 000Dow Chemicals) 154.2 mg 1233.6 mg
Total weight 244.2 mg 1.9536 g
54

PCT application WO 2006/082099 A
All components were mixed in a free-fall mixer. A tabletting tool with an upper punch, lower
punch and die for tablets with a diameter of 10 mm and a radius of curvature of 8 mm were
heated in a heating cabinet to 80°C. The heated tool was used to press the powder mixture
wherein the powder mixture was maintained for at least 15 s by clamping the tabletting tool in
a vice.
The resistance to breaking of the tablets was determined in accordance with the stated method
with the stated apparatus. The tablets did not crush when exposed to a force of 500 N. The
tablet could not be comminuted with a hammer. This could not be achieved by means of a
pestle and mortar either.
In vitro release of the active ingredient from the preparation was determined in a paddle stirrer
apparatus in accordance with Pharm Eur (paddle with sinker). The temperature of the release
medium was 37°C and the rotational speed of the stirrer 50 min . At the beginning of the
investigation, each tablet was placed in a 900 ml portion of artificial gastric juice, pH 1.2.
After 30 minutes, the pH value was increased to 2.3 by addition of alkali solution, after a
further 90 minutes to pH 6.5 and after a further 60 minutes to pH 7.2. The quantity of active
ingredient released in each case into the dissolution medium at any one time was determined
by spectrophotometry at 236 nm in 2 mm measurement cells.

Time Quantity released
30 min 12%
240 min 43%
480 min 63%
600 min 71%
720 min 77%
Example 2:
As in Example 1, oblong tablets with a diameter of 9 mm and a longitudinal extension of 20
mm were produced with the following composition:

Components Per tablet Complete batch
Verapamil HC1 240.0 mg 1920 mg
Polyethylene oxide, NF, MW 7 000 000(Polyox WSR 303, Dow Chemicals) 411.4 mg 3291.2 mg
Total weight 651.4 mg 4.2112g
55

PCT application WO 2006/082099 A
The resistance to breaking of the tablets was determined in accordance with the stated method
by means of the stated apparatus. The tablets did not break when exposed to an application of
force of 500 N.
The in-vitro-release of the active substance was determined in a manner similar to Example 1
(UV detection at 279 nm) and was:

Time Quantity released
30min 6%
240 min 20%
480 min 30%
600 min 35%
720 min 39%
Example 3:
Similarly to Example 1, round tablets with a diameter of 20 mm and the following
composition were produced:

Components Per tablet Complete batch
Carbamazepine 600 mg 4800 mg
Polyethylene oxide, NF, MW 7 000 000(Polyox WSR 303, Dow Chemicals) 1028.5 mg 8228.0 mg
Total weight 1628.5 mg 13.028 g
The resistance to breaking of the tablets was determined according to the stated method by
means of the stated apparatus. The tablets did not break when exposed to an application of
force of 500 N.
The in-vitro-release of the active substance was determined in a manner similar to Example 1
(UV detection at 285 nm) and was:

Time Quantity released
30 min 1 %
240 min 5%
480 min 9%
600 min 11%
720 min 13%
In a further series of examples, nifedipine was used as the active ingredient (substance (A)).
56

PCT application WO 2006/082099 A
Example 4:
Tablets with the following composition were produced:

Nifedipine and polyethylene oxide were mixed in a free-fall mixer. The mixture was
compressed on an eccentric tablet press (model EK 0, Korsch) to form circular tablets with a
weight of 200 mg, a diameter of 8 mm and a radius of curvature of 8 mm. Then, the tabletting
tool comprising a die, upper punch, lower punch and with a diameter of 10 mm and a radius
of curvature of 8 mm was heated in a heating cabinet to 100°C. Once again, the tablets
produced were pressed by means of the heated tool, wherein pressure was maintained for at
least 15 seconds.
The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not crush when exposed to an application
of force of 500 N. The tablet could not be comminuted with a hammer and this could not be
achieved by means of a pestle and mortar either.
Example 5:
Similarly to Example 4, tablets with the following composition were produced:

The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not crush when exposed to the application
of a force of 500 N. The tablet could not be comminuted with a hammer and this could not be
achieved by means of a pestle and mortar either.
57

PCT application WO 2006/082099 A
Example 6:
Similarly to Example 4, tablets with the following composition were produced:

The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not crush when exposed to the application
of a force of 500 N. The tablet could not be comminuted with a hammer and this could not be
achieved by means of a pestle and mortar either
Example 7:
Similarly to Example 4, tablets with the following composition were produced:

The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not crush when exposed to the application
of a force of 500 N. The tablet could not be comminuted with a hammer. This could not be
achieved by means of a pestle and mortar either.
In a further series, tablets with tramadol HC1 as the physiologically active substance (A) were
produced:
Example 8:


PCT application WO 2006/082099 A

Tramadol hydrochloride and polyethylene oxide powder were mixed in a free-fall mixer. A
tabletting tool with upper punch, lower punch and die for tablets with a diameter of 10 mm
and a radius of curvature of 8 mm was heated in a heating cabinet to 80°C. 300 mg portions of
the powder mixture were pressed with the heated tool, wherein pressure was maintained for at
least 15 seconds by clamping the tabletting tool in a vice.
The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not break when exposed to the application
of a force of 500 N.
The tablet could not be comminuted using a hammer, nor with the assistance of a mortar and
pestle.
In vitro release of the active ingredient from the preparation was determined in a paddle stirrer
apparatus in accordance with Pharm Eur. The temperature of the release medium was 37°C
and the rotational speed of the stirrer 75 min"1. At the beginning of the investigation, each
tablet was placed in a 600 ml portion of artificial gastric juice, pH 1.2. After 30 minutes, the
pH value was increased to 2.3 by addition of alkali solution, after a further 90 minutes to pH
6.5 and after a further 60 minutes to pH 7.2. The released quantity of active ingredient present
in the dissolution medium at each point in time was determined by spectrophotometry.

Time Quantity released
30 min 15%
240 min 52%
480 min 80%
720 min 99%
Example 9:
The powder mixture from Example 8 was heated in portions of 300 mg to 80°C and placed in
the die of the tabletting tool. This was followed by pressing. The tablet has the same
properties as the tablet in Example 8.
59

PCT application WO 2006/082099 A
Example 10:

Raw material Per tablet Complete batch
Tramadol hydrochloride 50 mg 100 g
Polyethylene oxide, NF, MW 7 000 000(Polyox WSR 303, Dow Chemicals) 100 mg 200 g
Total weight 150 ma 300 e
Tramadol hydrochloride and the components stated above were mixed in a free-fall mixer. A
tabletting tool with upper punch, lower punch and die for tablets with a diameter of 7 mm was
heated in a heating cabinet to 80°C. 150 mg portions of the powder mixture were each pressed
with the heated tool, wherein pressure was maintained for at least 15 seconds by clamping the
tabletting tool in a vice.
The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not break when exposed to the application
of a force of 500 N.
The in-vitro-release of the active substance was determined as in Example 8 and was:

Time Quantity released
30min 15%
240 min 62%
480 min 88%
720 min 99%
Example 11:

Raw material Per tablet Complete batch
Tramadol hydrochloride 100 mg 100 g
Polyethylene oxide, NF, MW 7 000 000(Polyox WSR 303, Dow Chemicals) 180 mg 180 g
Xanthan, NF 20 mg 20 g
Total weight 300 mg 300 g
Tramadol hydrochloride, xanthan and polyethylene oxide were mixed in a free-fall mixer. A
tabletting tool with an upper punch, lower punch and die for tablets with a diameter of 10 mm
60

PCT application WO 2006/082099 A
and a radius of curvature of 8 mm was heated to 80°C in a heating cabinet. 300 mg portions of
the powder mixture were each pressed with the heated tool, wherein pressure was maintained
for at least 15 seconds by clamping the tabletting tool in a vice.
The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not break when exposed to the application
of a force of 500 N. The tablets did suffer a little plastic deformation.
In vitro release of the active ingredient was determined as in Example 8 and was:

Time Quantity released
30min 14%
240 min 54%
480 min 81%
720 min 99%
Example 12:

Raw material Per tablet Complete batch
Tramadol hydrochloride 50 mg 100 g
Polyethylene oxide, NF, MW 7 000 000(Polyox WSR 303, Dow Chemicals) 90 mg 180 g
Xanthan, NF 10 mg 20 g
Total weight 300 mg 300 g
Tramadol hydrochloride, xanthan and polyethylene oxide were mixed in a free-fall mixer. A
tabletting tool with a upper punch, lower punch and die for oblong tablets 10 mm in length
and 5 mm in width was heated in a heating cabinet to 90°C. 150 mg portions of the powder
mixture were each pressed with the heated tool, wherein pressure was maintained for at least
15 seconds by clamping the tabletting tool in a vice.
The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not break when exposed to the application
of a force of 500 N. The tablets did suffer a little plastic deformation
In vitro release of the active ingredient was determined as in Example 8 and was:
61

PCT application WO 2006/082099 A
Time Quantity released
30 min 22 %
120 min 50%
240 min 80 %
360 min 90 %
480 min 99 %
Example 13:
A tablet with the following composition was produced as described in Example 8:

Components Per tablet Per batch
Oxycodon hydrochloride 20.0 mg 0.240 g
Xanthan NF 20,0 mg 0,240 g
Polyethylene oxide, NF, MFI (190°C at 21.6 kg/10 min Total weight 150.0 mg 1.800 g
The release of the active substance was determined as follows:
The in-vitro-release of the active substance from the tablet was determined in a paddle stirrer
apparatus in accordance with Pharm Eur. The temperature of the release medium was 37°C
and the rotational speed 75 rpm. The phosphate buffer, pH 6.8, described in DSP served as the
release medium. The quantity of active ingredient present in the solvent at the particular time
of testing was determined by spectrophotometry.

Time Mean
0 min 0%
30 min 17%
240 min 61%
480 min 90%
720 min 101.1 %
The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not break when exposed to the application
of a force of 500 N.
Example 14:
62

PCT application WO 2006/082099 A
Tablets of the following composition were produced:

Tramadol hydrochloride, polyethylene oxide and carnauba wax were mixed in a free-fall
mixer. The mixture was compressed on an eccentric tablet press (model EK 0, Korsch) to
form tablets, the weight of the tablets was 500 mg. Round tablets with a diameter of 10 mm
and a radius of curvature of 8 mm were produced. Then, the tabletting tool comprising a die,
upper punch, lower punch and a diameter of 10 mm and a radius of curvature of 8 mm was
heated in a heating cabinet to 130°C. Once again the tablets produced were pressed by means
of the heated tool, wherein pressure was maintained for at least 15 seconds.
The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not crush when exposed to the application
of a force of 500 N. The tablet could not be comminuted with a hammer and this could not be
achieved by means of a pestle and mortar either.
Example 15:
Similarly to Example 14, tablets with the following composition were produced:

Raw material Pertablet Perbatch Proportion
Tramadol HC1 100 mg 10 g 20%
Polyethylene oxide 5 000 000 (Polyox WSR Coagulant DowChemicals) 375 mg 37.5 g 75%
Carnauba wax 25 mg 2.5 g 5.0%
The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not crush when exposed to the application
of a force of 500 N. The tablet could not be comminuted with a hammer and this could not be
achieved by means of a pestle and mortar either.
Example 16:
63

PCT application WO 2006/082099 A

Tablets with the following composition were produced:
50 g of the polyethylene oxide, 5 g of a-tocopherol and Aerosil was processed in a mortar to
produce a homogeneous mixture. This was mixed with the further components in a free-fall
mixer for 15 minutes. Subsequently, the mixture was extruded by means of a planetary-gear
extruder, type BCG 10, LBB Bohle (Ennigerloh). 4 planetary spindles were used. The die
diameter was 8 mm. The dosing of the powder was performed gravimetrically, 10 kg per
hour. The following parameters were adjusted for extrusion: rotational speed: 50 rpm; jacket
temperature: 100°C; temperature of the central spindle: 100°C; temperature of the jet heating:
120°C. After production, the extrudates were allowed to cool down to room temperature.
Thereafter, they were cut into discs of the desired tablet weight. Moulding of the tablets was
performed by means of an eccentric press, type EKO, made by Korsch. Circular punches
(diameter of 10 mm) and a radius of curvature of 8 mm were used as the tabletting tool.
The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not crush when exposed to the application
of a force of 500 N. The tablet could not be comminuted with a hammer, and this could not be
achieved by means of a pestle and mortar either.
The in vitro release of the active ingredient from the preparation was determined in a paddle
stirrer apparatus with sinker in accordance with Pharm Eur. The temperature of the release
medium was 37°C and the rotational speed of the stirrer was 75 min"1. 600 ml of intestinal
juice, pH 6.8, was used as the release medium. The quantity of active ingredient present in the
solvent at the particular time of testing was determined by spectrophotometry.

Time Quantity of active substancereleased
64

PCT application WO 2006/082099 A

30min 17%
240 min 65%
480 min 93%
720 min 99%
Example 17:
Similarly to Example 16, tablets of the following composition were produced:

The resistance to breaking of the tablets was determined with the stated apparatus in
accordance with the stated method. The tablets did not crush when exposed to the application
of a force of 500 N. The tablet could not be comminuted with a hammer, and this could not be
achieved by means of a pestle and mortar either.
The in vitro release of the active substance from the preparation was determined in a paddle
stirrer apparatus with sinker in accordance with Pharm Eur. The temperature of the release
medium was 37°C and the rotational speed of the stirrer 75 min"1. 600 ml of intestinal fluid,
pH 6.8, were used as the release medium. The quantity of active ingredient released in each
case into the dissolution medium at any one time was determined by spectrophotometry.

Time Quantity of active substancereleased
30 min 17%
240 min 62%
480 min 85%
720 min 94%
65

PCT application WO 2006/082099 A
Claims
1. Form of administration comprising
a physiologically active substance (A),
optionally one or a plurality of physiologically compatible excipients (B),
a synthetic or natural polymer (C), and
optionally a natural, semi-synthetic or synthetic wax (D);
wherein the form of administration has a resistance to breaking of at least 400 N and, under
physiological conditions, the release of the physiologically active substance (A) is at least
partially delayed.
2. Form of administration according to claim 1, characterised in that it does not comprise
any psychotropically active substance.
3. Form of administration according to claim 1 or claim 2, characterised in that it has a
resistance to breaking of at least 500 N.
4. Form of administration according to any one of the preceding claims, characterised in
that it is present in the form of a tablet.
5. Form of administration according to any one of the preceding claims, characterised in
that it is present in multiparticulate form, wherein the individual particles have a resistance to
breaking of at least 400 N.
6. Form of administration according to claim 5, characterised in that the particles are
pressed into tablets or packaged in capsules.
7. Form of administration according to any one of the preceding claims, characterised in
that the polymer (C) is selected from the group consisting of polyalkylene oxide,
polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate,
the copolymers thereof and mixtures thereof.
66

PCT application WO 2006/082099 A
8. Form of administration according to any one of the preceding claims, characterised in
that the polymer (C) is a polyalkylene oxide selected from the group consisting of
polymethylene oxide, polyethylene oxide, polypropylene oxide, the copolymers thereof, the
block copolymers thereof and mixtures thereof.
9. Form of administration according to claim 7 or 8, characterised in that the polymer (C)
has a viscosity-average molecular weight of at least 0.5 106 g/mol.

10. Form of administration according to any one of the preceding claims, characterised in
that it comprises a sleeve-shaped region (82) and a core (83) located therein, wherein the
sleeve-shaped region (82) is connected to the core in a seamless manner and the material
forming the sleeve-shaped region (82) and the material forming the core (83) substantially
have the same chemical composition, but different morphology.
11. Form of administration according to claim 10, characterised in that the material forming
the sleeve-shaped region (82) and the material forming the core (83) have different optical
properties.
12. Form of administration according to claim 10 or 11, characterised in that the layer
thickness of the sleeve-shaped region (82) is within the range of 0.1 to 4 mm.
13. Form of administration according to any one of the preceding claims, characterised in
that on storage for at least 12 h at a temperature of 20°C below the melting range of the
mixture of components (A), (C), optionally (B) and optionally (D), the volume of the form of
administration increases by no more than 20%.
14. Form of administration according to any one of the preceding claims, characterised in
that it comprises at least one wax (D) with a softening point of at least 50°C.
15. Form of administration according to claim 14, characterised in that the wax (D) is
carnauba wax or beeswax.
16. Form of administration according to any one of the preceding claims, characterised in
that the substance (A) is present in a delayed-release matrix.
67

PCT application WO 2006/082099 A
17. Form of administration according to claim 16, characterised in that the delayed-release
matrix comprises the polymer (C) and/or the optionally present wax (D) as a delayed-release
matrix material.
18. Form of administration according to any one of the preceding claims, characterised in
that, under physiological conditions, after 5 hours it releases at the most 99% of the substance
(A).
19. Form of administration according to claim 18, characterised in that it contains neither
tramadol hydrochloride nor oxycodone hydrochloride.
20. Form of administration according to any one of the preceding claims, characterised in
that the substance (A) is a therapeutic agent, selected from the group consisting of agents for
the treatment and prevention of diseases of the alimentary system and metabolism, agents for
the treatment and prevention of diseases of the blood and the blood-forming organs, agents
for the treatment and prevention of diseases of the cardiovascular system, dermatologicals,
agents for the treatment and prevention of diseases of the genitourinary system and sex
hormones, systemic hormone preparations excluding sex hormones and insulins,
antiinfectives for systemic use, antineoplastic and immunomodulating agents, agents for the
treatment and prevention of diseases of the musculo-skeletal system, agents for the treatment
and prevention of diseases of the nervous system, antiparasitic products, insecticides and
repellents; agents for the treatment and prevention of diseases of the respiratory system,
agents for the treatment and prevention of diseases of the sensory organs, general diet
products and therapeutic radiopharmaceuticals.
21. A method for the production of a form of administration according to any one of claims
1 to 20 comprising the following steps:,

(a) mixing of component (A), optionally (B), (C), optionally (D),
(b) optionally preforming the mixture obtained from step (a), preferably with the exposure
to heat and/or force of the mixture obtained from (a), wherein the quantity of heat
supplied is preferably not sufficient to heat component (C) to its softening point,
68

PCT application WO 2006/082099 A
(c) hardening the mixture by exposure to heat and force, wherein the heat can be supplied
during and/or before the exposure to force and the quantity of heat supplied is sufficient
to heat component (C) at least to its softening point,
(d) optionally singulating the hardened mixture,
(e) optionally shaping the form of administration and
(f) optionally coating with a film coating.

22. Method according to claim 21, characterised in that in step (c) a twin-screw extruder or
a planetary-gear extruder is used.
23. Method according to claim 22, characterised in that step (e) is performed in the
plasticised state of the mixture of components (A), (C), optionally (B) and optionally (D).
24. Method according to any one of claims 21 to 23, characterised in that step (c) is
performed under the action of ultrasound.
25. Product obtainable by a method according to any one of claims 21 to 24.
26. Use of a physiologically active substance (A) and/or a synthetic or natural polymer (C)
to produce a form of administration according to any one of claims 1 to 20 for the prevention
and/or treatment of a disease with the prevention of an overdose of the physiologically active
substance (A), in particular due to the comminution of the form of administration by
mechanical action.
27. Use of a physiologically active substance (A) and/or a synthetic or natural polymer (C)
to produce a form of administration according to any one of claims 1 to 20 to prevent an
unintentional disruption of the delayed release of the physiologically active substance (A) due
to the comminution of the form of administration by mechanical action.
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PCT application WO 2006/082099 A
70
28. Use of a form of administration according to any one of claims 1 to 20 to produce a
medicine for the prevention and/or treatment of a disease with the prevention of an overdose
of the physiologically active substance (A), in particular due to the comminution of the
medicine by mechanical action.
29. Use of a form of administration according to any one of claims 1 to 20 to produce a
medicine for the prevention and/or treatment of a disease with the prevention of an
unintentional disruption of the delayed release of the physiologically active substance (A) due
to the comminution of the form of medicine by mechanical action.
30. Use according to any one of claims 26 to 29, characterised in that the mechanical action
is selected from the group consisting of chewing, grinding in a mortar, pounding and the use
of apparatus for the pulverisation of conventional forms of administration.

The invention relates to a form of administration comprising a physiologically effective
substance (A); one or several optional physiologically acceptable adjuvants (B); a
synthetic or natural polymer (C); and an optional natural, semisynthetic, or synthetic
wax (D). Said form of administration is provided with a minimum breaking strength of
400 N while releasing the physiologically effective substance (A) at least partly in a
delayed manner in physiological conditions.

Documents:

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Patent Number 272820
Indian Patent Application Number 2728/KOLNP/2007
PG Journal Number 18/2016
Publication Date 29-Apr-2016
Grant Date 28-Apr-2016
Date of Filing 24-Jul-2007
Name of Patentee GRUNENTHAL GMBH
Applicant Address ZIEGLERSTRASSE 6, 52078 AACHEN
Inventors:
# Inventor's Name Inventor's Address
1 ARKENAU-MARIC, ELISABETH STADTWALDGURTEL 50 50931, KOLN
2 ASHWORTH, JUDY LUISENSTR. 18, 42929 WERMELSKIRCHEN
3 BARTHOLOMAUS, JOHANNES BURGHOHENWEG 5 52080 AACHEN
4 KUGELMANN HEINRICH, BLUCHERPLATZ 7, 52068 AACHEN, GERMANY,
PCT International Classification Number A61K 9/20
PCT International Application Number PCT/EP2006/001027
PCT International Filing date 2006-02-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 10 2005 005 446.3 2005-02-04 Germany