U.S. patent application number 14/994691 was filed with the patent office on 2016-05-05 for crush resistant delayed-release dosage forms.
This patent application is currently assigned to Grunenthal GmbH. The applicant listed for this patent is Grunenthal GmbH. Invention is credited to Elisabeth Arkenau-Maric, Judy Ashworth, Johannes Bartholomaus, Heinrich Kugelmann.
Application Number | 20160120810 14/994691 |
Document ID | / |
Family ID | 36384542 |
Filed Date | 2016-05-05 |
United States Patent
Application |
20160120810 |
Kind Code |
A1 |
Ashworth; Judy ; et
al. |
May 5, 2016 |
CRUSH RESISTANT DELAYED-RELEASE DOSAGE FORMS
Abstract
The invention relates to a dosage form comprising a
physiologically effective amount of a physiologically active
substance (A), a synthetic, semi-synthetic or natural polymer (C),
optionally one or more physiologically acceptable auxiliary
substances (B) and optionally a synthetic, semi-synthetic or
natural wax (D), wherein the dosage form exhibits a resistance to
crushing of at least 400 N and wherein under physiological
conditions the release of the physiologically active substance (A)
from the dosage form is at least partially delayed.
Inventors: |
Ashworth; Judy;
(Wermelskirchen, DE) ; Arkenau-Maric; Elisabeth;
(Koln, DE) ; Bartholomaus; Johannes; (Aachen,
DE) ; Kugelmann; Heinrich; (Aachen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Grunenthal GmbH |
Aachen |
|
DE |
|
|
Assignee: |
Grunenthal GmbH
Aachen
DE
|
Family ID: |
36384542 |
Appl. No.: |
14/994691 |
Filed: |
January 13, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14324366 |
Jul 7, 2014 |
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14994691 |
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12140568 |
Jun 17, 2008 |
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14324366 |
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11348295 |
Feb 6, 2006 |
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12140568 |
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Current U.S.
Class: |
424/452 ;
264/115; 264/141; 264/176.1; 264/331.11; 264/443; 424/489;
514/211.07; 514/217; 514/282; 514/356; 514/523; 514/646 |
Current CPC
Class: |
A61P 37/00 20180101;
A61K 31/55 20130101; A61J 3/06 20130101; B29C 43/24 20130101; B29C
48/40 20190201; A61K 9/2086 20130101; A61P 1/00 20180101; A61P 7/00
20180101; B29B 9/12 20130101; B29C 35/0261 20130101; B29K 2105/251
20130101; B29L 2031/772 20130101; A61K 9/2072 20130101; A61K
31/4418 20130101; B29C 43/02 20130101; A61K 9/2009 20130101; B29C
48/21 20190201; A61K 9/2031 20130101; B29B 7/002 20130101; B29C
48/44 20190201; B29K 2105/0044 20130101; B29C 48/0022 20190201;
A61K 9/0053 20130101; B29C 48/0011 20190201; B29K 2995/0056
20130101; A61P 25/04 20180101; B29C 2793/009 20130101; A61P 17/00
20180101; B29C 45/0001 20130101; B29L 2031/753 20130101; A61K
31/135 20130101; B29K 2105/0035 20130101; A61K 31/277 20130101;
A61K 9/2095 20130101; A61K 31/485 20130101; A61P 9/00 20180101;
B29C 48/146 20190201; A61K 9/20 20130101; A61K 9/2013 20130101;
A61P 25/30 20180101; A61K 9/2893 20130101; A61P 13/00 20180101;
A61J 3/10 20130101; A61K 31/554 20130101; A61K 9/2054 20130101;
B29B 9/02 20130101; A61K 9/205 20130101; B29C 48/022 20190201; A61J
3/005 20130101; A61K 9/2068 20130101; A61P 5/00 20180101; A61P
19/00 20180101; A61P 27/00 20180101; A61K 9/4808 20130101; A61K
31/4422 20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 9/28 20060101 A61K009/28; A61K 31/277 20060101
A61K031/277; A61K 31/55 20060101 A61K031/55; B29B 9/02 20060101
B29B009/02; A61K 31/135 20060101 A61K031/135; A61K 31/485 20060101
A61K031/485; B29C 43/02 20060101 B29C043/02; B29B 9/12 20060101
B29B009/12; B29B 7/00 20060101 B29B007/00; A61K 31/554 20060101
A61K031/554; A61K 31/4422 20060101 A61K031/4422 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 4, 2005 |
DE |
102005005446.3 |
Claims
1. A dosage form comprising a physiologically effective amount of a
physiologically active substance (A), a synthetic, semi-synthetic
or natural polymer (C), optionally one or more physiologically
acceptable auxiliary substances (B) and optionally a synthetic,
semi-synthetic or natural wax (D), wherein the dosage form exhibits
a resistance to crushing of at least 400 N and wherein under
physiological conditions the release of the physiologically active
substance (A) from the dosage form is at least partially
delayed.
2. The dosage form according to claim 1, which exhibits a
resistance to crushing of at least 500 N.
3. The dosage form according to claim 1, which is in the form of a
tablet.
4. The dosage form according to claim 1 which is in
multiparticulate form, the individual particles exhibiting a
resistance to crushing of at least 400 N.
5. The dosage form according to claim 4, wherein the particles are
pressed into tablets or packaged in capsules.
6. The dosage form according to claim 1, wherein polymer (C) is
selected from the group consisting of polyalkylene oxide,
polyethylene, polypropylene, polyvinyl chloride, polycarbonate,
polystyrene, polyacrylate, the copolymers thereof and mixtures
thereof.
7. The dosage form according to claim 1, wherein polymer (C) is an
polyalkylene oxide selected from the group consisting of
polymethylene oxide, polyethylene oxide, polypropylene oxide, the
copolymers thereof, the block-copolymers thereof, and the mixtures
of any of the foregoing.
8. The dosage form according to claim 6, wherein polymer (C) has a
molecular weight of at least 0.5 million according to rheological
measurements.
9. The dosage form according to claim 1, which comprises a tubular
domain (82) and a core (83) located therein, wherein the tubular
domain (82) is connected with the core (83) in a seamless manner
and the material forming the tubular domain (82) and the material
forming the core (83) have substantially the same chemical
composition but different morphology.
10. The dosage form according to claim 9, wherein the material
forming the tubular domain (82) and the material forming the core
(83) have different optical properties.
11. The dosage form according to claim 9, wherein the thickness of
the tubular domain (82) is within the range of 0.1 to 4 mm.
12. The dosage form according to claim 1, wherein upon storage for
at least 12 hour at a temperature of 20.degree. C. below the
melting range of the mixture of components (A), (C), optionally (B)
and optionally (D) the volume of the dosage form increases by not
more than 20%.
13. The dosage form according to claim 1, wherein wax (D) is at
least one synthetic, semi-synthetic or natural wax with a softening
point of at least 50.degree. C.
14. The dosage form according to claim 13, wherein wax (D) is
carnauba wax or beeswax.
15. The dosage form according to claim 1, wherein substance (A) is
present in a delayed-release matrix.
16. The dosage form according to claim 15, wherein the
delayed-release matrix comprises polymer (C) and/or the optionally
present wax (D).
17. The dosage form according to claim 1, wherein after 5 hours
under physiological conditions it has released not more than 99% of
substance (A).
18. The dosage form according to claim 1, wherein substance (A) is
a nutritional supplement or a pharmaceutical substance.
19. The dosage form according to claim 18, wherein substance (A) is
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.
20. A process for the production of a dosage form according to
claim 1 comprising the following steps: (a) mixing of component
(A), (C), optionally (B) and optionally (D); (b) optionally
preforming the mixture obtained from step (a), preferably by
applying heat and/or force to the mixture obtained from step (a),
the quantity of heat supplied preferably not being sufficient to
heat component (C) up to its softening point; (c) hardening the
mixture by applying heat and force, where the heat is supplied
during and/or before the application of force and the quantity of
heat supplied is sufficient to heat component (C) at least up to
its softening point; (d) optionally singulating the hardened
mixture; (e) optionally shaping the dosage form; and (f) optionally
providing a film coating.
21. The process according to claim 20, wherein step (c) is
performed by means of a twin-screw-extruder or a planetary-gear
extruder.
22. The process according to claim 21, wherein step (e) is
performed in the plasticized state of the mixture of components
(A), (C), optionally (B) and optionally (D).
23. The process according to claim 20, wherein step (c) is
performed by the effect of ultrasound and force.
24. The product of the process of claim 20.
25. The product of the process of claim 21.
26. The product of the process of claim 22.
27. The product of the process of claim 23.
28. A method of preventing the misuse or abuse of a dosage form
containing a physiologically active substance (A), due to
comminution of the dosage form by mechanical action comprising
administering the active substance to a patient in need thereof in
a dosage form in accordance with claim 1.
29. The use according to claim 25 or the method according to claim
26, wherein the mechanical action is selected from the group
consisting of chewing, grinding in a mortar, pounding, and using
apparatuses for pulverising conventional dosage forms.
30. A method for the prophylaxis and/or the treatment of a disorder
treatable by the administration of a therapeutically effective
amount of an agent capable of treating such disorder comprising
administering a dosage form according to claim 1 to prevent the
unintentional disruption of the controlled release mechanism of the
physiologically active substance (A) which can result from crushing
or chewing the dosage form.
31. A method of preventing an accidental overdose of a
physiologically active substance comprising administering the
active substance to a patient in need thereof in a dosage form in
accordance with claim 1.
32. A method of preventing the misuse or abuse of a physiologically
active substance comprising administering the active substance to a
patient in need thereof in a dosage form in accordance with claim
1.
33. A method of preventing the disruption of a controlled release
mechanism in a dosage form comprising a physiologically active
substance intended for controlled release of such active substance
comprising administering the active substance in a dosage form
according to claim 1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/324,366, filed Jul. 7, 2014, pending, which is a
continuation of U.S. application Ser. No. 12/140,568, filed Jun.
17, 2008, abandoned, which is a division of Ser. No. 11/348,295
filed Feb. 6, 2006, abandoned, which claims priority from German
Patent Application No. 10 2005 005 446.3, filed Feb. 4, 2005, all
incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to a dosage form for
administering a physiologically active substance (A), wherein the
dosage form is mechanically stabilised, such that it cannot be
comminuted by conventional methods, such as pounding, crushing,
grinding in a mortar etc., or at least comminuted only with very
great difficulty. The substance (A) is released from the dosage
form according to the invention under physiologically conditions
with an at least partially delayed release profile.
[0003] Numerous physiologically active substances, such as
nutritional supplements, pharmaceutical substances etc., are
provided as delayed-release formulations, i.e., in contrast to
conventional formulations (for example "immediate release"
formulations), release of the substances from these formulations
into the body is delayed for a comparatively long period, which
often amounts to several hours. Release of the substance from the
dosage form, on the one hand, and metabolisation or excretion by
the organism; on the other hand, ensure a relatively uniform blood
plasma level for the administered substance. As a consequence
thereof, the number of dosage units which need to be taken per day
by patients can frequently by reduced, intake often being required
only once or twice a day.
[0004] In certain cases, delayed-release formulations may also
reduce the extent of side-effects caused by the substance. Thus,
for example, some pharmaceutical substances produce intensified
side-effects if a given limit concentration of the pharmaceutical
substance in the blood plasma is exceeded at least transiently.
Such pharmaceutical substances are therefore generally unsuitable
for "immediate release" formulations, in particular if it is
desired to administer said formulations only two or three times
daily. Such pharmaceutical substances are therefore conventionally
administered as delayed-release formulations, whereby continuous
release of the active ingredient is ensured and short-term
occurrence of elevated concentrations is prevented.
[0005] In delayed-release formulations, the physiologically active
substance is conventionally either embedded in a matrix controlling
release and/or the dosage form is coated with a film which controls
release.
[0006] However, older patients in particular frequently have
difficulties in taking solid dosage forms, such as tablets,
gelatine capsules, etc. They choke on them and sometimes develop
pronounced aversion to such dosage forms.
[0007] To counter this problem, various apparatuses have been
developed by means of which solid dosage forms may be comminuted or
pulverised ("tablet crushers"). Such apparatuses are used, for
example, by the care staff in old people's homes. The dosage forms
are then administered to the people being cared for not as tablets
etc. but rather as powder, for example to get round the
difficulties involved in swallowing tablets.
[0008] However, the comminution of dosage forms with such
apparatuses is problematic if the dosage forms are delayed-release
formulations. As a rule, comminution then results in destruction of
the inner structure of the dosage form, which is responsible for
the delayed release, so doing away with the delayed-release action.
As a result of comminution, the diffusion paths of the
physiologically active substances contained therein are shortened
and/or the diffusion barriers are removed. For instance, a
delayed-release formulation in which delayed release is achieved by
means of a film coating exhibits the film coating over only a small
percentage of its solid surface after comminution. Consequently,
after administration, frequently all the physiologically active
substance originally contained in the dosage form is released in a
relatively short time, whereby a comparatively very high plasma
concentration of the substance is abruptly reached for a relatively
short period. In this way, the original delayed-release
formulations become "immediate release" formulations.
[0009] Depending on the physiological activity of the substance,
this may cause considerable side-effects however, and in extreme
cases may even lead to the death of the patient. Examples of
substances with such a hazard potential are antiparkinson drugs,
antiepileptics, antidiabetics, antihypertensives, antiarrhythmics,
etc.
[0010] As a rule, the people who comminute the dosage forms for
themselves or for others are not aware of these risks. Cases are
known in which patients have died probably as a result of
pulverisation of delayed-release formulations by nurses or carers.
For further details, reference may be made for example to J. E.
Mitchell, Oral Dosage Forms That Should Not Be Crushed: 2000
Update, Hospital Pharmacy, 2000; H. Miller et al., To Crush or Not
to Crush, Nursing 2000; R. Griffith et al., Tablet Crushing and the
law: the implications for nursing; Prof. Nurse 2003; J. G. 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.
[0011] Delayed-release formulations may also cause problems for
small children. For instance, children frequently cannot
distinguish solid dosage forms from sweets. If children find such
dosage forms, for example because their parents have carelessly
left them lying around in the home, there is a risk that the
children may think that the dosage forms are sweets and put them in
their mouths and chew them. If said dosage forms are
delayed-release formulations, which contain a pharmaceutical
substance in a dosage intended for adults, the child may in such a
case already be at risk of overdose due to the relatively large
amount of pharmaceutical substance contained therein. By chewing
the dosage form and thus cancelling out the delayed-release action,
this risk is increased still further, however, since the
excessively high dose already contained therein is additionally
released over a greatly reduced period of time, a situation which
would be very hazardous even for an adult and which may have all
the more drastic consequences for a child.
[0012] The chewing of delayed-release formulations may also lead to
an overdose of the substance contained therein in adults. Sometimes
adults chew the dosage forms deliberately, though often in
ignorance of the type and purpose of a delayed-release formulation,
because they hope for a quicker effect.
[0013] A known way of reducing the risks involved in comminuting
delayed-release formulations consists in adding to the dosage form
antagonists, i.e. antidotes, or compounds which produce defensive
reactions, wherein the physiological action of these additives are
as far as possible manifested only if the dosage form has been
comminuted prior to administration. This method has the
disadvantage, however, that the physiologically active substance is
nonetheless administered in non-delayed form and that the organism
is additionally exposed to a further physiologically active
substance, for example an antidote, or to a defensive reaction,
such as for example vomiting.
[0014] There is a need for pharmaceutical dosage forms with delayed
release which reduce the risk of overdose, such that e.g. antidotes
etc. may be dispensed with.
[0015] Thus, it is an object of the invention to provide a dosage
form having advantages over the dosage forms of the prior art. The
dosage form should release a physiologically active substance on a
delayed-release basis but should reduce the risk of overdose, in
particular as a consequence of improper handling of the dosage
form, such as chewing, crushing, grinding in a mortar etc.
SUMMARY OF THE INVENTION
[0016] It has surprisingly been found that this object is achieved
by a dosage form comprising
[0017] a physiologically effective amount of a physiologically
active substance (A) (=component (A));
[0018] optionally one or more physiologically acceptable auxiliary
substances (B) (=component (B));
[0019] a synthetic, semi-synthetic or natural polymer (C)
(=component (C)); and
[0020] optionally a physiologically acceptable synthetic,
semi-synthetic or natural wax (=component (D));
[0021] wherein the dosage form exhibits a resistance to crushing of
at least 400 N, and in increasingly preferred embodiments of at
least 420 N, at least 440 N, at least 460 N, at least 480 N or of
at least 500 N, and wherein under physiological conditions the
release of the physiologically active substance (A) from the dosage
form is at least partially delayed.
[0022] The dosage form according to the invention exhibits
mechanical strength over a wide temperature range, in addition to
the resistance to crushing optionally also sufficient hardness and
impact strength for it to be virtually impossible to comminute or
pulverise by chewing, grinding in a mortar, pounding, etc., even by
means of commercially available apparatuses for pulverising
conventional dosage forms. This is not necessarily achieved by the
hardness of the dosage form. For instance, the impact strength of
the dosage form according to the invention and its resistance to
crushing, respectively, may in particular also mean that it may be
deformed as a result of external mechanical action, for example
using a hammer, but does not crumble into a number of fragments.
Comminution is not even successful when the dosage form is
initially chilled to increase its brittleness, for example to
temperatures below -25.degree. C., below -40.degree. C. or indeed
in liquid nitrogen.
[0023] As a consequence of the resistance to crushing, delayed
release is maintained and an overdose due to improper handling of
the dosage form is effectively prevented.
[0024] The advantageous properties of the dosage form according to
the invention, in particular also its mechanical properties, may
not automatically be achieved by simply processing components (A),
(C), optionally (B) and optionally (D) by means of conventional
methods for the preparation of dosage forms. In fact, usually
suitable apparatuses must be selected for the preparation and
critical processing parameters must be adjusted, particularly
pressure/force, temperature and time. Only if in the course of the
preparation of the dosage form the components are exposed to a
sufficient pressure at a sufficient temperature for a sufficient
period of time, dosage forms exhibiting the desired properties may
be obtained. Thus, even if conventional apparatuses are used, the
process protocols usually must be adapted in order to meet the
required criteria.
[0025] Delayed release is understood according to the invention
preferably to mean a release profile in which the physiologically
active substance is released over a relatively long period with
reduced intake frequency with the purpose of extended therapeutic
action. This is achieved in particular with peroral administration.
The expression "with at least partially delayed release" covers
according to the invention any dosage forms which ensure modified
release of the physiologically active substances contained therein.
The dosage forms preferably comprise coated or uncoated dosage
forms, which are produced with specific auxiliary substances, by
particular processes or by a combination of the two possible
options in order purposefully to change the release rate or
location of release.
[0026] In the case of the dosage forms according to the invention,
the release time profile may be modified e.g. as follows: extended
release, repeat action release, prolonged release and sustained
release.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 depicts an ultrasound device used to supply energy
for production of the dosage form.
[0028] FIG. 2 shows a section through a planetary gear
extruder.
[0029] FIG. 3 shows the mode of operation of the planetary gear
extruder.
[0030] FIG. 4 shows a schematic view of the extrudate of the
composition.
[0031] FIGS. 5A and 5B show schematic views of the preferred
arrangements of the tubular domain within the dosage form.
[0032] FIG. 6 shows the measurement of the crush resistance of a
tablet.
[0033] FIG. 7 shows a probe for measurement of the crush
resistance.
DETAILED DESCRIPTION OF THE INVENTION
[0034] For the purpose of the specification "extended release"
means a product in which the release of active substance is delayed
for a finite lag time, after which release is unhindered.
[0035] For the purpose of the specification "repeat action release"
means a product in which a first portion of active substance is
released initially, followed by at least one further portion of
active substance being released subsequently.
[0036] For the purpose of the specification "prolonged release"
means a product in which the rate of release of active substance
from the formulation after administration has been reduced, in
order to maintain therapeutic activity, to reduce toxic effects, or
for some other therapeutic purpose.
[0037] For the purpose of the specification "sustained release"
means a way of formulating a medicine so that it is released into
the body steadily, over a long period of time, thus reducing the
dosing frequency. For further details, reference may be made, for
example, to K. H. Bauer, Lehrbuch der Pharmazeutischen Technologie,
6th edition, WVG Stuttgart, 1999; and European Pharmacopoeia.
[0038] In increasingly preferred embodiments, after 5 hours under
physiological conditions, the dosage form has released not more
than 99%, or not more than 90%, or not more than 75%, or not more
than 50%, or not more than 40% or not more than 30% of substance
(A). It is particularly preferable for the dosage form in this case
to contain neither tramadol hydrochloride, nor oxycodone
hydrochloride, or more desirably, no opioid [N02A] (for the meaning
of "N02A" see below). Release is determined using the standardised
method in the European Pharmacopoeia, preferably under the
conditions stated in Example 1.
[0039] In a preferred embodiment, under physiological conditions
the dosage form according to the invention has released after 30
minutes 0.1 to 75%, after 240 minutes 0.5 to 95%, after 480 minutes
1.0 to 100% and after 720 minutes 2.5 to 100% of substance (A).
[0040] Further embodiments exhibit release profiles 1 to 5 and are
summarised in the table here below [all data in wt.-% of released
component (A)]:
TABLE-US-00001 time [h] No. 1 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
[0041] The release properties of the dosage form according to the
invention are substantially independent from the pH value of the
release medium, i.e. preferably the release profile in artificial
intestinal juice substantially corresponds to the release profile
in artificial gastric juice. At any given time point the release
profiles deviate from one another by not more than 20%, in
increasingly preferred embodiments, the deviation is not more than
15%, or not more than 10%, or not more than 7.5%, or not more than
5.0% or not more than 2.5%.
[0042] Preferably, the dosage form according to the invention
exhibits an uniform release profile. Preferably, the release
profile of the physiologically active substance (A) is
interindividually uniform (i.e. when comparing dosage forms
obtained from the same process) and/or uniform within a single
dosage form (i.e. when comparing segments of the same dosage form).
Desirably, when comparing two probes each having a mass of
preferably 500 mg, the total amount of the released active
substance for any given time point of the measurement does not
deviate by more than 20%, or not more than 15%, or not more than
10%, or not more than 7.5%, or not more than 5.0% or not more than
2.5%.
[0043] The release profile of the dosage form according to the
present invention is stable upon storage, such as upon storage at
elevated temperature, e.g. 37.degree. C., for 3 months in sealed
containers. In this regard "stable" means that when comparing the
initial release profile with the release profile after storage, at
any given time point the release profiles deviate from one another
by not more than 20%, or not more than 15%, or not more than 10%,
or not more than 7.5%, or not more than 5.0% or not more than 2.5%,
with the later being most preferred.
[0044] By using certain polymers in suitable quantities and under
suitable conditions, a resistance to crushing is achieved according
to the invention for the dosage form of at least 400 N, or of at
least 420 N, or of at least 440 N, or of at least 460 N, or of at
least 480 N or of at least 500 N (measured as stated in the
description; the preferred method for measuring the resistance to
crushing according to the invention is a modification of the method
disclosed in the European Pharmacopoeia 5.0, page 235, 2.9.8
"Resistance to Crushing of Tablets"). It is thereby possible
effectively to prevent comminution, for example pulverisation, of
the dosage form using conventional means.
[0045] For the purpose of the specification, "comminution" means
pulverisation of the dosage form by the application of force with
conventional means, such as for example a pestle and mortar, a
hammer, a mallet or other usual means for pulverisation, in
particular devices developed for this purpose (tablet crushers),
wherein the proportion of fines which may arise (particle size
equal to or smaller than 0.3 mm) must not exceed 5 wt. %.
[0046] The dosage form according to the invention is therefore
suitable for preventing overdosing on physiologically active
substances, in particular nutritional supplements and
pharmaceutical substances, which are provided in delayed-release
formulations. It is then possible to dispense with antidotes,
irritants etc. In addition to preventing overdoses and the
accompanying risks for patients, the dosage forms according to the
invention additionally ensure that the other advantages of
delayed-release formulation, such as for example uniform release
over a relatively long period, are retained and cannot easily be
overcome.
[0047] To achieve the necessary resistance to crushing of the
dosage form according to the invention, at least one synthetic,
semi-synthetic or natural polymer (C) is used, which contributes
considerably to the elevated resistance to crushing of the dosage
form. The resistance to crushing of the dosage form amounts to at
least 400 N, to at least 420 N, to at least 440 N, to at least 460
N or to at least 480 N, wherein the resistance to crushing is
determined using the method stated in the description. In a
preferred embodiment, the resistance to crushing of the dosage form
amounts to at least 500 N, to at least 600 N, to at least 700 N, to
at least 800 N, to at least 900 N, to at least 1000 N or even to at
least 1100 N.
[0048] Besides its resistance to crushing, the dosage form
according to the invention is preferably featured by further
mechanical properties, e.g. its hardness, impact resistance, impact
elasticity and/or modulus of elasticity, optionally also at low
temperatures (e.g. below -24.degree. C., below -40.degree. C. or in
liquid nitrogen).
[0049] In increasingly preferred embodiments, the dosage form
according to the invention has a density of at least 0.80 or at
least 0.85 g/cm.sup.3, at least 0.90 or at least 0.95 g/cm.sup.3,
at least 1.00, at least 1.05 or at least 1.10 g/cm.sup.3, in the
range from 0.80 to 1.35 g/cm.sup.3, and in particular in the range
from 0.95 to 1.25 g/cm.sup.3.
[0050] The dosage form according to the invention is characterized
by a comparatively homogeneous distribution of density. Preferably,
the densities of two segments of the dosage form having a volume of
1.0 mm.sup.3 each, deviate from one another by not more than
.+-.10%, or by not more than more than .+-.7.5%, or by not more
than .+-.5.0%, or by not more than .+-.2.5%, and in particular by
not more than .+-.1.0%.
[0051] The dosage form according to the invention is characterized
by a comparatively homogeneous distribution of the physiologically
active substance (A). Preferably, the content of component (A) in
two segments of the dosage form having a volume of 1.0 mm.sup.3
each, deviates from one another by not more than .+-.1.0%, more
preferably not more than more than 17.5%, still more preferably not
more than .+-.5.0%, most preferably not more than .+-.2.5%, and in
particular not more than .+-.1.0%.
[0052] Preferably, the total weight of the dosage form according to
the invention is within the range from 0.01 g to 1.5 g, more
preferably 0.05 g to 1.2 g, still more preferably 0.1 g to 1.0 g,
most preferably 0.2 g to 0.9 g and in particular 0.25 g to 0.8
g.
[0053] The dosage form according to the invention preferably
contains at least one synthetic, semi-synthetic or natural polymer
(C). For the purpose of the specification a "semi-synthetic"
product has been produced by chemical manipulation of naturally
occurring substances.
[0054] Particularly preferred are high molecular weight polymers
with a preferably weight average molecular weight (M.sub.w) or
viscosity average molecular weight (M.sub..quadrature.) of at least
0.510.sup.6 g/mol, of at least 1.010.sup.6 g/mol, of at least
2.510.sup.6 g/mol, of at least 5.010.sup.6 g/mol, of at least
7.510.sup.6 g/mol or of at least 1010.sup.6 g/mol, preferably
1.010.sup.6 g/mol to 1510.sup.6 g/mol. Suitable methods for
determining M.sub.w or M.sub..quadrature. are known to the person
skilled in the art. Preferably, M.sub..quadrature. is determined
using rheological measurements and M.sub.w is determined using gel
permeation chromatography (GPC) on suitable phases.
[0055] The polymers (C) preferably have a viscosity at 25.degree.
C. of 4,500 to 17,600 cP, measured in a 5 wt. % aqueous solution
using a model RVF Brookfield viscosimeter (spindle no. 2/rotational
speed 2 rpm), of 400 to 4,000 cP, measured on a 2 wt. % aqueous
solution using the stated viscosimeter (spindle no. 1 or
3/rotational speed 10 rpm) or of 1,650 to 10,000 cP, measured on a
1 wt. % aqueous solution using the stated viscosimeter (spindle no.
2/rotational speed 2 rpm).
[0056] Individual or combinations of polymers may be selected from
the group comprising 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.RTM.),
poly(hydroxyvaleric acid); polycaprolactone, polyvinyl alcohol,
polyesteramide, polyethylene succinate, polylactone, polyglycolide,
polyurethane, polyvinylpyrrolidone, polyamide, polylactide,
polyacetal (for example polysaccharides optionally with modified
side chains), polylactide/glycolide, polylactone, polyglycolide,
polyorthoester, polyanhydride, block polymers of polyethylene
glycol and polybutylene terephthalate (Polyactive.RTM.),
polyanhydride (Polifeprosan), copolymers thereof, block-copolymers
thereof, and mixtures of at least two of the stated polymers, or
other polymers with the above characteristics.
[0057] Thermoplastic polyalkylene oxides having a weight average
molecular weight (M.sub.w) or a viscosity average molecular weight
(M.sub..quadrature.) of at least 0.510.sup.6 g/mol are particularly
preferred, e.g. polyethylene oxides, polypropylene oxides or the
(block-)copolymers thereof.
[0058] In a preferred embodiment according to the invention
component (C) comprises
[0059] a polyalkylene oxide having a weight average molecular
weight (M.sub.w) or viscosity average molecular weight
(M.sub..quadrature.) of at least 0.510.sup.6 g/mol
[0060] in combination with at least one further polymer, preferably
also having a weight average molecular weight (M.sub.w) or
viscosity average molecular weight (M.sub..quadrature.) of at least
0.510.sup.6 g/mol, selected from the group consisting of
polyethylene, polypropylene, polyvinyl chloride, polycarbonate,
polystyrene, polyacrylate, poly(hydroxy fatty acids),
polycaprolactone, polyvinyl alcohol, polyesteramide, polyethylene
succinate, polylactone, polyglycolide, polyurethane,
polyvinylpyrrolidone, polyamide, polylactide, polyacetal,
polylactide/glycolide, polylactone, polyglycolide, polyorthoester,
polyanhydride, block polymers of polyethylene glycol and
polybutylene terephthalate, polyanhydride and copolymers
thereof.
[0061] Preferably, the content of said further polymer amounts to
1.0 to 25 wt.-%, more preferably 5.0 to 10 wt.-%, based on the
total weight of polymer (C).
[0062] The polymer (C) is preferably used in the form of powder. It
may be water-soluble.
[0063] In one embodiment, the polymer (C) is used in a quantity of
at least 20 wt. %, preferably at least 30 wt. %, more preferably at
least 40 wt. %, most preferably at least 50 wt. % and in particular
at least 60 wt. %, relative to the total weight of the dosage form.
In a preferred embodiment it is used in a quantity of from about 20
to about 49 wt.-%, relative to the total weight of the dosage
form.
[0064] The dosage form according to the invention is suitable for
the administration of a number of physiologically active substances
(A) in a single dosage form. Preferably, the dosage form contains
only one particular physiologically active substance (A),
preferably a nutritional supplement or a pharmaceutical substance
(=pharmaceutical active ingredient).
[0065] The amount of the physiologically active substance (A),
based on the total amount of the dosage form, is preferably within
the range from 0.01 to 95 wt.-%, more preferably from 0.5 to 80
wt.-%, still more preferably 1.0 to 70 wt.-%, most preferably 5.0
to 60 wt.-% and in particular 10 to 50 wt.-%. In a preferred
embodiment it is more than 20 wt.-%.
[0066] In a preferred embodiment the dosage form according to the
invention does not contain a psychotropically acting substance as
the physiologically active substance (A). The person skilled in the
art knows which substances have a psychotropic action. Substances
which influence psychological processes commonly have a
psychotropic action, i.e. they act specifically on psychological
functions. Substances with a psychotropic action may thus influence
mood, either raising or lowering it. For the purpose of the
description, substances with a psychotropic action include in
particular opioids, stimulants, tranquillisers (e.g. barbiturates
and benzodiazepines) and other narcotics. Substances with a
psychotropic action preferably comprise substances which, in
particular when improperly administered (in particular with the
intention of abuse), cause an accelerated increase in active
ingredient levels relative to proper oral administration, giving
the abuser the desired effect, namely the "kick" or "rush". This
kick is also obtained if the powdered dosage form is administered
nasally, i.e. is sniffed. Substances with a psychotropic action are
preferably substances which (in the appropriate dose and dosage
form and when administered appropriately) influence human mental
activity and/or sensory perception in such a way that they are
fundamentally suited to abuse.
[0067] The following opiates, opioids, tranquillisers or other
narcotics are substances with a psychotropic action, i.e. have a
potential of abuse, and hence are preferably not contained in the
dosage form according to the invention: 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, fencamfamin, fenethylline, fenpipramide,
fenproporex, fentanyl, fludiazepam, flunitrazepam, flurazepam,
halazepam, haloxazolam, heroin, hydrocodone, hydromorphone,
hydroxypethidine, isomethadone, hydroxymethylmorphinan, 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, vinylbital,
N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide,
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,
(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphen-
yl)cyclohexanol,
(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,
(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,
(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,
(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-d-
iol, preferably as racemate,
3-(2-dimethylaminomethyl-1-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-1-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-1-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR--SS)-2-hydroxy-4-methoxy-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR--SS)-2-hydroxy-5-nitro-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR--SS)-2',4'-difluoro-3-hydroxy-biphenyl-4-carboxylic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, and
corresponding stereoisomeric compounds, in each case the
corresponding derivatives thereof, physiologically acceptable
enantiomers, stereoisomers, diastereomers and racemates and the
physiologically acceptable derivatives thereof, e.g. ethers, esters
or amides, and in each case the physiologically acceptable
compounds thereof, in particular the salts thereof and solvates,
e.g. hydrochlorides.
[0068] In particular, the dosage form according to the invention
preferably does not contain a psychotropically acting substance
selected from the group consisting of opioids [A07DA, N01AH, N02A,
R05DA, R05FA,]; barbiturates [N01AF, N01AG, N03AA]; benzodiazepine
derivatives [N03AE]; agents for treating opiate dependency [N07BC];
anxiolytics [N05B]; hypnotics and sedatives [N05C];
psychostimulants, agents for treating
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 abbreviations stated in square brackets here
correspond to the ATC Index, as used by the WHO for classifying
pharmaceutical substances (preferred version: January 2005 or
2006). Further details regarding the ATC Index may, for example, be
found in U. Fricke, J. Gunther, Anatomisch-therapeutisch-chemische
Klassifikation mit Tagesdosen fur den deutschen Arzneimittelmarkt:
Methodik der ATC-Klassifikation und DDD-Festlegung [Anatomical
therapeutic chemical classification with daily doses for the German
pharmaceuticals market: methodology of ATC classification and DDD
assignment]. ATC index with DDDs, Wissenschaftliches Institut der
AOK; and Swiss Pharmaceutical Society, Index Nominum: International
Drug Directory, CRC Press; 18th edition (Jan. 31, 2004).
[0069] In a preferred embodiment the dosage form according to the
invention does not contain a compounds selected from the group
consisting of
[0070] analgesics such as aspirin, acetaminophen, deflunisal and
the like;
[0071] anesthetics such as lidocaine, procaine, benzocaine,
xylocaine and the like;
[0072] antiarthritics and anti-inflammatory agents such as
phenylbutazone, indomethacin, sulindac, dexamethasone, ibuprofen,
allopurinol, oxyphenbutazone probenecid, cortisone, hydrocortisone,
betamethasone, dexamethasone, fluocortolone, prednisolone,
triamcinolone, indomethacin, sulindac and its salts and
corresponding sulfide and the like;
[0073] antiasthma drugs such as theophylline, ephedrine,
beclomethasone dipropionate, epinephrine and the like;
[0074] urinary tract disinfectives such as sulfarmethoxazole,
trimethoprim, nitrofurantoin, norfloxicin, and the like;
[0075] anticoagulants such as heparin, bishydroxy coumarin,
warfarin and the like;
[0076] anticonvulsants such as diphenylhydantoin, diazepam and the
like;
[0077] antidepressants such as amitriptyline, chlordiazepoxide,
perphenazine, protriptyline, imipramine, doxepin and the like;
[0078] agents useful in the treatment of diabetics and regulation
of blood sugar, such as insulin, tolbutamide, tolazamide,
somatotropin, acetohexamide, chlorpropamide and the like;
[0079] antineoplastics such as adriamycin, fluouracil,
methotrexate, asparaginase and the like;
[0080] antipsychotics such as prochlorperazine, lithium carbonate,
lithium citrate, thioridazine, molindone, fluphenazine,
trifluoperazine, perphenazine, amitriptyline, triflupromazine and
the like;
[0081] antihypertensives such as spironolactone, methyldopa,
hydralazine, clonidine, chlorothiazide, deserpidine, timolol,
propanolol, metaprotol, prazosin hydrochloride, reserpine and the
like;
[0082] muscle relaxants such as mephalan, danbrolene,
cyclobenzaprine, methocarbarnol, diazepam, succinoyl chloride and
the like;
[0083] antiprotozoals such as chloramphenicol, chloroquine,
trimethoprim and sulfamethoxazole;
[0084] spermicidals such as nonoxynol;
[0085] antibacterial substances such as beta-lactam antibiotics,
tetracyclines, chloramphenicol, neomycin, cefoxitin, thienamycin,
gramicidin, bacitracin, sulfonamides, aminoglycoside antibiotics,
tobramycin, nitrofurazone, nalidixic acid und analogs and the
antimicrobial combination of fludalanine/pentizidone;
[0086] antihistamines and decongestants such as perilamine,
chlorpheniramine (e.g. chlorpheniramine maleate), tetrahydrozoline
und antazoline;
[0087] antiparasitic compounds such as ivermectin;
[0088] antiviral compounds such as acyclovir and interferon;
[0089] antifungal, amoebicidal, trichomonacidal agents or
antiprotozoals such as polyoxyethylene nonylphenol, alkylaryl
sulfonate, oxyquinoline sulfate, miconazole nitrate, sulfanil
amide, candicidin, sulfisoxazole, nysatidin, clotrimazole,
metronidazol and the like; and
[0090] losoxanthrone, theophylline or
.quadrature.-hydroxyethyl-theophylline (etophylline),
diphenhydramine and its hydrochloride, diltiazem and its
hydrochlorid, and diphenylethyl(adenosine).
[0091] In a preferred embodiment, the dosage form according to the
invention contains no substances which irritate the nasal passages
and/or pharynx, i.e. 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 does not
wish to or cannot continue administration, for example burning, or
physiologically counteracts taking of the corresponding active
ingredient, for example due to increased nasal secretion or
sneezing. Further examples of substances which irritate the nasal
passages and/or pharynx are those which cause burning, itching, an
urge to sneeze, increased formation of secretions or a combination
of at least two of these stimuli. Corresponding substances and the
quantities thereof which are conventionally to be used are known to
the person skilled in the art. Some of the substances which
irritate the nasal passages and/or pharynx are accordingly based on
one or more constituents 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.
[0092] The dosage form according to the invention furthermore
preferably contains no antagonists for the physiologically active
substance (A), preferably no antagonists against psychotropic
substances, in particular no antagonists against opioids.
Antagonists suitable for a given physiologically active substance
(A) are known to the person skilled in the art and may 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 acceptable compounds, in particular in the form of
the salts or solvates thereof. The dosage form according to the
invention preferably contains no antagonists selected from among
the group comprising naloxone, naltrexone, nalmefene, nalide,
nalmexone, nalorphine or naluphine, in each case optionally in the
form of a corresponding physiologically acceptable compound, in
particular in the form of a base, a salt or solvate; and no
neuroleptics, for example a compound selected from among the group
comprising haloperidol, promethacine, fluphenazine, perphenazine,
levomepromazine, thioridazine, perazine, chlorpromazine,
chlorprothixine, zuclopenthixol, flupentixol, prothipendyl,
zotepine, benperidol, pipamperone, melperone and bromperidol.
[0093] The dosage form according to the invention furthermore
preferably contains no emetic. Emetics are known to the person
skilled in the art and may 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 acceptable
compounds, in particular in the form of the salts or solvates
thereof. The dosage form according to the invention preferably
contains no emetic based on one or more constituents of ipecacuanha
(ipecac) root, for example based on the constituent emetine, as
are, for example, described 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. The dosage
form according to the invention preferably also contains no
apomorphine as an emetic.
[0094] Finally, the dosage form according to the invention
preferably also contains no bitter substance. Bitter substances and
the quantities effective for use may be found in US-2003/0064099
A1, the corresponding disclosure of which is incorporated herein
and mare a part hereof. Examples of bitter substances are aromatic
oils, such as peppermint oil, eucalyptus oil, bitter almond oil,
menthol, fruit aroma substances, aroma substances from lemons,
oranges, limes, grapefruit or mixtures thereof, and/or denatonium
benzoate.
[0095] The dosage form according to the invention accordingly
preferably contains neither substances with a psychotropic action,
nor substances which irritate the nasal passages and/or pharynx,
nor antagonists for the physiologically active substance (A), nor
emetics, nor bitter substances.
[0096] In a preferred embodiment, the dosage form according to the
invention contains a nutritional supplement as the physiologically
active substance (A). Nutritional supplements preferably contain
one or more nutrients in a concentrated, measured dose form which
is atypical of foodstuffs. They are intended to supplement daily
food intake in those cases in which intake with the food is
inadequate or supplementation is desired. The nutritional
supplement is preferably selected from the group consisting of
vitamins, minerals, 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.
Active Substance (A)
[0097] In a preferred embodiment, the dosage form according to the
invention contains as the physiologically active substance (A) a
pharmaceutically effective amount of a pharmaceutical substance
(=pharmaceutical active ingredient), which justifies use of the
dosage form as a pharmaceutical preparation and is the cause of the
activity thereof. Pharmaceutical substances which may in principle
be considered in the dosage form according to the invention are any
known pharmaceutical substances, wherein the pharmaceutical
substances may be present in the dosage form according to the
invention as such, in the form the derivatives thereof, in
particular esters or ethers, or in each case in the form of
corresponding physiologically acceptable compounds, in particular
in the form of the corresponding salts or solvates thereof, as
racemates or in a form enriched in one or more stereoisomers
(enantiomers or diastereomers).
[0098] Particularly preferably the dosage form according to the
invention contains a substance (A) or two or more substances (A)
selected from the group consisting of
[0099] 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 tract disorders [A03],
serotonin 5HT.sub.3 antagonists [A04AA], antihistamine preparations
[A04AB], agents for bile and liver therapy [A05], laxatives [A06],
intestinal antiinfectives [A07A], intestinal adsorbents [A07B],
electrolytes with carbohydrates [A07C], intestinal antiinflammatory
agents [A07E], microbial antidiarrhoeals [A07F], digestives
including enzymes [A09], drugs used in diabetes [A10], vitamins
[A11], minerals [A12], anabolic agents for systemic applications
[A14] and appetite stimulants [A15];
[0100] 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
preparations [B03] and other haematological agents [B06];
[0101] 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
vasodilatators [C04], vasoprotectives [C05], antihypotensives
[C06A], .quadrature.-adrenoceptor antagonists [C07], calcium
channel blockers [C08], agents acting on the renin-angiotensin
system [C09] and lipid reducing agents [C10];
[0102] dermatologicals [D]; in particular antifungals for systemic
use [D01B], antipsoriatics for systemic use [D58], antiacne
preparations for systemic use [D10B];
[0103] agents for the treatment and prevention of diseases of the
genitourinary system and sex hormones [G]; in particular
gynaecological antiinfectives and antiseptics [G01], oxytocics
[G02A], sympathomimetic labour repressants [G02CA], prolactin
inhibitors [G02CR], hormonal contraceptives for systemic use [G03]
and urologicals [G04];
[0104] systemic hormone preparations excluding sex hormones and
insulins [H]; in particular pituitary and hypothalamic hormones and
analogue [H01], corticosteroids for systemic use [H02], thyroid
preparations [H03], pancreatic hormones [H04], and agents for
regulating calcium homeostatis [H05];
[0105] 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 immunoglobulins [J06], and vaccines [J07]);
[0106] antineoplastic and immunomodulating agents [L] (in
particular antineoplastistic agents [L01], agents for endocrine
therapy [L02], immunostimulants [L03] and immunosuppressive agents
[L04];
[0107] agents for the treatment and prevention of diseases of the
musculo-skeletal system [M]; in particular antiinflammatory and
antirheumatic agents [M01], peripherally acting muscle relaxants
[M03A], directly acting muscle relaxants [M03C], antigout
preparations [M04] and agents for the treatment of bone diseases
[M05];
[0108] agents for the treatment and prevention of diseases of the
nervous system [N]; in particular salicylic acid the derivatives
thereof [N02BA], pyrazolones [N02BB], anilides [N02BE], ergot
alkaloids [N02CA], corticosteroid derivatives [N02CB], selective
serotonin-5HT.sub.1 agonists [N02CC], hydantoin derivatives
[N03AB], oxazolidine derivatives [N03AC], succinimide derivatives
[N03AD], carboxamide derivatives [N03AF], fatty acid derivatives
[N03AG], antiparkinson drugs [N04]), antipsychotics [N05A],
antidepressants [N06A], antidementia drugs [N06D],
parasympathomimetics [N07A] and antivertigo preparations
[N07C];
[0109] antiparasitic products, insecticides and repellents [P]; in
particular antiprotozoals [P01], anthelmintics [P02] and
ectoparasiticides, including scabicides, insecticides and
repellents [P03];
[0110] agents for the treatment and prevention of diseases of the
respiratory system [R]; in particular nasal preparations [R01],
throat preparations [R02], drugs for obstructive airways diseases
[R03], expectorants, excluding combinations with cough suppressants
[R05C] and antihistamines for systemic use [R06];
[0111] agents for the treatment and prevention of diseases of the
sensory organs [S]; in particular otologicals [S02]; and
[0112] general diet products [V06] and therapeutic
radiopharmaceuticals [V10],
[0113] wherein the abbreviations stated in square brackets here
correspond to the ATC Index, as used by the WHO for classifying
pharmaceutical substances (preferred version: January 2005 or
2006).
[0114] The dosage form according to the invention preferably
contains a substance (A) or two or more 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, acetoacetic acid, acetyldigoxin,
acetylandromedol, acetylcysteine, .quadrature.-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, .quadrature.-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.
[0115] bacampicillin, bacitracin, baclofen, balsalazide,
bambuterol, bamethan, bamipine, barbexaclone, barium sulfate F,
barnidipine, basiliximab, batroxobin, becaplermin, beclomethasone,
bendamustine, befunolol, bemiparin, benactyzine, benazepril,
bencyclane, bendazac, bendroflumethiazide, benproperine,
benserazide, benzaseride, benzathine, benzatropine, benzbromarone,
benzocaine, benzoyl peroxide, benzyclane, benzydamine,
benzylpenicillin, benzylphenyl glycolate, betacarotene,
betahistidine, betahistine, betamethasone, bethanechol, 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,
butexamac, buflomedil, bumetanide, bunazosin, buphenine,
bupivacaine, bupranolol, bupropion, buserelin, buspirone, busulfan,
butalamine, butanilicaine, butenafine, butethamate, butinoline,
butizide, butylscopolaminium,
[0116] 5-chlorcarvacrol, C1 esterase inhibitor, cabergoline,
cadexomer iodine, catedrine, 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, cetpodoxime, cetpodoxime-proxetil, cefprozil,
ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime,
celecoxib, celiprolol, certoparin, cetirizine, cetrimide,
cetrimonium bromide, cetrorelix, cetuximab, cetylpyridinium,
chenodeoxycholic acid, quinidine, quinine, quinine iron citrate F,
quinine tannate F, chlorambucil, chloramphenicol, chlorobutynol,
chlorhexidine, chlormidazole, chlorobutanol, chloroquine,
chloroxylenol, chlorphenamine, chlorphenesin, chlorphenoxamine,
chlorpromazine, chlorprotheaxine, chlorprothixine, 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, coumarin,
cyanamide, cyanocobalamin, cyclizine, cyclobutyrol, cyclopentolate,
cyclophosphamide, cycloserine, cyproheptadine, cyproterone,
cysteine, cytarabine, cytarabine,
[0117] 2,4-dichlorobenzyl alcohol, 2-diethylaminoethanol,
dacarbazine, daclizumab, dactinomycin, dalfopristin, dalteparin,
danaparoid, danazol, dantrolene, dapiprazole, dapsone, darbepoetin
alfa, darifenacin, Daunorubicin, deanol, deanolace, decarbazine,
dectaflur F, deferiprone, deferoxamine, delapril, demeclocycline,
denaverine, depreotide, dequalinium, desftlurane, desipramine,
desirudin, dealanoside, desloratadine, desmeninol, desmopressin,
desogestrel, desoximetasone, deoxyribonuclease, detajmium,
dexamethasone, dexchlorpheniramine, dexibuprofen, dexketoprofen,
dexrazoxane, dextran, dextromethorphan, diacerein, diacetyl
morphine, dibenzepin, dibotermin alfa, diclotenac, diclofenamide,
didanosine, dienestrol, dienogest, diethylstilbestrol, difloxacin,
diflucortolone, diflunisal, digitoxin, digoxin, dihydralazine,
dihydroergocornine, dihydroergocristine, dihydroergocryptine,
dihydroergotamine, dihydroergotoxine, dihydrotachysterol,
diisopropylamine, dipotassium clorazepate, diltiazem,
dimenhydrinate, dimepranol, dimercaprol, dimethyl sulfoxide,
dimethindene, disodium selenite, dinoprost, dinoprostone, 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,
[0118] 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, etomsidate, etonogestrel, etoposide,
etoricoxib, everolimus, exametazime, exemestane, ezetimibe,
[0119] 3-fluorotyrosine, famciclovir, famotidine, felbamate,
felbinac, felodipine, fenbufene, fendiline, fenofibrate, fenoterol,
fenticonazole, fexofenadine, fibrinogen, fibrinolysin, filgrastim,
finasteride, flavoxate, flecainide, flucloxacillin, fluconazole,
fludarabine, fludeoxyglucose [.sup.18F], fludrocortisone,
flufenamic acid, flumazenil, flumetasone, flunarizine, flunisolide,
fluocinolone acetonide, fluocinonide, fluocortolone, fluophenozine,
fluorescein dilaurate, fluorescein sodium, fluorometholone,
fluorouracil, fluorophosphoric acid, fluorosilane, fluoxetil,
fluoxetine, flupentixol, fluphenazine, flupirtine, fluprednidene,
flurbiprofen, flutamide, fluticasone, flutrimazole, fluvastatin,
fluvoxamine, folic 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,
[0120] gabapentin, gadobenic acid, gadobutrol, gadodiamide,
gadopentetic acid, gadoteridol, gadoteric acid, gadoteric
acid-meglumine, gadoxetic acid, galantamine, gallopamil,
ganciclovir, ganirelix, gatifloxacin, gemcitabine, gemfibrozil,
gentamicin, gepefrine, gostodene, 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,
[0121] .sup.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,
[0122] ibandronic acid, ibopamine, ibritumomab tiuxetan, ibuprofen,
ibutilide, idarubicin, ifosfamide, iloprost, imatinib, imatinib
mesylate, imidapril, imiglucerase, imipenem, imipramine, imiquimod,
immunocyanin, indanazoline, indapamide, indinavir, indium chloride
[.sup.111In], 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-1a, interferon beta-1b, interferon gamma,
iobitridol, iodine, iodamide, iodixanol, ioflupane [.sup.123l],
iohexol, iomeprol, iopemidol, 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,
[0123] josamycin,
[0124] potassium permanganate, kallidinogenase, kanamycin, kawain,
kebuzone, ketamine, ketoconazole, ketoproten, ketorolac, ketotifen,
collagenase, creosote,
[0125] labetalol, lacidipine, lactitol, lamivudine, lamotrigine,
lanreotide, lansoprazole, laronidase, latanoprost, leflunomide,
lenograstim, lepirudin, lercanidipine, letrozole, leucine,
leuprorelin, levallorphan, levamisole, levetiracetam, levobunolol,
levobupivacaine, levocabastine, levccetirizine, levodopa,
levofloxacin, levofolinate calcium, levomepromazine, levomethadyl,
levonorgestrel, levopropyihexedrine, 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,
[0126] magaldrate F, magnesium pidolate, magnesium L-aspartate,
mnangafodipir, manidipine, maprotiline, mebendazole, mebevetine,
meclofenoxate, mecloxamuine, meclozine, medrogestone,
medroxyprogesterone, mefenamic acid, mefloquine, megestrol,
melagatrane, melitracen, melperol, melperone, 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, 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, mioroctocog alfa,
moxaverine, moxifloracin, moxonidine, muupirocin, mycophenolate
mofetil,
[0127] nadifloxacin, nadrolon decanonate, nadroparin calcium,
naftidrofuryl, naftifine, nalbuphine, nalide, nalmefene, nalmexone,
naloxone, naltrexone, naluphine, naphazoline, 2-naphthol, naproxen,
naratriptan, naratriptan, nateglinide, sodium aurothiomalate,
sodium phenylbutyrate, sodium fluoride, sodium hyaluronate, sodium
iodide [.sup.131I], sodium molybdate [.sup.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, nicotine resinate, nicotinic acid,
nicotinic acid ester, nicotinyl alcohol, nifedipine, niflumic acid,
nifuratel, nilvadipine, nimesulide, nimodipine, nimorazole,
nimustine, nisoldipine, nitisinone, nicrendipine, nitric oxide,
nitrofurantoin, nitroglycerine, nizatidine, N-methylephedrine,
nonacog alfa, nonivamide, noradrenalin, norelgestromin,
norepinephrine, norethisterone, norfenefrine, norfloxacin,
norgestimate, norgestrel, nortriptyline, noscapine, nystatin,
[0128] obidoxime chloride, octafluoropropone, octocog alfa,
octodrine, octreotide, odansetron, ofloxacin, olaflur F,
olanzapine, olmesartan medoxomil, olopatadine, olsalazine,
omeprazole, oxoconazole, ondansetron, opiprainol, oral cholera
vaccine, orciprenaline, orlistat, ornipressin, orphenadrine,
oseltamivir, osteogenic protein-1: BMP-7, oxaprozin, oxatomnide,
oxcarbazepine, oxedrine tartrate, oxetacaine, oxiconazole,
oxilofrine, oxitropium, 2-oxo-3-mothylbutyric acid,
2-oxo-3-methylvaleric acid, 2-oxo-3-phenylpropionic acid,
2-oxo-4-methylvaleric acid, oxprenolol, oxybuprocaine,
oxybuprocaine, oxybutynin, oxybutynin, oxyfedrine, oxymetozoline,
oxytetracycline, oxytocin,
[0129] paclitaxel, palinavir, palivizumab, palonosetrone,
pamidronic acid, pancuronium, pantoprazole, papaverine,
paracetamol, paraldehyde, parecoxib, paricalcitol, parnaparin,
paromomycin, paroxetine, pefloxacin, pegfilgrastim, peginterferon
alfa, pegvisomant, pemetrexed, penbutolol, penciclovir,
penfluridol, penicillamine, benperidol, pentaerithrityl
tetranitrate, penitamidine, 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, phthalylsulfathiazole, physostigmine, phytomenadione,
phytosterol, picric acid, pilocarpine, pimecrolimus, pimozide,
pinaverium bromide, pindolol, pioglitazone, pipamperone,
pipazetate, pipecuronium bromide, pipemidic acid, pipenzolate,
piperacillin, piprinhydrinate, piracetam, pirarubicin, pirbuterol,
pirenizepine, 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,
pridinol, prilocaine, primaquine, primidone, prithipendyl,
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, prothrombin, protionamide, protirelin,
proxymetacaine, proxyphylline, pseudoephedrine, Pulmonal, pyrantel,
pyrazinamide, pyridostigmine, pyridostigmine bromide, pyridoxine,
3-pyridylmethanol, pyrimethamine, pyrithione zinc, pyritinol,
pyrogallol, pyrvinium, pyrvinium embonate,
[0130] mercury amide chloride, quetiapine, quinagolide, quinapril,
quinupristin,
[0131] rabeprazole, racephedrine, racecadotrile, raloxifene,
raltitrexed, ramipril, ranitidine, rasagiline, rasburicase,
raubasine, reboxetine, repaglinide, reproterol, reserpine,
resorcinol, reteplase, retinol, reviparin, ribavirin, riboflavin,
rifabutin, rifampicin, rifamycin, rifaximin, rilmenidine, riluzole,
rimexolone, risedronic acid, risperidone, ritonavir, rituximab,
rivastigmine, rizatriptan, rocuronium bromide, rotecoxib,
ropinirole, ropivacaine, ropivacaine, rosiglitazone, red mercuric
sulfide F, roxatidine, roxithromycin,
[0132] salbutamol, salicylic acid, salmeterol, nitric acid, nitrous
acid, salverine, samarium [.sup.153Sm] lexidronam, saquinavir,
sulfur hexafluoride, scopolamine, selegiline, selenium sulfide,
serine, sermorelin, sertaconazole, sertindole, sertraline,
sevelamer, sevoflurane, sibutramine, silver chloride F, sildenafil,
silibinin, simvastatin, sirolimus, formaldehyde solution,
solifenacine, 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,
sulfaguanidine, sulfamerazine, sulfametboxazole,
sulfamethoxydiazine, sulfametrole, sulfanilamide, sulfasalazine,
sulfathiazole, sulfisomidine, sulindac, sulodexide, sulfur
hexafluoride, sulpiride, sulprostone, sultamicillin, sultiame,
sumatriptan, suxamethonium,
[0133] tacalcitol, tacrolimus, tadalafil, tamoxifen, tamsulosin,
tasonermin, taurolidine, tazarotene, tazobactam, tegafur,
teicoplanin, telithromycin, telmisartan, temoportin, temozolomide,
tenecteplase, teniposide, tenofovir, tenofovir disoproxil,
tenoxicam, terazosin, terbinafine, terbutaline, terfenadine,
teriparatide, terizidone, terlipressin, testosterone, testosterone
propionate, testosterone undecanoate, tetracaine, tetracosactide,
tetracycline, tetrafluoroborate-1+, tetrofosmin, tetryzoline,
thallium chloride [.sup.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, tolfenamic 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, trimethopriam, trimipramine, tripelennamine,
triprolidine, triptorelin, tritoqualine, trofosfamide,
tromantadine, trometamol, tropicamide, tropisetron, trospium,
tryptophan, tubocurarine chloride, tulobuterol, tyloxapol,
tyrosine, tyrothricin, unoprostone, urapid, urapidil, urokinase,
ursodeoxycholic acid,
[0134] valaciclovir, valdecoxib, valganciclovir, valine, valproic
acid, valsartan, vancomycin, vardenafil, vecuronium, vecuronium
bromide, venlafaxine, verapamil, verteporfin, vigabatrin,
viloxazine, vinblastine, vincamine, vincristine, vindesine,
vinorelbine, vinpocetine, viquidil, voriconazole, votumumab,
[0135] hydrogen peroxide,
[0136] xantinol nicotinate, ximelagatrane, xipamide,
xylometazoline,
[0137] yohimbine, yttrium .sup.90Y chloride,
[0138] zalcitabine, zaleplon, zanamivir, zidovudine, zinc acetate
dihydrate, zinc chloride, zinc citrate, zinc sulfate, ziprasidone,
zofenopril, zoledronic acid, zolmitriptan, zolpidem, zolpidem
tartrate, zonisamide, zopiclone, zotepine, zucklopantexol, and
zuclopenthixol.
[0139] The above-stated compounds are predominantly stated by their
international nonproprietary name (INN) and are known to the person
skilled in the art. Further details may be found, for example, by
referring to International Nonproprietary Names (INN) for
Pharmaceutical Substances, World Health Organization (WHO).
[0140] In a preferred embodiment the dosage form according to the
invention contains one physiologically active substance (A) or more
physiologically active substances (A) selected from the group
consisting of
1,1-(3-dimethylamino-3-phenylpentamethylen)-6-fluor-1,3,4,9-tetrahydro-
pyrano[3,4-b]indole, in particular its hemicitrate;
1,1-(3-dimethylamino-3-(2-thienyl)pentamethylen)-1,3,4,9-tetrahydropyrano-
[3,4-b]indole, in particular its citrate; and
1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1,3,4,9-tetrahydropyrano-
[3,4-b]-6-fluoro-indole, in particular its hemicitrate. These
compounds are known, for example, from WO 2004/043967 or WO
2005/066183. The corresponding descriptions are hereby introduced
as a reference and are deemed to be part of the disclosure.
Wax
[0141] At least one natural, semi-synthetic or synthetic wax (D)
(=component (D)) may be used in order to achieve the necessary
breaking strength of the dosage form according to the invention.
Preferred waxes are those with a softening point of at least
50.degree. C., or of at least 55.degree. C., or of at least
60.degree. C., or of at least 65.degree. C., or of at least
70.degree. C. Carnauba wax and beeswax are particularly preferred.
Carnauba wax is very particularly preferred. Carnauba wax is a
natural wax which is obtained from the leaves of the carnauba palm
and has a softening point of at least 80.degree. C. When the wax
component is additionally used, it is used together with at least
one polymer (C) in quantities such that the dosage form has a
breaking strength of at least 400 N, preferably of at least 500
N.
Auxiliary Substances (B)
[0142] Auxiliary substances (B) which may be used are those known
auxiliary substances which are conventional for the formulation of
solid dosage forms. These are preferably plasticisers, such as
triacetin and polyethylene glycol, preferably a low molecular
weight polyethylene glycol, auxiliary substances which influence
active ingredient release, preferably hydrophobic or hydrophilic,
preferably hydrophilic polymers, very particularly preferably
hydroxypropylmethylcellulose, and/or antioxidants. 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 very particularly preferably used as matrix
materials.
[0143] 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
.alpha.-tocopherol.
[0144] The antioxidant is preferably used in quantities of 0.01 to
10 wt. %, preferably of 0.03 to 5 wt. %, relative to the total
weight of the dosage form.
Dosage Forms
[0145] The dosage forms according to the invention are
distinguished in that, by virtue of their resistance to crushing,
they cannot be pulverised with the assistance of conventional
comminution tools, such as a pestle and mortar. Overdosing is
consequently virtually ruled out. However, in order to increase the
resistance to crushing of the dosage form still further, the dosage
forms according to the invention may contain further
resistance-to-crushing-enhancing agents as auxiliary substances
(B).
[0146] The dosage form according to the invention is preferably
solid and suitable for taking orally, vaginally or rectally,
preferably orally. The dosage form is preferably not in film form.
In a further preferred embodiment, the dosage form according to the
invention assumes the form of a tablet, a capsule or the form of an
oral osmotic therapeutic system (OROS).
[0147] In a preferred embodiment, the dosage form according to the
invention assumes the form of a tablet.
[0148] The dosage form according to the invention may assume
multiparticulate form, preferably the form of microtablets,
microcapsules, micropellets, granules, spheroids, beads or pellets,
optionally packaged in capsules or press-formed into tablets,
preferably for oral administration. The individual particles
themselves exhibit a resistance to crushing of at least 400 N,
optionally also a tablet obtained therefrom.
[0149] The multiparticulate forms preferably have a size or size
distribution in the range from 0.1 to 3 mm, particularly preferably
in the range from 0.5 to 2 mm. Depending on the desired dosage
form, conventional auxiliary substances (B) are optionally also
used for the formulation of the dosage form.
Process of Preparation
[0150] The dosage form according to the invention may be produced
by different processes, which are explained in greater detail
below; the present invention also relates to dosage forms that are
obtainable by any of the processes described here below:
[0151] In general, the process for the production of the dosage
form according to the invention preferably comprises the following
steps:
[0152] mixing of component (A), (C), optionally (B) and optionally
(D);
[0153] optionally preforming the mixture obtained from step (a),
preferably by applying heat and/or force to the mixture obtained
from step (a), the quantity of heat supplied preferably not being
sufficient to heat component (C) up to its softening point;
[0154] hardening the mixture by applying heat and force, it being
possible to supply the heat during and/or before the application of
force and the quantity of heat supplied being sufficient to heat
component (C) at least up to its softening point; [0155] (d)
optionally singulating the hardened mixture; [0156] (e) optionally
shaping the dosage form; and [0157] (f) optionally providing a film
coating.
[0158] Heat may be supplied directly or with the assistance of
ultrasound. Force may be applied and/or the dosage form may be
shaped for example by direct tabletting or with the assistance of a
suitable extruder, particularly by means of a screw extruder
equipped with two screws (twin-screw-extruder) or by means of a
planetary gear extruder.
[0159] In general, when the dosage formed is prepared utilizing an
extruder, the following parameters are critical in extrusion
processes and have the consequences described.
1. Throughput (kg Per Hour)
[0160] If the throughput is too low the extruder is not correctly
filled and the material is stressed thereby affecting the viscosity
and the release profile of the final product If the throughput is
too high, the load of the extruder is higher than 100% and the
extruder shuts down automatically; and if the throughput is
tolerable but close to the upper limit significant expansion of the
extruded strand occurs (also known as "die swelling").
2. Screw Geometry
[0161] A minimum number of kneading elements is required in order
to obtain a homogeneous mixture; if the number is too high, the
material is stressed thereby affecting the viscosity and the
release profile of the final product. The number and lead of the
conveying elements influences the homogeneity of the mixture and
its residence time in the extruder and controls the increase of the
pressure in front of the die. Mixing elements improve the
homogeneity of the mixture; and eccentric screw heads allow for a
continuous discharge of the extrudate without density
variations.
3. Die and Merge Element Geometry
[0162] The geometry of the element which merges the extrusion
strands in front of the die, and geometry of the die itself, the
residence time in said element, and the ratio length of the die to
diameter of the die influence the compression of the material
thereby affecting the melt pressure. The die pressure depends on
revolution, throughput and melt temperature and affects the
viscosity and the release profile of the final product.
4. Temperature (Melt Zones)
[0163] The feeding cylinder should not be heated to prevent the
starting material from melting in the feeder and causing an
accumulation. The number of cylinders is variable, the longer the
extruder the longer the residence time. The temperature of the
cylinders (except feeding cylinder) destroys the material if it is
too high; if too low the material dos not sufficiently melt thereby
resulting in an inhomogeneous mixture and degradation. If the die
temperature, if separately set too low, causes the "extrusion skin"
to not properly form thereby making further processing of the
extrudate difficult.
5. Revolution of the Extruder
[0164] If the extruder revolution speed is too high the material is
stressed thereby affecting the viscosity and the release profile of
the final product. If the extruder revolution speed is too low the
load of the extruder is higher than 100% and the extruder shuts
down automatically; and inter alia the residence time depends on
the revolution.
6. Arrangement of Cylinders
[0165] The position of feeding cylinder, the length of extruder are
important. The degassing should be located close to the feeder in
order to avoid air pockets in the product; and if one of the
components is thermo-labile it may be separately fed into one of
the rear cylinders.
7. Temperature of Cooling Water
[0166] Cooling of the engine and control of the temperature of the
extrusion cylinders are important parameters.
[0167] The following process variants are preferred embodiments of
the various techniques which may be utilized to produce the dosage
forms:
Process Embodiment 1
[0168] In this embodiment, the dosage form according to the
invention is preferably produced without using an extruder by
preferably mixing components (A), (C), optionally (B) and the
optionally present component (D) and, optionally after granulation,
shaping the resultant mixture by application of force to yield the
dosage form with preceding and/or simultaneous exposure to
heat.
[0169] This heating and application of force for the production of
the dosage form proceeds without using an extruder.
[0170] Components (A), (C), optionally (B) and optionally (D) are
mixed in a mixer known to the person skilled in the art. The mixer
may, for example, be a roll mixer, shaking mixer, shear mixer or
compulsory mixer.
[0171] The resultant mixture is preferably directly shaped into the
dosage form according to the invention by application of force with
preceding and/or simultaneous exposure to heat. The mixture may,
for example, be formed into tablets by direct tabletting. In direct
tabletting with preceding exposure to heat, the material to be
pressed is heated immediately prior to tabletting at least to the
softening temperature of component (C) and then pressed. In the
case of direct tabletting with simultaneous application of heat,
the mixture to be press-formed is heated at least to the softening
point of polymeric component (C) with the assistance of the
tabletting tool, i.e. the bottom punch, top punch and the die, and
is so press-formed.
[0172] By such process using a tabletting tool with bottom punch,
top punch and die for tablets having a diameter of 10 mm and a
radius of curvature of 8 mm, e.g. 300 mg of a powder mixture may be
compressed at a temperature of e.g. 80.degree. C., the pressure
caused by a force of e.g. 2 kN or 4 kN being maintained for e.g. 15
seconds.
[0173] The resultant mixture of components (A), (C), optionally (B)
and optionally component (D) may also first be granulated and then,
with preceding and/or simultaneous exposure to heat, be shaped into
the dosage form according to the invention by application of
force.
[0174] When force is applied, it is applied until the dosage form
has achieved a resistance to crushing of at least 400 N, 420 N, 440
N, 460 N, 480 N, or preferably of at least 500 N.
[0175] Granulation may be performed in known granulators by wet
granulation or melt granulation.
[0176] Each of the above-mentioned process steps, in particular the
heating steps and simultaneous or subsequent application of force
for production of the dosage form according to the invention
proceeds without using an extruder.
Process Embodiment 2
[0177] In this process variant, the dosage form according to the
invention is produced by thermoforming with the assistance of an
extruder, without there being any observable consequent
discoloration of the extrudate.
[0178] In order to investigate the extent of discoloration due to
this thermoforming, the color of the mixture of starting components
of which the dosage form consists is first determined without
addition of a color-imparting component, such as for example a
coloring pigment or an intrinsically coloured component (for
example .alpha.-tocopherol). This composition is then thermoformed
according to the invention, wherein all process steps, including
cooling of the extrudate, are performed under an inert gas
atmosphere. By way of comparison, the same composition is produced
by the same process, but without an inert gas atmosphere. The color
of the dosage form produced according to the invention from the
starting composition and of the dosage form produced by way of
comparison is determined. The determination is performed with the
assistance of "Munsell Book of Color" from Munsell Color Company
Baltimore, Md., USA, 1966 edition. If the colour of the dosage form
thermoformed according to the invention has a color with
identification no. N 9.5, but at most a color with the
identification no. 5Y 9/1, thermoforming is classed as being
"without discoloration". If the dosage form has a color with the
identification no. 5Y 9/2 or greater, as determined according to
the Munsell Book of Color, the thermoforming is classed as being
"with discoloration".
[0179] Surprisingly, the dosage forms according to the invention
exhibit no discoloration classed in accordance with the above
classification, if the entire production process is performed under
an inert gas atmosphere, preferably under a nitrogen atmosphere
with the assistance of an extruder for thermoforming.
[0180] This variant according to the invention for the production
of dosage forms according to the invention is characterised in
that
[0181] z) components (A), (C), optionally (B) and the optionally
present component (D) are mixed,
[0182] y) the resultant mixture is heated in the extruder at least
up to the softening point of component (C) and extruded through the
outlet orifice of the extruder by application of force,
[0183] x) the still plastic extrudate is singulated and formed into
the dosage form or
[0184] w) the cooled and optionally reheated singulated extrudate
is formed into the dosage form,
[0185] wherein process steps y) and x) and optionally process steps
z) and w) are performed under an inert gas atmosphere, preferably a
nitrogen atmosphere.
[0186] Mixing of the components according to process step z) may
also proceed in the extruder.
[0187] Components (A), (C), optionally (B) and optionally (D) may
also be mixed in a mixer known to the person skilled in the art.
The mixer may, for example, be a roll mixer, shaking mixer, shear
mixer or compulsory mixer.
[0188] Before blending with the remaining components, component (C)
and the optionally present component (D) is preferably provided
according to the invention with an antioxidant. This may proceed by
mixing the two components, (C) and 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.
[0189] The, preferably molten, mixture which has been heated in the
extruder at least up to the softening point of component (C) is
extruded from the extruder through a die with at least one
bore.
[0190] The process according to the invention requires the use of
suitable extruders, preferably screw extruders. Screw extruders
which are equipped with two screws (twin-screw-extruders) are
particularly preferred.
[0191] The extrusion is preferably performed so that the expansion
of the strand due to extrusion is not more than 50%, i.e. that when
using a die with a bore having a diameter of e.g. 6 m, the extruded
strand should have a diameter of not more than 9 m. More
preferably, the expansion of the strand is not more than 40%, still
more preferably not more than 35%, most preferably not more than
30% and in particular not more than 25%. It has been surprisingly
found that if the extruded material in the extruder is exposed to a
mechanical stress exceeding a certain limit, a significant
expansion of the strand occurs thereby resulting in undesirable
irregularities of the properties of the extruded strand,
particularly its mechanical properties.
[0192] The extruder preferably comprises at least two temperature
zones, with heating of the mixture at least up to the softening
point of component (C) proceeding in the first zone, which is
downstream from a feed zone and optionally mixing zone. The
throughput of the mixture is preferably from 2.0 kg to 8.0
kg/hour.
[0193] After heating at least up to the softening point of
component (C), the molten mixture is conveyed with the assistance
of the screws, further homogenised, compressed or compacted such
that, immediately before emerging from the extruder die, it
exhibits a minimum pressure of 5 bar, preferably of at least 10
bar, and is extruded through the die as an extruded strand or
strands, depending on the number of bores which the die comprises.
The die geometry or the geometry of the bores is freely selectable.
The die or the bores may accordingly 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. Preferably, the die or the bores have
a round cross-section. The casing of the extruder used according to
the invention may be heated or cooled. The corresponding
temperature control, i.e. heating or cooling, is so arranged that
the mixture to be extruded exhibits at least an average temperature
(product temperature) corresponding to the softening temperature 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.degree. C., preferably below 150.degree.
C., but at least to the softening temperature of component (C).
[0194] After extrusion of the molten mixture and optional cooling
of the extruded strand or extruded strands, the extrudates are
preferably singulated. This singulation may 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.
[0195] An inert gas atmosphere is not necessary for intermediate or
final storage of the optionally singulated extrudate or the final
shape of the dosage form according to the invention.
[0196] The singulated extrudate may be pelletised with conventional
methods or be press-formed into tablets in order to impart the
final shape to the dosage form. It is, however, also possible not
to singulate the extruded strands and, with the assistance 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.
[0197] Should the optionally singulated extrudate not immediately
be formed 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
definitive shaping to yield the dosage form.
[0198] 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 extruding the plasticised mixture is built
up in the extruder, preferably immediately prior to extrusion. The
extrusion parameters which, for each particular composition, are
necessary to give rise to a dosage form with a resistance to
crushing of at least 400 N, preferably of at least 500 N, may be
established by simple preliminary testing.
[0199] For example, extrusion may be performed by means of a
twin-screw-extruder type Micro 27 GL 40 D (Leistritz, Nurnberg,
Germany), screw diameter 18 m. Screws having eccentric ends may be
used. A heatable die with a round bore having a diameter of 8 mm
may be used. The entire extrusion process should be performed under
nitrogen atmosphere. The extrusion parameters may be adjusted e.g.
to the following values: rotational speed of the screws: 100 Upm;
delivery rate: 4 kg/h; product temperature: 125.degree. C.; and
jacket temperature: 120.degree. C.
Process Embodiment 3
[0200] In this process variant for the production of the dosage
form according to the invention energy is applied to a mixture of
the components by means of ultrasonication.
[0201] First of all a homogeneous mixture of at least component (A)
and component (C) (a binder) is produced. Further auxiliary
substances, such as for example fillers, plasticisers, slip agents
or dyes, may also be incorporated into this mixture. A low
molecular weight polyethylene glycol is preferably used as
plasticiser.
[0202] Mixing may be performed with the assistance 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.
[0203] Selection of the suitable mixer is determined inter alia by
the flowability and cohesiveness of the material to be mixed.
[0204] The mixture is then subjected to shaping. The mixture is
preferably shaped during or after ultrasonication, preferably by
compaction.
[0205] It is particularly preferred during ultrasonication that
there is direct contact between the mixture and the sonotrode of
the ultrasound device. An ultrasound device as shown in FIG. 1 is
preferably used in the process according to the invention.
[0206] In this FIG. 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 bottom punch, (7) the
base plate, (8) and (9) the ultrasound generator and device
controller. The reference numerals used relate solely to FIG.
1.
[0207] A frequency of 1 kHz to 2 MHz, preferably of 15 to 40 kHz,
should be maintained during ultrasonication. 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.
[0208] Ultrasonication and the application of force ensure uniform
energy transfer, so bringing about rapid and homogeneous sintering
of the mixture. In this manner, dosage forms are obtained which
have a resistance to crushing of at least 400 N, preferably of at
least 500 N, and thus cannot be pulverised.
[0209] Before shaping is performed, the mixture may be granulated
after the mixing operation, after which the resultant granules are
shaped into the dosage form with ultrasonication and application of
force.
[0210] Granulation may be performed in machinery and apparatus
known to the person skilled in the art.
[0211] 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.
[0212] 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 exposure to
force and then extruded through a dies. The strands or strand
obtained in this manner may be singulated to the desired length
using known apparatus. The formed articles singulated in this
manner may optionally furthermore be converted into the final shape
with ultrasonication and application of force.
[0213] Final shaping to yield the dosage form preferably proceeds
with application of force in appropriate moulds.
[0214] The above-described formed articles may also be produced
with a calendering process by initially plasticising the mixture or
the granules produced therefrom by means of ultrasonication and
application of force and performing extrusion through an
appropriate die. These extrudates are then shaped into the final
shape between two contrarotating shaping rolls, preferably with
application of force.
[0215] As already mentioned, shaping to yield the final shape of
the dosage form by using a mixture comprising substance (A) and the
polymer (C) with a resistance to crushing of at least 400 N,
preferably of at least 500 N, proceeds preferably in powder form by
direct compression with application of force, wherein
ultrasonication of this mixture is provided before or during the
application of force. The force is at most the force which is
conventionally used for shaping dosage forms, such as tablets, or
for press-forming granules into the corresponding final shape.
[0216] The tablets produced according to the invention may also be
multilayer tablets.
[0217] In multilayer tablets, at least the layer which contains
substance (A) should be ultrasonicated and exposed to force.
[0218] The corresponding necessary application of force may also be
applied to the mixture with the assistance of extruder rolls or
calender rolls. Shaping of the dosage forms preferably proceeds by
direct press-forming of a pulverulent mixture of the components of
the dosage form or corresponding granules formed therefrom, wherein
ultrasonication preferably proceeds during or before shaping. Such
exposure continues until the polymer (C) has softened, which is
conventionally achieved in less than 1 second to at most 5
seconds.
[0219] A suitable press is e.g. a Branson WPS, 94-003-A,
pneumatical (Branson Ultraschall, Dietzenbach, Germany) having a
plain press surface. A suitable generator (2000 W) is e.g. a
Branson PG-220A, 94-001-A analogue (Branson Ultraschall) with a
sonotrode having a diameter of 12 m. A die having a diameter of 12
mm may be used, the bottom of the die being formed by a bottom
punch having a plain press-surface and a diameter of 12 mm.
Suitable parameters for plastification are frequency: 20 kHz;
amplitude: 50%; force: 250 N. The effect of ultrasound and force by
means of the sonotrode may be maintained for e.g. 0.5 seconds, and
preferably both effects take place simultaneously.
Process Embodiment 4
[0220] In this process variant for the production of the dosage
form according to the invention, components (A), (C), optionally
present auxiliary substances (B), such as antioxidants,
plasticisers and/or delayed-release auxiliary substances, and
optionally component (D), are processed with the assistance of a
planetary-gear extruder to yield the dosage form according to the
invention.
[0221] Planetary-gear extruders are known and described inter alia
in detail in 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.
[0222] Below, the use of a planetary-gear extruder in the process
according to the invention is explained with reference to FIGS. 2
and 3. These explanations are given merely by way of example and do
not restrict the general concept of the invention.
[0223] FIG. 2 shows a section through a planetary-gear extruder
and
[0224] FIG. 3 shows the mode of operation of the planetary-gear
extruder.
[0225] FIG. 2 shows a planetary-gear extruder which may be used in
the process according to the invention. This extruder substantially
comprises a shaft 1, which, relative to the transport direction 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.
[0226] In the planetary-gear extruder, extrusion of the composition
used in the process according to the invention for the production
of a pharmaceutical dosage form preferably proceeds as follows,
with reference to FIG. 2. As shown by 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 dosage
form 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 at least to the
softening point of component (C), the mixture is melted and the
molten mixture is conveyed into the area of the central spindle,
i.e. 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 temperature 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.degree. C., preferably below 150.degree.
C., but at least to the softening temperature of component (C). The
reference numerals used relate solely to FIGS. 2 and 3.
[0227] After extrusion of the molten mixture and optional cooling
of the extruded strand or extruded strands, the extrudates are
singulated (not shown in FIG. 2). This singulation may 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.
[0228] 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 dosage form,
wherein they may be exposed to heat again if necessary.
[0229] 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, the
construction of which recesses determines the tablet shape.
[0230] 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 may preferably be used. Apart from being press-formed into
tablets, these granules or other multiparticulate shapes obtained,
such as pellets or spheroids, may also be packaged into capsules in
order to be used as a dosage form produced according to the
invention.
[0231] In a further preferred embodiment, the extruded strands
extruded through a plurality of bores in the extrusion die may,
after cooling thereof, optionally be brought together by
interlacing or wrapping in the manner of rope production to yield a
thicker strand than the individual extruded strands. This strand
may optionally be further processed by solvent attack 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.
[0232] FIG. 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,
whose flanks 41 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. Through rotation of the
central spindle 3 and rolling of the respective flanks over one
another, the planetary spindles 4 each 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 dosage forms produced according
to the invention is achieved. The reference numerals used relate
solely to FIGS. 2 and 3.
[0233] If necessary, the planetary-gear extruder used may comprise
not only an extrusion zone but also at least one further zone, so
that the mixture to be extruded may optionally also be
degassed.
[0234] The process according to the invention may be performed
discontinuously or continuously, preferably continuously.
[0235] A suitable extruder, for example, is a planetary gear
extruder type BCG 10 (LBB Bohle, Ennigerloh, Germany) having four
planetary spindles and an extrusion die with bores having a
diameter of 8 mm. A gravimetrical dosing of 3.0 kg/h is suitable.
The extrusion may be performed, for example, at a rotational speed
of 28.6 rmp and a product temperature of about 88.degree. C.
Process Embodiment 5
[0236] This variant for the production of the dosage form according
to the invention is performed by processing at least the components
(A), (C), optionally present auxiliary substances (B), such as
antioxidants, plasticisers and/or delayed-release auxiliary
substances, and optionally component (D), with addition of a
solvent for component (C), i.e. for the polymer or polymers (C), to
yield the dosage form.
[0237] To this end, components (A), (C), optionally (B) 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 yield the dosage form.
[0238] Components (A), (C), optionally (B) and optionally (D) are
mixed in a mixer known to the person skilled in the art. The mixer
may, for example, be a roll mixer, shaking mixer, shear mixer or
compulsory mixer.
[0239] The solvent for the polymer (C) is added at least in such
quantities that the formulation mixture is uniformly moistened.
[0240] Solvents which are suitable for the polymer (C) are
preferably aqueous solvents, such as water, mixtures of water and
aliphatic alcohols, preferably C1 to C6 alcohols, esters, ethers,
hydrocarbons, particularly preferably distilled water, short-chain
alcohols, such as methanol, ethanol, isopropanol, butanol or
aqueous alcohol solutions.
[0241] The solvent is preferably added with stirring. The uniformly
moistened composition is then dried. Drying preferably proceeds
with exposure to heat at temperatures at which it is possible to
rule out any discoloration of the composition. This temperature may
be established by simple preliminary testing.
[0242] Before or after drying, the composition may be divided into
sub-portions which preferably in each case correspond to the mass
of a unit of the dosage form. The corresponding dried portions are
then shaped to yield the dosage form.
[0243] This is preferably achieved by using tablet presses.
[0244] The formulation mixture may also be moistened in such a
manner that, before addition of the solvent, the formulation
mixture is divided, preferably in moulds, into sub-portions, is
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.
[0245] Suitable dispersants are preferably hydrophilic solvents,
such as aliphatic alcohols, ketones, esters. Short-chain alcohols
are preferably used.
[0246] Alternatively, the formulation mixture may 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 assistance 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.
[0247] The foam is also preferably incorporated into the
formulation mixture with stirring, a granulated composition so
preferably being obtained.
[0248] Before or after being divided into sub-portions, which
preferably correspond to the mass of a unit of the dosage form, the
granulated composition is dried and then shaped into the dosage
form.
[0249] Drying and shaping may preferably proceed as described
above. The process according to the invention may 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.
[0250] Before or after being dried, which may proceed as explained
above, such a paste may 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 dosage form, are shaped
or converted to yield the dosage form.
[0251] It is here possible to form the sub-portions in the form of
strands, which may be produced with the assistance of a screen or a
strand former. The dried strands are preferably singulated and
shaped to yield the dosage form. This shaping preferably proceeds
with the assistance of a tablet press, using shaping rollers or
shaping belts equipped with rollers.
[0252] It is also possible to convert the paste into a planar
structure and to stamp the dosage form out of it once it has
dried.
[0253] The paste is advantageously processed with an extruder,
wherein, depending on the configuration of the extrusion, strands
or planar structures articles are produced, which are singulated by
chopping, cutting or stamping. The singulated sub-portions may be
shaped, formed or stamped as described above to yield the dosage
form. Corresponding apparatuses are known to the person skilled in
the art.
[0254] The process according to the invention may here be performed
continuously or discontinuously.
[0255] It is also possible to add solvent to the formulation
mixture in such a quantity that at least the polymer component (C)
is dissolved. Such a solution or dispersion/suspension is
preferably converted into a planar structure, an extruder with a
flat die preferably being used or the solution being cast onto a
planar support.
[0256] As stated above, after drying, the dosage forms may be
obtained from the planar structures by stamping or calendering. It
is also possible, as stated above, to convert the solution into
strands and to singulate these, preferably after they have been
dried, and shape them to yield the dosage form.
[0257] Alternatively, the solution may also be divided into
portions such that, after drying, they each correspond to the mass
of a unit of the dosage form, with moulds which already correspond
to the shape of the unit of the dosage form preferably being used
for this purpose.
[0258] If the solution is divided into any desired portions, the
portions may, after drying, optionally be combined again and be
shaped to form the dosage form, being fox example packaged in a
capsule or press-formed to form a tablet.
[0259] The formulation mixtures combined with solvent are
preferably processed at temperatures of 20.degree. C. to 40.degree.
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. After shaping to yield the dosage
form, further drying corresponding to the above-described drying
may optionally be performed.
[0260] Combinations of individual process steps of the above
process variants are also possible in order to produce the dosage
form according to the invention.
[0261] Process variants 2 and 4 as described above involve 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, twin-screw extruders being particularly
preferred.
Morphology
[0262] It has been surprisingly found that extrudates exhibiting an
advantageous morphology are obtainable by means of
planetary-gear-extruders and twin-screw-extruders. It has been
found that under suitable conditions the extrudate is surrounded by
a shell which may be denoted as "extrusion skin". Said extrusion
skin can be regarded as a collar-like or tubular structure forming
a circumferential section of the extrudate about its longitudinal
extrusion axis so that the outer surface of said collar-like or
tubular structure forms the closed shell of the extrudate. Usually,
only the front faces of the extrudate are not covered by said
extrusion skin.
[0263] The extrusion skin surrounds the core of the extrudate in a
collar-like or tubular arrangement and preferably is connected
therewith in a seamless manner. The extrusion skin differs from
said core in its morphology. 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 extrusion skin and the
material forming the core, the optical properties differ as well.
It seems that during extrusion the material forming the extrusion
skin is exposed to mechanical and thermal conditions differing from
the conditions the core of the extrudate is exposed to. In
consequence, a heterogeneous morphology of the extruded strand is
obtained, which e.g. assumes radial symmetry when an extrusion die
having circular shape is used. The material forming the extrusion
skin and the material forming the core are usually distinguished by
their morphology, preferably, however, not by their composition,
particularly not by the relative content of components (A), (C),
optionally (B) and optionally (D).
[0264] Usually the extrusion skin covers the entire shell of the
extrudate like a one-piece collar, independently of what geometry
has been chosen for the extrusion die. Therefore, the extrudate may
assume circular, elliptic or other cross-sections.
[0265] The extrusion skin is preferably characterized by a unitary
thickness. Preferably, the thickness of the extrusion skin is
within the range from 0.1 to 4.0 mm, or, in increasing order of
preference 0.15 to 3.5 mm, 0.2 to 3.0 mm, 0.2 to 2.5 mm or 0.2 to
2.0 mm. In a preferred embodiment the thickness of the extrusion
skin in the sum over both opposing sides amounts to 0.5 to 50%, or
in increasing order of preference 1.0 to 40%, 1.5 to 35%, 2.0 to
30% or 2.5 to 25% of the diameter of the extrudate.
[0266] FIG. 4 show, a schematic view of extrudate (71) having a
collar-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).
[0267] It has been surprisingly found that extrudates having an
extrusion skin exhibit beneficial mechanical properties. They are
particularly suitable as intermediates in the production of the
dosage forms according to the invention, because they may be
advantageously processed, in particular by singulating and/or
forming.
[0268] When the dosage forms according to the invention are
prepared by means of extrusion processes which lead to
intermediates having an extrusion skin as described above, the
dosage forms obtained therefrom are preferably also characterized
by a particular morphology.
[0269] 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 dosage form. This is because usually by
further processing the extrudate, particularly by singulating
and/or shaping, the different nature and thereby also the different
optical properties of the material forming the extrusion skin and
the material forming the core are maintained. In the following,
that domain of the dosage forms which has emerged from the
extrusion skin in the course of further processing the extruded
intermediate, will be denoted as "tubular domain".
[0270] Preferably, the dosage form according to the invention
comprises a tubular domain and a core located therein. Preferably,
the tubular domain is connected with the core in a seamless manner.
Preferably the tubular domain as well as the core have
substantially the same chemical composition, i.e. substantially the
same relative content of components (A), (C), optionally (B) and
optionally (D). The material forming the tubular domain 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 tubular domain and the core are
visible with the naked eye in the cross-section of the dosage
form.
[0271] In case that the dosage form has been coated, e.g. by a film
coating, the tubular domain is located between the film coating and
the core.
Since the dosage form according to the invention may be obtained in
different ways from the extrudate containing the extrusion skin
(intermediate), the tubular domain may take different arrangements
and extensions within the dosage form according to the invention.
All arrangements have in common, however, that the tubular domain
partially covers the surface of the core, but usually not its
entire surface. Preferably, two opposing surfaces of the core are
not, or at least not fully covered by the tubular domain. In other
words, preferably the tubular domain has two openings/blanks on
opposing sides.
[0272] The thickness of the tubular domain may be uniform. It is
also possible, however, that in the course of the processing, i.e.
due to the subsequent shaping (e.g. press-forming) of the
extrudate, various sections of the extrusion skin are expanded or
compressed differently thereby leading to a variation of the
thickness of the tubular domain within the dosage form.
[0273] Preferably the thickness of the tubular domain is within the
range from 0.1 to 4.0 mm, or in increasing order of preference 0.15
to 3.5 mm, 0.2 to 3.0 mm, 0.2 to 2.5 mm or 0.2 to 2.0 mm.
[0274] FIGS. 5A and 5B show schematic views of preferred
arrangements of the tubular domain within the dosage form according
to the invention. The dosage forms (81) contain a tubular domain
(82) partially surrounding the core (83). The opposing surfaces
(84a) and (84b) of the core (83), however, are not covered by the
tubular domain (82).
[0275] The process for the preparation of the dosage form according
to the invention is preferably performed continuously. Preferably,
the process involves the extrusion of a homogeneous mixture of
components (A), (C), optionally (B) and optionally (D). It is
particularly advantageous if the obtained intermediate, e.g. the
strand obtained by extrusion, exhibits uniform properties.
Particularly desirable are uniform density, uniform distribution of
the active substance, uniform mechanical properties, uniform
porosity, uniform appearance of the surface, etc. Only under these
circumstances the uniformity of the pharmacological properties,
such as the stability of the release profile, may be ensured and
the amount of rejects can be kept low.
[0276] Preferably, the process according to the present invention
may be performed with less than 25% rejects, more preferably less
than 20%, most preferably less than 15% and in particular less than
10% rejects, wherein the criteria for rejection are the FDA
standards regarding the intervariability of the content of
component (A), its release profile and/or the density of the dosage
form when comparing two dosage forms, preferably taken from the
same batch.
[0277] It has been surprisingly found that the above properties may
be obtained by means of twin-screw-extruders and
planetary-gear-extruders, twin-screw-extruders being particularly
preferred.
[0278] The process 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 dosage form.
[0279] In a preferred embodiment of the process according to the
invention, shaping is performed in the plasticized state of the
mixture of components (A), (C), optionally (B) and optionally (D).
It has been surprisingly found that the extrusion of certain
polymers (C), particular of high molecular weight polyethylene
oxides, yields intermediates exhibiting some kind of memory effect:
when the singulated extrudates are shaped at ambient temperature,
e.g. by press-forming, dosage forms are obtained which tend to
regain their original outer form upon storage under stressed
storage conditions, i.e. they return to the form they had prior to
shaping.
[0280] The shape of the dosage form upon storage at stressed
conditions, e.g. at 40.degree. C. and 75% RH, may also be unstable
for other reasons.
[0281] The memory effect significantly deteriorates the storage
stability of the dosage form, as by regaining its outer form
several properties of the dosage form are changed. The same applies
to any changes of the outer form due to other reasons.
[0282] 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 of the volume of the
extrudate, i.e. a decrease of its density. Such expansion may 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.
[0283] However, if press-forming has been performed at ambient
temperature, the memory effect of the compressed extrudate will
cause it to swell and to expand upon storage, thereby significantly
increasing the volume of the dosage form.
[0284] It has been surprisingly found that such memory effect may
be suppressed if shaping of the singulated extrudate is performed
at increased temperature, i.e. in the plasticized state of the
mixture of components (A), (C), optionally (B) and optionally (D).
Preferably, shaping is performed at a pressure of at least 1 kN,
more preferably within the range from 2 kN to 50 kN, e.g. by means
of a tablet press. Preferably, shaping is performed at a
temperature which preferably is about 40.degree. C., more
preferably about 30.degree. C. and in particular about 25.degree.
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 (e.g. 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 ramp speed 10.degree. C./min).
[0285] In a preferred embodiment the outer shape of the dosage form
according to the invention does not substantially change when being
stored for at least 12 h, preferably for at least 24 h, at
40.degree. C. and 75% RH, preferably in an open container.
[0286] In a preferred embodiment the volume of the dosage form
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% when
being stored for at least 12 h, preferably for at least 24 h, at a
temperature of 20.degree. C. below the melting range of the mixture
of components (A), (C), optionally (R) and optionally (D),
optionally at a temperature of 40.degree. C. and 75% RH.
[0287] The dosage form according to the invention exhibits
controlled release of the active ingredient. It is preferably
suitable for twice daily administration to patients.
[0288] The dosage form according to the invention may comprise one
or more substances (A) at least in part in a further
delayed-release form, wherein delayed release may be achieved with
the assistance of conventional materials and processes known to the
person skilled in the art, for example by embedding the substance
in a delayed-release matrix or by applying one or more
delayed-release coatings. Substance release must, however, be
controlled such that addition of delayed-release materials does not
impair the necessary hardness.
[0289] Controlled release from the dosage form according to the
invention is preferably achieved by embedding the substance in a
matrix. The auxiliary substances acting as matrix materials control
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.
[0290] Physiologically acceptable, hydrophobic 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 very particularly preferably used as matrix materials.
[0291] Matrix materials prepared from hydrophobic materials, such
as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty
alcohols or corresponding esters or ethers or mixtures thereof are
also preferred. 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.
[0292] It is also possible to use mixtures of the above-stated
hydrophilic and hydrophobic materials as matrix materials.
[0293] Component (C) and the optionally present component (D),
which serve to achieve the resistance to crushing of at least 400 N
which is necessary according to the invention, may furthermore
themselves serve as additional matrix materials.
[0294] If the dosage form according to the invention is intended
for oral administration, it may also preferably comprise a coating
which 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 dosage form according to the
invention passes through the stomach undissolved and the active
ingredient is only released in the intestines. The coating which is
resistant to gastric juices preferably dissolves at a pH value of
between 5 and 7.5.
[0295] Corresponding materials and methods for the delayed release
of active ingredients and for the application of coatings which 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.
[0296] 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 for the manufacture of the
dosage form according to the invention for the prophylaxis and/or
the treatment of a disorder, thereby preventing an overdose of the
physiologically active substance (A), particularly due to
comminution of the dosage form by mechanical action.
[0297] Further, the invention relates to a method for the
prophylaxis and/or the treatment of a disorder comprising the
administration of the dosage form according to the invention,
thereby preventing an overdose of the physiologically active
substance (A), particularly due to comminution of the dosage form
by mechanical action.
[0298] Preferably, the mechanical action is selected from the group
consisting of chewing, grinding in a mortar, pounding, and using
apparatuses for pulverising conventional dosage forms.
[0299] The resistance to crushing of the dosage forms obtained
according to the invention is determined by the stated measurement
method, with dosage forms other than tablets also being tested.
[0300] The resistance to crushing of the dosage form according to
the invention may be determined by producing dosage forms,
preferably tablets, with a diameter of 10 mm and a height of 5
mm.
[0301] Using these dosage forms, preferably tablets, the resistance
to crushing of the dosage form is determined in accordance with the
method for determining the resistance to crushing of tablets,
published in the European Pharmacopoeia 1997, page 143, 144, method
no. 2.9.8. using the apparatus stated 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 1
column and 1 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 (diam. 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 to DIN 55350-18
(Zwick gross force Fmax=1.45 kN) (all apparatus from Zwick GmbH
& Co. KG, Ulm, Germany) with order no. BTC-PR 2.5 TH. D09 for
the tester, order no. BTC-LC 0050N. P01 for the force transducer,
order no. BO 70000 S06 for the centering device.
[0302] FIG. 6 shows the measurement of the resistance to crushing
of a tablet, in particular the tablet (4) adjustment device (6)
used for this purpose before and during the 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 fastened (not shown) with 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
numerals used relate solely to FIG. 6.
[0303] In case that the dosage form according to the invention is
in multiparticulate form, the resistance to crushing may be
alternatively be determined by means of two pressure plates, such
as depicted e.g. in FIG. 7.
[0304] FIG. 7 shows a probe (12), e.g. a pellet, which is placed
between a top pressure plate (10) and a bottom pressure plate (11).
Force is effected to the probe by means of the two pressure plates.
The result of the measurement is analysed analogously to the method
that has been described above in connection with FIG. 6.
[0305] The tablets deemed to be resistant to crushing under a
specific load include not only those which have not broken but also
those which may have suffered plastic deformation under the action
of the force.
[0306] 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.
[0307] In a first series of examples diltiazem hydrochloride,
verapamil hydrochloride and carbamazepine were used as the active
ingredients (substance (A)):
Example 1
TABLE-US-00002 [0308] per Complete Components tablet batch
diltiazem HCl 90.0 mg 720 mg polyethylene oxide, NF, MW 7 000 000
154.2 mg 1233.6 mg (Polyox WSR 303, Dow Chemicals) total weight
244.2 mg 1.9536 g
[0309] All the components were mixed in a free-fall mixer. A
tabletting tool with top punch, bottom punch and die for tablets
with a diameter of 10 mm and a radius of curvature (concavity) of 8
mm was heated to 80.degree. C. in a heating cabinet. 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.
[0310] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. 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
with the assistance of a pestle and mortar either.
[0311] 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.degree. C. and the rotational speed of
the stirrer 50 min.sup.-1. 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
an measurement cells.
TABLE-US-00003 time released quantity 30 min 12% 240 min 43% 480
min 63% 600 min 71% 720 min 77%
Example 2
[0312] In a manner similar to Example 1, oblong tablets having a
width of 9 mm and a lengthwise extension of 20 mm were produced
with the following composition:
TABLE-US-00004 per complete Components tablet batch verapamil HCl
240.0 mg 1920 mg polyethylene oxide, NF, MW 7 000 000 411.4 mg
3291.2 mg (Polyox WSR 303, Dow Chemicals) total weight 651.4 mg
4.2112 g
[0313] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. The
tablets did not crush when exposed to a force of 500 N.
[0314] In vitro release of the active ingredient was determined in
a manner similar to Example 1 (UV detector at 279 nm) and was:
TABLE-US-00005 Time released quantity 30 min 6% 240 min 20% 480 min
30% 600 min 35% 720 min 39%
Example 3
[0315] In a similar manner to Example 1, round tablets with a
diameter of 20 mm and of the following composition were
produced:
TABLE-US-00006 per complete Components tablet batch Carbamazepine
600 mg 4800 mg polyethylene oxide, NF, MW 7 000 000 1028.5 mg
8228.0 mg (Polyox WSR 303, Dow Chemicals) total weight 1628.5 mg
13.028 g
[0316] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. The
tablets did not crush when exposed to a force of 500 N.
[0317] In vitro release of the active ingredient was determined in
a manner similar to Example 1 (UV detector at 235 nm) and was:
TABLE-US-00007 time released quantity 30 min 1% 240 min 5% 480 min
9% 600 min 11% 720 min 13%
[0318] In a further series of examples nifedipine was used as the
active ingredient (substance (A)):
Example 4
[0319] Tablets having the following composition were produced:
TABLE-US-00008 per complete content components tablet batch [%]
nifedipine 20 mg 2 g 10 polyethylene oxide 900 000 180 mg 18 g 90
(Polyox WSR 1105 Dow Chemicals)
[0320] Nifedipine and polyethylene oxide were mixed in a free-fall
mixer. The mixture was compressed on an excentric tablet press
(model EK 0, Korsch) to circular tablets having a weight of 200 mg,
a diameter of 8 mm and a radius of curvature of 8 mm. Then, the
tabletting tool with top punch, bottom punch and die for tablets
with a diameter of 10 mm and a radius of curvature of 8 mm was
heated to 100.degree. C. in a heating cabinet. Once again the
tablets were compressed by means of the heated tool, wherein
pressure was maintained for at least 15 seconds.
[0321] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. 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
with the assistance of a pestle and mortar either.
Example 5
[0322] Tablets having the following composition were produced as
described in Example 4:
TABLE-US-00009 per complete content Components tablet batch [%]
Nifedipine 20 mg 2 g 10 polyethylene oxide 600 000 180 mg 18 g 90
(Polyox WSR 205 Dow Chemicals)
[0323] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. 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
with the assistance of a pestle and mortar either.
Example 6
[0324] Tablets having the following composition were produced as
described in Example 4:
TABLE-US-00010 per complete content Components tablet batch [%]
Nifedipine 20 mg 2 g 10 polyethylene oxide 5 000 000 180 mg 18 g 90
(Polyox WSR Coagulant Dow Chemicals)
[0325] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. 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
with the assistance of a pestle and mortar either.
Example 7
[0326] Tablets having the following composition were produced as
described in Example 4:
TABLE-US-00011 per complete content Components tablet batch [%]
Nifedipine 20 mg 2 g 10 polyethylene oxide 100 000 20 mg 2 g 10
(Polyox WSR N 10 Dow Chemicals) polyethylene oxide 5 000 000 160 mg
160 g 80 (Polyox WSR Coagulant Dow Chemicals)
[0327] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. 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
with the assistance of a pestle and mortar either.
[0328] In a further series of examples tramadol hydrochloride and
oxycodone hydrochloride were used as active ingredients (substance
(A)).
Example 6
TABLE-US-00012 [0329] per complete Components tablet batch tramadol
HCl 100 mg 100 g polyethylene oxide, NF, MFI (190.degree. C. at 200
mg 200 g 21.6 kg/10 min) <0.5 g MW 7 000 000 (Polyox WSR 303,
Dow Chemicals) total weight 300 mg 300 g
[0330] Tramadol hydrochloride and polyethylene oxide powder were
mixed in a free-fall mixer. A tabletting tool with top punch,
bottom punch and die for tablets with a diameter of 10 mm and a
radius of curvature of 8 mm was heated to 80.degree. C. in a
heating cabinet. 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.
[0331] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. The
tablets did not break when exposed to a force of 500 N.
[0332] The tablet could not be comminuted using a hammer, nor with
the assistance of a mortar and pestle.
[0333] 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.degree. C. and the rotational speed of the stirrer 75
min.sup.-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.
TABLE-US-00013 time released quantity 30 min 15% 240 min 52% 480
min 80% 720 min 99%
Example 9
[0334] 300 mg portions of the powder mixture from Example 8 were
heated to 80.degree. C. and in placed in the die of the tabletting
tool. Pressing was then performed. The tablet exhibits the same
properties such as the tablet in Example 8.
Example 10
TABLE-US-00014 [0335] per complete Components tablet batch tramadol
HCl 50 mg 100 g polyethylene oxide, NF, MW 7 000 000 100 mg 200 g
(Polyox WSR 303, Dow Chemicals) total weight 150 mg 300 g
[0336] Tramadol hydrochloride and the above-stated components were
mixed in a free-fall mixer. A tabletting tool with top punch,
bottom punch and die for tablets with a diameter of 7 mm was heated
to 80.degree. C. in a heating cabinet. 150 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.
[0337] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. The
tablets did not break when exposed to a force of 500 N.
[0338] In vitro release of the active ingredient was determined as
in Example 8 and was:
TABLE-US-00015 time released quantity 30 min 15% 240 min 62% 480
min 88% 720 min 99%
Example 11
TABLE-US-00016 [0339] per complete Components tablet batch tramadol
HCl 100 mg 100 g polyethylene oxide, NF, MW 7 000 000 180 mg 180 g
(Polyox WSR 303, Dow Chemicals) Xanthan, NF 20 mg 20 g total weight
300 mg 300 g
[0340] Tramadol hydrochloride, xanthan and polyethylene oxide were
mixed in a free-fall mixer. A tabletting tool with top punch,
bottom punch and die for tablets with a diameter of 10 mm and a
radius of curvature (concavity) of 8 mm was heated to 80.degree. C.
in a heating cabinet. 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.
[0341] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. The
tablets did not break when exposed to a force of 500 N. The tablets
did suffer a little plastic deformation.
[0342] In vitro release of the active ingredient was determined as
in Example 8 and was:
TABLE-US-00017 time released quantity 30 min 14% 240 min 54% 480
min 81% 720 min 99%
Example 12
TABLE-US-00018 [0343] per complete Components tablet batch tramadol
HCl 50 mg 100 g polyethylene oxide, NF, MW 7 000 000 90 mg 180 g
(Polyox WSR 303, Dow Chemicals) Xanthan, NF 10 mg 20 g total weight
300 mg 300 g
[0344] Tramadol hydrochloride, xanthan and polyethylene oxide were
mixed in a free-fall mixer. A tabletting tool with a top punch,
bottom punch and die for oblong tablets 10 mm in length and 5 mm in
width was heated to 90.degree. C. in a heating cabinet. 150 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.
[0345] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. The
tablets did not break when exposed to a force of 500 N. The tablets
did suffer a little plastic deformation.
[0346] In vitro release of the active ingredient was determined as
in Example 8 and was:
TABLE-US-00019 time released quantity 30 min 22% 120 min 50% 240
min 80% 360 min 90% 480 min 99%
Example 13
[0347] A tablet with the following composition was produced as
described in Example 8:
TABLE-US-00020 per per Components tablet batch oxycodone HCl 20.0
mg 0.240 g Xanthan, NF 20.0 mg 0.240 g polyethylene oxide, NF, MFI
110.0 mg 1.320 g (190.degree. C. at 21.6 kg/10 min) <0.5 g MW 7
000 000 (Polyox WSR 303, Dow Chemicals) total weight 150.0 mg 1.800
g
[0348] Release of the active ingredient was determined as
follows:
[0349] 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.degree. 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.
TABLE-US-00021 Time mean 0 min 0% 30 min 17% 240 min 61% 480 min
90% 720 min 101.1%
[0350] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. The
tablets did not break when exposed to a force of 500 N.
Example 14
[0351] Tablets having the following composition were produced:
TABLE-US-00022 per complete content components tablet batch [%]
tramadol HCl 100 mg 10 g 20 polyethylene oxide 7 000 000 375 mg
37.5 g 75 (Polyox WSR 303, Dow Chemicals) Carnauba wax 25 mg 2.5 g
5.0
[0352] Tramadol hydrochlorid, polyethylene oxide and Carnauba wax
were mixed in a free-fall mixer. The mixture was compressed on an
excentric tablet press (model EK 0, Korsch) to circular tablets
having a weight of 500 mg, a diameter of 10 m and a radius of
curvature of 8 mm. Then, the tabletting tool with top punch, bottom
punch and die for tablets with a diameter of 10 mm and a radius of
curvature of S mm was heated to 130.degree. C. in a heating
cabinet. Once again the tablets were compressed by means of the
heated tool, wherein pressure was maintained for at least 15
seconds.
[0353] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. 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
with the assistance of a pestle and mortar either.
Example 15
[0354] Tablets having the following composition were produced as
described in Example 14:
TABLE-US-00023 per complete content Components tablet batch [%]
tramadol HCl 100 mg 10 g 20 polyethylene oxide 5 000 000 375 mg
37.5 g 75 (Polyox WSR Coagulant Dow Chemicals) Carnauba wax 25 mg
2.5 g 5.0
[0355] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. 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
with the assistance of a pestle and mortar either.
Example 16
[0356] Tablets having the following composition were produced:
TABLE-US-00024 per complete content Components tablet batch [%]
tramadol HCl 100.0 mg 1490 g 29.8 polyethylene oxide 7 000 000
151.0 mg 2250 g 45.0 (Polyox WSR 303, Dow Chemicals) Hypromellose
(Metholose 90 33.6 mg 500 g 10.0 SH 100 000 cP, ShinEtsu) Eudragit
E Granulate (Rohm) 16.8 mg 250 g 5.0 PEG 6000 33.6 mg 500 g 10.0
.quadrature.-tocopherol 0.1 mg 5 g 0.1 Aerosil (highly disperse
SiO.sub.2) 0.1 mg 5 g 0.1
[0357] A homogeneous mixture of 50 g of the polyethylene oxide, 5 g
of .quadrature.-tocopherol and Aerosil was prepared in a mortar.
Said homogeneous mixture was mixed with the further components in a
free-fall mixer for 15 minutes. Subsequently, the mixtures was
extruded by means of a planetary-gear extruder, type BCC 10, LBB
Bohle (Ennigerloh). 4 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:
rotation speed: 50 UpM; cover temperature: 100.degree. C.;
temperature of the central spindle: 100.degree. C.; temperature of
the jet heating: 120.degree. C. After preparation the extrudates
were allowed to cool down to room temperature. Thereafter, they
were cut into slides having the desired tablet weight. Moulding of
the tablets was performed by means of an excenter press, type EKO,
Korsch. Circular punches having a diameter of 10 mm and a radius of
curvature of 8 mm were used as tabletting cool.
[0358] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. 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
with the assistance of a pestle and mortar either.
[0359] 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
(600 ml) was 37.degree. 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.
TABLE-US-00025 Time amount released 30 min 17% 240 min 65% 480 min
93% 720 min 99%
Example 1
[0360] Tablets having the following composition were produced as
described in Example 16:
TABLE-US-00026 per complete content components tablet batch [%]
tramadol HCl 100.0 mg 1490 g 29.8 polyethylene oxide 7 000 000
151.0 mg 2250 g 45.0 (Polyox WSR 303, Dow Chemicals) Hypromellose
(Metholose 90 33.6 mg 500 g 10.0 SH 100 000 cP, ShinEtsu) Stamylan
LD 1965 (SABIC .RTM. 16.8 mg 250 g 5.0 LDPE 1965T) (Sabic
Europetrochemicals) PEG 6000 33.6 mg 500 g 10.0
.quadrature.-tocopherol 0.1 mg 5 g 0.1 Aerosil (highly disperse
SiO.sub.2) 0.1 mg 5 g 0.1
[0361] The resistance to crushing of the tablets was determined
with the stated apparatus in accordance with the stated method. The
tablets did not crush when exposed to a force of 500 N. The tablet
could not be comminuted with a hammer. Nor could this be achieved
with the assistance of a pestle and mortar.
[0362] 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.degree. C. and the rotational speed of
the stirrer 75 min.sup.-1. 600 ml of artificial intestinal fluid pH
6.8 were used as release medium. The quantity of active ingredient
released in each case into the dissolution medium at any one time
was determined by spectrophotometry.
TABLE-US-00027 time amount released 30 min 17% 240 min 62% 480 min
85% 720 min 94%
* * * * *