U.S. patent application number 14/261625 was filed with the patent office on 2014-10-30 for pharmaceutical dosage form.
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, LUTZ BARNSCHEID, JOHANNES BARTHOLOMAUS, ANNE FAURE, MARC FREVEL, ERIC GALIA, EUGEEN MARIE JOZEF JANS, FILIP RENE IRENA KIEKENS, ANDREA SCHUESSELE, JODY FIRMIN MARCELINE VOORSPOELS, IRIS ZIEGLER.
Application Number | 20140322323 14/261625 |
Document ID | / |
Family ID | 40511977 |
Filed Date | 2014-10-30 |
United States Patent
Application |
20140322323 |
Kind Code |
A1 |
JANS; EUGEEN MARIE JOZEF ;
et al. |
October 30, 2014 |
PHARMACEUTICAL DOSAGE FORM
Abstract
The invention relates to a pharmaceutical dosage form,
preferably with controlled release of a pharmacologically active
compound (A) contained therein, the pharmaceutical dosage form very
preferably being tamper-resistant and most preferably having a
breaking strength B.sub.1 of at least 500 N in direction of
extension E.sub.1 and having a breaking strength B.sub.2 of less
than 500 N in direction of extension E.sub.2.
Inventors: |
JANS; EUGEEN MARIE JOZEF;
(Meerhout, BE) ; KIEKENS; FILIP RENE IRENA; (Geel,
BE) ; VOORSPOELS; JODY FIRMIN MARCELINE; (Reningelst,
BE) ; FAURE; ANNE; (Vosselaar, BE) ; ZIEGLER;
IRIS; (Neusass, DE) ; ARKENAU-MARIC; ELISABETH;
(Koln, DE) ; BARNSCHEID; LUTZ; (Monchengladbach,
DE) ; BARTHOLOMAUS; JOHANNES; (Aachen, DE) ;
FREVEL; MARC; (Monschau, DE) ; GALIA; ERIC;
(Inden, DE) ; SCHUESSELE; ANDREA; (Berlin,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRUNENTHAL GMBH |
Aachen |
|
DE |
|
|
Assignee: |
GRUNENTHAL GMBH
Aachen
DE
|
Family ID: |
40511977 |
Appl. No.: |
14/261625 |
Filed: |
April 25, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13742851 |
Jan 16, 2013 |
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14261625 |
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12358415 |
Jan 23, 2009 |
8383152 |
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13742851 |
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Current U.S.
Class: |
424/468 ; 428/81;
514/654 |
Current CPC
Class: |
A61K 31/137 20130101;
A61K 9/2031 20130101; A61K 9/2018 20130101; Y10T 428/24479
20150115; A61K 9/2059 20130101; A61K 9/2072 20130101; A61P 25/04
20180101; A61P 25/18 20180101; A61K 9/2054 20130101; A61K 31/135
20130101 |
Class at
Publication: |
424/468 ; 428/81;
514/654 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/137 20060101 A61K031/137 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 25, 2008 |
EP |
08001415.2 |
Jan 25, 2008 |
EP |
08001416.0 |
Oct 17, 2008 |
EP |
08018221.5 |
Claims
1. A pharmaceutical dosage form comprising at least one
pharmaceutically active ingredient, and having a shape comprising a
longitudinal axis and two opposite longitudinal edges, a
transversal axis perpendicular to the longitudinal axis and two
opposite transversal edges, a front side, an opposite back side and
a circumferential rim between said front and back side, wherein the
front side and/or the back side comprise a basis area and wherein
the front side and/or the back side comprise at least one bulge
which extends above said basis area, said at least one bulge being
present at and/or adjacent to at least a section of one or both
longitudinal edges and/or at and/or adjacent to at least a section
of one or both transversal edges and/or between both longitudinal
edges and both transversal edges.
2. The pharmaceutical dosage form according to claim 1, which is a
tablet having an oblong shape.
3. The pharmaceutical dosage form according to claim 1, wherein the
front side and the back side each comprise at least one bulge at
least along a section at and/or adjacent to both longitudinal edges
and/or at least along a section at and/or adjacent to both
transversal edges.
4. The pharmaceutical dosage form according to claim 1, wherein
said front side and said back side comprise an at least essentially
continuous bulge at and/or adjacent to at least two third of both
opposite longitudinal edges.
5. The pharmaceutical dosage form according to claim 1, wherein one
or both longitudinal edges are essentially straight over at least a
major part of their length and/or wherein one or both transversal
edges are curved over a major part of their length.
6. The pharmaceutical dosage form according to claim 1, wherein the
front side and/or the back side comprise an essentially
circumferential bulge at and/or adjacent to the circumferential
edge of the front side and/or the back side of said pharmaceutical
dosage form.
7. The pharmaceutical dosage form according to claim 1, wherein
said pharmaceutical dosage form in its oblong form comprises at
and/or adjacent to major portions of both opposite longitudinal
edges of the front side at least one bulge, or wherein said
pharmaceutical dosage form in its oblong form comprises at least
one bulge at and/or adjacent to major portions of both opposite
longitudinal edges of both the front side and the back side of said
pharmaceutical dosage form, or wherein said pharmaceutical dosage
form comprises in its oblong form a circumferential bulge at and/or
adjacent to the circumferential edge of the front side of said
pharmaceutical dosage form, or wherein said pharmaceutical dosage
form in its oblong form comprises a circumferential bulge at and/or
adjacent to the circumferential edge of both the front side and the
back side of said pharmaceutical dosage form.
8. The pharmaceutical dosage form according to claim 7, wherein
said pharmaceutical dosage form in its oblong form comprises at
major portions of both opposite longitudinal edges of the front
side at least one bulge, or wherein said pharmaceutical dosage form
in its oblong form comprises at least one bulge at major portions
of both opposite longitudinal edges of both the front side and the
back side of said pharmaceutical dosage form, or wherein said
pharmaceutical dosage form comprises in its oblong form a
circumferential bulge at the circumferential edge of the front side
of said pharmaceutical dosage form, or wherein said pharmaceutical
dosage form in its oblong form comprises a circumferential bulge at
the circumferential edge of both the front side and the back side
of said pharmaceutical dosage form.
9. The pharmaceutical dosage form according to claim 7, wherein
said pharmaceutical dosage form in its oblong form comprises
adjacent to major portions of both opposite longitudinal edges of
the front side at least one bulge, or wherein said pharmaceutical
dosage form in its oblong form comprises at least one bulge
adjacent to major portions of both opposite longitudinal edges of
both the front side and the back side of said pharmaceutical dosage
form, or wherein said pharmaceutical dosage form comprises in its
oblong form a circumferential bulge adjacent to the circumferential
edge of the front side of said pharmaceutical dosage form, or
wherein said pharmaceutical dosage form in its oblong form
comprises a circumferential bulge adjacent to the circumferential
edge of both the front side and the back side of said
pharmaceutical dosage form.
10. The pharmaceutical dosage form according to claim 7, wherein
said pharmaceutical dosage form in its oblong form comprises a
circumferential bulge adjacent to the circumferential edge of both
the front side and the back side of said pharmaceutical dosage
form.
11. The pharmaceutical dosage form according to claim 1, wherein
the front side and/or the back side comprise, in addition to at
least one bulge on the front side and/or the back side, at least
one indentation.
12. The pharmaceutical dosage form according to claim 11, wherein
the front and the back side comprise at least one indentation.
13. The pharmaceutical dosage form according to claim 12, wherein
the indentation(s) in the front side and the back side are at least
once at least partially off-set.
14. The pharmaceutical dosage form according to claim 12, wherein
all the indentations of the front side and all the indentations of
the back side are at least partially off-set.
15. The pharmaceutical dosage form according to claim 12, wherein
at least one indentation of the front side and at least one
indentation of the back side are positioned in a congruent
manner.
16. The pharmaceutical dosage form according to claim 15, wherein
all indentations of the front side and all indentations of the back
side are positioned in a congruent manner.
17. The pharmaceutical dosage form according to claim 11, wherein
the indentations have a cylindrical or cube-like or cuboid-like
shape or the shape of a half-sphere.
18. The pharmaceutical dosage form according to claim 1, comprising
one or more hydrophilic polymers.
19. The pharmaceutical dosage form according to claim 18, wherein
the one or more hydrophilic polymers are hydroxypropyl methyl
cellulose and/or hydroxypropyl cellulose.
20. The pharmaceutical dosage form according to claim 18, further
comprising pregelatinized starch.
21. The pharmaceutical dosage form according to claim 1, wherein
the longitudinal length of the pharmaceutical dosage form does not
exceed 30 mm.
22. The pharmaceutical dosage form according to claim 1, having an
average thickness over the basis areas of the front and the back
side of about at least 1 mm.
23. The pharmaceutical dosage form according to claim 1, wherein
the bulge extends perpendicular from the basis area of the front
side and/or from the basis area of the back side in average from
about 0.5 mm to about 2 mm.
24. The pharmaceutical dosage form according to claim 1, having a
length in the longitudinal direction in the range of about 5 mm to
about 30 mm, a width in the range of about 5 mm to about 15 mm, and
a thickness over the basis areas in the range of about 1 mm to
about 6 mm.
25. The pharmaceutical dosage form according to claim 1, further
comprising at least partially a coating.
26. Tamper-resistant pharmaceutical dosage form, which has a
retarded release profile for pharmaceutical application as an oral
dosage form, comprising at least one pharmaceutically active
ingredient with potential for abuse, and having a shape comprising
a longitudinal axis and two opposite longitudinal edges, a
transversal axis perpendicular to the longitudinal axis and two
opposite transversal edges, a front side, an opposite back side and
a circumferential rim between said front and back side, wherein the
front side and/or the back side comprise a basis area and wherein
the front side and/or the back side comprise at least one bulge
which extends above said basis area, said at least one bulge being
present at and/or adjacent to at least a section of one or both
longitudinal edges and/or at and/or adjacent to at least a section
of one or both transversal edges and/or between both longitudinal
edges and both transversal edges.
27. The pharmaceutical dosage form according to claim 26, which is
a tablet having an oblong shape.
28. The pharmaceutical dosage form according to claim 26, wherein
the front side and the back side each comprise at least one bulge
at least along a section at and/or adjacent to both longitudinal
edges and/or at least along a section at and/or adjacent to both
transversal edges.
29. The pharmaceutical dosage form according to claim 26, wherein
said front side and said back side comprise an at least essentially
continuous bulge at and/or adjacent to at least two third of both
opposite longitudinal edges.
30. The pharmaceutical dosage form according to claim 26, wherein
one or both longitudinal edges are essentially straight over at
least a major part of their length and/or wherein one or both
transversal edges are curved over a major part of their length.
31. The pharmaceutical dosage form according to claim 26, wherein
the front side and/or the back side comprise an essentially
circumferential bulge at and/or adjacent to the circumferential
edge of the front side and/or the back side of said pharmaceutical
dosage form.
32. The pharmaceutical dosage form according to claim 26, wherein
said pharmaceutical dosage form in its oblong form comprises at
and/or adjacent to major portions of both opposite longitudinal
edges of the front side at least one bulge, or wherein said
pharmaceutical dosage form in its oblong form comprises at least
one bulge at and/or adjacent to major portions of both opposite
longitudinal edges of both the front side and the back side of said
pharmaceutical dosage form, or wherein said pharmaceutical dosage
form comprises in its oblong form a circumferential bulge at and/or
adjacent to the circumferential edge of the front side of said
pharmaceutical dosage form, or wherein said pharmaceutical dosage
form in its oblong form comprises a circumferential bulge at and/or
adjacent to the circumferential edge of both the front side and the
back side of said pharmaceutical dosage form.
33. The pharmaceutical dosage form according to claim 32, wherein
said pharmaceutical dosage form in its oblong form comprises at
major portions of both opposite longitudinal edges of the front
side at least one bulge, or wherein said pharmaceutical dosage form
in its oblong form comprises at least one bulge at major portions
of both opposite longitudinal edges of both the front side and the
back side of said pharmaceutical dosage form, or wherein said
pharmaceutical dosage form comprises in its oblong form a
circumferential bulge at the circumferential edge of the front side
of said pharmaceutical dosage form, or wherein said pharmaceutical
dosage form in its oblong form comprises a circumferential bulge at
the circumferential edge of both the front side and the back side
of said pharmaceutical dosage form.
34. The pharmaceutical dosage form according to claim 32, wherein
said pharmaceutical dosage form in its oblong form comprises
adjacent to major portions of both opposite longitudinal edges of
the front side at least one bulge, or wherein said pharmaceutical
dosage form in its oblong form comprises at least one bulge
adjacent to major portions of both opposite longitudinal edges of
both the front side and the back side of said pharmaceutical dosage
form, or wherein said pharmaceutical dosage form comprises in its
oblong form a circumferential bulge adjacent to the circumferential
edge of the front side of said pharmaceutical dosage form, or
wherein said pharmaceutical dosage form in its oblong form
comprises a circumferential bulge adjacent to the circumferential
edge of both the front side and the back side of said
pharmaceutical dosage form.
35. The pharmaceutical dosage form according to claim 32, wherein
said pharmaceutical dosage form in its oblong form comprises a
circumferential bulge adjacent to the circumferential edge of both
the front side and the back side of said pharmaceutical dosage
form.
36. The pharmaceutical dosage form according to claim 26, wherein
the front side and/or the back side comprise, in addition to at
least one bulge on the front side and/or the back side, at least
one indentation.
37. The pharmaceutical dosage form according to claim 36, wherein
the front and the back side comprise at least one indentation.
38. The pharmaceutical dosage form according to claim 37, wherein
the indentation(s) in the front side and the back side are at least
once at least partially off-set.
39. The pharmaceutical dosage form according to claim 37, wherein
all the indentations of the front side and all the indentations of
the back side are at least partially off-set.
40. The pharmaceutical dosage form according to claim 36, wherein
at least one indentation of the front side and at least one
indentation of the back side are positioned in a congruent
manner.
41. The pharmaceutical dosage form according to claim 40, wherein
all indentations of the front side and all indentations of the back
side are positioned in a congruent manner.
42. The pharmaceutical dosage form according to claim 36, wherein
the indentations have a cylindrical or cube-like or cuboid-like
shape or the shape of a half-sphere.
43. The pharmaceutical dosage form according to claim 26,
comprising a polyalkylene oxide.
44. The pharmaceutical dosage form according to claim 26,
comprising at least one cellulose ether derivative.
45. The pharmaceutical dosage form according to claim 44, wherein
the cellulose ether derivative is HPMC.
46. The pharmaceutical dosage form according to claim 43, wherein
the polyalkylene oxide is polyethylene oxide.
47. The pharmaceutical dosage form according to claim 46, wherein
the polyethylene oxide has a molecular weight in the range of about
2,000,000 to about 7,000,000.
48. The pharmaceutical dosage form according to claim 26, wherein
the pharmaceutical dosage form further comprises a polyalkylene
glycol.
49. The pharmaceutical dosage form according to claim 48, wherein
the polyalkylene glycol is polyethylene glycol.
50. The pharmaceutical dosage form according to claim 26, wherein
the pharmaceutically active ingredient with potential for abuse is
a pain-killing drug.
51. The pharmaceutical dosage form according to claim 50, wherein
the pharmaceutically active ingredient is tapentadol.
52. The pharmaceutical dosage form according to claim 26,
comprising at least one pharmaceutically active ingredient with
potential for abuse; at least one poly(alkylene oxide); at least
one cellulose ether derivative; and at least one polyalkylene
glycol; and optionally an additive.
53. The pharmaceutical dosage form according to claim 52, wherein
the active ingredient with potential for abuse is present in an
amount of at least 5 weight percent; poly(alkylene oxide) is
present in an amount of at least 15 weight percent; cellulose ether
derivative is present in an amount of at least 5 weight percent;
and polyalkylene glycol is present in an amount of at least 5
weight percent.
54. The pharmaceutical dosage form according to claim 26, wherein
the longitudinal length of the pharmaceutical dosage form does not
exceed 30 mm.
55. The pharmaceutical dosage form according to claim 26, having an
average thickness over the basis areas of the front and the back
side of about at least 1 mm.
56. The pharmaceutical dosage form according to claim 26, wherein
the bulge extends perpendicular from the basis area of the front
side and/or from the basis area of the back side in average from
about 0.5 mm to about 2 mm.
57. The pharmaceutical dosage form according to claim 26, having a
length in the longitudinal direction in the range of about 5 mm to
about 30 mm, a width in the range of about 5 mm to about 15 mm, and
a thickness over the basis areas in the range of about 1 mm to
about 6 mm.
58. The pharmaceutical dosage form according to claim 26, wherein
said pharmaceutical dosage form is a monolith.
59. The pharmaceutical dosage form according to claim 26, which has
been prepared via compression using a die and a punch from a
monolithic mass obtained by melt extrusion.
60. The pharmaceutical dosage form according to claim 58, wherein
said pharmaceutical dosage form has been obtained by compressing a
melt extruded monolithic mass which exhibits ambient
temperature.
61. The pharmaceutical dosage form according to claim 58, wherein
the extruded monolithic mass has been cut prior to compression.
62. The pharmaceutical dosage form according to claim 58, wherein
melt extrusion has been conducted with a twin-screw extruder.
63. The pharmaceutical dosage form according to claim 26, further
comprising at least partially a coating.
64. A method of treating pain in a patient in need of such
treatment, said method comprising administering to said patient an
effective amount therefor of a pharmaceutical dosage form according
to claim 1, wherein the pharmaceutically active ingredient, the
pharmaceutically active ingredient with potential for abuse and the
pharmacologically active compound (A) are each selected from the
group consisting of analgesics.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/742,851, filed Jan. 16, 2013, now pending,
which is, in turn, a division of U.S. patent application Ser. No.
12/358,415 filed Jan. 23, 2009, now U.S. Pat. No. 8,383,152, which
claims foreign priority of European Patent Application No.
08018221.5 filed Oct. 17, 2008; European Patent Application No.
08001416.0 filed Jan. 25, 2008; and European Patent Application No.
08001415.2 filed Jan. 25, 2008, the disclosures of all of which
patent applications are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates to a pharmaceutical dosage form,
preferably a tablet for oral administration.
BACKGROUND ART
[0003] For many pharmaceutically active compounds it is still
preferred to have them orally administered by way of tablets. It is
also well known that depending on how a pharmaceutically active
ingredient is formulated into a tablet its release pattern can be
modified. In this regard, tablets providing a retarded release
profile are of primary importance. With retarded release tablets
care has to be taken that under no circumstances the
pharmaceutically active ingredient will be released completely and
instantaneously in an uncontrolled manner ("dose-dumping") since
regularly the dosage used for retarded release tablets is much
higher than for non-retarded release tablets. This may cause
serious adverse effects or even death depending on the active
ingredient and potency thereof.
[0004] Controlled release (e.g. delayed release, prolonged release,
sustained release, and the like) may be based upon various concepts
such as coating the pharmaceutical dosage form with a controlled
release membrane, embedding the pharmacologically active compound
in a matrix, binding the pharmacologically active compound to an
ion-exchange resin, forming a complex of the pharmacologically
active compound, and the like. In this context it can be referred
to, e.g., W. A. Ritschel, Die Tablette, 2. Auflage, Editio Cantor
Verlag Aulendorf, 2002.
[0005] In WO 01/97783 A1 a controlled-release, in particular a
retarded release oral drug dosage form for releasing a drug into at
least a portion of a region defined by the stomach and the front
gastrointestinal tract is obtained by employing a solid monolithic
matrix having a non-circular shape wherein the longitudinal axis
has a maximum length of 3.0 cm and the transversal axis achieves a
minimum length of 1.2 cm within one hour of immersion in water.
Furthermore, it is required that the matrix has a shape which when
projected onto a plane is either an oval or a parallelogram.
[0006] U.S. Pat. No. 4,353,887 discloses a divisible tablet which
exhibits controlled and delayed release of an active substance.
This is achieved by use of a coating on a compacted tablet having
an oblong shape in which the ratio of length to width to depth is
approximately 2.5 to 5: approximately 0.9 to 2:1 and the width
constitute at most 2/3 of the length. In addition, one or more
relatively deep dividing grooves have to be present which run
perpendicular to the length and depth and have a total depth of
from approximately 1/3 to approximately 1/2 of the depth of the
tablet.
[0007] WO 01/08661 is directed to a controlled release formulation,
capable of providing sustained, prolonged, repeat and/or delayed
release of oxycodone.
[0008] WO 03/094812 relates to abuse-resistant opioid-containing
solid dosage pharmaceuticals comprising a sustained release carrier
and an analgesically effective amount of an opioid analgesic in
combination with an opioid euphoria-inhibiting amount of an
isolated nontoxic N-methyl-D-aspartate receptor antagonist which is
substantially not released when the dosage form is administered
intact.
[0009] WO 99/48481 discloses a tablet for the controlled release of
an active pharmaceutical ingredient. The tablet comprises a core
having a donut-like configuration with a cylindrical hole extending
through the center of the core. The core is coated with a
hydrophobic, water-insoluble material covering all of the core
except that which is defined by the cylindrical hole.
[0010] GB-A 2 057 878 discloses a divisible tablet having
controlled and delayed release of the active substance, consisting
of a compact that is formed by at least one active substance in an
adjunct composition that effects a delayed and controlled release
of the active substance, the compact being of an oblong shape in
which the ratio of length to width to depth is approximately 2.5 to
5:approximately 0.9 to 2:1 and the width constitutes at most 2/3 of
the length, and in which one or more relatively deep dividing
grooves are present which run perpendicularly to the length and
depth and have a total depth of from approximately 113 to
approximately `12 of the depth of the tablet, but are at least so
deep that one fracture surface area multiplied by the number of
possible fragments constitutes a maximum of 15% of the surface area
of the undivided tablet, the base and top faces independently of
one another are planar or are convexly curved about the
longitudinal axis or about parallels to this axis, the side faces
are planar, the end faces can be of any shape and edges are
optionally bevelled or rounded.
[0011] DE-A 198 56 147 discloses a solid, elongate dosage form with
a long axis and with a length which is defined by projection of the
ends of the dosage form onto the long axis, where a cross-sectional
area oriented perpendicular to the long axis has an area which is
variable along the long axis and increases from a cross-sectional
area which is located between the ends and has a minimal area
essentially continuously toward the two ends up to in each case a
cross-sectional area with a maximal area, wherein the distance of
the maximal cross-sectional area which is located near one end from
the maximal cross-sectional area which is located near the other
end is, projected on the long axis, more than half the length of
the dosage form.
[0012] DE 28 08 505 C2 discloses a tablet which dissolves at
essentially constant speed and which contains a water soluble
component as well as a water insoluble coating. It is required that
the side of the tablet has to comprise one or more cavities having
a breadth of 0.1 to 1.0 mm, a depth of 0.1 to 0.4 mm and a length
of more than 0.1 mm, wherein the side of said cavities is less than
1/6 of the total side of the tablet.
[0013] In DE 692 29 881 T2 it is proposed to obtain a tablet having
a retarded release profile by use of a water soluble gel as well as
of a specific coating having a specific thickness. The coating has
to contain either ethylcellulose or acetylcellulose and has to be
water insoluble as well as insoluble in gastric liquids.
[0014] A tablet having a controlled release profile will according
to WO 99/48481 A1 be obtained by use of a doughnut-shaped core
material with a cylindrical hole. A hydrophobic, water-insoluble
coating is applied to the doughnut-shaped core except for the side
of said core which surrounds the cylindrical hole. In such a manner
an inherent limitation of compressed monolithic tablets for
extended release dosages shall be overcome, namely the increase in
diffusion length resistance over time due to the insolubility of
the polymer. Apparently, this problem has been solved by insuring
that the inner exposed area of the doughnut-shaped configuration is
clear of any coating.
[0015] In DE 42 39 085 A1 it is described to make use of an oblong
tablet only the opposed edges of which are in contact with an
underlying side but not the intermediate section. In this manner
the tablet is easily divisible by use of one hand only. The two
parts forming such an oblong tablet may have the form of spherical
sectors.
[0016] It is well known that a pharmaceutical formulation or its
mode of manufacture, e.g. for an oral dosage form, might undergo
modifications during clinical testing, for example with respect to
the ingredients used or to the relative amounts of the excipients,
or with respect to the reaction conditions and reactants used
during manufacture. Frequently, such modifications at least to some
extent have an impact on the release profile of pharmaceutically
active ingredients. This is particularly unpleasant if for a
specific formulation an approved optimized release profile has
already been found which can not be reproduced with the modified
formulation. In such a case, the clinical tests have either to be
interrupted or have to be started from the beginning. Given the
huge expenditures necessary to bring a new drug formulation up to
and through clinical testing the above scenario has indeed proven
to be rather unsatisfactory.
[0017] Pharmaceutical dosage forms having an increased breaking
strength (resistance to crushing) have been recently reported.
Dosage forms of this type may also exhibit a certain degree of
controlled release of the pharmacologically active compound
contained therein. The major advantage of such pharmaceutical
dosage forms is that comminuting, particularly pulverization, by
conventional means, such as grinding in a mortar or fracturing by
means of a hammer, is impossible or at least substantially
impeded.
[0018] On the one hand, pharmaceutical dosage forms having an
increased breaking strength are useful for avoiding drug abuse of
the pharmacologically active compound contained therein. Many
pharmaceutical active compounds, in addition to having excellent
activity in their appropriate application, also have abuse
potential, i.e., they can be used by an abuser to bring about
effects other than those intended. Opiates, for example, which are
highly active in combating severe to very severe pain, are
frequently used by abusers to induce a state of narcosis or
euphoria. In order to make abuse possible, the corresponding
pharmaceutical dosage forms, such as tablets or capsules are
comminuted, for example ground in a mortar, by the abuser, the
active compound is extracted from the resultant powder using a
preferably aqueous liquid and the resultant solution, optionally
after being filtered through cotton wool or cellulose wadding, and
is administered parenterally, in particular intravenously. An
additional phenomenon of this kind of administration, in comparison
with abusive oral administration, is a further accelerated increase
in active compound levels giving the abuser the desired effect,
namely the "kick" or "rush". This kick is also obtained if the
powdered pharmaceutical dosage form is administered nasally, i.e.
is sniffed. Since controlled-release pharmaceutical dosage forms
containing active compounds with abuse potential do not give rise
to the kick desired by the abuser when taken orally even in
abusively high quantities, such pharmaceutical dosage forms are
also comminuted and extracted in order to be abused. Pharmaceutical
dosage forms exhibiting an increased breaking strength, however,
may not be powdered by conventional means and thus, cannot be
administered nasally thereby avoiding drug abuse. In the context of
such tamper resistant dosage forms, it can be referred to, e.g., WO
2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO
2006/002883, WO 2006/002884, WO 2006/002886, and WO
2006/082097.
[0019] These dosage forms have a breaking strength of at least 500
N in every direction of extension.
[0020] On the other hand, pharmaceutical dosage forms having an
increased breaking strength are useful for avoiding an
(unintentional) overdose of the pharmacologically active compound
contained therein, which overdose would otherwise be caused by
diminishing the retardant effect due to pulverization. It is known
that many patients, particularly older patients frequently have
difficulties in taking solid pharmaceutical dosage forms, such as
tablets, gelatine capsules, etc. They choke on them and sometimes
develop pronounced aversion to such pharmaceutical dosage forms. To
counter this problem, various apparatuses have been developed by
means of which conventional solid pharmaceutical dosage forms may
be comminuted or pulverized ("tablet crushers"). Such apparatuses
are used, for example, by the care staff in old people's homes. The
pharmaceutical 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. However, the comminution of pharmaceutical dosage forms
with such apparatuses is problematic if the pharmaceutical dosage
forms are prolonged-release formulations. As a rule, comminution
results in destruction of the inner structure of the pharmaceutical
dosage form, which is responsible for the prolonged release, so
doing away with the prolonged-release action. Consequently, after
administration, frequently all the physiologically active substance
originally contained in the pharmaceutical dosage form is released
in a relatively short time, whereby a comparatively very high
plasma concentration of the substance is abruptly reached within a
relatively short time frame. In this way, the originally
prolonged-release formulations become immediate release
formulations. 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.
Pharmaceutical dosage forms having an increased breaking strength,
however, cannot be comminuted by tablet crushers and thus, have to
be swallowed as a whole thereby avoiding any (unintentional)
overdose. In this context, it can be further referred to, e.g., WO
2006/082099.
[0021] These dosage forms also have a breaking strength of at least
500 N in every direction of extension.
[0022] The release profile of controlled-release formulations
depends on a variety of factors, such as properties of the
pharmaceutical dosage form per se, nature and content of the
matrix, nature of the release medium, nature and content of the
active compound, nature and content of further pharmaceutical
excipients as well as the interrelationship of these factors. When
the control of the release profile relies on a polymer matrix in
which the active compound is embedded, the release rate depends on
the properties of the pharmaceutical dosage form as such, e.g. its
geometry, method of manufacture, additives and excipients contained
therein, and the like. Further, the release rate depends on the
properties of the matrix polymer, such as molecular weight,
viscosity, particle properties, interaction with other polymers,
chain entanglements, degree of cross-linking, chemical nature of
monomer units, interaction of the matrix material with the release
medium (e.g., swelling and gelling), and the like. Still further,
the release rate depends on the properties of the active compound,
e.g., its dose, particle size, particle form and its solubility in
the release medium, which in turn is a function of various
properties, such as molecular size, molecular weight, ionogenicity,
acidity, steric hindrance, arrangement of dipols, hydrophilicity,
etc. Furthermore, the release rate depends on the individual
interactions of a given matrix material with a given active
compound (cf. Ning Wu et al., Journal of Controlled Release 102
(2005) 569-81; V. S. Manthena et al., Am J Drug Deliv. 2004 2(1)
43-57).
[0023] The release profile of conventional pharmaceutical dosage
forms that do not exhibit an increased breaking strength can
usually be adjusted within certain limits, usually by the variation
of the content and/or the nature of the pharmaceutical excipients,
such as the matrix forming polymer.
[0024] In some cases it has also been reported that the release of
a drug in the body can be controlled by the surface area to volume
ratio of a conventional dosage form which does not exhibit an
increased breaking strength. For example, U.S. Pat. No. 5,427,798
discloses film coated tablets containing bupropion hydrochloride
and having a surface area to tablet volume of 3:1 to 25:1 cm.sup.-1
for tablets of 50, 100 and 150 mg drug content. Similarly, U.S.
Pat. No. 4,940,556 and U.S. Pat. No. 5,198,226 disclose spheroids
containing dihydropyridine calcium channel blockers and having area
radius to circumference radius ratios in the range of 0.85 to
1.0.
[0025] With respect of pharmaceutical dosage forms exhibiting an
increased breaking strength, however, the variation of the content,
the nature of the pharmaceutical excipients and/or the surface area
to volume ratio also affects the mechanical properties. This is
because the increased breaking strength of the pharmaceutical
dosage form typically relies on the presence of a particular
polymer that is processed by a particular method when manufacturing
the pharmaceutical dosage form. It seems that said polymer also
serves as a matrix embedding the pharmacologically active compound.
In consequence, the polymer matrix that is essential to the
breaking strength of the pharmaceutical dosage form simultaneously
serves as a controlled release matrix and thus, varying the
content, nature and/or spacial distribution of the polymer causes
both, a change of the release profile as well as a change of the
mechanical properties of the pharmaceutical dosage form.
[0026] Particular problems arise when the dose of the
pharmacologically active compound and thus, also the total weight
of the pharmaceutical dosage form is comparatively high. Depending
upon the content and the nature of the pharmacologically active
compound and of the pharmaceutical excipients, the retardant effect
of the polymer may be so strong that the pharmaceutical dosage form
cannot be adapted to a specific dosing regimen, e.g., twice daily,
particularly when the increased breaking strength is to be
maintained.
[0027] On the one hand, a decrease of the content of the retardant
polymer for the purpose of accelerating drug release would
substantially affect the mechanical properties of the
pharmaceutical dosage form and in a worst case scenario, would
completely diminish its specific and unique mechanical properties
(breaking strength). Further, a decrease of the content of the
matrix polymer beyond a certain limit may cause a deterioration or
even loss of other desired properties, such as storage stability. A
poor storage stability results, e.g., in a change of the release
profile over time.
[0028] On the other hand, the addition of non-retardant
pharmaceutical excipients (auxiliaries) for the purpose of
weakening the retardant effect of the retardant polymer would
increase the total weight of the dosage form. As highly dosed
pharmaceutical dosage forms have comparatively high total weights
anyway, a further increase of the total weight is disadvantageous
and could deteriorate patient compliance (e.g. swallowability).
[0029] Thus, there is a demand for pharmaceutical dosage forms,
particularly tamper-resistant pharmaceutical dosage forms, the
release profile of which may be varied within certain limits
without diminishing the tamper resistance and without deteriorating
the compliance of the pharmaceutical dosage form.
[0030] It, thus, has been an object of the present invention to
provide an oral dosage form which does not exhibit the shortcomings
of the dosage forms of the state of the art and which in particular
allows for an improved control of the release profile of the active
pharmaceutical ingredient incorporated in the oral dosage form. It
has been another object of the present invention to be able to
regain the original release profile of an elaborated formulation
for an oral dosage form, the release pattern of which has
experienced changes due to modifications to the composition of said
formulation.
[0031] This object has been solved by the subject-matter described
hereinbelow.
SUMMARY OF THE INVENTION
[0032] The present invention relates in a first aspect to a
pharmaceutical dosage form, especially an oral dosage form,
particularly a tablet, comprising at least one pharmaceutically
active ingredient, and having a shape comprising a longitudinal
axis and two opposite longitudinal edges, a transversal axis
perpendicular to the longitudinal axis and two opposite transversal
edges, a front side, an opposite back side and a circumferential
rim between said front and back side, wherein the front side and/or
the back side comprise a basis area and wherein the front side
and/or the back side comprise at least one bulge which extends
above said basis area, said at least one bulge being present at
and/or adjacent to at least a section of one or both longitudinal
edges and/or at and/or adjacent to at least a section of one or
both transversal edges and/or between both longitudinal edges and
both transversal edges. The front side and/or the back side of the
dosage form, in particular the basis area of the front side and/or
the basis area of the back side, can further comprise at least one
indentation.
[0033] The present invention relates in a second aspect to a
tamper-resistant pharmaceutical dosage form having a retarded
release profile, especially a tamper-resistant oral dosage form
having a retarded release profile, particularly a tamper-resistant
tablet having a retarded release profile, comprising at least one
pharmaceutically active ingredient with potential for abuse, and
having a shape comprising a longitudinal axis and two opposite
longitudinal edges, a transversal axis perpendicular to the
longitudinal axis and two opposite transversal edges, a front side,
an opposite back side and a circumferential rim between said front
and back side, wherein the front side and/or the back side comprise
a basis area and wherein the front side and/or the back side
comprise at least one bulge which extends above said basis area,
said at least one bulge being present at and/or adjacent to at
least a section of one or both longitudinal edges and/or at and/or
adjacent to at least a section of one or both transversal edges
and/or between both longitudinal edges and both transversal edges.
The front side and/or the back side of the dosage form, in
particular the basis area of the front side and/or the basis area
of the back side, can further comprise at least one
indentation.
[0034] The present invention relates in a third aspect to a
pharmaceutical dosage form with controlled release of a
pharmacologically active compound (A) contained therein, the
pharmaceutical dosage form having a breaking strength B.sub.1 of at
least 500 N in direction of extension E.sub.1 and having a breaking
strength B.sub.2 of less than 500 N in direction of extension
E.sub.2.
[0035] The pharmaceutical dosage forms according to the invention
preferably exhibit anisotropic mechanical properties (i.e.,
different mechanical properties in different directions).
[0036] With the dosage form of the invention, preferably a tablet,
it is possible to have in general a greater control on the release
profile of pharmaceutically active ingredients. The release profile
can be finely adjusted or tailored in a more accurate, predictable
and reliable manner; the release profile can be manipulated or
tailored so that a variety of retarded release profiles can be
provided for the same formulation. Control of the release profile
with the dosage form of the present invention can be achieved for
dosage forms designed for immediate release or dosage forms
designed for retarded (sustained) release. It is also an advantage
that it is no longer necessary to rely on the choice and amount of
hydrophilic polymer(s) to modify the dissolution profile of a
retarded release formulation which in various circumstances has
proven to not even be possible under realistic conditions.
[0037] It has also been surprisingly found that by modifying the
outer shape of the pharmaceutical dosage form the release profile
may be modified without simultaneously diminishing the breaking
strength of the pharmaceutical dosage form. In particular, it has
been surprisingly found that in spite of a modified outer shape of
the pharmaceutical dosage form which causes a certain degree of
fragility, the overall tamper resistance of the pharmaceutical
dosage form can be maintained.
[0038] Furthermore, it has been surprisingly found that by
modifying the outer shape of the pharmaceutical dosage form the
storage stability, e.g. the storage stability of the release
profile, can be increased compared to conventional dosage forms
having a comparable release profile before storage.
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] FIG. 1A) is a schematic top view of a tablet of the
invention. FIG. 1B) is a cross-sectional view along A-A of the
tablet of FIG. 1A).
[0040] FIG. 2A) is a schematic top view of another embodiment of
the tablet of the invention. FIG. 2B) is a cross-sectional view
along A-A of the tablet of FIG. 2A).
[0041] FIG. 3A) is a schematic top view of another embodiment of a
tablet of the invention. FIG. 3B) is a cross-sectional view along
line A-A of the tablet of FIG. 3A). FIG. 3C) is a cross-sectional
side view along B-B of the tablet of FIG. 3A).
[0042] FIG. 4A) is a schematic top view of another embodiment of a
tablet of the invention. FIG. 4B) is a cross-sectional view along
line A-A of the tablet of FIG. 4A). FIG. 4C) is a cross-sectional
side view along B-B of the tablet of FIG. 4A).
[0043] FIG. 5A) is a schematic top view of another embodiment of a
tablet of the invention. FIG. 5B) is a cross-sectional view along
line A-A of the tablet of FIG. 5A). FIG. 5C) is a cross-sectional
side view along B-B of the tablet of FIG. 5A).
[0044] FIG. 6 is a schematic top view of another embodiment of the
tablet of the invention. FIG. 6B) is a cross-sectional view along
A-A of the tablet of FIG. 6A). FIG. 6C) is a cross-sectional side
view along B-B of the tablet of FIG. 6A).
[0045] FIG. 7A) is a schematic view of a conventional oblong
tablet. FIG. 7B) is a schematic view of an embodiment of a
pharmaceutical dosage form according to the invention having an
increased ratio of surface to volume and surface to weight,
respectively, achieved by a taper right in the middle of the
pharmaceutical dosage form.
[0046] FIG. 8A) is a schematic view of a preferred pharmaceutical
dosage form according to the invention having two recesses on
opposing sides ("inner courtyards"). FIG. 8B) is a schematic view
of the cross-section of the pharmaceutical dosage form depicted in
FIG. 8A) showing that the face of the cross-section assumes the
shape of a H.
[0047] FIG. 9A) is a schematic view of the cross-sectional face of
the pharmaceutical dosage form depicted in FIG. 8A). FIG. 9B) is a
schematic view of the cross-sectional face of a pharmaceutical
dosage form according to the invention that is similar to the
cross-sectional face of the pharmaceutical dosage form depicted in
FIG. 9A). FIG. 9C) is a schematic view of the cross-sectional face
of a pharmaceutical dosage form according to the invention that is
similar to the cross-sectional face of pharmaceutical dosage forms
depicted in FIGS. 9A) and 9B).
[0048] FIG. 10 is a schematic view of a particularly preferred
pharmaceutical dosage form according to the invention. FIG. 10A) is
a top view, FIG. 10B) is a side view.
[0049] FIG. 11 is a schematic view of a conventional pharmaceutical
dosage form comprising a cylindrical central element (53) and two
spherical caps (54a) and (54b).
[0050] FIG. 12 is a schematic view of a cross-section of a
preferred pharmaceutical dosage form divided into voxels (55) of
identical volume and surface to roughly estimate the overall
surface of the dosage form.
[0051] FIG. 13 is a schematic view of pharmaceutical dosage forms
according to the invention. The pharmaceutical dosage form depicted
in FIG. 13A) assumes the shape of a cross, the pharmaceutical
dosage form depicted in FIG. 13B) assumes the shape of a star.
[0052] FIG. 14 is a schematic view of various pharmaceutical dosage
forms according to the invention. The pharmaceutical dosage form
depicted in FIG. 14A) assumes the shape of an eight, the
pharmaceutical dosage form depicted in FIG. 14B) assumes the shape
of a flattened peanut, the pharmaceutical dosage form depicted in
FIG. 14C) assumes the shape of a parallel double cylinder, the
pharmaceutical dosage form depicted in FIG. 14D) assumes the shape
of a parallel double tube, the pharmaceutical dosage form depicted
in FIG. 14E) assumes the shape of a square with a round hole in the
middle, and the pharmaceutical dosage form depicted in FIG. 14F)
assumes the shape of a wavy or corrugated item.
[0053] FIG. 15 is a schematic view of pharmaceutical dosage forms
according to the invention. The pharmaceutical dosage form depicted
in FIG. 15A) assumes the shape of a short tube, the pharmaceutical
dosage form depicted in FIG. 15B) assumes the shape of a ring.
[0054] FIG. 16 is a schematic view of pharmaceutical dosage forms
according to the invention. The pharmaceutical dosage form depicted
in FIG. 16A) assumes the shape of a triangle with two recesses on
opposing sides, the pharmaceutical dosage form depicted in FIG.
16B) assumes the shape of a pentagon with two recesses on opposing
sides.
[0055] FIG. 17 is a schematic view of the cross-sectional face of
the preferred pharmaceutical dosage form depicted in FIG. 10. In
FIG. 17A) the maximum extension (56) of the dosage form orthogonal
to the main area of extension (57) of the dosage form is spaced
from the centre of mass (58) of the dosage form parallel to said
main area of extension (57). In FIG. 17B) the centre of mass (58)
is surrounded by concentric rings (60a) to (60d) indicating
increasing distances from the centre of mass.
[0056] FIG. 18 is a schematic view of the pharmaceutical dosage
form shown in FIG. 10 and the set-up for measuring the breaking
strength in directions of extension E.sub.1, E.sub.2 and E.sub.3,
respectively. FIG. 18A) shows how the pharmaceutical dosage form
should be placed between the two plain jaws (61a) and (61b) of the
measuring device in order to measure the breaking strength in
direction of extension E.sub.1. FIG. 18B) shows how the
pharmaceutical dosage form should be placed between the two plain
jaws (61a) and (61b) of the measuring device in order to measure
the breaking strength in direction of extension E.sub.2. FIG. 18C)
shows how the pharmaceutical dosage form should be placed between
the two plain jaws (61a) and (61b) of the measuring device in order
to measure the breaking strength in direction of extension
E.sub.3.
[0057] FIG. 19 is a preferred embodiment of the measuring system
that is used in order to measure the breaking strength of the
pharmaceutical dosage form according to the invention. The two jaws
(61a) and (61b) of this measuring system are not plain, but contain
an embossment (62) and a cavity (63, 64), respectively. FIG. 19A)
shows a schematic view of jaw (61a) containing embossment (62) and
jaw (61b) containing indentation (63/64). FIG. 19B) shows a
schematic view of jaws (61a) and (61b) on faces (65a) and (65b),
respectively.
[0058] FIG. 20A) shows how the pharmaceutical dosage form shown in
FIG. 10 should be placed between the two jaws (61a) and (61b) of
the measuring device shown in FIG. 19 in order to measure the
breaking strength in direction of extension E.sub.1. FIG. 20B)
shows how the pharmaceutical dosage form should be placed between
the two jaws (61a) and (61b) of the measuring device in order to
measure the breaking strength in direction of extension E.sub.2.
FIG. 20C) shows how the pharmaceutical dosage form should be placed
between the two jaws (61a) and (61b) of the measuring device in
order to measure the breaking strength in direction of extension
E.sub.3.
[0059] FIG. 21 shows the release profile of the tablet according to
inventive example I-2 (H-shape) and of the tablet according to
comparative example C-1 (oblong) immediately after manufacture.
[0060] FIG. 22 shows the release profile of the tablet according to
inventive example I-1 (H-shape) and of the tablet according to
inventive example I-2 (H-shape).
[0061] FIG. 23 shows the release profile of the tablet according to
comparative example C-1 (oblong) before and after storage under
various conditions (40.degree. C., 6 months; 25.degree. C., 9
months; and 30.degree. C., 9 months, respectively).
[0062] FIG. 24 shows that the release profile of the tablet
according to inventive example I-2 (H-shape) before and after
storage under various conditions (40.degree. C., 6 months;
25.degree. C., 9 months; and 30.degree. C., 9 months,
respectively).
DETAILED DESCRIPTION OF THE INVENTION
[0063] Unless expressly stated otherwise, any preferred embodiment
of the invention that will be described in connection with a
particular aspect of the invention hereinafter shall also apply to
the other aspects of the invention. In this regard, embodiments
that have been described in terms of key words that are synonymous
to or at least partially overlap with similar key words mentioned
elsewhere in the specification, such as "pharmaceutically active
ingredient" and "pharmacologically active compound (A)", or
"pharmaceutical dosage form" and "tablet", shall be understood as
being also applicable in terms of said similar key words.
[0064] A first aspect of the invention relates to a pharmaceutical
dosage form, especially an oral dosage form, particularly a tablet,
comprising at least one pharmaceutically active ingredient, and
having a shape comprising a longitudinal axis and two opposite
longitudinal edges, a transversal axis perpendicular to the
longitudinal axis and two opposite transversal edges, a front side,
an opposite back side and a circumferential rim between said front
and back side, wherein the front side and/or the back side comprise
a basis area and wherein the front side and/or the back side
comprise at least one bulge which extends above said basis area,
said at least one bulge being present at and/or adjacent to at
least a section of one or both longitudinal edges and/or at and/or
adjacent to at least a section of one or both transversal edges
and/or between both longitudinal edges and both transversal edges.
The front side and/or the back side of the dosage form, in
particular the basis area of the front side and/or the basis area
of the back side, can further comprise at least one
indentation.
[0065] Although it is also possible that the longitudinal axis and
the transversal axis of the tablet have essentially the same
length, it is preferred that the tablet of the invention has a
longitudinal axis being longer than its transversal axis. That is,
preferred embodiments of the tablet of the invention exhibit an
oblong shape. The longitudinal axis is typically extending through
the middle part of the tablet between both opposing longitudinal
edges from one transversal edge to the opposite transversal edge,
in particular in such a way that its length is maximized. The
transversal axis is typically extending from one longitudinal edge
to the opposite longitudinal edge, in particular in such a way that
its length is maximized. The transversal axis is oriented
perpendicular to the longitudinal axis.
[0066] The basis area of the front side and/or the back side of the
tablet of the invention does not necessarily have to be flat, but
can in one embodiment exhibit an irregular or regular three
dimensional pattern, which, however, is not extending to any
significant degree towards the dimension of a bulge or an
indentation.
[0067] The average distance between the front basis area and the
back basis area of one embodiment of the tablet of the invention
usually is smaller than the length of its transversal axis. Those
opposite sides of the tablet which have the smallest average
distance are usually comprising the front and the back basis
areas.
[0068] According to another preferred embodiment, a tablet is
provided, wherein the front side and the back side each comprise at
least one bulge at least along a section at and/or adjacent to both
longitudinal edges and/or at least along a section at and/or
adjacent to both transversal edges. In this respect it is even more
preferred in certain cases that said front side and said back side
comprise an at least essentially continuous bulge at and/or
adjacent to at least two third of both opposite longitudinal edges
and/or at and/or adjacent to at least two third of both opposite
transversal edges.
[0069] The bulge may have any geometric cross-section, and can, for
example, be rounded or can have a rectangular, triangular or square
cross-section. The bulges preferably have a width which is less
than half the width, more preferably less than one third of the
width of the tablet. The length of the bulges can vary to a great
extent. It is preferred that the overall length of an individual
bulge is at least one half of the length of the longitudinal edge
or of the transversal edge, depending on its location. Typically,
the overall length of a bulge is much longer than its width, e.g.
several times the width of the bulge, such as more than 2, 3, 4, 5
or 6 times of its width, in particular when oriented in the
longitudinal direction, or more than 2, 3 or 4 times of its width,
in particular when oriented in the transversal direction. A bulge
in the meaning of the present invention shall also comprise a
series of adjacent bulge portions. These bulge portions, when
viewed from above, can, for example, have the circumferential form
of a circle, an oval, a rectangle, a square, a triangle or any
other polygonal form, or may come close to these forms, or may even
have an irregular form.
[0070] A bulge which is located at a longitudinal and/or at a
transversal edge regularly passes over from the circumferential rim
of the tablet without a significant transition zone or transition
step, i.e. without a "land". In such an embodiment there is a
smooth transition from the rim part to the bulge part so that the
outer surfaces of the rim and the bulge form a continuous surface
at least over a section. A bulge which is positioned adjacent to a
longitudinal or adjacent to a transversal edge is in contrast
thereto not directly placed at the circumferential rim of the
tablet but is separated from the rim in the plane of the basis area
by a portion, in particular a minor portion, which can be
attributed to be part of the basis area. Said minor portion is
known in the field of tablet technology as "the land". This minor
area usually has a width being smaller than the average width of
the bulge itself. In a preferred embodiment, the land is in the
range from about 0.05 mm to about 0.5 mm, e.g. about 0.1 mm.
[0071] In a particularly suitable embodiment, the tablet of the
invention is provided with bulges at both longitudinal edges and/or
both transversal edges of both the front side and the back side of
the tablet, wherein these bulges extend at least over one half,
more preferably over two thirds of the length of the longitudinal
and/or transversal edges, even more preferably over the whole
length of the longitudinal and/or transversal edges. In another
preferred embodiment, the bulges continuously circumscribe the
basis area of the front side and/or the back side, preferably the
front and the back side, at and/or adjacent to the respective
longitudinal and transversal edges. Most desirable results in terms
of an improved release profile can for example be obtained with
tablets of the invention having bulges at both longitudinal edges
of both sides of the tablet. The cross-section of these tablets can
be described to have or come close to an H-shape. By use of the
expression H-shape it shall just be indicated that a tablet body
having opposite, in particular rather flat, basis areas is provided
with opposing bulges at the longitudinal edges on both sides of the
tablet body. For example, in one H-shape embodiment the bulges can
protrude above their respective basis areas only to a minor extent
compared to the lateral distance between the bulges along opposite
longitudinal edges, e.g. up to about 1 or 2 mm.
[0072] In one preferred embodiment, a tablet of the invention, in
particular its oblong form, comprises at or adjacent to, in
particular adjacent to, major portions of both opposite
longitudinal edges, in particular at least along two thirds of the
longitudinal edges, of the front side at least one bulge. In
another preferred embodiment, a tablet of the invention, in
particular its oblong form, comprises at least one bulge at or
adjacent to, in particular adjacent to, major portions of both
opposite longitudinal edges, in particular at least along two
thirds of the longitudinal edges, of both the front side and the
back side of the tablet. In another preferred embodiment, the
tablet of the invention, in particular its oblong form, comprises a
circumferential bulge at or adjacent to, in particular adjacent to,
the circumferential edge of the front side of said tablet. In
another preferred embodiment, the tablet of the invention, in
particular its oblong form, comprises a circumferential bulge at or
adjacent to, in particular adjacent to, the circumferential edge of
both the front side and the back side of said tablet.
[0073] According to another suitable embodiment of the tablet of
the invention, it is provided that one or both longitudinal edges
are essentially straight over at least a major part of their length
and/or wherein one or both transversal edges are curved over a
major part of their length, in particular curved in the form of an
essentially circular arc. It is of course also possible that the
longitudinal edges exhibit any other irregular or regular shape,
for example, having a wave-like edge portion at least over a
section. It is also possible that the transversal edge exhibits the
shape of a triangle or any other polygonal shape. In general, both
longitudinal and transversal edges form the circumference of the
front side and the back side of the tablet.
[0074] For most applications it is sufficient that the longitudinal
length, that is, the length of the longitudinal axis, of the tablet
does not exceed 30 mm.
[0075] According to another embodiment, the tablet of the invention
preferably has an average thickness over the basis areas of the
front and the back side of at least about 1 mm, and in particular
of no more than about 6 mm, more in particular ranging from about 1
mm to about 3 mm or more in particular ranging from about 2 mm to
about 4 mm.
[0076] According to one embodiment of the tablet of the invention,
the bulge extends perpendicular from the basis area of the front
side and/or from the basis area of the back side in average from
about 0.5 mm to about 2 mm, in particular from about 0.5 mm to
about 1 mm.
[0077] Tablets of the invention preferably have a length in the
longitudinal direction in the range of about 5 mm to about 30 mm,
in particular in the range of about 15 mm to about 25 mm, more in
particular about 17 mm to about 23 mm, even more in particular
about 21 mm; a width in the range of about 5 mm to about 15 mm, in
particular in the range of about 7 mm to about 12 mm, more in
particular about 7 mm to about 10 mm, even more in particular 7 mm,
9 mm or 10 mm; and a thickness over the basis areas in the range of
about 1 mm to about 6 mm, in particular in the range of about 1.5
mm to about 4 mm, even more in particular from 2 mm to about 4 mm,
even further in particular from about 2.5 mm to about 3.5 mm.
[0078] As indicated above, the front side and/or the back side of
the tablet of the invention, in particular the basis area of the
front side and/or the basis area of the back side, can in one
embodiment further comprise at least one indentation. As has been
found, this generally allows for a further improvement of the
control of the release profile. The indentation in general in one
embodiment represents a hollow space which is provided or embedded
in the overall surface of the tablet. For example, the front side,
the back side, in particular the basis areas of the front side
and/or the back side, the rim and/or at least one bulge can be
provided with at least one indentation.
[0079] Indentations, when viewed from above, can have any irregular
or regular shape, for example, the form of a square, rectangle,
triangle, oval or circle. In one embodiment the indentations can
take the form of a cylinder, a cube, a cuboid or a half-sphere,
that is the walls and the opening forming the indentation come
close to describing the form of a cylinder, a cube, a cuboid or a
half-sphere. When viewed from above, the silhouette shape of the
indentations has essentially the same width and length dimensions.
It is also possible that when viewed from above, the silhouette
shape of an indentation has a longer length dimension than a width
dimension, for example, a length dimension which is at least 2, 3
or 4 times the width dimension. Accordingly, when viewed from
above, the silhouette shape can be rather elongate, e.g. a
rectangle, and can have a regular silhouette form, e.g. straight,
wave-like, or zig-zag, or can be rather irregular. In another
embodiment an array of indentations can be formed, for example on
the front side and/or the back side. For many applications it has
been found to be sufficient that when viewed from above, the
silhouette-shape of the indentation has a length dimension which is
essentially identical to its width dimension as, for example, can
be found with a circular, square-like or slightly oval or slightly
rectangular shape. Said width dimension of the indentations, which
is regularly determined parallel to the transversal axis, usually
is less than one half of the transversal length of the tablet, in
particular less than one third of the transversal length of the
tablet. In one embodiment the width dimension is essentially
identical to the depth of the indentation or is no more than 2 or 3
times the depth of the indentation. The length dimension of the
indentation, which is regularly determined parallel to the
longitudinal axis, usually is no longer than three quarters of the
longitudinal length of the tablet, in particular no longer than one
half of the longitudinal length of the tablet, and preferably no
longer than one third of the longitudinal length of the tablet. A
hole in a tablet is not an indentation in the meaning of the
present invention. The silhouette shape and the depth of said
indentations can vary depending on the desired release profile.
Usually care should be taken that the depths of these indentations
does not come too close to the thickness of the tablet in order to
prevent that upon handling a hole through the tablet will be
formed. Preferably the indentations have a depth which does not go
beyond half the thickness of the tablets of the invention. For most
applications it is frequently already sufficient that the maximum
depth of said indentations does not go beyond one third of the
thickness of the tablet of the invention. The average thickness of
the tablet of the invention in general is determined as the
distance between the front and back side of the tablet or
preferably between the basis area of the front side and the basis
area of the back side.
[0080] By using the expressions front side and back side it shall
be indicated that the tablet of the invention has two opposite
sides which each can be provided with bulges and/or indentations.
In consequence, the selection of which is the front side and which
is the back side is rather arbitrary. Accordingly, the expressions
front side and back side could also be replaced by first side and
opposite second side, respectively.
[0081] In one embodiment of the invention, there is provided a
tablet wherein the front side and/or the back side, in particular
the, in particular essentially flat, basis area of the front side
and/or the, in particular essentially flat, basis area of the back
side, comprise in addition to at least one bulge at least one
indentation, in particular between opposite longitudinal and/or
transversal bulges.
[0082] In one embodiment of the invention it is provided that both
the front and the back side comprise at least one indentation.
[0083] The indentations on the front side and on the back side of
the tablet of the invention can at least once be at least partially
off-set or can at least once be positioned in a congruent manner.
In one preferred embodiment, all the indentations of the front side
and all indentations on the back side are at least partially
off-set or are positioned in a congruent manner.
[0084] The indentations are regularly positioned in the basis area
of the front and/or the back side of the tablet of the invention.
It is for example possible to place two or more of such
indentations adjacent to each other, e.g. in a row located between
the longitudinal edges of the front and/or the back side. The
indentations are preferably located between opposite longitudinally
extending bulges at or adjacent to the longitudinal edges of the
front and/or the back side of the tablet of the invention.
[0085] In one preferred embodiment, a tablet of the invention, in
particular its oblong form, comprises at or adjacent to, in
particular adjacent to, major portions of both longitudinal edges,
in particular at least along two thirds of the longitudinal edges
of the front side at least one bulge, and, in particular between
the bulges along opposite longitudinal edges, at least one
indentation.
[0086] In another preferred embodiment, a tablet of the invention,
in particular its oblong form, comprises at least one bulge at or
adjacent to, in particular adjacent to, major portions of both
opposite longitudinal edges, in particular at least along two
thirds of the longitudinal edges of both the front side and the
back side of the tablet as well as at least one indentation on the
front side and/or the back side, in particular on the basis area of
the front side and/or the basis of the back side, of the tablet, in
particular between the bulges which are located along opposite
longitudinal edges on the front side and/or the back side,
respectively. In another preferred embodiment, the tablet of the
invention, in particular its oblong form, comprises a
circumferential bulge at or adjacent to, in particular adjacent to,
the circumferential edge of the front side and/or back side of said
tablet, and at least one indentation on the front side and/or back
side, in particular on the basis area circumscribed by the
circumferential bulge on the front and/or on the back side. In
another preferred embodiment, the tablet of the invention, in
particular its oblong form, comprises a circumferential bulge at or
adjacent to, in particular adjacent to, the circumferential edge of
both the front side and the back side of said tablet and at least
one indentation on the front side and the back side, in particular
on the basis area circumscribed by the circumferential bulge of the
front side and on the basis area circumscribed by the
circumferential bulge of the back side.
[0087] There are generally no limitations as to the
pharmaceutically active ingredient(s) which can be incorporated
into the tablet of the invention.
[0088] Suitable active ingredients are those which exert a local
physiological effect, as well as those which exert a systemic
effect, after oral administration. Examples of suitable active
ingredients encompass:
analgesic and anti-inflammatory drugs (NSAIDs, fentanyl,
indomethacin, ibuprofen, ketoprofen, nabumetone, paracetamol,
piroxicam, tramadol, COX-2 inhibitors such as celecoxib and
rofecoxib); anti-arrhythmic drugs (procainamide, quinidine,
verapamil); antibacterial and antiprotozoal agents (amoxicillin,
ampicillin, benzathine penicillin, benzylpenicillin, cefaclor,
cefadroxil, cefprozil, cefuroxime axetil, cephalexin,
chloramphenicol, chloroquine, ciprofloxacin, clarithromycin,
clavulanic acid, clindamycin, doxyxycline, erythromycin,
flucloxacillin sodium, halofantrine, isoniazid, kanamycin sulphate,
lincomycin, mefloquine, minocycline, nafcillin sodium, nalidixic
acid, neomycin, norfloxacin, ofloxacin, oxacillin,
phenoxymethyl-penicillin potassium, pyrimethamine-sulfadoxime,
streptomycin, TMC207); anti-coagulants (warfarin); antidepressants
(amitriptyline, amoxapine, butriptyline, clomipramine, desipramine,
dothiepin, doxepin, fluoxetine, reboxetine, amineptine, selegiline,
gepirone, imipramine, lithium carbonate, mianserin, milnacipran,
nortriptyline, paroxetine, sertraline;
3-[2-[3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl]ethyl]-2-methyl-4H-pyri-
do[1,2-a]pyrimidin-4-one); anti-diabetic drugs (glibenclamide,
metformin); anti-epileptic drugs (carbamazepine, clonazepam,
ethosuximide, gabapentin, lamotrigine, levetiracetam,
phenobarbitone, phenytoin, primidone, tiagabine, topiramate,
valpromide, vigabatrin); antifungal agents (amphotericin,
clotrimazole, econazole, fluconazole, flucytosine, griseofulvin,
itraconazole, ketoconazole, miconazole nitrate, nystatin,
terbinafine, voriconazole); antihistamines (astemizole,
cinnarizine, cyproheptadine, decarboethoxyloratadine, fexofenadine,
flunarizine, levocabastine, loratadine, norastemizole, oxatomide,
promethazine, terfenadine); anti-hypertensive drugs (captopril,
enalapril, ketanserin, lisinopril, minoxidil, prazosin, ramipril,
reserpine, terazosin); anti-muscarinic agents (atropine sulphate,
hyoscine); antineoplastic agents and antimetabolites (platinum
compounds, such as cisplatin, carboplatin; taxanes, such as
paclitaxel, docetaxel; tecans, such as camptothecin, irinotecan,
topotecan; vinca alkaloids, such as vinblastine, vindecine,
vincristine, vinorelbine; nucleoside derivatives and folic acid
antagonists such as 5-fluorouracil, capecitabine, gemcitabine,
mercaptopurine, thioguanine, cladribine, methotrexate; alkylating
agents, such as the nitrogen mustards, e.g. cyclophosphamide,
chlorambucil, chlormethine, iphosphamide, melphalan, or the
nitrosoureas, e.g. carmustine, lomustine, or other alkylating
agents, e.g. busulphan, dacarbazine, procarbazine, thiotepa;
antibiotics, such as daunorubicin, doxorubicin, idarubicin,
epirubicin, bleomycin, dactinomycin, mitomycin; HER 2antibody, such
as trastuzumab; podophyllotoxin derivatives, such as etoposide,
teniposide; farnesyl transferase inhibitors; anthrachinon
derivatives, such as mitoxantron); anti-migraine drugs (alniditan,
naratriptan, sumatriptan); anti-Parkinsonian drugs (bromocryptine
mesylate, levodopa, selegiline); antipsychotic, hypnotic and
sedating agents (alprazolam, buspirone, chlordiazepoxide,
chlorpromazine, clozapine, diazepam, flupenthixol, fluphenazine,
flurazepam, 9-hydroxyrisperidone, lorazepam, mazapertine,
olanzapine, oxazepam, pimozide, pipamperone, piracetam, promazine,
risperidone, selfotel, seroquel, sertindole, sulpiride, temazepam,
thiothixene, triazolam, trifluperidol, ziprasidone, zolpidem);
anti-stroke agents (lubeluzole, lubeluzole oxide, riluzole,
aptiganel, eliprodil, remacemide); antitussive (dextromethorphan,
laevodropropizine); antivirals (acyclovir, ganciclovir, loviride,
tivirapine, zidovudine, lamivudine, zidovudine+lamivudine,
didanosine, zalcitabine, stavudine, abacavir, lopinavir,
amprenavir, nevirapine, efavirenz, delavirdine, indinavir,
nelfinavir, ritonavir, saquinavir, adefovir, hydroxyurea, TMC120,
TMC125, TMC278); beta-adrenoceptor blocking agents (atenolol,
carvedilol, metoprolol, nebivolol, propanolol); cardiac inotropic
agents (amrinone, digitoxin, digoxin, milrinone); corticosteroids
(beclomethasone dipropionate, betamethasone, budesonide,
dexamethasone, hydrocortisone, methylprednisolone, prednisolone,
prednisone, triamcinolone); disinfectants (chlorhexidine);
diuretics (acetazolamide, frusemide, hydrochlorothiazide,
isosorbide); enzymes; essential oils (anethole, anise oil, caraway,
cardamom, cassia oil, cineole, cinnamon oil, clove oil, coriander
oil, dementholised mint oil, dill oil, eucalyptus oil, eugenol,
ginger, lemon oil, mustard oil, neroli oil, nutmeg oil, orange oil,
peppermint, sage, spearmint, terpineol, thyme); gastro-intestinal
agents (cimetidine, cisapride, clebopride, diphenoxylate,
domperidone, famotidine, lansoprazole, loperamide, loperamide
oxide, mesalazine, metoclopramide, mosapride, nizatidine,
norcisapride, olsalazine, omeprazole, pantoprazole, perprazole,
prucalopride, rabeprazole, ranitidine, ridogrel, sulphasalazine);
haemostatics (aminocaproic acid); lipid regulating agents
(atorvastatin, lovastatin, pravastatin, probucol, simvastatin);
local anaesthetics (benzocaine, lignocaine); opioid analgesics
(buprenorphine, codeine, dextromoramide, dihydrocodeine,
hydrocodone, oxycodone, morphine); parasympathomimetics and
anti-dementia drugs (ATT-082, eptastigmine, galanthamine,
metrifonate, milameline, neostigmine, physostigmine, tacrine,
donepezil, rivastigmine, sabcomeline, talsaclidine, xanomeline,
memantine, lazabemide); peptides and proteins (antibodies,
becaplermin, cyclosporine, erythropoietin, immunoglobulins,
insuline); sex hormones (oestrogens; conjugated oestrogens,
ethinyloestradiol, mestranol, oestradiol, oestriol, oestrone;
progestogens; chlormadinone acetate, cyproterone acetate,
17-deacetyl norgestimate, desogestrel, dienogest, dydrogesterone,
ethynodiol diacetate, gestodene, 3-keto desogestrel,
levonorgestrel, lynestrenol, medroxy-progesterone acetate,
megestrol, norethindrone, norethindrone acetate, norethisterone,
norethisterone acetate, norethynodrel, norgestimate, norgestrel,
norgestrienone, progesterone, quingestanol acetate); stimulating
agents (sildenafil); vasodilators (amlodipine, buflomedil, amyl
nitrite, diltiazem, dipyridamole, glyceryl trinitrate, isosorbide
dinitrate, lidoflazine, molsidomine, nicardipine, nifedipine,
oxpentifylline, pentaerythritol tetranitrate); their N-oxides,
their pharmaceutically acceptable acid or base addition salts and
their stereochemically isomeric forms.
[0089] Pharmaceutically acceptable acid addition salts comprise the
acid addition salt forms which can conveniently be obtained by
treating the base form of the active ingredient with appropriate
organic and inorganic acids. Active ingredients containing an
acidic proton may be converted into their non-toxic metal or amine
addition salt forms by treatment with appropriate organic and
inorganic bases. The term addition salt also comprises the hydrates
and solvent addition forms which the active ingredients are able to
form. Examples of such forms are e.g. hydrates, alcoholates and the
like. The N-oxide forms of the active ingredients comprise those
active ingredients wherein one or several nitrogen atoms are
oxidized to the so-called N-oxide.
[0090] The active ingredient(s) is (are) present in the dosage form
in a therapeutically effective amount. The amount that constitutes
a therapeutically effective amount varies according to the
ingredients being used, the condition being treated, the severity
of said condition, the patient being treated, and whether the
dosage form is designed for an immediate or retarded release. The
amount of active ingredient(s) used in the present invention
preferably ranges from about 0.01% to about 90% (w/w), in
particular from about 0.01% to about 50% (w/w), more in particular
from about 20% to about 50% (w/w).
[0091] Unless explicitly stated otherwise, in the meaning of the
present invention the indication "w/w" shall mean weight of the
compound specified per total weight of the composition forming the
tablet.
[0092] In one embodiment, the one or more active ingredients are
incorporated in a tablet for immediate release.
[0093] In another embodiment, the one or more active ingredients
are incorporated in a tablet for retarded release. In this case,
the active ingredient(s) of the tablet of the invention is (are)
conventionally embedded in conventional formulating aids and/or one
or more hydrophilic polymers. These hydrophilic polymers tend to
swell upon contact with aqueous fluids following administration,
and result in a viscous, drug release regulating gel layer.
Preferably the viscosity of these polymers ranges from 150 to
100.000 mPas (apparent viscosity of a 2% aqueous solution at
20.degree. C.). Examples of suitable hydrophilic polymers include:
[0094] alkylcelluloses, such as, methylcellulose; [0095]
hydroxyalkylcelluloses, for example, hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose and
hydroxybutylcellulose; [0096] hydroxyalkyl alkylcelluloses, such
as, hydroxyethyl methylcellulose and hydroxypropyl methylcellulose;
[0097] carboxyalkylcelluloses, such as, carboxymethylcellulose;
[0098] alkali metal salts of carboxyalkylcelluloses, such as,
sodium carboxymethylcellulose; [0099] carboxyalkylalkylcelluloses,
such as, carboxymethylethylcellulose; [0100] carboxyalkylcellulose
esters; [0101] other natural, semi-synthetic, or synthetic
polysaccharides, such as, alginic acid, alkali metal and ammonium
salts thereof, carrageenans, galactomannans, tragacanth, agar-agar,
gummi arabicum, guar gummi, xanthan gummi, starches, pectins, such
as sodium carboxymethylamylopectin, chitin derivates such as
chitosan, polyfructans, inulin; polyacrylic acids and the salts
thereof; [0102] polymethacrylic acids and the salts thereof,
methacrylate copolymers; [0103] polyvinylalcohol; [0104]
polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl
acetate; [0105] combinations of polyvinylalcohol and
polyvinylpyrrolidone; [0106] polyalkylene oxides such as
polyethylene oxide and polypropylene oxide and copolymers of
ethylene oxide and propylene oxide.
[0107] Preferably the one or more hydrophilic polymers are
cellulose derivatives, in particular cellulose ether derivatives,
such as for example alkylcelluloses or hydroxyalkylcelluloses or
hydroxyalkyl alkylcelluloses, more in particular
hydroxyalkylcelluloses or hydroxyalkyl alkylcelluloses.
[0108] Most preferred cellulose ether derivatives are hydroxypropyl
methylcellulose (HMPC) and hydroxypropyl cellulose (HPC). Different
viscosity grades of hydroxypropyl cellulose and hydroxypropyl
methylcellulose are commercially available. Hydroxypropyl
methylcellulose preferably used in the present invention has a
viscosity grade ranging from about 3,500 mPas to about 100,000
mPas, in particular ranging from about 4,000 mPas to about 20,000
mPas and most in particular a viscosity grade of about 6,500 mPas
to about 15,000 mPas (apparent viscosity of a 2% aqueous solution
at 20.degree. C.), e.g. hypromellose 2208 (DOW, Antwerp, Belgium).
Hydroxypropyl cellulose having a viscosity lower than 1,500 mPas
(apparent viscosity of a 2% aqueous solution at 20.degree. C.) is
preferred, in particular hydroxypropyl cellulose having a viscosity
in the range from about 150 to about 700 mPas, preferably from 200
to 600 mPas, e.g. Klucel EF (Hercules, Wilmington, USA).
[0109] Preferably, the amount of viscous hydrophilic polymers, in
particular HPMC and HPC, in the present formulation ranges from
about 0.01 to about 80% (w/w), in particular from about 10 to about
60% (w/w), more in particular between 30 and 60% (w/w).
[0110] In addition to the one or more hydrophilic polymers, the
retarded release formulation can in one embodiment comprise
pregelatinized starch. The amount of pregelatinized starch
preferably is in the range from 5 to 80% (w/w), in particular from
5 to 15% (w/w).
[0111] In one embodiment, the tablet of the invention comprises at
least one pharmaceutically active ingredient, pregelatinized
starch, and HPC and/or HPMC, in particular at least one
pharmaceutically active ingredient, pregelatinized starch, HPC and
HPMC.
[0112] The tablets according to the invention are preferably
prepared by way of compression using a die and a punch.
[0113] The tablets of the invention can optionally be provided,
partially or completely, with a conventional tablet coating. The
tablets of the present invention are preferably film coated with
art-known film coating compositions. The coating is applied to
improve the aesthetic impression and/or the taste of the tablets
and the ease with which they can be swallowed. Coating the tablets
of the present invention can also serve other purposes, e.g.
improving stability and shelf-life. Suitable coating formulations
comprise a film forming polymer such as, for example, hydroxypropyl
methylcellulose, e.g. hypromellose 2910 (5 mPas), a plasticizer
such as, for example, a glycol, e.g. propylene glycol or
polyethylene glycol, an opacifier, such as, for example, titanium
dioxide, and a film smoothener, such as, for example, talc.
Suitable coating solvents are water as well as organic solvents.
Examples of organic solvents are alcohols, e.g. ethanol or
isopropanol, ketones, e.g. acetone, or halogenated hydrocarbons,
e.g. methylene chloride. Optionally, the coating can contain a
therapeutically effective amount of one or more active ingredients
to provide for an immediate release of said active ingredient(s)
and thus for an immediate relief of the symptoms treated by said
active ingredient(s). Coated tablets of the present invention are
prepared by first making the tablet cores in the way as described
above and subsequently coating said tablet cores using conventional
techniques, such as coating in a coating pan. For example, PEG,
e.g. PEG 20.000, or HPMC can be used for the coating.
[0114] Beside active ingredient(s) and optional hydrophilic
polymers, the tablet of the present invention can also optionally
comprise pharmaceutically acceptable formulation agents such as
fillers, glidants, binding agents, granulating agents, anti-caking
agents, lubricants, flavors, dyes, and preservatives.
[0115] The filler may be selected from soluble fillers, for
example, sucrose, lactose, trehalose, maltose, mannitol, sorbitol,
inulin, and from insoluble fillers, for example, dicalcium or
tricalcium phosphate, talc. An interesting filler is lactose, in
particular, lactose monohydrate. Different grades of lactose can be
used. One type of lactose preferably used in the present invention
is lactose monohydrate 200 mesh (DMV, Veghel, the Netherlands).
Another lactose monohydrate, lactose monohydrate of the type DCL 11
(DMV, Veghel, the Netherlands), can also preferably be used. The
notation DCL refers to "Direct Compression Lactose". The number 11
is a reference number of the manufacturer. This type of lactose is
characterised in that 98% (w/w) of the particles, based on the
total amount of lactose employed, have a diameter smaller than 250
.mu.m, 30% (w/w) to 60% (w/w) of the particles, based on the total
amount of lactose employed, have a diameter of 100 .mu.m, and at
maximum 15% (w/w) of the particles, based on the total amount of
lactose employed, have a diameter of smaller than 45 .mu.m. The
weight percentage of filler ranges between about 6% and about 54%
(w/w).
[0116] Among the optional formulating agents that further can be
comprised in the present formulation there can be mentioned agents
such as polyvidone; starch; acacia gum; gelatin; seaweed
derivatives, e.g. alginic acid, sodium and calcium alginate;
cellulose derivatives, e.g. ethylcellulose, hyoroxypropyl
methylcellulose, having useful binding and granulating properties;
glidants such as colloidal silica, starch or talc; lubricants such
as magnesium stearate and/or palmitate, calcium stearate, stearic
acid, polyethylene glycol, liquid paraffin, sodium or magnesium
lauryl sulphate; anti-adherents such as talc and corn starch.
[0117] The first aspect of the present invention can be more
readily understood by reference to FIGS. 1-6.
[0118] In FIG. 1A) a tablet 1 is depicted showing its front side 2
from the top. The tablet 1 has a longitudinal axis 4 in the
longitudinal direction and a transversal axis 6, perpendicular
thereto, in the transversal direction. The two opposing
longitudinal edges 8 and 10 and the two opposing transversal edges
12 and 14 are forming the circumference of the front side 2 of the
tablet 1. In the depicted embodiment the longitudinal edges 8, 10
are essentially straight whereas the transversal edges 12, 14 are
rounded. Tablet 1 of FIG. 1A) has a circumferential bulge 16, 20 on
both the upper side 2 and the lower side 18 (FIG. 1B)) having
reference sign 20. The bulges 16 and 20 are positioned adjacent to
the longitudinal and transversal edges and raise above the basis
area 22 of the front side 2, and above the basis area 24 of the
back side 18, respectively. In the embodiment shown in FIG. 1A),
1B) the basis areas 22, 24 have a transversal width "a" which is
smaller than the transversal width "b" of the bulges.
[0119] In FIG. 2A) tablet 1 is depicted which is rather similar to
the tablet shown in FIG. 1A) with the difference that the lateral
width a of the basis area 22 of the front side 2 is larger than the
transversal width b of the respective bulges 16, 20 of the front
side 2 and the back side 18, respectively. The embodiment of the
tablet 1 of FIG. 2A) also differs from that of FIG. 1A) insofar as
the basis areas 22, 24 are no longer completely flat as depicted in
FIG. 1B) but can be curved inwardly, in particular in a symmetrical
manner towards the center, as depicted in FIG. 2B).
[0120] Both embodiments as shown in FIGS. 1 and 2 have in common
that the circumferential rim 26 which connects the front side 2 and
the back side 18 has a rather flat profile as can be derived from
FIGS. 1B) and 2B).
[0121] In FIG. 3A) another embodiment of tablet 1 of the invention
is shown which differs from the tablet as depicted in FIG. 2A)
insofar as the basis areas 22 and 24 of the front side 2 and the
back side 18, respectively, each are provided with four
indentations 28. These indentations 28 have an essentially circular
shape and are positioned in a row within the basis areas 22 and 24
(s.a. FIG. 3B) and FIG. 3C)). As can be derived from FIGS. 3B) and
3C) the indentations 28 of the front side 2 are placed in a
congruent manner with respect to the indentations 30 in the basis
area 24 of the back side 18. Again, the rim 26 has a rather flat
profile. The indentations 28, 30 have a trough-like, hollow form in
the depicted embodiment, that is, from the circumferential rim of
the indentations the depth is slightly increasing up to the center
of the indentations, which can, for example be derived from FIG.
3B).
[0122] The embodiment of tablet 1 according to the invention as
depicted in FIG. 4A) differs from the embodiment of FIG. 3A) in
that the bulges 16 and 20 of the front and back sides 2, 18 are no
longer present along the entire circumference of the tablet. In the
embodiment of FIG. 4 sections of the opposite transversal edges 12
and 14 of the front side 2 and back side 18 are no longer provided
with a bulge section. Accordingly, the bulge 16 of the front side 2
extends only along the longitudinal edges 8 and 10 of the front
side as well as over portions of opposing transversal edges 12 and
14 of the front side leaving on both opposing transversal edges of
the front and back side significant portions without any bulge. The
same applies to the back side in the present case. The individual
bulge portions of the front side of the embodiment of FIG. 4 have
been assigned reference numbers 17a and 17b for the front side 2
and 21a and 21b for the back side 18. The indentations 28 and 30 of
the front and back side are lying within the basis areas 22 and 24,
respectively, and are placed in a congruent manner as with the
embodiment of FIG. 3 (s.a. FIG. 4C)). Again, the circumferential
rim 26 has an essentially flat configuration.
[0123] The embodiment of a tablet 1 of the present invention as
depicted in FIG. 5A) differs from the tablet as shown in FIG. 4
only insofar as the indentations 28 of the front side 2 and the
indentations 30 of the back side 18 are no longer located in a
congruent manner, but are at least partially off-set as can be best
derived from FIG. 5C).
[0124] FIG. 6A) shows another embodiment of a tablet 1 of the
invention which is rather similar to the embodiment depicted in
FIG. 1, for example, as to the circumferential bulge 16 on the
front side 2 as well as to the circumferential bulge 20 on the back
side 18 (not shown in FIG. 6A, but in FIGS. 6B) and 6C)) and as to
its oblong shape and dimensions. Different from the tablet of FIG.
1 the embodiment shown in FIG. 6 makes use of a circumferential
land 32 on the front side 2 of a tablet as well as of such a
corresponding circumferential land 34 on back side 18 (not shown in
FIG. 6A), but in FIGS. 6B) and 6C)). That is, the circumferential
bulges 16 and 20 are not extending up to circumferential rim 26,
but are located adjacent to, i.e. spaced apart from said rim 26. As
can be derived from FIGS. 6B) and 6C) the bulge 16 does not
smoothly go over into the rim section 26, but terminates adjacent
to the rim section thereby furnishing a small portion which is
located at a height somewhat similar to that of the basis area 22
of the front side 2. The same applies to the circumferential land
34 and the bulge 20 on the back side 18. In the embodiment shown in
FIGS. 6A) to 6C) the land 32 of the front side 2 is not exactly
lying in the plane of the basis area 22, but slightly above. This
can be best derived from FIG. 6C). The same applies to the land 34
of the back side 18. For certain tablet formulations it has been
found advantageous to make use of, in particular circumferential,
land sections, for example, in order to alleviate the die punching
cycle in mass production.
[0125] A second aspect of the invention relates to a
tamper-resistant pharmaceutical dosage form having a retarded
release profile, especially a tamper-resistant oral dosage form
having a retarded release profile, particularly a tamper-resistant
tablet having a retarded release profile, comprising at least one
pharmaceutically active ingredient with potential for abuse, and
having a shape comprising a longitudinal axis and two opposite
longitudinal edges, a transversal axis perpendicular to the
longitudinal axis and two opposite transversal edges, a front side,
an opposite back side and a circumferential rim between said front
and back side, wherein the front side and/or the back side comprise
a basis area and wherein the front side and/or the back side
comprise at least one bulge which extends above said basis area,
said at least one bulge being present at and/or adjacent to at
least a section of one or both longitudinal edges and/or at and/or
adjacent to at least a section of one or both transversal edges
and/or between both longitudinal edges and both transversal edges.
The front side and/or the back side of the dosage form, in
particular the basis area of the front side and/or the basis area
of the back side, can further comprise at least one
indentation.
[0126] In general, the foregoing teachings relating to the first
aspect of the present invention are also applicable to this second
aspect of the present invention. However, there are emphasized the
following:
[0127] A preferred embodiment of the tablet of the present
invention is a tablet with a length (longitudinal axis) of about 21
mm; a width (transversal axis) of about 9 mm; a thickness from the
top of the bulge on the front side to the top of the opposite bulge
on the back side of about 5 mm; a thickness over the basis area of
about 3 mm and an extension of the top of the bulge from the basis
area of about 1 mm, and in particular having a circumferential
bulge on the front and/or on the back side of the tablet, and
preferably without any indentations, as for example derivable from
FIG. 1A.
[0128] Active ingredients with potential for abuse are known to the
person skilled in the art and comprise tranquillisers, stimulants,
barbiturates, narcotics, opioids or opioid derivatives.
[0129] A pharmaceutically active ingredient which is preferably
used with the tamper-resistant tablets of the invention is an
analgesic compound or a pain-killing compound, such as for example
an opioid or an opioid derivative, in particular tapentadol or
salts thereof, more in particular tapentadol.
[0130] By tamper-resistant it is meant that the active ingredient
can not readily be separated from the tablet in a form suitable for
abuse because the tablet is such that it can not easily be grinded.
This renders extraction of the active ingredient, which could be
used for drug-abuse, from the tablet difficult or this renders it
very difficult to transform the tablet into a powder for
sniffing.
[0131] The tablet of the invention can in one embodiment be
rendered tamper-resistant by incorporating at least one synthetic
or natural polymer which increases the breaking strength of the
tablet so that it is much higher than a conventional tablet. In
this way, pulverization of the tablet by conventional means, such
as for example by a pestle and mortar, is rendered almost
impossible, and, hence, the conversion of the active ingredient
incorporated in the tablet in a form which is suitable for abuse is
complicated.
[0132] In one embodiment of the present invention, said at least
one synthetic or natural polymer is a polyalkylene oxide such as
polyethylene oxide and polypropylene oxide and copolymers of
ethylene oxide and propylene oxide.
[0133] Preferably, the polyalkylene oxide is polyethylene oxide, in
particular polyethylene oxide having a molecular weight above
500,000, preferably above 1,000,000, and more preferably in the
range of about 2,000,000 to about 7,000,000. The amount of
polyethylene oxide can in one embodiment range from about 20 to
about 80% (w/w), in particular from about 20 to 50% (w/w), more in
particular from about 30 to about 50% (w/w).
[0134] In one embodiment, the tablet of the present invention has a
breaking strength of at least 300 N, in particular at least 350N,
more in particular at least 400N, even more in particular at least
450 N. The breaking strength of the tablet of the invention can be
determined by the method for determining breaking strength of
tablets described in the European Pharmacopoeia 1997, page 143,
144, method No. 2.9.8.
[0135] Retarded release of an active ingredient from an oral dosage
form is known to a person skilled in the art. For a retarded
release tablet, it usually is sufficient to administer the tablet
once or twice daily. The retarded release profile of the tablet of
the present invention can be achieved by embedding the active
ingredient in an amount of hydrophilic polymer or of a blend of
hydrophilic polymers, optionally also containing conventional
formulating agents. These hydrophilic polymers tend to swell upon
contact with aqueous fluids following administration, and result in
a viscous, drug release regulating gel layer. Preferably the
viscosity of these polymers ranges from 150 to 100.000 mPas
(apparent viscosity of a 2% aqueous solution at 20.degree. C.).
Examples of suitable hydrophilic polymers include: [0136]
alkylcelluloses, such as, methylcellulose; [0137]
hydroxyalkylcelluloses, for example, hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose and
hydroxybutylcellulose; [0138] hydroxyalkyl alkylcelluloses, such
as, hydroxyethyl methylcellulose and hydroxypropyl methylcellulose;
[0139] carboxyalkylcelluloses, such as, carboxymethylcellulose;
[0140] alkali metal salts of carboxyalkylcelluloses, such as,
sodium carboxymethylcellulose; [0141] carboxyalkylalkylcelluloses,
such as, carboxymethylethylcellulose; [0142] carboxyalkylcellulose
esters; [0143] other natural, semi-synthetic, or synthetic
polysaccharides, such as, alginic acid, alkali metal and ammonium
salts thereof, carrageenans, galactomannans, tragacanth, agar-agar,
gummi arabicum, guar gummi, xanthan gummi, starches, pectins, such
as sodium carboxymethylamylopectin, chitin derivates such as
chitosan, polyfructans, inulin; polyacrylic acids and the salts
thereof; [0144] polymethacrylic acids and the salts thereof,
methacrylate copolymers; [0145] polyvinylalcohol; [0146]
polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl
acetate; [0147] combinations of polyvinylalcohol and
polyvinylpyrrolidone.
[0148] In one embodiment of the invention, the hydrophilic polymer
in which the active ingredient is embedded is selected from a
cellulose derivative. Preferably, the cellulose derivative is a
cellulose ether derivative, more preferably the cellulose ether
derivative is HPMC. The amount of cellulose derivative can in one
embodiment range from about 1 to about 20% (w/w), in particular
from about 10 to about 20% (w/w).
[0149] In addition to said synthetic or natural polymer which
increases the breaking strength of the tablet, in particular
polyalkylene oxide, and to said hydrophilic polymers, the tablet
formulation in one embodiment can further comprise a polyalkylene
glycol, such as for example PEG 6000. The amount of polyalkylene
glycol can for example range from about 1 to about 20% (w/w), in
particular from about 1 to about 10% (w/w).
[0150] In one embodiment, the tamper-resistant tablet of the
invention comprises at least one pharmaceutically active ingredient
with potential for abuse, in particular a pain-killing drug, more
in particular an opioid or an opioid derivative, e.g. tapentadol;
at least one polyalkylene oxide, in particular polyethylene oxide,
more in particular polyethylene oxide having a molecular weight in
the range of about 2,000,000 to 7,000,000; at least one cellulose
ether derivative, in particular hydroxypropyl methylcellulose
(HMPC); and at least one polyalkylene glycol, in particular
polyethylene glycol, such as PEG 6000. In preferred compositions
further components can be present such as anti-oxidants, for
example vitamin E. In another embodiment, the tablet comprises
pharmaceutically active ingredient with potential for abuse in an
amount of at least 5 weight percent; polyethylene oxide in an
amount of at least 15 weight percent; cellulose ether derivatives,
in particular HPMC, in an amount of at least 5 weight percent; and
polyalkylene glycol, in particular polyethylene glycol, in an
amount of at least 5 weight percent.
[0151] The tamper-resistant tablets of the present invention are
preferably prepared by melt-extruding the tablet formulation. The
thus obtained melt-extruded strands are preferably cut into
monoliths, which are then compressed into tablets.
[0152] It has, for example, been found that in particular when the
tablet of the invention is produced from melt extruded monolithic
masses, very hard compacted tablets are obtained which can no
longer be easily grinded or crushed thereby allowing for a very
high degree of tamper-resistance. With these very hard tablets an
improved control of the drug release profile can be obtained by the
tablet of the present invention.
[0153] The tablets according to the invention are preferably
prepared by way of compression using a die and a punch, preferably
from a monolithic mass obtained by melt extrusion. If obtained via
melt extrusion, the compressing step is preferably carried out with
a monolithic mass exhibiting ambient temperature, that is, a
temperature in the range from 20 to 25.degree. C.
[0154] The strands obtained by way of extrusion can either be
subjected to the compression step as such or can be cut prior to
the compression step. It is of course also possible to subject the
extruded strands to the compression step or to the cutting step
when still warm, that is more or less immediately after the
extrusion step. The extrusion is preferably carried out by way of
twin-screw extruder.
[0155] The aforementioned polymers used for the preparation of the
tablet of the invention, that is, the chains of these polymers are
preferably predominantly oriented along the direction of the
extrusion. In case the monolith resulting from extrusion has a
length greater than its width, the compression of said monolith is
preferably performed with a compression direction perpendicular to
the length.
[0156] A third aspect of the invention relates to a pharmaceutical
dosage form with controlled release of a pharmacologically active
compound (A) contained therein, the pharmaceutical dosage form
having a breaking strength B.sub.1 of at least 500 N in a direction
of extension E.sub.1, and having a breaking strength B.sub.2 of
less than 500 N in a direction of extension E.sub.2.
[0157] In general, the foregoing teachings relating to the first
aspect of the invention and the second aspect of the invention are
also applicable to this third aspect of the invention. However,
there are emphasized the following:
[0158] Direction of extension E.sub.1 and direction of extension
E.sub.2, respectively, can principally be any directions of
extension of the pharmaceutical dosage form, i.e., any arbitrarily
chosen directions of extension, provided that the corresponding
requirement for the breaking strength B.sub.1 and B.sub.2,
respectively, is satisfied.
[0159] The "breaking strength" (resistance to crushing) of a
pharmaceutical dosage form is known to the skilled person. In this
regard it can be referred to, e.g., W. A. Ritschel, Die Tablette,
2. Auflage, Editio Cantor Verlag Aulendorf, 2002; H Liebermann et
al., Pharmaceutical dosage forms: Tablets, Vol. 2, Informa
Healthcare; 2 edition, 1990; and Encyclopedia of Pharmaceutical
Technology, Informa Healthcare; 1 edition.
[0160] For the purpose of the specification, the breaking strength
is preferably defined as the amount of force that is necessary in
order to fracture the pharmaceutical dosage form (=breaking force).
Therefore, for the purpose of the specification the dosage form
does preferably not exhibit the desired breaking strength when it
breaks, i.e., is fractured into at least two independent parts that
are separated from one another. In another preferred embodiment,
however, the pharmaceutical dosage form is regarded as being broken
if the force decreases by 25% (threshold value) of the highest
force measured during the measurement (see below).
[0161] The dosage forms according to the invention are preferably
distinguished from conventional dosage forms in that, due to their
breaking strength, they cannot be pulverized 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 pulverization,
in particular devices developed for this purpose (tablet crushers).
In this regard "pulverization" means crumbling into small particles
that would immediately release the pharmacologically active
compound (A) in a suitable medium. Avoidance of pulverization
virtually rules out oral or parenteral, in particular intravenous
or nasal abuse.
[0162] Conventional tablets typically have a breaking strength well
below 200 N in any direction of extension. The breaking strength of
conventional round tablets may be estimated according to the
following empirical formula: Breaking Strength [in
N]=10.times.Diameter Of The Tablet [in mm]. Thus, according to said
empirical formula, a round tablet having a breaking strength of at
least 500 N would require a diameter of at least 50 mm (about 2
inches). Such a tablet, however, could not be swallowed. The above
empirical formula does not apply to the pharmaceutical dosage forms
of the invention, which are not conventional but rather
special.
[0163] Further, the actual mean chewing force is about 220 N (cf.,
e.g., P. A. Proeschel et al., J Dent Res, 2002, 81(7), 464-468,
copy attached). This means that conventional tablets having a
breaking strength well below 200 N may be crushed upon chewing,
whereas the dosage forms according to the invention may not, at
least not in direction of extension E.sub.1.
[0164] Still further, when applying a gravitational acceleration of
about 9.81 m/s.sup.2, 500 N correspond to a gravitational force of
more than 50 kg, i.e. the pharmaceutical dosage forms according to
the invention can withstand a weight of more than 50 kg, at least
in direction of extension E.sub.1.
[0165] Methods for measuring the breaking strength of a
pharmaceutical dosage form are known to the skilled artisan.
Suitable devices are commercially available.
[0166] For example, the breaking strength (resistance to crushing)
can be measured in accordance with the European Pharmacopoeia 5.0,
2.9.8 or 6.0, 2.09.08 "Resistance to Crushing of Tablets". The test
is intended to determine, under defined conditions, the resistance
to crushing of tablets, measured by the force needed to disrupt
them by crushing. The apparatus consists of 2 jaws facing each
other, one of which moves towards the other. The flat surfaces of
the jaws are perpendicular to the direction of movement. The
crushing surfaces of the jaws are flat and larger than the zone of
contact with the tablet. The apparatus is calibrated using a system
with a precision of 1 Newton. The tablet is placed between the
jaws, taking into account, where applicable, the shape, the
break-mark and the inscription; for each measurement the tablet is
oriented in the same way with respect to the direction of
application of the force (and the direction of extension in which
the breaking strength is to be measured). The measurement is
carried out on 10 tablets, taking care that all fragments of
tablets have been removed before each determination. The result is
expressed as the mean, minimum and maximum values of the forces
measured, all expressed in Newton.
[0167] A similar description of the breaking strength (breaking
force) can be found in the US Pharmacopoeia. The breaking strength
can alternatively be measured in accordance with the method
described therein where it is stated that the breaking strength is
the force required to cause a tablet to fail (i.e., break) in a
specific plane. The tablets are generally placed between two
platens, one of which moves to apply sufficient force to the tablet
to cause fracture. For conventional, round (circular cross-section)
tablets, loading occurs across their diameter (sometimes referred
to as diametral loading), and fracture occurs in the plane. The
breaking force of tablets is commonly called hardness in the
pharmaceutical literature; however, the use of this term is
misleading. In material science, the term hardness refers to the
resistance of a surface to penetration or indentation by a small
probe. The term crushing strength is also frequently used to
describe the resistance of tablets to the application of a
compressive load. Although this term describes the true nature of
the test more accurately than does hardness, it implies that
tablets are actually crushed during the test, which is often not
the case.
[0168] Alternatively, the breaking strength (resistance to
crushing) can be measured in accordance with WO 2006/082099, which
can be regarded as a modification of the method described in the
European Pharmacopoeia. The apparatus used for the measurement is
preferably a "Zwick Z 2.5" materials tester, F.sub.max=2.5 kN with
a maximum draw of 1150 mm, which should be set up with one column
and one spindle, a clearance behind of 100 mm and a test speed
adjustable between 0.1 and 800 mm/min together with testControl
software. Measurement is performed using a pressure piston with
screw-in inserts and a cylinder (diameter 10 mm), a force
transducer, F.sub.max. 1 kN, diameter=8 mm, class 0.5 from 10 N,
class 1 from 2 N to ISO 7500-1, with manufacturer's test
certificate M according to DIN 55350-18 (Zwick gross force
F.sub.max=1.45 kN) (all apparatus from Zwick GmbH & Co. KG,
Ulm, Germany) with Order No BTC-FR 2.5 TH. D09 for the tester,
Order No BTC-LC 0050N. P01 for the force transducer, Order No BO
70000 S06 for the centring device.
[0169] In a preferred embodiment of the invention, the breaking
strength is measured by means of a breaking strength tester
Sotax.RTM., type HT100 (Allschwil, Switzerland). Preferably, the
Auto Alignment.TM. device of the Sotax.RTM. HT100 is not used, just
to allow placing the dosage form individually between the jaws in
order to measure the breaking strength in specific directions of
extension. The Sotax.RTM. HT100 can measure the breaking strength
according to two different measurement principles: constant speed
(where the test jaw is moved at a constant speed adjustable from
5-200 mm/min) or constant force (where the test jaw increases force
linearly adjustable from 5-100 N/sec). In principle, both
measurement principles are suitable for measuring the breaking
strength of the dosage form according to the invention. Preferably,
the breaking strength is measured at constant speed, preferably at
a constant speed of 120 mm/min.
[0170] In a preferred embodiment, the pharmaceutical dosage form is
regarded as being broken if it is fractured into at least two
separate pieces.
[0171] In another preferred embodiment, the pharmaceutical dosage
form is regarded as being broken if the force decreases by 25%
(threshold value) of the highest force measured during the
measurement. For example, if the highest force measured during the
measurement is 144 N, the tablet is regarded as being broken when
the force decreases below 108 N (=75% of 144 N; decrease by 25%).
The value of the breaking strength in the respective direction of
extension is then 144 N. In a preferred embodiment, said threshold
value is 30%, more preferably 35%, still more preferably 40%, most
preferably 45% and in particular 50%. Under these circumstances, a
dosage form may have to be regarded as being broken although it has
not been fractured into at least two separate pieces. For example,
a dosage form that has been torn in the middle but that has not
been fragmented, may have to be regarded as being broken in
accordance with this definition of the breaking strength. Thus, in
accordance with this definition, failure of the breaking strength
test at a particular force may be due to fracture of the dosage
form or any other deformation that causes the force to drop below
the above threshold value, e.g. rupture, cracking, dunting,
cleaving, fissure, and the like.
[0172] FIG. 18 schematically illustrates the measurement of the
breaking strength of the dosage form depicted in FIG. 10, in
particular the adjustment device for the dosage form used for this
purpose before and during the measurement, in three different
directions of extension a) to c). This measurement set-up is
applicable to the various methods for measuring the breaking
strength of the dosage form, including the above method according
to the European Pharmacopeia, the variation thereof (according to
Zwick) and the preferred method using the Sotax.RTM. HT100. To this
end, the dosage form is held between the plain jaw (61a) and the
plain jaw (61b) of the force application apparatus (not shown) with
the assistance of two 2-part clamping devices, which are in each
case firmly attached (not shown) to the jaws once the spacing
necessary for accommodating and centering the tablet to be measured
has been established. The spacing may be established by moving the
2-part clamping devices horizontally outwards or inwards in each
case on the jaw on which they are mounted. The measurement of the
breaking strength in different directions of extensions is
illustrated in FIG. 18A) to FIG. 18C). FIG. 18A) illustrates the
arrangement for measuring the breaking strength in direction of
extension E.sub.1 that is perpendicular to the main direction of
extension E.sub.2 of the dosage form. FIG. 18B) illustrates the
arrangement for measuring the breaking strength in the main
direction of extension E.sub.2 of the dosage form. This arrangement
is the standard arrangement when measuring the breaking strength of
conventional oblong tablets. The Auto Alignment.TM. device of the
Sotax.RTM. HT100 serves the purpose of aligning the tablet shapes
automatically in order to ensure reproducible results in this
direction of extension. According to the present invention,
however, the breaking strength of the dosage form needs to be
measured in different directions of extension and the main
direction of extension may be among said different directions of
extension, but does not have to necessarily. FIG. 18C) illustrates
the arrangement for measuring the breaking strength in direction of
extension E.sub.3 that is perpendicular to the main direction of
extension E.sub.2 of the dosage form as well as perpendicular to
direction of extension E.sub.1.
[0173] In a preferred embodiment, the breaking strength tester,
preferably the Sotax.RTM. HT100, is equipped with two plain jaws
(cf. FIG. 18).
[0174] In another preferred embodiment, the breaking strength
tester, preferably the Sotax.RTM. HT100, is equipped with two jaws
that are not plain (cf. FIGS. 19, 20). Preferably, one jaw contains
an embossment and the other jaw contains an indentation. Embossment
and indentation can be congruent with one another (like positive
and negative), but do not have to.
[0175] Preferably, the embossment serves as an arbor, spike or
mandrel and can be round of angular (e.g., triangular, rectangular,
etc.). In a preferred embodiment, the embossment assumes the shape
of a hemisphere. In another preferred embodiment, the embossment
assumes the shape of a cone. In yet another preferred embodiment,
the embossment assumes the shape of a trigonal or rectangular
pyramid. Most preferably, the embossment assumes the shape of a
half cylinder, preferably having a radius of curvature of 2.5 mm.
In a preferred embodiment, the centre of said half cylinder lies
within the surface of the main area of extension of the jaw. In
another preferred embodiment, the centre lies about 0.5 mm away
from said surface, just in the inside of the jaw.
[0176] Preferably, the indentation serves as a recess for the
embossment. In a preferred embodiment, the indentation assumes the
shape of a hollow hemisphere. In another preferred embodiment, the
indentation assumes the shape of a hollow cone. In yet another
preferred embodiment, the indentation assumes the shape of a hollow
trigonal or rectangular pyramid. Most preferably, the indentation
assumes the shape of a chamfering, kerf or notch with an angle of
preferably 90.degree..
[0177] FIG. 19A) shows a schematic view of jaw (61a) containing
embossment (62) and jaw (61b) containing indentation (63/64). The
embossment (62) assumes the shape of a half cylinder that is
characterized by radius r. Preferably, r=2.5 mm. The center of the
circular cross-section of the half cylinder may lie within the
surface main area of extension of the jaw so that the entire half
cylinder forms the embossment (62). Alternatively, the center of
the circular cross-section of the half cylinder may lie within the
body of the jaw, e.g. at a distance r' from the surface of the main
area of extension, so that the only a part of the half cylinder
forms the embossment (62). Preferably, r'=0 or 0.5 mm. The
indentation is located in a rectangular recess (64) having a side
length of 2 x.sub.1+2 x.sub.2 and a height of y.sub.2. In the
centre of said rectangular recess (64) is located a chamfering,
kerf or notch (63) having a side length of 2 x.sub.1 and a
height/depth of y.sub.1. In a preferred embodiment, x.sub.1=3 mm,
x.sub.2=6 mm, y.sub.1=3 mm and y.sub.2=2 mm. In another preferred
embodiment, x.sub.1=4 mm, x.sub.2=7 mm, y.sub.1=4 mm and y.sub.2=2
mm. Preferably, the chamfering, kerf or notch (63) assumes an angle
of 90.degree.. FIG. 19B) shows a schematic view of jaws (61a) and
(61b) on faces (65a) and (65b), respectively.
[0178] FIG. 20 shows in analogy to FIG. 18 how the dosage form
depicted in FIG. 10 should be placed between the two jaws having
embossment and indentation, respectively, in order to measure the
breaking strength in directions of extension E.sub.1, E.sub.2 and
E.sub.3. The skilled person recognizes that during the measurement,
i.e. the movement of the jaws towards one another, it may become
necessary to additionally clamp the dosage form, e.g. by means of
suitable guiding shafts or leading tracks (not shown), in order to
avoid that the dosage form is tilted or evades to the side.
[0179] In general, a measuring set-up with jaws equipped with
embossment and indentation (cf. FIG. 20) realizes harsher measuring
conditions than a measuring set-up with plain jaws (cf. FIG. 18).
Thus, it may happen that a given dosage form which passes the
measurement in accordance with FIG. 18 fails when being measured in
the same direction of extension in accordance with FIG. 20.
[0180] As far as tablet orientation during the measurement of the
breaking force is concerned, the US Pharmacopoeia (USP) states that
in general, tablets are tested either across the diameter or
parallel to the longest axis. Scored tablets have two orientation
possibilities. When they are oriented with their scores
perpendicular to the platen faces, the likelihood that tensile
failure will occur along the scored line increases. This provides
information about the strength of the matrix at the weakest point
in the structure. When scored tablets are oriented with their
scores parallel to the platen faces, more general information about
the strength of the matrix is derived. Capsule-shaped tablets or
scored tablets may best be broken in a three-point flexure test. A
fitting, which is either installed on the platens or substituted
for the platens, supports the tablet at its ends and permits the
breaking load to be applied to the opposite face at the unsupported
midpoint of the tablet. The fittings are often available from the
same source that supplies the hardness tester. FIG. 20 is in
accordance with this description in the USP.
[0181] The pharmaceutical dosage form according to the invention
preferably has a breaking strength B.sub.1 of at least 500 N in
direction of extension E.sub.1. Preferably, direction of extension
E.sub.1 is perpendicular to the main direction of extension of the
dosage form.
[0182] Preferably, the breaking strength in direction of extension
E.sub.1 is at least 500 N regardless of whether the measuring
device is equipped with plain jaws or with two jaws one of which
containing an embossment and the other containing an indentation,
as described above.
[0183] Further, the pharmaceutical dosage form according to the
invention preferably has a breaking strength B.sub.2 of less than
500 N in direction of extension E.sub.2. Preferably, direction of
extension E.sub.2 is the main direction of extension of the dosage
form. Preferably, the breaking strength in direction of extension
E.sub.2 is less than 500 N when being measured with two plain jaws.
However, it is not required (but possible) that the breaking
strength in direction of extension E.sub.2 is less than 500 N when
being measured with two jaws one of which containing an embossment
and the other containing an indentation, as described above.
[0184] In a preferred embodiment according to the invention, the
breaking strength B.sub.1 of the pharmaceutical dosage form in
direction of extension E.sub.1 is measured in accordance with FIG.
20A), i.e. orthogonal to the main direction of extension and by
means of embossment and indentation. The breaking strength B.sub.2
in direction of extension E.sub.2, however, is preferably measured
in accordance with FIG. 18B), i.e. along the main direction of
extension and by means of plain jaws.
[0185] The pharmaceutical dosage form according to the invention
preferably exhibits mechanical strength over a wide temperature
range, in addition to the breaking strength (resistance to
crushing) optionally also sufficient hardness, impact resistance,
impact elasticity, tensile strength and/or modulus of elasticity,
optionally also at low temperatures (e.g. below -24.degree. C.,
below -40.degree. C. or in liquid nitrogen), for it to be virtually
impossible to pulverize by spontaneous chewing, grinding in a
mortar, pounding, etc. Thus, preferably, in direction of extension
E.sub.1 the comparatively high breaking strength of the
pharmaceutical dosage form according to the invention is maintained
even at low or very low temperatures, e.g., when the pharmaceutical
dosage form is initially chilled to increase its brittleness, for
example to temperatures below -25.degree. C., below -40.degree. C.
or even in liquid nitrogen.
[0186] The pharmaceutical dosage form according to the invention is
preferably characterized by a certain degree of breaking strength.
This does not mean that the pharmaceutical dosage form must also
exhibit a certain degree of hardness. Hardness and breaking
strength are different physical properties. Therefore, the tamper
resistance of the pharmaceutical dosage form does not necessarily
depend on the hardness of the pharmaceutical dosage form. For
instance, due to its breaking strength, impact strength, elasticity
modulus and tensile strength, respectively, the pharmaceutical
dosage form can preferably be deformed when exerting an external
force, for example using a hammer, but cannot be pulverized, i.e.,
crumbled into a high number of fragments. In other words, the
pharmaceutical dosage form according to the invention is
characterized by a certain degree of breaking strength, but not
necessarily also by a certain degree of form stability.
[0187] Therefore, in the meaning of the specification, a
pharmaceutical dosage form that is deformed when being exposed to a
force in a particular direction of extension but that does not
break is to be regarded as having the desired breaking strength in
said direction of extension.
[0188] Due to the anisotropic mechanical properties in directions
of extension E.sub.1 and E.sub.2, the application of force with
conventional means, e.g. the application of 400 N, may cause
disruption of the dosage form to a certain and limited degree, but
may not cause pulverization thereof. For example, when the breaking
strength in direction of extension E.sub.2 is below 400 N, the
dosage form is disrupted into pieces by applying 400 N in direction
of extension E.sub.2. Preferably, however, said pieces may not be
disrupted any further by applying 400 N or more.
[0189] It has been surprisingly found that the outer shape of the
pharmaceutical dosage forms may be varied within wide limits
without diminishing their breaking strength. Although a variation
of the outer shape of the pharmaceutical dosage forms may cause a
decrease of the breaking strength in a certain direction of
extension, it has been found that specific forms and shapes
establish a certain degree of fragility at predetermined sites of
fracture (weakening points) without completely diminishing the
overall breaking strength of the remainder of the pharmaceutical
dosage forms (fragments).
[0190] The degree of weakening can be controlled and when exerting
a force on the pharmaceutical dosage forms, said weakening points
can serve as predetermined sites of fracture, provided that the
amount of force is sufficiently high.
[0191] The degree of fragility may be adjusted to values that are
still well above the typical breaking strength of conventional
pharmaceutical dosage forms, e.g. well above 100 N or 200 N. In
particular, it has been surprisingly found that pharmaceutical
dosage forms can be designed which can be fractured into large
pieces, e.g. into halves or thirds, by conventional means (e.g.
tablet crushers), but not any further. In consequence, the
resultant fragments (subunits) in turn exhibit a breaking strength
which is far above the breaking strength at the predetermined site
of fracture, e.g. well above 500 N, preferably in any direction of
extension.
[0192] FIG. 7A) is a schematic view of a conventional oblong
tablet. Cross-sectional areas (35) and (35') are smaller than
cross-sectional areas (36) and (36') which in turn are smaller than
cross-sectional area (37). When exerting external force (F.sub.2)
in direction of extension (E.sub.2), the implied pressure is not
constant but varies with varying cross-sectional areas. For
example, the pressure implied at the section having cross-sectional
area (37) is lower than the pressure at the section having
cross-sectional areas (35) and (35'), respectively, because
cross-sectional area (37) is larger than cross-sectional areas (35)
and (35').
[0193] FIG. 7B) is a schematic view of an embodiment of a
pharmaceutical dosage form according to the invention. An increased
surface to volume ratio and surface to weight ratio, respectively,
is achieved by taper T right in the middle of the pharmaceutical
dosage form. Under these circumstances, when exerting external
force (F.sub.2) in direction of extension (E.sub.2), the implied
pressure at the section having cross-sectional area (42) is higher
than the pressure at the section having cross-sectional areas (38)
and (38'), respectively, because cross-sectional area (42) is
smaller than cross-sectional areas (38) and (38'). The
pharmaceutical dosage form depicted in FIG. 7B) exhibits a breaking
strength in direction of extension (E.sub.2) that is substantially
lower than the breaking strength of the pharmaceutical dosage form
depicted in FIG. 7A) in direction of extension (E.sub.2).
[0194] In FIGS. 7A) and 7B), direction of extension (E.sub.2) is
the principal direction of extension of the pharmaceutical dosage
forms (main direction of extension, major direction of
extension).
[0195] The predetermined sites of fracture (weakening points) can
improve the patient compliance, as patients having problems in
swallowing large pharmaceutical dosage forms can fracture the
pharmaceutical dosage forms along the predetermined sites of
fracture (weakening points) prior to swallowing. Those patients can
limitedly fracture the pharmaceutical dosage form into fragments of
a size they can swallow. However, as the resultant fragments in
turn cannot be comminuted any further, at least not by conventional
means, the pharmaceutical dosage forms are still tamper resistant,
i.e. efficiently avoid drug abuse and (unintentional) drug
overdose, respectively. In other words, the pharmaceutical dosage
forms according to the invention realize both, a very high
mechanical resistance in order to avoid misuse as well as a certain
degree of a mechanical weakness in order to improve patient
compliance.
[0196] In a preferred embodiment, the pharmaceutical dosage form
according to the invention provides fragments when exerting a force
higher than B.sub.2 in direction of extension E.sub.2, preferably
under the standard conditions for measuring the breaking strength
set forth above, said fragments in turn having a breaking strength
of preferably at least 500 N, at least 550 N or at least 600 N;
more preferably at least 650 N, at least 700 N or at least 750 N;
still more preferably at least 800 N, at least 850 N or at least
900 N; yet more preferably at least 950 N, at least 1000 N or at
least 1100 N; and in particular at least 1200 N, at least 1300 N,
at least 1400 N or at least 1500 N; preferably in any (each and
every) of their directions of extension.
[0197] Preferably, the dosage form provides at most 10, more
preferably at most 8, still more preferably at most 6, yet more
preferably at most 5, most preferably at most 4 and in particular
at most 3 fragments when exerting a force that is higher than
B.sub.2 in direction of extension E.sub.2.
[0198] Preferably the volume of each fragment is at least 5%, more
preferably at least 10%, still more preferably at least 15%, yet
more preferably at least 20%, most preferably at least 25% and in
particular at least 30% of the volume of the pharmaceutical dosage
form.
[0199] It has been surprisingly found that the release profile of
the pharmaceutical dosage form may be varied within certain limits
by varying the outer shape of the pharmaceutical dosage form
without diminishing its tamper resistance. Therefore, particularly
at a high drug load, the pharmaceutical dosage forms according to
the invention allow to realize release profiles that may not be
achieved with conventional pharmaceutical dosage forms having an
increased breaking strength (e.g. oblong tablets).
[0200] Typically, the pharmaceutical dosage form according to the
invention assumes the form of a tablet. The pharmaceutical dosage
form is preferably not in film form.
[0201] The pharmaceutical dosage form according to the invention
may assume various shapes. Preferably, from top view, the shape of
the pharmaceutical dosage form can be substantially hexagonal,
elliptic, cyclic, oblong, rectangular, squared, triangular, and the
like. Preferably, from side view, the shape of the pharmaceutical
dosage form can be substantially flat-convex, biconvex, flat with
facet, flat without facet, cyclic, and the like.
[0202] For example, the pharmaceutical dosage form according to the
invention may assume simple geometries, such as spherical, planar,
cubic, hexagonal and cylindrical, or complex geometries, such as
convex, hollow cylindrical, doughnut-shaped, hemispheric,
cruciform, astral (cf. FIGS. 13, 14 and 15).
[0203] Particularly preferred shapes of the dosage form according
to the invention have already been described in connection with the
first and second aspects of the invention above.
[0204] In a particularly preferred embodiment, the pharmaceutical
dosage form according to the invention can be described as a body
having a recess or cavity on at least one side, preferably two
recesses or two cavities on two sides, preferably on opposing
sides. Alternatively, said cavities and recesses, respectively, may
be regarded as bulges, indentations, troughs, hollows, depressions,
synclines, deepenings, and the like. Examples of such embodiments
are depicted in FIGS. 8-10, 16A) and 16B).
[0205] The pharmaceutical dosage form is preferably adapted for
oral administration, i.e., should be capable of being swallowed.
Thus, obscure geometrical forms which are obviously harmful cannot
be regarded as pharmaceutical dosage forms according to the
invention.
[0206] According to a preferred embodiment, the pharmaceutical
dosage form is characterized by a specific aspect ratio. For the
purpose of the specification, the aspect ratio is defined as the
ratio of the main direction of extension of the dosage form to the
maximum extension of the pharmaceutical dosage form orthogonal to
said main direction of extension, e.g. maximum length to maximum
height (and maximum length to maximum width, respectively).
Preferably, said aspect ratio is within the range of 2.4.+-.1.3:1,
more preferably 2.4.+-.1.0:1, still more preferably 2.4.+-.0.8:1,
yet more preferably 2.4.+-.0.6:1, most preferably 2.4.+-.0.4:1 and
in particular 2.4.+-.0.2:1.
[0207] According to a preferred embodiment, the pharmaceutical
dosage form is characterized by a specific length to height to
width ratio, where length>height.gtoreq.width. For the purpose
of the specification, in this embodiment the length corresponds to
the main direction of extension of the dosage form, the height
corresponds to the maximum extension of the pharmaceutical dosage
form orthogonal to the length, and the width corresponds to the
maximum extension orthogonal to the length and orthogonal to the
width (Cartesian space). Preferably, the length to height to width
ratio is within the range of 4.7.+-.2.0:2.0.+-.1.0:1, more
preferably 4.7.+-.1.6:2.0.+-.0.8:1, still more preferably
4.7.+-.1.2:2.0.+-.0.6:1, yet more preferably
4.7.+-.0.8:2.0.+-.0.4:1, most preferably 4.7.+-.0.6:2.0.+-.0.3:1,
and in particular 4.7.+-.0.4:2.0.+-.0.2:1.
[0208] Preferably, a portion of the surface of the pharmaceutical
dosage form is convex, i.e. curved out or bulged outward, and
another portion of its surface is concave, i.e. curved in or
hollowed inward. For the purpose of the specification, the radius
of curvature is not critical.
[0209] Preferably, the overall surface of the pharmaceutical dosage
form can be divided into concave portions, convex portions and
planar portions. Typically, the sum of the concave portions, convex
portions and planar portions corresponds to the overall surface of
the dosage form. However, at least theoretically, a given portion
can be convex and concave simultaneously (saddle). Under these
circumstances, the sum of the concave portions, convex portions and
planar portions exceeds the overall surface of the dosage form.
[0210] In a preferred embodiment, the convex portion of the surface
of the dosage form is at most 95%, more preferably at most 90% or
at most 85%, still more preferably at most 80% or at most 75%, yet
more preferably at most 70% or at most 65%, most preferably at most
60% or at most 55% and on particular at most 50% or at most 45%,
based on the sum of concave portions, convex portions and planar
portions.
[0211] In another preferred embodiment, the concave portion of the
surface of the dosage form is at least 5%, more preferably at least
10% or at least 15%, still more preferably at least 20% or at least
25%, yet more preferably at least 30% or at least 35%, most
preferably at least 40% or at least 45% and in particular at least
50% or at least 55%, based on the sum of concave portions, convex
portions and planar portions.
[0212] In a preferred embodiment of the pharmaceutical dosage form
according to the invention, the maximum extension of the dosage
form orthogonal to the main area of extension of the dosage form is
spaced from the centre of mass of the dosage form parallel to said
main area of extension. For the purpose of the specification, the
main area of extension of the dosage form is preferably the largest
plain area that can be placed along a cut of the body of the dosage
form. This embodiment is further illustrated in FIG. 17A) which
shows a schematic view of the cross-sectional face of the preferred
pharmaceutical dosage form depicted in FIG. 10. The maximum
extension (56) of the dosage form orthogonal to the main area of
extension (57) of the dosage form is spaced from the centre of mass
(58) of the dosage form parallel to said main area of extension
(57).
[0213] Preferably, the closest distance (59) from the maximum
extension of the dosage form orthogonal to the main area of
extension of the dosage form to the centre of mass of the dosage
form is at least 0.5 mm, more preferably at least 1.0 mm, still
more preferably at least 1.5 mm, yet more preferably at least 2.0
mm, most preferably at least 2.5 mm and in particular at least 3.0
mm.
[0214] Preferably, the pharmaceutical dosage form according to the
invention has a shape so that when exerting an increasing amount of
force in direction of extension E.sub.2, the dosage form is firstly
deformed and, when the amount of force reaches the breaking
strength B.sub.2, deformation causes tractive forces that lead to
disruption of the dosage form.
[0215] In a preferred embodiment, the cross sectional area of the
pharmaceutical dosage form that is orthogonal to the main direction
of extension and that contains the centre of mass of the dosage
form has a shape so that at least 50%, more preferably at least 60%
and in particular at least 75% of its area is spaced at least 0.2
mm, at least 0.3 mm, at least 0.4 mm or at least 0.5 mm, more
preferably at least 0.6 mm, at least 0.7 mm, at least 0.8 mm or at
least 0.9 mm, still more preferably at least 1.0 mm, at least 1.1
mm, at least 1.2 mm or at least 1.3 mm, yet more preferably at
least 1.4 mm, at least 1.5 mm, at least 1.6 mm or at least 1.7 mm,
most preferably at least 1.8 mm, at least 1.9 mm, at least 2.0 mm
or at least 2.1 mm and in particular at least 2.2 mm, at least 2.3
mm, at least 2.4 mm or at least 2.5 mm from the centre of mass.
Preferably, said cross sectional area contains the centre of mass
as well as direction of extension E.sub.1, or the centre of mass as
well as direction of extension E.sub.2. This embodiment is further
illustrated in FIG. 17B) in which the centre of mass (58) is
surrounded by concentric rings (60a) to (60d) indicating increasing
distances from the centre of mass (58). The portions of the cross
sectional area which do not overlap with any of the concentric
rings are spaced from the centre of mass by more than the radius of
ring (60d).
[0216] In a preferred embodiment of the pharmaceutical dosage form
according to the invention, the closest distance of each and every
geometrical point within the dosage form to the surface of the
dosage form is at most 10 mm, at most 9 mm, at most 8 mm or at most
7.5 mm; more preferably at most 7.0 mm, at most 6.5 mm or at most
6.0 mm; still more preferably at most 5.8 mm, at most 5.6 mm, at
most 5.4 mm, at most 5.2 mm or at most 5.0 mm; yet more preferably
at most 4.8 mm, at most 4.6 mm, at most 4.4 mm, at most 4.2 mm or
at most 4.0 mm; yet more preferably at most 3.8 mm, at most 3.6 mm,
at most 3.4 mm, at most 3.2 mm or at most 3.0 mm; most preferably
at most 2.8 mm, at most 2.6 mm, at most 2.4 mm, at most 2.2 mm or
at most 2.0 mm; and in particular at most 1.8 mm, at most 1.6 mm,
at most 1.4 mm, at most 1.2 mm or at most 1.0 mm.
[0217] Preferably, the pharmaceutical dosage form according to the
invention is not radial symmetric about its main direction of
extension (principal direction of extension), preferably the
pharmaceutical dosage form is not radial symmetric at all.
[0218] In a preferred embodiment, the symmetry of the
pharmaceutical dosage form is selected from the group consisting of
C.sub.i, C.sub.s, C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5,
C.sub.6, C.sub.7, C.sub.8, C.sub..infin., C.sub.2h, C.sub.3h,
C.sub.4h, C.sub.5h, C.sub.6h, C.sub.7h, C.sub.8h, C.sub..infin.h,
C.sub.2v, C.sub.3v, C.sub.4v, C.sub.5v, C.sub.6v, C.sub.7v,
C.sub.8v, Coov, C.sub.3i, D.sub.2, D.sub.3, D.sub.4, D.sub.5,
D.sub.6, D.sub.7, D.sub.8, D.sub..infin., D.sub.2h, D.sub.3h,
D.sub.4h, D.sub.5h, D.sub.6h, D.sub.7h, D.sub.8h, D.sub..infin.h,
D.sub.2d, D.sub.3d, D.sub.4d, D.sub.5d, D.sub.6d, D.sub.7d,
D.sub.8d, D.sub..infin.d, S.sub.2, S.sub.4, S.sub.6, S.sub.8, T,
T.sub.h, T.sub.d, O, O.sub.h and I.sub.h according to Schoenflies
notation. D.sub.2h and D.sub.4h are particularly preferred.
[0219] In a preferred embodiment, the centre of mass of the
pharmaceutical dosage form lies within the main area of extension
of the dosage form. Preferably, the pharmaceutical dosage form is
symmetric about its main area of extension.
[0220] The pharmaceutical dosage form according to the invention
preferably has a breaking strength B.sub.1 of at least 500 N in at
least one of its directions of extension, namely E.sub.1,
preferably, however, in more than one of its directions of
extension, more preferably in a plurality of directions of
extension.
[0221] In direction of extension E.sub.1 the pharmaceutical dosage
form according to the invention preferably has a breaking strength
B.sub.1 of at least 500 N, preferably of at least 510 N, at least
520 N, at least 530 N, at least 540 N or at least 550 N; more
preferably at least 560 N, at least 570 N, at least 580 N, at least
590 N or at least 600 N; still more preferably at least 620 N, at
least 640 N, at least 660 N, at least 680 N or at least 700 N; yet
more preferably at least 720 N, at least 740 N, at least 760 N, at
least 780 N or at least 800 N; most preferably at least 850 N, at
least 900 N, at least 950 N, at least 1000 N or at least 1050 N;
and in particular at least 1100 N, at least 1200 N, at least 1300
N, at least 1400 N, at least 1500 N, at least 1600 N, at least 1700
N, at least 1800 N, at least 1900 N or at least 2000 N.
[0222] E.sub.1 may be any direction of extension of the
pharmaceutical dosage form, i.e. any straight line connecting any
first point on the surface of the pharmaceutical dosage form with
any second point on the surface of the pharmaceutical dosage form.
Preferably, said straight line lies completely within the body of
the pharmaceutical dosage form, i.e., preferably does not "leave"
the pharmaceutical dosage form somewhere and "reenters" the
pharmaceutical dosage form elsewhere. Preferably, the distance
between said first point and said second point of direction of
extension E.sub.1 is at least 50%, more preferably at least 75% of
the main direction of extension of the pharmaceutical dosage form.
The latter is defined as the maximal distance between two points on
the surface of the pharmaceutical dosage form (principal direction
of extension), regardless of whether it completely lies within the
body of the dosage form or not. Preferably, the main direction of
extension of the dosage form goes through the centre of mass of the
dosage form.
[0223] In a preferred embodiment, the main direction of extension
of the pharmaceutical dosage form according to the invention is not
longer than 32 mm, more preferably not longer than 30 mm, still
more preferably not longer than 28 mm, yet more preferably not
longer than 26 mm, most preferably not longer than 24 mm, and in
particular not longer than 22 mm.
[0224] In a preferred embodiment, the pharmaceutical dosage form
according to the invention is deformed in the breaking strength
tester when the measurement of the breaking strength is conducted.
Deformation means typically compression, although bending, turning
and other modes of deformation are also possible. When exerting a
force of 100 N in direction of extension E.sub.1, the dosage form
is preferably deformed by at least 0.1 mm but does not break. When
exerting a force of 200 N in direction of extension E.sub.1, the
dosage form is preferably deformed by at least 0.2 mm, more
preferably at least 0.3 mm, but does not break. When exerting a
force of 300 N in direction of extension E.sub.1, the dosage form
is preferably deformed by at least 0.5 mm, more preferably at least
0.7 mm, but does not break. When exerting a force of 400 N in
direction of extension E.sub.1, the dosage form is preferably
deformed by at least 1.0 mm, more preferably at least 1.2 mm, but
does not break. When exerting a force of 500 N in direction of
extension E.sub.1, the dosage form is preferably deformed by at
least 1.5 mm, more preferably at least 2.0 mm, but does not break.
When exerting a force of 1000 N in direction of extension E.sub.1,
the dosage form is preferably deformed by at least 3.0 mm, more
preferably at least 4.0 mm, but does not break.
[0225] For theoretical reasons, every pharmaceutical dosage form
comprises an unlimited number of directions of extension.
[0226] Some typical directions of extension of a preferred
pharmaceutical dosage form according to the invention are
illustrated in FIG. 8. FIG. 8A) shows different directions of
extension. Directions of extension E.sub.9 and E.sub.10 are
parallel to one another, directions of extension E.sub.10, E.sub.11
and E.sub.12 (and E.sub.9, respectively) are orthogonal to one
another. Directions of extension E.sub.9, E.sub.10, E.sub.11 and
E.sub.12 enter the body of the pharmaceutical dosage form at sites
(43), (44), (45) and (46), respectively. Direction of extension
E.sub.9 lies completely within the body of the pharmaceutical
dosage form; it enters the body of the pharmaceutical dosage form
at site (43 and leaves the body of the pharmaceutical dosage form
at its rear side (not shown). Direction of extension E.sub.10,
however, enters the body of the pharmaceutical dosage form at site
(44), transiently leaves the body of the pharmaceutical dosage form
at the rear side of the upper front edge (not shown) and re-enters
the body of the pharmaceutical dosage form at site (44'), before it
finally leaves the body of the pharmaceutical dosage form at its
rear side (not shown). Direction of extension E.sub.13 enters the
body of the pharmaceutical dosage form at corner (47) and leaves
the pharmaceutical dosage form at the diagonally opposite corner.
The dotted line of direction of extension E.sub.13 represents the
maximal distance between two points on the surface of the
pharmaceutical dosage form, i.e., direction of extension E.sub.13
is the main direction of extension of the pharmaceutical dosage
form. In total, the pharmaceutical dosage form depicted in FIG. 8A)
has four of such main directions of extension.
[0227] FIG. 8B) shows a cross-sectional view of the pharmaceutical
dosage form according to FIG. 8A). The cross-sectional face (48,
hatched) assumes the shape of an H. The pharmaceutical dosage form
assumes a rectangular shape with two recesses (50, 50') on opposing
sides. In other words, the pharmaceutical dosage form has the size
of a comparatively flat rectangle with an edge (49) circumventing
the upper side and an edge (49') circumventing the opposite side.
Pharmaceutical dosage forms of this type may be manufactured by a
tabletting tool that is equipped with a so-called H-plunger.
[0228] FIG. 9A) is a schematic view of the cross-sectional face
(48) of the pharmaceutical dosage form depicted in FIG. 8A). FIG.
9B) is a schematic view of the cross-sectional face of a
pharmaceutical dosage form according to the invention that is
similar to the cross-sectional face of the pharmaceutical dosage
form depicted in FIG. 9A). The rim (49) of the cross-sectional
face, however, is rounded (51) thereby forming a convex surface
area. FIG. 9C is a schematic view of the cross-sectional face of a
pharmaceutical dosage form according to the invention that is
similar to the cross-sectional face of pharmaceutical dosage forms
depicted in FIGS. 9A) and 9B). The edge at the bottom of the recess
is rounded (52) thereby forming a concave surface area.
[0229] FIG. 10 is a schematic view of a particularly preferred
pharmaceutical dosage form according to the invention. FIG. 10A) is
a top view which is identical from both opposing sides and FIG.
10B) is a side-view which is also identical from both opposing
sides.
[0230] In the Cartesian space, the principal dimensions of the
pharmaceutical dosage form schematically illustrated in FIG. 10 can
be defined as a, b and c, where a=a.sub.1+a.sub.2+a.sub.3,
b=b.sub.1+b.sub.2+b.sub.3 and c=c.sub.1+c.sub.2+c.sub.3. Preferred
relative dimensions D1 to D6 of the pharmaceutical dosage form
depicted in FIG. 10 can be defined in relative relations of a, b
and c; a.sub.1, a.sub.2 and a.sub.3; b.sub.1, b.sub.2 and b.sub.3;
and c.sub.1, c.sub.2 and c.sub.3, respectively:
[0231] D1: c>a.gtoreq.b; c>a>b;
[0232] D2: c>1.5a; c>2a; c>2.5a; c>3a;
[0233] D3: a.sub.2>a.sub.1.apprxeq.a.sub.3; a.sub.2>1.1
a.sub.1.apprxeq.1.1 a.sub.3;
a.sub.2>1.2a.sub.1.apprxeq.1.2a.sub.3;
a.sub.2>1.3a.sub.1.apprxeq.1.3a.sub.3;
[0234] D4: b.sub.2.gtoreq.b.sub.1.apprxeq.b.sub.3;
b.sub.2.gtoreq.1.1 b.sub.1.apprxeq.1.1 b.sub.3; b.sub.2.gtoreq.1.2
b.sub.1.apprxeq.1.2 b.sub.3; b.sub.2.gtoreq.1.3 b.sub.1.apprxeq.1.3
b.sub.3;
[0235] D5: b.sub.2.ltoreq.b.sub.1.apprxeq.b.sub.3;
b.sub.2.ltoreq.0.9 b.sub.1.apprxeq.0.9 b.sub.3; b.sub.2.ltoreq.0.8
b.sub.1.apprxeq.0.8 b.sub.3; b.sub.2.ltoreq.0.7 b.sub.1.apprxeq.0.7
b.sub.3; and/or
[0236] D6: c.sub.2>c.sub.1.apprxeq.c.sub.3; c.sub.2>1.1
C.sub.1.apprxeq.1.1 c.sub.3; c.sub.2>1.2 c.sub.1.apprxeq.1.2
c.sub.3; c.sub.2>1.3 c.sub.1.apprxeq.1.3 c.sub.3.
[0237] Preferred embodiments D7 to D18 regarding the absolute
dimensions of the pharmaceutical dosage form depicted in FIG. 10
are displayed in the table here below:
TABLE-US-00001 [mm] D7 D8 D9 D10 D11 D12 a 8.6 .+-. 4.3 8.6 .+-.
2.1 8.6 .+-. 1.0 9.0 .+-. 4.5 9.0 .+-. 2.2 9.0 .+-. 1.1 b 4.9 .+-.
2.5 4.9 .+-. 1.3 4.9 .+-. 0.7 4.3 .+-. 2.1 4.3 .+-. 1.0 4.3 .+-.
0.6 c 21.9 .+-. 11.0 21.9 .+-. 5.5 21.9 .+-. 2.7 20.4 .+-. 10.2
20.4 .+-. 5.1 20.4 .+-. 2.5 [mm] D13 D14 D15 D16 D17 D18 a 9.0 .+-.
4.3 9.0 .+-. 2.1 9.0 .+-. 1.0 9.1 .+-. 4.5 9.1 .+-. 2.2 9.1 .+-.
1.1 b 4.1 .+-. 2.5 4.1 .+-. 1.3 4.1 .+-. 0.7 4.5 .+-. 2.1 4.5 .+-.
1.0 4.5 .+-. 0.6 c 20.5 .+-. 11.0 20.5 .+-. 5.5 20.5 .+-. 2.7 20.5
.+-. 10.2 20.5 .+-. 5.1 20.5 .+-. 2.5
[0238] Preferred embodiments D19 to D30 regarding the absolute
dimensions of the pharmaceutical dosage form depicted in FIG. 10
are displayed in the table here below:
TABLE-US-00002 [mm] D19 D20 D21 D22 D23 D24 a 8.6 .+-. 4.3 8.6 .+-.
2.1 8.6 .+-. 1.0 9.0 .+-. 4.5 9.0 .+-. 2.2 9.0 .+-. 1.1 a.sub.1 3.3
.+-. 1.6 3.3 .+-. 0.8 3.3 .+-. 0.4 3.5 .+-. 1.8 3.5 .+-. 0.9 3.5
.+-. 0.5 a.sub.2 2.1 .+-. 1.0 2.1 .+-. 0.5 2.1 .+-. 0.3 2.1 .+-.
1.1 2.1 .+-. 0.6 2.1 .+-. 0.3 a.sub.3 3.3 .+-. 1.6 3.3 .+-. 0.8 3.3
.+-. 0.4 3.5 .+-. 1.8 3.5 .+-. 0.9 3.5 .+-. 0.5 b 4.9 .+-. 2.5 4.9
.+-. 1.3 4.9 .+-. 0.7 4.3 .+-. 2.1 4.3 .+-. 1.0 4.3 .+-. 0.6
b.sub.1 0.9 .+-. 0.5 0.9 .+-. 0.3 0.9 .+-. 0.2 0.9 .+-. 0.4 0.9
.+-. 0.2 0.9 .+-. 0.1 b.sub.2 3.1 .+-. 1.5 3.1 .+-. 0.7 3.1 .+-.
0.4 2.6 .+-. 1.3 2.6 .+-. 0.6 2.6 .+-. 0.3 b.sub.3 0.9 .+-. 0.5 0.9
.+-. 0.3 0.9 .+-. 0.2 0.9 .+-. 0.4 0.9 .+-. 0.2 0.9 .+-. 0.1 c 21.9
.+-. 11.0 21.9 .+-. 5.5 21.9 .+-. 2.7 20.4 .+-. 10.2 20.4 .+-. 5.1
20.4 .+-. 2.5 c.sub.1 3.2 .+-. 1.6 3.2 .+-. 0.8 3.2 .+-. 0.4 3.3
.+-. 1.7 3.3 .+-. 0.9 3.3 .+-. 0.4 c.sub.2 15.6 .+-. 7.8 15.6 .+-.
3.9 15.6 .+-. 2.0 13.8 .+-. 6.9 13.8 .+-. 3.5 13.8 .+-. 1.7 c.sub.3
3.2 .+-. 1.6 3.2 .+-. 0.8 3.2 .+-. 0.4 3.3 .+-. 1.7 3.3 .+-. 0.9
3.3 .+-. 0.4 D25 D26 D27 D28 D29 D30 a 9.0 .+-. 4.3 9.0 .+-. 2.1
9.0 .+-. 1.0 9.1 .+-. 4.5 9.1 .+-. 2.2 9.1 .+-. 1.1 a.sub.1 3.2
.+-. 1.6 3.2 .+-. 0.8 3.2 .+-. 0.4 3.2 .+-. 1.8 3.2 .+-. 0.9 3.2
.+-. 0.5 a.sub.2 2.6 .+-. 1.0 2.6 .+-. 0.5 2.6 .+-. 0.3 2.7 .+-.
1.1 2.7 .+-. 0.6 2.7 .+-. 0.3 a.sub.3 3.2 .+-. 1.6 3.2 .+-. 0.8 3.2
.+-. 0.4 3.2 .+-. 1.8 3.2 .+-. 0.9 3.2 .+-. 0.5 b 4.1 .+-. 2.5 4.1
.+-. 1.3 4.1 .+-. 0.7 4.5 .+-. 2.1 4.5 .+-. 1.0 4.5 .+-. 0.6
b.sub.1 1.0 .+-. 0.5 1.0 .+-. 0.3 1.0 .+-. 0.2 1.0 .+-. 0.4 1.0
.+-. 0.2 1.0 .+-. 0.1 b.sub.2 2.1 .+-. 1.5 2.1 .+-. 0.7 2.1 .+-.
0.4 2.5 .+-. 1.3 2.5 .+-. 0.6 2.5 .+-. 0.3 b.sub.3 1.0 .+-. 0.5 1.0
.+-. 0.3 1.0 .+-. 0.2 1.0 .+-. 0.4 1.0 .+-. 0.2 1.0 .+-. 0.1 c 20.5
.+-. 11.0 20.5 .+-. 5.5 20.5 .+-. 2.7 20.5 .+-. 10.2 20.5 .+-. 5.1
20.5 .+-. 2.5 c.sub.1 3.3 .+-. 1.6 3.3 .+-. 0.8 3.3 .+-. 0.4 3.3
.+-. 1.7 3.3 .+-. 0.9 3.3 .+-. 0.4 c.sub.2 13.9 .+-. 7.8 13.9 .+-.
3.9 13.9 .+-. 2.0 13.9 .+-. 6.9 13.9 .+-. 3.5 13.9 .+-. 1.7 c.sub.3
3.3 .+-. 1.6 3.3 .+-. 0.8 3.3 .+-. 0.4 3.3 .+-. 1.7 3.3 .+-. 0.9
3.3 .+-. 0.4
[0239] The pharmaceutical dosage form according to the invention
preferably has a breaking strength B.sub.2 in a second direction of
extension E.sub.2, wherein B.sub.2<500 N.
[0240] Direction of extension E.sub.1 differs from direction of
extension E.sub.2. E.sub.2 may be any direction of extension of the
pharmaceutical dosage form, i.e. any straight line connecting any
first point on the surface of the pharmaceutical dosage form with
any second point on the surface of the pharmaceutical dosage form.
Preferably, said straight line lies completely within the body of
the pharmaceutical dosage form, i.e., preferably does not "leave"
the pharmaceutical dosage form somewhere and "re-enters" the
pharmaceutical dosage form elsewhere. Preferably, the distance
between said first point and said second point is at least 50%,
more preferably at least 75% of the main direction of extension of
the pharmaceutical dosage form, the latter being defined as the
maximal distance between two points on the surface of the
pharmaceutical dosage form.
[0241] Preferably, E.sub.1 and E.sub.2 assume an angle with one
another of from 10 to 170.degree., more preferably 20 to
160.degree., still more preferably 30 to 150.degree., yet more
preferably 40 to 140.degree., most preferably 50 to 130.degree.,
and in particular 60 to 120.degree.. In a particularly preferred
embodiment, E.sub.1 is orthogonal to E.sub.2.
[0242] Preferably, E.sub.2 is the main direction (principal
direction) of extension of the pharmaceutical dosage form, i.e.,
B.sub.2 can preferably be measured by placing the pharmaceutical
dosage form between the jaws of the measuring device so that the
two jaws have the maximum distance from one another but are each in
contact the pharmaceutical dosage form.
[0243] In a preferred embodiment, E.sub.1 and E.sub.2, which both
are preferably orthogonal to each another, lie within the main area
of extension of the dosage form, which main area of extension
preferably also contains the centre of mass of the dosage form.
[0244] In a preferred embodiment, B.sub.2 is below 490 N, below 480
N, below 460 N, below 440 N, or below 420 N; more preferably below
400 N, below 380 N, below 360 N, below 340 N, or below 320 N; still
more preferably below 300 N, below 280 N, below 260 N, below 240 N
or below 220 N.
[0245] In another preferred embodiment, B.sub.2 is at least 200 N,
at least 220 N, at least 240 N, at least 260 N, or at least 280 N;
more preferably at least 300 N, at least 320 N, at least 340 N, at
least 360 N, or at least 380 N; still more preferably at least 420
N, at least 440 N, at least 460 N, or at least 480 N.
[0246] Preferably, the ratio of B.sub.1 to B.sub.2 is within the
range of from 100:1 to 1.1:1, more preferably 75:1 to 1.2:1, still
more preferably 50:1 to 1.3:1, yet more preferably 25:1 to 1.4:1,
most preferably 10:1 to 1.5:1 and in particular 5:1 to 1.6:1.
[0247] Preferably, the difference B.sub.1-B.sub.2 is at least 10 N,
at least 20 N, at least 30 N, at least 40 N or at least 50 N, more
preferably at least 60 N, at least 70 N, at least 80 N or at least
90 N, still more preferably at least 100 N, at least 125 N, at
least 150 N, at least 175 N or at least 200 N, most preferably at
least 250 N, at least 300 N, at least 350 N, at least 400 or at
least 450 N, and in particular at least 500 N, at least 600 N, at
least 750 or at least 1000 N.
[0248] In a preferred embodiment of the pharmaceutical dosage form
according to the invention, B.sub.1 and B.sub.2 satisfy one of the
following conditions C 1 to C 72:
TABLE-US-00003 C B.sub.2 B.sub.1 1 100 N < B.sub.2 < 500 N
500 N < B.sub.1 2 100 N < B.sub.2 < 500 N 600 N <
B.sub.1 3 100 N < B.sub.2 < 500 N 700 N < B.sub.1 4 100 N
< B.sub.2 < 500 N 800 N < B.sub.1 5 100 N < B.sub.2
< 500 N 900 N < B.sub.1 6 100 N < B.sub.2 < 500 N 1000
N < B.sub.1 7 100 N < B.sub.2 < 500 N 1500 N < B.sub.1
8 100 N < B.sub.2 < 500 N 2000 N < B.sub.1 9 200 N <
B.sub.2 < 500 N 500 N < B.sub.1 10 200 N < B.sub.2 <
500 N 600 N < B.sub.1 11 200 N < B.sub.2 < 500 N 700 N
< B.sub.1 12 200 N < B.sub.2 < 500 N 800 N < B.sub.1 13
200 N < B.sub.2 < 500 N 900 N < B.sub.1 14 200 N <
B.sub.2 < 500 N 1000 N < B.sub.1 15 200 N < B.sub.2 <
500 N 1500 N < B.sub.1 16 200 N < B.sub.2 < 500 N 2000 N
< B.sub.1 17 300 N < B.sub.2 < 500 N 500 N < B.sub.1 18
300 N < B.sub.2 < 500 N 600 N < B.sub.1 19 300 N <
B.sub.2 < 500 N 700 N < B.sub.1 20 300 N < B.sub.2 <
500 N 800 N < B.sub.1 21 300 N < B.sub.2 < 500 N 900 N
< B.sub.1 22 300 N < B.sub.2 < 500 N 1000 N < B.sub.1
23 300 N < B.sub.2 < 500 N 1500 N < B.sub.1 24 300 N <
B.sub.2 < 500 N 2000 N < B.sub.1 25 400 N < B.sub.2 <
500 N 500 N < B.sub.1 26 400 N < B.sub.2 < 500 N 600 N
< B.sub.1 27 400 N < B.sub.2 < 500 N 700 N < B.sub.1 28
400 N < B.sub.2 < 500 N 800 N < B.sub.1 29 400 N <
B.sub.2 < 500 N 900 N < B.sub.1 30 400 N < B.sub.2 <
500 N 1000 N < B.sub.1 31 400 N < B.sub.2 < 500 N 1500 N
< B.sub.1 32 400 N < B.sub.2 < 500 N 2000 N < B.sub.1
33 100 N < B.sub.2 < 400 N 500 N < B.sub.1 34 100 N <
B.sub.2 < 400 N 600 N < B.sub.1 35 100 N < B.sub.2 <
400 N 700 N < B.sub.1 36 100 N < B.sub.2 < 400 N 800 N
< B.sub.1 37 100 N < B.sub.2 < 400 N 900 N < B.sub.1 38
100 N < B.sub.2 < 400 N 1000 N < B.sub.1 39 100 N <
B.sub.2 < 400 N 1500 N < B.sub.1 40 100 N < B.sub.2 <
400 N 2000 N < B.sub.1 41 200 N < B.sub.2 < 400 N 500 N
< B.sub.1 42 200 N < B.sub.2 < 400 N 600 N < B.sub.1 43
200 N < B.sub.2 < 400 N 700 N < B.sub.1 44 200 N <
B.sub.2 < 400 N 800 N < B.sub.1 45 200 N < B.sub.2 <
400 N 900 N < B.sub.1 46 200 N < B.sub.2 < 400 N 1000 N
< B.sub.1 47 200 N < B.sub.2 < 400 N 1500 N < B.sub.1
48 200 N < B.sub.2 < 400 N 2000 N < B.sub.1 49 300 N <
B.sub.2 < 400 N 500 N < B.sub.1 50 300 N < B.sub.2 <
400 N 600 N < B.sub.1 51 300 N < B.sub.2 < 400 N 700 N
< B.sub.1 52 300 N < B.sub.2 < 400 N 800 N < B.sub.1 53
300 N < B.sub.2 < 400 N 900 N < B.sub.1 54 300 N <
B.sub.2 < 400 N 1000 N < B.sub.1 55 300 N < B.sub.2 <
400 N 1500 N < B.sub.1 56 300 N < B.sub.2 < 400 N 2000 N
< B.sub.1 57 100 N < B.sub.2 < 300 N 500 N < B.sub.1 58
100 N < B.sub.2 < 300 N 600 N < B.sub.1 59 100 N <
B.sub.2 < 300 N 700 N < B.sub.1 60 100 N < B.sub.2 <
300 N 800 N < B.sub.1 61 100 N < B.sub.2 < 300 N 900 N
< B.sub.1 62 100 N < B.sub.2 < 300 N 1000 N < B.sub.1
63 100 N < B.sub.2 < 300 N 1500 N < B.sub.1 64 100 N <
B.sub.2 < 300 N 2000 N < B.sub.1 65 200 N < B.sub.2 <
300 N 500 N < B.sub.1 66 200 N < B.sub.2 < 300 N 600 N
< B.sub.1 67 200 N < B.sub.2 < 300 N 700 N < B.sub.1 68
200 N < B.sub.2 < 300 N 800 N < B.sub.1 69 200 N <
B.sub.2 < 300 N 900 N < B.sub.1 70 200 N < B.sub.2 <
300 N 1000 N < B.sub.1 71 200 N < B.sub.2 < 300 N 1500 N
< B.sub.1 72 200 N < B.sub.2 < 300 N 2000 N <
B.sub.1
[0249] Further preferred embodiments C 73 to C 96 are summarized in
the table here below:
TABLE-US-00004 C B.sub.2 B.sub.1 73 320 N < B.sub.2 < 420 N
500 N < B.sub.1 74 320 N < B.sub.2 < 420 N 600 N <
B.sub.1 75 320 N < B.sub.2 < 420 N 700 N < B.sub.1 76 320
N < B.sub.2 < 420 N 800 N < B.sub.1 77 320 N < B.sub.2
< 420 N 900 N < B.sub.1 78 320 N < B.sub.2 < 420 N 1000
N < B.sub.1 79 320 N < B.sub.2 < 420 N 1500 N < B.sub.1
80 320 N < B.sub.2 < 420 N 2000 N < B.sub.1 81 330 N <
B.sub.2 < 420 N 500 N < B.sub.1 82 330 N < B.sub.2 <
420 N 600 N < B.sub.1 83 330 N < B.sub.2 < 420 N 700 N
< B.sub.1 84 330 N < B.sub.2 < 420 N 800 N < B.sub.1 85
330 N < B.sub.2 < 420 N 900 N < B.sub.1 86 330 N <
B.sub.2 < 420 N 1000 N < B.sub.1 87 330 N < B.sub.2 <
420 N 1500 N < B.sub.1 88 330 N < B.sub.2 < 420 N 2000 N
< B.sub.1 89 340 N < B.sub.2 < 420 N 500 N < B.sub.1 90
340 N < B.sub.2 < 420 N 600 N < B.sub.1 91 340 N <
B.sub.2 < 420 N 700 N < B.sub.1 92 340 N < B.sub.2 <
420 N 800 N < B.sub.1 93 340 N < B.sub.2 < 420 N 900 N
< B.sub.1 94 340 N < B.sub.2 < 420 N 1000 N < B.sub.1
95 340 N < B.sub.2 < 420 N 1500 N < B.sub.1 96 340 N <
B.sub.2 < 420 N 2000 N < B.sub.1
[0250] Due to the property B.sub.2<B.sub.1, the pharmaceutical
dosage form according to the invention preferably has anisotropic
mechanical properties, i.e., is mechanically weakened with respect
of at least one of its directions of extension (E.sub.2) compared
to its mechanical strength with respect of at least another of its
directions of extension (E.sub.1). In a preferred embodiment, the
quality of the mechanical weakening is such that the pharmaceutical
dosage form may be fractured once by exerting a sufficient amount
of force in direction of extension E.sub.2, but the thus obtained
fragments are substantially break resistant in any (each and every)
of their directions of extension, i.e., may not be fractured any
further by exerting the same amount of force in any (each and
every) of their directions of extension. Preferably, said amount of
force is 400 N, 500 N, 600 N, 700 N, 800 N, 900 N, 1000 N, 1100 N,
1200 N, 1300 N, 1400 N, or 1500 N. In consequence, according to
this embodiment the pharmaceutical dosage form may be fractured
once by exerting a sufficient amount of force in direction of
extension E.sub.2, but may not be fractured any further unless the
exerted force is increased. Preferably, the number of fragments
that are obtained when the pharmaceutical dosage form is fractured
once is limited, preferably only two, three, four, five or six
fragments, preferably of substantially identical or different size
and/or weight, are obtained.
[0251] In a preferred embodiment, the surface S [mm.sup.2] to
weight W [mg] ratio S/W of the pharmaceutical dosage form according
to the invention is at least 0.50 mm.sup.2/mg. Preferably, S/W is
at least 0.51, at least 0.52, at least 0.53, at least 0.54 or at
least 0.55; more preferably at least 0.56, at least 0.57, at least
0.58, at least 0.59 or at least 0.60; still more preferably at
least 0.61, at least 0.62, at least 0.63, at least 0.64 or at least
0.65; yet more preferably at least 0.66, at least 0.67, at least
0.68, at least 0.69 or at least 0.70; most preferably at least
0.705, at least 0.710, at least 0.715, at least 0.720, at least
0.725, at least 0.730, at least 0.735, at least 0.740, at least
0.745 or at least 0.750; and in particular at least 0.755, at least
0.760, at least 0.765, at least 0.770, at least 0.775, at least
0.780, at least 0.785, at least 0.790, at least 0.795 or at least
0.80 mm.sup.2/mg.
[0252] In a preferred embodiment, the pharmaceutical dosage form
according to the invention has a total surface S defined by the
formula
S.gtoreq.AW.sup.2/3,
[0253] wherein A is at least 4.5, i.e. S>4.5W.sup.213.
[0254] For example, when the pharmaceutical dosage form according
to the invention has a total weight of 623 mg, its total surface S
is preferably at least 328 mm.sup.2 (4.5623.sup.2/3) and when the
pharmaceutical dosage form according to the invention has a total
weight of 983 mg, its total surface S is preferably at least 445
mm.sup.2 (4.5983.sup.2/3).
[0255] Methods for measuring the total surface of a pharmaceutical
dosage form are known to the skilled artisan. For example, the
total surface may be calculated from the three dimensional
extension of the pharmaceutical dosage form based on simple
geometrical considerations (cf., e.g., Eudragit.RTM. Application
Guidelines, 10th edition, July 2007, Rohm GmbH, Darmstadt).
[0256] For example, the geometry of the conventional tablet that is
depicted in FIG. 11 may be described by a cylindrical element (53)
that is located between two spherical caps (54a) and (54b). The
volumes V(53), V(54a) and V(54b) as well as the surfaces S(53),
S(54a) and S(54b) can be calculated according to the following
formulas:
V(53)=.pi.r.sub.2.sup.2h.sub.2
V(54a)=V(54b)=1/6.pi.h.sub.1(3r.sub.2.sup.2+h.sub.1.sup.2)
V.sub.t=V(53)+V(54a)+V(54b)
S(53)=2.pi.r.sub.2h.sub.2 S(54a)=S(54b)=2.pi.r.sub.1h.sub.1
S.sub.t=S(53)+S(54a)+S(54b)
[0257] In approximation, the pharmaceutical dosage form may also be
mentally divided into a plurality of identical cubic volume
elements of suitable size (voxels) and the total surface may be
determined by counting the squared area elements (pixels) being
located at the surface. This approximation is further illustrated
in FIG. 12 where the pharmaceutical dosage form according to FIG.
8B) is divided into a plurality of voxels (55).
[0258] Preferably, when measuring the total surface of the
pharmaceutical dosage form, the micro-fine structure of the
pharmacologically active compound (A) and of all other constituents
of the dosage form including polymers and pharmaceutical
excipients, e.g. their porosity, is not taken into account. For the
purpose of the specification, the term "surface" of the
pharmaceutical dosage form preferably refers to the macroscopic
surface (outer dimensions, silhouette). In other words, for the
purpose of determining the surface of the pharmaceutical dosage
form, the surface structure is preferably considered perfectly
smooth.
[0259] In a preferred embodiment of the pharmaceutical dosage form
according to the invention, A is 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2,
5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 or 6.0; more preferably 6.05,
6.1, 6.15, 6.2, 6.25, 6.3, 6.35, 6.4, 6.45, 6.5, 6.55, 6.6, 6.65,
6.7, 6.75, 6.8, 6.85, 6.9, 6.95, 7.0, 7.05, 7.1, 7.15, 7.2, 7.25,
7.3, 7.35, 7.4, 7.45 or 7.5.
[0260] In another preferred embodiment of the pharmaceutical dosage
form according to the invention, A is 7.6, 7.7, 7.8, 7.9, 8.0, 8.1,
8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9 or 9.0; more preferably 9.1,
9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3,
10.4 or 10.5; most preferably 10.6, 10.7, 10.8, 10.9, 11.0, 11.1,
11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9 or 12.0; and in
particular 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9,
13.0, 13.1, 13.2, 13.3, 13.4 or 13.5.
[0261] In a preferred embodiment, the total surface S of the
pharmaceutical dosage form according to the invention satisfies the
following requirement
BW.sup.2/3.gtoreq.S.gtoreq.AW.sup.2/3 [0262] where [0263] A and W
are defined as above and [0264] B is at most 20, more preferably at
most 19, still more preferably at most 18, yet more preferably at
most 17, most preferably at most 16 and in particular at most
15.
[0265] In a preferred embodiment, the total surface S of the
pharmaceutical dosage form according to the invention is at least
50 mm.sup.2, at least 75 mm.sup.2, at least 100 mm.sup.2, at least
125 mm.sup.2, at least 150 mm.sup.2, at least 175 mm.sup.2 or at
least 200 mm.sup.2; more preferably at least 225 mm.sup.2, at least
250 mm.sup.2, at least 275 mm.sup.2, at least 300 mm.sup.2, at
least 325 mm.sup.2, at least 350 mm.sup.2, at least 375 mm.sup.2 or
at least 400 mm.sup.2; still more preferably at least 425 mm.sup.2,
at least 450 mm.sup.2, at least 475 mm.sup.2, at least 500
mm.sup.2, at least 525 mm.sup.2; at least 550 mm.sup.2, at least
575 mm.sup.2 or at least 600 mm.sup.2; yet more preferably at least
625 mm.sup.2, at least 650 mm.sup.2, at least 675 mm.sup.2, at
least 700 mm.sup.2, at least 725 mm.sup.2, at least 750 mm.sup.2,
at least 775 mm.sup.2 or at least 800 mm.sup.2; most preferably at
least 825 mm.sup.2, at least 850 mm.sup.2, at least 875 mm.sup.2,
at least 900 mm.sup.2, at least 925 mm.sup.2, at least 950
mm.sup.2, at least 975 mm.sup.2 or at least 1000 mm.sup.2; and in
particular at least 1025 mm.sup.2, at least 1050 mm.sup.2, at least
1075 mm.sup.2, at least 1100 mm.sup.2, at least 1125 mm.sup.2, at
least 1150 mm.sup.2, at least 1175 mm.sup.2 or at least 1200
mm.sup.2.
[0266] In a preferred embodiment, the total surface S of the
pharmaceutical dosage form according to the invention is at most
1500 mm.sup.2, more preferably at most 1400 mm.sup.2, still more
preferably at most 1300 mm.sup.2, yet more preferably at most 1200
mm.sup.2, most preferably at most 1100 mm.sup.2, and in particular
at most 1000 mm.sup.2.
[0267] In a preferred embodiment the pharmaceutical dosage form
according to the invention is manufactured, particularly shaped, by
means of a so-called H-plunger. The silhouette of a dosage form
obtainable by means of such a H-plunger is schematically
illustrated in FIG. 10. H-plungers of suitable size and shape are
commercially available. Typically, the volume and the surface of
the dosage forms that are obtainable by a given H-plunger can be
calculated with a formula usually provided by the manufacturer of
the H-plunger.
[0268] For example, Notter GmbH, Germany offers a H-plunger forming
a volume of 94.3+171.6 h [mm.sup.3] and a surface of 382+52.3 h
[mm.sup.2], where h is the height of the dosage form (corresponding
to distance b.sub.2 in FIG. 10). Therefore, for example, when
shaping 650 mg of a compacted composition having an overall density
of 1.000 mg/mm.sup.3 with such H-plunger, a dosage form is obtained
having a height of h=(650-94.3)/171.6=3.24 mm. Thus, said dosage
form has a surface of 382+52.33.24=551 mm.sup.2. When A=4.5, the
requirement of 551 mm.sup.2.gtoreq.4.5 650.sup.2/3 (=337.6
mm.sup.2) is satisfied. When A is about 7.3, the requirement of 551
mm.sup.2.gtoreq.7.3 650.sup.2/3 (=547 mm.sup.2) is still satisfied,
but when A is 7.4, the requirement 551 mm.sup.2.gtoreq.7.4
650.sup.2/3 (=555 mm.sup.2) is not satisfied.
[0269] In a preferred embodiment, the pharmaceutical dosage form
according to the invention has a total weight W of at least 50 mg,
at least 75 mg, at least 100 mg, at least 125 mg or at least 150
mg; more preferably at least 175 mg, at least 200 mg, at least 225
mg, at least 250 mg or at least 275 mg; still more preferably at
least 300 mg, at least 325 mg, at least 350 mg, at least 375 mg or
at least 400 mg; yet more preferably at least 425 mg, at least 450
mg, at least 475 mg, at least 500 mg or at least 525 mg; most
preferably at least 550 mg, at least 575 mg, at least 600 mg, at
least 625 mg or at least 650 mg; and in particular at least 675 mg,
at least 700 mg, at least 725 mg, at least 750 mg or at least 775
mg. Preferably, the total weight of the pharmaceutical 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.
[0270] Once the breaking strength of the pharmaceutical dosage form
has been measured in a particular direction of extension, its
tensile strength in said direction of extension may be calculated
taking into account the outer shape of the dosage form. For
example, the tensile strength of conventional tablets can be
calculated according to the following equation: T
S=2.times.P/.pi..times.D.times.t, where TS is the tensile strength
(Ncm.sup.-2, MPa), P is the breaking strength of the tablet (N), D
is the tablet diameter (cm), and t is the tablet thickness (cm).
The skilled person knows how to modify the above formula when
modifying the outer shape of the dosage form. In this regard it can
be referred to, e.g., J. T. Fell et al., J Pharm Sci. 1970, 59,
688-691; M. P. Summers et al., J Pharm Sci., 1977, 66, 1172-1175;
and P. N. Davies et al., Eur J Pharm Biopharm. 2007, 67(1),
268-76.
[0271] Preferably, the pharmaceutical dosage form according to the
invention has a tensile strength of at least 2.5 N/cm.sup.2, at
least 3.0 N/cm.sup.2, at least 3.5 N/cm.sup.2, at least 4.0
N/cm.sup.2, at least 4.5 N/cm.sup.2, at least 5.0 N/cm.sup.2, at
least 6.0 N/cm.sup.2, at least 7.5 N/cm.sup.2, at least 10.0
N/cm.sup.2, at least 12.5 N/cm.sup.2 or at least 15.0 N/cm.sup.2;
more preferably at least 17.5 N/cm.sup.2, at least 20.0 N/cm.sup.2,
at least 22.5 N/cm.sup.2 or at least 25.0 N/cm.sup.2; still more
preferably at least 27.5 N/cm.sup.2, at least 30.0 N/cm.sup.2, at
least 32.5 N/cm.sup.2 or at least 35.0 N/cm.sup.2; yet more
preferably at least 37.5 N/cm.sup.2, at least 40.0 N/cm.sup.2, at
least 42.5 N/cm.sup.2 or at least 45.0 N/cm.sup.2; most preferably
at least 47.5 N/cm.sup.2, at least 50.0 N/cm.sup.2, at least 52.5
N/cm.sup.2 or at least 55.0 N/cm.sup.2; and in particular at least
57.5 N/cm.sup.2, at least 60.0 N/cm.sup.2, at least 62.5 N/cm.sup.2
or at least 65.0 N/cm.sup.2; preferably at least in direction of
extension E.sub.1.
[0272] The pharmaceutical dosage forms according to the invention
preferably exhibit high impact strength.
[0273] For example, the falling impact strength of the
pharmaceutical dosage forms is preferably about 0%. The falling
impact strength is a breakage ratio obtained when a tablet is
allowed to fall from the height of 50 cm onto a stainless steel
plate and defined by: {(broken tablets)/(tested tablets)}
100(%).
[0274] Preferably, the impact strength of the pharmaceutical dosage
form according to the invention is sufficiently high so that it
cannot be comminuted by means of a hammer. Preferably, when
applying five manual hammer strokes by means of a hammer having a
weight of 500 g, the pharmaceutical dosage form cannot be
comminuted. In a preferred embodiment, the pharmaceutical dosage
form does not only exhibit this impact strength at ambient
temperature, but also below +4.degree. C. (refrigerator), more
preferably below -33.degree. C. (deep freezer), most preferably
below -77.degree. C. (dry ice) and in particular below -190.degree.
C. (liquid nitrogen).
[0275] Preferably, the pharmaceutical dosage form according to the
invention exhibits a cutting resistance of at least 75 N, more
preferably at least 100 N, still more preferably at least 125 N,
yet more preferably at least 140 N, most preferably at least 150 N
and in particular at least 160 N, in at least one direction of
extension, preferably in direction of extension E.sub.1.
Preferably, the cutting test is performed according to DIN EN ISO
604, preferably at a testing speed of 30 mm/min and by means of a
universal glass cleaning blade having a thickness of 0.30 mm.
[0276] The friability of the pharmaceutical dosage form according
to the invention can be measured, e.g., by means of a Pharmatest
PTF-E apparatus (Hainburg, Germany) following, e.g., the European
Pharmacopeia (Ph. Eur.) specifications. Preferably, the friability
of the pharmaceutical dosage form according to the invention is at
most 0.50%, more preferably at most 0.40%, still more preferably at
most 0.30%, yet more preferably at most 0.20%, most preferably at
most 0.10% and in particular at most 0.05%.
[0277] In a preferred embodiment the pharmaceutical dosage form
according to the invention has an overall density of at least 0.80
or at least 0.85 g/cm.sup.3, more preferably at least 0.90 or at
least 0.95 g/cm.sup.3, still more preferably at least 1.00, at
least 1.05 or at least 1.10 g/cm.sup.3, most preferably 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.
[0278] In a preferred embodiment, the pharmaceutical dosage form
according to the invention has an overall density within the range
of 1.00.+-.0.30 g/cm.sup.3, more preferably 1.00.+-.0.25
g/cm.sup.3, still more preferably 1.00.+-.0.20 g/cm.sup.3, yet more
preferably 1.00.+-.0.15 g/cm.sup.3, most preferably 1.00.+-.0.10
g/cm.sup.3, and in particular 1.00.+-.0.05 g/cm.sup.3. In another
preferred embodiment, the pharmaceutical dosage form according to
the invention has an overall density within the range of
1.10.+-.0.30 g/cm.sup.3, more preferably 1.10.+-.0.25 g/cm.sup.3,
still more preferably 1.10.+-.0.20 g/cm.sup.3, yet more preferably
1.10.+-.0.15 g/cm.sup.3, most preferably 1.10.+-.0.10 g/cm.sup.3,
and in particular 1.10.+-.0.05 g/cm.sup.3. In still another
preferred embodiment, the pharmaceutical dosage form according to
the invention has an overall density within the range of
1.20.+-.0.30 g/cm.sup.3, more preferably 1.20.+-.0.25 g/cm.sup.3,
still more preferably 1.20.+-.0.20 g/cm.sup.3, yet more preferably
1.20.+-.0.15 g/cm.sup.3, most preferably 1.20.+-.0.10 g/cm.sup.3,
and in particular 1.20.+-.0.05 g/cm.sup.3. Preferably, the overall
density of the pharmaceutical dosage form according to the
invention is 1.00.+-.0.02 g/cm.sup.3, 1.02.+-.0.02 g/cm.sup.3,
1.04.+-.0.02 g/cm.sup.3, 1.06.+-.0.02 g/cm.sup.3, 1.08.+-.0.02
g/cm.sup.3, 1.10.+-.0.02 g/cm.sup.3, 1.12.+-.0.02 g/cm.sup.3,
1.14.+-.0.02 g/cm.sup.3, 1.16.+-.0.02 g/cm.sup.3, 1.18.+-.0.02
g/cm.sup.3, 1.20.+-.0.02 g/cm.sup.3, 1.22.+-.0.02 g/cm.sup.3,
1.24.+-.0.02 g/cm.sup.3, 1.26.+-.0.02 g/cm.sup.3, 1.28.+-.0.02
g/cm.sup.3, 1.30.+-.0.02 g/cm.sup.3, 1.32.+-.0.02 g/cm.sup.3,
1.34.+-.0.02 g/cm.sup.3, 1.36.+-.0.02 g/cm.sup.3, 1.38.+-.0.02
g/cm.sup.3, or 1.40.+-.0.02 g/cm.sup.3.
[0279] Preferably, the pharmaceutical dosage form according to the
invention is characterized by a comparatively homogeneous
distribution of density. Preferably, the densities of two segments
of the pharmaceutical dosage form having a volume of 1.0 mm.sup.3
each, deviate from one another by not more than .+-.10%, more
preferably not more than more than .+-.7.5%, still more preferably
not more than .+-.5.0%, most preferably not more than .+-.2.5%, and
in particular not more than .+-.1.0%. When the pharmaceutical
dosage form is film coated, said two segments of the pharmaceutical
dosage form having a volume of 1.0 mm.sup.3 each are preferably
segments of the core, i.e. do not contain any coating material.
[0280] In a preferred embodiment, the pharmaceutical dosage form
according to the invention is thermoformed, preferably by
extrusion, although also other methods of thermoforming may be used
in order to manufacture the dosage form according to the invention
such as press-molding at elevated temperature.
[0281] The pharmaceutical dosage form according to the invention
contains a pharmacologically active compound (A), for the purpose
of the specification also referred to as "component (A)".
[0282] Preferred pharmacologically active compounds (A) have
already been mentioned as pharmaceutically active ingredients and
pharmaceutically active ingredients with potential for abuse in
connection with the first and second aspects of the invention.
[0283] In a preferred embodiment, under ambient conditions, the
solubility of component (A) in pure water is at least 1.0 g/L, more
preferably at least 5.0 g/L, still more preferably at least 10 g/L,
yet more preferably at least 25 g/L, most preferably at least 50
g/L and in particular at least 100 g/L.
[0284] In another preferred embodiment, under ambient conditions,
the solubility of component (A) in pure water is at most 1.0 g/L,
more preferably at most 0.5 g/L, still more preferably at most 0.1
g/L, yet more preferably at most 0.05 g/L, most preferably at most
0.01 g/L and in particular at most 0.005 g/L.
[0285] In a preferred embodiment, the pharmaceutical dosage form
according to the invention contains a pharmaceutically effective
amount of a pharmacologically active compound (A), which justifies
use of the pharmaceutical dosage form as a pharmaceutical
preparation and is the cause of the activity thereof.
Pharmacologically active compounds (A) which may in principle be
considered in the pharmaceutical dosage form according to the
invention are any known pharmaceutical substances, wherein these
substances may be present in the pharmaceutical 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).
[0286] The pharmaceutical dosage form according to the invention is
suitable for the administration of a number of pharmacologically
active compounds (A) in a single pharmaceutical dosage form.
Preferably, the pharmaceutical dosage form contains only one
particular pharmacologically active compound (A).
[0287] The amount of the pharmacologically active compound (A),
based on the total amount of the pharmaceutical 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.-%.
[0288] In a preferred embodiment the pharmaceutical dosage form
according to the invention contains a psychotropically acting
substance as the pharmacologically active compound (A).
[0289] 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 compound 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
pharmaceutical dosage form is administered nasally, i.e. is
sniffed. Substances with a psychotropic action are preferably
substances which (in the appropriate dose and pharmaceutical 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.
[0290] In particular, the pharmaceutical dosage form according to
the invention preferably contains 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 ("Gelbe Liste"), as used by the WHO for
classifying pharmaceutical substances (preferred version: 2007 or
2008).
[0291] The pharmaceutical dosage form according to the invention
preferably contains a psychotropically acting substance selected
from the group consisting of opioids, vanilloid receptor
modulators, serotonin/norepinephrine/dopamine modulators, GABA
modulators, NMDA antagonists, ion channel blockers/modulators,
cannabionoids, and other NSAIDS.
[0292] 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 contained in the
pharmaceutical dosage form according to the invention: alfentanil,
allobarbital, allylprodine, alphaprodine, alprazolam, amfepramone,
amphetamine, amphetaminil, amobarbital, anileridine, apocodeine,
axomadol, barbital, bemidone, benzylmorphine, bezitramide,
bromazepam, brotizolam, buprenorphine, butobarbital, butorphanol,
camazepam, carfentanil, cathine/D-norpseudoephedrine,
chlordiazepoxide, clobazam clofedanol, clonazepam, clonitazene,
clorazepate, clotiazepam, cloxazolam, cocaine, codeine,
cyclobarbital, cyclorphan, cyprenorphine, delorazepam,
desomorphine, dextromoramide, dextropropoxyphene, dezocine,
diampromide, diamorphone, diazepam, dihydrocodeine,
dihydromorphine, dihydromorphone, dimenoxadol, dimephetamol,
dimethylthiambutene, dioxaphetylbutyrate, dipipanone, dronabinol,
eptazocine, estazolam, ethoheptazine, ethylmethylthiambutene, ethyl
loflazepate, ethylmorphine, etonitazene, etorphine, fencamfamine,
fenethylline, fenpipramide, fenproporex, fentanyl, fludiazepam,
flunitrazepam, flurazepam, halazepam, haloxazolam, heroin,
hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
hydroxymethylmorphinan, ketazolam, ketobemidone, levacetylmethadol
(LAAM), levo-methadone, levorphanol, levophenacylmorphane,
levoxemacin, lisdexamfetamine dimesylate, 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, tapentadol, 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-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.
[0293] In a preferred embodiment the pharmaceutical dosage form
according to the invention contains an opioid selected from the
group consisting of DPI-125, M6G (CE-04-410), ADL-5859, CR-665,
NRP290 and sebacoyl dinalbuphine ester.
[0294] In a preferred embodiment the pharmaceutical dosage form
according to the invention contains one pharmacologically active
compound (A) or more pharmacologically active compounds (A)
selected from the group consisting of oxymorphone, hydromorphone
and morphine.
[0295] In another preferred embodiment, the pharmacologically
active compound (A) is selected from the group consisting of
tapentadol, faxeladol and axomadol.
[0296] For the purposes of the description, the pharmacokinetic
parameters, which may be determined from the blood plasma
concentrations of the pharmacologically active compound (A), are
defined as follows:
TABLE-US-00005 C.sub.max maximum measured plasma concentration of
the active ingredient after single administration (.ident.average
peak plasma level) t.sub.max interval of time from administration
of the active ingredient until C.sub.max is reached t.sub.1/2
half-life AUC.sub.0-.infin. total area under the curve
[0297] The above parameters are in each case stated as mean values
of the individual values for all investigated patients/test
subjects.
[0298] A person skilled in the art knows how the pharmacokinetic
parameters of the active ingredient may be calculated from the
measured concentrations of the active ingredient in the blood
plasma. In this connection, reference may be made, for example, to
Willi Cawello (ed.) Parameters for Compartment-free
Pharmacokinetics, Shaker Verlag Aachen (1999).
[0299] In a preferred embodiment, after preferably oral
administration of the dosage form according to the invention, in
vivo the average peak plasma level (C.sub.max) is on average
reached after t.sub.max 4.0.+-.2.5 h, more preferably after
t.sub.max 4.0.+-.2.0 h, still more preferably after t.sub.max
4.0.+-.1.5 h, most preferably after t.sub.max 4.0.+-.1.0 h and in
particular after t.sub.max4.0.+-.0.5h. In another preferred
embodiment, after preferably oral administration of the dosage form
according to the invention, in vivo the average peak plasma level
(C.sub.max) is on average reached after t.sub.max 5.0.+-.2.5 h,
more preferably after t.sub.max 5.0.+-.2.0 h, still more preferably
after t.sub.max 5.0.+-.1.5 h, most preferably after t.sub.max
5.0.+-.1.0 h and in particular after t.sub.max 5.0.+-.0.5 h. In
still another preferred embodiment, after preferably oral
administration of the dosage form according to the invention, in
vivo the average peak plasma level (C.sub.max) is on average
reached after t.sub.max 6.0.+-.2.5 h, more preferably after
t.sub.max 6.0.+-.2.0 h, still more preferably after t.sub.max
6.0.+-.1.5 h, most preferably after t.sub.max 6.0.+-.1.0 h and in
particular after t.sub.max 6.0.+-.0.5 h.
[0300] In a preferred embodiment, the average value for t.sub.1/2
after preferably oral administration of the dosage form according
to the invention in vivo is 4.3.+-.2.5 h, more preferably
4.3.+-.2.0 h, still more preferably 4.3.+-.1.5 h, most preferably
4.3.+-.1.0 h, and in particular 4.3.+-.0.5 h. In another preferred
embodiment, the average value for t.sub.v2 after preferably oral
administration of the dosage form according to the invention in
vivo is preferably 5.3.+-.2.5 h, more preferably 5.3.+-.2.0 h,
still more preferably 5.3.+-.1.5 h, most preferably 5.3.+-.1.0 h,
and in particular 5.3.+-.0.5 h. In still another preferred
embodiment, the average value for t.sub.1/2 after preferably oral
administration of the dosage form according to the invention in
vivo is preferably 6.3.+-.2.5 h, more preferably 6.3.+-.2.0 h,
still more preferably 6.3.+-.1.5 h, most preferably 6.3.+-.1.0 h,
and in particular 6.3.+-.0.5 h.
[0301] In a preferred embodiment, the pharmacologically active
compound (A) is tapentadol or a physiologically acceptable salt
thereof, and after preferably oral administration of the dosage
form according to the invention, in vivo the average value for the
total area under the curve AUC.sub.0-.infin. is 825.+-.600 ngh/mL,
more preferably 825.+-.500 ngh/mL, still more preferably 825.+-.400
ngh/mL, yet more preferably 825.+-.300 ngh/mL, most preferably
825.+-.200 ngh/mL, and in particular 825.+-.100 ngh/mL. In another
preferred embodiment, the pharmacologically active compound (A) is
tapentadol or a physiologically acceptable salt thereof, and after
preferably oral administration of the dosage form according to the
invention, in vivo the average value for the total area under the
curve AUC.sub.0-.infin. is 1100.+-.600 ngh/mL, more preferably
1100.+-.500 ngh/mL, still more preferably 1100.+-.400 ngh/mL, yet
more preferably 1100.+-.300 ngh/mL, most preferably 1100.+-.200
ngh/mL, and in particular 1100.+-.100 ngh/mL.
[0302] In a preferred embodiment, the pharmacologically active
compound (A) is tapentadol or a physiologically acceptable salt
thereof, and after preferably oral administration of the dosage
form according to the invention, in vivo the average value of
C.sub.max is 63.+-.40 ng/mL, more preferably 63.+-.30 ng/mL, still
more preferably 63.+-.20 ng/mL, yet more preferably 63.+-.15 ng/mL,
most preferably 63.+-.10 ng/mL and in particular 63.+-.5 ng/mL. In
another preferred embodiment, the pharmacologically active compound
(A) is tapentadol or a physiologically acceptable salt thereof, and
after preferably oral administration of the dosage form according
to the invention, in vivo the average value of C.sub.max is
89.+-.40 ng/mL, more preferably 89.+-.30 ng/mL, still more
preferably 89.+-.20 ng/mL, yet more preferably 89.+-.15 ng/mL, most
preferably 89.+-.10 ng/mL and in particular 89.+-.5 ng/mL.
[0303] In a particularly preferred embodiment the pharmacologically
active compound (A) is tapentadol or a physiologically acceptable
salt thereof and the pharmaceutical dosage form according to the
invention is bioequivalent to a formulation that contains
tapentadol or a physiologically acceptable salt thereof in a dosage
of 200 mg and 250 mg, respectively, and is characterized by the
following pharmacokinetic data:
TABLE-US-00006 Parameter dosage 200 mg dosage 250 mg
AUC.sub.0-.infin. 825 ng h/mL 1096 ng h/mL C.sub.max 62.5 ng/mL
89.3 ng/mL t.sub.max 5.00 h 5.00 h t.sub.1/2 5.2 h 5.4 h
[0304] The skilled person is aware what requirement have to be
satisfied in order to achieve bioequivalence. In this regard it can
be referred e.g. to "Note for Guidance on the Investigation of
Bioavailability and Bioequivalence", EMEA, London, 26 Jul. 2001
(CPMP/EWP/QWP/1401/98); "Guidance for Industry--Bioavailability and
Bioequivalence--Studies for Orally Administered Drug
Products--General Considerations", FDA, BP, Announced in the
Federal Register: Volume 68, Number 53/Mar. 19, 2003; and "Guidance
for Industry--Statistical Approaches to Establishing
Bioequivalence", FDA, BP, January 2001.
[0305] In general, two medicinal products are bioequivalent if they
are pharmaceutically equivalent or pharmaceutical alternatives and
if their bioavailabilities after administration in the same molar
dose are similar to such degree that their effects, with respect to
both efficacy and safety, will be essentially the same. Preferably,
statistical data should be analyzed using ANOVA based on a 90%
confidence interval. For example, as regards AUC-ratio, the 90%
confidence interval for this measure of relative bioavailability
should lie within an acceptance interval of 0.80-1.25, and as
regards Cmax-ratio, the 90% confidence interval for this measure of
relative bioavailability should lie within an acceptance interval
of 0.80-1.25.
[0306] In a preferred embodiment the pharmaceutical dosage form
according to the invention contains one pharmacologically active
compound (A) or more pharmacologically active compounds (A)
selected from the group consisting of
1,1-(3-dimethylamino-3-phenyl-pentamethylen)-6-fluor-1,3,4,9-tetrahydropy-
rano[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.
[0307] In a preferred embodiment, the pharmaceutical 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 compound, 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
and 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.
[0308] The pharmaceutical dosage form according to the invention
furthermore preferably contains no antagonists for the
pharmacologically active compound (A), preferably no antagonists
against psychotropic substances, in particular no antagonists
against opioids. Antagonists suitable for a given pharmacologically
active compound (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 pharmaceutical
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.
[0309] The pharmaceutical 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 pharmaceutical 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 and ihre Inhaltsstoffe" by Prof. Dr. Hildebert
Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart,
N.Y., 1982. The corresponding literature description is hereby
introduced as a reference and is deemed to be part of the
disclosure. The pharmaceutical dosage form according to the
invention preferably also contains no apomorphine as an emetic.
[0310] Finally, the pharmaceutical 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 should be
deemed to be the disclosure of the present application and is
hereby introduced as a reference. 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.
[0311] The pharmaceutical dosage form according to the invention
accordingly preferably contains neither substances which irritate
the nasal passages and/or pharynx, nor antagonists for the
pharmacologically active compound (A), nor emetics, nor bitter
substances.
[0312] In a preferred embodiment the pharmaceutical dosage form
according to the invention contains a non-psychotropically acting
substance as the pharmacologically active compound (A).
[0313] Particularly preferably the pharmaceutical dosage form
according to the invention contains a pharmacologically active
compound (A) or two or more such compounds selected from the group
consisting of [0314] 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 [A04 a)A],
antihistamine preparations [A04 a)B], 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]; [0315] 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]; [0316]
agents for the treatment and prevention of diseases of the
cardiovascular system
[0317] [C]; in particular agents for cardiac therapy [C01],
antihypertensives [C02], diuretics [C03], peripheral vasodilatators
[C04], vasoprotectives [005], antihypotensives [C06A],
.quadrature.-adrenoceptor antagonists [C07], calcium channel
blockers [C08], agents acting on the renin-angiotensin system [C09]
and lipid reducing agents [C10]; [0318] dermatologicals [D]; in
particular antifungals for systemic use [D01B], antipsoriatics for
systemic use [D05B], antiacne preparations for systemic use [D10B];
[0319] 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 [G02CB], hormonal contraceptives for systemic use [G03]
and urologicals [G04]; [0320] 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]; [0321]
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]); [0322]
antineoplastic and immunomodulating agents [L] (in particular
antineoplastistic agents [L01], agents for endocrine therapy [L02],
immunostimulants [L03] and immunosuppressive agents [L04]; [0323]
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 [M030], antigout
preparations [M04] and agents for the treatment of bone diseases
[M05]; [0324] agents for the treatment and prevention of diseases
of the nervous system [N]; in particular salicylic acid the
derivatives thereof [N02 b)A], pyrazolones [N02 b)B], anilides [N02
b)E], ergot alkaloids [N02CA], corticosteroid derivatives [N02CB],
selective serotonin-5HT.sub.1 agonists [N02CC], hydantoin
derivatives [N03 a)B], oxazolidine derivatives [N03 a)C],
succinimide derivatives [N03 a)D], carboxamide derivatives [N03
a)F], fatty acid derivatives [N03 a)G], antiparkinson drugs [N04]),
antipsychotics [N05A], antidepressants [N06A], antidementia drugs
[N06D], parasympathomimetics [N07A] and antivertigo preparations
[N07C]; [0325] antiparasitic products, insecticides and repellents
[P]; in particular antiprotozoals [P01], anthelmintics [P02] and
ectoparasiticides, including scabicides, insecticides and
repellents [P03]; [0326] 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]; [0327] agents for the treatment and prevention
of diseases of the sensory organs [S]; in particular otologicals
[S02]; and [0328] general diet products [V06] and therapeutic
radiopharmaceuticals [V10],
[0329] wherein the abbreviations stated in square brackets here
correspond to the ATC Index, as used by the WHO for classifying
pharmaceutical substances (preferred version: 2007 or 2008).
[0330] The pharmaceutical dosage form according to the invention
preferably contains one, two or more pharmacologically active
compounds (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, .beta.-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, .alpha.-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,
[0331] 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,
bufexamac, buflomedil, bumetanide, bunazosin, buphenine,
bupivacaine, bupranolol, bupropion, buserelin, buspirone, busulfan,
butalamine, butanilicaine, butenafine, butethamate, butinoline,
butizide, butylscopolaminium,
[0332] 5-chlorcarvacrol, C1 esterase inhibitor, cabergoline,
cadexomer iodine, cafedrine, calcipotriol, calcitonin, calcitriol,
camylofine, candesartan cilexetil, canrenoic acid, capecitabine,
capreomycin, capsaicin, captopril, carazolol, carbaldrate F,
carbamazepine, carbasalate calcium, carbenoxolone, carbidopa,
carbimazole, carbinoxamine, carboplatin, carglumic acid,
carmustine, caroverine, carteolol, carvedilol, caspofungin,
cefaclor, cefadroxil, cefalexin, cefaloridine, cefamandole,
cefazolin, cefdinir, cefepime, cefetamet-pivotil, cefixime,
cefodizime, cefoperazone, cefotaxime, cefotiam, cefoxitin,
cefpirome, cefpodoxime, cefpodoxime-proxetil, cefprozil,
ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime,
celecoxib, celiprolol, certoparin, cetirizine, cetrimide,
cetrimonium bromide, cetrorelix, cetuximab, 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,
[0333] 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, desflurane, desipramine,
desirudin, deslanoside, desloratadine, desmeninol, desmopressin,
desogestrel, desoximetasone, deoxyribonuclease, detajmium,
dexamethasone, dexchlorpheniramine, dexibuprofen, dexketoprofen,
dexrazoxane, dextran, dextromethorphan, diacerein, diacetyl
morphine, dibenzepin, dibotermin alfa, diclofenac, diclofenamide,
didanosine, dienestrol, dienogest, diethylstilbestrol, difloxacin,
diflucortolone, diflunisal, digitoxin, digoxin, dihydralazine,
dihydroergocornine, dihydroergocristine, dihydroergocryptine,
dihydroergotamine, dihydroergotoxine, dihydrotachysterol,
diisopropylamine, 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,
[0334] ebastine, econazole, ecothiopate iodide, efalizumab,
efavirenz, eflornithine, iron(III) ammonium citrate F,
superparamagnetic iron oxide, elcatonin, eletriptan, emedastine,
emepronium, emepronium carrageenate, emetine, emtricitabine,
enalapril, enalaprilat, enflurane, enfuvirtide, enoxacin,
enoxaparin, entacapone, ephedrine, ephedrine racephedrine,
epinastine, epinephrine, epirubicin, eplerenone, epoetin alfa,
epoetin beta, epoetin delta, epoprostenol, eprazinone, eprosartan,
eptacog alfa, eptifibatide, eptotermin alfa, erdosteine,
ergocalciferol, ergometrine, ergotamide, ertapenem, erythromycin,
escitalopram, esmolol, esomeprazole, estradiol, estramustine,
estriol, estrone, etacrynic acid, etamivan, etanercept,
ethacridine, ethambutol, ethaverine, ethinylestradiol, ethisterone,
ethosuximide, etidronic acid, etilefrine, etodolac, etofenamate,
etofibrate, etofylline, etomidate, etonogestrel, etoposide,
etoricoxib, everolimus, exametazime, exemestane, ezetimibe,
[0335] 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,
[0336] gabapentin, gadobenic acid, gadobutrol, gadodiamide,
gadopentetic acid, gadoteridol, gadoteric acid, gadoteric
acid-meglumine, gadoxetic acid, galantamine, gallopamil,
ganciclovir, ganirelix, gatifloxacin, gemcitabine, gemfibrozil,
gentamicin, gepefrine, gestodene, glatiramer, glibenclamide,
glibornuride, gliclazide, glimepiride, glipizide, gliquidone,
glisoxepide, glucagon, glutamine, glutamic acid, glycopyrronium,
glycopyrronium bromide, glycyrrhetinic acid, gonadorelin,
goserelin, gramicidin, granisetron, grepafloxacin, griseofulvin,
g-strophanthin, guajacol, guanethidine, guanfacine,
[0337] .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,
[0338] 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-2 b), interferon alfacon-1, interferon beta,
interferon beta-1 a), interferon beta-1 b), interferon gamma,
iobitridol, iodine, iodamide, iodixanol, ioflupane [.sup.123I],
iohexol, iomeprol, iopamidol, iopentol, iopromide, iosarcol,
iotrolan, iotroxic acid, ioversol, ioxaglic acid, ioxitalamic acid,
ipatropium, irbesartan, irinotecan, irinotecan, isepamicin,
isoaminile, isoconazole, isoflurane, isoleucine, isoniazid,
isonicotinic acid, isoprenaline, isosorbide, isospaglumic acid,
isotretinoin, isoxsuprine, isradipine, itraconazole,
[0339] josamycin,
[0340] potassium permanganate, kallidinogenase, kanamycin, kawain,
kebuzone, ketamine, ketoconazole, ketoprofen, ketorolac, ketotifen,
collagenase, creosote,
[0341] labetalol, lacidipine, lactitol, lamivudine, lamotrigine,
lanreotide, lansoprazole, laronidase, latanoprost, leflunomide,
lenograstim, lepirudin, lercanidipine, letrozole, leucine,
leuprorelin, levallorphan, levamisole, levetiracetam, levobunolol,
levobupivacaine, levocabastine, levocetirizine, levodopa,
levofloxacin, levofolinate calcium, levomepromazine, levomethadyl,
levonorgestrel, levopropylhexedrine, levosimendan, levothyroxine,
lidocaine, lincomycin, lindane, linezolid, liothyronine,
lisinopril, lisuride, lobeline, lodoxamide, lofepramine,
lomefloxacin, lomustine, lonazolac, loperamide, lopinavir,
loratadine, lorazepam oxide, lornoxicam, losartan, loteprednole,
lovastatin, lumefantrine, lutropin alfa, lymecycline, lynestrenol,
lypressin, lysine,
[0342] magaldrate F, magnesium pidolate, magnesium L-aspartate,
mangafodipir, manidipine, maprotiline, mebendazole, mebeverine,
meclofenoxate, mecloxamine, 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, moroctocog alfa,
moxaverine, moxifloxacin, moxonidine, mupirocin, mycophenolate
mofetil,
[0343] 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, nitrendipine, nitric oxide,
nitrofurantoin, nitroglycerine, nizatidine, N-methylephedrine,
nonacog alfa, nonivamide, noradrenalin, norelgestromin,
norepinephrine, norethisterone, norfenefrine, norfloxacin,
norgestimate, norgestrel, nortriptyline, noscapine, nystatin,
[0344] obidoxime chloride, octafluoropropane, octocog alfa,
octodrine, octreotide, odansetron, ofloxacin, olaflur F,
olanzapine, olmesartan medoxomil, olopatadine, olsalazine,
omeprazole, omoconazole, ondansetron, opipramol, oral cholera
vaccine, orciprenaline, orlistat, ornipressin, orphenadrine,
oseltamivir, osteogenic protein-1: BMP-7, oxaprozin, oxatomide,
oxcarbazepine, oxedrine tartrate, oxetacaine, oxiconazole,
oxilofrine, oxitropium, 2-oxo-3-methylbutyric acid,
2-oxo-3-methylvaleric acid, 2-oxo-3-phenylpropionic acid,
2-oxo-4-methylvaleric acid, oxprenolol, oxybuprocaine,
oxybuprocaine, oxybutynin, oxybutynin, oxyfedrine, oxymetazoline,
oxytetracycline, oxytocin,
[0345] 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, pentamidine, pentetrazol, pentetreotide, pentosan
polysulfate sodium, pentoxifylline, pentoxyverine, perazine,
perchloric acid, perflenapent, perflisopent, perflutren, pergolide,
perindopril, perphenazine, phenacetin, phenamazid, phenazone,
phenazopyridine, pheniramine, phenol, phenolphthalein,
phenoxybenzamine, phenoxymethylpenicillin, phenprocoumon,
phentolamine, phenylalanine, phenylbutazone, phenylephrine,
phenylpropanolamine, phenyltoloxamine, phenytoin, phloroglucinol,
pholedrine, 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,
pirenzepine, piritramide, piroxicam, pivmecillinam, pizotifen,
podophyllotoxin, polidocanol, polycarbophil, polyestradiol
phosphate, polymyxin B, polymyxin-B, polystyrenesulfonic acid,
porfimer, prajmaline, prajmalium bitartrate, pramipexole,
pranoprofen, prasterone, pravastatin, prazepam, prazosin,
prednicarbate, prednisolone, prednisone, pregabalin, proglumetacin,
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,
[0346] mercury amide chloride, quetiapine, quinagolide, quinapril,
quinupristin,
[0347] 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, rofecoxib,
ropinirole, ropivacaine, ropivacaine, rosiglitazone, red mercuric
sulfide F, roxatidine, roxithromycin,
[0348] 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, sulfamethoxazole,
sulfamethoxydiazine, sulfametrole, sulfanilamide, sulfasalazine,
sulfathiazole, sulfisomidine, sulindac, sulodexide, sulfur
hexafluoride, sulpiride, sulprostone, sultamicillin, sultiame,
sumatriptan, suxamethonium,
[0349] tacalcitol, tacrolimus, tadalafil, tamoxifen, tamsulosin,
tasonermin, taurolidine, tazarotene, tazobactam, tegafur,
teicoplanin, telithromycin, telmisartan, temoporfin, 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, trimethoprim, trimipramine, tripelennamine,
triprolidine, triptorelin, tritoqualine, trofosfamide,
tromantadine, trometamol, tropicamide, tropisetron, trospium,
tryptophan, tubocurarine chloride, tulobuterol, tyloxapol,
tyrosine, tyrothricin,
[0350] unoprostone, urapid, urapidil, urokinase, ursodeoxycholic
acid,
[0351] 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,
[0352] hydrogen peroxide,
[0353] xantinol nicotinate, ximelagatrane, xipamide,
xylometazoline,
[0354] yohimbine, yttrium .sup.90Y chloride,
[0355] 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.
[0356] 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).
[0357] In a preferred embodiment, the pharmaceutical dosage form is
monolithic.
[0358] The pharmaceutical dosage form according to the invention is
characterized by a comparatively homogeneous distribution of the
pharmacologically active compound (A). Preferably, the content of
the pharmacologically active compound (A) in two segments of the
pharmaceutical dosage form having a volume of 1.0 mm.sup.3 each,
deviates from one another by not more than .+-.10%, more preferably
not more than more than .+-.7.5%, still more preferably not more
than .+-.5.0%, most preferably not more than .+-.2.5%, and in
particular not more than .+-.1.0%. When the pharmaceutical dosage
form is film coated, said two segments of the pharmaceutical dosage
form having a volume of 1.0 mm.sup.3 each are preferably segments
of the core, i.e. do not contain any coating material.
[0359] Preferably, all components of the pharmaceutical dosage form
according to the invention have a comparatively homogeneous
distribution within the pharmaceutical dosage form. Preferably, the
content of each component in two segments of the pharmaceutical
dosage form having a volume of 1.0 mm.sup.3 each, deviates from one
another by not more than .+-.10%, more preferably not more than
more than .+-.7.5%, still more preferably not more than .+-.5.0%,
most preferably not more than .+-.2.5%, and in particular not more
than .+-.1.0%. When the pharmaceutical dosage form is film coated,
said two segments of the pharmaceutical dosage form having a volume
of 1.0 mm.sup.3 each are preferably segments of the core, i.e. do
not contain any coating material.
[0360] Preferably, the pharmaceutical dosage form according to the
invention is adapted for oral administration. It is also possible,
however, to administer the pharmaceutical dosage form via different
routes and thus, the pharmaceutical dosage form may alternatively
be adapted for buccal, lingual, rectal or vaginal administration.
Implants are also possible.
[0361] In a preferred embodiment, the pharmaceutical dosage form
according to the invention is adapted for administration once
daily. In another preferred embodiment, the pharmaceutical dosage
form according to the invention is adapted for administration twice
daily. In still another preferred embodiment, the pharmaceutical
dosage form according to the invention is adapted for
administration thrice daily.
[0362] For the purpose of the specification, "twice daily" means
equal time intervals, i.e., every 12 hours, or different time
intervals, e.g., 8 and 16 hours or 10 and 14 hours, between the
individual administrations.
[0363] For the purpose of the specification, "thrice daily" means
equal time intervals, i.e., every 8 hours, or different time
intervals, e.g., 6, 6 and 12 hours; or 7, 7 and 10 hours, between
the individual administrations.
[0364] Preferably, the pharmaceutical dosage form according to the
invention effects an at least partially delayed release of the
pharmacologically active compounds (A).
[0365] Delayed release is understood according to the invention
preferably to mean a release profile in which the pharmacologically
active compound (A) 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 "at least partially delayed release" covers
according to the invention any pharmaceutical dosage forms which
ensure modified release of the pharmacologically active compounds
(A) contained therein. The pharmaceutical dosage forms preferably
comprise coated or uncoated pharmaceutical 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.
[0366] In the case of the pharmaceutical 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.
[0367] For the purpose of the specification "extended release"
preferably means a product in which the release of active compound
is delayed for a finite lag time, after which release is
unhindered. For the purpose of the specification "repeat action
release" preferably means a product in which a first portion of
active compound is released initially, followed by at least one
further portion of active compound being released subsequently. For
the purpose of the specification "prolonged release" preferably
means a product in which the rate of release of active compound
from the formulation after administration has been reduced, in
order to maintain therapeutic activity, to reduce toxic effects, or
for some other therapeutic purpose. For the purpose of the
specification "sustained release" preferably 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.
[0368] The pharmaceutical dosage form according to the invention
may comprise one or more pharmacologically active compounds (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 breaking strength.
Controlled release from the pharmaceutical dosage form according to
the invention is preferably achieved by embedding the substance in
a matrix. Component (C) may serve as such 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.
[0369] Preferably, the release profile is substantially matrix
controlled, preferably by embedding component (A) in a matrix
comprising component (C) and optionally, further matrix materials.
Preferably, the release profile is not osmotically driven.
Preferably, release kinetics is not zero order.
[0370] Preferably, under physiological conditions the
pharmaceutical 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 the
pharmacologically active compound (A). Further preferred release
profiles R.sub.1 to R.sub.5 are summarized in the table here below
[all data in wt.-% of released pharmacologically active compound
(A)]:
TABLE-US-00007 time R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 60 min
0-30 0-50 0-50 15-25 20-50 120 min 0-40 0-75 0-75 25-40 40-75 240
min 3-55 3-95 10-95 40-70 60-95 480 min 10-65 10-100 35-100 60-90
80-100 720 min 20-75 20-100 55-100 70-100 90-100 960 min 30-88
30-100 70-100 >80 1440 min 50-100 50-100 >90 2160 min >80
>80
[0371] Preferably, under in vitro conditions the pharmaceutical
dosage form has released after 0.5 h 1.0 to 35 wt.-%, after 1 h 5.0
to 45 wt.-%, after 2 h 10 to 60 wt.-%, after 4 h at least 15 wt.-%,
after 6 h at least 20 wt.-%, after 8 h at least 25 wt.-% and after
12 h at least 30 wt.-% of the pharmacologically active compound (A)
that was originally contained in the pharmaceutical dosage
form.
[0372] Suitable in vitro conditions are known to the skilled
artisan. In this regard it can be referred to, e.g., the European
Pharmacopoeia and to the experimental section. Preferably, the
release profile is measured under the following conditions: Paddle
apparatus equipped with sinker, 50 rpm, 37.+-.5.degree. C., 900 mL
simulated intestinal fluid pH 6.8 (phosphate buffer). In a
preferred embodiment, to rotational speed of the paddle is
increased to 100 rpm.
[0373] Preferred release profiles R.sub.6 to R.sub.11 of the
pharmacologically active compound (A) contained in the
pharmaceutical dosage form are summarized in the following
table:
TABLE-US-00008 [wt.-%] R.sub.6 R.sub.7 R.sub.8 R.sub.9 R.sub.10
R.sub.11 after 30 min 16.3 .+-. 7.5 16.3 .+-. 5.0 16.3 .+-. 2.5
15.8 .+-. 7.5 15.8 .+-. 5.0 15.8 .+-. 2.5 after 60 min 27.5 .+-.
7.5 25.0 .+-. 5.0 25.0 .+-. 2.5 24.3 .+-. 7.5 24.3 .+-. 5.0 24.3
.+-. 2.5 after 90 min 32.1 .+-. 7.5 32.1 .+-. 5.0 32.1 .+-. 2.5
31.2 .+-. 7.5 31.2 .+-. 5.0 31.2 .+-. 2.5 after 120 min 38.2 .+-.
7.5 38.2 .+-. 5.0 38.2 .+-. 2.5 37.4 .+-. 7.5 37.4 .+-. 5.0 37.4
.+-. 2.5 after 150 min 43.4 .+-. 7.5 43.4 .+-. 5.0 43.4 .+-. 2.5
42.7 .+-. 7.5 42.7 .+-. 5.0 42.7 .+-. 2.5 after 180 min 48.2 .+-.
7.5 48.2 .+-. 5.0 48.2 .+-. 2.5 47.6 .+-. 7.5 47.6 .+-. 5.0 47.6
.+-. 2.5 after 210 min 52.7 .+-. 7.5 52.7 .+-. 5.0 52.7 .+-. 2.5
52.2 .+-. 7.5 52.2 .+-. 5.0 52.2 .+-. 2.5 after 240 min 56.8 .+-.
7.5 56.8 .+-. 5.0 56.8 .+-. 2.5 56.5 .+-. 7.5 56.5 .+-. 5.0 56.5
.+-. 2.5 after 270 min 60.7 .+-. 7.5 60.7 .+-. 5.0 60.7 .+-. 2.5
60.4 .+-. 7.5 60.4 .+-. 5.0 60.4 .+-. 2.5 after 300 min 64.5 .+-.
7.5 64.5 .+-. 5.0 64.5 .+-. 2.5 64.2 .+-. 7.5 64.2 .+-. 5.0 64.2
.+-. 2.5 after 330 min 67.9 .+-. 7.5 67.9 .+-. 5.0 67.9 .+-. 2.5
67.7 .+-. 7.5 67.7 .+-. 5.0 67.7 .+-. 2.5 after 360 min 71.1 .+-.
7.5 71.1 .+-. 5.0 71.1 .+-. 2.5 71.0 .+-. 7.5 71.0 .+-. 5.0 71.0
.+-. 2.5 after 390 min 74.2 .+-. 7.5 74.2 .+-. 5.0 74.2 .+-. 2.5
74.0 .+-. 7.5 74.0 .+-. 5.0 74.0 .+-. 2.5 after 420 min 77.0 .+-.
7.5 77.0 .+-. 5.0 77.0 .+-. 2.5 76.9 .+-. 7.5 76.9 .+-. 5.0 76.9
.+-. 2.5 after 450 min 79.5 .+-. 7.5 79.5 .+-. 5.0 79.5 .+-. 2.5
79.5 .+-. 7.5 79.5 .+-. 5.0 79.5 .+-. 2.5 after 480 min 81.9 .+-.
7.5 81.9 .+-. 5.0 81.9 .+-. 2.5 82.0 .+-. 7.5 82.0 .+-. 5.0 82.0
.+-. 2.5 after 510 min 84.2 .+-. 7.5 84.2 .+-. 5.0 84.2 .+-. 2.5
84.2 .+-. 7.5 84.2 .+-. 5.0 84.2 .+-. 2.5 after 540 min 86.3 .+-.
7.5 86.3 .+-. 5.0 86.3 .+-. 2.5 86.3 .+-. 7.5 86.3 .+-. 5.0 86.3
.+-. 2.5 after 570 min 88.3 .+-. 7.5 88.3 .+-. 5.0 88.3 .+-. 2.5
88.1 .+-. 7.5 88.1 .+-. 5.0 88.1 .+-. 2.5 after 600 min 90.1 .+-.
7.5 90.1 .+-. 5.0 90.1 .+-. 2.5 89.8 .+-. 7.5 89.8 .+-. 5.0 89.8
.+-. 2.5 after 630 min 91.9 .+-. 7.5 91.9 .+-. 5.0 91.9 .+-. 2.5
91.4 .+-. 7.5 91.4 .+-. 5.0 91.4 .+-. 2.5 after 660 min 93.3 .+-.
7.5 93.3 .+-. 5.0 93.3 .+-. 2.5 92.7 .+-. 7.5 92.7 .+-. 5.0 92.7
.+-. 2.5 after 690 min 94.3 .+-. 7.5 94.3 .+-. 5.0 94.3 .+-. 2.5
94.0 .+-. 7.5 94.0 .+-. 5.0 94.0 .+-. 2.5 after 720 min 95.8 .+-.
7.5 95.8 .+-. 5.0 95.8 .+-. 2.5 95.1 .+-. 7.5 95.1 .+-. 5.0 95.1
.+-. 2.5
[0374] Preferably, the release properties of the pharmaceutical
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. Preferably, at any given time point the release
profiles deviate from one another by not more than 20%, more
preferably not more than 15%, still more preferably not more than
10%, yet more preferably not more than 7.5%, most preferably not
more than 5.0% and in particular not more than 2.5%.
[0375] Preferably, the pharmaceutical dosage form according to the
invention exhibits a uniform release profile. Preferably, the
release profile of the pharmacologically active compound (A) is
interindividually uniform (i.e. when comparing pharmaceutical
dosage forms obtained from the same process) (c.f. FIG. 22) and/or
uniform within a single pharmaceutical dosage form (i.e. when
comparing segments of the same pharmaceutical dosage form).
Preferably, when comparing two probes each having a mass of
preferably 500 mg, the total amount of the released active compound
for any given time point of the measurement does not deviate by
more than 20%, more preferably not more than 15%, still more
preferably not more than 10%, yet more preferably not more than
7,5%, most preferably not more than 5,0% and in particular not more
than 2,5%.
[0376] Preferably, the entire outer surface of the dosage form,
preferably tablet, according to the invention is permeable for
water and for component (A), i.e., preferably the water penetration
characteristics of the surface are identical everywhere. This means
that preferably, the dosage form, preferably tablet, is not
partially coated with a material having a barrier effect which
would impede the penetration of water at the location of the
surface where it is applied.
[0377] Preferably, the release profile of the pharmaceutical dosage
form according to the present invention is stable upon storage,
preferably 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%, more
preferably not more than 15%, still more preferably not more than
10%, yet more preferably not more than 7.5%, most preferably not
more than 5.0% and in particular not more than 2.5% (cf. FIG.
24).
[0378] It has been surprisingly found that by modifying the outer
shape of the pharmaceutical dosage form the storage stability, e.g.
the storage stability of the release profile, can be increased
compared to conventional dosage forms having a comparable release
profile before storage.
[0379] Preferably, the pharmaceutical dosage form according to the
invention contains at least one polymer (C), for the purpose of the
specification also referred to as "component (C)". Preferably, the
pharmaceutical dosage form contains at least one synthetic,
semi-synthetic or natural polymer (C), which contributes
considerably to the elevated breaking strength (resistance to
crushing) of the pharmaceutical dosage form. For the purpose of the
specification a "semi-synthetic" product has been produced by
chemical manipulation of naturally occurring substances.
[0380] Preferably, the mechanical properties of the pharmaceutical
dosage form according to the invention, particularly its breaking
strength, substantially rely on the presence of polymer (C),
although its mere presence does not suffice in order to achieve
said properties. The advantageous properties of the pharmaceutical
dosage form according to the invention, in particular also its
mechanical properties, may not automatically be achieved by simply
processing the pharmacologically active compound (A), polymer (C),
and optionally further excipients by means of conventional methods
for the preparation of pharmaceutical 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. Thus, even if conventional
apparatuses are used, the process protocols usually must be adapted
in order to meet the required criteria.
[0381] Preferably, polymer (C) is water-soluble. Preferably,
polymer (C) is substantially unbranched.
[0382] Polymer (C) may comprise a single type of polymer having a
particular average molecular weight, or a mixture (blend) of
different polymers, such as two, three, four or five polymers,
e.g., polymers of the same chemical nature but different average
molecular weight, polymers of different chemical nature but same
average molecular weight, or polymers of different chemical nature
as well as different molecular weight.
[0383] 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,
polyvinylpyrrolidone, poly(alk)acrylate, 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, 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), polyanhydride
(Polifeprosan), copolymers thereof, block-copolymers thereof, and
mixtures of at least two of the stated polymers, or other polymers
with the above characteristics.
[0384] Preferably, polymer (C) comprises a polyalkylene oxide, more
preferably a polyethylene oxide, a polypropylene oxide, an ethylene
oxide-propylene oxide copolymerisate, which may be e.g. a random
copolymer, alternating copolymer or block copolymer, or a mixture
of any of the foregoing.
[0385] Particularly preferred are high molecular weight polymers
with a preferably weight average molecular weight (M.sub.w) or
viscosity average molecular weight (M.sub.n) of at least of at
least 0.110.sup.6 g/mol, of at least 0.210.sup.6 g/mol, 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, or M.sub.n are known to the person skilled in the
art. Preferably, M.sub..eta. is determined using rheological
measurements and M.sub.w is determined using gel permeation
chromatography (GPC) on suitable phases.
[0386] Preferably, the molecular weight dispersity M.sub.w/M.sub.n
of polymer (C) is within the range of 2.5.+-.2.0, more preferably
2.5.+-.1.5, still more preferably 2.5.+-.1.0, yet more preferably
2.5.+-.0.8, most preferably 2.5.+-.0.6, and in particular
2.5.+-.0.4.
[0387] The polymers 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).
[0388] Most preferred are thermoplastic polyalkylene oxides having
a weight average molecular weight (M.sub.w) or a viscosity average
molecular weight (M.sub..eta.) of at least 0.210.sup.6 g/mol, more
preferably at least 0.310.sup.6 g/mol, still more preferably at
least 0.410.sup.6 g/mol, yet more preferably at least 0.510.sup.6
g/mol, most preferably at least 1.010.sup.6 g/mol and in particular
within the range of 1.010.sup.6 to 1510.sup.6 g/mol are preferred,
e.g. polyethylene oxides, polypropylene oxides or the
(block-)copolymers thereof.
[0389] In a preferred embodiment according to the invention the
polymer (C) comprises [0390] a polyalkylene oxide having a weight
average molecular weight (M.sub.w) or viscosity average molecular
weight (M.sub.n) of at least 0.210.sup.6 g/mol
[0391] in combination with [0392] at least one further polymer,
preferably but not necessarily also having a weight average
molecular weight (M.sub.w) or viscosity average molecular weight
(M.sub..eta.) of at least 0.210.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,
polylactide/glycolide, polylactone, polyglycolide, polyorthoester,
polyanhydride, block polymers of polyethylene glycol and
polybutylene terephthalate, polyanhydride, polyacetal, cellulose
esters, cellulose ethers and copolymers thereof. Cellulose esters
and cellulose ethers are particularly preferred, e.g.
methylcellulose, ethylcellulose, hydroxymethylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, and the
like.
[0393] In a preferred embodiment, said further polymer is neither a
polyalkylene oxide nor a polyalkylene glycol. Nonetheless, the
pharmaceutical dosage form may contain polyalkylene glycol, e.g. as
plasticizer, but then, the pharmaceutical dosage form preferably is
a ternary mixture of polymers: component (C)+further
polymer+plasticizer.
[0394] In a particularly preferred embodiment, said further polymer
is a hydrophilic cellulose ester or cellulose ether, preferably
hydroxypropylmethylcellulose, preferably having an average
viscosity of 100,000.+-.50,000 mPas, more preferably
100,000.+-.20,000 mPas.
[0395] Preferably, the content of said further polymer amounts to
0.5 to 25 wt.-%, more preferably 1.0 to 20 wt.-%, still more
preferably 2.0 to 17.5 wt.-%, yet more preferably 3.0 to 15 wt.-%
and most preferably 4.0 to 12.5 wt.-% and in particular 5.0 to 10
wt.-%, based on the total weight of the polyalkylene oxide.
[0396] In a preferred embodiment the relative weight ratio of said
polyalkylene oxide and said further polymer is within the range of
from 20:1 to 1:20, more preferably 10:1 to 1:10, still more
preferably 7:1 to 1:5, yet more preferably 5:1 to 1:1, most
preferably 4:1 to 1,5:1 and in particular 3:1 to 2:1.
[0397] Preferably, the content of said further polymer amounts to
0.5 to 25 wt.-%, more preferably 1.0 to 20 wt.-%, still more
preferably 2.0 to 22.5 wt.-%, yet more preferably 3.0 to 20 wt.-%
and most preferably 4.0 to 17.5 wt.-% and in particular 5.0 to 15
wt.-%, based on the total weight of the pharmaceutical dosage
form.
[0398] It is not intended to be bound by any theory, but it is
believed that the further polymer may serve as a supplementary
matrix material that guarantees a minimal retardant effect on the
release of the pharmacologically active compound (A) even if the
molecular chains of the polyalkylene oxide have been partially
damaged in the course of the manufacture of the pharmaceutical
dosage form, e.g. by extrusion, thereby decreasing the average
molecular weight. Furthermore, it seems that the further polymer
contributes to the storage stability of the dosage form,
particularly with respect to its release profile.
[0399] Physiologically acceptable, hydrophobic materials which are
known to the person skilled in the art may be used as supplementary
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. 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. It is also
possible to use mixtures of the above-stated hydrophilic and
hydrophobic materials as matrix materials.
[0400] Preferably, the overall content of polymer (C) is preferably
at least 5 wt.-%, at least 10 wt.-%, at least 15 wt.-% or at least
20 wt.-%, more preferably at least 30 wt.-%, still more preferably
at least 40 wt.-%, most preferably at least 50 wt.-% and in
particular at least 60 wt.-%, of the total weight of the
pharmaceutical dosage form. In a preferred embodiment the content
of the polymer (C) is within the range of from about 20 to about 49
wt.-% of the total weight of the pharmaceutical dosage form.
[0401] In a preferred embodiment, the overall content of polymer
(C) is within the range of 25.+-.20 wt.-%, more preferably 25.+-.15
wt.-%, most preferably 25.+-.10 wt.-%, and in particular 25.+-.5
wt.-%. In another preferred embodiment, the overall content of
polymer (C) is within the range of 35.+-.20 wt.-%, more preferably
35.+-.15 wt.-%, most preferably 35.+-.10 wt.-%, and in particular
35.+-.5 wt.-%. In still another preferred embodiment, the overall
content of polymer (C) is within the range of 45.+-.20 wt.-%, more
preferably 45.+-.15 wt.-%, most preferably 45.+-.10 wt.-%, and in
particular 45.+-.5 wt.-%. In yet another preferred embodiment, the
overall content of polymer (C) is within the range of 55.+-.20
wt.-%, more preferably 55.+-.15 wt.-%, most preferably 55.+-.10
wt.-%, and in particular 55.+-.5 wt.-%. In a further preferred
embodiment, the overall content of polymer (C) is within the range
of 65.+-.20 wt.-%, more preferably 65.+-.15 wt.-%, most preferably
65.+-.10 wt.-%, and in particular 65.+-.5 wt.-%. In still a further
a preferred embodiment, the overall content of polymer (C) is
within the range of 75.+-.20 wt.-%, more preferably 75.+-.15 wt.-%,
most preferably 75.+-.10 wt.-%, and in particular 75.+-.5
wt.-%.
[0402] In a preferred embodiment, polymer (C) is homogeneously
distributed in the pharmaceutical dosage form according to the
invention. Preferably, polymer (C) forms a matrix in which the
pharmacologically active compound (A) is embedded. In a
particularly preferred embodiment, the pharmacologically active
compound (A) and polymer (C) are intimately homogeneously
distributed in the pharmaceutical dosage form so that the
pharmaceutical dosage form does not contain any segments where
either pharmacologically active compound (A) is present in the
absence of polymer (C) or where polymer (C) is present in the
absence of pharmacologically active compound (A).
[0403] When the pharmaceutical dosage form is film coated, the
polymer (C) is preferably homogeneously distributed in the core of
the pharmaceutical dosage form, i.e. the film coating preferably
does not contain polymer (C). Nonetheless, the film coating as such
may of course contain one or more polymers, which however,
preferably differ from the polymer (C) contained in the core.
[0404] Preferably, the pharmaceutical dosage form according to the
invention contains a coating, preferably a film-coating. Suitable
coating materials are known to the skilled person. Suitable coating
materials are commercially available, e.g. under the trademarks
Opadry.RTM. and Eudragit.RTM..
[0405] Examples of suitable materials include cellulose esters and
cellulose ethers, such as methylcellulose (MC),
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
hydroxyethylcellulose (HEC), sodium carboxymethylcellulose
(Na-CMC), ethylcellulose (EC), cellulose acetate phthalate (CAP),
hydroxypropylmethylcellulose phthalate (HPMCP);
poly(meth)acrylates, such as aminoalkylmethacrylate copolymers,
ethylacrylate methylmethacrylate copolymers, methacrylic acid
methylmethacrylate copolymers, methacrylic acid methylmethacrylate
copolymers; vinyl polymers, such as polyvinylpyrrolidone,
polyvinylacetatephthalate, polyvinyl alcohol, polyvinylacetate; and
natural film formers, such as shellack.
[0406] In a particularly preferred embodiment, the coating is
water-soluble. Preferably, the coating is based on polyvinyl
alcohol, such as polyvinyl alcohol-part. hydrolyzed, and may
additionally contain polyethylene glycol, such as macrogol 3350,
and/or pigments.
[0407] The coating of the pharmaceutical dosage form can increase
its storage stability.
[0408] The coating can be resistant to gastric juices and dissolve
as a function of the pH value of the release environment. By means
of this coating, it is possible to ensure that the pharmaceutical
dosage form according to the invention passes through the stomach
undissolved and the active compound 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.
Corresponding materials and methods for the delayed release of
active compounds 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.
[0409] It has been surprisingly found that the pharmaceutical
dosage forms can be easily film coated, although the outer shape of
the pharmaceutical dosage forms may deviate from conventional
shapes of dosage forms. For example, when the pharmaceutical dosage
forms according to the invention are shaped by means of an
H-plunger, a skilled person would expect that substantial stapling
or stacking and pair formation occurs when spraying the coating
material on the dosage form in suitable devices. Such stacking and
agglomeration of the dosage form would deteriorate the coating
performance and hence, the film quality. However, it has been
surprisingly found that even pharmaceutical dosage forms having
irregular shapes may be smoothly coated.
[0410] In a particularly preferred embodiment, [0411] the
pharmaceutical dosage form is thermoformed, preferably by
extrusion; and/or [0412] a portion of the surface of the
pharmaceutical dosage form is convex, another portion of its
surface is concave; and/or [0413] the pharmacologically active
compound (A) is a psychotropically acting substance, preferably an
analgesic, more preferably a drug selected from the group
consisting of opioids, stimulants, tranquillisers (e.g.
barbiturates and benzodiazepines) and other narcotics; and/or
[0414] the content of the pharmacologically active compound (A) is
at least 0.5 wt.-%, based on the total weight of the dosage form;
and/or [0415] polymer (C) is an polyalkylene oxide having a weight
average molecular weight of at least 200,000 g/mol, preferably at
least 500,000 g/mol, more preferably within the range of from
1,000,000 to 10,000,000 g/mol; and/or [0416] the content of the
polyalkylene oxide is at least 15 wt.-%, based on the total weight
of the dosage form; and/or [0417] the opioid is embedded in the
polyalkylene oxide, i.e., in a matrix formed by the polyalkylene
oxide; and/or [0418] the pharmaceutical dosage form contains a
plasticizer, preferably polyethylene glycol; and/or [0419] the
content of said plasticizer is at least 5 wt.-%, based on the total
weight of the dosage form; and/or [0420] besides polymer (C), the
pharmaceutical dosage form contains a further polymer selected from
the group consisting of cellulose ethers, cellulose esters and
acrylates, preferably HPMC; and/or [0421] the content of said
further polymer is at least 1 wt.-%, based on the total weight of
the dosage form; and/or [0422] the pharmaceutical dosage form
contains an antioxidant, preferably .quadrature.-tocopherol; and/or
[0423] the content of said antioxidant is at least 0.05 wt.-%,
based on the total weight of the dosage form; and/or [0424] the
pharmaceutical dosage form is adapted for oral administration once
daily or twice daily; and/or [0425] the pharmaceutical dosage form
contains a coating, preferably a film-coating.
[0426] Besides the pharmacologically active compound (A) and
polymer (C) the pharmaceutical dosage form according to the
invention may contain further constituents, such as conventional
pharmaceutical excipients.
[0427] In a preferred embodiment, the pharmaceutical dosage form
contains at least one natural, semi-synthetic or synthetic wax (D),
for the purpose of the specification also referred to as "component
(D)". Preferred waxes are those with a softening point of at least
50.degree. C., more preferably of at least 55.degree. C., still
more preferably of at least 60.degree. C., most preferably of at
least 65.degree. C. and in particular at least 70.degree. C.
[0428] 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 contained, its content is sufficiently
high so that the desired mechanical properties of the
pharmaceutical dosage form are achieved.
[0429] Auxiliary substances (B), further purpose of the
specification also referred to as "component (B)", which may be
contained in the pharmaceutical dosage form according to the
invention are those known auxiliary substances which are
conventional for the formulation of solid pharmaceutical dosage
forms.
[0430] Examples of auxiliary substances (B) are plasticizers,
(further) matrix materials, antioxidants and the like.
[0431] Suitable plasticizers include triacetin and polyethylene
glycol, preferably a low molecular weight polyethylene glycol (e.g.
macrogol 6000).
[0432] Matrix materials are auxiliary substances which influence
active compound 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 contained as hydrophilic matrix
materials. Ethylcellulose, hydroxypropylmethylcellulose,
hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic
acid and/or the derivatives thereof, such as the copolymers, salts,
amides or esters thereof are very particularly preferably contained
as matrix materials.
[0433] Suitable antioxidants are ascorbic acid, butylhydroxyanisole
(BHA), butylhydroxytoluene (BHT), salts of ascorbic acid,
monothioglycerol, phosphorous acid, vitamin C, vitamin E and the
derivatives thereof, coniferyl benzoate, nordihydroguajaretic acid,
gallus acid esters, sodium bisulfite, particularly preferably
butylhydroxytoluene or butylhydroxyanisole and a-tocopherol. 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
pharmaceutical dosage form.
[0434] Preferred compositions X.sub.1 to X.sub.4 of the
pharmaceutical dosage form according to the invention are
summarized in the table here below:
TABLE-US-00009 wt.-% X.sub.1 X.sub.2 X.sub.3 X.sub.4 component (A)
26.5 .+-. 25 26.5 .+-. 20 26.5 .+-. 15 26.5 .+-. 13 polyalkylene
oxide (e.g. PEO) 46.5 .+-. 25 46.5 .+-. 17 46.5 .+-. 12 46.5 .+-.
10 cellulose ester or ether (e.g. HPMC) 14 .+-. 7 14 .+-. 5 14 .+-.
2.5 14 .+-. 0.5 plasticizer (e.g. PEG) 12.5 .+-. 10 12.5 .+-. 7
12.5 .+-. 5 12.5 .+-. 3 antioxidant (e.g. .alpha.-tocopherol) 0.125
.+-. 0.12 0.125 .+-. 0.1 0.125 .+-. 0.05 0.125 .+-. 0.03
[0435] The pharmaceutical 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
pharmaceutical dosage forms that are obtainable by any of the
processes described here below:
[0436] In general, the process for the production of the
pharmaceutical dosage form according to the invention preferably
comprises the following steps: [0437] (a) mixing of components (A),
(C), optionally (B) and/or (D); [0438] (b) optionally pre-forming
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; [0439] (c) 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; [0440] (d) optionally singulating the hardened
mixture; [0441] (e) optionally shaping the pharmaceutical dosage
form; and [0442] (f) optionally providing a film coating.
[0443] Heat may be supplied directly or with the assistance of
ultrasound. Force may be applied and/or the pharmaceutical 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.
[0444] The shaping of the pharmaceutical dosage form according to
the invention is of particular importance. The final shape of the
pharmaceutical dosage form may either be provided during the
hardening of the mixture by applying heat and force (step (c)) or
in a subsequent step (step (e)). In both cases, the mixture of all
components is preferably in the plastified state, i.e. preferably,
shaping is performed at a temperature at least above the softening
point of component (C).
[0445] Shaping can be performed, e.g., by means of a tabletting
press comprising die and plunger of appropriate shape. Preferably,
the plunger is a H-plunger so that the cross section of the
pharmaceutical dosage form assumes the form of a H.
[0446] The following process variants are particularly
preferred:
[0447] Process Variant 1:
[0448] In this embodiment, the pharmaceutical dosage form according
to the invention is preferably produced without using an extruder
by preferably mixing components (A), (C), optionally (B) and/or (D)
and, optionally after granulation, shaping the resultant mixture by
application of force to yield the pharmaceutical dosage form with
preceding and/or simultaneous exposure to heat.
[0449] This heating and application of force for the production of
the pharmaceutical dosage form proceeds without using an
extruder.
[0450] Components (A), (C), optionally (B) and/or (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.
[0451] The resultant mixture is preferably directly shaped into the
pharmaceutical 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),
preferably to its melting temperature, 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.
[0452] This method may also be regarded as a sintering method and
the dosage form thus obtained may be regarded as a sintered dosage
form. In this regard, sintering means the solidification of
crystalline, granular or powdered material by growing together of
the crystallites when heated appropriately. The growing together
can take place, e.g., by diffusion (solid/solid-reaction). The
sintered structure can be analyzed by methods known in the art,
e.g., by (electron)microscopy. As the dosage form contains several
components, the sintering method is preferably a so-called "fusion
sintering" where one of the components involved melts, wets and
coats the higher-melting components. When cooling down, the melted
component (re)solidifies. In a preferred embodiment, component (C)
is the component that melts while the other components do not melt
under the given conditions. Nonetheless, the other components
may--but do not have to--at least partially dissolve in the melted
component (C).
[0453] By such process using a tabletting tool with bottom punch,
top punch and die, e.g. a powder mixture of all components 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.
[0454] The resultant mixture of components (A), (C), optionally (B)
and/or (D) may also first be granulated and then, with preceding
and/or simultaneous exposure to heat, be shaped into the
pharmaceutical dosage form according to the invention by
application of force.
[0455] Granulation may be performed in known granulators by wet
granulation or melt granulation.
[0456] Each of the above-mentioned process steps, in particular the
heating steps and simultaneous or subsequent application of force
for production of the pharmaceutical dosage form according to the
invention proceeds without using an extruder.
[0457] Process Variant 2:
[0458] In this process variant, the pharmaceutical dosage form
according to the invention is produced by thermoforming with the
assistance of an extruder, preferably without there being any
observable consequent discoloration of the extrudate.
[0459] In order to investigate the extent of discoloration due to
this thermoforming, the colour of the mixture of starting
components of which the pharmaceutical dosage form consists is
first determined without addition of a color-imparting component,
such as for example a coloring pigment or an intrinsically colored
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 pharmaceutical dosage form produced according to
the invention from the starting composition and of the
pharmaceutical 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 color of the pharmaceutical 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 pharmaceutical 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".
[0460] Surprisingly, the pharmaceutical 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.
[0461] This variant according to the invention for the production
of pharmaceutical dosage forms according to the invention is
characterized in that [0462] z) components (A), (C), optionally (B)
and/or (D) are mixed, [0463] 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, [0464] x) the still plastic extrudate is
singulated and formed into the pharmaceutical dosage form or [0465]
w) the cooled and optionally reheated singulated extrudate is
formed into the pharmaceutical dosage form,
[0466] wherein process steps y) and x) and optionally process steps
z) and w) are performed under an inert gas atmosphere, preferably a
nitrogen atmosphere.
[0467] Mixing of the components according to process step z) may
also proceed in the extruder.
[0468] Components (A), (C), optionally (B) and/or (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.
[0469] Before blending with the remaining components, component (C)
and/or (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.
[0470] 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.
[0471] 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.
[0472] 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 mm, the
extruded strand should have a diameter of not more than 9 mm. 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.
[0473] Preferably, extrusion is performed in the absence of water,
i.e., no water is added. However, traces of water (e.g., caused by
atmospheric humidity) may be present.
[0474] 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.
[0475] 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 7.5
bar, more preferably at least 10 bar, still more preferably at
least 12.5 bar, yet more preferably at least 15 bar, most
preferably at least 17.5 bar and in particular at least 20 bar, and
is extruded through the die as an extruded strand or strands,
depending on the number of bores which the die comprises.
[0476] In a preferred embodiment, the die head pressure is within
the range of from 25 to 85 bar. The die head pressure can be
adjusted inter alia by die geometry, temperature profile and
extrusion speed.
[0477] 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 pharmacologically active compound (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). Typical extrusion temperatures are
120.degree. C. and 130.degree. C.
[0478] In a preferred embodiment, the extruder torque is within the
range of from 25 to 55 N/m. Extruder torque can be adjusted inter
alia by die geometry, temperature profile and extrusion speed.
[0479] 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.
[0480] An inert gas atmosphere is not necessary for intermediate or
final storage of the optionally singulated extrudate or the final
shape of the pharmaceutical dosage form according to the
invention.
[0481] The singulated extrudate may be pelletized with conventional
methods or be press-formed into tablets in order to impart the
final shape to the pharmaceutical dosage form.
[0482] 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.
[0483] 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 plasticization and
definitive shaping to yield the pharmaceutical dosage form.
[0484] The application of force in the extruder onto the at least
plasticized 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 plasticized 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 pharmaceutical 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.
[0485] For example, extrusion may be performed by means of a
twin-screw-extruder type Micro 27 GL 40 D (Leistritz, Nurnberg,
Germany), screw diameter 27 mm. 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.
[0486] Process Variant 3:
[0487] In this process variant for the production of the
pharmaceutical dosage form according to the invention energy is
applied to a mixture of the components by means of
ultrasonication.
[0488] First of all a homogeneous mixture of at least component (A)
and component (C) (=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
plasticizser.
[0489] 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.
[0490] Selection of the suitable mixer is determined inter alia by
the flowability and cohesiveness of the material to be mixed.
[0491] The mixture is then subjected to shaping. The mixture is
preferably shaped during or after ultrasonication, preferably by
compaction.
[0492] It is particularly preferred during ultrasonication that
there is direct contact between the mixture and the sonotrode of
the ultrasound device.
[0493] 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.
[0494] Ultrasonication and the application of force ensure uniform
energy transfer, so bringing about rapid and homogeneous sintering
of the mixture. In this manner, pharmaceutical 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 pulverized.
[0495] Before shaping is performed, the mixture may be granulated
after the mixing operation, after which the resultant granules are
shaped into the pharmaceutical dosage form with ultrasonication and
application of force.
[0496] Granulation may be performed in machinery and apparatus
known to the person skilled in the art.
[0497] 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.
[0498] 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.
[0499] Final shaping to yield the pharmaceutical dosage form
preferably proceeds with application of force in appropriate
moulds.
[0500] 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.
[0501] As already mentioned, shaping to yield the final shape of
the pharmaceutical dosage form by using a mixture comprising
pharmacologically active compound (A) and polymer (C) 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 pharmaceutical dosage
forms, such as tablets, or for press-forming granules into the
corresponding final shape.
[0502] The tablets produced according to the invention may also be
multilayer tablets.
[0503] In multilayer tablets, at least the layer which contains
pharmacologically active compound (A) should be ultrasonicated and
exposed to force.
[0504] 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 pharmaceutical dosage forms
preferably proceeds by direct press-forming of a pulverulent
mixture of the components of the pharmaceutical 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.
[0505] 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 mm. 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.
[0506] Process Variant 4:
[0507] In this process variant for the production of the
pharmaceutical dosage form according to the invention, components
(A), (C), optionally (B), such as antioxidants, plasticizers and/or
delayed-release auxiliary substances, and optionally component (D),
are processed with the assistance of a planetary-gear extruder to
yield the pharmaceutical dosage form according to the
invention.
[0508] 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.
[0509] 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 homogenized, 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 component (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).
[0510] After extrusion of the molten mixture and optional cooling
of the extruded strand or extruded strands, the extrudates are
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.
[0511] 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 pharmaceutical
dosage form, wherein they may be exposed to heat again if
necessary.
[0512] 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.
[0513] 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 pharmaceutical dosage form produced according
to the invention.
[0514] 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.
[0515] 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.
[0516] The process according to the invention may be performed
discontinuously or continuously, preferably continuously.
[0517] 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.
[0518] Process Variant 5:
[0519] This variant for the production of the pharmaceutical dosage
form according to the invention is performed by processing at least
the components (A), (C), optionally (B), such as antioxidants,
plasticizers 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
pharmaceutical dosage form.
[0520] To this end, components (A), (C), optionally (B) and/or (D)
are mixed and, after addition of the solvent and optionally after
granulation, the resultant formulation mixture is shaped to yield
the pharmaceutical dosage form.
[0521] Components (A), (C), optionally (B) and/or (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.
[0522] The solvent for the polymer (C) is added at least in such
quantities that the formulation mixture is uniformly moistened.
[0523] Solvents which are suitable for the polymer (C) are
preferably aqueous solvents, such as water, mixtures of water and
aliphatic alcohols, preferably C.sub.1 to C.sub.6 alcohols, esters,
ethers, hydrocarbons, particularly preferably distilled water,
short-chain alcohols, such as methanol, ethanol, isopropanol,
butanol or aqueous alcohol solutions.
[0524] 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.
[0525] 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 pharmaceutical dosage form. The corresponding
dried portions are then shaped to yield the pharmaceutical dosage
form.
[0526] This is preferably achieved by using tablet presses.
[0527] 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.
[0528] Suitable dispersants are preferably hydrophilic solvents,
such as aliphatic alcohols, ketones, esters. Short-chain alcohols
are preferably used.
[0529] 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 stabilizers.
Suitable stabilizers are, for example, hydrophilic polymers such as
for example hydroxypropylmethylcellulose.
[0530] The foam is also preferably incorporated into the
formulation mixture with stirring, a granulated composition so
preferably being obtained.
[0531] Before or after being divided into sub-portions, which
preferably correspond to the mass of a unit of the pharmaceutical
dosage form, the granulated composition is dried and then shaped
into the pharmaceutical dosage form.
[0532] 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.
[0533] 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 pharmaceutical dosage
form, are shaped or converted to yield the pharmaceutical dosage
form.
[0534] 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 pharmaceutical dosage form. This shaping
preferably proceeds with the assistance of a tablet press, using
shaping rollers or shaping belts equipped with rollers.
[0535] It is also possible to convert the paste into a planar
structure and to stamp the pharmaceutical dosage form out of it
once it has dried.
[0536] 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
pharmaceutical dosage form. Corresponding apparatuses are known to
the person skilled in the art.
[0537] The process according to the invention may here be performed
continuously or discontinuously.
[0538] 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.
[0539] As stated above, after drying, the pharmaceutical 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 pharmaceutical dosage
form.
[0540] Alternatively, the solution may also be divided into
portions such that, after drying, they each correspond to the mass
of a unit of the pharmaceutical dosage form, with moulds which
already correspond to the shape of the unit of the pharmaceutical
dosage form preferably being used for this purpose.
[0541] If the solution is divided into any desired portions, the
portions may, after drying, optionally be combined again and be
shaped to form the pharmaceutical dosage form, being for example
packaged in a capsule or press-formed to form a tablet.
[0542] 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
pharmaceutical dosage form, further drying corresponding to the
above-described drying may optionally be performed.
[0543] Combinations of individual process steps of the above
process variants are also possible in order to produce the
pharmaceutical dosage form according to the invention.
[0544] Process variants 2 and 4 as described above involve the
extrusion of a composition comprising components (A), (C),
optionally (B) and/or (D). Preferably, extrusion is performed by
means of twin-screw-extruders or planetary-gear-extruders,
twin-screw extruders being particularly preferred.
[0545] The process for the preparation of the pharmaceutical 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/or
(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 compound, 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.
[0546] 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
pharmaceutical dosage form when comparing two pharmaceutical dosage
forms, preferably taken from the same batch.
[0547] 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.
[0548] Further, 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.
[0549] 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/or (D).
[0550] 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.
[0551] 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, more preferably 0.15 to 3.5
mm, still more preferably 0.2 to 3.0 mm, most preferably 0.2 to 2.5
mm and in particular 0.2 to 2.0 mm. In a preferred embodiment the
thickness of the extrusion skin in the sum over both opposing sides
amounts to 0.5 to 50%, more preferably 1.0 to 40%, still more
preferably 1.5 to 35%, most preferably 2.0 to 30% and in particular
2.5 to 25% of the diameter of the extrudate.
[0552] When the pharmaceutical 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
pharmaceutical dosage forms obtained therefrom are preferably also
characterized by a particular morphology.
[0553] 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 pharmaceutical 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 pharmaceutical dosage forms which
has emerged from the extrusion skin in the course of further
processing the extruded intermediate, will be denoted as "skin
domain".
[0554] Preferably, the pharmaceutical dosage form according to the
invention comprises a skin domain and a core located therein.
Preferably, the skin domain is connected with the core in a
seamless manner. Preferably the skin 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/or (D). The material forming the skin 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 skin domain and the core are
visible with the naked eye in the cross-section of the
pharmaceutical dosage form.
[0555] In case that the pharmaceutical dosage form has been coated,
e.g. by a film coating, the skin domain is located between the film
coating and the core.
[0556] Since the pharmaceutical dosage form according to the
invention may be obtained in different ways from the extrudate
containing the extrusion skin (intermediate), the skin domain may
take different arrangements and extensions within the
pharmaceutical dosage form according to the invention. All
arrangements have in common, however, that the skin 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 skin domain. In other
words, preferably the skin domain has two openings/blanks on
opposing sides.
[0557] The thickness of the skin 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
skin domain within the pharmaceutical dosage form.
[0558] Preferably the thickness of the skin domain is within the
range from 0.1 to 4.0 mm, more preferably 0.15 to 3.5 mm, still
more preferably 0.2 to 3.0 mm, most preferably 0.2 to 2.5 mm and in
particular 0.2 to 2.0 mm.
[0559] The process according to the invention preferably involves
the extrusion of a mixture of components (A), (C), optionally (B)
and/or (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 pharmaceutical dosage form.
[0560] 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/or (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, pharmaceutical 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.
[0561] The shape of the pharmaceutical dosage form upon storage at
stressed conditions, e.g. at 40.degree. C./75% RH, may also be
unstable for other reasons.
[0562] Said memory effect significantly deteriorates the storage
stability of the pharmaceutical dosage form, as by regaining its
outer form several properties of the pharmaceutical dosage form are
changed. The same applies to any changes of the outer form due to
other reasons.
[0563] 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. Said 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.
[0564] 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 pharmaceutical dosage form.
[0565] 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/or (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/or (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).
[0566] In a preferred embodiment the outer shape of the
pharmaceutical 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.
[0567] In a preferred embodiment the volume of the pharmaceutical
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 (B) and/or
(D), optionally at a temperature of 40.degree. C. and 75% RH.
[0568] A further aspect of the invention relates to a packaging
containing the pharmaceutical dosage form according to the
invention and an oxygen scavenger. Suitable packages include
blister packages and bottles, such as glass bottles or bottles made
from thermoplastic polymers.
[0569] Oxygen scavengers and the application thereof in
pharmaceutical packaging are known to the skilled artisan. In a
preferred embodiment, the oxygen scavenger is selected from the
group consisting of metal-catalyzed oxidizable organic polymers and
anti-oxidants. It has been surprisingly found that the storage
stability of the pharmaceutical dosage form can be increased when
keeping the oxygen content of the atmosphere within the packaging
low. Methods for packaging pharmaceutical dosage forms and the
application of suitable oxygen scavengers are known to the skilled
artisan. In this regard it can be referred to e.g. D. A. Dean,
Pharmaceutical Packaging Technology, Taylor & Francis, 1st ed.;
F. A. Paine et al., Packaging Pharmaceutical and Healthcare
Products, Springer, 1st ed.; and O. G. Piringer et al., Plastic
Packaging: Interactions with Food and Pharmaceuticals, Wiley-VCH,
2nd ed.
[0570] The pharmaceutical dosage form according to the invention is
suitable to avoid various misuses, particularly [0571] accidental
misuse (e.g. unintentional); [0572] recreational misuse; and [0573]
experienced drug misuse.
[0574] A further aspect of the invention relates to the use of an
opioid for the manufacture of the pharmaceutical dosage form as
described avove for the treatment of pain.
[0575] A further aspect of the invention relates to the use of a
pharmaceutical dosage form as described above for avoiding or
hindering the abuse of the pharmacologically active compound (A)
contained therein.
[0576] A further aspect of the invention relates to the use of a
pharmaceutical dosage form as described above for avoiding or
hindering the unintentional overdose of the pharmacologically
active compound (A) contained therein.
[0577] In this regard, the invention also relates to the use of a
pharmacologically active compound (A) as described above and/or a
synthetic or natural polymer (C) as described above for the
manufacture of the pharmaceutical dosage form according to the
invention for the prophylaxis and/or the treatment of a disorder,
thereby preventing an overdose of the pharmacologically active
compound (A), particularly due to comminution of the pharmaceutical
dosage form by mechanical action.
[0578] Further, the invention relates to a method for the
prophylaxis and/or the treatment of a disorder comprising the
administration of the pharmaceutical dosage form according to the
invention, thereby preventing an overdose of the pharmacologically
active compound (A), particularly due to comminution of the
pharmaceutical dosage form by mechanical action. Preferably, the
mechanical action is selected from the group consisting of chewing,
grinding in a mortar, pounding, and using apparatuses for
pulverizing conventional pharmaceutical dosage forms.
[0579] The invention is explained below with reference to examples.
These explanations are given merely by way of example and do not
limit the general concept and scope of the invention.
EXAMPLE 1
Formulation Examples
A. Formulation Examples for Retarded Release Formulations
TABLE-US-00010 [0580] Active ingredient(s) 0.01-50% (w/w) Viscous
hydrophilic polymer(s) 0.01-80% (w/w) Pregelatinized starch 5-80%
(w/w) Pharmaceutically acceptable formulating agents ad 100% (w/w).
Active ingredient(s) 0.01-50% (w/w) Viscous hydrophilic polymer(s)
comprising 0.01-80% (w/w) hydroxypropyl cellulose Pregelatinized
starch 5-80% (w/w) Pharmaceutically acceptable formulating agents
ad 100% (w/w). Active ingredient(s) 0.01-50% (w/w) Viscous
hydrophilic polymer(s) 0.01-80% (w/w) Pregelatinized starch 5-15%
(w/w) Pharmaceutically acceptable formulating agents ad 100% (w/w).
Active ingredient(s) 0.01-50% (w/w) Viscous hydrophilic polymer(s)
comprising 0.01-80% (w/w) hydroxypropyl cellulose Pregelatinized
starch 5-15% (w/w) Pharmaceutically acceptable formulating agents
ad 100% (w/w). Active ingredient(s) 0.01-50% (w/w) Viscous
hydrophilic polymer(s) 0.01-80% (w/w) Pregelatinized starch 5%
(w/w) Pharmaceutically acceptable formulating agents ad 100% (w/w).
Active ingredient(s) 0.01-50% (w/w) Viscous hydrophilic polymer(s)
comprising 0.01-80% (w/w) hydroxypropyl cellulose Pregelatinized
starch 5% (w/w) Pharmaceutically acceptable formulating agents ad
100% (w/w). Active ingredient(s) 0.01-50% (w/w) Hydroxypropyl
cellulose 25-62% (w/w) Hydroxypropyl methylcellulose 0-16% (w/w)
Pregelatinized starch 5-15% (w/w) Pharmaceutically acceptable
formulating agents ad 100% (w/w).
[0581] The above formulations can generally be prepared according
to the following process: [0582] (1.a) one or more active
ingredients, pregelatinized starch, one or more viscous hydrophilic
polymers and optionally some or all of the pharmaceutically
acceptable formulating agents are mixed; [0583] (1.b) the powder
mixture prepared under (1.a) is run through a compactor, thus
yielding plates; [0584] (1.c) the resulting plates are broken down
and sieved, thus yielding granules; [0585] (1.d) the resulting
granules are optionally mixed with all or the remainder of the
pharmaceutically acceptable formulating agents, preferably until
homogeneous.
[0586] In case the active ingredient(s) is a sparingly water
soluble, slightly water soluble, very slightly water soluble,
practically water insoluble or water insoluble drug or a drug with
a pH dependent solubility, in particular an alkaline drug, the
active ingredient(s) can in one embodiment be incorporated in the
controlled release formulation as an intimate mixture with a
cyclodextrin or derivatives thereof or another water soluble
polymer, as described hereinabove. In said case, the preparation of
the present controlled release formulation comprises an additional
first step, namely [0587] (2.a) one or more active ingredients and
the water soluble polymer are intimately mixed; [0588] (2.b) the
intimate mixture prepared under (2.a) is mixed with pregelatinized
starch, one or more viscous hydrophilic polymers and optionally
some or all of the pharmaceutically acceptable formulating agents;
[0589] (2.c) the powder mixture prepared under (2.b) is run through
a compactor, thus yielding plates; [0590] (2.d) the resulting
plates are broken down and sieved, thus yielding granules; [0591]
(2.e) the resulting granules are optionally mixed with all or the
remainder of the pharmaceutically acceptable formulating agents,
preferably until homogeneous.
[0592] The formulation obtained by the processes as described
hereinabove in one embodiment can then be compressed in a tablet
according to the invention by tabletting in a tabletting machine
with punches and dies adapted for the tablet of the invention the
final blend resulting from the above described processes, i.e. the
blend resulting under (1.d) or (2.e).
[0593] A compactor as mentioned in step (1.b) or (2.c) of the above
described processes is an apparatus wherein the powdery mixture is
run between two rollers exerting pressure on the powdery mixture.
In this way the mixture is compacted and sheets or plates are
formed. Compactors are commercially available, for instance, from
the company Gerteis (Jona, Swiss), e.g. a Polygran 3W
compactor.
[0594] The above general route of preparation of the controlled
release formulation may be modified by a person skilled in the art
by for instance adding certain ingredients at other stages than
indicated above.
[0595] As an alternative to the above described route of
preparation involving a compaction step, the above described
mixture can also be tabletted using direct compression. When using
the technique of direct compression, dies or matrices in the form
of the desired tablets of the invention are filled with a powdery
mixture having the tablet composition and then are punched with
punches adapted for the desired tablet. The advantage of this way
of tabletting is that it usually requires less steps. Apparatuses
for direct compression tabletting are known to the skilled parson.
These apparatuses require forced feeding systems whenever the
rheological properties of the mixture are not appropriate to fill
the dies or matrices without forced feeding.
[0596] Example of a Retarded Release Formulation According to the
Invention
TABLE-US-00011 Cisapride-(L)-tartrate 52.92 mg Lactose monohydrate
200 mesh 149.43 mg Hydroxypropyl methylcellulose 2208 74.1 mg
Hydroxypropyl cellulose 228.00 mg Drum dried waxy maize starch 28.5
mg Magnesium stearate 2.85 mg Colloidal anhydrous silica 5.7 mg
Talc 28.5 mg
[0597] Preparation of the Above Powder Mixture
Cisapride-(L)-tartrate, hydroxypropyl methylcellulose,
hydroxypropyl cellulose, drum dried waxy maize starch, the lactose
filler, are mixed in a planetary mixer, and than compacted using a
dry compactor. The compact is broken down, sieved and mixed in a
planetary mixer with colloidal anhydrous silica. Magnesium stearate
is added and mixed.
[0598] The above mixture can then be compressed into a tablet
according to the invention.
B. Formulation Examples for Immediate Release Formulations
[0599] A mixture of 100 g of active ingredient(s), 570 g lactose
and 200 g starch is mixed well and thereafter humidified with a
solution of 5 g sodium dodecyl sulfate and 10 g
polyvinyl-pyrrolidone (Kollidon-K 90.RTM.) in about 200 ml of
water. The wet powder mixture is sieved, dried and sieved again.
Then there are added 100 g microcrystalline cellulose (Avicel.RTM.)
and 15 g hydrogenated vegetable oil (Sterotex.RTM.). The whole is
mixed well.
[0600] The above mixture can then be compressed into tablets
according to the invention, giving 10.000 tablets, each comprising
10 mg of the active ingredient.
EXAMPLE 2
[0601] Pharmaceutical dosage forms were manufactured from the
following compositions:
TABLE-US-00012 I-1 (#1) I-2 (#2) C-1 tapentadol HCl 291.20 291.20
291.20 PEO Mw 7 Mio g/mol 245.00 245.00 PEO Mw 5 Mio g/mol 247.70
polyethylene glycole 6000 65.10 65.10 65.00 HPMC 100,000 mPas 98.00
98.00 45.50 .alpha.-tocopherole 0.70 0.70 0.65 SUM 700.00 700.00
650.00 tablet format 9 .times. 21 H0 9 .times. 21 H0 9 .times. 21
oblong
[0602] 291.20 mg tapentadol HCl correspond to 250 mg tapentadol
free base.
[0603] General Procedure:
[0604] The polyethylene oxide was melted at 90.degree. C. and the
total amount of .alpha.-tocopherol was dissolved therein. Then,
tapentadol and hydroxypropyl methyl cellulose (HPMC) were mixed in
a fast mixer for 5 min at a temperature of 70.degree. C. The melt
of polyethylene oxide and .alpha.-tocopherole was added to the
mixture dropwise within 10 minutes. The thus obtained granulate was
sieved on a taper sieving machine and then mixed in a free fall
mixer for 15 min. The powder mixture was dosed gravimetrically to
an extruder. Extrusion was performed by means of a twin screw
extruder of type Micro 27 GL 40 D (Leistritz, Nurnberg, Germany)
that was equipped with a heatable round die having a diameter of 8
mm.
[0605] The following extrusion conditions were adjusted:
[0606] Number of revolutions of screws: 100 Upm
[0607] Throughput: 4 kg/h
[0608] Product temperature: 120.degree. C.
[0609] Shell temperature: 100.degree. C.
[0610] The hot extrudate was cooled on a conveyor belt and the
cooled extrusion strand was comminuted to cut pieces weighing 700
mg each. The cut pieces were shaped by means of an excenter press.
The tablets of inventive examples 1-1 and 1-2 were shaped by means
of an H-plunger (9*21 H0, type 21x9 WR 1.9 with "inner courtyard",
Notter, Olbronn-Durrn, Germany) and the tablets of comparative
example C-1 were shaped by means of a conventional oblong
plunger.
[0611] The tablets of inventive examples I-1 and I-2 had the
following dimensions (base height H according to FIG. 9B); width,
height and length a, b and c according to FIG. 10) (average values
n=10):
TABLE-US-00013 a 9.06 The manufacturer of the H0-plunger provides
a.sub.1 3.17 the following formula for the surface and the a.sub.2
2.72 volume of the shaped tablets as a function a.sub.3 3.17 of the
base height (H): b 4.52 volume = 94.3 + 171.6 .times. H [mm.sup.3]
= 638.3 mm.sup.3 b.sub.1 0.99 surface = 382 + 52.3 .times. H
[mm.sup.2] = 547.8 mm.sup.2 b.sub.2 2.54 b.sub.3 0.99 c 20.49
c.sub.1 3.26 c.sub.2 13.97 c.sub.3 3.26 H 3.17
[0612] In comparison, the surface of the pharmaceutical dosage form
according to comparative example C-1 was estimated to be about 459
mm.sup.2 (estimation in accordance with Eudragit.RTM. Application
Guidelines, 10th edition, July 2007, Rohm GmbH, Darmstadt, page
25).
[0613] The correlation of the pharmaceutical dosage forms according
to inventive examples I-1 and I-2 and according to comparative
example C-1 with the requirement S.gtoreq.AW.sup.2/3 are summarized
in the following table:
TABLE-US-00014 I-1/I-2 C-1 weight W 700 mg 650 mg surface S 548
mm.sup.2 459 mm.sup.2 S/W 0.783 0.706 A [for S = A W.sup.2/3] 6.95
6.12
EXAMPLE 3
[0614] The dissolution profile of the tablets was investigated
under the following conditions: Paddle apparatus equipped with
sinker, 50 rpm, 37.+-.5.degree. C., 900 mL simulated intestinal
fluid pH 6.8 (phosphate buffer).
[0615] The results are displayed in FIGS. 21 to 24.
[0616] FIG. 21 shows that immediately after manufacture the release
profile of the tablet according to inventive example I-2 (H-shape)
is comparable to the release profile of the tablet according to
comparative example C-1 (oblong).
[0617] FIG. 22 shows that the release profile of the tablet
according to inventive example I-1 (H-shape) is comparable to the
release profile of the tablet according to inventive Example I-2
(H-shape), i.e. that different batches provide reproducible
results.
[0618] FIG. 23 shows that the release profile of the tablet
according to comparative example C-1 (oblong) changes upon storage
(40.degree. C., 6 months; 25.degree. C. 9 months; and 30.degree. C.
9 months, respectively).
[0619] FIG. 24 shows that the release profile of the tablet
according to inventive example I-2 (H-shape) is stable, i.e. does
not change upon storage (40.degree. C., 6 months; 25.degree. C. 9
months; and 30.degree. C. 9 months, respectively).
[0620] These experimental findings demonstrate that the
pharmaceutical dosage forms according to the invention have a
storage stability in terms of the release profile that is better
than the storage stability of comparative pharmaceutical dosage
forms.
EXAMPLE 4
[0621] In accordance with example 2, pharmaceutical dosage forms
were manufactured from the following compositions:
TABLE-US-00015 [mg] C-2 C-3 C-4 I-3 I-4 tapentadol HCl 58.24 116.48
174.72 232.96 291.20 PEO Mw 7 Mio g/mol 225.16 187.12 166.83 260.39
245.00 polyethylene glycole 6000 60.00 40.00 45.00 65.00 65.10 HPMC
100,000 mPas 56.00 56.00 63.00 91.00 98.00 .alpha.-tocopherole 0.60
0.40 0.45 0.65 0.70 SUM 400 400 450 650 700 tablet format oblong
oblong oblong H-shape H-shape 7 .times. 17 mm 7 .times. 17 mm 7
.times. 17 mm 9 .times. 21 mm 9 .times. 21 mm
[0622] Furthermore, two comparative H-shaped tablets (9.times.21
mm) containing 232.96 mg tapentadol HCl (C-5) and 291.20 mg
tapentadol HCl (C-6) were manufactured without extrusion from
conventional excipients not comprising polyalkylene oxide of high
molecular weight.
[0623] The breaking strength of the pharmaceutical dosage forms was
measured by means of a Sotax.RTM. HT100 at a constant speed of 120
mm/min. A tablet was regarded as failing the breaking strength test
when during the measurement the force dropped below the threshold
value of 25% of the maximum force that was observed during the
measurement, regardless of whether the dosage form was fractured
into separate pieces or not.
[0624] All values are given as mean of 10 measurements (n=10).
[0625] The results of the breaking strength measurements are
summarized in the table here below:
TABLE-US-00016 direction breaking form type of jaws according to
strength C-2 oblong plain FIG. 18B) >500N C-3 oblong plain FIG.
18B) >500N C-4 oblong plain FIG. 18B) >500N C-5 H-shape plain
FIG. 18B) 188N C-6 H-shape plain FIG. 18B) 188N I-3 H-shape plain
FIG. 18B) 349N I-4 H-shape plain FIG. 18B) 399N I-3 H-shape
embossment/indentation FIG. 20A) >500N I-4 H-shape
embossment/indentation FIG. 20A) >500N I-3 H-shape
embossment/indentation FIG. 20C) >500N I-4 H-shape
embossment/indentation FIG. 20C) >500N
[0626] The above breaking strength data demonstrate that the dosage
forms according to the invention I-3 and I-4 exhibit a breaking
strength of more than 500 N (B.sub.1) when measured in accordance
with FIGS. 20A) and 20C) (E.sub.1), even when equipping the tester
jaws with embossment and indentation, whereas they exhibit a
breaking strength of less than 500 N (B.sub.2) when measured in
accordance with FIG. 18B) (E.sub.2).
[0627] Nonetheless, the breaking strength (B.sub.2) of the dosage
forms according to the invention I-3 and I-4 when measured in
accordance with FIG. 18B) (E.sub.2) is still much higher than that
of H-shaped dosage forms that are manufactured from conventional
excipients without extrusion (C-5 and C-6).
[0628] Still further, comparative oblong tablets having an
increased breaking strength, such as described in WO2005/016314 or
WO2005/016313 (C-2, C-3, and C-4), exhibit a breaking strength of
more than 500 N when measured in accordance with FIG. 18B). Such
oblong tablets exhibit a breaking strength of at least 500 N in
each and every direction of extension and thus, are distinguished
from the pharmaceutical dosage forms according to the
invention.
EXAMPLE 5
[0629] Tablets eq200 mg Tapentadol were prepared by extrusion (3.5
kg/h) in two different tablet shapes. The compositions were
practically identical (minimal variation in a tocopherol), and had
the same weight.
[0630] Composition of the tablets eq200 mg Tapentadol (in mg):
TABLE-US-00017 tablets 5.1 5.2 Tapentadol HCL 232.96 mg 34.9%
232.96 mg 34.9%.sup. PEO Mw 5 Mio 300.38 mg 45% 300.38 mg 45% HPMC
100 000 66.75 mg 10% 66.76 mg 10% PEG 66.58 mg 9.975% 66.76 mg 10%
.alpha. tocopherol 0.83 mg 0.125% 0.66 mg 0.1% tablet weight 667.5
mg 667.5 mg
[0631] Percentage drug released for the Tapentadol eq200 mg TRF
tested in dissolution at 50 rpm paddle speed, USP apparatus II, USP
buffer pH 6.8:
TABLE-US-00018 5.1 5.2 standard shape H0 shape [%] average average
30 min 10.8 14.9 120 min 29.8 34.5 240 min 44.3 51.3 600 min 77.3
84.8
EXAMPLE 6
[0632] Tablets eq250 mg Tapentadol were prepared by extrusion (3.5
kg/h) in different tablet shapes. The composition is shown in the
next table.
[0633] Composition of the eq250 mg Tapentadol TRF tablets (in
mg):
TABLE-US-00019 Experiment 6 Tapentadol HCL 291.20 mg 34.9%.sup. PEO
Mw 5 Mio 375.47 mg 45% HPMC 100 000 83.44 mg 10% PEG 83.44 mg 10%
.alpha. tocopherol 0.83 mg 0.1% tablet weight 834.38 mg
[0634] Percentage drug released for the Tapentadol eq250 mg TRF
tested in dissolution at 50 rpm paddle speed, USP apparatus II, USP
buffer pH 6.8:
TABLE-US-00020 standard shape (9 .times. 21 mm) H1-shape [%]
average average 30 min 12.0 14.1 120 min 29.3 32.2 240 min 46.2
48.2 600 min 78.7 79.3
[0635] A first set of comparative tablets was shaped by means of a
conventional oblong plunger, 9.times.21 mm, and a second set of
inventive tablets was shaped by means of an H-plunger (22.6*8.6 H1,
type CPS Batonett, C7084-1, Elisabeth EPMO, France).
* * * * *