U.S. patent application number 15/636957 was filed with the patent office on 2017-10-19 for tamper resistant dosage form with bimodal release profile.
This patent application is currently assigned to GRUNENTHAL GMBH. The applicant listed for this patent is GRUNENTHAL GMBH. Invention is credited to Lutz BARNSCHEID, Anja Geissler, Jana Patz, Sebastian Schwier, Stefanie Strauch, Klaus Wening.
Application Number | 20170296472 15/636957 |
Document ID | / |
Family ID | 48485060 |
Filed Date | 2017-10-19 |
United States Patent
Application |
20170296472 |
Kind Code |
A1 |
BARNSCHEID; Lutz ; et
al. |
October 19, 2017 |
Tamper resistant dosage form with bimodal release profile
Abstract
The invention relates to a pharmaceutical dosage form comprising
(i) at least one formed segment (S.sub.1), which contains a first
pharmacologically active ingredient (A.sub.1) and provides
prolonged release thereof, and (ii) at least one further segment
(S.sub.2), which contains a second pharmacologically active
ingredient (A.sub.2) and provides immediate release thereof,
wherein the at least one formed segment (S.sub.1) exhibits a higher
breaking strength than the at least one further segment (S.sub.2)
and the at least one formed segment (S.sub.1) exhibits a breaking
strength of more than 500 N.
Inventors: |
BARNSCHEID; Lutz;
(Monchengladbach, DE) ; Geissler; Anja; (Stolberg,
DE) ; Wening; Klaus; (Koln, DE) ; Strauch;
Stefanie; (Aachen, DE) ; Patz; Jana;
(Bornheim, DE) ; Schwier; Sebastian; (Aachen,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRUNENTHAL GMBH |
Aachen |
|
DE |
|
|
Assignee: |
GRUNENTHAL GMBH
Aachen
DE
|
Family ID: |
48485060 |
Appl. No.: |
15/636957 |
Filed: |
June 29, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14287348 |
May 27, 2014 |
9737490 |
|
|
15636957 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/209 20130101;
A61K 31/167 20130101; A61K 31/485 20130101; A61K 9/2086 20130101;
A61K 31/485 20130101; A61P 43/00 20180101; A61P 25/04 20180101;
A61K 31/167 20130101; A61K 9/2095 20130101; A61P 25/18 20180101;
A61K 2300/00 20130101; A61K 9/2031 20130101; A61K 2300/00 20130101;
A61P 29/00 20180101; A61K 45/06 20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/485 20060101 A61K031/485; A61K 31/167 20060101
A61K031/167; A61K 9/20 20060101 A61K009/20; A61K 9/24 20060101
A61K009/24; A61K 45/06 20060101 A61K045/06; A61K 9/20 20060101
A61K009/20 |
Foreign Application Data
Date |
Code |
Application Number |
May 29, 2013 |
EP |
13 169 658.5 |
Claims
1. A pharmaceutical dosage form comprising: (i) at least one formed
segment (S.sub.1), which contains a first pharmacologically active
ingredient (A.sub.1) and provides prolonged release thereof; and
(ii) at least one further segment (S.sub.2), which contains a
second pharmacologically active ingredient (A.sub.2) and provides
immediate release thereof; wherein the at least one formed segment
(S.sub.1) exhibits a higher breaking strength than the at least one
further segment (S.sub.2) and the at least one formed segment
(S.sub.1) exhibits a breaking strength of more than 500 N.
2. The pharmaceutical dosage form according to claim 1, wherein the
at least one further segment (S.sub.2) exhibits a breaking strength
of at most 500 N.
3. The pharmaceutical dosage form according to claim 1, wherein the
second pharmacologically active ingredient (A.sub.2) is different
from the first pharmacologically active ingredient (A.sub.1).
4. The pharmaceutical dosage form according to claim 1, wherein (i)
the first pharmacologically active ingredient (A.sub.1) has a
psychotropic effect; and/or (ii) the second pharmacologically
active ingredient (A.sub.2) is selected from ATC classes [M01A],
[M01C], [N02B] and [N02C] according to the WHO.
5. The pharmaceutical dosage form according to claim 1, wherein the
first pharmacologically active ingredient (A.sub.1) is an opioid or
a physiologically acceptable salt thereof.
6. The pharmaceutical dosage form according to claim 1, wherein the
second pharmacologically active ingredient (A.sub.2) is selected
from the group consisting of acetylsalicylic acid, aloxiprin,
choline salicylate, sodium salicylate, salicylamide, salsalate,
ethenzamide, morpholine salicylate, dipyrocetyl, benorilate,
diflunisal, potassium salicylate, guacetisal, carbasalate calcium,
imidazole salicylate, phenazone, metamizole sodium, aminophenazone,
propyphenazone, nifenazone, paracetamol, phenacetin, bucetin,
propacetamol, rimazolium, glafenine, floctafenine, viminol,
nefopam, flupirtine, ziconotide, methoxyflurane, nabiximols,
dihydroergotamine, ergotamine, methysergide, lisuride,
flumedroxone, sumatriptan, naratriptan, zolmitriptan, rizatriptan,
almotriptan, eletriptan, frovatriptan, pizotifen, clonidine,
iprazochrome, dimetotiazine, oxetorone, phenylbutazone,
mofebutazone, oxyphenbutazone, clofezone, kebuzone, indomethacin,
sulindac, tolmetin, zomepirac, diclofenac, alclofenac, bumadizone,
etodolac, lonazolac, fentiazac, acemetacin, difenpiramide,
oxametacin, proglumetacin, ketorolac, aceclofenac, bufexamac,
piroxicam, tenoxicam, droxicam, lornoxicam, meloxicam, ibuprofen,
naproxen, ketoprofen, fenoprofen, fenbufen, benoxaprofen, suprofen,
pirprofen, flurbiprofen, indoprofen, tiaprofenic acid, oxaprozin,
ibuproxam, dexibuprofen, flunoxaprofen, alminoprofen,
dexketoprofen, naproxcinod, mefenamic acid, tolfenamic acid,
flufenamic acid, meclofenamic acid, celecoxib, rofecoxib,
valdecoxib, parecoxib, etoricoxib, lumiracoxib, nabumetone,
niflumic acid, azapropazone, glucosamine, benzydamine,
glucosaminoglycan polysulfate, proquazone, orgotein, nimesulide,
feprazone, diacerein, morniflumate, tenidap, oxaceprol, chondroitin
sulfate, oxycinchophen, sodium aurothiomalate, sodium
aurotiosulfate, auranofin, aurothioglucose, aurotioprol,
penicillamine and bucillamine.
7. The pharmaceutical dosage form according to claim 1, wherein the
first pharmacologically active ingredient (A.sub.1) is hydrocodone
or a physiologically acceptable salt thereof and the second
pharmacologically active ingredient (A.sub.2) is paracetamol.
8. The pharmaceutical dosage form according to claim 1, wherein the
first pharmacologically active ingredient (A.sub.1) is embedded in
a prolonged release matrix comprising a synthetic or natural
polymer (C).
9. The pharmaceutical dosage form according to claim 8, wherein (i)
the content of the synthetic or natural polymer (C) is at least 30
wt.-% relative to the total weight of the formed segment(s)
(S.sub.1); and/or (ii) the synthetic or natural polymer (C) is
selected from acrylic polymers and polyalkylene oxides.
10. The pharmaceutical dosage form according to claim 1, which
under in vitro conditions in 600 mL 0.1 N HCl using the basket
method according to Ph. Eur. at 75 rpm, after 1 h under
physiological conditions has released at most 50% of the first
pharmacologically active ingredient (A.sub.1) relative to the total
amount of A.sub.1 originally contained in the pharmaceutical dosage
form.
11. The pharmaceutical dosage form according to claim 1, which
under in vitro conditions in 600 mL 0.1 N HCl using the basket
method according to Ph. Eur. at 75 rpm, after 1 h under
physiological conditions has released at least 60% of the second
pharmacologically active ingredient (A.sub.2) relative to the total
amount of the second pharmacologically active ingredient (A.sub.2)
originally contained in the pharmaceutical dosage form.
12. The pharmaceutical dosage form according to claim 1, wherein
the at least one formed segment (S.sub.1) is tamper resistant and
provides resistance against grinding and/or resistance against
solvent extraction and/or resistance against dose-dumping in
aqueous ethanol.
13. The pharmaceutical dosage form according to claim 1, which is
selected from the group consisting of capsules, sugar-coated
tablets, dry-coated tablets, mantle tablets, and layered
tablets.
14. The pharmaceutical dosage form according to claim 1, wherein
the at least one formed segment (S.sub.1) is thermoformed.
15. The pharmaceutical dosage form according to claim 1, which
contains a single, monolithic formed segment (S.sub.1), or a
multitude of particulate formed segments (S.sub.1).
16. The pharmaceutical dosage form according to claim 15, wherein
the formed segment/s (S.sub.1) has/have an extension in any
direction of at least 2.0 mm.
17. The pharmaceutical dosage form according to claim 1, which is
to be administered orally.
18. The pharmaceutical dosage form according to claim 1, which is
to be administered as a whole.
19. A process for the production of a pharmaceutical dosage form
according to claim 1 comprising the steps of: (i) thermoforming at
least one formed segment (S.sub.1) comprising a first
pharmacologically active ingredient (A.sub.1) and a natural or
synthetic polymer (C); (ii) providing at least one further segment
(S.sub.2) comprising a second pharmacologically active ingredient
(A.sub.2); and (iii) combining the at least one formed segment
(S.sub.1), the at least one further segment (S.sub.2) and
optionally further excipients.
20. A method of treating pain in a patient in need of such
treating, said method comprising orally administering to said
patient a pharmaceutical dosage form according to claim 1, wherein
the dosage form is swallowed by said patient as a whole.
Description
[0001] Tamper resistant dosage form with bimodal release
profile
[0002] This application claims priority of U.S. patent application
Ser. No. 14/287,348, filed May 27, 2014, now allowed, which claims
priority of European Patent Application No. 13 169 658.5, filed on
May 29, 2013, the entire contents of which are incorporated herein
by reference.
FIELD OF THE INVENTION
[0003] The invention relates to a pharmaceutical dosage form
comprising [0004] (i) at least one formed segment (S.sub.1), which
contains a first pharmacologically active ingredient (A.sub.1) and
provides prolonged release thereof, and [0005] (ii) at least one
further segment (S.sub.2), which contains a second
pharmacologically active ingredient (A.sub.2) and provides
immediate release thereof,
[0006] wherein the at least one formed segment (S.sub.1) exhibits a
higher breaking strength than the at least one further segment
(S.sub.2) and the at least one formed segment (S.sub.1) exhibits a
breaking strength of more than 500 N.
BACKGROUND OF THE INVENTION
[0007] A large number of pharmacologically active substances have a
potential for being abused or misused, i.e. they can be used to
produce effects which are not consistent with their intended use.
Thus, e.g. opioids which exhibit an excellent efficacy in
controlling severe to extremely severe pain, are frequently abused
to induce euphoric states similar to being intoxicated. In
particular, active substances which have a psychotropic effect are
abused accordingly.
[0008] To enable abuse, the corresponding pharmaceutical dosage
forms, such as pharmaceutical dosage forms or capsules are crushed,
for example ground by the abuser, the active substance is extracted
from the thus obtained powder using a preferably aqueous liquid and
after being optionally filtered through cotton wool or cellulose
wadding, the resultant solution is administered parenterally, in
particular intravenously. This type of dosage results in an even
faster diffusion of the active substance compared to the oral
abuse, with the result desired by the abuser, namely the kick. This
kick or these intoxication-like, euphoric states are also reached
if the powdered pharmaceutical dosage form is administered nasally,
i.e. is sniffed.
[0009] Various concepts for the avoidance of drug abuse have been
developed.
[0010] It has been proposed to incorporate in pharmaceutical dosage
forms aversive agents and/or antagonists in a manner so that they
only produce their aversive and/or antagonizing effects when the
pharmaceutical dosage forms are tampered with. However, the
presence of such aversive agents is principally not desirable and
there is a need to provide sufficient tamper-resistance without
relying on aversive agents and/or antagonists.
[0011] Another concept to prevent abuse relies on the mechanical
properties of the pharmaceutical dosage forms, particularly an
increased breaking strength (resistance to crushing). 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. Thus, the pulverization, necessary for
abuse, of the pharmaceutical dosage forms by the means usually
available to a potential abuser is prevented or at least
complicated. Such pharmaceutical dosage forms are useful for
avoiding drug abuse of the pharmacologically active ingredient
contained therein, as they may not be powdered by conventional
means and thus, cannot be administered in powdered form, e.g.
nasally. The mechanical properties, particularly the high breaking
strength of these pharmaceutical dosage forms renders them
tamper-resistant. In the context of such tamper-resistant
pharmaceutical 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, WO 2006/082097, WO
2006/082099, and WO2009/092601.
[0012] Besides tampering of pharmaceutical dosage forms in order to
abuse the drugs contained therein, the potential impact of
concomitant intake of ethanol on the in vivo release of drugs from
modified release oral formulations (dose-dumping) has recently
become an increasing concern. Controlled or modified release
formulations typically contain a higher amount of the
pharmacologically active ingredient relative to its immediate
release counterpart. If the controlled release portion of the
formulation is easily defeated, the end result is a potential
increase in exposure to the active drug and possible safety
concerns. In order to improve safety and circumvent intentional
tampering (e.g. dissolving a controlled release pharmaceutical
dosage form in ethanol to extract the drug), a reduction in the
dissolution of the modified release fractions of such formulations,
in ethanol, may be of benefit. Accordingly, the need exists to
develop new formulations having reduced potential for dose dumping
in alcohol.
[0013] Furthermore, the release kinetics of the pharmacologically
active ingredients is an important factor. It is well known that
depending on how a pharmaceutically pharmacologically active
ingredient is formulated into a tablet its release pattern can be
modified.
[0014] On the one hand, formulations providing immediate release
upon oral administration have the advantage that they lead to a
fast release of the pharmacologically active ingredient in the
gastrointestinal tract. As a result, a comparatively high dose of
the pharmacologically active ingredient is quickly absorbed leading
to high plasma levels within a short period of time and resulting
in a rapid onset of medicinal action, i.e. medicinal action begins
shortly after administration. At the same time, however, a rapid
reduction in the medicinal action is observed, because
metabolization and/or excretion of the pharmacologically active
ingredient cause a decrease of plasma levels. For that reason,
formulations providing immediate release of pharmacologically
active ingredients typically need to be administered frequently,
e.g. six times per day. This may cause comparatively high peak
plasma pharmacologically active ingredient concentrations and high
fluctuations between peak and trough plasma pharmacologically
active ingredient concentrations which in turn may deteriorate
tolerability.
[0015] 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 ingredient
in a matrix, binding the pharmacologically active ingredient to an
ion-exchange resin, forming a complex of the pharmacologically
active ingredient, 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.
[0016] In comparison to formulations providing immediate release,
formulations providing prolonged release upon oral administration
have the advantage that they need to be administered less
frequently, typically once daily or twice daily. This can reduce
peak plasma pharmacologically active ingredient concentrations and
fluctuations between peak and trough plasma pharmacologically
active ingredient concentrations which in turn may improve
tolerability.
[0017] However, especially patients starting their treatment with
controlled release formulations often desire a rapid onset of
medicinal action. Therefore, a need exists to develop tamper
resistant formulations which provide a quick medicinal action while
at the same time having the benefits of controlled or modified
release formulations.
[0018] US 2009/0005408 relates to a process for the production of
solid pharmaceutical dosage forms with at least reduced potential
for abuse, by a) shaping a formulation mixture containing at least
one active ingredient with potential for abuse and at least one
synthetic or natural polymer (C), which exhibits a breaking
strength of at least 500 N, into formed articles by application of
force, b) optionally singulating the formed articles and optionally
in each case grading them by size and, c) after or during heating
at least to the softening point of the polymer (C), exposing the
formed articles to force until they have a breaking hardness of at
least 500 N, optionally providing them with a cover and optionally
mixing all the formed articles back together again.
[0019] US 2009/0022798 and WO 2009/014534, respectively, discloses
formulations and methods for the delivery of drugs, particularly
drugs of abuse, having an abuse-relevant drug substantially
confined in the core and a non-abuse relevant drug in a non-core
region. These formulations have reduced potential for abuse. In the
formulation, preferably the abuse relevant drug is an opioid and
the non-abuse relevant drug is acetaminophen or ibuprofen. More
preferably, the opioid is hydrocodone, and the non-abuse relevant
analgesic is acetaminophen. In certain preferred embodiments, the
dosage forms are characterized by resistance to solvent extraction;
tampering, crushing or grinding. In a preferred embodiment, the
dosage forms have a breaking strength of at least 500 N. Certain
embodiments relate to dosage forms providing an initial burst of
release of drug followed by a prolonged period of controllable drug
release. When providing these dosage forms with tamper resistant
properties, however, the initial burst of release of drug is
difficult to achieve, as tamper-resistance and in particular the
breaking strength typically relies on the presence of polymers that
act as release matrix material slowing down the release of the drug
from the dosage form. Therefore, it is only meaningful to provide a
combination of tamper resistance, in particular a high breaking
strength, and an initial burst of release of the drug when this
drug has a potential for being abused. Further, the non-core layer
of the drug product is explicitly applied using a film-coating
process. A film-coating process is disadvantageous due to the high
cost it produces during manufacturing. The film-forming layer
material is first dissolved, then sprayed on the core and finally
the solvent is removed, all leading to long process times with high
energy consumption. Due to the high amount of active that needs to
be present in the film-layer, this is a significant disadvantage
for a cost-competitive manufacturing of the drug product.
[0020] EP 1 980 245 A1 relates to a bilayer dosage form comprising:
(i) an upper layer (a) comprising a lyophilized dosage form of
active pharmaceutical ingredient(s) (API(s)); and (ii) a base line
layer (b) formulated to adhere to the oral mucosa and intended for
delayed, sustained or extended release of API(s) and/or
excipient(s).
[0021] WO 2009/005803 A1 relates to a pharmaceutical composition in
the form of a combination tablet. The tablet has a rapidly absorbed
component that enters the circulation by traversing the buccal
mucosa, and a more slowly absorbed component that is swallowed. The
therapeutic agent in the swallowed portion is absorbed across the
gastric mucosa. The rapid and slow components may have identical or
different therapeutic agents depending on the application to a
specific medical condition One embodiment of the combination tablet
includes a prostaglandin inhibitor in the rapidly absorbed
component in order to mitigate the side effects of immediate
release niacin that is in the slow absorbing component.
[0022] The properties of the pharmaceutical dosage forms of the
prior art are not satisfactory in every respect.
[0023] It is an object of the invention to provide pharmaceutical
dosage forms which have advantages over the pharmaceutical dosage
forms of the prior art. The pharmaceutical dosage forms should
provide prolonged release of a first pharmacologically active
ingredient and immediate release of a second pharmacologically
active ingredient, wherein particularly the first pharmacologically
active ingredient is safeguarded from abuse.
[0024] This object has been achieved by the subject-matter
described herein below.
[0025] A first aspect of the invention relates to a pharmaceutical
dosage form comprising [0026] (i) at least one formed segment
(S.sub.1), which contains a first pharmacologically active
ingredient (A.sub.1) and provides prolonged release thereof, and
[0027] (ii) at least one further segment (S.sub.2), which contains
a second pharmacologically active ingredient (A.sub.2) and provides
immediate release thereof, wherein the at least one formed segment
(S.sub.1) exhibits a higher breaking strength than the at least one
further segment (S.sub.2) and the at least one formed segment
(S.sub.1) exhibits a breaking strength of more than 500 N.
[0028] Another aspect of the invention relates to a process for the
production of said pharmaceutical dosage form comprising the steps
of [0029] (i) thermoforming at least one formed segment (S.sub.1)
comprising a first pharmacologically active ingredient (A.sub.1)
and a natural or synthetic polymer (C), preferably such that said
formed segment (S.sub.1) provides prolonged release of said first
pharmacologically active ingredient (A,);
[0030] (ii) providing at least one further segment (S.sub.2)
comprising a second pharmacologically active ingredient (A.sub.2)
and preferably providing immediate release thereof; and [0031]
(iii) combining the at least one formed segment (S.sub.1), the at
least one further segment (S.sub.2) and optionally further
excipients.
[0032] A further aspect of the invention relates to said
pharmaceutical dosage form for use in the treatment of pain,
wherein the dosage form is swallowed as a whole.
[0033] It has been surprisingly found that tamper-resistant
pharmaceutical dosage forms can be provided that contain a first
pharmacologically active ingredient in a prolonged release form and
a second pharmacologically active ingredient in an immediate
release form. Patient compliance can be improved by providing a
rapid but also prolonged medicinal effect.
[0034] Unless expressly stated otherwise, all percentages are by
weight (wt.-%).
[0035] For the purpose of specification, the term "pharmaceutical
dosage form" refers to a pharmaceutical entity which contains the
first pharmacologically active ingredient (A.sub.1) and the second
pharmacologically active ingredient (A.sub.2) and which is to be
administered to a patient (dose unit). It may be compressed or
molded during manufacture, and it may be of almost any size, shape,
weight, and color. The pharmaceutical dosage form is preferably
solid or semisolid.
[0036] The pharmaceutical dosage form is preferably intended for
oral administration. It is preferably provided in form of a single
body that can be easily swallowed by a patient. Typical examples of
pharmaceutical dosage forms according to the invention include, but
are not limited to tablets (e.g. coated tablets, multilayer
tablets, and the like) and capsules.
[0037] For the purpose of specification, the term "segment" as used
herein refers to any physically distinct entity of the
pharmaceutical dosage form that contains the first
pharmacologically active ingredient (A.sub.1) or the second
pharmacologically active ingredient (A.sub.2) and that can be
distinguished from another physically distinct entity of the
pharmaceutical dosage form. Preferably, every segment is solid or
semisolid.
[0038] The formed segment (S.sub.1) and the further segment
(S.sub.2) of the pharmaceutical dosage form preferably do not
consist of the first pharmacologically active ingredient (A.sub.1)
and the second pharmacologically active ingredient (A.sub.2),
respectively, but contain further ingredients such as
pharmaceutical excipients. Thus, the formed segment (S.sub.1) and
the further segment (S.sub.2) can be regarded as greater units of
compacted, granulated, congealed or otherwise agglomerated
material, comprising inter alia but preferably not consisting of
the first pharmacologically active ingredient (A.sub.1) and the
second pharmacologically active ingredient (A.sub.2),
respectively.
[0039] In a preferred embodiment, besides the first
pharmacologically active ingredient (A.sub.1) the formed segment(s)
(S.sub.1) comprise(s) at least a portion of the total amount of the
second pharmacologically active ingredient (A.sub.2) that is
contained in the pharmaceutical dosage form.
[0040] In another preferred embodiment, besides the first
pharmacologically active ingredient (A.sub.2) the further
segment(s) (S.sub.2) comprise(s) at least a portion of the total
amount of the first pharmacologically active ingredient (A.sub.1)
that is contained in the pharmaceutical dosage form.
[0041] Besides the content of the first pharmacologically active
ingredient (A.sub.1) and the second pharmacologically active
ingredient (A.sub.2), the formed segment (S.sub.1) and the further
segment (S.sub.2) of the pharmaceutical dosage form preferably
differ in at least one of the following properties and can be
distinguished by said property: composition of ingredients (e.g.
nature and/or amount), total weight, density, hardness, breaking
strength, size, shape, color, morphology, coherence (e.g.
monolithic mass vs. multitude of particulates) and/or porosity.
[0042] Typically, any segment of the pharmaceutical dosage form
covers at least 1 vol.-%, or at least 2 vol.-%, or at least 5
vol.-%, more preferably at least 10 vol.-% or at least 15 vol.-%,
still more preferably at least 17.5 vol.-% or at least 20 vol.-%,
yet more preferably at least 22.5 vol.-% or at least 25 vol.-%,
even more preferably at least 30 vol.-% or at least 35 vol.-%, most
preferably at least 40 vol.-%, and in particular at least 45
vol.-%, of the total volume of the pharmaceutical dosage form.
Thus, physically distinct entities that are so small that they do
not cover such portion of the total volume of the pharmaceutical
dosage form are typically not to be regarded as "segment" in the
meaning of the invention.
[0043] The formed segment (S.sub.1) and the further segment
(S.sub.2) of the pharmaceutical dosage form are separate of one
another, i.e. are at different locations of the pharmaceutical
dosage form. However, it is possible that one segment partially or
completely surrounds the other segment. Nevertheless, it is not
possible that a given location of the pharmaceutical dosage form
contains both, matter of the formed segment (S.sub.1) and
simultaneously matter of the further segment (S.sub.2).
[0044] For example, a segment may be a powdery material, a coherent
matrix material in which e.g. another segment may be embedded, or a
spatially confined area within the pharmaceutical dosage form such
as a layer of the pharmaceutical dosage form or a coating of the
pharmaceutical dosage form.
[0045] In particular, when the pharmaceutical dosage form is
provided in form of a multilayered tablet, every layer of the
multilayered tablet constitutes a segment of the dosage form. When
the pharmaceutical dosage form is provided in form of a coated
tablet, the tablet core constitutes one segment whereas the coating
constitutes another segment of the dosage form.
[0046] When the pharmaceutical dosage form is particulate, e.g.
provided in form of a capsule filled with a multitude of pellets
and a powder, respectively, the situation can be different. Under
these circumstances, every pellet that contains the first
pharmacologically active ingredient (A.sub.1) or the second
pharmacologically active ingredient (A.sub.2) can be regarded as an
individual formed segment (S.sub.1) within a plurality of formed
segments (S.sub.1) and as an individual further segment (S.sub.2)
within a plurality of further segments (S.sub.2), respectively.
[0047] When the first pharmacologically active ingredient (A.sub.1)
or the second pharmacologically active ingredient (A.sub.2) is
contained as a constituent of a powdery material, however, the
mesoscopic or microscopic particles of the first pharmacologically
active ingredient (A.sub.1) or the second pharmacologically active
ingredient (A.sub.2) are typically not to be regarded as formed
segment (S.sub.1) and further segment (S.sub.2), respectively;
under these circumstances, the entire powdery material is to be
regarded as formed segment (S.sub.1) and further segment (S.sub.2),
respectively. Accordingly, when the pharmaceutical dosage form is a
capsule filled with a multitude of pellets containing the first
pharmacologically active ingredient (A.sub.1) and with a powdery
material containing the second pharmacologically active ingredient
(A.sub.2) in powderous form, said multitude of pellets constitutes
a multitude of formed segments (S.sub.1), whereas said powdery
material constitutes a (single) further segment (S.sub.2), although
the pellets and the powdery material may be homogeneously admixed
with one another.
[0048] The formed segment (S.sub.1) and the further segment
(S.sub.2) of the pharmaceutical dosage form can be distinguished
from one another.
[0049] The pharmaceutical dosage form according to the invention
comprises at least one formed segment (S.sub.1) (monolith) but may
also contain a plurality of formed segments (S.sub.1) (e.g.
multitude of particles). When the pharmaceutical dosage form
according to the invention comprises a plurality of formed segments
(S.sub.1), the individual formed segments (S.sub.1) are preferably
of essentially the same type and nature, e.g. composition, total
weight, density, hardness, breaking strength, size, shape, color,
morphology, coherence and/or porosity. Preferably, the
pharmaceutical dosage form contains not more than 10 formed
segments (S.sub.1), more preferably not more than 9, still more
preferably not more than 8, yet more preferably not more than 7,
even more preferably not more than 6, most preferably not more than
5, and in particular not more than 4 formed segments (S.sub.1).
Preferably, the pharmaceutical dosage form contains 1, 2 or 3
formed segments (S.sub.1).
[0050] The pharmaceutical dosage form according to the invention
comprises at least one further segment (S.sub.2) (monolith) but may
also contain a plurality of further segments (S.sub.2) (multitude
of particles). When the pharmaceutical dosage form according to the
invention comprises a plurality of further segments (S.sub.2), the
individual further segments (S.sub.2) are preferably of essentially
the same type and nature, e.g. composition, total weight, density,
hardness, breaking strength, size, shape, color, morphology,
coherence and/or porosity. Preferably, the pharmaceutical dosage
form contains not more than 10 further segments (S.sub.2), more
preferably not more than 9, still more preferably not more than 8,
yet more preferably not more than 7, even more preferably not more
than 6, most preferably not more than 5, and in particular not more
than 4 further segments (S.sub.2). Preferably, the pharmaceutical
dosage form contains 1, 2 or 3 further segments (S.sub.2). When the
pharmaceutical dosage form contains 1 further segment (S.sub.2),
said further segment (S.sub.2) can preferably be a coherent mass or
in form of a powdery material.
[0051] When the pharmaceutical dosage form contains more than one
formed segment (S.sub.1) and/or more than one further segment
(S.sub.2), the pharmaceutical dosage form is particulate.
[0052] In a preferred embodiment, the pharmaceutical dosage form
contains additional segments (S.sub.3), e.g. segments which contain
pharmacologically active ingredient but are essentially not of the
same type and nature as formed segments (S.sub.1) and further
segments (S.sub.2), respectively. For example, the additional
segments (S.sub.3) may contain the first pharmacologically active
ingredient (A.sub.1) and/or the second pharmacologically active
ingredient (A.sub.2) and/or a third pharmacologically active
ingredient (A.sub.3) and provide e.g. prolonged release thereof.
Prolonged release may be achieved e.g. by embedding the
pharmacologically active ingredient in a polymer matrix differing
from the polymer matrix that is preferably contained in formed
segment(s) (S.sub.1). Thus, under these circumstances, the polymer
matrices of formed segment(s) (S.sub.1) and additional segments
(S.sub.3) differ from one another and accordingly, the in vitro
release profile may differ as well.
[0053] While the pharmaceutical dosage form may contain additional
segments (S.sub.3), e.g. segments which contain pharmacologically
active ingredient but are essentially not of the same type and
nature as formed segments (S.sub.1) and further segments (S.sub.2),
respectively, the pharmaceutical dosage form preferably consists of
the at least one formed segment (S.sub.1) and the at least one
further segment (S.sub.2), but does not contain additional segments
(S.sub.3). In a preferred embodiment, the at least one formed
segment (S.sub.1) and the at least one further segment (S.sub.2)
are present in a container, e.g. a hard gelatine capsule.
[0054] Preferably, when the pharmaceutical dosage form is
particulate, [0055] (i) the formed segments (S.sub.1) as well as
the further segments (S.sub.2), or [0056] (ii) the formed segments
(S.sub.1) but not the further segment (S.sub.2), or [0057] (iii)
the further segments (S.sub.2) but not the formed segment (S.sub.1)
are particulate.
[0058] When (i) the formed segment (S.sub.1) as well as the further
segment (S.sub.2) are each particulate (but not powdery), the
formed segments (S.sub.1) can be admixed with the further segments
(S.sub.2). Nevertheless, even under these specific circumstances,
the formed segments (S.sub.1) each constitute a physically distinct
entity of the pharmaceutical dosage form that can be distinguished
from the further segments (S.sub.2) each constituting another
physically distinct entity of the pharmaceutical dosage form.
[0059] In a preferred embodiment, the formed segment(s) (S.sub.1)
and the further segment(s) (S.sub.2) each constitute a spatially
confined area within the pharmaceutical dosage form. According to
this embodiment, the formed segment (S.sub.1) and/or further
segment (S.sub.2) preferably forms a layer, a coating, a core or a
mantle of the pharmaceutical dosage form which is preferably in the
form of a tablet.
BRIEF DESCRIPTION OF THE DRAWINGS
[0060] Preferred embodiments of tablets comprising the formed
segment (S.sub.1) and the further segment (S.sub.2) are illustrated
in FIG. 1.
[0061] FIG. 1A schematically illustrates a two-layer tablet
comprising a formed segment (S.sub.1) as first layer (1) and a
further segment (S.sub.2) as second layer (2).
[0062] FIG. 1B schematically illustrates a mantle tablet comprising
a formed segment (S.sub.1) as a core (3) and a further segment
(S.sub.2) (4) surrounding said core (3).
[0063] FIG. 1C schematically illustrates a three-layer tablet
comprising a formed segment (S.sub.1) as first layer (5) and two
further segments (S.sub.2) as layer (6) and layer (7).
[0064] FIG. 1D schematically illustrates a multicomponent tablet
comprising two formed segments (S.sub.1) (8) and (9) that are
embedded and form a discontinuous phase in a further segment
(S.sub.2) forming a matrix (10).
[0065] In another preferred embodiment, the formed segment(s)
(S.sub.1) and the further segment(s) (S.sub.2) are both contained
in a container, e.g. a hard gelatine capsule.
[0066] Preferred embodiments of capsules comprising formed
segment(s) (S.sub.1) and further segment(s) (S.sub.2) are
illustrated in FIG. 2.
[0067] FIG. 2A schematically illustrates a capsule formed of
capsule body (11) and capsule lid (12). The capsule contains a
formed segment (S.sub.1) (13) as well as a further segment
(S.sub.2) (14).
[0068] FIG. 2B schematically illustrates a capsule containing a
formed segment (S.sub.1) (15) as well as a plurality of further
segments (S.sub.2) (16).
[0069] FIG. 2C schematically illustrates a capsule containing a
plurality of formed segments (S.sub.1) (17) as well as a plurality
of further segments (S.sub.2) (18).
[0070] FIG. 2D schematically illustrates a capsule containing a
plurality of formed segments (S.sub.1) (19) as well as a plurality
of particles (20) that are smaller than further segments (S.sub.2)
(18) of FIG. 2C. Nevertheless, every particle (20) contains the
second pharmacologically active ingredient (A.sub.2) and thus,
every particle (20) constitutes an individual further segment
(S.sub.2) so that this capsule also contains a plurality of further
segments (S.sub.2) (20).
[0071] FIG. 2E schematically illustrates a capsule containing a
plurality of formed segments (S.sub.1) (21), a plurality of
particles (22), and a plurality of particles (23). Particles (22)
contain the second pharmacologically active ingredient (A.sub.2),
whereas particles (23) contain neither the first pharmacologically
active ingredient (A.sub.1) nor the second pharmacologically active
ingredient (A.sub.2). Every particle (22) constitutes an individual
further segment (S.sub.2) so that this capsule also contains a
plurality of further segments (S.sub.2) (20). However, particles
(23) do not constitute a segment within the meaning of the
invention.
[0072] FIG. 2F schematically illustrates a capsule containing a
plurality of formed segments (S.sub.1) (24) as well as a powdery
material (25). The powdery material (25) contains the second
pharmacologically active ingredient (A.sub.2), but not as a
constituent of a greater physical entity, but if appropriate,
simply in admixture with other excipients that are contained in the
powdery material. Under these circumstances, the entirety of the
powdery material (25) constitutes one further segment
(S.sub.2).
[0073] FIG. 3 shows the force distance diagram of cut rods having a
breaking strength of more than 500 N.
[0074] FIG. 4 shows the release profiles of one cut rod determined
under in vitro conditions (n=3) using the basket method with sinker
according to Ph. Eur. at 75 rpm in 600 mL of SGF (pH 1.2) and SGF
(pH 1.2)+40% ethanol, respectively.
[0075] FIG. 5 shows the release profiles of two cut rods determined
under in vitro conditions (n=3) using the basket method with sinker
according to Ph. Eur. (one sinker per cut rod) at 75 rpm in 600 mL
of SGF (pH 1.2) and SGF (pH 1.2)+40% ethanol, respectively.
[0076] FIG. 6 shows the release profiles of one cut rod in a
capsule determined under in vitro conditions (n=3) using the basket
method with sinker according to Ph. Eur. at 75 rpm in 600 mL of SGF
(pH 1.2) and SGF (pH 1.2)+40% ethanol, respectively.
[0077] FIG. 7 shows the release profiles of two cut rods and a
lactose tablet in a capsule determined under in vitro conditions
(n=3) using the basket method with sinker according to Ph. Eur. at
75 rpm in 600 mL of SGF (pH 1.2) and SGF (pH 1.2)+40% ethanol,
respectively.
[0078] FIG. 8 shows the release profiles of a mantle tablet
determined under in vitro conditions (n=3) using the basket method
with sinker according to Ph. Eur. at 75 rpm in 600 mL of SGF (pH
1.2) and SGF (pH 1.2)+40% ethanol, respectively.
[0079] FIG. 9 shows the release profiles of a mantle tablet
determined under in vitro conditions (n=3) using the basket method
with sinker according to Ph. Eur. at 75 rpm in 600 mL of SGF (pH
1.2) and SGF (pH 1.2)+40% ethanol, respectively.
[0080] FIGS. 10 to 14 show combinations of the release profiles
obtained in Reference Examples 2 to 7 (FIGS. 4 to 9).
[0081] Preferably, the total content of the formed segment(s)
(S.sub.1) in the pharmaceutical dosage form according to the
invention is at most 95 wt.-%, more preferably at most 85 wt.-%,
still more preferably at most 75 wt.-%, yet more preferably at most
65 wt.-%, most preferably at most 55 wt.-% and in particular at
most 50 wt.-%, based on the total weight of the pharmaceutical
dosage form.
[0082] Preferably, the total content of the formed segment(s)
(S.sub.1) in the pharmaceutical dosage form according to the
invention is at least 5 wt.-% or at least 10 wt.-%, more preferably
at least 15 wt.-% or at least 20 wt.-%, still more preferably at
least 25 wt.-% or at least 30 wt.-%, even more preferably at least
35 wt.-% or at least 40 wt.-%, yet more preferably at least 45
wt.-% or at least 50 wt.-%, most preferably at least 55 wt.-% or at
least 60 wt.-%, and in particular at least 65 wt.-% or at least 70
wt.-%; based on the total weight of the pharmaceutical dosage
form.
[0083] In a preferred embodiment, the formed segment (S.sub.1)
and/or the further segment (S.sub.2) is monolithic, i.e. the dosage
form contains a single formed segment (S.sub.1) and/or a single
further segment (S.sub.2), respectively.
[0084] In this regard, monolithic preferably refers to a single
coherent entity (monolith) preferably having a weight of 100 mg or
more. According to this embodiment, the monolith preferably has a
weight of at least 120 mg, more preferably at least 140 mg, still
more preferably at least 160 mg, most preferably at least 180 mg
and in particular at least 200 mg. Preferably, the monolith has a
weight of from 100 to 1000 mg, more preferably 120 to 900 mg, still
more preferably 140 to 800 mg, yet more preferably 150 to 700 mg,
even more preferably 160 to 600 mg, most preferably 170 to 500 mg
and in particular 200 to 400 mg. For the purpose of definition, a
monolithic segment that is film-coated is also to be regarded as a
monolithic segment according to the invention.
[0085] In another preferred embodiment, the formed segments
(S.sub.1) and/or the further segments (S.sub.2) are particulate,
preferably oligoparticulate or multiparticulate, i.e. the dosage
form contains a multitude of formed segments (S.sub.1) and/or a
multitude of further segment (S.sub.2), respectively.
[0086] For the purpose of the specification, the term
"particulate", "oligoparticulate" or "multiparticulate" refers to a
discrete mass of material, i.e. multitude of particles, which are
solid, e.g. at 20.degree. C. or at room temperature or ambient
temperature. Preferably a particle is solid at 20.degree. C.
[0087] In a preferred embodiment, the formed segments (S.sub.1)
and/or the further segments (S.sub.2) are oligoparticulate. In this
regard, oligoparticulate preferably means that all individual
oligoparticles, i.e. formed segments (S.sub.1) and/or further
segments (S.sub.2), each have a weight of 20 mg or more. According
to this embodiment, all individual oligoparticles, i.e. formed
segments (S.sub.1) and/or further segments (S.sub.2), each
preferably have a weight of at least 30 mg, more preferably at
least 40 mg, still more preferably at least 50 mg, most preferably
at least 60 mg and in particular at least 100 mg. Preferably, all
individual oligoparticles, i.e. formed segments (S.sub.1) and/or
further segments (S.sub.2), each have a weight of from 20 to 1000
mg, more preferably 30 to 800 mg, still more preferably 40 to 600
mg, yet more preferably 50 to 400 mg, even more preferably 60 to
200 mg, most preferably 70 to 150 mg and in particular 80 to 120
mg.
[0088] Further, according to this embodiment, the pharmaceutical
dosage form preferably comprises at most 10, more preferably at
most 9, still more preferably at most 8, yet more preferably at
most 7, even more preferably at most 6, most preferably at most 5,
and in particular at most 4 or 3 or 2 formed segments (S.sub.1)
and/or further segments (S.sub.2). When the formed segments
(S.sub.1) and/or the further segments (S.sub.2) are
oligoparticulate, the pharmaceutical dosage form may further
comprise drug-free particles, which may each have an individual
weight of less than 20 mg.
[0089] In another preferred embodiment, the formed segments
(S.sub.1) and/or the further segments (S.sub.2) are
multiparticulate. In this regard, multiparticulate preferably means
that all individual multiparticles, i.e. formed segments (S.sub.1)
and/or further segments (S.sub.2), each have a weight of less than
20 mg. According to this embodiment, all multiparticles, i.e.
formed segments (S.sub.1) and/or further segments (S.sub.2), each
preferably have a weight of less than 18 mg, more preferably less
than 16 mg, still more preferably less than 14 mg, yet more
preferably less than 12 mg, even more preferably less than 10 mg,
most preferably less than 8 mg, and in particular less than 6 or 4
mg. Further, according to this embodiment, the pharmaceutical
dosage form preferably comprises at least 2, more preferably at
least 4, still more preferably at least 6, yet more preferably at
least 8, even more preferably at least 10, most preferably at least
15 and in particular at least 20 or at least 100 or at least 1000
particles, i.e. formed segments (S.sub.1) and/or further segments
(S.sub.2).
[0090] However, multiparticulate segments are less preferred than
monolithic segments and oligoparticulate segments.
[0091] In a preferred embodiment, the pharmaceutical dosage form
contains a single, monolithic formed segment (S.sub.1), or a
multitude of particulate formed segments (S.sub.1).
[0092] In a particularly preferred embodiment, monolithic or
particulate formed segment(s) (S.sub.1) and/or further segment(s)
(S.sub.2) of the pharmaceutical dosage form each has/have an
extension in any given direction of at least 2.0 mm, more
preferably at least 2.2 mm, still more preferably at least 2.5 mm,
yet more preferably at least 2.8 mm, even more preferably at least
3.0 mm, most preferably at least 3.2 mm, and in particular at least
3.5 mm or 4.0 mm. According to this embodiment, the monolithic or
particulate formed segment(s) (S.sub.1) and/or further segment(s)
(S.sub.2) particularly preferably each have an extension in any
given direction of at least 2.0 mm or 3.0 mm and have a weight of
at least 20 mg.
[0093] Particularly preferably, the pharmaceutical dosage form
contains a single, monolithic formed segment (S.sub.1) having an
extension in any direction of at least 2.0 mm; or a multitude of
particulate formed segments (S.sub.1) each having an extension in
any direction of at least 2.0 mm.
[0094] For the purpose of specification, "in any direction"
preferably means in every direction in the three-dimensional
space.
[0095] The size of the particles or the monolith may be determined
by any conventional procedure known in the art, e.g. laser light
scattering, sieve analysis, light microscopy or image analysis.
[0096] The shape of the particles and/or monoliths, i.e. the shape
of the formed segment(s) (S.sub.1) and/or the further segment(s)
(S.sub.2), is not particularly limited. Preferably, the particles
and/or the monolith are essentially cylindrical in shape, e.g. cut
extruded rods. The diameter of such particles and/or monolith is
therefore the diameter of their circular cross section. The
cylindrical shape can be caused by hot-melt extrusion according to
which the diameter of the circular cross section is a function of
the extrusion die and the length of the cylinders is a function of
the cutting length according to which the extruded strand of
material is cut into pieces of preferably more or less
predetermined length.
[0097] The segment (S.sub.1) is "formed". In this regard, the term
"formed" refers to any measure providing the material of segment
(S.sub.1) with a predetermined or arbitrary outer shape. Forming
may but does not need to be achieved by means of a die. Preferably,
formed segment (S.sub.1) is thermoformed. For example, extruding a
heated material, e.g. by means of hot-melt extrusion, and
subsequently cutting the extruded strand into segments of
predetermined length provides formed segments (S.sub.1) according
to the invention.
[0098] In a preferred embodiment, the formed segment(s) (S.sub.1)
and/or the further segment(s) (S.sub.2) is/are not film coated.
[0099] In another preferred embodiment, the formed segment(s)
(S.sub.1) and/or the further segment(s) (S.sub.2) is/are film
coated. The formed segment(s) (S.sub.1) and/or the further
segment(s) (S.sub.2) according to the invention can optionally be
provided, partially or completely, with a conventional coating. The
formed segment(s) (S.sub.1) and/or the further segment(s) (S.sub.2)
are preferably film coated with conventional film coating
compositions. Suitable coating materials are commercially
available, e.g. under the trademarks Opadry.RTM. and
Eudragit.RTM..
[0100] Examples of suitable materials include cellulose esters and
cellulose ethers, such as methyl-cellulose (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 methyl-methacrylate copolymers, methacrylic acid
methylmethacrylate copolymers, methacrylic acid methylmethacrylate
copolymers; vinyl polymers, such as polyvinylpyrrolidone,
polyvinyl-acetatephthalate, polyvinyl alcohol, polyvinyl
alcohol-polyethylene glycol graft copolymers, polyvinylacetate; and
natural film formers.
[0101] The coating material may contain excipients such as
stabilizers (e.g. surfactants such as macrogol cetostearylether,
sodium dodecylsulfate, and the like). Suitable excipients of film
coating materials are known to the skilled person.
[0102] In a particularly preferred embodiment, the coating is
water-soluble.
[0103] Though less preferred, the coating can principally 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.
[0104] A particularly preferred coating contains polyvinyl alcohol
and optionally, further excipients such as xanthan gum and/or
talcum.
[0105] For the purpose of specification, the term
"pharmacologically active ingredient" as used herein may refer to
either one or more pharmacologically active ingredients, i.e. the
terms "first pharmacologically ingredient (A.sub.1)" and "second
pharmacologically ingredient (A.sub.2)" may each refer to a single
pharmacologically active ingredient or a combination of one or more
pharmacologically active ingredients.
[0106] There are generally no limitations as to the
pharmacologically active ingredient (pharmacologically active
compound) which can be incorporated in the segments of the
pharmaceutical dosage form according to the invention. Furthermore,
the term "pharmacologically active ingredient" preferably includes
any physiologically acceptable salt, e.g. physiologically
acceptable acid addition salt, of the base form of the
pharmacologically active ingredient. Physiologically acceptable
acid addition salts comprise any acid addition salts which can
conveniently be obtained by treating the base form of a
pharmacologically active ingredient with appropriate organic and
inorganic acids. Pharmacologically 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 a pharmacologically active
ingredient is able to form. Examples of such forms are e.g.
hydrates, alcoholates and the like.
[0107] Unless explicitly stated otherwise, all amounts of the first
pharmacologically active ingredient (A.sub.r) and the second
pharmacologically active ingredient (A.sub.2) specified in the
following are given according to the corresponding amount of the
free compound.
[0108] Preferably, the first pharmacologically active ingredient
(A.sub.1) is an opioid and the second pharmacologically active
ingredient (A.sub.2) is another analgesic, but preferably no
opioid, e.g. paracetamol (acetaminophen), an NSAID or
COX-2-inhibitor.
[0109] In a particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is hydrocodone or a
physiologically acceptable salt thereof and the second
pharmacologically active ingredient (A.sub.2) is paracetamol.
[0110] In a preferred embodiment, the first pharmacologically
active ingredient (A.sub.1) and the second pharmacologically active
ingredient (A.sub.2) are spatially separated from one another.
According to this embodiment, the formed segment (S.sub.1)
preferably contains less than 0.1 ppm, more preferably less than
0.01 ppm, most preferably less than 0.001 ppm and in particular
less than 0.0001 ppm of the second pharmacologically active
ingredient (A.sub.2). Further, according to this embodiment, the
further segment (S.sub.2) preferably contains less than 0.1 ppm,
more preferably less than 0.01 ppm, most preferably less than 0.001
ppm and in particular less than 0.0001 ppm of the first
pharmacologically active ingredient (A.sub.1). In a particularly
preferred embodiment, the formed segment (S.sub.1) contains no
second pharmacologically active ingredient (A.sub.2) and the
further segment (S.sub.2) contains no first pharmacologically
active ingredient (A.sub.1).
[0111] Preferably, at least 99 wt.-%, more preferably at least 99.9
wt.-%, most preferably at least 99.99 wt.-% and in particular at
least 99.999 wt.-% of the total amount of the first
pharmacologically active ingredient (A.sub.1) contained in the
pharmaceutical dosage form are contained in the formed segment
(S.sub.1).
[0112] Preferably, at least 99 wt.-%, more preferably at least 99.9
wt.-%, most preferably at least 99.99 wt.-% and in particular at
least 99.999 wt.-% of the total amount of the second
pharmacologically active ingredient (A.sub.2) contained in the
pharmaceutical dosage form are contained in the further segment
(S.sub.2).
[0113] The term "prolonged release" is known to the skilled
artisan. For the purpose of specification, the term "prolonged
release" preferably refers to a release rate of the
pharmacologically active ingredient from the formulation that has
been reduced over time in order to maintain therapeutic activity,
to reduce toxic effects, or for some other therapeutic purpose such
as reducing the dosing frequency.
[0114] The term "immediate release" is known to the skilled
artisan. For the purpose of specification, the term "immediate
release" preferably refers to a release rate of the
pharmacologically active ingredient from the formulation that is
comparatively fast and not retarded.
[0115] Preferably, when the formed segment(s) (S.sub.1) and/or the
further segment(s) (S.sub.2) are particulate, the pharmaceutical
dosage form according to the invention comprises the particles as a
discontinuous phase, i.e. the particles form a discontinuous phase
in an outer matrix material which in turn preferably forms a
continuous phase (cf. FIG. 1D). In this regard, discontinuous means
that not each and every particle is in intimate contact with
another particle but that the particles are at least partially
separated from one another by the outer matrix material in which
the particles are embedded. In other words, the particles
preferably do not form a single coherent mass within the
pharmaceutical dosage forms according to the invention
(multicomponent tablet).
[0116] In a preferred embodiment, the further segment(s) (S.sub.2)
form(s) an outer matrix material in which the formed segment(s)
(S.sub.1) is/are embedded. According to this embodiment, the
pharmaceutical dosage form according to the invention can
preferably be a MUPS formulation (multiple unit pellet system) or a
capsule.
[0117] Preferably, the formed segment(s) (S.sub.1) and the further
segment(s) (S.sub.2) have different morphology and properties, more
preferably the formed segment (S.sub.1) is monolithic or
particulate and the further segment (S.sub.2) forms the outer
matrix material. When the formed segments (S.sub.1) are
particulate, the particles preferably form a discontinuous phase
within the outer matrix material formed by the further segment
(S.sub.2) (cf. FIG. 1D) (multicomponent tablet). When the formed
segment (S.sub.1) contains a prolonged release matrix material, the
outer matrix material is to be distinguished from said prolonged
release matrix material, since the outer matrix material preferably
does not provide for a prolonged release.
[0118] When the formed segment (S.sub.1) is monolithic or
particulate and the further segment (S.sub.2) forms the outer
matrix material, the pharmaceutical dosage form according to the
invention preferably is in form of a capsule, i.e. a soft capsule
or a hard capsule.
[0119] The formed segment(s) (S.sub.1) typically has/have
mechanical properties that differ from the mechanical properties of
the outer matrix material. Preferably, the formed segment(s)
(S.sub.1) has/have a higher mechanical strength than the outer
matrix material. The formed segment(s) (S.sub.1) can preferably be
visualized by conventional means such as solid state nuclear
magnetic resonance spectroscopy, scanning electron microscopy,
terahertz spectroscopy and the like.
[0120] In a further preferred embodiment, the formed segment
(S.sub.1) and/or the further segment (S.sub.2) constitute a
spatially confined area within the pharmaceutical dosage form.
According to this embodiment, the formed segment (S.sub.1) and/or
further segment (S.sub.2) preferably form a layer, a coating, a
core or a mantle of the pharmaceutical dosage form.
[0121] When the formed segment (S.sub.1) and/or further segment
(S.sub.2) forms a layer, the pharmaceutical dosage form preferably
is in form of a layered tablet (cf. FIG. 1A and FIG. 1C).
[0122] The formed segment (S.sub.1) or the further segment
(S.sub.2) may also form the coating of the pharmaceutical dosage
form. Preferably, the formed segment (S.sub.1) forms the core of
the pharmaceutical dosage form that is coated by the further
segment (S.sub.2). Preferably, however, neither the formed segment
(S.sub.1) nor the further segment (S.sub.2) forms a coating of the
pharmaceutical dosage form, particularly no spray coating. Rather,
the first segment (S.sub.1) and the further segment (S.sub.2) are
preferably both coated by another material such as a sugar
coating.
[0123] In a preferred embodiment, the pharmaceutical dosage form is
in form of a mantle tablet (cf. FIG. 1B). According to this
embodiment, the formed segment (S.sub.1) preferably forms the core
and the further segment (S.sub.2) preferably forms the mantle.
[0124] In a preferred embodiment, the pharmaceutical dosage form
according to the invention is a tablet, which comprises [0125] (i)
a single formed segment (S.sub.1) and a single further segment
(S.sub.2) that are arranged to form a bilayer tablet (cf. FIG. 1A);
[0126] (ii) a single formed segment (S.sub.1) forming a core that
is surrounded by a single further segment (S.sub.2) such that
formed segment (S.sub.1) and further segment (S.sub.2) are arranged
to form a mantle tablet (cf. FIG. 1B); [0127] (iii) a single formed
segment (S.sub.1) and two further segments (S.sub.2) that are
arranged to form a trilayer tablet, wherein formed segment
(S.sub.1) forms the middle layer and the two further segments
(S.sub.2) form the outer layers (cf. FIG. 1C); [0128] (iv) a
plurality of formed segments (S.sub.1) and a plurality of further
segments (S.sub.2) that are arranged to form a multilayer tablet,
wherein preferably each of the formed segments (S.sub.1) is
arranged in between two adjacent further segments (S.sub.2); [0129]
(v) a plurality of formed segments (S.sub.1) which form a
discontinuous phase embedded in further segment (S.sub.2) which
forms a matrix (cf. FIG. 1D) (multicomponent tablet); or [0130]
(vi) a single formed segment (S.sub.1) and one or more further
segments (S.sub.2) that are together coated by a sugar coating thus
forming a sugar-coated tablet (dragee).
[0131] In another preferred embodiment, the pharmaceutical dosage
form according to the invention is a capsule, which is filled with
[0132] (i) a single formed segment (S.sub.1) and a single further
segment (S.sub.2), which can optionally be present in form of a
monolith or in form of a powdery material (cf. FIG. 2A); [0133]
(ii) a single formed segment (S.sub.1) and a plurality of further
segments (S.sub.2) (cf. FIG. 2B); [0134] (iii) a plurality of
formed segments (S.sub.1) and a single further segment (S.sub.2),
which can optionally be present in form of a monolith or in form of
a powdery material (cf. FIG. 2F); or [0135] (iv) a plurality of
formed segments (S.sub.1) and a plurality of further segment
(S.sub.2) (cf. FIGS. 2C, D and E).
[0136] The pharmaceutical dosage form comprises a formed segment
(S.sub.1), l which contains a first pharmacologically active
ingredient (A.sub.1) and provides prolonged release thereof.
[0137] In a preferred embodiment, the first pharmacologically
active ingredient (A.sub.1) is only a single pharmacologically
active ingredient. In another preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is a combination of
two or more pharmacologically active ingredients.
[0138] Preferably, the first pharmacologically active ingredient
(A.sub.1) has potential for being abused. Pharmacologically active
ingredients with potential for being abused are known to the person
skilled in the art and comprise e.g. tranquillizers, stimulants,
barbiturates, narcotics, opioids or opioid derivatives.
[0139] Preferably, the first pharmacologically active ingredient
(A.sub.1) has a psychotropic effect, i.e. crosses the blood-brain
barrier and acts primarily upon the central nervous system where it
affects brain function, resulting in alterations in perception,
mood, consciousness, cognition, and behavior.
[0140] Preferably, the first pharmacologically active ingredient
(A.sub.1) is selected from the group consisting of opioids,
stimulants, tranquilizers, and other narcotics.
[0141] Particularly preferably, the first pharmacologically active
ingredient (A.sub.1) is an opioid or a physiologically acceptable
salt thereof. According to the Anatomical Therapeutic Chemical
(ATC) classification system by WHO (ATC index), opioids are divided
into natural opium alkaloids, phenylpiperidine derivatives,
diphenylpropylamine derivatives, benzomorphan derivatives,
oripavine derivatives, morphinan derivatives and others.
Preferably, the second pharmacologically active ingredient
(A.sub.2) is selected from ATC classes [M01A], [M01C], [N02B] and
[NO2C] according to the WHO.
[0142] The following opioids, tranquillizers or other narcotics are
substances with a psychotropic action, i.e. have a potential of
abuse, and hence are preferably contained in the formed segment
(S.sub.1) of 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, dimethyl-thiambutene, dioxaphetylbutyrate,
dipipanone, dronabinol, eptazocine, estazolam, ethoheptazine,
ethylmethylthiambutene, ethyl loflazepate, ethylmorphine,
etonitazene, etorphine, faxeladol, fencamfamine, fenethylline,
fenpipramide, fenproporex, fentanyl, fludiazepam, flunitrazepam,
flurazepam, halazepam, haloxazolam, heroin, hydrocodone,
hydromorphone, hydroxypethidine, isomethadone,
hydroxymethylmorphinan, ketazolam, ketobemidone, levacetylmethadol
(LAAM), levomethadone, 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, pemoline,
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, (1
R,2R)-3-(3-dimthylamino -1-ethyl-2-methyl-propyl)phenol, (1
R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl-
)cyclohexanol, (1 R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,
(1 S,2 S)-3-(3-dimthylamino -1-ethyl-2-methyl-propyl)phenol, (2 R,3
R)-1-dimthylamino -3 (3-methoxyphenyl)-2-methyl-pentan-3-ol, (1RS
,3 RS ,6
RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,
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-dimethyl
aminomethyl-cyclohex-1-enyl)-phenyl 2-(4-isobutyl-phenyl)propinate,
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl
2-(6-methoxy-naphthalen-2-yl)propionate,
(RR-SS)-2-acetoxy-4-trifluoro methyl-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-chlo ro-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-dimthylamino
methyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR-SS)-2-hydroxy-5-nitro-benzoic acid 3-(2-dimethyl-amino
methyl-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 acid or base addition salts
thereof and solvates, e.g. hydrochlorides.
[0143] In a preferred embodiment, the formed segment (S.sub.1)
contains an opioid selected from the group consisting of DPI-125,
M6G (CE-04-410), ADL-5859, CR-665, NRP290 and sebacoyl dinalbuphine
ester.
[0144] In a preferred embodiment, the formed segment (S.sub.1)
contains the first pharmacologically active ingredient (A.sub.1)
which is one pharmacologically active ingredient or more
pharmacologically active ingredients selected from the group
consisting of oxycodone, oxymorphone, hydromorphone, hydrocodone,
morphine, tapentadol, tramadol, buprenorphine, and the
physiologically acceptable salts thereof.
[0145] In another preferred embodiment, the first pharmacologically
active ingredient (A.sub.1) is selected from the group consisting
of tapentadol, faxeladol, axomadol and the physiologically
acceptable salts thereof.
[0146] In still another preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is selected from the
group consisting of
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydrop-
yrano [3,4-b]indole (cebranopadol), particularly its hemicitrate;
1,1-[3-dimthylamino-3-(2-thienyl)pentamethylene]-1 ,3
,4,9-tetrahydropyrano[3 ,4-b]ind, particularly its citrate; and
1,1-13-dimethylamino-3-(2-thienyopentamethylene1-1,3,4,9-tetra-hydropyran-
o[3,4-b]-6-fluoroindole, particularly its hemicitrate. These
compounds are known from, e.g., WO 2004/043967, WO 2005/066183.
[0147] The first pharmacologically active ingredient (A.sub.1) is
present in the pharmaceutical dosage form in a therapeutically
effective amount. In general, the amount that constitutes a
therapeutically effective amount varies according to the
pharmacologically active ingredients being used, the condition
being treated, the severity of said condition, the patient being
treated, and whether the pharmaceutical dosage form or the segment
in which the pharmacologically active ingredient is contained is
designed for an immediate or retarded release.
[0148] The content of the first pharmacologically active ingredient
(A.sub.1) preferably ranges from about 0.01 wt.-% to about 95
wt.-%, more preferably from about 0.1 wt.-% to about 80 wt.-%, even
more preferably from about 1.0 wt.-% to about 50 wt.-%, yet more
preferably from about 1.5 wt.-% to about 30 wt.-%, and most
preferably from about 2.0 wt.-% to 20 wt.-%, based on the total
weight of the formed segment(s) (S.sub.1) or based on the total
weight of the pharmaceutical dosage form.
[0149] Preferably, the content of the first pharmacologically
active ingredient (A.sub.1) is within the range of from 0.01 to 80
wt.-%, more preferably 0.1 to 50 wt.-%, still more preferably 1 to
25 wt.-%, based on the total weight of the pharmaceutical dosage
form. In a preferred embodiment, the content of the first
pharmacologically active ingredient (A.sub.1) is within the range
of from 7.+-.6 wt.-%, more preferably 7.+-.5 wt.-%, still more
preferably 5.+-.4 wt.-%, 7.+-.4 wt.-% or 9.+-.4 wt.-%, most
preferably 5.+-.3 wt.-%, 7.+-.3 wt.-% or 9.+-.3 wt.-%, and in
particular 5.+-.2 wt.-%, 7.+-.2 wt.-% or 9.+-.2 wt.-%, based on the
total weight of the pharmaceutical dosage form. In another
preferred embodiment, the content of the first pharmacologically
active ingredient (A.sub.1) is within the range of from 11.+-.10
wt.-%, more preferably 11.+-.9 wt.-%, still more preferably 9.+-.6
wt.-%, 11.+-.6 wt.-%, 13.+-.6 wt.-% or 15.+-.6 wt.-%, most
preferably 11.+-.4 wt.-%, 13.+-.4 wt.-% or 15.+-.4 wt.-%, and in
particular 11.+-.2 wt.-%, 13.+-.2 wt.-% or 15.+-.2 wt.-%, based on
the total weight of the pharmaceutical dosage form. In a further
preferred embodiment, the content of the first pharmacologically
active ingredient (A.sub.1) is within the range of from 20.+-.6
wt.-%, more preferably 20.+-.5 wt.-%, still more preferably 20.+-.4
wt.-%, most preferably 20.+-.3 wt.-%, and in particular 20.+-.2
wt.-%, based on the total weight of the pharmaceutical dosage
form.
[0150] Preferably, the content of the first pharmacologically
active ingredient (A.sub.1) is within the range of from 0.01 to 80
wt.-%, more preferably 0.1 to 60 wt.-%, still more preferably 5 to
50 wt.-%, based on the total weight of the formed segment(s)
(S.sub.1). In a preferred embodiment, the content of the first
pharmacologically active ingredient (A.sub.r) is within the range
of from 7.+-.6 wt.-%, more preferably 7.+-.5 wt.-%, still more
preferably 5.+-.4 wt.-%, 7.+-.4 wt.-% or 9.+-.4 wt.-%, most
preferably 5.+-.3 wt.-%, 7.+-.3 wt.-% or 9.+-.3 wt.-%, and in
particular 5.+-.2 wt.-%, 7.+-.2 wt.-% or 9.+-.2 wt.-%, based on the
total weight of the formed segment(s) (S.sub.1). In another
preferred embodiment, the content of the first pharmacologically
active ingredient (A.sub.1) is within the range of from 11.+-.10
wt.-%, more preferably 11.+-.9 wt.-%, still more preferably 9.+-.6
wt.-%, 11.+-.6 wt.-%, 13.+-.6 wt.-% or 15.+-.6 wt.-%, most
preferably 11.+-.4 wt.-%, 13.+-.4 wt.-% or 15.+-.4 wt.-%, and in
particular 11.+-.2 wt.-%, 13.+-.2 wt.-% or 15.+-.2 wt.-%, based on
the total weight of the formed segment(s) (S.sub.1). In a further
preferred embodiment, the content of the first pharmacologically
active ingredient (A.sub.1) is within the range of from 20.+-.6
wt.-%, 25.+-.6 wt.-% or 30.+-.6 wt.-%, more preferably 20.+-.5
wt.-%, 25.+-.5 wt.-% or 30.+-.5 wt.-%, still more preferably
20.+-.4 wt.-%, 25.+-.4 wt.-% or 30.+-.4 wt.-%, most preferably
20.+-.3 wt.-%, 25.+-.3 wt.-% or 30.+-.3 wt.-% and in particular
20.+-.2 wt.-%, 25.+-.2 wt.-% or 30.+-.2 wt.-%, based on the total
weight of the formed segment(s) (S.sub.1).
[0151] The total dose of the first pharmacologically active
ingredient (A.sub.1) in the formed segment (S.sub.1) and the
pharmaceutical dosage form, respectively, is not limited. The dose
of the first pharmacologically active ingredient (A.sub.1) which is
adapted for administration preferably is in the range of 0.01 mg to
2,000 mg or 0.01 mg to 1,000 mg or 0.1 mg to 500 mg, more
preferably in the range of 1.0 mg to 400 mg, even more preferably
in the range of 1.0 mg to 10.0 mg or 5.0 mg to 300 mg, and most
preferably in the range of 1.5 mg to 8 mg or 10 mg to 250 mg. In a
preferred embodiment, the total amount of the first
pharmacologically active ingredient (A.sub.1) which is contained in
the formed segment (S.sub.1) and the pharmaceutical dosage form,
respectively, is within the range of from 0.01 to 200 mg, more
preferably 0.1 to 190 mg, still more preferably 1.0 to 180 mg, yet
more preferably 1.5 to 160 mg, most preferably 2.0 to 100 mg and in
particular 2.5 to 80 mg. In another preferred embodiment, the total
amount of the first pharmacologically active ingredient (A.sub.1)
which is contained in the formed segment (S.sub.1) and the
pharmaceutical dosage form, respectively, is within the range of
from 10 to 500 mg, more preferably 12 to 450 mg, still more
preferably 14 to 400 mg, yet more preferably 16 to 350 mg, most
preferably 18 to 325 mg and in particular 20 to 300 mg.
[0152] In a preferred embodiment, the first pharmacologically
active ingredient (A.sub.1) is contained in the formed segment(s)
(S.sub.1) and the pharmaceutical dosage form, respectively, in a
total amount of 10.+-.5 .mu.g, 20.+-.5 .mu.g, 30.+-.5 .mu.g,
40.+-.5 .mu.g, 50.+-.5 .mu.g, 60.+-.5 .mu.g, 70.+-.5 .mu.g, 80.+-.5
.mu.g, 90.+-.5 .mu.g, 100.+-.5 .mu.g, 125.+-.25 .mu.g, 150.+-.25
.mu.g, 175.+-.25 .mu.g, 200.+-.25 .mu.g, 250.+-.50 .mu.g, 300.+-.50
.mu.g, 350.+-.50 .mu.g, 400.+-.50 .mu.g, 450.+-.50 .mu.g, 500.+-.50
.mu.g, 550.+-.50 .mu.g, 600.+-.50 .mu.g, 650.+-.50 .mu.g, 700.+-.50
.mu.g, 750.+-.50 .mu.g, 800.+-.50 .mu.g, 850.+-.50 .mu.g, 900.+-.50
.mu.g, 950.+-.50 .mu.g, or 1000.+-.50 .mu.g. In another preferred
embodiment, the first pharmacologically active ingredient (A.sub.1)
is contained in the formed segment(s) (S.sub.1) and the
pharmaceutical dosage form, respectively, in a total amount of
7.5.+-.5 mg, 10.+-.5 mg, 20.+-.5 mg, 30.+-.5 mg, 40.+-.5 mg,
50.+-.5 mg, 60.+-.5 mg, 70.+-.5 mg, 80.+-.5 mg, 90.+-.5 mg,
100.+-.5 mg, 110.+-.5 mg, 120.+-.5 mg, 130.+-.5, 140.+-.5 mg,
150.+-.5 mg, 160.+-.5 mg, 170.+-.5 mg, 180.+-.5 mg, 190.+-.5 mg,
200.+-.5 mg, 210.+-.5 mg, 220.+-.5 mg, 230.+-.5 mg, 240.+-.5 mg, or
250.+-.5 mg. In another preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is contained in the
formed segment (S.sub.1) and the pharmaceutical dosage form,
respectively, in a total amount of 5.+-.2.5 mg, 7.5.+-.2.5 mg,
10.+-.2.5 mg, 15.+-.2.5 mg, 20.+-.2.5 mg, 25.+-.2.5 mg, 30.+-.2.5
mg, 35.+-.2.5 mg, 40.+-.2.5 mg, 45.+-.2.5 mg, 50.+-.2.5 mg,
55.+-.2.5 mg, 60.+-.2.5 mg, 65.+-.2.5 mg, 70.+-.2.5 mg, 75.+-.2.5
mg, 80.+-.2.5 mg, 85.+-.2.5 mg, 90.+-.2.5 mg, 95.+-.2.5 mg,
100.+-.2.5 mg, 105.+-.2.5 mg, 110.+-.2.5 mg, 115.+-.2.5 mg,
120.+-.2.5 mg, 125.+-.2.5 mg, 130.+-.2.5 mg, 135.+-.2.5 mg,
140.+-.2.5 mg, 145.+-.2.5 mg, 150.+-.2.5 mg, 155.+-.2.5 mg,
160.+-.2.5 mg, 165.+-.2.5 mg, 170.+-.2.5 mg, 175.+-.2.5 mg,
180.+-.2.5 mg, 185.+-.2.5 mg, 190.+-.2.5 mg, 195.+-.2.5 mg,
200.+-.2.5 mg, 205.+-.2.5 mg, 210.+-.2.5 mg, 215.+-.2.5 mg,
220.+-.2.5 mg, 225.+-.2.5 mg, 230.+-.2.5 mg, 235.+-.2.5 mg,
240.+-.2.5 mg, 245.+-.2.5 mg, or 250.+-.2.5 mg. In still another
preferred embodiment, the first pharmacologically active ingredient
(A.sub.1) is contained in the formed segment(s) (S.sub.1) and the
pharmaceutical dosage form, respectively, in a total amount of
250.+-.10 mg, 275.+-.10 mg, 300.+-.10 mg, 325.+-.10 mg, 350.+-.10
mg, 375.+-.10 mg, 400.+-.10 mg, 425.+-.10 mg, 450.+-.10 mg,
475.+-.10 mg, 500.+-.10 mg, 525.+-.10 mg, 550.+-.10 mg, 575.+-.10
mg or 600.+-.10 mg.
[0153] In a particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is oxycodone,
preferably its HCl salt, and the pharmaceutical dosage form is
adapted for administration twice daily. In this embodiment, the
first pharmacologically active ingredient (A.sub.1) is preferably
contained in the formed segment(s) (S.sub.1) and the pharmaceutical
dosage form, respectively, in a total amount of from 1 to 80 mg. In
another particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is oxycodone,
preferably its HCl salt, and the pharmaceutical dosage form is
adapted for administration once daily. In this embodiment, the
first pharmacologically active ingredient (A.sub.1) is preferably
contained in the formed segment(s) (S.sub.1) and the pharmaceutical
dosage form, respectively, in a total amount of from 2 to 320
mg.
[0154] In another particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is oxymorphone,
preferably its HCl salt, and the pharmaceutical dosage form is
adapted for administration twice daily. In this embodiment, the
first pharmacologically active ingredient (A.sub.1) is preferably
contained in the formed segment(s) (S.sub.1) and the pharmaceutical
dosage form, respectively, in a total amount of from 5 to 40 mg. In
another particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is oxymorphone,
preferably its HCl salt, and the pharmaceutical dosage form is
adapted for administration once daily. In this embodiment, the
first pharmacologically active ingredient (A.sub.1) is preferably
contained in the formed segment(s) (S.sub.1) and the pharmaceutical
dosage form, respectively, in a total amount of from 10 to 80
mg.
[0155] In another particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is tapentadol,
preferably its HCl salt, and the pharmaceutical dosage form is
adapted for administration once daily or twice daily. In this
embodiment, the first pharmacologically active ingredient (A.sub.1)
is preferably contained in the formed segment(s) (S.sub.1) and the
pharmaceutical dosage form, respectively, in a total amount of from
25 to 250 mg.
[0156] In still another particularly preferred embodiment, the
first pharmacologically active ingredient (A.sub.1) is
hydromorphone, preferably its HCl salt, and the pharmaceutical
dosage form is adapted for administration twice daily. In this
embodiment, the first pharmacologically active ingredient (A.sub.1)
is preferably contained in the formed segment(s) (S.sub.1) and the
pharmaceutical dosage form, respectively, in a total amount of from
2 to 52 mg. In another particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is hydromorphone,
preferably its HCl salt, and the pharmaceutical dosage form is
adapted for administration once daily. In this embodiment, the
first pharmacologically active ingredient (A.sub.1) is preferably
contained in the formed segment(s) (S.sub.1) and the pharmaceutical
dosage form, respectively, in a total amount of from 4 to 104
mg.
[0157] In yet another particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is tramadol,
preferably its HCl salt, and the pharmaceutical dosage form is
adapted for administration twice daily. In this embodiment, the
first pharmacologically active ingredient (A.sub.1) is preferably
contained in the formed segment(s) (S.sub.1) and the pharmaceutical
dosage form, respectively, in a total amount of from 5 to 300 mg.
In another particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is tramadol,
preferably its HCl salt, and the pharmaceutical dosage form is
adapted for administration once daily. In this embodiment, the
first pharmacologically active ingredient (A.sub.1) is preferably
contained in the formed segment(s) (S.sub.1) and the pharmaceutical
dosage form, respectively, in a total amount of from 10 to 500
mg.
[0158] In another particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is hydrocodone,
preferably its HCl salt, and the pharmaceutical dosage form is
adapted for administration twice daily. In this embodiment, the
first pharmacologically active ingredient (A.sub.1) is preferably
contained in the formed segment(s) (S.sub.1) and the pharmaceutical
dosage form, respectively, in a total amount of from 5 to 250 mg.
In another particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is hydrocodone,
preferably its HCl salt, and the pharmaceutical dosage form is
adapted for administration once daily. In this embodiment, the
first pharmacologically active ingredient (A.sub.1) is preferably
contained in the formed segment(s) (S.sub.1) and the pharmaceutical
dosage form, respectively, in a total amount of from 5 to 250
mg.
[0159] In still another particularly preferred embodiment, the
first pharmacologically active ingredient (A.sub.1) is morphine,
preferably its HCl or H.sub.250.sub.4 salt, and the pharmaceutical
dosage form is adapted for administration twice daily. In this
embodiment, the first pharmacologically active ingredient (A.sub.1)
is preferably contained in the formed segment(s) (S.sub.1) and the
pharmaceutical dosage form, respectively, in a total amount of from
5 to 250 mg. In another particularly preferred embodiment, the
first pharmacologically active ingredient (A.sub.1) is morphine,
preferably its HCl or H.sub.2SO.sub.4 salt, and the pharmaceutical
dosage form is adapted for administration once daily. In this
embodiment, the first pharmacologically active ingredient (A.sub.1)
is preferably contained in the formed segment(s) (S.sub.1) and the
pharmaceutical dosage form, respectively, in a total amount of from
5 to 250 mg.
[0160] In another particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is buprenorphine,
preferably its HCl salt, and the pharmaceutical dosage form is
adapted for administration twice daily. In this embodiment, the
first pharmacologically active ingredient (A.sub.1) is preferably
contained in the formed segment(s) (S.sub.1) and the pharmaceutical
dosage form, respectively, in a total amount of from 1 to 12 mg. In
another particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is buprenorphine,
preferably its HCl salt, and the pharmaceutical dosage form is
adapted for administration once daily. In this embodiment, the
first pharmacologically active ingredient (A.sub.1) is preferably
contained in the formed segment(s) (S.sub.1) and the pharmaceutical
dosage form, respectively, in a total amount of from 2 to 12
mg.
[0161] The first pharmacologically active ingredient (A.sub.1) that
is employed in the preparation of the formed segment(s) (S.sub.1)
preferably has an average particle size of less than 500 microns,
still more preferably less than 300 microns, yet more preferably
less than 200 or 100 microns. There is no lower limit on the
average particle size and it may be, for example, 50 microns. The
particle size of pharmacologically active ingredients may be
determined by any technique conventional in the art, e.g. laser
light scattering, sieve analysis, light microscopy or image
analysis.
[0162] The formed segment(s) (S.sub.1) provide prolonged release of
the first pharmacologically active ingredient (A.sub.1). While such
prolonged release may principally be achieved by providing the
formed segment(s) (S.sub.1) with a prolonged release coating
containing pore formers, prolonged release is preferably achieved
by a prolonged release matrix.
[0163] Thus, the formed segment(s) (S.sub.1) preferably comprise(s)
a prolonged release matrix. The prolonged release matrix in turn
preferably comprises a prolonged release matrix material that
serves the function of providing prolonged release of the first
pharmacologically active ingredient (A.sub.1), optionally further
pharmaceutical excipients that do not substantially influence the
release profile, and the first pharmacologically active ingredient
(A.sub.1).
[0164] The first pharmacologically active ingredient (A.sub.1) is
preferably embedded, particularly preferably dispersed in the
prolonged release matrix material.
[0165] The total content of the prolonged release matrix (first
pharmacologically active ingredient (A.sub.1)+prolonged release
matrix material+optionally present excipients that do not
substantially influence the release profile) that is contained in
the formed segment(s) (S.sub.1) is preferably at least 30 wt.-%,
more preferably at least 40 wt.-%, still more preferably at least
50 wt.-%, yet more preferably at least 60 wt.-%, even more
preferably at least 70 wt.-%, most preferably at least 80 wt.-%,
and in particular at least 90 wt.-%, relative to the total weight
of the formed segment(s) (S.sub.1).
[0166] The total content of the prolonged release matrix (first
pharmacologically active ingredient (A.sub.1)+prolonged release
matrix material+optionally present excipients that do not
substantially influence the release profile) that is contained in
the formed segment(s) (S.sub.1) is preferably within the range of
from 5 to 95 wt.-%, more preferably 7 to 90 wt.-%, still more
preferably 9 to 80 wt.-%, yet more preferably 11 to 70 wt.-%, even
more preferably 13 to 60 wt.-%, most preferably 14 to 50 wt.-%, and
in particular 15 to 40 wt.-%, relative to the total weight of the
pharmaceutical dosage form.
[0167] Preferably, the first pharmacologically active ingredient
(A.sub.1) and the prolonged release matrix material are intimately
homogeneously distributed within the formed segment(s) (S.sub.1) so
that the formed segment(s) (S.sub.1) do(es) not contain any
portions where either the first pharmacologically active ingredient
(A.sub.1) is present in the absence of prolonged release matrix
material or where prolonged release matrix material is present in
the absence of the first pharmacologically active ingredient
(A.sub.1).
[0168] When the formed segment (S.sub.1) is film coated, the
prolonged release matrix material is preferably homogeneously
distributed in the body of the formed segment (S.sub.1), i.e. the
film coating preferably does not contain prolonged release matrix
material.
[0169] Apart from the prolonged release matrix material, the formed
segment(s) (S.sub.1) preferably contain(s) conventional
pharmaceutical excipients that do not substantially influence the
release profile.
[0170] Preferably, the total content of the prolonged release
matrix material, i.e. material that serves the function of
providing prolonged release of the first pharmacologically active
ingredient (A.sub.1), is within the range of from 20 to 99 wt.-%,
relative to the total weight of the formed segment(s) (S.sub.1).
When the formed segments (S.sub.1) are particulate, these percent
values preferably are related to the total weight of all particles
of the formed segment(s) (S.sub.1).
[0171] In a preferred embodiment, the content of the prolonged
release matrix material is at least 5 wt.-%, or at least 10 wt.-%,
or at least 15 wt.-%, more preferably at least 20 wt.-%, or at
least 25 wt.-%, or at least 30 wt.-%, still more preferably at
least 35 wt.-%, or at least 40 wt.-%, or at least 45 wt.-%, yet
more preferably at least 50 wt.-%, or at least 55 wt.-%, or at
least 60 wt.-%, most preferably at least 65 wt.-%, or at least 70
wt.-%, or at least 75 wt.-%, and in particular at least 80 wt.-%,
or at least 85 wt.-%, or at least 90 wt.-%, based on the total
weight of the formed segment(s) (S.sub.1).
[0172] In a preferred embodiment, the total content of prolonged
release matrix material is within the range of 25.+-.20 wt.-%, more
preferably 25.+-.15 wt.-%, most preferably 25.+-.10 wt.-%, and in
particular 25.+-.5 wt.-%, based on the total weight of the formed
segment(s) (S.sub.1).
[0173] In another preferred embodiment, the total content of
prolonged release matrix material is within the range of 30.+-.20
wt.-%, more preferably 30.+-.15 wt.-%, most preferably 30.+-.10
wt.-%, and in particular 30.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0174] In still another preferred embodiment, the total content of
prolonged release matrix material is within the range of 35.+-.20
wt.-%, more preferably 35.+-.15 wt.-%, most preferably 35.+-.10
wt.-%, and in particular 35.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0175] In a yet another preferred embodiment, the total content of
prolonged release matrix material is within the range of 40.+-.20
wt.-%, more preferably 40.+-.15 wt.-%, and most preferably 40.+-.10
wt.-%, and in particular 40.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0176] In a further preferred embodiment, the total content of
prolonged release matrix material is within the range of 45.+-.20
wt.-%, more preferably 45.+-.15 wt.-%, and most preferably 45.+-.10
wt.-%, and in particular 45.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0177] In still a further preferred embodiment, the total content
of prolonged release matrix material is within the range of
50.+-.20 wt.-%, more preferably 50.+-.15 wt.-%, and most preferably
50.+-.10 wt.-%, and in particular 50.+-.5 wt.-%, based on the total
weight of the formed segment(s) (S.sub.1).
[0178] In yet a further preferred embodiment, the total content of
prolonged release matrix material is within the range of 55.+-.20
wt.-%, more preferably 55.+-.15 wt.-%, and most preferably 55.+-.10
wt.-%, and in particular 55.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0179] In another preferred embodiment, the total content of
prolonged release matrix material is within the range of 60.+-.20
wt.-%, more preferably 60.+-.15 wt.-%, and most preferably 60.+-.10
wt.-%, and in particular 60.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0180] In still another preferred embodiment, the total content of
prolonged release matrix is within the range of 65.+-.20 wt.-%,
more preferably 65.+-.15 wt.-%, and most preferably 65.+-.10 wt.-%,
and in particular 65.+-.5 wt.-%, based on the total weight of the
formed segment(s) (S.sub.1).
[0181] In yet another preferred embodiment, the total content of
prolonged release matrix material is within the range of 70.+-.20
wt.-%, more preferably 70.+-.15 wt.-%, and most preferably 70.+-.10
wt.-%, and in particular 70.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0182] In a further preferred embodiment, the total content of
prolonged release matrix material is within the range of 75.+-.20
wt.-%, more preferably 75.+-.15 wt.-%, and most preferably 75.+-.10
wt.-%, and in particular 75.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0183] In still a further preferred embodiment, the total content
of prolonged release matrix material is within the range of
80.+-.15 wt.-%, more preferably 80.+-.12 wt.-%, and most preferably
80.+-.10 wt.-%, and in particular 80.+-.5 wt.-%, based on the total
weight of the formed segment(s) (S.sub.1).
[0184] In yet a further preferred embodiment, the total content of
prolonged release matrix material is within the range of 85.+-.10
wt.-%, more preferably 85.+-.8 wt.-%, and most preferably 85.+-.6
wt.-%, and in particular 85.+-.4 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0185] In another preferred embodiment, the total content of
prolonged release matrix material is within the range of 90.+-.8
wt.-%, more preferably 90.+-.7 wt.-%, and most preferably 90.+-.6
wt.-%, and in particular 90.+-.4 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0186] In still another preferred embodiment, the total content of
prolonged release matrix material is within the range of 95.+-.3
wt.-%, more preferably 95.+-.2 wt.-%, and most preferably 95.+-.1
wt.-%, and in particular 95.+-.0.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0187] Preferably, the total content of the prolonged release
matrix material, i.e. material that serves the function of
providing prolonged release of the first pharmacologically active
ingredient (A.sub.1), contained in the formed segment(s) (S.sub.1)
is within the range of from 5 to 95 wt.-%, more preferably 15 to 80
wt.-% or 20 to 80 wt.-% relative to the total weight of the
pharmaceutical dosage form.
[0188] In a preferred embodiment, the content of the prolonged
release matrix material is at least 5 wt.-% or at least 10 wt.-%,
more preferably at least 15 wt.-%, still more preferably at least
20 wt.-%, yet more preferably at least 25 wt.-% and in particular
at least 30 wt.-%, or at least 35 wt.-%, or at least 40 wt.-%, or
at least 45 wt.-%, or at least 50 wt.-%, or at least 55 wt.-%, or
at least 60 wt.-%, based on the total weight of the pharmaceutical
dosage form.
[0189] In still another preferred embodiment, the total content of
prolonged release matrix material is within the range of 20.+-.16
wt.-%, more preferably 20.+-.12 wt.-%, most preferably 20.+-.8
wt.-%, and in particular 20.+-.4 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0190] In yet another preferred embodiment, the total content of
prolonged release matrix material is within the range of 25.+-.20
wt.-%, more preferably 25.+-.15 wt.-%, most preferably 25.+-.10
wt.-%, and in particular 25.+-.5 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0191] In a further preferred embodiment, the total content of
prolonged release matrix material is within the range of 30.+-.20
wt.-%, more preferably 30.+-.15 wt.-%, most preferably 30.+-.10
wt.-%, and in particular 30.+-.5 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0192] In still a further preferred embodiment, the total content
of prolonged release matrix material is within the range of
35.+-.20 wt.-%, more preferably 35.+-.15 wt.-%, most preferably
35.+-.10 wt.-%, and in particular 35.+-.5 wt.-%, based on the total
weight of the pharmaceutical dosage form.
[0193] In a still further preferred embodiment, the total content
of prolonged release matrix material is within the range of
40.+-.20 wt.-%, more preferably 40.+-.15 wt.-%, and most preferably
40.+-.10 wt.-%, and in particular 40.+-.5 wt.-%, based on the total
weight of the pharmaceutical dosage form.
[0194] In a yet further preferred embodiment, the total content of
prolonged release matrix material is within the range of 45.+-.20
wt.-%, more preferably 45.+-.15 wt.-%, and most preferably 45.+-.10
wt.-%, and in particular 45.+-.5 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0195] In another preferred embodiment, the total content of
prolonged release matrix material is within the range of 50.+-.20
wt.-%, more preferably 50.+-.15 wt.-%, and most preferably 50.+-.10
wt.-%, and in particular 50.+-.5 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0196] In a yet further preferred embodiment, the total content of
prolonged release matrix material is within the range of 55.+-.20
wt.-%, more preferably 55.+-.15 wt.-%, and most preferably 55.+-.10
wt.-%, and in particular 55.+-.5 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0197] In another preferred embodiment, the total content of
prolonged release matrix material is within the range of 60.+-.20
wt.-%, more preferably 60.+-.15 wt.-%, and most preferably 60.+-.10
wt.-%, and in particular 60.+-.5 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0198] In still another preferred embodiment, the total content of
prolonged release matrix material is within the range of 65.+-.20
wt.-%, more preferably 65.+-.15 wt.-%, and most preferably 65.+-.10
wt.-%, and in particular 65.+-.5 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0199] Preferably, the relative weight ratio of the prolonged
release matrix material, i.e. material that serves the function of
providing prolonged release of the first pharmacologically active
ingredient (A.sub.1), to the first pharmacologically active
ingredient (A.sub.1) is within the range of from 40:1 to 1:40 or
35:1 to 1:35 or 30:1 to 1:30 or 20:1 to 1:20, more preferably 15:1
to 1:15, still more preferably 10:1 to 1:10, yet more preferably
7:1 to 1:7, most preferably 5:1 to 1:5, and in particular 2:1 to
1:2.
[0200] The prolonged release matrix material, i.e. material that
serves the function of providing prolonged release of the first
pharmacologically active ingredient (A.sub.1), preferably comprises
at least one synthetic or natural polymer (C) and/or optionally a
waxy material. Preferably, the prolonged release matrix material
comprises only one synthetic or natural polymer (C). In a preferred
embodiment, the prolonged release matrix material consists of
synthetic or natural polymer (C).
[0201] In a preferred embodiment, the first pharmacologically
active ingredient (A.sub.1) is embedded in a prolonged release
matrix comprising a synthetic or natural polymer (C).
[0202] The total content of the synthetic or natural polymer (C) is
preferably at least 65 wt.-%, more preferably at least 70 wt.-%,
still more preferably at least 75 wt.-%, yet more preferably at
least 80 wt.-%, even more preferably at least 85 wt.-%, most
preferably at least 90 wt.-%, and in particular at least 95 wt.-%,
relative to the total weight of the prolonged release matrix
material, i.e. material that serves the function of providing
prolonged release of the first pharmacologically active ingredient
(A.sub.1).
[0203] The total content of the synthetic or natural polymer (C) is
preferably at least 20 wt.-%, more preferably at least 30 wt.-%,
still more preferably at least 40 wt.-%, yet more preferably at
least 50 wt.-%, even more preferably at least 60 wt.-%, most
preferably at least 70 wt.-%, and in particular at least 80 wt.-%,
relative to the total weight of the prolonged release matrix (first
pharmacologically active ingredient (A.sub.1)+prolonged release
matrix material+optionally present excipients that do not
substantially influence the release profile).
[0204] Preferably, the total content of the synthetic or natural
polymer (C) is at least 20 wt.-%, more preferably at least 30
wt.-%, still more preferably at least 40 wt.-%, yet more preferably
at least 50 wt.-%, even more preferably at least 60 wt.-%, most
preferably at least 70 wt.-%, and in particular at least 80 wt.-%,
relative to the total weight of the formed segment(s)
(S.sub.1).
[0205] In a preferred embodiment, the total content of the
synthetic or natural polymer (C) is at least 5 wt.-%, more
preferably at least 10 wt.-%, still more preferably at least 15
wt.-%, yet more preferably at least 20 wt.-% and in particular at
least 25 wt.-%, relative to the total weight of the formed
segment(s) (S.sub.1). In a particularly preferred embodiment, the
content of the synthetic or natural polymer (C) is at least 30
wt.-% relative to the total weight of the formed
segment(s)(S.sub.1).
[0206] In a preferred embodiment, the total content of the
synthetic or natural polymer (C) is within the range of 10.+-.8
wt.-%, more preferably 10.+-.6 wt.-%, most preferably 10.+-.4
wt.-%, and in particular 10.+-.2 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0207] In another preferred embodiment, the total content of the
synthetic or natural polymer (C) is within the range of 15.+-.12
wt.-%, more preferably 15.+-.10 wt.-%, most preferably 15.+-.7
wt.-%, and in particular 15.+-.3 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0208] In still another preferred embodiment, the total content of
the synthetic or natural polymer (C) is within the range of
20.+-.16 wt.-%, more preferably 20.+-.12 wt.-%, most preferably
20.+-.8 wt.-%, and in particular 20.+-.4 wt.-%, based on the total
weight of the formed segment(s) (S.sub.1).
[0209] In yet another preferred embodiment, the total content of
the synthetic or natural 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.-%, based on the total
weight of the formed segment(s) (S.sub.1).
[0210] In a further preferred embodiment, the total content of the
synthetic or natural polymer (C) is within the range of 30.+-.20
wt.-%, more preferably 30.+-.15 wt.-%, most preferably 30.+-.10
wt.-%, and in particular 30.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0211] In still a further preferred embodiment, the total content
of the synthetic or natural 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.-%, based on the total
weight of the formed segment(s) (S.sub.1).
[0212] In a still further preferred embodiment, the total content
of the synthetic or natural polymer (C) is within the range of
40.+-.20 wt.-%, more preferably 40.+-.15 wt.-%, and most preferably
40.+-.10 wt.-%, and in particular 40.+-.5 wt.-%, based on the total
weight of the formed segment(s) (S.sub.1).
[0213] In a yet further preferred embodiment, the total content of
the synthetic or natural polymer (C) is within the range of
45.+-.20 wt.-%, more preferably 45.+-.15 wt.-%, and most preferably
45.+-.10 wt.-%, and in particular 45.+-.5 wt.-%, based on the total
weight of the formed segment(s) (S.sub.1).
[0214] In another preferred embodiment, the total content of the
synthetic or natural polymer (C) is within the range of 50.+-.20
wt.-%, more preferably 50.+-.15 wt.-%, and most preferably 50.+-.10
wt.-%, and in particular 50.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0215] In a yet further preferred embodiment, the total content of
the synthetic or natural polymer (C) is within the range of
55.+-.20 wt.-%, more preferably 55.+-.15 wt.-%, and most preferably
55.+-.10 wt.-%, and in particular 55.+-.5 wt.-%, based on the total
weight of the formed segment(s) (S.sub.1).
[0216] In another preferred embodiment, the total content of the
synthetic or natural polymer (C) is within the range of 60.+-.20
wt.-%, more preferably 60.+-.15 wt.-%, and most preferably 60.+-.10
wt.-%, and in particular 60.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0217] In a yet further preferred embodiment, the total content of
the synthetic or natural polymer (C) is within the range of
65.+-.20 wt.-%, more preferably 65.+-.15 wt.-%, and most preferably
65.+-.10 wt.-%, and in particular 65.+-.5 wt.-%, based on the total
weight of the formed segment(s) (S.sub.1).
[0218] In another preferred embodiment, the total content of the
synthetic or natural polymer (C) is within the range of 70.+-.20
wt.-%, more preferably 70.+-.15 wt.-%, and most preferably 70.+-.10
wt.-%, and in particular 70.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0219] In a yet further preferred embodiment, the total content of
the synthetic or natural polymer (C) is within the range of
75.+-.20 wt.-%, more preferably 75.+-.15 wt.-%, and most preferably
75.+-.10 wt.-%, and in particular 75.+-.5 wt.-%, based on the total
weight of the formed segment(s) (S.sub.1).
[0220] In another preferred embodiment, the total content of the
synthetic or natural polymer (C) is within the range of 80.+-.20
wt.-%, more preferably 80.+-.15 wt.-%, and most preferably 80.+-.10
wt.-%, and in particular 80.+-.5 wt.-%, based on the total weight
of the formed segment(s) (S.sub.1).
[0221] Preferably, the total content of the polymer (C) is within
the range of from 1 to 99 wt.-%, more preferably 3 to 90 wt.-%,
still more preferably 5 to 75 wt.-%, yet more preferably 7 to 70
wt.-%, most preferably 10 to 65 wt.-% and in particular 10 to 60
wt.-%, based on the total weight of the pharmaceutical dosage
form.
[0222] In a preferred embodiment, the total content of the polymer
(C) is at least 2 wt.-%, more preferably at least 5 wt.-%, still
more preferably at least 10 wt.-%, yet more preferably at least 15
wt.-% and in particular at least 20 wt.-%, based on the total
weight of the pharmaceutical dosage form.
[0223] In a preferred embodiment, the total content of the
synthetic or natural polymer (C) is within the range of 10.+-.8
wt.-%, more preferably 10.+-.6 wt.-%, most preferably 10.+-.4
wt.-%, and in particular 10.+-.2 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0224] In another preferred embodiment, the total content of the
synthetic or natural polymer (C) is within the range of 15.+-.12
wt.-%, more preferably 15.+-.10 wt.-%, most preferably 15.+-.7
wt.-%, and in particular 15.+-.3 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0225] In still another preferred embodiment, the total content of
the synthetic or natural polymer (C) is within the range of
20.+-.16 wt.-%, more preferably 20.+-.12 wt.-%, most preferably
20.+-.8 wt.-%, and in particular 20.+-.4 wt.-%, based on the total
weight of the pharmaceutical dosage form.
[0226] In yet another preferred embodiment, the total content of
the synthetic or natural 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.-%, based on the total
weight of the pharmaceutical dosage form.
[0227] In a further preferred embodiment, the total content of the
synthetic or natural polymer (C) is within the range of 30.+-.20
wt.-%, more preferably 30.+-.15 wt.-%, most preferably 30.+-.10
wt.-%, and in particular 30.+-.5 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0228] In still a further preferred embodiment, the total content
of the synthetic or natural 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.-%, based on the total
weight of the pharmaceutical dosage form.
[0229] In a still further preferred embodiment, the total content
of the synthetic or natural polymer (C) is within the range of
40.+-.20 wt.-%, more preferably 40.+-.15 wt.-%, and most preferably
40.+-.10 wt.-%, and in particular 40.+-.5 wt.-%, based on the total
weight of the pharmaceutical dosage form.
[0230] In a yet further preferred embodiment, the total content of
the synthetic or natural polymer (C) is within the range of
45.+-.20 wt.-%, more preferably 45.+-.15 wt.-%, and most preferably
45.+-.10 wt.-%, and in particular 45.+-.5 wt.-%, based on the total
weight of the pharmaceutical dosage form.
[0231] In another preferred embodiment, the total content of the
synthetic or natural polymer (C) is within the range of 50.+-.20
wt.-%, more preferably 50.+-.15 wt.-%, and most preferably 50.+-.10
wt.-%, and in particular 50.+-.5 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0232] In still another preferred embodiment, the total content of
the synthetic or natural polymer (C) is within the range of
60.+-.20 wt.-%, more preferably 60.+-.15 wt.-%, and most preferably
60.+-.10 wt.-%, and in particular 60.+-.5 wt.-%, based on the total
weight of the pharmaceutical dosage form.
[0233] In yet another preferred embodiment, the total content of
the synthetic or natural polymer (C) is within the range of
70.+-.20 wt.-%, more preferably 70.+-.15 wt.-%, and most preferably
70.+-.10 wt.-%, and in particular 70.+-.5 wt.-%, based on the total
weight of the pharmaceutical dosage form.
[0234] Preferably, the relative weight ratio of the polymer (C) to
the first pharmacologically active ingredient (A.sub.1) is within
the range of 40:1 to 1:40 or 35:1 to 1:35 or 30:1 to 1:30 or 20:1
to 1:20, more preferably 15:1 to 1:15, still more preferably 10:1
to 1:10, yet more preferably 7:1 to 1:7, most preferably 5:1 to
1:5, and in particular 2:1 to 1:2.
[0235] The synthetic or natural polymer (C) is preferably selected
from the group consisting of polyalkylene oxides (preferably
polymethylene oxide, polyethylene oxide, polypropylene oxide),
polyethylenes, polypropylenes, polyvinyl chlorides, polycarbonates,
polystyrenes, polyacrylates, poly(hydroxy fatty acids),
poly(hydroxyvaleric acids); polycaprolactones, polyvinyl alcohols,
polyesteramides, polyethylene succinates, polylactones,
polyglycolides, cellulose ethers (preferably methylcellulose,
ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose), polyurethanes,
polyvinylpyrrolidones, poly-amides, polylactides, polyacetals,
polylactide/glycolides, polylactones, polyglycolides,
polyorthoesters, polyanhydrides, copolymers thereof,
block-copolymers thereof, and mixtures of at least two of the
stated polymers.
[0236] In a preferred embodiment, polymer (C) is non-ionic. In
another preferred embodiment, polymer (C) is anionic. In still
another preferred embodiment, polymer (C) is cationic.
[0237] Preferably, the synthetic or natural polymer (C) is selected
from acrylic polymers or polyalkylene oxides.
[0238] In a particularly preferred embodiment, [0239] (i) the
content of the synthetic or natural polymer (C) is at least 30
wt.-% relative to the total weight of the formed segment(s)
(S.sub.1); and/or [0240] (ii) polymer (C) is selected from acrylic
polymers or polyalkylene oxides.
[0241] In a preferred embodiment, polymer (C) is an acrylic polymer
which is preferably derived from a monomer mixture comprising a
first C.sub.1-4-alkyl (meth)acrylate and a second C.sub.1-4-alkyl
(meth)acrylate differing from said first C.sub.1-4-alkyl
(meth)acrylate.
[0242] When the prolonged release matrix material of the prolonged
release matrix comprises an acrylic polymer, it preferably does not
additionally comprise an polyalkylene oxide or a waxy material, and
vice versa. However, it is principally possible that the prolonged
release matrix material of the prolonged release matrix comprises a
combination of an acrylic polymer, a polyalkylene oxide and/or a
waxy material.
[0243] Preferred C.sub.1-4-alkyl (meth)acrylates include methyl
methacrylate, methyl acrylate, ethyl methacrylate, ethyl acrylate,
propyl methacrylate, propyl acrylate, butyl methacrylate, and butyl
acrylate.
[0244] For the purpose of the specification, "(meth)acryl" refers
to acryl as well as methacryl.
[0245] Preferably, the acrylic polymer has a weight average
molecular weight within the range of from 100,000 g/mol to
2,000,000 g/mol. In a preferred embodiment, the acrylic polymer has
a weight average molecular weight (M.sub.w) or viscosity average
molecular weight (M.sub..eta.) of at least 150,000 or at least
200,000 g/mol, preferably at least 250,000 g/mol or at least
300,000 g/mol, more preferably in the range of about 300,000 g/mol
to about 2,000,000 g/mol, and most preferably in the range of about
300,000 g/mol to about 1,000,000 g/mol. Suitable methods to
determine M.sub.w and M.sub..eta..quadrature. known to a person
skilled in the art. M.sub..eta.is preferably determined by
rheological measurements, whereas M.sub.w can be determined by gel
permeation chromatography (GPC).
[0246] The acrylic polymer can be a nonionic acrylic polymer or an
ionic acrylic polymer. For the purpose of specification, "nonionic
polymer" refers to a polymer not containing more than 1 mole.-%
ionic, i.e. anionic or cationic, monomer units, preferably
containing no ionic monomer units at all.
[0247] In a preferred embodiment, the synthetic or natural polymer
(C) is a nonionic acrylic polymer which is preferably derived from
a monomer mixture comprising a first C.sub.1-4-alkyl (meth)acrylate
and a second C.sub.1-4-alkyl (meth)acrylate differing from said
first C.sub.1-4-alkyl (meth)acrylate.
[0248] Preferably, the first C.sub.1-4-alkyl (meth)acrylate is
ethyl acrylate and the second C.sub.1-4-alkyl (meth)acrylate is
methyl methacrylate.
[0249] Preferably, the relative molar content of the ethyl acrylate
within the nonionic acrylic polymer is greater than the relative
molar content of the methyl methacrylate within the nonionic
acrylic polymer.
[0250] Preferably, the molar ratio of the first C.sub.1-4-alkyl
(meth)acrylate, which is preferably ethyl acrylate, to the second
C.sub.1-4-alkyl (meth)acrylate, which is preferably methyl
methacrylate, is within the range of from 5:1 to 1:3, more
preferably from 4.5:1 to 1:2.5, still more preferably from 4:1 to
1:2, yet more preferably from 3.5:1 to 1:1.5, even more preferably
from 3:1 to 1:1, most preferably from 2.5:1 to 1.5:1, and in
particular about 2:1.
[0251] Preferably, the nonionic acrylic polymer has a weight
average molecular weight within the range of from 100,000 g/mol to
2,000,000 g/mol. In a preferred embodiment, the nonionic acrylic
polymer has a weight average molecular weight (M.sub.w) or
viscosity average molecular weight (M.sub..eta.) of at least
150,000 or at least 200,000 g/mol, preferably at least 250,000
g/mol or at least 300,000 g/mol, more preferably in the range of
about 300,000 g/mol to about 2,000,000 g/mol, and most preferably
in the range of about 300,000 g/mol to about 1,000,000 g/mol.
Suitable methods to determine M.sub.w and M.sub..eta., are known to
a person skilled in the art. M.sub..eta.is preferably determined by
rheological measurements, whereas M.sub.w can be determined by gel
permeation chromatography (GPC).
[0252] In a preferred embodiment, the weight average molecular
weight of the nonionic acrylic polymer is within the range of
675,000.+-.500,000 g/mol, more preferably 675,000.+-.450,000 g/mol,
still more preferably 675,000.+-.400,000 g/mol, yet more preferably
675,000.+-.350,000 g/mol, even more preferably 675,000.+-.300,000
g/mol, most preferably 675,000.+-.250,000 g/mol, and in particular
675,000.+-.200,000 g/mol.
[0253] The nonionic acrylic polymer may comprise a single nonionic
acrylic polymer having a particular average molecular weight, or a
mixture (blend) of different nonionic acrylic polymers, such as
two, three, four or five nonionic acrylic polymers, e.g., nonionic
acrylic polymers of the same chemical nature but different average
molecular weight, nonionic acrylic polymers of different chemical
nature but same average molecular weight, or nonionic acrylic
polymers of different chemical nature as well as different
molecular weight.
[0254] In a preferred embodiment, the nonionic acrylic polymer is
homogeneously distributed in the formed segment(s) (S.sub.1).
According to this embodiment, the first pharmacologically active
ingredient (A.sub.1) and the nonionic acrylic polymer are
intimately homogeneously distributed in the formed segment(s)
(S.sub.1), so that the formed segment(s) (S.sub.1) do(es) not
contain any portions where either the first pharmacologically
active ingredient (A.sub.1) is present in the absence of nonionic
acrylic polymer or where nonionic acrylic polymer is present in the
absence of the first pharmacologically active ingredient
(A.sub.1).
[0255] When the formed segment(s) (S.sub.1) is/are film coated, the
nonionic acrylic polymer is preferably homogeneously distributed in
the body of the formed segment(s) (S.sub.1), i.e. the film coating
preferably does not contain nonionic acrylic polymer. Nonetheless,
the film coating as such may of course contain one or more
polymers, which however, preferably differ from the nonionic
acrylic polymer contained in the body.
[0256] The nonionic acrylic polymer preferably has a glass
transition temperature (T.sub.g) within the range of
1.+-.15.degree. C., more preferably 1.+-.11.degree. C.
[0257] The nonionic acrylic polymer preferably has a minimum film
forming temperature (MFT) within the range of 5.+-.5.degree. C.,
more preferably 5.+-.2.degree. C.
[0258] Nonionic acrylic polymers that are suitable for use in the
formed segment (S.sub.1) according to the invention are
commercially available, e.g. from Evonik. For example,
Eudragit.RTM. NE30D, Eudragit.RTM. NE40D and Eudragit.RTM. NM30D,
which are provided as aqueous dispersions of poly(ethyl
acrylate-co-methyl methacrylate) 2:1, may be used in the formed
segment (S.sub.1) according to the invention. For details
concerning the properties of these products, it can be referred to
e.g. the product specification.
[0259] In a preferred embodiment, the synthetic or natural polymer
(C) is an ionic acrylic polymer.
[0260] In a preferred embodiment, the ionic acrylic polymer is
homogeneously distributed in the formed segment(s) (S.sub.1).
According to this embodiment, the first pharmacologically active
ingredient (A.sub.1) and the ionic acrylic polymer are intimately
homogeneously distributed in the formed segment(s) (S.sub.1), so
that the formed segment(s) (S.sub.1) do(es) not contain any
portions where either the first pharmacologically active ingredient
(A.sub.1) is present in the absence of ionic acrylic polymer or
where ionic acrylic polymer is present in the absence of the first
pharmacologically active ingredient (A.sub.1).
[0261] When the formed segment(s) (S.sub.1) is/are film coated, the
ionic acrylic polymer is preferably homogeneously distributed in
the body of the formed segment(s) (S.sub.1), i.e. the film coating
preferably does not contain ionic acrylic polymer. Nonetheless, the
film coating as such may of course contain one or more polymers,
which however, preferably differ from the ionic acrylic polymer
contained in the body.
[0262] Preferred ionic acrylic polymers are anionic acrylic
polymers. Preferred anionic acrylic polymers include but are not
limited to copolymers of one or two different C.sub.1-4-alkyl
(meth)acrylate monomers and copolymerizable anionic monomers such
as acrylic acid. Preferred representatives are ternary copolymers
of methyl acrylate, methyl methacrylate and methacrylic acid,
wherein the relative molar content of the monomers is preferably
methyl acrylate >methyl methacrylate >methacrylic acid.
Preferably, the anionic acrylic polymer has a weight average
molecular weight within the range of 280,000.+-.250,000 g/mol, more
preferably 280,000.+-.200,000 g/mol, still more preferably
280,000.+-.180,000 g/mol, yet more preferably 280,000.+-.160,000
g/mol, even more preferably 280,000.+-.140,000 g/mol, most
preferably 280,000.+-.120,000 g/mol, and in particular
280,000.+-.100,000 g/mol. Poly(methyl acrylate-co-methyl
methacrylate-co-methacrylic acid) 7:3:1 having an average molecular
weight of about 280,000 g/mol is commercially available as
Eudragit.RTM. FS.
[0263] Other preferred ionic acrylic polymers are cationic acrylic
polymers. Preferred cationic acrylic polymers include but are not
limited to copolymers of one or two different C.sub.1-4-alkyl
(meth)acrylate monomers and copolymerizable cationic monomers such
as trimethyl-ammonioethyl methacrylate chloride. Preferred
representatives are ternary copolymers of ethyl acrylate, methyl
methacrylate and a low content of methacrylic acid ester with
quaternary ammonium groups, preferably trimethylammonioethyl
methacrylate chloride, wherein the relative molar content of the
monomers is preferably methyl methacrylate >ethyl acrylate
>copolymerizable cationic monomers. Preferably, the cationic
acrylic polymer has a weight average molecular weight within the
range of 32,000.+-.30,000 g/mol, more preferably 32,000.+-.27,000
g/mol, still more preferably 32,000.+-.23,000 g/mol, yet more
preferably 32,000.+-.20,000 g/mol, even more preferably
32,000.+-.17,000 g/mol, most preferably 32,000.+-.13,000 g/mol, and
in particular 32,000.+-.10,000 g/mol. Poly(ethyl acrylate-co-methyl
methacrylate-co-trimethylammonioethyl methacrylate chloride)
1:2:0.1 and 1:2:0.2, respectively, having an average molecular
weight of about 32,000 g/mol is commercially available as
Eudragit.RTM. RS-PO and Eudragit.RTM. RL-PO, respectively. Because
of its lower content of trimethylammonioethyl methacrylate
chloride, Eudragit.RTM. RS-PO is particularly preferred. Another
preferred cationic acrylic polymer is Eudragit.RTM. RL 100 which is
a copolymer of ethyl acrylate, methyl methacrylate and a low
content of methacrylic acid ester with quaternary ammonium
groups.
[0264] In a preferred embodiment, the synthetic or natural polymer
(C) is a polyalkylene oxide, preferably a polyethylene oxide,
particularly preferably having an weight average molecular weight
of at least 500,000 g/mol.
[0265] When the prolonged release matrix material of the prolonged
release matrix comprises a polyalkylene oxide, it preferably does
not additionally comprise an acrylic polymer or a waxy material,
and vice versa.
[0266] In a preferred embodiment, the polyalkylene oxide is
homogeneously distributed in the formed segment(s) (S.sub.1).
According to this embodiment, the first pharmacologically active
ingredient (A.sub.1) and the polyalkylene oxide are intimately
homogeneously distributed in the formed segment(s) (S.sub.1), so
that the formed segment(s) (S.sub.1) do(es) not contain any
portions where either the first pharmacologically active ingredient
(A.sub.1) is present in the absence of polyalkylene oxide or where
polyalkylene oxide is present in the absence of the first
pharmacologically active ingredient (A.sub.1).
[0267] When the formed segment(s) (S.sub.1) is/are film coated, the
polyalkylene oxide is preferably homogeneously distributed in the
body of the formed segment(s) (S.sub.1), i.e. the film coating
preferably does not contain polyalkylene oxide. Nonetheless, the
film coating as such may of course contain one or more polymers,
which however, preferably differ from the polyalkylene oxide
contained in the body.
[0268] Preferably, the polyalkylene oxide is selected from
polymethylene oxide, polyethylene oxide and polypropylene oxide, or
copolymers or mixtures thereof.
[0269] Preferably, the polyalkylene oxide has a weight average
molecular weight (M.sub.w), preferably also a viscosity average
molecular weight (M.sub..eta.) of more than 200,000 g/mol or at
least 500,000 g/mol, preferably at least 1,000,000 g/mol or at
least 2,500,000 g/mol, more preferably in the range of about
1,000,000 g/mol to about 15,000,000 g/mol, and most preferably in
the range of about 5,000,000 g/mol to about 10,000,000 g/mol.
Suitable methods to determine M.sub.w and M.sub..eta..quadrature.
known to a person skilled in the art. M.sub..eta..quadrature., is
preferably determined by rheological measurements, whereas M.sub.w
can be determined by gel permeation chromatography (GPC).
[0270] Preferably, the molecular weight dispersity M.sub.w/M.sub.n
of the polyalkylene oxide 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.
[0271] The polyalkylene oxide preferably has a viscosity at
25.degree. C. of 30 to 17,600 mPas, more preferably 55 to 17,600
mPas, still more preferably 600 to 17,600 mPas, yet more preferably
4,500 to 17,600 mPas, even more preferably 4,500 to 12,000 mPas,
most preferably 5,000 to 10,500 mPas and in particular 5,500 to
7,500 mPas or 7,500 to 10,000 mPas, measured in a 1 wt.-% aqueous
solution.
[0272] The polyalkylene oxide may comprise a single polyalkylene
oxide 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.
[0273] For the purpose of specification, a polyalkylene glycol has
a molecular weight of up to 20,000 g/mol whereas a polyalkylene
oxide has a molecular weight of more than 20,000 g/mol. The weight
average over all molecular weights of all polyalkylene oxides that
are contained in the pharmaceutical dosage form is more than
200,000 g/mol. Thus, polyalkylene glycols, if any, are preferably
not taken into consideration when determining the weight average
molecular weight of polyalkylene oxide.
[0274] In a particularly preferred embodiment, the synthetic or
natural polymer (C) is a polyalkylene oxide the content of which is
at least 30 wt.-% relative to the total weight of the formed
segment(s) (S.sub.1).
[0275] Preferably, the polyalkylene oxide is combined with another
polymer, preferably a cellulose ether, particularly preferably a
cellulose ether selected from the group consisting of
methylcellulose, ethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, and hydroxy-propylmethylcellulose.
Hydroxypropylmethylcellulose is particularly preferred.
[0276] Preferably, the relative weight ratio of the polyalkylene
oxide and the cellulose ether is within the range of from 14:1 to
1:2, more preferably 13:1 to 1:1, still more preferably 12:1 to
2:1, yet more preferably 11:1 to 3:1, even more preferably 10:1 to
4:1, most preferably 9:1 to 5:1, and in particular 8:1 to 6:1.
[0277] In another preferred embodiment, the prolonged release
matrix material comprises a waxy material, preferably selected from
the group consisting of [0278] glycerides, especially
monoglycerides, diglycerides, triglycerides, [0279] esters of fatty
acids with fatty alcohols, and [0280] paraffins.
[0281] When the prolonged release matrix material of the prolonged
release matrix comprises a waxy material, it preferably does not
additionally comprise an acrylic polymer or a polyalkylene oxide,
and vice versa.
[0282] As used herein a "waxy material" refers to a material which
melts into liquid form having low viscosity upon heating and sets
again to a solid state upon cooling. Preferably, the waxy material
has a melting point of at least 30.degree. C., more preferably at
least 35.degree. C., still more preferably at least 40.degree. C.,
yet more preferably at least 45.degree. C., even more preferably at
least 50 .degree. C., most preferably at least 55.degree. C., and
in particular at least 60.degree. C.
[0283] When the waxy material is or comprises a monoglyceride,
diglyceride, triglyceride or a mixture thereof, it is preferably a
mono-, di- or triester of glycerol and carboxylic acids, whereas
the carboxylic acid is preferably selected from the group
consisting of fatty acids, hydroxy fatty acids and aromatic
acids.
[0284] In another preferred embodiment, the glyceride is a fatty
acid macrogolglyceride, e.g. lauroyl macrogolglyceride, such as
Gelucire 44/14 that can be regarded as a non-ionic water
dispersible surfactant composed of well-characterized PEG-esters, a
small glyceride fraction and free PEG.
[0285] Preferred glycerides of fatty acids include monoglycerides,
diglycerides, triglycerides, and mixtures thereof; preferably of
C.sub.6 to C.sub.22 fatty acids. Especially preferred are partial
glycerides of the C.sub.16 to C.sub.22 fatty acids such as glycerol
behenat, glycerol monostearate, glycerol palmitostearate and
glyceryl distearate as well as triglycerides of the C.sub.16 to
C.sub.22 fatty acids such as glycerol tristearate.
[0286] The term "fatty acid" is well acknowledged in the art and
includes for example unsaturated representatives such as
myristoleic acid, palmitoleic acid, sapienic acid, oleic acid,
elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid,
.alpha.-linolenic acid, arachidonic acid, eicosapentaenoic acid,
erucic acid, and docosahexaenoic acid; as well as saturated
representatives such as caprylic acid, capric acid, lauric acid,
myristic acid, palmitic acid, stearic acid, arachidic acid, behenic
acid, lignoceric acid, and cerotic acid.
[0287] The term "hydroxy fatty acid" is also well acknowledged in
the art and includes for example 2-hydroxyhexanoic acid,
2-hydroxyoctanoic acid, 2-hydroxydecanoic acid,
2-hydroxy-dodecanoic acid, 0-hydroxylauric acid,
2-hydroxytetradecanoic acid, .beta.-hydroxymyristic acid,
15-hydroxypentadecanoic acid, 16-hydroxyhexadecanoic acid,
.beta.-hydroxypalmitic acid, 12-hydroxyoctadecanoic acid,
.alpha.-hydroxystearic acid, and .alpha.-hydroxyarachidic acid.
[0288] The fatty acids and the hydroxy fatty acids are preferably
saturated.
[0289] When the waxy material is or comprises a diglyceride or a
triglyceride, the fatty acids, hydroxy fatty acids and aromatic
acids, respectively, may be identical or different.
[0290] According to this embodiment of the invention, the waxy
material is preferably a hard fat (adeps solidus) in accordance
with Ph. Eur.
[0291] Preferably, the waxy material is a monoglyceride,
diglyceride, triglyceride or a mixture thereof, selected from the
group consisting of hydrogenated soybean oil, hydrogenated palm
oil, hydrogenated castor oil, hydrogenated cottonseed oil, and
mixtures thereof.
[0292] When the waxy material is or comprises an ester of a fatty
acid with a fatty alcohol, the fatty acid is preferably a saturated
fatty acid. Preferred examples of fatty acids are already mentioned
above in connection with the glycerides. The fatty alcohol is
preferably derived from a fatty acid and preferably also
saturated.
[0293] Preferred representatives of esters of fatty acids with
fatty alcohols include but are not limited to natural waxes such as
beeswax, carnaubawax, candelilla wax, ouricury wax, sugarcane wax,
cetyl palmitate, oleyl oleate, cetaceum and retamo wax.
[0294] When the waxy material is or comprises paraffin, the
paraffin is preferably a hard paraffin (paraffinum solidum,
ceresin, zeresin) in accordance with Ph. Eur.
[0295] The waxy material may comprise a single waxy material, or a
mixture (blend) of different waxy materials, such as two, three,
four or five waxy materials, each of which preferably being
selected from the group consisting of glycerides, especially
monoglycerides, diglycerides, triglycerides; esters of fatty acids
with fatty alcohols; and paraffins.
[0296] In a preferred embodiment, the waxy material is
homogeneously distributed in the formed segment(s) (S.sub.1).
According to this embodiment, the first pharmacologically active
ingredient (A.sub.1) and the waxy material are intimately
homogeneously distributed in the formed segment(s) (S.sub.1), so
that the formed segment(s) (S.sub.1) do(es) not contain any
portions where either the first pharmacologically active ingredient
(A.sub.1) is present in the absence of waxy material or where waxy
material is present in the absence of the first pharmacologically
active ingredient (A.sub.1).
[0297] When the formed segment(s) (S.sub.1) is/are film coated, the
waxy material is preferably homogeneously distributed in the formed
segment(s) (S.sub.1), i.e. the film coating preferably does not
contain waxy material. Nonetheless, the film coating as such may of
course contain one or more waxy materials, which however,
preferably differ from the waxy materials contained in the
body.
[0298] Waxy materials that are suitable for use in the
pharmaceutical dosage forms according to the invention are
commercially available, e.g. Cera alba, Cera flava, Kolliwax.TM.
HCO, Dynasan.RTM. 118, Compritol.RTM. 888 ATO, Precirol.RTM. ATO 5,
Gelucire.RTM. 44/14, and the like. For details concerning the
properties of these products, it can be referred to e.g. the
product specification.
[0299] The total content of the waxy material is preferably within
the range of from 5.0 to 95 wt.-%, more preferably 10 to 90 wt.-%,
still more preferably 15 to 85 wt.-%, yet more preferably 20 to 80
wt.-%, even more preferably 25 to 75 wt.-%, most preferably 30 to
70 wt.-%, and in particular 35 to 75 wt.-%, relative to the total
weight of the prolonged release matrix.
[0300] Preferably, the total content of the waxy material is within
the range of from 1 to 90 wt.-%, more preferably 3 to 85 wt.-%,
still more preferably 5 to 80 wt.-%, yet more preferably 7 to 75
wt.-%, most preferably 10 to 70 wt.-% and in particular 15 to 65
wt.-%, based on the total weight of the formed segment(s)
(S.sub.1).
[0301] In a preferred embodiment, the total content of the waxy
material is at least 2 wt.-%, more preferably at least 5 wt.-%,
still more preferably at least 10 wt.-%, yet more preferably at
least 15 wt.-% and in particular at least 20 wt.-%, based on the
total weight of the formed segment(s) (S.sub.1).
[0302] In a preferred embodiment, the total content of waxy
material is within the range of 10.+-.8 wt.-%, more preferably
10.+-.6 wt.-%, most preferably 10.+-.4 wt.-%, and in particular
10.+-.2 wt.-%, based on the total weight of the formed segment(s)
(S.sub.1).
[0303] In another preferred embodiment, the total content of waxy
material is within the range of 15.+-.12 wt.-%, more preferably
15.+-.10 wt.-%, most preferably 15.+-.7 wt.-%, and in particular
15.+-.3 wt.-%, based on the total weight of the formed segment(s)
(S.sub.1).
[0304] In still another preferred embodiment, the total content of
waxy material is within the range of 20.+-.16 wt.-%, more
preferably 20.+-.12 wt.-%, most preferably 20.+-.8 wt.-%, and in
particular 20.+-.4 wt.-%, based on the total weight of the formed
segment(s) (S.sub.1).
[0305] In yet another preferred embodiment, the total content of
waxy material is within the range of 25.+-.20 wt.-%, more
preferably 25.+-.15 wt.-%, most preferably 25.+-.10 wt.-%, and in
particular 25.+-.5 wt.-%, based on the total weight of the formed
segment(s) (S.sub.1).
[0306] In a further preferred embodiment, the total content of waxy
material is within the range of 30.+-.20 wt.-%, more preferably
30.+-.15 wt.-%, most preferably 30.+-.10 wt.-%, and in particular
30.+-.5 wt.-%, based on the total weight of the formed segment(s)
(S.sub.1).
[0307] In still a further preferred embodiment, the total content
of waxy material is within the range of 35.+-.20 wt.-%, more
preferably 35.+-.15 wt.-%, most preferably 35.+-.10 wt.-%, and in
particular 35.+-.5 wt.-%, based on the total weight of the formed
segment(s) (S.sub.1).
[0308] In a still further preferred embodiment, the total content
of waxy material is within the range of 40.+-.20 wt.-%, more
preferably 40.+-.15 wt.-%, and most preferably 40.+-.10 wt.-%, and
in particular 40.+-.5 wt.-%, based on the total weight of the
formed segment(s) (S.sub.1).
[0309] In a yet further preferred embodiment, the total content of
waxy material is within the range of 45.+-.20 wt.-%, more
preferably 45.+-.15 wt.-%, and most preferably 45.+-.10 wt.-%, and
in particular 45.+-.5 wt.-%, based on the total weight of the
formed segment(s) (S.sub.1).
[0310] In another preferred embodiment, the total content of waxy
material is within the range of 50.+-.20 wt.-%, more preferably
50.+-.15 wt.-%, and most preferably 50.+-.10 wt.-%, and in
particular 50.+-.5 wt.-%, based on the total weight of the formed
segment(s) (S.sub.1).
[0311] In a yet further preferred embodiment, the total content of
waxy material is within the range of 55.+-.20 wt.-%, more
preferably 55.+-.15 wt.-%, and most preferably 55.+-.10 wt.-%, and
in particular 55.+-.5 wt.-%, based on the total weight of the
formed segment(s) (S.sub.1).
[0312] In another preferred embodiment, the total content of waxy
material is within the range of 60.+-.20 wt.-%, more preferably
60.+-.15 wt.-%, and most preferably 60.+-.10 wt.-%, and in
particular 60.+-.5 wt.-%, based on the total weight of the formed
segment(s) (S.sub.1).
[0313] In a yet further preferred embodiment, the total content of
waxy material is within the range of 65.+-.20 wt.-%, more
preferably 65.+-.15 wt.-%, and most preferably 65.+-.10 wt.-%, and
in particular 65.+-.5 wt.-%, based on the total weight of the
formed segment(s) (S.sub.1).
[0314] In another preferred embodiment, the total content of waxy
material is within the range of 70.+-.20 wt.-%, more preferably
70.+-.15 wt.-%, and most preferably 70.+-.10 wt.-%, and in
particular 70.+-.5 wt.-%, based on the total weight of the formed
segment(s) (S.sub.1).
[0315] In a yet further preferred embodiment, the total content of
waxy material is within the range of 75.+-.20 wt.-%, more
preferably 75.+-.15 wt.-%, and most preferably 75.+-.10 wt.-%, and
in particular 75.+-.5 wt.-%, based on the total weight of the
formed segment(s) (S.sub.1).
[0316] In another preferred embodiment, the total content of waxy
material is within the range of 80.+-.20 wt.-%, more preferably
80.+-.15 wt.-%, and most preferably 80.+-.10 wt.-%, and in
particular 80.+-.5 wt.-%, based on the total weight of the formed
segment(s) (S.sub.1).
[0317] Preferably, the relative weight ratio of the waxy material
to the first pharmacologically active ingredient (A.sub.1) is
within the range of 20:1 to 1:20, more preferably 15:1 to 1:15,
still more preferably 10:1 to 1:10, yet more preferably 7:1 to 1:7,
most preferably 5:1 to 1:5, and in particular 2:1 to 1:2.
[0318] Besides the first pharmacologically active ingredient
(A.sub.1) and the optionally present prolonged release matrix
material the formed segment(s) (S.sub.1) may optionally further
comprise additional pharmaceutical excipients conventionally
contained in pharmaceutical dosage forms in conventional amounts,
such as antioxidants, preservatives, lubricants, plasticizer,
fillers/binders, and the like.
[0319] The skilled person will readily be able to determine
appropriate further excipients as well as the quantities of each of
these excipients. Specific examples of pharmaceutically acceptable
carriers and excipients are described in the Handbook of
Pharmaceutical Excipients, American Pharmaceutical Association
(1986).
[0320] In a preferred embodiment, the formed segment (S.sub.1) does
not contain a disintegrant.
[0321] Preferably, the formed segment(s) (S.sub.1) further
comprise(s) an antioxidant. Suitable antioxidants include ascorbic
acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene
(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
present in quantities of 0.01 wt.-% to 10 wt.-%, more preferably of
0.03 wt.-% to 5 wt.-%, most preferably of 0.05 wt.-% to 2.5 wt.-%,
based on the total weight of the formed segment(s) (S.sub.1).
[0322] In a preferred embodiment, the formed segment(s) (S.sub.1)
further comprise(s) an acid, preferably a carboxylic acid, more
preferably a multicarboxylic acid, particularly citric acid. The
content of acid is preferably in the range of 0.01 wt.-% to about
20 wt.-%, more preferably in the range of 0.02 wt.-% to about 10
wt.-%, and still more preferably in the range of 0.05 wt.-% to
about 5 wt.-%, and most preferably in the range of 0.1 wt.-% to
about 1.0 wt.-%, based on the total weight of the formed segment(s)
(S.sub.1).
[0323] In a preferred embodiment, the formed segment(s) (S.sub.1)
contain(s) at least one lubricant. In another preferred embodiment,
the formed segment(s) (S.sub.1) contain(s) no lubricant.
[0324] Especially preferred lubricants are selected from
[0325] magnesium stearate, calcium stearate and stearic acid;
[0326] polyoxyethylene glycerol fatty acid esters, such as mixtures
of mono-, di- and triesters of glycerol and di- and monoesters of
macrogols having molecular weights within the range of from 200 to
4000 g/mol, e.g., macrogolglycerolcaprylocaprate,
macrogolglycerollaurate, macrogolglycerolococoate,
macrogolglycerollinoleate, macrogol-20-glycerolmonostearate,
macrogol-6-glycerolcaprylocaprate, macrogolglycerololeate;
macrogolglycerolstearate, macrogolglycerolhydroxystearate, and
macrogolglycerolrizinoleate;
[0327] polyglycolyzed glycerides, such as the one known and
commercially available under the trade name "Labrasol";
[0328] fatty alcohols that may be linear or branched, such as
cetylalcohol, stearylalcohol, cetylstearyl alcohol,
2-octyldodecane-1-ol and 2-hexyldecane-1-ol; and
[0329] polyethylene glycols having a molecular weight between
10.000 and 60.000 g/mol.
[0330] Particularly preferred lubricants comprise stearic acid,
calcium stearate and stearyl alcohol or a mixture thereof.
[0331] Preferably, the content of the lubricant ranges from 0.01
wt.-% to about 10 or 15 wt.-%, more preferably in the range of 0.05
wt.-% to about 7.5 wt.-%, most preferably in the range of 0.1 wt.-%
to about 5 wt.-% or 1.5 wt.-% to about 4 wt, and in particular in
the range of 0.1 wt.-% to about 1 wt.-% or 3.5 to about 5.5 wt.-%,
based on the total weight of the formed segment(s) (S1).
[0332] When the formed segment(s) (S.sub.1) contain(s) more than
one lubricant, preferably, the overall content of the lubricant
ranges from 3 wt.-% to about 20 wt.-%, more preferably in the range
of 5 wt.-% to about 15 wt.-%, most preferably in the range of 7
wt.-% to about 12 wt.-%, and in particular in the range of 8 wt.-%
to about 10 wt.-%, based on the total weight of the formed
segment(s) (S.sub.1).
[0333] Preferably, the formed segment(s) (S.sub.1) further
comprise(s) a plasticizer. The plasticizer improves the
processability of the prolonged release matrix material. A
preferred plasticizer is polyalkylene glycol, like polyethylene
glycol, triethyl citrate (TEC), triacetin, fatty acids, fatty acid
esters, waxes and/or microcrystalline waxes. Particularly preferred
plasticizers are polyethylene glycols, such as PEG 6000. Further
particularly preferred plasticizers comprise triethyl citrate
(TEC), stearic acid, calcium stearate and stearyl alcohol or a
mixture thereof.
[0334] Preferably, the content of the plasticizer is within the
range of from 0.5 to 30 wt.-%, more preferably 1.0 to 25 wt.-%,
still more preferably 2.5 wt.-% to 22.5 wt.-%, yet more preferably
5.0 wt.-% to 20 wt.-%, most preferably 6 to 20 wt.-% and in
particular 7 wt.-% to 17.5 wt.-%, based on the total weight of the
formed segment(s) (S.sub.1).
[0335] When the formed segment (S.sub.1) contains more than one
plasticizer, preferably, the overall amount of the plasticizer
ranges from 3 wt.-% to about 20 wt.-%, more preferably in the range
of 5 wt.-% to about 20 wt.-% or to about 15 wt.-%, most preferably
in the range of 7 wt.-% to about 20 wt.-% or to about 12 wt.-%, and
in particular in the range of 8 wt.-% to about 20 wt.-% or to about
10 wt.-%, based on the total weight of the formed segment(s)
(S.sub.1).
[0336] Plasticizers can sometimes act as a lubricant, and
lubricants can sometimes act as a plasticizer.
[0337] Preferably, the formed segment(s) (S.sub.1) further
comprise(s) a filler/binder. A preferred filler/binder is selected
from celluloses, cellulose derivatives such as cellulose ethers and
cellulose esters, and tricalcium phosphate. A particularly
preferred filler/binder is selected from cellulose esters and
cellulose ethers, in particular hydroxypropyl methylcellulose
(HPMC).
[0338] The content of the filler/binder, preferably HPMC,
preferably ranges from 0.1 wt.-% to about 30 wt.-%, more preferably
in the range of 1.0 wt.-% to about 20 wt.-%, and most preferably in
the range of 2.0 wt.-% to about 15 wt.-% relative to the total
weight of the formed segment(s) (S.sub.1).
[0339] In a preferred embodiment, besides the first
pharmacologically active ingredient (A.sub.1) that may have any
solubility in aqueous ethanol, relative to the total weight of the
formed segment(s) (S.sub.1), the formed segment(s) (S.sub.1)
according to the invention preferably contain(s) at most 25 wt.-%,
more preferably at most 20 wt.-%, still more preferably at most 15
wt.-%, yet more preferably at most 10 wt.-%, even more preferably
at most 5.0 wt.-%, most preferably at most 2.5 wt.-%, and in
particular at most 1.0 wt.-% of ingredients (prolonged release
matrix material, excipients, and the like) having at room
temperature in aqueous ethanol (40 vol.-%) a solubility of at least
100 mg/ml, more preferably a solubility of at least 75 mg/ml, still
more preferably a solubility of at least 50 mg/ml, yet more
preferably a solubility of at least 25 mg/ml, even more preferably
a solubility of at least 10 mg/ml, most preferably a solubility of
at least 5.0 mg/ml, and in particular a solubility of at least 1.0
mg/ml.
[0340] Preferred contents of the first pharmacologically active
ingredient (A.sub.1), prolonged release matrix material, and
excipients, relative to the total weight of the formed segment(s)
(S.sub.1), are summarized as embodiments B.sup.1 to B.sup.28 in the
tables here below:
TABLE-US-00001 wt.-% B.sup.1 B.sup.2 B.sup.3 B.sup.4 first
pharmacologically 40 .+-. 30 40 .+-. 20 40 .+-. 10 40 .+-. 5 active
ingredient (A.sub.1) synthetic or natural 50 .+-. 30 50 .+-. 20 50
.+-. 10 50 .+-. 5 polymer (C) pharmaceutical excipients 20 .+-. 20
20 .+-. 20 20 .+-. 20 20 .+-. 20
TABLE-US-00002 wt.-% B.sup.5 B.sup.6 B.sup.7 B.sup.8 first
pharmacologically 30 .+-. 25 30 .+-. 20 30 .+-. 10 30 .+-. 5 active
ingredient (A.sub.1) synthetic or natural 50 .+-. 30 50 .+-. 20 50
.+-. 10 50 .+-. 5 polymer (C) pharmaceutical excipients 20 .+-. 20
20 .+-. 20 20 .+-. 20 20 .+-. 20
TABLE-US-00003 wt.-% B.sup.9 B.sup.10 B.sup.11 B.sup.12 first
pharmacologically 20 .+-. 15 .sup. 20 .+-. 12.5 20 .+-. 10 20 .+-.
5 active ingredient (A.sub.1) synthetic or natural 50 .+-. 30 50
.+-. 20 50 .+-. 10 50 .+-. 5 polymer (C) pharmaceutical excipients
20 .+-. 20 20 .+-. 20 20 .+-. 20 20 .+-. 20
TABLE-US-00004 wt.-% B.sup.13 B.sup.14 B.sup.15 B.sup.16 first
pharmacologically 10 .+-. 7.5 10 .+-. 7.5 10 .+-. 5 10 .+-. 5
active ingredient (A.sub.1) synthetic or natural 50 .+-. 30 50 .+-.
20 50 .+-. 10 50 .+-. 10 polymer (C) pharmaceutical excipients 20
.+-. 20 20 .+-. 20 20 .+-. 20 20 .+-. 20
TABLE-US-00005 wt.-% B.sup.17 B.sup.18 B.sup.19 B.sup.20 first
pharmacologically 20 .+-. 15 .sup. 20 .+-. 12.5 20 .+-. 10 20 .+-.
5 active ingredient (A.sub.1) synthetic or natural 40 .+-. 30 40
.+-. 20 40 .+-. 10 40 .+-. 5 polymer (C) pharmaceutical excipients
20 .+-. 20 20 .+-. 20 20 .+-. 20 20 .+-. 20
TABLE-US-00006 wt.-% B.sup.21 B.sup.22 B.sup.23 B.sup.24 first
pharmacologically 20 .+-. 15 .sup. 20 .+-. 12.5 20 .+-. 10 20 .+-.
5 active ingredient (A.sub.1) synthetic or natural 60 .+-. 40 60
.+-. 30 60 .+-. 20 60 .+-. 10 polymer (C) pharmaceutical excipients
20 .+-. 20 20 .+-. 20 20 .+-. 20 20 .+-. 20
TABLE-US-00007 wt.-% B.sup.25 B.sup.26 B.sup.27 B.sup.28 first
pharmacologically 10 .+-. 9 10 .+-. 7 10 .+-. 5 10 .+-. 3 active
ingredient (A.sub.1) synthetic or natural 70 .+-. 40 60 .+-. 30 60
.+-. 20 60 .+-. 10 polymer (C) pharmaceutical excipients 20 .+-. 20
20 .+-. 20 20 .+-. 20 20 .+-. 20
[0341] The formed segment(s) (S.sub.1) provide(s) prolonged release
of the first pharmacologically active ingredient (A.sub.1).
Preferably, the prolonged release matrix provides for a prolonged
release of the first pharmacologically active ingredient (A.sub.1)
from the formed segment (S.sub.1).
[0342] Preferably, under in vitro conditions the pharmaceutical
dosage form 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 first pharmacologically active
ingredient (A.sub.1).
[0343] Suitable in vitro conditions are known to the skilled
artisan. In this regard it can be referred to, e.g., the Eur. Ph.
Preferably, the release profile is measured under the following
conditions: Paddle apparatus equipped without sinker, 50 rpm,
37.+-.5.degree. C., 600 mL simulated intestinal fluid pH 6.8
(phosphate buffer) or pH 4.5. In a preferred embodiment, the
rotational speed of the paddle is increased to 75 rpm. In another
preferred embodiment, the release profile is determined under the
following conditions:basket method, 75 rpm, 37.+-.5.degree. C., 600
mL 0.1 N HCl or 600 mL of SIF sp (pH 6.8) or 600 mL of 0.1 N
HCl+40% ethanol.
[0344] Preferred release profiles R.sup.1 to R.sup.6 are summarized
in the table here below [all data in wt.-% of released first
pharmacologically active ingredient (A.sub.1)]:
TABLE-US-00008 time R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6
60 min 0-30 0-50 0-50 15-25 20-30 20-50 120 min 0-40 0-75 0-75
25-40 35-50 40-75 240 min 3-55 3-95 10-95 40-70 55-75 60-95 480 min
10-65 10-100 35-100 60-90 80-95 80-100 720 min 20-75 20-100 55-100
70-100 90-100 90-100 960 min 30-88 30-100 70-100 >80 95-100 1440
min 50-100 50-100 >90 2160 min >80 >80
[0345] Further preferred release profiles R.sup.7 to R.sup.13 are
summarized in the table here below [all data in wt.-% of released
first pharmacologically active ingredient (A.sub.1)]:
TABLE-US-00009 time R.sup.7 R.sup.8 R.sup.9 R.sup.10 R.sup.11
R.sup.12 R.sup.13 30 min 17.5 .+-. 7.5 17.5 .+-. 6.5 17.5 .+-. 5.5
17.5 .+-. 4.5 17.5 .+-. 3.5 17.5 .+-. 2.5 15 .+-. 6.5 60 min 27.0
.+-. 8.0 27.0 .+-. 7.0 27.0 .+-. 6.0 27.0 .+-. 5.0 27.0 .+-. 4.0
27.0 .+-. 3.0 20 .+-. 7.0 120 min 41.5 .+-. 9.5 41.5 .+-. 8.5 41.5
.+-. 7.5 41.5 .+-. 6.5 41.5 .+-. 5.5 41.5 .+-. 4.5 25 .+-. 8.5 240
min 64.5 .+-. 12.5 64.5 .+-. 11.5 64.5 .+-. 10.5 64.5 .+-. 9.5 64.5
.+-. 8.5 64.5 .+-. 7.5 37 .+-. 11.5 480 min 88.0 .+-. 12.0 88.0
.+-. 11.0 88.0 .+-. 10.0 88.0 .+-. 9.0 88.0 .+-. 8.0 88.0 .+-. 7.0
50 .+-. 11.0 720 min 96.0 .+-. 9.0 96.0 .+-. 8.0 96.0 .+-. 7.0 96.0
.+-. 6.0 96.0 .+-. 5.0 96.0 .+-. 4.0 58 .+-. 8.0 840 min 97.5 .+-.
7.5 97.5 .+-. 6.5 97.5 .+-. 5.5 97.5 .+-. 4.5 97.5 .+-. 3.5 97.5
.+-. 2.5 67 .+-. 15
[0346] In a particularly preferred embodiment; under in vitro
conditions in 600 mL 0.1 N HCl, using the basket method according
to Ph. Eur. at 75 rpm, after 1 h under physiological conditions,
the pharmaceutical dosage form has released at most 50%, more
preferably at most 45%, still more preferably at most 40%, yet more
preferably at most 30%, even more preferably at most 28%, most
preferably at most 25% and in particular at most 23% of the first
pharmacologically active ingredient (A.sub.1) relative to the total
amount of the first pharmacologically active ingredient (A.sub.1)
originally contained in the pharmaceutical dosage form.
[0347] Preferably, the release profile, the first pharmacologically
active ingredient (A.sub.1) and optionally present pharmaceutical
excipients of the formed segment (S.sub.1) are stable upon storage,
preferably upon storage at elevated temperature, e.g. 40.degree.
C., for 3 months in sealed containers.
[0348] In connection with the release profile "stable" preferably
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%.
[0349] In connection with a pharmacologically active ingredient and
pharmaceutical excipients "stable" preferably means that the
segments and the pharmaceutical dosage form satisfy the
requirements of EMA concerning shelf-life of pharmaceutical
products.
[0350] Preferably, after storage for 4 weeks, more preferably 6
months, at 40.degree. C. and 75% rel. humidity, the content of the
first pharmacologically active ingredient (A.sub.1) in the formed
segment(s) (S.sub.1) and the pharmaceutical dosage form,
respectively, amounts to at least 98.0%, more preferably at least
98.5%, still more preferably at least 99.0%, yet more preferably at
least 99.2%, most preferably at least 99.4% and in particular at
least 99.6%, of its original content before storage.
[0351] The formed segment(s) (S.sub.1) exhibit(s) a higher breaking
strength than the further segment (S.sub.2). Further, the formed
segment(s) (S.sub.1) exhibit(s) a breaking strength of more than
500 N. When the formed segments (S.sub.1) are particulate,
preferably at least a fraction of the individual particles, i.e. at
least one formed segment (S.sub.1) has a breaking strength of more
than 500 N.
[0352] Preferably, the mechanical properties, particularly the
breaking strength, substantially relies on the presence and spatial
distribution of the prolonged release matrix material, although its
mere presence does typically not suffice in order to achieve said
properties. The advantageous mechanical properties may not
automatically be achieved by simply processing first
pharmacologically active ingredient (A.sub.1), prolonged release
matrix material, 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.
[0353] In general, the desired properties may be obtained only if,
during preparation of the formed segment(s) (S.sub.1), [0354]
suitable components [0355] in suitable amounts are exposed to
[0356] a sufficient pressure [0357] at a sufficient temperature
[0358] for a sufficient period of time.
[0359] Thus, regardless of the apparatus used, the process
protocols must be adapted in order to meet the required criteria.
Therefore, the breaking strength is separable from the
composition.
[0360] The formed segment(s) (S.sub.1) has/have a breaking strength
of more than 500 N. Preferably, the formed segment(s) (S.sub.1)
has/have a breaking strength of at least 600 N, more preferably at
least 700 N, still more preferably at least 800 N, yet more
preferably at least 1000 N, most preferably at least 1250 N and in
particular at least 1500 N.
[0361] The "breaking strength" (resistance to crushing) of a
pharmaceutical dosage form or a segment 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:Pharmaceutical
dosage forms, Vol. 2, Informa Healthcare; 2 edition, 1990; and
Encyclopedia of Pharmaceutical Technology, Informa Healthcare; 1
edition.
[0362] For the purpose of the specification, the breaking strength
is preferably defined as the amount of force that is necessary in
order to fracture a pharmaceutical dosage form and a segment,
respectively (=breaking force). Therefore, for the purpose of the
specification a pharmaceutical dosage form and segment,
respectively, 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 and
segment, respectively, is regarded as being broken if the force
decreases by 25% (threshold value) of the highest force measured
during the measurement (see below).
[0363] When the pharmaceutical dosage form is a capsule, e.g. a
hard gelatine capsule, the true quantitative breaking strength of
the capsule is difficult to measure; it may occur that the capsule
does not fracture in the course of the measurement because of its
flexibility. As conventional capsules apparently to not exhibit any
increased breaking strength, for the purpose of specification the
quantitative breaking strength of a capsule can preferably be
regarded as being 0 N.
[0364] The formed segment (S.sub.1) according to the invention is
distinguished from conventional pharmaceutical dosage forms and
particulate or monolithic segments, respectively, in that due to
its breaking strength, it 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 (pharmaceutical
dosage form crushers). In this regard "pulverization" means
crumbling into small particles. Avoidance of pulverization
virtually rules out oral or parenteral, in particular intravenous
or nasal abuse.
[0365] Preferably, the formed segment (S.sub.1) is tamper resistant
and provides resistance against grinding.
[0366] Conventional pharmaceutical dosage forms and particulate or
monolithic segments, respectively, typically have a breaking
strength well below 200 N.
[0367] The breaking strength of conventional round pharmaceutical
dosage forms/particulate or monolithic segments may be estimated
according to the following empirical formula:
[0368] Breaking Strength [in N]=10.times.Diameter of pharmaceutical
dosage form/particulate [in mm].
[0369] Thus, according to said empirical formula, a round
pharmaceutical dosage form/particulate or monolithic segment having
a breaking strength of at least 300 N would require a diameter of
at least 30 mm. Such a particle however, could not be swallowed,
let alone a pharmaceutical dosage form containing a plurality of
such particles. The above empirical formula preferably does not
apply to the formed segment (S.sub.1) according to the invention,
which is not conventional but rather special.
[0370] 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).
This means that conventional pharmaceutical dosage forms and
particles, respectively, having a breaking strength well below 200
N may be crushed upon spontaneous chewing, whereas the formed
segment (S.sub.1) according to the invention may preferably
not.
[0371] Still further, when applying a gravitational acceleration of
about 9.81 m/s.sup.2, 300 N correspond to a gravitational force of
more than 30 kg, i.e. the formed segment (S.sub.1) according to the
invention can preferably withstand a weight of more than 30 kg
without being pulverized.
[0372] Methods for measuring the breaking strength are known to the
skilled artisan. Suitable devices are commercially available.
[0373] For example, the breaking strength (resistance to crushing)
can be measured in accordance with the Eur. Ph. 5.0, 2.9.8 or 6.0,
2.09.08 "Resistance to Crushing of Pharmaceutical dosage forms".
The segments may be subjected to the same or similar breaking
strength test as the pharmaceutical dosage form. The test is
intended to determine, under defined conditions, the resistance to
crushing of pharmaceutical dosage forms, segments and individual
particles, respectively, 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 pharmaceutical dosage form, segments and
individual particle, respectively. The apparatus is calibrated
using a system with a precision of 1 Newton. The pharmaceutical
dosage form, segment and particle, respectively, is placed between
the jaws, taking into account, where applicable, the shape, the
break-mark and the inscription; for each measurement the
pharmaceutical dosage form, segment and particle, respectively, 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 pharmaceutical dosage forms, segments and
particles, respectively, taking care that all fragments 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.
[0374] A similar description of the breaking strength (breaking
force) can be found in the USP. 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 pharmaceutical dosage form, segments and
individual particles, respectively, to fail (i.e., break) in a
specific plane. The pharmaceutical dosage form, segment and
individual particle, respectively, is generally placed between two
platens, one of which moves to apply sufficient force to the
pharmaceutical dosage form, segment and individual particle,
respectively, to cause fracture. For conventional, round (circular
cross-section) pharmaceutical dosage form, segments and individual
particles, respectively, loading occurs across their diameter
(sometimes referred to as diametral loading), and fracture occurs
in the plane. The breaking force of pharmaceutical dosage form,
segment and individual particle, respectively, 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 pharmaceutical dosage form, segments and
individual particles, respectively, 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
pharmaceutical dosage form, segments and individual particles,
respectively, are actually crushed during the test, which is often
not the case.
[0375] Alternatively, the breaking strength (resistance to
crushing) can be measured in accordance with WO 2008/107149, which
can be regarded as a modification of the method described in the
Eur. Ph. 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.
[0376] In a preferred embodiment, the pharmaceutical dosage form,
segment and individual particle, respectively, is regarded as being
broken if it is fractured into at least two separate pieces.
[0377] The formed segment(s) (S.sub.1) according to the invention
preferably exhibit(s) 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 possibly even in liquid nitrogen), for it
to be virtually impossible to pulverize by spontaneous chewing,
grinding in a mortar, pounding, etc. Thus, preferably, the
comparatively high breaking strength of the formed segment(s)
(S.sub.1) 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.
[0378] The formed segment(s) (S.sub.1) according to the invention
is/are characterized by a certain degree of breaking strength. This
does not mean that it must also exhibit a certain degree of
hardness. Hardness and breaking strength are different physical
properties. Therefore, the preferred tamper-resistance of the
formed segment(s) (S.sub.1) does not necessarily depend on the
hardness of the formed segment(s) (S.sub.1). For instance, due to
its breaking strength, impact strength, elasticity modulus and
tensile strength, respectively, the formed segment(s) (S.sub.1) can
preferably be deformed, e.g. plastically, 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
formed segment(s) (S.sub.1) according to the invention is/are
characterized by a certain degree of breaking strength, but not
necessarily also by a certain degree of form stability.
[0379] Therefore, in the meaning of the specification, a
pharmaceutical dosage form, segment and individual particle,
respectively, that is deformed when being exposed to a force in a
particular direction of extension but that does not break (plastic
deformation or plastic flow) is preferably to be regarded as having
the desired breaking strength in said direction of extension.
[0380] Preferred pharmaceutical dosage forms, segments and
individual particles, respectively, are those having a suitable
tensile strength as determined by a test method currently accepted
in the art. Further pharmaceutical dosage form, segments and
individual particles, respectively, are those having a Youngs
Modulus as determined by a test method of the art. Still further
pharmaceutical dosage form, segments and individual particles,
respectively, are those having an acceptable elongation at
break.
[0381] In a preferred embodiment, the formed segment(s) (S.sub.1)
is/are tamper resistant and provide(s) resistance against grinding
and/or resistance against solvent extraction and/or resistance
against dose-dumping in aqueous ethanol.
[0382] Tamper-resistant preferably means that the formed segment(s)
(S.sub.1) [0383] (i) preferably provide(s) resistance against
solvent extraction, and/or [0384] (ii) preferably provide(s)
resistance against grinding, and/or [0385] (iii) preferably
provide(s) resistance against dose-dumping in aqueous ethanol.
[0386] Thus, the formed segment(s) (S.sub.1) according to the
invention do(es) not necessarily need to exhibit any of resistances
(i) to (iii); but may preferably exhibit any of resistances (i) to
(iii) as well as any combination thereof; namely only (i); only
(ii); only (iii); a combination of only (i) and (ii); a combination
of only (i) and (iii); a combination of only (ii) and (iii); or a
combination of (i) and (ii) and (iii).
[0387] Preferably, prolonged release of the first pharmacologically
active ingredient (A.sub.1) is achieved by a prolonged release
matrix contained in the formed segment(s) (S.sub.1) which prolonged
release matrix additionally provides tamper resistance in terms of
resistance against solvent extraction, resistance against grinding,
and resistance against dose-dumping in aqueous ethanol.
[0388] As used herein, the term "tamper-resistant" refers to
pharmaceutical dosage forms or segments that are resistant to
conversion into a form suitable for misuse or abuse, particular for
nasal and/or intravenous administration, by conventional means.
[0389] In this regard, the pharmaceutical dosage form as such it
may be crushable by conventional means such as grinding in a mortar
or crushing by means of a hammer. However, the formed segment(s)
(S.sub.1) contained in the pharmaceutical dosage form preferably
exhibit(s) mechanical properties such that they cannot be
pulverized by conventional means any further. As the formed
segment(s) (S.sub.1) is/are of macroscopic size and contain(s) the
pharmacologically active ingredient, it/they cannot be administered
nasally thereby rendering the pharmaceutical dosage form
tamper-resistant.
[0390] Further, when trying to disrupt the pharmaceutical dosage
forms by means of a hammer or mortar, the formed segments (S.sub.1)
tend to adhere to one another thereby forming aggregates and
agglomerates, respectively, which are larger in size than the
untreated particles.
[0391] Preferably, the prolonged release matrix of the formed
segment(s) (S.sub.1) provides resistance against solvent
extraction.
[0392] Preferably, when trying to tamper the pharmaceutical dosage
form in order to prepare a formulation suitable for abuse by
intravenous administration, the liquid part of the formulation that
can be separated from the remainder by means of a syringe at room
temperature is as less as possible, preferably it contains not more
than 45 or 40 wt.-%, more preferably not more than 35 wt.-%, still
more preferably not more than 30 wt.-%, yet more preferably not
more than 25 wt.-%, even more preferably not more than 20 wt.-%,
most preferably not more than 15 wt.-% and in particular not more
than 10 wt.-% of the originally contained first pharmacologically
active ingredient (A.sub.1).
[0393] Preferably, this property is tested by (i) dispensing a
pharmaceutical dosage form that is either intact or has been
manually comminuted by means of two spoons in 5 ml of solvent,
either purified water or aqueous ethanol (40 vol. %), (ii) allowing
the dispersion to stand for 10 min at room temperature, (iii)
drawing up the hot liquid into a syringe (needle 21G equipped with
a cigarette filter), and (iv) determining the amount of the
pharmacologically active ingredient contained in the liquid within
the syringe.
[0394] Preferably, the prolonged release matrix of the formed
segment(s) (S.sub.1) contained in the pharmaceutical dosage form
according to the invention provides resistance against
grinding.
[0395] Preferably, when the formed segment(s) (S.sub.1) is/are
treated with a commercial coffee mill, preferably type Bosch
MKM6000, 180W, Typ KM13 for 2 minutes, 42.+-.17.5 wt.-%, more
preferably 42.+-.15 wt.-%, still more preferably 42.+-.12.5 wt.-%,
yet more preferably 42.+-.10 wt.-%, even more preferably 42.+-.7.5
wt.-%, most preferably 42.+-.5 wt.-%, and in particular 42.+-.2.5
wt.-%, of the total weight of the thus obtained material does not
pass a sieve having a mesh size of 1.000 mm.
[0396] Preferably, when the formed segment(s) (S.sub.1) is/are
treated with a commercial coffee mill, preferably type Bosch
MKM6000, 180W, Typ KM13, for 2 minutes, 57.+-.17.5 wt.-%, more
preferably 57.+-.15 wt.-%, still more preferably 57.+-.12.5 wt.-%,
yet more preferably 57.+-.10 wt.-%, even more preferably 57.+-.7.5
wt.-%, most preferably 57.+-.5 wt.-%, and in particular 57.+-.2.5
wt.-%, of the total weight of the thus obtained material does not
pass a sieve having a mesh size of 1.000 mm.
[0397] Preferably, when the formed segment(s) (S.sub.1) is/are
treated with a commercial coffee mill, preferably type Bosch
MKM6000, 180W, Typ KM13, for 2 minutes, at least 50 wt.-%, more
preferably at least 55 wt.-%, still more preferably at least 60
wt.-%, yet more preferably at least 65 wt.-%, even more preferably
at least 70 wt.-%, most preferably at least 75 wt.-%, and in
particular at least 80 wt.-%, of the total weight of the thus
obtained material does not pass a sieve having a mesh size of 1.000
mm.
[0398] Preferably, when the pharmaceutical dosage form treated with
a commercial coffee mill, preferably type Bosch MKM6000, 180W, Typ
KM13 for 2 minutes, 42.+-.17.5 wt.-%, more preferably 42.+-.15
wt.-%, still more preferably 42.+-.12.5 wt.-%, yet more preferably
42.+-.10 wt.-%, even more preferably 42.+-.7.5 wt.-%, most
preferably 42.+-.5 wt.-%, and in particular 42.+-.2.5 wt.-%, of the
total weight of the thus obtained material does not pass a sieve
having a mesh size of 1.000 mm.
[0399] Preferably, when the pharmaceutical dosage form is/are
treated with a commercial coffee mill, preferably type Bosch
MKM6000, 180W, Typ KM13, for 2 minutes, 57.+-.17.5 wt.-%, more
preferably 57.+-.15 wt.-%, still more preferably 57.+-.12.5 wt.-%,
yet more preferably 57.+-.10 wt.-%, even more preferably 57.+-.7.5
wt.-%, most preferably 57.+-.5 wt.-%, and in particular 57.+-.2.5
wt.-%, of the total weight of the thus obtained material does not
pass a sieve having a mesh size of 1.000 mm.
[0400] Preferably, when the pharmaceutical dosage form is treated
with a commercial coffee mill, preferably type Bosch MKM6000, 180W,
Typ KM13, for 2 minutes, at least 50 wt.-%, more preferably at
least 55 wt.-%, still more preferably at least 60 wt.-%, yet more
preferably at least 65 wt.-%, even more preferably at least 70
wt.-%, most preferably at least 75 wt.-%, and in particular at
least 80 wt.-%, of the total weight of the thus obtained material
does not pass a sieve having a mesh size of 1.000 mm.
[0401] Particle size distributions of the ground pharmaceutical
dosage form are preferably determined by sieve analysis.
[0402] In a preferred embodiment, after treatment with a commercial
coffee mill as described above, more than 55%, more preferably more
than 60%, still more preferably more than 65%, yet more preferably
more than 70%, most preferably 75% and in particular more than 80%
of the particles of the ground formed segment (S.sub.1) and
pharmaceutical dosage form, respectively, have a size in the range
of from 0.2 to 3.3 nm, more preferably of from 0.4 to 3.1 nm, most
preferably of from 0.6 to 2.9 and in particular of from 0.7 to 2.8
nm.
[0403] Preferred particle size distributions P.sup.1 to P.sup.6 are
summarized in the table underneath:
TABLE-US-00010 particle size amount [wt.-%] [nm] P.sup.1 P.sup.2
P.sup.3 P.sup.4 P.sup.5 P.sup.6 <0.045 0.5 .+-. 0.4 0.1 .+-.
0.09 0.3 .+-. 0.29 0.3 .+-. 0.29 0.3 .+-. 0.29 0.3 .+-. 0.29
0.045-0.063 0.5 .+-. 0.4 0.3 .+-. 0.29 0.3 .+-. 0.29 0.3 .+-. 0.29
0.3 .+-. 0.29 0.3 .+-. 0.29 0.063-0.090 0.5 .+-. 0.4 0.3 .+-. 0.29
0.3 .+-. 0.29 1.0 .+-. 0.9 0.3 .+-. 0.29 0.3 .+-. 0.29 0.090-0.125
0.5 .+-. 0.4 0.3 .+-. 0.29 0.3 .+-. 0.29 1.0 .+-. 0.9 0.3 .+-. 0.29
1.0 .+-. 0.9 0.125-0.180 0.5 .+-. 0.4 3.0 .+-. 2.9 2.0 .+-. 1.5 2.0
.+-. 1.5 1.0 .+-. 0.9 1.0 .+-. 0.9 0.180-0.250 1.5 .+-. 1.4 1.0
.+-. 0.8 2.0 .+-. 1.5 1.0 .+-. 0.9 2.0 .+-. 1.5 1.0 .+-. 0.9
0.250-0.355 4.0 .+-. 3.5 5.0 .+-. 4.0 4.0 .+-. 3.5 3.5 .+-. 2.5 5.0
.+-. 4.0 3.0 .+-. 2.9 0.355-0.500 7.0 .+-. 6.0 5.0 .+-. 4.0 6.0
.+-. 4.5 7.0 .+-. 6.0 7.0 .+-. 6.0 7.0 .+-. 6.0 0.500-0.710 11.0
.+-. 8.0 9.0 .+-. 7.0 11.0 .+-. 8.0 10.0 .+-. 7.0 13.0 .+-. 10.0
9.0 .+-. 7.0 0.710-1.000 15.0 .+-. 12.0 10.0 .+-. 7.0 17.0 .+-.
14.0 18.0 .+-. 15.0 18.0 .+-. 15.0 13.0 .+-. 10.0 1.000-1.400 20.0
.+-. 17.0 18.0 .+-. 15.0 23.0 .+-. 20.0 28.0 .+-. 25.0 25.0 .+-.
22.0 20.0 .+-. 17.0 1.400-2.000 23.0 .+-. 20.0 19.0 .+-. 16.0 12.0
.+-. 9.0 18.0 .+-. 15.0 10.0 .+-. 7.0 22.0 .+-. 19.0 2.000-2.800
13.0 .+-. 10.0 16.0 .+-. 13.0 13.0 .+-. 10.0 11.0 .+-. 8.0 14.0
.+-. 11.0 12.0 .+-. 9.0 2.800-4.000 1.0 .+-. 0.8 14.0 .+-. 11.0
12.0 .+-. 9.0 0.3 .+-. 0.29 4.0 .+-. 3.5 9.0 .+-. 7.0 >4.00 0.5
.+-. 0.45 0.3 .+-. 0.29 0.3 .+-. 0.29 0.5 .+-. 0.45 0.3 .+-. 0.29
0.5 .+-. 0.45
[0404] Preferably, the prolonged release matrix of the formed
segment(s) (S.sub.1) contained in the pharmaceutical dosage form
according to the invention provides resistance against dose-dumping
in aqueous ethanol.
[0405] The pharmaceutical dosage form can be tested in vitro using
ethanol/simulated gastric fluid of 0%, 20% and 40% to evaluate
alcohol extractability. Testing is preferably performed using
standard procedures, e.g. USP Apparatus 1 (basket) or USP Apparatus
2 (paddle) at e.g. 50 rpm in e.g. 500 ml of media at 37.degree. C.,
using a Perkin Elmer UV/VIS Spectrometer Lambda 20, UV at an
appropriate wavelength for detection of the first pharmacologically
active ingredient (A.sub.1) present therein. Sample time points
preferably include 0.5 and 1 hour.
[0406] Preferably, when comparing the in vitro release profile at
37.degree. C. in simulated gastric fluid with the in vitro release
profile in ethanol/simulated gastric fluid (40 vol.-%) at
37.degree. C., the in vitro release in ethanol/simulated gastric
fluid (40 vol.-%) is preferably not substantially accelerated
compared to the in vitro release in simulated gastric fluid.
Preferably, in this regard "substantially" means that at any given
time point the in vitro release in ethanol/simulated gastric fluid
(40 vol.-%) relatively deviates from the in vitro release in
simulated gastric fluid by not more than+25%, more preferably not
more than+20%, still more preferably not more than+15%, yet more
preferably not more than+10%, even more preferably not more
than+7.5%, most preferably not more than+5.0% and in particular not
more than+2.5%.
[0407] A substantial relative acceleration of the in vitro release
in ethanol/simulated gastric fluid (40 vol.-%) compared to the in
vitro release in simulated gastric fluid is to be prevented
according to the invention. However, a substantial relative
deceleration of the in vitro release in ethanol/simulated gastric
fluid (40 vol.-%) compared to the in vitro release in simulated
gastric fluid, e.g., a relative deviation by -25% or more, may be
possible and can even be desirable.
[0408] The further segment(s) (S.sub.2) comprise(s) the second
pharmacologically active ingredient (A.sub.2) and provide immediate
release thereof.
[0409] Preferably, the second pharmacologically active ingredient
(A.sub.2) is different from the first pharmacologically active
ingredient (A.sub.1).
[0410] In a preferred embodiment, the second pharmacologically
active ingredient (A.sub.2) exhibits no psychotropic action.
[0411] In another preferred embodiment, the second
pharmacologically active ingredient (A.sub.2) is selected from ATC
classes [M01A], [M01C], [N02B] and [N02C] according to the WHO.
[0412] In a particularly preferred embodiment, [0413] (i) the first
pharmacologically active ingredient (A.sub.1) has a psychotropic
effect; and/or [0414] (ii) the second pharmacologically active
ingredient (A.sub.2) is selected from ATC classes [M01A], [M01C],
[N02B] and [N02C] according to the WHO.
[0415] Preferably, the second pharmacologically active ingredient
(A.sub.2) is selected from the group consisting of acetylsalicylic
acid, aloxiprin, choline salicylate, sodium salicylate,
salicylamide, salsalate, ethenzamide, morpholine salicylate,
dipyrocetyl, benorilate, diflunisal, potassium salicylate,
guacetisal, carbasalate calcium, imidazole salicylate, phenazone,
metamizole sodium, aminophenazone, propyphenazone, nifenazone,
paracetamol, phenacetin, bucetin, propacetamol, rimazolium,
glafenine, floctafenine, viminol, nefopam, flupirtine, ziconotide,
methoxyflurane, nabiximols, dihydroergotamine, ergotamine,
methysergide, lisuride, flumedroxone, sumatriptan, naratriptan,
zolmitriptan, rizatriptan, almotriptan, eletriptan, frovatriptan,
pizotifen, clonidine, iprazochrome, dimetotiazine, oxetorone,
phenylbutazone, mofebutazone, oxyphenbutazone, clofezone, kebuzone,
indomethacin, sulindac, tolmetin, zomepirac, diclofenac,
alclofenac, bumadizone, etodolac, lonazolac, fentiazac, acemetacin,
difenpiramide, oxametacin, proglumetacin, ketorolac, aceclofenac,
bufexamac, piroxicam, tenoxicam, droxicam, lornoxicam, meloxicam,
ibuprofen, naproxen, ketoprofen, fenoprofen, fenbufen,
benoxaprofen, suprofen, pirprofen, flurbiprofen, indoprofen,
tiaprofenic acid, oxaprozin, ibuproxam, dexibuprofen,
flunoxaprofen, alminoprofen, dexketoprofen, naproxcinod, mefenamic
acid, tolfenamic acid, flufenamic acid, meclofenamic acid,
celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib,
lumiracoxib, nabumetone, niflumic acid, azapropazone, glucosamine,
benzydamine, glucosaminoglycan polysulfate, proquazone, orgotein,
nimesulide, feprazone, diacerein, morniflumate, tenidap, oxaceprol,
chondroitin sulfate, oxycinchophen, sodium aurothiomalate, sodium
aurotiosulfate, auranofin, aurothioglucose, aurotioprol,
penicillamine, bucillamine, their physiologically acceptable salts,
as well as mixtures thereof.
[0416] In a preferred embodiment, the second pharmacologically
active ingredient (A.sub.2) is paracetamol (acetaminophen) or
ibuprofen, more preferably paracetamol.
[0417] In a particularly preferred embodiment, the first
pharmacologically active ingredient (A.sub.1) is hydrocodone or a
physiologically acceptable salt thereof and the second
pharmacologically active ingredient (A.sub.2) is paracetamol.
[0418] Preferred combinations C.sup.1 to C.sup.32 of the first
pharmacologically active ingredient (A.sub.1) and the second
pharmacologically active ingredient (A.sub.2) are summarized in the
table here below, wherein the first pharmacologically active
ingredient (A.sub.1) as well as the second pharmacologically active
ingredient (A.sub.2) each also refer to the physiologically
acceptable salts thereof, particularly to the hydrochlorides:
TABLE-US-00011 A.sub.1 A.sub.2 C.sup.1 oxycodone ibuprofen C.sup.2
oxymorphone ibuprofen C.sup.3 hydrocodone ibuprofen C.sup.4
hydromorphone ibuprofen C.sup.5 morphine ibuprofen C.sup.6
tapentadol ibuprofen C.sup.7 tramadol ibuprofen C.sup.8
buprenorphine ibuprofen C.sup.9 oxycodone paracetamol C.sup.10
oxymorphone paracetamol C.sup.11 hydrocodone paracetamol C.sup.12
hydromorphone paracetamol C.sup.13 morphine paracetamol C.sup.14
tapentadol paracetamol C.sup.15 tramadol paracetamol C.sup.16
buprenorphine paracetamol C.sup.17 oxycodone diclofenac C.sup.18
oxymorphone diclofenac C.sup.19 hydrocodone diclofenac C.sup.20
hydromorphone diclofenac C.sup.21 morphine diclofenac C.sup.22
tapentadol diclofenac C.sup.23 tramadol diclofenac C.sup.24
buprenorphine diclofenac C.sup.25 oxycodone acetylsalicylic acid
C.sup.26 oxymorphone acetylsalicylic acid C.sup.27 hydrocodone
acetylsalicylic acid C.sup.28 hydromorphone acetylsalicylic acid
C.sup.29 morphine acetylsalicylic acid C.sup.30 tapentadol
acetylsalicylic acid C.sup.31 tramadol acetylsalicylic acid
C.sup.32 buprenorphine acetylsalicylic acid
[0419] The second pharmacologically active ingredient (A.sub.2) is
present in the pharmaceutical dosage form in a therapeutically
effective amount. In general, the amount that constitutes a
therapeutically effective amount varies according to the
pharmacologically active ingredients being used, the condition
being treated, the severity of said condition, the patient being
treated, and whether the pharmaceutical dosage form or the segment
in which the pharmacologically active ingredient is contained is
designed for an immediate or retarded release.
[0420] The total content of the second pharmacologically active
ingredient (A.sub.2) preferably ranges from about 0.01 wt.-% to
about 95 wt.-%, more preferably from about 0.1 wt.-% to about 80
wt.-%, even more preferably from about 1.0 wt.-% to about 50 wt.-%,
yet more preferably from about 1.5 wt.-% to about 30 wt.-%, and
most preferably from about 2.0 wt.-% to 20 wt.-%, based on the
total weight of the further segment(s) (S.sub.2) or based on the
total weight of the pharmaceutical dosage form.
[0421] Preferably, the total content of the second
pharmacologically active ingredient (A.sub.2) is within the range
of from 0.01 to 80 wt.-%, more preferably 0.1 to 50 wt.-%, still
more preferably 1 to 25 wt.-%, based on the total weight of the
pharmaceutical dosage form. In a preferred embodiment, the total
content of the second pharmacologically active ingredient (A.sub.2)
is within the range of from 20.+-.15 wt.-%, more preferably
20.+-.12 wt.-%, still more preferably 20.+-.10 wt.-%, most
preferably 20.+-.7 wt.-%, and in particular 20.+-.5 wt.-%, based on
the total weight of the pharmaceutical dosage form. In a preferred
embodiment, the total content of the second pharmacologically
active ingredient (A.sub.2) is within the range of from 30.+-.15
wt.-%, more preferably 30.+-.12 wt.-%, still more preferably
30.+-.10 wt.-%, most preferably 30.+-.7 wt.-%, and in particular
30.+-.5 wt.-%, based on the total weight of the pharmaceutical
dosage form. In a preferred embodiment, the total content of the
second pharmacologically active ingredient (A.sub.2) is within the
range of from 40.+-.15 wt.-%, more preferably 40.+-.12 wt.-%, still
more preferably 40.+-.10 wt.-%, most preferably 40.+-.7 wt.-%, and
in particular 40.+-.5 wt.-%, based on the total weight of the
pharmaceutical dosage form. In a preferred embodiment, the total
content of the second pharmacologically active ingredient (A.sub.2)
is within the range of from 50.+-.15 wt.-%, more preferably
50.+-.12 wt.-%, still more preferably 50.+-.10 wt.-%, most
preferably 50.+-.7 wt.-%, and in particular 50.+-.5 wt.-%, based on
the total weight of the pharmaceutical dosage form. In a preferred
embodiment, the total content of the second pharmacologically
active ingredient (A.sub.2) is within the range of from 60.+-.15
wt.-%, more preferably 60.+-.12 wt.-%, still more preferably
60.+-.10 wt.-%, most preferably 60.+-.7 wt.-%, and in particular
60.+-.5 wt.-%, based on the total weight of the pharmaceutical
dosage form.
[0422] Preferably, the total content of the second
pharmacologically active ingredient (A.sub.2) is within the range
of from 0.01 to more than 99.99 wt.-%, more preferably 0.1 to 99.9
wt.-%, still more preferably 5 to 95 wt.-%, based on the total
weight of the further segment(s) (S.sub.2). In a preferred
embodiment, the total content of the second pharmacologically
active ingredient (A.sub.2) is within the range of from 20.+-.6
wt.-%, 30.+-.6 wt.-% or 40.+-.6 wt.-%, more preferably 20.+-.5
wt.-%, 30.+-.5 wt.-% or 40.+-.5 wt.-%, still more preferably
20.+-.4 wt.-%, 30.+-.4 wt.-% or 40.+-.4 wt.-%, most preferably
20.+-.3 wt.-%, 30.+-.3 wt.-% or 40.+-.3 wt.-% and in particular
20.+-.2 wt.-%, 30.+-.2 wt.-% or 40.+-.2 wt.-%, based on the total
weight of the further segment(s) (S.sub.2). In another preferred
embodiment, the total content of the second pharmacologically
active ingredient (A.sub.2) is within the range of from 50.+-.20
wt.-%, 60.+-.20 wt.-%, 70.+-.20 wt.-% or 80.+-.20 wt.-%, more
preferably 50.+-.15 wt.-%, 60.+-.15 wt.-%, 70.+-.15 wt.-% or
80.+-.15 wt.-%, still more preferably 50.+-.12 wt.-%, 60.+-.12
wt.-%, 70.+-.12 wt.-% or 80.+-.12 wt.-%, most preferably 50.+-.10
wt.-%, 60.+-.10 wt.-%, 70.+-.10 wt.-% or 80.+-.10 wt.-%, and in
particular 50.+-.5 wt.-%, 60.+-.5 wt.-%, 70.+-.5 wt.-% or 80.+-.5
wt.-%,based on the total weight of the further segment(s)
(S.sub.2). In still another preferred embodiment, the total content
of the second pharmacologically active ingredient (A.sub.2) is
within the range of from 90.+-.10 wt.-%, more preferably 90.+-.8
wt.-%, still more preferably 90.+-.6 wt.-%, most preferably 90.+-.4
wt.-% and in particular 90.+-.2 wt.-%, based on the total weight of
the further segment(s) (S.sub.2).
[0423] The total amount of the second pharmacologically active
ingredient (A.sub.2) in the further segment (S.sub.2) and the
pharmaceutical dosage form, respectively, is not limited. The total
amount of the second pharmacologically active ingredient (A.sub.2)
which is adapted for administration preferably is in the range of
0.1 mg to 2,000 mg or 0.1 mg to 1,000 mg or 0.1 mg to 500 mg, more
preferably in the range of 1.0 mg to 400 mg, even more preferably
in the range of 5.0 mg to 300 mg, and most preferably in the range
of 10 mg to 250 mg. In a preferred embodiment, the total amount of
the second pharmacologically active ingredient (A.sub.2) which is
contained in the further segment (S.sub.2) and the pharmaceutical
dosage form, respectively, is within the range of from 10 to 1,000
mg, more preferably 50 to 900 mg, still more preferably 100 to 800
mg, yet more preferably 200 to 600 mg, most preferably 250 to 500
mg and in particular 300 to 400 mg. In another preferred
embodiment, the total amount of the second pharmacologically active
ingredient (A.sub.2) which is contained in the further segment
(S.sub.2) and the pharmaceutical dosage form, respectively, is
within the range of from 10 to 500 mg, more preferably 12 to 450
mg, still more preferably 14 to 400 mg, yet more preferably 16 to
350 mg, most preferably 18 to 325 mg and in particular 20 to 300
mg.
[0424] In a preferred embodiment, the second pharmacologically
active ingredient (A.sub.2) is contained in the further segment(s)
(S.sub.2) and the pharmaceutical dosage form, respectively, in an
amount of 7.5.+-.5 mg, 10.+-.5 mg, 20.+-.5 mg, 30.+-.5 mg, 40.+-.5
mg, 50.+-.5 mg, 60.+-.5 mg, 70.+-.5 mg, 80.+-.5 mg, 90.+-.5 mg,
100.+-.5 mg, 110.+-.5 mg, 120.+-.5 mg, 130.+-.5, 140.+-.5 mg,
150.+-.5 mg, 160.+-.5 mg, 170.+-.5 mg, 180.+-.5 mg, 190.+-.5 mg,
200.+-.5 mg, 210.+-.5 mg, 220.+-.5 mg, 230.+-.5 mg, 240.+-.5 mg, or
250.+-.5 mg. In another preferred embodiment, the second
pharmacologically active ingredient (A.sub.2) is contained in the
further segment(s) (S.sub.2) and the pharmaceutical dosage form,
respectively, in an amount of 5.+-.2.5 mg, 7.5.+-.2.5 mg, 10.+-.2.5
mg, 15.+-.2.5 mg, 20.+-.2.5 mg, 25.+-.2.5 mg, 30.+-.2.5 mg,
35.+-.2.5 mg, 40.+-.2.5 mg, 45.+-.2.5 mg, 50.+-.2.5 mg, 55.+-.2.5
mg, 60.+-.2.5 mg, 65.+-.2.5 mg, 70.+-.2.5 mg, 75.+-.2.5 mg,
80.+-.2.5 mg, 85.+-.2.5 mg, 90.+-.2.5 mg, 95.+-.2.5 mg, 100.+-.2.5
mg, 105.+-.2.5 mg, 110.+-.2.5 mg, 115.+-.2.5 mg, 120.+-.2.5 mg,
125.+-.2.5 mg, 130.+-.2.5 mg, 135.+-.2.5 mg, 140.+-.2.5 mg,
145.+-.2.5 mg, 150.+-.2.5 mg, 155.+-.2.5 mg, 160.+-.2.5 mg,
165.+-.2.5 mg, 170.+-.2.5 mg, 175.+-.2.5 mg, 180.+-.2.5 mg,
185.+-.2.5 mg, 190.+-.2.5 mg, 195.+-.2.5 mg, 200.+-.2.5 mg,
205.+-.2.5 mg, 210.+-.2.5 mg, 215.+-.2.5 mg, 220.+-.2.5 mg,
225.+-.2.5 mg, 230.+-.2.5 mg, 235.+-.2.5 mg, 240.+-.2.5 mg,
245.+-.2.5 mg, or 250.+-.2.5 mg. In still another preferred
embodiment, the second pharmacologically active ingredient
(A.sub.2) is contained in the further segment(s) (S.sub.2) and the
pharmaceutical dosage form, respectively, in an amount of 250.+-.10
mg, 275.+-.10 mg, 300.+-.10 mg, 325.+-.10 mg, 350.+-.10 mg,
375.+-.10 mg, 400.+-.10 mg, 425.+-.10 mg, 450.+-.10 mg, 475.+-.10
mg, 500.+-.10 mg, 525.+-.10 mg, 550.+-.10 mg, 575.+-.10 mg or
600.+-.10 mg.
[0425] In a particularly preferred embodiment, the second
pharmacologically active ingredient (A.sub.2) is paracetamol
(acetaminophen). In this embodiment, the paracetamol is preferably
contained in the further segment(s) (S.sub.2) or the pharmaceutical
dosage form in an amount of from 100 to 600 mg, more preferably 150
to 550 mg, still more preferably 200 to 500 mg, most preferably 250
to 450 mg and in particular 275 to 400 mg.
[0426] In another particularly preferred embodiment, the second
pharmacologically active ingredient (A.sub.2) is ibuprofen. In this
embodiment, the ibuprofen is preferably contained in the further
segment(s) (S.sub.2) or the pharmaceutical dosage form in an amount
of from 100 to 600 mg, more preferably 150 to 550 mg, still more
preferably 200 to 500 mg, most preferably 250 to 450 mg and in
particular 275 to 400 mg.
[0427] In a preferred embodiment, the relative weight ratio of the
total content of the first pharmacologically active ingredient
(A.sub.1) to the total content of the second pharmacologically
active ingredient (A.sub.2) [A.sub.1:A.sub.2] is within the range
of (8.+-.1):1, more preferably (7.+-.1):1, still more preferably
(6.+-.1):1, yet more preferably (5.+-.1):1, even more preferably
(4.+-.1):1, most preferably (3.+-.1):1 and in particular
(2.+-.1):1.
[0428] In still another preferred embodiment, the relative weight
ratio of the total content of the second pharmacologically active
ingredient (A.sub.2) to the total content of the first
pharmacologically active ingredient (A.sub.1) [A.sub.2:A.sub.1] is
within the range of (8.+-.1):1, more preferably (7.+-.1):1, still
more preferably (6.+-.1):1, yet more preferably (5.+-.1):1, even
more preferably (4.+-.1):1, most preferably (3.+-.1):1 and in
particular (2.+-.1):1.
[0429] The further segment(s) (S.sub.2) provide(s) immediate
release of the second pharmacologically active ingredient
(A.sub.2).
[0430] Preferably, under physiological conditions the
pharmaceutical dosage form has released after 5 minutes at least
10%, after 10 minutes at least 20%, after 15 minutes at least 30%,
after 20 minutes at least 40%, after 30 minutes at least 60%, after
40 minutes at least 70%, after 50 minutes at least 80%, after 60
minutes at least 90% or 99% of the second pharmacologically active
ingredient (A.sub.2).
[0431] Suitable in vitro conditions are known to the skilled
artisan. In this regard it can be referred to, e.g., the Eur. Ph.
Preferably, the release profile is measured under the following
conditions: Paddle apparatus equipped without sinker, 50 rpm,
37.+-.5.degree. C., 600 mL simulated intestinal fluid pH 6.8
(phosphate buffer) or pH 4.5. In a preferred embodiment, the
rotational speed of the paddle is increased to 75 rpm. In another
preferred embodiment, the release profile is determined under the
following conditions: basket method, 75 rpm, 37.+-.5.degree. C.,
600 mL 0.1 N HCl or 600 mL of SIF sp (pH 6.8) or 600 mL of 0.1 N
HCl+40% ethanol.
[0432] In a particularly preferred embodiment; under in vitro
conditions in 600 mL 0.1 N HCl, using the basket method according
to Ph. Eur. at 75 rpm, after 1 h under physiological conditions the
pharmaceutical dosage form has released at least 60% more
preferably at least 65%, still more preferably at least 70%, yet
more preferably at least 75%, even more preferably at least 80%,
most preferably at least 85% and in particular at least 90% or at
least 95% or at least 99% of the second pharmacologically active
ingredient (A.sub.2) relative to the total amount of A.sub.2
originally contained in the pharmaceutical dosage form.
[0433] Preferably, the content of the further segment(s) (S.sub.2)
is at least 2.5 wt.-%, at least 5 wt.-%, at least 7.5 wt.-% or at
least 10 wt.-%; at least 12.5 wt.-%, at least 15 wt.-%, at least
17.5 wt.-% or at least 20 wt.-%; at least 22.5 wt.-%, at least 25
wt.-%, at least 27.5 wt.-% or at least 30 wt.-%; at least 32.5
wt.-%, at least 35 wt.-%, at least 37.5 wt.-% or at least 40 wt.-%;
more preferably at least 42.5 wt.-%, at least 45 wt.-%, at least
47.5 wt.-% or at least 50 wt.-%; still more preferably at least
52.5 wt.-%, at least 55 wt.-%, at least 57.5 wt.-% or at least 60
wt.-%; yet more preferably at least 62.5 wt.-%, at least 65 wt.-%,
at least 67.5 wt.-% or at least 60 wt.-%; most preferably at least
72.5 wt.-%, at least 75 wt.-%, at least 77.5 wt.-% or at least 70
wt.-%; and in particular at least 82.5 wt.-%, at least 85 wt.-%, at
least 87.5 wt.-% or at least 90 wt.-%; based on the total weight of
the pharmaceutical dosage form.
[0434] Preferably, the content of the further segment(s) (S.sub.2)
is at most 90 wt.-%, at most 87.5 wt.-%, at most 85 wt.-%, or at
most 82.5 wt.-%; more preferably at most 80 wt.-%, at most 77.5
wt.-%, at most 75 wt.-% or at most 72.5 wt.-%; still more
preferably at most 70 wt.-%, at most 67.5 wt.-%, at most 65 wt.-%
or at most 62.5 wt.-%; yet more preferably at most 60 wt.-%, at
most 57.5 wt.-%, at most 55 wt.-% or at most 52.5 wt.-%; most
preferably at most 50 wt.-%, at most 47.5 wt.-%, at most 45 wt.-%
or at most 42.5 wt.-%; and in particular at most 40 wt.-%, at most
37.5 wt.-%, or at most 35 wt.-%; based on the total weight of the
pharmaceutical dosage form.
[0435] Preferably, the relative weight ratio of the formed
segment(s) (S.sub.1) to the further segment(s) (S.sub.2) in the
pharmaceutical dosage form is from 1:10 to 10:1, more preferably
1:8 to 8:1, still more preferably 1:7 to 6:1, even more preferably
1:6 to 5:1, yet more preferably 1:5 to 4:1, most preferably 1:4 to
3:1 and in particular 1:3 to 2:1 or 1:2 to 1:1, based on the total
weight of the formed segment(s) (S.sub.1) and on the total weight
of the further segments (S.sub.2).
[0436] The further segment(s) (S.sub.2) may optionally comprise
conventional pharmaceutical excipients.
[0437] Preferably, the further segment(s) (S.sub.2) comprise(s) one
or more fillers or binders. As many fillers can be regarded as
binders and vice versa, for the purpose of the specification
"filler/binder" refers to any excipient that is suitable as filler,
binder or both. Thus, the further segment(s) (S.sub.2) preferably
comprise(s) a filler/binder.
[0438] Preferred fillers (=filler/binders) are selected from the
group consisting of silicium dioxide (e.g. Aerosel.RTM.),
microcrystalline cellulose (e.g. Avicel.RTM., Elcema.RTM.,
Emocel.RTM., ExCel.RTM., Vitacell.RTM.); cellulose ether (e.g.
Natrosol.RTM., Klucel.RTM., Methocel.RTM., Blanose.RTM.,
Pharmacoat.RTM., Viscontran.RTM.); mannitol; dextrines; dextrose;
calciumhydrogen phosphate (e.g. Emcompress.RTM.); tricalcium
phosphate, maltodextrine (e.g. Emdex.RTM.); lactose (e.g. Fast-Flow
Lactose.RTM.; Ludipress.RTM., Pharmaceutical dosage formtose.RTM.,
Zeparox.RTM.); polyvinylpyrrolidone (PVP) (e.g. Kollidone.RTM.,
Polyplasdone.RTM., Polydone.RTM.); saccharose (e.g. Nu-Tab.RTM.,
Sugar Tab.RTM.); magnesium salts (e.g. MgCO.sub.3, MgO,
MgSiO.sub.3); starches and pretreated starches (e.g. Prejel.RTM.,
Primotab.RTM. ET, Starch.RTM. 1500). Preferred binders are selected
from the group consisting of alginates; chitosanes; and any of the
fillers mentioned above (=fillers/binders).
[0439] Some fillers/binders may also serve other purposes. It is
known, for example, that silicium dioxide exhibits excellent
function as a glidant. Preferably, the further segment(s) (S.sub.2)
comprise(s) a glidant such as silicium dioxide.
[0440] In a preferred embodiment, the content of the filler/binder
or mixture of fillers/binders in the further segment(s) (S.sub.2)
is within the range of 50.+-.25 wt.-%, more preferably 50.+-.20
wt.-%, still more preferably 50.+-.15 wt.-%, yet more preferably
50.+-.10 wt.-%, most preferably 50.+-.7.5 wt.-%, and in particular
50.+-.5 wt.-%, based on the total weight of further segment(s)
(S.sub.2). In another preferred embodiment, the content of the
filler/binder or mixture of fillers/binders in the further
segment(s) (S.sub.2) is within the range of 65.+-.25 wt.-%, more
preferably 65.+-.20 wt.-%, still more preferably 65.+-.15 wt.-%,
yet more preferably 65.+-.10 wt.-%, most preferably 65.+-.7.5
wt.-%, and in particular 65.+-.5 wt.-%, based on the total weight
of further segment(s) (S.sub.2). In still another preferred
embodiment, the content of the filler/binder or mixture of
fillers/binders in further segment(s) (S.sub.2) is within the range
of 80.+-.19 wt.-%, more preferably 80.+-.17.5 wt.-%, still more
preferably 80.+-.15 wt.-%, yet more preferably 80.+-.10 wt.-%, most
preferably 80.+-.7.5 wt.-%, and in particular 80.+-.5 wt.-%, based
on the total weight of further segment(s) (S.sub.2). In another
preferred embodiment, the content of the filler/binder or mixture
of fillers/binders in the further segment(s) (S.sub.2) is within
the range of 90.+-.9 wt.-%, more preferably 90.+-.8 wt.-%, still
more preferably 90.+-.7 wt.-%, yet more preferably 90.+-.6 wt.-%,
most preferably 90.+-.5 wt.-%, and in particular 90.+-.4 wt.-%,
based on the total weight of further segment(s) (S.sub.2).
[0441] In a preferred embodiment, the total content of the
filler/binder or mixture of fillers/binders in the pharmaceutical
dosage form is within the range of 25.+-.24 wt.-%, more preferably
25.+-.20 wt.-%, still more preferably 25.+-.16 wt.-%, yet more
preferably 25.+-.12 wt.-%, most preferably 25.+-.8 wt.-%, and in
particular 25.+-.4 wt.-%, based on the total weight of
pharmaceutical dosage form. In another preferred embodiment, the
total content of the filler/binder or mixture of fillers/binders in
the pharmaceutical dosage form is within the range of 30.+-.29
wt.-%, more preferably 30.+-.25 wt.-%, still more preferably
30.+-.20 wt.-%, yet more preferably 30.+-.15 wt.-%, most preferably
30.+-.10 wt.-%, and in particular 30.+-.5 wt.-%, based on the total
weight of pharmaceutical dosage form. In still another preferred
embodiment, the total content of the filler/binder or mixture of
fillers/binders in the pharmaceutical dosage form is within the
range of 35.+-.34 wt.-%, more preferably 35.+-.28 wt.-%, still more
preferably 35.+-.22 wt.-%, yet more preferably 35.+-.16 wt.-%, most
preferably 35.+-.10 wt.-%, and in particular 35.+-.4 wt.-%, based
on the total weight of pharmaceutical dosage form. In another
preferred embodiment, the total content of the filler/binder or
mixture of fillers/binders in the pharmaceutical dosage form is
within the range of 40.+-.39 wt.-%, more preferably 40.+-.32 wt.-%,
still more preferably 40.+-.25 wt.-%, yet more preferably 40.+-.18
wt.-%, most preferably 40.+-.11 wt.-%, and in particular 40.+-.4
wt.-%, based on the total weight of pharmaceutical dosage form.
[0442] Preferably, the filler/binder is contained in the further
segment(s) (S.sub.2) but not in the formed segment(s) (S.sub.1) of
the pharmaceutical dosage form according to the invention.
[0443] Preferably, the further segment(s) (S.sub.2) comprise(s) one
or more diluents or lubricants, preferably selected from the group
consisting of calcium stearate; magnesium stearate; glycerol
monobehenate (e.g. Compritol.RTM.); Myvatex.RTM., Precirol.RTM.,
Precirol.RTM. Ato5; sodium stearylfumarate (e.g. Pruv.RTM.); and
talcum. Magnesium stearate is particularly preferred. Preferably,
the content of the lubricant in the further segment(s) (S.sub.2) is
at most 10.0 wt.-%, more preferably at most 7.5 wt.-%, still more
preferably at most 5.0 wt.-%, yet more preferably at most 2.0
wt.-%, even more preferably at most 1.0 wt.-%, and most preferably
at most 0.5 wt.-%, based on the total weight of the further
segment(s) (S.sub.2) or based on the total weight of pharmaceutical
dosage form.
[0444] Preferably, the further segment(s) (S.sub.2) comprise(s) one
or more disintegrants, preferably selected from the group
consisting of carmellose and salts thereof, croscarmellose sodium,
crospovidone, sodium carboxymethyl starch, sodium starch glycolate,
partly pregelatinized starch and low-substituted hydroxypropyl
cellulose. Crosscarmellose is particularly preferred. Preferably,
the content of the disintegrant in the further segment(s) (S.sub.2)
is at most 20.0 wt.-%, more preferably at most 15 wt.-%, still more
preferably at most 12.5 wt.-%, yet more preferably at most 10
wt.-%, even more preferably at most 8.0 wt.-%, and most preferably
within the range of from 6.0 wt.-% to 8.0 wt.-%, based on the total
weight of the further segment(s) (S.sub.2) or based on the total
weight of pharmaceutical dosage form.
[0445] Preferably, the further segment(s) (S.sub.2) comprise(s) one
or more dispersing agents or a wetting agents, preferably selected
from the group consisting of poloxamers such as Lutrol F68.
Preferably, the content of the dispersing agent or a wetting agent
in the further segment(s) (S.sub.2) is at most 50 wt.-%, more
preferably at most 45 wt.-%, still more preferably at most 40
wt.-%, yet more preferably at most 35 wt.-%, even more preferably
at most 30 wt.-%, and most preferably within at most 30 wt.-%,
based on the total weight of the further segment(s) (S.sub.2) or
based on the total weight of pharmaceutical dosage form.
[0446] In particularly preferred embodiment, the further segment(s)
(S.sub.2) comprise(s) a combination of filler/binder and lubricant
and optionally disintegrant and optionally dispersing agent/wetting
agent.
[0447] The further segment(s) (S.sub.2) of the pharmaceutical
dosage form according to the invention may additionally contain
other excipients that are conventional in the art, e.g. diluents,
binders, granulating aids, colorants, flavourants, glidants,
wet-regulating agents and disintegrants. The skilled person will
readily be able to determine appropriate quantities of each of
these excipients.
[0448] In a preferred embodiment, however, besides the second
pharmacologically active ingredient (A.sub.2), the further
segment(s) (S.sub.2) of the pharmaceutical dosage form according to
the invention consists of one or more disintegrants, one or more
filler/binder's and one or more lubricants, but does not contain
any other constituents.
[0449] In a particularly preferred embodiment, the further
segment(s) (S.sub.2) of the pharmaceutical dosage form according to
the invention do(es) not contain one or more gel-forming agents
and/or a silicone.
[0450] In a preferred embodiment, the further segment(s) (S.sub.2)
of the pharmaceutical dosage form according to the invention do(es)
not contain polyalkylene oxides, acrylic polymers or waxy
materials. If the further segment(s) (S.sub.2) contain(s)
polyalkylene oxides, acrylic polymers and/or waxy materials, the
total content of polyalkylene oxides, acrylic polymers and waxy
materials preferably is not more than 30 wt.-%, more preferably not
more than 25 wt.-%, still more preferably not more than 20 wt.-%,
yet more preferably not more than 15 wt.-%, even more preferably
not more than 10 wt.-%, most preferably not more than 5.0 wt.-%,
and in particular not more than 1.0 wt.-%, relative to the total
weight of the further segment(s) (S.sub.2).
[0451] As used herein the term "gel-forming agent" is used to refer
to a compound that, upon contact with a solvent (e.g. water),
absorbs the solvent and swells, thereby forming a viscous or
semi-viscous substance. Preferred gel-forming agents are not
cross-linked. This substance may moderate pharmacologically active
ingredient release from the embedded particulates in both aqueous
and aqueous alcoholic media. Upon full hydration, a thick viscous
solution or dispersion is typically produced that significantly
reduces and/or minimizes the amount of free solvent which can
contain an amount of solubilized pharmacologically active
ingredient, and which can be drawn into a syringe. The gel that is
formed may also reduce the overall amount of pharmacologically
active ingredient extractable with the solvent by entrapping the
pharmacologically active ingredient within a gel structure. Thus
the gel-forming agent may play an important role in conferring
tamper-resistance to the pharmaceutical dosage forms according to
the invention.
[0452] Gel-forming agents that preferably are not contained in the
further segment(s) (S.sub.2) include pharmaceutically acceptable
polymers, typically hydrophilic polymers, such as hydrogels.
Representative examples of gel-forming agent include polyalkylene
oxide such as polyethylene oxide, polyvinyl alcohol,
hydroxypropylmethyl cellulose, carbomers, poly(uronic) acids and
mixtures thereof.
[0453] The optional excipients preferably do not impart to the
further segment(s) (S.sub.2) any significant resistance against
dose-dumping in aqueous ethanol. According to this embodiment, the
further segment(s) (S.sub.2) preferably do(es) not contain any
compound which would impart to the further segment(s) (S.sub.2) any
substantial resistance against dose-dumping in aqueous ethanol such
as polyalkylene oxides, nonionic acrylic polymers or waxy
materials.
[0454] The formed segment(s) (S.sub.1) may be incorporated in an
outer matrix material formed by the further segment(s) (S.sub.2).
From a macroscopic perspective, the outer matrix material formed by
the further segment(s) (S.sub.2) preferably forms a continuous
phase in which the formed segment(s) (S.sub.1) is/are embedded.
When the formed segments (S.sub.1) are particulate, the particles
preferably form a discontinuous phase within an outer matrix
material that is formed by further segment (S.sub.2).
[0455] For the purpose of definition, the "outer matrix material"
is preferably the further segment (S.sub.2) and thus, preferably
comprises the second pharmacologically active ingredient (A.sub.2)
and optionally conventional pharmaceutical excipients which have
already been described above.
[0456] In a preferred embodiment, the further segment(s) (S.sub.2)
essentially consist(s) of the second pharmacologically active
ingredient (A.sub.2), i.e. the further segment(s) (S.sub.2) do(es)
not comprise any pharmaceutical excipient. According to this
embodiment, the pharmaceutical dosage form is preferably a capsule
that is filled with the formed segment(s) (S.sub.1) and the second
pharmacologically active ingredient (A.sub.2), which may be powdery
or agglomerated, e.g. granulated, and which preferably forms a
further segment (S.sub.2) as an outer matrix material.
[0457] Preferably, the outer matrix material is a homogenous
powdery or coherent mass, preferably a homogeneous mixture of solid
constituents, in which the monolithic or particulate formed
segment(s) (S.sub.1) is/are embedded. According to this embodiment,
when the formed segment (S.sub.1) is particulate, the particulate
formed segments (S.sub.1) are preferably spatially separated from
one another. While it is possible that the surfaces of particulate
formed segments (S.sub.1) are in contact or at least in very close
proximity with one another, the plurality of particulate formed
segments (S.sub.1) preferably cannot be regarded as a single
continuous coherent mass within the pharmaceutical dosage form.
[0458] In other words, when the formed segments (S.sub.1) are
particulate and the particles are contained in an outer matrix
material formed by the further segments (S.sub.2), the
pharmaceutical dosage form according to the invention preferably
comprises the particles of the formed segment (S.sub.1) as volume
elements of a first type and the outer matrix material formed by
the further segment (S.sub.2) as volume element of a second type
differing from the material that forms the particles of the formed
segment (S.sub.1), and preferably containing no prolonged release
matrix.
[0459] When the formed segment(s) (S.sub.1) is/are contained in an
outer matrix material formed by the further segment (S.sub.2), the
relative weight ratio of the monolith or the particles of the
formed segment(s) (S.sub.1) to the outer matrix material is not
particularly limited. Preferably, said relative weight ratio is
within the range of 1:2.00.+-.1.75, more preferably 1:2.00.+-.1.50,
still more preferably 1:1.00.+-.1.00, most preferably
1:1.00.+-.0.75, and in particular 1:1.00.+-.0.50.
[0460] The further segment (S.sub.2) in turn may also be in
particulate form. When the further segment (S.sub.2) is particulate
form, however, the particles are preferably not thermoformed and
preferably do not contain synthetic or natural polymer (C). When
the further segment (S.sub.2) is in particulate form, the particles
are preferably obtained by conventional methods for the preparation
of aggregates and agglomerates from powder mixtures such as
granulating and compacting.
[0461] The further segment(s) (S.sub.2) exhibit(s) a breaking
strength that is lower than that of formed segment(s) (S.sub.1).
Typically, the breaking strength of further segment(s) is not
increased compared to the breaking strength of conventional dosage
forms, i.e. well below 200 N. When the further segment(s) (S.sub.2)
are powdery, the "breaking strength" of the powder is so low that
it cannot be measured by conventional means. Thus, for the purpose
of specification, the breaking strength of the powder should be
regarded as "0 Newton". When quantifying the breaking strength of
the further segment(s) (S.sub.2) by "0 Newton", the further
segment(s) is/are typically present in form of a (free-flowing)
powder, and when quantifying the breaking strength of the further
segment(s) (S.sub.2) by values above "0 Newton", this implies that
according to these embodiments the further segment(s) (S.sub.2)
is/are at least to some minimal degree present in form of
granulated, compacted, congealed or otherwise agglomerated matter,
but not as a (free-flowing) powder.
[0462] In a preferred embodiment, the further segment(s) (S.sub.2)
exhibit(s) a breaking strength within the range of from 0 N to at
most 500 N. Preferably, the further segment(s) (S.sub.2) exhibit(s)
a breaking strength within the range of from 0 N to 450 N, more
preferably 0 N to 400 N, still more preferably 0 N to 350 N, yet
more preferably 0 N to 300 N, most preferably 0 N to 250 N and in
particular 0 N to 200 N.
[0463] The at least one formed segment (S.sub.1) of the
pharmaceutical dosage form exhibits a higher breaking strength than
the at least one further segment (S.sub.2) of the pharmaceutical
dosage form.
[0464] Preferably, the breaking strength of the formed segment(s)
(S.sub.1) is relatively at least 50 N higher, more preferably at
least 100 N higher, still more preferably at least 150 N higher,
yet more preferably at least 200 N higher, even more preferably at
least 250 N higher, most preferably at least 300 N higher, and in
particular at least 350 N higher than the breaking strength of the
further segment(s) (S.sub.2).
[0465] In a preferred embodiment, the further segment (S.sub.2)
exhibits a breaking strength of at most 500 N, more preferably at
most 300 N, still more preferably at most 250 N, yet more
preferably at most 200 N, even more preferably at most 150 N, most
preferably at most 100 N, and in particular at most 50 N.
[0466] According to this embodiment, the second pharmacologically
active ingredient (A.sub.2) preferably does not have potential for
being abused; more preferably, the second pharmacologically active
ingredient (A.sub.2) is selected from ATC classes [M01A], [M01 C],
[N02B] and [N02C] according to the WHO; and most preferably, the
second pharmacologically active ingredient (A.sub.2) is selected
from paracetamol and ibuprofen.
[0467] In general, it is very difficult to provide any segment
exhibiting a high breaking strength, preferably such a high
breaking strength that crushing of the segment is impeded, while at
the same time providing immediate release of a pharmacologically
active ingredient contained in said segment. This is because the
breaking strength typically relies on the presence of polymers that
act as release matrix material slowing down the release of the
pharmacologically active ingredient. Therefore, it is only
meaningful to provide a segment exhibiting a combination of a high
breaking strength and immediate release of the pharmacologically
active ingredient contained therein when said pharmacologically
active ingredient has a potential for being abused.
[0468] In a preferred embodiment, [0469] (i) the formed segment
(S.sub.1) exhibits a breaking strength of preferably at least 750
N, more preferably at least 1000 N, most preferably at least 1250
N, and in particular at least 1500 N; and/or [0470] (ii) the
further segment (S.sub.2) exhibits a breaking strength of at most
500 N, more preferably at most 300 N, still more preferably at most
250 N, yet more preferably at most 200 N, even more preferably at
most 150 N, most preferably at most 100 N, and in particular at
most 50 N.
[0471] Because of the different breaking strength of the formed
segment(s) (S.sub.1) and the further segment(s) (S.sub.2), when
measuring the breaking strength of the pharmaceutical dosage form
according to the invention, a distance-to-force diagram can be
obtained that contains at least two steps; the first platform in
the distance-to-force diagram is reached once the further
segment(s) (S.sub.2) fracture and the second platform in the
distance-to-force diagram is reached once the formed segment(s)
(S.sub.1) fracture. When the further segment (S.sub.2) is present
in powdery form, however, the "first platform" corresponds to the
baseline, i.e. is not visible. Furthermore, depending upon the
upper measuring limit of the breaking strength tester, the formed
segment(s) (S.sub.1) might not have fractured once said upper limit
is reached.
[0472] In a preferred embodiment, the at least one formed segment
(S.sub.1) of the pharmaceutical dosage form exhibits a higher
breaking strength than the overall pharmaceutical dosage form
comprising the formed segment(s) (S.sub.1) and the further
segment(s) (S.sub.2). According to this embodiment, the breaking
strength of the pharmaceutical dosage form is preferably defined as
the amount of force that is necessary in order to fracture a
pharmaceutical dosage form into two or more fragments, wherein said
fragments preferably contain the still intact formed segment(s)
(S.sub.1).
[0473] Preferably, the breaking strength of the formed segment(s)
(S.sub.1) is relatively at least 50 N higher, more preferably at
least 100 N higher, still more preferably at least 150 N higher,
yet more preferably at least 200 N higher, even more preferably at
least 250 N higher, most preferably at least 300 N higher, and in
particular at least 350 N higher than the breaking strength of the
pharmaceutical dosage form comprising the formed segment(s)
(S.sub.1) and the further segment(s) (S.sub.2).
[0474] Another aspect of the invention relates to a process for the
production of a pharmaceutical dosage form comprising the steps of
[0475] (i) thermoforming at least one formed segment (S.sub.1)
comprising a first pharmacologically active ingredient (A.sub.1)
and a natural or synthetic polymer (C);
[0476] (ii) providing at least one further segment (S.sub.2)
comprising a second pharmacologically active ingredient (A.sub.2);
and [0477] (iii) combining the at least one formed segment
(S.sub.1), the at least one further segment (S.sub.2) and
optionally further excipients.
[0478] In a preferred embodiment, the formed segment(s) (S.sub.1)
is/are thermoformed. According to this embodiment, the formed
segment(s) (S.sub.1) is/are preferably melt-extruded. Further
according to this embodiment, the formed segment(s) (S.sub.1)
is/are preferably monolithic or particulate.
[0479] Thermoforming preferably means that in the course of the
manufacture of the formed segment(s) (S.sub.1) the mass is heated
to a temperature above ambient temperature, preferably to at least
30.degree. C., at least 40.degree. C., at least 50.degree. C., at
least 60.degree. C., at least 70.degree. C., or at least 80.degree.
C., and compressed, preferably at pressures that are sufficient to
yield a coherent, not dripping form, preferably at pressures of at
least 10 bar or at least 30 bar. The compression force may be
exerted prior to, during or subsequent to application of heat.
[0480] The formed segment(s) (S.sub.1) is/are preferably
thermoformed, preferably by melt-extrusion, although also other
methods of thermoforming may be useful, such as press-molding at
elevated temperature or heating of compacts that were manufactured
by conventional compression in a first step and then heated above
the softening temperature of the prolonged release matrix material
in a second step to form break resistant, hardened compacts, i.e.
monolithic formed segment(s) (S.sub.1). In this regard,
thermoforming preferably means the forming, or molding of a mass
after, before or during the application of heat. In a preferred
embodiment, thermoforming is performed by hot-melt extrusion.
[0481] In a preferred embodiment, hot melt-extrusion is performed
by means of a twin-screw-extruder. Melt extrusion preferably
provides a melt-extruded strand that is preferably cut into
monoliths, which are then optionally compressed and formed.
Preferably, compression is achieved by means of 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.
[0482] 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. This cutting can be performed by usual
techniques, for example using rotating knives or compressed air, at
elevated temperature, e.g. when the extruded stand is still warm
due to hot-melt extrusion, or at ambient temperature, i.e. after
the extruded strand has been allowed to cool down. When the
extruded strand is still warm, singulation of the extruded strand
into extruded monoliths and particles, respectively, is preferably
performed by cutting the extruded strand immediately after it has
exited the extrusion die.
[0483] However, when the extruded strand is cut in the cooled
state, subsequent singulation of the extruded strand is preferably
performed by optionally transporting the still hot extruded strand
by means of conveyor belts, allowing it to cool down and to
congeal, and subsequently cutting it. Alternatively, the shaping
can take place as described in EP-A 240 906 by the extrudate being
passed between two counter-rotating calender rolls and being shaped
directly to the formed segment (S.sub.1). 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 means of a twin-screw extruder.
[0484] The preferably monolithic or particulate formed segment
(S.sub.1) according to the invention may be produced by different
processes, the particularly preferred of which are explained in
greater detail below. Several suitable processes have already been
described in the prior art. In this regard 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, WO
2006/082097, and WO 2006/082099.
[0485] In general, the process for the production of the preferably
monolithic or particulate formed segment (S.sub.1), according to
the invention preferably comprises the following steps: [0486] (a)
mixing all ingredients; [0487] (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 the prolonged
release matrix material, preferably the natural or synthetic
polymer (C), up to its softening point; [0488] (c) hardening the
mixture by applying heat and force, it being possible to supply the
heat during and/or before and/or after the application of force and
the quantity of heat supplied being sufficient to heat the
prolonged release matrix material, preferably the natural or
synthetic polymer (C), at least up to its softening point; and
thereafter allowing the material to cool and removing the force;
[0489] (d) optionally singulating the hardened mixture; [0490] (e)
optionally shaping the monoliths or particles; and [0491] (f)
optionally providing a film coating.
[0492] Heat may be supplied directly, e.g. by contact or by means
of hot gas such as hot air, or with the assistance of ultrasound;
or is indirectly supplied by friction and/or shear. Force may be
applied and/or the monoliths or particles may be shaped for example
by direct formed segment (S.sub.1) forming or with the assistance
of a suitable extruder, particularly by means of a screw extruder
equipped with one or two screws (single-screw-extruder and
twin-screw-extruder, respectively) or by means of a planetary gear
extruder.
[0493] The final shape of the monoliths and particles,
respectively, 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
the prolonged release matrix material. However, extrusion at lower
temperatures, e.g. ambient temperature, is also possible and may be
preferred.
[0494] Shaping can be performed, e.g., by means of a forming press
comprising die and punches of appropriate shape.
[0495] A particularly preferred process for the manufacture of the
formed segment(s) (S.sub.1) according to the invention involves
hot-melt extrusion. In this process, the formed segment(s)
(S.sub.1) is/are produced by thermoforming with the assistance of
an extruder, preferably without there being any observable
consequent discoloration of the extrudate.
[0496] This process is preferably characterized in that [0497] a)
all components are mixed, [0498] b) the resultant mixture is heated
in the extruder at least up to the softening point of the prolonged
release matrix material and extruded through the outlet orifice of
the extruder by application of force, [0499] c) the still plastic
extrudate is singulated and formed into the monoliths or particles
of the formed segment (S.sub.1), or [0500] d) the cooled and
optionally reheated singulated extrudate is formed into the
monoliths or particles of the formed segment (S.sub.1),
respectively.
[0501] Mixing of the components according to process step a) may
also proceed in the extruder.
[0502] The components 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.
[0503] The, preferably molten, mixture which has been heated in the
extruder at least up to the softening point of prolonged release
matrix material is extruded from the extruder through a die with at
least one bore.
[0504] The hot-melt extrusion 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.
[0505] In a preferred embodiment, 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.
[0506] In another preferred embodiment, particularly when the
prolonged release matrix material is employed in the form of an
aqueous dispersion, extrusion is performed in the presence of water
and the water is evaporated from the extruded material in the
course of the extrusion process, i.e. preferably before the
extruded material exits the outlet orifice of the extruder.
Therefore a vacuum pump mechanism is used to extract the
(evaporated) water from the extruded material. Thus, the extruded
strand is preferably water-free, which preferably means that the
water content of the extruded strand is preferably at most 10
wt.-%, or at most 7.5 wt.-%, or at most 5.0 wt.-%, or at most 4.0
wt.-%, or at most 3.0 wt.-%, or at most 2.0 wt.-%, more preferably
at most 1.7 wt.-%, still more preferably at most 1.5 wt.-%, yet
more preferably at most 1.3 wt.-%, even more preferably at most 1.0
wt.-%, most preferably at most 0.7 wt.-%, and in particular at most
0.5 wt.-%. For that purpose, extrusion is preferably performed at a
temperature above the boiling point of water under the given
conditions; when extrusion is performed under vacuum, the boiling
point of water may be substantially below 100.degree. C. However,
even if extrusion is performed under vacuum the preferred extrusion
temperature is above 100.degree. C.
[0507] The extruder preferably comprises at least two temperature
zones, with heating of the mixture at least up to the softening
point of the prolonged release matrix material proceeding in the
first zone, which is downstream from a feed zone and optionally
mixing zone. The throughput of the mixture is preferably from 1.0
kg to 15 kg/hour. In a preferred embodiment, the throughtput is
from 0.2 kg/hour to 3.5 kg/hour. In another preferred embodiment,
the throughtput is from 4 to 15 kg/hour.
[0508] In a preferred embodiment, the die head pressure is within
the range of from 0.5 to 200 bar. The die head pressure can be
adjusted inter alia by die geometry, temperature profile, extrusion
speed, number of bores in the dies, screw configuration, first
feeding steps in the extruder, and the like.
[0509] In a preferred embodiment, the die head pressure is within
the range of from 20.+-.19 bar, more preferably 20.+-.15 bar, and
in particular 20.+-.10 bar; or the die head pressure is within the
range of from 30.+-.20 bar, more preferably 30.+-.15 bar, and in
particular 30.+-.10 bar; or the die head pressure is within the
range of from 40.+-.20 bar, more preferably 40.+-.15 bar, and in
particular 40.+-.10 bar; or the die head pressure is within the
range of from 50.+-.20 bar, more preferably 50.+-.15 bar, and in
particular 50.+-.10 bar; or the die head pressure is within the
range of from 60.+-.20 bar, more preferably 60.+-.15 bar, and in
particular 60.+-.10 bar; or the die head pressure is within the
range of from 70.+-.20 bar, more preferably 70.+-.15 bar, and in
particular 70.+-.10 bar; or the die head pressure is within the
range of from 80.+-.20 bar, more preferably 80.+-.15 bar, and in
particular 80.+-.10 bar; or the die head pressure is within the
range of from 90.+-.20 bar, more preferably 90.+-.15 bar, and in
particular 90.+-.10 bar; or the die head pressure is within the
range of from 100.+-.20 bar, more preferably 100.+-.15 bar, and in
particular 100.+-.10 bar.
[0510] The die geometry or the geometry of the bores is freely
selectable. The die or the bores may accordingly exhibit a flat
(film), round, oblong or oval cross-section, wherein the round
cross-section preferably has a diameter of 0.1 mm to 2 mm for
extruded particles and a larger diameter for extruded monolithic
pharmaceutical dosage forms. 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
the prolonged release matrix material and does not rise above a
temperature at which the pharmacologically active ingredient 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 prolonged release matrix material. Typical extrusion
temperatures are 120.degree. C. and 150.degree. C.
[0511] In a preferred embodiment, the extruder torque is within the
range of from 30 to 95%. Extruder torque can be adjusted inter alia
by die geometry, temperature profile, extrusion speed, number of
bores in the dies, screw configuration, first feeding steps in the
extruder, and the like.
[0512] 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, wires, blades or with the assistance of laser cutters.
[0513] Preferably, intermediate or final storage of the optionally
singulated extrudate or the final shape of the monoliths or
particles of the formed segment (S.sub.1) is performed under
oxygen-free atmosphere which may be achieved, e.g., by means of
oxygen-scavengers.
[0514] The singulated extrudate may be press-formed in order to
impart the final shape to the monolithic or particulate formed
segment(s) (S.sub.1).
[0515] 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 desired
mechanical properties, may be established by simple preliminary
testing.
[0516] For example but not limiting, extrusion may be performed by
means of a twin-screw-extruder type ZSE 18 or ZSE27 (Leistritz,
Nurnberg, Germany), screw diameters of 18 or 27 mm. Screws having
eccentric or blunt ends may be used. A heatable die with a round
bore or with a multitude of bores each having a diameter of 0.2,
0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0 or 0.6
mm may be used. The extrusion parameters may be adjusted e.g. to
the following values: rotational speed of the screws: 120 Upm;
delivery rate 2 kg/h for a ZSE 18 or 8 kg/h for a ZSE27; product
temperature: in front of die 125.degree. C. and behind die
135.degree. C.; and jacket temperature: 110.degree. C. Another
suitable extruder that is equipped with a vacuum pump is a Thermo
Scientific* Pharma 16 TAME hot melt twin-screw extruder.
[0517] Preferably, extrusion is performed by means of
twin-screw-extruders or planetary-gear-extruders, twin-screw
extruders (co-rotating or contra-rotating) being particularly
preferred.
[0518] The preferably monolithic or particulate formed segment(s)
(S.sub.1) according to the invention is preferably produced by
thermoforming with the assistance of an extruder without any
observable consequent discoloration of the extrudates.
[0519] The process for the preparation of the preferably monolithic
or particulate formed segment (S.sub.1) according to the invention
is preferably performed continuously. Preferably, the process
involves the extrusion of a homogeneous mixture of all components.
It is particularly advantageous if the thus 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.
[0520] Preferably, the formed segment(s) (S.sub.1) is/are
monolithic or particulate, preferably oligoparticular or
multiparticulate, and the monolith or particles according to the
invention can be regarded as "extruded pellet(s)". The term
"extruded pellets" has structural implications which are understood
by persons skilled in the art. A person skilled in the art knows
that pelletized segments or pharmaceutical dosage forms can be
prepared by a number of techniques, including: [0521] drug layering
on nonpareil sugar or microcrystalline cellulose beads, [0522]
spray drying, [0523] spray congealing, [0524] rotogranulation,
[0525] hot-melt extrusion, [0526] spheronization of low melting
materials, or [0527] extrusion-spheronization of a wet mass.
[0528] Accordingly, "extruded pellets" can be obtained either by
hot-melt extrusion or by extrusion-spheronization.
[0529] "Extruded pellets" can be distinguished from other types of
pellets because they are structurally different. For example, drug
layering on nonpareils yields multilayered pellets having a core,
whereas extrusion typically yields a monolithic mass comprising a
homogeneous mixture of all ingredients. Similarly, spray drying and
spray congealing typically yield spheres, whereas extrusion
typically yields cylindrical extrudates which can be subsequently
spheronized.
[0530] The structural differences between "extruded pellets" and
"agglomerated pellets" are significant because they may affect the
release of active substances from the pellets and consequently
result in different pharmacological profiles. Therefore, a person
skilled in the pharmaceutical formulation art would not consider
"extruded pellets" to be equivalent to "agglomerated pellets".
[0531] The pharmaceutical dosage forms according to the invention
may be prepared from the formed segment(s) (S.sub.1) and the
further segment(s) (S.sub.2) by any conventional method.
[0532] When the pharmaceutical dosage forms are prepared by
compression, the particles or monoliths of the formed segment(s)
(S.sub.1), are preferably mixed, e.g. blended and/or granulated
(e.g. wet granulated), with the material of the further segment(s)
(S.sub.2) as outer matrix material and the resulting mix (e.g.
blend or granulate) is then either filled in capsules or
compressed, preferably in molds, to form pharmaceutical dosage
forms. It is also envisaged that the monoliths or particles herein
described may be incorporated into a matrix using other processes,
such as by melt granulation (e.g. using fatty alcohols and/or
water-soluble waxes and/or water-insoluble waxes) or high shear
granulation, followed by compression.
[0533] When the pharmaceutical dosage forms according to the
invention are manufactured by means of an eccentric press, the
compression force is preferably within the range of from 5 to 15
kN. When the pharmaceutical dosage forms according to the invention
are manufactured by means of a rotating press, the compression
force is preferably within the range of from 5 to 40 kN, in certain
embodiments >25 kN, in other embodiments about 13 kN.
[0534] Another aspect of the invention relates to a pharmaceutical
dosage for that is obtainable by any of the methods described
above.
[0535] Examples of pharmaceutical dosage forms according to the
invention include, but are not limited to, capsules, tablets,
pills, granules, pellets, films, sachets and effervescent, powders,
and the like.
[0536] In a preferred embodiment, the pharmaceutical dosage form is
selected from the group consisting of capsules, sugar-coated
tablets, dry-coated tablets, mantle tablets, and layered
tablets.
[0537] In a particularly preferred embodiment of the invention, the
composition is formulated in a capsule. In accordance with this
embodiment, the pharmaceutical dosage form comprises a hard or soft
gelatin capsule.
[0538] Most pharmaceutical dosage forms are intended to be
swallowed whole and accordingly, preferred pharmaceutical dosage
forms according to the invention are designed for oral
administration.
[0539] In a preferred embodiment, the pharmaceutical dosage form is
to be administered orally.
[0540] Particularly preferably, the pharmaceutical dosage form is
to be administered as a whole. This preferably means that the
dosage form is neither intended to be chewed on nor to be sucked on
prior to being swallowed. Further, the dosage forms are preferably
not intended to adhere to the oral mucosa. It is preferably not
possible to completely crush or comminute the dosage form by
chewing because of the high breaking strength of the segment(s)
(S.sub.1). Thus, preferably the dosage form according to the
invention is swallowed as a whole, i.e. in one piece.
[0541] However, alternatively pharmaceutical dosage forms may be
dissolved in the mouth, chewed, and some may be placed in a body
cavity. Thus, the pharmaceutical dosage form according to the
invention may alternatively be adapted for buccal, lingual, rectal
or vaginal administration. Implants are also possible.
[0542] The pharmaceutical dosage form according to the invention
has preferably a total weight in the range of 0.01 to 1.5 g, more
preferably in the range of 0.05 to 1.2 g, still more preferably in
the range of 0.1 g to 1.0 g, yet more preferably in the range of
0.2 g to 0.9 g, and most preferably in the range of 0.3 g to 0.8 g.
In a preferred embodiment, the total weight of the pharmaceutical
dosage form is within the range of 600.+-.450 mg, more preferably
600.+-.300 mg, still more preferably 600.+-.200 mg, yet more
preferably 600.+-.150 mg, most preferably 600.+-.100 mg, and in
particular 600.+-.50 mg.
[0543] In a preferred embodiment, the pharmaceutical dosage form
according to the invention is a capsule, more preferably a hard
capsule and most preferably a hard gelatin capsule. Pharmaceutical
dosage forms of this embodiment preferably have a lengthwise
extension (longitudinal extension) of about 1 mm to about 30 mm, in
particular in the range of about 2 mm to about 25 mm, more in
particular about 5 mm to about 23 mm, even more in particular about
7 mm to about 20 mm; a width in the range of about 1 mm to about 30
mm, in particular in the range of about 2 mm to about 25 mm, more
in particular about 5 mm to about 23 mm, even more in particular
about 7 mm to about 13 mm; and a thickness in the range of about
1.0 mm to about 12 mm, in particular in the range of about 2.0 mm
to about 10 mm, even more in particular from 3.0 mm to about 9.0
mm, even further in particular from about 4.0 mm to about 8.0
mm.
[0544] In another preferred embodiment, the pharmaceutical dosage
form according to the invention is a round pharmaceutical dosage
form. Pharmaceutical dosage forms of this embodiment preferably
have a diameter in the range of about 1 mm to about 30 mm, in
particular in the range of about 2 mm to about 25 mm, more in
particular about 5 mm to about 23 mm, even more in particular about
7 mm to about 13 mm; and a thickness in the range of about 1.0 mm
to about 12 mm, in particular in the range of about 2.0 mm to about
10 mm, even more in particular from 3.0 mm to about 9.0 mm, even
further in particular from about 4.0 mm to about 8.0 mm.
[0545] In still another preferred embodiment, the pharmaceutical
dosage form according to the invention is an oblong pharmaceutical
dosage form. Pharmaceutical dosage forms of this embodiment
preferably have a lengthwise extension (longitudinal extension) of
about 1 mm to about 30 mm, in particular in the range of about 2 mm
to about 25 mm, more in particular about 5 mm to about 23 mm, even
more in particular about 7 mm to about 20 mm; a width in the range
of about 1 mm to about 30 mm, in particular in the range of about 2
mm to about 25 mm, more in particular about 5 mm to about 23 mm,
even more in particular about 7 mm to about 13 mm; and a thickness
in the range of about 1.0 mm to about 12 mm, in particular in the
range of about 2.0 mm to about 10 mm, even more in particular from
3.0 mm to about 9.0 mm, even further in particular from about 4.0
mm to about 8.0 mm.
[0546] Preferably, the pharmaceutical dosage form according to the
invention is not in form of a film.
[0547] The pharmaceutical dosage form according to the invention
may optionally comprise a coating, e.g. a cosmetic coating. In a
preferred embodiment, the coated pharmaceutical dosage form
according to the invention is monolithic. The coating is preferably
applied after formation of the pharmaceutical dosage form. The
coating may be applied prior to or after the curing process. The
pharmaceutical dosage forms according to the invention are
preferably film coated with conventional film coating compositions.
Suitable coating materials are commercially available, e.g. under
the trademarks Opadry.degree. and Eudragit.RTM..
[0548] Examples of suitable materials include cellulose esters and
cellulose ethers, such as methyl-cellulose (MC),
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
hydroxyethylcellulose (HEC), sodium carboxymethylcellulose
(Na-CMC), poly(meth)-acrylates, such as aminoalkylmethacrylate
copolymers, methacrylic acid methylmethacrylate copolymers,
methacrylic acid methylmethacrylate copolymers; vinyl polymers,
such as polyvinylpyrrolidone, polyvinyl alcohol, polyvinylacetate;
and natural film formers.
[0549] 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.
[0550] The coating can also be applied e.g. to improve the
aesthetic impression and/or the taste of the pharmaceutical dosage
forms and the ease with which they can be swallowed. Coating the
pharmaceutical dosage forms according to the 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, polyvinyl alcohol or hydroxypropyl
methylcellulose, e.g. hypromellose, 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. Coated
pharmaceutical dosage forms according to the invention are
preferably prepared by first making the cores and subsequently
coating said cores using conventional techniques, such as coating
in a coating pan.
[0551] Preferably, the coating does not contain the second
pharmacologically active ingredient (A.sub.2), more preferably the
coating does not contain any pharmacologically active
ingredient.
[0552] Apart from the formed segment(s) (S.sub.1) and the further
segment(s) (S.sub.2), the pharmaceutical dosage form may optionally
further comprise conventional pharmaceutical excipients.
[0553] Preferred pharmaceutical excipients are those which may also
be contained in the further segment (S.sub.2) and have already been
disclosed above, in particular fillers/binders, lubricants,
diluents, granulating aids, colorants, flavourants, glidants,
wet-regulating agents and disintegrants.
[0554] The skilled person will readily be able to determine
appropriate quantities of each of these excipients.
[0555] 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, 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.
[0556] The pharmaceutical dosage form according to the invention
furthermore preferably contains no antagonists for the
pharmacologically active ingredients, preferably no antagonists
against psychotropic substances, in particular no antagonists
against opioids. Antagonists suitable for a given pharmacologically
active ingredient 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.
[0557] 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, New
York, 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.
[0558] 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.
[0559] 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 ingredients, nor emetics, nor bitter
substances.
[0560] Preferably, the formed segment(s) (S.sub.1), more preferably
the entire pharmaceutical dosage form according to the invention
contains more than 20 wt.-%, more preferably more than 30 wt.-%,
still more preferably more than 40 wt.-%, yet more preferably more
than 50 wt.-%, most preferably more than 60 wt.-%, and in
particular more than 70 wt.-% of compounds which are not or hardly
soluble in ethanol with respect to the total weight of the
pharmaceutical dosage form.
[0561] For the purpose of specification, compounds which are not or
hardly soluble in ethanol have a maximum solubility in aqueous
ethanol (96%) at room temperature of preferably less than 1000
mg/L, more preferably less than 800 mg/L, even more preferably less
than 500 mg/L, most preferably less than 100 mg/L and in particular
less than 10 mg/L or less than 1 mg/L.
[0562] Preferably, the formed segment (S.sub.1), more preferably
the entire pharmaceutical dosage form according to the invention
contains more than 50 wt.-%, more preferably more than 60 wt.-%,
still more preferably more than 70 wt.-%, yet more preferably more
than 80 wt.-%, most preferably more than 90 wt.-%, and in
particular more than 95 wt.-% of polymers which are not or hardly
soluble in ethanol with respect to the overall amount of polymers
contained in the pharmaceutical dosage form.
[0563] Preferred polymers which are not or hardly soluble in
ethanol according to the invention are xanthan, guar gum and some
types of HPMC. The skilled person knows what types of HPMC are not
or hardly soluble in ethanol within the sense of the invention.
[0564] In a particularly preferred embodiment, formed segment
(S.sub.1), more preferably the entire pharmaceutical dosage form
according to the invention contains polymers which are not or
hardly soluble in ethanol and polymers which are soluble in
ethanol, wherein the amount of polymers which are not or hardly
soluble in ethanol relative to the total amount of polymers
contained in the dosage form is 30 to 100 wt.-%, more preferably 50
to 100 wt.-%, still more preferably 60 to 95 wt.-% or 100 wt.-%,
yet more preferably 70 to 90 wt.-% or 100 wt.-%, most preferably 80
to 90 wt.-% or 90 to 100 wt.-%, and in particular more than 95
wt.-% or more than 99 wt.-%.
[0565] In a preferred embodiment, the pharmaceutical dosage form
according to the invention is adapted for administration once
daily, preferably orally. In another preferred embodiment, the
pharmaceutical dosage form according to the invention is adapted
for administration twice daily, preferably orally. In still another
preferred embodiment, the pharmaceutical dosage form according to
the invention is adapted for administration thrice daily,
preferably orally. In yet another preferred embodiment, the
pharmaceutical dosage form according to the invention is adapted
for administration more frequently than thrice daily, for example 4
times daily, 5 times daily, 6 times daily, 7 times daily or 8 times
daily, in each case preferably orally.
[0566] For the purpose of the specification, "twice daily" means
equal or nearly equal time intervals, i.e., about every 12 hours,
or different time intervals, e.g., 8 and 16 hours or 10 and 14
hours, between the individual administrations.
[0567] For the purpose of the specification, "thrice daily" means
equal or nearly equal time intervals, i.e., about every 8 hours, or
different time intervals, e.g., 6, 6 and 12 hours; or 7, 7 and 10
hours, between the individual administrations.
[0568] In preferred embodiments, the pharmaceutical dosage form
according to the invention is a tablet, preferably selected from
the group consisting of bilayer tablets, mantle tablets, trilayer
tablets, multilayer tablets (preferably having more than three
layers), multicomponent tablets, and sugar coated tablets
(dragees). As all these embodiments relate to tablets, the formed
segment(s) (S.sub.1) and further segment(s) (S.sub.2) form a
coherent compacted mass so that the overall tablet constitutes a
single unit of matter that can be administered to a patient. In
particular, the further segment(s) (S.sub.2) contained in the
tablets is/are not present in form of a powdery material. The total
weight of the tablets is not particularly limited. Typically, it is
within the range of from 50 mg to 1250 mg. The number of formed
segment(s) (S.sub.1) and further segment(s) (S.sub.2) that are
contained in the tablets according to the invention is not
particularly limited. Typically, the tablets according to the
invention contain 1, 2, or 3, but not more formed segments
(S.sub.1), as well as 1, 2, or 3, but not more further segments
(S.sub.2). All preferred embodiments that have been generally
defined above fully apply to the preferred tablets according to the
invention and are therefore not reiterated. Nevertheless,
particularly preferred embodiments of tablets according to the
invention will be described in further detail hereinafter.
[0569] Preferably, [0570] (a) the tablet is configured for oral
administration once daily, twice daily or thrice daily; and/or
[0571] (b) the formed segment(s) (S.sub.1) contain(s) as first
pharmacologically active ingredient (A.sub.1) an opioid, preferably
selected from the group consisting of oxycodone, oxymorphone,
hydromorphone, hydrocodone, morphine, tapentadol, tramadol,
buprenorphine, and the physiologically acceptable salts thereof;
and/or [0572] (c) the formed segment(s) (S.sub.1) contain(s) a
release matrix material in which the first pharmacologically active
ingredient (A.sub.1) is embedded such that prolonged release
thereof is achieved; and/or [0573] (d) the formed segment(s)
(S.sub.1) contain(s) a release matrix material comprising a polymer
(C) that is preferably selected from the group consisting of
polyalkylene oxides, nonionic acrylates, anionic acrylates or
cationic acrylates; more preferably a polyethylene oxide having a
weight average molecular weight of at least 500,000 g/mol; [0574]
(e) the formed segment(s) (S.sub.1) contain(s) a release matrix
material comprising a polymer (C), wherein the content of said
polymer (C) is preferably at least 20 wt.-%, at least 25 wt.-% or
at least 30 wt.-%, still more preferably at least 35 wt.-%, yet
more preferably at least 40 wt.-%, even more preferably at least 45
wt.-%, most preferably at least 50 wt.-%, and in particular at
least 55 wt.-%, relative to the total weight of the single formed
segment (S.sub.1); and/or [0575] (f) the further segment(s)
(S.sub.2) contain(s) as second pharmacologically active ingredient
(A.sub.2) an analgesic, preferably selected from the group
consisting of ibuprofen, diclofenac, paracetamol, acetylsalicylic
acid and the physiologically acceptable salts thereof; and/or
[0576] (g) the first pharmacologically active ingredient (A.sub.1)
is hydrocodone or a physiologically acceptable salt thereof and the
second pharmacologically active ingredient (A.sub.2) is
paracetamol; and/or [0577] (h) the tablet is to be administered as
a whole.
[0578] In the above definition, the features (a), (b), (c) . . .
(h) are linked with "and/or". For the purpose of specification,
this means that the tablet according to the invention preferably
realizes all of said features (a), (b), (c) . . . (h) or merely a
subgroup of said features (a), (b), (c) . . . (h). Preferred
tablets according to the invention realize at least feature (a); or
at least features (a) and (b); or at least features (a), (b) and
(c); or at least features (a), (b), (c) and (d); or at least
features (a), (b), (c), (d), and (e); or at least features (a),
(b), (c), (d), (e) and (f); or at least features (a), (b), (c),
(d), (e), (f) and (g).
[0579] Preferably, the pharmaceutical dosage form according to the
invention is a bilayer tablet. In the bilayer tablet according to
the invention, a single formed segment (S.sub.1) and a single
further segment (S.sub.2) are arranged to form a bilayer tablet
(cf. FIG. 1A). Optionally, the bilayer tablet can be sugar coated
(dragee).
[0580] Preferably, [0581] (a) the bilayer tablet is configured for
oral administration once daily, twice daily or thrice daily; and/or
[0582] (b) the total weight of the single formed segment (S.sub.1)
that forms one layer of the bilayer tablet is within the range of
210.+-.200 mg (i.e. 10 mg to 410 mg), more preferably 210.+-.180
mg, still more preferably 210.+-.160 mg, yet more preferably
210.+-.140 mg, even more preferably 210.+-.120 mg, most preferably
210.+-.100 mg, and in particular 210.+-.80 mg; and/or [0583] (c)
the single formed segment (S.sub.1) contains as first
pharmacologically active ingredient (A.sub.1) an opioid, preferably
selected from the group consisting of oxycodone, oxymorphone,
hydromorphone, hydrocodone, morphine, tapentadol, tramadol,
buprenorphine, and the physiologically acceptable salts thereof;
and/or [0584] (d) the single formed segment (S.sub.1) contains a
release matrix material in which the first pharmacologically active
ingredient (A.sub.1) is embedded such that prolonged release
thereof is achieved; and/or [0585] (e) the single formed segment
(S.sub.1) contains a release matrix material comprising a polymer
(C) that is preferably selected from the group consisting of
polyalkylene oxides, nonionic acrylates, anionic acrylates or
cationic acrylates; more preferably a polyethylene oxide having a
weight average molecular weight of at least 500,000 g/mol; [0586]
(f) the single formed segment (S.sub.1) contains a release matrix
material comprising a polymer (C), wherein the content of said
polymer (C) is preferably at least 30 wt.-%, still more preferably
at least 35 wt.-%, yet more preferably at least 40 wt.-%, even more
preferably at least 45 wt.-%, most preferably at least 50 wt.-%,
and in particular at least 55 wt.-%, relative to the total weight
of the single formed segment (S.sub.1); and/or [0587] (g) the total
weight of the single further segment (S.sub.2) that forms another
layer of the bilayer tablet is within the range of 485.+-.450 mg
(i.e. 35 mg to 935 mg), more preferably 485.+-.300 mg, still more
preferably 485.+-.250 mg, yet more preferably 485.+-.200 mg, even
more preferably 485.+-.150 mg, most preferably 485.+-.75 mg, and in
particular 485.+-.35 mg; and/or [0588] (h) the single further
segment (S.sub.2) contains as second pharmacologically active
ingredient (A.sub.2) an analgesic, preferably selected from the
group consisting of ibuprofen, diclofenac, paracetamol,
acetylsalicylic acid and the physiologically acceptable salts
thereof; and/or [0589] (i) the single further segment (S.sub.2)
contains a filler, preferably microcrystalline cellulose;
[0590] wherein the content of said filler is preferably 30.+-.25
wt.-%, more preferably 30.+-.20 wt.-%, still more preferably
30.+-.15 wt.-%, yet more preferably 30.+-.13 wt.-%, even more
preferably 30.+-.10 wt.-%, most preferably 30.+-.7 wt.-%, and in
particular 30.+-.5 wt.-%, relative to the total weight of the
single further segment (S.sub.2); and/or [0591] (j) the first
pharmacologically active ingredient (A.sub.1) is hydrocodone or a
physiologically acceptable salt thereof and the second
pharmacologically active ingredient (A.sub.2) is paracetamol;
and/or [0592] (k) the bilayer tablet is to be administered as a
whole.
[0593] In the above definition, the features (a), (b), (c) . . .
(k) are linked with "and/or". For the purpose of specification,
this means that the bilayer tablet according to the invention
preferably realizes all of said features (a), (b), (c) . . . (k) or
merely a subgroup of said features (a), (b), (c) . . . (k).
Preferred bilayer tablets according to the invention realize at
least feature (a); or at least features (a) and (b); or at least
features (a), (b) and (c); or at least features (a), (b), (c) and
(d); or at least features (a), (b), (c), (d), and (e); or at least
features (a), (b), (c), (d), (e), and (f); or at least features
(a), (b), (c), (d), (e), (f), and (g); or at least features (a),
(b), (c), (d), (e), (f), (g) and (h); or at least features (a),
(b), (c), (d), (e), (f), (g), (h) and (i); or at least features
(a), (b), (c), (d), (e), (f), (g), (h), (i) and (j).
[0594] Preferably, the pharmaceutical dosage form according to the
invention is a mantle tablet. In the mantle tablet according to the
invention, a single formed segment (S.sub.1) forming a core is
surrounded by a single further segment (S.sub.2) forming a shell
such that formed segment (S.sub.1) and further segment (S.sub.2)
are arranged to form a mantle tablet (cf. FIG. 1B). Optionally, the
mantle tablet can be sugar coated (drage).
[0595] Preferably, [0596] (a) the mantle tablet is configured for
oral administration once daily, twice daily or thrice daily; and/or
[0597] (b) the total weight of the single formed segment (S.sub.1)
that forms the core of the mantle tablet is within the range of
210.+-.200 mg (i.e. 10 mg to 410 mg), more preferably 210.+-.180
mg, still more preferably 210.+-.160 mg, yet more preferably
210.+-.140 mg, even more preferably 210.+-.120 mg, most preferably
210.+-.100 mg, and in particular 210.+-.80 mg; and/or [0598] (c)
the single formed segment (S.sub.1) contains as first
pharmacologically active ingredient (A.sub.1) an opioid, preferably
selected from the group consisting of oxycodone, oxymorphone,
hydromorphone, hydrocodone, morphine, tapentadol, tramadol,
burprenorphine, and the physiologically acceptable salts thereof;
and/or [0599] (d) the single formed segment (S.sub.1) contains a
release matrix material in which the first pharmacologically active
ingredient (A.sub.1) is embedded such that prolonged release
thereof is achieved; and/or [0600] (e) the single formed segment
(S.sub.1) contains a release matrix material comprising a polymer
(C) that is preferably selected from the group consisting of
polyalkylene oxides, nonionic acrylates, anionic acrylates or
cationic acrylates; more preferably a polyethylene oxide having a
weight average molecular weight of at least 500,000 g/mol; [0601]
(f) the single formed segment (S.sub.1) contains a release matrix
material comprising a polymer (C), wherein the content of said
polymer (C) is preferably at least 30 wt.-%, still more preferably
at least 35 wt.-%, yet more preferably at least 40 wt.-%, even more
preferably at least 45 wt.-%, most preferably at least 50 wt.-%,
and in particular at least 55 wt.-%, relative to the total weight
of the single formed segment (S.sub.1); and/or [0602] (g) the total
weight of the single further segment (S.sub.2) that forms the shell
of the mantle tablet is within the range of 485.+-.450 mg (i.e. 35
mg to 935 mg), more preferably 485.+-.300 mg, still more preferably
485.+-.250 mg, yet more preferably 485.+-.200 mg, even more
preferably 485.+-.150 mg, most preferably 485.+-.75 mg, and in
particular 485.+-.35 mg; and/or [0603] (h) the single further
segment (S.sub.2) contains as second pharmacologically active
ingredient (A.sub.2) an analgesic, preferably selected from the
group consisting of ibuprofen, diclofenac, paracetamol,
acetylsalicylic acid and the physiologically acceptable salts
thereof; and/or [0604] (i) the single further segment (S.sub.2)
contains a filler, preferably microcrystalline cellulose;
[0605] wherein the content of said filler is preferably 30.+-.25
wt.-%, more preferably 30.+-.20 wt.-%, still more preferably
30.+-.15 wt.-%, yet more preferably 30.+-.13 wt.-%, even more
preferably 30.+-.10 wt.-%, most preferably 30.+-.7 wt.-%, and in
particular 30.+-.5 wt.-%, relative to the total weight of the
single further segment (S.sub.2); and/or [0606] (j) the first
pharmacologically active ingredient (A.sub.1) is hydrocodone or a
physiologically acceptable salt thereof and the second
pharmacologically active ingredient (A.sub.2) is paracetamol;
and/or [0607] (k)the mantle tablet is to be administered as a
whole.
[0608] In the above definition, the features (a), (b), (c) . . .
(k) are linked with "and/or". For the purpose of specification,
this means that the mantle tablet according to the invention
preferably realizes all of said features (a), (b), (c) . . . (k) or
merely a subgroup of said features (a), (b), (c) . . . (k).
Preferred mantle tablets according to the invention realize at
least feature (a); or at least features (a) and (b); or at least
features (a), (b) and (c); or at least features (a), (b), (c) and
(d); or at least features (a), (b), (c), (d), and (e); or at least
features (a), (b), (c), (d), (e), and (f); or at least features
(a), (b), (c), (d), (e), (f), and (g); ; or at least features (a),
(b), (c), (d), (e), (f), (g) and (h); or at least features (a),
(b), (c), (d), (e), (f), (g), (h) and (i); or at least features
(a), (b), (c), (d), (e), (f), (g), (h), (i) and (j).
[0609] Preferably, the pharmaceutical dosage form according to the
invention is a trilayer tablet. In the trilayer tablet according to
the invention, a single formed segment (S.sub.1) and two further
segments (S.sub.2) are arranged to form a trilayer tablet, wherein
formed segment (S.sub.1) forms the middle layer and the two further
segments (S.sub.2) form the outer layers (cf. FIG. 1C). Preferably,
the outer layers of the trilayer tablet formed by said two further
segments (S.sub.2) have essentially the same compoistion and total
weight. Optionally, the trilayer tablet can be sugar coated
(drage).
[0610] Preferably, [0611] (a) the trilayer tablet is configured for
oral administration once daily, twice daily or thrice daily; and/or
[0612] (b) the total weight of the single formed segment (S.sub.1)
that forms the middle layer of the trilayer tablet is within the
range of 210.+-.200 mg (i.e. 10 mg to 410 mg), more preferably
210.+-.180 mg, still more preferably 210.+-.160 mg, yet more
preferably 210.+-.140 mg, even more preferably 210.+-.120 mg, most
preferably 210.+-.100 mg, and in particular 210.+-.80 mg; and/or
[0613] (c) the single formed segment (S.sub.1) contains as first
pharmacologically active ingredient (A.sub.1) an opioid, preferably
selected from the group consisting of oxycodone, oxymorphone,
hydromorphone, hydrocodone, morphine, tapentadol, tramadol,
buprenorphine, and the physiologically acceptable salts thereof;
and/or [0614] (d) the single formed segment (S.sub.1) contains a
release matrix material in which the first pharmacologically active
ingredient (A.sub.1) is embedded such that prolonged release
thereof is achieved; and/or [0615] (e) the single formed segment
(S.sub.1) contains a release matrix material comprising a polymer
(C) that is preferably selected from the group consisting of
polyalkylene oxides, nonionic acrylates, anionic acrylates or
cationic acrylates; more preferably a polyethylene oxide having a
weight average molecular weight of at least 500,000 g/mol; [0616]
(f) the single formed segment (S.sub.1) contains a release matrix
material comprising a polymer (C), wherein the content of said
polymer (C) is preferably at least 30 wt.-%, still more preferably
at least 35 wt.-%, yet more preferably at least 40 wt.-%, even more
preferably at least 45 wt.-%, most preferably at least 50 wt.-%,
and in particular at least 55 wt.-%, relative to the total weight
of the single formed segment (S.sub.1); and/or [0617] (g) the total
weight of each of the two further segment (S.sub.2) that form the
outer layers of the trilayer tablet is within the range of
250.+-.220 mg (i.e. 30 mg to 470 mg), more preferably 250.+-.200
mg, still more preferably 250.+-.175 mg, yet more preferably
250.+-.150 mg, even more preferably 250.+-.100 mg, most preferably
250.+-.75 mg, and in particular 250.+-.35 mg; and/or [0618] (h)
each of the two further segments (S.sub.2) contains as second
pharmacologically active ingredient (A.sub.2) an analgesic,
preferably selected from the group consisting of ibuprofen,
diclofenac, paracetamol, acetylsalicylic acid and the
physiologically acceptable salts thereof; and/or [0619] (i) each of
the two further segments (S.sub.2) contains a filler, preferably
microcrystalline cellulose; wherein the content of said filler is
preferably 30.+-.25 wt.-%, more preferably 30.+-.20 wt.-%, still
more preferably 30.+-.15 wt.-%, yet more preferably 30.+-.13 wt.-%,
even more preferably 30.+-.10 wt.-%, most preferably 30.+-.7 wt.-%,
and in particular 30.+-.5 wt.-%, relative to the total weight of
one of the two further segments (S.sub.2); and/or [0620] (j) the
first pharmacologically active ingredient (A.sub.1) is hydrocodone
or a physiologically acceptable salt thereof and the second
pharmacologically active ingredient (A.sub.2) is paracetamol;
and/or [0621] (k) the trilayer tablet is to be administered as a
whole.
[0622] In the above definition, the features (a), (b), (c) . . .
(k) are linked with "and/or". For the purpose of specification,
this means that the trilayer tablet according to the invention
preferably realizes all of said features (a), (b), (c) . . . (k) or
merely a subgroup of said features (a), (b), (c) . . . (k).
Preferred trilayer tablets according to the invention realize at
least feature (a); or at least features (a) and (b); or at least
features (a), (b) and (c); or at least features (a), (b), (c) and
(d); or at least features (a), (b), (c), (d), and (e); or at least
features (a), (b), (c), (d), (e), and (f); or at least features
(a), (b), (c), (d), (e), (f), and (g); or at least features (a),
(b), (c), (d), (e), (f), (g) and (h); or at least features (a),
(b), (c), (d), (e), (f), (g), (h) and (i); or at least features
(a), (b), (c), (d), (e), (f), (g), (h), (i) and (j).
[0623] Preferably, the pharmaceutical dosage form according to the
invention is a multilayer tablet. In the multilayer tablet
according to the invention, a plurality of formed segments
(S.sub.1) and a plurality of further segments (S.sub.2) are
arranged to form a multilayer tablet, wherein preferably each of
the formed segments (S.sub.1) is arranged in between two adjacent
further segments (S.sub.2). Preferably, the multilayer tablet
comprises 4, 5, or 6 layers, but not more. Preferably, the
multilayer tablet comprises m layers that are each formed by a
formed segment (S.sub.1), i.e. m formed segments (S.sub.1), and n
layers that are each formed by a further segment (S.sub.2), i.e. m
further segment (S.sub.2), wherein m and n are independently
integers of 1, 2, 3 or 4, preferably with the proviso that m+n
<6. Optionally, the multilayer tablet can be sugar coated
(drage).
[0624] Preferably, [0625] (a) the multilayer tablet is configured
for oral administration once daily, twice daily or thrice daily;
and/or [0626] (b) the total weight of each of the m formed segments
(S.sub.1) that form layers of the multilayer tablet is within the
range of 120.+-.90 mg (i.e. 30 mg to 210 mg), more preferably
120.+-.80 mg, still more preferably 120.+-.70 mg, yet more
preferably 120.+-.60 mg, even more preferably 120.+-.50 mg, most
preferably 120.+-.40 mg, and in particular 120.+-.30 mg; and/or
[0627] (c) each of the m formed segments (S.sub.1) contains as
first pharmacologically active ingredient (A.sub.1) an opioid,
preferably selected from the group consisting of oxycodone,
oxymorphone, hydromorphone, hydrocodone, morphine, tapentadol,
tramadol, buprenorphine, and the physiologically acceptable salts
thereof; and/or [0628] (d) each of the m formed segments (S.sub.1)
contains a release matrix material in which the first
pharmacologically active ingredient (A.sub.1) is embedded such that
prolonged release thereof is achieved; and/or [0629] (e) each of
the m formed segments (S.sub.1) contains a release matrix material
comprising a polymer (C) that is preferably selected from the group
consisting of polyalkylene oxides, nonionic acrylates, anionic
acrylates or cationic acrylates; more preferably a polyethylene
oxide having a weight average molecular weight of at least 500,000
g/mol; [0630] (f) each of the m formed segments (S.sub.1) contains
a release matrix material comprising a polymer (C), wherein the
content of said polymer (C) is preferably at least 30 wt.-%, still
more preferably at least 35 wt.-%, yet more preferably at least 40
wt.-%, even more preferably at least 45 wt.-%, most preferably at
least 50 wt.-%, and in particular at least 55 wt.-%, relative to
the total weight of one of the m formed segments (S.sub.1); and/or
[0631] (g) the total weight of each of the n further segments
(S.sub.2) that form layers of the multilayer tablet is within the
range of 160.+-.120 mg (i.e. 40 mg to 280 mg), more preferably
160.+-.105 mg, still more preferably 160.+-.80 mg, yet more
preferably 160.+-.65 mg, even more preferably 160.+-.50 mg, most
preferably 160.+-.35 mg, and in particular 160.+-.20 mg; and/or
[0632] (h) each of the n further segments (S.sub.2) contains as
second pharmacologically active ingredient (A.sub.2) an analgesic,
preferably selected from the group consisting of ibuprofen,
diclofenac, paracetamol, acetylsalicylic acid and the
physiologically acceptable salts thereof; and/or [0633] (i) each of
the n further segments (S.sub.2) contains a filler, preferably
microcrystalline cellulose; wherein the content of said filler is
preferably 30.+-.25 wt.-%, more preferably 30.+-.20 wt.-%, still
more preferably 30.+-.15 wt.-%, yet more preferably 30.+-.13 wt.-%,
even more preferably 30.+-.10 wt.-%, most preferably 30.+-.7 wt.-%,
and in particular 30.+-.5 wt.-%, relative to the total weight of
one of then further segments (S.sub.2); and/or [0634] (j) the first
pharmacologically active ingredient (A.sub.1) is hydrocodone or a
physiologically acceptable salt thereof and the second
pharmacologically active ingredient (A.sub.2) is paracetamol;
and/or [0635] (k) the multilayer tablet is to be administered as a
whole.
[0636] In the above definition, the features (a), (b), (c) . . .
(k) are linked with "and/or". For the purpose of specification,
this means that the multilayer tablet according to the invention
preferably realizes all of said features (a), (b), (c) . . . (k) or
merely a subgroup of said features (a), (b), (c) . . . (k).
Preferred multilayer tablets according to the invention realize at
least feature (a); or at least features (a) and (b); or at least
features (a), (b) and (c); or at least features (a), (b), (c) and
(d); or at least features (a), (b), (c), (d), and (e); or at least
features (a), (b), (c), (d), (e), and (f); or at least features
(a), (b), (c), (d), (e), (f), and (g); or at least features (a),
(b), (c), (d), (e), (f), (g) and (h); or at least features (a),
(b), (c), (d), (e), (f), (g), (h) and (i); or at least features
(a), (b), (c), (d), (e), (f), (g), (h), (i) and (j).
[0637] Preferably, the pharmaceutical dosage form according to the
invention is a multicomponent tablet. In the multicomponent tablet
according to the invention, a plurality of formed segments
(S.sub.1) form a discontinuous phase embedded in a single further
segment (S.sub.2) which forms a matrix (cf. FIG. 1D). Preferably,
the multicomponent tablet comprises m formed segments (S.sub.1) and
a single further segment (S.sub.2) forming a matrix in which the m
formed segments (S.sub.1) are embedded, wherein m is an integer of
2, 3, 4, 5 or 6; preferably 2 or 3. Optionally, the multicomponent
tablet can be sugar coated (drage).
[0638] Preferably, [0639] (a) the multicomponent tablet is
configured for oral administration once daily, twice daily or
thrice daily; and/or [0640] (b) the total weight of each of the m
formed segments (S.sub.1) that form layers of the multilayer tablet
is within the range of 120.+-.90 mg (i.e. 30 mg to 210 mg), more
preferably 120.+-.80 mg, still more preferably 120.+-.70 mg, yet
more preferably 120.+-.60 mg, even more preferably 120.+-.50 mg,
most preferably 120.+-.40 mg, and in particular 120.+-.30 mg;
and/or [0641] (c) each of the m formed segments (S.sub.1) contains
as first pharmacologically active ingredient (A.sub.1) an opioid,
preferably selected from the group consisting of oxycodone,
oxymorphone, hydromorphone, hydrocodone, morphine, tapentadol,
tramadol, buprenorphine, and the physiologically acceptable salts
thereof; and/or [0642] (d) each of the m formed segments (S.sub.1)
contains a release matrix material in which the first
pharmacologically active ingredient (A.sub.1) is embedded such that
prolonged release thereof is achieved; and/or [0643] (e) each of
the m formed segments (S.sub.1) contains a release matrix material
comprising a polymer (C) that is preferably selected from the group
consisting of polyalkylene oxides, nonionic acrylates, anionic
acrylates or cationic acrylates; more preferably a polyethylene
oxide having a weight average molecular weight of at least 500,000
g/mol; [0644] (f) each of the m formed segments (S.sub.1) contains
a release matrix material comprising a polymer (C), wherein the
content of said polymer (C) is preferably at least 30 wt.-%, still
more preferably at least 35 wt.-%, yet more preferably at least 40
wt.-%, even more preferably at least 45 wt.-%, most preferably at
least 50 wt.-%, and in particular at least 55 wt.-%, relative to
the total weight of one of the m formed segments (S.sub.1); and/or
[0645] (g) the total weight of the single further segment (S.sub.2)
that forms a matrix of the multicomponent tablet in which the m
formed segments (S.sub.1) are embedded is within the range of
485.+-.450 mg (i.e. 35 mg to 935 mg), more preferably 485.+-.300
mg, still more preferably 485.+-.250 mg, yet more preferably
485.+-.200 mg, even more preferably 485.+-.150 mg, most preferably
485.+-.75 mg, and in particular 485.+-.35 mg; and/or [0646] (h) the
single further segment (S.sub.2) contains as second
pharmacologically active ingredient (A.sub.2) an analgesic,
preferably selected from the group consisting of ibuprofen,
diclofenac, paracetamol, acetylsalicylic acid and the
physiologically acceptable salts thereof; and/or [0647] (i) the
single further segment (S.sub.2) contains a filler, preferably
microcrystalline cellulose;
[0648] wherein the content of said filler is preferably 30.+-.25
wt.-%, more preferably 30.+-.20 wt.-%, still more preferably
30.+-.15 wt.-%, yet more preferably 30.+-.13 wt.-%, even more
preferably 30.+-.10 wt.-%, most preferably 30.+-.7 wt.-%, and in
particular 30.+-.5 wt.-%, relative to the total weight of one of
the two further segments (S.sub.2); and/or [0649] (j) the first
pharmacologically active ingredient (A.sub.1) is hydrocodone or a
physiologically acceptable salt thereof and the second
pharmacologically active ingredient (A.sub.2) is paracetamol;
and/or [0650] (k)the multicomponent tablet is to be administered as
a whole.
[0651] In the above definition, the features (a), (b), (c) . . .
(k) are linked with "and/or". For the purpose of specification,
this means that the multicomponent tablet according to the
invention preferably realizes all of said features (a), (b), (c) .
. . (k) or merely a subgroup of said features (a), (b), (c) . . .
(k). Preferred multicomponent tablets according to the invention
realize at least feature (a); or at least features (a) and (b); or
at least features (a), (b) and (c); or at least features (a), (b),
(c) and (d); or at least features (a), (b), (c), (d), and (e); or
at least features (a), (b), (c), (d), (e), and (f); or at least
features (a), (b), (c), (d), (e), (f), and (g); or at least
features (a), (b), (c), (d), (e), (f), (g) and (h); or at least
features (a), (b), (c), (d), (e), (f), (g), (h) and (i); or at
least features (a), (b), (c), (d), (e), (f), (g), (h), (i) and
(j).
[0652] In other preferred embodiments, the pharmaceutical dosage
form according to the invention is a capsule, preferably selected
from the group consisting of capsules filled with a single formed
segment (S.sub.1) and a single further segment (S.sub.2), capsules
filled with a single formed segment (S.sub.1) and a plurality of
further segments (S.sub.2), capsules filled with a plurality of
formed segments (S.sub.1) and a single further segment (S.sub.2),
and capsules filled with a plurality of formed segments (S.sub.1)
and a plurality of further segment (S.sub.2). As all these
embodiments relate to capsules that are filled with the formed
segment(s) (S.sub.1) and further segment(s) (S.sub.2). While formed
segment(s) (S.sub.1) typically form(s) a coherent compacted mass,
the further segment(s) may either form a coherent compacted mass or
may be present in form of a powdery material. The overall capsule
constitutes a single unit of matter that can be administered to a
patient. The total weight of the capsules is not particularly
limited. Typically, it is within the range of from 50 mg to 1250
mg. The number of formed segment(s) (S.sub.1) and further
segment(s) (S.sub.2) that are contained in the capsules according
to the invention is not particularly limited. Typically, the
capsules according to the invention contain 1, 2, or 3, but not
more formed segments (S.sub.1), as well as 1, 2, or 3, but not more
further segments (S.sub.2). All preferred embodiments that have
been generally defined above fully apply to the preferred capsules
according to the invention and are therefore not reiterated.
Nevertheless, particularly preferred embodiments of capsules
according to the invention will be described in further detail
hereinafter.
[0653] Preferably, the pharmaceutical dosage form according to the
invention is a capsule filled with formed segment(s) (S.sub.1) and
further segment(s) (S.sub.2). In these capsules according to the
invention, the formed segment(s) (S.sub.1) is/are preferably
present as cut rods and the further segment(s) (S.sub.2) is/are
preferably present as tablets of such a size that they fit into the
interior of the capsule.
[0654] Preferably, [0655] (a) the capsule is configured for oral
administration once daily, twice daily or thrice daily; and/or
[0656] (b) the total weight of each of the formed segment(s)
(S.sub.1) is within the range of 270.+-.210 mg (i.e. 60 mg to 480
mg), more preferably 270.+-.180 mg, still more preferably
270.+-.150 mg, yet more preferably 270.+-.120 mg, even more
preferably 270.+-.90 mg, most preferably 270.+-.60 mg, and in
particular 270.+-.30 mg; and/or [0657] (c) each of the formed
segment(s) (S.sub.1) contain(s) as first pharmacologically active
ingredient (A.sub.1) an opioid, preferably selected from the group
consisting of oxycodone, oxymorphone, hydromorphone, hydrocodone,
morphine, tapentadol, tramadol, buprenorphine, and the
physiologically acceptable salts thereof; and/or [0658] (d) each of
the formed segment(s) (S.sub.1) contain(s) a release matrix
material in which the first pharmacologically active ingredient
(A.sub.1) is embedded such that prolonged release thereof is
achieved; and/or [0659] (e) each of the formed segment(s) (S.sub.1)
contain(s) a release matrix material comprising a polymer (C) that
is preferably selected from the group consisting of polyalkylene
oxides, nonionic acrylates, anionic acrylates or cationic
acrylates; more preferably a polyethylene oxide having a weight
average molecular weight of at least 500,000 g/mol; [0660] (f) each
of the formed segment(s) (S.sub.1) contain(s) a release matrix
material comprising a polymer (C), wherein the content of said
polymer (C) is preferably at least 30 wt.-%, still more preferably
at least 35 wt.-%, yet more preferably at least 40 wt.-%, even more
preferably at least 45 wt.-%, most preferably at least 50 wt.-%,
and in particular at least 55 wt.-%, relative to the total weight
of one formed segment (S.sub.1); and/or [0661] (g) the total weight
of each of the further segment(s) (S.sub.2) is within the range of
360.+-.350 mg (i.e. 10 mg to 710 mg), more preferably 360.+-.300
mg, still more preferably 360.+-.250 mg, yet more preferably
360.+-.200 mg, even more preferably 360.+-.150 mg, most preferably
360.+-.100 mg, and in particular 360.+-.50 mg; and/or [0662] (h)
each of the further segment(s) (S.sub.2) contain(s) as second
pharmacologically active ingredient (A.sub.2) an analgesic,
preferably selected from the group consisting of ibuprofen,
diclofenac, paracetamol, acetylsalicylic acid and the
physiologically acceptable salts thereof; and/or [0663] (i) each of
the further segment(s) (S.sub.2) contain(s) a filler, preferably
pregelled maize starch;
[0664] wherein the content of said filler is preferably 10.+-.9
wt.-%, more preferably 10.+-.8 wt.-%, still more preferably 10.+-.7
wt.-%, yet more preferably 10.+-.6 wt.-%, even more preferably
10.+-.5 wt.-%, most preferably 10.+-.4 wt.-%, and in particular
10.+-.3 wt.-%, relative to the total weight of one further segment
(S.sub.2); and/or [0665] (j) the first pharmacologically active
ingredient (A.sub.1) is hydrocodone or a physiologically acceptable
salt thereof and the second pharmacologically active ingredient
(A.sub.2) is paracetamol; and/or [0666] (k) the capsule is to be
administered as a whole.
[0667] In the above definition, the features (a), (b), (c) . . .
(k) are linked with "and/or". For the purpose of specification,
this means that the capsule according to the invention preferably
realizes all of said features (a), (b), (c) . . . (k) or merely a
subgroup of said features (a), (b), (c) . . . (k). Preferred
capsules according to the invention realize at least feature (a);
or at least features (a) and (b); or at least features (a), (b) and
(c); or at least features (a), (b), (c) and (d); or at least
features (a), (b), (c), (d), and (e); or at least features (a),
(b), (c), (d), (e), and (f); or at least features (a), (b), (c),
(d), (e), (f), and (g); or at least features (a), (b), (c), (d),
(e), (f), (g) and (h); or at least features (a), (b), (c), (d),
(e), (f), (g), (h) and (i); or at least features (a), (b), (c),
(d), (e), (f), (g), (h), (i) and (j).
[0668] The pharmaceutical dosage forms according to the invention
may be used in medicine, e.g. as an analgesic. The pharmaceutical
dosage forms are therefore particularly suitable for the treatment
or management of pain. In such pharmaceutical dosage forms, the
pharmaco-logically active ingredients (A.sub.1) and (A.sub.2)
preferably are analgesically effective. Preferably, the first
pharmacologically active ingredient (A.sub.1) is hydrocodone or a
physiologically acceptable salt thereof and the second
pharmacologically active ingredient (A.sub.2) is paracetamol.
[0669] A further aspect of the invention relates to the
pharmaceutical dosage form as described above for use in the
treatment of pain.
[0670] A further aspect of the invention relates to the use of the
first pharmacologically active ingredient (A.sub.1) and of the
second pharmacologically active ingredient (A.sub.2) for the
manufacture of a pharmaceutical dosage form as described above for
treating pain.
[0671] A further aspect of the invention relates to the
pharmaceutical dosage form as described above for use in the
treatment of pain, wherein the dosage form is swallowed as a
whole.
[0672] A further aspect of the invention relates to a method of
treating pain comprising the administration of the pharmaceutical
dosage form as described above to a subject in need thereof.
[0673] A further aspect according to the invention relates to the
use of a pharmaceutical dosage form as described above for avoiding
or hindering the abuse of the first pharmacologically active
ingredient (A.sub.1) contained therein.
[0674] A further aspect according to the invention relates to the
use of a pharmaceutical dosage form as described above for avoiding
or hindering the unintentional overdose of the first
pharmacologically active ingredient (A.sub.1) contained
therein.
[0675] In this regard, the invention also relates to the use of a
pharmaceutical dosage form as described above for the prophylaxis
and/or the treatment of a disorder, thereby preventing an overdose
of the first pharmacologically active ingredient (A.sub.1),
particularly due to comminution of the pharmaceutical dosage form
by mechanical action.
EXAMPLES
[0676] The following prophetic and non-prophetic examples further
illustrate the invention but are not to be construed as limiting
its scope:
Prophetic Examples A1 to A6-Tablets
Example A1
[0677] A single formed segment (S.sub.1) and a single further
segment (S.sub.2) that are arranged to form a bilayer tablet (cf
FIG. 1A). Bilayer tablets of the following composition can be
prepared:
[0678] Formed segment (S.sub.1):
TABLE-US-00012 A1-S.sub.1-1 A1-S.sub.1-2 A1-S.sub.1-3 A1-S.sub.1-4
Excipient mg wt.-% mg wt.-% mg wt.-% mg wt.-% Oxycodone HCl 5.00
2.33 5.00 3.33 50.00 18.60 50.00 20.00 Polyethylene Oxide 150.51
70.00 143.50 95.67 152.65 56.80 197.50 79.00 7,000,000 Hypromellose
21.50 10.00 -- 26.88 10.00 -- Polyethylene Glycol 35.75 16.63 --
36.44 13.56 -- Alpha-Tocopherole 0.43 0.20 -- 0.54 0.20 -- Citric
acid, 1.81 0.84 -- 2.26 0.84 -- anhydrous Magnesium stearate --
1.50 1.00 -- 2.50 1.00 Total 215.00 100.00 150.00 100.00 268.77
100.00 250.00 100.00
[0679] Further segment (S.sub.2):
TABLE-US-00013 A1-S.sub.2-1 A1-S.sub.2-2 Excipient mg wt.-% mg
wt.-% Paracetamol 325.00 64.94 325.00 69.04 Microcrystalline
cellulose 174.96 34.96 115.24 24.48 Crosscarmellose -- 30.03 6.38
Magnesium stearate 0.50 0.10 0.47 0.10 Total 500.46 100.00 470.74
100.00
Example A2
[0680] A single formed segment (S.sub.1) forming a core that is
surrounded by a single further segment (S.sub.2) forming a shell
such that formed segment (S.sub.1) and further segment (S.sub.2)
are arranged to form a mantle tablet (cf FIG. 1B). Mantle tablets
of the following composition can be prepared:
[0681] Formed segment (S.sub.1)--core:
TABLE-US-00014 A2-S.sub.1-1 A2-S.sub.1-2 A2-S.sub.1-3 A2-S.sub.1-4
Excipient mg wt.-% mg wt.-% mg wt.-% mg wt.-% Oxycodone HCl 5.00
2.33 5.00 3.33 50.00 18.60 50.00 20.00 Polyethylene Oxide 150.51
70.00 143.50 95.67 152.65 56.80 197.50 79.00 7.000.000 Hypromellose
21.50 10.00 -- 26.88 10.00 -- Polyethylene Glycol 35.75 16.63 --
36.44 13.56 -- Alpha-Tocopherole 0.43 0.20 -- 0.54 0.20 -- Citric
acid, anhydrous 1.81 0.84 -- 2.26 0.84 -- Magnesium stearate --
1.50 1.00 -- 2.50 1.00 Total 215.00 100.00 150.00 100.00 268.77
100.00 250.00 100.00
[0682] Further segment (S.sub.2)--shell:
TABLE-US-00015 A2-S.sub.2-1 A2-S.sub.2-2 Excipient mg wt.-% mg
wt.-% Paracetamol 325.00 64.94 325.00 69.04 Microcrystalline
cellulose 174.96 34.96 115.24 24.48 Crosscarmellose -- 30.03 6.38
Magnesium stearate 0.50 0.10 0.47 0.10 Total 500.46 100.00 470.74
100.00
Example A3
[0683] A single formed segment (S.sub.1) and two further segments
(S.sub.2) that are arranged to form a trilayer tablet, wherein
formed segment (S.sub.1) forms the middle layer and the two further
segments (S.sub.2) form the outer layers (cf FIG. 1C). Trilayer
tablets of the following composition can be prepared:
[0684] Formed segment (S.sub.1):
TABLE-US-00016 A3-S.sub.1-1 A3-S.sub.1-2 A3-S.sub.1-3 A3-S.sub.1-4
Excipient mg wt.-% mg wt.-% mg wt.-% mg wt.-% Oxycodone HCl 5.00
2.33 5.00 3.33 50.00 18.60 50.00 20.00 Polyethylene Oxide 150.51
70.00 143.50 95.67 152.65 56.80 197.50 79.00 7.000.000 Hypromellose
21.50 10.00 -- 26.88 10.00 -- Polyethylene Glycol 35.75 16.63 --
36.44 13.56 -- Alpha-Tocopherole 0.43 0.20 -- 0.54 0.20 -- Citric
acid, anhydrous 1.81 0.84 -- 2.26 0.84 -- Magnesium stearate --
1.50 1.00 -- 2.50 1.00 Total 215.00 100.00 150.00 100.00 268.77
100.00 250.00 100.00
[0685] Further segments (S.sub.2):
TABLE-US-00017 A3-S.sub.2-1 A3-S.sub.2-2 Excipient mg wt.-% mg
wt.-% Paracetamol 162.50 64.94 162.50 69.04 Microcrystalline
cellulose 87.48 34.96 57.62 24.48 Crosscarmellose -- 15.02 6.38
Magnesium stearate 0.25 0.10 0.24 0.10 Total 250.23 100.00 235.38
100.00
Example A4
[0686] A plurality of formed segments (S.sub.1) and a plurality of
further segments (S.sub.2) that are arranged to form a multilayer
tablet, wherein preferably each of the formed segments (S.sub.1) is
arranged in between two adjacent further segments (S.sub.2).
Multilayer tablets of the following composition can be
prepared:
[0687] Formed segments (S.sub.1):
TABLE-US-00018 A4-S.sub.1-1 A4-S.sub.1-2 A4-S.sub.1-3 Excipient mg
wt.-% mg wt.-% mg wt.-% Oxycodone HCl 2.50 2.33 25.00 18.60 25.00
18.60 Polyethylene Oxide 7.000.000 75.25 70.00 76.33 56.80 72.30
53.80 Hypromellose 10.75 10.00 13.44 10.00 13.44 10.00 Xanthan-Gum
-- -- -- -- 4.03 3.00 Polyethylene Glycol 17.87 16.62 18.22 13.56
18.22 13.56 Alpha-Tocopherole 0.22 0.20 0.27 0.20 0.27 0.20 Citric
acid, anhydrous 0.91 0.85 1.13 0.84 1.13 0.84 Total 107.50 100.00
134.39 100.00 134.39 100.00
[0688] Further segments (S.sub.2):
TABLE-US-00019 A4-S.sub.2-1 A4-S.sub.2-2 Excipient mg wt.-% mg
wt.-% Paracetamol 108.33 64.94 108.33 69.04 Microcrystalline
cellulose 58.32 34.96 38.41 24.48 Crosscarmellose -- 10.01 6.38
Magnesium stearate 0.16 0.10 0.16 0.10 Total 166.81 100.00 156.91
100.00
Example A5
[0689] A plurality of formed segments (S.sub.1) which form a
discontinuous phase embedded in further segment (S.sub.2) which
forms a matrix (cf. FIG. 1D). Multicomponent tablets of the
following composition can be prepared:
[0690] Formed segments (S.sub.1):
TABLE-US-00020 A5-S.sub.1-1 A5-S.sub.1-2 Excipient mg wt.-% mg
wt.-% Oxycodone HCl 2.50 2.33 25.00 18.60 Polyethylene Oxide
7.000.000 75.25 70.00 76.33 56.80 Hypromellose 10.75 10.00 13.44
10.00 Polyethylene Glycol 17.87 16.62 18.22 13.56 Alpha -
Tocopherole 0.22 0.20 0.27 0.20 Citric acid, anhydrous 0.91 0.85
1.13 0.84 Total 107.50 100.00 134.39 100.00
[0691] Further segment (S.sub.2):
TABLE-US-00021 A5-S.sub.2-1 A5-S.sub.2-2 Excipient mg wt.-% mg
wt.-% Paracetamol 325.00 64.94 325.00 69.04 Microcrystalline
cellulose 174.96 34.96 115.24 24.48 Crosscarmellose -- 30.03 6.38
Magnesium stearate 0.50 0.10 0.47 0.10 Total 500.46 100.00 470.74
100.00
Example A6
[0692] A single formed segment (S.sub.1) and one or more further
segments (S.sub.2) that are together coated by a sugar coating thus
forming a sugar-coated tablet (dragee). Sugar coated tablets of the
compositions according to any of above Examples A1 to A3 can be
prepared.
PROPHETIC EXAMPLES B1 TO B4 -FILLED CAPSULES
Example B1
[0693] A single formed segment (S.sub.1) and a single further
segment (S.sub.2) (cf FIG. 2A). Capsules of the following
composition can be prepared:
TABLE-US-00022 Excipient mg wt.-% Segment Oxycodone HCl 50.00 6.31
S.sub.1 Polyethylene oxide 7.000.000 152.65 19.28 Hypromellose
100000 mPa*s Ph. Eur 26.88 3.65 Macrogol 6000 Ph. Eur. 36.44 4.60
.alpha.-Tocopherol Ph. Eur. 0.54 0.06 Critic acid anhydrous Ph.
Eur. 2.26 0.28 Paracetamol 325.00 41.05 S.sub.2 Pregelled maize
starch 36.00 4.55 Hard gelatin capsule size 000 162.00 20.46
Capsule Total 791.77 100.00
[0694] Capsule containing paracetamol and a cut rod comprising
oxycodone HCl
[0695] Cut rods of 268.77 mg can be produced by weighing the
ingredients (S.sub.1), sieving (Mesh size 1.0 mm), blending in a
Bohle LM 40 MC 20, followed by extrusion using a ZSE 27 Micro PH 40
D (melt temperature 124.degree. C., screw rotation speed 100 rpm,
die diameter 5.0 mm, melt pressure ca. 80 bar) equipped with 6
cooling injectors. The extruded strands can be cut with a Combi
Cutting unit CC 250.
[0696] Tablets of 361.00 mg can be prepared by directly compressing
a granulate of the ingredients (S.sub.2) by direct compression. The
granulate is commercially available as "Paracetamol DC APC 230
F/MS" from manufacturer Atabay/Turkey.
[0697] One cut rod and one tablet can be filled in a hard gelatin
capsule.
Example B2
[0698] A single formed segment (S.sub.1) and a plurality of further
segments (S.sub.2) (cf FIG. 2B). Capsules of the following
composition can be prepared:
TABLE-US-00023 [0698] Excipient mg wt.-% Segment Oxycodone HCl
50.00 6.31 S.sub.1 Polyethylene oxide 7.000.000 152.65 19.28
Hypromellose 100000 mPa*s Ph. Eur 26.88 3.65 Macrogol 6000 Ph. Eur.
36.44 4.60 .alpha.-Tocopherol Ph. Eur. 0.54 0.06 Critic acid
anhydrous Ph. Eur. 2.26 0.28 Paracetamol 325.00 41.05 S.sub.2
Pregelled maize starch 36.00 4.55 Hard gelatin capsule size 000
162.00 20.46 Capsule Total 791.77 100.00
[0699] Capsule containing paracetamol and a cut rod comprising
oxycodone HCl
[0700] Cut rods of 268.77 mg can be produced by weighing the
ingredients (S.sub.1), sieving (Mesh size 1.0 mm), blending in a
Bohle LM 40 MC 20, followed by extrusion using a ZSE 27 Micro PH 40
D (melt temperature 124.degree. C., screw rotation speed 100 rpm,
die diameter 5.0 mm, melt pressure ca. 80 bar) equipped with 6
cooling injectors. The extruded strands can be cut with a Combi
Cutting unit CC 250.
[0701] Tablets of 180.50 mg can be prepared by directly compressing
a granulate of the ingredients (S.sub.2) by direct compression. The
granulate is commercially available as "Paracetamol DC APC 230
F/MS" from manufacturer Atabay/Turkey.
[0702] One cut rod and two tablets can be filled in a hard gelatin
capsule.
Example B3
[0703] A plurality of formed segments (S.sub.1) and a single
further segment (S.sub.2), which can optionally be present in form
of a monolith or in form of a powdery material (cf. FIG. 2F).
Capsules of the following composition can be prepared:
TABLE-US-00024 Excipient mg wt.-% Segment Oxycodone HCl 50.00 6.31
S.sub.1 Polyethylene oxide 7.000.000 152.65 19.28 Hypromellose
100000 mPa*s Ph. Eur 26.88 3.65 Macrogol 6000 Ph. Eur. 36.44 4.60
.alpha.-Tocopherol Ph. Eur. 0.54 0.06 Critic acid anhydrous Ph.
Eur. 2.26 0.28 Paracetamol 325.00 41.05 S.sub.2 Pregelled maize
starch 36.00 4.55 Hard gelatin capsule size 000 162.00 20.46
Capsule Total 791.77 100.00
[0704] Capsule containing paracetamol and a cut rod comprising
oxycodone HCl
[0705] Cut rods of 134.385 mg can be produced by weighing the
ingredients (S.sub.1), sieving (Mesh size 1.0 mm), blending in a
Bohle LM 40 MC 20, followed by extrusion using a ZSE 27 Micro PH 40
D (melt temperature 124.degree. C., screw rotation speed 100 rpm,
die diameter 5.0 mm, melt pressure ca. 80 bar) equipped with 6
cooling injectors. The extruded strands can be cut with a Combi
Cutting unit CC 250.
[0706] Tablets of 361.00 mg can be prepared by directly compressing
a granulate of the ingredients (S.sub.2) by direct compression. The
granulate is commercially available as "Paracetamol DC APC 230
F/MS" from manufacturer Atabay/Turkey.
[0707] Two cut rods and one tablet can be filled in a hard gelatin
capsule.
Example B4
[0708] A plurality of formed segments (S.sub.1) and a plurality of
further segment (S.sub.2) (cf FIGS. 2C, D and E). Capsules of the
following composition can be prepared:
TABLE-US-00025 Excipient mg wt.-% Segment Oxycodone HCl 50.00 6.31
S.sub.1 Polyethylene oxide 7.000.000 152.65 19.28 Hypromellose
100000 mPa*s Ph. Eur 26.88 3.65 Macrogol 6000 Ph. Eur. 36.44 4.60
.alpha.-Tocopherol Ph. Eur. 0.54 0.06 Critic acid anhydrous Ph.
Eur. 2.26 0.28 Paracetamol 325.00 41.05 S.sub.2 Pregelled maize
starch 36.00 4.55 Hard gelatin capsule size 000 162.00 20.46
Capsule Total 791.77 100.00
[0709] Capsule containing paracetamol and a cut rod comprising
oxycodone HCl
[0710] Cut rods of 134.385 mg can be produced by weighing the
ingredients (S.sub.1), sieving (Mesh size 1.0 mm), blending in a
Bohle LM 40 MC 20, followed by extrusion using a ZSE 27 Micro PH 40
D (melt temperature 124.degree. C., screw rotation speed 100 rpm,
die diameter 5.0 mm, melt pressure ca. 80 bar) equipped with 6
cooling injectors. The extruded strands can be cut with a Combi
Cutting unit CC 250.
[0711] Tablets of 180.50 mg can be prepared by directly compressing
a granulate of the ingredients (S.sub.2) by direct compression. The
granulate is commercially available as "Paracetamol DC APC 230
F/MS" from manufacturer Atabay/Turkey.
[0712] Two cut rods and two tablets can be filled in a hard gelatin
capsule.
NON-PHOPHETIC EXAMPLES
Example 1
[0713] Capsule containing paracetamol and a cut rod comprising
oxycodone HCl
[0714] Cut rods were produced by weighing the ingredients, sieving
(Mesh size 1.0 mm), blending in a Bohle LM 40 MC 20, followed by
extrusion using a ZSE 27 Micro PH 40 D (melt temperature
124.degree. C., screw rotation speed 100 rpm, die diameter 5.0 mm,
melt pressure ca. 80 bar) equipped with 6 cooling injectors. The
extruded strands were cut with a Combi Cutting unit CC 250. One cut
rod and paracetamol in powder form were filled in a hard gelatin
capsule. Composition of capsule containing paracetamol and a cut
rod comprising oxycodone HCl:
TABLE-US-00026 Excipient mg wt.-% Oxycodone HCl 50.00 7.26
Polyethylene oxide 7.000.000 152.65 22.16 Hypromellose 100000 mPa*s
Ph. Eur 26.88 3.90 Macrogol 6000 Ph. Eur. 36.44 5.29
.alpha.-Tocopherol Ph. Eur. 0.54 0.08 Critic acid anhydrous Ph.
Eur. 2.26 0.33 Paracetamol Ph. Eur. 325.00 47.19 Hard gelatin
capsule size 0 95.00 13.79 Total 688.77 100
[0715] The capsules were subjected to different tests in order to
assess the tamper-resistance with respect to the oxycodone HCl
contained in the cut rods.
[0716] The hammer test was performed with a weight of 500 g falling
from a height of 1000 mm. After the test, the cut rods were still
intact.
[0717] The breaking strength (resistance to crushing) was measured
using a Zwick Z 2.5 materials tester, F.sub.max=2.5 kN with a
maximum draw of 1150 mm. The cut rods displayed a breaking strength
of >500 N. FIG. 3 shows the corresponding force distance
diagram.
[0718] The release profiles of oxycodone HCl from the capsules were
determined under in vitro conditions using the basket method
according to Ph. Eur. at 75 rpm in 600 mL of 0.1 N HCl SIF sp (pH
6.8) and 0.1 N HCl+40% ethanol, respectively. The results are
summarized in the table here below.
[0719] Results of the dissolution tests:
TABLE-US-00027 dissolution [%] t [min] in 0.1N HCl in SIFsp pH 6.8
in 0.1N HCl + 40% ethanol 60 23 25 16 120 36 39 26 480 82 84 65 600
88 90 73 720 93 93 78
[0720] Extraction of oxycodone HCl from the capsule was tested (30
mL, 30 min) in 40% ethanol, water at room temperature and boiling
water, respectively. The results are summarized in the below
table.
[0721] To simulate an addict's attempt at preparing an i.v.
injection, a capsule was ground with a commercial coffee mill, type
Bosch MKM6000, 180W, Typ KM13 for 2 min followed by extraction in
boiled water for 5 min. The results are summarized in the below
table.
[0722] Results of the extraction test and the i.v. injection
preparation:
TABLE-US-00028 amount of oxycodone HCl [%] intact dosage form 96.5
extraction in water at room temperature 0.6 extraction in boiled
water 25.7 extraction in 40% ethanol 0.9 i.v. injection preparation
21.9 (n = 2)
REFERENCE EXAMPLES
[0723] The following Examples 2-7 are Reference Examples which
relate to segments comprising a pharmacologically active ingredient
and having a breaking strength of more than 500 N.
[0724] Reference Examples 2 to 4 and 6 relate to only one segment
and a dosage form comprising said one segment, respectively.
Reference Example 5 relates to a dosage form comprising two
identical segments having the same breaking strength.
[0725] The skilled person is able to combine any of these segments
exemplified in the Reference Examples with another segment
comprising a pharmacologically active ingredient and having e.g. a
lower breaking strength than the segments of the Reference
Examples.
Reference Example 2
[0726] Cut rods were produced according to the procedure disclosed
in Example 1 and having the composition as disclosed in
A1-S.sub.1-1 with a total weight of each cut rod of 215 mg. The
composition is summarized in the table below:
TABLE-US-00029 m per capsule [mg] wt.-% Oxycodone HCl 5.00 2.33
Polyethylene oxide 7.000.000 150.51 70.00 Hypromellose 100000 mPa*s
Ph. Eur 21.50 10.00 Macrogol 6000 Ph. Eur. 35.75 16.63
.alpha.-Tocopherol Ph. Eur. 0.43 0.20 Critic acid anhydrous Ph.
Eur. 1.81 0.84 Total 215.00 100.00
[0727] The breaking strength (resistance to crushing) was measured
using a Sotax HT 100 (DEAC-IN-00705). The cut rods displayed a
breaking strength of 1000 N (mean value; n=3, with measured values
b.sub.1=b.sub.2=b.sub.3=1000N).
[0728] FIG. 4 shows the release profiles of one cut rod determined
under in vitro conditions (n=3) using the basket method with sinker
according to Ph. Eur. at 75 rpm in 600 mL of SGF (pH 1.2) and SGF
(pH 1.2)+40% ethanol, respectively.
Reference Example 3
[0729] Cut rods were produced according to the procedure disclosed
in Example 1 and having the composition as disclosed in
A1-S.sub.1-1 with the only exception that the total weight of each
cut rod was adjusted to 107.5 mg. The composition is summarized in
the table below:
TABLE-US-00030 m per capsule [mg] wt.-% Oxycodone HCl 2.50 2.33
Polyethylene oxide 7.000.000 75.255 70.00 Hypromellose 100000 mPa*s
Ph. Eur 10.75 10.00 Macrogol 6000 Ph. Eur. 17.875 16.63
.alpha.-Tocopherol Ph. Eur. 0.215 0.20 Critic acid anhydrous Ph.
Eur. 0.905 0.84 Total 107.50 100.00
[0730] FIG. 5 shows the release profiles of two cut rods determined
under in vitro conditions (n=3) using the basket method with sinker
according to Ph. Eur. (one sinker per cut rod) at 75 rpm in 600 mL
of SGF (pH 1.2) and SGF (pH 1.2)+40% ethanol, respectively.
Reference Example 4
[0731] Capsules comprising one cut rod were produced according to
the procedure disclosed in Example 1. One cut rod (215 mg) was
filled in a capsule (size 1). The composition of the capsule is
summarized in the table below:
TABLE-US-00031 m per capsule [mg] wt.-% Oxycodone HCl 5.00 1.72
Polyethylene oxide 7.000.000 150.51 51.90 Hypromellose 100000 mPa*s
Ph. Eur 21.50 7.41 Macrogol 6000 Ph. Eur. 35.75 12.33
.alpha.-Tocopherol Ph. Eur. 0.43 0.15 Critic acid anhydrous Ph.
Eur. 1.81 0.62 empy capsule size 1 75.00 25.86 Total 290.00
100.00
[0732] The breaking strength (resistance to crushing) was measured
using a Sotax HT 100 (DEAC-IN-00705). The capsules displayed a
breaking strength of 63 N (mean value; n=3*; with measured values
b.sub.1=50 N; b.sub.2 =76 N; b.sub.3 =1000 N*).
[0733] *The measured value b.sub.3 was not included in the mean
value of the breaking strength because it was obtained from an
incorrect measurement (the capsule was crushed and the breaking
strength of the cut rod was measured instead).
[0734] FIG. 6 shows the release profiles of one cut rod in a
capsule determined under in vitro conditions (n=3) using the basket
method with sinker according to Ph. Eur. at 75 rpm in 600 mL of SGF
(pH 1.2) and SGF (pH 1.2)+40% ethanol, respectively.
Reference Example 5
[0735] Capsules comprising two cut rods and a lactose tablet were
produced according to the procedure disclosed in Example 1. Two cut
rods (107.5 mg each) and a lactose tablet (72 mg) as spacer were
filled in a capsule (size 1). The composition of the capsule is
summarized in the table below:
TABLE-US-00032 m per capsule [mg] wt.-% Oxycodone HCl 5.00 1.38
Polyethylene oxide 7.000.000 150.51 41.58 Hypromellose 100000 mPa*s
Ph. Eur 21.50 5.94 Macrogol 6000 Ph. Eur. 35.75 9.88
.alpha.-Tocopherol Ph. Eur. 0.43 0.12 Critic acid anhydrous Ph.
Eur. 1.81 0.50 empy capsule size 1 75.00 20.72 Lactose tablet 72.00
19.89 Total 362.00 100.00
[0736] The breaking strength (resistance to crushing) was measured
using a Sotax HT 100 (DEAC-IN-00705). The capsules displayed a
breaking strength of 38 N (mean value; n=3*; with measured values
b.sub.1=1000 N*; b.sub.2 =31 N; b.sub.3 =45 N).
[0737] *The measured value b.sub.1 was not included in the mean
value of the breaking strength because it was obtained from an
incorrect measurement (the capsule was crushed and the breaking
strength of the cut rod was measured instead).
[0738] FIG. 7 shows the release profiles of two cut rods and a
lactose tablet in a capsule determined under in vitro conditions
(n=3) using the basket method with sinker according to Ph. Eur. at
75 rpm in 600 mL of SGF (pH 1.2) and SGF (pH 1.2)+40% ethanol,
respectively.
Reference Example 6
[0739] Layer-core-tablets (mantle-core-tablets) (9.times.21 mm,
oblong) were produced using one cut rod (215 mg) as the core and an
MCC-based mixture as the mantle. The MCC-based mixture was a
mixture of microcrystalline cellulose (MCC) with 2 wt.-% maize
starch as disintegrant and 1 wt.-% magnesium stearate. The
composition of the mantle-core-tablets is summarized in the table
below:
TABLE-US-00033 m per capsule [mg] wt.-% Oxycodone HCl 5.00 0.61
Polyethylene oxide 7.000.000 150.51 18.47 Hypromellose 100000 mPa*s
Ph. Eur 21.50 2.64 Macrogol 6000 Ph. Eur. 35.75 4.39
.alpha.-Tocopherol Ph. Eur. 0.43 0.05 Critic acid anhydrous Ph.
Eur. 1.81 0.22 MCC 582.00 71.41 Maize starch 12.00 1.47 Magnesium
stearate 6.00 0.74 Total 815.00 100.00
[0740] The breaking strength (resistance to crushing) was measured
using a Sotax HT 100 (DEAC-IN-00705). The mantle tablets displayed
a breaking strength of 65 N (mean value; n =3; with measured values
b.sub.1=63 N; b.sub.2 =58 N; b.sub.3 =73 N).
[0741] FIG. 8 shows the release profiles of a mantle tablet
determined under in vitro conditions (n=3) using the basket method
with sinker according to Ph. Eur. at 75 rpm in 600 mL of SGF (pH
1.2) and SGF (pH 1.2)+40% ethanol, respectively.
Reference Example 7
[0742] Layer-core-tablets (mantle-core-tablets) (9.times.21 mm,
oblong) were produced using two cut rods and a lactose tablet (72
mg) as cores and an MCC-based mixture as the mantle. The MCC-based
mixture was a mixture of microcrystalline cellulose (MCC) with 2
wt.-% maize starch as disintegrant and 1 wt.-% magnesium stearate.
The composition of the mantle-core-tablets is summarized in the
table below:
TABLE-US-00034 m per capsule [mg] wt.-% Oxycodone HCl 5.00 0.64
Polyethylene oxide 7.000.000 150.51 19.12 Hypromellose 100000 mPa*s
Ph. Eur 21.50 2.73 Macrogol 6000 Ph. Eur. 35.75 4.54
.alpha.-Tocopherol Ph. Eur. 0.43 0.05 Critic acid anhydrous Ph.
Eur. 1.81 0.23 Lactose tablet 72.00 9.15 MCC 485.00 61.63 Maize
starch 10.00 1.27 Magnesium stearate 5.00 0.64 Total 787.00
100.00
[0743] The breaking strength (resistance to crushing) was measured
using a Sotax HT 100 (DEAC-IN-00705). The mantle tablets displayed
a breaking strength of 19 N (mean value; n =3; with measured values
b.sub.1=18 N; b.sub.2 =21 N; b.sub.3 =17 N).
[0744] FIG. 9 shows the release profiles of a mantle tablet
determined under in vitro conditions (n=3) using the basket method
with sinker according to Ph. Eur. at 75 rpm in 600 mL of SGF (pH
1.2) and SGF (pH 1.2)+40% ethanol, respectively.
[0745] FIGS. 10 to 14
[0746] FIGS. 10 to 14 show combinations of the release profiles
obtained in Reference Examples 2 to 7.
[0747] FIG. 10 shows the release profiles of the cut rod (m=215 mg)
as such (Reference Example 2, FIG. 4), in a capsule (Reference
Example 4, FIG. 6), and in form of a mantle tablet (Reference
Example 6, FIG. 8).
[0748] FIG. 11 shows the release profiles of one cut rod (m=215 mg)
(Reference Example 2, FIG. 4) and two cut rods (m=107.5 mg)
(Reference Example 3, FIG. 5).
[0749] FIG. 12 shows the release profile of a capsule containing
one cut rod (Reference Example 4, FIG. 6) and a capsule containing
two cut rods (Reference Example 5, FIG. 7).
[0750] FIG. 13 shows the release profiles of a mantle tablet
containing one cut rod (Reference Example 6, FIG. 8) and a mantle
tablet containing two cut rods (Reference Example 7, FIG. 9).
[0751] FIG. 14 shows the release profiles of two cut rods (m=107.5
mg) as such (Reference Example 3, FIG. 5), in a capsule (Reference
Example 5, FIG. 7), and in form of a mantle tablet (Reference
Example 7, FIG. 9).
* * * * *