U.S. patent application number 15/073920 was filed with the patent office on 2016-07-14 for tamper-resistant tablet providing immediate drug release.
This patent application is currently assigned to Grunenthal GmbH. The applicant listed for this patent is Grunenthal GmbH. Invention is credited to Lutz Barnscheid, Marcel Haupts, Jana Patz, Udo Ruttgers, Sebastian Schwier.
Application Number | 20160199306 15/073920 |
Document ID | / |
Family ID | 44951601 |
Filed Date | 2016-07-14 |
United States Patent
Application |
20160199306 |
Kind Code |
A1 |
Schwier; Sebastian ; et
al. |
July 14, 2016 |
Tamper-resistant tablet providing immediate drug release
Abstract
The invention relates to a tamper-resistant tablet comprising
(i) a matrix material in an amount of more than one third of the
total weight of the tablet; and (ii) a plurality of particulates in
an amount of less than two thirds of the total weight of the
tablet; wherein said particulates comprise a pharmacologically
active compound and a polyalkylene oxide; and form a discontinuous
phase within the matrix material; and method of using said tablet
to treat pain and other conditions.
Inventors: |
Schwier; Sebastian; (Aachem,
DE) ; Haupts; Marcel; (Stolberg, DE) ;
Ruttgers; Udo; (Stolberg, DE) ; Barnscheid; Lutz;
(Monchengladbach, DE) ; Patz; Jana; (Bonn,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Grunenthal GmbH |
Aachen |
|
DE |
|
|
Assignee: |
Grunenthal GmbH
Aachen
DE
|
Family ID: |
44951601 |
Appl. No.: |
15/073920 |
Filed: |
March 18, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13559635 |
Jul 27, 2012 |
|
|
|
15073920 |
|
|
|
|
61512939 |
Jul 29, 2011 |
|
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Current U.S.
Class: |
424/465 ;
514/646; 514/654 |
Current CPC
Class: |
A61P 25/26 20180101;
A61K 31/485 20130101; A61P 25/04 20180101; A61K 9/2081 20130101;
A61K 31/137 20130101; A61P 25/00 20180101; A61K 9/28 20130101; A61K
9/2077 20130101; A61P 25/36 20180101; A61K 31/135 20130101; A61K
31/138 20130101; A61K 9/2031 20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/137 20060101 A61K031/137; A61K 9/28 20060101
A61K009/28; A61K 31/135 20060101 A61K031/135 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 29, 2011 |
EP |
11 006 253.6 |
Claims
1. A tamper-resistant tablet comprising (i) a matrix material in an
amount of more than one third of the total weight of the tablet;
and (ii) a plurality of particulates in an amount of less than two
thirds of the total weight of the tablet; wherein said particulates
comprise a pharmacologically active compound and a polyalkylene
oxide; and form a discontinuous phase within the matrix
material.
2. The tablet according to claim 1, which provides under in vitro
conditions immediate release of the pharmacologically active
compound in accordance with Ph. Eur.
3. The tablet according to claim 2, which has under in vitro
conditions a disintegration time measured in accordance with Ph.
Eur. of at most 3 minutes.
4. The tablet according to claim 1, wherein the content of the
matrix material is at least 40 wt.-%, based on the total weight of
the tablet.
5. The tablet according to claim 1, wherein the pharmacologically
active compound is an opioid.
6. The tablet according to claim 1, wherein the particulates have
an average diameter of about 1000.+-.250 .mu.m and/or an average
length of about 750.+-.250 .mu.m.
7. The tablet according to claim 1, wherein the pharmacologically
active compound is dispersed in the polyalkylene oxide.
8. The tablet according to claim 1, wherein the content of the
polyalkylene oxide is at least 25 wt.-%, based on the total weight
of a particulate.
9. The tablet according to claim 1, wherein the content of the
pharmacologically active compound is at least 25 wt.-%, based on
the total weight of a particulate.
10. The tablet according to claim 1, wherein the particulates are
hot melt-extruded.
11. The tablet according to claim 1, wherein the particulates are
film coated.
12. The tablet according to claim 1, wherein the matrix material is
also present in particulate form.
13. The tablet according to claim 1, wherein the matrix material is
dry granulated or compacted.
14. The tablet according to claim 1, wherein the matrix material
comprises binder, filler, disintegrant and/or lubricant.
15. The tablet according to claim 14, wherein the disintegrant is
crosslinked.
16. A method of treating a condition in a patient in need thereof
by administering to a patient in need of such treating a tablet
comprising an effective amount therefor of a pharmacologically
active compound, wherein the tablet is a tablet according to claim
1.
17. The method according to claim 16, wherein the condition is
pain.
18. The method according to claim 17, wherein the pharmacologically
active compound is an opioid.
Description
PRIORITY
[0001] This application is a continuation of U.S. application Ser.
No. 13/559,635, filed Jul. 27, 2012, which claims priority of U.S.
Provisional Patent Application No. 61/512,939, filed on Jul. 29,
2011, and European Patent Application No. 11 006 253.6, filed on
Jul. 29, 2011, the contents of which patent applications are
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The invention relates to tamper-resistant tablets comprising
a matrix material and a plurality of particulates which comprise a
pharmacologically active compound and form a discontinuous phase
within the matrix material.
BACKGROUND OF THE INVENTION
[0003] 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.
[0004] To enable abuse, the corresponding dosage forms, such as
tablets 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
dosage form is administered nasally, i.e. is sniffed.
[0005] Various concepts for the avoidance of drug abuse have been
developed.
[0006] It has been proposed to incorporate in dosage forms aversive
agents and/or antagonists in a manner so that they only produce
their aversive and/or antagonizing effects when the 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.
[0007] 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 dosage forms by the means usually available to a
potential abuser is prevented or at least complicated.
[0008] Such pharmaceutical dosage forms are useful for avoiding
drug abuse of the pharmacologically active compound 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.
[0009] These dosage forms secured against abuse are distinguished
by a controlled, preferably retarded release of the active
substance which has abuse potential. However, a rapid release of
the active substance is necessary for numerous therapeutic
applications, for example pain relief using active substances with
abuse potential.
[0010] WO 2010/140007 discloses dosage forms comprising
melt-extruded particulates comprising a drug, wherein said
melt-extruded particulates are present as a discontinuous phase in
a matrix. The dosage forms provide prolonged release of the
drug.
[0011] WO 2008/107149 discloses multiparticulate dosage forms with
impeded abuse containing, one or more active substances having
abuse potential, at least one synthetic or natural polymer, and at
least one disintegrant, with the individual particles of the tablet
having a breaking strength of at least 500 N and a release of the
active substance of at least 75% after 45 minutes. The exemplified
capsules provide rapid release of the pharmacologically active
compound.
[0012] US 2010/0092553 discloses solid multiparticulate oral
pharmaceutical forms whose composition and structure make it
possible to avoid misuse. The microparticles have an extremely
thick coating layer which assures the modified release of the drug
and simultaneously imparts crushing resistance to the coated
microparticles so as to avoid misuse.
[0013] WO 2008/033523 discloses a pharmaceutical composition that
may include a granulate which may at least include one active
pharmaceutical ingredient susceptible to abuse. The particle
contains both an alcohol soluble and alcohol insoluble and at least
partially water soluble material. Both materials are granulated in
the presence of alcohol and water. The granulate may also include a
coating on the granulate exhibiting crush resistance. Material
deposition on the granule is performed using an alcohol based
solvent.
[0014] The properties of capsules, however, are not satisfactory in
every respect, e.g. with respect to disintegration time, patient
compliance (e.g. swallowability) and ease of manufacture. Further,
capsules frequently contain gelatine thus causing the risk of
bovine spongiform encephalopathy (BSE, or TSE). As far as
tamper-resistant dosage forms are concerned, capsules are
disadvantageous as they can typically be opened easily thereby
releasing the ingredients in powdery or particulate form without
requiring any mechanical impact. If components of different type
are contained in a capsule, e.g. drug-containing particles besides
drug-free particles, a potential abuser might be able to visually
distinguish the intact, undisrupted components of different type
(e.g. according to their color, size or other macroscopic
properties) allowing for manual separation.
[0015] The properties of these tamper-resistant dosage forms,
however, are not satisfactory in every respect. There is a need for
tamper-resistant dosage forms that possess crush resistance and
release the pharmacologically active compound as quick as possible
(immediate release), i.e. should show a gradual increase reaching
85% to 100% at about 30 to 45 minutes or earlier. The dosage form
should advantageously be of a shape, size and weight that can be
taken orally with ease. Of course, the dosage form should also be
easy to make in a cost effective manner. When trying to tamper the
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 should be
as less as possible, e.g. should contain not more than 20 wt.-% of
the pharmacologically active compound originally contained in the
dosage form.
[0016] It is an object according to the invention to provide
tamper-resistant pharmaceutical dosage forms that provide rapid
release of the pharmacologically active compound and that have
advantages compared to the tamper-resistant pharmaceutical dosage
forms of the prior art.
[0017] This object has been achieved by the patent claims.
SUMMARY OF THE INVENTION
[0018] The invention relates to a tamper-resistant tablet,
preferably for oral administration, comprising [0019] (i) a matrix
material in an amount of more than one third of the total weight of
the tablet; and [0020] (ii) a plurality of particulates in an
amount of less than two thirds of the total weight of the tablet;
wherein said particulates comprise a pharmacologically active
compound and a polyalkylene oxide; and form a discontinuous phase
within the matrix material.
[0021] It has been surprisingly found that the in vitro release
profile of tamper-resistant dosage forms can be accelerated by
embedding particulates containing the pharmacologically active
compound in a matrix material and increasing the relative weight
ratio of the matrix material to the particulates.
[0022] Further, it has been surprisingly found that mixtures of
matrix material, optionally in pre-compacted or pre-granulated
form, can be mixed with the particulates and subsequently be
compacted to tablets which in turn exhibit excellent, i.e.
accelerated disintegration times and in vitro release
characteristics.
[0023] Still further, it has been surprisingly found that oral
dosage forms can be designed that provide the best compromise
between tamper-resistance, disintegration time and drug release,
drug load, processability (especially tablettability) and patient
compliance.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] The invention will now be described in greater detail with
reference to the drawings, wherein:
[0025] FIG. 1 schematically illustrates a preferred embodiment of
the tablets according to the invention.
[0026] FIG. 2 schematically illustrates another preferred
embodiment of the tablets according to the invention.
[0027] FIG. 3 shows in vitro release profiles of different tablets
according to the invention having different compositions and
particulate sizes.
[0028] FIG. 4 shows in vitro release profiles of different tablets
according to the invention having different compositions.
[0029] FIG. 5 illustrates the behavior of the particulates
contained in the tablets according to the invention when being
subjected to a breaking strength test, in particular their
deformability.
[0030] FIG. 6 illustrates the behavior of conventional particulates
when being subjected to a breaking strength test.
[0031] FIG. 7 shows the distance-force-diagram obtained by
measuring the mechanical properties of conventional
particulates.
[0032] FIG. 8 shows the distance-force-diagram obtained by
measuring the mechanical properties of particulates according to
the invention.
[0033] FIG. 9 shows the distance-force-diagram obtained by
measuring the mechanical properties of particulates according to
the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0034] As used herein, the term "tablet" refers to a pharmaceutical
entity that is comprised of a pharmacologically active compound and
which is actually administered to, or taken by, a patient. It may
be compressed or molded in its manufacture, and it may be of almost
any size, shape, weight, and color. Most tablets are intended to be
swallowed whole and accordingly, preferred tablets according to the
invention are designed for oral administration. However,
alternatively tablets may be dissolved in the mouth, chewed, or
dissolved in liquid before swallowing, and some may be placed in a
body cavity. Thus, the tablet according to the invention may
alternatively be adapted for buccal, lingual, rectal or vaginal
administration. Implants are also possible.
[0035] The tablet according to the invention preferably can be
regarded as a MUPS formulation (multiple unit pellet system). In a
preferred embodiment, the tablet according to the invention is
monolithic. In another preferred embodiment, the tablet according
to the invention is not monolithic. In this regard, monolithic
preferably means that the tablet is formed or composed of material
without joints or seams or consists of or constitutes a single
unit.
[0036] Preferably, the tablet according to the invention contains
all ingredients in a dense compact unit which in comparison to
capsules has a comparatively high density.
[0037] The tablets according to the invention comprise subunits
having different morphology and properties, namely drug-containing
particulates and matrix material, wherein the particulates form a
discontinuous phase within the matrix material. The particulates
typically have mechanical properties that differ from the
mechanical properties of the matrix material. Preferably, the
particulates have a higher mechanical strength than the matrix
material. The particulates within the tablets according to the
invention can be visualized by conventional means such as solid
state nuclear magnetic resonance spectroscopy, raster electron
microscopy, terahertz spectroscopy and the like.
[0038] An advantage of the tablets according to the invention is
that the same particulates may be mixed with matrix material in
different amounts to thereby produce tablets of different
strengths.
[0039] The tablet 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 tablet weight is within the range of
500.+-.450 mg, more preferably 500.+-.300 mg, still more preferably
500.+-.200 mg, yet more preferably 500.+-.150 mg, most preferably
500.+-.100 mg, and in particular 500.+-.50 mg.
[0040] It has been surprisingly found that the total tablet weight,
which is a function of the total size of the tablet, can be
optimized in order to provide the best compromise between
tamper-resistance, disintegration time and drug release, drug load,
processability (especially tablettability) and patient
compliance.
[0041] In a preferred embodiment, the tablet according to the
invention is a round tablet. Tablets 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.
[0042] In another preferred embodiment, the tablet according to the
invention is an oblong tablet. Tablets 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.
[0043] The tablets according to the invention can optionally be
provided, partially or completely, with a conventional coating. The
tablets 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.RTM.
and Eudragit.RTM..
[0044] Examples of suitable materials include cellulose esters and
cellulose ethers, such as methylcellulose (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.
[0045] In a particularly preferred embodiment, the coating is
water-soluble. In a preferred embodiment, the coating is based on
polyvinyl alcohol, such as polyvinyl alcohol-part, hydrolyzed, and
may additionally contain polyethylene glycol, such as macrogol
3350, and/or pigments. In another preferred embodiment, the coating
is based on hydroxypropylmethylcellulose, preferably hypromellose
type 2910 having a viscosity of 3 to 15 mPas.
[0046] 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 tablet 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.
[0047] The coating can also be applied e.g. to improve the
aesthetic impression and/or the taste of the tablets and the ease
with which they can be swallowed. Coating the tablets 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 tablets 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.
[0048] As used herein, the term "tamper-resistant" refers to
tablets that are resistant to conversion into a form suitable for
misuse or abuse, particular for nasal and/or intravenous
administration, by conventional means such as grinding in a mortar
or crushing by means of a hammer. In this regard, the tablets as
such may be crushable by conventional means. However, the
particulates contained in the tablets according to the invention
exhibit mechanical properties such that they cannot be pulverized
by conventional means any further. As the particulates are of
macroscopic size and contain the pharmacologically active compound,
they cannot be administered nasally thereby rendering the tablets
tamper-resistant. Preferably, when trying to tamper the 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 is as less as
possible, preferably it contains not more than 20 wt.-%, more
preferably not more than 15 wt.-%, still more preferably not more
than 10 wt.-%, and most preferably not more than 5 wt.-% of the
originally contained pharmacologically active compound. Preferably,
this property is tested by (i) dispensing a tablet that is either
intact or has been manually comminuted by means of two spoons in 5
ml of purified water, (ii) heating the liquid up to its boiling
point, (iii) boiling the liquid in a covered vessel for 5 min
without the addition of further purified water, (iv) drawing up the
hot liquid into a syringe (needle 21 G equipped with a cigarette
filter), (v) determining the amount of the pharmacologically active
compound contained in the liquid within the syringe.
[0049] Further, when trying to disrupt the tablets by means of a
hammer or mortar, the particulates tend to adhere to one another
thereby forming aggregates and agglomerates, respectively, which
are larger in size than the untreated particulates.
[0050] The subjects to which the tablets according to the invention
can be administered are not particularly limited. Preferably, the
subjects are animals, more preferably human beings.
[0051] In the tablets according to the invention, the particulates
are incorporated into a matrix material. From a macroscopic
perspective, the matrix material preferably forms a continuous
phase in which the particulates are embedded as discontinuous
phase.
[0052] Preferably, the matrix material is a homogenous coherent
mass, preferably a homogeneous mixture of solid constituents, in
which the particulates are embedded thereby spatially separating
the particulates from one another. While it is possible that the
surfaces of particulates are in contact or at least in very close
proximity with one another, the plurality of particulates
preferably cannot be regarded as a single continuous coherent mass
within the tablet.
[0053] In other words, the tablet according to the invention
comprises the particulates as volume element(s) of a first type in
which the pharmacologically active compound and the polyalkylene
oxide are contained, preferably homogeneously, and the matrix
material as volume element of a second type differing from the
material that forms the particulates, preferably containing neither
pharmacologically active compound nor polyalkylene oxide, but
optionally polyethylene glycol which differs from polyethylene
oxide in its molecular weight.
[0054] A purpose of the matrix material in the tablet according to
the invention is to ensure rapid disintegration and subsequent
release of the pharmacologically active compound from the
disintegrated tablets, i.e. from the particulates. Thus, the matrix
material preferably does not contain any excipient that might have
a retardant effect on disintegration and drug release,
respectively. Thus, the matrix material preferably does not contain
any polymer that is typically employed as matrix material in
prolonged release formulations.
[0055] FIG. 1 schematically illustrates a preferred embodiment of
the tablet according to the invention. Tablet (1) contains a
plurality of particulates (2) that form a discontinuous phase
within matrix material (3) which in turn forms a continuous
phase.
[0056] The tamper-resistant tablet according to the invention
comprises the matrix material in an amount of more than one third
of the total weight of the tablet.
[0057] It has been surprisingly found that the content of the
matrix material in the tablet can be optimized in order to provide
the best compromise between tamper-resistance, disintegration time
and drug release, drug load, processability (especially
tablettability) and patient compliance.
[0058] Preferably, the content of the matrix material is 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
tablet.
[0059] Preferably, the content of the matrix material 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 tablet.
[0060] In a preferred embodiment, the content of the matrix
material is within the range of 40.+-.5 wt.-%, more preferably
40.+-.2.5 wt.-%, based on the total weight of the tablet. In
another preferred embodiment, the content of the matrix material is
within the range of 45.+-.10 wt.-%, more preferably 45.+-.7.5
wt.-%, still more preferably 45.+-.5 wt.-%, and most preferably
45.+-.2.5 wt.-%, based on the total weight of the tablet. In still
another preferred embodiment, the content of the matrix material is
within the range of 50.+-.10 wt.-%, more preferably 50.+-.7.5
wt.-%, still more preferably 50.+-.5 wt.-%, and most preferably
50.+-.2.5 wt.-%, based on the total weight of the tablet. In yet
another preferred embodiment, the content of the matrix material is
within the range of 55.+-.10 wt.-%, more preferably 55.+-.7.5
wt.-%, still more preferably 55.+-.5 wt.-%, and most preferably
55.+-.2.5 wt.-%, based on the total weight of the tablet.
[0061] Preferably, the matrix material is a mixture, preferably a
homogeneous mixture of at least two different constituents, more
preferably of at least three different constituents.
[0062] In a preferred embodiment, all constituents of the matrix
material are homogeneously distributed in the continuous phase that
is formed by the matrix material.
[0063] In a preferred embodiment, the mixture of all constituents
of the matrix material is blended and employed as a powder, i.e. in
non-pre-compacted form, subsequently mixed with the particulates
that contain the pharmacologically active compound and the
polyalkylene oxide, and then compressed into tablets. Tablets
having acceptance values between about 5 and 6 according to Ph.
Eur. 2.9.40 "Uniformity of Dosage Units" (UDU) can be obtained when
properly adjusting the tablet press. Vibrations should be avoided
to a maximal extent (e.g. by decoupling of hopper and tablet press)
and clearance of equipment parts should be as small as possible.
For example, on a rotary tablet press IMA S250 plus with 26
stations, the following parameters are suitable: round punches 10
mm diameter, radius of curvature 8 mm without debossing; fill curve
13 mm; tablet weight 500 mg; speed: 13700-13800 tablets per hour;
pre compression force 4.7 kN; main compression force 6.7 kN and 8.7
kN; fill depth 14.5 mm and 15 mm; height of tablet bar (pre
compression): 3.5 mm; height of tablet bar (main compression): 3.3
mm and 3.1 mm; revolution speed of feeder (Filomat): 40 rmp.
[0064] In another preferred embodiment, the matrix material is also
provided in particulate form, i.e. in the course of the manufacture
of the tablets according to the invention, the constituents of the
matrix material are preferably processed into particulates,
subsequently mixed with the particulates that contain the
pharmacologically active compound and the polyalkylene oxide, and
then compressed into the tablets.
[0065] Preferably, the average size of the particulates of the
matrix material is within the range of .+-.60%, more preferably
.+-.50%, still more preferably .+-.40%, yet more preferably
.+-.30%, most preferably .+-.20%, and in particular .+-.10% of the
average size of the particulates that contain the pharmacologically
active compound and the polyalkylene oxide.
[0066] It has been surprisingly found that when proceeding this
way, segregation phenomena upon blending the particulates can be
reduced or even completely suppressed, thereby substantially
improving the content uniformity of the tablets according to the
invention.
[0067] This is particularly surprising, as the larger the
particulates are which are to be mixed and compressed to tablets,
the more difficult it typically is to satisfy content uniformity
requirements. Compared to conventional tablets, the tablets
according to the invention are manufactured from comparatively
large particulates and optionally, also from comparatively large
pre-compacted particulates of matrix material. Preferably, the AV
(acceptance value) concerning the content uniformity of the tablets
according to the invention is at most 15, more preferably at most
14, still more preferably at most 13, yet more preferably at most
12, even more preferably at most 11, most preferably at most 10 and
in particular at most 9. Methods to determine the AV are known to
the skilled artisan. Preferably, the AV is determined in accordance
with Eur. Ph.
[0068] This preferred embodiment of the tablets according to the
invention is schematically illustrated in FIG. 2. Tablet (1)
contains a plurality of particulates (2) that form a discontinuous
phase within matrix material (3) which in turn forms a continuous
phase and is also provided in particulate form, the individual
particulates being in intimate contact with one another at
boundaries (4). As the particulates of the matrix material
typically have a mechanical strength lower than that of the
particulates (2), the particulates of the matrix material are
deformed in the course of the manufacture of the tablets by
compression.
[0069] The particulates of the matrix material can be manufactured
by conventional methods for the preparation of aggregates and
agglomerates from powder mixtures such as granulating and
compacting.
[0070] In a preferred embodiment, the mixture of all constituents
of the matrix material is blended and pre-compacted thereby
yielding a pre-compacted matrix material.
[0071] Suitable methods for the manufacture of such a pre-compacted
matrix material are known to the skilled person. Preferably,
pre-compaction proceeds by dry granulation, preferably slugging or
roller compaction. When proceeding this way, the process parameters
are typically to be adjusted in order to achieve the desired
properties (see below). Typical process parameters are compaction
force (preferably adjusted within the range of 2 to 12 kN), roller
displacement (preferably adjusted within the range of 2 to 5 mm)
and granule sieve (preferably adjusted within the range of 1.0 to
2.0 mm). The desired properties of the pre-compacted material
include primarily the particle size and the content of fine
particles. The density may also play a role. The particle size is
preferably within the range for the size of the particulates
(preferably at least 60%>700 .mu.m for particulates having
dimensions of 0.8.times.0.8 mm). The content of fine particles
(i.e. particles having a size of less than 600 .mu.m) is preferably
at most 40%, more preferably at most 30%, most preferably at most
20%. The effect of said process parameters on said desired
properties can be easily determined by a skilled person by routine
experimentation.
[0072] In another preferred embodiment, the mixture of all
constituents of the matrix material is dry granulated thereby
yielding a granulated matrix material. In still another preferred
embodiment, the mixture of all constituents of the matrix material
is wet granulated by means of a non-aqueous solvent e.g. ethanol
thereby yielding another granulated matrix material. Aqueous
granulation, however, is preferably avoided, as this typically has
a detrimental influence on disintegration of the tablet. In yet
another preferred embodiment, the mixture of all constituents of
the matrix material is melt granulated, e.g. by means of an
extruder, a heatable high-shear mixer or a granulator.
[0073] As already mentioned above, the matrix material in the
tablet according to the invention should ensure rapid
disintegration and subsequent release of the pharmacologically
active compound from the disintegrated tablets, i.e. from the
particulates. Thus, the matrix material preferably does not contain
any excipient that might have a retardant effect on disintegration
and drug release, respectively. Further, the matrix material
preferably does not contain any pharmacologically active
compound.
[0074] Preferably, the matrix material comprises a disintegrant.
Suitable disintegrants are known to the skilled person and are
preferably selected from the group consisting of crosslinked sodium
carboxymethylcellulose (Na-CMC) (e.g. Crosscarmellose,
Ac-Di-Sol.RTM.), crosslinked casein (e.g. Esma-Sprene),
polysaccharide mixtures obtained from soybeans (e.g. Emcosoy.RTM.);
pretreated maize starch (e.g. Amijel.RTM.); sodium alginate;
polyvinylpyrrolidone (PVP) (e.g. Kollidone.RTM., Polyplasdone.RTM.,
Polydone.RTM.); crosslinked polyvinylpyrrolidone (PVP Cl) (e.g.
Polyplasdone.RTM. XL); starch and pretreated starch such as sodium
carboxymethyl starch (e.g. Explotab.RTM., Prejel.RTM.,
Primotab.RTM. ET, Starch.RTM. 1500, Ulmatryl.RTM.). Crosslinked
polymers are particularly preferred disintegrants, especially
crosslinked sodium carboxymethylcellulose (Na-CMC) or crosslinked
polyvinylpyrrolidone (PVP Cl).
[0075] Preferably, the disintegrant is contained in the matrix
material but not in the particulates of the tablet according to the
invention.
[0076] In a preferred embodiment, the content of the disintegrant
in the matrix material is within the range of 5.+-.4 wt.-%, more
preferably 5.+-.3 wt.-%, still more preferably 5.+-.2.5 wt.-%, yet
more preferably 5.+-.2 wt.-%, most preferably 5.+-.1.5 wt.-%, and
in particular 5.+-.1 wt.-%, based on the total weight of matrix
material. In another preferred embodiment, the content of the
disintegrant in the matrix material is within the range of 7.5.+-.4
wt.-%, more preferably 7.5.+-.3 wt.-%, still more preferably
7.5.+-.2.5 wt.-%, yet more preferably 7.5.+-.2 wt.-%, most
preferably 7.5.+-.1.5 wt.-%, and in particular 7.5.+-.1 wt.-%,
based on the total weight of matrix material. In still another
preferred embodiment, the content of the disintegrant in the matrix
material is within the range of 10.+-.4 wt.-%, more preferably
10.+-.3 wt.-%, still more preferably 10.+-.2.5 wt.-%, yet more
preferably 10.+-.2 wt.-%, most preferably 10.+-.1.5 wt.-%, and in
particular 10.+-.1 wt.-%, based on the total weight of matrix
material. In another preferred embodiment, the content of the
disintegrant in the matrix material is within the range of
12.5.+-.4 wt.-%, more preferably 12.5.+-.3 wt.-%, still more
preferably 12.5.+-.2.5 wt.-%, yet more preferably 12.5.+-.2 wt.-%,
most preferably 12.5.+-.1.5 wt.-%, and in particular 12.5.+-.1
wt.-%, based on the total weight of matrix material.
[0077] In a preferred embodiment, the content of the disintegrant
in the tablet is within the range of 2.+-.1.8 wt.-%, more
preferably 2.+-.1.5 wt.-%, still more preferably 2.+-.1.3 wt.-%,
yet more preferably 2.+-.1.0 wt.-%, most preferably 2.+-.0.8 wt.-%,
and in particular 2.+-.0.5 wt.-%, based on the total weight of
tablet. In another preferred embodiment, the content of the
disintegrant in the tablet is within the range of 4.+-.1.8 wt.-%,
more preferably 4.+-.1.5 wt.-%, still more preferably 4.+-.1.3
wt.-%, yet more preferably 4.+-.1.0 wt.-%, most preferably 4.+-.0.8
wt.-%, and in particular 4.+-.0.5 wt.-%, based on the total weight
of tablet. In still another preferred embodiment, the content of
the disintegrant in the tablet is within the range of 6.+-.1.8
wt.-%, more preferably 6.+-.1.5 wt.-%, still more preferably
6.+-.1.3 wt.-%, yet more preferably 6.+-.1.0 wt.-%, most preferably
6.+-.0.8 wt.-%, and in particular 6.+-.0.5 wt.-%, based on the
total weight of tablet. In another preferred embodiment, the
content of the disintegrant in the tablet is within the range of
8.+-.1.8 wt.-%, more preferably 8.+-.1.5 wt.-%, still more
preferably 8.+-.1.3 wt.-%, yet more preferably 8.+-.1.0 wt.-%, most
preferably 8.+-.0.8 wt.-%, and in particular 8.+-.0.5 wt.-%, based
on the total weight of tablet.
[0078] Preferably, the matrix material comprises a disintegrant in
combination with one or more water insoluble pharmaceutical
excipients, preferably fillers/binders and/or lubricants.
[0079] Preferably, the matrix material comprises a filler or a
binder. 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
matrix material preferably comprises a filler/binder.
[0080] Preferred fillers (=filler/binders) are selected from the
group consisting of silicium dioxide (e.g. Aerosil.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.); maltodextrine
(e.g. Emdex.RTM.); lactose (e.g. Fast-Flow Lactose.RTM.;
Ludipress.RTM., Tablettose.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).
[0081] Some fillers/binders may also serve other purposes. It is
known, for example, that silicium dioxide exhibits excellent
function as a glidant. Thus, preferably, the matrix material
comprises a glidant such as silicium dioxide.
[0082] In a preferred embodiment, the content of the filler/binder
or mixture of fillers/binders in the matrix material 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 matrix material. In another preferred
embodiment, the content of the filler/binder or mixture of
fillers/binders in the matrix material 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 matrix material. In still another preferred
embodiment, the content of the filler/binder or mixture of
fillers/binders in the matrix material 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 matrix material. In another preferred
embodiment, the content of the filler/binder or mixture of
fillers/binders in the matrix material 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 matrix material.
[0083] In a preferred embodiment, the content of the filler/binder
or mixture of fillers/binders in the tablet 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 tablet. In another preferred embodiment, the
content of the filler/binder or mixture of fillers/binders in the
tablet 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 tablet. In
still another preferred embodiment, the content of the
filler/binder or mixture of fillers/binders in the tablet 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 tablet. In another preferred
embodiment, the content of the filler/binder or mixture of
fillers/binders in the tablet 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 tablet.
[0084] Preferably, the filler/binder is contained in the matrix
material but not in the particulates of the tablet according to the
invention.
[0085] In a preferred embodiment, a portion (e.g. 10% of the total
tablet mass) of the matrix is granulated on the particulates
(preferably by non-aqueous wet granulation, e.g. with isopropylic
alcohol) and the remaining matrix material is added to the thus
granulated particulates and blended prior to compression/processing
to tablets. Thus, according to this embodiment, the particulates
are coated by a portion of the matrix material, whereas the
remainder of the matrix material is preferably employed in
non-granulated form.
[0086] Preferably, the matrix material comprises a diluent or
lubricant, 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 matrix material 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 matrix material and based on the total
weight of tablet.
[0087] In particularly preferred embodiment, the matrix material
comprises a combination of disintegrant, filler/binder and
lubricant.
[0088] Particularly preferred contents of disintegrant,
filler/binder and lubricant of the matrix material, relative to the
total weight of the matrix material, are summarized as embodiments
A.sup.1 to A.sup.6 in the table here below:
TABLE-US-00001 wt.-% A.sup.1 A.sup.2 A.sup.3 A.sup.4 A.sup.5
A.sup.6 disintegrant 11 .+-. 10 11 .+-. 7.5 11 .+-. 5.0 11 .+-. 3.5
11 .+-. 2.5 11 .+-. 1.5 filler/binder 88 .+-. 12 88 .+-. 10 88 .+-.
8 88 .+-. 6 88 .+-. 4 88 .+-. 2.5 lubricant 0.30 .+-. 0.28 0.30
.+-. 0.26 0.30 .+-. 0.24 0.30 .+-. 0.22 0.30 .+-. 0.20 0.30 .+-.
0.15
wherein the disintegrant is preferably crosslinked sodium
carboxymethyl cellulose (Na-CMC) or crosslinked
polyvinylpyrrolidone (PVP Cl); the filler binder is preferably
microcrystalline cellulose or a combination of microcrystalline
cellulose with colloidal silicon dioxide; and the lubricant is
preferably magnesium stearate.
[0089] The matrix material of the tablets according to the
invention may additionally contain other excipients that are
conventional in the art, e.g. diluents, binders, granulating aids,
colourants, flavourants, pore formers, surfactants, glidants,
wet-regulating agents and disintegrants. The skilled person will
readily be able to determine appropriate quantities of each of
these excipients.
[0090] Preferred pore formers include, but are not limited to
glucose, fructose, mannitol, mannose, galactose, sorbitol,
pullulan, dextran, water-soluble hydrophilic polymers,
hydroxyalkylcelluloses, carboxyalkylcelluloses,
hydroxypropylmethylcellulose, cellulose ethers, acrylic resins,
polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone,
polyethylene oxide, carbowaxes, carbopol, diols, polyols,
polyhydric alcohols, polyalkylene glycols, polyethylene glycols,
polypropylene glycols or block polymers thereof, polyglycols,
poly(.alpha.-.omega.)alkylenediols, inorganic compounds; alkali
metal salts; alkaline earth metal salts, or combinations
thereof.
[0091] Preferred surfactants are nonionic, anionic, cationic or
amphoteric surfactants.
[0092] In a preferred embodiment, the matrix material contains an
ionic surfactant, in particular an anionic surfactant.
[0093] Suitable anionic surfactants include but are not limited to
sulfuric acid esters such as sodium lauryl sulfate (sodium dodecyl
sulfate, e.g. Texapon.RTM. K12), sodium cetyl sulfate (e.g. Lanette
E.RTM.), sodium cetylstearyl sulfate, sodium stearyl sulfate,
sodium dioctylsulfosuccinate (docusate sodium); and the
corresponding potassium or calcium salts thereof.
[0094] Preferably, the anionic surfactant has the general formula
(II-a)
C.sub.nH.sub.2n+1O--SO.sub.3.sup.-M.sup.+ (II-a),
wherein n is an integer of from 8 to 30, preferably 10 to 24, more
preferably 12 to 18; and M is selected from Li.sup.+, Na.sup.+,
K.sup.+, NH.sub.4.sup.+ 1/2 Mg.sup.2+and 1/2 Ca.sup.2+.
[0095] Further suitable anionic surfactants include salts of cholic
acid including sodium glycocholate (e.g. Konakion.RTM. MM,
Cernevit.RTM.), sodium taurocholate and the corresponding potassium
or ammonium salts.
[0096] In another preferred embodiment, the matrix material
contains a non-ionic surfactant. Suitable non-ionic surfactants
include but are not limited to [0097] fatty alcohols that may be
linear or branched, such as cetylalcohol, stearylalcohol,
cetylstearyl alcohol, 2-octyldodecane-1-ol and 2-hexyldecane-1-ol;
[0098] sterols, such as cholesterole; [0099] partial fatty acid
esters of sorbitan such as sorbitanmonolaurate,
sorbitanmonopalmitate, sorbitanmonostearate, sorbitantristearate,
sorbitanmonooleate, sorbitansesquioleate and sorbitantrioleate;
[0100] partial fatty acid esters of polyoxyethylene sorbitan
(polyoxyethylene-sorbitan-fatty acid esters), preferably a fatty
acid monoester of polyoxyethylene sorbitan, a fatty acid diester of
polyoxyethylene sorbitan, or a fatty acid triester of
polyoxyethylene sorbitan; e.g. mono- and tri-lauryl, palmityl,
stearyl and oleyl esters, such as the type known under the name
"polysorbat" and commercially available under the trade name
"Tween" including Tween.RTM. 20 [polyoxyethylene(20)sorbitan
monolaurate], Tween.RTM. 21 [polyoxyethylene(4)sorbitan
monolaurate], Tween.RTM. 40 [polyoxyethylene(20)sorbitan
monopalmitate], Tween.RTM. 60 [polyoxyethylene(20)-sorbitan
monostearate], Tween.RTM. 65 [polyoxyethylene(20)sorbitan
tristearate], Tween.RTM. 80 [polyoxyethylene(20)sorbitan
monooleate], Tween 81 [polyoxyethylene(5)sorbitan monooleate], and
Tween.RTM. 85 [polyoxyethylene(20)sorbitan trioleate]; preferably a
fatty acid monoester of polyoxyethylene-sorbitan according to
general formula (II-b)
[0100] ##STR00001## [0101] wherein (w+x+y+z) is within the range of
from 15 to 100, preferably 16 to 80, more preferably 17 to 60,
still more preferably 18 to 40 and most preferably 19 to 21; and
alkylene is an optionally unsaturated alkylene group comprising 6
to 30 carbon atoms, more preferably 8 to 24 carbon atoms and most
preferably 10 to 16 carbon atoms; [0102] polyoxyethyleneglycerole
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 (e.g.
Cremophor.RTM. RH 40), and macrogolglycerolrizinoleate (e.g.
Cremophor.RTM. EL); [0103] polyoxyethylene fatty acid esters, the
fatty acid preferably having from about 8 to about 18 carbon atoms,
e.g. macrogololeate, macrogolstearate, macrogol-15-hydroxystearate,
polyoxyethylene esters of 12-hydroxystearic acid, such as the type
known and commercially available under the trade name "Solutol HS
15"; preferably according to general formula (II-c)
[0103]
CH.sub.3CH.sub.2--(OCH.sub.2CH.sub.3).sub.n--O--CO--(CH.sub.2).su-
b.mCH.sub.3 (II-c) [0104] wherein n is an integer of from 6 to 500,
preferably 7 to 250, more preferably 8 to 100, still more
preferably 9 to 75, yet more preferably 10 to 50, even more
preferably 11 to 30, most preferably 12 to 25, and in particular 13
to 20; and wherein m is an integer of from 6 to 28; more preferably
6 to 26, still more preferably 8 to 24, yet more preferably 10 to
22, even more preferably 12 to 20, most preferably 14 to 18 and in
particular 16; [0105] polyoxyethylene fatty alcohol ethers, e.g.
macrogolcetylstearylether, macrogollarylether, macrogololeylether,
macrogolstearylether; [0106] polyoxypropylene-polyoxyethylene block
copolymers (poloxamers); [0107] fatty acid esters of saccharose;
e.g. saccharose distearate, saccharose dioleate, saccharose
dipalmitate, saccharose monostearate, saccharose monooleate,
saccharose monopalmitate, saccharose monomyristate and saccharose
monolaurate; [0108] fatty acid esters of polyglycerol, e.g.
polyglycerololeate; [0109] polyoxyethylene esters of
alpha-tocopheryl succinate, e.g.
D-alpha-tocopheryl-PEG-1000-succinate (TPGS); [0110] polyglycolyzed
glycerides, such as the types known and commercially available
under the trade names "Gelucire 44/14", "Gelucire 50/13 and
"Labrasol"; [0111] reaction products of a natural or hydrogenated
castor oil and ethylene oxide such as the various liquid
surfactants known and commercially available under the trade name
"Cremophor"; and [0112] partial fatty acid esters of
multifunctional alcohols, such as glycerol fatty acid esters, e.g.
mono- and tri-lauryl, palmityl, stearyl and oleyl esters, for
example glycerol monostearate, glycerol monooleate, e.g. glyceryl
monooleate 40, known and commercially available under the trade
name "Peceol"; glycerole dibehenate, glycerole distearate,
glycerole monolinoleate; ethyleneglycol monostearate,
ethyleneglycol monopalmitostearate, pentaerythritol
monostearate.
[0113] In a preferred embodiment, the matrix material according to
the invention comprises a surfactant or mixture of different
surfactants obtainable by [0114] (i) esterifying saturated or
unsaturated C.sub.12-C.sub.18-fatty acids, optionally bearing a
hydroxyl group, with a polyethylene glycol and optionally,
glycerol; wherein the polyethylene glycol preferably comprises 10
to 40 ethylene oxide units (--CH.sub.2CH.sub.2O--); and/or [0115]
(ii) etherifying triglycerides of saturated or unsaturated
C.sub.12-C.sub.18-fatty acids bearing a hydroxyl group with
ethylene oxide so that a polyethylene glycol moiety is linked to
the hydroxyl group of the C.sub.12-C.sub.18-fatty acids via an
ether bond; wherein the polyethylene glycol moiety preferably
comprises 30 to 50 ethylene oxide units (--CH.sub.2CH.sub.2O).
[0116] In a preferred embodiment, the content of the surfactant is
at least 0.001 wt.-% or at least 0.005 wt.-%, more preferably at
least 0.01 wt.-% or at least 0.05 wt.-%, still more preferably at
least 0.1 wt.-%, at least 0.2 wt.-%, or at least 0.3 wt.-%, yet
more preferably at least 0.4 wt.-%, at least 0.5 wt.-%, or at least
0.6 wt.-%, and in particular at least 0.7 wt.-%, at least 0.8
wt.-%, at least 0.9 wt.-%, or at least 1.0 wt.-%, based on the
total weight of the tablet.
[0117] In a preferred embodiment, however, the matrix material of
the tablet 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.
[0118] In a particularly preferred embodiment, the matrix material
of the tablet according to the invention does not contain one or
more gel-forming agents and/or a silicone.
[0119] 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
compound 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 compound,
and which can be drawn into a syringe. The gel that is formed may
also reduce the overall amount of pharmacologically active compound
extractable with the solvent by entrapping the pharmacologically
active compound within a gel structure. Thus the gel-forming agent
may play an important role in conferring tamper-resistance to the
tablets according to the invention.
[0120] Gel-forming agents that preferably are not contained in the
matrix material include pharmaceutically acceptable polymers,
typically hydrophilic polymers, such as hydrogels. Representative
examples of gel-forming agent include polyethylene oxide, polyvinyl
alcohol, hydroxypropylmethyl cellulose, carbomers, poly(uronic)
acids and mixtures thereof.
[0121] Thus, the polyalkylene oxide that is contained in the
particulates of the tablets according to the invention is
preferably not also contained in the matrix material.
[0122] Preferably, the pharmacologically active compound which is
contained in the particulates of the tablet according to the
invention is preferably not also contained in the matrix
material.
[0123] Thus, in a preferred embodiment, the total amount of
pharmacologically active compound contained in the tablet according
to the invention is present in the particulates which form a
discontinuous phase within the matrix material; and the matrix
material forming a continuous phase does not contain any
pharmacologically active compound.
[0124] The tablet according to the invention contains a plurality
of particulates. The particulates comprise a pharmacologically
active compound and a polyalkylene oxide. Preferably, the
pharmacologically active compound is dispersed in the polyalkylene
oxide.
[0125] For the purpose of the specification, the term "particulate"
refers to a discrete mass of material that is solid, e.g. at
20.degree. C. or at room temperature or ambient temperature.
Preferably a particulate is solid at 20.degree. C. Preferably, the
particulates are monoliths.
[0126] Preferably, the pharmacologically active compound and the
polyalkylene oxide are intimately homogeneously distributed in the
particulates so that the particulates do not contain any segments
where either pharmacologically active compound is present in the
absence of polyalkylene oxide or where polyalkylene oxide is
present in the absence of pharmacologically active compound.
[0127] When the particulates are film coated, the polyalkylene
oxide is preferably homogeneously distributed in the core of the
pharmaceutical dosage form (tablet), i.e. the film coating
preferably does not contain polyalkylene oxide, but optionally
polyalkylene glycol that differs from polyalkylene oxide in its
lower molecular weight. 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 core.
[0128] The particulates are of macroscopic size, typically the
average diameter is within the range of from 100 .mu.m to 1500
.mu.m, preferably 200 .mu.m to 1500 .mu.m, more preferably 300
.mu.m to 1500 .mu.m, still more preferably 400 .mu.m to 1500 .mu.m,
most preferably 500 .mu.m to 1500 .mu.m, and in particular 600
.mu.m to 1500 .mu.m. The tablets according to the invention
comprise particulates as a discontinuous phase, i.e. the
particulates form a discontinuous phase in the matrix material
which in turn preferably forms a continuous phase. In this regard,
discontinuous means that not each and every particulate is in
intimate contact with another particulate but that the particulates
are at least partially separated from one another by the matrix
material in which the particulates are embedded. In other words,
the particulates preferably do not form a single coherent mass
within the tablets according to the invention.
[0129] The tablet according to the invention comprises particulates
in an amount of less than two thirds of the total weight of the
tablet.
[0130] It has been surprisingly found that the content of
particulates in the tablet can be optimized in order to provide the
best compromise between tamper-resistance, disintegration time and
drug release, drug load, processability (especially tablettability)
and patient compliance.
[0131] Preferably, the content of the particulates in the tablets
according to the invention is at most 65 wt.-%, more preferably at
most 62.5 wt.-%, still more preferably at most 60 wt.-%, yet more
preferably at most 57.5 wt.-%, most preferably at most 55 wt.-% and
in particular at most 52.5 wt.-%, based on the total weight of the
tablets.
[0132] Preferably, the content of the particulates in the tablets
according to the invention is at least 10 wt.-%, at least 12.5
wt.-%, at least 15 wt.-% or at least 17.5 wt.-%; more preferably at
least 20 wt.-%, at least 22.5 wt.-%, at least 25 wt.-% or at least
27.5 wt.-%; most preferably at least 30 wt.-%, at least 32.5 wt.-%,
at least 35 wt.-% or at least 37.5 wt.-%; and in particular at
least 40 wt.-%, at least 42.5 wt.-%, at least 45 wt.-% or at least
47.5 wt.-%; based on the total weight of the tablet.
[0133] In a preferred embodiment, the content of the particulates
in the tablets according to the invention is within the range of
35.+-.30 wt.-%, more preferably 35.+-.25 wt.-%, still more
preferably 35.+-.20 wt.-%, yet more preferably 35.+-.15 wt.-%, most
preferably 35.+-.10 wt.-%, and in particular 35.+-.5 wt.-%, based
on the total weight of the tablet. In another preferred embodiment,
the content of the particulates in the tablets according to the
invention is within the range of 40.+-.30 wt.-%, more preferably
40.+-.25 wt.-%, still more preferably 40.+-.20 wt.-%, yet more
preferably 40.+-.15 wt.-%, most preferably 40.+-.10 wt.-%, and in
particular 40.+-.5 wt.-%, based on the total weight of the tablet.
In still another preferred embodiment, the content of the
particulates in the tablets according to the invention is within
the range of 45.+-.30 wt.-%, more preferably 45.+-.25 wt.-%, still
more preferably 45.+-.20 wt.-%, yet more preferably 45.+-.15 wt.-%,
most preferably 45.+-.10 wt.-%, and in particular 45.+-.5 wt.-%,
based on the total weight of the tablet. In yet another preferred
embodiment, the content of the particulates in the tablets
according to the invention is within the range of 50.+-.30 wt.-%,
more preferably 50.+-.25 wt.-%, still more preferably 50.+-.20
wt.-%, yet more preferably 50.+-.15 wt.-%, most preferably 50.+-.10
wt.-%, and in particular 50.+-.5 wt.-%, based on the total weight
of the tablet. In another preferred embodiment, the content of the
particulates in the tablets according to the invention is within
the range of 55.+-.30 wt.-%, more preferably 55.+-.25 wt.-%, still
more preferably 55.+-.20 wt.-%, yet more preferably 55.+-.15 wt.-%,
most preferably 55.+-.10 wt.-%, and in particular 55.+-.5 wt.-%,
based on the total weight of the tablet. In still another preferred
embodiment, the content of the particulates in the tablets
according to the invention is within the range of 60.+-.30 wt.-%,
more preferably 60.+-.25 wt.-%, still more preferably 60.+-.20
wt.-%, yet more preferably 60.+-.15 wt.-%, most preferably 60.+-.10
wt.-%, and in particular 60.+-.5 wt.-%, based on the total weight
of the tablet.
[0134] The shape of the particulates is not particularly limited.
As the particulates are preferably manufactured by hot-melt
extrusion, preferred particulates present in the tablets according
to the invention are generally cylindrical in shape. The diameter
of such particulates is therefore the diameter of their circular
cross section. The cylindrical shape is caused by the extrusion
process 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.
[0135] The suitability of cylindrical, i.e. a spherical
particulates for the manufacture of the tablets according to the
invention is unexpected. Typically, the aspect ratio is regarded as
an important measure of the spherical shape. The aspect ratio is
defined as the ratio of the maximal diameter (d.sub.max) and its
orthogonal Feret-diameter. For aspherical particulates, the aspect
ratio has values above 1. The smaller the value the more spherical
is the particulate. Aspect ratios below 1.1 are typically
considered satisfactory, aspect ratios above 1.2, however, are
typically considered not suitable for the manufacture of
conventional tablets. The inventors have surprisingly found that
when manufacturing the tablets according to the invention, even
particulates having aspect ratios above 1.2 can be processed
without difficulties and that it is not necessary to provide
spherical particulates. In a preferred embodiment, the aspect ratio
of the particulates is at most 1.40, more preferably at most 1.35,
still more preferably at most 1.30, yet more preferably at most
1.25, even more preferably at most 1.20, most preferably at most
1.15 and in particular at most 1.10. In another preferred
embodiment, the aspect ratio of the particulates is at least 1.10,
more preferably at least 1.15, still more preferably at least 1.20,
yet more preferably at least 1.25, even more preferably at least
1.30, most preferably at least 1.35 and in particular at least
1.40.
[0136] The particulates in the tablets according to the invention
are of macroscopic size, i.e. typically have an average particle
size of at least 50 .mu.m, more preferably at least 100 .mu.m,
still more preferably at least 150 .mu.m or at least 200 .mu.m, yet
more preferably at least 250 .mu.m or at least 300 .mu.m, most
preferably at least 400 .mu.m or at least 500 .mu.m, and in
particular at least 550 .mu.m or at least 600 .mu.m.
[0137] Preferred particulates have an average length and average
diameter of about 1000 .mu.m or less. When the particulates are
manufactured by extrusion technology, the "length" of particulates
is the dimension of the particulates that is parallel to the
direction of extrusion. The "diameter" of particulates is the
largest dimension that is perpendicular to the direction of
extrusion.
[0138] Particularly preferred particulates have an average diameter
of less than about 1000 .mu.m, more preferably less than about 800
.mu.m, still more preferably of less than about 650 .mu.m.
Especially preferred particulates have an average diameter of less
than 700 .mu.m, particularly less than 600 .mu.m, still more
particularly less than 500 .mu.m, e.g. less than 400 .mu.m.
Particularly preferred particulates have an average diameter in the
range 200-1000 .mu.m, more preferably 400-800 .mu.m, still more
preferably 450-700 .mu.m, yet more preferably 500-650 .mu.m, e.g.
about 500-600 .mu.m. Further preferred particulates have an average
diameter of between about 300 .mu.m and about 400 .mu.m, of between
about 400 .mu.m and 500 .mu.m, or of between about 500 .mu.m and
600 .mu.m, or of between 600 .mu.m and 700 .mu.m or of between 700
.mu.m and 800 .mu.m.
[0139] Preferred particulates that are present in the tablets
according to the invention have an average length of less than
about 1000 .mu.m, preferably an average length of less than about
800 .mu.m, still more preferably an average length of less than
about 650 .mu.m, e.g. a length of about 800 .mu.m, about 700 .mu.m
about 600 .mu.m, about 500 .mu.m, about 400 .mu.m or about 300
.mu.m. Especially preferred particulates have an average length of
less than 700 .mu.m, particularly less than 650 .mu.m, still more
particularly less than 550 .mu.m, e.g. less than 450 .mu.m.
Particularly preferred particulates therefore have an average
length in the range 200-1000 .mu.m, more preferably 400-800 .mu.m,
still more preferably 450-700 .mu.m, yet more preferably 500-650
.mu.m, e.g. about 500-600 .mu.m. The minimum average length of the
microparticulates is determined by the cutting step and may be,
e.g. 500 .mu.m, 400 .mu.m, 300 .mu.m or 200 .mu.m.
[0140] In a preferred embodiment, the particulates have (i) an
average diameter of about 750.+-.300 .mu.m, more preferably
750.+-.250 .mu.m, still more preferably 750.+-.200 .mu.m, yet more
preferably 750.+-.150 .mu.m, most preferably 750.+-.100 .mu.m, and
in particular 750.+-.50 .mu.m; and/or (ii) an average length of
about 750.+-.300 .mu.m, more preferably 750.+-.250 .mu.m, still
more preferably 750.+-.200 .mu.m, yet more preferably 750.+-.150
.mu.m, most preferably 750.+-.100 .mu.m, and in particular
750.+-.50 .mu.m.
[0141] It has been surprisingly found that the size of the
particulates in the tablet can be optimized in order to provide the
best compromise between tamper-resistance, disintegration time and
drug release, drug load, processability (especially tablettability)
and patient compliance.
[0142] The size of particulates may be determined by any
conventional procedure known in the art, e.g. laser light
scattering, sieve analysis, light microscopy or image analysis.
[0143] Preferably, the plurality of particulates that is contained
in the tablet according to the invention has an arithmetic average
weight, in the following referred to as "aaw", wherein at least
70%, more preferably at least 75%, still more preferably at least
80%, yet more preferably at least 85%, most preferably at least 90%
and in particular at least 95% of the individual particles
contained in said plurality of particulates has an individual
weight within the range of aaw.+-.30%, more preferably aaw.+-.25%,
still more preferably aaw.+-.20%, yet more preferably aaw.+-.15%,
most preferably aaw.+-.10%, and in particular aaw.+-.5%. For
example, if the tablet according to the invention contains a
plurality of 100 particulates and aaw of said plurality of
particulates is 1.00 mg, at least 75 individual particles (i.e.
75%) have an individual weight within the range of from 0.70 to
1.30 mg (1.00 mg.+-.30%).
[0144] In a preferred embodiment, the particulates are not film
coated.
[0145] In another preferred embodiment, the particulates are film
coated. It has been surprisingly found that when the particulates
are film coated, the disintegration time and/or the drug release
from the tablets can be further accelerated, which is particularly
significant for tablets with immediate drug release.
[0146] The particulates according to the invention can optionally
be provided, partially or completely, with a conventional coating.
The particulates 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.RTM. and Eudragit.RTM..
[0147] Examples of suitable materials include cellulose esters and
cellulose ethers, such as methylcellulose (MC),
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
hydroxyethylcellulose (HEC), sodium carboxymethylcellulose
(Na-CMC), ethylcellulose (EC), cellulose acetate phthalate (CAP),
hydroxypropylmethylcellulose phthalate (HPMCP);
poly(meth)acrylates, such as aminoalkylmethacrylate copolymers,
ethylacrylate methylmethacrylate copolymers, methacrylic acid
methylmethacrylate copolymers, methacrylic acid methylmethacrylate
copolymers; vinyl polymers, such as polyvinylpyrrolidone,
polyvinylacetatephthalate, polyvinyl alcohol, polyvinyl
alcohol-polyethylene glycol graft copolymers, polyvinylacetate; and
natural film formers.
[0148] 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.
[0149] In a particularly preferred embodiment, the coating is
water-soluble. In a preferred embodiment, the coating is based on
polyvinyl alcohol, such as polyvinyl alcohol-part, hydrolyzed, and
may additionally contain polyethylene glycol, such as macrogol
3350, and/or pigments. In another preferred embodiment, the coating
is based on hydroxypropylmethylcellulose, preferably hypromellose
type 2910 having a viscosity of 3 to 15 mPas.
[0150] 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 tablet 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.
[0151] A particularly preferred coating contains polyvinyl alcohol
and optionally, further excipients such as xanthan gum and/or
talkum.
[0152] When the particulates are film coated, the content of the
dried film coating is preferably at most 5 wt.-%, more preferably
at most 4 wt.-%, still more preferably at most 3.5 wt.-%, yet more
preferably at most 3 wt.-%, most preferably at most 2.5 wt.-%, and
in particular at most 2 wt.-%, based on the total weight of the
particulates. In a particularly preferred embodiment, the weight
increase relative to the total weight of the particulates (uncoated
starting material) is within the range of from 3.0 to 4.7 wt.-%,
more preferably 3.1 to 4.6 wt.-%, still more preferably 3.2 to 4.5
wt.-%, yet more preferably 3.3 to 4.4 wt.-%, most preferably 3.4 to
4.3 wt.-%, and in particular 3.5 to 4.2 wt.-%.
[0153] It has been surprisingly found that the relative weight
ratio of matrix material:particulates in the tablet can be
optimized in order to provide the best compromise between
tamper-resistance, disintegration time and drug release, drug load,
processability (especially tablettability) and patient
compliance.
[0154] Preferably, said relative weight ratio is within the range
of 1:1.00.+-.0.75, more preferably 1:1.00.+-.0.50, still more
preferably 1:1.00.+-.0.40, yet more preferably 1:1.00.+-.0.30, most
preferably 1:1.00.+-.0.20, and in particular 1:1.00.+-.0.10.
[0155] The particulates contain at least a pharmacologically active
compound and a polyalkylene oxide. Preferably, however, the
particulates contain additional pharmaceutical excipients such as
antioxidants and plasticizers.
[0156] The pharmacologically active compound is not particularly
limited. Preferably, the pharmacologically active compound is an
opioid.
[0157] In a preferred embodiment, the particulates and the tablet,
respectively, contain only a single pharmacologically active
compound. In another preferred embodiment, the particulates and the
tablet, respectively, contain a combination of two or more
pharmacologically active compounds.
[0158] Preferably, pharmacologically active compound is an active
ingredient with potential for being abused. 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.
[0159] Preferably, the pharmacologically active compound exhibits
psychotropic action.
[0160] Preferably, the pharmacologically active compound is
selected from the group consisting of opiates, opioids, stimulants,
tranquilizers, and other narcotics.
[0161] Particularly preferably, the pharmacologically active
compound is an opioid. According to the ATC index, opioids are
divided into natural opium alkaloids, phenylpiperidine derivatives,
diphenylpropylamine derivatives, benzomorphan derivatives,
oripavine derivatives, morphinan derivatives and others.
[0162] The following opiates, 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
tablet and the particulates, respectively: alfentanil,
allobarbital, allylprodine, alphaprodine, alprazolam, amfepramone,
amphetamine, amphetaminil, amobarbital, anileridine, apocodeine,
axomadol, barbital, bemidone, benzylmorphine, bezitramide,
bromazepam, brotizolam, buprenorphine, butobarbital, butorphanol,
camazepam, carfentanil, cathine/D-norpseudoephedrine,
chlordiazepoxide, clobazam clofedanol, clonazepam, clonitazene,
clorazepate, clotiazepam, cloxazolam, cocaine, codeine,
cyclobarbital, cyclorphan, cyprenorphine, delorazepam,
desomorphine, dextromoramide, dextropropoxyphene, dezocine,
diampromide, diamorphone, diazepam, dihydrocodeine,
dihydromorphine, dihydromorphone, dimenoxadol, dimephetamol,
dimethylthiambutene, dioxaphetylbutyrate, dipipanone, dronabinol,
eptazocine, estazolam, ethoheptazine, ethylmethylthiambutene, ethyl
loflazepate, ethylmorphine, etonitazene, etorphine, 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,
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,
(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphen-
yl)cyclohexanol,
(1R,2R)-3-(2-dimethylamino-methyl-cyclohexyl)phenol,
(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,
(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,
(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-d-
iol, preferably as racemate,
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl
2-(4-isobutyl-phenyl)propionate,
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl
2-(6-methoxy-naphthalen-2-yl)propionate,
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl
2-(4-isobutyl-phenyl)propionate,
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl
2-(6-methoxy-naphthalen-2-yl)propionate,
(RR--SS)-2-acetoxy-4-trifluoromethyl-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR--SS)-2-hydroxy-4-trifluoromethyl-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR--SS)-4-chloro-2-hydroxy-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR--SS)-2-hydroxy-4-methyl-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR--SS)-2-hydroxy-4-methoxy-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR--SS)-2-hydroxy-5-nitro-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR--SS)-2',4'-difluoro-3-hydroxy-biphenyl-4-carboxylic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester, and
corresponding stereoisomeric compounds, in each case the
corresponding derivatives thereof, physiologically acceptable
enantiomers, stereoisomers, diastereomers and racemates and the
physiologically acceptable derivatives thereof, e.g. ethers, esters
or amides, and in each case the physiologically acceptable
compounds thereof, in particular the acid or base addition salts
thereof and solvates, e.g. hydrochlorides.
[0163] In a preferred embodiment, the pharmacologically active
compound is selected from the group consisting of DPI-125, M6G
(CE-04-410), ADL-5859, CR-665, NRP290 and sebacoyl dinalbuphine
ester.
[0164] In a preferred embodiment, the pharmacologically active
compound is selected from the group consisting of oxymorphone,
hydromorphone and morphine.
[0165] In another preferred embodiment, the pharmacologically
active compound is selected from the group consisting of
tapentadol, faxeladol and axomadol.
[0166] In still another preferred embodiment, the pharmacologically
active compound 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, particularly its hemicitrate;
1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyran-
o[3,4-b]indole, particularly its citrate; and
1,1-[3-dimethylamino-3-(2-thienyl)pentamethylene]-1,3,4,9-tetrahydropyran-
o[3,4-b]-6-fluoroindole, particularly its hemicitrate. These
compounds are known from, e.g., WO 2004/043967, WO 2005/066183.
[0167] The pharmacologically active compound may be present in form
of a physiologically acceptable salt, e.g. physiologically
acceptable acid addition salt.
[0168] Physiologically acceptable acid addition salts comprise the
acid addition salt forms which can conveniently be obtained by
treating the base form of the active ingredient with appropriate
organic and inorganic acids. Active ingredients containing an
acidic proton may be converted into their non-toxic metal or amine
addition salt forms by treatment with appropriate organic and
inorganic bases. The term addition salt also comprises the hydrates
and solvent addition forms which the active ingredients are able to
form. Examples of such forms are e.g. hydrates, alcoholates and the
like.
[0169] It has been surprisingly found that the content of the
pharmacologically active compound in the tablet and in the
particulates, respectively, can be optimized in order to provide
the best compromise between tamper-resistance, disintegration time
and drug release, drug load, processability (especially
tablettability) and patient compliance.
[0170] The pharmacologically active compound is present in the
tablet in a therapeutically effective amount. The amount that
constitutes a therapeutically effective amount varies according to
the active ingredients being used, the condition being treated, the
severity of said condition, the patient being treated, and the
frequency of administration.
[0171] The content of the pharmacologically active compound in the
tablet is not limited. The dose of the pharmacologically active
compound which is adapted for administration preferably is in the
range of 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 pharmacologically active
compound that is contained in the tablet 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.
[0172] Preferably, the content of the pharmacologically active
compound 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 tablet.
[0173] In a preferred embodiment, the content of pharmacologically
active compound is within the range of from 5.0.+-.4.5 wt.-%, or
7.5.+-.7.0 wt.-%, or 10.+-.9.0 wt.-%, or 12.5.+-.12.0 wt.-%, or
15.+-.14 wt.-%, or 17.5.+-.17.0 wt.-%, or 20.+-.19 wt.-%, or
22.5.+-.22.0 wt.-%, or 25.+-.24 wt.-%; more preferably 5.0.+-.4.0
wt.-%, or 7.5.+-.6.0 wt.-%, or 10.+-.8.0 wt.-%, or 12.5.+-.12.0
wt.-%, or 15.+-.12 wt.-%, or 17.5.+-.15.0 wt.-%, or 20.+-.19 wt.-%,
or 22.5.+-.22.0 wt.-%, or 25.+-.24 wt.-%; still more preferably
5.0.+-.3.5 wt.-%, or 7.5.+-.5.0 wt.-%, or 10.+-.7.0 wt.-%, or
12.5.+-.10.0 wt.-%, or 15.+-.10 wt.-%, or 17.5.+-.13.0 wt.-%, or
20.+-.17 wt.-%, or 22.5.+-.19.0 wt.-%, or 25.+-.21 wt.-%; yet more
preferably 5.0.+-.3.0 wt.-%, or 7.5.+-.4.0 wt.-%, or 10.+-.6.0
wt.-%, or 12.5.+-.8.0 wt.-%, or 15.+-.8.0 wt.-%, or 17.5.+-.11.0
wt.-%, or 20.+-.15 wt.-%, or 22.5.+-.16.0 wt.-%, or 25.+-.18 wt.-%;
even more preferably 5.0.+-.2.5 wt.-%, or 7.5.+-.3.0 wt.-%, or
10.+-.5.0 wt.-%, or 12.5.+-.6.0 wt.-%, or 15.+-.6.0 wt.-%, or
17.5.+-.9.0 wt.-%, or 20.+-.13 wt.-%, or 22.5.+-.13.0 wt.-%, or
25.+-.15 wt.-%; most preferably 5.0.+-.2.0 wt.-%, or 7.5.+-.2.0
wt.-%, or 10.+-.4.0 wt.-%, or 12.5.+-.4.0 wt.-%, or 15.+-.4.0
wt.-%, or 17.5.+-.7.0 wt.-%, or 20.+-.11 wt.-%, or 22.5.+-.10.0
wt.-%, or 25.+-.12 wt.-%; and in particular 5.0.+-.1.5 wt.-%, or
7.5.+-.1.0 wt.-%, or 10.+-.3.0 wt.-%, or 12.5.+-.2.0 wt.-%, or
15.+-.2.0 wt.-%, or 17.5.+-.5.0 wt.-%, or 20.+-.9 wt.-%, or
22.5.+-.7.0 wt.-%, or 25.+-.9 wt.-%; in each case based on the
total weight of the tablet.
[0174] In a further preferred embodiment, the content of
pharmacologically active compound 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 tablet. In another
preferred embodiment, the content of pharmacologically active
compound is within the range of from 25.+-.6 wt.-%, more preferably
25.+-.5 wt.-%, still more preferably 25.+-.4 wt.-%, most preferably
25.+-.3 wt.-%, and in particular 25.+-.2 wt.-%, based on the total
weight of the tablet.
[0175] The skilled person may readily determine an appropriate
amount of pharmacologically active compound to include in a tablet.
For instance, in the case of analgesics, the total amount of
pharmacologically active compound present in the tablet is that
sufficient to provide analgesia. The total amount of
pharmacologically active compound administered to a patient in a
dose will vary depending on numerous factors including the nature
of the pharmacologically active compound, the weight of the
patient, the severity of the pain, the nature of other therapeutic
agents being administered etc.
[0176] In a preferred embodiment, the pharmacologically active
compound is contained in the tablet 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, 250.+-.5 mg, 260.+-.5 mg,
270.+-.5 mg, 280.+-.5 mg, 290.+-.5 mg, or 300.+-.5 mg. In another
preferred embodiment, the pharmacologically active compound is
contained in the tablet 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, 250.+-.2.5 mg, 255.+-.2.5 mg,
260.+-.2.5 mg, or 265.+-.2.5 mg.
[0177] In a particularly preferred embodiment, the
pharmacologically active compound is tapentadol, preferably its HCl
salt, and the tablet is adapted for administration once daily,
twice daily, thrice daily or more frequently. In this embodiment,
pharmacologically active compound is preferably contained in the
tablet in an amount of from 25 to 100 mg.
[0178] In a particularly preferred embodiment, the
pharmacologically active compound is oxymorphone, preferably its
HCl salt, and the tablet is adapted for administration once daily,
twice daily, thrice daily or more frequently. In this embodiment,
the pharmacologically active compound is preferably contained in
the tablet in an amount of from 5 to 40 mg. In another particularly
preferred embodiment, the pharmacologically active compound is
oxymorphone, preferably its HCl salt, and the tablet is adapted for
administration once daily. In this embodiment, the
pharmacologically active compound is preferably contained in the
tablet in an amount of from 10 to 80 mg.
[0179] In another particularly preferred embodiment, the
pharmacologically active compound is oxycodone, preferably its HCl
salt, and the tablet is adapted for administration once daily,
twice daily, thrice daily or more frequently. In this embodiment,
the pharmacologically active compound is preferably contained in
the tablet in an amount of from 5 to 80 mg.
[0180] In still another particularly preferred embodiment, the
pharmacologically active compound is hydromorphone, preferably its
HCl, and the tablet is adapted for administration once daily, twice
daily, thrice daily or more frequently. In this embodiment, the
pharmacologically active compound is preferably contained in the
tablet in an amount of from 2 to 52 mg. In another particularly
preferred embodiment, the pharmacologically active compound is
hydromorphone, preferably its HCl, and the tablet is adapted for
administration once daily, twice daily, thrice daily or more
frequently. In this embodiment, the pharmacologically active
compound is preferably contained in the tablet in an amount of from
4 to 104 mg.
[0181] The particulates present in the tablets according to the
invention preferably comprise 3 to 75 wt.-% of pharmacologically
active compound, more preferably 5 to 70 wt.-% of pharmacologically
active compound, still more preferably 7.5 to 65 wt.-% of
pharmacologically active compound, based on the total weight of a
particulate.
[0182] Preferably, the content of the pharmacologically active
compound is at least 25 wt.-%, more preferably at least 30 wt.-%,
still more preferably at least 35 wt.-%, yet more preferably at
least 40 wt.-%, most preferably at least 45 wt.-%, based on the
total weight of a particulate.
[0183] Preferably, the content of the pharmacologically active
compound is at most 70 wt.-%, more preferably at most 65 wt.-%,
still more preferably at most 60 wt.-%, yet more preferably at most
55 wt.-%, most preferably at most 50 wt.-%, based on the total
weight of a particulate.
[0184] In a preferred embodiment, the content of the
pharmacologically active compound is within the range of 35.+-.30
wt.-%, more preferably 35.+-.25 wt.-%, still more preferably
35.+-.20 wt.-%, yet more preferably 35.+-.15 wt.-%, most preferably
35.+-.10 wt.-%, and in particular 35.+-.5 wt.-%, based on the total
weight of a particulate. In another preferred embodiment, the
content of the pharmacologically active compound is within the
range of 45.+-.30 wt.-%, more preferably 45.+-.25 wt.-%, still more
preferably 45.+-.20 wt.-%, yet more preferably 45.+-.15 wt.-%, most
preferably 45.+-.10 wt.-%, and in particular 45.+-.5 wt.-%, based
on the total weight of a particulate. In still another preferred
embodiment, the content of the pharmacologically active compound is
within the range of 55.+-.30 wt.-%, more preferably 55.+-.25 wt.-%,
still more preferably 55.+-.20 wt.-%, yet more preferably 55.+-.15
wt.-%, most preferably 55.+-.10 wt.-%, and in particular 55.+-.5
wt.-%, based on the total weight of a particulate.
[0185] The pharmacologically active compound that is included in
the preparation of the tablets according to the invention
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 compounds may be
determined by any technique conventional in the art, e.g. laser
light scattering, sieve analysis, light microscopy or image
analysis. Generally speaking it is preferable that the largest
dimension of the pharmacologically active compound particle be less
than the size of the particulates (e.g. less than the smallest
dimension of the particulates).
[0186] A skilled person knows how to determine pharmacokinetic
parameters such as t.sub.1/2, T.sub.max, C.sub.max, AUC and
bioavailability. For the purposes of the description, the
pharmacokinetic parameters, which may be determined from the blood
plasma concentrations of 3-(2-dimethylaminomethylcyclohexyl)phenol,
are defined as follows:
TABLE-US-00002 C.sub.max maximum measured plasma concentration of
the active ingredient after single administration (.ident. average
peak plasma level) t.sub.max interval of time from administration
of the active ingredient until C.sub.max is reached AUC total area
of the plasma concentration/time curve including the subarea from
the final measured value extrapolated to infinity t.sub.1/2
half-life
[0187] The above parameters are in each case stated as mean values
of the individual values for all investigated patients/test
subjects.
[0188] A person skilled in the art knows how the pharmacokinetic
parameters of the active ingredient may be calculated from the
measured concentrations of the active ingredient in the blood
plasma. In this connection, reference may be made, for example, to
Willi Cawello (ed.) Parameters for Compartment-free
Pharmacokinetics, Shaker Verlag Aachen (1999).
[0189] In a preferred embodiment, the pharmacologically active
compound is tapentadol or a physiologically acceptable salt
thereof, e.g. the hydrochloride. Preferably, the tablet according
to the invention provides a mean absolute bioavailability of
tapentadol of at least 22%, more preferably at least 24%, still
more preferably at least 26%, yet more preferably at least 28%,
most preferably at least 30%, and in particular at least 32%.
T.sub.max of tapentadol is preferably within the range of
1.25.+-.1.20 h, more preferably 1.25.+-.1.00 h, still more
preferably 1.25.+-.0.80 h, yet more preferably 1.25.+-.0.60 h, most
preferably 1.25.+-.0.40 h, and in particular 1.25.+-.0.20 h.
t.sub.112 of tapentadol is preferably within the range of
4.0.+-.2.8 h, more preferably 4.0.+-.2.4 h, still more preferably
4.0.+-.2.0 h, yet more preferably 4.0.+-.1.6 h, most preferably
4.0.+-.1.2 h, and in particular 4.0.+-.0.8 h. Preferably, when
normalized to a dose of 100 mg tapentadol, C.sub.max of tapentadol
is preferably within the range of 90.+-.85 ng/mL, more preferably
90.+-.75 ng/mL, still more preferably 90.+-.65 ng/mL, yet more
preferably 90.+-.55 ng/mL, most preferably 90.+-.45 ng/mL, and in
particular 90.+-.35 ng/mL; and/or AUC of tapentadol is preferably
within the range of 420.+-.400 ng/mLh, more preferably 420.+-.350
ng/mLh, still more preferably 420.+-.300 ng/mLh, yet more
preferably 420.+-.250 ng/mLh, most preferably 420.+-.200 ng/mLh,
and in particular 420.+-.150 ng/mLh.
[0190] In another preferred embodiment, the pharmacologically
active compound is oxymorphone or a physiologically acceptable salt
thereof, e.g. the hydrochloride. Preferably, the tablet according
to the invention provides a mean absolute bioavailability of
oxymorphone of at least 1%, more preferably at least 2%, still more
preferably at least 4%, yet more preferably at least 6%, most
preferably at least 8%, and in particular at least 10%. T.sub.max
of oxymorphone is preferably within the range of 0.5.+-.0.45 h,
more preferably 0.5.+-.0.40 h, still more preferably 0.5.+-.0.35 h,
yet more preferably 0.5.+-.0.30 h, most preferably 0.5.+-.0.25 h,
and in particular 0.5.+-.0.20 h. t.sub.12 of oxymorphone is
preferably within the range of 9.5.+-.8.0 h, more preferably
9.5.+-.7.0 h, still more preferably 9.5.+-.6.0 h, yet more
preferably 9.5.+-.5.0 h, most preferably 9.5.+-.4.0 h, and in
particular 9.5.+-.3.0 h. Preferably, when normalized to a dose of
20 mg oxymorphone, C.sub.max of oxymorphone is preferably within
the range of 4.4.+-.3.5 ng/mL, more preferably 4.4.+-.3.0 ng/mL,
still more preferably 4.4.+-.2.5 ng/mL, yet more preferably
4.4.+-.2.0 ng/mL, most preferably 4.4.+-.1.5 ng/mL, and in
particular 4.4.+-.1.0 ng/mL; and/or AUC of oxymorphone is
preferably within the range of 20.0.+-.15.0 ng/mLh, more preferably
20.0.+-.12.5 ng/mLh, still more preferably 20.0.+-.10.0 ng/mLh, yet
more preferably 20.0.+-.7.5 ng/mLh, most preferably 20.0.+-.6.0
ng/mLh, and in particular 20.0.+-.5.0 ng/mLh.
[0191] In another preferred embodiment, the pharmacologically
active compound is oxycodone or a physiologically acceptable salt
thereof, e.g. the hydrochloride. Preferably, the tablet according
to the invention provides a mean absolute bioavailability of
oxycodone of at least 40%, more preferably at least 45%, still more
preferably at least 50%, yet more preferably at least 55%, most
preferably at least 60%, and in particular at least 70%. T.sub.max
of oxycodone is preferably within the range of 2.6.+-.2.5 h, more
preferably 2.6.+-.2.0 h, still more preferably 2.6.+-.1.8 h, yet
more preferably 2.6.+-.0.1.6 h, most preferably 2.6.+-.1.4 h, and
in particular 2.6.+-.1.20 h. t.sub.112 of oxycodone is preferably
within the range of 3.8.+-.3.5 h, more preferably 3.8.+-.3.0 h,
still more preferably 3.8.+-.2.5 h, yet more preferably 3.8.+-.2.0
h, most preferably 3.8.+-.1.5 h, and in particular 3.8.+-.1.0 h.
Preferably, when normalized to a dose of 30 mg oxycodone, C.sub.max
of oxycodone is preferably within the range of 40.+-.35 ng/mL, more
preferably 40.+-.30 ng/mL, still more preferably 40.+-.25 ng/mL,
yet more preferably 40.+-.20 ng/mL, most preferably 40.+-.15 ng/mL,
and in particular 40.+-.10 ng/mL; and/or AUC of oxycodone is
preferably within the range of 270.+-.250 ng/mLh, more preferably
270.+-.200 ng/mLh, still more preferably 270.+-.150 ng/mLh, yet
more preferably 270.+-.100 ng/mLh, most preferably 270.+-.75
ng/mLh, and in particular 270.+-.50 ng/mLh.
[0192] In still another preferred embodiment, the pharmacologically
active compound is morphine or a physiologically acceptable salt
thereof, e.g. the sulfate. Preferably, the tablet according to the
invention provides a mean absolute bioavailability of morphine of
at least 15%, more preferably at least 20%, still more preferably
at least 25%, yet more preferably at least 30%, most preferably at
least 35%, and in particular at least 40%. T.sub.max of morphine is
preferably within the range of 0.625.+-.0.60 h, more preferably
0.625.+-.0.50 h, still more preferably 0.625.+-.0.40 h, yet more
preferably 0.625.+-.0.30 h, most preferably 0.625.+-.0.20 h, and in
particular 0.625.+-.0.15 h. Preferably, when normalized to a dose
of 30 mg morphine sulfate, C.sub.max of morphine is preferably
within the range of 25.+-.20 ng/mL, more preferably 25.+-.15 ng/mL,
still more preferably 25.+-.10 ng/mL, yet more preferably 25.+-.5
ng/mL; and/or AUC of morphine is preferably within the range of
50.+-.45 ng/mLh, more preferably 50.+-.40 ng/mLh, still more
preferably 50.+-.35 ng/mLh, yet more preferably 50.+-.30 ng/mLh,
most preferably 50.+-.25 ng/mLh, and in particular 50.+-.20
ng/mLh.
[0193] The tablets according to the invention may also comprise one
or more additional pharmacologically active compounds. The
additional pharmacologically active compound may be susceptible to
abuse or another pharmaceutical. Additional pharmacologically
active compounds may be present within the particulates
("intragranular") or within the matrix ("extragranular"). Where an
additional pharmacologically active compound is present
intragranularly, it may be present either in combination with one
or more pharmacologically active compounds within the same
particulates or in a discrete population of particulates alone and
separate from any other pharmacologically active compounds present
in the tablet.
[0194] In a preferred embodiment, the tablet according to the
invention, preferably the particulates, comprise an opioid
(agonist) as well as an opioid antagonist.
[0195] Any conventional opioid antagonist may be present, e.g.
naltrexone or naloxone or their pharmaceutically acceptable salts.
Naloxone, including its salts, is particularly preferred. The
opioid antagonist may be present within the particulates or within
the matrix. Alternatively, opioid antagonist may be provided in
separate particulates to the pharmacologically active compounds.
The preferred composition of such particulates is the same as that
described for pharmacologically active compound-containing
particulates.
[0196] The ratio of opioid agonist to opioid antagonist in the
tablets according to the invention is preferably 1:1 to 3:1 by
weight, for example, about 2:1 by weight.
[0197] In another preferred embodiment, neither the particulates
nor the tablet comprise any opioid antagonist.
[0198] The particulates according to the invention contain a
polyalkylene oxide.
[0199] Preferably, the polyalkylene oxide is selected from
polymethylene oxide, polyethylene oxide and polypropylene oxide, or
copolymers thereof. Polyethylene oxide is preferred.
[0200] In a preferred embodiment, the polyalkylene oxide has a
weight average molecular weight (M.sub.w) or viscosity average
molecular weight (M.sub..eta.) of at least 200,000 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. 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).
[0201] 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.
[0202] For the purpose of the 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. In a
preferred embodiment, the weight average over all molecular weights
of all polyalkylene oxides that are contained in the tablet is at
least 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.
[0203] In a preferred embodiment, polyalkylene oxide is
homogeneously distributed in the particulates according to the
invention. Preferably, the pharmacologically active compound and
polyalkylene oxide are intimately homogeneously distributed in the
particulates so that the particulates do not contain any segments
where either pharmacologically active compound is present in the
absence of polyalkylene oxide or where polyalkylene oxide is
present in the absence of pharmacologically active compound.
[0204] When the particulates are film coated, the polyalkylene
oxide is preferably homogeneously distributed in the core of the
particulates, 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 core.
[0205] The polyalkylene oxide may be combined with one or more
different polymers selected from the group consisting of
polyalkylene oxide, preferably polymethylene oxide, polyethylene
oxide, polypropylene oxide; polyethylene, polypropylene, polyvinyl
chloride, polycarbonate, polystyrene, polyvinylpyrrolidone,
poly(alk)acrylate, poly(hydroxy fatty acids), such as for example
poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (Biopol.RTM.),
poly(hydroxyvaleric acid); polycaprolactone, polyvinyl alcohol,
polyesteramide, polyethylene succinate, polylactone, polyglycolide,
polyurethane, polyamide, polylactide, polyacetal (for example
polysaccharides optionally with modified side chains),
polylactide/glycolide, polylactone, polyglycolide, polyorthoester,
polyanhydride, block polymers of polyethylene glycol and
polybutylene terephthalate (Polyactive.RTM.), polyanhydride
(Polifeprosan), copolymers thereof, block-copolymers thereof (e.g.,
Poloxamer.RTM.), and mixtures of at least two of the stated
polymers, or other polymers with the above characteristics.
[0206] Preferably, the molecular weight dispersity M.sub.w/M.sub.n
of 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.
[0207] The polyalkylene oxide preferably has a viscosity at
25.degree. C. of 30 to 17,600 cP, more preferably 55 to 17,600 cP,
still more preferably 600 to 17,600 cP and most preferably 4,500 to
17,600 cP, measured in a 5 wt.-% aqueous solution using a model RVF
Brookfield viscosimeter (spindle no. 2/rotational speed 2 rpm); of
400 to 4,000 cP, more preferably 400 to 800 cP or 2,000 to 4,000
cP, measured on a 2 wt.-% aqueous solution using the stated
viscosimeter (spindle no. 1 or 3/rotational speed 10 rpm); or of
1,650 to 10,000 cP, more preferably 1,650 to 5,500 cP, 5,500 to
7,500 cP or 7,500 to 10,000 cP, measured on a 1 wt.-% aqueous
solution using the stated viscosimeter (spindle no. 2/rotational
speed 2 rpm).
[0208] Polyethylene oxide that is suitable for use in the tablets
according to the invention is commercially available from Dow. For
example, Polyox WSR N-12K, Polyox N-60K, Polyox WSR 301 NF or
Polyox WSR 303NF may be used in the tablets according to the
invention. For details concerning the properties of these products,
it can be referred to e.g. the product specification.
[0209] Preferably, the content of the polyalkylene oxide is within
the range of from 1 to 60 wt.-%, more preferably 3 to 55 wt.-%,
still more preferably 5 to 50 wt.-%, yet more preferably 7 to 45
wt.-%, most preferably 10 to 40 wt.-% and in particular 15 to 35
wt.-%, based on the total weight of the tablet. In a preferred
embodiment, the content of the polyalkylene oxide 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
tablet.
[0210] In a preferred embodiment, the overall content of
polyalkylene oxide 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 tablet.
In another preferred embodiment, the overall content of
polyalkylene oxide 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 tablet.
In still another preferred embodiment, the overall content of
polyalkylene oxide 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 tablet.
In yet another preferred embodiment, the overall content of
polyalkylene oxide 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 tablet.
In a further preferred embodiment, the overall content of
polyalkylene oxide 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 tablet.
In still a further a preferred embodiment, the overall content of
polyalkylene oxide is within the range of 35.+-.20 wt.-%, more
preferably 35.+-.15 wt.-%, most preferably 35.+-.10 wt.-%, and in
particular 35.+-.5 wt.-%. In a still further a preferred
embodiment, the overall content of polyalkylene oxide 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 tablet.
[0211] Preferably, the content of the polyalkylene oxide is within
the range of from 1 to 99 wt.-%, more preferably 5 to 95 wt.-%,
still more preferably 10 to 90 wt.-%, yet more preferably 15 to 85
wt.-%, most preferably 20 to 80 wt.-% and in particular 25 to 75
wt.-%, based on the total weight of the particulates. In a
preferred embodiment, the content of the polyalkylene oxide is 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.-%, based on the total weight of
the particulates.
[0212] In a preferred embodiment, the overall content of
polyalkylene oxide 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
particulates. In another preferred embodiment, the overall content
of polyalkylene oxide 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
particulates. In still another preferred embodiment, the overall
content of polyalkylene oxide is within the range of 40.+-.20
wt.-%, more preferably 40.+-.15 wt.-%, most preferably 40.+-.10
wt.-%, and in particular 40.+-.5 wt.-%, based on the total weight
of the particulates. In yet another preferred embodiment, the
overall content of polyalkylene oxide is within the range of
45.+-.20 wt.-%, more preferably 45.+-.15 wt.-%, most preferably
45.+-.10 wt.-%, and in particular 45.+-.5 wt.-%, based on the total
weight of the particulates. In a further preferred embodiment, the
overall content of polyalkylene oxide is within the range of
50.+-.20 wt.-%, more preferably 50.+-.15 wt.-%, most preferably
50.+-.10 wt.-%, and in particular 50.+-.5 wt.-%, based on the total
weight of the particulates. In still a further a preferred
embodiment, the overall content of polyalkylene oxide is within the
range of 55.+-.20 wt.-%, more preferably 55.+-.15 wt.-%, most
preferably 55.+-.10 wt.-%, and in particular 55.+-.5 wt.-%. In a
still further a preferred embodiment, the overall content of
polyalkylene oxide is within the range of 60.+-.15 wt.-%, more
preferably 60.+-.10 wt.-%, most preferably 60.+-.5 wt.-%, and in
particular 60.+-.5 wt.-%, based on the total weight of the
particulates.
[0213] Preferably, the relative weight ratio of the polyalkylene
oxide to the pharmacologically active compound is within the range
of 1:1.00.+-.0.75, more preferably 1:1.00.+-.0.50, still more
preferably 1:1.00.+-.0.40, yet more preferably 1:1.00.+-.0.30, most
preferably 1:1.00.+-.0.20, and in particular 1:1.00.+-.0.10.
[0214] The particulates according to the invention may contain
additional pharmaceutical excipients conventionally contained in
tablets in conventional amounts, such as antioxidants,
preservatives, lubricants, plasticizer, fillers, binders, and the
like.
[0215] 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 that may be used to formulate the tablets
according to the invention are described in the Handbook of
Pharmaceutical Excipients, American Pharmaceutical Association
(1986).
[0216] In a preferred embodiment, the particulates do not contain a
disintegrant.
[0217] Preferably, the particulates further comprise 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 .alpha.-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 particulates.
[0218] In a preferred embodiment, the particulates further comprise
an acid, preferably citric acid. The amount 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 particulates.
[0219] In a preferred embodiment, the particulates further comprise
another polymer which is preferably selected from cellulose esters
and cellulose ethers, in particular hydroxypropyl methylcellulose
(HPMC).
[0220] Other preferred polymers are polyvinyl caprolactam-polyvinyl
acetate-polyethylene glycol graft co-polymers, such as the one
commercially available under the trade name Soluplus.RTM..
[0221] The amount of the further polymer, preferably hydroxypropyl
methylcellulose, preferably ranges from 0.1 wt.-% to about 30
wt.-%, more preferably in the range of 1.0 wt.-% to about 20 wt.-%,
most preferably in the range of 2.0 wt.-% to about 15 wt.-%, and in
particular in the range of 3.5 wt.-% to about 10.5 wt.-%, based on
the total weight of the particulates.
[0222] In a preferred embodiment, the relative weight ratio of the
polyalkylene oxide to the further polymer is within the range of
4.5.+-.2:1, more preferably 4.5.+-.1.5:1, still more preferably
4.5.+-.1:1, yet more preferably 4.5.+-.0.5:1, most preferably
4.5.+-.0.2:1, and in particular 4.5.+-.0.1:1. In another preferred
embodiment, the relative weight ratio of the polyalkylene oxide to
the further polymer is within the range of 8.+-.7:1, more
preferably 8.+-.6:1, still more preferably 8.+-.5:1, yet more
preferably 8.+-.4:1, most preferably 8.+-.3:1, and in particular
8.+-.2:1. In still another preferred embodiment, the relative
weight ratio of the polyalkylene oxide to the further polymer is
within the range of 11.+-.8:1, more preferably 11.+-.7:1, still
more preferably 11.+-.6:1, yet more preferably 11.+-.5:1, most
preferably 11.+-.4:1, and in particular 11.+-.3:1.
[0223] In another preferred embodiment, the particulates according
to the invention do not contain any further polymer besides the
polyalkylene oxide and optionally, polyethylene glycol.
[0224] In a preferred embodiment, the particulates contain at least
one lubricant. In another preferred embodiment, the particulates
contain no lubricant. Especially preferred lubricants are selected
from [0225] magnesium stearate and stearic acid; [0226] glycerides
of fatty acids, including 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 palmitostearate and glycerol monostearate; [0227]
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, [0228] polyglycolyzed glycerides, such
as the one known and commercially available under the trade name
"Labrasol"; [0229] fatty alcohols that may be linear or branched,
such as cetylalcohol, stearylalcohol, cetylstearyl alcohol,
2-octyldodecane-1-ol and 2-hexyldecane-1-ol; [0230] polyethylene
glycols having a molecular weight between 10.000 and 60.000 g/mol;
and [0231] natural semi-synthetic or synthetic waxes, preferably
waxes with a softening point of at least 50.degree. C., more
preferably 60.degree. C., and in particular carnauba wax and bees
wax.
[0232] Preferably, the amount of the lubricant ranges from 0.01
wt.-% to about 10 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.-%, and in particular in the range of 0.1 wt.-% to about
1 wt.-%, based on the total weight of the particulates.
[0233] Preferably, the particulates further comprise a plasticizer.
The plasticizer improves the processability of the polyalkylene
oxide. A preferred plasticizer is polyalkylene glycol, like
polyethylene glycol, triacetin, fatty acids, fatty acid esters,
waxes and/or microcrystalline waxes. Particularly preferred
plasticizers are polyethylene glycols, such as PEG 6000.
[0234] 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
particulates.
[0235] In a preferred embodiment, the plasticizer is a polyalkylene
glycol having a content within the range of 7.+-.6 wt.-%, more
preferably 7.+-.5 wt.-%, still more preferably 7.+-.4 wt.-%, yet
more preferably 7.+-.3 wt.-%, most preferably 7.+-.2 wt.-%, and in
particular 7.+-.1 wt.-%, based on the total weight of the
particulates.
[0236] In another preferred embodiment, the plasticizer is a
polyalkylene glycol having a content within the range of 10.+-.8
wt.-%, more preferably 10.+-.6 wt.-%, still more preferably 10.+-.5
wt.-%, yet more preferably 10.+-.4 wt.-%, most preferably 10.+-.3
wt.-%, and in particular 10.+-.2 wt.-%, based on the total weight
of the particulates.
[0237] In a preferred embodiment, the relative weight ratio of the
polyalkylene oxide to the polyalkylene glycol is within the range
of 5.4.+-.2:1, more preferably 5.4.+-.1.5:1, still more preferably
5.4.+-.1:1, yet more preferably 5.4.+-.0.5:1, most preferably
5.4.+-.0.2:1, and in particular 5.4.+-.0.1:1. This ratio satisfies
the requirements of relative high polyalkylene oxide content and
good extrudability.
[0238] Plasticizers can sometimes act as a lubricant, and
lubricants can sometimes act as a plasticizer.
[0239] The particulates and the matrix material of the tablets
according to the invention preferably do not contain any polymers
selected from the group consisting of [0240] acrylates (such as
acrylic and methacrylic polymers including acrylic acid and
methacrylic acid copolymers, methyl methacrylate copolymers,
ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic
acid), poly(methacrylic acid), methacrylic acid alkylamide
copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl
methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate
copolymer, poly(methacrylic acid anhydride), and glycidyl
methacrylate copolymers; e.g., Eudragit.RTM. NE, NM, RS or RL).
[0241] alkylcelluloses and hydroxy alkyl celluloses (such as
methylcellulose, ethylcellulose, hydroxy propyl cellulose and
hydroxylpropyl methylcellulose); and [0242] gelling agents which
hydrate to form gels to control the movement of water, such as high
molecular weight grade (high viscosity) hydroxypropylmethyl
cellulose (HPMC), pectin, locust bean gum and xanthan gum.
[0243] In a preferred embodiment, the tablet 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.
[0244] The tablet according to the invention furthermore preferably
contains no antagonists for the pharmacologically active compound,
preferably no antagonists against psychotropic substances, in
particular no antagonists against opioids. Antagonists suitable for
a given pharmacologically active compound 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 tablet 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.
[0245] The tablet 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 tablet
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 tablet according to the invention preferably also
contains no apomorphine as an emetic.
[0246] Finally, the tablet 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.
[0247] The tablet according to the invention accordingly preferably
contains neither substances which irritate the nasal passages
and/or pharynx, nor antagonists for the pharmacologically active
compound, nor emetics, nor bitter substances.
[0248] Particularly preferred contents of pharmacologically active
compound, polyalkylene oxide, plasticizer and antioxidant of the
particulates, relative to the total weight of the particulates, are
summarized as embodiments B.sup.1 to B.sup.6 in the table here
below:
TABLE-US-00003 wt.-% B.sup.1 B.sup.2 B.sup.3 B.sup.4 B.sup.5
B.sup.6 active compound 45 .+-. 30 45 .+-. 25 45 .+-. 20 45 .+-. 15
45 .+-. 10 45 .+-. 5 polyalkylene oxide 45 .+-. 30 45 .+-. 25 45
.+-. 20 45 .+-. 15 45 .+-. 10 45 .+-. 5 plasticizer 8 .+-. 6 8 .+-.
5 8 .+-. 4 8 .+-. 3 8 .+-. 2 8 .+-. 1 antioxidant 0.10 .+-. 0.08
0.10 .+-. 0.06 0.10 .+-. 0.04 0.10 .+-. 0.03 0.10 .+-. 0.02 0.10
.+-. 0.01
wherein the pharmacologically active compound is preferably an
opioid, particularly preferably tapentadol or a physiologically
acceptable salt thereof; the polyalkylene oxide preferably is a
polyethylene oxide having a weight average molecular weight of at
least 500,000 g/mol; the plasticizer preferably is a polyethylene
glycol; and the antioxidant preferably is .alpha.-tocopherol.
[0249] Besides the particulates and the preferably pre-compacted or
granulated matrix material, the tablet according to the invention
may comprise one or more pharmaceutical excipients such as binders,
fillers, lubricants and the like.
[0250] In a preferred embodiment, the table additionally comprises
a lubricant. Magnesium stearate is preferred. Further preferred
lubricants are described above and therefore are not repeated
hereinafter.
[0251] If the tablet contains an additional lubricant outside the
preferably pre-compacted or pre-granulated matrix material, its
content is preferably not more than 1 wt.-%, more preferably not
more than 0.5 wt.-%, based on the total weight of the tablet.
[0252] While the particulates that are contained in the tablet
according to the invention preferably exhibit increased mechanical
strength, the tablet as such preferably has conventional mechanical
properties. Typically, the tablet according to the invention can be
crushed e.g. by means of a hammer thereby yielding a fractured
composition containing the matrix material, the particulates and
any other ingredients contained in the tablet. However, the
particulates thereby obtained in more or less isolated form
preferably cannot be further crushed and fractured by means of a
hammer.
[0253] Preferably, the particulates are hot melt-extruded and/or
have a breaking strength of at least 300 N.
[0254] The tablet according to the invention is tamper-resistant.
Preferably, tamper-resistance is achieved based on the mechanical
properties of the particulates so that comminution is avoided or at
least substantially impeded. According to the invention, the term
comminution means the pulverization of the particulates using
conventional means usually available to an abuser, for example a
pestle and mortar, a hammer, a mallet or other conventional means
for pulverizing under the action of force. Thus, tamper-resistance
preferably means that pulverization of the particulates using
conventional means is avoided or at least substantially
impeded.
[0255] Preferably, the mechanical properties of the particulates
according to the invention, particularly their breaking strength
and deformability, substantially rely on the presence and spatial
distribution of polyalkylene oxide, although their mere presence
does typically not suffice in order to achieve said properties. The
advantageous mechanical properties of the particulates according to
the invention may not automatically be achieved by simply
processing pharmacologically active compound, polyalkylene oxide,
and optionally further excipients by means of conventional methods
for the preparation of tablets. 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.
[0256] In general, the particulates exhibiting the desired
properties may be obtained only if, during preparation of the
particulates, [0257] suitable components [0258] in suitable amounts
[0259] are exposed to [0260] a sufficient pressure [0261] at a
sufficient temperature [0262] for a sufficient period of time.
[0263] Thus, regardless of the apparatus used, the process
protocols must be adapted in order to meet the required criteria.
Therefore, the breaking strength and deformability of the
particulates is separable from the composition.
[0264] The particulates contained in the tablet according to the
invention preferably have a breaking strength of at least 300 N, at
least 400 N, or at least 500 N, preferably 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.
[0265] In order to verify whether a particulate exhibits a
particular breaking strength of e.g. 300 N or 500 N it is typically
not necessary to subject said particulate to forces much higher
than 300 N and 500 N, respectively. Thus, the breaking strength
test can usually be terminated once the force corresponding to the
desired breaking strength has been slightly exceeded, e.g. at
forces of e.g. 330 N and 550 N, respectively.
[0266] The "breaking strength" (resistance to crushing) of a tablet
and of a particulate 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.,
Tablets: Tablets, Vol. 2, Informa Healthcare; 2 edition, 1990; and
Encyclopedia of Pharmaceutical Technology, Informa Healthcare; 1
edition.
[0267] For the purpose of the specification, the breaking strength
is preferably defined as the amount of force that is necessary in
order to fracture the particulate (=breaking force). Therefore, for
the purpose of the specification a particulate 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
particulate is regarded as being broken if the force decreases by
50% (threshold value) of the highest force measured during the
measurement (see below).
[0268] The particulates according to the invention are
distinguished from conventional particulates that can be contained
in tablets in that, due to their breaking strength, they cannot be
pulverized by the application of force with conventional means,
such as for example a pestle and mortar, a hammer, a mallet or
other usual means for pulverization, in particular devices
developed for this purpose (tablet crushers). In this regard
"pulverization" means crumbling into small particles. Avoidance of
pulverization virtually rules out oral or parenteral, in particular
intravenous or nasal abuse.
[0269] Conventional particulates typically have a breaking strength
well below 200 N.
[0270] The breaking strength of conventional round
tablets/particulates may be estimated according to the following
empirical formula: Breaking Strength [in N]=10.times. Diameter Of
The Tablet/Particulate [in mm]. Thus, according to said empirical
formula, a round tablet/particulate having a breaking strength of
at least 300 N would require a diameter of at least 30 mm). Such a
particulate, however, could not be swallowed, let alone a tablet
containing a plurality of such particulates. The above empirical
formula preferably does not apply to the particulates according to
the invention, which are not conventional but rather special.
[0271] 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 particulates having a breaking
strength well below 200 N may be crushed upon spontaneous chewing,
whereas the particulates according to the invention may preferably
not.
[0272] 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 particulates according to the invention
can preferably withstand a weight of more than 30 kg without being
pulverized.
[0273] Methods for measuring the breaking strength of a tablet are
known to the skilled artisan. Suitable devices are commercially
available.
[0274] 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 Tablets". The test is intended
to determine, under defined conditions, the resistance to crushing
of tablets and particulates, 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 tablet and particulate,
respectively. The apparatus is calibrated using a system with a
precision of 1 Newton. The tablet and particulate, respectively, is
placed between the jaws, taking into account, where applicable, the
shape, the break-mark and the inscription; for each measurement the
tablet and particulate, 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 tablets and
particulates, 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.
[0275] 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 tablet and particulate, respectively, to fail
(i.e., break) in a specific plane. The tablets and particulates,
respectively, are generally placed between two platens, one of
which moves to apply sufficient force to the tablet and
particulate, respectively, to cause fracture. For conventional,
round (circular cross-section) tablets and particulates,
respectively, loading occurs across their diameter (sometimes
referred to as diametral loading), and fracture occurs in the
plane. The breaking force of tablets and particulates,
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 tablets and particulate, 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 tablets and particulate, respectively, are actually
crushed during the test, which is often not the case.
[0276] 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. A
skilled person knows how to properly adjust the test speed, e.g. to
10 mm/min, 20 mm/min, or 40 mm/min, for example. 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 manufacturers 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.
[0277] When using the testControl software (testXpert V10.11), the
following exemplified settings and parameters have revealed to be
useful: LE-position: clamping length 150 mm. LE-speed: 500 mm/min,
clamping length after pre-travel: 195 mm, pre-travel speed: 500
mm/min, no pre-force control--pre-force: pre-force 1N, pre-force
speed 10 mm/min--sample data: no sample form, measuring length
traverse distance 10 mm, no input required prior to
testing--testing/end of test; test speed: position-controlled 10
mm/min, delay speed shift: 1, force shut down threshold 50%
F.sub.max, no force threshold for break-tests, no max length
variation, upper force limit: 600N--expansion compensation: no
correction of measuring length--actions after testing: LE to be set
after test, no unload of sample--TRS: data memory: TRS distance
interval until break 1 .mu.m, TRS time interval 0.1 s, TRS force
interval 1N--machine; traverse distance controller: upper soft end
358 mm, lower soft end 192 mm--lower test space. Parallel
arrangement of the upper plate and the ambos should be
ensured--these parts must not touch during or after testing. After
testing, a small gap (e.g. 0.1 or 0.2 mm) should still be present
between the two brackets in intimated contact with the tested
particulate, representing the remaining thickness of the deformed
particulate.
[0278] In a preferred embodiment, the particulate is regarded as
being broken if it is fractured into at least two separate pieces
of comparable morphology. Separated matter having a morphology
different from that of the deformed particulate, e.g. dust, is not
considered as pieces qualifying for the definition of breaking.
[0279] The particulates according to the invention preferably
exhibit mechanical strength over a wide temperature range, in
addition to the breaking strength (resistance to crushing)
optionally also sufficient hardness, yield strength, fatigue
strength, impact resistance, impact elasticity, tensile strength,
compressive 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 particulate according to the invention is
maintained even at low or very low temperatures, e.g., when the
tablet is initially chilled to increase its brittleness, for
example to temperatures below -25.degree. C., below -40.degree. C.
or even in liquid nitrogen.
[0280] The particulate according to the invention is characterized
by a certain degree of breaking strength. This does not mean that
the particulate must also exhibit a certain degree of hardness.
Hardness and breaking strength are different physical properties.
Therefore, the tamper-resistance of the tablet does not necessarily
depend on the hardness of the particulates. For instance, due to
its breaking strength, impact strength, elasticity modulus and
tensile strength, respectively, the particulates 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 particulates
according to the invention are characterized by a certain degree of
breaking strength, but not necessarily also by a certain degree of
form stability.
[0281] Therefore, in the meaning of the specification, a
particulate 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.
[0282] Preferred particulates present in the tablets according to
the invention are those having a suitable tensile strength as
determined by a test method currently accepted in the art. Further
preferred particulates are those having a Youngs Modulus as
determined by a test method of the art. Still further preferred
particulates are those having an acceptable elongation at
break.
[0283] Irrespective of whether the particulates according to the
invention have an increased breaking strength or nor, the
particulates according to the invention preferably exhibit a
certain degree of deformability. The particulates contained in the
tablet according to the invention preferably have a deformability
such that they show an increase, preferably a substantially steady
increase of the force at a corresponding decrease of the
displacement in the force-displacement-diagram when being subjected
to a breaking strength test as described above.
[0284] This mechanical property, i.e. the deformability of the
individual particulates, is illustrated in FIGS. 5 and 6.
[0285] FIG. 5 schematically illustrates the measurement and the
corresponding force-displacement-diagram. In particular, FIG. 5A
shows the initial situation at the beginning of the measurement.
The sample particulate (9) is placed between upper jaw (8a) and
lower jaw (8b) which each are in intimate contact with the surface
of the particulate (9). The initial displacement d.sub.0 between
upper jaw (8a) and lower jaw (8b) corresponds to the extension of
the particulate orthogonal to the surfaces of upper jaw (8a) and
lower jaw (8b). At this time, no force is exerted at all and thus,
no graph is displayed in the force-displacement-diagram below. When
the measurement is commenced, the upper jaw is moved in direction
of lower jaw (8b), preferably at a constant speed. FIG. 5B shows a
situation where due to the movement of upper jaw (8a) towards lower
jaw (8b) a force is exerted on particulate (9). Because of its
deformability, the particulate (9) is flattened without being
fractured. The force-displacement-diagram indicates that after a
reduction of the displacement d.sub.0 of upper jaw (8a) and lower
jaw (8b) by distance x.sub.1, i.e. at a displacement of
d.sub.1=d.sub.0-x.sub.1, a force F.sub.1 is measured. FIG. 5C shows
a situation where due to the continuous movement of upper jaw (8a)
towards lower jaw (8b), the force that is exerted on particulate
(9) causes further deformation, although the particulate (9) does
not fracture. The force-displacement-diagram indicates that after a
reduction of the displacement d.sub.0 of upper jaw (8a) and lower
jaw (8b) by distance x.sub.2, i.e. at a displacement of
d.sub.2=d.sub.0-x.sub.2, a force F.sub.2 is measured. Under these
circumstances, the particulate (9) has not been broken (fractured)
and a substantially steady increase of the force in the
force-displacement-diagram is measured.
[0286] In contrast, FIG. 6 schematically illustrates the
measurement and the corresponding force-displacement-diagram of a
conventional comparative particulate not having the degree of
deformability as the particulates according to the invention. FIG.
6A shows the initial situation at the beginning of the measurement.
The comparative sample particulate (9) is placed between upper jaw
(8a) and lower jaw (8b) which each are in intimate contact with the
surface of the comparative particulate (9). The initial
displacement d.sub.0 between upper jaw (8a) and lower jaw (8b)
corresponds to the extension of the comparative particulate
orthogonal to the surfaces of upper jaw (8a) and lower jaw (8b). At
this time, no force is exerted at all and thus, no graph is
displayed in the force-displacement-diagram below. When the
measurement is commenced, the upper jaw is moved in direction of
lower jaw (8b), preferably at a constant speed. FIG. 6B shows a
situation where due to the movement of upper jaw (8a) towards lower
jaw (8b) a force is exerted on comparative particulate (9). Because
of some deformability, the comparative particulate (9) is slightly
flattened without being fractured. The force-displacement-diagram
indicates that after a reduction of the displacement d.sub.0 of
upper jaw (8a) and lower jaw (8b) by distance x.sub.1, i.e. at a
displacement of d.sub.1=d.sub.0-x.sub.1, a force F.sub.1 is
measured. FIG. 6C shows a situation where due to the continuous
movement of upper jaw (8a) towards lower jaw (8b), the force that
is exerted on particulate (9) causes sudden fracture of the
comparative particulate (9). The force-displacement-diagram
indicates that after a reduction of the displacement d.sub.0 of
upper jaw (8a) and lower jaw (8b) by distance x.sub.2, i.e. at a
displacement of d.sub.2=d.sub.0-x.sub.2, a force F.sub.2 is
measured that suddenly drops when the particulate fractures. Under
these circumstances, the particulate (9) has been broken
(fractured) and no steady increase of the force in the
force-displacement-diagram is measured. The sudden drop (decrease)
of the force can easily be recognized and does not need to be
quantified for the measurement. The steady increase in the
force-displacement-diagram ends at displacement
d.sub.2=d.sub.0-x.sub.2 when the particulate breaks.
[0287] In a preferred embodiment, the particulates contained in the
tablet according to the invention have a deformability such that
they show an increase, preferably a substantially steady increase
of the force at a corresponding decrease of the displacement in the
force-displacement-diagram when being subjected to a breaking
strength test as described above ("Zwick Z 2.5" materials tester,
constant speed), preferably at least until the displacement d of
upper jaw (8a) and lower jaw (8b) has been reduced to a value of
90% of the original displacement d.sub.0 (i.e. d=0.9d.sub.0),
preferably to a displacement d of 80% of the original displacement
d.sub.0, more preferably to a displacement d of 70% of the original
displacement d.sub.0, still more preferably to a displacement d of
60% of the original displacement d.sub.0, yet more preferably to a
displacement d of 50% of the original displacement d.sub.0, even
more preferably to a displacement d of 40% of the original
displacement d.sub.0, most preferably to a displacement d of 30% of
the original displacement d.sub.0, and in particular to a
displacement d of 20% of the original displacement d.sub.0, or to a
displacement d of 15% of the original displacement d.sub.0, to a
displacement d of 10% of the original displacement d.sub.0, or to a
displacement d of 5% of the original displacement d.sub.0.
[0288] In another preferred embodiment, the particulates contained
in the tablet according to the invention have a deformability such
that they show an increase, preferably a substantially steady
increase of the force at a corresponding decrease of the
displacement in the force-displacement-diagram when being subjected
to a breaking strength test as described above ("Zwick Z 2.5"
materials tester, constant speed), preferably at least until the
displacement d of upper jaw (8a) and lower jaw (8b) has been
reduced to 0.80 mm or 0.75 mm, preferably 0.70 mm or 0.65 mm, more
preferably 0.60 mm or 0.55 mm, still more preferably 0.50 mm or
0.45 mm, yet more preferably 0.40 mm or 0.35 mm, even more
preferably 0.30 mm or 0.25 mm, most preferably 0.20 mm or 0.15 mm
and in particular 0.10 or 0.05 mm.
[0289] In still another preferred embodiment, the particulates
contained in the tablet according to the invention have a
deformability such that they show an increase, preferably a
substantially steady increase of the force at a corresponding
decrease of the displacement in the force-displacement-diagram when
being subjected to a breaking strength test as described above
("Zwick Z 2.5" materials tester, constant speed), at least until
the displacement d of upper jaw (8a) and lower jaw (8b) has been
reduced to 50% of the original displacement d.sub.0 (i.e.
d=d.sub.0/2), whereas the force measured at said displacement
(d=d.sub.0/2) is at least 25 N or at least 50 N, preferably at
least 75 N or at least 100 N, still more preferably at least 150 N
or at least 200 N, yet more preferably at least 250 N or at least
300 N, even more preferably at least 350 N or at least 400 N, most
preferably at least 450 N or at least 500 N, and in particular at
least 625 N, or at least 750 N, or at least 875 N, or at least 1000
N, or at least 1250 N, or at least 1500 N.
[0290] In another preferred embodiment, the particulates contained
in the tablet according to the invention have a deformability such
that they show an increase, preferably a substantially steady
increase of the force at a corresponding decrease of the
displacement in the force-displacement-diagram when being subjected
to a breaking strength test as described above ("Zwick Z 2.5"
materials tester, constant speed), at least until the displacement
d of upper jaw (8a) and lower jaw (8b) has been reduced by at least
0.1 mm, more preferably at least 0.2 mm, still more preferably at
least 0.3 mm, yet more preferably at least 0.4 mm, even more
preferably at least 0.5 mm, most preferably at least 0.6 mm, and in
particular at least 0.7 mm, whereas the force measured at said
displacement is within the range of from 5.0 N to 250 N, more
preferably from 7.5 N to 225 N, still more preferably from 10 N to
200 N, yet more preferably from 15 N to 175 N, even more preferably
from 20 N to 150 N, most preferably from 25 N to 125 N, and in
particular from 30 N to 100 N.
[0291] In yet another embodiment, the particulates contained in the
tablet according to the invention have a deformability such that
they are deformed without being fractured when subjected to a
constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or
600 N in a breaking strength test as described above ("Zwick Z 2.5"
materials tester, constant force), until the displacement d of
upper jaw (8a) and lower jaw (8b) is reduced so that no further
deformation takes place at said constant force, whereas at this
equilibrated state the displacement d of upper jaw (8a) and lower
jaw (8b) is at most 90% of the original displacement d.sub.0 (i.e.
d.ltoreq.0.9d.sub.0), preferably at most 80% of the original
displacement d.sub.0 (i.e. d.ltoreq.0.8d.sub.0), more preferably at
most 70% of the original displacement d.sub.0 (i.e.
d.ltoreq.0.7d.sub.0), still more preferably at most 60% of the
original displacement d.sub.0 (i.e. d.ltoreq.0.6d.sub.0), yet more
preferably at most 50% of the original displacement d.sub.0 (i.e.
d.ltoreq.0.5d.sub.0), even more preferably at most 40% of the
original displacement d.sub.0 (i.e. d.ltoreq.0.4d.sub.0), most
preferably at most 30% of the original displacement d.sub.0 (i.e.
d.ltoreq.0.3d.sub.0), and in particular at most 20% of the original
displacement d.sub.0 (i.e. d.ltoreq.0.2d.sub.0), or at most 15% of
the original displacement d.sub.0 (i.e. d.ltoreq.0.15d.sub.0), at
most 10% of the original displacement d.sub.0 (i.e.
d.ltoreq.0.1d.sub.0), or at most 5% of the original displacement
d.sub.0 (i.e. d.ltoreq.0.05d.sub.0).
[0292] Preferably, the particulates contained in the tablet
according to the invention have a deformability such that they are
deformed without being fractured when subjected to a constant force
of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a
breaking strength test as described above ("Zwick Z 2.5" materials
tester, constant force), until the displacement d of upper jaw (8a)
and lower jaw (8b) is reduced so that no further deformation takes
place at said constant force, whereas at this equilibrated state
the displacement d of upper jaw (8a) and lower jaw (8b) is at most
0.80 mm or at most 0.75 mm, preferably at most 0.70 mm or at most
0.65 mm, more preferably at most 0.60 mm or at most 0.55 mm, still
more preferably at most 0.50 mm or at most 0.45 mm, yet more
preferably at most 0.40 mm or at most 0.35 mm, even more preferably
at most 0.30 mm or at most 0.25 mm, most preferably at most 0.20 mm
or at most 0.15 mm and in particular at most 0.10 or at most 0.05
mm.
[0293] In another embodiment, the particulates contained in the
tablet according to the invention have a deformability such that
they are deformed without being fractured when subjected to a
constant force of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or
600 N in a breaking strength test as described above ("Zwick Z 2.5"
materials tester, constant force), until the displacement d of
upper jaw (8a) and lower jaw (8b) is reduced so that no further
deformation takes place at said constant force, whereas at this
equilibrated state the displacement d of upper jaw (8a) and lower
jaw (8b) is at least 5% of the original displacement d.sub.0 (i.e.
d.gtoreq.0.05d.sub.0), preferably at least 10% of the original
displacement d.sub.0 (i.e. d.gtoreq.0.1d.sub.0), more preferably at
least 15% of the original displacement d.sub.0 (i.e.
d.gtoreq.0.15d.sub.0), still more preferably at least 20% of the
original displacement d.sub.0 (i.e. d.gtoreq.0.2d.sub.0), yet more
preferably at least 30% of the original displacement d.sub.0 (i.e.
d.gtoreq.0.3d.sub.0), even more preferably at least 40% of the
original displacement d.sub.0 (i.e. d.gtoreq.0.4d.sub.0), most
preferably at least 50% of the original displacement d.sub.0 (i.e.
d.gtoreq.0.5d.sub.0), and in particular at least 60% of the
original displacement d.sub.0 (i.e. d.gtoreq.0.6d.sub.0), or at
least 70% of the original displacement d.sub.0 (i.e.
d.gtoreq.0.7d.sub.0), at least 80% of the original displacement
d.sub.0 (i.e. d.gtoreq.0.8d.sub.0), or at least 90% of the original
displacement d.sub.0 (i.e. d.gtoreq.0.9d.sub.0).
[0294] Preferably, the particulates contained in the tablet
according to the invention have a deformability such that they are
deformed without being fractured when subjected to a constant force
of e.g. 50 N, 100 N, 200 N, 300 N, 400 N, 500 N or 600 N in a
breaking strength test as described above ("Zwick Z 2.5" materials
tester, constant force), until the displacement d of upper jaw (8a)
and lower jaw (8b) is reduced so that no further deformation takes
place at said constant force, whereas at this equilibrated state
the displacement d of upper jaw (8a) and lower jaw (8b) is at least
0.05 mm or at least 0.10 mm, preferably at least 0.15 mm or at
least 0.20 mm, more preferably at least 0.25 mm or at least 0.30
mm, still more preferably at least 0.35 mm or at least 0.40 mm, yet
more preferably at least 0.45 mm or at least 0.50 mm, even more
preferably at least 0.55 mm or at least 0.60 mm, most preferably at
least 0.65 mm or at least 0.70 mm and in particular at least 0.75
or at least 0.80 mm.
[0295] Preferably, the tablet according to the invention provides
under in vitro conditions immediate release of the
pharmacologically active compound in accordance with Ph. Eur.
[0296] The term "immediate release" as applied to tablets is
understood by persons skilled in the art which has structural
implications for the respective tablets. The term is defined, for
example, in the current issue of the US Pharmacopoeia (USP),
General Chapter 1092, "THE DISSOLUTION PROCEDURE: DEVELOPMENT AND
VALIDATION", heading "STUDY DESIGN", "Time Points". For
immediate-release dosage forms, the duration of the procedure is
typically 30 to 60 minutes; in most cases, a single time point
specification is adequate for Pharmacopeia purposes. Industrial and
regulatory concepts of product comparability and performance may
require additional time points, which may also be required for
product registration or approval. A sufficient number of time
points should be selected to adequately characterize the ascending
and plateau phases of the dissolution curve. According to the
Biopharmaceutics Classification System referred to in several FDA
Guidances, highly soluble, highly permeable drugs formulated with
rapidly dissolving products need not be subjected to a profile
comparison if they can be shown to release 85% or more of the
active drug substance within 15 minutes. For these types of
products a one-point test will suffice. However, most products do
not fall into this category. Dissolution profiles of
immediate-release products typically show a gradual increase
reaching 85% to 100% at about 30 to 45 minutes. Thus, dissolution
time points in the range of 15, 20, 30, 45, and 60 minutes are
usual for most immediate-release products.
[0297] Preferably, under physiological conditions the tablet
according to the invention has released after 30 minutes at least
70%, more preferably at least 75%, still more preferably at least
80%, yet more preferably at least 82%, most preferably at least 84%
and in particular at east 86% of the pharmacologically active
compound originally contained in the tablet.
[0298] Preferably, under physiological conditions the tablet
according to the invention has released after 10 minutes at least
70%, more preferably at least 73%, still more preferably at least
76%, yet more preferably at least 78%, most preferably at least 80%
and in particular at east 82% of the pharmacologically active
compound originally contained in the tablet.
[0299] Further preferred release profiles C.sup.1 to C.sup.10 are
summarized in the table here below [all data in wt.-% of released
pharmacologically active compound]:
TABLE-US-00004 time C.sup.1 C.sup.2 C.sup.3 C.sup.4 C.sup.5 C.sup.6
C.sup.7 C.sup.8 C.sup.9 C.sup.10 10 min .gtoreq.30 .gtoreq.35
.gtoreq.40 .gtoreq.45 .gtoreq.50 .gtoreq.60 .gtoreq.70 .gtoreq.80
.gtoreq.80 .gtoreq.80 20 min .gtoreq.50 .gtoreq.55 .gtoreq.60
.gtoreq.65 .gtoreq.70 .gtoreq.75 .gtoreq.80 .gtoreq.85 .gtoreq.90
.gtoreq.95 30 min .gtoreq.55 .gtoreq.60 .gtoreq.65 .gtoreq.70
.gtoreq.75 .gtoreq.85 .gtoreq.90 .gtoreq.95 .gtoreq.95 .gtoreq.95
40 min .gtoreq.60 .gtoreq.65 .gtoreq.70 .gtoreq.80 .gtoreq.85
.gtoreq.90 .gtoreq.95 .gtoreq.95 .gtoreq.95 .gtoreq.95 50 min
.gtoreq.65 .gtoreq.70 .gtoreq.80 .gtoreq.85 .gtoreq.88 .gtoreq.92
.gtoreq.95 .gtoreq.95 .gtoreq.95 .gtoreq.95 60 min .gtoreq.75
.gtoreq.80 .gtoreq.85 .gtoreq.90 .gtoreq.92 .gtoreq.94 .gtoreq.95
.gtoreq.95 .gtoreq.95 .gtoreq.95
[0300] Preferably, the release profile, the drug and the
pharmaceutical excipients of the tablet according to the invention
are stable upon storage, preferably upon storage at elevated
temperature, e.g. 40.degree. C., for 3 months in sealed
containers.
[0301] In connection with the release profile "stable" means that
when comparing the initial release profile with the release profile
after storage, at any given time point the release profiles deviate
from one another by not more than 20%, more preferably not more
than 15%, still more preferably not more than 10%, yet more
preferably not more than 7.5%, most preferably not more than 5.0%
and in particular not more than 2.5%.
[0302] In connection with the drug and the pharmaceutical
excipients "stable" means that the tablets satisfy the requirements
of EMEA concerning shelf-life of pharmaceutical products.
[0303] 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., 900 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.
[0304] In a preferred embodiment, the tablet according to the
invention is adapted for administration once daily. In another
preferred embodiment, the tablet according to the invention is
adapted for administration twice daily. In still another preferred
embodiment, the tablet according to the invention is adapted for
administration thrice daily. In yet another preferred embodiment,
the tablet 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.
[0305] 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.
[0306] 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.
[0307] Preferably, the tablet according to the invention has under
in vitro conditions a disintegration time measured in accordance
with Ph. Eur. of at most 5 minutes, more preferably at most 4
minutes, still more preferably at most 3 minutes, yet more
preferably at most 2.5 minutes, most preferably at most 2 minutes
and in particular at most 1.5 minutes.
[0308] It has been surprisingly found that oral dosage forms can be
designed that provide the best compromise between
tamper-resistance, disintegration time and drug release, drug load,
processability (especially tablettability) and patient
compliance.
[0309] It has been found that the disintegration time of the
tablets according to the invention can be influenced by the
relative weight ratio of matrix material:particulates. In general,
it was observed that the higher this ratio the faster
disintegration. However, this ratio cannot be increased ad ultimo,
as further tablet properties need to be taken into account,
particularly drug load and total tablet size and weight. As a
certain dosage of pharmacologically active compound needs to be
administered, the content of particulates should still be
sufficiently high and the total tablet weight should not exceed a
certain limit, as this would deteriorate patient compliance, e.g.
swallowability.
[0310] The situation is more complicated by trends in opposite
direction. In particular, it has been found that the tablettability
of the tablets according to the invention can also be influenced by
the relative weight ratio of matrix material:particulates. In
general, it was observed that the lower this ratio the better the
tablettability. This trend parallels the trend of the drug
load.
[0311] Thus, disintegration time on the one hand and
tablettability/drug load on the other hand can be optimized by
finding the best compromise.
[0312] Similarly, tamper-resistance and drug release also
antagonize each other. While smaller particulates should typically
show a faster release of the pharmacologically active compound,
tamper-resistance requires some minimal size of the particulates in
order to effectively prevent abuse, e.g. i.v. administration. The
larger the particulates are the less they are suitable for being
abused nasally. The smaller the particulates are the faster gel
formation occurs.
[0313] Thus, drug release on the one hand and tamper-resistance on
the other hand can be optimized by finding the best compromise.
[0314] Preferred embodiments D.sup.1 to D.sup.4 of the tablets
according to the invention are summarized in the table here
below:
TABLE-US-00005 [wt.-%, relative to weight of tablet] D.sup.1
D.sup.2 D.sup.3 D.sup.4 tablet total weight [mg] 500 .+-. 300 500
.+-. 250 500 .+-. 200 500 .+-. 150 particulates total content
[wt.-%] 50 .+-. 15 50 .+-. 12.5 50 .+-. 10 50 .+-. 7.5 average
particle size [.mu.m] 800 .+-. 400 800 .+-. 300 800 .+-. 200 800
.+-. 100 content of ph. active compound 23 .+-. 20 23 .+-. 15 23
.+-. 10 23 .+-. 5 content of polyalkylene oxide [wt.-%] 22 .+-. 12
22 .+-. 10 22 .+-. 8 22 .+-. 6 content of plasticizer [wt.-%] 4
.+-. 3.5 4 .+-. 3 4 .+-. 2.5 4 .+-. 2 content of further excipients
[wt.-%] 0.05 .+-. 0.05 0.05 .+-. 0.04 0.05 .+-. 0.03 0.05 .+-. 0.02
matrix material total content [wt.-%] 49 .+-. 15 49 .+-. 12 49 .+-.
9 49 .+-. 6 content of filler(s)/binder(s) [wt.-%] 43 .+-. 10 43
.+-. 8 43 .+-. 6 43 .+-. 4 content of disintegrant [wt.-%] 5 .+-. 4
5 .+-. 3.5 5 .+-. 3 5 .+-. 2.5 content of lubricant [wt.-%] 0.15
.+-. 0.15 0.15 .+-. 0.14 0.15 .+-. 0.13 0.15 .+-. 0.12
[0315] The particulates according to the invention are preferably
prepared by melt-extrusion, although also other methods of
thermoforming may be used in order to manufacture the particulates
according to the invention such as press-molding at elevated
temperature or heating of particulates that were manufactured by
conventional compression in a first step and then heated above the
softening temperature of the polyalkylene oxide in the particulates
in a second step to form hard tablets. In this regards,
thermoforming means the forming, or molding of a mass after the
application of heat. In a preferred embodiment, the particulates
are thermoformed by hot-melt extrusion.
[0316] In a preferred embodiment, the particulates are prepared by
hot melt-extrusion, preferably 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 into particulates. 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. 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 particulates is preferably performed by cutting the
extruded strand immediately after it has exited the extrusion die.
However, when the extruded strand is cut in the cooled state,
subsequent singulation of the extruded strand into extruded
particulates 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 into
extruded particulates. 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
particulates. 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.
[0317] The particulates 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.
[0318] In general, the process for the production of the
particulates according to the invention preferably comprises the
following steps: [0319] (a) mixing all ingredients; [0320] (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 polyalkylene oxide up to its softening
point; [0321] (c) hardening the mixture by applying heat and force,
it being possible to supply the heat during and/or before the
application of force and the quantity of heat supplied being
sufficient to heat the polyalkylene oxide at least up to its
softening point; and thereafter allowing the material to cool and
removing the force [0322] (d) optionally singulating the hardened
mixture; [0323] (e) optionally shaping the particulates; and [0324]
(f) optionally providing a film coating.
[0325] 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 particulates may be shaped for example by direct
tabletting or with the assistance of a suitable extruder,
particularly by means of a screw extruder equipped with one or two
screws (single-screw-extruder and twin-screw-extruder,
respectively) or by means of a planetary gear extruder.
[0326] The final shape of the particulates 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 polyalkylene oxide. However,
extrusion at lower temperatures, e.g. ambient temperature, is also
possible and may be preferred.
[0327] Shaping can be performed, e.g., by means of a tabletting
press comprising die and punches of appropriate shape.
[0328] A particularly preferred process for the manufacture of the
particulates according to the invention involves hot-melt
extrusion. In this process, the particulates according to the
invention are produced by thermoforming with the assistance of an
extruder, preferably without there being any observable consequent
discoloration of the extrudate.
[0329] This process is characterized in that [0330] a) all
components are mixed, [0331] b) the resultant mixture is heated in
the extruder at least up to the softening point of the polyalkylene
oxide and extruded through the outlet orifice of the extruder by
application of force, [0332] c) the still plastic extrudate is
singulated and formed into the particulates or [0333] d) the cooled
and optionally reheated singulated extrudate is formed into the
particulates.
[0334] Mixing of the components according to process step a) may
also proceed in the extruder.
[0335] 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.
[0336] The, preferably molten, mixture which has been heated in the
extruder at least up to the softening point of polyalkylene oxide
is extruded from the extruder through a die with at least one
bore.
[0337] The process according to the invention requires the use of
suitable extruders, preferably screw extruders. Screw extruders
which are equipped with two screws (twin-screw-extruders) are
particularly preferred.
[0338] Preferably, extrusion is performed in the absence of water,
i.e., no water is added. However, traces of water (e.g., caused by
atmospheric humidity) may be present.
[0339] The extruder preferably comprises at least two temperature
zones, with heating of the mixture at least up to the softening
point of the polyalkylene oxide 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 throughput is from 0.5 kg/hour to
3.5 kg/hour. In another preferred embodiment, the throughput is
from 4 to 15 kg/hour.
[0340] In a preferred embodiment, the die head pressure is within
the range of from 25 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.
[0341] The die geometry or the geometry of the bores is freely
selectable. The die or the bores may accordingly exhibit a round,
oblong or oval cross-section, wherein the round cross-section
preferably has a diameter of 0.1 mm to 2 mm. Preferably, the die or
the bores have a round cross-section. The casing of the extruder
used according to the invention may be heated or cooled. The
corresponding temperature control, i.e. heating or cooling, is so
arranged that the mixture to be extruded exhibits at least an
average temperature (product temperature) corresponding to the
softening temperature of the polyalkylene oxide and does not rise
above a temperature at which the pharmacologically active compound
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 polyalkylene oxide. Typical extrusion temperatures
are 120.degree. C. and 150.degree. C.
[0342] 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.
[0343] 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.
[0344] Preferably, intermediate or final storage of the optionally
singulated extrudate or the final shape of the particulates
according to the invention is performed under oxygen-free
atmosphere which may be achieved, e.g., by means of
oxygen-scavengers.
[0345] The singulated extrudate may be press-formed into
particulates in order to impart the final shape to the
particulates.
[0346] 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 tablet with desired mechanical
properties, may be established by simple preliminary testing.
[0347] 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 or 1.0 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 3 kg/h, 8 kg/h, or even 10 kg/h and more for a ZSE27,
product temperature: in front of die 125.degree. C. and behind die
135.degree. C., and jacket temperature: 110.degree. C. The
throughput can generally be increased by increasing the number of
dies at the extruder outlet.
[0348] 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.
[0349] The particulates according to the invention are preferably
produced by thermoforming with the assistance of an extruder
without any observable consequent discoloration of the
extrudates.
[0350] The process for the preparation of the particulates
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.
[0351] Preferably, the particulates according to the invention can
be regarded as "extruded pellets". 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 dosage
forms can be prepared by a number of techniques, including: [0352]
drug layering on nonpareil sugar or microcrystalline cellulose
beads, [0353] spray drying, [0354] spray congealing, [0355]
rotogranulation, [0356] hot-melt extrusion, [0357] spheronization
of low melting materials, or [0358] extrusion-spheronization of a
wet mass.
[0359] Accordingly, "extruded pellets" can be obtained either by
hot-melt extrusion or by extrusion-spheronization.
[0360] "Extruded pellets" can be distinguished from other types of
pellets, as extruded pellets typically have a different shape. The
shape of the extruded pellets is typically more cut-rod-like than
perfectly globated round.
[0361] "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.
[0362] 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".
[0363] The tablets according to the invention may be prepared by
any conventional method. Preferably, however, the tablets are
prepared by compression. Thus, particulates as hereinbefore defined
are preferably mixed, e.g. blended and/or granulated (e.g. wet
granulated), with matrix material and the resulting mix (e.g. blend
or granulate) is then compressed, preferably in moulds, to form
tablets. It is also envisaged that the particulates 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.
[0364] When the tablets 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 tablets 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.
[0365] The tablets according to the invention may optionally
comprise a coating, e.g. a cosmetic coating. The coating is
preferably applied after formation of the tablet. The coating may
be applied prior to or after the curing process. Preferred coatings
are Opadry.RTM. coatings available from Colorcon. Other preferred
coating are Opaglos.RTM. coatings, also commercially available from
Colorcon.
[0366] The tablet according to the invention is characterized by
excellent storage stability. Preferably, after storage for 4 weeks
at 40.degree. C. and 75% rel. humidity, the content of
pharmacologically active compound 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. Suitable methods for measuring the content of the
pharmacologically active compound in the tablet are known to the
skilled artisan. In this regard it is referred to the Eur. Ph. or
the USP, especially to reversed phase HPLC analysis. Preferably,
the tablet is stored in closed, preferably sealed containers.
[0367] Further aspects according to the invention--basis for
additional claim categories
[0368] The particulates and tablets according to the invention may
be used in medicine, e.g. as an analgesic. The particulates and
tablets are therefore particularly suitable for the treatment or
management of pain. In such tablets, the pharmacologically active
compound is preferably an analgesic.
[0369] A further aspect according to the invention relates to the
tablet as described above for use in the treatment of pain.
[0370] A further aspect according to the invention relates to the
use of a tablet as described above for avoiding or hindering the
abuse of the pharmacologically active compound contained
therein.
[0371] A further aspect according to the invention relates to the
use of a tablet as described above for avoiding or hindering the
unintentional overdose of the pharmacologically active compound
contained therein.
[0372] In this regard, the invention also relates to the use of a
pharmacologically active compound as described above and/or a
polyalkylene oxide as described above for the manufacture of the
tablet according to the invention for the prophylaxis and/or the
treatment of a disorder, thereby preventing an overdose of the
pharmacologically active compound, particularly due to comminution
of the tablet by mechanical action.
EXAMPLES
[0373] The following examples further illustrate the invention but
are not to be construed as limiting its scope.
Example 1
[0374] The relevance of the particulate size on tamper resistance
was investigated.
[0375] It was found that comparatively small particulates, e.g.
particulates having a diameter and length of 0.5 mm.times.0.5 mm
already provide a certain degree of tamper resistance: when
administered nasally they cause an unpleasant feeling and
furthermore, due to the lack of water on the mucous membrane, do
not release the pharmacologically active compound as quick as when
being administered orally. Therefore, a kick or rush can unlikely
be achieved by nasal administration of such particulates. Thus,
even when being administered nasally, such comparatively small
particulates already provide tamper resistance, i.e. avoid drug
abuse or at least make drug abuse substantially more difficult.
Furthermore, such comparatively small particulates have excellent
swelling properties thereby effectively preventing conversion into
a liquid formulation for intravenous administration.
[0376] It was found that tamper-resistance can even further be
improved by increasing the particulate size, e.g. to a diameter and
length of 1.0 mm.times.1.0 mm. Such particulates even provide a
more unpleasant feeling when being administered nasally and in the
absence of sufficient water, rather slowly release the
pharmacologically active compound. Further, they cannot be easily
converted into a liquid formulation for intravenous administration
either.
[0377] As such a more pronounced retardant effect, however, is
detrimental for the desired immediate release upon prescribed oral
administration of the tablets, a compromise must be found between
tamper resistance on the one hand and immediate drug release upon
prescribed oral administration on the other hand, particularly with
respect to disintegration time and drug release kinetics.
Furthermore, drug load, processability (especially tablettability)
and patient compliance are also important requirements to be
satisfied with.
[0378] A predetermined particulate size of 800 .mu.m.times.800
.mu.m was considered most appropriate, i.e. it was considered most
appropriate to adjust the diameter of the extrusion die as well as
cutting length of the extruded stand to 800 .mu.m taking into
consideration that die swelling may occur during the extrusion
process, particularly when the strand exits the die, so that the
diameter of the extruded strand in fact is expanded, depending upon
the composition and the extrusion parameters to a diameter of about
1000 .mu.m. Thus, when proceedings this way, it was considered most
appropriate to manufacture extruded particulates having a diameter
of about 1000 .mu.m (after die swelling, diameter of extrusion die
800 .mu.m) and a length of about 800 .mu.m.
Example 2
[0379] Different particulate compositions were investigated and
particulates of different sizes were manufactured thereform.
[0380] The particulate compositions are summarized in the table
here below:
TABLE-US-00006 [wt.-%] 1 2 3 4 5 6 7 8 9 Tramadol HCl 46.59 46.59
46.59 38.83 -- -- -- -- 45.59 Tapentadol HCl -- -- -- -- 46.59
46.59 46.59 33.28 -- PEG 6000 5.31 6.32 4.31 8.33 8.31 8.31 8.32
10.00 8.40 HPMC 100 000 5.00 6.00 4.00 9.33 -- -- 8.00 12.57 8.00
PEO 7 Mio 33.00 35.99 45.00 43.49 45.00 45.00 36.99 44.14 36.99
.alpha.-tocopherol 0.10 0.10 0.10 0.01 0.10 0.10 0.1 0.01 0.01
Lutrol 127 10.00 -- -- -- -- -- -- -- -- PVP CL -- 5.00 -- -- -- --
-- -- -- total weight [mg] 250 mg 250 mg 250 mg 300 mg 250 mg 250
mg 250 mg 350 mg 250 mg film coating AMB -- -- -- -- -- 3.88 -- --
-- varnish
[0381] All materials were weighed, sieved (manual sieve, 1 mm),
blended (Bohle LM40 with MC5 or MC10, depending on size of bath)
for 15 minutes at 14 rpm, and hot-melt extruded (Leistritz extruder
Type ZSE18 with different configuration of screws).
[0382] The compositions 1 to 9 were extruded under the following
extrusion conditions:
TABLE-US-00007 1, 4, 7, 9 2 3 5 and 6 8 Heating zone 1 20.degree.
C. 20.degree. C. 20.degree. C. 20 25 Heating zone 2 100.degree. C.
100.degree. C. 100.degree. C. 100 100 Heating zone 3 100.degree. C.
100.degree. C. 100.degree. C. 100 100 Heating zone 4 120.degree. C.
140.degree. C. 120.degree. C. 120 100 Heating zone 5 120.degree. C.
120.degree. C. 120.degree. C. 120 100 Heating zone 6 120.degree. C.
120.degree. C. 120.degree. C. 120 100 Heating zone 7 120.degree. C.
140.degree. C. 120.degree. C. 120 100 Heating zone 8 120.degree. C.
140.degree. C. 120.degree. C. 120 100 Heating zone 10 120.degree.
C. 140.degree. C. 120.degree. C. 120 120 Heating zone 11
130.degree. C. 150.degree. C. 130.degree. C. 130 120 Screw speed
[rpm] 100 100 100 100 100 Throughput 10.00-16.66 16.66-28.04 16.66
16.66 16.66 [g/min] Screw low low low extreme low configuration
shear shear shear shear shear
[0383] For larger scales, screw configuration can be adopted and
temperatures can be raised (e.g., HZ8 and 10: 130.degree. C., HZ11:
145.degree. C.; or HZ11: 150.degree. C. and extreme shear
configuration, throughput 25 g/min).
[0384] The in vitro release characteristics were monitored in 900
mL 0.1N HCl at 37.degree. C., using a paddle apparatus 50 rpm. The
results are depicted in FIG. 3.
Example 3
[0385] The influence of the content of particulates in the tablet
was investigated.
[0386] The following compositions were tested:
300 mg particulates in tablets having a total weight of 600 mg 250
mg particulates in tablets having a total weight of 600 mg 200 mg
particulates in tablets having a total weight of 600 mg
[0387] The most promising compromise between tablettability and
size revealed to be 250 mg particulates in tablets having a total
weight of 500 mg. Tablets having a total weight of 600 mg were
considered too large with respect to patient compliance, although
the relative weight ratio of particulates to matrix material of
about 1:1 appeared advantageous with respect to disintegration time
and dissolution time.
Example 4-1
[0388] The influence of the matrix material was investigated--wet
granulation.
[0389] Granules having the following composition were prepared for
manufacturing of pellet-tablets. Granules for outer the phase, i.e.
the matrix material, were manufactured by wet granulation. Granules
and pellets were blended. Segregation (optically) and
disintegration of tablets after compression were evaluated. Tablets
were manufactured "manually" (components were separately weighed
for each tablet and mixed directly prior to tabletting) using a
single station press (Korsch EK0):
TABLE-US-00008 a Galen IQ, Na no segregation in mixture
disintegration test: no carboxymethylstarch (5%) detectable,
detectable disintegration aqueous granulation in Diosna after 3
min. b Galen IQ, Kollidon CL (5%) no segregation in mixture
disintegration test: aqueous granulation in Diosna detectable
slightly dissolved mixture showed substantial surface after 3 min.
punch deposit upon compression of 3 tablets already c Avicel with
PVP-solution significant segregation in disintegration test:
granulated mixture detectable partial disintegration after 3 min. d
MCC + lactose(20:80) with PVP- no segregation in mixture
disintegration test: no solution granulated detectable detectable
disintegration after 3 min. d MCC + lactose (50:50) with PVP-
slight segregation in mixture disintegration test: solution
granulated detectable partial disintegration after 3 min. e
Gelcarin + lactose (20% + 80%) + no segregation in mixture
disintegration test: no water (57% + 43%) detectable detectable
disintegration after 3 min. f sugar ester S-1570 + tricalcium-
significant segregation in disintegration test: no phosphate +
Acivel + Gelcarin mixture detectable detectable disintegration
after 3 min. g incrustation granulate from the granulate could not
be no tablets manufactured saccharose processed or only with
difficulties blending with particulates is not possible -> thus,
no tablets were manufactured
[0390] It was not possible to manufacture rapidly disintegrating
tablets from the above compositions, probably because the
disintegrants lose the disintegrating capacity in the course of the
wet granulation process.
Example 4-2
[0391] The influence of the matrix material was investigated--dry
granulation--roller compaction.
[0392] The following compositions were processed by slugging
involving the steps of: [0393] weighing/dispensing of components
[0394] sieving/blending [0395] manufacture of bi-planar tablets of
20 mm diameter using a single station press (Korsch EK0), 25 kN
compression force [0396] breaking the tablets into parts (manually)
and sieving using a Frewitt Sieving machine (1.5 mm mesh size)
[0397] employing granules as outer phase/matrix material for
pellet-tablets
[0398] The experimental results are summarized in the following
table:
TABLE-US-00009 compacted material tablet surface released Tramadol
Mg- PVP Esma- (compression (compression film after 30 min excipient
Pellets Avicel 101 Lactose stearate CL spreng Primojel NaCMC force
20-25 kN) force 7.5 kN) disintegration coated form a 87.4 50.00%
22.25% 22.25% 0.50% 5.00% OK - + no Round 12 mm (5 kN) biplan (5 kN
and 10 kN), oblong 7 .times. 17 mm (7.5 kN) b 64.1 50.00% 45.00%
5.00% OK 0 + no Round 12 mm biplan c n.d. 15% 50.00% 29.5% 0.50%
5.00% OK - -- no Round 12 mm PEG6000 biplan d 87.7 50.00% 45.00%
5.00% slightly ++ ++ no Round 12 mm unstable biplan e 72.2 50.00%
45.00% 5.00% OK 0 + no Round 12 mm biplan f n.d. 50.00% 45.00%
5.00% OK 0 - no Round 12 mm biplan g n.d. 15% 50.00% 25.00% adheres
- -- no Round 12 mm NaHCO.sub.3 punch to biplan 10% citric acid
matrix i 71.1 1% xanthan 50.00% 44.00% 5.00% can only be - 0 no
Round 12 mm compacted biplan with difficulties j-1 77.4 45% Prosolv
50.00% 5.00% OK + ++ no Round 12 mm SMCCHD90 biplan j-2 81.2 50%
Prosolv 50.00% OK 0 ++ no Round 12 mm SMCCHD90 biplan k 28.4 45%
Parteck 50.00% 5.00% OK 0 + no l n.d. 50% Zaldiar 50.00% adheres -
-- no Round 12 mm effervescent punch to biplan tablet matrix m 77.6
50.00% 22.25% 22.25% 0.50% 5.00% OK + no Round 12 mm biplan m' 89.9
50.98% 21.81% 21.81% 0.49% 4.90% OK + yes Round 12 mm biplan n 78.2
50.00% 22.25% 22.25% 0.50% 5.00% OK 0 no Round 12 mm biplan n' 92.9
50.98% 21.81% 21.81% 0.49% 4.90% OK 0 yes Round 12 mm biplan n''
86.3 50.98% 21.81% 21.81% 0.49% 4.90% OK 0 yes penta- gonal o 60.0
45% Prosolv 50.00% 5.00% OK 0 no Round 12 mm SMCCHD90 biplan o'
90.5 44.12% 50.98% 4.90% OK 0 yes Round 12 mm Prosolv biplan
SMCCHD90 o'' 75.4 44.12% 50.98% 4.90% OK 0 yes penta- Prosolv gonal
SMCCHD90 p 74.3 45% Prosolv 50.00% 5.00% OK 0 no Round 12 mm
SMCCHD90 biplan p' 93.5 44.12% 50.98% 4.90% OK 0 yes Round 12 mm
Prosolv biplan SMCCHD90 q 54.3 50.00% 42.50% 7.50% OK 0 no Round 12
mm biplane q' 60.2 50.98% 41.67% 7.35% OK 0 yes Round 12 mm biplane
r 69.3 50.00% 42.50% 7.50% OK 0 no Round 12 mm biplane r' 84.8
50.98% 41.67% 7.35% OK 0 yes Round 12 mm biplane u 39.9 50% 50.00%
no Round 12 mm MicroceLac biplane u' 70.3 50% 50.00% yes Round 12
mm MicroceLac biplane v 78.6 50% 50.00% no Round 12 mm EASYtab SP
biplane v' 93.5 50% 50.00% + + yes Round 12 mm EASYtab SP biplane w
n.d. 50% 50.00% + ++ no Round 12 mm EASYtab SP biplane w' n.d. 50%
50.00% yes Round 12 mm EASYtab SP biplan ++ good, + satisfactory, 0
acceptable, - deficient, -- inacceptable
[0399] The release characteristics of tablets containing the thus
compacted matrix material were investigated. The results are
depicted in FIG. 4 (900 mL HCl, 50 rpm, paddle apparatus without
sinker).
Example 4-3
[0400] Since the slugging method is not state of the art for dry
granulation, corresponding tests concerning dry granulation were
conducted by means of a roller compactor. This has the advantage
that all relevant parameters (roller displacement, compression
force, granulator size) can be adjusted such that a granulate
having the desired properties is obtained (particle size, hardness,
compressibility, density).
Parameters (Gerteis MiniFactor):
[0401] roller displacement: 2 to 3 mm revolution velocity: 2 to 5
rpm compaction force: 3 to 15 kN/cm screen size: 1.0 to 1.25 to 1.5
to 2.0 mm
[0402] The thus prepared compacts (dry granulates) were blended
with particulates and compressed to tablets. Upon blending,
lubricant (magnesium stearate and sodium stearylfumarate,
respectively) was added as an external excipient neither contained
in the compacts nor in the particulates.
TABLE-US-00010 Batch #1 #2 #3 #4 #5 Avicel PH 101 95.00% 50.00%
Esma Spreng 5.00% Prosolv SMCC HD 90 95.00% 100.00% Na-CMC 5.00%
Lactose Monohydrate 230 50.00% Prosolv Easytab 100.00%
[0403] The experiments revealed that tablets made from compacts and
made from slugging-granulates show a similarly fast release.
Confirming Experiments:
TABLE-US-00011 [0404] Batch #6 #7 #8 #9 #10 #11 #12 Avicel PH 101
89.5% 94.5 89% 89.50% 89.70% Avicel DG 89.5% Esma Spreng 10.00% 5%
Prosolv SMCC HD 90 87.5% Na-CMC 12% PVP CL 10% 10% 10% 10%
Na-stearylfumarate 1% Mg stearate 0.5 0.5 0.5% 0.5 0.5% 0.3%
Example 4-4
[0405] Tablets (500 mg) were prepared from the particulates
according to Example 2-5 (250 mg) and the matrix material according
to Example 4-3 #12 (250 mg).
[0406] The in vitro release was determined according to Ph.
Eur.:
TABLE-US-00012 time % released (n = 6) 0 0.0 5 56.8 10 83.4 15 93.3
20 98.1 25 99.9 30 101.1 35 101.4 40 101.7 45 101.9 50 102.0 55
102.0 60 102.0
[0407] The in vitro release of the tablets was compared to a
non-tamper resistant commercial product containing Tapentadol HCl
(film coated tablets). After 30 minutes (according to Ph. Eur.
2.9.3), both formulations released the entire amount of the
pharmacologically active ingredient (100%).
Example 5
[0408] The mechanical properties of conventional, commercial
neutral pellets were investigated under the following
conditions:
TABLE-US-00013 5-1 (comparative) 5-2 5-3 pellets neutral (Hans G.
tramadol TRF tramadol TRF product Werner GmbH & Co.) IR pellets
IR pellets Tramadol HCl 46.59 wt.-% 4.17 wt.-% PEG 6000 8.31 wt.-%
8.33 wt.-% vitamin E 0.10 wt.-% 0.20 wt.-% PEO 45.00 wt.-% 87.30
wt.-% diameter pellets 0.85 mm-1.00 mm test equipment Zwick/Roell
type BTC-FR2.5TH.D09 force sensor KAF-TC/2.5 kN software
applications testXpert V10.11 measuring equipment plate 2.5 cm
.times. 9.0 cm + ambos 2.0 cm .times. 4.0 cm speed 10 mm/min soft
end 192 mm 192 mm 192 mm
[0409] The reduction of the displacement between plate and ambos x
in mm (="compression [c]") and the corresponding force f in N were
measured. The maximum force f.sub.max measured during the
measurement and the corresponding reduction of displacement
x.sub.max are summarized in the table here below:
TABLE-US-00014 5-1 (FIG. 7) 5-2 (FIG. 8) 5-3 (FIG. 9) f.sub.max [N]
x.sub.max [mm] f.sub.max [N] x.sub.max [mm] f.sub.max [N] x.sub.max
[mm] mean 5.272 0.01 587.285 0.87 588.255 0.89 s 2.129 0.03 2.320
0.06 2.897 0.05 .nu. 40.37 198.70 0.40 6.73 0.49 5.13 min 2.260
0.00 585.226 0.82 583.385 0.82 max 8.432 0.08 592.581 1.00 592.413
0.96
[0410] It becomes clear from the above data that the comparative
particulates of example 5-1 break at very low forces of only about
5 N and can be deformed by less than 0.1 mm. In contrast, the
inventive particulates of examples 5-2 and 5-3 do not break at all,
and can be deformed (flattened) by more than 0.8 mm.
[0411] The corresponding force-displacement-diagrams are shown in
FIGS. 7, 8 and 9, respectively.
* * * * *