U.S. patent application number 13/781957 was filed with the patent office on 2013-08-15 for tamper resistant dosage form comprising inorganic salt.
This patent application is currently assigned to GRUNENTHAL GMBH. The applicant listed for this patent is GRUNENTHAL GMBH. Invention is credited to Lutz BARNSCHEID.
Application Number | 20130209557 13/781957 |
Document ID | / |
Family ID | 43708955 |
Filed Date | 2013-08-15 |
United States Patent
Application |
20130209557 |
Kind Code |
A1 |
BARNSCHEID; Lutz |
August 15, 2013 |
TAMPER RESISTANT DOSAGE FORM COMPRISING INORGANIC SALT
Abstract
The invention relates to a pharmaceutical dosage form exhibiting
a breaking strength of at least 500 N, said dosage form containing
a pharmacologically active ingredient (A); an inorganic salt (B);
and a polyalkylene oxide (C) having a weight average molecular
weight of at least 200,000 g/mol, wherein the content of the
polyalkylene oxide (C) is at least 20 wt.-%, based on the total
weight of the dosage form; wherein the pharmacologically active
ingredient (A) is present in a controlled-release matrix comprising
the inorganic salt (B) and the polyalkylene oxide (C) and wherein,
under in vitro conditions, the release profile of the
pharmacologically active ingredient (A) from said matrix comprises
at least a time interval during which the release follows zero
order kinetics.
Inventors: |
BARNSCHEID; Lutz;
(Monchengladbach, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRUNENTHAL GMBH; |
|
|
US |
|
|
Assignee: |
GRUNENTHAL GMBH
Aachen
DE
|
Family ID: |
43708955 |
Appl. No.: |
13/781957 |
Filed: |
March 1, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
PCT/EP2011/004406 |
Sep 1, 2011 |
|
|
|
13781957 |
|
|
|
|
61379513 |
Sep 2, 2010 |
|
|
|
Current U.S.
Class: |
424/464 ;
424/400; 514/282; 514/646 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 9/2009 20130101; A61K 31/485 20130101; A61P 25/36 20180101;
A61K 9/2031 20130101; A61K 47/02 20130101; A61P 23/00 20180101;
A61K 31/135 20130101 |
Class at
Publication: |
424/464 ;
424/400; 514/646; 514/282 |
International
Class: |
A61K 47/02 20060101
A61K047/02 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 2, 2010 |
EP |
10009121.4 |
Claims
1. A pharmaceutical dosage form exhibiting a breaking strength of
at least 500 N and containing a pharmacologically active ingredient
(A); an inorganic salt (B), wherein the content of the inorganic
salt (B) is from 5 to 70 wt.-%, based on the total weight of the
dosage form; a polyalkylene oxide (C) having a weight average
molecular weight of at least 200,000 g/mol, wherein the content of
the polyalkylene oxide (C) is at least 30 wt.-%, based on the total
weight of the dosage form; wherein the pharmacologically active
ingredient (A) is embedded in a controlled release matrix
comprising the inorganic salt (B) and the polyalkylene oxide (C),
and wherein, under in vitro conditions, the release profile of the
pharmacologically active ingredient (A) from said matrix comprises
at least a time interval during which the release follows a zero
order kinetics.
2. The pharmaceutical dosage form according to claim 1, wherein the
time interval during which the release follows zero order kinetics
is at least 20% of the total release time needed for a release of
95 wt.-% of the pharmacologically active ingredient (A) that was
originally contained.
3. The pharmaceutical dosage form according to claim 1, wherein the
release profile follows zero order kinetics within the range of
from pH 1 to pH 7
4. The pharmaceutical dosage form according to claim 1, which is
prepared by hot-melt extrusion.
5. The pharmaceutical dosage form according to claim 1, which is a
tablet.
6. The pharmaceutical dosage form according to claim 1, wherein the
pharmacologically active ingredient (A) is an opioid selected from
the group consisting of tapentadol, oxymorphone, hydromorphone,
oxycodone, morphine and the physiologically acceptable salts
thereof.
7. The pharmaceutical dosage form according to claim 1, wherein the
inorganic salt (B) contains at least one component selected from
the group consisting of alkali carbonates, earth alkali carbonates,
alkali hydrogen carbonates, earth alkali hydrogen carbonates,
alkali phosphates, earth alkali phosphates, alkali hydrogen
phosphates, earth alkali hydrogen phosphates, alkali dihydrogen
phosphates, earth alkali dihydrogen phosphates and pentaalkali
tri(poly)phosphates.
8. The pharmaceutical dosage form according to claim 7, wherein the
inorganic salt (B) is sodium carbonate or pentasodium triphosphate
or a mixture thereof.
9. The pharmaceutical dosage form according to claim 8, wherein the
amount of the inorganic salt (B) in the pharmaceutical dosage form
is within the range of from 25 to 45 wt.-%, based on the total
weight of the pharmaceutical dosage form.
10. The pharmaceutical dosage form according to claim 1, wherein
the polyalkylene oxide (C) has a molecular weight of at least 0.5
million g/mol.
11. The pharmaceutical dosage form according to claim 10, wherein
the polyalkylene oxide (C) has a molecular weight of at least 1
million g/mol.
12. The pharmaceutical dosage form according to claim 11, wherein
the polyalkylene oxide (C) has a molecular weight within the range
of from 1 to 15 million g/mol.
13. The pharmaceutical dosage form according to claim 1, which
comprises polyalkylenglycole.
14. The pharmaceutical dosage form according to claim 13, wherein
the polyalkylenglycole has a molecular weight of at least 1000
g/mol.
15. A method of treating pain in a patient in need of such
treatment, said method comprising administering to said patient a
pharmaceutical dosage form according to claim 6.
Description
[0001] This application is a continuation of International Patent
Application No. PCT/EP2011/004406, filed Sep. 1, 2011, and claims
priority of U.S. Provisional Patent Application No. 61/379,513,
filed on Sep. 2, 2010, and European Patent Application No.
10009121.4, filed on Sep. 2, 2010, the entire contents of which
patent applications are incorporated herein by reference.
[0002] The invention relates to a pharmaceutical dosage form
exhibiting a breaking strength of at least 500 N, said dosage form
containing a pharmacologically active ingredient (A); an inorganic
salt (B); and a polyalkylene oxide (C) having a weight average
molecular weight of at least 200,000 g/mol, wherein the content of
the polyalkylene oxide (C) is at least 20 wt.-%, based on the total
weight of the dosage form; wherein the pharmacologically active
ingredient (A) is present in a controlled-release matrix comprising
the inorganic salt (B) and the polyalkylene oxide (C) and wherein,
under in vitro conditions, the release profile of the
pharmacologically active ingredient (A) from said matrix comprises
at least a time interval during which the release follows zero
order kinetics.
[0003] Many pharmacologically active ingredients have a potential
of being abused and thus, are advantageously provided in form of
tamper resistant pharmaceutical dosage forms. Prominent examples of
such pharmacologically active ingredients are opioids.
[0004] It is known that abusers crush conventional tablets, which
contain opioids, to defeat the time-release "micro-encapsulation"
and then ingest the resulting powder orally, intra-nasally,
rectally, or by injection.
[0005] Various concepts for the avoidance of pharmacologically
active ingredient abuse have been developed. One concept 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.
[0006] Such pharmaceutical dosage forms are useful for avoiding
pharmacologically active ingredient abuse of the pharmacologically
active ingredient contained therein, as they may not be powdered by
conventional means and thus, cannot be administered in powdered
from, 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, WO 2008/107149, and WO 2009/092601.
[0007] The release kinetics of the pharmacologically active
ingredients from such tamper resistant dosage forms is an important
factor. It is well known that depending on how a pharmaceutically
active ingredient is formulated into a tablet its release pattern
can be modified.
[0008] On the one hand, formulations providing immediate release
upon oral administration have the advantage that they lead to a
fast release of the pharmacologically active ingredient in the
gastrointestinal tract. As a result, a comparatively high dose of
the pharmacologically active ingredient is quickly absorbed leading
to high plasma levels within a short period of time and resulting
in a rapid onset of medicinal action, i.e. medicinal action begins
shortly after administration. At the same time, however, a rapid
reduction in the medicinal action is observed, because
metabolization and/or excretion of the pharmacologically active
ingredient cause a decrease of plasma levels. For that reason,
formulations providing immediate release of pharmacologically
active ingredients typically need to be administered frequently,
e.g. six times per day. This may cause comparatively high peak
plasma pharmacologically active ingredient concentrations and high
fluctuations between peak and trough plasma pharmacologically
active ingredient concentrations which in turn may deteriorate
tolerability.
[0009] Controlled release (e.g. delayed release, prolonged release,
sustained release, and the like) may be based upon various concepts
such as coating the pharmaceutical dosage form with a controlled
release membrane, embedding the pharmacologically active ingredient
in a matrix, binding the pharmacologically active ingredient to an
ion-exchange resin, forming a complex of the pharmacologically
active ingredient, and the like. In this context it can be referred
to, e.g., W. A. Ritschel, Die Tablette, 2. Auflage, Editio Cantor
Verlag Aulendorf, 2002.
[0010] In comparison to formulations providing immediate release,
formulations providing prolonged release upon oral administration
have the advantage that they need to be administered less
frequently, typically once daily or twice daily. This can reduce
peak plasma pharmacologically active ingredient concentrations and
fluctuations between peak and trough plasma pharmacologically
active ingredient concentrations which in turn may improve
tolerability.
[0011] The ideal goal in designing a prolonged-release system is to
deliver the pharmacologically active ingredient to the desired site
at a rate according to the needs of the body. In the absence of
feed-back control, one is left with a simple prolonging effect,
where the pivotal question is at what rate a pharmacologically
active ingredient should be delivered to maintain a constant blood
pharmacologically active ingredient level. This constant rate
should be the same as that achieved by continuous intravenous
infusion where a pharmacologically active ingredient is provided to
the patient at a constant rate just equal to its rate of
elimination. This implies that the rate of delivery must be
independent from the amount of pharmacologically active ingredient
remaining in the dosage form and constant over time.
[0012] A perfectly invariant pharmacologically active ingredient
blood or tissue level versus time profile is the ideal starting
goal of a prolonged-release system. The way to achieve this, in the
simplest case, is use of a maintenance dose that releases its
pharmacologically active ingredient by zero-order kinetics.
[0013] U.S. Pat. No. 5,082,668 discloses an osmotically driven
dosage form, namely a device comprising a wall that surrounds a
compartment. The compartment comprises a beneficial agent
composition and a push composition. A passageway in the wall
connects the compartment with the exterior of the device for
delivering the beneficial agent at a rate governed, in combination,
by the wall, the beneficial agent composition and the push
composition through the passageway of the device over time.
[0014] U.S. Pat. No. 7,300,668 relates to a dosage form comprising:
a three-dimensionally printed innermost region comprising a first
regional concentration of at least one active pharmaceutical
ingredient; and plural three-dimensionally printed non-innermost
regions in nested arrangement and comprising: a) one or more nested
internal regions, wherein an internal region completely surrounds
and is in contact with the innermost regions, and any other
internal region present completely surrounds another internal
region located to the interior thereof; and b) an outermost region
completely surrounding an internal region, wherein the internal and
outermost regions are in nested arrangement, wherein the at least
one active pharmaceutical ingredient is released in approximately a
zero-order release.
[0015] WO 2008/086804 discloses abuse resistant polyglycol-based
pharmaceutical compositions. The composition contains one or more
polyglycols and one or more active substances and it is resistant
to crushing, melting and/or extraction. Moreover, such compositions
have the same or lower solubility in ethanolic-aqueous medium, i.e.
they are not subject to ethanol-induced dose dumping effect.
[0016] WO 2008/148798 discloses a layered pharmaceutical
composition suitable for oral use in the treatment of diseases
where absorption takes place over a large part of the
gastrointestinal tract.
[0017] WO 03/024426 discloses a controlled release pharmaceutical
composition for oral use comprising a solid dispersion of: i) at
least one therapeutically, prophylactically and/or diagnostically
active substance, which at least partially is in an amorphous form,
ii) a pharmaceutically acceptable polymer that has plasticizing
properties, and iii) optionally, a stabilizing agent, the at least
one active substance having a limited water solubility, and the
composition being designed to release the active substance with a
substantially zero order release. Zero order release is provided by
a coating that remains intact during the release phase and covers
the matrix composition in such a manner that only a specific
surface area is subject to erosion. Thereby the surface area from
which the active substance is released is kept substantially
constant during the time period.
[0018] WO 2010/057036 discloses a solid composition and methods for
making and using the solid composition are provided. The solid
composition comprises: (a) at least one active agent with a
solubility of less than about 0.3 mg/ml in an aqueous solution with
a pH of at most about 6.8 at a temperature of about 37.degree. C.;
and (b) a hydrophilic polymer matrix composition comprising: i) a
hydrophilic polymer selected from the group consisting of
METHOCEL.RTM., POLYOX.RTM. WSR 1105 and combinations thereof; and
optionally ii) a hydrophobic polymer selected from the group
consisting of Ethocel 20 premium; and (c) an alkalizer selected
from the group consisting of calcium carbonate, magnesium oxide
heavy and sodium bicarbonate; wherein the composition provides at
least about 70% release of the active between about 7 to about 12
hours following oral administration.
[0019] V. Pillay et al., Journal of Controlled Release, 67 (2000)
67-78 discloses an approach for constant rate delivery of highly
soluble bioactives from a simple monolithic system prepared by
direct compression at ambient conditions.
[0020] M. E. McNeill et al., J Biomater Sci Polym 1996, 7(11),
953-63 relates to properties controlling the diffusion and release
of water-soluble solutes from poly(ethylene oxide) hydrogels. Part
4 deals with extended constant rate release from partly-coated
spheres.
[0021] D. Henrist et al. relates to in vitro and in vivo evaluation
of starch-based hot stage extruded double matrix systems. The
objective of developing a double matrix system consisting of a hot
stage extruded starch pipe surrounding a hot stage extruded and
drug-containing starch core, was to obtain a monolithic matrix
system applicable in the domain of sustained drug release. The
behaviour of the systems was evaluated through dissolution testing
and through a randomised crossover bioavailability study on nine
male volunteers. All double matrix systems showed in vitro a nearly
constant drug release profile after an initial slower release phase
of 4 h. This initial slower release phase was avoided by loading
the starch pipe with a small amount of drug.
[0022] L. Yang et al., J. Pharm. Sciences, 85(2), 1996, 170-173
relates to zero-order release kinetics from a self-correcting
floatable asymmetric configuration drug delivery system.
[0023] It is an object of the invention to provide pharmaceutical
dosage forms having advantages compared to pharmaceutical dosage
forms of the prior art.
[0024] This object has been achieved by the subject-matter
described hereinbelow.
[0025] It has been surprisingly found that comparatively low
amounts of inorganic salts contained in a polymer matrix provide a
further delay of the release of the pharmacologically active
ingredients from tamper resistant dosage forms without leading to a
substantial increase of the overall weight. Further, it has been
surprisingly found that the incorporation of the inorganic salt
into the polymer matrix does not substantially alter the mechanical
properties of the tamper resistant dosage form which are based upon
the polymer matrix, especially the breaking strength. Still
further, it has been surprisingly found that the release profile
follows zero order kinetics and does not depend upon the pH value
of the release medium.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] The invention will now be described in greater detail with
reference to the drawings, wherein:
[0027] FIG. 1 shows the in vitro release profile of a
pharmaceutical dosage form according to the invention containing 30
wt.-% (Variation E) and 40 wt.-% (Variation F), respectively, of
sodium carbonate in comparison to the reference tablets.
[0028] FIG. 2 shows the in vitro release profiles of a
pharmaceutical dosage form according to the invention containing 15
wt.-% (Variation F) and 20 wt.-% (Variation G), respectively, each
of sodium carbonate and pentasodium triphosphate in comparison to
the reference tablets.
[0029] FIG. 3 shows the in vitro release profiles of a
pharmaceutical dosage form according to the invention in an acidic
medium, containing 30 wt.-% sodium carbonate (Variation E) and 15
wt.-% sodium carbonate with 15 wt.-% pentasodium triphosphate
(Variation F) in comparison to the reference tablets.
[0030] FIG. 4 shows the in vitro release profiles of a
pharmaceutical dosage form according to the invention in an acidic
medium (pH 1.2) and with phosphate buffer (pH 4.5), containing
oxymorphone and 30 wt.-% sodium carbonate (Example II) in
comparison to reference tablets.
[0031] FIG. 5 shows the in vitro release profiles of a
pharmaceutical dosage form according to the invention in an acidic
medium (pH 1.2) and with phosphate buffer (pH 4.5), containing
oxymorphone and 15 wt.-% each of sodium carbonate and pentasodium
triphosphate (Example III) in comparison to reference tablets.
[0032] A first aspect of the invention relates to a pharmaceutical
dosage form exhibiting a breaking strength of at least 500 N, said
dosage form containing [0033] a pharmacologically active ingredient
(A); [0034] an inorganic salt (B); and [0035] a polyalkylene oxide
(C) having a weight average molecular weight of at least 200,000
g/mol, wherein the content of the polyalkylene oxide (C) is at
least 20 wt.-%, based on the total weight of the dosage form;
wherein the pharmacologically active ingredient (A) is present in a
controlled-release matrix comprising the inorganic salt (B) and the
polyalkylene oxide (C), and wherein, under in vitro conditions, the
release profile of the pharmacologically active ingredient (A) from
said matrix comprises at least a time interval during which the
release follows zero order kinetics.
[0036] The dosage form according to the invention contains one or
more pharmacologically active ingredients (A).
[0037] There are generally no limitations as to the
pharmacologically active ingredient (A) (pharmacologically active
compound) which can be incorporated into the tablet of the
invention.
[0038] In a preferred embodiment, the pharmaceutical dosage form
contains only a single pharmacologically active ingredient (A). In
another preferred embodiment, the pharmaceutical dosage form
contains a combination of two or more pharmacologically active
ingredients (A).
[0039] Preferably, pharmacologically active ingredient (A) has
potential for being abused. Active ingredients with potential for
being abused are known to the person skilled in the art and
comprise e.g. tranquillisers, stimulants, barbiturates, narcotics,
opioids or opioid derivatives.
[0040] Preferably, the pharmacologically active ingredient (A)
exhibits psychotropic action.
[0041] Preferably, the pharmacologically active ingredient (A) is
selected from the group consisting of opiates, opioids, stimulants,
tranquilizers, and other narcotics.
[0042] Particularly preferably, the pharmacologically active
ingredient (A) 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.
[0043] 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
pharmaceutical dosage form according to the invention: alfentanil,
allobarbital, allylprodine, alphaprodine, alprazolam, amfepramone,
amphetamine, amphetaminil, amobarbital, anileridine, apocodeine,
axomadol, barbital, bemidone, benzylmorphine, bezitramide,
bromazepam, brotizolam, buprenorphine, butobarbital, butorphanol,
camazepam, carfentanil, cathine/D-norpseudoephedrine,
chlordiazepoxide, clobazam clofedanol, clonazepam, clonitazene,
clorazepate, clotiazepam, cloxazolam, cocaine, codeine,
cyclobarbital, cyclorphan, cyprenorphine, delorazepam,
desomorphine, dextromoramide, dextropropoxyphene, dezocine,
diampromide, diamorphone, diazepam, dihydrocodeine,
dihydromorphine, dihydromorphone, dimenoxadol, dimephetamol,
dimethylthiambutene, dioxaphetylbutyrate, dipipanone, dronabinol,
eptazocine, estazolam, ethoheptazine, ethylmethylthiambutene, ethyl
loflazepate, ethylmorphine, etonitazene, etorphine, 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, pernoline,
pentazocine, pentobarbital, pethidine, phenadoxone, phenomorphane,
phenazocine, phenoperidine, piminodine, pholcodeine, phenmetrazine,
phenobarbital, phentermine, pinazepam, pipradrol, piritramide,
prazepam, profadol, proheptazine, promedol, properidine,
propoxyphene, remifentanil, secbutabarbital, secobarbital,
sufentanil, tapentadol, temazepam, tetrazepam, tilidine (cis and
trans), tramadol, triazolam, vinylbital,
N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide,
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (1
R,2R,4S)-2-(dimethylamino)-methyl-4-(p-fluorobenzyloxy)-1-(m-methoxypheny-
l)cyclohexanol, (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,
(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,
(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,
(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-d-
iol, preferably as racemate,
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl
2-(4-isobutyl-phenyl)propionate,
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl
2-(6-methoxy-naphthalen-2-yl)propionate,
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl
2-(4-isobutyl-phenyl)propionate,
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl
2-(6-methoxy-naphthalen-2-yl)propionate,
(RR--SS)-2-acetoxy-4-trifluoromethyl-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)-phenyl ester,
(RR--SS)-2-hydroxy-4-trifluoromethyl-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR--SS)-4-chloro-2-hydroxybenzoic 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-hydroxycyclohexyl)-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.
[0044] In a preferred embodiment the pharmaceutical dosage form
according to the invention contains an opioid selected from the
group consisting of DPI-125, M6G (CE-04-410), ADL-5859, CR-665,
NRP290 and sebacoyl dinalbuphine ester.
[0045] In a preferred embodiment, the pharmaceutical dosage form
according to the invention contains one pharmacologically active
ingredient (A) or more pharmacologically active ingredients (A)
selected from the group consisting of oxymorphone, hydromorphone,
morphine and the physiologically acceptable salts thereof.
[0046] In another preferred embodiment, the pharmacologically
active ingredient (A) is selected from the group consisting of
tapentadol, faxeladol, axomadol and the physiologically acceptable
salts thereof.
[0047] In still another preferred embodiment, the pharmacologically
active ingredient (A) 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-tetrahydropyra-
no[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.
[0048] The pharmacologically active ingredient (A) may be present
in form of a physiologically acceptable salt, e.g. physiologically
acceptable acid addition salt.
[0049] 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.
[0050] The pharmacologically active ingredient (A) is present in
the dosage form 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 whether the dosage form is designed for an immediate or
retarded release. The amount of active ingredient(s) used in the
present invention preferably ranges from about 0.01 wt.-% to about
95 wt.-%, more preferably from about 0.1 wt.-% to about 80 wt.-%,
even more preferably from about 1.0 wt.-% to about 50 wt.-%, yet
more preferably from about 1.5 wt.-% to about 30 wt.-%, and most
preferably from about 2.0 wt.-% to 20 wt.-%, based on the total
weight of the pharmaceutical dosage form.
[0051] The content of the pharmacologically active ingredient (A)
in the pharmaceutical dosage form is not limited. The dose of the
pharmacologically active ingredient (A) 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 ingredient (A) that is contained in
the pharmaceutical dosage form 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.
[0052] Preferably, the content of the pharmacologically active
ingredient (A) is within the range of from 0.01 to 80 wt.-%, more
preferably 0.1 to 50 wt.-%, still more preferably 1 to 25 wt.-%,
based on the total weight of the pharmaceutical dosage form. In a
preferred embodiment, the content of pharmacologically active
ingredient (A) is within the range of from 7.+-.6 wt.-%, more
preferably 7.+-.5 wt.-%, still more preferably 5.+-.4 wt.-%, 7.+-.4
wt.-% or 9.+-.4 wt.-%, most preferably 5.+-.3 wt.-%, 7.+-.3 wt.-%
or 9.+-.3 wt.-%, and in particular 5.+-.2 wt.-%, 7.+-.2 wt.-% or
9.+-.2 wt.-%, based on the total weight of the pharmaceutical
dosage form. In another preferred embodiment, the content of
pharmacologically active ingredient (A) is within the range of from
11.+-.10 wt.-%, more preferably 11.+-.9 wt.-%, still more
preferably 9.+-.6 wt.-%, 11.+-.6 wt.-%, 13.+-.6 wt.-% or 15.+-.6
wt.-%, most preferably 11.+-.4 wt.-%, 13.+-.4 wt.-% or 15.+-.4
wt.-%, and in particular 11.+-.2 wt.-%, 13.+-.2 wt.-% or 15.+-.2
wt.-%, based on the total weight of the pharmaceutical dosage form.
In a further preferred embodiment, the content of pharmacologically
active ingredient (A) is within the range of from 20.+-.6 wt.-%,
more preferably 20.+-.5 wt.-%, still more preferably 20.+-.4 wt.-%,
most preferably 20.+-.3 wt.-%, and in particular 20.+-.2 wt.-%,
based on the total weight of the pharmaceutical dosage form.
[0053] In a preferred embodiment, the pharmacologically active
ingredient (A) is contained in the pharmaceutical dosage form in an
amount of 7.5.+-.5 mg, 10.+-.5 mg, 20.+-.5 mg, 30.+-.5 mg, 40.+-.5
mg, 50.+-.5 mg, 60.+-.5 mg, 70.+-.5 mg, 80.+-.5 mg, 90.+-.5 mg,
100.+-.5 mg, 110.+-.5 mg, 120.+-.5 mg, 130.+-.5, 140.+-.5 mg,
150.+-.5 mg, 160.+-.5 mg, 170.+-.5 mg, 180.+-.5 mg, 190.+-.5 mg,
200.+-.5 mg, 210.+-.5 mg, 220.+-.5 mg, 230.+-.5 mg, 240.+-.5 mg, or
250.+-.5 mg. In another preferred embodiment, the pharmacologically
active ingredient (A) is contained in the pharmaceutical dosage
form in an amount of 5.+-.2.5 mg, 7.5.+-.2.5 mg, 10.+-.2.5 mg,
15.+-.2.5 mg, 20.+-.2.5 mg, 25.+-.2.5 mg, 30.+-.2.5 mg, 35.+-.2.5
mg, 40.+-.2.5 mg, 45.+-.2.5 mg, 50.+-.2.5 mg, 55.+-.2.5 mg,
60.+-.2.5 mg, 65.+-.2.5 mg, 70.+-.2.5 mg, 75.+-.2.5 mg, 80.+-.2.5
mg, 85.+-.2.5 mg, 90.+-.2.5 mg, 95.+-.2.5 mg, 100.+-.2.5 mg,
105.+-.2.5 mg, 110.+-.2.5 mg, 115.+-.2.5 mg, 120.+-.2.5 mg,
125.+-.2.5 mg, 130.+-.2.5 mg, 135.+-.2.5 mg, 140.+-.2.5 mg,
145.+-.2.5 mg, 150.+-.2.5 mg, 155.+-.2.5 mg, 160.+-.2.5 mg,
165.+-.2.5 mg, 170.+-.2.5 mg, 175.+-.2.5 mg, 180.+-.2.5 mg,
185.+-.2.5 mg, 190.+-.2.5 mg, 195.+-.2.5 mg, 200.+-.2.5 mg,
205.+-.2.5 mg, 210.+-.2.5 mg, 215.+-.2.5 mg, 220.+-.2.5 mg,
225.+-.2.5 mg, 230.+-.2.5 mg, 235.+-.2.5 mg, 240.+-.2.5 mg,
245.+-.2.5 mg, or 250.+-.2.5 mg.
[0054] Preferably, the pharmaceutically dosage form provides a
release of the pharmacologically active ingredient (A) after 1 hour
of preferably at most 60%, more preferably at most 40%, yet more
preferably at most 30%, still more preferably at most 20% and most
preferably at most 17%; after 2 hours preferably at most 80%, more
preferably at most 60%, yet more preferably at most 50%, still more
preferably at most 40% and most preferably at most 32%; after 3
hours preferably at most 85%, more preferably at most 65%, yet more
preferably at most 55%, still more preferably at most 48% and most
preferably at most 42%; after 4 hours preferably at most 90%, more
preferably at most 75%, yet more preferably at most 65%, still more
preferably at most 55% and most preferably at most 49%; after 7
hours preferably at most 95%, more preferably at most 85%, yet more
preferably at most 80%, still more preferably at most 70% and most
preferably at most 68%; after 10 hours preferably at most 99%, more
preferably at most 90%, yet more preferably at most 88%, still more
preferably at most 83% and most preferably at most 80%; and after
13 hours preferably at most 99%, more preferably at most 95%, yet
more preferably at most 93%, still more preferably at most 91% and
most preferably at most 89%.
[0055] In a particularly preferred embodiment, the
pharmacologically active ingredient (A) is tapentadol, preferably
its HCI salt, and the pharmaceutical dosage form is adapted for
administration once daily or twice daily. In this embodiment, the
pharmacologically active ingredient (A) is preferably contained in
the pharmaceutical dosage form in an amount of from 25 to 250
mg.
[0056] In another particularly preferred embodiment, the
pharmacologically active ingredient (A) is oxymorphone, preferably
its HCI salt, and the pharmaceutical dosage form is adapted for
administration twice daily. In this embodiment, the
pharmacologically active ingredient (A) is preferably contained in
the pharmaceutical dosage form in an amount of from 5 to 40 mg. In
another particularly preferred embodiment, the pharmacologically
active ingredient (A) is oxymorphone, preferably its HCI, and the
pharmaceutical dosage form is adapted for administration once
daily. In this embodiment, the pharmacologically active ingredient
(A) is preferably contained in the pharmaceutical dosage form in an
amount of from 10 to 80 mg.
[0057] In another particularly preferred embodiment, the
pharmacologically active ingredient (A) is oxycodone, preferably
its HCI salt, and the pharmaceutical dosage form is adapted for
administration twice daily. In this embodiment, the
pharmacologically active ingredient (A) is preferably contained in
the pharmaceutical dosage form in an amount of from 5 to 80 mg. In
another particularly preferred embodiment, the pharmacologically
active ingredient (A) is oxycodone, preferably its HCI, and the
pharmaceutical dosage form is adapted for administration once
daily. In this embodiment, the pharmacologically active ingredient
(A) is preferably contained in the pharmaceutical dosage form in an
amount of from 10 to 320 mg.
[0058] In still another particularly preferred embodiment, the
pharmacologically active ingredient (A) is hydromorphone,
preferably its HCl, and the pharmaceutical dosage form is adapted
for administration twice daily. In this embodiment, the
pharmacologically active ingredient (A) is preferably contained in
the pharmaceutical dosage form in an amount of from 2 to 52 mg. In
another particularly preferred embodiment, the pharmacologically
active ingredient (A) is hydromorphone, preferably its HCl, and the
pharmaceutical dosage form is adapted for administration once
daily. In this embodiment, the pharmacologically active ingredient
(A) is preferably contained in the pharmaceutical dosage form in an
amount of from 4 to 104 mg.
[0059] The pharmaceutical dosage form according to the invention is
characterized by excellent durability of the pharmacologically
active ingredient (A). Preferably, after storage for 4 weeks at
40.degree. C. and 75% rel. humidity, the content of
pharmacologically active ingredient (A) 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 ingredient (A) in the pharmaceutical
dosage form 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 pharmaceutical dosage form is stored
in closed, preferably sealed containers, preferably as described in
the experimental section, most preferably being equipped with an
oxygen scavenger, in particular with an oxygen scavenger that is
effective even at low relative humidity.
[0060] The dosage form according to the invention contains the
pharmacologically active ingredient (A) in a controlled-release
matrix comprising inorganic salt (B), wherein, under in vitro
conditions, the release profile of the pharmacologically active
ingredient (A) from said matrix comprises at least a time interval
during which the release follows a zero order kinetics.
[0061] A skilled person knows which requirements need to be
satisfied with in order to qualify the in vitro release profile of
a pharmaceutical dosage form as being of zero order.
Pharmacologically active ingredient dissolution from solid dosage
forms has been described by kinetic models in which the dissolved
amount of pharmacologically active ingredient (Q) is a function of
the test time, t or Q =f(t). Some analytical definitions of the
Q(t) function are commonly used, such as zero order, first order,
Hixson-Crowell, Weibull, Higuchi, Baker-Lonsdale, Korsmeyer-Peppas
and Hopfenberg models. Other release parameters, such as
dissolution time (tx %), assay time (tx min), dissolution efficacy
(ED), difference factor (f1), similarity factor (f2) and Rescigno
index (xi1 and xi2) can be used to characterize pharmacologically
active ingredient dissolution/release profiles.
[0062] For the purpose of specification the term "zero order
kinetics" is preferably defined by the equation W.sub.0-W.sub.t=K
t, where W.sub.0 is the initial amount of pharmacologically active
ingredient (A) in the pharmaceutical dosage form, W.sub.t is the
amount of pharmacologically active ingredient (A) in the
pharmaceutical dosage form at time t and K is a proportionality
constant. Dividing this equation by W.sub.0 and simplifying
f.sub.t=K.sub.0 t, where f.sub.t=1-(W.sub.t/W.sub.0) and f.sub.t
represents the fraction of pharmacologically active ingredient (A)
dissolved in time t and K.sub.0 the apparent dissolution rate
constant or zero order release constant. In this way, a graphic of
the pharmacologically active ingredient-dissolved fraction versus
time will be linear. This relation can be used to describe the
dissolution of several types of modified release pharmaceutical
dosage forms, as in the case of matrix tablets with low soluble
pharmacologically active ingredients, coated forms, osmotic
systems, etc. The pharmaceutical dosage forms following this
profile release the same amount of pharmacologically active
ingredient by unit of time and it is the ideal method of
pharmacologically active ingredient release in order to achieve a
pharmacological prolonged action. The following relation can, in a
simple way, express this model: Q.sub.1=Q.sub.0+K.sub.0 t, where
Q.sub.t is the amount of pharmacologically active ingredient
dissolved in time t, Q.sub.0 is the initial amount of
pharmacologically active ingredient in the solution (most times,
Q.sub.0=0) and K.sub.0 is the zero order release constant (cf.
e.g., P. Costa et al., Eur J Pharm Sci. 2001, 13(2), 123-33).
[0063] It is evident to the skilled artisan that in praxis
pharmaceutical dosage forms usually do not provide exact zero order
release, particularly not over the full length of the release
period, i.e. from the very beginning until the release of 100% of
the pharmacologically active ingredient (A) that was originally
contained in the pharmaceutical dosage form. Rather, in praxis in
vitro release profiles can be described with a substantial degree
of accuracy by these mathematical models, particularly when not
considering the initial phase as well as the end phase of the
release.
[0064] Preferably, the in vitro release profile of the
pharmacologically active ingredient (A) from the pharmaceutical
dosage form according to the invention comprises a time interval
during which the release follows substantially a zero order
kinetics, which time interval is preferably the time needed in
order to release 50.+-.5%, more preferably 50.+-.10%, still more
preferably 50.+-.15%, yet more preferably 50.+-.20%, even more
preferably 50.+-.25%, most preferably 50.+-.30%, and in particular
50.+-.35%, of the pharmacologically active ingredient (A). For
example, the time needed in order to release 50.+-.30% of the
pharmacologically active ingredient (A) commences with the release
of 20% (e.g. after 2.5 hours) and terminates with the release of
80% (e.g. after 10.5 hours) of the pharmacologically active
ingredient (A). During such time interval, the in vitro release
profile of the pharmacologically active ingredient (A) from the
pharmaceutical dosage form follows substantially zero order
kinetics, i.e. is substantially linear.
[0065] In a preferred embodiment, the kinetics for the in vitro
release of the pharmacologically active ingredient (A) from the
pharmaceutical dosage form is approximated by the equation
M.sub.t/M.sub.0=k t.sup.n where t is time, M.sub.t is the amount of
the pharmacologically active ingredient (A) which has been released
at time t, M.sub.0 is the total amount of the pharmacologically
active ingredient (A) originally contained in the dosage form, i.e.
before exposing the pharmaceutical dosage form to the release
medium, k is a constant, and n is the release kinetics exponent.
Preferably, the in vitro release profile of the pharmaceutical
dosage form according to the invention provides a curve which
defines the retarded release in percent to the time. For a defined
time period, preferably from the beginning or from a point in time
after the beginning, e.g. from the time where 20% have been
released, to the time where 95% of the pharmacologically active
ingredient (A) have been released from the dosage form according to
the invention, the release profile is substantially linear.
[0066] Preferably, the time interval during which the release
follows zero order kinetics, e.g. where the second derivative of
the graph is substantially linear, is at least 20%, more preferably
at least 30%, still more preferably at least 40%, yet more
preferably at least 50%, even more preferably at least 60%, most
preferably at least 70% and in particular at least 80% of the total
release time needed for a release of 95 wt.-% of the
pharmacologically active ingredient (A) that was originally
contained in the pharmaceutical dosage form.
[0067] Preferably, the margins (limits) of "substantially linear"
can be assessed based on the second derivative of the curve fitted
to the measuring points. Ideally, said second derivative is zero.
Preferably, however, a certain degree of deviation is also within
the meaning of "substantially linear" according to the invention.
Preferably, said deviations from the ideal linear behavior can be
quantified by a Chi-square-test, which is known to a person skilled
in the art. Preferably, the value determined according to the
Chi-square-test is at most 2.5, more preferably at most 1.75, still
more preferably at most 1.0, yet more preferably at most 0.75, even
more preferably at most 0.5, most preferably at most 0.25, and in
particular at most 0.1.
[0068] Preferably, the zero-order in vitro release kinetics can
adequately be described by M.sub.t/M.sub..infin.=k.sub.0 t.sup.n,
where M.sub.t and M.sub..infin. are the amounts of drug released at
time t and the overall amount released, respectively, n is a
release exponent indicative of profile shape, and k.sub.0 is the
zero-order release rate constant.
[0069] In a preferred embodiment, when fitting the relevant portion
of the overall in vitro release profile that shows zero-order
release kinetics to the equation M.sub.t/M.sub..infin.=k.sub.0 t
(i.e. where n=1), the correlation coefficient of the fit is
preferably at least 0.75, more preferably at least 0.80, still more
preferably at least 0.85, yet more preferably at least 0.90, even
more preferably at least 0.925, most preferably at least 0.95 and
in particular at least 0.975.
[0070] In a preferred embodiment, the zero-order release rate
constant k.sub.0 is within the range of 0.030.+-.0.028 h.sup.-1,
more preferably 0.030.+-.0.026 h.sup.-1, still more preferably
0.030.+-.0.024 h.sup.-1, yet more preferably 0.030.+-.0.020
h.sup.-1, even more preferably 0.030.+-.0.015 h.sup.-1, most
preferably 0.030.+-.0.010 h.sup.-1, and in particular
0.030.+-.0.005 h.sup.-1. In another preferred embodiment, the
zero-order release rate constant k.sub.0 is within the range of
0.040.+-.0.035 h.sup.-1, more preferably 0.040.+-.0.030 h.sup.-1,
still more preferably 0.040.+-.0.025 h.sup.-1, yet more preferably
0.040.+-.0.020 even more preferably 0.040.+-.0.015 h.sup.-1, most
preferably 0.040.+-.0.010 h.sup.-1, and in particular
0.040.+-.0.005 h.sup.-1. In still another preferred embodiment, the
zero-order release rate constant k.sub.0 is within the range of
0.050.+-.0.035 h.sup.-1, more preferably 0.050.+-.0.030 h.sup.-1,
still more preferably 0.050.+-.0.025 h.sup.-1, yet more preferably
0.050.+-.0.020 h.sup.-1, even more preferably 0.050.+-.0.015
h.sup.-1, most preferably 0.050.+-.0.010 h.sup.-1, and in
particular 0.050.+-.0.005 h.sup.-1. In yet another preferred
embodiment, the zero-order release rate constant k.sub.0 is within
the range of 0.060.+-.0.035 h.sup.-1, more preferably
0.060.+-.0.030 h.sup.-1, still more preferably 0.060.+-.0.025
h.sup.-1, yet more preferably 0.060.+-.0.020 h.sup.-1, even more
preferably 0.060.+-.0.015 h.sup.-1, most preferably 0.060.+-.0.010
h.sup.-1, and in particular 0.060.+-.0.005 h.sup.-1. In a further
preferred embodiment, the zero-order release rate constant k.sub.0
is within the range of 0.070.+-.0.035 h.sup.-1, more preferably
0.070.+-.0.030 h.sup.-1, still more preferably 0.070.+-.0.025
h.sup.-1, yet more preferably 0.070.+-.0.020 even more preferably
0.070.+-.0.015 h.sup.-1, most preferably 0.070.+-.0.010 h.sup.-1,
and in particular 0.070.+-.0.005 h.sup.-1. In a still further
preferred embodiment, the zero-order release rate constant k.sub.0
is within the range of 0.080.+-.0.035 h.sup.-1, more preferably
0.080.+-.0.030 h.sup.-1, still more preferably 0.080.+-.0.025
h.sup.-1, yet more preferably 0.080.+-.0.020 h.sup.-1, even more
preferably 0.080.+-.0.015 h.sup.-1, most preferably 0.080.+-.0.010
h.sup.-1, and in particular 0.080.+-.0.005 h.sup.-1. In a yet
further preferred embodiment, the zero-order release rate constant
k.sub.0 is within the range of 0.090.+-.0.035 h.sup.-1, more
preferably 0.090.+-.0.030 h.sup.-1, still more preferably
0.090.+-.0.025 h.sup.-1, yet more preferably 0.090.+-.0.020
h.sup.-1, even more preferably 0.090.+-.0.015 h.sup.-1, most
preferably 0.090.+-.0.010 h.sup.-1, and in particular
0.090.+-.0.005 h.sup.-1. In another preferred embodiment, the
zero-order release rate constant k.sub.0 is within the range of
0.100.+-.0.035 h.sup.-1, more preferably 0.100.+-.0.030 h.sup.-1,
still more preferably 0.100.+-.0.025 h.sup.-1, yet more preferably
0.100.+-.0.020 even more preferably 0.100.+-.0.015 h.sup.-1, most
preferably 0.100.+-.0.010 h.sup.-1, and in particular
0.100.+-.0.005 h.sup.-1.
[0071] In a preferred embodiment, release exponent n is at least
0.65, more preferably at least 0.70, still more preferably at least
0.75, yet more preferably at least 0.80, even more preferably at
least 0.85, most preferably at least 0.90 and in particular at
least 0.95.
[0072] The zero-order release kinetics of the pharmaceutical dosage
form according to the invention preferably does not rely on a
coating that remains intact during the release phase and covers the
matrix composition in such a manner that only a specific surface
area is subject to erosion. Thus, the surface area of the
pharmaceutical dosage form according to the invention from which
the active substance is released is preferably not kept
substantially constant by means of such a coating. On the contrary,
the zero-order release kinetics of the pharmaceutical dosage form
according to the invention is preferably based on the properties of
the matrix in which the pharmacologically active ingredient (A) is
embedded so that inert coatings can be completely omitted. Thus,
while the pharmaceutical dosage form according to the invention may
be coated with conventional coating materials such as polyvinyl
alcohol, it is preferably not coated with inert coating materials
that serve the purpose of permanently covering a substantial
portion of the outer surface of the dosage form in order to allow
drug release only through a predetermined, uncoated portion. Thus,
in a preferred embodiment, the pharmaceutical dosage form according
to the invention is uncoated, or it is coated with a coating
material that substantially covers the complete outer surface of
the dosage form, but does not leave a certain portion uncoated.
[0073] The pharmaceutical dosage form according to the invention
comprises an inorganic salt (B).
[0074] In a preferred embodiment, the pharmaceutical dosage form
comprises a single inorganic salt (B).
[0075] In another preferred embodiment, the pharmaceutical dosage
form comprises a mixture of two or more inorganic salts (B). When
the pharmaceutical dosage form according to the invention contains
two different inorganic salts (B), e.g. pentasodium triphosphate
and sodium carbonate, the relative weight ratio thereof is
preferably within the range of from 8:1 to 1:8, more preferably 7:1
to 1:7, still more preferably 6:1 to 1:6, yet more preferably 5:1
to 1:5, even more preferably 4:1 to 1:4, most preferably 3:1 to
1:3, and in particular 2:1 to 1:2.
[0076] In another preferred embodiment, the pharmaceutical dosage
form comprises a mixture of two inorganic salts (B). When the
pharmaceutical dosage form according to the invention contains two
different inorganic salts (B), e.g. pentasodium triphosphate and
sodium carbonate, the storage stability at 5.degree. C. and
25.degree. C. is significantly increased. Concerning this matter
the decrease of the content of Vitamin E contained in the
pharmaceutical dosage form is more slowly in contrast to the
pharmaceutical dosage form containing only one inorganic salt, e.g.
sodium carbonate, and the release profile of the pharmacologically
active ingredient (A) does not change in comparison to the release
profile which is recorded before the storage stability was
tested.
[0077] Preferably, inorganic salt (B) is salt, preferably an alkali
metal or earth alkali metal salt, of a strong inorganic acid having
a pK.sub.A value of at most 3, preferably at most 2, more
preferably at most 1, still more preferably at most 0 and in
particular at most -1. If said inorganic acid is a multi-protonic
acid, preferably at least the first proton satisfies the above
requirement.
[0078] Preferably, the inorganic salt (B) is a salt of carbonic
acid (H.sub.2CO.sub.3), phosphoric acid (H.sub.3PO.sub.4),
phosphorous acid (H.sub.3PO.sub.3), pyrophosphoric acid
(H.sub.4P.sub.2O.sub.7), or triphosphoric acid
(H.sub.5P.sub.3O.sub.10), preferably an alkali and/or earth alkali
and/or hydrogenate salt thereof.
[0079] Preferably, the inorganic salt (B) is selected from the
group consisting of alkali carbonates (e.g., Na.sub.2CO.sub.3,
K.sub.2CO.sub.3, NaKCO.sub.3), earth alkali carbonates (e.g.,
MgCO.sub.3, CaCO.sub.3), alkali hydrogen carbonates (e.g.,
NaHCO.sub.3, KHCO.sub.3), earth alkali hydrogen carbonates (e.g.,
Mg(HCO.sub.3).sub.2, Ca(HCO.sub.3).sub.2), alkali phosphates (e.g.,
Na.sub.3PO.sub.4, Na.sub.2KPO.sub.4, NaK.sub.2PO.sub.4,
K.sub.3PO.sub.4), earth alkali phosphates (e.g.,
Mg.sub.3(PO.sub.4).sub.2, Ca.sub.3(PO.sub.4).sub.2,), alkali
pyrophosphates (e.g., Na.sub.4P.sub.2O.sub.7,
Na.sub.3KP.sub.2O.sub.7, Na.sub.2K.sub.2P.sub.2O.sub.7,
NaK.sub.3P.sub.2O.sub.7, K.sub.4P.sub.2O.sub.7), earth alkali
pyrophosphates (e.g., Mg.sub.2P.sub.2O.sub.7, CaMgP.sub.2O.sub.7,
Ca.sub.2P.sub.2O.sub.7), pentaalkali tri(poly)phosphates (alkali
triphosphate tribasic) (e.g., Na.sub.5P.sub.3O.sub.10,
Na.sub.4KP.sub.3O.sub.10, Na.sub.3K.sub.2P.sub.3O.sub.10,
Na.sub.2K.sub.3P.sub.3O.sub.10, NaK.sub.4P.sub.3O.sub.10,
K.sub.5P.sub.3O.sub.10, Na.sub.4KP.sub.3O.sub.10), alkali hydrogen
phosphates (e.g., Na.sub.2HPO.sub.4, NaKHPO.sub.4,
K.sub.2HPO.sub.4), earth alkali hydrogen phosphates (e.g.,
MgHPO.sub.4, CaHPO.sub.4), alkali dihydrogen phosphates (e.g.,
NaH.sub.2PO.sub.4, KH.sub.2PO.sub.4), earth alkali dihydrogen
phosphates (e.g., Mg(H.sub.2PO.sub.4).sub.2,
Ca(H.sub.2PO.sub.4).sub.2).
[0080] Preferably, the inorganic salt (B) is sodium carbonate or
pentasodium triphosphate or mixtures thereof.
[0081] It has been surprisingly found that the inorganic salt (B)
may further extend the release profile of the pharmaceutical dosage
form compared to a comparative dosage form not containing inorganic
salt (B).
[0082] In a preferred embodiment, the content of inorganic salt (B)
amounts to 1 to 80 wt.-%, more preferably 5 to 70 wt.-%, still more
preferably 12 to 60 wt.-%, yet more preferably 17 to 50 wt.-% and
most preferably 25 to 45 wt.-% and in particular 29 to 41 wt.-%,
based on the total weight of the pharmaceutical dosage form.
[0083] In a preferred embodiment, the content of inorganic salt (B)
is within the range of 30.+-.9 wt.-%, more preferably 30.+-.8
wt.-%, still more preferably 30.+-.7 wt.-%, yet more preferably
30.+-.6 wt.-%, most preferably 30.+-.5 wt.-%, and in particular
30.+-.2.5 wt.-%, based on the total weight of the pharmaceutical
dosage form.
[0084] In another preferred embodiment, the content of inorganic
salt (B) is within the range of 40.+-.9 wt.-%, more preferably
40.+-.8 wt.-%, still more preferably 40.+-.7 wt.-%, yet more
preferably 40.+-.6 wt.-%, most preferably 40.+-.5 wt.-%, and in
particular 40.+-.2.5 wt.-%, based on the total weight of the
pharmaceutical dosage form.
[0085] It has been surprisingly found that the mechanical
properties of the (tamper-resistant) pharmaceutical dosage form
according to the invention, particularly its increased breaking
strength are not diminished when adding substantial amounts of
inorganic salt (B). This is particularly surprising, as one would
expect that a high breaking strength can only be achieved by means
of suitable polymers in suitable amounts and processed under
appropriate conditions (typically pressure and heat). Inorganic
salt (B), however, is no polymer.
[0086] Still further, it has been surprisingly found that inorganic
salt (B) can influence the release characteristics of a controlled
release matrix comprising a polyalkylene oxide (C), although in
case of the pharmaceutical dosage forms according to the invention
said polyalkylene oxide (C) provides a breaking strength of at
least 500 N to the overall pharmaceutical dosage form. There is
indication that in conventional hydrophilic monolithic polymeric
matrices not exhibiting a breaking strength of at least 500 N,
matrix swelling, matrix stiffening, matrix scaffolding via
electrolyte interaction and constantly changing peripheral
densification play a central role in electrolyte-induced
compositional heterogeneity. Surprisingly, such processes also
appear to take place in the dosage forms according to the
invention, although one would expect a completely different
behavior due to the specific mechanical properties.
[0087] Furthermore said pharmaceutical dosage form can be produced
with a significantly reduced amount of process steps without losing
the tamper resistant abilities.
[0088] Furthermore, it has been surprisingly found that the in
vitro release profile of the pharmaceutical dosage form can be
substantially independent from the pH value. Preferably, the in
vitro release profile of the pharmaceutical dosage form follows
zero order kinetics within the range of from pH 1 to pH 7.
[0089] In a preferred embodiment, inorganic salt (B) is
homogeneously distributed in the pharmaceutical dosage form
according to the invention. Preferably, the pharmacologically
active ingredient (A) and inorganic salt (B) are intimately
homogeneously distributed in the pharmaceutical dosage form so that
the pharmaceutical dosage form does not contain any segments where
either pharmacologically active ingredient (A) is present in the
absence of inorganic salt (B) or where inorganic salt (B) is
present in the absence of pharmacologically active ingredient
(A).
[0090] When the pharmaceutical dosage form is film coated, the
inorganic salt (B) is preferably homogeneously distributed in the
core of the pharmaceutical dosage form, i.e. the film coating
preferably does not contain inorganic salt (B).
[0091] The pharmaceutical dosage form according to the invention
contains a polyalkylene oxide (C). The active ingredient (A) is
present, preferably embedded in a controlled-release matrix
comprising said polyalkylene oxide as well as inorganic salt
(B).
[0092] Preferably, the polyalkylene oxide (C) is selected from
polymethylene oxide, polyethylene oxide and polypropylene oxide, or
copolymers or mixtures thereof.
[0093] The polyalkylene oxide (C) has a weight average molecular
weight (M.sub.W), preferably also a viscosity average molecular
weight (M.sub..eta.) of at least 200,000 g/mol or at least 500,000
g/mol, preferably at least 1,000,000 g/mol or at least 2,500,000
g/mol, more preferably in the range of about 1,000,000 g/mol to
about 15,000,000 g/mol, and most preferably in the range of about
5,000,000 g/mol to about 10,000,000 g/mol. Suitable methods to
determine M.sub.W and M.sub..eta. 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).
[0094] Preferably, the content of the polyalkylene oxide (C) is
within the range of from 20 to 99 wt.-%, more preferably 25 to 95
wt.-%, still more preferably 30 to 90 wt.-%, yet more preferably 30
to 85 wt.-%, most preferably 30 to 80 wt.-% and in particular 30 to
75 wt.-% or 45 to 70 wt.-%, based on the total weight of the
pharmaceutical dosage form. The content of the polyalkylene oxide
is at least 20 wt.-%, preferably at least 25 wt.-%, more preferably
at least 30 wt.-%, still more preferably at least 35 wt.-% and in
particular at least 40 wt.-%, based on the total weight of the
pharmaceutical dosage form.
[0095] In a preferred embodiment, the overall content of
polyalkylene oxide (C) is within the range of 25.+-.5 wt.-%. In
another preferred embodiment, the overall content of polyalkylene
oxide (C) is within the range of 35.+-.15 wt.-%, more preferably
35.+-.10 wt.-%, and in particular 35.+-.5 wt.-%. In still another
preferred embodiment, the overall content of polyalkylene oxide (C)
is within the range of 45.+-.20 wt.-%, more preferably 45.+-.15
wt.-%, most preferably 45.+-.10 wt.-%, and in particular 45.+-.5
wt.-%. In yet another preferred embodiment, the overall content of
polyalkylene oxide (C) is within the range of 55.+-.20 wt.-%, more
preferably 55.+-.15 wt.-%, most preferably 55.+-.10 wt.-%, and in
particular 55.+-.5 wt.-%. In a further preferred embodiment, the
overall content of polyalkylene oxide (C) is within the range of
65.+-.20 wt.-%, more preferably 65.+-.15 wt.-%, most preferably
65.+-.10 wt.-%, and in particular 65.+-.5 wt.-%. In still a further
a preferred embodiment, the overall content of polyalkylene oxide
(C) is within the range of 75.+-.20 wt.-%, more preferably 75.+-.15
wt.-%, most preferably 75.+-.10 wt.-%, and in particular 75.+-.5
wt.-%. In a still further a preferred embodiment, the overall
content of polyalkylene oxide (C) is within the range of 80.+-.15
wt.-%, more preferably 80.+-.10 wt.-%, and most preferably 80.+-.5
wt.-%.
[0096] Polyalkylene oxide (C) 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.
[0097] 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 pharmaceutical
dosage form 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 (C).
[0098] In a preferred embodiment, polyalkylene oxide (C) is
homogeneously distributed in the pharmaceutical dosage form
according to the invention. Preferably, the pharmacologically
active ingredient (A) and polyalkylene oxide (C) are intimately
homogeneously distributed in the pharmaceutical dosage form so that
the pharmaceutical dosage form does not contain any segments where
either pharmacologically active ingredient (A) is present in the
absence of polyalkylene oxide (C) or where polyalkylene oxide (C)
is present in the absence of pharmacologically active ingredient
(A).
[0099] When the pharmaceutical dosage form is film coated, the
polyalkylene oxide (C) is preferably homogeneously distributed in
the core of the pharmaceutical dosage form, i.e. the film coating
preferably does not contain polyalkylene oxide (C). Nonetheless,
the film coating as such may of course contain one or more
polymers, which however, preferably differ from the polyalkylene
oxide (C) contained in the core.
[0100] The polyalkylene oxide (C) 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, and
mixtures of at least two of the stated polymers, or other polymers
with the above characteristics.
[0101] Preferably, the molecular weight dispersity M.sub.w/M.sub.n
of polyalkylene oxide (C) is within the range of 2.5.+-.2.0, more
preferably 2.5.+-.1.5, still more preferably 2.5.+-.1.0, yet more
preferably 2.5.+-.0.8, most preferably 2.5.+-.0.6, and in
particular 2.5.+-.0.4.
[0102] The polyalkylene oxide (C) 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).
[0103] In a preferred embodiment, the relative weight ratio of
polyalkylene oxide (C) to inorganic salt (B) is within the range of
from 20:1 to 0.1:1, more preferably 15:1 to 0.25:1, still more
preferably 10:1 to 0.4:1, yet more preferably 5:1 to 0.5:1, most
preferably 3:1 to 0.75:1 and in particular 1.6:1 to 0.85:1. In a
preferred embodiment, the content of polyalkylene oxide (C) in the
pharmaceutical dosage form exceeds the content of inorganic salt
(B). In another preferred embodiment, the content of inorganic salt
(B) in the pharmaceutical dosage form exceeds the content of
polyalkylene oxide (C).
[0104] Preferably, the relative weight ratio of the polyalkylene
oxide (C) to the pharmacologically active ingredient (A) is at
least 0.5:1, more preferably at least 1:1, at least 2:1, at least
3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at
least 8:1 or at least 9:1; still more preferably at least 10:1 or
at least 15:1, yet more preferably at least 20:1, most preferably
at least 30:1 and in particular at least 40:1. In a preferred
embodiment, the relative weight ratio of the polyalkylene oxide (C)
to the pharmacologically active ingredient (A) is within the range
of from 3:1 to 50:1, more preferably 3:1 to 40:1 and in particular
3:1 to 30:1.
[0105] Besides the pharmacologically active ingredient (A), the
inorganic salt (B) and the polyalkylene oxide (C), the
pharmaceutical dosage form according to the invention may contain
further ingredients, e.g. one or more conventional pharmaceutical
excipient(s), e.g. fillers, glidants, binding agents, granulating
agents, anti-caking agents, lubricants, flavours, dyes, and/or
preservatives.
[0106] Preferably, the pharmaceutical dosage form further comprises
a plasticizer. The plasticizer improves the processability of the
polyalkylene oxide (C) and optionally, also of the inorganic salt
(B). 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.
[0107] Preferably, the content of the plasticizer is within the
range of from 0.1 to 25 wt.-%, more preferably 0.5 to 22.5 wt.-%,
still more preferably 1.0 to 20 wt.-%, yet more preferably 2.5 to
17.5 wt.-%, most preferably 5.0 to 15 wt.-% and in particular 7.5
to 12.5 wt.-%, based on the total weight of the pharmaceutical
dosage form.
[0108] In a 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
pharmaceutical dosage form.
[0109] In another preferred embodiment, the plasticizer is a
polyalkylene glycol having a content within the range of 15.+-.8
wt.-%, more preferably 15.+-.6 wt.-%, still more preferably 15.+-.5
wt.-%, yet more preferably 15.+-.4 wt.-%, most preferably 15.+-.3
wt.-%, and in particular 15.+-.2 wt.-%, based on the total weight
of the pharmaceutical dosage form.
[0110] In a preferred embodiment, the relative weight ratio of the
polyalkylene oxide (C) to the polyalkylene glycol is within the
range of 4.2.+-.2:1, more preferably 4.2.+-.1.5:1, still more
preferably 4.2.+-.1:1, yet more preferably 4.2.+-.0.5:1, most
preferably 4.2.+-.0.2:1, and in particular 4.2.+-.0.1:1. This ratio
satisfies the requirements of relative high polyalkylene oxide (C)
content and good extrudability.
[0111] When manufacturing the dosage forms from slices that are
obtained by cutting the extrudate strand, the weight of the slices
determines the weight of the resulting dosage form. Pronounced
variation in weight of these slices results in an accordant weight
deviation of dosage forms from the target weight. The weight
variation of slices depends strongly on the surface properties of
the extrudate strand. A strand with a thoroughly smooth surface
allows the generation of slices exhibiting a low weight variation.
In contrast, a wavy or shark skinning strand results in slices
exhibiting a higher weight variation thereby increasing the number
of rejects. It has been surprisingly found that the surface
properties of the extrudate strand can be triggered by the
polyalkylene oxide : polyalkylene glycol weight ratio.
[0112] Preferably, the pharmaceutical dosage form further comprises
an anti-oxidant. 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 used in
quantities of 0.01 to 10 wt.-%, preferably of 0.03 to 5 wt.-%,
relative to the total weight of the pharmaceutical dosage form.
[0113] In a preferred embodiment, the pharmaceutical dosage form
further comprises an acid, preferably citric acid. The amount of
acid is preferably in the range of 0.01 to about 20 wt.-%, more
preferably in the range of 0.02 to about 10 wt.-%, and most
preferably in the range of 0.05 to about 5 wt.-%.
[0114] In a preferred embodiment, the pharmaceutical dosage form
contains a natural, semi-synthetic or synthetic wax. Waxes with a
softening point of at least 50.degree. C., more preferably
60.degree. C. are preferred. Carnauba wax and beeswax are
particularly preferred, especially carnauba wax.
[0115] In a preferred embodiment, the pharmaceutical dosage form
further comprises another polymer which is preferably selected from
cellulose esters and cellulose ethers, in particular hydroxypropyl
methylcellulose (HPMC). 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.-%, and most preferably in the range of 2.0
wt.-% to about 15 wt.-%.
[0116] In another preferred embodiment, the pharmaceutical dosage
form according to the invention does not contain any further
polymer besides the polyalkylene oxide (C) and optionally, the
polyethylene glycol.
[0117] The pharmaceutical dosage form according to the invention is
preferably an oral dosage form, particularly a tablet. It is also
possible, however, to administer the pharmaceutical dosage form via
different routes and thus, the pharmaceutical dosage form may
alternatively be adapted for buccal, lingual, rectal or vaginal
administration. Implants are also possible.
[0118] Preferably, the pharmaceutical dosage form is monolithic.
Preferably, the pharmaceutical dosage form is neither in film form,
nor multi-particulate.
[0119] In a preferred embodiment, the pharmaceutical dosage form
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.
[0120] In another preferred embodiment, the pharmaceutical dosage
form 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; 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.
[0121] The pharmaceutical dosage form according to the invention
has preferably a 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 0.25 g to 0.8
g.
[0122] The pharmaceutical dosage form according to the invention is
preferably prepared by thermoforming, preferably by hot-melt
extrusion, although also other methods of thermoforming may be used
in order to manufacture the pharmaceutical dosage form according to
the invention such as press-molding at elevated temperature or
heating of tablets that were manufactured by conventional
compression in a first step and then heated above the softening
temperature of the polymer in the tablet 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 pharmaceutical dosage form is thermoformed by
hot-melt extrusion.
[0123] In a preferred embodiment, the pharmaceutical dosage form is
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 compressed and formed into tablets. In this regard, the
term "tablets" is preferably not to be understood as dosage forms
being made by compression of powder or granules (compressi) but
rather, as shaped extrudates. 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. 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 tablets. 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.
[0124] The pharmaceutical dosage form of the invention can
optionally be provided, partially or completely, with a
conventional coating. The dosage forms of the present invention are
preferably film coated with conventional film coating compositions.
Particularly preferably, the dosage forms according to the
invention are either not coated at all or completely coated, but
preferably not partially coated.
[0125] Suitable coating materials are commercially available, e.g.
under the trademarks Opadry.RTM. and Eudragit.RTM..
[0126] Examples of suitable materials include cellulose esters and
cellulose ethers, such as methyl-cellulose (MC),
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),
hydroxyethylcellulose (HEC), sodium carboxymethylcellulose
(Na-CMC), ethylcellulose (EC), cellulose acetate phthalate (CAP),
hydroxypropylmethylcellulose phthalate (HPMCP);
poly(meth)acrylates, such as am inoalkylmethacrylate copolymers,
ethylacrylate methyl-methacrylate copolymers, methacrylic acid
methylmethacrylate copolymers, methacrylic acid methylmethacrylate
copolymers; vinyl polymers, such as polyvinylpyrrolidone,
polyvinyl-acetatephthalate, polyvinyl alcohol, polyvinylacetate;
and natural film formers, such as shellack.
[0127] 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 hydroxypropylmethyl-cellulose, preferably hypromellose
type 2910 having a viscosity of 3 to 15 mPas.
[0128] The coating can be resistant to gastric juices and dissolve
as a function of the pH value of the release environment. By means
of this coating, it is possible to ensure that the pharmaceutical
dosage form according to the invention passes through the stomach
undissolved and the active ingredient is only released in the
intestines. The coating which is resistant to gastric juices
preferably dissolves at a pH value of between 5 and 7.5.
Corresponding materials and methods for the delayed release of
active ingredients and for the application of coatings which are
resistant to gastric juices are known to the person skilled in the
art, for example from "Coated Pharmaceutical dosage
forms--Fundamentals, Manufacturing Techniques, Biopharmaceutical
Aspects, Test Methods and Raw Materials" by Kurt H. Bauer, K.
Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st edition,
1998, Medpharm Scientific Publishers.
[0129] The coating can also be applied e.g. to improve the
aesthetic impression and/or the taste of the dosage forms and the
ease with which they can be swallowed. Coating the dosage forms of
the present invention can also serve other purposes, e.g. improving
stability and shelf-life. Suitable coating formulations comprise a
film forming polymer such as, for example, 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. Optionally, the coating can contain a
therapeutically effective amount of one or more active ingredients
to provide for an immediate release of said active ingredient (A)
and thus for an immediate relief of the symptoms treated by said
active ingredient (A). Coated dosage forms of the present invention
are preferably prepared by first making the cores and subsequently
coating said cores using conventional techniques, such as coating
in a coating pan.
[0130] According to the invention, the active ingredient (A) is
present, preferably embedded in a controlled-release matrix
comprising inorganic salt (B) and polyalkylene oxide (C).
[0131] Controlled release of an active ingredient from an oral
dosage form is known to a person skilled in the art. For the
purpose of the specification, controlled release encompasses
delayed release, retarded release, sustained release, extended
release, prolonged release, and the like.
[0132] Controlled or prolonged release is understood according to
the invention preferably to mean a release profile in which the
pharmacologically active ingredient (A) is released over a
relatively long period with reduced intake frequency with the
purpose of extended therapeutic action. Preferably, the meaning of
the term "prolonged release" is in accordance with the European
guideline on the nomenclature of the release profile of
pharmaceutical dosage forms (CHMP). This is achieved in particular
with peroral administration. The expression "at least partially
delayed or prolonged release" covers according to the invention any
pharmaceutical dosage forms which ensure modified release of the
opioids (A) contained therein. The pharmaceutical dosage forms
preferably comprise coated or uncoated pharmaceutical dosage forms,
which are produced with specific auxiliary substances, by
particular processes or by a combination of the two possible
options in order purposefully to change the release rate or
location of release.
[0133] In the case of the pharmaceutical dosage forms according to
the invention, the release time profile of a controlled release
form may be modified e.g. as follows: extended release, repeat
action release, prolonged release and sustained release.
[0134] For the purpose of the specification "controlled release"
preferably means a product in which the release of active
ingredient over time is controlled by the type and composition of
the formulation. For the purpose of the specification "extended
release" preferably means a product in which the release of active
ingredient is delayed for a finite lag time, after which release is
unhindered. For the purpose of the specification "repeat action
release" preferably means a product in which a first portion of
active ingredient is released initially, followed by at least one
further portion of active ingredient being released subsequently.
For the purpose of the specification "prolonged release" preferably
means a product in which the rate of release of active ingredient
from the formulation after administration has been reduced over
time, in order to maintain therapeutic activity, to reduce toxic
effects, or for some other therapeutic purpose. For the purpose of
the specification "sustained release" preferably means a way of
formulating a medicine so that it is released into the body
steadily, over a long period of time, thus reducing the dosing
frequency. For further details, reference may be made, for example,
to K. H. Bauer, Lehrbuch der Pharmazeutischen Technologie, 6th
edition, WVG Stuttgart, 1999; and Eur. Ph.
[0135] Preferably, under physiological conditions the
pharmaceutical dosage form according to the invention has released
after 30 minutes 0.1 to 75%, after 240 minutes 0.5 to 95%, after
480 minutes 1.0 to 100% and after 720 minutes 2.5 to 100% of the
pharmacologically active ingredient (A). Further preferred release
profiles R.sub.1 to R.sub.6 are summarized in the table here below
[all data in wt.-% of released pharmacologically active ingredient
(A)]:
TABLE-US-00001 time R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 R.sub.6
60 min 0-30 0-50 0-50 15-25 20-30 20-50 120 min 0-40 0-75 0-75
25-40 35-50 40-75 240 min 3-55 3-95 10-95 40-70 55-75 60-95 480 min
10-65 10-100 35-100 60-90 80-95 80-100 720 min 20-75 20-100 55-100
70-100 90-100 90-100 960 min 30-88 30-100 70-100 >80 95-100 1440
min 50-100 50-100 >90 2160 min >80 >80
[0136] Further preferred release profiles R.sub.1 to R.sub.6 are
summarized in the table here below [all data in wt.-% of released
pharmacologically active ingredient (A)]:
TABLE-US-00002 time R.sub.7 R.sub.8 R.sub.9 R.sub.10 R.sub.11
R.sub.12 30 min 17.5 .+-. 7.5 17.5 .+-. 6.5 17.5 .+-. 5.5 17.5 .+-.
4.5 17.5 .+-. 3.5 17.5 .+-. 2.5 60 min 27.0 .+-. 8.0 27.0 .+-. 7.0
27.0 .+-. 6.0 27.0 .+-. 5.0 27.0 .+-. 4.0 27.0 .+-. 3.0 120 min
41.5 .+-. 9.5 41.5 .+-. 8.5 41.5 .+-. 7.5 41.5 .+-. 6.5 41.5 .+-.
5.5 41.5 .+-. 4.5 240 min 64.5 .+-. 12.5 64.5 .+-. 11.5 64.5 .+-.
10.5 64.5 .+-. 9.5 64.5 .+-. 8.5 64.5 .+-. 7.5 480 min 88.0 .+-.
12.0 88.0 .+-. 11.0 88.0 .+-. 10.0 88.0 .+-. 9.0 88.0 .+-. 8.0 88.0
.+-. 7.0 720 min 96.0 .+-. 9.0 96.0 .+-. 8.0 96.0 .+-. 7.0 96.0
.+-. 6.0 96.0 .+-. 5.0 96.0 .+-. 4.0 840 min 97.5 .+-. 7.5 97.5
.+-. 6.5 97.5 .+-. 5.5 97.5 .+-. 4.5 97.5 .+-. 3.5 97.5 .+-.
2.5
[0137] Preferably, the release profile of the pharmaceutical dosage
form according to the present invention is stable upon storage,
preferably upon storage at elevated temperature, e.g. 40.degree.
C., for 3 months in sealed containers. In this regard "stable"
means that when comparing the initial release profile with the
release profile after storage, at any given time point the release
profiles deviate from one another by not more than 20%, more
preferably not more than 15%, still more preferably not more than
10%, yet more preferably not more than 7.5%, most preferably not
more than 5.0% and in particular not more than 2.5%.
[0138] Preferably, under in vitro conditions the pharmaceutical
dosage form has released after 0.5 h 1.0 to 35 wt.-%, after 1 h 5.0
to 45 wt.-%, after 2 h 10 to 60 wt.-%, after 4 h at least 15 wt.-%,
after 6 h at least 20 wt.-%, after 8 h at least 25 wt.-% and after
12 h at least 30 wt.-% of the pharmacologically active ingredient
(A) that was originally contained in the pharmaceutical dosage
form.
[0139] 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 with sinker, 75 rpm,
37.+-.5.degree. C., 600 mL simulated intestinal fluid pH 6.8
(phosphate buffer) or pH 4.5. In a preferred embodiment, the
rotational speed of the paddle is increased to 100 rpm.
[0140] In a preferred embodiment, the pharmaceutical dosage form
according to the invention is adapted for administration once
daily. In another preferred embodiment, the pharmaceutical dosage
form according to the invention is adapted for administration twice
daily. In still another preferred embodiment, the pharmaceutical
dosage form according to the invention is adapted for
administration thrice daily.
[0141] 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.
[0142] 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.
[0143] Preferably, the pharmaceutical dosage form according to the
invention releases after 5 h at most 99%, more preferably at most
90%, still more preferably at most 75%, and most preferably at most
60% of the active ingredient (A).
[0144] The inorganic salt (B) is preferably hydrophilic, meaning
that a matrix comprising inorganic salt (B) and polyalkylene oxide
(C) tends to swell upon contact with aqueous fluids following
administration, and preferably results in a viscous,
pharmacologically active ingredient release regulating gel
layer.
[0145] In a preferred embodiment, the matrix comprising the
inorganic salt (B) and the polyalkylene oxide (C) contains
inorganic salt (B) in such a quantity that under in vitro
conditions the release of the active ingredient (A) is additionally
retarded, and the release profile of the pharmacologically active
ingredient (A) from said matrix comprises at least a time interval
during which the release follows a zero order kinetics, compared to
a thus identical, comparative pharmaceutical dosage form wherein
the inorganic salt (B) is substituted with the corresponding amount
of hydroxylpropyl methyl cellulose (HPMC) or lactose.
[0146] In a particular preferred embodiment, [0147] the
pharmaceutical dosage form is thermoformed, preferably by hot
melt-extrusion; and/or [0148] the pharmaceutical dosage form
exhibits a breaking strength of at least 1500 N; and/or [0149] the
pharmaceutical dosage form is adapted for administration
once-daily, twice daily or thrice-daily; and/or [0150] the
pharmacologically active ingredients (A) is selected from the group
of opioids and opiates; and or [0151] the content of inorganic salt
(B) ranges from 2.0 wt.-% to 50 wt.-%; and/or [0152] the
polyalkylene oxide (C) is selected from polymethylene oxide,
polyethylene oxide and polypropylene oxide, or copolymers or
mixtures thereof; having a weight average molecular weight
(M.sub.w) of at least 500,000 g/mol, more preferably within the
range of from 1,000,000 g/mol to 10,000,000 g/mol; and/or [0153]
the content of polyalkylene oxide (C) is at least 30 wt.-%, based
on the total weight of the dosage form.
[0154] In a preferred embodiment, the pharmaceutical dosage form
according to the invention contains no substances which irritate
the nasal passages and/or pharynx, i.e. substances which, when
administered via the nasal passages and/or pharynx, bring about a
physical reaction which is either so unpleasant for the patient
that he/she does not wish to or cannot continue administration, for
example burning, or physiologically counteracts taking of the
corresponding active ingredient, for example due to increased nasal
secretion or sneezing. Further examples of substances which
irritate the nasal passages and/or pharynx are those which cause
burning, itching, 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 pharmacologically active ingredient.
Corresponding hot substance pharmacologically active ingredients
are known per se to the person skilled in the art and are
described, for example, in "Pharmazeutische Biologie--Drogen und
ihre Inhaltsstoffe" by Prof. Dr. Hildebert Wagner, 2nd., revised
edition, Gustav Fischer Verlag, Stuttgart-N.Y., 1982, pages 82 et
seq. The corresponding description is hereby introduced as a
reference and is deemed to be part of the disclosure.
[0155] The pharmaceutical dosage form according to the invention
furthermore preferably contains no antagonists for the
pharmacologically active ingredient (A), preferably no antagonists
against psychotropic substances, in particular no antagonists
against opioids (A). Antagonists suitable for a given
pharmacologically active ingredient (A) are known to the person
skilled in the art and may be present as such or in the form of
corresponding derivatives, in particular esters or ethers, or in
each case in the form of corresponding physiologically acceptable
compounds, in particular in the form of the salts or solvates
thereof. The pharmaceutical dosage form according to the invention
preferably contains no antagonists selected from among the group
comprising naloxone, naltrexone, nalmefene, nalide, nalmexone,
nalorphine or naluphine, in each case optionally in the form of a
corresponding physiologically acceptable compound, in particular in
the form of a base, a salt or solvate; and no neuroleptics, for
example a compound selected from among the group comprising
haloperidol, promethacine, fluphenazine, perphenazine,
levomepromazine, thioridazine, perazine, chlorpromazine,
chlorprothixine, zuclopenthixol, flupentixol, prothipendyl,
zotepine, benperidol, pipamperone, melperone and bromperidol.
[0156] The pharmaceutical dosage form according to the invention
furthermore preferably contains no emetic. Emetics are known to the
person skilled in the art and may be present as such or in the form
of corresponding derivatives, in particular esters or ethers, or in
each case in the form of corresponding physiologically acceptable
compounds, in particular in the form of the salts or solvates
thereof. The pharmaceutical dosage form according to the invention
preferably contains no emetic based on one or more constituents of
ipecacuanha (ipecac) root, for example based on the constituent
emetine, as are, for example, described in "Pharmazeutische
Biologie--Drogen und ihre Inhaltsstoffe" by Prof. Dr. Hildebert
Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart,
N.Y., 1982. The corresponding literature description is hereby
introduced as a reference and is deemed to be part of the
disclosure. The pharmaceutical dosage form according to the
invention preferably also contains no apomorphine as an emetic.
[0157] Finally, the pharmaceutical dosage form according to the
invention preferably also contains no bitter substance. Bitter
substances and the quantities effective for use may be found in
US-2003/0064099 A1, the corresponding disclosure of which should be
deemed to be the disclosure of the present application and is
hereby introduced as a reference. Examples of bitter substances are
aromatic oils, such as peppermint oil, eucalyptus oil, bitter
almond oil, menthol, fruit aroma substances, aroma substances from
lemons, oranges, limes, grapefruit or mixtures thereof, and/or
denatonium benzoate.
[0158] The pharmaceutical dosage form according to the invention
accordingly preferably contains neither substances which irritate
the nasal passages and/or pharynx, nor antagonists for the
pharmacologically active ingredient (A), nor emetics, nor bitter
substances.
[0159] The pharmaceutical dosage form according to the invention
has a breaking strength of at least 500 N.
[0160] The pharmaceutical dosage form according to the invention is
preferably tamper-resistant. Preferably, tamper-resistance is
achieved based on the mechanical properties of the pharmaceutical
dosage form so that comminution is avoided or at least
substantially impeded. According to the invention, the term
comminution means the pulverization of the pharmaceutical dosage
form 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
pharmaceutical dosage form using conventional means is avoided or
at least substantially impeded.
[0161] Preferably, the mechanical properties of the pharmaceutical
dosage form according to the invention, particularly its breaking
strength, substantially rely on the presence and spatial
distribution of inorganic salt (B) and polyalkylene oxide (C),
although their mere presence does typically not suffice in order to
achieve said properties. The advantageous mechanical properties of
the pharmaceutical dosage form according to the invention may not
automatically be achieved by simply processing pharmacologically
active ingredient (A), inorganic salt (B), polyalkylene oxide (C),
and optionally further excipients by means of conventional methods
for the preparation of pharmaceutical dosage forms. In fact,
usually suitable apparatuses must be selected for the preparation
and critical processing parameters must be adjusted, particularly
pressure/force, temperature and time. Thus, even if conventional
apparatuses are used, the process protocols usually must be adapted
in order to meet the required criteria.
[0162] In general, the dosage forms exhibiting the desired
properties may be obtained only if, during preparation of the
dosage form, [0163] suitable components [0164] in suitable amounts
are exposed to [0165] a sufficient pressure [0166] at a sufficient
temperature [0167] for a sufficient period of time.
[0168] Thus, regardless of the apparatus used, the process
protocols must be adapted in order to meet the required criteria.
Therefore, the breaking strength is separable from the
composition.
[0169] The pharmaceutical dosage form according to the invention
has a breaking strength of 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.
[0170] The "breaking strength" (resistance to crushing) of a
pharmaceutical dosage form is known to the skilled person. In this
regard it can be referred to, e.g., W. A. Ritschel, Die Tablette,
2. Auflage, Editio Cantor Verlag Aulendorf, 2002; H Liebermann et
al., Pharmaceutical dosage forms: Tablets, Vol. 2, Informa
Healthcare; 2 edition, 1990; and Encyclopedia of Pharmaceutical
Technology, Informa Healthcare; 1 edition.
[0171] For the purpose of the specification, the breaking strength
is preferably defined as the amount of force that is necessary in
order to fracture the pharmaceutical dosage form (=breaking force).
Therefore, for the purpose of the specification the pharmaceutical
dosage form does preferably not exhibit the desired breaking
strength when it breaks, i.e., is fractured into at least two
independent parts that are separated from one another. In another
preferred embodiment, however, the pharmaceutical dosage form is
regarded as being broken if the force decreases by 25% (threshold
value) of the highest force measured during the measurement (see
below).
[0172] The pharmaceutical dosage forms according to the invention
are distinguished from conventional pharmaceutical dosage forms in
that, due to their breaking strength, they cannot be pulverized by
the application of force with conventional means, such as for
example a pestle and mortar, a hammer, a mallet or other usual
means for pulverization, in particular devices developed for this
purpose (tablet crushers). In this regard "pulverization" means
crumbling into small particles that would immediately release the
pharmacologically active ingredient (A) in a suitable medium.
Avoidance of pulverization virtually rules out oral or parenteral,
in particular intravenous or nasal abuse.
[0173] Conventional tablets typically have a breaking strength well
below 200 N in any direction of extension. The breaking strength of
conventional round tablets may be estimated according to the
following empirical formula: Breaking Strength [in
N]=10.times.Diameter Of The Tablet [in mm]. Thus, according to said
empirical formula, a round tablet having a breaking strength of at
least 300 N would require a diameter of at least 30 mm). Such a
tablet, however, could not be swallowed. The above empirical
formula preferably does not apply to the pharmaceutical dosage
forms of the invention, which are not conventional but rather
special.
[0174] 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 tablets having a breaking strength
well below 200 N may be crushed upon spontaneous chewing, whereas
the pharmaceutical dosage forms according to the invention may
not.
[0175] Still further, when applying a gravitational acceleration of
about 9.81 m/s.sup.2, 500 N correspond to a gravitational force of
more than 50 kg, i.e. the pharmaceutical dosage forms according to
the invention can preferably withstand a weight of more than 50 kg
without being pulverized.
[0176] Methods for measuring the breaking strength of a
pharmaceutical dosage form are known to the skilled artisan.
Suitable devices are commercially available.
[0177] 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, measured by the force needed to disrupt them by
crushing. The apparatus consists of 2 jaws facing each other, one
of which moves towards the other. The flat surfaces of the jaws are
perpendicular to the direction of movement. The crushing surfaces
of the jaws are flat and larger than the zone of contact with the
tablet. The apparatus is calibrated using a system with a precision
of 1 Newton. The tablet is placed between the jaws, taking into
account, where applicable, the shape, the break-mark and the
inscription; for each measurement the tablet is oriented in the
same way with respect to the direction of application of the force
(and the direction of extension in which the breaking strength is
to be measured). The measurement is carried out on 10 tablets,
taking care that all fragments of tablets have been removed before
each determination. The result is expressed as the mean, minimum
and maximum values of the forces measured, all expressed in
Newton.
[0178] 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 to fail (i.e., break) in a specific
plane. The tablets are generally placed between two platens, one of
which moves to apply sufficient force to the tablet to cause
fracture. For conventional, round (circular cross-section) tablets,
loading occurs across their diameter (sometimes referred to as
diametral loading), and fracture occurs in the plane. The breaking
force of tablets is commonly called hardness in the pharmaceutical
literature; however, the use of this term is misleading. In
material science, the term hardness refers to the resistance of a
surface to penetration or indentation by a small probe. The term
crushing strength is also frequently used to describe the
resistance of tablets to the application of a compressive load.
Although this term describes the true nature of the test more
accurately than does hardness, it implies that tablets are actually
crushed during the test, which is often not the case.
[0179] Alternatively, the breaking strength (resistance to
crushing) can be measured in accordance with WO 2005/ 016313, WO
2005/016314, and WO 2006/082099, which can be regarded as a
modification of the method described in the Eur. Ph. The apparatus
used for the measurement is preferably a "Zwick Z 2.5" materials
tester, F.sub.max=2.5 kN with a maximum draw of 1150 mm, which
should be set up with one column and one spindle, a clearance
behind of 100 mm and a test speed adjustable between 0.1 and 800
mm/min together with testControl software. Measurement is performed
using a pressure piston with screw-in inserts and a cylinder
(diameter 10 mm), a force transducer, F.sub.max. 1 kN, diameter=8
mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with
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 centering device.
[0180] In a preferred embodiment of the invention, the breaking
strength is measured by means of a breaking strength tester e.g.
Sotax.RTM., type HT100 or type HT1 (Allschwil, Switzerland). Both,
the Sotax.RTM. HT100 and the Sotax.RTM. HT1 can measure the
breaking strength according to two different measurement
principles: constant speed (where the test jaw is moved at a
constant speed adjustable from 5-200 mm/min) or constant force
(where the test jaw increases force linearly adjustable from 5-100
N/sec). In principle, both measurement principles are suitable for
measuring the breaking strength of the pharmaceutical dosage form
according to the invention. Preferably, the breaking strength is
measured at constant speed, preferably at a constant speed of 120
mm/min.
[0181] In a preferred embodiment, the pharmaceutical dosage form is
regarded as being broken if it is fractured into at least two
separate pieces.
[0182] The pharmaceutical dosage form according to the invention
preferably exhibits mechanical strength over a wide temperature
range, in addition to the breaking strength (resistance to
crushing) optionally also sufficient hardness, impact resistance,
impact elasticity, tensile strength and/or modulus of elasticity,
optionally also at low temperatures (e.g. below -24.degree. C.,
below -40.degree. C. or in liquid nitrogen), for it to be virtually
impossible to pulverize by spontaneous chewing, grinding in a
mortar, pounding, etc. Thus, preferably, in direction of extension
E.sub.1 the comparatively high breaking strength of the
pharmaceutical dosage form according to the invention is maintained
even at low or very low temperatures, e.g., when the pharmaceutical
dosage form is initially chilled to increase its brittleness, for
example to temperatures below -25.degree. C., below -40.degree. C.
or even in liquid nitrogen.
[0183] The pharmaceutical dosage form according to the invention is
characterized by a certain degree of breaking strength. This does
not mean that the pharmaceutical dosage form must also exhibit a
certain degree of hardness. Hardness and breaking strength are
different physical properties. Therefore, the tamper resistance of
the pharmaceutical dosage form does not necessarily depend on the
hardness of the pharmaceutical dosage form. For instance, due to
its breaking strength, impact strength, elasticity modulus and
tensile strength, respectively, the pharmaceutical dosage form can
preferably be deformed, 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
pharmaceutical dosage form according to the invention is
characterized by a certain degree of breaking strength, but not
necessarily also by a certain degree of form stability.
[0184] Therefore, in the meaning of the specification, a
pharmaceutical dosage form that is deformed when being exposed to a
force in a particular direction of extension but that does not
break (plastic deformation or plastic flow) is preferably to be
regarded as having the desired breaking strength in said direction
of extension.
[0185] In a preferred embodiment the invention relates to a
tamper-resistant pharmaceutical dosage form having a retarded
release profile, especially a tamper-resistant oral dosage form
having a retarded release profile, particularly a tamper-resistant
tablet having a retarded release profile comprising at least one
pharmaceutically active ingredient (A) (pharmacologically active
compound) with potential for abuse.
[0186] The pharmaceutical dosage form 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.
[0187] The present invention also relates to pharmaceutical dosage
forms that are obtainable by any of the processes described here
below.
[0188] In general, the process for the production of the
pharmaceutical dosage form according to the invention preferably
comprises the following steps: [0189] (a) mixing all ingredients;
[0190] (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 (C) up to its
softening point; [0191] (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 (C) at least up to
its softening point; [0192] (d) optionally singulating the hardened
mixture; [0193] (e) optionally shaping the pharmaceutical dosage
form; and [0194] (f) optionally providing a film coating.
[0195] 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.
Force may be applied and/or the pharmaceutical dosage form may be
shaped for example by direct tabletting or with the assistance of a
suitable extruder, particularly by means of a screw extruder
equipped with two screws (twin-screw-extruder) or by means of a
planetary gear extruder.
[0196] Preferably, hot-melt extrusion is performed in the absence
of additional water.
[0197] The final shape of the pharmaceutical dosage form may either
be provided during the hardening of the mixture by applying heat
and force (step (c)) or in a subsequent step (step (e)). In both
cases, the mixture of all components is preferably in the
plastified state, i.e. preferably, shaping is performed at a
temperature at least above the softening point of the polyalkylene
oxide (C). However, extrusion at lower temperatures, e.g. ambient
temperature, is also possible and may be preferred.
[0198] Shaping can be performed, e.g., by means of a tabletting
press comprising die and punches of appropriate shape.
[0199] A particularly preferred process for the manufacture of the
pharmaceutical dosage form of the invention involves hot-melt
extrusion. In this process, the pharmaceutical dosage form
according to the invention is produced by thermoforming with the
assistance of an extruder, preferably without there being any
observable consequent discoloration of the extrudate.
[0200] This process is characterized in that [0201] a) all
components are mixed, [0202] b) the resultant mixture is heated in
the extruder at least up to the softening point of the polyalkylene
oxide (C) and extruded through the outlet orifice of the extruder
by application of force, [0203] c) the still plastic extrudate is
singulated and formed into the pharmaceutical dosage form or [0204]
d) the cooled and optionally reheated singulated extrudate is
formed into the pharmaceutical dosage form.
[0205] Mixing of the components according to process step a) may
also proceed in the extruder.
[0206] 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.
[0207] The, preferably molten, mixture which has been heated in the
extruder at least up to the softening point of polyalkylene oxide
(C) is extruded from the extruder through a die with at least one
bore.
[0208] The extrusion process according to the invention requires
the use of suitable extruders, preferably screw extruders. Screw
extruders which are equipped with two screws (twin-screw-extruders)
are particularly preferred.
[0209] The extrusion is preferably performed so that the expansion
of the strand due to extrusion is not more than 30%, i.e. that when
using a die with a bore having a diameter of e.g. 6 mm, the
extruded strand should have a diameter of not more than 8 mm. More
preferably, the expansion of the strand is not more than 25%, still
more preferably not more than 20%, most preferably not more than
15% and in particular not more than 10%.
[0210] 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.
[0211] 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 (C) proceeding in the first zone,
which is downstream from a feed zone and optionally mixing zone.
The throughput of the mixture is preferably from 1.0 kg to 15
kg/hour. In a preferred embodiment, the throughput is from 1 to 3.5
kg/hour. In another preferred embodiment, the throughput is from 4
to 15 kg/hour.
[0212] In a preferred embodiment, the die head pressure is within
the range of from 25 to 100 bar. The die head pressure can be
adjusted inter alia by die geometry, temperature profile and
extrusion speed.
[0213] The die geometry or the geometry of the bores is freely
selectable. The die or the bores may accordingly exhibit a round,
oblong or oval cross-section, wherein the round cross-section
preferably has a diameter of 0.1 mm to 15 mm and the oblong
cross-section preferably has a maximum lengthwise extension of 21
mm and a crosswise extension of 10 mm. Preferably, the die or the
bores have a round cross-section. The casing of the extruder used
according to the invention may be heated or cooled. The
corresponding temperature control, i.e. heating or cooling, is so
arranged that the mixture to be extruded exhibits at least an
average temperature (product temperature) corresponding to the
softening temperature of the polyalkylene oxide (C) and does not
rise above a temperature at which the pharmacologically active
ingredient (A) to be processed may be damaged. Preferably, the
temperature of the mixture to be extruded is adjusted to below
180.degree. C., preferably below 150.degree. C., but at least to
the softening temperature of polyalkylene oxide (C). Typical
extrusion temperatures are 120 .degree. C. and 130.degree. C.
[0214] 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 and extrusion speed.
[0215] After extrusion of the molten mixture and optional cooling
of the extruded strand or extruded strands, the extrudates are
preferably singulated. This singulation may preferably be performed
by cutting up the extrudates by means of revolving or rotating
knives, water jet cutters, wires, blades or with the assistance of
laser cutters.
[0216] Preferably, intermediate or final storage of the optionally
singulated extrudate or the final shape of the pharmaceutical
dosage form according to the invention is performed under
oxygen-free atmosphere which may be achieved, e.g., by means of
oxygen-scavengers.
[0217] The singulated extrudate may be press-formed into tablets in
order to impart the final shape to the pharmaceutical dosage
form.
[0218] The application of force in the extruder onto the at least
plasticized mixture is adjusted by controlling the rotational speed
of the conveying device in the extruder and the geometry thereof
and by dimensioning the outlet orifice in such a manner that the
pressure necessary for extruding the plasticized mixture is built
up in the extruder, preferably immediately prior to extrusion. The
extrusion parameters which, for each particular composition, are
necessary to give rise to a pharmaceutical dosage form with desired
mechanical properties, may be established by simple preliminary
testing.
[0219] 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 ends may be used. A heatable die with a round bore having
a diameter of 7, 8, or 9 mm may be used. The extrusion parameters
may be adjusted e.g. to the following values: rotational speed of
the screws: 120 Upm; delivery rate 2 kg/h for a ZSE 18 or 8 kg/h
for a ZSE27; product temperature: in front of die 125.degree. C.
and behind die 135.degree. C.; and jacket temperature: 110.degree.
C.
[0220] 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.
[0221] The pharmaceutical dosage form according to the invention is
preferably produced by thermoforming with the assistance of an
extruder without any observable consequent discoloration of the
extrudates.
[0222] The process for the preparation of the pharmaceutical dosage
form according to the invention is preferably performed
continuously. Preferably, the process involves the extrusion of a
homogeneous mixture of 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
ingredient, 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.
[0223] A further aspect of the invention relates to the use of a
pharmacologically active ingredient (A) for the manufacture of the
pharmaceutical dosage form as described above for the treatment of
pain.
[0224] A further aspect of the invention relates to the use of a
pharmaceutical dosage form as described above for avoiding or
hindering the abuse of the pharmacologically active ingredient (A)
contained therein.
[0225] A further aspect of the invention relates to the use of a
pharmaceutical dosage form as described above for avoiding or
hindering the unintentional overdose of the pharmacologically
active ingredient (A) contained therein.
[0226] In this regard, the invention also relates to the use of a
pharmacologically active ingredient (A) as described above and/or a
polyalkylene oxide (C) as described above for the manufacture of
the pharmaceutical dosage form according to the invention for the
prophylaxis and/or the treatment of a disorder, thereby preventing
an overdose of the pharmacologically active ingredient (A),
particularly due to comminution of the pharmaceutical dosage form
by mechanical action.
[0227] Further, the invention relates to a method for the
prophylaxis and/or the treatment of a disorder comprising the
administration of the pharmaceutical dosage form according to the
invention, thereby preventing an overdose of the pharmacologically
active ingredient (A), particularly due to comminution of the
pharmaceutical dosage form by mechanical action. Preferably, the
mechanical action is selected from the group consisting of chewing,
grinding in a mortar, pounding, and using apparatuses for
pulverizing conventional pharmaceutical dosage forms.
[0228] The following examples further illustrate the invention but
are not to be construed as limiting its scope:
[0229] In all examples the dosage forms were tablets assuming a
round shape with a diameter of 12 mm.
[0230] General Procedure
[0231] Polyethylene oxide, .alpha.-tocopherol, tramadol
hydrochloride and all other excipients were weighted and sieved to
each other. The powder was mixed and dosed gravimetrically to an
extruder. Hot-melt extrusion was performed by means of a twin screw
extruder of type Micro 27 GL 40 D (Leistritz, Nurnberg, Germany)
that was equipped with a heatable round die having a diameter of 10
mm.
[0232] The hot extrudate was cooled on a conveyor belt and the
cooled extrusion strand was comminuted to cut pieces. The cut
pieces were shaped by means of an excenter press.
[0233] The breaking strength of the pharmaceutical dosage forms was
measured by means of a Sotax.RTM. HT100 at a constant speed of 120
mm/min and/or a Zwick Z 2.5 at a constant speed of 10 mm/min. A
tablet was regarded as failing the breaking strength test when
during the measurement the force dropped below the threshold value
of 25% of the maximum force that was observed during the
measurement, regardless of whether the dosage form was fractured
into separate pieces or not. All values are given as mean of 3
measurements (Zwick; n=3) or as a mean of 10 measurements (Sotax,
n=10).
EXAMPLE I
[0234] Tablets of the following composition containing tramadol
were formed:
TABLE-US-00003 Excipient Reference Variation D Variation E
Variation F Variation G Tramadol-HCl 80.0 mg 80.0 mg 80.0 mg 80.0
mg 80.0 mg Polyethyleneoxide 365.8 mg 211.0 mg 259.5 mg 259.5 mg
211.0 mg 7,000,000 Polyethylene glycole 6,000 90.0 mg 62.0 mg 76.3
mg 76.3 mg 62.3 mg Hypromellose 100,000 mPas 60.0 mg -- -- -- --
.alpha.-Tocopherol 1.2 mg 1.2 mg 1.2 mg 1.2 mg 1.2 mg Citric Acid
3.0 mg 3.0 mg 3.0 mg 3.0 mg 3.0 mg Sodium carbonate -- 242.8 mg
180.0 mg 90.0 mg 121.4 mg Pentasodium phosphate -- -- -- 90.0 mg
121.4 mg Sum 600.0 mg 600.0 mg 600.0 mg 600.0 mg 600.0 mg
[0235] For each composition, the in vitro release profile of the
pharmacologically active ingredient was measured in 600 ml of
artificial intestinal juice (pH 6.8, phosphate buffered) at
temperature of 37.degree. C. with sinker (type 4). The rotation
speed of the paddle was adjusted to 75/min. The pharmacologically
active ingredient was detected by means of a spectrometric
measurement with a wavelength of 271 nm.
[0236] According to the preceding table, variation D and E were
tested with sodium carbonate. Dissolution curves of the tablets
with 30 wt.-% and 40 wt.-% sodium carbonate in comparison to the
reference tablets are illustrated in FIG. 1. The retardant effect
is more pronounced for the formulation with 30 wt.-% sodium
carbonate.
[0237] Variation F and G were tested with sodium carbonate and
pentasodium triphosphate. The dissolution curves of the tablets
with 20 wt.-% and 15 wt.-% of each sodium carbonate and pentasodium
triphosphate in comparison to the reference are illustrated in FIG.
2. Again, the release profile shows a significantly retarded and
linear release of the pharmacologically active ingredient. The
release profile with the lower content of overall salts shows again
the best results.
[0238] A comparison of the dissolution in acidic medium with the
dissolution curves of the tablets with 30 wt.-% sodium carbonate
and 15 wt.-% of each sodium carbonate and pentasodium triphosphate
in comparison to the reference tablets in illustrated in FIG. 3.
The release profile of the 4 curves is comparable and hence does
not depend on the pH-value.
EXAMPLE II
[0239] Tablets of the following composition containing oxymorphone
were formed:
TABLE-US-00004 Excipient Per tablet [mg] [wt.-%] Oxymorphone HCL
anhydrous 80.0 11.1 Polyethylene oxide 7,000,000 337.3 46.9 Sodium
Carbonate 216.0 30.0 Macrogol 6000 81.7 11.3 .alpha.-Tocopherol 1.4
0.2 Citric Acid anhydrous 3.6 0.5 Sum 720.0
[0240] The in vitro release profile of the pharmacologically active
ingredient was measured in 900 ml acidic medium (pH 1.2) and in 900
mL acetate buffered medium (pH 4.5), both at temperature of
37.degree. C. with sinker (type 4). The rotation speed of the
paddle was adjusted to 50/min. The pharmacologically active
ingredient was detected by means of a spectrometric measurement
with a wavelength of 271 nm.
[0241] According to the preceding table, the formulation was made
with oxymorphone instead of tramadol. As illustrated in FIG. 4 the
release profile shows a retarded and linear release of the
pharmacologically active ingredient. In the acidic medium the
release was accelerated in comparison to the release in the acetate
buffered medium (pH 4.5).
EXAMPLE III
[0242] Tablets of the following composition were formed:
TABLE-US-00005 Excipient Per tablet [mg] [wt.-%] Oxymorphone HCL
anhydrous 80.0 11.1 Polyethylene oxide 7,000,000 337.3 46.9 Sodium
Carbonate 108.0 15.0 Pentasodium phosphate 108.0 15.0 Macrogol 6000
81.7 11.3 .alpha.-Tocopherol 1.4 0.2 Citric Acid anhydrous 3.6 0.5
Sum 720.0
[0243] According to Example II, the in vitro release profile of the
pharmacologically active ingredient was measured in 900 ml acidic
medium (pH 1.2) and in 900 mL acetate buffered medium (pH 4.5).
[0244] According to the preceding table the formulation was made
with oxymorphone instead of tramadol. Moreover the formulation
contains sodium carbonate and pentasodium triphosphate each 15
wt.-%. As illustrated in FIG. 5, the release profile shows a
retarded and linear release of the pharmacologically active
ingredient. In the acidic medium the release was accelerated in
comparison to the release in the acetate buffered medium (pH
4.5).
* * * * *