U.S. patent application number 16/455813 was filed with the patent office on 2019-10-24 for abuse-proofed dosage form.
This patent application is currently assigned to GRUNENTHAL GMBH. The applicant listed for this patent is GRUNENTHAL GMBH. Invention is credited to Elisabeth ARKENAU-MARIC, Johannes BARTHOLOMAEUS, Heinrich KUGELMANN.
Application Number | 20190321358 16/455813 |
Document ID | / |
Family ID | 36384542 |
Filed Date | 2019-10-24 |
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United States Patent
Application |
20190321358 |
Kind Code |
A1 |
ARKENAU-MARIC; Elisabeth ;
et al. |
October 24, 2019 |
ABUSE-PROOFED DOSAGE FORM
Abstract
The invention relates to a dosage form that is thermoformed
without discoloration and is safeguarded from abuse, comprising at
least one synthetic or natural polymer having a breaking strength
of at least 500 N in addition to one or more active substances that
could be subject to abuse. The invention also relates to a
corresponding method for producing said dosage form.
Inventors: |
ARKENAU-MARIC; Elisabeth;
(Koln, DE) ; BARTHOLOMAEUS; Johannes; (Aachen,
DE) ; KUGELMANN; Heinrich; (Aachen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRUNENTHAL GMBH |
Aachen |
|
DE |
|
|
Assignee: |
GRUNENTHAL GMBH
Aachen
DE
|
Family ID: |
36384542 |
Appl. No.: |
16/455813 |
Filed: |
June 28, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16032467 |
Jul 11, 2018 |
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16455813 |
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15459180 |
Mar 15, 2017 |
10058548 |
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16032467 |
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15132325 |
Apr 19, 2016 |
9629807 |
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15459180 |
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14875007 |
Oct 5, 2015 |
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15132325 |
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14138372 |
Dec 23, 2013 |
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14875007 |
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13723273 |
Dec 21, 2012 |
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14138372 |
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11462216 |
Aug 3, 2006 |
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13723273 |
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11349544 |
Feb 6, 2006 |
8075872 |
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11462216 |
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11348295 |
Feb 6, 2006 |
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11349544 |
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10718112 |
Nov 20, 2003 |
8114383 |
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11348295 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/30 20180101;
B29B 9/02 20130101; A61K 31/55 20130101; A61K 9/2009 20130101; A61K
31/4418 20130101; A61P 5/00 20180101; A61P 19/00 20180101; B29K
2105/0035 20130101; B29C 48/44 20190201; A61K 9/2013 20130101; A61K
9/2072 20130101; B29B 7/002 20130101; B29C 48/21 20190201; B29K
2105/0044 20130101; A61P 27/00 20180101; B29L 2031/772 20130101;
B30B 11/00 20130101; B29C 43/24 20130101; A61K 9/2086 20130101;
A61P 13/00 20180101; A61J 3/06 20130101; B29C 48/40 20190201; A61K
9/4808 20130101; B29C 48/022 20190201; A61P 9/00 20180101; A61K
9/0053 20130101; B29K 2105/251 20130101; A61K 9/205 20130101; A61P
1/00 20180101; B29C 48/0011 20190201; A61K 31/4422 20130101; B29K
2995/0056 20130101; A61K 9/2054 20130101; A61K 31/277 20130101;
A61K 9/2095 20130101; A61P 25/04 20180101; B29C 48/0022 20190201;
A61P 7/00 20180101; A61K 31/554 20130101; B29C 45/0001 20130101;
A61K 31/485 20130101; A61K 9/2893 20130101; B29C 43/02 20130101;
A61J 3/005 20130101; B29B 9/12 20130101; A61K 9/2031 20130101; A61P
17/00 20180101; A61J 3/10 20130101; A61K 9/20 20130101; B29C 48/146
20190201; B29C 2793/009 20130101; B29L 2031/753 20130101; A61K
31/135 20130101; B29C 35/0261 20130101; A61P 37/00 20180101; A61K
9/2068 20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; B29C 48/00 20060101 B29C048/00; A61K 9/20 20060101
A61K009/20; B29C 48/21 20060101 B29C048/21; B29C 48/14 20060101
B29C048/14; A61K 31/55 20060101 A61K031/55; B29C 43/02 20060101
B29C043/02; A61K 9/48 20060101 A61K009/48; A61J 3/00 20060101
A61J003/00; A61K 31/135 20060101 A61K031/135; A61K 31/554 20060101
A61K031/554; A61K 31/4418 20060101 A61K031/4418; B29B 7/00 20060101
B29B007/00; A61K 31/277 20060101 A61K031/277; B29B 9/02 20060101
B29B009/02; A61J 3/06 20060101 A61J003/06; A61K 31/4422 20060101
A61K031/4422; A61J 3/10 20060101 A61J003/10; B29B 9/12 20060101
B29B009/12; A61K 9/28 20060101 A61K009/28 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 6, 2003 |
DE |
10 336 400.5 |
Feb 4, 2005 |
DE |
10 2005 005 446.3 |
Claims
1. An abuse-proofed dosage form thermoformed by extrusion without
discoloration comprising one or more active ingredients with abuse
potential (A), optionally physiologically acceptable auxiliary
substances (B), at least one synthetic or natural polymer (C) and
optionally at least one wax (D), wherein the dosage form exhibits a
breaking strength of at least 500 N.
2. The dosage form according to claim 1, which in the form of a
tablet.
3. The dosage form according to claim 1, which contains as polymer
(C) at least one polymer selected from the group consisting of
polyalkylene-oxide, polyethylene, polypropylene, polyvinyl
chloride, polycarbonate, polystyrene, polyacrylate, copolymers
thereof and mixtures thereof.
4. The dosage form according to claim 3, wherein the polyalkylene
oxide is selected from the group consisting of polymethylene oxide,
polyethylene oxide, polypropylene oxide, copolymers thereof and
mixtures thereof.
5. The dosage form according to claim 1, wherein the polymer (C)
comprises polyethylene oxide having a molecular weight of at least
0.5 million.
6. The dosage form according to claim 5, wherein the molecular
weight of the polyethylene oxide (C) is at least 1 million.
7. The dosage form according to claim 6, wherein the molecular
weight of the polyethylene. oxide is in the range of from about 1
to about 15 million.
8. The dosage form according to claim 1, which contains the wax
(D), and the wax (D) is at least one natural, semi-synthetic or
synthetic wax with a softening point of at least 60.degree. C.
9. The dosage form according to claim 8, wherein the wax (D) is
carnauba wax or beeswax.
10. The dosage form according to claim 1, wherein the active
ingredient (A) is at least one active ingredient selected from the
group consisting of opioids, tranquilizers, stimulants,
barbiturates and further narcotics.
11. The dosage form according to claim 1, which additionally
comprises (a) at least one substance which irritates the nasal
passages and/or pharynx; and/or (b) at least one
viscosity-increasing agent, which in the presence of an active
ingredient extracted from the dosage form using a liquid medium,
forms a gel with the extract obtained from the dosage form, which
gel optionally remains visually distinguishable when introduced
into a further quantity of an aqueous liquid; and/or (c) at least
one antagonist for the active ingredient or active ingredients with
abuse potential; and/or (d) at least one emetic; and/or (e) at
least one dye; and/or (f) at least one bitter substance.
12. The dosage form according to claim 11, which comprises
component (b), wherein component (b) is at least one
viscosity-increasing agent selected from the group consisting of
microcrystalline cellulose combined with carboxymethylcellulose
sodium, polyacrylic acid, locust bean flour, pectins, waxy maize
starch, sodium alginate, guar flour, iota carrageen, karaya gum,
gellan gum, galactomannan, tara bean flour, propylene glycol
alginate, apple pectin, sodium hyaluronate; tragacanth, tara gum,
fermeted polysaccharide welan gum, and xanthan gum.
13. The dosage form according to claim 11, which comprises
component (c), wherein component (c) is at least one opioid
antagonist selected from the group consisting of naloxone,
naltrexone, nalmefene, nalid, nalmexone, nalorphine, naluphine and
a corresponding physiologically acceptable compound, a base, and a
salt thereof.
14. The dosage forth according to claim 1, which contains at least
one active ingredient with abuse potential (A) at least partially
in controlled release form.
15. The dosage form according to claim 14, wherein each of the
active ingredients with abuse potential (A) is present in a
controlled release matrix.
16. The dosage form according to claim 15, wherein the controlled
release matrix material, comprises component (C) and/or the
optionally present component (D).
17. The dosage form according to claim 1, which comprises a core
and a tubular domain surrounding the core, wherein said tubular
domain has a morphology different from that of the core.
18. The dosage form according to claim 17, wherein the core and the
tubular domain have substantially the same chemical
composition.
19. The dosage form according to claim 17, wherein the tubular
domain does not completely cover the core.
20. The dosage form according to claim 1, which comprises a
physiologically acceptable auxiliary substance (B), wherein the
physiologically acceptable auxiliary substance (B) is an
antioxidant.
21. The dosage form according to claim 20, wherein the antioxidant
is selected from the group consisting of ascorbic acid, salts of
ascorbic acid, butylhydroxyanisole, butylhydroxytoluene,
monothioglycerol, phosphorous acid, vitamin C, vitamin E and the
derivatives thereof, sodium bisulfite and <-tocopherol.
22. A process for the production of a dosage: form according to
claim 1, comprising I) mixing components (A), the optionally
present component (B), (C) and the optionally present component (D)
and co-mixing or separately mixing the optionally present
components (a) to (f) with the addition of component (C) and
optionally (D) to form a resultant mixture or plurality of
resultant mixtures; II) heating the resultant mixture or the
resultant mixtures in an extruder at least up to the softening
point of component (C) and extruding the mixture as a plastic
extrudate through an outlet orifice of the extruder by application
of force; and III) singulating and forming the still plastic
extrudate into the dosage form; or IV) cooling and forming the
optionally reheated singulated extrudate into the dosage form.
23. The process according to claim 22, wherein process step II) is
performed by means of a twin-screw-extruder.
24. The process according to claim 22, wherein process steps II)
and III) and optionally process steps I) and IV) are performed
under an inert gas atmosphere.
25. The process according to claim 24, wherein the inert gas
atmosphere is nitrogen.
26. The process according to claim 22, wherein mixing of the
components according to process step I) proceeds in the extruder
under an inert gas atmosphere.
27. The process according to claim 22, wherein the mixtures
according to process step I) are co-extruded or separately
extruded.
28. The process according to claim 22, wherein the mixture or the
mixtures according to process step 1) are extruded through a die
with at least one bore.
29. The process according to claim 22, wherein the extrudate is
singulated by cutting.
30. The process according to claim 22, wherein the extrudate is in
the form of a strand and is shaped and singulated with the
assistance of counter rotating calender rolls comprising opposing
recesses in their outer sleeve.
31. The process according to claim 22, wherein the singulated
extrudate is pelletized or pressed into tablets.
32. The process according to claim 22, wherein Swelling and
expansion of the dosage form upon storage is suppressed by press
forming the singulated extrudate at a pressure of at least 1 kN and
a temperature of between 25.degree. C. and 40.degree. C. below the
melting range of the mixture of the components.
33. The dosage form according to claim 1, wherein the one or more
ingredients with abuse potential (A) are selected from the group
consisting of oxycodone, oxymorphone, tapentadol, morphine and the
physiologically acceptable salts thereof.
34. The dosage form according to claim 1, wherein the content of
polymer (C) is at least 30 wt. % relative to the total weight of
the dosage form.
35. A dosage form obtainable by the process according to claim
22.
36. A method of reducing the incidence of drug abuse of an active
ingredient (A) with abuse potential, said method comprising
providing said active ingredient (A) in the form of a dosage form
according to claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. patent
application Ser. No. 16/032,467, filed Jul. 11, 2018, now allowed,
which is a Continuation of U.S. patent application Ser. No.
15/459,180 filed Mar. 15, 2017, now U.S. Pat. No. 10,058,548, which
is a Continuation of U.S. patent application Ser. No. 15/132,325
filed Apr. 19, 2016, now U.S. Pat. No. 9,629,807, which is a
continuation of U.S. patent application Ser. No. 14/875,007, filed
Oct. 5, 2015, now abandoned, which is a Continuation of U.S. patent
application Ser. No. 14/138,372, filed Dec. 23, 2013, now
abandoned, which is a Continuation of Ser. No. 13/723,273, filed
Dec. 21, 2012, now abandoned, which is a Continuation of U.S.
patent application Ser. No. 11/462,216, filed Aug. 3, 2006, now
abandoned, which is a Continuation-in-Part-application of U.S.
patent application Ser. No. 11/349,544 filed on Feb. 6, 2006, now
U.S. Pat. No. 8,075,872, a Continuation-in-Part-Application of U.S.
patent application Ser. No. 11/348,295, filed on Feb. 6, 2006, now
abandoned, and a Continuation-in-Part-Application of U.S. patent
application Ser. No. 10/718,112 filed on Nov. 20, 2003, now U.S.
Pat. No. 8,114,383, and claims priority of German Patent
Application No. 10 2005 005446.3 filed on Feb. 4, 2005 and German
Patent Application No. 10 336 400.5 filed on Aug. 6, 2003.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to an abuse-proofed dosage
form thermoformed by extrusion without discoloration and
containing, in addition to one or more active ingredients with
abuse potential (A) optionally together with physiologically
acceptable auxiliary substances (B), at least one synthetic or
natural polymer (C) and optionally at least one wax (D), wherein
the dosage form exhibits a breaking strength (=resistance to
crushing) of at least 500 N, and to a process for the production of
the dosage form according to the invention.
[0003] Many pharmaceutical active ingredients, in addition to
having excellent activity in their appropriate application, also
have abuse potential, i.e. they can be used by an abuser to bring
about effects other than those intended. Opiates, for example,
which are highly active in combating severe to very severe pain,
are frequently used by abusers to induce a state of narcosis or
euphoria.
[0004] In order to make abuse possible, the corresponding dosage
forms, such as tablets or capsules are comminuted, for example
ground in a mortar, by the abuser, the active ingredient is
extracted from the resultant powder using a preferably aqueous
liquid and the resultant solution, optionally after being filtered
through cotton wool or cellulose wadding, is administered
parenterally, in intravenously. An additional phenomenon of this
administration, in comparison with abusive oral administration, is
a further accelerated increase in active ingredient levels giving
the abuser the desired effect, namely the "kick" or "rush". This
kick is also obtained if the powdered dosage form is administered
nasally, i.e. is sniffed. Since controlled-release dosage forms
containing active ingredients with abuse potential do not give rise
to the kick desired by the abuser when taken orally even in
abusively high quantities, such dosage forms are also comminuted
and extracted in order to be abused.
[0005] U.S. Pat. No. 4,070,494 proposed adding a swellable agent to
the dosage form in order to prevent abuse. When water is added to
extract the active ingredient, this agent swells and ensures that
the filtrate separated from the gel contains only a small quantity
of active ingredient,
[0006] The multilayer tablet disclosed in WO 95/20947 is based on a
similar approach to preventing parenteral abuse, said tablet
containing the active ingredient with abuse potential and at least
one gel former, each in different layers.
[0007] WO 03/015531 A2 discloses another approach to preventing
parenteral abuse. A dosage form containing an analgesic opioid and
a dye as an aversive agent is described therein. The color released
by tampering with the dosage form is intended to discourage the
abuser from using the dosage form which has been tampered with.
[0008] Another known option for complicating abuse involves adding
antagonists to the active ingredients to the dosage form, for
example naloxone or naltexone in the case of opioids, or compounds
which cause a physiological defense response, such as for example
ipecacuanha (ipecac) root.
[0009] However, since in most cases of abuse it is still necessary
to pulverize the dosage form comprising an active ingredient
suitable for abuse, it is an object of the present invention to
complicate or prevent the pulverization preceding abuse of the
dosage form using the means conventionally available to a potential
abuser.
[0010] It is a further object to provide a dosage form for active
ingredients with potential for abuse which ensures the desired
therapeutic effect when correctly administered, but from which the
active ingredients cannot be converted into a form suitable for
abuse simply by pulverization.
[0011] An additional object is to provide a dosage form with
enhanced stability when maintained under adverse conditions.
[0012] Yet another object is to provide an extrusion process for
the manufacture of dosage forms having enhanced abuse prevention
and stability characteristics.
[0013] A further object is to provide a dosage form having a
surface morphology different from that of the core of the dosage
form.
[0014] An additional object is to provide a dosage form having a
non-uniform morphology in general and in particular a dosage form
having a layered morphology, in each case where the composition of
the dosage form remains uniform.
SUMMARY OF THE INVENTION
[0015] These objects have been achieved by the provision of the
abuse-proofed dosage form thermoformed by extrusion without
discoloration according to the invention which contains, in
addition to one or more active ingredients with abuse potential
(A), at least one synthetic or natural polymer (C) optionally at
least one wax (D), and optionally at least one physiologically
acceptable auxiliary substance (B), wherein the dosage form
exhibits a breaking strength of at least 500 N.
[0016] The breaking strength of at least 500 N (measured as stated
in the specification) means that pulverization of the dosage form
is considerably more difficult using conventional means, so
considerably complicating or preventing the subsequent abuse.
[0017] If comminution is inadequate, parenteral, in particular
intravenous, administration cannot be performed safely or
extraction of the active ingredient therefrom takes too long for
the abuser or there is no "kick" when taken orally, as release is
not instantaneous.
[0018] As used herein, comminution means pulverization of the
dosage form with conventional means which are available to an
abuser, such as, for example, a mortar and pestle, a hammer, a
mallet or other usual means for pulverization by application of
force.
[0019] The dosage form according to the invention is thus suitable
for preventing parenteral, nasal and/or oral abuse of active
ingredients, preferably of pharmaceutical active ingredients, with
abuse potential.
[0020] The advantageous properties of the dosage form according to
the invention, in particular also its mechanical properties, may
not automatically be achieved by simply processing components (A),
(C), optionally (B) and optionally (D) by means of conventional
methods for the preparation of dosage forms. In fact, usually
suitable apparatuses must be selected for the preparation and
critical processing parameters must be adjusted, particularly
pressure/force, temperature and time. Dosage forms exhibiting the
desired properties may be obtained only if in the course of the
preparation of the dosage form the components are exposed to a
sufficient pressure at a sufficient temperature for a sufficient
period of time. Thus, although it may be possible to utilize
conventional apparatuses, the process protocols usually must be
adapted in order to meet the required criteria.
[0021] Unlike prior art methods which involve the extrusion of
polymers in admixture with pharmaceutically active substances but
which fail to provide the dosage forms with the beneficial
characteristics according to the present invention because
unsuitable extruder types are chosen and/or improper extrusion
parameters are adjusted, it has now been discovered that the
combination of specific extruder type coupled with herein specified
extrusion process parameters provides dosage forms with the
enhanced properties disclosed herein.
[0022] For example, U.S. Pat. No. 6,488,963 relates to
pharmaceutical formulations comprising a hot-melt extrudable
mixture of a therapeutic compound and a high molecular weight
poly(ethylene oxide). It is disclosed that any commercially
available extruder model equipped to handle dry feed and having a
solid conveying zone, one or multiple heating zones, and an
extrusion die may be used. A single screw extruder is preferred and
used in the examples. Besides hot-met extrusion, other equivalent
processes such as injection molding, hot dipping, melt casting and
compression molding are said to be useful. The pharmaceutical
formulations obtained by the extrusion process according to U.S.
Pat. No. 6,488,963, however, fundamentally differ from the dosage
forms according to the present invention. This becomes directly
evident from the further processing of the extrudate of Example 2
of U.S. Pat. No. 6,488,963, which, upon exiting the die, may be
chopped to the desired length and then be ground to a powder.
According to U.S. Pat. No. 6,488,963, such powders are preferred
for oral, buccal, and sublingual administration.
[0023] In contrast to the grindable pharmaceutical formulations
according to. U.S. Pat. No. 6,488,963, it is an essential feature
of the dosage forms according to the present invention that they
exhibit a breaking strength of at least 500 N thereby preventing
them from being ground to a powder. In the preparation of the
dosage forms according to the invention, a suitable extruder type
has to be chosen and the extrusion parameters have to be properly
adjusted in order to achieve a breaking strength of at least 500 N.
In general, single screw extruders of the type disclosed in U.S.
Pat. No. 6,488,963 are not suitable to produce the dosage forms
according to the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 shows a schematic view of the extrudate of the
composition.
[0025] FIGS. 2A and 2B show schematic views of the preferred
arrangements of the tubular domain within the dosage form.
[0026] FIG. 3 shows the measurement of the breaking strength of a
tablet.
DETAILED DESCRIPTION OF THE INVENTION
[0027] Pharmaceutical active ingredients with abuse potential are
known to the person skilled in the art, as are the quantities
thereof to be used and processes for the production thereof, and
may be present in the dosage form according to the invention as
such, in the form of the corresponding derivatives thereof, in
particular esters or ethers, or in each case in the form of
corresponding physiologically acceptable compounds, in particular
in the form of the salts or solvates thereof, as racemates or
stereoisomers. The dosage form according to the invention is also
suitable for the administration of two or more pharmaceutical
active ingredients in one dosage form. The dosage form preferably
contains just one specific active ingredient.
[0028] The dosage form according to the invention is in particular
suitable for preventing abuse of a pharmaceutical active ingredient
selected from the group consisting of opioids, tranquilizers,
preferably benzodiazepines, barbiturates, stimulants and other
narcotics.
[0029] The dosage form according to the invention is very
particularly suitable for preventing abuse of an opioid,
tranquilizer or another narcotic selected from the group consisting
of
N-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperid-
yl} propionanilide (alfentanil), 5,5-diallylbarbituric acid
(allobarbital), allylprodine, alpha-prodine,
8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a]
[1,4]-benzodiazepine (alprazolam), 2-diethylaminopropiophenone
(amfepramone), (.+-.)-.alpha.-methyl-phenethylamine (amphetamine),
2-(.alpha.-methylphenethylamino)-2-phenylacetonitrile
(amphetaminil),5-ethyl-5-isopentylbarbituric acid (amobarbital),
anileridine, apocodeine, 5,5-diethylbarbituric acid(barbital),
benzylmorphine, bezitramide,
7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2 (3H)-one
(bromazepam), 2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]
[1,2,4] triazolo-[4,3-a] [1,4]diazepine (brotizolam),
17-cyclopropylmethyl-4,5a-epoxy-7.alpha. [(S)-1-hydroxy-1, 2, 2
trimethyl-propyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol
(buprenorphine), 5-butyl-5-ethylbarbituric acid (butobarbital),
butorphanol,
(7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)
dimethylcarbamate (camazepam), (1S, 2S)-2-amino-1-phenyl-1-propanol
(cathine/D-norpseudoephedrine),
7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-ylamine 4-oxide
(chlordiazepoxide),
7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4 (3H,5H)-dione
(clobazam),
5-(2-chloro-phenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one
(clonazepam), clonitazene, 7-chloro-2,
3-dihydro-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3-carboxylic acid
(clorazepate), 5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e]
[1,4]diazepin-2(3H)-one (clotiazepam),
10-chloro-11.beta.-(2-chlorophenyl)-2,3,7,11.beta.-tetrahydrooxazolo[3,2--
d] [1,4]benzodiazepin-6 (5H)-one (cloxazolam),
(-)-methyl-[3.beta.-benzoyloxy-2.beta. (1.alpha.H,
5.alpha.H)-tropancarboxylate] (cocaine), 4,
5.alpha.-epoxy-3-methoxy-17-methyl-7-morphinan-6.alpha.-ol
(codeine), 5-(1-cyclohexenyl)-5-ethylbarbituric acid
(cyclobarbital), cyclorphan, cyprenorphine,
7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2(3H)-one
(delorazepam), desomorphine, dextromoramide,
(+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate
(dextropropoxyphen), dezocine, diampromide, diamorphine,
7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one
(diazepam),
4,5.alpha.-epoxy-3-methoxy-17-methyl-6.alpha.-morphinano 1
(dihydrocodeine),
4,5.alpha.-epoxy-17-methyl-3,6.alpha.-morphinandiol
(dihydromorphine), dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, (6.alpha.R, 10.alpha.R)-6, 6,
9-trimethyl-3-pentyl-6.alpha.,7,8,10.alpha.-tetrahydro-6H-benzo[c]chromen-
-1-ol (dronabinol), eptazocine, 8-chloro-6-phenyl-4H-[1,2,4]
triazolo [4,3-a] [1,4] benzodiazepine (estazolam), ethoheptazine,
ethylmethylthiambutene, ethyl
[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-ca-
rboxylate] (ethyl loflazepate), 4,
5.alpha.-epoxy-3-ethoxy-17-methyl-7-morphinen-6.alpha.-ol
(ethylmorphine), etonitazene, 4, 5.alpha.,
epoxy-7.alpha.-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-et-
heno-morphinan-3-ol (etorphine),
N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine (fencamfamine),
7-[2-(.alpha.-methylphenethylamino)ethyl]-theophylline)
(fenethylline), 3-(.alpha.-methylphenethylamino)propionitrile
(fenproporex), N-(1-phenethyl-4-piperidyl)propionanilide
(fentanyl),
7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one
(fludiazepam),
5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2(3H)-one
(flunitrazepam),
7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepin--
2(3H-one (flurazepam),
7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one
(halazepam), 10-bromo-113-(2-fluorophenyl)-2, 3, 7,
11.beta.-tetrahydro [1,3] oxazolyl [3,2-d] [1,4]
benzodiazepin-6(5H)-one (haloxazolam), heroin, 4,
5.alpha.-epoxy-3-methoxy-17-methyl-6-morphinanone (hydrocodone),
4,5.alpha.-epoxy-3-hydroxy-17-methyl-6-morphinanone
(hydromorphone), hydroxypethidine, isomethadone, hydroxymethyl
morphinane, 11-chloro-8, 12.beta.-dihydro-2,
8-dimethyl-12.beta.-phenyl-4H-[1, 3]oxazino[3, 2-d] [1,
4]benzodiazepine-4,7(6H)-dione (ketazolam),
1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone
(ketobemidone), (3S,6S)-6-dimethyl-amino-4,4-diphenylheptan-3-yl
acetate (levacetylmethadol (LAAM)),
(-)-6-dimethylamino-4,4-diphenol-3-heptanone (levomethadone),
(-)-17-methyl-3-morphinanol (levorphanol), levophenacylmorphane,
lofentanil,
6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo
[1, 2-a] [1,4]-benzodiazepin-1 (4H)-one (loprazolam),
7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one
(lorazepam),
7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepin-2(3H)-
-one (lormetazepam), 5-(4-chlorophenyl)-2, 5-dihydro-3H-imidazo[2,
1-a]isoindol-5-ol (mazindol), 7-chloro-2,
3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine (medazepam),
N-(3-chloropropyl)-.alpha.-methylphenethylamine (mefenorex),
meperidine, 2-methyl-2-propyltrimethylene dicarbamate
(meprobamate), meptazinol, metazocine, methylmorphine, N,
.alpha.-dimethylphenethylamine (meth-amphetamine), (+)-6-dimethyl
amino-4, 4-diphenyl-3-heptanone (methadone),
2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone), methyl
[2-phenyl-2-(2-piperidyl)acetate] (methylphenidate),
5-ethyl-1-methyl-5-phenylbarbituric acid (methylphenobarbital), 3,
3-diethyl-5-methyl-2, 4-piperidinedione (methyprylon), metopon,
8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a]
[1,4]benzodiazepine (midazolam), 2-(benzhydrylsulfinyl)acetamide
(modafinil), 4,5.alpha.-epoxy-17-methyl-7-morphinan-3,
6.alpha.-diol (morphine), myrophine,
(.+-.)-trans-3-(1,1-dimethylheptyl)-7, 8, 10, 10
.alpha.-tetrahydro-1-hydroxy-6, 6-dimethyl-6H-dibenzo [-b, d)
pyran-9 (6.alpha.H)-one (nabilone), nalbuphine, nalorphine,
narceine, nicomorphine, 1-methyl-7-nitro-5-phenyl-1H-1,
4-benzodiazepin-2(3H)-one (nimetazepam),
7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nitrazepam),
7-chloro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nordazepam),
norlevorphanol, 6-dimethylamino-4, 4-diphenyl-3-hexanone
(normethadone), normorphine, norpipanone, the exudation for the
plants belonging to the species Papaver somniferum (opium),
7-chloro-3-hydroxy-5-phenyl-H-1, 4-benzodiazepin-2(3H)-one
(oxazepam), (cis-trans)-10-chloro-2, 3, 7, 1
b-tetrahydro-2-methyl-11b-phenyloxazolo[3, 2-d][1,
4]benzodiazepin-6-(5H)-one (oxazolam), 4,
5.alpha.-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone
(oxycodone), oxymorphone, plants and parts of plants belonging to
the species Papaver somniferum (including the subspecies
setigerum), papaveretum, 2-imino-5-phenyl-4-oxazolidinone
(pernoline), 1, 2, 3, 4, 5, 6-hexahydro-6,
11-dimethyl-3-(3-methyl-2-butenyl)-2, 6-methano-3-benzazocin-8-ol
(pentazocine), 5-ethyl 1-5-(1-methylbutyl)-barbituric acid
(pentobarbital), ethyl (1-methyl-4-phenyl-4-piperidine carboxylate)
(pethidine), phenadoxone, phenomorphan, phenazocine, phenoperidine,
piminodine, pholcodine, 3-methyl-2-phenylmorpholine
(phenmetrazine), 5-ethyl-5-phenylbarbituric acid (phenobarbital),
.alpha., .alpha.-dimethylphenethylamine (phentermine),
7-chloro-5-phenyl-1-(2-propynyl)-1H-1, 4-benzodiazepin-2 (3H)-one
(pinazepam) .alpha.-(2-piperidyl)benzhydryl alcohol (pipradrol)
1'-(3-cyano-3, 3-diphenylpropyl) [1,
4'-bipiperidine]-4'-carboxamide (piritramide),
7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,
4-benzodiazepin-2(3H)-one (prazepam), profadol, proheptazine,
promedol, properidine, propoxyphene,
N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl
(3-[4-methoxycarbonyl-4-(N-phenylpropanamido)-piperidino]propanoate)
(remifentanil), 5-sec-butyl-5-ethylbarbituric acid
(secobutabarbital), 5-allyl-5-(1-methylbutyl)-barbituric acid
(secobarbital),
N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}-propionanilide
(sufentanil), 7-chloro-2-hydroxy-methy l-5-phenyl-1H-1,
4-benzodiazepin-2(3H)-one (temazepam),
7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1, 4-benzodiazepin-2
(3H)-one (tetrazepam), ethyl
(2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine
(cis and trans)), tramadol,
8-chloro,-6-(2-chlorophenyl)-1-methyl-4H-[1, 2, 4]triazolo [4, 3-a]
[1, 4] benzodiazepine (triazolam),
5-(1-methylbutyl)-5-vinylbarbituric acid (vinylbital), (1R,
2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (1R, 2R,
4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cycl-
ohexanol, (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)-cyclohexan-1,
3-diol, preferably as racemate,
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl
2-(4-isobutyl-phenyl)-propionate,
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl
2-(6-methoxy-naphthalen-2-yl)-propionate,
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl
2-(4-isobutyl-phenyl)-propionate,
3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl
2-(6-methoxy-naphthalen-2-yl)-propionate,
(RR-SS)-2-acetoxy-4-trifluoromethyl-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR-SS)-2-hydroxy-4-trifluoromethyl-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR-SS)-4-chloro-2-hydroxy-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR-SS)-2-hydroxy-4-methyl-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR-SS)-2-hydroxy-4-methoxy-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR-SS)-2-hydroxy-5-nitro-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR-SS)-2',4'-difluoro-3-hydroxy-biphenyl-4-carboxylic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester and
corresponding stereoisomeric compounds, the corresponding
derivatives thereof in each case, in particular amides, esters or
ethers, and the physiologically acceptable compounds thereof in
each case, in particular the salts and solvates thereof,
particularly preferably hydrochlorides.
[0030] In a preferred embodiment the dosage form according to the
invention contains one active substance with abuse potential (A) or
more active substance with abuse potentials (A) selected from the
group consisting of
1,1-(3-dimethylamino-3-phenylpentamethylen)-6-fluor-1,3,4,9-tetrahydropyr-
ano[3,4-b]indole, in particular its hemicitrate;
1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1, 3, 4,
9-tetrahydropyrano[3,4-b]indole, in particular its citrate; and
1,1-[3-dimethylamino-3-(2-thienyl)pentamethylen]-1, 3, 4,
9-tetrahydropyrano[3, 4-b]-6-fluoro-indole, in particular its
hemicitrate. These compounds are known, for example, from WO
2004/043967 or WO 2005/066183. The disclosure of these references
is expressly incorporated herein and made a part of this present
application,
[0031] The amount of the active substance with abuse potential (A),
based on the total amount of the dosage form, is preferably within
the range from 0.01 to 95 wt.-%, more preferably from 0.5 to 80
wt.-%, still more preferably 1.0 to 70 wt.-%, most preferably 5.0
to 60 wt.-% and in particular 10 to 50 wt.-%. In a preferred
embodiment it is more than 20 wt.-%.
[0032] The dosage form according to the invention is in particular
suitable for preventing abuse of an opioid active ingredient
selected from the group comprising oxycodone, hydromorphone,
morphine, tramadol and the physiologically acceptable derivatives
or compounds thereof, preferably the salts and solvates thereof,
preferably the hydrochlorides thereof.
[0033] The dosage form according to the invention is furthermore in
particular suitable for preventing abuse of an opioid active
ingredient selected from the group comprising
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, (2R,
3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol,
(1RS, 3RS,
6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol,
(1R, 2R)-3-(2-dimethylaminoethyl-cyclohexyl)-phenol, the
physiologically acceptable salts thereof, preferably
hydrochlorides, physiologically acceptable enantiomers,
stereoisomers, diastereomers and racemates and the physiologically
acceptable derivatives thereof, preferably ethers, esters or
amides.
[0034] These compounds and processes for the production thereof are
described in EP-A-693475 or EP-A-780369. The disclosure of these
references is expressly incorporated herein and made a part of this
present application.
[0035] In order to achieve the necessary breaking strength of the
dosage form according to the invention, at least one synthetic or
natural polymer (C) is used. The polymer (C) contributes to the
breaking strength of the dosage form of at least 500 N, measured
using the method disclosed in the specification. At least one
polymer selected from the group comprising polyalkylene oxides,
preferably polymethylene oxide, polyethylene oxide, polypropylene
oxide; polyethylene, PolyPropylene, polyvinyl chloride,
polycarbonate, polystyrene, polyacrylate, copolymers thereof, and
mixtures of at least two of the stated polymers is preferably used
for this purpose. High molecular weight thermoplastic polyalkylene
oxides are preferred. High molecular weight polyethylene oxides
with a molecular weight of at least 0.5 million, preferably of at
least 1 million up to 15 million, determined by rheological
measurements, are particularly preferred. These polymers have a
viscosity at 25.degree. C. of 4500 to 17600 cP, measured on a 5 wt.
% aqueous solution using a model RVF Brookfield viscosimeter
(spindle no. 2/rotational speed 2 rpm), of 400 to 4000 cP, measured
on a 2 wt. % aqueous solution using the stated viscosimeter
(spindle no. 1 or 3/rotational speed 10 rpm) or of 1650 to 10000
cP, measured on a 1 wt. % aqueous solution using the stated
viscosimeter (spindle no. 2/rotational speed 2 rpm).
[0036] The polymers are preferably used in powder form. They may be
soluble in water.
[0037] In order to achieve the necessary breaking strength of the
dosage form according to the invention, it is furthermore possible
additionally to use at least one natural or synthetic wax (D). The
wax (D) contributes to the breaking strength of the dosage form of
at least 500 N, measured using the method disclosed in the
specification, Waxes with a softening point of at least 60.degree.
C. are preferred. Carnauba wax and beeswax are. particularly
preferred. Carnauba wax is very particularly preferred. Carnauba
wax is a natural wax which is obtained from the leaves of the
carnauba palm and has a softening point of at least 80.degree. C.
When the wax component is additionally used, it is used together
with at least one polymer (C) in quantities such that the dosage
form has a breaking strength of at least 500 N.
[0038] In a preferred embodiment, the breaking strength of the
dosage form amounts to at least 500 N, to at least 600 N, to at
least 700 N, to at least 800 N, to at least 900 N, to at least 1000
N or even to at least 1100 N.
[0039] Component (C) is preferably used in an amount of 20 to 99.9
wt. %, particularly preferably of at least 30 wt. %, very
particularly preferably of at least 40 wt. %, relative to the total
weight of the dosage form.
[0040] In increasingly preferred embodiments, the dosage form
according to the invention has a density of at least 0.80 or at
least 0.85 g/cm.sup.3, at least 0.90 or at least 0.95 g/cm.sup.3,
at least 1.00, at least 1.05 or at least 1.10 g/cm.sup.3, in the
range from 0.80 to 1.35 g/cm.sup.3, and in particular in the range
from 0.95 to 1.25 g/cm.sup.3.
[0041] The dosage form according to the invention is characterized
by a comparatively homogeneous distribution of density. Preferably,
the densities of two segments of the dosage form having a volume of
1.0 mm.sup.3 each, deviate from one another by not more than +10%,
or by not more than +7.5%, or by not more than +5.0%, most
preferably not more than +2.5%, and in particular not more than
+1.0%.
[0042] The dosage form according to the invention is characterized
by a comparatively. homogeneous distribution of the active
substance with abuse potential (A). Preferably, the content of
component (A) in two segments of the dosage form having a volume of
1.0 mm.sup.3 each, deviates from one another by not more than
.+-.10%, more preferably not more than more than .+-.7.5%, still
more preferably not more than .+-.5.0%, most preferably not more
than .+-.2.5%, and in particular not more than .+-.1.0%.
[0043] Preferably, the total weight of the dosage form according to
the invention is within the range from 0.01 g to 1.5 g, more
preferably 0.05 g to 1.2 g, still more preferably 0.1 g to 1.0 g,
most preferably 0.2 g to 0.9 g and in particular 0.25 g to 0.8
g.
[0044] Auxiliary substances (B) which may be used are those known
auxiliary substances which are conventional for the formulation of
solid dosage forms. These are preferably plasticizers, such as
polyethylene glycol, auxiliary substances which influence active
ingredient release, preferably hydrophobic or hydrophilic,
preferably hydrophilic polymers, very particularly preferably
hydroxypropylcellulose, and/or antioxidants. Suitable antioxidants
are ascorbic acid, butylhydroxyanisole, butylhydroxytoluene, salts
of ascorbic acid, monothioglycerol, phosphorous acid, vitamin C,
vitamin E and the derivatives thereof, sodium bisulfite,
particularly preferably butylhydroxytoluene (BHT) or
butylhydroxyanisole (BHA) and ca-tocopherol.
[0045] The antioxidant is preferably used in quantities of 0.01 to
10 wt. %, preferably of 0.03 to 5 wt. %, relative to the total
weight of the dosage form.
[0046] The dosage forms according to the invention are
distinguished in that, due their hardness, they cannot be
pulverized in conventional comminution means available to an
abuser, such as a mortar and pestle. This virtually rules out oral
or parenteral, in particular intravenous or nasal abuse. However,
in order to prevent any possible abuse of the dosage form according
to the invention, the dosage forms according to the invention may,
in a preferred embodiment, contain further agents which complicate
or prevent abuse as auxiliary substances (B).
[0047] The abuse-proofed dosage form according to the invention,
which comprises, apart from one or more active ingredients with
abuse potential, at least one hardening polymer (C) and optionally
at least one wax (D), may accordingly also comprise at least one of
the following components (a)-(e) as auxiliary substances (B):
[0048] at least one substance which irritates the nasal passages
and/or pharynx,
[0049] at least one viscosity-increasing agent, which, with the
assistance of a necessary minimum quantity of an aqueous liquid,
forms a gel with the extract obtained from the dosage form, which
gel preferably remains visually distinguishable when introduced
into a further quantity of an aqueous liquid,
[0050] at least one antagonist for each of the active ingredients
with abuse potential,
at least one emetic, at least one dye as an aversive agent, at
least one bitter substance.
[0051] Components (a) to (f) are additionally each individually
suitable for abuse-proofing the dosage form according to the
invention. Accordingly, component (a) is preferably suitable for
proofing the dosage form against nasal, oral and/or parenteral,
preferably intravenous, abuse, component (b) is preferably suitable
for proofing against parenteral, particularly preferably
intravenous and/or nasal abuse, component (c) is preferably
suitable for proofing against nasal and/or parenteral, particularly
preferably intravenous, abuse, component (d) is preferably suitable
for proofing against parenteral, particularly preferably
intravenous, and/or oral and/or nasal abuse, component (e) is
suitable as a visual deterrent against oral or parenteral abuse and
component (f) is suitable for proofing against oral or nasal abuse.
Combined use according to the invention of at least one of the
above-stated components makes it possible still more effectively to
prevent abuse of dosage forms according to the invention.
[0052] In one embodiment, the dosage form according to the
invention may also comprise two or more of components (a)-(f) in a
combination, preferably (a), (b) and optionally (c) and/or (f)
and/or (e) or (a), (b) and optionally (d) and/or (f) and/or
(e).
[0053] In another embodiment, the dosage form according to the
invention may comprise all of components (a)-(f).
[0054] If the dosage form according to the invention comprises
component (a) to counter abuse, substances which irritate the nasal
passages and/or pharynx which may be considered according to the
invention are any substances which, when administered via the nasal
passages and/or pharynx, bring about a physical reaction which is
either so unpleasant for the abuser 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. These substances which conventionally irritate the nasal
passages and/or pharynx may also bring about a very unpleasant
sensation or even unbearable pain when administered parenterally,
in particular intravenously, such that the abuser does not wish to
or cannot continue taking the substance.
[0055] Particularly suitable substances which irritate the nasal
passages and/or pharynx are those which cause burning, itching, an
urge to sneeze, increased formation of secretions or a combination
of at least two of these stimuli. Appropriate substances and the
quantities thereof which are conventionally to be used are known
per se to the person skilled or may be identified by simple
preliminary testing.
[0056] The substance which irritates the nasal passages and/or
pharynx of component (a) is preferably based on one or more
constituents or one or more plant parts of at least one hot
substance drug.
[0057] Corresponding hot substance drugs are known per se to the
person skilled in the art and are described, for example, in
"Pharmazeutische Biologie--Drogen and ihre Inhaltsstoffe" by Prof.
Dr. Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag,
Stuttgart-New York, 1982, pages 82 et seq. The disclosure of these
references is expressly incorporated herein and made a part of this
present application.
[0058] A dosage unit is taken to mean a separate or separable
administration unit, such as for example a tablet or a capsule.
[0059] One or more constituents of at least one hot substance drug
selected from the group consisting of Allii sativi bulbus (garlic),
Asari rhizoma cum herba (Asarum root and leaves), Calami rhizoma
(calamus root), Capsici fructus (capsicum), Capsici fructus acer
(cayenne pepper), Curcumae longae rhizoma (turmeric root), Curcumae
xanthorrhizae rhizome (Javanese turmeric root), Galangae rhizome
(galangal root), Myristicae semen (nutmeg), Piperis nigri fructus
(pepper), Sinapis albae semen (white mustard seed), Sinapis nigri
semen (black mustard seed), Zedoariae rhizome (zedoary root) and
Zingiberis rhizoma (ginger root), particularly preferably from the
group consisting of Capsici fructus (capsicum), Capsici fructus
acer (cayenne pepper) and Piperis nigri fructus (pepper) may
preferably be added as component (a) to the dosage form according
to the invention.
[0060] The constituents of the hot substance drugs preferably
comprise o-methoxy(methyl)phenol compounds, acid amide compounds,
mustard oils or sulfide compounds or compounds derived
therefrom.
[0061] Particularly preferably, at least one constituent of the hot
substance drugs is selected from the group consisting of
myristicin, elemicin, isoeugenol, .alpha.-asarone, safrole,
gingerols, xanthorrhizol, capsaicinoids, preferably capsaicin,
capsaicin derivatives, such as N-vanillyl-9E-octadecenamide,
dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, norcapsaicin
and nomorcapsaicin, piperine, preferably trans-piperine,
glucosinolates, preferably based on non-volatile mustard oils,
particularly preferably based on p-hydroxybenzyl mustard oil,
methylmercapto mustard oil or methylsulfonyl mustard oil, and
compounds derived from these constituents.
[0062] The dosage form according to the invention may preferably
contain the plant parts of the corresponding hot substance drugs in
a quantity of 0.01 to 30 wt. %, particularly preferably of 0.1 to
0.5 wt. %, in each case relative to the total weight of the dosage
unit.
[0063] If one or more constituents of corresponding hot substance
drugs are used, the quantity thereof in a dosage unit according to
the invention preferably amounts to 0.001 to 0.005 wt. %, relative
to the total weight of the dosage unit.
[0064] Another option for preventing abuse of the dosage form
according to the invention consists in adding at least one
viscosity-increasing agent as a further abuse-preventing component
(b) to the dosage form, which, with the assistance of a necessary
minimum quantity of an aqueous liquid, forms a gel with the extract
obtained from the dosage form, which gel is virtually impossible to
administer safely and preferably remains visually distinguishable
when introduced into a further quantity of an aqueous liquid.
[0065] For the purposes of the present invention, visually
distinguishable means that the active ingredient-containing gel
formed with the assistance of a necessary minimum quantity of
aqueous liquid, when introduced, preferably with the assistance of
a hypodermic needle, into a further quantity of aqueous liquid at
37.degree. C., remains substantially insoluble and cohesive and
cannot straightforwardly be dispersed in such a manner that it can
safely be administered parenterally, in particular intravenously.
The material preferably remains visually distinguishable for at
least one minute, preferably for at least 10 minutes.
[0066] The increased viscosity of the extract makes it more
difficult or even impossible for it to be passed through a needle
or injected. If the gel remains visually distinguishable, this
means that the gel obtained on introduction into a further quantity
of aqueous liquid, for example by injection into blood, initially
remains in the form of a largely cohesive thread, which, while it
may indeed be broken up into smaller fragments, cannot be disoersed
or even dissolved in such a manner that it can safely be
administered parenterally, in particular intravenously. In
combination with at least one optionally present component (a) to
(e), this additionally leads to unpleasant burning, vomiting, bad
flavor and/or visual deterrence.
[0067] Intravenous administration of such a gel would most probably
result in obstruction of blood vessels, associated with serious
harm to the health of the abuser.
[0068] In order to verify whether a viscosity-increasing agent is
suitable as component (b) for use in the dosage form according to
the invention, the active ingredient is mixed with the
viscosity-increasing agent and suspended in 10 ml of water at a
temperature of 25.degree. C. If this results in the formation of a
gel which fulfils the above-stated conditions, the corresponding
viscosity-increasing agent is suitable for preventing or averting
abuse of the dosage forms according to the invention.
[0069] If component (b) is added to the dosage form according to
the invention, one or more viscosity-increasing agents are used
which are selected from the group comprising microcrystalline
cellulose containing carboxymethylcellulose sodium (e.g.
Avicel.RTM. RC 591, FMC Corporation, Philadelphia, Pa., US),
carboxymethylcellulose sodium (Blanose.RTM. Hercules Inc.,
Wilmington, US; CMC-Na C300P.RTM., Cesalpinia Food S.p.A., Milano,
IT; Frimulsion BLC-5.RTM., Cesalpinia Food S.p.A., Milano, IT;
Tylose C300 P.RTM. SE Tylose GmbH & Co. KG, Wiesbaden, DE),
polyacrylic acid (Carbopol.RTM. 980 NF, Noveon IP Holdings Corp.,
Cleveland, Ohio, US, Carbopol.RTM. 981, Noveon IP Holdings Corp.,
Cleveland, Ohio, US), locust bean flour (Cesagum.RTM. LA-200,
Cesalpinia Food S.p.A., Milano, IT; Cesagum.RTM. LID/150,
Cesalpinia Food S.p.A., Milano, IT; Cesagum.RTM. LN-1, Cesalpinia
Food S.p.A., Milano, IT), pectins, preferably from citrus fruits or
apples (Cesapectin.RTM. HM Medium Rapid Set, Cesalpinia Food
S.p.A., Milano, IT), waxy maize starch (C*Gel 04201.RTM., Cerestar
Deutschland GmbH, Krefeld, DE), sodium alginate (Frimulsion ALG
(E401).RTM., Cesalpinia Food S.p.A., Milano, IT), guar flour
(Frimulsion BM.RTM., Cesalpinia Food S.p.A., Milano, IT; Polygum
26/1-75.RTM., Polygal AG, Marstetten, CH), iota carrageen
(Frimulsion D021.RTM., Cesalpinia Food S.p.A., Milano, IT), karaya
gum, gellan gum (Kelcogel F.RTM., Kelcogel LT100.RTM., CP Kelco
ApS, Lille Skensved, DK), galactomannan (Meyprogat 150.RTM.,
Meyhall Chemical, Kreuzlingen, CH), tara bean flour (Polygum
43/1.RTM., Polygal AG, Marstetten, CH), propylene glycol alginate.
(Protanal-Ester SD-LB.RTM., FCM Biopolymer AS, Drammen, NO), sodium
hyaluronate, tragacanth, tara gum (Vidogum SF 200.RTM. Unipektin
AG, Zirich, CH), fermented polysaccharide welan gum (K1A96),
xanthan gum (Xantural 180.RTM.). Xanthans are particularly
preferred. The names stated in brackets are the trade names by
which the materials are known commercially. In general, a quantity
of 0.1 to 20 wt. %, particularly preferably of 0.1 to 15 wt. % of
the stated viscosity-increasing agent(s) is sufficient to fulfill
the above-stated conditions.
[0070] The component (b) viscosity-increasing agents, where
provided, are preferably present in the dosage form according to
the invention in quantities of 25 mg per dosage unit, i.e. per
administration unit.
[0071] In a particularly preferred embodiment of the present
invention, the viscosity-increasing agents used as component (b)
are those which, on extraction from the dosage form with the
necessary minimum quantity of aqueous liquid, form a gel which
encloses air bubbles. The resultant gels are distinguished by a
turbid appearance, which provides the potential abuser with an
additional optical warning and discourages him/her from
administering the gel parenterally.
[0072] Component (C) may also optionally serves as an additional
viscosity-increasing agent which, with the assistance of a minimum
necessary quantity of an aqueous liquid, forms a gel.
[0073] It is also possible to formulate the viscosity increasing
agent and the other constituents in the dosage form according to
the invention in a mutually spatially separated arrangement.
[0074] In order to discourage and prevent abuse, the dosage form
according to the invention may furthermore comprise component (c),
namely one or more antagonists for the active ingredient or active
ingredients with abuse potential, wherein the antagonists are
preferably spatially separated from the remaining constituents of
the invention dosage according to the form and, when correctly
used, do not exert any effect.
[0075] Suitable antagonists for preventing abuse of the active
ingredients are known per se to the person skilled in the art and
may be present in the dosage form according to the invention 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.
[0076] If the active ingredient present in the dosage form is an
opioid, the antagonist used is preferably an antagonist selected
from the group comprising naloxone, naltrexone, nalmefene, nalid,
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. The
corresponding antagonists, where component (c) is provided, are
preferably used in a quantity of .gtoreq.1 mg, particularly
preferably in a quantity of 3 to 100 mg, very particularly
preferably in a quantity of 5 to 50 mg. per dosage form, i.e. per
administration unit.
[0077] If the dosage form according to the invention comprises a
stimulant as active ingredient, the antagonist is preferably a
neuroleptic, preferably at least one compound selected from the
group consisting of haloperidol, promethazine, fluphenazine,
perphenazine, levomepromazine, thioridazine, perazine,
chlorpromazine chlorprothixine, zuclopentixol, flupentixol,
prothipendyl, zetepine, benperidol, pipamperone, melperone and
bromperidol.
[0078] The dosage form according to the invention preferably
comprises these antagonists in a conventional therapeutic dose
known to the person skilled in the art, particularly preferably in
a quantity of twice to four times the conventional dose per
administration unit.
[0079] If the combination to discourage and prevent abuse of the
dosage form according to the invention comprises component (d), it
may comprise at least one emetic, which is preferably present in a
spatially separated arrangement from the other components of the
dosage form according to the invention and, when correctly used, is
intended not to exert its effect in the body.
[0080] Suitable emetics for preventing abuse of an active
ingredient are known per se to the person skilled in the art and
may be present in the dosage form according to the invention 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.
[0081] An emetic based on one or more constituents of ipecacuanha
(ipecac) root, preferably based on the constituent emetine may
preferably be considered in the dosage form according to the
invention, as are, for example, described in "Pharmazeutische
Biologie--Drogen und ihre Inhaltsstoffe" by Prof. Dr. Hildebert
Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart, New
York, 1982. The disclosure of these references is expressly
incorporated herein and made a part of this present
application.
[0082] The dosage form according to the invention may preferably
comprise the emetic emetine as component (d), preferably in a
quantity of .gtoreq.3 mg, particularly preferably of .gtoreq.10 mg
and very particularly preferably in a quantity of .gtoreq.20 mg per
dosage form, i.e. administration unit.
[0083] Apomorphine may likewise preferably be used as an emetic in
the abuse-proofing according to the invention, preferably in a
quantity of preferably .gtoreq.3 mg, particularly preferably of
.gtoreq.5 mg and very particularly preferably of .gtoreq.7 mg. per
administration unit.
[0084] If the dosage form according to the invention contains
component (e) as a further abuse-preventing auxiliary substance,
the use of a such a dye brings about an intense coloration of a
corresponding aqueous solution, in particular when the attempt is
made to extract the active ingredient for parenteral, preferably
intravenous administration, which coloration may act as a deterrent
to the potential abuser. Oral abuse, which conventionally begins by
means of aqueous extraction of the active ingredient, may also be
prevented by this coloration. Suitable dyes and the quantities
required for the necessary deterrence may be found in WO 03/015531.
The disclosure of this reference is expressly incorporated herein
and made a part of this present application.
[0085] If the dosage form according to the invention contains
component (f) as a further abuse-preventing auxiliary substance,
this addition of at least one bitter substance and the consequent
impairment of the flavor of the dosage form additionally prevents
oral and/or nasal abuse.
[0086] Suitable bitter substances and the quantities effective for
use may be found in US-2003/0064099 A1. The disclosure of this
reference is expressly incorporated herein and made a part of this
present application. Suitable bitter substances are preferably
aromatic oils, preferably peppermint oil, eucalyptus oil, bitter
almond oil, menthol, fruit aroma substances, preferably aroma
substances from lemons, oranges, limes, grapefruit or mixtures
thereof, and/or denatonium benzoate (Bitrex.RTM.). Denatonium
benzoate is particularly preferred.
[0087] The solid dosage form according to the invention is suitable
to be taken orally, vaginally or rectally, preferably orally. The
dosage form is preferably not in film form.
[0088] The dosage form according to the invention may assume
multiparticulate form, preferably in the form of microtablets,
microcapsules, micropellets, granules, spheroids, beads or pellets,
optionally packaged in capsules or pressed into tablets, preferably
for oral administration. The multiparticulate forms preferably have
a size or size distribution in the range from 0.1 to 3 mm,
particularly preferably in the range from 0.5 to 2 mm. Depending on
the desired dosage form, conventional auxiliary substances (B) are
optionally also used for the formulation of the dosage form.
[0089] The solid, abuse-proofed 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.
[0090] In order to investigate the extent of discoloration due to
this thermoforming, the color of the mixture of starting components
of which the dosage form consists is first determined without
addition of a color-imparting component, such as for example a
coloring pigment or an intrinsically colored component (for example
.alpha.-tocopherol). This composition is then thermoformed
according to the invention, wherein all process steps, including
cooling of the extrudate, are preferably performed under an inert
gas atmosphere. By way of comparison, the same composition is
produced by. the same process, but without an inert gas atmosphere.
The color of the dosage form produced according to the invention
from the starting composition and of the dosage form produced by
way of comparison is determined. The determination is performed
with the assistance of "Munsell Book of Color" from Munsell Color
Company Baltimore, Md., USA, 1966 edition. If the color of the
dosage form thermoformed according to the invention has a color
with identification no. N 9.5, but at most a color with the
identification no. 5Y 9/1, thermoforming is classed as being
"without discoloration". If the dosage form has a color with the
identification no. 5Y 9/2 or greater, as determined according to
the Munsell Book of Color, the thermoforming is classed as being
"with discoloration".
[0091] Surprisingly, the dosage forms according to the invention
exhibit no discoloration classed in accordance with the above
classification, if the entire production process is performed under
an inert gas atmosphere, preferably under a nitrogen atmosphere
with the assistance of an extruder for thermoforming.
[0092] In one embodiment of the present invention the abuse-proofed
dosage forms are produced by a process comprising
[0093] mixing components (A), the optionally present component (B),
(C) and the optionally present component (D) and co-mixing the
optionally present components a) to f) or, if necessary, separately
mixing with the addition of Component (C) and optionally (D),
[0094] heating the resultant mixture or the resultant mixtures in
the extruder at least up to the softening point of component (C)
and extruding the mixture through the outlet orifice of the
extruder by application of force,
[0095] singulating and forming the still plastic extrudate into the
dosage form or
[0096] cooling and forMing the extrudate into the dosage form,
[0097] wherein process steps II) and III) and optionally process
steps I) and IV) are optionally performed under an inert gas
atmosphere, preferably a nitrogen atmosphere.
[0098] Mixing of the components according to process step I) may
also proceed in the extruder.
[0099] Mixing of components (A), optionally (B), (C) and optionally
(D) and of the optionally present further components (a)-(f) and
optionally components (C) and the optionally present component (D)
may also optionally proceed 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.
[0100] Before blending with the remaining components, component (C)
and the optionally present component (D) is preferably provided
according to the invention with an antioxidant. This may proceed by
mixing the two components, (C) and the antioxidant, preferably by
dissolving or suspending the antioxidant in a highly volatile
solvent and homogeneously mixing this solution or suspension with
component (C) and the optionally present component (D) and removing
the solvent by drying, preferably under an inert gas atmosphere.
Alternatively, a physiologically acceptable auxiliary substance (B)
or a wax (D) may serve as the solvent, preferably at elevated
temperature. For example, when polyethylene glycol is used as a
plasticizer, it may be molten or liquefied at moderately elevated
temperature and the antioxidant may be dissolved therein. Under
these circumstances the highly volatile solvent can be omitted.
[0101] The dosage forms according to the invention which contain
subunits with further auxiliary substances which prevent or
complicate abuse may be produced by coextruding or separately
extruding the mixtures according to step I).
[0102] In any event, the, preferably molten, mixture or mixtures
which has/have been heated in the extruder at least up to the
softening point of component (C) is/are extruded from the extruder
through a die with at least one bore.
[0103] The process according to the invention is preferably
performed using conventional screw extruders, particularly
preferably twin-screw-extruders,
[0104] The extruder preferably comprises at least two temperature
zones, with heating of the mixture at least up to the softening
point of component (C) proceeding in the first zone, which is
downstream from a feed zone and optionally mixing zone, The
throughput of the mixture is preferably from 2.0 kg to 8.0
kg/hour.
[0105] After heating at least up to the softening point of
component (C), the molten mixture is conveyed with the assistance
of the screws, further homogenized, compressed or compacted such
that, immediately before emerging from the extruder die, it
exhibits a minimum pressure of 5 bar, preferably of at least 10
bar, and is extruded through the die as an extruded strand or
strands, depending on the number of bores which the die comprises.
The die geometry or the geometry of the bores is freely selectable.
The die or the bores may accordingly exhibit a round, oblong or
oval cross-section, wherein the round cross-section preferably has
a diameter of 0.1 mm to 15 mm and the oblong cross-section
preferably has a maximum lengthwise extension of 21 mm and a
crosswise extension of 10 mm. Preferably, the die or the bores have
a round cross-section. The casing of the extruder used according to
the invention may be heated or cooled. The corresponding
temperature control, i.e. heating or cooling, is so arranged that
the mixture to be extruded exhibits at least an average temperature
(product temperature) corresponding to the softening temperature of
component (C) and does not rise above a temperature at which the
active substance with abuse potential which is to be processed may
be damaged. Preferably, the temperature of the mixture to be
extruded is adjusted to below 180.degree. C., preferably below
150.degree. C., but at least to the softening temperature of
component (C).
[0106] In general, the following parameters are critical in
extrusion processes and have the consequences. described;
1. Throughput (Kg Per Hour)
[0107] If the throughput is too low the extruder is not correctly
filled and the material is stressed thereby affecting the viscosity
and the release profile of the final product; if the throughput is
too high the load of the extruder is higher than 100% and the
extruder shuts down automatically; and if the throughput is
tolerable but close to the upper limit significant expansion of the
extruded strand occurs (also known as "die swelling").
2. Screw Geometry
[0108] A minimum number of kneading elements is required in order
to obtain a homogeneous mixture; if the number is too high, the
material is stressed thereby affecting the viscosity and the
release profile of the final product. The number and lead of the
conveying elements influences the homogeneity of the mixture and
its residence time in the extruder and controls the increase of the
pressure in front of the die. Mixing elements improve the
homogeneity of the mixture; and eccentric screw heads allow for a
continuous discharge of the extrudate without density
variations.
3. Die and Merge Element Geometry
[0109] The geometry of the element which merges the extrusion
strands in front of the die, and geometry of the die itself, the
residence time in said element, and the ratio length of the die to
diameter of the die influence the compression of the material
thereby affecting the melt pressure. The die pressure depends on
revolution, throughput and melt temperature and affects the
viscosity and the release profile of the final product.
4. Temperature (Melt Zones)
[0110] The feeding cylinder should not be heated to prevent the
starting material from melting in the feeder and causing an
accumulation. The number of cylinders is variable, the longer the
extruder the longer the residence time. The temperature of the
cylinders (except feeding cylinder) destroys the material if it is
too high: if too low the material does not sufficiently melt
thereby resulting in an inhomogeneous mixture and degradation. The
die temperature, if separately set too low, causes the "extrusion
skin" to not properly form thereby making further processing of the
extrudate difficult.
5. Revolution of the Extruder
[0111] If the extruder revolution speed is too high the material is
stressed thereby affecting the viscosity and the release profile of
the final product. If the extruder revolution speed is too low the
load of the extruder is higher than 100% and the extruder shuts
down automatically; and inter alia the residence time depends on
the revolution.
6. Arrangement of Cylinders
[0112] The position of feeding cylinder and length of the extruder
are important. The degassing should be located close to the feeder
in order to avoid air pockets in the product; and if one of the
components is thermo-labile it may be separately fed into one of
the rear cylinders.
7. Temperature of the Water Cooling
[0113] Cooling of the engine and control of the temperature of the
extrusion cylinders are important parameters.
[0114] The process according to the invention requires the use of
suitable extruders, preferably screw extruders. Screw extruders
which are equipped with two screws (twin-screw-extruders) are
particularly preferred. Single-screw extruders are preferably
excluded.
[0115] The extrusion is preferably performed so that the expansion
of the strand due to extrusion is not more than 50%, i.e. that when
using a die with a bore having a diameter of e.g. 6 mm, the
extruded strand should have a diameter of not more than 9 mm. More
preferably, the expansion of the strand is not more than 40%, still
more preferably not more than 35%, most preferably not more than
30% and in particular not more than 25%. It has been surprisingly
found that if the extruded material in the extruder is exposed to a
mechanical stress exceeding a certain limit, a significant
expansion of the strand occurs thereby resulting in undesirable
irregularities most preferably not more than 30% and in particular
not more than 25%. It has been surprisingly found that if the
extruded material in the extruder is exposed to a mechanical stress
exceeding a certain limit, a significant expansion of the strand
occurs thereby resulting in undesirable irregularities of the
properties of the extruded strand, particularly its mechanical
properties.
[0116] For example, extrusion may be performed by means of a
twin-screw-extruder type Micro 27 GL 40 D (Leistritz, Niirnberg,
Germany), screw diameter 18 mm. Screws having eccentric ends may be
used. A heatable die with a round bore having a diameter of 8 mm
may be used. The entire extrusion process may be performed under
nitrogen atmosphere. The extrusion parameters may be adjusted e.g.
to the following values: rotational speed of the screws: 100 Upm;
delivery rate: 4 kg/h; product temperature: 125.degree. C.; and
jacket temperature: 120.degree. C.
[0117] 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.
[0118] An inert gas atmosphere is not necessary for intermediate or
final storage of the optionally singulated extrudate or the final
shape of the dosage form according to the invention.
[0119] The singulated extrudate may be pelletized with conventional
methods or be press-molded into tablets in order to impart the
final shape to the dosage form. It is, however, also possible not
to singulate the extruded strands and, with the assistance of
contrarotating calender rolls comprising opposing recesses in their
outer sleeve, to form them into the final shape, preferably a
tablet, and to singulate these by conventional methods.
[0120] Should the optionally singulated extrudate not immediately
be formed into the final shape, but instead cooled for storage,
after the period of storage an inert gas atmosphere, preferably a
nitrogen atmosphere, may optionally be provided and may be
maintained during heating of the stored extrudate up until
plasticization and definitive shaping to yield the dosage form.
[0121] 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 dosage form with a breaking strength of
at least 500 N, may be established by simple preliminary
testing.
[0122] The process according to the invention involves the
extrusion of a composition comprising components (A), (C),
optionally (B) and optionally (D). Preferably, extrusion is
performed by means of twin-screw-extruders.
[0123] It has been surprisingly found that extrudates exhibiting an
advantageous morphology are obtainable by means of
twin-screw-extruders. It has been found that under suitable
conditions the extrudate is surrounded by a shell which may be
denoted as "extrusion skin". Said extrusion skin can be regarded as
a collar-like or tubular structure forming a circumferential
section of the extrudate about its longitudinal extrusion axis so
that the outer surface of said collar-like or tubular structure
forms the closed shell of the extrudate. Usually, only the front
faces of the extrudate are not covered by said extrusion skin.
[0124] The extrusion skin surrounds the core of the extrudate in a
collar-like or tubular arrangement and preferably is connected
therewith in a seamless manner. The extrusion skin differs from
said core in its morphology. Usually, the extrusion skin is visible
with the naked eye in the cross-section of the extrudate,
optionally by means of a microscope, since due to the different
morphology of the material forming the extrusion skin and the
material forming the core, the optical properties differ as well.
It seems that during extrusion the material forming the extrusion
skin is exposed to mechanical and thermal conditions differing from
the conditions the core of the extrudate is exposed to. In
consequence, a heterogeneous morphology of the extruded strand is
obtained, which e.g. assumes radial symmetry when an extrusion die
having circular shape is used. The material forming the extrusion
skin and the material forming the core are usually distinguished by
their morphology, preferably, however, not by their composition,
particularly not by the relative content of components (A), (C),
optionally (B) and optionally (D).
[0125] Usually the extrusion skin covers the entire shell of the
extrudate like a one-piece collar, independently of what geometry
has been chosen for the extrusion die. Therefore, the extrudate may
assume circular, elliptic or other cross-sections.
[0126] The extrusion skin is preferably characterized by a. unitary
thickness. Preferably, the thickness of the extrusion skin is
within the range from 0.1 to 4.0 mm, more preferably 0.15 to 3.5
mm, still more preferably 0.2 to 3.0 mm, most preferably 0.2 to 2.5
mm and in particular 0.2 to 2.0 mm. In a preferred embodiment the
thickness of the extrusion skin in the sum over both opposing sides
amounts to 0.5 to 50%, more preferably 1.0 to 40%, still more
preferably 1.5 to 35%, most preferably 2.0 to 30% and in particular
2.5. to 25% of the diameter of the extrudate.
[0127] FIG. 1 shows a schematic view of extrudate (71) having a
collar-like extrusion skin (72) entirely surrounding the core (73)
about the longitudinal extrusion axis (74). The outer surface of
extrusion skin (72) forms the shell (75) of the extrudate (71).
[0128] It has been surprisingly found that extrudates having an
extrusion skin exhibit beneficial mechanical properties. They are
particularly suitable as intermediates in the production of the
dosage forms according to the invention, because they may be
advantageously processed, in particular by singulating and/or
forming.
[0129] When the dosage forms according to the invention are
prepared by means of extrusion processes which lead to
intermediates having an extrusion skin as described above, the
dosage forms obtained therefrom are preferably also characterized
by a particular morphology.
[0130] In a preferred embodiment those regions, which have formed
the extrusion skin in the extruded intermediate, are still visible
with the naked eye, optionally by means of a microscope, in the
cross-section of the dosage form. This is because usually by
further processing the extrudate, particularly by singulating
and/or shaping, the different nature and thereby also the different
optical properties of the material forming the extrusion skin and
the material forming the core are maintained. In the following,
that domain of the dosage forms which has emerged from the
extrusion skin in the course of further processing the extruded
intermediate, will be denoted as "tubular domain".
[0131] Preferably, the dosage form according to the invention
comprises a tubular domain and a core located therein. Preferably,
the tubular domain is connected with the core in a seamless manner.
Preferably the tubular domain as well as the core have
substantially the same chemical composition, i.e. substantially the
same relative content of components (A), (C), optionally (B) and
optionally (D). The material forming the tubular domain has a
morphology differing from the material forming the core. Usually,
this different morphology is also expressed in terms of different
optical oroperties, so that the tubular domain and the core are
visible with the naked eye in the cross-section of the dosage
form.
[0132] In case that the dosage form has been coated, e,g. by a film
coating, the tubular domain is located between the film coating and
the core.
[0133] Since the dosage form according to the invention may be
obtained in different ways from the extrudate containing the
extrusion skin (intermediate), the tubular domain may take
different arrangements and extensions within the dosage form
according to the invention. All arrangements have in common,
however, that the tubular domain partially covers the surface of
the core, but usually not its entire surface. Preferably, two
opposing surfaces of the core are not, or at least not fully
covered by the tubular domain. In other words, preferably the
tubular domain has two openings/blanks on opposing sides.
[0134] The thickness of the tubular domain may be uniform. It is
also possible, however, that in the course of the processing, i.e.
due to the subsequent shaping (e.g. press-forming) of the
extrudate, various sections of the extrusion skin are expanded or
compressed differently thereby leading to a variation of the
thickness of the tubular domain within the dosage form.
[0135] Preferably the thickness of the tubular domain is within the
range from 0.1 to 4.0 mm, more preferably 0.15 to 3.5 mm, still
more preferably 0.2 to 3.0 mm, most preferably 0.2 to 2.5 mm and in
particular 0.2 to 2.0 mm.
[0136] FIGS. 2A and 2B show schematic views of preferred
arrangements of the tubular domain within the dosage form according
to the invention. The dosage forms (81) contain a tubular domain
(82) partially surrounding the core (83). The opposing surfaces
(84a) and (84b) of the core (83), however, are not covered by the
tubular domain (82).
[0137] The process for the preparation of the dosage form according
to the invention is preferably performed continuously. Preferably,
the process involves the extrusion of a homogeneous mixture of
components (A), (C), optionally (B) and optionally (D). It is
particularly advantageous if the obtained intermediate, e.g. the
strand obtained by extrusion, exhibits uniform properties.
Particularly desirable are uniform density, uniform distribution of
the active substance, uniform mechanical properties, uniform
porosity, uniform appearance of the surface, etc. Only under these
circumstances the uniformity of the pharmacological properties,
such as the stability of the release profile, may be ensured and
the amount of rejects can be kept low.
[0138] Preferably, the process according to the present invention
may be performed with less than 25% rejects, more preferably less
than 20%, most preferably less than 15% and in particular less than
10% rejects, wherein the criteria for rejection are the FDA
standards regarding the intervariability of the content of
component (A), its release profile and/or the density of the dosage
form when comparing two dosage forms, preferably taken from the
same batch.
[0139] It has been surprisingly found that the above properties may
be obtained by means of twin-screw-extruders.
[0140] The process according to the invention preferably involves
the extrusion of a mixture of components (A), (C), optionally (B)
and optionally (D), preferably by means of a twin-screw-extruder.
After extrusion the extrudate is preferably singulated, shaped and
optionally coated in order to obtain the final dosage form.
[0141] In a preferred embodiment of the process according to the
invention, shaping is performed in the plasticized state of the
mixture of components (A), (C), optionally (B) and optionally (D).
It has been surprisingly found that the extrusion of certain
polymers (C), particular of high molecular weight polyethylene
oxides, yields intermediates exhibiting some kind of memory effect:
when the singulated extrudates are shaped at ambient temperature,
e.g. by press-forming, dosage forms are obtained which tend to
regain their original outer form upon storage under stressed
storage conditions, i.e. they return to the form they had prior to
shaping.
[0142] The shape of the dosage form upon storage at stressed
conditions, e.g. at 40.degree. C./75% RH, may also be unstable for
other reasons.
[0143] Said memory effect significantly deteriorates the storage
stability of the dosage form, as by regaining its outer form
several properties of the dosage form are changed. The same applies
to any changes of the outer form due to other reasons.
[0144] It has been found that, for example, depending on the
extrusion conditions a significant expansion of the strand may
occur thereby resulting in an increase of the volume of the
extrudate, i.e. a decrease of its density. Said expansion may be
compensated by subsequently press-forming the singulated extrudate
at a sufficient pressure, since under these conditions the
expansion of the material may be reversed.
[0145] However, if press-forming has been performed at ambient
temperature, the memory effect of the compressed extrudate will
cause it to swell and to expand upon storage, thereby significantly
increasing the volume of the dosage form.
[0146] It has been surprisingly found that such memory effect may
be suppressed if shaping of the singulated extrudate is performed
at increased temperature, i.e. in the plasticized state of the
mixture of components (A), (C), optionally (B) and optionally (D).
Preferably, shaping is performed at a pressure of at least 1 kN,
more preferably within the range from 2 kN to 50 kN, e.g. by means
of a tablet press. Preferably, shaping is performed at a
temperature which preferably is about 40.degree. C., more
preferably about 30.degree. C. and in particular about 25.degree.
C. below the melting range of the mixture of components (A), (C),
optionally (B) and optionally (D). The melting range of a given
mixture may be determined by conventional methods, preferably by
DSC (e.g. with a DSC model 2920 (TA Instruments, New Castle) and
ultrahigh pure nitrogen as purge gas at a flow rate of 150 ml./min;
approximate sample weight of 10-20 mg, sealed in nonhermetic
aluminium pans; temperature ramp speed 10.degree. C./min).
[0147] In a preferred embodiment the outer shape of the dosage form
according to the invention does not substantially change when being
stored for at least 12 h, preferably for at least 24 h, at
40.degree. C. and 75% RH, preferably in an open container.
[0148] In a preferred embodiment the volume of the dosage form
according to the invention increases by not more than 20% or 17.5%,
more preferably not more than 15% or 12.5%, still more preferably
not more than 10% or 7.5%, most preferably not more than 6.0%, 5.0%
or 4.0% and in particular not more than 3.0%, 2.0% or 1.0% when
being stored for at least 12 h, preferably for at least 24 h, at a
temperature of 20.degree. C. below the melting range of the mixture
of components (A), (C), optionally (B) and optionally (D),
optionally at a temperature of 40.degree. C. and 75% RH.
[0149] In a further preferred embodiment, the dosage form according
to the invention assumes the form of a tablet, a capsule or is in
the form of an oral osmotic therapeutic system (OROS), preferably
if at least one further abuse-preventing component (a)-(f) is also
present.
[0150] If components (c) and/or (d) and/or (f) are present in the
dosage form according to the invention, care must be taken to
ensure that they are formulated in such a manner or are present in
such a low dose that, when correctly administered, the dosage form
is able to bring about virtually no effect which impairs the
patient or the efficacy of the active ingredient.
[0151] If the dosage form according to the invention contains
component (d) and/or (f), the dosage must be selected such that,
when correctly orally administered, no negative effect is caused.
If, however, the intended dosage of the dosage form is exceeded in
the event of abuse, nausea or an inclination to vomit or a bad
flavor are produced. The particular quantity of component (d)
and/or (f) which can still be tolerated by the patient in the event
of correct oral administration may be determined by the person
skilled in the art by simple preliminary testing.
[0152] If, however, irrespective of the fact that the dosage form
according to the invention is virtually impossible to pulverize,
the dosage form containing the components (c) and/or (d) and/or (f)
is provided with protection, these components should preferably be
used at a dosage which is sufficiently high that, when abusively
administered, they bring about an intense negative effect on the
abuser. This is preferably achieved by spatial separation of at
least the active ingredient or active ingredients from components
(c) and/or (d) and/or (f), wherein the active ingredient or active
ingredients is/are present in at least one subunit (X) and
components (c) and/or (d) and/or (f) is/are present in at least one
subunit (Y), and wherein, when the dosage form is correctly
administered, components (c), (d) and (f) do not exert their effect
on taking and/or in the body and the remaining components of the
formulation, in particular component (C) and optionally (D), are
identical.
[0153] If the dosage form according to the invention comprises at
least 2 of components (c) and (d) or (f), these may each be present
in the same or different subunits (Y). Preferably, when present,
all the components (c) and (d) and (f) are present in one and the
same subunit (Y).
[0154] For the purposes of the present invention, subunits are
solid formulations, which in each case, apart from conventional
auxiliary substances known to the person skilled in the art,
contain the active ingredient(s), at least one polymer (C) and the
optionally present component (D) and optionally at least one of the
optionally present components (a) and/or (b) and/or (e) or in each
case at least one polymer (C) and optionally (D) and the
antagonist(s) and/or emetic(s) and/or component (e) and/or
component (f) and optionally at least one of the optionally present
components (a) and/or (b). Care must here be taken to ensure that
each of the subunits is formulated in accordance with the
above-stated process.
[0155] One substantial advantage of the separated formulation of
active ingredients from components (c) or (d) or (f) in subunits
(X) and (Y) of the dosage form according to the invention is that,
when correctly administered, components (c) and/or (d) and/or (f)
are hardly released on taking and/or in the body or are released in
such small quantities that they exert no effect which impairs the
patient or therapeutic success or, on passing through the patient's
body, they are only liberated in locations where they cannot be
sufficiently absorbed to be effective. When the dosage form is
correctly administered, preferably hardly any of components (c)
and/or (d) and/or (f) is released into the patient's body or they
go unnoticed by the patient.
[0156] The person skilled in the art will understand that the
above-stated conditions may vary as a function of the particular
components (c), (d) and/or (f) used and of the formulation of the
subunits or the dosage form. The optimum formulation for the
particular dosage form may be determined by simple preliminary
testing. What is vital is that each subunit contains the polymer
(C) and optionally component (D) and has been formulated in the
above-stated manner.
[0157] Should, contrary to expectations, the abuser succeed in
comminuting such a dosage form according to the invention, which
comprises components (c) and/or (e) and/or (d) and/or (f) in
subunits (Y), for the purpose of abusing the active ingredient and
obtain a powder which is extracted with a suitable extracting
agent, not only the active ingredient but also the particular
component (c) and/or (e) and/or (f) and/or (d) will be obtained in
a form in which it cannot readily be separated from the active
ingredient, such that when the dosage form which has been tampered
with is administered, in particular by oral and/or parenteral
administration, it will exert its effect on taking and/or in the
body combined with an additional negative effect on the abuser
corresponding to component (c) and/or (d) and/or (f) or, when the
attempt is made to extract the active ingredient, the coloration
will act as a deterrent and so prevent abuse of the dosage
form.
[0158] A dosage form according to the invention, in which the
active ingredient or active ingredients is/are spatially separated
from components (c), (d) and/or (e), preferably by formulation in
different subunits, may be formulated in many different ways,
wherein the corresponding subunits may each be present in the
dosage form according to the invention in any desired spatial
arrangement relative to one another, provided that the above-stated
conditions for the release of components (c) and/or (d) are
fulfilled.
[0159] The person skilled in the art will understand that
component(s) (a) and/or (b) which are optionally also present may
preferably be formulated in the dosage form according to the
invention both in the particular subunits (X) and (Y) and in the
form of independent subunits corresponding to subunits (X) and (Y),
provided that neither the abuse-proofing nor the active ingredient
release in the event of correct administration is impaired by the
nature of the formulation and the polymer (C) and optionally (D) is
included in the formulation and formulation is carried out in
accordance with the above-stated process in order to achieve the
necessary hardness.
[0160] In a preferred embodiment of the dosage form according to
the invention, subunits (X) and (Y) are present in multiparticulate
form, wherein microtablets, microcapsules, micropellets, granules,
spheroids, beads or pellets are preferred and the same form, i.e.
shape, is selected for both subunit (X) and subunit (Y), such that
it is not possible to separate subunits (X) from (Y) by mechanical
selection. The multiparticulate forms are preferably of a size in
the range from 0.1 to 3 mm, preferably of 0.5 to 2 mm.
[0161] The subunits (X) and (Y) in multiparticulate form may also
preferably be packaged in a capsule or be pressed into a tablet,
wherein the final formulation in each case proceeds in such a
manner that the subunits (X) and (Y) are also retained in the
resultant dosage form.
[0162] The multiparticulate subunits (X) and (Y) of identical shape
should also not be visually distinguishable from one another so
that the abuser cannot separate them from one another by simple
sorting. This may, for example, be achieved by the application of
identical coatings which, apart from this disguising function, may
also incorporate further functions, such as, for example,
controlled release of one or more active ingredients or provision
of a finish resistant to gastric juices on the particular
subunits.
[0163] The multiparticulate subunits may also be formulated as an
oral dosage form as a slurry or suspension in pharmaceutically safe
suspending media.
[0164] In a further preferred embodiment of the present invention,
subunits (X) and (Y) are in each case arranged in layers relative
to one another.
[0165] The layered subunits (X) and (Y) are preferably arranged for
this purpose vertically or horizontally relative to one another in
the dosage form according to the invention, wherein in each case
one or more layered subunits (X) and one or more layered subunits
(Y) may be present in the dosage form, such that, apart from the
preferred layer sequences (X)-(Y) or (X)-(Y)-(X), any desired other
layer sequences may be considered, optionally in combination with
layers containing components (a) and/or (b).
[0166] Another preferred dosage form according to the invention is
one in which subunit (Y) forms a core which is completely enclosed
by subunit (X), wherein a separation layer (z) may be present
between said layers. Such a structure is preferably also suitable
for the above-stated multiparticulate forms, wherein both subunits
(X) and (Y) and an optionally present separation layer (Z), which
must satisfy the hardness requirement according to the invention,
are formulated in one and the same multiparticulate form. In a
further preferred embodiment of the dosage form according to the
invention, the subunit (X) forms a core, which is enclosed by
subunit (Y), wherein the latter comprises at least one channel
which leads from the core to the surface of the dosage form.
[0167] The dosage form according to the invention may comprise,
between one layer of the subunit (X) and one layer of the subunit
(Y), in each case one or more, preferably one, optionally swellable
separation layer (Z) which serves to separate subunit (X) spatially
from (Y).
[0168] If the dosage form according to the invention comprises the
layered subunits (X) and (Y) and an optionally present separation
layer (Z) in an at least partially vertical or horizontal
arrangement, the dosage form preferably takes the form of a tablet,
a coextrudate or a laminate.
[0169] In one particularly preferred embodiment, the entirety of
the free surface of subunit (Y) and optionally at least part of the
free surface of subunit(s) (X) and optionally at least part of the
free surface of the optionally present separation layer(s) (Z) may
be coated with at least one barrier layer (Z') which prevents
release of component (c) and/or (e) and/or (d) and/or (f). The
barrier layer (Z') must also fulfill the hardness conditions
according to the invention.
[0170] Another particularly preferred embodiment of the dosage form
according to the invention comprises a vertical or horizontal
arrangement of the layers of subunits (X) and (Y) and at least one
push layer (p) arranged therebetween, and optionally a separation
layer (z), in which dosage form the entirety of the free surface of
layer structure consisting of subunits (X) and (Y), the push layer
and the optionally present separation layer (Z) is provided with a
semipermeable coating (E), which is Permeable to a release medium,
i.e. conventionally a physiological liquid, but substantially
impermeable to the active ingredient and to component (c) and/or
(d). and/or (f), and wherein this coating (E) comprises at least
one opening for release of the active ingredient in the area of
subunit (X).
[0171] A corresponding dosage form is known to the person skilled
in the art, for example under the name oral osmotic therapeutic
system (OROS), as are suitable materials and methods for the
production thereof, inter alia from U.S. Pat. Nos. 4,612,008,
4,765,989 and 4,783,337. The disclosure of these references is
expressly incorporated herein and made a part of this present
application.
[0172] In a further preferred embodiment, the subunit (X) of the
dosage form according to the invention is in the form of a tablet,
the edge face of which and optionally one of the two main faces is
covered with a barrier layer (Z') containing component (c) and/or
(d) and/or (f).
[0173] The person skilled in the art will understand that the
auxiliary substances of the subunit(s) (X) or (Y) and of the
optionally present separation layer(s) (Z) and/or of the barrier
layer(s) (Z') used in formulating the dosage form according to the
invention will vary as a function of the arrangement thereof in the
dosage form according to the invention, the mode of administration
and as a function of the particular active ingredient of the
optionally present components (a) and/or (b) and/or (e) and of
component (c) and/or (d) and/or (f). The materials which have the
requisite properties are in each case known per se to the person
skilled in the art.
[0174] If release of component (c) and/or (d) and/or (f) from
subunit (Y) of the dosage form according to the invention is
prevented with the assistance of a cover, preferably a barrier
layer, the subunit may consist of conventional materials known to
the person skilled in the art, providing that it contains at least
one polymer (C) and optionally (D) to fulfill the hardness
condition of the dosage form according to the invention.
[0175] If a corresponding barrier layer (Z') is not provided to
prevent release of component (c) and/or (d) and/or (f), the
materials of the subunits should be selected such that release of
the particular component (c) and/or (d) from subunit (Y) is
virtually ruled out. The materials which are stated below to be
suitable for production of the barrier layer may preferably be used
for this purpose.
[0176] Preferred materials are those which are selected from the
group comprising alkylcelluloses, hydroxyalkyl-celluloses, glucans,
scleroglucans, mannans, xanthans, copolymers of
poly[bis(p-carboxyphenoxy)propane and sebacic acid, preferably in a
molar ratio of 20:80 (commercially available under the name
Polifeprosan 20.RTM.), carboxymethyl celluloses, cellulose ethers,
cellulose esters, nitrocelluloses, polymers based on (meth)acrylic
acid and the esters thereof, polyamides, polycarbonates,
polyalkylenes, polyalkylene glycols, polyalkylene oxides,
polyalkylene terephthalates, polyvinyl alcohols, polyvinyl ethers,
polyvinyl esters, halogenated polyvinyls, polyglycolides,
polysiloxanes and polyurethanes and the copolymers thereof.
[0177] Particularly suitable materials may be selected from the
group comprising methylcellulose, ethylcellulose,
hydroxypropylcellulose, hydroxypropylmethylcellulose,
hydroxybutylmethylcellulose, cellulose acetate, cellulose
propionate (of low, medium or high molecular weight), cellulose
acetate propionate, cellulose acetate butyrate, cellulose acetate
phthalate, carboxymethylcellulose, cellulose triacetate, sodium
cellulose sulfate, polymethyl methacrylate, polyethyl methacrylate,
polybutyl methacrylate, polyisobutyl methacrylate, polyhexyl
methacrylate, polyisodecyl methacrylate, polylauryl methacrylate,
polyphenyl methacrylate, polymethyl acrylate, polyisopropyl
acrylate, polyisobutyl acrylate, polyoctadecyl acrylate,
polyethylene, low density polyethylene, high density polyethylene,
polypropylene, polyethylene glycol, polyethylene oxide,
polyethylene terephthalate, polyvinyl alcohol, polyvinyl isobutyl
ether, polyvinyl acetate and polyvinyl chloride.
[0178] Particularly suitable copolymers may be selected from the
group comprising copolymers of butyl methacrylate and isobutyl
methacrylate, copolymers of methyl vinyl ether and maleic acid with
high molecular weight, copolymers of methyl vinyl ether and maleic
acid monoethyl ester, copolymers of methyl vinyl ether and maleic
anhydride and copolymers of vinyl alcohol and vinyl acetate.
[0179] Further materials which are particularly suitable for
formulating the barrier layer are starch-filled polycaprolactone
(WO98/20073), aliphatic polyesteramides (DE 19 753 534 A1, DE 19
800 698 A1, EP 0 820 698 A1), aliphatic and aromatic polyester
urethanes (DE 19822979), polyhydroxyalkanoates, in particular
polyhydroxybutyrates, polyhydroxyvalerates, casein (DE 4 309 528),
polylactides and copolylactides (EP 0 980 894 A1). The disclosure
of these references is expressly incorporated herein and made a
part of this present application.
[0180] The above-stated materials nay optionally be blended with
further conventional auxiliary substances known to the person
skilled in the art, preferably selected from the group comprising
glyceryl monostearate, semi-synthetic triglyceride derivatives,
semi-synthetic glycerides, hydrogenated castor oil, glyceryl
palmitostearate, glyceryl behenate, polyvinyl-pyrrolidone,
gelatine, magnesium stearate, stearic acid, sodium stearate,
talcum, sodium benzoate, boric acid and colloidal silica, fatty
acids, substituted triglycerides, glycerides, polyoxyalkylene
glycols and the derivatives thereof.
[0181] If the dosage form according to the invention comprises a
separation layer (Z'), said layer, like the uncovered subunit (Y),
may preferably consist of the above-stated materials described for
the barrier layer. The person skilled in the art will understand
that release of the active ingredient or of component (c) and/or
(d) from the particular subunit may be controlled by the thickness
of the separation layer.
[0182] The dosage form according to the invention exhibits
controlled release of the active ingredient. It is preferably for
twice daily administration to patients.
[0183] The release properties of the dosage form according to the
invention are substantially independent from the pH value of the
release medium, i.e. preferably the release profile in artificial
intestinal juice substantially corresponds to the release profile
in artificial gastric juice. Preferably, at any given time point
the release profiles deviate from one another by not more than 20%,
more preferably not more than 15%, still more preferably not more
than 10%, yet more preferably not more than 7.5%, most preferably
not more than 5.0% and in particular not more than 2.5%.
[0184] Preferably, the dosage form according to the invention
exhibits a uniform release profile. Preferably, the release profile
of the active substance with abuse potential (A) is
inter-individually uniform (i.e. when comparing dosage forms
obtained from the same process) and/or uniform within a single
dosage form (i.e. when comparing segments of the same dosage form).
Preferably, when comparing two probes each having a mass of
preferably 500 mg, the total amount of the released active
substance for any given time point of the measurement does not
deviate by more than 20%, 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%.
[0185] Preferably, the release profile of the dosage form according
to the present invention is stable upon storage, preferably upon
storage at elevated temperature, e.g. 37.degree. C., for 3 month 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%.
[0186] The dosage form according to the invention may comprise one
or more active ingredients at least partially in controlled release
form, wherein controlled release may be achieved with the
assistance of conventional materials and methods known to the
person skilled in the art, for example by embedding the active
ingredient in a controlled release matrix or by the application of
one or more controlled release coatings. Active ingredient releaser
must, however, be controlled such that the above-stated conditions
are fulfilled in each case, for example that, in the event of
correct administration of the dosage form, the active ingredient or
active ingredients are virtually completely released before the
optionally present component (c) and/or (d) can exert an impairing
effect. Addition of materials effecting controlled release must
moreover not impair the necessary hardness.
[0187] Controlled release from the dosage form according to the
invention is preferably achieved by embedding the active ingredient
in a matrix. The auxiliary substances acting as matrix materials
control active ingredient release. Matrix materials may, for
example, be hydrophilic, gel-forming materials, from which active
ingredient release proceeds mainly by diffusion, or hydrophobic
materials, from which active ingredient release proceeds mainly by
diffusion from the pores in the matrix.
[0188] Physiologically acceptable, hydrophobic materials which are
known to the person skilled in the art may be used as matrix
materials. Polymers, particularly preferably cellulose ethers,
cellulose esters and/or acrylic resins are preferably used as
hydrophilic matrix materials. Ethylcellulose,
hydroxypropylmethylcellulose, hydroxypropylcellulose,
hydroxymethylcellulose, poly(meth)acrylic acid and/or the
derivatives thereof, such as the salts, amides or esters thereof
are very particularly preferably used as matrix materials.
[0189] Matrix materials prepared from hydrophobic materials, such
as hydrophobic polymers, waxes, fats, long chain fatty acids, fatty
alcohols or corresponding esters or ethers or mixtures thereof are
also preferred. Mono- or diglycerides of C12-C30 fatty acids and/or
C12-C30 fatty alcohols and/or waxes or mixtures thereof are
particularly preferably used as hydrophobic materials.
[0190] It is also possible to use mixtures of the above-stated
hydrophilic and hydrophobic materials as matrix materials.
[0191] Component (C) and the optionally present component (D),
which serve to achieve the breaking strength of at least 500 N
which is necessary according to the invention may furthermore also
optionally serve as additional matrix materials.
[0192] If the dosage form according to the invention is intended
for oral administration, it may also preferably comprise a coating
which is resistant to gastric juices and dissolves as a function of
the pH value of the release environment. By means of this coating,
it is possible to ensure that the dosage form according to the
invention passes through the stomach undissolved and the active
ingredient is only released in the intestines. The coating which is
resistant to gastric juices preferably dissolves at a pH value of
between 5 and 7.5.
[0193] Corresponding materials and methods for the controlled
release of active ingredients and for the application of coatings
which are resistant to gastric juices are known to the person
skilled in the art, for example from "Coated Pharmaceutical Dosage
Forms Fundamentals, Manufacturing Techniques, Biopharmaceutical
Aspects, Test Methods and Raw Materials" by Kurt H. Bauer, K.
Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st edition,
1998, Medpharm Scientific Publishers. The disclosure of these
references is expressly incorporated herein and made a part of this
present application.
[0194] Method for Determining the Breaking Strength
[0195] In order to verify whether a polymer may be used as
component (C) or (D), the polymer is pressed to form a tablet with
a diameter of 10 mm and a height of 5 mm using a force of 150 N at
a temperature which at least corresponds to the softening point of
the polymer and is determined with the assistance of a DSC diagram
of the polymer. Using tablets produced in this manner, breaking
strength is determined with the apparatus described below in
accordance with the method for determining the breaking strength of
tablets published in the European Pharmacopoeia 1997, page 143-144,
method no. 2.9.8. The apparatus used for the measurement is a
"Zwick Z 2.5" materials tester, Fmax=2.5 kN with a maximum draw of
1150 mm, which should be set up with 1 column and 1 spindle, a
clearance behind of 100 mm and a test speed adjustable between 0.1
and 800 mm/min together with testControl software. Measurement is
performed using a pressure piston with screw-in inserts and a
cylinder (diam. 10 mm), a force transducer, Fmax. 1 kN, diameter=8
mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with
manufacturer's test certificate M to DIN 55350-18 (Zwick gross
force Fmax=1.45 kN) (all apparatus from Zwick GmbH & Co. KG,
Ulm, Germany) with order no. BTC-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.
[0196] FIG. 3 shows the measurement of the breaking strength of a
tablet, in particular the tablet (4) adjustment device (6) used for
this purpose before and during the measurement. To this end, the
tablet (4) is held between the upper pressure plate (1) and the
lower pressure plate (3) of the force application apparatus (not
shown) with the assistance of two 2-part clamping devices, which
are in each case firmly fastened (not shown) with the upper and
lower pressure plate once the spacing (5) necessary for
accommodating and centring the tablet to be measured has been
established. The spacing (5) may be established by moving the
2-part clamping devices horizontally outwards or inwards in each
case on the pressure plate on which they are mounted.
[0197] The tablets deemed to be resistant to breaking under a
specific load include not only those which have not broken but also
those which may have suffered plastic deformation under the action
of the force.
[0198] In the case of the dosage forms according to the invention,
breaking strength is determined in accordance with the stated
method, dosage forms other than tablets also being tested.
[0199] The following Examples illustrate the invention purely by
way of example and without restricting the general concept of the
invention.
Example 1
TABLE-US-00001 [0200] Components Per tablet Per batch Tramadol HCl
100.0 mg 1495.0 g Polyethylene oxide, NF, 167.8 mg 2508.6 g MW 7
000 000 (Polyox WSR 303, Dow Chemicals)
Hydroxypropylmethylcellulose 33.5 mg 500.8 g 100 000 mPa-s
Polyethylene glycol (PEG 6000) 33.5 mg 500.8 g Butylhydroxytoluene
(BHT) 0.2 mg 3.0 g Total weight 335.0 mg 5008.2 g
[0201] The stated quantity of BHT was dissolved in ethanol (96%),
such that a 7.7% (mass/mass) ethanolic solution was obtained. This
was mixed initially with 150 g of polyethylene oxide in a high
speed mixer for 30 minutes and then the remaining quantity of
polyethylene oxide was added and stirring continued for a further
30 minutes. The composition was dried for 12 h at 40.degree. C. All
the further components were added and mixed for 15 min in a
free-fall mixer. The powder mixture was apportioned into an
extruder. Extrusion was performed using a model Micro 27 GL 40 D
double screw extruder with a spindle diameter of 18 mm manufactured
by Leistritz (Niirnberg). Screws with blunt ends were used, the hex
socket at the end of the screws being closed with a cap. The die
used is a heatable round die with a diameter of 8 mm. The entire
process was performed under an N.sub.2 atmosphere.
[0202] The following parameters were selected for extrusion:
Screw speed: 100 rpm Throughput: 4 kg/h Product temperature:
125.degree. C. Casing temperature: 120.degree. C.
[0203] The extrudate, which was still hot, was cooled under a
nitrogen atmosphere. The cooled strand was singulated into biplanar
tablets. The tablets did not break when exposed to a force of 500
N. The tablets could not be comminuted either with a hammer or with
the assistance of a mortar and pestle.
[0204] The color of the cooled strand or of the 10 tablets
singulated therefrom was determined at N 9.5/using the Munsell Book
of Color, such that the dosage form produced by the process
according to the invention did not exhibit any discoloration due to
the thermoforming with the assistance of an extruder.
Example 2
TABLE-US-00002 [0205] Components Per Tablet Per batch Oxycodon HC1
20.0 mg 410.1 g 13.7% Polyethylene oxide 7 000 000(Polyox 107.2 mg
2199.3 g 73.2% WSR 303, DOW Chemicals) Polyethylene glycol (PEG
6000) 15.0 mg 307.8 g 10.3% Hypromellose (Metholose 90 SH 3.8 mg
76.8 g 2.6% 100 000 cP, ShinEtsu) .alpha.-Tocopherol 0.2 mg 3.0 g
0.1% Aerosil (highly disperse Si0.sub.2) 0.2 mg 3.0 g 0.1% 146.4 mg
3000.0 g 100%
[0206] 50 g of the polyethylene oxide, 3 g ca-tocopherol and 3 g
Aerosil were mixed to a homogeneous mixture by means of a mortar.
All the further components were added and mixed for 15 minutes in a
free-fall mixer.
[0207] Extrusion was performed using a model Micro 27 PH 40 D twin
screw extruder manufactured by Leistritz Niirnberg). Screws having
eccentric ends were used. The die used is a heatable round die
having a diameter of 9 mm.
[0208] The following parameters were selected for extrusion: [0209]
Screw speed: 100 rpm [0210] Throughput: 4 kg/h [0211] Product
temperature: 134.degree. C. [0212] Casing temperature: heating
zones 1 to 10: 100.degree. C. [0213] heating zone 11 (die):
120.degree. C.
[0214] The extrudate, which was still hot, was cooled. No nitrogen
atmosphere was used. The product did not exhibit any yellowish
discoloration.
[0215] The cooled strand was singulated into biplanar slices. The
final press-forming was performed by means on an eccentric tablet
press (model EKO). Oblong punches (width 5 mm, length 12 mm) were
used as tabletting tool. The respective tablets (mass and form)
were punched from the slices and press-formed. One tablet was
obtained from one slice.
[0216] The breaking strength of the tablets was determined with the
stated apparatus in accordance with the stated method. The tablets
did not crush when exposed to a force of 500 N. The tablet could
not be comminuted with a hammer. This could not be achieved with
the assistance of a pestle and mortar either.
[0217] In vitro release of the active ingredient from the
preparation was determined in a paddle stirrer apparatus with
sinker in accordance with Pharm. Eur. The temperature of the
release medium was 37.degree. C. and the rotational speed of the
stirrer 75 min.sup.-1. 600 ml of artificial intestinal juice, pH
6.8 were used as release medium. The released quantity of active
ingredient present in the dissolution medium at each point in time
was determined by spectrophotometry.
TABLE-US-00003 Time Amount Released 60 min 36% 240 min 79% 480 min
99% 720 min 107%
Example 3
TABLE-US-00004 [0218] Per Per Components Table Batch % Oxycodon HC1
20.0 mg 333.3 g 11.1 Polyethylene oxide 7 000 000 122.6 mg 2060.7 g
68.7 (Polyox WSR 303, DOW Chemicals) Polyethylene glycol (PEG 6000)
18.0 mg 300.0 g 10.0 Hypromellose (Metholose 90 SH 18.0 mg 300.0 g
10.0 100 000 cP, ShinEtsu) .alpha.-Tocopherol 0.2 mg 3.0 g 0.1
Aerosil (highly disperse SiO.sub.2) 0.2 mg 3.0 g 0.1 180 mg 3000.0
g 100%
[0219] 50 g of the polyethylene oxide, 3 g .alpha.-todopherol and 3
g Aerosil were mixed to a homogeneous mixture by means of a mortar.
All the further components were added and mixed for 15 minutes in
free-fall mixer.
[0220] Extrusion was performed using a model Micro 27 PH 40 D twin
screw extruder manufactured by Leistritz (Niirnberg). Screws having
eccentric ends were used. The die used is a heatable round die
having a diameter of 9 mm.
[0221] The following parameters were selected for extrusion: [0222]
Screw speed: 100 rpm [0223] Throughput: 4 kg/h [0224] Product
temperature: 134.degree. C. [0225] Casing temperature: heating
zones 1 to 10: 100.degree. C. [0226] heating zone 11 (die):
120.degree. C.
[0227] The extrudate, which was still hot, was cooled. No nitrogen
atmosphere was used. The product did not exhibit any yellowish
discoloration.
[0228] The cooled strand was singulated into biplanar slices. The
final press-forming was performed by means on an eccentric tablet
press (model EKO). Oblong punches (width 5 mm, length 12 mm) were
used as tabletting tool. The respective tablets (mass and form)
were punched from the slices and press-formed. One tablet was
obtained from one slice.
[0229] The breaking strength of the tablets was determined with the
stated apparatus in accordance with the stated method. The tablets
did not crush when exposed to a force of 500 N. The tablet could
not be comminuted with a hammer. This could not be achieved with
the assistance of a pestle and mortar either.
[0230] In vitro release of the active ingredient from the
preparation was determined in a paddle stirrer apparatus with
sinker in accordance with Pharm. Eur. The temperature of the
release medium was 37.degree. C. and the rotational speed of the
stirrer 75 min-1. 600 ml of artificial intestinal juice, pH 6.8
were used as release medium. The released quantity of active
ingredient present in the dissolution medium at each point in time
was determined by spectrophotometry.
TABLE-US-00005 Amount Time released 60 min 33% 240 min 76% 480 min
100% 720 min 108%
Example 4
TABLE-US-00006 [0231] Per Per Components Table Batch % Tramadol
116.5 mg 349.0 g 34.9 Polyethylene oxide 7 000 000 150.2 mg 450.0 g
45.0 (Polyox WSR 303, DOW Chemicals) Polyethylene glycol (PEG 6000)
33.4 mg 100.0 g 10.0 Hypromellose (Metholose 90 SH 33.4 mg 100.0 g
10.0 100 000 cP, ShinEtsu) Butylhydroxytoluene 0.3 mg 1.0 g 0.1
333.8 mg 1000 g 100%
[0232] 45 g of the polyethylene oxide and 1 g butylhydroxytoluene
were mixed to a homogeneous mixture by means of a mortar. All the
further components were added and mixed for 15 minutes in a
free-fall mixer.
[0233] Extrusion was performed using a model Micro 27 PH 40 D twin
screw extruder manufactured by Leistritz (Niirnberg). Screws having
eccentric ends were used. The die used is a heatable round die
having a diameter of 9 mm.
[0234] The following parameters were selected for extrusion: [0235]
Screw speed: 100 rpm [0236] Throughput: 4 kg/h. [0237] Product
temperature: 134.degree. C. [0238] Casing temperature: heating
zones 1 to 10: 100.degree. C. [0239] heating zone 11 (die):
120.degree. C.
[0240] The extrudate, which was still hot, was cooled. No nitrogen
atmosphere was used. The product did not exhibit any yellowish
discoloration.
[0241] The cooled strand was singulated into biplanar slices. The
final press-forming was performed by means on an eccentric tablet
press (model EKO). Round punches (diameter 10 mm) having a radius
of curvature of 8 mm were used as tabletting tool. One tablet was
obtained from one slice.
[0242] The breaking strength of the tablets was determined with the
stated apparatus in accordance with the stated method. The tablets
did not crush when exposed to a force of 500 N. The tablet could
not be comminuted with a hammer. This could not be achieved with
the assistance of a pestle and mortar either.
Example 5
TABLE-US-00007 [0243] Per Per Components Table Batch % Oxycodon HCl
40.00 mg 133.3 g 13.3 Polyethylene oxide 5 000 000 190.0 mg 643.3 g
63.3 (Polyox WSR Coagulant, DOW Chemicals) Polyethylene glycol (PEG
6000) 30.0 mg 100.0 g 10.0 Hypromellose (Metholose 90 SH 30.0 mg
100.0 g 10.0 100 000 cP, ShinEtsu) .alpha.-Tocopherol 5.0 mg 16.7 g
1.7 Aerosil (highly disperse SiO.sub.2) 5.0 mg 16.7 g 1.7 300 mg
1000 g 100
[0244] 50 g of the polyethylene oxide, 5 g a-tocopherol and 5 g
Aerosil were mixed to a homogeneous mixture by means of a mortar.
All the further components were added and mixed for 15 minutes in a
free-fall mixer.
[0245] Extrusion was performed using a model Micro 27 PH 40 D twin
screw extruder manufactured by Leistritz (Nernberg). Screws having
eccentric ends were used. The die used is a heatable round die
having a diameter of 9 mm.
[0246] The following parameters were selected for extrusion: [0247]
Screw speed; 100 rpm [0248] Throughput: 4 kg/h [0249] Product
temperature: 134.degree. C. [0250] Casing temperature: heating
zones 1 to 10: 100.degree. C. [0251] heating zone 11 (die):
120.degree. C.
[0252] The extrudate, which was still hot, was cooled. No nitrogen
atmosphere was used. The product exhibited a slight yellowish
coloration. However, this coloration was merely caused by the
natural color of ca-tocopherol, but was not intensified by the
extrusion, i.e. the extrusion was performed without
discoloration.
[0253] The cooled strand was singulated into biplanar slices. The
final press-forming was performed by means on an eccentric tablet
press (model EKO). Round punches (diameter 10 mm) having a radius
of curvature of 8 mm were used as tabletting tool. One tablet was
obtained from one slice.
[0254] The breaking strength of the tablets was determined with the
stated apparatus in accordance with the stated method. The tablets
did not crush when exposed to a force of 500 N. The tablet could
not be comminuted with a hammer. This could not be achieved with
the assistance of a pestle and mortar either.
[0255] In vitro release of the active ingredient from the
preparation was determined in a paddle stirrer apparatus with
sinker in accordance with Pharm. Eur. The temperature of the
release medium was 37.degree. C. and the rotational speed of the
stirrer 75 min.sup.-1. 600 ml of artificial intestinal juice, pH
6.8 were used as release medium. The released quantity of active
ingredient present in the dissolution medium at each point in time
was determined by spectrophotometry.
TABLE-US-00008 Amount Time released 60 min 33% 240 min 76% 480 min
100% 720 min 108%
* * * * *