U.S. patent application number 15/255218 was filed with the patent office on 2016-12-22 for process for the production of an 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 BARTHOLOMAUS.
Application Number | 20160367485 15/255218 |
Document ID | / |
Family ID | 36218706 |
Filed Date | 2016-12-22 |
United States Patent
Application |
20160367485 |
Kind Code |
A1 |
ARKENAU-MARIC; Elisabeth ;
et al. |
December 22, 2016 |
PROCESS FOR THE PRODUCTION OF AN ABUSE-PROOFED DOSAGE FORM
Abstract
The present invention relates to a process for the production of
an abuse-proofed dosage form containing, apart from one or more
active ingredients with potential for abuse and optionally
physiologically acceptable auxiliary substances, at least one
synthetic or natural polymer (C) with a breaking strength of at
least 500 N, wherein the formulation mixture is combined with a
solvent for the polymer (C) at least in quantities such that the
formulation mixture is at least uniformly moistened, the at least
moistened composition is optionally divided into sub-portions,
dried and shaped to yield the dosage form.
Inventors: |
ARKENAU-MARIC; Elisabeth;
(Koln, DE) ; BARTHOLOMAUS; Johannes; (Aachen,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRUNENTHAL GMBH |
Aachen |
|
DE |
|
|
Assignee: |
GRUNENTHAL GMBH
Aachen
DE
|
Family ID: |
36218706 |
Appl. No.: |
15/255218 |
Filed: |
September 2, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14745661 |
Jun 22, 2015 |
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15255218 |
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12140609 |
Jun 17, 2008 |
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14745661 |
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11348276 |
Feb 6, 2006 |
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12140609 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/05 20130101;
A61P 25/04 20180101; A61K 9/2054 20130101; A61K 9/2095 20130101;
A61K 31/135 20130101; A61K 9/2013 20130101; A61K 9/1694 20130101;
A61K 9/2031 20130101; A61K 31/485 20130101; A61K 9/2027
20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/135 20060101 A61K031/135 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 4, 2005 |
DE |
10 2005 005 449.8 |
Claims
1. A process for the production of a solid dosage form with at
least reduced potential for abuse, said dosage form exhibiting a
breaking strength of at least 500 N, said process comprising: a)
providing a formulation mixture comprising at least one active
ingredient with potential for abuse (A) and at least one synthetic
or natural polymer (C), wherein the at least one active ingredient
with potential for abuse (A) is selected from the group consisting
of oxymorphone and physiologically acceptable compounds and
derivatives thereof, b) moistening the mixture with at least a
sufficient quantity of a solvent for the polymer (C) to uniformly
moisten the mixture, c) optionally dividing the mixture from step
b) into sub-portions, d) drying the sub-portion(s) from step c) or
the mixture from step b) and e) shaping the dried sub-portion or
mixture from step d) to yield the dosage form.
2. A process according to claim 1, where the dried sub-portions in
each case correspond to the mass of a unit of the dosage form.
3. A process according to claim 1, which further comprises
dispersing the formulation mixture in a liquid dispersant in which
the polymer component (C) is not soluble before addition of the
solvent.
4. A process according to claim 3, which further comprises dividing
the formulation mixture into sub-portions in each case
corresponding to the mass of a unit of the dosage form either
before or after the formulation mixture is dispersed.
5. A process according to claim 3, where the solvent and the
dispersant are miscible with one another.
6. A process according to claim 1, which further comprises
incorporating the solvent into the formulation mixture as a
foam.
7. A process according to claim 6, which further comprises
stabilizing the foam with the assistance of foam stabilizers.
8. A process according to claim 6, which further comprises drying
the sub-portion(s) or the mixture in granular form.
9. A process according to claim 8, which further comprises drying
the mixture in granular form, and then dividing the dried,
granulated mixture into sub-portions, which in each case correspond
to the mass of a unit of the dosage form, and shaping to yield the
dosage form.
10. A process according to claim 1, which further comprises adding
solvent to the formulation mixture in an amount such that a
shapeable paste is obtained.
11. A process according to claim 10, which further comprises drying
the paste and, before or after it is dried, dividing the paste into
sub-portions and shaping or converting into the dosage form the
dried portions, optionally after further dividing in each case into
a portion corresponding to the mass of a unit of the dosage
form.
12. A process according to claim 11, where the sub-portions have
the form of strands.
13. A process according to claim 12, which further comprises
producing the strands with the assistance of a screen or strand
former.
14. A process according to claim 12, which further comprises
singulating and shaping dried strands to yield the dosage form.
15. A process according to claim 14, where shaping proceeds with
the assistance of a tablet press.
16. A process according to claim 12, which further comprises
shaping dried strands with the assistance of shaping rollers or
shaping belts equipped with rollers to yield the dosage form.
17. A process according to claim 11, which further comprises
converting the paste into a planar structure, from which the dosage
form is stamped.
18. A process according to claim 10, where the process is performed
with the assistance of an extruder.
19. A process according to claim 1, which further comprises adding
a quantity of solvent sufficient to dissolve at least the polymer
component (C) to the formulation mixture.
20. A process according to claim 19, which further comprises
converting the solution into a planar structure.
21. A process according to claim 20, which further comprises
producing the planar structure with the assistance of an extruder
with a flat die or by casting the solution onto a level planar
support.
22. A process according to claim 19, which further comprises
shaping the dosage form by stamping from the dried planar structure
or by calendaring.
23. A process according to claim 19, where the mixture is divided
into portions such that, after drying, the portions correspond in
each case to the mass of a unit of the dosage form.
24. A process according to claim 23, which further comprises
placing the portions in molds corresponding to the shape of a unit
of the dosage form.
25. A process according to claim 19, which further comprises
dividing the mixture into any desired portions, and, after drying,
optionally recombining the portions, and shaping to yield the
dosage form.
26. A process according to claim 1, wherein the physiologically
acceptable compounds and derivatives are salts, solvates, esters,
ethers and amides.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/745,661, filed Jun. 22, 2015, now pending,
which is a continuation of U.S. patent application Ser. No.
12/140,609, filed Jun. 17, 2008, now abandoned, which is a division
of U.S. patent application Ser. No. 11/348,276, filed Feb. 6, 2006,
now abandoned, which claims priority of German Patent Application
No. 10 2005 005 449.8, filed Feb. 4, 2005, the contents of which
patent applications are incorporated herein by reference.
[0002] The present invention relates to a process for the
production of an abuse-proofed solid dosage form, in which there is
added to a formulation mixture containing, one or more active
ingredients with potential for abuse (A) and optionally
physiologically acceptable auxiliary substances (B) and at least
one synthetic or natural polymer (C), which exhibits a breaking
strength of at least 500 N, [0003] a) a solvent for the polymer (C)
at least in quantities such that the formulation mixture is
uniformly moistened, [0004] b) the composition which has been at
least moistened in this manner is optionally divided into
sub-portions, [0005] c) the portion(s) are dried and [0006] d)
shaped to yield the dosage form
BACKGROUND OF THE INVENTION
[0007] Many pharmaceutical active ingredients, in addition to
having excellent activity in their appropriate application, also
have potential for abuse, i.e. they can be used by an abuser to
bring about effects other than those intended.
[0008] 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.
[0009] 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 particular intravenously. An additional phenomenon
of this kind of 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.
[0010] Since delayed-release oral dosage forms containing active
ingredients with potential for abuse conventionally do not give
rise to the kick desired by the abuser even when taken orally in
abusively high quantities, such dosage forms are also comminuted
and extracted.
[0011] 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.
[0012] 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 potential for abuse and at
least one gel former, each in different layers.
[0013] 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 colour
released by tampering with the dosage form is intended to
discourage the abuser from using the dosage form which has been
tampered with.
[0014] 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 defence response, such as for example
ipecacuanha (ipecac) root.
[0015] Since, however, as in the past, it is in most cases
necessary for the purposes of abuse to pulverise the dosage form,
it was the object of the present invention to provide a process for
the production of dosage forms containing active ingredients with
potential for abuse, which, when correctly administered, ensure the
desired, preferably therapeutic action, but from which the active
ingredients cannot be converted into a form suitable for abuse
simply by pulverisation.
SUMMARY OF THE INVENTION
[0016] Said object has been achieved by the provision of the
process according to the invention for the production of a solid
dosage form with at least reduced potential for abuse which is
characterised in that [0017] a) there is added to a formulation
mixture containing at least one active ingredient with potential
for abuse (A) and at least one synthetic or natural polymer (C),
which exhibits a breaking strength of at least 500 N, a solvent for
the polymer (C) at least in quantities such that the formulation
mixture is uniformly moistened [0018] b) the composition which has
been at least moistened in this manner is optionally divided into
sub-portions, [0019] c) the portion(s) are dried and [0020] d)
shaped to yield the dosage form.
[0021] By using polymers having the stated minimum breaking
strength (measured as stated in the application), preferably in
quantities such that the dosage form also exhibits such a minimum
breaking strength of at least 500 N, preferably of at least 1000 N,
it is possible to prevent pulverisation of the dosage form with
conventional means and thus considerably to complicate or to
prevent any subsequent abuse.
[0022] If comminution is inadequate, parenteral, in particular
intravenous, administration cannot actually be performed safely or
extraction of the active ingredient therefrom takes too long for
the abuser or there is no "kick" when orally abused as release is
not instantaneous.
DETAILED DESCRIPTION
[0023] According to the invention, comminution is taken to mean
pulverisation of the dosage form by the application of force with
conventional means which are conventionally available to an abuser,
such as for example a pestle and mortar, a hammer, a mallet or
other usual means for pulverisation, wherein the proportion of
fines which may arise (particle size equal to or smaller than 0.3
mm) must not exceed 5 wt. %.
[0024] The dosage form produced according to the invention also
cannot be comminuted by these methods at low temperatures, for
example of below -25.degree. C., -40.degree. C. or even in liquid
nitrogen.
[0025] The dosage form produced according to the invention,
preferably a pharmaceutical dosage form, is thus suitable for
preventing parenteral, nasal and/or oral abuse of active
ingredients, preferably of pharmaceutical active ingredients, with
potential for abuse.
[0026] Active ingredients, preferably pharmaceutical active
ingredients with potential for abuse 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 produced according to the invention as such, in the
form of the corresponding derivatives thereof, in particular
esters, ethers or amides, or in each case in the form of
corresponding physiologically acceptable compounds, in particular
in the form of the corresponding salts or solvates thereof, as
racemates or stereoisomers. The dosage form produced according to
the invention may contain two or more pharmaceutical active
ingredients. The dosage form produced according to the invention
preferably contains only one specific active ingredient.
[0027] The dosage form according to the invention is in particular
suitable for preventing the abuse of at least one pharmaceutical
active ingredient, which is selected from the group comprising
opioids, tranquillisers, preferably benzodiazepines, barbiturates,
stimulants and further narcotics.
[0028] The dosage form according to the invention is very
particularly suitable for preventing abuse of an opioid,
tranquilliser or another narcotic selected from the group
comprising
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, alphaprodine,
8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine
(alprazolam), 2-diethylaminopropiophenone (amfepramone),
(.+-.)-.alpha.-methylphenethylamine (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-4,5.alpha.-epoxy-7.alpha.[(S)-1-hydroxy-1,2,2-trimet-
hyl-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-yiamine 4-oxide
(chlordiazepoxide),
7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione
(clobazam),
5-(2-chlorophenyl)-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)-o-
ne (clotiazepam), 10-chloro-11b-(2-chlorophenyl)-2,3,7,11
b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one
(cloxazolam),
(-)-methyl-[3.beta.-benzoyloxy-2.beta.(1.alpha.H,5.alpha.H)-tropane
carboxylate] (cocaine),
4,5.alpha.-epoxy-3-methoxy-17-methyl-7-morphinen-6.alpha.-ol
(codeine), 5-(1-cyclohexenyl)-5-ethyl barbituric 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
(dextropropoxyphene), dezocine, diampromide, diamorphone,
7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one
(diazepam),
4,5.alpha.-epoxy-3-methoxy-17-methyl-6.alpha.-morphinanol
(dihydrocodeine),
4,5.alpha.-epoxy-17-methyl-3,6.alpha.-morphinandiol
(dihydromorphine), dimenoxadol, dimephetamol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone,
(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,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-
rboxylatel (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-etheno-morphinan-3-ol (etorphine),
N-ethyl-3-phenyl-8,9,10-trinorboman-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-11b-(2-fluorophenyl)-2,3,7,11
b-tetrahydro[1,3]oxazolo[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,
hydroxymethylmorphinan,
11-chloro-8,12b-dihydro-2,8-dimethyl-12b-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-dimethylamino-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 (methamphetamine),
(.+-.)-6-dimethylamino-4,4-diphenol-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[1,5a][1,4]benzodiazepine
(midazolam), 2-(benzhydrylsulfinyl)acetamide (modafinil),
4,5.alpha.-epoxy-17-methyl-7-morphinen-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),
nalbuphene, 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 from plants belonging to
the species Papaver somniferum (opium),
7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one
(oxazepam), (cis-trans)-10-chloro-2,3,7,11
b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(5H)-o-
ne (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)
(Papaver somniferum), papaveretum, 2-imino-5-phenyl-4-oxazolidinone
(pemoline),
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-5-(1-methylbutyl)-barbituric
acid (pentobarbital),
ethyl-(1-methyl-4-phenyl-4-piperidinecarboxylate) (pethidine),
phenadoxone, phenomorphane, phenazocine, phenoperidine, piminodine,
pholcodeine, 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'-bipiperidinel-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
(secbutabarbital), 5-allyl-5-(1-methylbutyl)-barbituric acid
(secobarbithl),
N-{4-methoxymethyl-1[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide
(sufentanil),
7-chloro-2-hydroxy-methyl-5-phenyl-H-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[4,3a][1,4]benzodi-
azepine (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-methoxyphen-
yl)cyclohexanol,
(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol, (1
S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,
(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,
(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-d-
iol, preferably as racemate,
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl
2-(4-isobutoxy-phenyl)-propionate,
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl
2-(6-methoxy-naphthalen-2-yl)-propionate,
3-(2-dimethylarninomethyl-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-hydroxycyclohexyl)-phenyl ester,
(RR--SS)-2-hydroxy-5-nitro-benzoic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,
(RR--SS)-2',4'-difluoro-3-hydroxy-biphenyl-4-carboxylic acid
3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester
together with corresponding stereoisomeric compounds, in each case
the corresponding derivatives thereof, in particular amides, esters
or ethers, and in each case the physiologically acceptable
compounds thereof, in particular the salts and solvates thereof,
particularly preferably hydrochlorides.
[0029] The dosage forms produced according to the invention are
particularly suitable for preventing abuse of an opioid active
ingredient selected from among 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.
[0030] The dosage forms produced according to the invention are
furthermore in particular suitable for preventing abuse of an
opioid active ingredient selected from among the group comprising
(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,
(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol,
(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-d-
iol, (1R,2R)-3-(2-dimethylaminonethyl-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.
[0031] These compounds and the process for the production thereof
are described in EP-A-693475 and EP-A-780369 respectively. The
corresponding descriptions are hereby introduced as a reference and
are deemed to be part of the disclosure.
[0032] In order to achieve the necessary breaking strength, at
least one synthetic or natural polymer (C) which has a breaking
strength, measured using the method disclosed in the present
application, of at least 500 N is used in the process according to
the invention. 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 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).
[0033] The polymers are preferably used in powder form. They should
be soluble in water.
[0034] In order to achieve the necessary breaking strength with the
processes according to the invention, it is furthermore possible
additionally to use at least one natural or synthetic wax (D) with
a breaking strength, measured using the method disclosed in the
present application, of at least 500 N. Waxes with a softening
point of at least 60.degree. C. are preferred. Camauba wax and
beeswax are particularly preferred. Camauba wax is very
particularly preferred. Camauba wax is a natural wax which is
obtained from the leaves of the camauba 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 produced according to
the invention has a breaking strength of at least 500 N.
[0035] Component (C) is preferably used in a quantity 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 the dosage form.
[0036] 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 plasticisers, such as
triacetin and polyethylene glycol, auxiliary substances which
influence active ingredient release, preferably hydrophobic or
hydrophilic, preferably hydrophilic polymers, very particularly
preferably hydroxypropylmethylcellulose or hydroxypropylcellulose,
and/or antioxidants. 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. 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 .alpha.-tocopherol.
[0037] 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.
[0038] To perform the process according to the invention, at least
one active ingredient with potential for abuse (A), at least one
polymer (C) and optionally a wax (D), optionally at least one of
the further optionally present abuse-preventing components (a) to
(f) listed below and optionally present auxiliary substances (B)
such as antioxidants, plasticisers and/or delayed-release auxiliary
substances are processed with the addition of a solvent for the
polymer (C) to yield the dosage form.
[0039] To this end, components (A), (B), (C) and the optionally
present component (D) and optionally at least one of the optionally
present further abuse-preventing components (a) to (f) are mixed
or, if necessary, separately mixed with addition of component (C)
and optionally component (D) and the resultant formulation mixture
or the resultant formulation mixtures, after addition of the
solvent and optionally after granulation, are shaped to yield the
dosage form.
[0040] Mixing of components (A), (B), (C) and optionally (D) and of
the optionally present further components (a) to (f) with
components (C) and the optionally present component (D) optionally
proceeds in each case 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.
[0041] The solvent for the polymer (C) is added at least in such
quantities that the formulation mixture is uniformly moistened.
[0042] Solvents which are suitable as the solvent for the polymer
(C) are preferably aqueous solvents, such as water, mixtures of
water and aliphatic alcohols, preferably alcohols with C.sub.1 to
C.sub.6, esters, ethers, hydrocarbons, particularly preferably
distilled water, alone or mixed with short-chain alcohols, such as
methanol, ethanol,
isopropanol, butanol to yield aqueous alcohol solutions.
[0043] The solvent is preferably added by stirring. The uniformly
moistened composition is then dried. Drying preferably proceeds
with exposure to heat at temperatures at which it is possible to
rule out any discoloration of the composition. This temperature may
be established by simple preliminary testing.
[0044] Before or after drying, the composition may be divided into
sub-portions which preferably in each case correspond to the mass
of a unit of the dosage form. The corresponding dried portions are
then shaped to yield the dosage form.
[0045] This is preferably achieved by using tablet presses.
[0046] The formulation mixture may also be moistened in such a
manner that, before addition of the solvent, the formulation
mixture is divided, preferably in moulds, into sub-portions, is
dispersed in a liquid dispersant with stirring and then the solvent
is added. The polymer component (C) is not soluble in the
dispersant, which must be miscible with the solvent
[0047] Suitable dispersants are preferably hydrophilic solvents,
such as aliphatic alcohols, ketones, esters. Short-chain alcohols
are preferably used.
[0048] Alternatively, the formulation mixture may also be moistened
in such a manner that the solvent may be incorporated into the
formulation mixture as a foam. Such a foam of the solvent is
preferably produced with the assistance of a high-speed mixer,
preferably with the addition of conventional foam stabilisers.
Suitable stabilisers are, for example, hydrophilic polymers such
as
for example hydroxypropylmethylcellulose.
[0049] The foam is also preferably incorporated into the
formulation mixture with stirring, a granulated composition so
preferably being obtained.
[0050] Before or after being divided into sub-portions, which
preferably correspond to the mass of a unit of the dosage form, the
granulated composition is dried and then shaped into the dosage
form.
[0051] Drying and shaping may preferably proceed as described
above.
[0052] The process according to the invention may also be performed
in such a manner that solvent is added to the formulation mixture
in such a quantity that a shapeable paste is obtained.
[0053] Before or after being dried, which may proceed as explained
above, such a paste may be divided into sub-portions and the dried
portions, after further division in each case into a portion
corresponding to the mass of a unit of the dosage form, are shaped
or converted to yield the dosage form.
[0054] It is here possible to form the sub-portions in the form of
strands, which may be produced with the assistance of a screen or a
strand former. The dried strands are preferably singulated and
shaped to yield the dosage form. This shaping preferably proceeds
with the assistance of a tablet press, using shaping rollers or
shaping belts equipped with rollers.
[0055] It is also possible to convert the paste into a planar
structure and to stamp the dosage form out of it once it has
dried.
[0056] The paste is advantageously processed with an extruder,
wherein, depending on the configuration of the extrusion die,
strands or planar structures articles are produced, which are
singulated by chopping, cutting or stamping. The singulated
sub-portions may be shaped or formed as described above to yield
the dosage form. Corresponding apparatuses are known to the person
skilled in the art.
[0057] The process according to the invention may here be performed
continuously or discontinuously.
[0058] It is also possible to add solvent to the formulation
mixture in such a quantity that at least the polymer component (C)
is dissolved. Such a solution or dispersion/suspension is
preferably converted into a planar structure, an extruder with a
flat die preferably being used or the solution being cast onto a
planar support.
[0059] As stated above, after drying, the dosage forms may be
obtained from the planar structures by stamping or calendering. It
is also possible, as stated above, to convert
the solution into strands and to singulate these, preferably after
they have been dried, and shape them to yield the dosage form.
[0060] Alternatively, the solution may also be divided into
portions such that, after drying, they each correspond to the mass
of a unit of the dosage form, with moulds which already correspond
to the shape of the unit of the dosage form preferably being used
for this purpose.
[0061] If the solution is divided into any desired portions, the
portions may, after drying, optionally be combined again and be
shaped to form the dosage form, being for example packaged in a
capsule or press-moulded to form a tablet.
[0062] The formulation mixtures combined with solvent are
preferably processed at temperatures of 20.degree. C. to 40.degree.
C., wherein, apart from during drying to remove the solvent and the
optionally present dispersant, no higher temperatures are used.
After shaping to yield the dosage form, further drying
corresponding to the above-described drying may optionally be
performed.
[0063] As already explained, the dosage form produced according to
the invention may assume multiparticulate form, preferably the form
of microtablets, microcapsules, micropellets, granules, spheroids,
beads or pellets, optionally packaged in capsules or press-moulded
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.
[0064] The dosage forms obtained by the process according to the
invention are distinguished in that, by virtue of their hardness of
at least 500 N, they cannot be pulverised with the assistance of
conventional comminution means available to an abuser, such as a
pestle and mortar. This virtually rules out oral, parenteral in
particular intravenous, or nasal abuse. However, in order to
prevent any possible abuse of the dosage forms produced according
to the invention, in a preferred embodiment, the dosage forms
according to the invention may contain further abuse-complicating
or -preventing agents as auxiliary substances (B).
[0065] The abuse-proofed dosage form produced according to the
invention, which comprises, apart from one or more active
ingredients with potential for abuse (A), 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)-(f) as
auxiliary substances (B): [0066] a) at least one substance which
irritates the nasal passages and/or pharynx, [0067] b) at least one
viscosity-increasing agent, which, with the assistance of a
necessary minimum quantity of an aqueous liquid, preferably as an
aqueous extract obtained from the dosage form, forms a gel which
preferably remains visually distinguishable when introduced into a
further quantity of an aqueous liquid, [0068] c) at least one
antagonist for each of the active ingredients with potential for
abuse, [0069] d) at least one emetic, [0070] e) at least one dye as
an aversive agent, [0071] f) at least one bitter substance.
[0072] Components (a) to (f) are additionally each individually
suitable for abuse-proofing the dosage form obtained 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 obtained by the process according to
the invention.
[0073] For example, the dosage form obtained 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).
[0074] In another embodiment, the dosage form obtained according to
the invention may comprise all of components (a)-(f).
[0075] If the dosage form obtained according to the invention
comprises an abuse-preventing component (a), substances which
irritate the nasal passages and/or pharynx which may be considered
according to the invention are any substances which, when
administered accordingly 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.
[0076] 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 in the art or may be identified by
simple preliminary testing.
[0077] 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.
[0078] Corresponding hot substance drugs are known per se to the
person skilled in the art and are described, for example, in
"Pharmazeutische Biologie--Drogen and ihre Inhaltsstoffe" by Prof.
Dr. Hildebert Wagner, 2nd., revised edition, Gustav Fischer Verlag,
Stuttgart-New York, 1982, pages 82 et seq. The corresponding
description is hereby introduced as a reference and is deemed to be
part of the disclosure.
[0079] A dosage unit is taken to mean a separate or separable
administration unit, such as for example a tablet or a capsule.
[0080] 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 rhizoma (Javanese turmeric root), Galangae rhizoma
(galangal root), Myristicae semen (nutmeg), Piperis nigri fructus
(pepper), Sinapis albae semen (white mustard seed), Sinapis nigri
semen (black mustard seed), Zedoariae rhizoma (zedoary root) and
nngiberis 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,
The constituents of the hot substance drugs preferably comprise
.alpha.-methoxy(methyl)phenol compounds, acid amide compounds,
mustard oils or sulfide compounds or compounds derived
therefrom.
[0081] 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.
[0082] The dosage form obtained 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.
[0083] If one or more constituents of corresponding hot substance
drugs are used, the quantity thereof in a dosage unit obtained
according to the invention preferably amounts to 0.001 to 0.005 wt.
%, relative to the total weight of the dosage unit.
[0084] Another option for preventing abuse of the dosage form
obtained 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, preferably as an aqueous
extract obtained from the dosage form, forms a gel which is
virtually impossible to administer safely and preferably remains
visually distinguishable when introduced into a further quantity of
an aqueous liquid.
[0085] 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.
[0086] 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 mechanically into smaller fragments, cannot
be dispersed 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
flavour and/or visual deterrence.
[0087] Intravenous administration of such a gel would most probably
result in obstruction of blood vessels, associated with serious
damage to the health of the abuser.
[0088] In order to verify whether a viscosity-increasing agent is
suitable as component (b) for use in the dosage form obtained
according to the invention, the active ingredient is mitred 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 additionally preventing
or averting abuse of the dosage forms obtained according to the
invention.
[0089] If component (b) is added to the dosage form obtained
according to the invention, one or more viscosity-increasing agents
are used which are selected from the group comprising
microcrystalline cellulose with 11 wt. % carboxymethylcellulose
sodium (Avicel.RTM. RC 591), carboxymethylcellulose sodium
(Blanose.RTM., CMC-Na C300P.RTM., Frimulsion BLC-5.RTM., Tylose
C300 P.RTM.), polyacrylic acid (Carbopol.RTM. 980 NF, Carbopor.RTM.
981), locust bean flour (Cesagum.RTM. LA-200, Cesagum.RTM. LID/150,
Cesagum.RTM. LN-1), pectins, preferably from pectin fruit and
apples (Cesapectin.RTM. HM Medium Rapid Set), waxy maize starch
(C*Gel 04201.RTM., sodium alginate (Frimulsion ALG)(E401.RTM.),
guar flour (Frimulsion BM.RTM., Polygum 26/1-75.RTM., iota
carrageenan (Frimulsion D021.RTM., karaya gum, gellan gum (Kelcogel
F.RTM., Kelcogel LT100.RTM., galactomannan (Meyprogat 150.degree.),
tars stone flour (Polygum 43/1.RTM., propylene glycol alginate
(Protanal-Ester SD-LIA, sodium hyaluronate, tragacanth, tars gum
(Vidogum SP 200.RTM.), 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. %,
relative to the total weight of the dosage form, of the stated
viscosity-increasing agent(s) is sufficient to fulfil the
above-stated conditions.
[0090] The component (b) viscosity-increasing agents, where
provided, are preferably present in the dosage form obtained
according to the invention in quantities of z 5 mg per dosage unit,
i.e. per administration unit.
[0091] 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 for with the
necessary minimum quantity of aqueous liquid, for 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.
[0092] Component (C) may also optionally serve as an additional
viscosity-increasing agent, which forms a gel with the assistance
of a necessary minimum quantity of aqueous liquid.
[0093] It is also possible to formulate the viscosity-increasing
agents and the other constituents in the dosage form obtained
according to the invention in a mutually spatially separated
arrangement.
[0094] In order to discourage and prevent abuse, the dosage form
obtained according to the invention may furthermore comprise
component (c), namely one or more antagonists for the active
ingredient or active ingredients with potential for abuse, wherein
the antagonists are preferably spatially separated from the
remaining constituents of the dosage form obtained according to the
invention and, when correctly used, do not exert any effect.
[0095] 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.
[0096] 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.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.
[0097] If the dosage form obtained 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, chiorprothixine, zuclopentixol,
flupentixol, prothipendyl, zotepine, benperidol, pipamperone,
melperone and bromperidol.
[0098] The dosage form obtained 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 three times the
conventional dose per administration unit.
[0099] If the combination to further discourage and prevent abuse
of the dosage form produced according to the invention also
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 produced according to the
invention and, when correctly used, is intended not to exert its
effect in the body.
[0100] Suitable emetics for additionally 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 obtained 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.
[0101] 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 obtained according to
the invention, as are, for example, described in "Pharmazeutische
Biologie--Drogen and ihre inhaltsstoffe" by Prof. Dr. Hildebert
Wagner, 2nd, revised edition, Gustav Fischer Verlag, Stuttgart, New
York, 1982. The corresponding literature description is hereby
introduced as a reference and is deemed to be part of the
disclosure.
[0102] The dosage form obtained 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.
[0103] Apomorphine may likewise preferably be used as an emetic for
additional abuse-proofing, 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.
[0104] If the dosage form obtained according to the invention
contains component (e) as an additional abuse-preventing auxiliary
substance, the use of 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,
wherein the corresponding disclosure should be deemed to be part of
the present disclosure and is hereby introduced as a reference.
[0105] If the dosage form obtained according to the invention
contains component (f) as an additional abuse-preventing auxiliary
substance, this addition of at least one bitter substance and the
consequent impairment of the flavour of the dosage form
additionally prevents oral and/or nasal abuse.
[0106] Suitable bitter substances and the quantities effective for
use may be found in US-2003/0064099 A1, the corresponding
disclosure of which should be deemed to be the disclosure of the
present application and is hereby introduced as a reference.
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.
[0107] The solid dosage form obtained according to the invention is
suitable not only for oral, but also for vaginal or rectal
administration, but is preferably for oral intake. The dosage form
is preferably not in film form. The dosage form according to the
invention may assume multiparticulate form, preferably cylindrical
form, the form of microtablets, microcapsules, micropellets,
granules, spheroids, beads or pellets, optionally packaged in
capsules or press-moulded into tablets, preferably for oral
administration. The muitiparticulate 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.
[0108] In a further preferred embodiment, the dosage form obtained
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.
[0109] If components (c) and/or (d) and/or (f) are present in the
dosage form obtained 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.
[0110] If the dosage form obtained 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 is exceeded in the event
of abuse, nausea or an inclination to vomit or a bad flavour 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.
[0111] If, however, irrespective of the fact that the further
dosage form produced according to the invention is virtually
impossible to pulverise, components (c) and/or (d) and/or (f) are
used to protect the dosage form, 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.
[0112] If the dosage form obtained 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).
[0113] 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 stated subunits is formulated in accordance with the
above-stated process according to the invention.
[0114] 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 produced 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.
[0115] 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
stated manner and produced according to the invention.
[0116] Should, contrary to expectations, the abuser succeed in
comminuting such a dosage form produced 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.
[0117] A dosage form 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 according to the invention in many different ways,
wherein the corresponding subunits in the dosage form may each be
present 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.
[0118] 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 produced 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 preferably included in the formulation and
formulation is carried out in accordance with the above-stated
process in order to achieve the necessary hardness.
[0119] In a preferred embodiment of the dosage form produced
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), for example 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.
[0120] The subunits (X) and (Y) in multiparticulate form may also
preferably be packaged in a capsule or be press-moulded 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.
[0121] 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, delayed
release of one or more active ingredients or provision of a finish
resistant to gastric juices on the particular subunits.
[0122] The multiparticulate subunits may also be formulated as an
oral dosage form as a slurry or suspension in pharmaceutically safe
suspending media.
[0123] In a further preferred embodiment of the present invention,
subunits (X) and (Y) are in each case arranged in layers relative
to one another.
[0124] The layered subunits (X) and (Y) are preferably arranged for
this purpose vertically or horizontally relative to one another in
the dosage form produced 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).
[0125] Another preferred dosage form produced 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.
[0126] In a further preferred embodiment of the dosage form
produced 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.
[0127] The dosage form produced 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).
[0128] If the dosage form produced 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 or a laminate.
[0129] 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 (a) and/or (e) and/or (d) and/or (f). The
barrier layer (Z') must also fulfil the hardness conditions
according to the invention.
[0130] Another particularly preferred embodiment of the dosage form
produced 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 the 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).
[0131] 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. No. 4,612,008, U.S.
Pat. No. 4,765,989 and U.S. Pat. No. 4,783,337. The corresponding
descriptions are hereby introduced as a reference and are deemed to
be part of the disclosure.
[0132] In a further preferred embodiment, the subunit (X) of the
dosage form produced according to the invention is in the form of a
tablet, the edge face and optionally one of the two main faces of
which is covered with a barrier layer (Z') containing component (c)
and/or (d) and/or (f).
[0133] 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 the formulation according to the invention of
the dosage form will vary as a function of the arrangement thereof
in the dosage form, 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 (0) 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.
[0134] If release of component (c) and/or (d) and/or (f) from
subunit (Y) of the dosage form produced 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 fulfil the hardness condition
and has been produced according to the invention.
[0135] 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.
[0136] The materials which are stated below to be suitable for
production of the barrier layer may preferably be used for this
purpose.
[0137] Preferred materials are those which are selected from the
group comprising alkylcelluloses, hydroxyalkylcelluloses, 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.), carboxymethylcelluloses, 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.
[0138] 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.
[0139] Particularly suitable copolymers may be selected from the
group comprising copolymers of butyl methacrytate and isobutyl
methacrylate, copolymers of methyl vinyl ether and maleic acid of
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.
[0140] Further materials which are particularly suitable for
formulating the barrier layer are starch-filled polycaprolactone
(WO98/20073), aliphatic polyesteramides (DE 19 753 534 Al, DE 19
800 698 Al, EP 0 820 698 Al), aliphatic and aromatic polyester
urethanes (DE 19822979), polyhydroxyalkanoates, in particular
polyhydroxybutyrates, polyhydroxyvalerates, casein (DE 4 309 528),
polylactides and copolylactides (EP 0 980 894 Al). The
corresponding descriptions are hereby introduced as a reference and
are deemed to be part of the disclosure.
[0141] The above-stated materials may 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, polyvinylpyrrolidone, 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.
[0142] If the dosage form produced 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.
[0143] The dosage form produced according to the invention exhibits
controlled release of the active ingredient. It is preferably
suitable for twice daily administration to patients.
[0144] The dosage form produced according to the invention may
comprise one or more active ingredients with potential for abuse at
least partially in a further delayed-release form, wherein delayed
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 delayed-release
matrix or by the application of one or more delayed-release
coatings. Active ingredient release 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.
[0145] Controlled release from the dosage form obtained 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.
[0146] 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.
[0147] 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.
[0148] It is also possible to use mixtures of the above-stated
hydrophilic and hydrophobic materials as matrix materials.
[0149] 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
themselves serve as additional matrix materials.
[0150] If the dosage form produced 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
produced 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.
[0151] Corresponding materials and methods for the delayed release
of active ingredients and for the application of coatings which are
resistant to gastric juices are known to the person skilled in the
art, for example from "Coated Pharmaceutical Dosage
Forms--Fundamentals, Manufacturing Techniques, Biopharmaceutical
Aspects, Test Methods and Raw Materials" by Kurt H. Bauer, K.
Lehmann, Hermann P. Osterwald, Rothgang, Gerhart, 1st edition,
1998, Medpharm Scientific Publishers. The corresponding literature
description is hereby introduced as a reference and is deemed to be
part of the disclosure.
Method for Determining Breaking Strength
[0152] In order to verify whether a material may be used as
component (C) or (D), the material is dissolved in a tablet mould
with the assistance of a solvent for component (C) or (D) and, once
the solvent has been removed at temperatures below the softening
point of the material, is pressed to form a tablet with a diameter
of 10 mm and a height of 5 mm using a force of 150 N.
[0153] 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 Frrrax=1.45 kN)
(all apparatus from Zwick GmbH & Co. KG, Ulm, Germany) with
order no. BTC-FR 2.5 TH. D09 for the tester, order no. BTC-LC
0050N. P01 for the force transducer, order no. BO 70000 S06 for the
centring device.
BRIEF DESCRIPTION OF THE DRAWING
[0154] FIG. 1 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.
[0155] 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.
[0156] The breaking strength of the dosage forms obtained according
to the invention is determined by the stated measurement method for
determining breaking strength, with dosage forms other than tablets
also being tested.
[0157] The invention is explained below with reference to Examples.
These explanations are given merely by way of example and do not
restrict the general concept of the invention.
EXAMPLES
Example 1
TABLE-US-00001 [0158] Per tablet Complete batch Tramadol HCl 100.0
mg 1495.0 g Polyethylene oxide, 167.8 mg 2508.6 g MW 7 000 000
Hydroxypropylmethylcellulose 33.5 mg 500.8 g (Hypromellose 100 000
mPa) Butyihydroxytoluene (BHT) 0.2 mg 3.0 g Total mass 300.5 mg
4507.4 g
[0159] 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.
[0160] All the further components were added and mixed for 15 min
in a free-fall mixer. The powder mixture was divided between
moulds, each having a diameter of 13 mm and a depth of 6 mm. Using
a syringe with cannula, the mixture was suspended in each case in
0.5 ml of 96% ethanol and then in each case combined with 0.5 ml of
distilled water After 24 hours swelling time, the swollen
composition was dried for 24 h at 40.degree. C.
[0161] The divided up, dried portions were each press-moulded into
tablets using a model EK 0 eccentric press. The tabletting tool had
a diameter of 10 mm and a radius of curvature of 8 mm.
[0162] The breaking strength of the tablets was determined using
the above-described method. No breakage occurred when a force of
500 N was applied. The tablets could not be comminuted using a
hammer, nor with the assistance of a pestle and mortar.
[0163] In vitro release of the active ingredient from the tablets
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. The release medium used was 600 ml of intestinal juice,
pH 6.8. The quantity of active ingredient released in each case
into the dissolution medium at any one time was determined by
spectrophotometry.
TABLE-US-00002 Time Quantity of active ingredient released 30 min
20% 240 min 43% 480 min 83% 720 min 90%
Example 2
TABLE-US-00003 [0164] Powder mixture Complete batch Per tablet
Tramadol HCl 100.1 g 100 mg Polyethylene oxide 300.0 g 299.7 mg MW
5000 000 (Polyox WSR Coagulant, from Dow),
Hydroxypropylmethylcellulose 50.05 g 50.0 mg (Hypromellose 100 000
mPa) Butylhydroxytoluene (BHT) 0.25 g 0.25 mg Foam 0.250 g 0.25 mg
Hydroxypropylmethylcellulose (Hypromellose 100 000 mPa) Dist. water
49.8 g
[0165] The powder mixture was first produced as stated in Example
1.
[0166] The foam was produced by dissolving the stated quantity of
Hypromellose in distilled water. A foam was then produced using a
high performance homogeniser (IKA Ultraturrax 25 Basic) by stirring
initially for 2 minutes at level 1, then for 2 minutes with a
mixer/granulator at level 2 and finally for 3 minutes at level 3.
The powder mixture was slowly added to the foam with constant
stirring in a mixer (Kenwood Major Classic 25 Basic).
[0167] The granulated mixture was then dried for 24 hours--at
40.degree. C. and, after being passed through a screen (from
Frewitt, model GLA-A-ORV) with 1 mm orifices, was press-moulded
into tablets with a weight of 450.2 mg. A model EK 0 eccentric
press with a round tabletting tool having a diameter of 10 mm and a
radius of curvature of 8 mm was used for this purpose. These
tablets were dried for 1 hour at 70.degree. C.
[0168] The breaking strength of the tablets was determined using
the above-stated method. No breakage occurred when a force of 500 N
was applied. The tablet could not be comminuted using a hammer, nor
with the assistance of a pestle and mortar.
[0169] In vitro release of the active ingredient from the tablets
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. The release medium used was 600 ml of intestinal juice,
pH 6.8. The quantity of active ingredient released in each case
into the dissolution medium at any one time was determined by
spectrophotometry.
TABLE-US-00004 Time Quantity-of active ingredient released 30 min
12% 240 min 47% 480 min 71% 720 min 84%
* * * * *