U.S. patent application number 16/145936 was filed with the patent office on 2019-01-31 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 ARKENAU-MARIĆ, Johannes BARTHOLOMAUS, Heinrich KUGELMANN.
Application Number | 20190029976 16/145936 |
Document ID | / |
Family ID | 34112032 |
Filed Date | 2019-01-31 |
United States Patent
Application |
20190029976 |
Kind Code |
A1 |
BARTHOLOMAUS; Johannes ; et
al. |
January 31, 2019 |
ABUSE-PROOFED DOSAGE FORM
Abstract
The present invention relates to an abuse-proofed, thermoformed
dosage form containing, in addition to one or more active
ingredients with abuse potential optionally together with
physiologically acceptable auxiliary substances, at least one
synthetic or natural polymer with a breaking strength of at least
500 N and to a process for the production thereof.
Inventors: |
BARTHOLOMAUS; Johannes;
(Aachen, DE) ; KUGELMANN; Heinrich; (Aachen,
DE) ; ARKENAU-MARIĆ; Elisabeth; (Koln, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRUNENTHAL GMBH |
Aachen |
|
DE |
|
|
Assignee: |
GRUNENTHAL GMBH
Aachen
DE
|
Family ID: |
34112032 |
Appl. No.: |
16/145936 |
Filed: |
September 28, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15265263 |
Sep 14, 2016 |
10130591 |
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16145936 |
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14945598 |
Nov 19, 2015 |
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15265263 |
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14138323 |
Dec 23, 2013 |
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14945598 |
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13517891 |
Jun 14, 2012 |
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14138323 |
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13346257 |
Jan 9, 2012 |
8309060 |
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13517891 |
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10718112 |
Nov 20, 2003 |
8114383 |
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13346257 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/00 20180101;
A61K 31/485 20130101; A61P 25/30 20180101; A61K 9/205 20130101;
A61K 9/0053 20130101; A61P 25/22 20180101; A61K 9/2013 20130101;
A61K 9/2095 20130101; A61K 9/2027 20130101; A61K 9/2068 20130101;
A61K 9/2031 20130101; A61P 25/04 20180101; A61K 31/5513 20130101;
A61K 9/2054 20130101; A61K 31/515 20130101; A61K 47/10 20130101;
A61K 9/20 20130101; A61K 31/135 20130101 |
International
Class: |
A61K 31/135 20060101
A61K031/135; A61K 47/10 20170101 A61K047/10; A61K 31/5513 20060101
A61K031/5513; A61K 31/515 20060101 A61K031/515; A61K 31/485
20060101 A61K031/485; A61K 9/20 20060101 A61K009/20 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 6, 2003 |
DE |
103 36 400.5 |
Claims
1. An abuse-proofed, thermoformed dosage form comprising 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 component (C) exhibits a breaking
strength of at least 500 N.
2. A dosage form according to claim 1, which is in the form of a
tablet.
3. A dosage form according to claim 1, which is in multiparticulate
form.
4. A dosage form according to claim 1, wherein the polymer (C) is
at least one polymer selected from the group consisting of
polyethylene oxide, polymethylene oxide, polypropylene oxide,
polyethylene, polypropylene, polyvinyl chloride, polycarbonate,
polystyrene, polyacrylate, copolymers and mixtures thereof.
5. A dosage form according to claim 1, wherein the polymer (C) has
a molecular weight of at least 0.5 million according to rheological
measurements.
6. A dosage form according to claim 5, wherein the molecular weight
is 1-15 million.
7. A dosage form according to claim 1, which comprises 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.
8. A dosage form according to claim 7, wherein the wax (D) is
carnauba wax or beeswax.
9. A dosage form according to claim 1, wherein the component(s) (C)
is/are present in quantities such that the dosage form has a
breaking strength of at least 500 N.
10. A dosage form according to claim 1, wherein the active
ingredient (A) is at least one active ingredient selected from the
group consisting of opiates, opioids, tranquillisers, stimulants,
barbiturates and further narcotics.
11. A dosage form according to claim 1, which additionally
comprises at least one of the following components a)-f): (a) at
least one substance which irritates the nasal passages and/or
pharynx, (b) 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 optionally remains visually distinguishable when
introduced into a further quantity of an aqueous liquid, (c) at
least one antagonist for the active ingredient or active
ingredients with abuse potential, (d) at least one emetic, (e) at
least one dye as an aversive agent, (f) at least one bitter
substance.
12. A dosage form according to claim 11, wherein the component (a)
irritant substance causes burning, itching, an urge to sneeze,
increased formation of secretions or a combination of at least two
of these stimuli.
13. A dosage form according to claim 12, wherein the component (a)
irritant substance is based on one or more constituents of at least
one hot substance drug.
14. A dosage form according to claim 13, wherein the hot substance
drug is at least one 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
(erucae/white mustard seed), Sinapis nigri semen (black mustard
seed), Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma
(ginger root).
15. A dosage form according to claim 13, wherein the constituent of
the hot substance drug is an o-methoxy(methyl)phenol compound, an
acid amide compound, a mustard oil or a sulfide compound or is
derived from such a compound.
16. A dosage form according to claim 13, wherein the constituent of
the hot substance drug is at least one constituent selected from
the group consisting of myristicin, elemicin, isoeugenol,
.beta.-asarone, safrole, gingerols, xanthorrhizol, capsaicinoids,
piperine, glucosinolates, and a compound derived from these
constituents.
17. A dosage form according to claim 11, wherein component (b) is
at least one viscosity-increasing agent selected from the group
consisting of 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, Carbopol.RTM. 981), locust bean flour
(Cesagum.RTM. LA-200, Cesagum.RTM. LID/150, Cesagum.RTM. LN-1),
citrus pectin (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 carrageen (Frimulsion D021.RTM.), karaya gum,
gellan gum (Kelcogel F.RTM., Kelcogel LT100.RTM.), galactomannan
(Meyprogat 150.RTM.), tara bean flour (Polygum 43/1C)), propylene
glycol alginate (Protanal-Ester SD-LB.RTM.), sodium hyaluronate,
apple pectin, pectin from lemon peel, sodium hyaluronate,
tragacanth, tara gum (Vidogum SP 200.RTM.)), fermented
polysaccharide welan gum (K1A96) and xanthan gum (Xantural
180.RTM.).
18. A dosage form according to claim 11, wherein component (c) is
at least one opiate or opioid antagonist selected from the group
consisting of naloxone, naltrexone, nalmefene, nalid, nalmexone,
nalorphine, naluphine and a corresponding physiologically
acceptable compound.
19. A dosage form according to claim 11, wherein the component (c)
is at least one neuroleptic stimulant antagonist.
20. A dosage form according to claim 11, wherein the component (d)
emetic is based on one or more constituents of radix ipecacuanha
(ipecac root) and/or is apomorphine.
21. A dosage form according to claim 11, wherein component (e) is
at least one physiologically acceptable dye.
22. A dosage form according to claim 11, wherein component (f) is
at least one bitter substance selected from the group consisting of
aromatic oils, fruit aroma substances, denatonium benzoate and
mixtures thereof.
23. A dosage form according to claim 11, wherein the active
ingredient or active ingredients (A) is/are spatially separated
from component (c) and/or (d) and/or (f), wherein the active
ingredient or active ingredients (A) is/are optionally 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, when the dosage
form is correctly administered, components (c) and/or (d) and/or
(f) from subunit (Y) do not exert their effect in the body and/or
on taking.
24. A dosage form according to claim 1, which comprises at least
one active ingredient at least partially in controlled release
form.
25. A dosage form according to claim 24, wherein each of the active
ingredients with abuse potential (A) is present in a controlled
release matrix.
26. A dosage form according to claim 25, wherein component (C)
and/or component (D) also serve as a controlled release matrix
material.
27. A process for the production of a dosage form according to
claim 1, comprising: mixing components (A), (B), (C) and the
optionally present component (D) and the optionally present
components (a) to (f) to form a resultant mixture, and
press-forming the resultant mixture, optionally after granulation,
to yield the dosage form with preceding, simultaneous, or
subsequent exposure to heat.
28. A process according to claim 27, wherein granulation is
performed by means of a melt process.
29. A process according to claim 27, which comprises press-forming
the resultant mixture to yield a press-formed product, and exposing
the press-formed product to heat to yield the dosage form.
30. A dosage form obtainable by a process according to claim
27.
31. A dosage form obtainable by a process according to claim
29.
32. A method of treating a therapeutic condition in a patient
suffering therefrom, said method comprising administering to said
patient a dosage form according to claim 1.
33. A method according to claim 32, wherein the therapeutic
condition is pain.
34. A method of treating a therapeutic condition in a patient
suffering therefrom, said method comprising administering to said
patient a dosage form according to claim 30.
35. A method according to claim 34, wherein the therapeutic
condition is pain.
36. The dosage form according to claim 1, wherein the content of
component (C) is at least 60 wt. %, relative to the total weight of
the dosage form.
37. The dosage form according to claim 5, wherein the content of
component (C) is at least 60 wt. %, relative to the total weight of
the dosage form.
38. The dosage form according to claim 10, which comprises an
opioid, wherein the opioid is selected from the group consisting of
hydromorphone, morphine, oxycodone, oxymorphone, tramadol,
(1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, and
the physiologically acceptable salts thereof.
39. The dosage form according to claim 1, wherein the one or more
active ingredients with abuse potential (A) comprise oxycodone or a
physiologically acceptable salt thereof; wherein the at least one
synthetic or natural polymer (C) comprises a polyethylene oxide
having a molecular weight of 1-15 million according to rheological
measurements; and wherein the content of said polyethylene oxide is
at least 60 wt. %, relative to the total weight of the dosage
form.
40. The dosage form according to claim 1, which additionally
comprises at least one physiologically acceptable auxiliary
substance (B).
41. The dosage form according to claim 1, which additionally
comprises at least one wax (D).
42. The dosage form according to claim 1, which additionally
comprises at least one physiologically acceptable auxiliary
substance (B) and at least one wax (D).
43. The dosage form according to claim 1, wherein the at least one
synthetic or natural polymer (C) comprises a polyethylene oxide
having a molecular weight of at least 0.5 million according to
rheological measurements.
44. The dosage form according to claim 43, wherein the polyethylene
oxide has a molecular weight of 0.5-15 million according to
rheological measurements.
45. The dosage form according to claim 44, wherein the polyethylene
oxide has a molecular weight of at least 600,000 according to
rheological measurements.
46. The dosage form according to claim 45, wherein the polyethylene
oxide has a viscosity at 25.degree. C. measured on a 5 wt. %
aqueous solution using a model RVF Brookfield viscosimeter (spindle
no. 2/rotational speed 2 rpm) of 4500 to 17600 cP.
47. The dosage form according to claim 44, wherein the polyethylene
oxide has a molecular weight of at least 1,000,000 according to
rheological measurements.
48. The dosage form according to claim 47, wherein the polyethylene
oxide has a viscosity at 25.degree. C. measured on a 2 wt. %
aqueous solution using a model RVF Brookfield viscosimeter (spindle
no. 1 or 3/rotational speed 10 rpm) of 400 to 4000 cP.
49. The dosage form according to claim 44, wherein the polyethylene
oxide has a molecular weight of at least 4,000,000 according to
rheological measurements.
50. The dosage form according to claim 49, wherein the polyethylene
oxide has a viscosity at 25.degree. C. measured on a 1 wt. %
aqueous solution using a model RVF Brookfield viscosimeter (spindle
no. 2/rotational speed 2 rpm) of 1650 to 10000 cP.
51. 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
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/265,263, filed Sep. 14, 2016, now pending,
which is a continuation of U.S. patent application Ser. No.
14/945,598, filed Nov. 19, 2015, now abandoned, which is a
continuation of U.S. patent application Ser. No. 14/138,323, filed
Dec. 23, 2013, now abandoned, which is a continuation of U.S.
patent application Ser. No. 13/517,891, filed Jun. 14, 2012, now
abandoned, which is, in turn, a divisional of U.S. patent
application Ser. No. 13/346,257, filed Jan. 9, 2012, now U.S. Pat.
No. 8,309,060, which is, in turn, a divisional of U.S. patent
application Ser. No. 10/718,112, filed Nov. 20, 2003, now U.S. Pat.
No. 8,114,383, which claims priority of German Application No. 103
36 400.5, filed Aug. 6, 2003.
[0002] The present invention relates to an abuse-proofed,
thermoformed dosage form 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 component (C) exhibits a breaking strength 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 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. 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 colour
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 opiates, or compounds
which cause a physiological defence response, such as for example
Radix ipecacuanha=ipecac root.
[0009] However, since in most cases of abuse it is still necessary
to pulverise the dosage form comprising an active ingredient
suitable for abuse, it was the object of the present invention to
complicate or prevent the pulverisation preceding abuse of the
dosage form comprising the agents conventionally available for
potential abuse and accordingly to provide a dosage form for active
ingredients with abuse potential 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 pulverisation.
[0010] Said object has been achieved by the provision of the
abuse-proofed, thermoformed dosage form 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)
and optionally at least one wax (D), wherein component (C) exhibits
a breaking strength of at least 500 N.
[0011] The use of polymers having the stated minimum breaking
strength, preferably in quantities such that the dosage form also
exhibits such a minimum breaking strength, means that pulverisation
of the dosage form is considerably more difficult using
conventional means, so considerably complicating or preventing the
subsequent abuse.
[0012] 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 spontaneous.
[0013] According to the invention, comminution is taken to mean
pulverisation 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 pulverisation by
application of force.
[0014] The dosage form according to the invention is thus suitable
for preventing parenteral, nasal and/or oral abuse of
pharmaceutical active ingredients with abuse potential.
[0015] 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 several active ingredients. It
is preferably used to administer a specific active ingredient.
[0016] 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 opiates, opioids,
tranquillisers, preferably benzodiazepines, barbiturates,
stimulants and other narcotics.
[0017] The dosage form according to the invention is very
particularly suitable for preventing abuse of an opiate, opioid,
tranquilliser 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, alphaprodine,
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-4,5.alpha.-epoxy-7.alpha.[(S)-1-hydroxy-1,2,2-trimet-
hyl-propyl]-6-methoxy-6,14-endo-ethanomorphinane-3-ol
(buprenorphine), 5-butyl-5-ethylbarbituric acid (butobarbital),
butorphanol,
(7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine-3-yl)-
-dimethylcarbamate (camazepam), (1S,2S)-2-amino-1-phenyl-1-propanol
(cathine/D-norpseudoephedrine),
7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepine-2-ylamine-4-oxide
(chlorodiazepoxide),
7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione
(clobazam),
5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepine-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]diazepine-2(3H)--
one (clotiazepam),
10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]ben-
zodiazepine-6(5H)-one (cloxazolam),
(-)-methyl-[3.beta.-benzoyloxy-2.beta.(1.alpha.H,5.alpha.H)-tropancarboxy-
late] (cocaine),
4,5.alpha.-epoxy-3-methoxy-17-methyl-7-morphinene-6.alpha.-ol
(codeine), 5-(1-cyclohexenyl)-5-ethylbarbituric acid
(cyclobarbital), cyclorphan, cyprenorphine,
7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepine-2(3H)-one
(delorazepam), desomorphine, dextromoramide,
(+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate
(dextropropoxyphen), dezocine, diampromide, diamorphone,
7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one
(diazepam),
4,5.alpha.-epoxy-3-methoxy-17-methyl-6.alpha.-morphinanol
(dihydrocodeine), 4,5.alpha.-epoxy-17-methyl-3,6a-morphinandiol
(dihydromorphine), dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone,
(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chro-
mene-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-morphinene-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-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-benzodiazepine-2(3H)-one
(fludiazepam),
5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepine-2(3H)-one
(flunitrazepam),
7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-
-2(3H)-one (flurazepam),
7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepine-2(3H)-on-
e (halazepam),
10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolyl[3,2-d][1,-
4]benzodiazepine-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-8,12b-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]-benzodiazepine-1(4H)-one (loprazolam),
7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepine-2(3H)-one
(lorazepam),
7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepine-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-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-morphines-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]pyrane-9(6.alpha.H)-one (nabilone),
nalbuphine, nalorphine, narceine, nicomorphine,
1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one
(nimetazepam), 7-nitro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one
(nitrazepam), 7-chloro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one
(nordazepam), norlevorphanol,
6-dimethylamino-4,4-diphenyl-3-hexanone (normethadone),
normorphine, norpipanone, the exudation of plants belonging to the
species Papaver somniferum (opium),
7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one
(oxazepam),
(cis-trans)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-
-d][1,4]benzodiazepine-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-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-benzodiazepine-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-benzodiazepine-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
(secobarbital),
N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}-propionanilide
(sufentanil),
7-chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one
(temazepam),
7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepine-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]benzod-
iazepine (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,
(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,
(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,
(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-d-
iol, 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-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 for
corresponding stereoisomeric compounds, the corresponding
derivatives thereof in each case, in particular esters or ethers,
and the physiologically acceptable compounds thereof in each case,
in particular the salts and solvates thereof.
[0018] The compounds
(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 or the stereoisomeric compounds thereof or the
physiologically acceptable compounds thereof, in particular the
hydrochlorides thereof, the derivatives thereof, such as esters or
ethers, and processes for the production thereof are known, for
example, from EP-A-693475 or EP-A-780369. The corresponding
descriptions are hereby introduced as a reference and are deemed to
be part of the disclosure.
[0019] 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 which has a breaking strength, measured
using the method disclosed in the present application, of at least
500 N. At least one polymer selected from the group consisting of
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. The polymers are distinguished by a molecular weight of at
least 0.5 million, determined by rheological measurements.
Thermoplastic polyalkylene oxides, such as polyethylene oxides,
with a molecular weight of at least 0.5 million, preferably of up
to 15 million, determined by rheological measurements, are very
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).
[0020] The polymers are used in powder form.
[0021] 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) 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. 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 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.
[0022] The dosage forms according to the invention are
distinguished in that, due their hardness, they cannot be
pulverised, for example by grinding in a mortar. This virtually
rules out oral or parenteral, in particular intravenous or nasal
abuse. However, in order to prevent any possible abuse in the event
of comminution and/or pulverisation of the dosage form according to
the invention which has nevertheless been achieved by application
of extreme force, the dosage forms according to the invention may,
in a preferred embodiment, contain further agents which complicate
or prevent abuse as auxiliary substances (B).
[0023] 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)-(f) as auxiliary substances (B):
[0024] (a) at least one substance which irritates the nasal
passages and/or pharynx, [0025] (b) 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, [0026] (c) at least one antagonist
for each of the active ingredients with abuse potential, [0027] (d)
at least one emetic, [0028] (e) at least one dye as an aversive
agent, [0029] (f) at least one bitter substance.
[0030] 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.
[0031] 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).
[0032] In another embodiment, the dosage form according to the
invention may comprise all of components (a)-(f).
[0033] 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.
[0034] 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 skilled person or may be identified by simple
preliminary testing.
[0035] 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.
[0036] 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.
[0037] 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 dosage
unit.
[0038] 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.
[0039] A dosage unit is taken to mean a separate or separable
administration unit, such as for example a tablet or a capsule.
[0040] 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
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.
[0041] 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.
[0042] Particularly preferably, at least one constituent of the hot
substance drugs is selected from the group consisting of
myristicin, elemicin, isoeugenol, .beta.-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.
[0043] 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.
[0044] 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.
[0045] 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 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.
[0046] Intravenous administration of such a gel would most probably
result in obstruction of blood vessels, associated with serious
embolism or even death of the abuser.
[0047] 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.
[0048] 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 consisting of 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, Carbopol.RTM. 981), locust bean flour
(Cesagum.RTM. LA-200, Cesagum.RTM. LID/150, Cesagum.RTM. LN-1),
pectins such as citrus pectin (Cesapectin.RTM. HM Medium Rapid
Set), apple pectin, pectin from lemon peel, waxy maize starch
(C*Gel 04201.RTM.), sodium alginate (Frimulsion ALG (E401).RTM.),
guar flour (Frimulsion BM.RTM., Polygum 26/1-75.RTM.), iota
carrageen (Frimulsion D021.RTM.), karaya gum, gellan gum (Kelcogel
F.RTM., Kelcogel LT100.RTM.), galactomannan (Meyprogat 150.RTM.),
tara bean flour (Polygum 43/1.RTM.), propylene glycol alginate
(Protanal-Ester SD-LB.RTM.), sodium hyaluronate, tragacanth, tara
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 5 wt. % of the viscosity-increasing agent(s) is
sufficient to fulfil the above-stated conditions.
[0049] The component (b) viscosity-increasing agents, where
provided, are preferably present in the dosage form according to
the invention in quantities of 5 mg per dosage unit, i.e. per
administration unit.
[0050] 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] If the active ingredient present in the dosage form is an
opiate or an opioid, the antagonist used is preferably an
antagonist selected from the group consisting of 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.10 mg, particularly preferably in a quantity of 10 to 100
mg, very particularly preferably in a quantity of 10 to 50 mg per
dosage form, i.e. per administration unit.
[0055] 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, zotepine, benperidol, pipamperone, melperone and
bromperidol.
[0056] 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.
[0057] 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.
[0058] 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.
[0059] An emetic based on one or more constituents of radix
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 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.
[0060] The dosage form according to the invention may preferably
comprise the emetic emetine as component (d), preferably in a
quantity of .gtoreq.10 mg, particularly preferably of .gtoreq.20 mg
and very particularly preferably in a quantity of .gtoreq.40 mg per
dosage form, i.e. administration unit.
[0061] 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.
[0062] 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,
wherein the corresponding disclosure should be deemed to be part of
the present disclosure and is hereby introduced as a reference.
[0063] 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 flavour of the dosage form additionally prevents
oral and/or nasal abuse.
[0064] 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.
[0065] The solid dosage form according to the invention is suitable
to be taken orally or rectally, preferably orally. The orally
administrable 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. 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.
[0066] The solid, abuse-proofed dosage form according to the
invention is preferably produced by mixing the components (A), (B),
(C) and/optionally (D) and at least one of the optionally present
further abuse-preventing components (a)-(f) and, optionally after
granulation, press-forming the resultant mixture to yield the
dosage form with preceding, simultaneous, or subsequent exposure to
heat.
[0067] Mixing of components (A), (B), (C) and optionally (D) and of
the optionally present further components (a)-(f) proceeds 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.
[0068] The resultant mixture is preferably formed directly by
application of pressure to yield the dosage form according to the
invention with preceding, simultaneous or subsequent exposure to
heat. The mixture may, for example, be formed into tablets by
direct tabletting. In direct tabletting with simultaneous exposure
to heat, the tabletting tool, i.e. bottom punch, top punch and die
are briefly heated at least to the softening temperature of the
polymer (C) and pressed together. In direct tabletting with
subsequent exposure to heat, the formed tablets are briefly heated
at least to the softening temperature (glass transition
temperature, melting temperature; sintering temperature) of
component (C) and cooled again. In direct tabletting with preceding
exposure to heat, the material to be pressed is heated immediately
prior to tabletting at least to the softening temperature of
component (C) and then pressed.
[0069] The resultant mixture of components (A), (B), (C) and
optionally (D) and the optionally present components (a) to (f) may
also first be granulated and then be formed with preceding,
simultaneous, or subsequent exposure to heat to yield the dosage
form according to the invention.
[0070] 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.
[0071] 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.
[0072] 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
inadvertently, in particular by children, or 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.
[0073] If, however, irrespective of the fact that the dosage form
according to the invention is virtually impossible to pulverise,
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), are identical.
[0074] 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).
[0075] 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
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
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.
[0076] 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, 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.
[0077] 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 has been formulated in the stated manner.
[0078] 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.
[0079] 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.
[0080] 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) is included in the
formulation and formulation is carried out in accordance with the
above-stated process.
[0081] 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.
[0082] 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.
[0083] 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.
[0084] In a further preferred embodiment of the present invention,
subunits (X) and (Y) are in each case arranged in layers relative
to one another.
[0085] 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).
[0086] 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.
[0087] 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).
[0088] 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.
[0089] 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 fulfil the hardness conditions
according to the invention.
[0090] 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).
[0091] 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.
[0092] 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).
[0093] 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.
[0094] 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) to fulfil the hardness condition of the dosage form
according to the invention.
[0095] 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. The materials for the separation layer and/or
barrier layer must contain at least one polymer (C) in order to
fulfil the hardness conditions.
[0096] Preferred materials are those which are selected from the
group consisting of 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.
[0097] Particularly suitable materials may be selected from the
group consisting of 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.
[0098] Particularly suitable copolymers may be selected from the
group consisting of 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.
[0099] 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
corresponding descriptions are hereby introduced as a reference and
are deemed to be part of the disclosure.
[0100] 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 consisting
of 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.
[0101] 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.
[0102] 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 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.
[0103] 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.
[0104] 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.
[0105] 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.
[0106] It is also possible to use mixtures of the above-stated
hydrophilic and hydrophobic materials as matrix materials.
[0107] 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.
[0108] 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.
[0109] 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 corresponding literature
description is hereby introduced as a reference and is deemed to be
part of the disclosure.
Method for Determining Breaking Strength
[0110] A) In order to verify whether a polymer may be used as
component (C), 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
series 3300 universal tester, single column benchtop model no. 3345
from Instron.RTM., Canton, Mass., USA. The clamping tool used is a
pressure piston with a diameter of 25 mm, which can be subjected to
a load of up to 1 kN (item no. 2501-3 from Instron.RTM.). An
Instron.RTM. universal tester, single column benchtop model no.
5543, with the above-stated clamping tool may also be used to carry
out the measurement. 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. Providing that the dosage form is in
tablet form, breaking strength may be determined using the same
measurement method.
[0111] The following Examples illustrate the invention purely by
way of example and without restricting the general concept of the
invention.
EXAMPLES
[0112] Tramadol hydrochloride was used as the active ingredient in
a series of Examples. Tramadol hydrochloride was used, despite
tramadol not being an active ingredient which conventionally has
abuse potential, because it is not governed by German narcotics
legislation, so simplifying the experimental work. Tramadol is
moreover a member of the opioid class with excellent water
solubility.
Example 1
TABLE-US-00001 [0113] Components Per tablet Complete batch Tramadol
hydrochloride 100 mg 100 g Polyethylene oxide, NF, MFI 200 mg 200 g
(190.degree. C. at 21.6 kg/10 min) <0.5 g MW 7 000 000 (Polyox
WSR 303, Dow Chemicals) Total weight 300 mg 300 g
[0114] Tramadol hydrochloride and polyethylene oxide powder were
mixed in a free-fall mixer. A tabletting tool with top punch,
bottom punch and die for tablets with a diameter of 10 mm and a
radius of curvature of 8 mm was heated to 80.degree. C. in a
heating cabinet. 300 mg portions of the powder mixture were pressed
with the heated tool, wherein pressure was maintained for at least
15 seconds by clamping the tabletting tool in a vice.
[0115] The breaking strength of the tablets was determined with the
stated apparatus in accordance with the stated method. The tablets
did not break when exposed to a force of 500 N.
[0116] The tablet could not be comminuted using a hammer, nor with
the assistance of a mortar and pestle.
[0117] In vitro release of the active ingredient from the
preparation was determined in a paddle stirrer apparatus 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. At the beginning of the investigation, each tablet was
placed in a 600 ml portion of artificial gastric juice, pH 1.2.
After 30 minutes, the pH value was increased to 2.3 by addition of
alkali solution, after a further 90 minutes to pH 6.5 and after a
further 60 minutes to pH 7.2. The released quantity of active
ingredient present in the dissolution medium at each point in time
was determined by spectrophotometry.
TABLE-US-00002 Time Released quantity 30 min 15% 240 min 52% 480
min 80% 720 min 99%
Example 2
[0118] 300 mg portions of the powder mixture from Example 1 were
heated to 80.degree. C. and in placed in the die of the tabletting
tool. Pressing was then performed. The tablet exhibits the same
properties such as the tablet in Example 1.
Example 3
TABLE-US-00003 [0119] Raw material Per tablet Complete batch
Tramadol hydrochloride 50 mg 100 g Polyethylene oxide, NF, 100 mg
200 g MW 7 000 000 (Polyox WSR 303, Dow Chemicals) Total weight 150
mg 300 g
[0120] Tramadol hydrochloride and the above-stated components were
mixed in a free-fall mixer. A tabletting tool with top punch,
bottom punch and die for tablets with a diameter of 7 mm was heated
to 80.degree. C. in a heating cabinet. 150 mg portions of the
powder mixture were pressed with the heated tool, wherein pressure
was maintained for at least 15 seconds by clamping the tabletting
tool in a vice.
[0121] The breaking strength of the tablets was determined with the
stated apparatus in accordance with the stated method. The tablets
did not break when exposed to a force of 500 N.
[0122] In vitro release of the active ingredient was determined as
in Example 1 and was:
TABLE-US-00004 Time Released quantity 30 min 15% 240 min 62% 480
min 88% 720 min 99%
Example 4
TABLE-US-00005 [0123] Raw material Per tablet Complete batch
Tramadol hydrochloride 100 mg 100 g Polyethylene oxide, NF, 180 mg
180 g MW 7 000 000 (Polyox WSR 303, Dow Chemicals) Xanthan, NF 20
mg 20 g Total weight 300 mg 300 g
[0124] Tramadol hydrochloride, xanthan and polyethylene oxide were
mixed in a free-fall mixer. A tabletting tool with top punch,
bottom punch and die for tablets with a diameter of 10 mm and a
radius of curvature of 8 mm was heated to 80.degree. C. in a
heating cabinet. 300 mg portions of the powder mixture were pressed
with the heated tool, wherein pressure was maintained for at least
15 seconds by clamping the tabletting tool in a vice.
[0125] The breaking strength of the tablets was determined with the
stated apparatus in accordance with the stated method. The tablets
did not break when exposed to a force of 500 N. The tablets did
suffer a little plastic deformation.
[0126] In vitro release of the active ingredient was determined as
in Example 1 and was:
TABLE-US-00006 Time Released quantity 30 min 14% 240 min 54% 480
min 81% 720 min 99%
[0127] The tablets could be cut up with a knife into pieces of an
edge length of as small as approx. 2 mm. No further comminution
proceeding as far as pulverisation was possible. When the pieces
are combined with water, a highly viscous gel is formed. Only with
great difficulty could the gel be pressed through a 0.9 mm
injection cannula. When the gel was injected into water, the gel
did not spontaneously mix with water, but remained visually
distinguishable.
Example 5
TABLE-US-00007 [0128] Raw material Per tablet Complete batch
Tramadol hydrochloride 50 mg 100 g Polyethylene oxide, NF, 90 mg
180 g MW 7 000 000 (Polyox WSR 303, Dow Chemicals) Xanthan, NF 10
mg 20 g Total weight 300 mg 300 g
[0129] Tramadol hydrochloride, xanthan and polyethylene oxide were
mixed in a free-fall mixer. A tabletting tool with a top punch,
bottom punch and die for oblong tablets 10 mm in length and 5 mm in
width was heated to 90.degree. C. in a heating cabinet. 150 mg
portions of the powder mixture were pressed with the heated tool,
wherein pressure was maintained for at least 15 seconds by clamping
the tabletting tool in a vice.
[0130] The breaking strength of the tablets was determined with the
stated apparatus in accordance with the stated method. The tablets
did not break when exposed to a force of 500 N. The tablets did
suffer a little plastic deformation.
[0131] In vitro release of the active ingredient was determined as
in Example 1 and was:
TABLE-US-00008 Time Released quantity 30 min 22% 120 min 50% 240
min 80% 360 min 90% 480 min 99%
[0132] The tablets could be cut up into pieces of an edge length of
as small as approx. 2 mm, but could not be pulverised. When the
pieces are combined with water, a highly viscous gel is formed.
Only with great difficulty could the gel be pressed through a 0.9
mm injection cannula. When the gel was injected into water, the gel
did not spontaneously mix with water, but remained visually
distinguishable.
Example 6
[0133] A tablet with the following composition was produced as
described in Example 1:
TABLE-US-00009 Components Per tablet Per batch Oxycodone
hydrochloride 20.0 mg 0.240 g Xanthan, NF 20.0 mg 0.240 g
Polyethylene oxide, NF, MFI 110.0 mg 1.320 g (190.degree. C. at
21.6 kg/10 min) <0.5 g MW 7 000 000 (Polyox WSR 303, Dow
Chemicals) Total weight 150.0 mg 1.800 g
[0134] Release of the active ingredient was determined as
follows:
[0135] In vitro release of the active ingredient from the
preparation was determined in a paddle stirrer apparatus in
accordance with Pharm. Eur. The temperature of the release medium
was 37.degree. C. and the rotational speed 75 rpm. The phosphate
buffer, pH 6.8, described in DSP served as the release medium. The
quantity of active ingredient present in the solvent at the
particular time of testing was determined by spectrophotometry.
TABLE-US-00010 Time Mean 0 min 0% 30 min 17% 240 min 61% 480 min
90% 720 min 101.1%
[0136] The breaking strength of the tablets was determined with the
stated apparatus in accordance with the stated method. The tablets
did not break when exposed to a force of 500 N.
[0137] The tablets could be cut up into pieces of an edge length of
as small as approx. 2 mm, but could not be pulverised. When the
pieces are combined with water, a highly viscous gel is formed.
Only with great difficulty could the gel be pressed through a 0.9
mm injection cannula. When the gel was injected into water, the gel
did not spontaneously mix with water, but remained visually
distinguishable.
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