U.S. patent application number 15/587501 was filed with the patent office on 2017-08-24 for abuse-proofed dosage form.
This patent application is currently assigned to GRUNENTHAL GMBH. The applicant listed for this patent is GRUNENTHAL GMBH. Invention is credited to JOHANNES BARTHOLOMAEUS, HEINRICH KUGELMANN.
Application Number | 20170239185 15/587501 |
Document ID | / |
Family ID | 34743222 |
Filed Date | 2017-08-24 |
United States Patent
Application |
20170239185 |
Kind Code |
A1 |
BARTHOLOMAEUS; JOHANNES ; et
al. |
August 24, 2017 |
ABUSE-PROOFED DOSAGE FORM
Abstract
A solid administration form, protected from parenteral abuse and
containing at least one viscosity-increasing agent in addition to
one or more active substances that have parenteral abuse potential.
The agent forms, when a necessary minimum amount of an aqueous
liquid is added, on the basis of an extract obtained from the
administration form, a preferably injectable gel that remains
visually distinct when introduced into another quantity of an
aqueous liquid.
Inventors: |
BARTHOLOMAEUS; JOHANNES;
(Aachen, DE) ; KUGELMANN; HEINRICH; (Aachen,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRUNENTHAL GMBH |
Aachen |
|
DE |
|
|
Assignee: |
GRUNENTHAL GMBH
Aachen
DE
|
Family ID: |
34743222 |
Appl. No.: |
15/587501 |
Filed: |
May 5, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15245424 |
Aug 24, 2016 |
9675610 |
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15587501 |
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14527911 |
Oct 30, 2014 |
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15245424 |
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14069439 |
Nov 1, 2013 |
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14527911 |
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13803789 |
Mar 14, 2013 |
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14069439 |
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13572926 |
Aug 13, 2012 |
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13803789 |
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13365742 |
Feb 3, 2012 |
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13572926 |
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12822719 |
Jun 24, 2010 |
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13365742 |
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11007887 |
Dec 9, 2004 |
7776314 |
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12822719 |
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PCT/EP2003/006314 |
Jun 16, 2003 |
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11007887 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 31/485 20130101; A61K 31/137 20130101; A61K 31/137 20130101;
A61K 31/5513 20130101; A61K 9/0053 20130101; A61K 31/5513 20130101;
A61K 45/06 20130101; A61K 9/2009 20130101; A61P 25/26 20180101;
A61K 47/38 20130101; A61K 9/2013 20130101; A61P 25/04 20180101;
A61K 9/4866 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 9/205 20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/485 20060101 A61K031/485; A61K 9/00 20060101
A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 17, 2002 |
DE |
102 27 077.5 |
Oct 25, 2002 |
DE |
102 50 083.5 |
Claims
1. A solid dosage form for oral administration with reduced
potential for parenteral abuse, said dosage form comprising: (a)
one or more active ingredients having potential for abuse selected
from the group consisting of hydrocodone, morphine, oxycodone,
tramadol, and pharmaceutically acceptable salts and solvates
thereof; and (b) at least one viscosity-increasing agent in a
quantity such that an aqueous extract of a total content of the
dosage form when comminuted and combined with 10 ml of water at
25.degree. C. forms a gel that can be drawn up into and injected
back out of a hypodermic needle having a diameter of 0.9 mm, into a
further quantity of water, wherein threads of the gel injected from
said needle remain visible to the naked eye in said further
quantity of water at 37.degree. C.
2. The dosage form according to claim 1, wherein the active
ingredient is oxycodone or a salt or solvate thereof.
3. The dosage form according to claim 1, wherein the active
ingredient is hydrocodone or a salt or solvate thereof.
4. The dosage form according to claim 1, wherein the active
ingredient is morphine or a salt or solvate thereof.
5. The dosage form according to claim 1, comprising one or more
viscosity-increasing agents selected from the group consisting of
microcrystalline cellulose with 11 wt. % carboxymethylcellulose
sodium, carboxymethylcellulose sodium, polyacrylic acid, locust
bean flour, citrus pectin, waxy maize starch, sodium alginate, guar
flour, iota-carrageenan, karaya gum, gellan gum, galactomannan,
tara stone flour, propylene glycol alginate, apple pectin, lemon
peel pectin, sodium hyaluronate, tragacanth, tara gum, fermented
polysaccharide welan gum and xanthan gum.
6. The dosage form according to claim 1, in particulate form.
7. The dosage form according to claim 1, comprising at least one
active ingredient in controlled release form.
8. The dosage form according to claim 1, comprising a coating
resistant to gastric juices.
9. The dosage form according to claim 1, in multiparticulate form,
wherein said multiparticulate form is in the form of microtablets,
microcapsules, micropellets, granules, spheroids, beads or pellets,
packaged in capsules or press-molded into tablets.
10. The dosage form according to claim 1, wherein said threads
remain visible to the naked eye in said further quantity of water
for at least one minute.
11. The dosage form according to claim 1, wherein said threads
remain visible to the naked eye in said further quantity of water
for at least ten minutes.
12. The dosage form according to claim 1, which further comprises
microcrystalline cellulose.
13. The dosage form according to claim 1, which further comprises
hydroxypropylmethylcellulose.
14. A solid dosage form for oral administration with reduced
potential for parenteral abuse, said dosage form comprising: (a)
one or more active ingredients having potential for abuse selected
from the group consisting of hydrocodone, morphine, oxycodone,
tramadol, and pharmaceutically acceptable salts and solvates
thereof; and (b) one or more components having at least a
viscosity-increasing influence, in a total quantity, for all said
components combined, that is equal to or greater than 5 mg per
dosage form, that quantity being selected such that an aqueous
extract of a total content of the dosage form, when comminuted and
combined with 10 ml of water at 25.degree. C., forms a gel that is
capable of being drawn into and then expelled from a hypodermic
needle having a diameter of 0.9 mm, wherein threads of said gel,
formed upon exit from said needle into a further quantity of water
at 37.degree. C., remain substantially coherent and visible to the
naked eye.
15. The dosage form according to claim 14, wherein the active
ingredient is oxycodone or a salt or solvate thereof.
16. The dosage form according to claim 14, wherein the active
ingredient is hydrocodone or a salt or solvate thereof.
17. The dosage form according to claim 14, wherein the active
ingredient is morphine or a salt or solvate thereof.
18. The dosage form according to claim 14, wherein said threads
remain substantially coherent and visible to the naked eye in said
further quantity of water for at least one minute.
19. The dosage form according to claim 14, wherein said threads
remain substantially coherent and visible to the naked eye in said
further quantity of water for at least ten minutes.
20. The dosage form according to claim 14, comprising at least one
active ingredient in controlled release form.
21. The dosage form according to claim 14, which further comprises
microcrystalline cellulose.
22. The dosage form according to claim 14, which further comprises
hydroxypropylmethylcellulose.
23. A solid dosage form for oral administration with reduced
potential for parenteral abuse, said dosage form comprising: (a)
one or more active ingredients with potential for abuse selected
from the group consisting of hydrocodone, morphine, oxycodone,
tramadol and pharmaceutically acceptable salts and/or solvates
thereof; and (b) one or more viscosity-increasing agents; wherein
the dosage form when its total content is comminuted and combined
with 10 ml of water at 25.degree. C. forms an injectable gel that
can be drawn up into and injected back out of a syringe having a
diameter of 0.9 mm, but wherein the injectable gel cannot be safely
injected from said syringe into a blood vessel of an abuser because
the presence of the injectable gel in the abuser's blood vessels
would probably obstruct one or more of said abuser's blood
vessels.
24. The dosage form according to claim 23, wherein the active
ingredient is oxycodone or a salt or solvate thereof.
25. The dosage form according to claim 23, wherein the active
ingredient is hydrocodone or a salt or solvate thereof.
26. The dosage form according to claim 23, wherein the active
ingredient is morphine or a salt or solvate thereof.
27. The dosage form according to claim 23, which further comprises
microcrystalline cellulose.
28. The dosage form according to claim 23, which further comprises
hydroxypropylmethylcellulose.
29. The dosage form according to claim 23, comprising at least one
active ingredient in controlled release form.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/245,424, filed Aug. 24, 2016; allowed;
which is a continuation of U.S. patent application Ser. No.
14/527,911, filed Oct. 30, 2014, abandoned, which is a continuation
of U.S. patent application Ser. No. 14/069,439, filed Nov. 1, 2013,
abandoned, which is a continuation of U.S. patent application Ser.
No. 13/803,789, filed Mar. 14, 2013, abandoned, which is a
continuation of U.S. patent application Ser. No. 13/572,926, filed
Aug. 13, 2012, abandoned, which is a continuation of 13/365,742,
filed Feb. 3, 2012, abandoned, which is a continuation of U.S.
patent application Ser. No. 12/822,719, filed Jun. 24, 2010,
abandoned, which is a divisional of U.S. patent application Ser.
No. 11/007,887, filed Dec. 9, 2004, now U.S. Pat. No. 7,776,314,
which is a continuation-in-part of International Patent Application
No. PCT/EP2003/006314, filed Jun. 16, 2003, which claims foreign
priority benefit under 35 U.S.C. .sctn.119 of the German Patent
Applications Nos. 102 50 083.5, filed Oct. 25, 2002, and 102 27
077.5, filed Jun. 17, 2002, the entire disclosures of which patent
applications are incorporated herein by reference.
[0002] The present invention relates to a solid dosage form with
reduced parenteral abuse containing, in addition to one or more
active ingredients with potential for abuse, at least one
viscosity-increasing agent in quantities such that, on extraction
with the assistance of a necessary minimum quantity of aqueous
liquid, a gel is formed which can still preferably pass through a
needle, which gel, however, remains visually distinguishable even
after being introduced into a further quantity of an aqueous
liquid.
[0003] 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. 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] Dosage forms which contain active ingredients with potential
for abuse, even when taken orally in an abusively large quantity,
do not usually give rise to the result desired by the abuser,
namely a rapid rush or "kick", because blood levels of the active
ingredients increase only slowly. In order nevertheless to achieve
the desired effects and enable abuse, the corresponding dosage
forms are comminuted, for example ground, by the abuser and the
active ingredient is extracted from the powder obtained by
comminution of the dosage form with the assistance of a preferably
aqueous liquid, preferably the minimum quantity necessary, and the
resultant solution, optionally after filtration through cotton wool
or cellulose wadding, is administered parenterally, in particular
intravenously. Due to this parenteral administration, only the
smallest possible quantities of an aqueous liquid are used for
extraction, in particular so as to obtain the smallest possible
injection volume with active ingredient which results in the
desired rapid rush or "kick". In this manner, parenteral
administration, in comparison with oral administration, tends to
give rise to an accelerated rise in levels of the active ingredient
providing the abuser with the desired result.
[0005] In order to prevent this form of abuse, it has been proposed
in U.S. Pat. No. 4,070,494 to prevent the extraction of an active
ingredient from a dosage form by the addition of a swellable agent.
On addition of water, this agent swells and ensures that only a
small quantity of active ingredient containing liquid is obtained
which can be administered parenterally by the abuser. The majority
of this dosage form which has swollen is cannot be
administered.
[0006] A corresponding approach to the prevention of parenteral
abuse also underlies the multilayer tablet disclosed in WO 95/20947
which contains the active ingredient with potential for abuse and
one or more gel formers each in different layers.
[0007] According to this prior art teaching, the
viscosity-increasing agents are added in quantities such that the
corresponding gel cannot be administered with the assistance of
conventional hypodermic needles.
[0008] The object of the present invention was to provide a dosage
form with at least reduced potential for abuse for active
ingredients having with such potential, which dosage form prevents
any preferably still possible parenteral, in particular
intravenous, abuse of the active ingredients.
[0009] This object has been achieved by the provision of the solid
dosage form according to the invention with at least reduced
potential for parenteral abuse, which dosage form, in addition to
one or more active ingredients with potential for abuse, comprises
at least one viscosity-increasing agent in a quantity such that a
gel which may preferably still pass through a needle is formed in
an extract obtained from the dosage form with the assistance of a
necessary minimum quantity of an aqueous liquid, which gel remains
visually distinguishable when introduced into a further quantity of
an aqueous liquid.
[0010] For the purposes of the present invention, visually
distinguishable means that the active ingredient-containing gel
formed by extraction from the dosage form with the assistance of a
necessary minimum quantity of aqueous liquid, when introduced with
a hypodermic needle with a diameter of 0.9 mm 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
min.
[0011] The increase in viscosity of the gel with the assistance of
the selected viscosity-increasing agent means that, although this
has been rendered more difficult, the gel may still be passed
through a needle or injected. It also means that when the resultant
extract or gel is introduced at 37.degree. C. into a further
quantity of aqueous liquid, for example also by injection into
blood, a largely cohesive thread is initially obtained which, while
it may be broken up into smaller fragments by mechanical action, it
cannot be dispersed or even dissolved in such a manner that it may
safely be administered parenterally, in particular intravenously.
Intravenous administration of such an extract would most probably
result in obstruction of blood vessels, associated with serious
embolism or even death of the abuser.
[0012] For the purposes of the present invention, an extract or gel
obtained from the dosage form according to the invention with the
assistance of a necessary minimum quantity of an aqueous liquid,
preferably water, is deemed to be passable through a needle if the
gel formed in this manner can still be drawn up and injected back
out of a hypodermic needle with a diameter of 2 mm, preferably of
1.5 mm, particularly preferably of 0.6 mm. 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 according to the invention as such, in the form of
corresponding derivatives, in particular esters or ethers, or in
each case in the form of corresponding physiologically acceptable
compounds, in particular in the form of the salts or solvates
thereof. The dosage form according to the invention is also
suitable for the administration of a plurality of active
ingredients. It is preferably used for the administration of a
single active ingredient.
[0013] The present invention, thus, relates in one embodiment to a
method of treating a disease or disorder in a patient in need of
such treatment, said disease or disorder being treatable with one
or more active ingredients with potential for abuse, wherein said
one or more active ingredients with potential for abuse are
selected from the group consisting of opiates, opioids,
tranquilizers, stimulants and narcotics, said method comprising
administering to said patient the dosage form according to the
present invention, wherein said dosage form comprises one or more
of said active ingredients effective to treat said disease or
disorder.
[0014] 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, stimulants and other
narcotics.
[0015] The dosage form according to the invention is very
particularly preferably suitable for preventing abuse of an opiate,
opioid, tranquilliser or another narcotic, which is selected from
the group consisting of
N-{1-[2-(4-Ethyl-5-oxo-2-tetrazolin-1-l)ethyl]-4-methoxymethyl-4-piperidy-
l}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-ylamine 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)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]ben-
zodiazepin-6(5H)-one (cloxazolam),
(-)-methyl-[3.beta.-benzoylo-2.beta.(1.alpha.H,5.alpha.H)-tropane
carbolate] (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-3,6a-morphinandiol
(dihydromorphine), dimenoxadol, dimephetamol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone,
(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chro-
men-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-1
H-1,4-benzodiazepine-3-carboxylate] (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-trinorbornan-2-ylamine (fencamfamine),
7-[2-(.alpha.-methylphenethylamino)ethyl]-theophylline)
(fenethylline), 3-(.alpha.-methylphenethylamino)propionitrile
(fenproporex), N-(1-phenethyl-4-piperidyl)propionanilide
(fentanyl),
7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one
(fludiazepam),
5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2(3H)-one
(flunitrazepam),
7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepin--
2(3H)-one (flurazepam),
7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one
(halazepam),
10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolyl[3,2-d][1,-
4]benzodiazepin-6(5H)-one (haloxazolam), heroin,
4,5.alpha.-epoxy-3-methoxy-17-methyl-6-morphinanone (hydrocodone),
4,5.alpha.-epoxy-3-hydroxy-17-methyl-6-morphinanone
(hydromorphone), hydroxypethidine, isomethadone,
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 (LRAM)),
(-)-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]isoindo1-5-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 (metamphetamine),
(.+-.)-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[1,5-a][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-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-
-d][1,4]benzodiazepin-6-(5H)-one (oxazolam),
4,5.alpha.-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone
(oxycodone), oxymorphone, plants and parts of plants belonging to
the species Papaver somniferum (including the subspecies setigerum)
(Papaver somniferum), 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-piperidinecarbolate) (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'-bipiperidine]-4'-carboxamide
(piritramide),
7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one
(prazepam), profadol, proheptazine, promedol, properidine,
propoxyphene, N-(1-methyl
-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl
{3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]propanoate}
(remifentanil), 5-sec-butyl-5-ethylbarbituric acid
(secbutabarbital), 5-allyl-5-(1-methylbutyl)-barbituric acid
(secobarbital),
N-{4-methomethyl-1-[2-(2-thienypethyl]-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-benzodiazepin-2(3H)-one
(tetrazepam), ethyl
(2-dimethylamino-1-phenyl-3-cyclohexene-1-carbolate) (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 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.
[0016] The compounds
(1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol and
(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzylo)-1-(m-methoxyphenyl-
)cyclohexanol, the physiologically acceptable compounds thereof, in
particular the hydrochlorides thereof and processes for the
production thereof are respectively known, for example, from
EP-A-693475 and EP-A-780369. The corresponding descriptions are
hereby introduced as a reference and are deemed to be part of the
disclosure.
[0017] In order to verify whether a viscosity-increasing agent is
suitable for use in the dosage form according to the invention,
said agent is first formulated in a corresponding dosage form in
quantities such that there is no appreciable (.+-.5%) influence on
active ingredient release relative to a dosage form without
viscosity-increasing agent. The corresponding dosage form is
moreover comminuted, preferably ground, and extracted with 10 ml
water at 25.degree. C. If a gel is furthermore formed which meets
the above-stated conditions, the corresponding viscosity-increasing
agent is suitable for the production of a dosage form according to
the invention.
[0018] Preferably, one or more viscosity-increasing agents are used
in the dosage form according to the invention, said agents being
selected from the group consisting of microcrystalline cellulose
with 11 wt. % carboxymethylcellulose sodium (Avicel.RTM. RC 591),
carboxymethylcellulose sodium (Blanose.RTM., CMC-Na C3001P.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, preferably from citrus fruits or 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 2611-75.RTM.), iota-carrageenan (Frimulsion
D021.RTM.), karaya gum, gellan gum (Kelcogel F.RTM., Kelcogel
LT100.RTM.), galactomannan (Meyprogat 150.RTM.), tara stone flour
(Polygum 4311.RTM.), propylene glycol alginate (Protanal-Ester
SD-Le), sodium hyaluronate, tragacanth, tara gum (Vidogum SP
200.RTM.), fermented polysaccharide welan gum (K1A96), xanthans
such as xanthan gum (Xantural 180.RTM.). The names stated in
brackets are the trade names by which the materials are known
commercially.
[0019] In general, a quantity of 0.1 to 25 wt. %, preferably of 0.5
to 15 wt. %, particularly preferably of 1-10 wt. % of the
viscosity-increasing agent, relative to the total formulation, is
sufficient in order to meet the above-stated conditions.
[0020] The viscosity-increasing agents are preferably present in
the dosage form according to the invention in quantities of
.gtoreq.5 mg, particularly preferably of .gtoreq.10 mg per dosage
form, i.e. per administration unit.
[0021] In a particularly preferred embodiment of the present
invention, the viscosity-increasing agents used are those which, in
addition to the above-stated conditions, also form a gel which
encloses air bubbles on extraction from the dosage form with the
necessary minimum quantity of aqueous liquid. 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.
[0022] The active ingredient or ingredients with potential for
abuse and the viscosity-increasing agents and optionally
physiologically acceptable auxiliary substances may be formulated
to yield the dosage form according to the invention in accordance
with conventional methods known to the person skilled in the art.
Corresponding methods for formulating the dosage form according to
the invention are known per se 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.
[0023] Surprisingly, due to the inventive selection of the
viscosity-increasing agents, it is possible to combine the active
ingredients and the viscosity-increasing agents in the dosage form
according to the invention without spatial separation from one
another, without there being any impairment of release of the
active ingredient from the correctly administered dosage form
relative to a corresponding dosage form which does not comprise the
viscosity-increasing agent.
[0024] Obviously, however, it is also possible to combine the
viscosity-increasing agents and the active ingredients in the
dosage form in a mutually spatially separated arrangement.
[0025] The parenteral abuse-proofed solid dosage forms according to
the invention are preferably suitable for oral or rectal
administration, particularly preferably for oral
administration.
[0026] Where the dosage form according to the invention is intended
for rectal administration, it preferably assumes the form of a
suppository.
[0027] If the dosage form according to the invention is intended
for oral administration, it preferably assumes the form of a
tablet, a capsule or of an oral osmotic therapeutic system
(OROS).
[0028] Oral osmotic therapeutic systems and suitable materials and
processes for the production thereof are known per se to the person
skilled in the art, for example 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.
[0029] The corresponding oral osmotic therapeutic system may
preferably assume the form of a single or twin chamber system, in
each case with a single layer or multilayer structure. In these
systems, the push layer, i.e. the layer which produces the osmotic
pressure by swelling, by means of which the overlying layer is
expelled from the system, preferably at least in part consists of
the viscosity-increasing agents used according to the
invention.
[0030] In a further preferred embodiment of the present invention,
the orally administrable dosage form according to the invention
assumes multiparticulate form containing in each case the complete
mixture of active ingredient and viscosity-increasing agent,
preferably in the form of microtablets, microcapsules,
micropellets, granules, spheroids, beads or pellets, preferably
packaged in capsules or press-moulded into tablets The
multiparticulate forms preferably have a size in the range from 0.1
to 3 mm, particularly preferably in the range from 0.5 to 2 mm.
[0031] The dosage form according to the invention may preferably
also comprise one or more active ingredients, blended with the
viscosity-increasing agent, at least in part in delayed-release
form, wherein delayed release may be achieved with the assistance
of conventional materials and processes known to the person skilled
in the art, for example by embedding the active ingredient in a
delayed-release matrix or by applying one or more delayed-release
coatings.
[0032] Delayed release of the active ingredient may preferably also
be achieved by purposeful selection of one or more of the
above-stated viscosity-increasing agents in suitable quantities as
the matrix material. The person skilled in the art may determine
the agents and the quantity thereof suitable for the particular
desired release by simple preliminary testing, wherein it must, of
course, be ensured that, as described above, gel formation occurs
when the attempt is made to abuse the resultant dosage form.
[0033] In any event, it must be ensured that the delayed-release
auxiliary substances, and likewise further optionally present
auxiliary substances, do not interfere with gel formation or impair
the stability of the gel which is formed.
[0034] If the dosage form according to the invention is intended
for oral administration, it may also comprise a coating which is
resistant to gastric juices and dissolves as a function of the pH
value of the release environment.
[0035] By means of this coating, it is possible to ensure that,
when correctly administered, 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.
[0036] 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.
[0037] In a further preferred embodiment, the dosage form according
to the invention contains the active ingredient not only in its
delayed-release form, but also in its non-delayed-release form. By
combination with the immediately released active ingredient, it is
possible to obtain an initial dose for rapid pain relief. The slow
release from the delayed-release form then prevents any rapid
decline in action.
[0038] 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
[0039] Matrix tablets with the following composition per tablet
TABLE-US-00001
(-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)- 100 mg
phenol hydrochloride Hydroxypropylmethylcellulose (Metolose 90 SH
100,000 from 70 mg Shinetsu), 100,000 mPa s Xanthan, NF 10 mg
Microcrystalline cellulose (Avicel PH 102 from FMC) 123 mg Highly
disperse silicon dioxide 4 mg Magnesium stearate 3 mg Total
quantity 310 mg
were produced in the following manner in a batch size of 1000
tablets: All the constituents were weighed out and screened in
Quadro Comil U10 screening machine using a screen size of 0.813 mm,
mixed in a container mixer (Bohle LM 40) for 15 min.+-.15 s at a
rotational speed of 20.+-.1 rpm and pressed on a Korsch EKO
eccentric press to form biconvex tablets with a diameter of 10 mm,
a radius of curvature of 8 mm and an average tablet weight of 310
mg.
[0040] In vitro release was determined using the Ph. Eur. paddle
method at 75 rpm in 900 ml of pH 6.8 buffer to Ph. Eur. at
37.degree. C., with detection by UV spectrometry, and is shown in
the following Table, together with a comparison with a
corresponding tablet with 80 mg of hydroxypropylmethylcellulose
("HPMC") without addition of xanthan.
TABLE-US-00002 Total quantity of active ingredient Total quantity
of released [%] from active ingredient tablets according released
[%] to Example 1 from tablets with Time (70 mg HPMC + 80 mg HPMC
[min] 10 mg xanthan) (without xanthan) 0 0 0 30 19 18 240 62 59 480
83 80 600 88 87 720 93 93
[0041] One of the tablets containing xanthan was ground and shaken
with 10 ml of water. A viscous, turbid suspension formed. Once the
coarse, solid components of the suspension had settled out, the gel
which had formed was drawn up into a syringe with a 0.9 mm diameter
needle. The drawn up gel was injected into water at 37.degree. C.
and threads, which did not mix with the water, with the diameter of
the needle remained clearly discernible While the threads could be
broken up by stirring, they could not be dissolved and the thread
fragments remained visible to the naked eye. Were such an extract
to be injected into blood vessels, vessel blockages would
occur.
Example 2
Comparative Example Regarding Very Poor Needle Passage
Properties
[0042] Matrix tablets with the following composition per tablet
TABLE-US-00003
(-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)- 100 mg
phenol hydrochloride Hydroxypropylmethylcellulose (Metolose 90 SH
100,000 from 40 mg Shinetsu), 100,000 mPa s Xanthan, NF 40 mg
Microcrystalline cellulose (Avicel PH 102 from FMC) 123 mg Highly
disperse silicon dioxide 4 mg Magnesium stearate 3 mg Total
quantity 310 mg
were produced as stated in Example 1 and their release
characteristics were investigated.
TABLE-US-00004 Total quantity of active ingredient Time [min]
released [%] 0 0 30 19 240 61 480 81 600 87 720 91
[0043] One of the tablets was ground and shaken with 10 ml of
water. A viscous, turbid suspension with enclosed air bubbles
formed, the viscosity of which was greater than in Example 1. Once
the coarse, solid components of the suspension had settled out, the
gel which had formed was drawn up into a syringe with a 0.9 mm
diameter needle. The drawn up gel was injected into water at
37.degree. C. and threads, which did not mix with the water, with
the diameter of the needle were clearly discernible. While the
threads could be broken up by stirring, they could not be dissolved
and the thread fragments remained visible to the naked eye. Were
such a gel to be injected into blood vessels, vessel blockages
would occur.
Example 3
[0044] Matrix tablets with the following composition per tablet
TABLE-US-00005
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol 100
mg hydrochloride Xanthan, NF 80 mg Microcrystalline cellulose
(Avicel PH 102 from FMC) 123 mg Highly disperse silicon dioxide 4
mg Magnesium stearate 3 mg Total quantity 310 mg
were produced as stated in Example 1.
[0045] One of these tablets was ground and shaken with 10 ml of
water. A viscous, turbid suspension, which had enclosed air
bubbles, formed, the viscosity of which was higher than in Example
1. Once the coarse, solid components of the suspension had settled
out, the gel which had formed was drawn up into a syringe with a
0.9 mm diameter needle. The drawn up gel was injected into water at
37.degree. C. and clearly discernible threads, which did not mix
with the water, with the diameter of the needle were visible. While
the threads could be broken up by stirring, they could not be
dissolved and the thread fragments remained visible to the naked
eye. Were such a gel to be injected into blood vessels, vessel
blockages would occur.
Examples 4-7
[0046] Matrix tablets with the following composition per tablet
TABLE-US-00006 Example 4 5 6 7 (-)-(1R,2R)-3-(3-Dimethylamino- 100
mg 100 mg 100 mg 100 mg 1-ethyl-2-methyl-propyl)phenol
hydrochloride Hydroxypropylmethylcellulose 80 mg 80 mg 80 mg 80 mg
(Metolose 90 SH 100,000 from Shinetsu), 100,000 mPa s
Carboxymethylcellulose 10 mg (Tylose C300) Carboxymethylcellulose
10 mg (Tylose C600) Hydroxyethylcellulose 10 mg (Tylose H300)
Hydroxyethylcellulose 10 mg (Tylose H4000) Microcrystalline
cellulose 123 mg 123 mg 123 mg 123 mg (Avicel PH 102 from FMC)
Highly disperse silicon dioxide 4 mg 4 mg 4 mg 4 mg Magnesium
stearate 3 mg 3 mg 3 mg 3 mg Total quantity 320 mg 320 mg 320 mg
320 mg
were produced as stated in Example 1.
[0047] One of each of these tablets was ground and shaken with 10
ml of water. A viscous, turbid suspension with enclosed air bubbles
formed. Once the coarse, solid components of the suspension had
settled out, the [gel] was drawn up into a syringe with a 0.9 mm
diameter needle. The drawn up gel was injected into water at
37.degree. C. and clearly visible threads, which did not mix with
the water, with the diameter of the needle remained discernible.
While the threads could be broken up by stirring, they could not be
dissolved and the thread fragments remained visible to the naked
eye. Were such a gel to be injected into blood vessels, vessel
blockages would occur.
Examples 8-13
[0048] Matrix tablets with the following composition per tablet
TABLE-US-00007 Example 8 9 10 11 12 13 Morphine sulfate 60 mg 60 mg
60 mg 60 mg 60 mg 60 mg pentahydrate Hydroxypropylmethylcellulose
60 mg 60 mg 60 mg 60 mg 60 mg 60 mg (Metolose 90 SH 15,000 from
Shinetsu), 15,000 mPa s Xanthan, NF 10 mg 30 mg
Carboxymethylcellulose 10 mg (Tylose C300) Carboxymethylcellulose
10 mg (Tylose C600) Hydroxyethylcellulose (Tylose 10 mg H300)
Hydroxyethylcellulose (Tylose 10 mg H4000) Microcrystalline
cellulose 123 mg 123 mg 123 mg 123 mg 123 mg 123 mg (Avicel PH 102
from FMC) Highly disperse silicon dioxide 4 mg 4 mg 4 mg 4 mg 4 mg
4 mg Magnesium stearate 3 mg 3 mg 3 mg 3 mg 3 mg 3 mg
[0049] One of each of these tablets was ground and shaken with 10
ml of water. A viscous, turbid suspension with enclosed air bubbles
formed. Once the coarse, solid components of the suspension had
settled out, the [gel] was drawn up into a syringe with a 0.9 mm
diameter needle. The drawn up gel was injected into water at
37.degree. C. and clearly visible threads, which did not mix with
the water, with the diameter of the needle remained discernible.
While the threads could be broken up by stirring, they could not be
dissolved and the thread fragments remained visible to the naked
eye. Were such a gel to be injected into blood vessels, vessel
blockages would occur.
Examples 14-18
[0050] Capsules with the following composition of the simple powder
mixture per capsule (size 4 capsule)
TABLE-US-00008 Example 14 15 16 17 18 Morphine sulfate 20 mg 20 mg
20 mg 20 mg 20 mg pentahydrate Xanthan, NF 10 mg
Carboxymethylcellulose 10 mg (Tylose C300) Carboxymethylcellulose
10 mg (Tylose C600) Hydroxyethylcellulose 10 mg (Tylose H300)
Hydroxyethylcellulose 10 mg (Tylose H4000) Microcrystalline 68 mg
68 mg 68 mg 68 mg 68 mg cellulose (Avicel PH 102 from FMC) Highly
disperse silicon 1 mg 1 mg 1 mg 1 mg 1 mg dioxide Magnesium
stearate 1 mg 1 mg 1 mg 1 mg 1 mg
[0051] One of each of these tablets was ground and shaken with 10
ml of water. A viscous, turbid suspension with enclosed air bubbles
formed. Once the coarse, solid components of the suspension had
settled out, the [gel] was drawn up into a syringe with a 0.9 mm
diameter needle. The drawn up gel was injected into water at
37.degree. C. and clearly visible threads, which did not mix with
the water, with the diameter of the needle remained discernible.
While the threads could be broken up by stirring, they could not be
dissolved and the thread fragments remained visible to the naked
eye. Were such a gel to be injected into blood vessels, vessel
blockages would occur.
* * * * *