U.S. patent application number 15/726761 was filed with the patent office on 2018-04-05 for pharmaceutical composition comprising (1r,4r)-6'-fluoro-n, n-dimethyl-4-phenyl-4',9' -dihydro-3'h-spiro[cyclohexane-1,1' -pyrano[3,4,b]indol]-4-amine and paracetamol or propacetamol.
The applicant listed for this patent is Gruenenthal GmbH. Invention is credited to Stefanie FROSCH, Klaus LINZ, Klaus SCHIENE.
Application Number | 20180092867 15/726761 |
Document ID | / |
Family ID | 48468208 |
Filed Date | 2018-04-05 |
United States Patent
Application |
20180092867 |
Kind Code |
A1 |
FROSCH; Stefanie ; et
al. |
April 5, 2018 |
Pharmaceutical Composition Comprising (1r,4r)-6'-fluoro-N,
N-dimethyl-4-phenyl-4',9' -dihydro-3'H-spiro[cyclohexane-1,1'
-pyrano[3,4,b]indol]-4-amine and Paracetamol or Propacetamol
Abstract
The invention relates to a pharmaceutical composition comprising
a first pharmacologically active ingredient selected from
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine and the physiologically
acceptable salts thereof, and a second pharmacologically active
ingredient selected from paracetamol and propacetamol.
Inventors: |
FROSCH; Stefanie; (Aachen,
DE) ; LINZ; Klaus; (Rheinbach, DE) ; SCHIENE;
Klaus; (Juechen, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gruenenthal GmbH |
Aachen |
|
DE |
|
|
Family ID: |
48468208 |
Appl. No.: |
15/726761 |
Filed: |
October 6, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13892969 |
May 13, 2013 |
|
|
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15726761 |
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61648732 |
May 18, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/22 20180101;
A61P 25/08 20180101; A61P 43/00 20180101; A61P 25/04 20180101; A61P
25/00 20180101; A61K 31/223 20130101; A61K 31/407 20130101; A61P
29/00 20180101; A61K 31/167 20130101; A61K 31/407 20130101; A61K
2300/00 20130101; A61K 31/167 20130101; A61K 2300/00 20130101; A61K
31/223 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/167 20060101
A61K031/167; A61K 31/407 20060101 A61K031/407; A61K 31/223 20060101
A61K031/223 |
Foreign Application Data
Date |
Code |
Application Number |
May 18, 2012 |
EP |
12 003 897.1 |
Claims
1.-15. (canceled)
16. A pharmaceutical composition comprising: (a) a first
pharmacologically active ingredient selected from ##STR00003## and
physiologically acceptable salts thereof, and (b) paracetamol as a
second pharmacologically active ingredient, wherein the first and
second pharmacologically active ingredient are adapted for
simultaneous administration, by either the same or a different
pathway of administration.
17. The pharmaceutical composition according to claim 1, wherein
the first pharmacologically active ingredient is ##STR00004## in
form of a hydrochloride, hemicitrate or maleate salt.
18. A pharmaceutical dosage form comprising the pharmaceutical
composition according to claim 16.
19. The pharmaceutical dosage form according to claim 18, which is
for oral, intravenous, intraperitoneal, transdermal, intrathecal,
intramuscular, intranasal, transmucosal, subcutaneous, or rectal
administration.
20. The pharmaceutical dosage form according to claim 18, which
provides under in vitro conditions immediate release or controlled
release of the first pharmacologically active ingredient, the
second pharmacologically active ingredient, or both the first and
second pharmacologically active ingredient.
21. A kit comprising a first pharmaceutical dosage form, which
comprises the first pharmacologically active ingredient according
to claim 16, and a second pharmaceutical dosage form, which
comprises the second pharmacologically active ingredient according
to claim 16.
22. The kit according to claim 21, wherein the first and the second
pharmaceutical dosage form are adapted for administration by the
same pathway.
23. The kit according to claim 21, wherein the first and the second
pharmaceutical dosage form are adapted for administration by
different pathways.
24. A method of preventing or treating pain comprising simultaneous
administration of: (a) a first pharmacologically active ingredient
selected from ##STR00005## and physiologically acceptable salts
thereof, and (b) paracetamol as a second pharmacologically active
ingredient.
25. The method according to claim 24, wherein the first
pharmacologically active ingredient is in form of a hydrochloride,
hemicitrate or maleate salt.
26. The method according to claim 24, wherein the pain is chronic
pain.
27. The method according to claim 24, wherein the pain is moderate
to severe pain.
28. The method according to claim 24, wherein the pain is low back
pain, visceral pain, or headache.
29. The method according to claim 24, wherein the pain is
post-operative, cancer, or inflammatory pain.
30. The method according to claim 24, wherein the first and second
pharmacologically active ingredient are administered by the same
pathway.
31. The method according to claim 30, wherein the administration
pathway is selected from the group consisting of oral, intravenous,
intraperitoneal, transdermal, intrathecal, intramuscular,
intranasal, transmucosal, subcutaneous, or rectal.
32. The method according to claim 24, wherein the first and second
pharmacologically active ingredient are administered by two
different pathways.
33. The method according to claim 32, wherein each of the two
different administration pathways is selected from the group
consisting of oral, intravenous, intraperitoneal, transdermal,
intrathecal, intramuscular, intranasal, transmucosal, subcutaneous,
or rectal.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/892,969, filed May 13, 2017, which is a non-provisional of
U.S. Application No. 61/648,732, filed May 18, 2012, and which
claims priority from European Patent Application No. 12 003 897.1,
filed May 18, 2012, all of the disclosures of which are expressly
incorporated by reference herein.
[0002] The invention relates to a pharmaceutical composition
comprising a first pharmacologically active ingredient selected
from
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine and the physiologically
acceptable salts thereof, and a second pharmacologically active
ingredient selected from paracetamol and propacetamol.
[0003] (1r,4r)-6'-fluoro-N,
N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b-
]-indol]-4-amine and its corresponding physiologically acceptable
salts as well as methods for their preparation are well known, for
example, from WO2004/043967 and WO2008/040481. The compounds
exhibit analgesic properties and are particularly suitable for the
treatment of acute, visceral, neuropathic or chronic (nociceptive)
pain.
[0004] Paracetamol (acetaminophen) and its prodrug, propacetamol,
are widely used for the treatment of various pain conditions.
[0005] Though both of the aforementioned substance classes can be
used in the prevention and treatment of pain and are as such
therapeutically effective, side effects may occur, especially upon
prolonged use or when administered at high dosages.
[0006] It is further known that specific combinations of
pharmacologically active compounds exert supra-additive
(synergistic) therapeutic effects upon administration. An advantage
of these special cases is that the overall dose and accordingly the
risk of undesired side effects may be reduced.
[0007] In a further aspect, two pharmacologically active compounds
exerting a synergistic effect may be combined in one single
pharmaceutical dosage form, e.g. a tablet, thus enhancing patient
compliance.
[0008] It is an object of the invention to provide pharmaceutical
compositions which have advantages compared to pharmaceutical
compositions of the prior art. In particular, the pharmaceutical
compositions should provide rapid therapeutic effects, but also
should have a high tolerability, good compliance and safety.
[0009] This object has been achieved by the subject-matter of the
patent claims.
[0010] It has been surprisingly found that a pharmaceutical
composition comprising
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine and paracetamol or its prodrug
propacetamol is useful for the treatment of acute and chronic
pain.
[0011] Further it has been surprisingly found that said composition
exhibits a synergistic therapeutic effect upon administration.
Therefore, the overall administered dose may be lowered, so that
fewer undesired side-effects will occur.
[0012] A first aspect of the invention relates to a pharmaceutical
composition comprising: [0013] (a) a first pharmacologically active
ingredient selected from
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine and the physiologically
acceptable salts thereof, and [0014] (b) a second pharmacologically
active ingredient selected from paracetamol and propacetamol.
[0015] The pharmaceutical composition according to the invention
comprises a first pharmacologically active ingredient selected from
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine and the physiologically
acceptable salts thereof.
[0016] For the purpose of specification,
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine is the compound according to
formula (I) which can also be referred to as
1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydrop-
yrano[3,4-b]indole (trans)
##STR00001##
[0017] The definition of the first pharmacologically active
ingredient includes
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[-
cyclohexane-1,1'-pyrano-[3,4,b]indol]-4-amine in form of the free
base, i.e. the compound according to formula (I), in any possible
form including solvates, cocrystals and polymorphs, and its
physiologically acceptable salts, in particular acid addition salts
and corresponding solvates, cocrystals and polymorphs.
[0018] The pharmacologically active ingredient
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine may be present in the
pharmaceutical composition according to the invention in form of a
physiologically acceptable salt, preferably an acid addition salt,
whereby any suitable acid capable of forming such an addition salt
may be used.
[0019] The conversion of
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine into a corresponding addition
salt, for example, via reaction with a suitable acid may be
effected in a manner well known to those skilled in the art.
Suitable acids include but are not limited to hydrochloric acid,
hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid,
acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic
acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or
aspartic acid. Salt formation is preferably effected in a solvent,
for example, diethyl ether, diisopropyl ether, alkyl acetates,
acetone and/or 2-butanone. Moreover, trimethylchlorosilane in
aqueous solution is also suitable for the preparation of
hydrochlorides.
[0020] In a preferred embodiment, the first pharmacologically
active ingredient is
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine in form of the free base, i.e.
the compound according to formula (I).
[0021] In another preferred embodiment, the first pharmacologically
active ingredient is
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine in form of a physiologically
acceptable acid addition salt, in particular the hydrochloride,
hemicitrate or maleate salt.
[0022] Unless explicitly stated otherwise, all amounts of the first
pharmacologically active ingredient specified in the following are
given according to the corresponding amount of
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine in form of the free base, i.e.
the compound according to formula (I).
[0023] The pharmaceutical composition according to the invention
comprises a second pharmacologically active ingredient selected
from paracetamol and propacetamol.
[0024] Paracetamol and propacetamol have the structures according
to formulas (II) and (III), respectively:
##STR00002##
[0025] The definition of the second pharmacologically active
ingredient includes the compounds paracetamol and propacetamol in
any possible form including solvates, cocrystals and
polymorphs.
[0026] In a preferred embodiment, the second pharmacologically
active ingredient is paracetamol.
[0027] In another preferred embodiment, the second
pharmacologically active ingredient is propacetamol.
[0028] In a preferred embodiment, the first pharmacologically
active ingredient is
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine in form of the free base, i.e.
the compound according to formula (I), and the second
pharmacologically active ingredient is selected from paracetamol
and propacetamol.
[0029] In another preferred embodiment, the first pharmacologically
active ingredient is
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine in form of a physiologically
acceptable acid addition salt, in particular the hydrochloride,
hemicitrate or maleate salt, and the second pharmacologically
active ingredient is selected from paracetamol and
propacetamol.
[0030] In a preferred embodiment, the first pharmacologically
active ingredient is
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine in form of a physiologically
acceptable acid addition salt, in particular the hydrochloride,
hemicitrate or maleate salt, and the second pharmacologically
active ingredient is paracetamol.
[0031] In another preferred embodiment, the first pharmacologically
active ingredient is
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine in form of the free base, i.e.
the compound according to formula (I), and the second
pharmacologically active ingredient is paracetamol.
[0032] Another aspect of the invention relates to a pharmaceutical
dosage form comprising the pharmaceutical composition according to
the invention.
[0033] The first and the second pharmacologically active ingredient
are typically contained in the pharmaceutical dosage form according
to the invention in a therapeutically effective amount. The amount
that constitutes a therapeutically effective amount varies
according to the pharmacologically active ingredients, the
condition being treated, the severity of said condition, the
patient being treated, and whether the pharmaceutical dosage form
is designed for an immediate or controlled release.
[0034] In a preferred embodiment, the content of the first
pharmacologically active ingredient in the pharmaceutical dosage
form according to the invention and the pharmaceutical composition
according to the invention, respectively, is at most 10 wt.-% or at
most 5 wt.-% or at most 3 wt.-% or at most 1.0 wt.-%, more
preferably at most 0.8 wt.-%, yet more preferably at most 0.5
wt.-%, still more preferably at most 0.2 wt.-%, even more
preferably at most 0.1 wt.-%, most preferably at most 0.05 wt.-%,
and in particular at most 0.01 wt.-% or at most 0.005 wt.-% or at
most 0.001 wt.-%.
[0035] In a preferred embodiment, the content of the second
pharmacologically active ingredient in the pharmaceutical dosage
form according to the invention and the pharmaceutical composition
according to the invention, respectively, is at most 95 wt.-%, more
preferably at most 80 wt.-%, yet more preferably at most 70 wt.-%,
still more preferably at most 60 wt.-%, even more preferably at
most 55 wt.-%, most preferably at most 50 wt.-%, and in particular
at most 45 wt.-%.
[0036] In a preferred embodiment, the content of the first
pharmacologically active ingredient in the pharmaceutical dosage
form according to the invention and the pharmaceutical composition
according to the invention, respectively, is at least 0.0001 wt.-%,
more preferably at least 0.0003 wt.-%, yet more preferably at least
0.0005 wt.-%, still more preferably at least 0.0008 wt.-%, even
more preferably at least 0.001 wt.-%, most preferably at least
0.003 wt.-%, and in particular at least 0.005 wt.-%.
[0037] In a preferred embodiment, the content of the second
pharmacologically active ingredient in the pharmaceutical dosage
form according to the invention and the pharmaceutical composition
according to the invention, respectively, is at least 0.1 wt.-%,
more preferably at least 0.5 wt.-%, yet more preferably at least 1
wt.-%, still more preferably at least 3 wt.-%, even more preferably
at least 5 wt.-%, most preferably at least 7.5 wt.-%, and in
particular at least 10 wt.-%.
[0038] Unless explicitly stated otherwise, in the meaning of the
invention the indication "wt.-%" shall mean weight of the
respective ingredient per total weight of the pharmaceutical dosage
form or per total weight of the pharmaceutical composition,
respectively.
[0039] Preferably, in the pharmaceutical dosage form according to
the invention and the pharmaceutical composition according to the
invention, respectively, the relative weight ratio of the first
pharmacologically active ingredient to the second pharmacologically
active ingredient is within the range of from 1:2 to 1:1,000,000,
more preferably 1:30 to 1:1,000,000, still more preferably 1:100 to
1:1,000,000, most preferably 1:1,000 to 1:500,000, and in
particular 1:2,000 to 1:300,000.
[0040] In a preferred embodiment, in the pharmaceutical dosage form
according to the invention and the pharmaceutical composition
according to the invention, respectively, the relative weight ratio
of the first pharmacologically active ingredient to the second
pharmacologically active ingredient is within the range of from
1:100 to 1:10,000, more preferably 1:200 to 1:7,500, still more
preferably 1:500 to 1:5,000, most preferably 1:750 to 1:2,500, and
in particular 1:900 to 1:2,000.
[0041] In another preferred embodiment, in the pharmaceutical
dosage form according to the invention and the pharmaceutical
composition according to the invention, respectively, the relative
weight ratio of the first pharmacologically active ingredient to
the second pharmacologically active ingredient is within the range
of from 1:1,000 to 1:20,000, more preferably 1:2,000 to 1:15,000,
still more preferably 1:3,000 to 1:12,500, yet more preferably
1:4,000 to 1:12,000, most preferably 1:5,000 to 1:10,000, and in
particular 1:6,000 to 1:9,000.
[0042] In still another preferred embodiment, in the pharmaceutical
dosage form according to the invention and the pharmaceutical
composition according to the invention, respectively, the relative
weight ratio of the first pharmacologically active ingredient to
the second pharmacologically active ingredient is within the range
of from 1:1,000 to 1:100,000, more preferably 1:2,000 to 1:80,000,
still more preferably 1:4,000 to 1:50,000, yet more preferably
1:6,000 to 1:20,000, most preferably 1:8,000 to 1:15,000, and in
particular 1:9,000 to 1:12,500.
[0043] In yet another preferred embodiment, in the pharmaceutical
dosage form according to the invention and the pharmaceutical
composition according to the invention, respectively, the relative
weight ratio of the first pharmacologically active ingredient to
the second pharmacologically active ingredient is within the range
of from 1:5,000 to 1:500,000, more preferably 1:10,000 to
1:400,000, still more preferably 1:20,000 to 1:300,000, most
preferably 1:40,000 to 1:200,000, and in particular 1:50,000 to
1:100,000.
[0044] In a further preferred embodiment, in the pharmaceutical
dosage form according to the invention and the pharmaceutical
composition according to the invention, respectively, the relative
weight ratio of the first pharmacologically active ingredient to
the second pharmacologically active ingredient is within the range
of from 1:100,000 to 1:1,900,000, more preferably 1:250,000 to
1:1,800,000, still more preferably 1:300,000 to 1:700,000, most
preferably 1:350,000 to 1:650,000, and in particular 1:400,000 to
1:600,000.
[0045] Preferably, in the pharmaceutical dosage form according to
the invention and the pharmaceutical composition according to the
invention, respectively, the relative molar ratio of the first
pharmacologically active ingredient to the second pharmacologically
active ingredient is within the range of from 1:2 to 1:1,000,000,
more preferably 1:30 to 1:1,000,000, still more preferably 1:100 to
1:1,000,000, most preferably 1:1,000 to 1:500,000, and in
particular 1:2,000 to 1:300,000.
[0046] In a preferred embodiment, in the pharmaceutical dosage form
according to the invention and the pharmaceutical composition
according to the invention, respectively, the relative molar ratio
of the first pharmacologically active ingredient to the second
pharmacologically active ingredient is within the range of from
1:100 to 1:10,000, more preferably 1:200 to 1:7,500, still more
preferably 1:500 to 1:5,000, most preferably 1:750 to 1:2,500, and
in particular 1:900 to 1:2,000.
[0047] In another preferred embodiment, in the pharmaceutical
dosage form according to the invention and the pharmaceutical
composition according to the invention, respectively, the relative
molar ratio of the first pharmacologically active ingredient to the
second pharmacologically active ingredient is within the range of
from 1:1,000 to 1:20,000, more preferably 1:2,000 to 1:15,000,
still more preferably 1:3,000 to 1:12,500, yet more preferably
1:4,000 to 1:12,000, most preferably 1:5,000 to 1:10,000, and in
particular 1:6,000 to 1:9,000.
[0048] In still another preferred embodiment, in the pharmaceutical
dosage form according to the invention and the pharmaceutical
composition according to the invention, respectively, the relative
molar ratio of the first pharmacologically active ingredient to the
second pharmacologically active ingredient is within the range of
from 1:1,000 to 1:100,000, more preferably 1:2,000 to 1:80,000,
still more preferably 1:4,000 to 1:50,000, yet more preferably
1:6,000 to 1:20,000, most preferably 1:8,000 to 1:15,000, and in
particular 1:9,000 to 1:12,500.
[0049] In yet another preferred embodiment, in the pharmaceutical
dosage form according to the invention and the pharmaceutical
composition according to the invention, respectively, the relative
molar ratio of the first pharmacologically active ingredient to the
second pharmacologically active ingredient is within the range of
from 1:5,000 to 1:500,000, more preferably 1:10,000 to 1:400,000,
still more preferably 1:20,000 to 1:300,000, most preferably
1:40,000 to 1:200,000, and in particular 1:50,000 to 1:100,000.
[0050] In a further preferred embodiment, in the pharmaceutical
dosage form according to the invention and the pharmaceutical
composition according to the invention, respectively, the relative
molar ratio of the first pharmacologically active ingredient to the
second pharmacologically active ingredient is within the range of
from 1:100,000 to 1:1,900,000, more preferably 1:250,000 to
1:1,800,000, still more preferably 1:300,000 to 1:700,000, most
preferably 1:350,000 to 1:650,000, and in particular 1:400,000 to
1:600,000.
[0051] The amounts of the first and the second pharmacologically
active ingredient contained in the pharmaceutical dosage form
according to the invention may vary depending on different factors
well known to those skilled in the art, for example, the weight of
the patient, the route of administration, the severity of the
illness and the like.
[0052] In general, both pharmacologically active ingredients
contained in the pharmaceutical dosage form according to the
invention may be administered in amounts up to their maximum daily
dose, which is known to those skilled in the art. As the second
pharmacologically active ingredient, paracetamol may preferably be
administered to a patient in a maximum daily dose of up to 4,000
mg, and propacetamol may preferably be administered to a patient in
a maximum daily dose of up to 8,000 mg.
[0053] When administered in the prescribed manner, e.g. once daily
or twice daily, the pharmaceutical dosage form according to the
invention and the pharmaceutical composition according to the
invention, respectively, preferably contain the first and the
second pharmacologically active ingredient, independently of one
another, in an amount corresponding to 75.+-.15 wt.-%, 75.+-.10
wt.-%, 75.+-.5 wt.-%, 50.+-.15 wt.-%, 50.+-.10 wt.-%, 50.+-.5
wt.-%, 25.+-.15 wt.-%, 25.+-.10 wt.-% or 25.+-.5 wt.-% of the
respective maximum daily dose of the first and the second
pharmacologically active ingredient, respectively.
[0054] Preferably, the pharmaceutical dosage form according to the
invention contains the first pharmacologically active ingredient in
a dose of from 0.1 .mu.g to 5,000 .mu.g, more preferably, 0.1 .mu.g
to 2,500 .mu.g, still more preferably 1.0 .mu.g to 1,000 .mu.g, yet
more preferably 10 to 800 .mu.g, most preferably 15 .mu.g to 600
.mu.g, and in particular 20 .mu.g to 440 .mu.g.
[0055] In a preferred embodiment, the pharmaceutical dosage form
according to the invention contains the first pharmacologically
active ingredient in a dose within the range of 13.+-.12 .mu.g,
more preferably 13.+-.10 .mu.g, still more preferably 13.+-.8
.mu.g, yet more preferably 13.+-.6 .mu.g, even more preferably
13.+-.5 .mu.g, most preferably 13.+-.4 .mu.g, and in particular
13.+-.3 .mu.g.
[0056] In another preferred embodiment, the pharmaceutical dosage
form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
20.+-.15 .mu.g, more preferably 20.+-.13 .mu.g, still more
preferably 20.+-.12 .mu.g, yet more preferably 20.+-.10 .mu.g, even
more preferably 20.+-.8 .mu.g, most preferably 20.+-.6 .mu.g, and
in particular 20.+-.5 .mu.g.
[0057] In still another preferred embodiment, the pharmaceutical
dosage form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
40.+-.35 .mu.g, more preferably 40.+-.30 .mu.g, still more
preferably 40.+-.25 .mu.g, yet more preferably 40.+-.20 .mu.g, even
more preferably 40.+-.15 .mu.g, most preferably 40.+-.10 .mu.g, and
in particular 40.+-.5 .mu.g.
[0058] In yet another preferred embodiment, the pharmaceutical
dosage form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
60.+-.50 .mu.g, more preferably 60.+-.40 .mu.g, still more
preferably 60.+-.30 .mu.g, yet more preferably 60.+-.20 .mu.g, most
preferably 60.+-.10 .mu.g, and in particular 60.+-.5 .mu.g.
[0059] In a further preferred embodiment, the pharmaceutical dosage
form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
80.+-.70 .mu.g, more preferably 80.+-.60 .mu.g, still more
preferably 80.+-.50 .mu.g, yet more preferably 80.+-.40 .mu.g, even
more preferably 80.+-.20 .mu.g, most preferably 80.+-.10 .mu.g, and
in particular 80.+-.5 .mu.g.
[0060] In still a further preferred embodiment, the pharmaceutical
dosage form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
100.+-.90 .mu.g, more preferably 100.+-.80 .mu.g, still more
preferably 100.+-.60 .mu.g, yet more preferably 100.+-.40 .mu.g,
even more preferably 100.+-.20 .mu.g, most preferably 100.+-.10
.mu.g, and in particular 100.+-.5 .mu.g.
[0061] In yet a further preferred embodiment, the pharmaceutical
dosage form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
120.+-.100 .mu.g, more preferably 120.+-.80 .mu.g, still more
preferably 120.+-.60 .mu.g, yet more preferably 120.+-.40 .mu.g,
even more preferably 120.+-.20 .mu.g, most preferably 120.+-.10
.mu.g, and in particular 120.+-.5 .mu.g.
[0062] In another preferred embodiment, the pharmaceutical dosage
form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
150.+-.90 .mu.g, more preferably 150.+-.80 .mu.g, still more
preferably 150.+-.60 .mu.g, yet more preferably 150.+-.40 .mu.g,
even more preferably 150.+-.20 .mu.g, most preferably 150.+-.10
.mu.g, and in particular 150.+-.5 .mu.g.
[0063] In still another preferred embodiment, the pharmaceutical
dosage form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
170.+-.130 .mu.g, more preferably 170.+-.100 .mu.g, still more
preferably 170.+-.80 .mu.g, yet more preferably 170.+-.60 .mu.g,
even more preferably 170.+-.40 .mu.g, most preferably 170.+-.20
.mu.g, and in particular 170.+-.10 .mu.g.
[0064] In yet another preferred embodiment, the pharmaceutical
dosage form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
200.+-.175 .mu.g, more preferably 200.+-.150 .mu.g, still more
preferably 200.+-.125 .mu.g, yet more preferably 200.+-.100 .mu.g,
even more preferably 200.+-.75 .mu.g, most preferably 200.+-.50
.mu.g, and in particular 200.+-.25 .mu.g.
[0065] In a further preferred embodiment, the pharmaceutical dosage
form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
400.+-.350 .mu.g, more preferably 400.+-.300 .mu.g, still more
preferably 400.+-.250 .mu.g, yet more preferably 400.+-.200 .mu.g,
even more preferably 400.+-.150 .mu.g, most preferably 400.+-.100
.mu.g, and in particular 400.+-.50 .mu.g.
[0066] In another preferred embodiment, the pharmaceutical dosage
form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
600.+-.400 .mu.g, more preferably 600.+-.300 .mu.g, still more
preferably 600.+-.250 .mu.g, yet more preferably 600.+-.200 .mu.g,
even more preferably 600.+-.150 .mu.g, most preferably 600.+-.100
.mu.g, and in particular 600.+-.50 .mu.g.
[0067] In still another preferred embodiment, the pharmaceutical
dosage form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
800.+-.550 .mu.g, more preferably 800.+-.400 .mu.g, still more
preferably 800.+-.350 .mu.g, yet more preferably 800.+-.250 .mu.g,
even more preferably 800.+-.150 .mu.g, most preferably 800.+-.100
.mu.g, and in particular 800.+-.50 .mu.g.
[0068] In yet another preferred embodiment, the pharmaceutical
dosage form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
1,000.+-.800 .mu.g, more preferably 1,000.+-.600 .mu.g, still more
preferably 1,000.+-.500 .mu.g, yet more preferably 1,000.+-.300
.mu.g, even more preferably 1,000.+-.200 .mu.g, most preferably
1,000.+-.100 .mu.g, and in particular 1,000.+-.50 .mu.g.
[0069] In a further preferred embodiment, the pharmaceutical dosage
form according to the invention contains the first
pharmacologically active ingredient in a dose within the range of
1,200.+-.1,000 .mu.g, more preferably 1,200.+-.800 .mu.g, still
more preferably 1,200.+-.600 .mu.g, yet more preferably
1,200.+-.400 .mu.g, even more preferably 1,200.+-.200 .mu.g, most
preferably 1,200.+-.100 .mu.g, and in particular 1,200.+-.50
.mu.g.
[0070] Preferably, the pharmaceutical dosage form according to the
invention contains the second pharmacologically active ingredient
in a dose of from 1.0 mg to 12,500 mg, more preferably, 10 mg to
10,000 mg, and most preferably 100 mg to 8,000 mg, and in
particular 200 mg to 7,000 mg.
[0071] In a preferred embodiment, the pharmaceutical dosage form
according to the invention contains the second pharmacologically
active ingredient in a dose within the range of 150.+-.120 mg, more
preferably 150.+-.100 mg, still more preferably 150.+-.90 mg, yet
more preferably 150.+-.75 mg, even more preferably 150.+-.60 mg,
most preferably 150.+-.50 mg, and in particular 150.+-.25 mg.
[0072] In another preferred embodiment, the pharmaceutical dosage
form according to the invention contains the second
pharmacologically active ingredient in a dose within the range of
300.+-.250 mg, more preferably 300.+-.200 mg, still more preferably
300.+-.150 mg, yet more preferably 300.+-.125 mg, even more
preferably 300.+-.100 mg, most preferably 300.+-.75 mg, and in
particular 300.+-.50 mg.
[0073] In still another preferred embodiment, the pharmaceutical
dosage form according to the invention contains the second
pharmacologically active ingredient in a dose within the range of
500.+-.400 mg, more preferably 500.+-.300 mg, still more preferably
500.+-.200 mg, yet more preferably 500.+-.150 mg, even more
preferably 500.+-.100 mg, most preferably 500.+-.75 mg, and in
particular 500.+-.50 mg.
[0074] In yet another preferred embodiment, the pharmaceutical
dosage form according to the invention contains the second
pharmacologically active ingredient in a dose within the range of
750.+-.500 mg, more preferably 750.+-.400 mg, still more preferably
750.+-.250 mg, yet more preferably 750.+-.100 mg, even more
preferably 750.+-.75 mg, most preferably 750.+-.50 mg, and in
particular 750.+-.25 mg.
[0075] In a further preferred embodiment, the pharmaceutical dosage
form according to the invention contains the second
pharmacologically active ingredient in a dose within the range of
1,000.+-.500 mg, more preferably 1,000.+-.400 mg, still more
preferably 1,000.+-.250 mg, yet more preferably 1,000.+-.100 mg,
even more preferably 1,000.+-.75 mg, most preferably 1,000.+-.50
mg, and in particular 1,000.+-.25 mg.
[0076] In a still further preferred embodiment, the pharmaceutical
dosage form according to the invention contains the second
pharmacologically active ingredient in a dose within the range of
1,500.+-.500 mg, more preferably 1,500.+-.400 mg, still more
preferably 1,500.+-.250 mg, yet more preferably 1,500.+-.100 mg,
even more preferably 1,500.+-.75 mg, most preferably 1,500.+-.50
mg, and in particular 1,500.+-.25 mg.
[0077] In a preferred embodiment, the pharmaceutical dosage form
according to the invention contains the second pharmacologically
active ingredient in a dose within the range of 1,800.+-.1,000 mg,
more preferably 1,800.+-.750 mg, still more preferably 1,800.+-.500
mg, yet more preferably 1,800.+-.300 mg, even more preferably
1,800.+-.200 mg, most preferably 1,800.+-.100 mg, and in particular
1,800.+-.50 mg.
[0078] In another preferred embodiment, the pharmaceutical dosage
form according to the invention contains the second
pharmacologically active ingredient in a dose within the range of
2,000.+-.1,000 mg, more preferably 2,000.+-.750 mg, still more
preferably 2,000.+-.500 mg, yet more preferably 2,000.+-.300 mg,
even more preferably 2,000.+-.200 mg, most preferably 2,000.+-.100
mg, and in particular 2,000.+-.50 mg.
[0079] In a preferred embodiment, the pharmaceutical dosage form
contains paracetamol as the second pharmacologically active
ingredient in a dose within the range of 100 mg to 1,500 mg, more
preferably in the range of 200 mg to 1,200 mg, even more preferably
in the range of 250 mg to 900 mg, most preferably in the range of
300 mg to 750 mg and in particular in the range of 400 mg to 600
mg.
[0080] In another preferred embodiment, the pharmaceutical dosage
form contains paracetamol as the second pharmacologically active
ingredient in a dose within the range of 200 mg to 2,000 mg, more
preferably in the range of 400 mg to 1,800 mg, even more preferably
in the range of 600 mg to 1,500 mg, most preferably in the range of
750 mg to 1,300 mg, and in particular in the range of 800 mg to
1,200 mg.
[0081] In a further preferred embodiment, the pharmaceutical dosage
form contains paracetamol as the second pharmacologically active
ingredient in a dose within the range of 500 mg to 4,000 mg, more
preferably in the range of 1,000 mg to 3,000 mg, even more
preferably in the range of 1,400 mg to 2,600 mg, most preferably in
the range of 1,600 mg to 2,400 mg, and in particular in the range
of 1,800 mg to 2,200 mg.
[0082] In a preferred embodiment, the pharmaceutical dosage form
contains propacetamol as the second pharmacologically active
ingredient in a dose within the range of 200 mg to 2,000 mg, more
preferably in the range of 400 mg to 1,800 mg, even more preferably
in the range of 600 mg to 1,500 mg, most preferably in the range of
750 mg to 1,300 mg, and in particular in the range of 800 mg to
1,200 mg.
[0083] In another preferred embodiment, the pharmaceutical dosage
form contains propacetamol as the second pharmacologically active
ingredient in a dose within the range of 500 mg to 3,000 mg, more
preferably in the range of 800 mg to 2,400 mg, even more preferably
in the range of 1,000 mg to 2,000 mg, most preferably in the range
of 1,200 mg to 1,750 mg, and in particular in the range of 1,400 mg
to 1,600 mg.
[0084] In still another preferred embodiment, the pharmaceutical
dosage form contains propacetamol as the second pharmacologically
active ingredient in a dose within the range of 500 mg to 4,000 mg,
more preferably in the range of 750 mg to 3,500 mg, even more
preferably in the range of 1,000 mg to 3,000 mg, most preferably in
the range of 1,500 mg to 2,500 mg, and in particular in the range
of 1,800 mg to 2,200 mg.
[0085] In the pharmaceutical dosage form according to the
invention, the dose of the first pharmacologically active
ingredient is preferably within the range of from 1:20 to 20:1 of
the amount which is equieffective to the dosage of the second
pharmacologically active ingredient. In this regard,
"equieffective" preferably means the dosage that would be required
in order to achieve the equivalent desired therapeutic effect when
being administered alone. A skilled person recognizes that when the
desired therapeutic effect is an analgesic effect, the
equieffective dosage is determined with respect to the analgesic
properties of the first pharmacologically active ingredient and the
second pharmacological ingredient.
[0086] For example, when the dose of the second pharmacologically
active ingredient, which is contained in the pharmaceutical dosage
form according to the invention, amounts to e.g. 30 mg and provides
an analgesic effect E when being administered alone at this dose,
and when the equieffective amount of the first pharmacologically
active ingredient, i.e. the amount needed in order to provide the
same analgesic effect E when being administered alone, would be
e.g. 4 .mu.g, the dosage of the first pharmacologically active
ingredient, which is contained in the pharmaceutical dosage form
according to the invention, may vary from 0.2 .mu.g (4 .mu.g/20) to
80 .mu.g (20.4 .mu.g).
[0087] In a preferred embodiment, the dose of the first
pharmacologically active ingredient is within the range of from
1:15 to 15:1, preferably within the range of from 1:10 to 10:1,
more preferably within the range of from 1:8 to 8:1, still more
preferably within the range of from 1:6 to 6:1, yet more preferably
within the range of from 1:4 to 4:1, most preferably within the
range of from 1:3 to 3:1, and in particular preferably within the
range of from 1:2 to 2:1, of the amount which is equieffective to
the dose of the second pharmacologically active ingredient.
[0088] Suitable pathways of administration of the pharmaceutical
dosage form according to the invention include but are not limited
to oral, intravenous, intraperitoneal, intradermal, transdermal,
intrathecal, intramuscular, intranasal, transmucosal, subcutaneous,
local and/or rectal administration.
[0089] In a preferred embodiment, the pharmaceutical dosage form
according to the invention is for oral administration.
[0090] In another preferred embodiment, the pharmaceutical dosage
form according to the invention is for parenteral administration,
in particular intravenous, intraperitoneal, intrathecal,
intramuscular, or subcutaneous administration.
[0091] In still another preferred embodiment, the pharmaceutical
dosage form according to the invention is for rectal
administration.
[0092] The pharmaceutical dosage form according to the invention
and the pharmaceutical composition according to the invention,
respectively, can be solid, semi-solid or liquid.
[0093] The pharmaceutical dosage form according to the invention
and the pharmaceutical composition according to the invention,
respectively, may contain auxiliary agents, for example, carriers,
fillers, solvents, diluents, colorants and/or binders. The
selection of auxiliary agents and of the amounts of the same to be
used depends, for example, on how the first and the second
pharmacologically active ingredient are to be administered, e.g.
orally, intravenously, intraperitoneally, intradermally,
transdermally, intrathecally, intramuscularly, intranasally,
transmucosally, subcutaneously, rectally or locally.
[0094] Suitable auxiliary agents are in particular any substances
known to a person skilled in the art useful for the preparation of
galenical dosage forms. Examples of suitable auxiliary agents
include but are not limited to: water, ethanol, 2-propanol,
glycerol, ethylene glycol, propylene glycol, polyethylene glycol,
polypropylene glycol, glucose, fructose, lactose, saccharose,
dextrose, molasses, starch, modified starch, gelatine, sorbitol,
inositol, mannitol, microcrystalline cellulose, methyl cellulose,
carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol,
polyvinyl pyrrolidone, paraffins, waxes, natural and synthetic
gums, acacia gum, alginates, dextran, saturated and unsaturated
fatty acids, stearic acid, magnesium stearate, zinc stearate,
glycerol stearate, sodium lauryl sulphate, edible oils, sesame oil,
coconut oil, peanut oil, soybean oil, lecithin, sodium lactate,
polyoxyethylene and polypropylene fatty acid ester, sorbitan fatty
acid ester, sorbic acid, benzoic acid, citric acid, ascorbic acid,
tannic acid, sodium chloride, potassium chloride, magnesium
chloride, calcium chloride, magnesium oxide, zinc oxide, silicon
dioxide, titanium oxide, titanium dioxide, magnesium sulphate, zinc
sulphate, calcium sulphate, potash, calcium phosphate, dicalcium
phosphate, potassium bromide, potassium iodide, talcum, kaolin,
pectin, crosspovidone, agar and bentonite.
[0095] Pharmaceutical dosage forms which are suitable for oral
administration include but are not limited to tablets, effervescent
tablets, chewing tablets, dragees, capsules, drops, juices and
syrups. Oral pharmaceutical dosage forms may also be in the form of
multiparticulates such as granules, pellets, spheres, crystals and
the like, optionally compressed into a tablet, filled into a
capsule, filled into a sachet or suspended in a suitable liquid
medium. Oral pharmaceutical dosage forms may also be equipped with
an enteric coating.
[0096] Pharmaceutical dosage forms that are suitable for
parenteral, topical and inhalative administration include but are
not limited to solutions, suspensions, easily reconstitutable dry
preparations and sprays.
[0097] Suppositories are a suitable pharmaceutical dosage form for
rectal administration. Dosage forms in a deposit, in dissolved
form, for example, in a patch optionally with the addition of
agents to promote skin penetration, are examples of suitable dosage
forms for percutaneous administration.
[0098] In an especially preferred embodiment, the pharmaceutical
dosage form according to the invention is a tablet.
[0099] Preferably, the pharmaceutical dosage form according to the
invention is for administration six times daily, five times daily,
four times daily, thrice daily, twice daily, once daily, or less
frequently.
[0100] In a preferred embodiment, the pharmaceutical dosage form
according to the invention is for administration once daily.
[0101] In another preferred embodiment, the pharmaceutical dosage
form according to the invention is for administration multiple
daily, in particular twice daily, thrice daily, or up to six times
a day.
[0102] In a preferred embodiment, the pharmaceutical dosage form
according to the invention is for administration twice daily.
[0103] In another preferred embodiment, the pharmaceutical dosage
form according to the invention is for administration thrice
daily.
[0104] For the purpose of specification, "administration thrice
daily" (tid) preferably means that the pharmaceutical dosage form
according to the invention is adapted for being consecutively
administered according to a regimen comprising the administration
of three pharmaceutical dosage forms per day, wherein the time
interval between the consecutive administration of two
pharmaceutical dosage forms is at least 3 hours, preferably at
least 4 hours, more preferably not least 6 hours and in particular,
about 8 hours.
[0105] For the purpose of specification, "administration twice
daily" (bid) preferably means that the pharmaceutical dosage form
according to the invention is adapted for being consecutively
administered according to a regimen comprising the administration
of two pharmaceutical dosage forms per day, wherein the time
interval between the consecutive administration of two
pharmaceutical dosage forms is at least 6 hours, preferably at
least 8 hours, more preferably at least 10 hours and in particular,
about 12 hours.
[0106] For the purpose of specification, "administration once
daily" (sid) preferably means that the pharmaceutical dosage form
according to the invention is adapted for being consecutively
administered according to a regimen comprising the administration
of one pharmaceutical dosage form per day, wherein the time
interval between the consecutive administration of two
pharmaceutical dosage forms is at least 18 hours, preferably at
least 20 hours, more preferably at least 22 hours and in
particular, about 24 hours.
[0107] A skilled person is fully aware that the above
administration regimens may be realized by administering a single
pharmaceutical dosage form containing the full amount of the first
pharmacologically active ingredient and the full amount of the
second pharmacologically active ingredient to be administered at a
particular point in time or, alternatively, administering a
multitude of dose units, i.e. two, three or more dose units, the
sum of which multitude of dose units containing the full amount of
the first pharmacologically active ingredient and the second
pharmacologically active ingredient to be administered at said
particular point in time, where the individual dose units are
adapted for simultaneous administration or administration within a
short period of time, e.g. within 5, 10 or 15 minutes.
[0108] In the following, the doses of the first and the second
pharmacologically active ingredient are expressed according to the
number of prescribed administrations "n" per day, i.e. the number
of administrations of the pharmaceutical dosage form according to
the invention in the course of 24 hours. As an example, 100/n .mu.g
in case of an administration once daily (n=1) corresponds to a dose
of 100 .mu.g, and 100/n .mu.g in case of an administration twice
daily (n=2) corresponds to a dose of 50 .mu.g.
[0109] In a preferred embodiment, the pharmaceutical dosage form
according to the invention is for administration once daily (n=1),
wherein the pharmaceutical dosage form contains the first
pharmacologically active ingredient in a dose of from 15/n to 100/n
.mu.g, preferably 20/n to 80/n .mu.g, and the second
pharmacologically active ingredient in a dose of from 1,000/n to
8,000/n mg. According to this embodiment, the pharmaceutical dosage
form according to the invention is preferably for oral
administration, preferably in form of a tablet.
[0110] In another preferred embodiment, the pharmaceutical dosage
form according to the invention is for administration multiple
daily (n=2, 3, 4, 5 or 6), wherein the pharmaceutical dosage form
contains the first pharmacologically active ingredient in a dose of
from 15/n to 100/n .mu.g, preferably 20/n to 80/n .mu.g, and the
second pharmacologically active ingredient in a dose of from
1,000/n to 8,000/n mg. According to this embodiment, the
pharmaceutical dosage form according to the invention is preferably
for oral administration, preferably in form of a tablet. Further,
according to this embodiment, an administration thrice daily (n=3)
or four times daily (n=4), in particular of paracetamol, can be
especially preferred since the preferred dose of paracetamol may be
as high as 4,000/n mg, thus rendering a tablet containing e.g. a
maximum of 4,000/3 mg or 4,000/4 mg of paracetamol much more
patient compliant.
[0111] In still another preferred embodiment, the pharmaceutical
dosage form according to the invention is for administration once
daily (n=1), wherein the pharmaceutical dosage form contains the
first pharmacologically active ingredient in a dose of from 150/n
to 1,200/n .mu.g, preferably 200/n to 800/n .mu.g, and the second
pharmacologically active ingredient in a dose of from 1,000/n to
8,000/n mg. According to this embodiment, the pharmaceutical dosage
form according to the invention is preferably for oral
administration, preferably in form of a tablet.
[0112] In yet another preferred embodiment, the pharmaceutical
dosage form according to the invention is for administration
multiple daily (n=2, 3, 4, 5 or 6), wherein the pharmaceutical
dosage form contains the first pharmacologically active ingredient
in a dose of from 150/n to 1,200/n .mu.g, preferably 200/n to 800/n
.mu.g, and the second pharmacologically active ingredient in a dose
of from 1,000/n to 8,000/n mg. According to this embodiment, the
pharmaceutical dosage form according to the invention is preferably
for oral administration, preferably in form of a tablet. Further,
according to this embodiment, an administration thrice daily (n=3)
or four times daily (n=4), in particular of paracetamol, can be
especially preferred since the preferred dose of paracetamol may be
as high as 4,000/n mg, thus rendering a tablet containing e.g. a
maximum of 4,000/3 mg or 4,000/4 mg of paracetamol much more
patient compliant.
[0113] The pharmaceutical dosage form according to the invention
may provide under in vitro conditions immediate release or
controlled release of the first pharmacologically active ingredient
and/or the second pharmacologically active ingredient. In vitro
release is preferably determined in accordance with Ph. Eur.,
preferably paddle method with sinker, 75 rpm, 37.degree. C., 900 mL
artificial gastric juice, pH 6.8.
[0114] The first pharmacologically active ingredient and/or the
second pharmacologically active ingredient may independently of one
another be present in the pharmaceutical dosage form at least
partially in controlled-release form. For example, the first
pharmacologically active ingredient and/or the second
pharmacologically active ingredient may be released from the
pharmaceutical dosage form in a prolonged manner, e.g. if
administered orally, rectally or percutaneously. Such
pharmaceutical dosage forms are particularly useful for
"once-daily" or "twice-daily" preparations, which only have to be
taken once a day, respectively, twice a day. Suitable
controlled-release materials are well known to those skilled in the
art.
[0115] The pharmaceutical dosage form according to the invention
providing controlled release of the first pharmacologically active
ingredient and/or the second pharmacologically active ingredient
may be produced using materials, means, devices and processes that
are well known in the prior art of pharmaceutical dosage forms.
[0116] In order to obtain a solid pharmaceutical dosage form such
as a tablet, for example, the pharmacologically active ingredients
of the pharmaceutical composition may be granulated with a
pharmaceutical carrier, for example conventional tablet ingredients
such as corn starch, lactose, saccharose, sorbitol, talcum,
magnesium stearate, dicalcium phosphate or pharmaceutically
acceptable gums, and pharmaceutical diluents, for example water, in
order to form a solid composition that contains the
pharmacologically active ingredients in homogeneous distribution.
The term "homogeneous distribution" is taken to mean that the
pharmacologically active ingredients are distributed uniformly over
the entire composition, so that said composition may easily be
divided into equally effective dose units, such as tablets, pills
or capsules and the like. The solid composition is then divided
into dose units. The tablets or pills of the pharmaceutical
composition according to the invention may also be coated or
compounded in a different manner, in order to provide a dosage form
with a controlled release.
[0117] If one of the pharmacologically active ingredients is to be
released prior to the other pharmacologically active ingredient,
for example at least 30 minutes or 1 hour beforehand,
pharmaceutical dosage forms having a corresponding release profile
may be prepared. An example of such a pharmaceutical dosage form is
an osmotically-driven release system for achieving a delayed
release of either the first or the second pharmacologically active
ingredient from an inner part (core) of the pharmaceutical dosage
form via a coating that itself contains the other pharmacologically
active ingredient which is accordingly released earlier. In a
release system of this kind, which is particularly suitable for
oral administration, at least part, and preferably all, of the
surface of the release system, preferably those parts that will
come into contact with the release medium, is/are semipermeable,
preferably equipped with a semipermeable coating, so the surface(s)
is/are permeable to the release medium, but substantially,
preferably entirely, impermeable to the pharmacologically active
ingredient contained in the core, the surface(s) and/or optionally
the coating comprising at least one opening for releasing the
pharmacologically active ingredient contained in the core.
Moreover, precisely that/those surface(s) that is/are in contact
with the release medium is/are provided with a coating containing
and releasing the other pharmacologically active ingredient. This
is preferably taken to mean a system in tablet form comprising a
release opening, a core containing the first or the second
pharmacologically active ingredient, a polymer portion that exerts
pressure upon swelling, a semipermeable membrane and a coating
containing the other pharmacologically active ingredient.
Embodiments and examples of osmotically-driven release systems are,
for example, disclosed in U.S. Pat. Nos. 4,765,989, 4,783,337 and
4,612,008.
[0118] A further example of a suitable pharmaceutical dosage form
is a gel-matrix tablet. Suitable examples are provided in U.S. Pat.
Nos. 4,389,393, 5,330,761, 5,399,362, 5,472,711 and 5,455,046.
Particularly suitable is a retarding matrix dosage form, with an
inhomogeneous distribution of the pharmaceutical composition,
whereby, for example, one pharmacologically active ingredient, i.e.
the first or the second pharmacologically active ingredient, is
distributed in the outer region (the portion that comes into
contact with the release medium most quickly) of the matrix and the
other pharmacologically active ingredient is distributed inside the
matrix. On contact with the release medium, the outer matrix layer
initially (and rapidly) swells and firstly releases the
pharmacologically active ingredient contained therein, followed by
the significantly (more) controlled release of the other
pharmacologically active ingredient. Examples of a suitable matrix
include matrices with 1 to 80% by weight of one or more hydrophilic
or hydrophobic polymers as pharmaceutically acceptable matrix
formers.
[0119] Preferably, the pharmaceutical dosage form according to the
invention provides immediate release of the first pharmacologically
active ingredient, and immediate or controlled release of the
second pharmacologically active ingredient.
[0120] In a preferred embodiment, the pharmaceutical dosage form
according to the invention provides immediate release of both, the
first and the second pharmacologically active ingredient. In this
particular case, a multiple daily administration, in particular an
administration twice daily, thrice daily, or up to six times a day
is preferred.
[0121] In another preferred embodiment, the pharmaceutical dosage
form according to the invention provides immediate release of the
first pharmacologically active ingredient, and controlled release
of the second pharmacologically active ingredient. This release
profile may be realized by employing the aforementioned methods,
e.g. the osmotically-driven release system providing the first
pharmacologically active ingredient in the coating and the second
pharmacologically active ingredient in the core, or the retarding
matrix dosage form containing the first pharmacologically active
ingredient in the outer matrix layer and the second
pharmacologically active ingredient in the inside of the
matrix.
[0122] In yet another preferred embodiment, the pharmaceutical
dosage form according to the invention provides controlled release
of both the first and the second pharmacologically active
ingredient.
[0123] In a further aspect, the invention relates to the use of the
pharmaceutical composition according to the invention, and the
pharmaceutical dosage form according to the invention respectively,
in the prevention or treatment of pain, anxiety or epilepsy.
[0124] In a preferred embodiment, the pharmaceutical composition
according to the invention and the pharmaceutical dosage form
according to the invention, respectively, are for use in the
treatment of pain, wherein the pain is preferably [0125]
peripheral, central or muscle skeletal pain; and/or [0126] acute,
subacute or chronic pain; and/or [0127] moderate to severe pain;
and/or [0128] neuropathic or psychogenic or nociceptive or mixed
pain; and/or [0129] low back pain, visceral pain or headache;
and/or [0130] post-operative (post-surgical), cancer or
inflammatory pain.
[0131] For the purpose of specification, "acute pain" preferably
refers to pain that lasts up to about 4 weeks, "subacute pain"
preferably refers to pain that lasts from more than about 4 weeks
to about 12 weeks, and "chronic pain" preferably refers to pain
that lasts for more than about 12 weeks.
[0132] Preferably, the pain is selected from the group consisting
of cancer pain, peripheral neuropathic pain, osteoarthritis,
chronic visceral pain, neuropathic pain (diabetic polyneuropathy,
HIV-associated neuropathic pain, posttraumatic neuropathic pain,
postherpetic neuralgia, chemotherapy associated pain), postzosteric
neuralgia, postoperative neuropathic pain, inflammatory pain,
migraine, low-back pain, fibromyalgia and trigeminal neuralgia.
[0133] In a preferred embodiment, the pain is chronic pain, in
particular chronic nociceptive pain and/or chronic inflammatory
pain.
[0134] In another preferred embodiment, the pain is non-chronic or
acute pain, in particular post-operative pain (post-surgical
pain).
[0135] In a further preferred embodiment, the pain is selected from
the group consisting of diabetic polyneuropathy, postzosteric
neuralgia, postoperative neuropathic pain, low-back pain and
fibromyalgia.
[0136] In the following, the doses of the first and the second
pharmacologically active ingredient are again expressed according
to the number of administrations "n" per day, i.e. the number of
administrations of the pharmaceutical dosage form according to the
invention in the course of 24 hours.
[0137] In a preferred embodiment, the pharmaceutical dosage form is
for use in the treatment of neuropathic pain which may be
optionally superimposed by nociceptive pain, where the dose of the
first pharmacologically active ingredient contained in the
pharmaceutical dosage form preferably is in the range of 1/n .mu.g
to 800/n .mu.g or 1/n .mu.g to 600/n .mu.g or 1/n .mu.g to 400/n
.mu.g or 1/n .mu.g to 250/n .mu.g, more preferably in the range of
5/n .mu.g to 150/n .mu.g, even more preferably in the range of 10/n
.mu.g to 100/n .mu.g, most preferably in the range of 20/n .mu.g to
80/n .mu.g and in particular most preferably in the range of 30/n
.mu.g to 50/n .mu.g. According to this embodiment, the dose of the
second pharmacologically active ingredient contained in the
pharmaceutical dosage form preferably is in the range of 500/n mg
to 8,000/n mg.
[0138] In a preferred embodiment, in particular when the
pharmaceutical dosage form is for use in the treatment of
neuropathic pain and the second pharmacologically active ingredient
is paracetamol, the dose of the first pharmacologically active
ingredient contained in the pharmaceutical dosage form preferably
is in the range of 1/n .mu.g to 800/n .mu.g or 1/n .mu.g to 600/n
.mu.g or 1/n .mu.g to 400/n .mu.g or 1/n .mu.g to 250/n .mu.g, more
preferably in the range of 5/n .mu.g to 150/n .mu.g, even more
preferably in the range of 10/n .mu.g to 100/n .mu.g, most
preferably in the range of 20/n .mu.g to 80/n .mu.g and in
particular most preferably in the range of 30/n .mu.g to 50/n
.mu.g; and the dose of the second pharmacologically active
ingredient contained in the pharmaceutical dosage form preferably
is in the range of 500/n mg to 4,000/n mg, more preferably in the
range of 750/n mg to 3,900/n mg, even more preferably in the range
of 1,000/n mg to 3,800/n mg, most preferably in the range of
1,500/n mg to 3,650/n mg and in particular in the range of 2,000/n
mg to 3,500/n mg.
[0139] In another preferred embodiment, in particular when the
pharmaceutical dosage form is for use in the treatment of
neuropathic pain and the second pharmacologically active ingredient
contained in the pharmaceutical dosage form is propacetamol, the
dose of the first pharmacologically active ingredient preferably is
in the range of 1/n .mu.g to 800/n .mu.g or 1/n .mu.g to 600/n
.mu.g or 1/n .mu.g to 400/n .mu.g or 1/n .mu.g to 250/n .mu.g, more
preferably in the range of 5/n .mu.g to 150/n .mu.g, even more
preferably in the range of 10/n .mu.g to 100/n .mu.g, most
preferably in the range of 20/n .mu.g to 80/n .mu.g and in
particular most preferably in the range of 30/n .mu.g to 50/n
.mu.g; and the dose of the second pharmacologically active
ingredient contained in the pharmaceutical dosage form preferably
is in the range of 1,000/n mg to 8,000/n mg, more preferably in the
range of 1,500/n mg to 7,800/n mg, even more preferably in the
range of 2,000/n mg to 7,600/n mg, most preferably in the range of
3,000/n mg to 7,300/n mg and in particular in the range of 4,000/n
mg to 7,000/n mg.
[0140] In another preferred embodiment, the pharmaceutical dosage
form is for use in the treatment of nociceptive pain which may be
optionally superimposed by neuropathic pain, where the dose of the
first pharmacologically active ingredient contained in the
pharmaceutical dosage form preferably is in the range of 50/n .mu.g
to 2,000/n .mu.g or 50/n .mu.g to 1,400/n .mu.g or 50/n .mu.g to
1,200/n .mu.g or 50/n .mu.g to 1,000/n .mu.g, more preferably in
the range of 100/n .mu.g to 800/n .mu.g, still more preferably in
the range of 150/n .mu.g to 650/n .mu.g, even more preferably in
the range of 250/n .mu.g to 550/n .mu.g, and most preferably in the
range of 350/n .mu.g to 450/n .mu.g. According to this embodiment,
the dose of the second pharmacologically active ingredient
contained in the pharmaceutical dosage form preferably is in the
range of 500/n mg to 8,000/n mg.
[0141] In a preferred embodiment, in particular when the
pharmaceutical dosage form is for use in the treatment of
nociceptive pain and the second pharmacologically active ingredient
is paracetamol, the dose of the first pharmacologically active
ingredient contained in the pharmaceutical dosage form preferably
is in the range of 50/n .mu.g to 2,000/n .mu.g or 50/n .mu.g to
1,400/n .mu.g or 50/n .mu.g to 1,200/n .mu.g or 50/n .mu.g to
1,000/n .mu.g, more preferably in the range of 100/n .mu.g to 800/n
.mu.g, still more preferably in the range of 150/n .mu.g to 650/n
.mu.g, even more preferably in the range of 250/n .mu.g to 550/n
.mu.g, and most preferably in the range of 350/n .mu.g to 450/n
.mu.g; and the dose of the second pharmacologically active
ingredient contained in the pharmaceutical dosage form preferably
is in the range of 500/n mg to 4,000/n mg, more preferably in the
range of 750/n mg to 3,900/n mg, even more preferably in the range
of 1,000/n mg to 3,800/n mg, most preferably in the range of
1,500/n mg to 3,650/n mg and in particular in the range of 2,000/n
mg to 3,500/n mg.
[0142] In another preferred embodiment, in particular when the
pharmaceutical dosage form is for use in the treatment of
nociceptive pain and the second pharmacologically active ingredient
is propacetamol, the dose of the first pharmacologically active
ingredient contained in the pharmaceutical dosage form preferably
is in the range of 50/n .mu.g to 2,000/n .mu.g or 50/n .mu.g to
1,400/n .mu.g or 50/n .mu.g to 1,200/n .mu.g or 50/n .mu.g to
1,000/n .mu.g, more preferably in the range of 100/n .mu.g to 800/n
.mu.g, still more preferably in the range of 150/n .mu.g to 650/n
.mu.g, even more preferably in the range of 250/n .mu.g to 550/n
.mu.g, and most preferably in the range of 350/n .mu.g to 450/n
.mu.g; and the dose of the second pharmacologically active
ingredient contained in the pharmaceutical dosage form preferably
is in the range of 1,000/n mg to 8,000/n mg, more preferably in the
range of 1,500/n mg to 7,800/n mg, even more preferably in the
range of 2,000/n mg to 7,600/n mg, most preferably in the range of
3,000/n mg to 7,300/n mg and in particular in the range of 4,000/n
mg to 7,000/n mg.
[0143] Preferably, the pharmaceutical composition contains the
first and the second pharmacologically active ingredient in such a
weight ratio that they will exert a synergistic therapeutic effect
upon administration to a patient. Thereby, the term "synergistic
therapeutic effect" may refer to a synergistic therapeutic effect
with respect to the prevention or treatment of pain (synergistic
analgesic effect), a synergistic therapeutic effect with respect to
the prevention or treatment of anxiety (synergistic anxiolytic
effect) as well as a synergistic therapeutic effect with respect to
the prevention or treatment of epilepsy (synergistic
anti-convulsive effect). Suitable weight ratios of the
pharmacologically active ingredients generating the synergistic
therapeutic effect can be determined by methods well known to those
skilled in the art.
[0144] A further aspect of the invention relates to a method of
treating or preventing pain, anxiety or epilepsy comprising the
preferably twice daily or once daily, preferably oral
administration of the pharmaceutical dosage form according to the
invention to a subject in need thereof.
[0145] In a particular preferred embodiment, [0146] the first
pharmacologically active ingredient is
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine according to formula (I) in
form of its free base, or a hemicitrate, hydrochloride or maleate
salt thereof; and/or [0147] the second pharmacologically active
ingredient is paracetamol; and/or [0148] the pharmaceutical
composition and the pharmaceutical dosage form, respectively,
contain the first pharmacologically active ingredient in a dose of
from 20 .mu.g to 80 .mu.g or of from 80 .mu.g to 200 .mu.g or of
from 200 .mu.g to 800 .mu.g or of from 800 .mu.g to 1,200 .mu.g;
and/or [0149] the pharmaceutical composition and the pharmaceutical
dosage form, respectively, contain the second pharmacologically
active ingredient in a dose of from 200 mg to 7,000 mg, in
particular in a dose of from 500 mg to 4,000 mg; and/or [0150] the
relative weight ratio of the first pharmacologically active
ingredient to the second pharmacologically active ingredient is
within the range of from 1:30 to 1:1,000,000, preferably 1:1,000 to
1:500,000 in the pharmaceutical composition and the pharmaceutical
dosage form, respectively; and/or [0151] the pharmaceutical
composition is for use in the treatment of pain; and/or [0152] the
pharmaceutical composition is for use in the treatment of pain,
wherein the pain is peripheral, central or muscle skeletal pain;
and/or acute, subacute or chronic pain; and/or moderate to severe
pain; and/or neuropathic or psychogenic or nociceptive or mixed
pain; and/or low back pain, visceral pain or headache; and/or
post-operative (post-surgical), cancer or inflammatory pain; and/or
[0153] the pharmaceutical composition and the pharmaceutical dosage
form, respectively, contain the first pharmacologically active
ingredient and the second pharmacologically active ingredient in
such a weight ratio that upon administration to a patient they will
exert a synergistic therapeutic effect; and/or [0154] the
pharmaceutical dosage form provides immediate release of the first
pharmacologically active ingredient in vitro in accordance with Ph.
Eur.; and/or [0155] the pharmaceutical dosage form provides
immediate or controlled release of the second pharmacologically
active ingredient in vitro in accordance with Ph. Eur.; and/or
[0156] the pharmaceutical dosage form is for oral administration;
and/or [0157] the pharmaceutical dosage form is for administration
once, twice or thrice daily, or four times daily.
[0158] In a further aspect, the invention relates to a kit
comprising a first pharmaceutical dosage form comprising the first
pharmacologically active ingredient as described above, and a
second pharmaceutical dosage form comprising the second
pharmacologically active ingredient as described above.
[0159] A suitable embodiment is a kit in which the first
pharmaceutical dosage from comprising the first pharmacologically
active ingredient and the second pharmaceutical dosage form
comprising the second pharmacologically active ingredient, although
spatially separated, are provided in a common presentation form,
e.g. packaging.
[0160] Preferably, the first and the second pharmaceutical dosage
form are adapted for simultaneous or sequential administration,
wherein the first pharmaceutical dosage form may be administered
before or after the second pharmaceutical dosage form and wherein
the first and the second pharmaceutical dosage form are
administered either via the same or a different pathway of
administration.
[0161] For the purpose of specification, the term "simultaneous
administration" preferably refers to an administration of the first
and the second pharmaceutical dosage form within a time span of 15
minutes from each other, whereas the term "sequential
administration" preferably refers to an administration of the first
and the second pharmaceutical dosage form within a time span of
more than 15 minutes from each other.
[0162] In a preferred embodiment, the first and the second
pharmaceutical dosage form are adapted for administration to the
patient via the same pathway.
[0163] In another preferred embodiment, the first and the second
pharmaceutical dosage form are adapted for administration to the
patient via different pathways.
[0164] In a preferred embodiment, the first and the second
pharmaceutical dosage form are administered simultaneously.
[0165] In another preferred embodiment, the first and the second
pharmaceutical dosage form are administered sequentially.
[0166] In a preferred embodiment, the first and/or the second
pharmaceutical dosage form are adapted for once daily
administration.
[0167] In another preferred embodiment, the first and/or the second
pharmaceutical dosage form are adapted for multiple daily
administration, in particular twice daily or thrice daily.
[0168] In a preferred embodiment, the first pharmaceutical dosage
form is adapted for once daily administration and the second
pharmaceutical dosage form is adapted for multiple daily, in
particular twice daily or thrice daily, administration.
[0169] Suitable pathways of administration of the pharmaceutical
dosage forms contained in the kit include but are not limited to
oral, intravenous, intraperitoneal, intradermal, intrathecal,
intramuscular, intranasal, transmucosal, subcutaneous, and/or
rectal administration.
[0170] In a preferred embodiment, one or both of the pharmaceutical
dosage forms contained in the the kit are for oral
administration.
[0171] In another preferred embodiment, one or both of the
pharmaceutical dosage forms contained in the kit are for parenteral
administration, in particular intravenous, intraperitoneal,
intrathecal, intramuscular, or subcutaneous administration.
[0172] In a preferred embodiment, the first and the second
pharmaceutical dosage form are for oral, simultaneous
administration once daily.
[0173] In another preferred embodiment, the first and the second
pharmaceutical dosage form are for oral, simultaneous
administration multiple daily, in particular twice daily, thrice
daily or four times daily.
[0174] In still another preferred embodiment, the first and the
second pharmaceutical dosage form are each for oral, sequential
administration once daily.
[0175] In a preferred embodiment, the first and the second
pharmaceutical dosage form are for sequential administration once
daily each, where the first and the second pharmaceutical dosage
form are adapted for administration via different pathways, e.g.
oral and parenteral administration.
[0176] In another preferred embodiment, the first and the second
pharmaceutical dosage form are each for oral, sequential
administration multiple daily, in particular twice daily, thrice
daily or four times daily.
[0177] In another preferred embodiment, the first and the second
pharmaceutical dosage form are for sequential administration
multiple daily each, in particular twice daily, thrice daily or
four times daily, where the first and the second pharmaceutical
dosage form are adapted for administration via different pathways,
e.g. oral and parenteral administration.
[0178] The following examples further illustrate the invention but
are not to be construed as limiting its scope.
[0179] Pharmacological Methods:
[0180] In the following, the first pharmacologically active
ingredient
(1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexa-
ne-1,1'-pyrano[3,4,b]indol]-4-amine was employed in form of the
hemicitrate salt. Therefore, all amounts of the first
pharmacologically active ingredient are specified with respect to
the hemicitrate salt.
[0181] As the second pharmacologically active ingredient,
Paracetamol was employed.
EXAMPLE 1
Paw Incision Model in Rats (Postoperative Pain)
[0182] The experiments were carried out in male albino rats
(Sprague Dawley) with 170 g-230 g body weight from a commercial
breeder (Janvier; France). The animals were housed under
standardized conditions: light/dark rhythm (06.00 h-18.00 h light,
18.00 h-06.00 h dark); room temperature 20.degree. C.-24.degree.
C.; relative air humidity 35%-70%; 15 air changes per hour, air
movement <0.2 m/sec. The animals were given tap water and a diet
of standard laboratory food (Ssniff R/M-Haltung, Ssniff
Spezialdiaten GmbH, Soest, Germany) ad libitum. Both were withdrawn
during the test. All rats were used only once. Ten rats were used
per experimental group. There were at least five days between
delivery of the animals and the day of surgery.
[0183] The rats were placed in a plastic cage with a wire mesh
bottom which allowed full access to the paws. Hind paw withdrawal
threshold after mechanical stimulation was tested with electronic
von Frey hairs (Somedic Sales AB, Horby, Sweden). Animals were
placed in a plastic cage with a wire mesh bottom which allowed full
access to the paws. Behavioral accommodation was allowed for 30
min. In each case, withdrawal response was measured at an area
adjacent to the wound (ipsilateral) and to the same area on the
non-injured foot (contralateral). Two hours after surgery, primary
hypersensitivity was tested as tactile withdrawal threshold shortly
before drug administration and at different time points after drug
application. Animals injected with vehicle served as controls. The
pretest measurement was made prior to surgery and two thresholds
were taken per test and averaged.
[0184] Surgery was performed as previously described (Brennan T.
J., Vandermeulen E. P., and Gebhart G. F., Characterization of a
rat model of incisional pain, Pain 1996; 64:493-501). Briefly, rats
were anaesthetised with isoflurane, and a 1 cm longitudinal
incision was made, through skin and fascia of the plantar aspect of
the foot, starting from the proximal edge of the heel and extending
toward the metatarsal toes. The plantaris muscle was elevated and
incised longitudinally. The muscle origin and insertion remained
intact. After spreading of the muscle and haemostasis with gentle
pressure, the skin was closed with two single interrupted sutures.
After surgery, the rats were allowed to recover in their home cages
and the animals regained consciousness within 2 to 5 minutes. In
order to ensure a complete recovery from anaesthesia the baseline
value of each individual animal was recorded not until 2 hours
after surgery.
[0185] The first pharmacologically active ingredient was dissolved
in 5% DMSO and 95% glucose solution (5%). The second
pharmacologically active ingredient was dissolved in 1% CMC in aqua
dest. Intravenous (i.v.) and intraperitoneal (i.p.) applications
were made in a volume of 5 mL/kg.
[0186] Data were recorded and the median was calculated from five
values of each animal and measurement.
[0187] The median values of the individual latencies are calculated
as the percentage of the Maximum Possible Effect (% MPE) according
to the following formula:
% MPE=100-[(value after application-pretest before
surgery)/(pretest after surgery-pretest before surgery)100]
[0188] The individual % MPE values were averaged for the respective
treatment group and expressed as mean % MPE.+-.standard error of
the mean (SEM).
[0189] The pharmacologically active ingredients were administered
using a logarithmically staggered dose scheme. The results are
presented in graphs as means.+-.SEM against the time after
surgery.
[0190] Data were analyzed by means of two-factor analysis of
variance (ANOVA) with repeated measures. Significance of
treatment-, time- or treatment.times.time interaction effects was
analyzed by means of Wilks' Lambda statistics. In case of a
significant treatment effect, pair-wise comparison was performed at
the different time points effect by Fisher's least significant
difference test. Results were considered statistically significant
if p<0.05.
[0191] The interaction studies presented herein were performed by
comparison of the theoretically additive effect of defined doses of
the first and the second pharmacologically active ingredient with
the experimental determined effect of their combination.
[0192] The application route was intravenous (i.v.) for the first
pharmacologically active ingredient and intraperitoneal (i.p.) for
the second pharmacologically active ingredient.
[0193] Tests were performed using doses of 0.00464 mg/kg body
weight to 0.0068 mg/kg body weight of the first pharmacologically
active ingredient and 215 mg/kg body weight of Paracetamol as the
second pharmacologically active ingredient.
[0194] When administered in combination, the first
pharmacologically active ingredient (0.00464 mg/kg body weight
i.v.) and the second pharmacologically active ingredient
(Paracetamol, 215 mg/kg body weight i.p.) showed an analgesic
efficacy with a maximal effect of 33% MPE at 30 min. The analysis
showed additive interaction of the first pharmacologically active
ingredient and the second pharmacologically active ingredient.
[0195] When administered in combination, a dose of 0.0068 mg/kg
body weight (i.v.) of the first pharmacologically active ingredient
and a dose of 215 mg/kg body weight (i.p.) of the second
pharmacologically active ingredient led to side effects
(sedation).
[0196] FIG. 1 shows the withdrawal threshold in g in dependence of
the time elapsed after administration.
TABLE-US-00001 dose [mg/kg] .circle-solid. 0.0 + 0.0 vehicle
.largecircle. 0.00464 + 215 Combination of first pharmacologically
{close oversize brace} .tangle-solidup. 0.0068 + 215 active
Ingredient and second pharmacologically active ingredient
(Paracetamol) ipsilateral contralateral OP: operation
[0197] FIG. 2 shows % MPE (Maximum possible effect) of the first
and the second pharmacologically active ingredient and of the
combined administration of the first and the second
pharmacologically active ingredient, and the theoretical % MPE of
the combined administration of the first and the second
pharmacologically active ingredient in dependence of the time post
administration.
[0198] Experimental results demonstrating additive effect of the
combination of the first and the second pharmacologically active
ingredient are summarized in the following tables 1 to 5.
TABLE-US-00002 TABLE 1 % MPE (Maximum possible effect) of the
combined administration of different doses of the first and the
second pharmacologically active ingredient in dependence of the
time post administration: % MPE 30 min. 60 min. 90 min. dose (n =
10) (n = 10) (n = 10) [mg/kg] Mean SEM Mean SEM Mean SEM vehicle
0.0 + 0.0 -0.48 .+-. 0.71 -1.14 .+-. 0.65 0.47 .+-. 1.45
Combination of first 0.00464 + 215 33.1 .+-. 6.71 6.13 .+-. 3.49
4.35 .+-. 2.40 pharmacologically active p .ltoreq. 0.001 p .ltoreq.
0.05 n.s. ingredient and second 0.0068 + 215 41.2 .+-. 8.14 17.0
.+-. 2.56 3.46 .+-. 1.32 pharmacologically active p .ltoreq. 0.001
p .ltoreq. 0.001 n.s. ingredient p: level of statistical
significance; n.s. : not significant
TABLE-US-00003 TABLE 2 % MPE: GLM Repeated Measures and Statistical
evaluation of the data following two-factor analysis of variance
(ANOVA) and Fisher's LSD: GLM (General Linear Model) %MPE treatment
time interaction F(2, 22) = 15.465 F(2, 44) = 37.591 F(4, 44) =
11.904 p < 0.001 p < 0.001 p < 0.001 ANOVA [Fisher's LSD]
dose [mg/kg] 30 min. 60 min. 90 min. 0.00464 + 215 p < 0.001 p =
0.043 p = 0.150 0.0068 + 215 p < 0.001 p < 0.001 p = 0.358 p:
level of statistical significance.
TABLE-US-00004 TABLE 3 ipsilateral: GLM Repeated Measures and
Statistical evaluation of the data following two-factor analysis of
variance (ANOVA) and Fisher's LSD: GLM (General Linear Model)
ipsilateral treatment time interaction F(2, 22) = 11.006 F(2, 44) =
37.049 F(4, 44) = 12.008 p < 0.001 p < 0.001 p < 0.001
ANOVA [Fisher's LSD] dose [mg/kg] 30 min. 60 min. 90 min. 0.00464 +
215 p < 0.001 p = 0.111 p = 0.398 0.0068 + 215 p < 0.001 p
< 0.01 p = 0.732 p: level of statistical significance.
TABLE-US-00005 TABLE 4 contralateral: GLM Repeated Measures and
Statistical evaluation of the data following two-factor analysis of
variance (ANOVA) and Fisher's LSD: GLM (General Linear Model)
contralateral treatment time interaction F(2, 22) = 6.464 F(2, 44)
= 13.172 F(4, 44) = 4.617 p < 0.001 p < 0.001 p = 0.003 ANOVA
[Fisher's LSD] dose [mg/kg] 30 min. 60 min. 90 min. 0.00464 + 215 p
= 0.004 p = 0.059 p = 0.356 0.0068 + 215 p = 0.051 p = 0.057 p <
0.001 p: level of statistical significance.
TABLE-US-00006 TABLE 5 % MPE (Maximum possible effect) of the first
and the second pharmacologically active ingredient and of the
combined administration of the first and the second
pharmacologically active ingredient, and the theoretical % MPE of
the combined administration of the first and the second
pharmacologically active ingredient in dependence of the time post
administration: % MPE 30 min. 60 min. 90 min. dose (n = 10) (n =
10) (n = 10) [mg/kg] Mean SEM Mean SEM Mean SEM first
pharmacologically 0.00464 12.2 .+-. 2.69 10.6 .+-. 3.51 2.88 .+-.
2.27 active ingredient second pharmacologically 215 16.3 .+-. 3.06
4.35 .+-. 1.53 -0.21 .+-. 0.75 active ingredient combination of
first 0.00464/215 33.1 .+-. 6.71 6.13 .+-. 3.49 4.35 .+-. 2.4
pharmacologically active (theoretical (theoretical (theoretical
ingredient and second additive value: additive value: additive
value: pharmacologically active 28.5 .+-. 4.07) 15.0 .+-. 3.83)
2.67 .+-. 2.39) ingredient p = 0.507 p = 0.032 p = 0.502
EXAMPLE 2
Randall Selitto Test in Rats (Chronic Inflammatory Pain)
[0199] The weight ratios of the first and the second
pharmacologically active ingredient that will lead to a
supra-additive effect (synergistic effect) may be determined via
the test of Randall and Selitto as described in Arch. Int.
Pharmacodyn., 1957, 111: 409-419, which is a model for inflammatory
pain. The respective part of the literature is hereby incorporated
by reference and forms part of the present disclosure.
[0200] By means of injection of 0.1 ml of Carrageenin-suspension
ventrally into a hind paw of a rat an oedema is induced, on which
pain is generated 4 hours later by continuously increasing pressure
with a stamp (2 mm tip diameter). The antinociceptive and
antihyperalgesic activity of the tested pharmacologically active
ingredient is determined at different points in time after
administration of the pharmacologically active ingredient. The
measured value to be determined and at the same time also the end
point of the pain test is the pressure at which the vocalisation
reaction of the rat occurs. The percentage maximum possible effect
(% MPE) is calculated. The maximum pressure of the stamp is 250 g.
The group size is n=12.
[0201] ED.sub.50-values were determined by regression analysis in
case of dose-dependent results (according to Litchfield J. T. and
Wilcoxon F. A., A simplified method of evaluating dose-effect
experiments, J. Pharmacol. Exp. Ther. 1949; 96: 99-113). The
analysis of the results with respect to a supra-additive effect of
the first and the second pharmacologically active ingredient is
carried out via statistical comparison of the theoretical additive
ED.sub.50-value with the experimentally determined ED.sub.50-value
of a so-called fixed ratio combination (isobolographic analysis
according to Tallarida J. T., Porreca F., and Cowan A., Statistical
analysis of drug-drug and site-site interactions with isobolograms,
Life Sci. 1989; 45: 947-961).
[0202] The interactions studies presented herein were performed
using equieffective doses of the first and the second
pharmacologically active ingredient, calculated from the ratio of
the respective ED.sub.50 values of the first and the second
pharmacologically active ingredient if administered alone.
[0203] The application route was intravenous (i.v.) for the first
pharmacologically active ingredient and intraperitoneal (i.p.) for
the second pharmacologically active ingredient. The first and the
second pharmacologically active ingredient were dissolved in 5%
DMSO, 5% Cremophor, 90% glucose solution (5%) and in 1% CMC in aqua
dest., respectively. Intravenous (i.v.) and intraperitoneal (i.p.)
applications were made in a volume of 5 mL/kg.
[0204] In case of the combined, simultaneous administration, the
relative dose ratio of first pharmacologically active ingredient to
the second pharmacologically active ingredient was 1:56,453.
[0205] When the first pharmacologically active ingredient was
applied alone, the peak effect was reached 15 min p. appl.
(timepoint of first measurement) and ED.sub.50-value of 3.364
(2.896-3.815) .mu.g/kg i.v. was calculated. The second
pharmacologically active ingredient Paracetamol induced a
dose-dependent analgesic effect with ED.sub.50-value of 189,914
(181,292-198,419) .mu.g/kg i.p., reaching the peak effect 120 min
p. appl. According to their respective timepoint of peak effect,
the first pharmacologically active ingredient was applied 15 min
and the second pharmacologically active ingredient 120 min before
timepoint of measurement of the interaction-experiments (i. e. the
second pharmacologically active ingredient was applied 105 min
before the first pharmacologically active ingredient). Thus, the
time point of ED.sub.50 calculation of the pharmaceutical
composition according to the invention corresponds to the timepoint
of the peak effect of the respective pharmacologically active
ingredient. The isobolographic analysis revealed that in case of
the combined administration of the first and the second
pharmacologically active ingredient the experimental
ED.sub.50-values were significantly lower than the respective
theoretical ED.sub.50-values. Thus, the combination studies
demonstrate significant synergistic interaction of the first
pharmacologically active ingredient with the second
pharmacologically active ingredient. The results of the
isobolographic analysis are summarized in the following table
6.
[0206] FIG. 3 shows the graphical analysis of experimental
ED.sub.50-values corresponding to the single administration of the
first pharmacologically active ingredient and the second
pharmacologically active ingredient, respectively, and the
corresponding theoretic additive values for the combined
administration of the first and the second pharmacologically active
ingredient compared to the experimental ED.sub.50-values determined
for said combination.
ED.sub.50 (95% Cl)[.mu.g/kg] (i.v./i.p.) [0207] first
pharmacologically active ingredient=3.36 (2.90-3.82) [0208] second
pharmacologically active ingredient=189,914 (181,292-198,419)
[0209] .box-solid. theoretical additive value=94,957
(88,212-101,701) [0210] part of first pharmacologically active
ingredient=1.68 (1.56-1.80) [0211] part of second pharmacologically
active ingredient=94,955 (88,211-101,700) [0212] .circle-solid.
experimental value of the combination=68,427 (64,864-71,835) [0213]
part of first pharmacologically active ingredient=1.21 (1.05-1.38)
[0214] part of second pharmacologically active ingredient=68,426
(65,340-71,511)
TABLE-US-00007 [0214] TABLE 6 Experimental ED.sub.50 values of the
first and the second pharmacologically active ingredient and
isobolographic analysis of the interaction between the first and
the second pharmacologically active ingredient: Substance/ED.sub.50
[.mu.g/kg] (confidence interval) first second Theoretical ED.sub.50
Experimental ED.sub.50 pharmacologically pharmacologically
[.mu.g/kg] of the [.mu.g/kg] of the active ingredient active
ingredient combination combination Interaction 3.36 189,914 94,957
68,427 supra- (2.90-3.82) (181,292-198,419) (88,212-101,701)
(64,864-71,835) additive (p < 0.001) p: level of statistical
signifigance.
* * * * *