U.S. patent application number 15/421569 was filed with the patent office on 2017-05-18 for pharmaceutical salts.
This patent application is currently assigned to GRUNENTHAL GMBH. The applicant listed for this patent is GRUNENTHAL GMBH. Invention is credited to JOHANNES BARTHOLOMAUS, HEINRICH KUGELMAN.
Application Number | 20170137370 15/421569 |
Document ID | / |
Family ID | 34828061 |
Filed Date | 2017-05-18 |
United States Patent
Application |
20170137370 |
Kind Code |
A1 |
BARTHOLOMAUS; JOHANNES ; et
al. |
May 18, 2017 |
PHARMACEUTICAL SALTS
Abstract
The invention relates to pharmaceutical salts comprised of a
pharmaceutical active substance and of at least one sugar
substitute, to medicaments containing these salts, and to the use
of these salts for producing medicaments.
Inventors: |
BARTHOLOMAUS; JOHANNES;
(Aachen, DE) ; KUGELMAN; HEINRICH; (Aachen,
DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GRUNENTHAL GMBH |
AACHEN |
|
DE |
|
|
Assignee: |
GRUNENTHAL GMBH
AACHEN
DE
|
Family ID: |
34828061 |
Appl. No.: |
15/421569 |
Filed: |
February 1, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13295242 |
Nov 14, 2011 |
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15421569 |
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12487760 |
Jun 19, 2009 |
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13295242 |
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10647882 |
Aug 25, 2003 |
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12487760 |
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PCT/EP02/02169 |
Feb 28, 2002 |
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10647882 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 217/68 20130101;
C07D 291/06 20130101; C07B 2200/07 20130101; A61K 9/0058 20130101;
C07C 217/74 20130101; A61P 13/00 20180101; A61P 25/00 20180101;
C07C 215/64 20130101; A61K 9/0095 20130101; C07D 275/06 20130101;
C07C 2601/14 20170501; A61P 29/00 20180101; A61K 9/0056 20130101;
C07C 215/62 20130101; C07D 489/04 20130101; C07C 215/54
20130101 |
International
Class: |
C07C 215/54 20060101
C07C215/54; C07C 217/74 20060101 C07C217/74 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 28, 2001 |
DE |
101 09 763.8 |
Claims
1. A pharmaceutical salt of a salt-forming pharmaceutical active
compound and at least one salt-forming sugar substitute, wherein
the salt-forming pharmaceutical active compound is a salt-forming
1-phenyl-3-dimethylaminopropane compound selected from the group
consisting of: (a)
(-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol; (b)
(1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3--
diol; and (c)
(-)-(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol.
2. The pharmaceutical salt according to claim 1, wherein the
salt-forming pharmaceutical active compound is
(-)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol.
3. The pharmaceutical salt according to claim 1, wherein the
salt-forming pharmaceutical active compound is
(1RS,3RS,6RS)-6-Dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3--
diol.
4. The pharmaceutical salt according to claim 1, wherein the
salt-forming pharmaceutical active compound is
(-)-(1R,2R)-3-(2-Dimethylaminomethyl-cyclohexyl)-phenol.
5. A pharmaceutical composition comprising a therapeutically
effective amount of the pharmaceutical salt according to claim 1
and optionally one or more physiologically tolerable
excipients.
6. A method of controlling pain comprising administering to a
patient in need thereof a pain-controlling effective amount of the
pharmaceutical salt of claim 1.
7. A method of controlling urinary incontinence comprising
administering to a patient in need thereof an urinary
incontinence-controlling effective amount of the pharmaceutical
salt of claim 1.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 13/295,242 filed Nov. 14, 2011, now allowed; which is a
continuation of U.S. application Ser. No. 12/487,760 filed Jun. 19,
2009, now abandoned; which is a Division of U.S. application Ser.
No. 10/647,882 filed Aug. 25, 2003, now abandoned; which is a
continuation of PCT/EP02/02169 filed Feb. 28, 2002.
[0002] The present invention relates to pharmaceuticals salts of an
active compound and at least one sugar substitute, medicaments
comprising these salts, and the use of these salts for the
production of medicaments.
[0003] On oral administration, a large number of pharmaceutical
active compounds having excellent activity lead to a strongly
bitter, often nauseating taste sensation in the patient. In some
patients, lack of adherence to the dosage instructions and a lack
of acceptance of the corresponding medicaments which release such
an active compound as early as during taking result from this
negative taste experience.
[0004] The formulation of pharmaceutical active compounds having
very good water solubility to give medicaments frequently causes
problems in pharmaceutical practice. Thus the preparation of
pharmaceutical forms having controlled release is often made
difficult on account of the very good water solubiltiy of active
compound salts. A delaying of the release of these active compounds
can in fact be achieved, for example, by coating the pharmaceutical
forms with release-delaying film coatings. This manner of delaying
the release, however, is associated with a relatively high outlay,
since release-delaying film coatings from aqueous coating systems
are frequently only an inadequate diffusion barrier for active
compounds having very good water solubility. The preparation of
these delayed-release active compound preparations therefore
requires relatively complicated coating processes with multilayer
films. If such release-delaying coatings are applied from organic
solvents, the environmental and solvent residue problems associated
therewith additionally make the preparation of appropriate
preparations more expensive.
[0005] It was therefore the object of the present invention to make
available pharmaceutical combinations of active compounds which
have no bitter taste. Preferably, the corresponding active
compounds should be simpler to formulate and their release should
be more effectively delayed.
[0006] According to the invention, this object is achieved by the
provision of pharmaceutical salts, i.e. physiologically tolerable
salts, from a pharmaceutical active compound and at least one sugar
substitute.
[0007] The present invention therefore relates to pharmaceutical
salts of a pharmaceutical active compound and at least one sugar
substitute, the respective pharmaceutical salts of a sugar
substitute and tramadol, (+)-tramadol, (-)-tramadol,
(+)-demethyl-tramadol and (-)-demethyltramadol being excepted.
[0008] In a preferred embodiment of the present invention, the
solubility of the pharmaceutical salts according to the invention
in water is .ltoreq.250 mg/ml of water, preferably .ltoreq.200
mg/ml, particularly preferably .ltoreq.150 mg/ml, very particularly
preferably .ltoreq.100 mg/ml. This can also be seen in particular
in the fact that the water solubility of the pharmaceutical salts
according to the invention compared with the water solubility of
the best water-soluble salt of the corresponding active compound
according to Pharmazeutische Stoffliste [Pharmaceutical Substance
List], 12th edition ABDATA Pharma-Daten-Service, 65735
Eschborn/Taunus, is preferably lowered by at least 50%, preferably
by at least 65%, particularly preferably by at least 75%, very
particularly preferably by at least 85%, compared with the
corresponding hydrochloride. The corresponding literature
description is hereby inserted as a reference and is thus regarded
as part of the disclosure.
[0009] According to the invention, suitable sugar substitutes are
all sugar substitutes which can form a salt with the respective
pharmaceutical active compound with formation of an at least singly
negatively charged form. According to the invention, pharmaceutical
salts are also included in which the pharmaceutical active compound
has two or more different sugar substitutes as salt components.
Preferably, the pharmaceutical salts according to the invention
contain saccharin, cyclamate or acesulfam, particularly preferably
saccharin, as salt-forming sugar substitutes.
[0010] According to the invention, suitable active compounds are
all pharmaceutical active compounds which can form a salt in
anionic form with the respective sugar substitute(s) with formation
of an at least singly positively charged form.
[0011] In a further preferred embodiment of the present invention,
the salt-forming active compound in the pharmaceutical salt
according to the invention is selected from the group consisting of
the salt-forming analgesics, antiobesity agents, analeptics,
anti-hypoxemics, antirheumatics, opioid antagonists, anthelmintics,
antiallergics, antiarrhythmics, anti-biotics, antidementives
(nootropics), antidiabetics, antiemetics, antivertiginous agents,
antiepileptics, antihypertensives, antihypotensives, antimycotics,
antiinflammatories, antitussives, expectorants, arteriosclerosis
agents, .beta.-receptor blockers, calcium channel blockers,
broncholytics, antiasthmatics, cholinergics, diuretics,
circulation-promoting agents, weaning agents, geriatrics,
hypnotics, sedatives, immunomodulators, oral therapeutics,
pharyngeal therapeutics, coronary agents, hypolipidemics, local
anesthetics, neural therapeutics, gastric agents, intestinal
agents, migraine agents, muscle relaxants, anesthetics, neuropathy
preparations, ophthalmologicals, Parkinson agents,
psycho-pharmaceuticals, rhinologicals, sinusitis agents,
spasmolytics, platelet aggregation inhibitors, tuberculosis agents,
urologicals and cytostatics. Particularly preferably, the
salt-forming active compound is selected from the group consisting
of the salt-forming analgesics, analeptics, antihypoxemics,
antiallergics, antiarrhythmics, antiemetics, anti-vertiginous
agents, antihypertensives, anti-hypotensives, antitussives,
expectorants, .beta.-receptor blockers, calcium channel blockers,
ophthalmologicals, otologicals, spasmolytics and urologicals. Very
particularly preferably, the salt-forming active compound is
selected from the group consisting of the salt-forming analgesics,
tramadol, (+)-tramadol, (-)-tramadol, (+)-demethyltramadol and
(-)-demethyltramadol being excepted.
[0012] If the pharmaceutical active compound is a salt-forming
analgesic, it is preferably a salt-forming opioid or a salt-forming
opioid analog, such as disclosed in E. Friderichs, T. Christoph, H.
Buschmann, "Analgesics, and Antipyretics"; Ullmann's Encyclopedia
of Industrial Chemistry, Sixth Edition on CD-ROM, Wiley-VCH,
Weinheim, 2000 or in Pharmaceuticals, J. L. McGuire (Editor),
Analgesics and Antipyretics, Volume 2, pages 341-434, Wiley-VCH,
Weinheim or ephedrine, chloroquine, lidocaine, ethaverine,
preglumetacin or triflu-promazine. The corresponding disclosures
are hereby inserted as a reference and are thus regarded as part of
the present disclosure. Particularly preferably, the salt-forming
analgesic is selected from the group consisting of morphine,
codeine, ethylmorphine, diacetylmorphine, dihydrocodeine,
etorphine, hydrocodone, hydromorphone, levorphanol, oxycodone,
oxymorphone, pethidine, ketobemidone, fentanyl, alfentanil,
remifentanil, sufentanil, levomethadone, levomethadyl,
dextro-moramide, dextropropoxyphene, diphenoxylate, piri-tramide,
tilidine, buprenorphine, butorphanol, dezozine, meptazinol,
nalbuphine, nalorphine, pentazo-cine, flupirtin and nefopam or a
representative of the group consisting of ephedrine, chloroquine,
lidocaine, ethaverine, preglumetacin and triflupromazine. Very
particularly preferably, the salt-forming analgesic is a
salt-forming opioid or opioid analog selected from the group
consisting of morphine, codeine, hydrocodone, hydromorphone,
oxycodone, tilidine, fentanyl and buprenorphine.
[0013] Likewise preferably, the salt-forming active compound is a
salt-forming compound of 1-phenyl-3-dimethylamino-propane compounds
of the general formula I
##STR00001##
in which in each case
[0014] X is OH, F, Cl, H or an OCOR.sup.6 group,
[0015] R.sup.1 is a C.sub.1-4-alkyl group,
[0016] R.sup.2 is H or a C.sub.1-4-alkyl group and R.sup.3 is H or
a straight-chain C.sub.1-.sub.4-alkyl group or the radicals R.sup.2
and R.sup.3 together form a C.sub.4-7-cycloalkyl radical, and
[0017] if R.sup.5 is H, R.sup.4 is meta-O-Z where Z is H,
C.sub.1-3-alkyl, PO(O--C.sub.1-4-alkyl).sub.2,
CO(OC.sub.1-5-alkyl), CONH--C.sub.6H.sub.4--(C.sub.1-3-alkyl),
CO--C.sub.6H.sub.4--R.sup.7, where R.sup.7 is
ortho-OCOC.sub.1-3-alkyl or meta- or para-CH.sub.2N(R.sup.8).sub.2
where R.sup.8 is C.sub.1-4-alkyl or 4-morpholino, or R.sup.4 is
meta-S--C.sub.1-7-alkyl, meta-Cl, meta-F, meta-CR9R.sup.10R.sup.11
where R.sup.9, R.sup.10 and R.sup.11 are H or F, ortho-OH,
ortho-O--C.sub.2-3-alkyl, para-F or para-CR .sup.9R.sup.10R.sup.11
where R.sup.9, R.sup.10, R.sup.11 are H or F, or if R.sup.5 is
para-Cl, --F, --OH or --O--C.sub.1-3-alkyl, R.sup.4 is meta-Cl,
--F, -OH or --O--C.sub.1-3-alkyl, or R.sup.4 and R.sup.5 together
are 3,4-OCH.dbd.CH-- or 3,4-OCH.dbd.CHO--,
[0018] R.sup.6 is C.sub.1-3-alkyl,
[0019] in the form of their possible stereoisomers as racemates or
diastereomerically pure enantiomers or in the form of mixtures of
enantiomers, in which the respective enantiomers are present in
nonequimolar amounts.
[0020] Preferred is a salt-forming compound of
1-phenyl-3-dimethylaminopropane compounds of the general formula I
in which X is OH, F, Cl or H, R.sup.1 is a C.sub.1-4-alkyl group,
R.sup.2 is H or CH.sub.3 and R.sup.3 is H or CH.sub.3 and if
R.sup.5 is H, R.sup.4 is meta-O--C.sub.1-3-alkyl, meta-OH,
meta-S--C.sub.1-3-alkyl, meta-F, meta-Cl, meta-CH.sub.3,
meta-CF.sub.2H, meta-CF.sub.3 or para-CF.sub.3 or if R.sup.5 is a
para-Cl or --F, R.sup.4 is meta-Cl or --F, or R.sup.4 and R.sup.5
together are 3,4-OCH.dbd.CH--.
[0021] Particularly preferred is a salt-foaming compound of
1-phenyl-3-dimethylaminopropane compounds of the general formula I
in which the radicals R.sup.2 and R.sup.3 have different meanings
and which are present in the form of their diastereomers having the
configuration Ia
##STR00002##
[0022] Very particularly preferred is a salt-forming compound of
1-phenyl-3-dimethylaminopropane compounds of the general formula I,
selected from the group consisting of
[0023]
(1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)phenol,
[0024]
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol,
[0025]
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol,
[0026]
(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol,
[0027]
(-)-(1S,2S)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl)phen-
ol,
[0028]
(+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)phenol-
,
[0029]
(+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol
and
[0030]
(-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol-
.
[0031] The preparation of the salt-forming compounds of
1-phenyl-3-dimethylaminoprooane compounds of the general formula I
and, if appropriate, the separation into the pure optical antipodes
can be carried out according to customary methods known to the
person skilled in the art. Preferably, the preparation and, if
appropriate, the separation is carried out as described in
DE-A-4426245 or EP 0 693 475 B1, which are hereby inserted as
reference and are thus regarded as part of the disclosure.
[0032] In a further preferred embodiment of the present invention,
the pharmaceutical salt according to the invention contains as a
salt-forming active compound a salt-forming compound of
6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general
formula II,
##STR00003##
in which in each case
[0033] R.sup.1' is H, OH, Cl or F, preferably H, OH or F,
[0034] R.sup.2' and R.sup.3' are identical or different and are H,
C.sub.1-4-alkyl, benzyl, CF.sub.3, OH, OCH.sub.2--C.sub.6H.sub.5,
Cl or F with the proviso that at least one of the radicals R.sup.2'
or R.sup.3' is H,
[0035] R.sup.4' is H, CH.sub.3, PO(O--C.sub.1-4-alkyl).sub.2,
CO(OC.sub.1-5-alkyl), CO--NH-C6H.sub.4--C.sub.1-3-alkyl,
CO--C.sub.6H.sub.4--R.sup.5', CO--CHR.sup.6'--NHR.sup.7' or an
unsubstituted'or pyridyl, thienyl, thiazoyl [sic] or phenyl
group,
[0036] R.sup.5' is OC(O)C.sub.1-3-alkyl in the ortho-position or
CH.sub.2--N(R.sup.8').sub.2 in the meta- or para-position, where
R.sup.8' is C.sub.1-4-alkyl or both radicals R.sup.8' together with
N are the 4-morpholino radical, and
[0037] R.sup.6' and R7' are identical or different and are H or
C.sub.1-6-alkyl,
[0038] with the proviso that if both radicals R.sup.2' and R.sup.3'
are H, R.sup.4' is not CH.sub.3 if R.sup.1' is H, OH or Cl or
R.sup.4' is not H if R.sup.1' is OH,
[0039] in the form of their possible stereoisomers as racemates or
diastereomerically pure enantiomers or in the form of mixtures of
enantiomers, in which the respective enantiomers are present in
nonequimolar amounts.
[0040] Preferred are salt-forming compounds of
6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general
formula II, which are present in the configuration as in the
general formula IIa,
##STR00004##
[0041] in which the phenyl ring and the dimethylaminomethyl group
are in each case arranged in an equatorial position to one
another.
[0042] Particularly preferred is a salt-forming compound of
b-dimethylaminomethyl-1-phenylcyclohexane compounds of the general
formula II selected from the group consisting of
[0043] (-)-(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol,
[0044]
(1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-methoxy-phenyl)cyclohexa-
ne-1,3-diol and
[0045]
(1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-hydroxy-phenyl)cyclohexa-
ne-1,3-diol.
[0046] The preparation of the salt-forming compounds of
6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general
formula II and, if appropriate, the separation into the optically
pure antipodes can be carried out according to customary methods
known to the person skilled in the art. Preferably, the preparation
and, if appropriate, the separation are carried out as described in
DE-A-19525137. The corresponding literature description is hereby
inserted as reference and is thus regarded as part of the
disclosure.
[0047] In a further preferred embodiment of the present invention,
the pharmaceutical salt according to the invention contains as a
salt-forming active compound a salt-forming compound of
1-phenyl-2-dimethylamino-methylcyclohexan-1-ol compounds of the
general formula III,
##STR00005##
[0048] in which in each case
[0049] A is O or S,
[0050] R.sup.1'' is H, C.sub.2-6-alkenyl, C.sub.5-7-cycloalkyl or
halogenated C.sub.1-6-alkyl,
[0051] the group
##STR00006##
[0052] is the group
##STR00007##
[0053] R.sup.2'' is C.sub.1-6-alkyl, C.sub.2-6-alkenyl,
C.sub.5-7-cycloalkylmethyl, substituted or unsubstituted phenyl or
substituted or unsubstituted benzyl,
[0054] in the form of their possible stereoisomers as racemates or
diastereomerically pure enantiomers or in the form of mixtures of
enantiomers, in which the respective enantiomers are present in
nonequimolar amounts.
[0055] Preferred are salt-forming compounds of
1-phenyl-2-di-methylaminomethylcyclohexan-1-ol compounds of the
general formula III, in which R.sup.1'' is H, C.sub.1-4-alkyl,
2'-methyl-2'-propenyl, cyclopentyl or fluoroethyl, with the proviso
that R.sup.1'' is C.sub.1-4-alkyl if A is S,
[0056] R.sup.2'' is C.sub.1-4-alkyl, C.sub.2-4-alkenyl,
cyclopentylmethyl, phenyl, C.sub.1-4-alkoxyphenyl, benzyl,
C.sub.1-4-alkylbenzyl, mono- or dihalogenated phenyl or mono- or
dihalogenated benzyl.
[0057] Particularly preferred are salt-forming compounds of
1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compounds of the
general formula III, in which R.sup.1'' is H, methyl, ethyl,
isopropyl, 2'-methyl-2'-propenyl, cyclopentyl or fluoroethyl, with
the proviso that R.sup.1'' is methyl if A is S,
[0058] R.sup.2'' is methyl, propyl, 2'-methylpropyl, allyl,
2'-methyl-2'-propenyl, cyclopentylmethyl, phenyl, 3-methoxyphenyl,
benzyl, 4-tert-butylbenzyl, 4-chloro-benzyl, 4-fluorobenzyl or
3,4-dichlorobenzyl.
[0059] Very particularly preferred are salt-forming compounds of
1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compounds of the
general formula III which are present in the configuration of the
formula IIIa,
##STR00008##
[0060] in which the phenyl ring and the dimethylaminomethyl group
are in each case arranged in an equatorial position to one
another.
[0061] Most preferred is the salt-forming compound of
1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compounds of the
general formula III selected from the group consisting of
[0062]
(+)-(1R,2R,48)-2-(dimethylaminomethyl)-4-(4-fluoro-benzyloxy)-1-(3--
methoxyphenyl)cyclohexanol,
[0063]
(+)-(1R,2R,4S)-2-dimethylaminomethyl-4-(4-chloro-benzyloxy)-1-(3-me-
thoxyphenyl)cyclohexanol and
[0064]
(+)-(1R,2R,4S)-3-[2-dimethylaminomethyl-4-(4-fluoro-benzyloxy)-1-hy-
droxycyclohexyl]phenol.
[0065] The preparation of the salt-forming compounds of
1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compounds of the
general formula III and, if appropriate, the separation into the
optically pure antipodes can be carried out according to customary
methods known to the person skilled in the art. Preferably, the
preparation and, if appropriate, the separation are carried out as
described in DE-A-19547766, which is hereby inserted as reference
and is thus regarded as part of the disclosure.
[0066] In a further preferred embodiment of the present invention,
the pharmaceutical salt contains as a salt-forming active compound
a salt-forming compound of dimethyl-(3-arylbut-3-enyl) amine
compounds of the general formula IV, in which [sic]
##STR00009##
[0067] the radical R.sup.1''' is C.sub.1-5-alkyl and R.sup.2''' is
H or C.sub.1-5-alkyl or R.sup.1''' and R.sup.2''' together are
--(CH.sub.2).sub.2-4-, --(CH.sub.2).sub.2-CHR.sup.7''' or
--CH.sub.2--CHR.sup.7''' --CH.sub.2--,
[0068] R.sup.3''' is H or Cl.sub.1-5-alkyl,
[0069] R.sup.4''' is H, OH, C.sub.1-4-alkyl, O--C.sub.1-4-alkyl,
O-benzyl, CF.sub.3, O--CF.sub.3, Cl, F or OR.sup.8''',
[0070] R.sup.5''' is H, OH, C.sub.1-4-alkyl, O-benzyl, CHF.sub.2,
CF.sub.3, O--CF.sub.3, Cl, F or OR.sup.8''' and
[0071] R.sup.6''' is H, OH, C.sub.1-4-alkyl, O-benzyl, CF.sub.3,
O--CF.sub.3, Cl, F or OR.sup.8''',
[0072] with the proviso that two of the radicals R.sup.4''',
R.sup.5''' or R.sup.6''' are H, or
[0073] R.sup.4''' and R.sup.5''' together are
--CH.dbd.C(R.sup.9''')--O-- or --CH.dbd.C(R.sup.9''')--S--, with
the proviso that R.sup.6''' is H, or
[0074] R.sup.5''' and R.sup.6''' together are
--CH.dbd.CH--C(OR.sup.10''').dbd.CH--, with the proviso that
R.sup.4''' is H,
[0075] R.sup.7''' is C.sub.1-8-alkyl, C.sub.3-8-cycloalkyl,
O--C.sub.1-4-alkyl, O-benzyl, CF.sub.3, Cl or F,
[0076] R.sup.8''' is CO--C.sub.1-5-alkyl,
PO(O--C.sub.1-4-alkyl).sub.2, CO--C.sub.6H.sub.4--R.sup.11''',
CO(O--C.sub.1-5-alkyl), CO--CHR.sup.12'''--NHR.sup.13''',
CO--NH--C.sub.6H.sub.3--(.sub.R14''').sub.2 or an unsubstituted or
substituted pyridyl, thienyl, thiazoyl [sic] or phenyl group,
[0077] R.sup.9''' is H or C.sub.1-4-alkyl,
[0078] R10''' is H or C.sub.1-3-alkyl,
[0079] R.sup.11''' as OC(O)--C.sub.1-3-alkyl in the ortho-position
or CH.sub.2--N--(R.sup.15''').sub.2 in the meta- or para-position,
where R.sup.15''' is C.sub.1-4-alkyl or both radicals R.sup.15'''
together with N form the 4-morpholino radical,
[0080] R.sup.12''' and R.sup.13''' are identical or different and
are H, C.sub.1-6-alkyl or C.sub.3-8-cycloalkyl or R.sup.12''' and
R.sup.13''' together are --(CH.sub.2).sub.3-8-,
[0081] R.sup.14''' as H, OH, C.sub.1-7-alkyl, O--C.sub.1-7-alkyl,
phenyl, O-aryl, CF.sub.3, Cl or F, with the proviso that the two
radicals R.sup.14''' are identical or different,
[0082] in the form of their possible stereoisomers as racemates or
diastereomerically pure enantiomers or in the form of mixtures of
enantiomers, in which the respective enantiomers are present in
nonequimolar amounts.
[0083] Preferred are salt-forming compounds of
dimethyl-(3-arylbut-3-enyl)amine compounds of the general formula
IV, in which
[0084] R.sup.1''' is C.sub.1-3-alkyl and R.sup.2''' is H or
C.sub.1-3-alkyl, or R.sup.1''' and R.sup.2''' together are
--(CH.sub.2).sub.2-4- or --(CH.sub.2).sub.2--CHR.sup.7''', R.sup.3
i s H or C.sub.1-3-alkyl,
[0085] R.sup.4''' is H, OH, CF.sub.3, Cl, F or OR.sup.8''',
[0086] R.sup.5''' is H, OH, C.sub.1-4-alkyl, O--C.sub.1-4-alkyl,
O-benzyl, CHF.sub.2, CF.sub.3, Cl, F or OR.sup.8''' and
[0087] R.sup.6''' is H, OH, O--C.sub.1-4-alkyl, O-benzyl, CF.sub.3,
Cl, F or OR.sup.8''',
[0088] with the proviso that two of the radicals R.sup.4''',
R.sup.5''' or R.sup.6''' are H, or
[0089] R.sup.4''' and R.sup.5''' together are
--CH.dbd.C(R.sup.9''')--O-- or --CH.dbd.C(R.sup.9''')--S--, with
the proviso that R.sup.6''' is H, or
[0090] R.sup.5''' and R.sup.6''' together are
--CH.dbd.CH--C(OR.sup.10''').dbd.CH--, with the proviso that
R.sup.4''' is H, and
[0091] R.sup.7''' is C.sub.1-4-alkyl, CF.sub.3, Cl or F.
[0092] Particularly preferred are salt-forming compounds of
dimethyl-(3-arylbut-3-enyl)amine compounds of the general formula
IV, in which R.sup.1''' is CH.sub.3 or C.sub.3H.sub.7 and R2''' is
H, CH.sub.3 or CH.sub.2CH.sub.3, or R.sup.1''' and R.sup.2'''
together are --(CH.sub.2).sub.2-3- or
--(CH.sub.2).sub.2--CHR.sup.7''',
[0093] R.sup.3''' is H, CH.sub.3 or CH.sub.2CH.sub.3,
[0094] R.sup.4''' is H or OH, R.sup.5''' is H, OH, OCH.sub.3,
CHF.sub.2 or OR.sup.8''' and R.sup.6''' is H, OH or CF.sub.3, with
the proviso that two of the radicals R.sup.4''', R.sup.5''' or
R.sup.6''' are H, or
[0095] R.sup.4''' and R.sup.5''' together are
--CH.dbd.C(CH.sub.3)--S--, with the proviso that R.sup.6''' is H,
or
[0096] R.sup.5''' and R.sup.6''' together are
--CH.dbd.CH--C(OH).dbd.CH--, with the proviso that R.sup.4''' is H,
and
[0097] R.sup.8''' is CO--C.sub.6H.sub.4--R.sup.11''' where
R.sup.11''' is OC(O)--C.sub.1-3-alkyl in the ortho-position.
[0098] Very particularly preferred are salt-forming compounds of
dimethyl-(3-arylbut-3-enyl)amine compounds of the general formula
IV, in which
[0099] R.sup.1''' is CH.sub.3 and R.sup.2''' is H or CH.sub.3 or
R.sup.1''' and R.sup.2''' together are --(CH.sub.2).sub.2-3- or
--(CH.sub.2).sub.2--CH(CH.sub.3)--,
[0100] R.sup.3''' is H or CH.sub.3,
[0101] R.sup.4''' is H, R.sup.5''' is OH or OR.sup.8''', R.sup.6'''
is H, and R.sup.8''' is CO--C.sub.6H.sub.4--R.sup.11''' where
R.sup.11''' is OC(O)--CH.sub.3 in the ortho-position.
[0102] Most preferred is the salt-forming compound of
dimethyl-(3-arylbut-3-enyl)amine compounds of the general formula
IV
trans-(-)-(1R)-3-[1-(2-dimethylamino-1-methylethyl)propenyl]phenol.
[0103] The preparation of the salt-forming compounds of
dimethyl-(3-arylbut-3-enyl)amine compounds of the general formula
IV and, if appropriate, the separation into the optically pure
antipodes can be carried out according to customary methods known
to the person skilled in the art. Preferably, the preparation and,
if appropriate, the separation of these compounds are carried out
as described in EP 0 799 819 A1. The corresponding literature
description is hereby inserted as reference and is thus regarded as
part of the disclosure.
[0104] As salt-forming antiobesity agents, the pharmaceutical salt
according to the invention can preferably contain
D-norpseudoephedrine, phenylpropanolamine, amfepramone, mefenorex
or ephedrine.
[0105] As salt-forming analeptics and/or antihypoxemics, the
pharmaceutical salt according to the invention can preferably
contain norfenefrine, heptaminol or amezinium, particularly
preferably amezinium.
[0106] As salt-forming opioid antagonists, the pharmaceutical salt
according to the invention can preferably contain levallorphan,
naloxone or naltrexone.
[0107] As a salt-forming anthelmintic, the pharmaceutical salt
according to the invention can preferably contain pyrvinium.
[0108] As salt-forming antiallergics, the pharmaceutical salt
according to the invention can preferably contain reproterol,
triprolidine, hydroxyzine, azelastine, diphenhydramine,
promethazine, pheniramine, dexchlorpheniramine, clemastine,
tramazoline, brompheniramine, dimetindene, levocabastine,
doxylamine, cyproheptadine, carbinoxamine, meclozine, bamipine,
chlorphenoxamine, ketotifen or cetirizine, particularly preferably
diphenhydramine.
[0109] As salt-forming antiarrhythmics, the pharmaceutical salt
according to the invention can preferably contain orciprenaline,
aprindine, verapamil, metoprolol, quinidine, amiodarone, sotalol,
propafenone, diltiazem, disopyramide, propranolol, ipatropium
[sic], mexiletine, prajmaline, procainamide, gallopamil,
propafenone, detajmium, flecainide, oxprenolol or tocainide,
particularly preferably verapamil or diltiazem.
[0110] As salt-forming antibiotics, the pharmaceutical salt
according to the invention can preferably contain vancomycin,
tetracycline, clindamycin, minocycline, lincomycin, bacampicillin,
amicacin, chlortetracycline, neomycin, tobramycin, netilmicin,
quinine, chloroquine, ciprofloxacin, clindamycin, colistine,
erythromycin, gentamicin, tobramycin [sic], cefetametpivotil,
amantadine, halofantrine, saquinavir, mefloquine, framycetin,
cefepime, bromhexine, cefpodoximeproxetil, oxytetracycline,
proguanil, pefloxacine, polymyxin B, hydroxychloroquine,
spectinomycin, sultamicillin, valaciclovir or grepafloxacin.
[0111] As salt-forming antidementive (nootropics), the
pharmaceutical salt according to the invention can preferably
contain butalamine, memantine, pyritinol, donepezil, moxaverine,
meclofenoxate, dihydroergotoxin, viquidil, naftidrofuryl,
dihydroergocornine, dihydroergocristine, benzyclan, procaine,
deamol, diisopropylamine or 3-pyridylmethanol.
[0112] As a salt-forming antidiabetic, the pharmaceutical salt
according to the invention can preferably contain metformin.
[0113] As salt-forming antiemetics and/or antivertiginous agents,
the pharmaceutical salt according to the invention can preferably
contain betahistidine, dolasetrone, meclozine, hydroxycine,
diphenhydramine, pyridoxine, granisetrone, triflupromazine,
triethyl-perazine, betahistine, alizapride or odansetrone,
particularly preferably diphenhydramine.
[0114] As a salt-forming antiepileptic, the pharmaceutical salt
according to the invention can preferably contain tiagabine.
[0115] As salt-forming antihypertensives, the pharmaceutical salt
according to the invention can preferably contain dihydralazine,
prazosine, amiloride, bunazosine, nicardipine, alprenolol,
candesartancilexetil, metoprolol, verapamil, propranolol,
penbutolol, doxazosine, clonidine, benazepril, phenoxybenzamine,
diltiazem, diisopropylamine, urapide, carteolol, guanethidine,
guanfacine, terazosine, oxprenolol, cicletanine, betaxolol,
nebivolol, acebutolol, enalapril or indoramine, particularly
preferably verapamil or diltiazem.
[0116] As salt-forming antihypotensives, the pharmaceutical salt
according to the invention can preferably contain etilefrine,
pholedrine, norfenefrine, cafedrine, theodrenaline, oxilofrine,
dobutamine, dopamine, phenylephrine, midodrine, heptaminol,
oxedrine tartrate, pholedrine or gepefrine, particularly preferably
phenylephrine.
[0117] As salt-forming antimycotics, the pharmaceutical salt
according to the invention can preferably contain benzalkonium,
econazole, miconazole, methyl-rosanilinium, terbinafine,
amorolfine, fenticonazole, dequalinium, oxyconazole, croconazole,
isoconazole or sertaconazole.
[0118] As a salt-forming antiinflammatory, the pharmaceutical salt
according to the invention can preferably contain orphenadrine.
[0119] As salt-forming antitussives and/or expectorants, the
pharmaceutical salt according to the invention can preferably
contain ambroxole, doxycycline, bromhexine, dextromethorphan,
diphenhydramine, terbutaline, chlorphenamine, eprazinone,
ephedrine, chlorbutinol, pentoxyverine, pipazetate or benproperine,
particularly preferably diphenhydramine.
[0120] As a salt-forming antisclerosis agent, the pharmaceutical
salt according to the invention can preferably contain
butalamine.
[0121] As .beta.-receptor blockers and/or calcium channel hlnekers,
the pharmaceutical salt according to the invention can preferably
contain acebutolol, nicardipine, alprenolol, metoprolol, verapamil,
enalapril, bupranolol, penbutolol, propranolol, bisoprolol,
esmolol, celiprolol, benazepril, diltiazem, mepindolol, sotalol,
carteolol, gallopamil or oxprenolol, particularly preferably
verapamil or diltiazem.
[0122] As salt-forming broncholytics and/or antiasthmatics, the
pharmaceutical salt according to the invention can preferably
contain ketotifen, reproterol, orciprenaline, salbutamol,
terbutaline, ephedrine, tulobuterol, ipatropium [sic], fenoterol,
terbutaline [sic], formoterol, salbutamol [sic], oxytropium or
pirbuterol.
[0123] As salt-forming cholinergics, the pharmaceutical salt
according to the invention can preferably contain pyridostigmine,
betanechol or neostigmine.
[0124] As salt-forming diuretics, the pharmaceutical salt according
to the invention can preferably contain amiloride or
oxprenolol.
[0125] As salt-forming, circulation-promoting agents, the
pharmaceutical salt according to the invention can preferably
contain butalamine, naftidrofuryl, buflomedil, moxaverine,
bencyclan or meclofenoxate.
[0126] As a salt-forming weaning agent, the pharmaceutical salt
according to the invention can preferably contain naltrexone,
methadone, buprenorphine.
[0127] As salt-forming geriatrics, the pharmaceutical salt
according to the invention can preferably contain procaine or
deanolace.
[0128] As salt-forming hypnotics and/or sedatives, the
pharmaceutical salt according to the invention can preferably
contain promethazine, zolpidem tartrate, midazolam, melperone or
flurazepam.
[0129] As a salt-forming immunomodulator, the pharmaceutical salt
according to the invention can preferably contain levamisole.
[0130] As salt-forming oral and/or pharyngeal therapeutics, the
pharmaceutical salt according to the invention can preferably
contain chlorhexidine or cetylpyridinium.
[0131] As a salt-forming coronary agent, the pharmaceutical salt
according to the invention can preferably contain oxyfedrine.
[0132] As a salt-forming hypolipidemic, the pharmaceutical salt
according to the invention can preferably contain colestipol.
[0133] As salt-forming local anesthetics and/or neural
therapeutics, the pharmaceutical salt according to the invention
can preferably contain bupivacaine, lidocaine, mepivacaine,
ropivacaine, procaine, articaine or prilocaine.
[0134] As salt-forming gastric and/or intestinal agents, the
pharmaceutical salt according to the invention can preferably
contain pizotifen, pirenzepine, roxatidine, ranitidine, butinoline,
methanthelinium or metoclopramide.
[0135] As salt-forming migraine agents, the pharmaceutical salt
according to the invention can preferably contain lisuride,
methysergide, dihydroergotamine, ergotamine, sumatriptan,
rizatriptan or naratriptan.
[0136] As salt-forming muscle relaxants, the pharmaceutical salt
according to the invention can preferably contain alcuronium,
mivacuronium, atracurium, vecurmium, pancurmium, suxamethonium,
tolperisone, pridinol, orphenadrine or tizamidine.
[0137] As a salt-forming anesthetic, the pharmaceutical salt
according to the invention can preferably contain ketamine or
midazolam.
[0138] As a salt-forming neuropathy preparation, the pharmaceutical
salt according to the invention can preferably contain
thiamine.
[0139] As salt-forming ophthalmologicals and/or otologicals, the
pharmaceutical salt according to the invention can preferably
contain oxybuprocaine, proxymetacaine, kanamycin, tolazoline,
tetryzoline, tramazoline, phenylephrine, xylomethazoli [sic],
naphazoline, timolol, metipranolol, betaxolol, befunolol,
levobunolol, brimonidine, clonidine, pilocarpine, dipivefrine,
aceclidine, apraclonidine, neostigmine, dorzolamide, atropine,
scopolamine, cyclopentolate or homatropine, particularly preferably
phenylephrine.
[0140] As salt-forming Parkinson agents, the pharmaceutical salt
according to the invention can preferably contain amantadine,
biperidene, selegiline, bromocriptine, trihexyphenidyl, metrixene,
benzaseride, lisuride, benzatropine, ropinirol, pergolide,
bupidine, procyclidine, pramipexol, bomapine or tiapride.
[0141] As salt-forming psychopharmaceutical agents, the
pharmaceutical salt according to the invention can preferably
contain tranylcypromine, amitriptyline, doxepine, maprotiline,
clomipramine, opipramol, imipramine, trimipramine, lofepramine,
desipramine, dibenzepine, nortriptyline, mianserine, citalopram,
fluvoxamine, fluoxetil, trazodone, paroxetin, nefazodone,
sertralin, viloxacin, venlafaxine, promethazine, chlorprothixene,
zuclopenthixol, pipamperone, fluphenazine, flupentixol, melperone,
prothipendyl, thioridazine, levomepromazine, quetiapine,
triflupromazine, perazine, fenetylline, methylphenidate,
hydroxycine, buspirone, deanolace or memantine.
[0142] As salt-forming rhinologicals/sinusitis agents, the
pharmaceutical salt according to the invention can preferably
contain diphenylpyraline, xylometazoline, oxymetazoline,
tramazoline, indanazoline, naphazoline or tetryzoline.
[0143] As salt-forming spasmolytics, the pharmaceutical salt
according to the invention can preferably contain atropine,
phenamazide, butylscopolaminium, propiverine, mebeverine,
pipenzolate, oxybutynine, flavoxate, trospium, denaverine or
glycopyrronium.
[0144] As salt-forming platelet aggregation inhibitors, the
pharmaceutical salt according to the invention can preferably
contain tirofiban, ticlopidine or clopidogrel.
[0145] As a salt-forming tuberculosis agent, the pharmaceutical
salt according to the invention can preferably contain
ethambutol.
[0146] As salt-forming urologicals, the pharmaceutical salt
according to the invention can preferably contain choline,
tolterodine, phenoxybenzamine, atropine, propiverine, distigmine,
emepronium, tamsulosine, doxazosine, terazosine, alfuzosine,
bamethane, yohimbine or sildenafil.
[0147] As salt-forming cytostatics, the pharmaceutical salt
according to the invention can preferably contain aclarubicin,
nimustatin, doxorubicin, bleomycin, vinblastine, vincristine,
daunorubicin, decarbazine, vindesine, epirubicin, gemcitabine,
procarbazil, mitoxantrone, bedamustine, idarubicin, aclarubicin
[sic], irinotecan, topotecan, toremifen or tamoxifen.
[0148] The pharmaceutical salts according to the invention can be
prepared according to customary methods known to the person skilled
in the art. Preferably, for the preparation of the pharmaceutical
salts according to the invention, at least one salt of the
respective active compound and at least one salt of the respective
sugar substitute are in each case dissolved separately from one
another in an amount of a solvent or solvent mixture which is as
small as possible, optionally with warming.
[0149] Both solutions are then combined, optionally mixed and
optionally cooled. If the pharmaceutical salt according to the
invention of the active compound and the sugar substitute
precipitates at least partially from the optionally cooled
solution, this is separated off according to customary methods,
preferably by suction filtration. The pharmaceutical salt separated
off is then purified, if necessary, according to customary methods
known to the person skilled in the art, for example by
recrystallization, washing or by stirring in a suitable
solvent.
[0150] If the pharmaceutical salt has still not completely
precipitated, the remaining solution is preferably concentrated
completely on a rotary evaporator and the pharmaceutical salt
according to the invention is extracted from the residue according
to customary methods known to the person skilled in the art and
purified as described above.
[0151] The solvent or solvent mixture suitable in each case for the
preparation and the suitable reaction conditions, such as, for
example, temperature or reaction time, can be determined by the
person skilled in the art with the aid of simple preliminary tests.
If both the active compound salt and the salt of the sugar
substitute have an adequate solubility in water, the solvent used
is preferably water. The salt of the respective active compound
employed is preferably its hydrochloride, hydrobromide, phosphate,
hydrogen-phosphate, hydrogensulfate, sulfate, nitrate or
metilsulfate. The salt of the respective sugar substitute employed
is preferably its sodium, potassium, calcium or ammonium salt.
[0152] Of course, it is also possible to react the respective
active compound per se with [sic] the free acid of a sugar
substitute with one another in a suitable reaction medium and to
isolate and, if appropriate, to purify the pharmaceutical salt thus
obtained according to customary methods known to the person skilled
in the art.
[0153] A further subject of the present invention are medicaments
comprising at least one pharmaceutical salt according to the
invention and, if appropriate, physiologically tolerable
excipients. The corresponding medicaments can be used for the
treatment of the indications known for the respective active
compounds.
[0154] Preferably, medicaments according to the invention which
contain at least one pharmaceutical salt according to the invention
of a salt-forming opioid, opioid analog, ephedrine, chloroquine,
lidocaine, ethaverine, preglumetacin or triflupromaazine or a
salt-forming compound of the general formula I, II, III or IV
indicated above and a sugar substitute are employed for the control
of pain. Preferably, the medicaments according to the invention
contain the corresponding saccharinates as pharmaceutical salts of
these active compounds.
[0155] For the treatment of urinary incontinence, medicaments
according to the invention are preferably employed which contain at
least one pharmaceutical salt of a salt-forming compound of the
general formula I, II, III or IV indicated above, or a compound
from the group consisting of oxybutymine, tolterodine, propiverine
and trospium and a sugar substitute. Preferably, the medicaments
according to the invention contain the corresponding saccharinates
as pharmaceutical salts of these active compounds.
[0156] The medicaments according to the invention can be present in
solid, semisolid or liquid form. Preferably, the medicaments
according to the invention are suitable for oral
administration.
[0157] In a preferred embodiment, the medicament according to the
invention is present formulated as a gel, chewing gum, juice,
spray, tablet, chewable tablet, coated tablet, powder, if
appropriate filled into capsules, easily reconstitutable dry
preparations, preferably as a gel, as an aqueous or oily juice, as
a sublingual spray, tablets or chewable tablets.
[0158] Likewise preferably, the medicament according to the
invention can also be present formulated in multiparticulate form,
preferably in the form of micro-tablets, microcapsules, granules,
active compound crystals or pellets, particularly preferably in the
form of microtablets, granules or pellets, optionally filled into
capsules or compressed to give tablets.
[0159] If the medicament according to the invention is present in
the form of granules or pellets, these can preferably have a size
in the range from 0.1 to 3 mm, particularly preferably in the range
from 0.5 to 2 mm.
[0160] If the medicament according to the invention is present in
the form of microtablets, these can preferably have a diameter in
the range from 0.5 to 5 mm, particularly preferably in the range
from 1 to 3 mm and very particularly preferably in the range from 1
to .sub.2 mm.
[0161] If the medicament according to the invention is present in
the form of active compound crystals, micro-particles, micropellets
or microcapsules, these can preferably have a diameter in the range
from 10 .mu.m to 1 mm, particularly preferably in the range from 15
.mu.m to 0.5 mm and very particularly preferably in the range from
30 .mu.m to 200 .mu.m.
[0162] Depending on embodiment, the medicaments according to the
invention can moreover contain the customary physiologically
tolerable excipients known to the person skilled in the art as
further constituents.
[0163] If the medicaments according to the invention are present in
the form of tablets or microtablets, these can be present as
physiologically tolerable excipients, preferably microcrystalline
cellulose, cellulose ethers, lactose, starch, starch derivatives,
sugar alcohols, calcium hydrogenphosphate and the customary
binders, flow regulators, lubricants and/or disintegrants known to
the person skilled in the art.
[0164] If the medicaments according to the invention are present in
the form of gels or chewing gums, these can preferably contain
methylparaben, propylparaben, xylitol and/or xanthan gum as
physiologically tolerable excipients.
[0165] If the medicaments according to the invention are present in
the form of pellets, granules or micro-pellets, these can
preferably contain microcrystalline cellulose, cellulose ethers,
lactose, starch and starch derivatives, sugar alcohols, calcium
hydrogenphosphate, fatty alcohols, esters of glycerol or fatty acid
esters as physiologically tolerable excipients.
[0166] If the medicaments according to the invention are present in
the form of microcapsules or microparticles, these can contain,
depending on the nature of the process employed for their
preparation, the customary physiologically tolerable excipients
known to the person skilled in the art.
[0167] The medicaments according to the invention can be prepared
by customary methods known to the person skilled in the art.
[0168] If the medicaments according to the invention are present in
the form of tablets, preferably the pharmaceutical salt according
to the invention and, if appropriate, the physiologically tolerable
excipients are preferably mixed homogeneously with one another,
processed to give granules by means of moist, dry or melt
granulation and compressed to give tablets or produced by direct
tableting of the pharmaceutical salt with further excipients. In
addition, the tablets can preferably be produced by compression of
optionally coated pellets, active compound crystals,
micro-particles or microcapsules.
[0169] The medicaments according to the invention in the form of
pellets can preferably be produced by mixing the pharmaceutical
salt and physiologically tolerable excipients, extrusion and
spheronization, by build-up pelletization or by direct
pelletization in a high-speed mixer or in the rotor fluidized bed.
The pellets are particularly preferably prepared by extrusion of
moist masses and subsequent spheronization.
[0170] Microcapsules are prepared according to customary
microencapsulation processes, such as, for example, by spray
drying, spray solidification or coacervation.
[0171] The medicaments according to the invention in semisolid
form, such as, for example, gels or chewing guns, are preferably
suitable for the administration of the pharmaceutical salt
according to the invention via the oral mucosa, the medicaments
according to the invention in solid or liquid form, such as, for
example, oily or aqueous juices, tablets or multiparticulate forms
are preferably suitable for the administration of the
pharmaceutical salt according to the invention via the gastric
tract. If the absorption of active compound from the medicament
according to the invention in solid form is only intended via the
gastric tract, they must have at least one enteric coating. This
enteric coating enables them to pass through the gastric tract
undissolved and the pharmaceutical salt is only released in the
intestinal tract. Preferably, the enteric coating dissolves at a pH
of between 5 and 7.5.
[0172] The medicament according to the invention can contain the
pharmaceutical salt according to the invention also partially or
completely in delayed-release form.
[0173] The delaying of the release of active compound is preferably
based on the application of a release-delaying coating, on
embedding in a release-delaying matrix, binding to an ion-exchange
resin or on a combination of these abovementioned release-delaying
methods.
[0174] Preferably, the release-delaying coating is based on a
water-insoluble, optionally modified natural or synthetic polymer
or on a natural, semisynthetic or synthetic wax or fat or fatty
alcohol or a mixture of at least two of these abovementioned
components.
[0175] Water-insoluble polymers employed for the preparation of a
release-delaying coating are preferably poly-(meth)acrylates,
particularly preferably poly(C.sub.1-.sub.4) alkyl (meth)acrylates,
poly(C.sub.1-.sub.4)dialkylamino-(C.sub.1-C.sup.4)-alkyl
(meth)acrylates and/or their copolymers, very particularly
preferably ethyl acrylate/methyl methacrylate copolymers having a
molar ratio of the monomers of 2:1, ethyl acrylate/methyl
methacrylate/trimethylammonium ethyl methacrylate chloride
copolymers having a molar ratio of the monomers of 1:2:0.1, ethyl
acrylate/methyl methacrylate/trimethylammonium ethyl methacrylate
chloride copolymers having a molar ratio of the monomers of 1:2:0.2
or a mixture of at least two of these abovementioned polymers as a
coating material.
[0176] These coating materials are obtainable on the market as 30%
strength by weight aqueous latex dispersions under the names
Eudragit RS30D.RTM., Eudragit NE30D.RTM. and Eudragit RL30D.RTM.
and are preferably also employed as a coating material as such.
[0177] Likewise preferably, the water-insoluble polymers employed
for the preparation of the release-delaying coating for the
medicaments according to the invention can be polyvinyl acetates,
optionally in combination with further excipients. These are
obtainable on the market as an aqueous dispersion containing 27% by
weight of polyvinyl acetate, 2.5% by weight of povidone and 0.3% by
weight of sodium lauryl sulphate (Kollicoat SR 30 D.RTM.)
[0178] In a further preferred embodiment, the release-delaying
coatings of the medicaments according to the invention are based on
water-insoluble cellulose derivatives, preferably alkylcelluloses,
such as, for example, ethylcellulose, or on cellulose esters, such
as, for example, cellulose acetate, as a coating material. The
coatings of ethylcellulose or cellulose acetate are preferably
applied from aqueous pseudolatex dispersion. Aqueous
ethylcellulose-pseudolatex dispersions are stocked on the market as
30% strength by weight dispersions (Aquacoat.RTM.) or as 25%
strength by weight dispersions (Surelease.RTM.) and as such are
preferably also employed as a coating material.
[0179] As natural, semisynthetic or synthetic waxes, fats or fatty
alcohols, the release-delaying coating in the medicament according
to the invention can preferably contain carnauba wax, beeswax,
glycerol monostearate, glycerol monobehenate (Compritol
AT0888.RTM.), glycerol ditripalmitostearate (Precirol AT05.RTM.),
microcrystalline wax, cetyl alcohol, cetylstearyl alcohol, or a
mixture of at least two of these components.
[0180] If the release-delaying coating is based on a
water-insoluble, optionally modified natural and/or synthetic
polymer, the coating dispersion or solution can contain, in
addition to the corresponding polymer, a customary physiologically
tolerable plasticizer known to the person skilled in the art in
order to lower the minimum film temperature necessary.
[0181] Suitable plasticizers are, for example, lipophilic diesters
of an aliphatic or aromatic dicarboxylic acid of C.sub.6-C.sub.40
and an aliphatic alcohol of C.sub.1-C.sub.8, such as, for example,
dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl
sebacate, hydrophilic or lipophilic esters of citric acid, such as,
for example, triethyl citrate, tributyl citrate, acetyltributyl
citrate or acetyltriethyl citrate, polyalkylene glycols, such as,
for example, polyethylene glycols or propylene glycols, esters of
glycerol, such as, for example, triacetin, Myvacet.RTM. (acetylated
mono- and diglycerides, C.sub.23H.sub.44O.sub.5 to
C.sub.25H.sub.47O.sub.7), medium-chain triglycerides
(Miglyol.RTM.), oleic acid or mixtures of at least two of the
abovementioned plasticizers.
[0182] Preferably, aqueous dispersions of Eudragit RS.RTM. and
optionally Eudragit RL.RTM. contain triethyl citrate as a
plasticizer.
[0183] Preferably, the release-delaying coating contains the
plasticizer(s) in amounts of 5 to 50% by weight, particularly
preferably 10 to 40% by weight and very particularly preferably 10
to 30% by weight, based on the amount of the polymer employed.
[0184] In individual cases, for example for cellulose acetate,
higher amounts of plasticizers, preferably up to 110% by weight,
based on the amount of cellulose acetate, can also be employed.
[0185] In addition, the release-delaying coating can contain
further customary excipients known to the person skilled in the
art, such as, for example, lubricants, preferably talc or glycerol
monostearate, color pigments, preferably iron oxides or titanium
dioxide, or surfactants, such as, :for example, Tween 80.RTM..
[0186] The release profile of the delayed active compound component
can be adjusted by the customary methods known to the person
skilled in the art, such as, for example, by the thickness of the
coating or by the use of further excipients as constituents of the
coating. Suitable excipients are, for example, hydrophilic or
pH-dependent pore-forming agents, such as, for example, sodium
carboxymethylcellulose, cellulose acetate phthalate,
hydroxypropylmethylcellulose acetate succinate, lactose,
polyethylene glycol or mannitol or water-soluble polymers, such as,
for example, polyvinylpyrrolidone or water-soluble celluloses,
preferably hydroxypropylmethylcellulose or
hydroxy-propylcellulose.
[0187] The release-delaying coating can also contain insoluble or
lipophilic excipients, such as, for example, alkylized silicone,
which is stocked on the market, for example, as Aerosil R972.RTM.,
or magnesium stearate for the further intensification of the
delaying.
[0188] The respective formulation of the medicament according to
the invention can optionally also contain, in addition to the
release-delaying coating, at least one further coating. This can
be, for example, a coating for improving the taste or an enteric
coating.
[0189] The enteric coating is preferably based on methacrylic
acid/methyl methacrylate copolymers having a molar ratio of the
respective monomers of 1:1 (Eudragit L.RTM.), methacrylic
acid/methyl methacrylate copolymers having a molar ratio of the
respective monomers of 1:2 (Eudragit S.RTM.), methacrylic
acid/ethyl acrylate copolymers having a molar ratio of the
respective monomers of 1:1 (Eudragit L300-55.degree.), methacrylic
acid/methyl acrylate/methyl methacrylate copolymers having a molar
ratio of the respective monomers of 7:3:1 (Eudragit FS.RTM.),
shellac hydroxy-propylmethylcellulose acetate succinate, cellulose
acetate phthalate or a mixture of at least two of these
abovementioned components, which can optionally also be employed in
combination with the abovementioned water-insoluble
poly(meth)acrylates, preferably in combination with Eudragit
NE30D.RTM. and/or Eudragit RL.RTM. and/or Eudragit RE.RTM..
[0190] The coatings can be applied by customary processes suitable
for the respective coating and known to the person skilled in the
art, such as, for example, by spraying on solutions, dispersions or
suspensions, by melt processes or by powder application processes.
The solutions, dispersions or suspensions can be employed in the
form of aqueous and/or organic solutions or dispersions. In this
context, aqueous dispersions are preferably employed. Organic
solvents which can preferably be used are alcohols, for example
ethanol or isopropanol, ketones, such as, for example, acetone,
esters, for example ethyl acetate, chlorinated hydrocarbons, such
as, for example, dichloromethane, with alcohols or ketones being
particularly preferably employed. It is also possible to employ
mixtures of at least two of the abovementioned solvents.
[0191] If the medicament is present in multiparticulate fount and
the active compound is to be released at least partially in delayed
form, the release-delaying coating is preferably applied such that
the multiparticulate forms comprising the active compound salt are
coated after their preparation with the corresponding polymers and,
if appropriate, another active compound and/or the same active
compound salt and, if appropriate, further physiologically
tolerable excipients from aqueous and/or organic media, preferably
from aqueous media, with the aid of the fluidized bed process and
the coating is preferably simultaneously dried in the fluidized bed
at customary temperatures and, if appropriate, annealed if
necessary.
[0192] Preferably, the drying of the coating is carried out for
poly(meth)acrylate coatings at a feed air temperature in the range
from 30 to 50.degree., particularly preferably in the range from 35
to 45.degree. C.
[0193] For coatings based on cellulose, such as, for example,
ethylcellulose or cellulose acetate, the drying is preferably
carried out at a temperature in the range from 50 to 80.degree. C.,
particularly preferably in the range from 55 to 65.degree. C.
[0194] Wax coatings can be applied by melt coating in the fluidized
bed and cooled at temperatures below the respective melt range
after the coating for complete solidification. The application of
wax coatings can also be carried out by spraying on their solutions
in organic solvents.
[0195] For the modification of the active compound release profile,
the medicament according to the invention can contain the
pharmaceutical salt whose release is to be delayed also in a
release-delaying matrix, preferably uniformly dispersed.
[0196] Matrix materials which can be used are physiologically
tolerable, hydrophilic materials which are known to the person
skilled in the art. Preferably, the hydrophilic matrix materials
used are polymers, particularly preferably cellulose ethers,
cellulose esters and/or acrylic resins. Very particularly
preferably, the matrix materials employed are ethylcellulose,
hydroxy-propylmethylcellulose, hydroxypropylcellulose,
hydroxy-methylcellulose, poly(meth)acrylic acid and/or their
derivatives, such as, for example, their salts, amides or
esters.
[0197] Likewise preferred are matrix materials made of hydrophobic
materials, such as hydrophobic polymers, waxes, fats, long-chain
fatty acids, fatty alcohols or appropriate esters or ethers or
mixtures of at least two of the abovementioned materials.
Particularly preferably, the hydrophobic materials employed are
mono- or diglycerides of C.sub.12-C.sub.30-fatty acids and/or
C.sub.12-C.sub.30-fatty alcohols and/or waxes or mixtures of at
least two of the abovementioned materials.
[0198] It is also possible to employ mixtures of the
above-mentioned hydrophilic and hydrophobic materials as a
release-delaying matrix material.
[0199] The release-delaying matrix can be prepared by the customary
methods known to the person skilled in the art.
[0200] A further subject of the invention is also the use of at
least one pharmaceutical salt according to the invention and, if
appropriate, physiologically tolerable excipients for the
production of a medicament. The corresponding medicaments can be
used for the treatment of the indications known for the respective
active compounds.
[0201] Preferred is the use of at least one pharmaceutical salt of
a salt-forming opioid, opioid analog, ephedrine, chloroquine,
lidocaine, ethaverine, preglumetacin, truflupromazine or a
salt-forming compound of the general formula I, II, III or IV
indicated above for the production of a medicament for the control
of pain, the salts of these active compounds used preferably being
their saccharinates.
[0202] Likewise preferred is the use of at least one pharmaceutical
salt of a salt-forming compound of the general formula I, II, III
or IV indicated above for the production of a medicament for the
treatment of urinary incontinence, the salts of these active
compounds used preferably being their saccharinates.
[0203] The total amount of the respective pharmaceutical salt to be
administered to the patient varies, for example, depending on the
the weight of the patient, on the indication and the degree of
severity of the pain or of the disorder. It is known to the person
skilled in the art on account of the properties of the respective
active compounds in what doses these are to be administered in
order to achieve the desired effect.
[0204] The pharmaceutical salts according to the invention of a
pharmaceutical active compound and a sugar substitute are
distinguished compared with the conventionally used salts of these
active compounds customarily by a lower solubility in water.
Preferably, these are the saccharinates of the respective active
compounds, whose water solubility is usually .ltoreq.250 mg/ml and,
compared with the water solubility of the conventional salts of the
corresponding active compound, is usually lowered by at least
50%.
[0205] By this means, the formulation of these pharmaceutical salts
to give medicaments, for example the preparation of granules by
extrusion, is also simplified. On account of the altered
solubility, the pharmaceutical salts according to the invention
further enable more effective release-delaying of the active,
compound using customary delaying processes in comparison to salts
customarily used. Delayed-release medicaments which contain these
pharmaceutical salts according to the invention can therefore be
produced more simply and more inexpensively. This also applies for
other modifications of the medicaments according to the invention,
such as, for example, with enteric coatings.
[0206] From the medicaments according to the invention, which are
employed for the administration of the respective pharmaceutical
salt via the oral mucosa or the gastric tract, a largely controlled
release of the respective active compound without the use of a
release-delaying matrix and/or a release-delaying coating, but if
appropriate with an enteric coating, is moreover achieved.
[0207] The medicaments according to the invention in the form to be
administered orally, which release the respective active compound
as early as on or immediately after administration, furthermore
have the advantage that their strongly bitter or nauseating taste
is compensated by the simultaneous release of the sugar substitute.
The adherence to the dosage instructions in the patients thereby
improves and the medicaments which contain the respective active
compound as a salt experience a greater acceptance. The medicaments
according to the invention are moreover also suitable for
diabetics.
[0208] For a large number of the abovementioned active compounds,
the water solubility of the conventional active compound salts is
known, for example from Pharmazeutische Stoffliste [Pharmaceutical
Substance List], 12th edition'ABDATA Pharma-Daten-Service, 65735
Eschborn/Taunus. The corresponding disclosure [sic] is hereby
inserted as reference and is thus regarded as part of the
disclosure.
[0209] If the water solubility of an active compound salt is not
known, it can be determined according to the method indicated
below, according to which the water solubility of the
pharmaceutical salts according to the invention has also been
determined:
[0210] In a clear colorless vessel made of transparent material,
such as, for example, glass or plastic, 1 ml of ion-free water or a
fraction (amount A in ml) thereof is introduced at a temperature of
20.degree. C. While stirring with a magnetic stirrer rod, the
conventional active compound salt to be tested or the
pharmaceutical salt according to the invention was then added in
portions.
[0211] If the amount of salt B added (in mg) completely dissolved,
further amounts of the respective salt were slowly added. Each
further addition was recorded and the solution behavior observed.
As soon as the first turbidity due to undissolved salt was found by
observation against a suitable background, stirring was continued
for a further 10 minutes. If undissolved constituents subsequently
remained, the sum C (in mg) of the amount of substance employed was
determined. If a clear solution resulted again on stirring, further
small amounts of the respective salt were added and the mixture was
in each case stirred again for 10 minutes until a first turbidity
remained on account of undissolved salts. The excess amount of
undissolved substance was then brought into solution with stirring
by addition of small amounts of water. After a clear solution had
been obtained, the sum D (in ml) of the amount of water employed
was determined. The solubility of the respective salt per 1 ml of
water was then calculated according to the following formula:
Water solubility of the active compound salt in mg / ml of water =
( C / A ) + ( C / D ) 2 ##EQU00001##
[0212] If the amount B added (in mg) of the respective salt did not
dissolve immediately and a turbidity resulted, after the addition
of the salt the mixture was stirred for a further 10 minutes. If
undissolved salt still remained then, the undissolved portion was
brought into solution by addition of small amounts of water with
stirring. After obtainment of a clear solution, the sum E (in ml)
of the amounts of water employed was determined. The solubility of
the respective salt per 1 ml of water was then calculated according
to the following formula:
Water solubility of the active compound salt in mg / ml of water =
B E ##EQU00002##
[0213] The invention is explained below with the aid of examples.
These explanations are only by way of example and do not restrict
the general inventive concept.
EXAMPLES
Example 1
[0214] The preparation and the subsequent separation of the
optically pure compound
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol was
carried out according to DE-A-4426245. The corresponding part of
the disclosure [sic] is hereby inserted as reference and is thus
regarded as part of the disclosure.
[0215] For the preparation of
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol
saccharinate, 2.58 g (10 mmol) of
(+)-(1S,23)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol
hydrochloride and 2.42 g (10 mmol) of saccharin-sodium dihydrate
were in each case completely dissolved with warming in an amount of
water which was as small as possible. Both solutions were then
mixed with one another with stirring and then placed in a cool
place overnight. The precipitated
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl.sup.-2-methylpropyl)-phenol
saccharinate was separated off from the supernatant mother liquor,
purified with ethanol and isolated according to conventional
methods.
Example 2
[0216] For the preparation of diphenhydramine saccharinate, 5.0 g
(17.1 mmol) of diphenhydramine hydrochloride and 4.13 g (17.1 mmol)
of saccharin-sodium dihydrate were in each case completely
dissolved with warming in an amount of water which was as small as
possible. Both solutions were then mixed with one another with
stirring and then placed in a cool place overnight. The
precipitated diphenhydramine saccharinate was separated off from
the supernatant mother liquor, purified with ethanol and isolated
according to conventional methods.
Example 3
[0217] For the preparation of verapamil saccharinate, 415 mg (0.845
mmol) of verapamil hydrochloride and 204 mg (0.845 mmol) of
saccharin-sodium dihydrate were in each case completely dissolved
with warming in an amount of water which was as small as possible.
Both solutions were then mixed with one another with stirring and
then placed in a cool place overnight. The precipitated verapamil
saccharinate was separated off from the supernatant mother liquor,
purified with ethanol and isolated according to conventional
methods.
Example 4
[0218] For the preparation of morphine saccharinate, 285 mg (0.76
mmol) of morphine hydrochloride trihydrate and 183 mg (0.76 mmol)
of saccharin-sodium dihydrate were in each case completely
dissolved with warming in an amount of water which was as small as
possible. Both solutions were then mixed with one another with
stirring and then placed in a cool place overnight. The
precipitated morphine saccharinate was separated off from the
supernatant mother liquor, purified with ethanol and isolated
according to conventional methods.
Example 5
[0219] For the preparation of an oral gel, 0.33 g of methylparaben,
0.05 g of propylparaben and 75.0 g of xylitol were first dissolved
in 198.0 g of purified water at a temperature of 80.degree. C. and
the mixture was then cooled to 40.degree. C. Then, initially 0.94 g
of diphenhydramine saccharinate obtained according to example 2 and
subsequently 2 g of xanthan gum were added with stirring, stirring
was continued for one hour and evaporated water was replaced. After
cooling to a temperature of 20 to 25.degree. C., the mixture was
flavored with 0.625 g of Tutti-Frutti 9/008897 (Dragoco Gerberding
& Co. AG, 37603 Holzminden) while stirring.
Example 6
[0220] 5 g of comminuted chewing gum mass (Popye Amural
Confections, Yorkville, Ill., USA) were warmed to a temperature of
30 to 40.degree. C. in a Fanta dish. 187.9 mg of diphenhydramine
saccharinate obtained according to example 2 were then incorporated
into the viscous chewing gum mass using a pestle. The homogeneous
mass was then portioned into teflonized molds to give portions of 1
g each.
[0221] The taste test showed that the chewing gums which contained
the diphenhydramine saccharinate had an excellent taste at the
start and were still enjoyable even after a relatively long chewing
time.
Example 7
[0222] For the preparation of a juice on an aqueous basis, 0.33 g
of methylparaben, 0.05 g of propylparaben and 75.0 g of xylitol
were dissolved in 199.22 g of purified water at a temperature of
80.degree. C. The mixture was cooled to 40.degree. C. and 78.5 mg
of (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol
saccharin-ate obtained according to example 1 were added with
stirring. 0.25 g of xanthan gum was then added, stirring was
continued for one hour and evaporated water was replaced. After
cooling to (lacuna) temperature of 20 to 25.degree. C., the mixture
was flavored while stirring with 0.075 g of orange-mandarin flavor
10888-56 (Givaudan Roure Flavors Ltd. CH 8600 Diabendorr).
Example 8
[0223] In this example, the water solubility of certain
pharmaceutical salts and of conventional salts of the corresponding
active compound was determined according to the method indicated
above. The solubility values thus obtained are presented in table 1
below:
TABLE-US-00001 TABLE 1 Comparison of the water solubilities of
certain pharmaceutical salts according to the invention and
corresponding conventional salts of these active compounds. The
conventional salt employed in each case is indicated in brackets.
Solubility of Solubility of the active the active compound compound
salt saccharinate in mg/ml of in mg/ml of Active compound water
water (-)-(1R,2R)-3-(3- 261 31 dimethylamino-1-ethyl-
(hydrochloride) 2-methylpropyl)phenol (1RS,3RS,6RS)-6- 500 71
dimethylaminomethyl-1- (hydrochloride) (3-methoxy-
phenyl)cyclohexane- 1,3-diol [sic] (+)-(1S,2S)-3-(3- 650 55
dimethylamino-1-ethyl- (hydrochloride) 2-methylpropyl)phenol
(-)-(1S,2S)-3-(3- 568 130 dimethylamino-1-ethyl- (hydrochloride)
1-fluoro-2-methyl- propyl)phenol (-)-(2S,3S)-1- 2000 90
dimethylamino-3-(3- (hydrochloride) methoxyphenyl)-
2-methylpentan-3-ol (+)-(1R,2R,4S)-2- 33 10 dimethylaminomethyl-4-
(hydrochloride) (4-fluorobenzyl-oxy)- 1-(3-methoxy-
phenyl)cyclohexanol Morphine 52 25 (hydrochloride trihydrate)
Amezinium 25 8 (metilsulfate) Phenylephrine 1250 380
(hydrochloride) Verapamil 200 7 (hydrochloride) Diphenhydramine
1000 7 (hydrochloride) Benzalkonium 500 <2 (hydrochloride)
Codeine 250 200 (phosphate hemihydrate) Hydromorphone 330 130
(hydrochloride) Buprenorphine 14 2 (hydrochloride)
[0224] As can be seen from the solubility values according to table
1, the solubility of the respective active compound saccharinates
is lowered compared with the corresponding conventional active
compound salts.
* * * * *