Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL SALTS OF 1-PHENYL-3-DINETHYLAMINOPROPANE
COMPOUNDS
The present invention relates to pharmaceutical 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.
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.
The formulation of pharmaceutical active compounds
having very good water solubility to give medicaments
frequently causes problems in pharmaceutical practice.
Thus the---_preparation of pfiarmaceu~ical forms having
controlled release is often made difficult on account
of the very good water solubility 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.
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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.
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.
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, (+)-demethyltramadol and (-)-demethyltramadol
being excepted.
In accordance with an aspect of the present invention,
there is provided a pharmaceutical salt of a pharmaceutical
active compound and at least one sugar substitute, wherein
the salt-forming active compound is a salt-forming 1-
phenyl-3-dimethylaminopropane compound of the general
formula I
X R1
R2
3
R5
~\ CH3
R 4
I
CH3
in which
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X is OH, F, Cl, H or an OCOR6 group,
R1 is a C1-4-alkyl group,
R2 is H or a C1_4-alkyl group and R3 is H or a straight-
chain C1_4-alkyl group or the radicals R2 and R3 together
form a C4-7-cycloalkyl radical, and
if R5 is H, R4 is meta-O-Z where Z is H, C1_3-alkyl,
PO (0-C1-4-alkyl) 2, CO (OC1_5-alkyl) , CONH-C6H4- (C1_3-alkyl) , CO-
C6H4-R7, where R7 is ortho-OCOC1-3-alkyl or meta- or para-
CH2N (R8) 2 where R8 is C1_4-alkyl or 4-morpholino, or R4 is
meta-S-C1-3-alkyl, meta-C1, meta-F, meta-CR9R10R" where R9,
Rio, R" are H or F, ortho-OH, ortho-O-C2_3-alkyl, para-F or
para-CR9R1 R11 where R9, Rio, R'1 are H or F, or if R5 is para-
Cl, -F, -OH or -0-C1_3-alkyl, R4 is meta-C1, -F, -OH or -O-C1_
3-alkyl, or
R4 and R5 together are 3,4-OCH=CH- or 3,4-OCH=CHO-,
R6 is C1-3-alkyl,
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.
In a preferred embodiment of the present invention, the
solubility of the pharmaceutical salts according to
the invention in water is S 250 mg/ml of water,
preferably < 200 mg/ml, particularly preferably -<
150 mg/ml, very particularly preferably - 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
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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.
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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.
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.
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, R-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, ophthalmo-
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logicals, otologicals, 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, R-receptor
blockers, calcium channel blockers, ophthalmological s,
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.
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.
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,
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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.
Likewise preferably, the salt-forming active compound
is a salt-forming compound of 1-phenyl-3-dimethylamino-
propane compounds of the general formula I
X R1
R2
R3
R.
/CH3
N
R4
CH3
I
in which in each case
X is OH, F, Cl, H or an OCOR6 group,
R1 is a C1_4-alkyl group,
R2 is H or a C1-4-alkyl group and R3 is H or a straight-
chain C1_4-alkyl group or the radicals R2 and R3 together
form a C4_7-cycloalkyl radical, and
if R5 is H, R4 is meta-O-Z where Z is H, C1_3-alkyl,
PO (O-C1_4-alkyl) 2, CO (OC1-5-alkyl) , CONH-C6H4- (C1_3-alkyl) ,
CO-C6H4-R7, where R7 is ortho-OCOC1_3-alkyl or meta- or
para-CH2N (R8) 2 where R8 is C1_4-alkyl or 4-morpholino, or
R4 is meta- S-C1-3-alkyl, meta-Cl, meta-F, meta-CR9R1 R11
where R9, R10 and R'1 are H or F, ortho-OH, ortho-O-C2_3-
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alkyl, para-F or para-CR9R10R11 where R9, R10, R11 are H
or F, or if R5 is para-Cl, -F, -OH or -0-C1_3-alkyl, R4
is meta-Cl, -F, -OH or -O-Cl-3-alkyl, or
R4 and R5 together are 3,4-OCH=CH- or 3,4-OCH=CHO-,
R6 is C1_3-alkyl,
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.
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, R1 is a C1_4-alkyl group,
R2 is H or CH3 and R3 is H or CH3 and if R5 is H, R4 is
meta-O-C1-3-alkyl, meta-OH, meta-S-C1_3-alkyl, meta-F,
meta-C1, meta-CH3, meta-CF2H, meta-CF3 or para-CF3 or if
R5 is a para-C1 or -F, R4 is meta-C1 or -F, or R4 and R5
together are 3,4-OCH=CH-.
Particularly preferred is a salt-forming compound of 1-
phenyl-3-dimethylaminopropane compounds of the general
formula I in which the radicals R2 and R3 have different
meanings and which are present in the form of their
diastereomers having the configuration Ia
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R6
R4
X H
R'
H3C . CH3
la
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
(1RS,2RS)-3-(3-dimethylamino-l-hydroxy-l,2-dimethyl-
propyl)phenol,
(-)-(1R,2R)-3-(3-dimethylamino-l-ethyl-2-methylpropyl)-
phenol,
(+)-(lS,2S)-3-(3-dimethylamino-l-ethyl-2-methylpropyl)-
phenol,
(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-
pentan-3-ol,
(-)-(1S,2S)-3-(3-dimethylamino-l-ethyl-l-fluoro-
2-methylpropyl) phenol,
(+)-(1R,2R)-3-(3-dimethylamino-l-hydroxy-l,2-dimethyl-
propyl)phenol,
(+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-
2-methylpentan-3-ol and
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(-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-
2-methylpentan-3-ol.
The preparation of the salt-forming compounds of
1-phenyl-3-dimethylaminopropane 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,
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,
OR4'
R
CH3
Rr
R3, CH3
II
in which in each case
R" is H, OH, Cl or F, preferably H, OH or F,
R2' and R3' are identical or different and are H, C1_4-
alkyl, benzyl, CF3, OH, OCH2-C6H5, O-C1_4-alkyl, C1 or F
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with the proviso that at least one of the radicals R2.
or R31 is H,
R4' is H, CH3, PO (O-C1_4-alkyl) 2, CO (OC1_5-alkyl) , CO-NH-
C6H4-C1_3-alkyl, CO-C6H4-R5" CO-C1-5-alkyl, CO-CHR6'-NHR7'
or an unsubstituted or substituted pyridyl, thienyl,
thiazoyl [sic] or phenyl group,
R5' is OC (0) C1_3-alkyl in the ortho-position or CH2-
N (R8') 2 in the meta- or para-position, where R8' is C1-4-
alkyl or both radicals R8' together with N are the
4-morpholino radical, and
R6` and R7' are identical or different and are H or C1-6-
alkyl,
with the proviso that if both radicals R2' and R3 ' are
H, R4' is not CH3 if R" is H, OH or Cl or R4' is not H if
R11 is OH,
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.
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,
Rr W,
C
R3I
H3C CH3
IIa
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in which the phenyl ring and the dimethylaminomethyl
group are in each case arranged in an equatorial
position to one another.
Particularly preferred is a salt-forming compound of
6-dimethylaminomethyl-l-phenylcyclohexane compounds of
the general formula II selected from the group
consisting of
(-)-(1R,2R)-3-(2-dimethylaminomethylcyclohexyl)phenol,
(1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-methoxy-
phenyl)cyclohexane-1,3-diol and
(1RS,3RS,6RS)-6-(dimethylaminomethyl)-l-(3-hydroxy-
phenyl)cyclohexane-1,3-diol.
The preparation of the salt-forming compounds of
6-dimethylaminomethyl-l-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.
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,
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1'
/R
A
Rr/Y------Z
OH
H3C/ CH3
Ill
in which in each case
A is 0 or S,
R"' is H, C1_6-alkyl, C2_6-alkenyl, C5-7-cycloalkyl or
halogenated C1_6-alkyl,
the group -Y=Z\
is the group
/ /
CFi~--C; I ---CH-< or -~-O--C~
R2 is C1_6-alkyl, C2-6-alkenyl, C5-7-cycloalkylmethyl,
substituted or unsubstituted phenyl or substituted or
unsubstituted benzyl,
in the form of their possible stereoisomers as
racemates or diastereomerically pure enantiomers or in
the form of mixtures of enantiomers, in which the
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respective enantiomers are present in nonequimolar
amounts.
Preferred are salt-forming compounds of 1-phenyl-2-di-
methylaminomethylcyclohexan-l-ol compounds of the
general formula III, in which R" is H, C1_4-alkyl, 2' -
methyl-2'-propenyl, cyclopentyl or fluoroethyl, with
the proviso that R"' is C1-4-alkyl if A is S,
R2. f is C1_4-alkyl, C2_4-alkenyl, cyclopentylmethyl,
phenyl, C1_4-alkoxyphenyl, benzyl, C1_4-alkylbenzyl,
mono- or dihalogenated phenyl or mono- or dihalogenated
benzyl.
Particularly preferred are salt-forming compounds of
1-phenyl-2-dimethylaminomethylcyclohexan-l-ol compounds
of the general formula III, in which R"' is H, methyl,
ethyl, isopropyl, 2'-methyl-2'-propenyl, cyclopentyl or
fluoroethyl, with the proviso that R11' is methyl if A
is S,
R2" 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.
Very particularly preferred are salt-forming compounds
of 1-phenyl-2-dimethylaminomethylcyclohexan-l-o1
compounds of the general formula III which are present
in the configuration of the formula IIIa,
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R1
A'
OH
Rte/
N
"-CH3
,
H3C
Ilia
in which the phenyl ring and the dimethylaminomethyl
group are in each case arranged in an equatorial
position to one another.
Most preferred is the salt-forming compound of
1-phenyl-2-dimethylaminomethylcyclohexan-l-ol compounds
of the general formula III selected from the group
consisting of
(+)-(1R,2R,4S)-2-(dimethylaminomethyl)-4-(4-fluoro-
benzyloxy)-1-(3-methoxyphenyl)cyclohexanol,
(+)-(1R,2R,4S)-2-dimethylaminomethyl-4-(4-chloro-
benzyloxy)-1-(3-methoxyphenyl)cyclohexanol and
(+)-(1R,2R,4S)-3-[2-dimethylaminomethyl-4-(4-fluoro-
benzyloxy)-l-hydroxycyclohexyl]phenol.
The preparation of the salt-forming compounds of
1-phenyl-2-dimethylaminomethylcyclohexan-l-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.
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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]
Rs~
R57
4-1
R
H
Rr, CH3
Rr R''" CH3
IV
the radical R1, . . is C1_5-alkyl and R2. . . is H or C1_5-alkyl
or R1... and R2... together are - (CH2) 2-4-, - (CH2) 2-CHR7"' or
-CH2-CHR71 " -CH2-,
R 3" is H or C1_5-alkyl,
pd" is H, OH, C1_4-alkyl, O-C1_4-alkyl, O-benzyl, CF3r 0-
CF3r Cl, F or ORB",
R5,,, is H, OH, C1_4-alkyl, O-C1-4-alkyl, O-benzyl, CHF2,
CF3, O-CF3, Cl, F or OR8and
R6" is H, OH, C1_4-alkyl, O-C1_4-alkyl, O-benzyl, CF3r 0-
CF3, Cl, F or OR8t ,
with the proviso that two of the radicals R4111 , R511' or
R6are H, or
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R4 '. , and R5... together are -CH=C (R9...) -0- or
-CH=C (R9. . .) -S-, with the proviso that R6. . . is H, or
R5 . . . and R6 ' . , together are -CH=CH-C (OR10 ') =CH- , with the
proviso that R4. . . is H,
R7... is C1_8-alkyl, C3_8-cycloalkyl, O-C1-4-alkyl, 0-
benzyl, CF3, Cl or F,
R8... is CO-C1-5-alkyl, PO (O-C1_4-alkyl) 2, CO-C6H4-R11 ,
CO (O-C1-5-alkyl) , CO-CHR12 ' -NHR13' ' ' , CO-NH-C6H3- (R14...) 2 or
an unsubstituted or substituted pyridyl, thienyl,
thiazoyl [sic] or phenyl group,
R9. . . is H or Cl_4-alkyl,
R10.. . is H or C1-3-alkyl,
R11. . . is OC (O) -C1-3-alkyl in the ortho-position or CH2-N-
(R15" ) 2 in the meta- or para-position, where R15... is
C1-4-alkyl or both radicals R151 ' together with N form
the 4-morpholino radical,
R12' II and R13. . . are identical or different and are H,
C1-6-alkyl or C3-8-cycloalkyl or R12" , and R13together
are - (CH2) 3-8-,
R14. . . is H, OH, C1-7-alkyl, O-C1_7-alkyl, phenyl, 0-aryl,
CF3, Cl or F, with the proviso that the two radicals
R14... are identical or different,
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.
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Preferred are salt-forming compounds of dimethyl-(3-
arylbut-3-enyl)amine compounds of the general formula
IV, in which
R1"' is C1_3-alkyl and R2"' is H or C1-3-alkyl, or R1"' and
R2"' together are - (CH2) 2_4- or - (CH2) 2-CHR7"',
R3' " is H or C1_3-alkyl,
R4''' is H, OH, CF3, Cl, F or OR8"',
R5"' is H, OH, C1_4-alkyl, O-C1-4-alkyl, 0-benzyl, CHF2,
CF3, Cl, F or OR8' B", and
R6"' is H, OH, O-C1-4-alkyl, 0-benzyl, CF3, Cl, F or
OR$
with the proviso that two of the radicals R4"', R5"' or
R6''' are H, or
R4and R5"' together are -CH=C(R 9... )_O_ or
-CH=C(R9"')-S-, with the proviso that R6"' is H, or
R5' ' ' and R6' ' ' together are -CH=CH-C (OR10' ' ')=CH-, with the
proviso that R4'" is H, and
R7"' is C1_4-alkyl, CF3, Cl or F.
Particularly preferred are salt-forming compounds of
dimethyl-(3-arylbut-3-enyl)amine compounds of the
general formula IV, in which R1"' is CH3 or C3H7 and R2"'
is H, CH3 or CH2CH3, or Rl"' and R2"' together are
- (CH2) 2-3- or - (CH2) 2-CHR7"' ,
R3"' is H, CH3 or CH2CH3,
R4"' is H or OH, R5"' is H, OH, OCH3, CHF2 or OR 8... and
R6" . is H, OH or CF3, with the proviso that two of the
radicals R4"' , R5"' or R6"' are H, or
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R4. . . and R5... together are -CH=C (CH3) -S-, with the
proviso that R6111 is H, or
R51,, and R61 together are -CH=CH-C (OH) =CH-, with the
proviso that R4. . . is H, and
R" is CO-C6H4-Rl" where R11... is OC (O) -C1_3-alkyl in
the ortho-position.
Very particularly preferred are salt-forming compounds
of dimethyl-(3-arylbut-3-enyl)amine compounds of the
general formula IV, in which
R1... is CH3 and R2. ' is H or CH3 or R1... and R2.. . together
are - (CH2) 2_3- or - (CH2) 2-CH (CH3) -,
R3... is H or CH3,
4õ
Ris H, R-"" is OH or ORB"', R6õ . is H, and R"õ is CO-
C6H4-R1110' where R11... is OC (O) -CH3 in the ortho-position.
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-l-methylethyl)propenyl]phenol.
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 Al.
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As salt-forming antiobesity agents, the pharmaceutical
salt according to the invention can preferably contain
D-norpseudoephedrine, phenylpropanolamine, amfepramone,
mefenorex or ephedrine.
As salt-forming analeptics and/or antihypoxemics, the
pharmaceutical salt according to the invention can
preferably contain norfenefrine, heptaminol or
amezinium, particularly preferably amezinium.
As salt-forming opioid antagonists, the pharmaceutical
salt according to the invention can preferably contain
levallorphan, naloxone or naltrexone.
As a salt-forming anthelmintic, the pharmaceutical salt
according to the invention can preferably contain
pyrvinium.
As salt-forming antiallergics, the pharmaceutical salt
according to the invention can preferably contain
reproterol, triprolidine, hydroxyzine, azelastine,
diphenhydramine, promethazine, pheniramine, dexchlor-
pheniramine, clemastine, tramazoline, brompheniramine,
dimetindene, levocabastine, doxylamine, cyproheptadine,
carbinoxamine, meclozine, bamipine, chlorphenoxamine,
ketotifen or cetirizine, particularly preferably
diphenhydramine.
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.
CA 02439269 2003-08-26
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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,
hydroxychioroquine, spectinomycin, sultamicillin,
valaciclovir or grepafloxacin.
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.
As a salt-forming antidiabetic, the pharmaceutical salt
according to the invention can preferably contain
metformin.
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.
As a salt-forming antiepileptic, the pharmaceutical
salt according to the invention can preferably contain
tiagabine.
As salt-forming antihypertensives, the pharmaceutical
salt according to the invention can preferably contain
CA 02439269 2003-08-26
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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.
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.
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.
As a salt-forming antiinflammatory, the pharmaceutical
salt according to the invention can preferably contain
orphenadrine.
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.
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As a salt-forming antisclerosis agent, the
pharmaceutical salt according to the invention can
preferably contain butalamine.
As (3-receptor blockers and/or calcium channel blockers,
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.
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.
As salt-forming cholinergics, the pharmaceutical salt
according to the invention can preferably contain
pyridostigmine, betanechol or neostigmine..
As salt-forming diuretics, the pharmaceutical salt
according to the invention can preferably contain
amiloride or oxprenolol.
As salt-forming, circulation-promoting agents, the
pharmaceutical salt according to the invention can
preferably contain butalamine, naftidrofuryl,
buflomedil, moxaverine, bencyclan or meclofenoxate.
As a salt-forming weaning agent, the pharmaceutical
salt according to the invention can preferably contain
naltrexone, methadone, buprenorphine.
CA 02439269 2003-08-26
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As salt-forming geriatrics, the pharmaceutical salt
according to the invention can preferably contain
procaine or deanolace.
As salt-forming hypnotics and/or sedatives, the
pharmaceutical salt according to the invention can
preferably contain promethazine, zolpidem tartrate,
midazolam, melperone or flurazepam.
As a salt-forming immunomodulator, the pharmaceutical
salt according to the invention can preferably contain
levamisole.
As salt-forming oral and/or pharyngeal therapeutics,
the pharmaceutical salt according to the invention can
preferably contain chlorhexidine or cetylpyridinium.
As a salt-forming coronary agent, the pharmaceutical
salt according to the invention can preferably contain
oxyfedrine.
As a salt-forming hypolipidemic, the pharmaceutical
salt according to the invention can preferably contain
colestipol.
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.
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.
As salt-forming migraine agents, the pharmaceutical
salt according to the invention can preferably contain
CA 02439269 2003-08-26
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lisuride, methysergide, dihydroergotamine, ergotamine,
sumatriptan, rizatriptan or naratriptan.
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.
As a salt-forming anesthetic, the pharmaceutical salt
according to the invention can preferably contain
ketamine or midazolam.
As a salt-forming neuropathy preparation, the
pharmaceutical salt according to the invention can
preferably contain thiamine.
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.
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.
As salt-forming psychopharmaceutical agents, the
pharmaceutical salt according to the invention can
preferably contain tranylcypromine, amitriptyline,
doxepine, maprotiline, clomipramine, opipramol,
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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.
As salt-forming rhinologicals/sinusitis agents, the
pharmaceutical salt according to the invention can
preferably contain diphenylpyraline, xylometazoline,
oxymetazoline, tramazoline, indanazoline, naphazoline
or tetryzoline.
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.
As salt-forming platelet aggregation inhibitors, the
pharmaceutical salt according to the invention can
preferably contain tirofiban, ticlopidine or
clopidogrel.
As a salt-forming tuberculosis agent, the
pharmaceutical salt according to the invention can
preferably contain ethambutol.
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.
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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.
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.
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.
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.
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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.
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.
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.
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
CA 02439269 2003-08-26
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corresponding saccharinates as pharmaceutical salts of
these active compounds.
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.
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.
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.
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.
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.
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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 2 mm.
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 pm to
1 mm, particularly preferably in the range from 15 pm
to 0.5 mm and very particularly preferably in the range
from 30 pm to 200 pm.
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.
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.
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.
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
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derivatives, sugar alcohols, calcium hydrogenphosphate,
fatty alcohols, esters of glycerol or fatty acid esters
as physiologically tolerable excipients.
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.
The medicaments according to the invention can be
prepared by customary methods known to the person
skilled in the art.
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.
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.
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Microcapsules are prepared according to customary
microencapsulation processes, such as, for example, by
spray drying, spray solidification or coacervation.
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.
The medicament according to the invention can contain
the pharmaceutical salt according to the invention also
partially or completely in delayed-release form.
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.
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.
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Water-insoluble polymers employed for the preparation
of a release-delaying coating are preferably poly-
(meth)acrylates, particularly preferably poly (C14)
alkyl (meth) acrylates, poly (C1_4) dialkylamino- (C1-4) -
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.
These coating materials are obtainable on the market as
30% strength by weight aqueous latex dispersions under
the names Eudragit RS30D , Eudragit NE30D and Eudragit
RL30D and are preferably also employed as a coating
material as such.
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 ) .
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
CA 02439269 2003-08-26
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preferably applied from aqueous pseudolatex dispersion.
Aqueous ethylcellulose-pseudolatex dispersions are
stocked on the market as 30% strength by weight
dispersions (Aquacoat ) or as 25% strength by weight
dispersions (Surelease ) and as such are preferably
also employed as a coating material.
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 ), glycerol
ditripalmitostearate (Precirol AT05 ), microcrystalline
wax, cetyl alcohol, cetylstearyl alcohol, or a mixture
of at least two of these components.
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.
Suitable plasticizers are, for example, lipophilic
diesters of an aliphatic or aromatic dicarboxylic acid
of C6-C40 and an aliphatic alcohol of C1-C8, 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 (acetylated mono- and diglycerides, C23H4405 to
C25H4707) , medium-chain triglycerides (Miglyol ) , oleic
acid or mixtures of at least two of the abovementioned
plasticizers.
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Preferably, aqueous dispersions of Eudragit RS and
optionally Eudragit RL contain triethyl citrate as a
plasticizer.
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.
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.
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 .
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.
The release-delaying coating can also contain insoluble
or lipophilic excipients, such as, for example,
alkylized silicone, which is stocked on the market, for
CA 02439269 2003-08-26
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example, as Aerosil R972 , or magnesium stearate for
the further intensification of the delaying.
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.
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 ),
methacrylic acid/methyl methacrylate copolymers having
a molar ratio of the respective monomers of 1:2
(Eudragit S ), methacrylic acid/ethyl acrylate
copolymers having a molar ratio of the respective
monomers of 1:1 (Eudragit L30D-55 ), methacrylic
acid/methyl acrylate/methyl methacrylate copolymers
having a molar ratio of the respective monomers of
7:3:1 (Eudragit FS ), 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 and/or Eudragit RL
and/or Eudragit RS .
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,
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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.
If the medicament is present in multiparticulate form
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.
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 , particularly
preferably in the range from 35 to 45 C.
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 C, particularly preferably in the range
from 55 to 65 C.
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.
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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.
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.
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 C12-C30-fatty acids and/or C12-
C30-fatty alcohols and/or waxes or mixtures of at least
two of the abovementioned materials.
It is also possible to employ mixtures of the above-
mentioned hydrophilic and hydrophobic materials as a
release-delaying matrix material.
The release-delaying matrix can be prepared by the
customary methods known to the person skilled in the
art.
A further subject of the invention is also the use of
at least one pharmaceutical salt according to the
invention and, if appropriate, physiologically
CA 02439269 2003-08-26
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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.
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.
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.
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.
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 -< 250 mg/ml and, compared
with the water solubility of the conventional salts of
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the corresponding active compound, is usually lowered
by at least 50%.
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.
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.
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.
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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.
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:
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 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.
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
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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
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
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.
CA 02439269 2010-12-06
41 -
Examples:
Example 1:
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.
For the preparation of (+)-(1S,2S)-3-(3-dimethylamino-
1-ethyl-2-methylpropyl)phenol saccharinate, 2.58 g
(10 mmol) of (+)-(1S,2S)-3-(3-dimethylamino-l-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-l-ethyl-2-methylpropyl)-
phenol saccharinate was separated off from the
supernatant mother liquor, purified with ethanol and
isolated according to conventional methods.
Example 2:
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.
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Example 3:
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:
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:
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 C and the mixture was then
cooled to 40 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 C, the mixture was
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flavored with 0.625 g of Tutti-Frutti 9/008897 (Dragoco
Gerberding & Co. AG, 37603 Holzminden) while stirring.
Example 6:
5 g of comminuted chewing gum mass (Popeye Amural
Confections, Yorkville, Illinois, USA) were warmed to a
temperature of 30 to 40 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.
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:
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 C. The mixture
was cooled to 40 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 C, the mixture was flavored
while stirring with 0.075 g of orange-mandarin flavor
10888-56 (Givaudan Roure Flavors Ltd. CH 8600
Dtibendorf).
Example 8:
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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 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.
Active compound Solubility of Solubility of
the active the active
compound salt compound
in mg/ml of saccharinate
water in mg/ml of
water
(-)-(1R,2R)-3-(3-
dimethylamino-1-ethyl- 261 31
2-methylpropyl)phenol (hydrochloride)
(1RS, 3RS, 6RS) -6-
dimethylaminomethyl-1- 500 71
(3-methoxy- (hydrochloride)
phenyl) cyclohexane-
1,3-diol [sic]
(+)- (1S, 2S) -3- (3-
dimethylamino-1-ethyl- 650 55
2-methylpropyl)phenol (hydrochloride)
(-) - (1S, 2S) -3- (3-
dimethylamino-1-ethyl- 568 130
1-fluoro-2-methyl- (hydrochloride)
propyl)phenol
(-) - (2S, 3S) -1-
dimethylamino-3-(3- 2000 90
methoxyphenyl)- (hydrochloride)
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Active compound Solubility of Solubility of
the active the active
compound salt compound
in mg/ml of saccharinate
water in mg/ml of
water
2-methylpentan-3-ol
(+)-(1R, 2R, 4S) -2-
dimethylaminomethyl-4- 33 10
(4-fluorobenzyl-oxy)- (hydrochloride)
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)
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.
