NZ551440A

NZ551440A - Pharmaceutical salts

Info

Publication number: NZ551440A
Application number: NZ551440A
Authority: NZ
Inventors: Johannes Bartholomaus; Heinrich Kugelmann
Original assignee: Gruenenthal Chemie
Priority date: 2001-02-28
Filing date: 2002-02-28
Publication date: 2007-08-31
Also published as: CN100352431C; EP1390023B1; SK287574B6; HUP0303325A2; JP4737583B2; AR033423A1; CA2725635A1; ATE395053T1; IL157477A0; DE10109763A1; HUP0303325A3; NO20033815D0; PT1390023E; CZ20032315A3; CA2439269A1; NZ528302A; KR20030078943A; DE50212273D1; ZA200306529B; PL218187B1

Abstract

Disclosed is a pharmaceutical salt of a pharmaceutically active compound and at least one sugar substitute, wherein the salt form active compound is a salt-forming dimethyl-(3arylbut-3-enyl)amine compound of general formula IV as defined in the specification. Salts of the type disclosed are useful in the treatment of pain and urinary incontinence.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 551440 *10053002670* 55u40 PATENTS FORM NO. 5 Our ref: FIP226880NZPR Divisional application out of NZ Patent Appln No. 528302 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION PHARMACEUTICAL SALTS We, Griinenthal GmbH a German company of Zieglerstrasse 6, D-52078 Aachen, Germany hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: intellectual property office of N.Z. 2 1 nov 2006 RECEIVFn (followed by page 1 a) 100892148_1 ,DOC:FIP:lbm Pharmaceutical salts The present invention and the invention of New Zealand Patent Application No. 528302, from which this 5 application was divided, relate 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. 10 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 15 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 20 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 solubility of active compound 25 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, 30 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 35 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 - la - (followed by page 2) - 2 - additionally make the preparation of appropriate preparations more expensive. It was therefore the object of the present invention to 5 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. These objects should be read disjunctively 10 with the further object of at least providing a useful alternative to known compounds. According to the invention, this object is achieved by the provision of pharmaceutical salts, i.e. 15 physiologically tolerable salts, from a pharmaceutical active compound and at least one sugar substitute. The present invention therefore provides a pharmaceutical salt of a pharmaceutical active compound 20 and at least one sugar substitute, wherein the salt-forming active compound is a salt-forming dimethyl-(3-arylbut-3-enyl)amine compound of the general formula IV, h ,3" r2" r1" ch3 iv 25 - 3 - in which the radical R1'" is Ci_5-alkyl and R2"' is H or Ci-5-alkyl or R1"' and R2'" together are -(CH2)2_4-, - (CH2) 2-CHR7'" or -CH2-CHR7"'-CH2-, 5 R3'" is H or Ci-5-alkyl, R4"' is H, OH, Ci-4-alkyl, 0-Ci_4-alkyl, O-benzyl, CF3, 0-CF3, CI, F or OR8'", 10 R5'" is H, OH, Ci-4-alkyl, 0-Ci_4-alkyl, O-benzyl, CHF2, CF3, O-CF3, CI, F or OR8'" and R6"' is H, OH, Ci-4-alkyl, 0-Ci-4-alkyl, O-benzyl, CF3, 0-CF3, CI, F or OR8"' , 15 with the proviso that two of the radicals R4"', R5"' or R6 '' are H, or R4"' and R5'" together are -CH=C (R9"')-O- or -CH=C(R9"')-20 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, 25 R7"' is Ci_8-alkyl, C3_8-cycloalkyl, 0-Ci_4-alkyl, 0-benzyl, CF3, CI or F, R8"' is CO-Ci-5-alkyl, PO (O-Ci-4-alkyl) 2, CO-C6H4-R11"', CO (O-Ci-5-alkyl) , CO-CHR12''' -NHR13''', CO-NH-C6H3- (R14'" ) 2 or 30 an unsubstituted or substituted pyridyl, thienyl, thiazoyl or phenyl group, R9"' is H or Ci-4-alkyl, 35 R10"' is H or Ci_3-alkyl, R11'" is OC (0) -Ci-3-alkyl in the ortho-position or CH2-N- (R15'")2 in the meta- or para-position, where R15"' PROPERI office of n.z. 11 may 2007 i receive _ 4 - 4-alkyl or both radicals R15'" together with N form the 4-morpholino radical, R12'" and R13'" are identical or different and are H, C\~ 5 6-alkyl or C3-8-cycloalkyl or R12'" and R13"' together are ~ (CH2) 3-8~ r R14'" is H, OH, Ci-7-alkyl, 0-Ci_7-alkyl, phenyl, O-aryl, CF3, CI or F, with the proviso that the two radicals 10 R14'" are identical or different, in the form of a stereoisomer, a racemate or diastereomerically pure enantiomer or in the form of a mixture of enantiomers, in which the respective 15 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 ^ 250 mg/ml of water, preferably 20 ^ 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 compared with the water solubility of the 25 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 30 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 35 disclosure. According to the invention, suitable sugar substitutes are all sugar substitutes which can form a salt with _ . the respective pharmaceutical active compound with1" <■ 11 mm 2007 CElVj 5 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 5 salt components. Preferably, the pharmaceutical salts according to the invention contain saccharin, cyclamate or acesulfam, particularly preferably saccharin, as salt-forming sugar substitutes. 10 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. NZ 528302 discloses and claims a salt-forming active compound which is a salt-forming compound of 1-phenyl-3-dimethylaminopropane compounds of the general formula I 15 20 ch3 in which in each case 25 X is OH, F, CI, H or an OCOR6 group R1 is a Ci-4-alkyl group, R2 is H or a Ci_4-alkyl group and R3 is H or a straight-30 chain Ci_4-alkyl group or the radicals R2 and R3 together form a C4_7~cycloalkyl radical, and - 6 - if R5 is H, R4 is meta-O-Z where Z is H, Ci-3-alkyl, PO (0-Ci_4-alkyl) 2, CO (OCi-s-alkyl) , CONH-C6H4- (Ci_3-alkyl) , CO-C6H4-R7, where R7 is ortho-OCOCi-3-alkyl or meta- or para-CH2N (R8) 2 where R8 is Ci_4-alkyl or 4-morpholino, or 5 R4 is meta-S-Ci-3-alkyl, meta-Cl, meta-F, meta-CR9R10Ri:L where R9, R10 and R11 are H or F, ortho-OH, ortho-0-C2-3-alkyl, para-F or para-CR9R10R11 where R9, R10, R11 are H or F, or if R5 is para-Cl, -F, -OH or -0-Ci-3-alkyl, R4 is meta-Cl, -F, -OH or -O-Ci-3-alkyl, or 10 R4 and R5 together are 3,4-OCH=CH- or 3,4-OCH=CHO-, R6 is Ci-3-alkyl, in the form of their possible stereoisomers as 15 racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts. 20 Preferred in NZ 528302 is a salt-forming compound of 1-phenyl-3-dimethylaminopropane compounds of the general formula I in which X is OH, F, CI 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-Ci-3-alkyl, meta-OH, meta-S-Ci-3-25 alkyl, meta-F, meta-Cl, meta-CH3, meta-CF2H, meta-CF3 or para-CF3 or if R5 is a para-Cl or -F, R4 is meta-Cl or -F, or R4 and R5 together are 3,4-OCH=CH-. Particularly preferred in NZ 528302 is a salt-forming 30 compound of l-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 la intellectual property office of n.z. 1 1 may 2007 H3C ^CH3 ip4 II K Very particularly preferred in NZ 528302 is a salt-forming compound of l-phenyl-3-dimethylaminopropane compounds of the general formula I, selected from the group consisting of (IRS,2RS)-3-(3-dimethylamino-l-hydroxy-l,2-dimethyl-propyl)phenol, (-)-(1R,2R)-3-(3-dimethylamino-l-ethyl-2-methylpropyl)-phenol, (+)-(IS,2S)-3-(3-dimethylamino-l-ethyl-2-methylpropyl)-phenol, (2RS,3RS)-l-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol, (-)-(IS,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)-l-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and office of n.z 11 may 2007 - 8 - (—)—(2S,3S)-l-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol. The preparation of the salt-forming compounds of 5 l-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 10 appropriate, the separation is carried out as described in DE-A-4426245 or EP 0 693 475 Bl, which are hereby inserted as reference and are thus regarded as part of the disclosure. 15 In a further preferred embodiment of the invention of NZ 528302, 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 20 II, or4' 25 in which in each case R1' is H, OH, CI or F, preferably H, OH or F, R2' and R3' are identical or different and are H, Ci-4-alkyl, benzyl, CF3, OH, OCH2-C6H5, O-Ci-4-alkyl, CI or F intellectual propef office of n.z. 11 may 2007 6ceive - 9 - with the proviso that at least one of the radicals R2 or R3' is H, R4' is H, CH3, POCO-Ci-^-alkyDa, CO (OCi-5-alkyl) , CO-NH-C6H4-Ci-3-alkyl, CO-C6H4-R5', CO-Ci_5-alkyl, CO-CHR6' -NHR7' 5 or an unsubstituted or substituted pyridyl, thienyl, thiazoyl or phenyl group, R5' is OC (0) Ci_3-alkyl in the ortho-position or CH2-N (R8') 2 in the meta- or para-position, where R8' is Ci_4-10 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 Ci_6-alkyl, 15 with the proviso that if both radicals R2' and R3 are H, R4' is not CH3 if R1' is H, OH or CI or R4' is not H if R1' is OH, 20 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 in NZ 528302 are salt-forming compounds of 6-dimethylaminomethyl-l-phenylcyclohexane compounds of the general formula II, which are present in the configuration as in the general formula Ila, 25 30 r2' rr h3c ch3 Ila -10- in which the phenyl ring and the dimethylaminomethyl group are in each case arranged in an equatorial position to one another. 5 Particularly preferred in NZ 528302 is a salt-forming compound of 6-dimethylaminomethyl-l-phenylcyclohexane compounds of the general formula II selected from the group consisting of 10 (-)- (1R,2R) -3- (2-dimethylaminomethylcyclohexyl)phenol, (IRS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-methoxyphenyl )cyclohexane-1,3-diol and 15 (IRS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-hydroxy-phenyl)cyclohexane-1, 3-diol. The preparation of the salt-forming compounds of 6-dimethylaminomethyl-l-phenylcyclohexane compounds of 20 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 25 described in DE-A-19525137. The corresponding literature description is hereby inserted as reference and is thus regarded as part of the disclosure. Turning now to the compounds of the present invention, 30 preferred are pharmaceutical salts that contain as a salt-forming active compound a salt-forming compound of dimethyl-(3-arylbut-3-enyl)amine compounds of the general formula IV, Intellectual ?ropervy" office of n.z 1 1 may 2007 p f r. eiv e d - 11 - IV in which the radical R1'" is Ci-5-alkyl and R2'" or R1'" and R2'" together are -(CH2)2-4-/ - (CH2) 2-CHR7"' or -ch2-chr7'"-ch2-, is H or Ci-5-alkyl R is H or Ci-5-alkyl, R4 ' is H, OH, Ci-4-alkyl, 0-Ci-4-alkyl, O-benzyl, CF3, 0-10 CF3, CI, F or OR8'", R ' is H, OH, Cx-4-alkyl, O-Ci-4-alkyl, O-benzyl, CHF2, CF3, 0-CF3, CI, F or OR8"' and 15 R is H, OH, Ci-4-alkyl, O-Ci-4-alkyl, O-benzyl, CF3, O-CF3, CI, F or OR8"', with the proviso that two of the radicals R4'", R5"' or 20 R6'" are H, or R and R together are -CH=C(R )-0- or -CH=C(R ")-S-, with the proviso that R is H, or R5"' and R6"' together are -CH=CH-C (OR10"') =CH-, with the 25 proviso that R4"' is H, R is Ci-8-alkyl, C3-8-cycloalkyl, benzyl, CF3, CI or F, O-Ci-4-alkyl, 0- office 1 1 mm m7 received - 12 - R8'" is CO-Ci-5-alkyl, PO (O-C^-alkyl) 2, CO-C6H4-Ru"', CO (0-Ci_5-alkyl) , CO-CHR12''' -NHR13''', CO-NH-C6H3- (R14"' ) 2 or an unsubstituted or substituted pyridyl, thienyl, thiazoyl or phenyl group, 5 R9'" is H or Ci-4-alkyl, R10'" is H or Ci-3-alkyl, 10 R11"' is OC (0)-Ci-3-alkyl in the ortho-position or CH2-N-(R15'")2 in the met a- or para-position, where R15'" is Ci-4-alkyl or both radicals R15'" together with N form the 4-morpholino radical, 15 R12'" and R13'" are identical or different and are H, Ci-6-alkyl or C3-8-cycloalkyl or R12"' and R13'" together are -(CH2)3-8-, R14'" is H, OH, Ci_7-alkyl, 0-Ci_7-alkyl, phenyl, O-aryl, 20 CF3, CI 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 25 the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts. Preferred are salt-forming compounds of dimethyl-(3-30 arylbut-3-enyl)amine compounds of the general formula IV, in which 35 is Ci_3-alkyl and R is H or Ci_3-alkyl, or R R2'" together are -(CH2)2_4- or - (CH2) 2-CHR7' and R is H or Ci_3-alkyl, R4 is H, OH, CF3, CI, F or OR8 *ur ' off»ce mm 2007 - 13 - R5'" is H, OH, Ci-4-alkyl, O-Ci-4-alkyl, O-benzyl, CHF2, CF3, CI, F or OR8'" and R6'" is H, OH, O-Ci-4-alkyl, O-benzyl, CF3, CI, F or — Q r f r 5 OR8 , with the proviso that two of the radicals R4 ', R5 or R6"' are H, or 15 30 10 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, and R7"' is Ci-4-alkyl, CF3, CI or F. Particularly preferred are salt-forming compounds of dimethyl-(3-arylbut-3-enyl)amine compounds of the 20 general formula IV, in which R1'" is CH3 or C3H7 and R2'" is H, CH3 or CH2CH3, or R1' and R2"' together are -(CH2)2_3- or - (CH2) 2-CHR7'" , 25 R3"' is H, CH3 or CH2CH3, R4"' is H or OH, R5"' is H, OH, OCH3, CHF2 or OR8"' and R5"' is H, OH or CF3, with the proviso that two of the radicals R4"', R5'" or R6"' are H, or R4"' and R5"' together are -CH=C (CH3)-S-, with the proviso that R6"' is H, or R5"' and R6"' together are -CH=CH-C (OH) =CH-, with the 35 proviso that R4"' is H, and R8"' is CO-C6H4-R11"' where R11"' is OC (0)-Ci_3-alkyl in the ortho-position. OFFICE OF N./. t1 MM ®7 RECEIVED. 14 10 30 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, R4"' is H, R5'" is OH or OR8'", R6"' is H, and R8"' is CO-C6H4-R11'" where R11"' is 0C(0)-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 A1. The corresponding literature description is hereby inserted as reference and is thus regarded as part of the disclosure. 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, c warming. - 15 - 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 5 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 10 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 15 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 20 purified as described above. The solvent or solvent mixture suitable in each case for the preparation and the suitable reaction conditions, such as, for example, temperature or 25 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 30 respective active compound employed is preferably its hydrochloride, hydrobromide, phosphate, hydrogen-phosphate, hydrogensulfate, sulfate, nitrate or metilsulf ate. The salt of the respective sugar substitute employed is preferably its sodium, 35 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 , i ..; i [Tir h \ 1 \ 11 m 2007 Lcr.plved 16 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 10 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 salt-forming compound of the 15 general formula I or II (NZ 528302) or IV (the present invention) as 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 20 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 25 salt-forming compound of the general formula I or II (NZ 528302) or IV (the present invention) as indicated above, and a sugar substitute. Preferably, the medicaments according to the invention contain the corresponding saccharinates as pharmaceutical salts of 30 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 35 for oral administration. In a preferred embodiment, the medicament according to the invention is present formulated as a ge1 5 gum, juice, spray, tablet, chewable tabl - 17 - 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. 5 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 10 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 15 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. If the medicament according to the invention is present 20 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. 25 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 jam 30 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 35 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, ^ ■ OFFICE OF N Z- | 11 may 2007 eceived - 18 - can be present as physiologically tolerable excipients, preferably microcrystalline cellulose, cellulose ethers, lactose, starch, starch derivatives, sugar alcohols, calcium hydrogenphosphate and the customary 5 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 10 preferably contain methylparaben, propylparaben, xylitol and/or xanthan gum as physiologically tolerable excipients. If the medicaments according to the invention are 15 present in the form of pellets, granules or micropellets, 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 20 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 25 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 30 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 35 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 table lry or intellectual property ts fece of n.z. ' 1 1 may 2007 received - 19 - 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-5 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 10 excipients, extrusion and spheronization, by build-up pelletization or by direct pelletization in a highspeed mixer or in the rotor fluidized bed. The pellets are particularly preferably prepared by extrusion of moist masses and subsequent spheronization. 15 Microcapsules are prepared according to customary microencapsulation processes, such as, for example, by spray drying, spray solidification or coacervation. 20 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 25 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 30 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 35 released in the intestinal tract. Preferably, the enteric coating dissolves at a pH of between 5 and 7.5. intellectual property office of N.Z. 1 l may 2007 eceived - 20 - The medicament according to the invention can contain the pharmaceutical salt according to the invention also partially or completely in delayed-release form. 5 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 10 methods. Preferably, the release-delaying coating is based on a water-insoluble, optionally modified natural or synthetic polymer or on a natural, semisynthetic or 15 synthetic wax or fat or fatty alcohol or a mixture of at least two of these abovementioned components. Water-insoluble polymers employed for the preparation of a release-delaying coating are preferably poly-20 (meth) acrylates, particularly preferably poly(Ci_4) alkyl (meth) acrylates, poly (Ci_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 25 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 30 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 35 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. intellectual property i office of n.z i 11 may 2087 i received 10 - 21 - 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, 15 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 20 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. 25 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 30 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- 35 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 knov.,, "Tmt^lTeCTUAL property office of n.z 11 m 2007 received - 22 - to the person skilled in the art in order to lower the minimum film temperature necessary. Suitable plasticizers are, for example, lipophilic 5 diesters of an aliphatic or aromatic dicarboxylic acid of C6-C4o and an aliphatic alcohol of Cx-Cg, 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 10 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, C23H44O5 to 15 C25H47O7), medium-chain triglycerides (Miglyol®) , oleic acid or mixtures of at least two of the abovementioned plasticizers. Preferably, aqueous dispersions of Eudragit RS® and 20 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, 25 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, 30 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 35 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 di^vin^ or surfactants, such as, for example, Tween 80®. 1 ^ 1 may 2007 - 23 - 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 5 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 10 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-15 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 20 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 25 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 30 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 35 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 fg®mtjal property ' office of n.z 11 may 2007 d t: r. FIV E D - 24 - 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-5 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 10 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 15 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, 20 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. 25 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 30 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 35 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. intellectual property office of n.z. 1 1 may 2007 received - 25 - 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 5 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 10 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 15 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. 20 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. 25 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 30 preferably cellulose ethers, cellulose esters and/or acrylic resins. Very particularly preferably, the matrix materials employed are ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxy-methylcellulose, poly(meth)acrylic acid and/or their 35 derivatives, such as, for example, their salts, amides or esters. Likewise preferred are matrix materials made of hydrophobic materials, such as hydrophobic pol1 BBS? CTUALPROPERTY OFFICE of n.z. 11 may 2007 received - 26 - 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 5 mono- or diglycerides of Ci2-C30-fatty acids and/or Ci2-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-10 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 15 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 20 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. 25 Preferred is the use of at least one salt-forming compound of the general formula I or II (NZ 528302) or IV (the present invention) as indicated above for the production of a medicament for the control of pain, the salts of these active compounds used preferably being 30 their saccharinates. Likewise preferred is the use of at least one pharmaceutical salt of a salt-forming compound of the general formula I or II (NZ 528302) or IV (the present 35 invention) as 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. INTELLECTUAL propers OFFICE OF N.z I 11 may 2007 ' p f r. 1= IV E D 27 The total amount of the respective pharmaceutical salt to be administered to the patient varies, for example, depending on the weight of the patient, on the indication and the degree of severity of the pain or of 5 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. 10 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 15 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 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 25 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 30 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. 35 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-de I ut-i-ioc — 20 11 may 2007 q c r.FIV E C - 28 - matrix and/or a release-delaying coating, but if appropriate with an enteric coating, is moreover achieved. 5 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 10 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 15 according to the invention are moreover also suitable for diabetics. For a large number of the abovementioned active compounds, the water solubility of the conventional 20 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 25 part of the disclosure. 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 30 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 35 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 _ OFFICE OF N.Z. i 11 may 2007 i receive! - 29 - salt according to the invention was then added in portions. If the amount of salt B added (in mg) completely 5 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 10 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 15 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 20 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: 25 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 30 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 35 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 htfrellectualproper1 following formula: I OFFICE OF N.Z. i \\m 2007 RECEIVE. - 30 - 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. Examples: - 31 - Although the compounds of these Examples may fall outside the scope of the claims of this application, 5 these Examples help to illustrate the invention and are therefore retained for clarity and completeness. Example 1: 10 The preparation and the subsequent separation of the optically pure compound (+)-(IS,2S)-3-(3-dimethylamino-l-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 15 thus regarded as part of the disclosure. For the preparation of (+)-(IS,2S)-3-(3-dimethylamino-l-ethyl-2-methylpropyl)phenol saccharinate, 2.58 g (10 mmol) of ( + )-(IS, 2S)-3-(3-dimethylamino-l-ethyl-2-20 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 25 placed in a cool place overnight. The precipitated ( + )-(IS,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. 30 Example 2: For the preparation of diphenhydramine saccharinate, 5.0 g (17.1 mmol) of diphenhydramine hydrochloride and 35 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 intellectual property office of n.z 11 may 2007 received - 32 - 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 5 ethanol and isolated according to conventional methods. Example 3: For the preparation of verapamil saccharinate, 415 mg 10 (0.84 5 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 15 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. 2 0 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 25 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 30 from the supernatant mother liquor, purified with ethanol and isolated according to conventional methods. Example 5: 35 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 l^rtLLECTUAL PROPER OFFICE OF N.Z. 11 may 2007 RFCEIVE - 33 - 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 5 to a temperature of 20 to 25°C, the mixture was flavored with 0.625 g of Tutti-Frutti 9/008897 (Dragoco Gerberding & Co. AG, 37603 Holzminden) while stirring. Example 6: 10 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 15 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. 20 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. 25 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 30 purified water at a temperature of 80°C. The mixture was cooled to 40°C and 78.5 mg of ( + ) - (IS, 2S)-3- (3-dimethylamino-l-ethyl-2-methylpropyl)phenol saccharinate obtained according to example 1 were added with stirring. 0.25 g of xanthan gum was then added, 35 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 intellectual prope office of n.z. 11 may 2007 receive 10888-56 (Givaudan Diibendorf) . - 34 -Roure Flavors Ltd. CH 8600 Example 8: 10 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 15 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 (-)-(lR,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol (IRS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl) cyclohexane-1,3-diol [sic] (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol (-) - (IS, 2S)-3- (3-dimethylamino-1-ethyl- Solubility of the active compound salt in mg/ml of water 261 (hydrochloride) 500 (hydrochloride) 650 (hydrochloride) 568 Solubility of the active compound saccharinate in mg/ml of water 31 71 55 130 intellectual property qepice of n.z 11 may 2007 DECEIVED - 35 - Active compound Solubility of the active compound salt in mg/ml of water Solubility of the active compound saccharinate in mg/ml of water 1-fluoro-2-methyl-propyl)phenol (hydrochloride) (-)-(2S,3S)-1-dimethylamino-3-(3- methoxyphenyl)-2-methylpentan-3-ol 2000 (hydrochloride) 90 (+)-(1R,2R,4S)-2-dimethylaminomethyl-4-(4-fluorobenzyl-oxy)- 1-(3-methoxyphenyl) cyclohexanol 33 (hydrochloride) 10 Morphine 52 (hydrochloride trihydrate) 25 Amezinium 25 (metilsulfate) 8 Phenylephrine 1250 (hydrochloride) 380 Verapamil 200 (hydrochloride) 7 Diphenhydramine 1000 (hydrochloride) 7 Benzalkonium 500 (hydrochloride) < 2 Codeine 250 (phosphate hemihydrate) 200 Hydromorphone 330 (hydrochloride) 130 Buprenorphine 14 (hydrochloride) 2 intellectual proper-TV office of n.Z. 11 may 2007 RECEIVES </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 36 - 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. IffilEcTtHTROPS , office of n-z. 11 may 2007 receive - 37 - Patent claims:

1. A pharmaceutical salt of a pharmaceutical active compound and at least one sugar substitute, wherein the salt-forming active compound is a salt-forming dimethyl-(3-arylbut-3-enyl)amine compound of the general formula IV, in which the radical R1'" is Ci_5-alkyl and R2'" is H or Ci_ 5-alkyl or R1"' and R2'" together are -(CH2)2-4", -(CH2)2-CHR7'" or -CH2-CHR7'"-CH2-, R3'" is H or Ci-5-alkyl, R4'" is H, OH, Ci_4-alkyl, 0-Ci_4-alkyl, O-benzyl, CF3, 0-CF3, CI, F or OR8'", R5"' is H, OH, Ci-4-alkyl, 0-Ci_4-alkyl, O-benzyl, CHF2, CF3, 0-CF3, CI, F or OR8"' and R6'" is H, OH, Ci-4-alkyl, O-C^-alkyl, O-benzyl, CF3, 0-CF3, CI, F or OR8"', with the proviso that two of the radicals R4"', R5"' or H ,3" R2" R1" CH3 IV R6"' are H, or - 38 - 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 Ci-s-alkyl, C3-8-cycloalkyl, 0-Ci-4-alkyl, O-benzyl, CF3, CI or F, R8'" is CO-Cx-5-alkyl, PO (0-Ci-4-alkyl) 2, CO-C6H4-Rn"', C0(0-Ci_5-alkyl) , CO-CHR12''' -NHR13''', CO-NH-C6H3- (R14'" ) 2 or an unsubstituted or substituted pyridyl, thienyl, thiazoyl or phenyl group, R9"' is H or Ci-4-alkyl, R10'" is H or Ci_3-alkyl, R11'" is OC (0) -Ci_3—alkyl in the ortho-position or CH2-N-(R15'")2 in the meta- or para-position, where R15'" is Ci_4-alkyl or both radicals R15'" together with N form the 4-morpholino radical, R12'" and R13'" are identical or different and are H, Ci_6-alkyl or C3_8-cycloalkyl or R12'" and R13'" together are -( CH2 ) 3-8" , R14'" is H, OH, Ci_7-alkyl, 0-Ci-7-alkyl, phenyl, 0-aryl, CF3, CI or F, with the proviso that the two radicals R14'" are identical or different, in the form of a stereoisomer, a racemate or diastereomerically pure enantiomer or in the form of a mixture of enantiomers, in which the respective enantiomers are present in nonequimolar amounts. intellectual proper i office of n.z 11 may 200? i p f p. eiv e d - 39 -

2. The pharmaceutical salt as claimed in claim 1, wherein the solubility of the salt in water is ^ 250 mg/ml of water.

3. The pharmaceutical salt as claimed in claim 1 or 2, wherein the solubility of the salt in water is ^ 200 mg/ml.

4. The pharmaceutical salt as claimed in any one of claims 1 to 3, wherein the solubility of the salt in water is ^ 150 mg/ml.

5. The pharmaceutical salt as claimed in any one of claims claim 1 to 4, wherein the solubility of the salt in water is ^ 100 mg/ml.

6. The pharmaceutical salt as claimed in any one of claims 1 to 6, wherein the salt-forming sugar substitute is saccharin, cyclamate or acesulfam.

7. The pharmaceutical salt as claimed in claim 6, wherein the salt-forming sugar substitute is saccharin.

8. The pharmaceutical salt as claimed in any one of claims 1 to 7, wherein R1'" is Ci-3-alkyl and R2'" is H or C1-3-alkyl, or R1"' and R2'" together are -(CH2)2-4_ or -(CH2)2- 7 f r r CHR7 , R3'" is H or Ci_3-alkyl, R4"' is H, OH, CF3, CI, F or OR8'", R5"' is H, OH, Ci_4-alkyl, 0-Ci_4-alkyl, O-benzyl, CHF2, CF3, CI, F or OR8"' and R6'" is H, OH, 0-Ci_4-alkyl, O-benzyl, CF3, CI, F or OR8"', ,ntellectual propers office of n.z i 11 may 2007 1 [RECEIVED! - 40 - with the proviso that two of the radicals R4" , R5 or R6"' are H, or R4'" and R5'" together are -CH=C(R9 ')-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 Ci-4-alkyl, CF3, CI or F.

9. The pharmaceutical salt as claimed in any one of claims 1 to 8, wherein R1'" is CH3 or C3H7 and R2 is H, CH3 or CH2CH3, or R1'" 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 OR8'" and R6"' is H, OH or CF3, with the proviso that two of the radicals Att' cittt ct t r R , R or R are H, or R4'" and R5'" together are -CH=C (CH3)-S-, with the proviso that R6"' is H, or R5"' and R6"' together are -CH=CH-C (OH) =CH-, with the proviso that R4"' is H, and R8"' is CO-C6H4-R11'" where R11"' is OC (0)-Ci-3-alkyl in the ortho-position.

10. The pharmaceutical salt as claimed in any one of claims 1 to 9, wherein 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, intellectual property office of n.z. 11 may 2007 RECEIVED - 41 - R4'" is H, R5'" is OH or OR8'", R6"' is H, and R8"' is CO-C6H4-R11'" where R11"' is OC(O)-CH3 in the ortho-position.

11- The pharmaceutical salt as claimed in any one of claims 1 to 10, wherein the salt-forming dimethyl-(3-arylbut-3-enyl)amine compound present is trans-(-)-(1R)-3-[1-(2-dimethylamino-l-methylethyl)propenyl]phenol.

12. A medicament comprising at least one pharmaceutical salt as claimed in any one of claims 1 to 11 and, optionally, physiologically tolerable excipients.

13. A medicament comprising at least one pharmaceutical salt as claimed in any one of claims 1 to 11 for the control of pain.

14. A medicament comprising at least one pharmaceutical salt as claimed in any one of claims 1 to 11 for the control of urinary incontinence.

15. The medicament as claimed in any one of claims 12 to 14, in the form of a gel, chewing gum, juice, spray, tablet, chewable tablet, coated tablet, powder, if appropriate filled into capsules or an easily reconstitutable dry preparation.

16. The medicament as claimed in claim 15, in the form of a gel, aqueous or oily juice, sublingual spray, tablet or chewable tablet.

17. The medicament as claimed in any one of claims 12 to 14, formulated in multiparticulate form

18. The medicament as claimed in claim 17, in the form of a microtablet, microcapsule, granule, active compound crystal or pellet. office of n.z i 11 may 200? i RECEIVED- - 42 -

19. The medicament as claimed in claim 17 or 18, in the form of a microtablet, granule or pellet, optionally filled into capsules or compressed to give tablets.

20. The medicament as claimed in any one of claims 12 to 19, wherein the salt is present at least partially in delayed-release form.

21. The medicament as claimed in claim 20, wherein delaying of the release is carried out by applying a release-delaying coating, embedding in a release-delaying matrix, binding to an ion-exchange resin or by a combination of at least two of these methods.

22. The medicament as claimed in claim 21, wherein the release-delaying coating is based on a water-insoluble, optionally modified natural or synthetic polymer, optionally in combination with a customary plasticizer, or on a natural, semisynthetic or synthetic wax or fat or fatty alcohol or a mixture of at least two of these components.

23. The medicament as claimed in claim 21, wherein the matrix is based on a hydrophilic matrix material.

24. The medicament as claimed in claim 23, wherein the hydrophilic matrix material is a hydrophilic polymer.

25. The medicament as claimed in claim 23 or 24, wherein the hydrophilic matrix material is a cellulose ether, cellulose ester and/or acrylic resin.

26. The medicament as claimed in any one of claims 23 to 25, wherein the hydrophilic matrix material is ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, - 43 - poly(meth)acrylic acid and/or a salt, amide and/or ester thereof.

27. The medicament as claimed in claim 21, wherein the matrix is based on a hydrophobic matrix material.

28. The medicament as claimed in claim 27, wherein the hydrophobic matrix material is a hydrophobic polymer, wax, fat, long-chain fatty acid, fatty alcohol or an appropriate ester or ether or a mixture thereof.

29. The medicament as claimed in claim 27, wherein the hydrophobic matrix material is a mono- or diglyceride of a C12-C30 fatty acid and/or a Ci2-C3o-fatty alcohol and/or a wax or a mixture thereof.

30. The medicament as claimed in any one of claims 12 to 29, wherein it has a protective coating.

31. The medicament as claimed in claim 30, wherein the protective coating is an enteric protective coating.

32. The use of at least one pharmaceutical salt as claimed in any one of claims 1 to 11 for the production of a medicament for the control of pain.

33. The use of at least one pharmaceutical salt as claimed in any one of claims 1 to 11 for the production of a medicament for the treatment of urinary incontinence.

34. The pharmaceutical salt as claimed in claim 1, substantially as herein described with reference to any one of the Examples thereof.

35- The pharmaceutical salt as claimed in any one of claims 1 to 11, substantially as herein described. intellectual property i office of n.z 1 \ 1 MAY 2007 j »-k *— /■* C I \/ t— P - 44 -

36. The medicament as claimed in any one of claims 12 to 14, wherein the pharmaceutical salt as claimed in any one of claims 1 to 11 is substantially as herein described with reference to any one of the Examples thereof.

37. The medicament as claimed in any one of claims 12 to 31, substantially as herein described.

38. The use as claimed in claim 32 or 33, wherein the pharmaceutical salt as claimed in any one of claims 1 to 11 is substantially as herein described with reference to any one of the Examples thereof.

39. The use as claimed in claim 32 or 33, substantially as herein described. intellectual property OFFICE OF N.Z 11 may 2007 n r C I \/ F D </div>