Pharmaceutical salts and medicinal agent

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.

EFFECT: valuable medicinal properties of salts and drug.

14 cl, 1 tbl, 8 ex

 

The present invention relates to pharmaceutical salts derived from biologically active substance and at least one sugar substitute to medicines containing these salts and to the use of these salts to obtain the drugs.

Many pharmaceutical active substances with extremely high efficiency, oral often cause the patient the most unpleasant sensations such as bitterness, nausea, until the complete rejection. Such a negative taste sensations lead to the fact that some patients do not follow exactly the prescribed dosage and not treated with due understanding to appropriate medicines which relieve such active substance already at the reception.

When getting medicines with the use of well water-soluble pharmaceutical active substances pharmaceuticals in many cases, have to deal with certain problems. Thus, in particular, obtaining dosage forms with controlled release of active salt is often associated with serious difficulties, due to the high solubility of these salts. Reagirovanie such active substances though, and it can to some extent be provided by, for example the EP, drawing on the dosage form of the corresponding film coating, however, firstly, this type of reagirovania associated with relatively high logistical costs, and secondly, such a film coating of an aqueous coating systems often do not represent a sufficiently reliable diffusion barrier to possessing good solubility of active substances. Therefore, to obtain such a retard-songs of active substances requires relatively expensive methods of deposition of multilayer thin film coatings. If retardery coatings to use organic solvents, then the associated problems of ecology and the disposal or recycling of residual solvents additionally increases the cost of obtaining the relevant compositions.

Based on the foregoing, the present invention was based on the task to provide pharmaceutical compounds active ingredients not having a bitter taste. In addition, it was envisaged the possibility of obtaining such compounds simpler way and more efficient retardation.

According to the invention this problem is solved thanks to its proposed pharmaceutical, i.e. physiologically compatible salts obtained from the pharmaceutical active substance and at least one Deputy who preserver sugar.

The object of the invention in accordance with this are the pharmaceutical salts, obtained from the pharmaceutical active substance (hereinafter: salt-forming active substance and at least one sugar substitute, except pharmaceutical salts, which are obtained from sugar substitute and tramadol, (+)-tramadol, (-)-tramadol, (+)-demethyltramadol, respectively (-)-demethyltramadol.

According to one of preferred embodiments of the invention the solubility of the proposed therein pharmaceutical salts in water is ≤250 mg/ml of water, preferably ≤200 mg/ml, particularly preferably ≤150 mg/ml and most preferably ≤100 mg/ml. the advantage of the proposed invention in pharmaceutical salts will become even more compelling when compared to their water-solubility of this indicator has the best ability to dissolve in water salts of the respective active substance specified in the list of pharmaceutical substances Pharmazeutische Stoffliste, 12th ed. ABDATA Pharma-Daten-Service, 65735 Eschborn/Taunus, preferably in comparison with the corresponding hydrochloride, namely, the solubility of the salts according to the invention is lower by at least 50%, preferably at least 65%, particularly preferably at least 75% and most preferably at measures is 85%. The publication is included in this part of the present description by reference.

As substitutes for sugar are acceptable according to the invention all sugar substitutes that with education at least once negatively charged forms can form with the appropriate reactant salt. According to the invention refers to such pharmaceutical salts, in addition to the pharmaceutical active substance contains two or more different sugar substitutes. Preferably proposed in the invention pharmaceutical salts contain as salt-forming sweeteners saccharin, cyclamate or Acesulfame, particularly preferably saccharin.

As active substances is acceptable according to the invention all pharmaceutical active substances, with at least once a positively charged form can form a salt with the corresponding(s) substitute(s) sugar, audience(s) in the anionic form.

According to one of the preferred embodiments of the invention salt-forming active substance in the composition of the pharmaceutical salt according to the invention is selected from the group comprising soleobrazutaya analgesics, anti-obesity, analeptics, protivogipoksicescoe means is, Antirheumatic means antagonists opioids, sedative, antiallergenic, antiarrhythmic agent, antibiotics, nootropic agents, antidiabetic agents, antiemetics, anti-vertigo, anti-epileptic tools, antihypertensives, antihypotensive tools, antifungal agents, anti-inflammatories, antitussives, expectorants, anti-arteriosclerosis, blockers βreceptors, calcium channel blockers, broncholytic, anti-asthma drugs, anticholinergics, diuretics, tools, promoting blood circulation, tools for breaking the bad habits, geriatric remedies, sleeping pills, sedatives, immunomodulators means for treatment of the oral cavity, means for treatment of the throat, means for treatment of coronary circulation, funds reduce the level of lipids in the blood, local anaesthetics, tools, neural therapy, stomachic, intestinal tools, anti-migraines, muscle relaxants, narcotic drugs, neuropathic medications, eye tools, otological funds funds against Parkinson's disease, psychopharmaceuticals funds sinologicheskoj means is estva for the treatment of sinusitis, antispasmodic, tools, inhibit platelet aggregation, anti-tuberculosis drugs, urological tools and cytostatics. Particularly preferably salt-forming active substance selected from the group comprising soleobrazutaya analgesics, analeptics, protivogipoksicescoe tools, antiallergenic, antiarrhythmic agent, an antiemetic, anti-vertigo, antihypertensives, antihypotensive tools, antitussives, expectorants, blockers βreceptors, calcium channel blockers, eye tools, otological tools, antispasmodic and urological tools. Most preferred is a salt-forming active substance selected from the group of salt-forming analgesics, with the exception of tramadol, (+)-tramadol, (-)-tramadol, (+)-demethyltramadol, respectively (-)-demethyltramadol.

In the case where the pharmaceutical active substance is a salt-forming analgesic, it is preferably about salt-forming the opioid or the salt-forming similar opioid described in .Friderichs, .Christoph, H.Buschmann in "Analgesics and Antipyretics", Ullmann`s Encyclopedia of Industrial Chemistry, 6th edition on CD-ROM, published by Wiley-VCH, Weinheim (2000) or in Pharmaceuticals, edited J.L.McGuire, Analgesics and Antipyretics, volume 2, her. 341-434, and the d-Wiley-VCH, Weinheim, or talking about ephedrine, chloroquine, lidocaine, ethaverine, proglumetacin or triflupromazine. The above publications are included in this part of the present description by reference. Particularly preferred is a salt-forming analgesic selected from the group including morphine, codeine, Ethylmorphine, diacetylmorphine, Dihydrocodeine, Etorphine, hydrocodone, hydromorphone, Levorphanol, oxycodone, Oxymorphone, pethidine, Ketobemidone, fentanyl, Alfentanil, Remifentanil, Sufentanil, levomethadone, levomethadyl, dextromoramide, dextropropoxyphene, Diphenoxylate, piritramid, tilidin, buprenorphine, butorphanol, dessin, meptazinol, nalbuphine, nalorfin, pentazocine, flupirtine and nefopam, or representative of the group, including ephedrine, chloroquine, lidocaine, ethaverine, proglumetacin and triflupromazine. Most preferred as the salt-forming analgesic is salt-forming opioid or similar opioid selected from the group including morphine, codeine, hydrocodone, hydromorphone, oxycodone, tilidin, fentanyl and buprenorphine.

Preferred as the salt-forming active substance is equally salt-forming compound from among 1-phenyl-3-dimethylaminopropane compounds of General formula I

in which, respectively

X indicates About the, F, Cl, H or OCOR group6,

R1represents an alkyl group,

R2represents N or C1-4alkyl group, and

R3represents N or C1-4alkyl group with straight chain or

R2and R3together form4-7cycloalkyl group and,

if R5denotes H, R4is a group O-Z in the meta position, where Z denotes H, C1-3alkyl, PO(O-C1-4alkyl)2, CO1-5alkyl), CONH-C6H4-(C1-3alkyl),-C6H4-R7while R7is EA1-3alkyl in the ortho-position or the group CH2N(R8)2in the meta - or para-position, where R8stands With1-4alkyl or 4-morpholinopropan, or R4is a S-C1-3alkyl in the meta-position, meta-Cl, meta-F, group CR9R10R11in the meta-position, where R9, R10and R11denote H or F, IT-group in ortho-position, O-C2-3alkyl in the ortho-position, para-F or group CR9R10R11in the para-position, where R9, R10and R11denote H or F, or, if R5means located in the para-position Cl, F, IT is a group or O-C1-3alkyl, R4is a located in the meta-position Cl, F, IT is a group or O-C1-3alkyl, or

R4 5together form a group of 3,4-och=CH - or 3,4-och=SNO-,

R6stands With1-3alkyl,

in view of its possible stereoisomers, in the form of racemates or diastereomeric enantiomers or as mixtures of enantiomers, in which the enantiomers are not presented in equimolar amounts.

Preferably as a salt-forming component 1-phenyl-3-dimethylaminopropane compound of General formula I,

in which

X IT denotes F, Cl or H,

R1represents a C1-4alkyl group,

R2represents N or CH3and

R3represents N or CH3and,

if R5denotes H, R4represents O-C1-3alkyl in the meta-position, IT is a group in meta-position, S-C1-3alkyl in the meta-position, meta-F, meta-Cl, meta-CH3meta-CF2H, meta-CF3or a pair of CF3or,

if R5means located in the time-position Cl or F, R4is a located in the meta-position Cl or F, or R4and R5together form a group of 3,4-och=CH-.

Particularly preferred is a salt-forming compound from among 1-phenyl-3-dimethylaminopropane compounds of General formula I, in which R2and R3are different from each value and which are presented in the form of their diet is remeron configuration Ia

The most preferred salt-forming compound from among 1-phenyl-3-dimethylaminopropane compounds of General formula I selected from the group including

(1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,

(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl " phenol,

(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl " phenol,

(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol,

(-)-(1S,2S)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl " phenol,

(+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,

(+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and

(-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol.

Soleobrazutaya connection from among 1-phenyl-3-dimethylaminopropane compounds of General formula I can be obtained and split them if necessary to clean the optical antipodes using conventional, well-known specialists in the field of methods. Preferably such access and if necessary split to the methods described in DE-A 4426245 and EP 0693475 B1, which publications are included in this part of the present description by reference.

According to another preferred variant of the invention, the proposed therein pharmaceutical salt comprises a salt-forming active substance of Salobre the existing connection from numbers 6-dimethylaminomethyl-1-phenylcyclohexane compounds of General formula II

in which, respectively

R1'represents H, HE, Cl or F, preferably H, HE, or F,

R2'and R3'have identical or different meanings and represent H, C1-4alkyl, benzyl, CF3HE co2-C6H5, O-C1-4alkyl, Cl or F, provided that at least one of the radicals R2'or R3'denotes H,

R4'represents N, CH3, RO(OS1-4alkyl)2, CO1-5alkyl), CO-NH-C6H4-C1-3alkyl,-C6H4-R5'WITH-C1-5alkyl, CO-CHR6'-Other7'or unsubstituted or substituted pyridyloxy, thienyl, thiazolidine or phenyl group,

R5'represents OC(O)1-3alkyl in the ortho-position or CH2-N(R8')2meta - or para-position, where R8'stands With1-4alkyl or both radicals

R8'together with N form a 4-morpholinopropan, and

R6'and R7'have identical or different meanings and represent N or C1-6alkyl,

provided that if both the radical R2'and R3'represent H, R4'doesn't mean CH3when advanced R1'represents H, HE or Cl, or R4'does not denote N when optional R1'HE is a,

in view of its possible stereoisomers, in the form of racemates or diastereomeric enantiomers or as mixtures of enantiomers, in which the enantiomers are not presented in equimolar amounts.

It is preferable include soleobrazutaya connection from numbers 6-dimethylaminomethyl-1-phenylcyclohexane compounds of General formula II, which are represented in the configuration according to the General formula IIa

where the phenyl ring and dimethylaminomethylene group are respectively in the Equatorial position relative to each other.

Particularly preferred is a salt-forming compound from numbers 6-dimethylaminomethyl-1-phenylcyclohexane compounds of General formula II, selected from the group including

(-)-(1R,2R)-3-(2-dimethylaminomethylene)phenol,

(1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexane-1,3-diol and

(1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-hydroxyphenyl)cyclohexane-1,3-diol.

Soleobrazutaya connection from numbers 6-dimethylaminomethyl-1-phenylcyclohexane compounds of General formula II can be obtained and, if necessary, to divide them into optically pure antipodes by using conventional, well-known specialists in the field of methods. These processes and, if necessary, separation preferably prototipo methods as described in the application DE-A 19525137, which in this part is included in the present description by reference.

According to another preferred variant of the invention, the proposed invention the pharmaceutical salt as salt-forming active substance contains a salt-forming compound from among 1-phenyl-2-dimethylaminomethylene-1-elovich compounds of General formula III

in which, respectively

And denotes O or S,

R1"represents H, C1-6alkyl, C2-6alkenyl,5-7cycloalkyl or halogenated1-6alkyl, the groupgroup,or,

R2"represents a C1-6alkyl, C2-6alkenyl,5-7cycloalkenyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl,

in view of its possible stereoisomers, in the form of racemates or diastereomeric enantiomers or as mixtures of enantiomers, in which the enantiomers are not presented in equimolar amounts.

Preferred are soleobrazutaya connection from among 1-phenyl-2-dimethylaminomethylene-1-elovich compounds of General formula III, in which

1"represents H, C1-4alkyl, 2'-methyl-2'-propenyl, cyclopentyl or foretel, provided that R1"represents a C1-4alkyl, And indicates if S,

R2"represents a C1-4alkyl, C2-4alkenyl, cyclopentylmethyl, phenyl, C1-4alkoxyphenyl, benzyl,1-4alkylbenzene, one - or twofold halogenated phenyl, or mono - or doubly halogenated benzyl.

Particularly preferred are such soleobrazutaya connection from among 1-phenyl-2-dimethylaminomethylene-1-elovich compounds of General formula III, in which

R1"represents H, methyl, ethyl, isopropyl, 2'-methyl-2'-propenyl, cyclopentyl or foretel, provided that R1"represents methyl, And indicates if S,

R2"represents methyl, propyl, 2'-methylpropyl, allyl, 2'-methyl-2'-propenyl, cyclopentylmethyl, phenyl, 3-methoxyphenyl, benzyl, 4-tert-butylbenzyl, 4-Chlorobenzyl, 4-terbisil or 3,4-dichlorobenzyl.

The most preferred such soleobrazutaya connection from among 1-phenyl-2-dimethylaminomethylene-1-elovich compounds, which are represented in the configuration of the formula IIIa

where the phenyl ring and dimethylaminomethylene group are respectively in the Equatorial position relative to each the other.

The most preferred from among 1-phenyl-2-dimethylaminomethylene-1-elovich compounds of General formula III is a salt-forming compound selected from the group including

(+)-(1R,2R,4S)-2-(dimethylaminomethyl)-4-(4-forbindelse)-1-(3-methoxyphenyl)cyclohexanol,

(+)-(1R,2R,4S)-2-dimethylaminomethyl-4-(4-chlorobenzoyloxy)-1-(3-methoxyphenyl)cyclohexanol and

(+)-(1R,2R,4S)-3-[2-dimethylaminomethyl-4-(4-forbindelse)-1-hydroxycyclohexyl]phenol.

Soleobrazutaya connection from among 1-phenyl-2-dimethylaminomethylene-1-elovich compounds of General formula III can be obtained and, if necessary, to divide them into optically pure antipodes by using conventional, well-known specialists in the field of methods. These processes and, if necessary, the separation is preferably carried out according to the methods described in the application DE-A 19547766, which in this part is included in the present description by reference.

According to another preferred variant of the invention, the proposed therein pharmaceutical salt as salt-forming active substance contains a salt-forming compound from among dimethyl(3-arival-3-enyl)amino compounds of General formula IV

in which

R1"'represents a C1-5alkyl, and

R2"'represents N or C1-5

R1"'and R2"'together form a group -(CH2)2-4-, -(CH2)2-CHR7"'or-CH2-CHR7"'-CH2-,

R3"'represents N or C1-5alkyl,

R4"'represents H, HE, C1-4alkyl, O-C1-4alkyl, O-benzyl, CF3About-CF3, Cl, F or or8"',

R5"'represents H, HE, C1-4alkyl, O-C1-4alkyl, O-benzyl, CHF2, CF3, O-CF3, Cl, F or or8"'and

R6"'represents H, HE, C1-4alkyl, O-C1-4alkyl, O-benzyl, CF3About-CF3, Cl, F or or8"',

provided that two of the radicals R4"', R5"'and R6"'represent H, or R4"'and R5"'together form the group-CH=C(R9"')-O - or-CH=C(R9"')-S-, provided that R6"'denotes H, or

R5"'and R6"'together form the group-CH=CH-C(OR10"')=CH-, provided that R represents H,

R7"'represents a C1-8alkyl, C3-8cycloalkyl, O-C1-4alkyl, O-benzyl, CF3, Cl or F,

R8"'is a CO1-5alkyl, PO(O-C1-4alkyl)2WITH-C6H4-R11"', CO(O-C1-5alkyl),-CHR12"'-Other13"', CO-NH-C6H3-(R14"')2or unsubstituted or substituted pyridyloxy, thienyl, thiazolidine or fanilo the group,

R9"'represents N or C1-4alkyl,

R10"'represents N or C1-3alkyl,

R11"'represents OC(O)-C1-3alkyl in the ortho-position or CH2-N(R15"')2in the meta - or para-position, where R15"'stands With1-4alkyl or both radicals R15"'together with N form a 4-morpholinopropan,

R12"'and R13"'have identical or different meanings and represent H, C1-6alkyl or C3-8cycloalkyl or R12"'and R13"'together form a group -(CH2)3-8-,

R14"'represents H, HE, C1-7alkyl, O-C1-7alkyl, phenyl, O-aryl, CF3, Cl or F, provided that both of the radical R14"'have identical or different meanings,

in view of its possible stereoisomers, in the form of racemates or diastereomeric enantiomers or as mixtures of enantiomers, in which the enantiomers are not presented in equimolar amounts.

Preferred are soleobrazutaya connection from among dimethyl(3-arival-3-enyl)amino compounds of General formula IV, in which

R1"'represents a C1-3alkyl, and

R2"'represents N or C1-3alkyl or

R1"'and R2"'together form a group -(CH2)2-4- or -(CH2)2-CHR7"',

R3"'represents N or C1-3alkyl,

R4"'represents H, HE, CF3, Cl, F or or8"',

R5"'represents H, HE, C1-4alkyl, O-C1-4alkyl, O-benzyl, CHF3, CF3, Cl, F or or and

R6"'represents H, HE, O-C1-4alkyl, O-benzyl, CF3, Cl, F or or8"'provided that two of the radicals R4"', R5"'and R6"'represent H, or R4"'and R5"'together form the group-CH=C(R9"')-O - or-CH=C(R9"')-S-, provided that R6"'denotes H, or

R5"'and R6"'together form the group-CH=CH-C(OR10"')=CH-, provided that R4"'represents N, and

R7"'represents a C1-4alkyl, CF3, Cl or F.

Particularly preferred are such soleobrazutaya connection from among dimethyl(3-arival-3-enyl)amino compounds of General formula IV, in which

R1"'represents CH3or3H7and

R2"'represents N, CH3or CH2CH3or

R1"'and R2"'together form a group -(CH2)2-3- or -(CH2)2-CHR7"',

R3"'represents N, CH3or CH2CH3,

R4"'represents H or HE,

R5"'represents H, HE, co3, CHF or or8"'and

R6"'represents H, HE or CF3provided that two of the radicals R4"',

R5"'and R6"'represent H, or

R4"'and R5"'together form the group-CH=C(CH3)-S-, provided that R6"'denotes H, or

R5"'and R6"'together form the group-CH=CH-C(OH)=CH-, provided that R4"'denotes N, and

R8"'represents a group-C6H4-R11"'where R11"'represents OC(O)-C1-3alkyl in the ortho-position.

The most preferred such soleobrazutaya connection from among dimethyl(3-arival-3-enyl)amino compounds of General formula IV, in which

R1"'represents CH3and

R2"'represents N or CH3or

R1"'and R2"'together form a group -(CH2)2-3- or -(CH2)2-CH(CH3)-,

R3"'represents N or CH3,

R4"'represents H,

R5"'is a HE or or8"',

R6"'represents H and

R8"'is a CO6H4-R11"'where R11"'denotes OC(O)-CH3in the ortho-position.

The most preferred from among dimethyl(3-arival-3-enyl)amino compounds of General formula IV is a salt-forming compounds is their TRANS-(-)-(1R)-3-[1-(2-dimethylamino-1-methylethyl)propenyl]phenol.

Soleobrazutaya connection from among dimethyl(3-arival-3-enyl)amino compounds of General formula IV can be obtained and, if necessary, be divided into optically pure antipodes by using conventional, well-known specialists in the field of methods. Such access and, if necessary, the separation is preferably carried out according to the methods described in the application EP 0799819 A1, which in this part is included in the present description by reference.

As salt-forming agents against obesity proposed in the invention is a pharmaceutical salt preferably may contain D-norpseudoephedrine, phenylpropanolamine, amfepramone, mefenorex or ephedrine.

As analeptics and/or protivoepidemicheskih funds proposed in the invention is a pharmaceutical salt may preferably contain norfenefrine, heptaminol or Amazin, particularly preferably of Amazin.

As salt-forming antagonists opioids proposed in the invention is a pharmaceutical salt preferably may contain levallorphan, naloxone or naltrexone.

As salt-forming sedative proposed in the invention is a pharmaceutical salt preferably may contain parvini.

As salt-forming of antiallergenic proposed in the invention is a pharmaceutical salt predpochtite the flax may contain reproterol, triprolidine, hydroxyzine, azelastin, diphenhydramine, promethazine, Pheniramine, dexchlorpheniramine, clemastin, tramazoline, brompheniramine, dimetindene, levocabastine, doxylamine, cyproheptadine at, carbinoxamine, meclozine, bamipine, chlorphenoxamine, ketotifen or cetirizine, particularly preferably diphenhydramine.

As salt-forming antiarrhythmic drugs proposed in the invention is a pharmaceutical salt may preferably contain ortsiprenalin, aprindine, verapamil, metoprolol, quinidine, amiodarone, sotalol, propafenone, diltiazem, disopyramide, propanolol, ipatropium, meksiletin, primulin, procainamide, gallopamil, propafenone, Detajmium, flecainide, oxprenolol or cocaine, particularly preferably verapamil or diltiazem.

As salt-forming antibiotics offered in the invention is a pharmaceutical salt may preferably contain vancomycin, tetracycline, clindamycin, minocycline, lincomycin, bacampicillin, amikacin, chlortetracycline, neomycin, tobramycin, netilmicin, quinine, chloroquine, ciprofloxacin, clindamycin, colistin, erythromycin, gentamicin, tobramycin, zeitmeister, amantadine, halofantrine, saquinavir, mefloquine, framycetin, cefepime, Bromhexine, cefpodoxime, oxytetracycline, proguanil, pefloxacin, polymyxin-B, hydroxychloroquine, spectinomycin, Soult is icillin, valacyclovir or grepafloxacin.

As salt-forming nootropic funds proposed in the invention is a pharmaceutical salt preferably may contain butylamine, memantine, pyritinol, donepezil, moxaverine, meclofenoxate provided dihydroergotoxine, liquidy, naftidrofuryl, dihydroergotamine, dihydroergocristine, benzilan, procaine, deanol, Diisopropylamine or 3-pyridinemethanol.

As antidiabetic agents proposed in the invention is a pharmaceutical salt may preferably contain Metformin.

As salt-forming antiemetics and/or anti-dizziness proposed in the invention is a pharmaceutical salt preferably may contain betahistine, dolasetron, meclozine, hydroxyzine, diphenhydramine, pyridoxine, granisetron, triflupromazine, triterpenoid, betahistine, alizapride or odansetron, particularly preferably diphenhydramine.

As salt-forming anti-epileptic funds proposed in the invention is a pharmaceutical salt preferably may contain tiagabine.

As salt-forming antihypertensive drugs proposed in the invention is a pharmaceutical salt preferably may contain dihydralazine, prazosin, amiloride, bunazosin, nicardipine, alprenolol, candesartanzapomnit, metoprolol, verap is nice, propranolol, penbutolol, doxazosin, clonidine, benazepril, phenoxybenzamine, diltiazem, Diisopropylamine, rapid, carteolol, guanethidine, guanfacine, terazosin, oxprenolol, cicletanine, betaxolol, nebivolol, acebutolol, enalapril or indoramin, particularly preferably verapamil or diltiazem.

As salt-forming antihyperuricemic funds proposed in the invention is a pharmaceutical salt preferably may contain etilefrine, pholedrine, norfenefrine, efedrin, adrenalin, oxilofrine, dobutamine, dopamine, phenylephrine, midodrin, heptaminol, oxedrine tartrate, fredrin or heparin, particularly preferably phenylephrine.

As salt-forming antifungal agents proposed in the invention is a pharmaceutical salt may preferably contain benzalconi, econazole, miconazole, methylrosaniline, terbinafine, amorolfine, fenticonazole, decaline, oxiconazole, croconazole, isoconazole or sertaconazole.

As salt-forming anti-inflammatory agents proposed in the invention is a pharmaceutical salt preferably may contain orphenadrine.

As salt-forming antitussive funds and/or face means proposed in the invention is a pharmaceutical salt may preferably contain Ambroxol, doxycycline, Bromhexine, Dec is tromethane, diphenhydramine, terbutaline, chlorphenamine, eprazinone, ephedrine, chlorbutanol, pentoxyverine, pipestat or benproperine, particularly preferably diphenhydramine.

As salt-forming anti-sclerotic tools proposed in the invention is a pharmaceutical salt preferably may contain butylamine.

As blockers βreceptors and/or calcium channel blockers proposed in the invention is a pharmaceutical salt preferably may contain acebutolol, nicardipine, alprenolol, metoprolol, verapamil, enalapril, bupranolol, penbutolol, bisoprolol, esmolol, celiprolol, benazepril, diltiazem, mepindolol, sotalol, carteolol, gallopamil or oxprenolol, particularly preferably verapamil or diltiazem.

As salt-forming of broncholytics and/or anti-asthmatic medications offered in the invention is a pharmaceutical salt may preferably contain ketotifen, reproterol, ortsiprenalin, salbutamol, terbutaline, ephedrine, tulobuterol, ipratropium, fenoterol, terbutaline, salbutamol, formoterol, oxitropium or pirbuterol.

As salt-forming anticholinergics proposed in the invention is a pharmaceutical salt may preferably contain pyridostigmine, bethanechol or neostigmine.

As salt-forming diuretics offers is proposed in the invention is a pharmaceutical salt may preferably contain amiloride or oxprenolol.

As salt-forming, promoting the circulation of funds proposed in the invention is a pharmaceutical salt preferably may contain butylamine, naftidrofuryl, buflomedil, moxaverine, benzilan or meklofenoxat.

As salt-forming agent intended for breaking the bad habits that are proposed in the invention is a pharmaceutical salt preferably may include naltrexone, methadone or buprenorphine.

As salt-forming geriatric funds proposed in the invention is a pharmaceutical salt preferably may contain procaine or Deanolace.

As salt-forming sleeping pills and/or sedatives proposed in the invention is a pharmaceutical salt may preferably contain promethazine, zolpidem tartrate, midazolam, malpura or flurazepam.

As salt-forming immunomodulator proposed in the invention is a pharmaceutical salt may preferably contain levamisole.

As salt-forming means for the treatment of oral cavity and/or pharynx proposed in the invention is a pharmaceutical salt may preferably contain chlorhexidine or pyridinium.

As salt-forming means for treatment of coronary circulation proposed in the invention is a pharmaceutical salt is predpochtitelno may contain oksifedrin.

As salt-forming means lowering the level of blood lipids, proposed in the invention is a pharmaceutical salt may preferably contain colestipol.

As salt-forming local anaesthetics and/or means of neural therapy proposed in the invention is a pharmaceutical salt may preferably contain bupivacaine, lidocaine, mepivacaine, ropivacaine, procaine, articaine or prilocaine.

As salt-forming gastric and/or intestinal funds proposed in the invention is a pharmaceutical salt preferably may contain pizotifen, pirenzepine, roksatidina, ranitidine, butirosin, methantheline or metoclopramide.

As salt-forming agents against migraines proposed in the invention is a pharmaceutical salt preferably may contain lisuride, methylsergide digidroergotamin, ergotamine, sumatriptan, rizatriptan or naratriptan.

As salt-forming muscle relaxants proposed in the invention is a pharmaceutical salt may preferably contain alkorani, miwakuriyu, atricure, vacarme, pankuri, suxamethonium, tolperison, pridinol, orphenadrine or tizanidin.

As salt-forming narcotic drugs proposed in the invention is a pharmaceutical salt may preferably contain ketamine or midazolam is.

As salt-forming neuropathic drug proposed in the invention is a pharmaceutical salt may preferably contain thiamin.

As salt-forming eye of funds and/or otological funds proposed in the invention is a pharmaceutical salt preferably may contain oxybuprocaine, proxymetacaine, kanamycin, tolazoline, tetrazolyl, tramazoline, phenylephrine, Xylometazoline, nafazolina, timolol, metipranolol, betaxolol, befunolol, levobunolol, brimonidine, clonidine, pilocarpine, dipivefrin, aceclidine, apraclonidine, neostigmine, dorzolamide, atropine, scopolamine, cyclopentolate or gomatropin, particularly preferably phenylephrine.

As salt-forming agents against Parkinson's disease proposed in the invention is a pharmaceutical salt preferably may include amantadine, biperiden, selegiline, parlodel, trihexyphenidyl, matrixes, Bensberg, lisuride, benzatropine, ropinirole, pergolid, budipine, procyclidine, pramipexol, bompin or tiaprid.

As salt-forming psychopharmaceuticals funds proposed in the invention is a pharmaceutical salt may preferably contain tranilcipromin, amitriptyline, doxepin, maprotiline, clomipramine, opipramol, imipramine, trimipramine, lofepramine, desipramine, dibenzepin, nortriptyline, means is Rin, citalopram, fluvoxamine, fluoxetine, trazodone, paroxetine, nefazodone, sertraline, viloxazine, venlafaxine, promethazine, chlorprothixene, zuclopentixol, pipamperone, fluphenazine, flupentixol, melperone, prothipendyl, thioridazine, levomepromazine, quetiapine, triflupromazine, persin, Fretilin, methylphenidate, hydroxyzine, buspirone, Deanolace or memantine.

As salt-forming sinologicheskoj funds and/or funds for the treatment of sinusitis proposed in the invention is a pharmaceutical salt may preferably contain diphenylpyraline, Xylometazoline, Oxymetazoline, tramazoline, Indianapolis or tetrazolyl.

As salt-forming spasmolytic proposed in the invention is a pharmaceutical salt may preferably contain atropine, fenamate, butylscopolamine, propiverine, mebeverine, pipenzolate, oxybutinin, flavoxate, tropi, denamarin or glycopyrronium.

As salt-forming means suppressing platelet aggregation proposed in the invention is a pharmaceutical salt preferably may contain tirofiban, ticlopidine or clopidogrel.

As salt-forming drug proposed in the invention is a pharmaceutical salt may preferably contain ethambutol.

As salt-forming urological funds offered from the britanii pharmaceutical salt may preferably contain choline, tolterodine, phenoxybenzamine, atropine, propiverine, distigmine, Amarone, tamsulosin, doxazosin, terazosin, alfuzosin, Bamyan, or yohimbine sildenafil.

As salt-forming drugs proposed in the invention is a pharmaceutical salt may preferably contain aclarubicin, nyastatin, doxorubicin, bleomycin, vinblastine, vincristine, daunorubicin, dacarbazin, vindesin, epirubicin, gemcitabine, procarbazine, mitoxantrone, bendamustine, idarubitsin, aclarubicin, irinotecan, topotecan, toremifene or tamoxifen.

Proposed in the invention pharmaceutical salts can be obtained using conventional methods known to experts in this field. It is preferable to obtain a pharmaceutical salt according to the invention in each case separately from one another in an extremely small amount of solvent or solvent mixture, optionally under heating dissolving at least one salt of the corresponding active substance and at least one salt of the corresponding sugar substitute. After this, two solutions are combined, if necessary, are mixed and cooled. When proposed in the invention is a pharmaceutical salt formed from the active substance and sugar substitute, at least partially falls out optional cooled solution, it is separated by ordinary the m methods, preferably vacuum filtration. Then the separated thus pharmaceutical salt if necessary, clean using conventional, well-known specialists in the field of methods, for example by recrystallization, washing or mixing in an appropriate solvent. If a pharmaceutical salt was precipitated not completely, then in this case, the remaining part of the solution preferably is fully concentrated in a rotary evaporator and the pharmaceutical salt can be extracted from the residue by conventional, well-known specialists in the field of methods, then to clean it the above way.

The choice is suitable for the proposed salt solvent or mixture of solvents, as well as the choice of appropriate reaction conditions, such as temperature or duration of reaction, experts can identify themselves with the help of simple preliminary experiments. In those cases, when the salt of the active substance, and a salt of a sugar substitute have sufficient solubility in water, as a solvent, it is preferable to use water. As salts of the respective active substance preferably the hydrochloride, hydrobromide, phosphate, hydrogen phosphate, hydrosulfate, sulfate, nitrate or methyl sulfate. As salts of the corresponding substitute Saha is and it is preferable to use sodium, potassium, calcium or ammonium salt.

However, there is another approach, namely the corresponding active substance to be subjected as such to the interaction with the free acid of sugar substitute suitable for such purposes, the environment, and then thus obtained pharmaceutical salt to allocate and, if necessary, be purified by conventional methods known to experts in this field.

Another object of the present invention are drugs, containing at least one proposed in the invention is a pharmaceutical salt, and optionally used physiologically compatible excipients. Such drugs can be used to treat diseases using the appropriate active substances known and is shown in such cases.

Preferably proposed in the invention of medicines designed to fight the pain, when it refers to medicines that contain at least one pharmaceutical salt according to the invention, obtained from the salt-forming opioid analogue opioid, ephedrine, chloroquine, lidocaine, ethaverine, proglumetacin or triflupromazine, or salt-forming compounds of one of the above General formulas I, II, III or IV and sugar substitute. P is edocfile proposed in the invention medicines contain as pharmaceutical salts of these active substances relevant Shariati.

For the treatment of urinary incontinence, it is preferable to use such medicinal product according to the invention, which contain at least one pharmaceutical salt derived from a salt-forming compounds of one of the above General formulas I, II, III or IV or of the compounds from the group comprising oxybutynin, tolterodine, propiverine, Crespi, and sugar substitute. Preferably proposed in the invention medicines contain as pharmaceutical salts of these active substances relevant Shariati.

Proposed in the invention medications may be presented in solid, semisolid, or liquid form. Preferably the medicinal product according to the invention are intended for oral administration.

According to one of preferred embodiments of the invention its proposed remedy presented in the form of a gel, chewing gum, medicine, spray, tablets, chewable tablets, pills, powder, under certain conditions, packaged in capsules, easily recoverable dry composition, preferably in the form of a gel, in the form of mixtures in aqueous or oil-based, in the form of a sublingual spray, tablets or chewable tablets.

Preferably equally medicinal product on izaberete the Oia may also be composed of many particles, preferably in the form of microtablets, microcapsules, granules, crystals of the active substance or spherical granules, particularly preferably in the form of microtablets, granules or spherical granules, optionally packaged in capsules or compressed into tablet form.

If the medicinal product according to the invention is represented in the form of granules or spherical granules, the amount of such granules may be from 0.1 to 3 mm, particularly preferably from 0.5 to 2 mm.

If the medicinal product according to the invention is presented in the form of microtablets, such microtablets can have a diameter of from 0.5 to 5 mm, particularly preferably from 1 to 3 mm and most preferably from 1 to 2 mm.

If the medicinal product according to the invention is represented in the form of crystals of the active substance, particulate, spherical microgranules or microcapsules, these microform medicines can have a diameter of from 10 μm to 1 mm, particularly preferably from 15 μm to 0.5 mm, and most preferably from 30 μm to 200 μm.

Depending on the particular variant of the invention, the proposed therein medicines may contain, in addition, as an additional component normal physiologically compatible auxiliary substances known to specialists in this field.

If the Lek is stennie means according to the invention is presented in the form of tablets or microtablets, as physiologically compatible auxiliary substances they may contain microcrystalline cellulose, ethers of cellulose, lactose, starch, derivatives of starch, polyalcohols, xylytol, phosphate of calcium, as well as the usual, well-known experts in this field binder, means regulating the fluidity of the substance, which imparts lubricity and/or baking powder.

If the medicinal product according to the invention is presented in the form of gels or chewing gum, as physiologically compatible auxiliary substances such forms of medicines preferably may contain methylparaben, propylparaben, xylitol and/or xanthan gum.

If the medicinal product according to the invention is presented in the form of spherical pellets, granules or microgranules, as physiologically compatible auxiliary substances these forms of medicines preferably may contain microcrystalline cellulose, ethers of cellulose, lactose, starch and derivatives of starch, polyalcohols, xylytol, calcium phosphate, fatty alcohols, esters of glycerin or esters of fatty acids.

If the medicinal product according to the invention is presented in the form of microcapsules or microparticles, depending on the type used for their production method, these forms of drug medium which can contain conventional physiologically compatible auxiliary substances, well-known experts in this field.

The above forms of medicines according to the invention can be produced using conventional, well-known specialists in the field of methods.

If the medicinal product according to the invention is represented in the form of tablets, in these cases, it is preferable proposed in the invention is a pharmaceutical salt and a physiologically compatible auxiliary substances, if used, are mixed with each other, preferably to achieve homogeneity, then, wet granulation, dry granulation or granulation of the melt processed into granules, and finally pressed tablets or pills are made directly to pelletizing pharmaceutical salt together with additional excipients. In addition, the tablets can be produced by extrusion optional coated spherical granules, crystals of active substances, microparticles, or microcapsules.

Medicinal product according to the invention in the form of spherical granules can be obtained preferably by mixing the pharmaceutical salts and physiologically compatible auxiliary substances, by means of extrusion and spheronization by granulation capacity or direct pelletization in a high speed mixer or rotary is m fluidized bed. Especially, it is preferable to obtain spherical granules by extrusion of the wet mass and the subsequent spheronization.

Microcapsules produced using conventional methods of microencapsulation, such as, for example, spray drying, curing by spraying or coacervation.

Proposed in the invention of the medicinal product in semi-solid form, for example in the form of gels or chewing gum are preferable for use in the pharmaceutical salt according to the invention through the mucous membrane of the oral cavity, whereas the proposed invention medicines in solid or liquid form, for example medicine on an oil or water-based, tablet or consisting of many particles forms suitable mainly for the introduction of the pharmaceutical salt according to the invention through the gastrointestinal tract.

Since the release of the active substance of the medicinal product according to the invention in solid form occurs only when passing through the intestinal tract, such drugs must have at least floor (shell), are resistant to gastric juice. Because of this resistant to the action of gastric juice coating the drug passes through the gastrointestinal tract without dissolving, and pharmaceutical salt is released only once in cichecki is. Preferably resistant to gastric juice coating dissolves at a pH value of from 5 to 7.5.

The drug according to the invention may contain proposed therein pharmaceutical salt also partially or completely in retardirovannah form, i.e. to have a prolonged action.

The gradual release of the active substance (retardation) can be achieved by applying the relevant (reagiruyushih) coating (shell), filling in the appropriate (retardiculous) matrix, linking with ion exchange resins or by combinations of these methods retardation.

Preferably the basis reagiruyushih coating is water-insoluble, optionally modified natural or synthetic polymer or natural, semi-synthetic or synthetic wax or fat or fatty alcohol or a mixture of at least two of the above components.

As water-insoluble polymers to obtain reagiruyushih coating, it is preferable to use poly(meth)acrylates, particularly preferably poly(C1-4)alkyl(meth)acrylates, poly(C1-4)dialkylamino-(C1-4)alkyl(meth)acrylates and/or copolymers, most preferably copolymers of acrylate and methyl methacrylate at a molar ratio of monomers 2:1, the copolymers of the acrylate is, methyl methacrylate and chloride methacrylate trimethylammonium when the molar ratio of the monomers of 1:2:0.1, copolymers of acrylate, methacrylate and chloride methacrylate trimethylammonium when the molar ratio of the monomers of 1:2:0,2 or a mixture of at least two of the above polymers.

These coating materials in the form of a 30 wt.%-different aqueous latex dispersions are commercially available products under the trade names Eudragit RS30D®, Eudragit NE30D® and Eudragit RL30D® and, as such, is also preferably used for coating.

Equally preferred for use as water-insoluble polymers when receiving reagiruyushih coatings for pharmaceuticals according to the invention the polyvinyl acetate used in some cases in combination with other excipients. These coating materials are also commercially available products in the form of an aqueous dispersion containing 27 wt.% polyvinyl acetate, 2.5 wt.% of povidone and 0.3 wt.% lauryl sulphate sodium (Kollicoat SR30D®).

According to another preferred variant the basis retardery coatings for pharmaceuticals according to the invention comprise derivatives of cellulose, preferably alkylaryl, such as ethylcellulose, or esters of cellulose, such, for example, the R, as cellulose acetate, which is used as the coating material. Coating of ethyl cellulose or cellulose acetate is preferably applied from aqueous pseudorotaxanes dispersion. Water pseudolarix dispersion of ethyl cellulose are commercially available products offered in the form of a 30 wt.%-data dispersion (trade name Aquacoat®) or in the form of a 25 wt.%-data dispersion (trade name Surelease®), and as such is also preferably used for coating.

As a natural, semisynthetic or synthetic waxes, fats, respectively, fatty alcohols retardirane coverage for pharmaceuticals according to the invention may contain preferably Carnauba wax, beeswax, glycerol monostearate, monobactam glycerol (Compritol ATO®), detribalisation glycerol (Precirol ATO®), microcrystalline wax, cetyl alcohol, cetylstearyl alcohol or a mixture of at least two of the above components.

If the basis reagiruyushih coating is water-insoluble, optionally modified natural and/or synthetic polymer, the coating dispersion or solution to reduce the required minimum temperature of the resulting film may contain, along with the corresponding polymer is also conventional, well-known special is there in this field, physiologically compatible plasticizer. Suitable as such plasticizers, for example, lipophilic diesters derived from aliphatic or aromatic With6-C40dicarboxylic acids and aliphatic C1-C8alcohol, such as dibutyl phthalate, diethylphthalate, dibutylsebacate or diethylsilane, hydrophilic or lipophilic esters of citric acid, such as triethylcitrate, tributyltin, acetyltributyl or acetyltributyl, polyalkylene glycols such as polyethylene glycols or polypropylenglycol, esters of glycerol, such as triacetin, Myvacet® (acetylated mono - and diglycerides,23H44O5- C25H47O7), triglycerides of medium chain length (Miglyol®), oleic acid or a mixture of at least two of the above plasticizers. Preferably the aqueous dispersion coating materials Eudragit RS® and Eudragit RL® (in the case of the last) contain, as a plasticizer triethylcitrate. Preferably retardirane coating contains a plasticizer(s) in an amount of from 5 to 50 wt.%, particularly preferably from 10 to 40 wt.% and most preferably from 10 to 30 wt.%, in terms of the amount of the polymer. In some cases, for example when using acetate call the vine, may be present and the large quantities of plasticizers, preferably up to 110 wt.%, in terms of the amount of cellulose acetate.

Part reagiruyushih coating may include, in addition, more conventional, well-known specialists in the field of auxiliary substances, such as substances which impart lubricity, preferably talc or glycerol monostearate, pigments, preferably iron oxides or titanium dioxide, or surfactants, such as, for example, Tween 80®.

The mechanism of release retardirovannah share of the active substance can be controlled by conventional, well-known specialists in the field of methods, such as selection of the proper thickness of the coating or the use of additional auxiliary substances as components of the coating. Suitable for such purposes auxiliary substances are amongst the hydrophilic or dependent on the pH of the pore, such as sodium carboxymethyl cellulose, acatitla cellulose, acetosella hydroxypropylmethylcellulose, lactose, polyethylene glycol or mannitol, or water-soluble polymers, such as polyvinylpyrrolidone or water-soluble types of cellulose, preferably hypromellose or hydroc propylethylene.

The composition reagiruyushih coverage in order to increase the degree of prolongation may also include insoluble, respectively lipophilic excipients, such as alkilirovanny silicon dioxide, commercially available product known under the trade name Aerosil R972®or magnesium stearate.

In addition reagiruya shell, if any, proposed in the invention, the drug may also have at least one coating, designed, for example, to improve the taste or providing resistance to the action of gastric juice.

The basis is resistant to the action of gastric juice coatings preferably are copolymers of methacrylic acid and methyl methacrylate at a molar ratio of the respective monomers of 1:1 (Eudragit L®), copolymers of methacrylic acid and methyl methacrylate at a molar ratio of the respective monomers of 1:2 (Eudragit S®), copolymers of methacrylic acid and ethyl acrylate in a molar ratio of the respective monomers of 1:1 (Eudragit L30D-55®), copolymers of methacrylic acid, methyl acrylate and methyl methacrylate at a molar ratio of respective monomers 7:3:1 (Eudragit FS®), shellac, acetosella hydroxypropylmethylcellulose, acatitla cellulose or a mixture of at least two wiseness is the R component, which if necessary can also be used in combination with the above-mentioned water-insoluble poly(meth)acrylates, preferably in combination with Eudragit NE30D® and/or Eudragit RL® and/or Eudragit RS®.

Cover of medicines can be applied using conventional, suitable in each case of the methods known to experts in this field, such as plating solutions, dispersions or suspensions, drawing from the melt or powder coating materials. Solutions, dispersions or suspensions may be used in aqueous and/or organic solutions or dispersions. Preferably the use of aqueous dispersions. As organic solvents can preferably be used alcohols, for example ethanol or isopropanol, ketones, such as acetone, esters such as ethyl acetate, chlorinated hydrocarbons such as dichloromethane, is particularly preferable to apply of these alcohols or ketones. However, you can also use a mixture of at least two of the above solvents.

If the medicinal product is presented consisting of many particles and if it provides for the release of the active substance at least partially slow (partial retardation), retardirane pok the eve ENT it is advisable to apply so to consisting of many particles and containing a salt of the active substance form after receiving them can cover the corresponding polymers and other active substance in the case of its use and/or the same salt of the active substance and optionally used additional physiologically compatible auxiliary substances from aqueous and/or organic medium, preferably aqueous medium, a method of fluidized bed and then the formed coating preferably at the same time under normal temperature drying in the fluidized bed and, if necessary, be subjected to a heat treatment.

Drying of poly(meth)acrylate coating is preferably performed at a supply air temperature in the range from 30 to 50°S, particularly preferably in the range from 35 to 45°C.

Drying of coatings based on cellulose, such as EliLilly or cellulose acetate, preferably at a temperature in the range from 50 to 80°S, particularly preferably in the range from 55 to 65°C.

The wax coating can be applied from the melt in the fluidized bed and after their formation to cool for complete curing at temperatures below the corresponding melt. For applying wax coatings there is another approach, namely, spraying their RA the solutions in organic solvents.

According to one embodiments of the invention release the active substance can be ensured due to the fact that the medicinal product according to the invention contains retardiranu pharmaceutical salt in the corresponding (reagiruya) matrix, preferably in a uniformly distributed form.

To obtain such a matrix can be used physiologically compatible, hydrophilic materials known to specialists in this field. As hydrophilic materials for the matrix, it is preferable to use polymers, particularly preferably ethers, cellulose, esters of cellulose and/or acrylic resin. It is most preferable to be used as materials for the matrix ethylcellulose, hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or its derivatives such as its salts, amides or esters.

As materials for the matrix also preferred hydrophobic materials such as hydrophobic polymers, waxes, fats, fatty acids long chain fatty alcohols or corresponding simple or esters or a mixture of at least two of these materials. Particularly preferably used as the hydrophobic materials are mono - or diglycerides With12-C0 fatty acids and/or C12-C30fatty alcohols and/or waxes or a mixture of at least two of these materials.

Equally can also be used as reagiruyushih material for the matrix mixtures of the above hydrophilic and hydrophobic materials.

Retardiculous matrix can be obtained using conventional methods known to experts in this field.

Another object of the invention is the use of at least one proposed therein pharmaceutical salts and used if necessary physiologically compatible auxiliary substances for the corresponding drug. Such drugs can be used to treat diseases using the appropriate active substances known and is shown in such cases.

It is preferable to use at least one pharmaceutical salt derived from a salt-forming opioid analogue opioid, ephedrine, chloroquine, lidocaine, ethaverine, proglumetacin, triflupromazine or salt-forming compounds of one of the above General formulas I, II, III or IV, for obtaining a medicinal product intended for the treatment of pain, in the form of salts of these active substances is preferable to use saccharin is you.

Preferred is also the use of at least one pharmaceutical salt derived from a salt-forming compounds of one of the above General formulas I, II, III or IV, for obtaining a medicinal product intended for the treatment of urinary incontinence, the salts of these active substances, it is preferable to apply Shariati.

Assigned to the patient the total number of appropriate pharmaceutical salt varies, for example, depending on the weight of the patient, from the readings, as well as on the severity of the pain, according to the severity of the disease. Specialist taking into account known properties of the respective active substances determines the dosage required to achieve the desired effect.

Proposed in the invention is a pharmaceutical salt obtained from the pharmaceutical active substance and sugar substitute, basically differ in comparison with the commonly used salts of these active substances lower solubility in water. Preferably it is of sabarinath relevant active substances, the solubility of which in most cases is ≤250 mg/ml of water, whereas this indicator normal salts of the active substances, as a rule, is higher by at least 50%. Due to this it is possible to simplify those is the technology of obtaining medicines from such pharmaceutical salts, for example, the formation of pellets by extrusion. In addition, in contrast to the commonly used pharmaceutical salts, the pharmaceutical salt according to the invention due to the significantly reduced solubility allows recordroute active substances using traditional methods retardation. As a result, the opportunity to obtain medicines prolonged action, containing the proposed pharmaceutical salts, a simple and economical way. This applies also to other modifications of medicines according to the invention, such as, for example, which have a coating (shell), are resistant to gastric juice.

In addition, it should be noted such positive factors:

practically controlled release of the respective active substance of the medicinal products according to the invention, designed to be inserted through the mucous membrane of the mouth or through the intestinal tract, is achieved without the use of reagiruya matrix and/or reagiruyushih coverage, except for those cases, when a coating resistant to gastric juice.

Another advantage of the pharmaceuticals according to the invention, intended for oral administration and releasing applicable to the company during or immediately after administration, is that they are extremely bitter or harsh unpleasant taste is compensated by the simultaneous release of sugar substitute. Due to this it is possible to more accurately observe the prescribed dosage by patients, and medicines containing the relevant active substance in the form of salt, is they have greater demand. The advantages of the proposed invention medicines should be considered and the possibility of their use for diabetics.

For many of the above mentioned active substances, the solubility of the usual salts of such active substances are known, for example from the list of pharmaceutical substances Pharmazeutische Stoffliste, 12th edition ABDATA Pharma-Daten-Service, 65735 Eschborn/Taunus. This publication is included in this part of the present description by reference. If the solubility of one or another salt of the active substance is not known, it can be determined by the method described below, which was determined by the solubility of the pharmaceutical salt according to the invention.

In a vessel made of a colorless transparent material, such as glass or plastic, at a temperature of 20°With pre-placed 1 ml of deionized water or some smaller number (the number in ml). Then under stirring with a magnetic stirrer portions were added ... the target normal salt of the active substance, accordingly, the pharmaceutical salt according to the invention. After complete dissolution of the added amount of salt (in mg) was slowly added a certain quantity of the appropriate salt. Each of the following additives were log and watched in solution processes. When the first signs due to nerastvorimaya salt opacities, which visually was determined by the loss of transparency at the appropriate background, the stirring was continued for another 10 minutes. If after that the components remained insoluble, determine the amount (in mg) used amount of substance. If under stirring again formed a clear solution, then continued to add small amounts of the corresponding salt and again stirred for 10 minutes, repeating these operations until the first signs of turbidity caused by nerastvorimaya salt. Then by adding under stirring some amounts of water an excessive amount of nerastvorimaya salt was dissolved. After obtaining a clear solution was determined by the sum of D (ml) amount of water used. The solubility of the corresponding salts in terms of 1 ml of water was calculated by the following formula:

If the added amount (in mg)of the corresponding salt was dissolved at once, and appeared blurred, after adding salt was stirred for further 10 minutes. If some part of the salt remains undissolved, this nerastvorim share with stirring by adding some amount of water was dissolved. After formation of a transparent solution was determined by the sum of E (in ml) used quantities of water. The solubility of the corresponding salts in terms of 1 ml of water was calculated by the following formula:

Below the invention is explained in more detail by way of examples, which serve only for illustration and do not limit the scope of the invention.

Examples

Example 1

Optically pure compound (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl " phenol was obtained and then allocated according to the method described in the application DE-A 4426245, which in this part is included in the present description by reference.

To obtain saharinata (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol in each case, when heated in the limiting case of a small quantity of water is completely dissolved 2.58 g (10 mmol) of the hydrochloride of (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol and 2,42 (10 moles) of the dihydrate saharanafrica. Then both the solution with stirring mixed with each other, and then left overnight to cool. Fallen in sediment saccharinate (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)Fe is Ola was separated from the supernatant mother liquor, purified ethanol and identified using conventional methods.

Example 2

To obtain saharinata diphenhydramine 5.0 g (17.1 mmole) of diphenhydramine hydrochloride and 4.13 g (17.1 mmole) of the dihydrate saharanafrica in each case, when heated completely dissolved in a very small amount of water. Then both the solution with stirring mixed with each other, and then left overnight to cool. Fallen in sediment saccharinate diphenhydramine was separated from the supernatant mother liquor was purified by ethanol and identified using conventional methods.

Example 3

To obtain saharinata verapamil 415 mg (0,845 mmole) of the hydrochloride verapamil and 204 mg (0,845 mmole) of the dihydrate saharanafrica in each case, when heated completely dissolved in a very small amount of water. Then both the solution with stirring mixed with each other, and then left overnight to cool. Fallen in sediment saccharinate verapamil was separated from the supernatant mother liquor was purified by ethanol and identified using conventional methods.

Example 4

To obtain saharinata morphine 285 mg (from 0.76 mmole) of three-hydrate of the hydrochloride of morphine and 183 mg (from 0.76 mmole) of the dihydrate saharanafrica in each case, when heated completely dissolved in a very small amount of water. Then both the solution with stirring mixed with each other, after h is th left overnight to cool. Fallen in sediment saccharinate morphine was separated from the supernatant mother liquor was purified by ethanol and identified using conventional methods.

Example 5

To obtain oral gel, first at a temperature of 80°in purified water was dissolved 0.33 g of methylparaben, 0.05 g propyl paraben and 75.0 g of xylitol, after which the mixture was cooled to 40°C. Next, under stirring was added first 0,94 g obtained according to example 2 saharinata diphenhydramine, and then 2 g of xanthan gum, the mixture for 1 h, stirred and lack of evaporated water was replenished by its appropriate number. After cooling to a temperature of 20-25°to the mixture under stirring was added 0.625 g of flavor Tutti Frutti 9/008897 (Dragoco Gerberding & Co. AG, 37603 Hoizminden).

Example 6

5 g of the crushed mass of chewing gum (Popeye Amural Confections, Yorkville, Illinois, USA) was heated in the bowl to a temperature of 30-40°C. Then this plastic mass by grinding with a pestle and mortar was added 187,9 g obtained according to example 2 saharinata diphenhydramine. Then the homogeneous mass was divided portions 1 g, respectively, in shape with a Teflon coating. Tasting samples of chewing gum containing saccharinate diphenhydramine, confirmed that they, having initially excellent flavor, preserved them, and during the whole time "chewing".

Example 7

DL is getting medicine water-based 0.33 g of methylparaben, 0.05 g propyl paraben and 75.0 g of xylitol at a temperature of 80°was dissolved in 199,22 g of purified water. The mixture was cooled to 40°and with stirring, thereto was added 78.5 per mg obtained according to example 1 saharinata (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol. Then added 0.25 g of xanthan gum was stirred for 1 h and the lack of evaporated water was replenished by its appropriate number. After cooling to a temperature of 20-25°to the mixture under stirring was added 0.075 g of Orange flavor-Mandarine Flavor 10888-56 (Givaudan Roure Flavors Ltd. CH 8600 Dübendorf).

Example 8

In this example, the above described method determined the solubility of some pharmaceutical salts according to the invention and the conventional salts of the respective active substances. Thus obtained indicators solubility is presented in the following table 1:

Table 1

Comparison of water solubility of some of the proposed invention the pharmaceutical salts with water-soluble relevant customary salts of these active substances. Used in each case, common salt are shown in parentheses.
The active ingredientThe solubility of the salts of the active substance in mg/ml waterThe solubility of saharinata de the respective substance in mg/ml water
(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl " phenol261 (hydrochloride)31
(1RS,3RS,6RS)-6-dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexane-1,3-diol500 (hydrochloride)71
(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl " phenol650 (hydrochloride)55
(-)-(1S,2S)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl " phenol568 (hydrochloride)130
(-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol2000 (hydrochloride)90
(+)-(1R,2R,4S)-2-dimethylaminomethyl-4-(4-forbindelse)-1-(3-methoxyphenyl)cyclohexanol33 (hydrochloride)10

1. Soluble pharmaceutical salt obtained from the pharmaceutical active substance and sugar substitute, characterized in that the salt-forming active substance is a salt-forming compound from among 1-phenyl-3-dimethylaminopropane compounds of General formula I

in which X denotes a HE, F, Cl, H or OCOR group6,

R1represents a C1-4alkyl group,

R2represents N or C1-4alkyl group, and

R3is the Wallpaper N or C 1-4alkyl group with a straight chain

or

R2and R3together form4-7cycloalkyl group and,

if R5denotes H, R4is a group O-Z in the meta position, where Z denotes H, C1-3alkyl, PO(O-C1-4alkyl)2, CO1-5alkyl), CONH-C6H4-(C1-3alkyl),-C6H4-R7while R7represents OCOC1-3alkyl in anthopology or group CH2N(R8)2in the meta - or paraprotein, where R8represents C1-4alkyl or 4-morpholinopropan, or R4is a S-C1-3alkyl in metabologia, meta-Cl, meta-F, group CR9R10R11in metabologia, where R9, R10and R11denote H or F, IT-group anthopology, O-C2-3alkyl in anthopology, para-F or group CR9R10R11in paraprotein, where R9, R10and R11denote H or F, or

if R5means located in paraprotein Cl, F, IT is a group or O-C1-3-alkyl,

R4is a located in metaprogram Cl, F, IT is a group or O-C1-3-alkyl

or R4and R5together form a group of 3,4-och=CH - or 3,4-och=SNO-,

R6represents C1-3alkyl,

in view of its possible stereoisomer is in the form of racemates or diastereomeric enantiomers or as mixtures of enantiomers, in Kotayk corresponding enantiomers represented not in equimolecular quantities

or salt-forming active substance is a salt-forming compound from numbers 6-dimethylaminomethyl-1-phenylcyclohexane compounds of General formula II

in which R1'represents H, HE, Cl or F,

R2'and R3'have identical or different meanings and represent H, C1-4alkyl, benzyl, CF3HE co2-C6H5,- C1-4alkyl, Cl or F, provided that at least one of the radicals R2'or R3'denotes H,

R4'represents N, CH3, RO(OC1-4alkyl)2, CO1-5alkyl), CO-NH-C6H4-C1-3alkyl,-C6H4-R5'WITH-C1-4alkyl, CO-CHR6'-Other7'or unsubstituted or substituted pyridyloxy, thienyl, thiazolidine or phenyl group,

R5'represents OC(O)1-3alkyl in anthopology or CH2-N(R8')2in the meta - or paraprotein, where R8'represents C1-4alkyl or both radicals R8'together with N form a 4-morpholinopropan, and

R6'and R7'have identical or different meanings and represent N or C1-6alkyl,

when the CA is ovii, what if both radical R2'and R3'represent H, R4'doesn't mean CH3when advanced R1'represents H, HE or Cl, or R4'does not denote N when optional R1'is a HE,

in view of its possible stereoisomers, in the form of racemates or diastereomeric enantiomers or as mixtures of enantiomers, in which the enantiomers are not equimolecular quantities.

2. The pharmaceutical salt according to claim 1, characterized in that the solubility of salt in water is ≤250 mg/ml of water, preferably ≤200 mg/ml, particularly preferably ≤150 mg/ml and most preferably ≤100 mg/ml

3. The pharmaceutical salt according to claim 1 or 2, characterized in that the salt-forming the sweetener is saccharin, cyclamate or Acesulfame, preferably saccharin.

4. The pharmaceutical salt according to any one of claims 1 to 3, characterized in that the salt contains a pharmaceutical active substance of General formula I, where X denotes HE, F, Cl or H,

R1represents a C1-4alkyl group,

R2represents N or CH3and

R3also represents N or CH3and

R4and R5together form a group of 3,4-och=CH-.

5. The pharmaceutical salt according to any of the C claims 1 to 4, wherein R2and R3are different from each value, and compounds of General formula I according to claim 4 represented in the form of their diastereomers configuration Ia

6. The pharmaceutical salt according to any one of claims 1 to 5, characterized in that the salt-forming 1-phenyl-3-dimethylaminopropane compound selected from the group including

(1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,

(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl " phenol,

(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methylpropyl " phenol,

(2RS,3RS)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol,

(-)-(1S,2S)-3-(3-dimethylamino-1-ethyl-1-fluoro-2-methylpropyl " phenol,

(+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethylpropyl)phenol,

(+)-(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol and

(-)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol.

7. The pharmaceutical salt according to any one of claims 1 to 3, characterized in that the salt contains a pharmaceutical active substance of General formula II, where R1'represents H, HE or F.

8. The pharmaceutical salt according to any one of claims 1 to 3 or 7, characterized in that compounds of General formula II is represented in the configuration in which the phenyl ring and dimethylaminomethylene group are in one plane.

9. Pharmaceutical with the l according to any one of claims 1 to 3, 7 or 8, characterized in that the salt-forming 6-dimethylaminomethyl-1-phenylcyclohexane compound selected from the group including

(-)-(1R,2R)-3-(2-dimethylaminomethylene)phenol,

(1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexane-1,3-diol and (1RS,3RS,6RS)-6-(dimethylaminomethyl)-1-(3-hydroxyphenyl)cyclohexane-1,3-diol.

10. Drug for dealing with pain or treatment of urinary incontinence, containing at least one soluble pharmaceutical salt according to any one of claims 1 to 9 and optionally a physiologically compatible auxiliary substances.

11. The drug of claim 10, characterized in that it presents in the form of a gel, chewing gum, medicine, spray, tablets, chewable tablets, pills, powder, packaged, if necessary, in capsules, easily recoverable dry composition, preferably in the form of a gel, medicine, water or oil-based, sublingual spray, tablets or chewable tablets.

12. The drug of claim 10, characterized in that it presents in consists of many particles, preferably in the form of microtablets, microcapsules, granules, crystals of the active substance or spherical granules, particularly preferably in the form of microtablets, granules or spherical granules, optionally packaged in capsules the crystals or compressed into tablet form.

13. The use of soluble pharmaceutical salt according to any one of claims 1 to 9 for obtaining a medicinal product intended for dealing with pain.

14. The use of soluble pharmaceutical salt according to any one of claims 1 to 9 for obtaining a medicinal product intended for the treatment of urinary incontinence.



 

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