USE AND COMPOSITION FOR TREATING DEMENTIA

Abstract

There is described a method for increasing the maximal tolerated dose and thus the efficacy of an acetyl choline esterase inhibitor (AChEI) in a patient suffering from an Alzheimer type dementia by decreasing concomitant adverse effects by administration of said AChEI in combination with a non-selective, peripheral anticholinergic agent, whereby an enhanced acetyl choline esterase inhibition in the CNS of said patient is achieved and alleviation of the symptoms of Alzheimer type dementia in said patient is thereby improved to a greater extent. The use of a non-selective, peripheral anticholinergic agent (nsPAChA) for the preparation of a pharmaceutical composition for increasing the maximal tolerated dose and thus the efficacy of an acetyl choline esterase inhibitor (AChEI) in a patient suffering from an Alzheimer type dementia and pharmaceutical compositions comprising a non-selective peripheral anticholinergic agent of formula II as illustrated in the description and an acetylcholine esterase inhibitor are also described.

Claims

1. Use of a non-selective, peripheral anticholinergic agent (nsPAChA) for the preparation of pharmaceutical compositions for the treatment of Alzheimer type dementia in combination with an acetyl choline esterase inhibitor (AChEI), whereby the maximal tolerated dose of said AChEI is increased, a higher acetyl choline esterase inhibition in the CNS is achieved and relief of the symptoms of Alzheimer type dementia is improved, by concomitantly decreasing concurrent adverse effects.

2. The use of claim 1 wherein said nsPAChA is selected from the group consisting of quaternary ammonium nsPAChAs, sulfonium nsPAChAs, (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)-iso-quinolinecarboxylate (solifenacin) and its pharmaceutically acceptable salts, 1-methylpiperidin-4-yl) 2,2-di(phenyl)-2-propoxyacetate (propiverine) and its pharmaceutically acceptable salts, 1,4,5,6-tetrahydro-1-methylpyrimidin-2-ylmethyl -cyclohexyl--hydroxy--phenylacetate (oxyphencyclimine) and its pharmaceutically acceptable salts, (R)N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine (tolterodine) and its pharmaceutically acceptable salts.

3. The use of claim 2 wherein said quaternary ammonium nsPAChAs or sulfonium nsPAChAs has the formula (II) ##STR00006## wherein R is a radical selected from the group consisting of those of formulas (a)-(e) ##STR00007## A being methyl and A being (C.sub.1-C.sub.4)alkyl or 2-fluoroethyl group or A and A forming a 1,4-butylene or 1,5-pentylene chain, L being hydrogen or methoxy, Alk and Alk each being (C.sub.1-C.sub.4)alkyl and Y being a bivalent radical selected from the group consisting of 1,2-ethylene, 1,3-propylene, 1,4-butylene and 2-oxa-1,3-propylene; the corresponding counter ion being a pharmaceutically acceptable anion; n and m, independently, are zero or 1; X is a (C.sub.2-C.sub.3)alkylene group; R.sub.1 and R.sub.2 are each phenyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 2-thienyl and, when R is a radical (a), also each represents (C.sub.1-C.sub.4)alkyl; R.sub.3 is H or OH or, only when R is a radical (a), also a COOAlk group, Alk being a (C.sub.1-C.sub.4)alkyl group.

4. The use of claim 1 wherein said nsPAChA selected from the group consisting of pharmaceutically acceptable salts of azoniaspiro[3-benziloyloxy-(1,5)-nortropane-8,1-pyrrolidine] (trospium), solifenacin and the compound thereof with succinic acid, propiverine and the hydrochloride thereof, oxyphencyclimine and the hydrochloride thereof, tolterodine and the hydrogen tartrate thereof.

5. The use of claim 1 wherein said AChEI is selected from the group consisting of 1,2,3,4-tetrahydro-9-acridinamine (tacrine), ()-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one (donepezil) and its pharmaceutically acceptable salts, (S)N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate (rivastigmine) and its pharmaceutically acceptable salts, 4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol (galantamine); and (1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,10-trien-5-one (huperzine A).

6. The use of claim 5 wherein the dose of said AChEI is from 100% to 400% of the maximal tolerated dose of said AChEI when used alone.

7. A pharmaceutical unit form which comprises (a) a nsPAChA selected from the group consisting of solifenacin, pharmaceutically acceptable salts of solifenacin, propiverine, pharmaceutically acceptable salts of propiverine, oxyphencyclimine, pharmaceutically acceptable salts of oxyphencyclimine, tolterodine, pharmaceutically acceptable salts of tolterodine and quarternary ammonium or sulfonium compound of formula II ##STR00008## wherein R is a radical selected from the group consisting of those of formulas (a)-(e) ##STR00009## A being methyl and A being (C.sub.1-C.sub.4)alkyl or 2-fluoroethyl group or A and A forming a 1,4-butylene or 1,5-pentylene chain, L being hydrogen or methoxy, Alk and Alk each being (C.sub.1-C.sub.4)alkyl and Y being a bivalent radical selected from the group consisting of 1,2-ethylene, 1,3-propylene, 1,4-butylene and 2-oxa-1,3-propylene; the corresponding counter ion being a pharmaceutically acceptable anion; n and m, independently, are zero or 1; X is a (C.sub.2-C.sub.3)alkylene group; R.sub.1 and R.sub.2 are each phenyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 2-thienyl and, when R is a radical (a), also each represents (C.sub.1-C.sub.4)alkyl; R.sub.3 is H or OH or, only when R is a radical (a), also a COOAlk group, Alk being a (C.sub.1-C.sub.4)alkyl group; and (b) an AChEI; in admixture with at least a pharmaceutical carrier.

8. The unit form of claim 7, wherein said nsPAChA is a selected from the group consisting of pharmaceutical acceptable salts of trospium, pharmaceutically acceptable salts of solifenacin, pharmaceutically acceptable salts of propiverine, pharmaceutically acceptable salts of oxyphencyclimine and pharmaceutically acceptable salts of tolterodine.

9. The unit form of claim 7, wherein said nsPAChA is a pharmaceutical acceptable salt of trospium in an amount of from 4 mg to 120 mg.

10. The unit form of claim 7, wherein said nsPAChA is a pharmaceutically acceptable salt of trospium and AChEI is selected from the group consisting of tacrine, in an amount of from 10 mg to 160 mg, donepezil and its pharmaceutically acceptable salts, in an amount of from 5 mg to 40 mg, rivastigmine and its pharmaceutically acceptable salts, in an amount of from 1.5 to 36 mg, galantamine, in an amount of from 4 to 48 mg and huperzine A, in an amount of from 100 g to 1.2 mg.

11. A method for increasing the maximal tolerated dose of an acetyl choline esterase inhibitor (AChEI) in a patient suffering from an Alzheimer type dementia without concurrent, appreciable adverse effects, which comprises administering to said patient said AChEI in combination with a non-selective, peripheral anticholinergic agent (nsPAChA), whereby an enhanced acetyl choline esterase inhibition in the CNS of said patient is achieved and the symptoms of an Alzheimer type dementia in said patient are improved.

12. A pharmaceutical composition for inducing a higher acetyl choline esterase inhibition in the CNS of a patient suffering from Alzheimer type dementia, said patient taking a dose of acetyl choline esterase inhibitor (AChEI) higher than the maximal tolerated dose attainable when given alone, comprising, as an active ingredient, a non-selective, peripheral anticholinergic agent (nsPAChA) in admixture with a pharmaceutical carrier.

Description

DETAILED DESCRIPTION

[0057] The present invention proposes an improved method to augment the efficacy of conventional cholinergic therapies for Alzheimer type dementias by mitigating the common adverse events of cholinomimetic treatments of said Alzheimer type dementias that arise as a result of the concomitant stimulation of cholinergic receptors in the PNS. Drugs that act to selectively inhibit the activation of all the muscarinic receptors in the PNS, but not in the CNS, resulting from cholinomimetic therapy have the potential to reduce the adverse effects, such that higher cholinomimetic doses can be administered leading to higher and more prolonged antidementia efficacy with fewer peripherally mediated side effects. By combining an extended release cholinomimetic with a peripheral anticholinergic having an advantageous duration of pharmacologic action, in a single dosage form, the benefits to patients of an even longer duration of action is also achieved.

[0058] Thus, it is an object of the present invention to provide a method for increasing the maximal tolerated dose of an acetyl choline esterase inhibitor in a patient suffering from an Alzheimer type dementia without concurrent, appreciable adverse effects, which comprises administering to said patient said AChEI in combination with a non-selective, peripheral anticholinergic agent (nsPAChA), whereby an enhanced acetyl choline esterase inhibition in the CNS of said patient is achieved and the symptoms of an Alzheimer type dementia in said patient are improved.

[0059] The invention also provides the use of a non-selective, peripheral anticholinergic agent (nsPAChA) for the preparation of pharmaceutical compositions for the treatment of Alzheimer type dementias in combination with an AChEI, whereby the maximal tolerated dose of said AChEI is increased, a higher degree of acetyl choline esterase inhibition in the CNS is achieved and the symptoms of Alzheimer type dementia are improved to a greater extent without concurrent, appreciable adverse effects.

[0060] The efficacy of the nsPAChAs in improving the symptoms of Alzheimer type dementia is due to the fact that said nsPAChAs allow the increase of the therapeutic doses of all the AChEIs up to a factor of 4.

[0061] Advantageous AChEIs are those currently used or tested for this indication, such as 1,2,3,4-tetrahydro-9-acridinamine (tacrine), 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline (ipidacrine); ()-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one (donepezil) and its pharmaceutically acceptable salts, in particular the hydrochloride, 3-[2-(1-benzyl-4-piperidypethyl]-5,7,-dihydro-6H-pyrrolo[3,2-f]-1,2-benzisoxazol-6-one (icopezil) and its pharmaceutically acceptable salts, in particular the maleate, 3-[1-benzylpiperdin-4-yl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)propan-1-one (zanapezil) and its pharmaceutically acceptable salts, in particular the fumarate, (5)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) and its pharmaceutically acceptable salts, in particular the hydrogen (2R,3R)-tartrate, 4aS,6R,8aS-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol (galantamine); (1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0.sup.2,7] trideca-2(7),3,10-trien-5-one (huperzine A) and phenserine and its analogs encompassed by the general formula I

##STR00001##

wherein Q is a phenyl group optionally substituted with a (C.sub.1-C.sub.4)alkyl or with a methoxy group, Z is an oxygen or sulfur atom or a N-E radical, E and E, independently, are hydrogen or a methyl group optionally substituted with a phenyl or benzyl group.

[0062] Exemplary AChEIs of formula (I), described in U.S. Pat. No. 6,683,105, are phenserine (Q=phenyl; E=CH.sub.3; ZNCH.sub.3); ()-N.sup.1,N.sup.8-bisnorphenserine (Q=phenyl; E=H; Z=NH); 4-methoxyphenserine (Q=4-methoxyphenyl; E=CH.sub.3; ZNCH.sub.3); ()-N.sup.1,N.sup.8-bisbenzylnorphenserine (Q=phenyl; E=CH.sub.2C.sub.6H.sub.5; ZNCH.sub.2C.sub.6H.sub.5); tolserine (Q=o-tolyl; E=CH.sub.3; ZNCH.sub.3); N.sup.1-benzylnortolserine (Q=o-tolyl; E=CH.sub.3; ZNCH.sub.2-C.sub.6H.sub.5); N.sup.1-phenethylnortolserine (Q=o-tolyl; E=CH.sub.3; ZNCH.sub.2CH.sub.2C.sub.6H.sub.5); N.sup.1-nortolserine (Q=o-tolyl; E=CH.sub.3; ZNH); N.sup.8-benzylnortolserine (Q=o-tolyl; E=NCH.sub.2C.sub.6H.sub.5; ZNCH.sub.3); N.sup.8-phenethylnortolserine (Q=o-tolyl; E=NCH.sub.2CH.sub.2C.sub.6H.sub.5; ZNCH.sub.3); N.sup.8-nortolserine (Q=o-tolyl; E=H; ZNCH.sub.3); N.sup.1,N.sup.8-bisnortolserine (Q=o-tolyl; E=H; ZNH); ()-N.sup.1,N.sup.8-bisbenzylnortolserine (Q=o-tolyl; E=CH.sub.2C.sub.6H.sub.5; ZNCH.sub.2C.sub.6H.sub.5); cymserine (Q=p-isopropylphenyl; E=CH.sub.3; ZNCH.sub.3); N.sup.1-benzylnorcymserine (Q=p-isopropylphenyl; E=CH.sub.3; ZNCH.sub.2C.sub.6H.sub.5); N.sup.1-phenethylnorcymserine (Q=p-isopropylphenyl; E=CH.sub.3; ZNCH.sub.2CH.sub.2C.sub.6H.sub.5); N.sup.1-norcymserine (Q=p-isopropylphenyl; E=CH.sub.3; ZNH); N.sup.8-benzylnorcymserine (Q=p-isopropylphenyl; E=NCH.sub.2C.sub.6H.sub.5; ZNCH.sub.3); N.sup.8-phenethylnorcymserine (Q=p-isopropylphenyl; E=NCH.sub.2CH.sub.2C.sub.6H.sub.5; ZNCH.sub.3); N.sup.8-norcymserine (Q=p-isopropylphenyl; E=H; ZNCH.sub.3); N.sup.1,N.sup.8-bisnorcymserine (Q=p-isopropylphenyl; E=H; ZNH); ()-N.sup.1,N.sup.8-bisbenzylnorcymserine (Q=p-isopropylphenyl; E=CH.sub.2C.sub.6H.sub.5; ZNCH.sub.2C.sub.6H.sub.5); thiacymserine (Q=p-isopropylphenyl; E=CH.sub.3; ZS); thiatolserine (Q=o-tolyl; E=CH.sub.3; ZS).

[0063] Donepezil hydrochloride, rivastigmine hydrogen (2R,3R)-tartrate and galantamine are the preferred AIChEIs.

[0064] Advantageously, the used nsPAChAs are quaternary ammonium nsPAChAs, sulfonium nsPAChAs, (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)-iso-quinolinecarboxylate (solifenacin) and its pharmaceutically acceptable salts, 1-methylpiperidin-4-yl) 2,2-di(phenyl)-2-propoxyacetate (propiverine) and its pharmaceutically acceptable salts, 1,4,5,6-tetrahydro-1-methylpyrimidin-2-ylmethyl -cyclohexyl--hydroxy--phenylacetate (oxyphencyclimine) and its pharmaceutically acceptable salts, (R)N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine (tolterodine) and its pharmaceutically acceptable salts. Said nsPAChAs, preferably, are compounds with a duration of action of at least 6 hours, advantageously from 8 to 24 hours, more advantageously from 10 to 24 hours, preferably from 12 to 24 hours, even though nsPAChAs having an appropriate duration of action corresponding to the duration of action of the concomitantly administered AChEI may be successfully used.

[0065] Particularly advantageous quaternary ammonium nsPAChAs or sulfonium nsPAChAs are compounds of formula II

##STR00002##

wherein [0066] R is a radical selected from the group consisting of those of formulas (a)-(e)

##STR00003## [0067] A being methyl and A being (C.sub.1-C.sub.4)alkyl or 2-fluoroethyl group or A and A forming a 1,4-butylene or 1,5-pentylene chain, L being hydrogen or methoxy, Alk and Alk each being (C.sub.1-C.sub.4)alkyl and Y being a bivalent radical selected from the group consisting of 1,2-ethylene, 1,3-propylene, 1,4-butylene and 2-oxa-1,3-propylene; the corresponding counter ion being a pharmaceutically acceptable anion, such as a chloro, bromo, iodo, tartrate, hydrogen tartrate, succinate, maleate, fumarate, sulfate, hydrogen sulfate or methylsulfate anion; [0068] n and m, independently, are zero or 1; [0069] X is a (C.sub.2-C.sub.3)alkylene group; [0070] R.sub.1 and R.sub.2 are each phenyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 2-thienyl and, when R is a radical (a), also each represents (C.sub.1-C.sub.4)alkyl; [0071] R.sub.3 is H or OH or, only when R is a radical (a), also a COOAlk group, Alk being a (C.sub.1-C.sub.4)alkyl group.

[0072] Exemplary nsPAChAs of formula II above used for preparing medicaments for the treatment of Alzheimer type dementia in combination with AchEIs are [0073] anisotropine methylbromide [R=(a), A=A=CH.sub.3, L=H; n=1; m=0; R.sub.1R.sub.2=n-C.sub.3H.sub.7; R.sub.3H;]; [0074] ciclotropium bromide [R=(a), A=CH.sub.3, A=isopropyl, L=H; n=1; m=0; R.sub.1=phenyl; R.sub.2=cyclopentyl; R.sub.3H]; [0075] flutropium bromide [R=(a), A=CH.sub.3, A=2-fluoroethyl, L=H; n=1; m=0; R.sub.1R.sub.2=phenyl; R.sub.3OH]; [0076] homatropine methylbromide [R=(a), A=A=CH.sub.3, L=H; n=1; m=0; R=phenyl; R.sub.2R.sub.3H]; [0077] sintropium bromide; [R=(a), A=CH.sub.3, A=isopropyl, L=H; n=1; m=0; R.sub.1R.sub.2=n-C.sub.3H.sub.7; R.sub.3H]; [0078] tematropium metilsulfate [R=(a), A=A=CH.sub.3, L=H; n=1; m=0; R.sub.1=phenyl; R.sub.2COOC.sub.2H.sub.5; R.sub.3H]; [0079] tropenziline bromide [R=(a), A=A=CH.sub.3, L=methoxy; n=1; m=0; R.sub.1R.sub.2=phenyl, R.sub.3OH]; [0080] trospium chloride [R=(a), A+A=1,4-butylene, L=H; n=1; m=0; R.sub.1R.sub.2=phenyl; R.sub.3OH]; [0081] clidinium bromide [R=(b)-3-, Alk=methyl; n=1; m=0; R.sub.1R.sub.2=phenyl; R.sub.3OH]; [0082] droclidinium bromide [R=(b)-3-, Alk=methyl; n=1; m=0; R.sub.1=phenyl; R.sub.2=cyclopentyl; R.sub.3OH]; [0083] benzilonium bromide [R=(c)-3-, both Alk and Alk=ethyl; n=1; m=0; R.sub.1R.sub.2=phenyl; R.sub.3OH]; [0084] benzopyrronium bromide [R=(c)-3-, both Alk and Alk=methyl; n=1; m=0; R.sub.1R.sub.2=phenyl; R.sub.3OH]; [0085] cyclopyrronium bromide [R=(c)-3-, Alk=methyl and Alk=ethyl; n=1; m=0; R.sub.1=phenyl; R.sub.2=cyclopentyl; R.sub.3H]; [0086] glycopyrronium bromide (glycopyrrolate) [R=(c)-3-, both Alk and Alk=methyl; n=1; m=0; R.sub.1=phenyl; R.sub.2=cyclopentyl; R.sub.3H]; [0087] heteronium bromide [R=(c)-3-, both Alk and Alk=methyl n=1; m=0; R.sub.1=phenyl; R.sub.2=2-thienyl; R.sub.3OH]; [0088] hexopyrronium bromide [R=(c)-3-, both Alk and Alk=methyl; n=1; m=0; R.sub.1=phenyl; R.sub.2=cyclohexyl; R.sub.3H]; [0089] oxypyrronium bromide [R=(c)-2-, both Alk and Alk=methyl; n=1; m=1; X=1,2-ethylene; R.sub.1=phenyl; R.sub.2=cyclohexyl; R.sub.3OH]; [0090] ritropirronium bromide [R=(c)-3-, both Alk and Alk=methyl; n=1; m=0; R.sub.1=phenyl; R.sub.2=cyclopentyl; R.sub.3OH]; [0091] etipirium iodide [R=(d), Alk=methyl, Y=1,2-ethylene; n=1; m=1; X=1,2-ethylene; R.sub.1R.sub.2=phenyl; R.sub.3OH]; [0092] fenclexonium methylsulfate [R=(d), Alk=CH.sub.3, Y=1,3-propylene; n=0; m=1; X=1,2-ethylene; R.sub.1=phenyl; R.sub.2=1-cyclohexenyl; R.sub.3H]; [0093] tricyclamol chloride (procyclidine methochloride) [R=(d), Alk=methyl, Y=1,2-ethylene; n=0; m=1; X=1,2-ethylene; R.sub.1=phenyl; R.sub.2=cyclohexyl; R.sub.3OH]; [0094] tiemonium iodide [R=(d), Alk=methyl, Y=2-oxa-1,3-propylene; n=0; m=1; X=1,2-ethylene; R.sub.1=phenyl; R.sub.2=2-thienyl; R.sub.3OH]; [0095] hexasonium iodide [R=(e); n=1; m=1; X=1,2-ethylene; R.sub.1=phenyl; R.sub.2=cyclohexyl; R.sub.3=H]; and [0096] oxysonium iodide [R=(e); n=1; m=1; X=1,2-ethylene; R.sub.1=phenyl; R.sub.2=cyclohexyl; R.sub.3OH.

[0097] Azoniaspiro[3-benziloyloxy-(1,5)-nortropane-8,1-pyrrolidine] chloride (formula II, A+A=1,4-butylene) described in U.S. Pat. No. 3,480,626, known under its International Non-proprietary Name trospium chloride, the tartrate, maleate, fumarate and succinate salts of trospium, solifenacin, described in U.S. Pat. No. 6,017,927 and the compound thereof with succinic acid, propiverine, described in DD 106643, and the hydrochloride thereof, oxyphencyclimine, described in GB 795758, and the hydrochloride thereof, tolterodine, described in U.S. Pat. No. 5,382,600, and the hydrogen tartrate thereof are the preferred nsPAChAs. Other pharmaceutical acceptable salts of trospium, in particular those with succinic and tartaric acids, are cited in US 2006/0293356. Trospium is a long-acting nsPAChA whose absorbed amount has an average plasma half life of about 18 hours.

[0098] The fact that nsPAChAs allow the increase of the maximal tolerated, therapeutic doses of the AChEIs from a randomized, controlled safety, tolerability, pharmacokinetic and pharmacodynamic study of an AChEI agent alone, such as rivastigmine, and with a nsPAChA, such as trospium chloride, in normal volunteers.

[0099] Standard approved oral dosage forms of both rivastigmine [as hydrogen-(2R,3R)-tartrate] and trospium chloride (simply named trospium in the study) are used. Trospium placebo tablets are essentially identical in appearance to standard trospium tablets. All drugs are administered orally, once daily in the morning.

[0100] The primary objective of the study is to determine the maximum tolerated dose (MTD) of the representative AChEI rivastigmine as monotherapy, i.e. when rivastigmine is administered alone orally at daily doses ranging from 3 mg to 36 mg, and as combination therapy, i.e. when rivastigmine is administered together with orally administered, representative nsPAChA trospium at daily doses of 20 or 40 mg.

[0101] The secondary objective of the study is to determine the ability of trospium to affect EEG activity when given with the MTD of rivastigmine.

[0102] This is a randomized, blinded, placebo-controlled, cross-over and parallel groups, rising-dose, non-therapeutic study conducted on 36 subjects at a single center, during up to 14 days. Medical procedures including clinical history, physical examination, vital signs and laboratory tests are performed at screening, at regular prespecified intervals throughout the study, and at a follow up visit 7 days after last drug administration. An EEG is obtained 5 hours after administration of the first and last trospium dose. During the study, single daily doses of rivastigmine or rivastigmine placebo and trospium or trospium placebo are both administered orally at 8 AM. All subjects are maintained nothing per os (NPO) for the preceding 8 hours and until 4 hours after drug administration. Daily doses of rivastigmine hydrogen tatrate begin at 3 mg and may range up to 36 mg (in rivastigmine base) in small increments, as deemed clinically appropriate; daily doses of trospium begin at 20 mg and may increase to 40 mg, as clinically appropriate.

[0103] The subjects are aged 18 to 80 years, inclusive, who are considered in good general health. No concomitant medications are allowed, except those known to neither enter the central nervous system nor affect cholinergic function peripherally and given at stable doses throughout the study.

[0104] Safety and tolerability are evaluated based on clinical adverse experiences (AEs), vital signs (sitting systolic and diastolic blood pressure; radial pulse rate), 12-lead ECG, laboratory tests including urinalysis, and physical examination. Specifically in relation to rivastigmine AEs, the following are always evaluated: anorexia, nausea, vomiting. In relation to trospium AEs, the following are always evaluated: dry mouth, constipation, dyspepsia, abdominal pain, blurred vision, headache, dizziness, somnolence and confusion.

[0105] For pharmacokinetic evaluation, venous blood samples are drawn on Study Days when rivastigmine is given at its MTD as monotherapy and when rivastigmine is given at its MTD with trospium (nominally on Study Days 5 and 11) to measure serum concentrations of both drugs 75 minutes after their oral administration.

[0106] The analysis of primary and secondary objective measures is performed both in the intent-to-treat (ITT) population and in study completers. The ITT population includes all the randomized subjects who have received all baseline assessments and at least one post-randomization assessment.

[0107] For the intended use, the nsPAChA is formulated in pharmaceutical compositions comprising, as an active ingredient thereof, said nsPAChA in admixture with a pharmaceutical carrier.

[0108] The nsPAChA is present in an amount that reduces peripherally mediated adverse effects that would be caused by the administration of a dose of AChEI sufficient to maximally alleviate disease-associated dementia and other neurobehavioral symptoms.

[0109] Thus, according to another of its aspects, the present invention provides a pharmaceutical composition for inducing a higher acetyl choline esterase inhibition in the CNS of a patient suffering from Alzheimer type dementia, said patient taking a dose of acetyl choline esterase inhibitor (AChEI) higher than the maximal tolerated dose, comprising, as an active ingredient, a non-selective, peripheral anticholinergic agent (nsPAChA) in admixture with a pharmaceutical carrier. By such an induction of higher acetyl choline esterase inhibition, not otherwise attainable when AChEIs are taken alone, the symptoms of Alzheimer type dementia in said patients are thus further improved.

[0110] Advantageously, these pharmaceutical compositions comprise the nsPAChA active ingredient in an amount of from 20% to 200% of the dosage used in the compositions currently used for the treatment of disorders such as gastro-intestinal cramping, bladder spasms, asthma, motion sickness, muscular spasms, and smooth muscle contractive disorders. The compositions prepared using the nsPAChAs according to the present invention allow the administration of 1.5- up to 4-times the maximal tolerated dose of AChEI to patients suffering of Alzheimer type dementia without clinically significant symptoms of peripheral cholinergic system overstimulation.

[0111] The compositions are preferably formulated in dosage unit forms for oral or parenteral, in particular transdermic, administration, wherein the active ingredient is mixed with a pharmaceutical carrier.

[0112] The pharmaceutical compositions prepared using the nsPAChAs according to the present invention are indicated in the treatment of the symptoms of Alzheimer type dementias in order to improve to a greater extent said symptoms by allowing an increase of the currently used doses of an AChEI, concurrently or sequentially administered therewith, without the side-effects that would hinder said increase of said therapeutic doses.

[0113] Preferred pharmaceutical compositions for oral administration using trospium chloride as preferred active ingredient may contain from 4 to 40 mg, preferably from 10 to 40 mg, of said active ingredient in IR formulations or from 15 to 120 mg, preferably from 30 to 120 mg, in ER formulations. Said preferred pharmaceutical compositions allow the concurrent or sequential administration of, for example, from 5 to 40 mg of donepezil hydrochloride, from 3 to 20 mg of rivastigmine tartrate or from 8 to 40 mg of galantamine without appreciable side-effects.

[0114] According to an advantageous embodiment, the pharmaceutical compositions prepared by using the nsPAChAs according to the present invention are present in unit forms also containing other active ingredients, in particular an AChEI which acts as cholinergic agent in the CNS to improve the symptoms of Alzheimer type dementia, in a quantity sufficient to maximally alleviate disease-associated neurobehavioral symptoms, with minimum of treatment-associated adverse effects. Thus, it is another object of the present invention to provide a pharmaceutical unit form which comprises [0115] (a) a nsPAChA selected from the group consisting of solifenacin, pharmaceutically acceptable salts of solifenacin, propiverine, pharmaceutically acceptable salts of propiverine, oxyphencyclimine, pharmaceutically acceptable salts of oxyphencyclimine, tolterodine, pharmaceutically acceptable salts of tolterodine and quaternary ammonium or sulfonium compounds of formula II

##STR00004##

wherein [0116] R is a radical selected from the group consisting of those of formulas (a)-(e)

##STR00005## [0117] A being methyl and A being (C.sub.1-C.sub.4)alkyl or 2-fluoroethyl group or A and A forming a 1,4-butylene or 1,5-pentylene chain, L being hydrogen or methoxy, Alk and Alk each being (C.sub.1-C.sub.4)alkyl and Y being a bivalent radical selected from the group consisting of 1,2-ethylene, 1,3-propylene, 1,4-butylene and 2-oxa-1,3-propylene; the corresponding counter ion being a pharmaceutically acceptable anion; [0118] n and m, independently, are zero or 1; [0119] X is a (C.sub.2-C.sub.3)alkylene group; [0120] R.sub.1 and R.sub.2 are each phenyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 2-thienyl and, when R is a radical (a), also each represents (C.sub.1-C.sub.4)alkyl; [0121] R.sub.3 is H or OH or, only when R is a radical (a), also a COOAlk group, Alk being a (C.sub.1-C.sub.4)alkyl group; and [0122] (b) an AChEI;
in admixture with at least a pharmaceutical carrier.

[0123] The pharmaceutical composition to improve the treatment of human dementias of the Alzheimer type according to the present invention may comprise a mixture of a nsPAChA [component (a)] and of an AChEI [component (b)], wherein component (b) is present in a quantity sufficient to maximally alleviate disease-associated neurobehavioral symptoms and wherein component (a), which does not appreciably penetrate the blood brain barriers, is present in a second quantity that reduces peripherally mediated adverse effects that would be caused by the AChEI if administered without the accompanying nsPAChA.

[0124] Advantageous nsPAChAs are solifenacin and its salts, propiverine and its salts, oxyphencyclimine and its salts and quaternary ammonium salts or sulfonium salts of formula II above, such as homatropine quaternary salts, anisotropine quaternary salts, trospium quaternary salts, clidinium quaternary salts, benzilonium quaternary salts and glycopyrronium quaternary salts.

[0125] Preferred component (a) is a pharmaceutically acceptable salt of trospium, especially trospium chloride, succinate, maleate, fumarate or tartrate, a pharmaceutically acceptable salt of solifenacin, especially its compound with succinic acid 1:1, a pharmaceutically acceptable salt of propiverine, especially its hydrochloride, a pharmaceutically acceptable salt of oxyphencyclimine, especially its hydrochloride or a pharmaceutically acceptable salt of tolterodine, especially its L-hydrogen tartrate.

[0126] Advantageous components (b) are 1,2,3,4-tetrahydro-9-acridinamine (tacrine), 9-amino-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinoline (ipidacrine); ()-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one (donepezil) and its pharmaceutically acceptable salts, (S)N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate (rivastigmine) and its pharmaceutically acceptable salts, 4aS,6R,8aS-3-mthoxy-11-methyl-4a,5,9,10,11,12-hexahydroxy-6H-benzofuro[3a,3,2-e,f]benzazepin-6-ol (galantamine); (1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0.sup.2,7]trideca-2(7),3,10-trien-5-one (huperzine A) and phenserine and its analogs encompassed by the general formula I.

[0127] Advantageous AChEIs include those now part of standard care for patients suffering from a dementia of the Alzheimer type and that are also widely used off-label for various other chronic progressive disorders of cognitive function. AChEIs have as a general mechanism of action the enhancement of acetylcholine-mediated neurotransmission. All act in the human CNS to increase and prolong the availability of acetylcholine by inhibiting its degradatory enzyme acetylcholinesterase, such as donepezil; pharmaceutically acceptable salts of donepezil, especially the hydrochloride thereof; icopezil, pharmaceutically acceptable salts of icopezil, especially the maleate thereof, zanapezil, pharmaceutically acceptable salts of zanapezil, especially the fumarate thereof, rivastigmine; pharmaceutically acceptable salts of rivastigmine, especially the hydrogen tartrate thereof; galantamine; pharmaceutically acceptable salts of galantamine; Huperzine A.

[0128] Preferred component (b) is an AChEI selected from the group consisting of tacrine; huperzine A, donepezil hydrochloride; the hydrogen-(2R,3R)-tartrate of rivastigmine (rivastigmine tartrate); galantamine, the last three compounds being particularly preferred. As set forth above, these AChEIs vary in their pharmacological profiles and in their affinities for AChE and butyrylcholinesterase.

[0129] The dose of the component (b) may vary according to intrinsic acetylcholine esterase inhibiting potency of said component. Advantageously, said dose is from 1.5-fold to 4-times higher than the maximal tolerated one currently used when the same AChEI is administered alone.

[0130] In the unit forms of the present invention, for immediate release or extended release, the nsPAChA component (a) is present in an amount of from 20% to 600% of the amount of said nsPAChA contained in the currently administered IR dosage unit forms for the treatment of disorders such as gastrointestinal cramps, urinary bladder spasm, asthma, motion sickness, muscular spasms and the AChEI component (b) is present in an amount of from 100% to 600% of the amount of said AChEI contained in the currently administered IR dosage unit forms for the treatment of Alzheimer type dementia.

[0131] More particularly, the nsPAChA is present, in an IR unit form, in an amount ranging from 20% to 200% of the amount of said nsPAChA contained in the currently administered IR dosage unit forms for the treatment of the above-cited disorders or, in an ER unit form, in an amount ranging from 75% to 600% of the amount of said nsPAChA contained in the currently administered unit dosage IR forms for the treatment of the above-cited disorders. For example, trospium chloride, which is a preferred anticholinergic agent used as component (a), is present in an amount of from 4 mg to 120 mg per dosage unit, in particular from about 4 to about 40 mg, preferably from 10 to 40 mg, per dosage unit in an IR unit form or in an amount of from 15 to 120 mg, preferably from 30 to 120 mg, in an ER unit form, i.e. in amount of from 20% to 600% of the amount of trospium chloride which is present in IR unit forms for the treatment of overactive bladder.

[0132] In unit form for immediate release or extended release, the AChEI component (b) is present in an amount of from about 100% to about 600% of the amount of said AChEI contained in the currently administered IR dosage unit forms for the treatment of Alzheimer type dementia.

[0133] More particularly, the AChEI component (b) is present in an IR unit form, in an amount ranging from about 100% to about 400%, preferably from 150% to 400%, of the amount of said AChEI contained in the currently administered IR dosage unit forms for the palliative treatment of Alzheimer type dementia or, in an ER unit form, in an amount ranging from 150% to 600%, preferably from 200% to 600%, of the amount of said AChEI contained in the currently administered unit dosage IR forms for the treatment of Alzheimer type dementia. For example, among the preferred components (b), donepezil hydrochloride is present in an amount of from 5 mg to 60 mg, preferably from 7.5 to 60 mg, per dosage unit, rivastigmine, as the hydrogen tartrate thereof, is present in an amount of from 1.5 mg to 36 mg, preferably from 2.25 mg to 36 mg per dose unit, galantamine is present in an amount of from 4 to 72 mg per dose unit. Huperzine A is present in an amount of from 100 g to 1.2 mg, preferably from 150 g to 1.2 mg per dose unit.

[0134] Advantageously, said AChEI can be administered in a dose that is higher than the maximal tolerated dose of the same AChEI when administered alone and will preferably be from 1.5 to 4 times higher than the currently recommended doses in the treatment of Alzheimer type dementia.

[0135] The unit form of the present invention may be a tablet, a capsule, a pre-measured volume of a liquid solution or suspension for oral administration or a patch for transdermal application. In said unit form the nsPAChA and the AChEI may be mixed together or separated according to known technologies in admixture with a pharmaceutical carrier in a pharmaceutical composition.

[0136] Component (a) and component (b) are formulated with conventional pharmaceutical carriers in known formulations for oral use wherein said components are mixed together or separated, for example in two tablets introduced in a capsule or in a two-compartment capsule or in a multilayer (di-layer) tablet wherein the two components are both in IR or in ER form or one of the two components is in IR form and the other is in ER form, according to known technologies.

[0137] The pharmaceutical carriers and vehicles are those commonly used for the preparation of compositions for oral, buccal and parenteral, in particular transdermal, administration. Appropriate unit forms comprise the oral forms such as tablets, soft or hard gelatine capsules, powders or granulates in sachets and suitably measured oral solutions or suspensions as well as patches for transdermal administration.

[0138] Component (a) and component (b) may also be present in form of one of their complexes with a cyclodextrin, for example -cyclodextrin, -cyclodextrin, -cyclodextrin, 2-hydroxypropyl--cyclodextrin or methyl--cyclodextrin.

[0139] Component (a) and component (b) may also be formulated in the form of microcapsules, optionally with one or more carriers or additives.

[0140] For oral administration, component (a) and component (b), together or separately, are formulated by mixing the active ingredient with conventional pharmaceutical acceptable carriers enabling said active ingredients to be formulated in tablets, dragees, orally disintegrating tablets, capsules, liquid solutions or suspensions, syrups and the like.

[0141] Carriers for IR tablets include for example starches, cellulose and derivatives thereof; lubricants such as talc, stearic acid or magnesium stearate; diluents such as talc, powdered cellulose, lactose, starches such as maize or corn starch, mannitol, sorbitol; disaggregating agents such as microcrystalline cellulose or crospovidone; lubrifiants such as polyethylenglycol or magnesium stearate; ligands such as methylcellulose, sodium carboxymethylcellulose, alginic acid, alginates; sweeteners, such as saccharose, dextrose, mannitol, saccharin; or flavoring agents such as natural or synthetic oils.

[0142] Carriers for orally disintegrating tablets include for example lubricants, aggregating, sweetening, flavoring or disaggregating agents as well as agents improving the buccal mucosa absorption of components (a) and (b) such as sorbitol, mannitol, lactose and cellulose.

[0143] Carriers for liquid, normally aqueous, suspensions or solutions include for example antioxidants, such as sodium metabisulfite or sodium sulfite, thickening agents, such as microcrystalline cellulose, hydroxypropylcellulose, carboxymethylcellulose or polyvinylpyrrolidone, presevatives such as methyl paraben, ethyl paraben, sodium ethylenediaminotetracetate, sodium benzoate or an alkaline salt of sorbic acid, as well as flavoring and sweetening agents.

[0144] The sweeteners contained in the orally disintegrating tablets and the liquid suspensions or solutions may be natural, optional reduced sugars such as sucrose, dextrose, xylitol, mannitol or sorbitol, or synthetic product such as sodium saccharine or aspartame.

[0145] The flavoring agents are pharmaceutically acceptable flavors and tastes of synthetic and natural oils, the latter extracted from plants, leaves, flowers, fruits and their combinations, such as cinnamon, peppermint, anise and citron leaves, bitter almond, citrus fruits, in particular orange and/or lemon, linden and grapefruit oils. Also chocolate, vanilla or eucalyptus flavor and essences of fruit, in particular apple, pear, peach, strawberry, cherry, apricot, orange, lemon and grapes may be advantageously used.

[0146] The composition according to the present invention may be in form of a capsule containing two tablets as described herein above, one of them comprising component (a) and the other comprising component (b).

[0147] The association nsPAChA/AChEI may be formulated in tablets in which one or both of the two components is in controlled-release formulation, for example as a dispersion of said component in hydroxypropyl methyl cellulose or in a film-coated microgranule. Advantageously, the AChEI, in a ER-formulation is in the core and the nsPAChA, in IR-formulation, is in the outer layer in multi-layer tablets in which, for example, both the core and the outer layer are coated with a film. Analogously, capsules made of two separated parts, one containing component (a), in IR- or ER-formulation and the other containing component (b), in IR- or ER-formulation, may be used

[0148] Carriers and vehicles for ER tablets include retardant materials such as is acrylic and methacrylic acid polymers and copolymers; cellulose derivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylethylcellulose, hydroxypropylcelluloses, methylcellulose, ethylcellulose, or sodium carboxymethylcellulose; gums; waxes; glycerides or aliphatic alcohols or a mixture thereof.

[0149] In particular, the unit forms of the present invention comprise a pharmaceutically acceptable salt of trospium as a nsPAChA and a member selected from the group consisting of tacrine, in an amount of from 10 mg to 160 mg, donepezil and its pharmaceutically acceptable salts, in an amount of from 5 mg to 40 mg, rivastigmine and its pharmaceutically acceptable salts, in an amount of from 1.5 to 36 mg, galantamine, in an amount of from 4 to 48 mg, and huperzine A, in an amount of from 100 g to 1.2 mg as an AChEI.

[0150] According to an embodiment, the compositions of the present invention are formulated by mixing the component (a) and the component (b) together, in admixture with a pharmaceutical carrier for an immediate or extended release. An advantageous composition according to this embodiment comprises from 4 to 40 mg of trospium chloride, as component (a); and [0151] from 5 to 50 mg of donepezil (as hydrochloride); or [0152] from 1.5 to 30 mg of rivastigmine (as hydrogen tartrate); or [0153] from 4 to 60 mg of galantamine,
as component (b), wherein components (a) and (b) are mixed together and with a pharmaceutical carrier in an IR-formulation, said composition being destined to be administered once or twice per day.

[0154] According to another embodiment, the compositions of the present invention are formulated by mixing the component (a) with a pharmaceutical carrier for an immediate or extended release in tablets (Tablet A) and the component (b), separately, with a pharmaceutical carrier for an immediate or extended release in tablets (Tablet B) and introducing Tablet A and Tablet B in a capsule for oral administration as described for example in GB 1204580 or in US 2007/0224259. An advantageous composition according to this embodiment consists of soft or hard gelatine capsules each containing Tablet A comprising from 4 to 40 mg of trospium chloride, as component (a); in admixture with a pharmaceutical carrier in a IR formulation; and

Tablet B, comprising [0155] from 5 to 50 mg of donepezil (as hydrochloride); or [0156] from 1.5 to 30 mg of rivastigmine (as hydrogen tartrate); or [0157] from 4 to 50 mg of galantamine,
as component (b), with a pharmaceutical carrier in an IR-formulation said composition being destined to be administered once or twice per day.

[0158] According to a further embodiment, the compositions according to the present invention are formulated in a di-layer tablet which releases two drug doses, in which the release of a drug from one drug-containing layer does not interfere with the release of a drug from the other drug-containing layer as described for example in WO 2006/089493. An advantageous composition according to this embodiment consists of [0159] Layer A, comprising from 4 to 40 mg of trospium chloride, as component (a), with a pharmaceutical carrier in a IR formulation and [0160] Layer B, comprising 4 to 60 mg of galantamine,
as component (b), in admixture with a pharmaceutical carrier in an IR-formulation, said composition being destined to be administered once or twice per day.

[0161] According to another embodiment, the compositions of the present invention are formulated in oral disintegrable tablets. Particularly advantageous compositions according to this embodiment are orally disintegrable tablets comprising [0162] from 4 to 40 mg of trospium chloride, as component (a); and [0163] from 5 to 50 mg of donepezil hydrochloride, as component (b),
in admixture with a pharmaceutical carrier in an IR-formulation for buccal mucosa absorption, said composition being destined to be administered once per day.

[0164] According to another embodiment, the compositions of the present invention are formulated in solutions for oral administration wherein component (a) and component (b) are dissolved or suspended in water in admixture with conventional carrier or vehicles. Particularly advantageous compositions according to this embodiment are oral solutions or suspensions comprising [0165] from 4 to 40 mg of trospium chloride, as component (a); and [0166] from 4 to 50 mg of galantamine, as component (b),
in admixture with a pharmaceutical carrier in a liquid IR-formulation for oral administration, said composition being destined to be administered once or twice per day.

[0167] According to another embodiment, the compositions of the present invention are formulated in patch for transdermal administration. Particularly advantageous compositions according to this embodiment are transdermal patch formulations comprising [0168] from 4 mg/24 hours to 120 mg/24 hours of trospium chloride, as component (a); and [0169] from 4.6 mg/24 hours to 30 mg/24 hours of rivastigmine (as hydrogen tartrate), as component (b),
with a pharmaceutically acceptable carrier or diluent which is suitable for systemic transdermal administration.

[0170] Another embodiment of the present invention provide units forms consisting of tablets comprising [0171] from 5 to 15 mg of solifenacin succinate, as component (a); and [0172] from 4 to 50 mg of galantamine, as component (b),
in admixture with a pharmaceutical carrier in a IR-formulation for oral administration, said composition being destined to be administered once or twice per day.

[0173] As compared to known drugs of the acetylcholine esterase inhibitor type now used alone in the treatment of Alzheimer type dementias, the above combined pharmaceutical composition shows greater and longer efficacy and less adverse effects by allowing the safe and tolerable administration of larger and thus more therapeutically effective quantities of said acetylcholine esterase inhibitor. In particular, the acetylcholine esterase inhibitor of the pharmaceutical compositions of the present invention is safe and effective, alone or in combination with other pharmaceuticals, in treating patients in need of an acetylcholine esterase inhibition, in particular dementias of the Alzheimer type on a once or twice daily basis.

[0174] The pathologic conditions treated with the composition of the present invention include, but are not limited to, Alzheimer's disease, Parkinson's disease dementia, and other disorders of human cognitive and neurobehavioral function that are treated, in part, by pharmaceuticals intended to augment brain acetylcholine-mediated neurotransmission.

[0175] The therapeutic efficacy is measured by the degree to which cognitive and other neurobehavioral disabilities associated with dementias of the Alzheimer type, as documented by the use of standard scales, are reduced.

[0176] The following examples illustrate the invention.

EXAMPLE 1

[0177] Orally Disintegrating Tablets Containing 15 mg of Donepezil Hydrochloride and 20 mg of Trospium Chloride.

[0178] One and a half kilogram of donepezil hydrochloride and 1.8 kg of corn starch are mixed thoroughly until complete homogenizing of the mixture which, after a passage through a 35 mesh sieve, is added with a previously prepared mixture of 2 kg of trospium chloride, thoroughly stirred together with 2.4 kg of corn starch and sieved at 35 mesh. The mixture thus obtained is added with 0.6 kg of strawberry flavor powder, 0.2 kg of sodium saccharin, 13.08 kg of lactose, 4.4 kg of microcrystalline cellulose, and 2.9 kg of sorbitol. The mixture is mixed until complete homogenization, then it is added with 0.1 kg of magnesium stearate, mixed again and compressed with punches of 7 mm to obtain 100,000 orally disintegrating tablets having the following composition

TABLE-US-00001 Donepezil hydrochloride 15.00 mg Trospium chloride 20.00 mg Corn starch 42.00 mg Strawberry flavor powder 6.00 mg Sodium saccharin 2.00 mg Lactose 130.00 mg Microcrystalline cellulose 44.00 mg Sorbitol 29.00 mg Magnesium stearate 1.00 mg

EXAMPLE 2

[0179] Capsules for Oral Administration are Prepared by Mixing the Following Ingredients:

TABLE-US-00002 Ingredients Parts by weight Rivastigmine (as hydrogen tartrate) 900 Trospium chloride 2.000 Lactose USP 7.350 Colloidal silicon dioxide (Aerosil) 50

[0180] After mixing, the mixture is screened through a 40 mesh screen and introduced in two-piece hard gelatine capsule No. 3 containing 9 mg of rivastigmine and 20 mg of trospium chloride

EXAMPLE 3

[0181] Immediate release tablets for oral administration are prepared by mixing 1.8 kg of galantamine and 2.0 kg of trospium chloride, 0.25 kg of gelatin, 0.25 kg of magnesium stearate and 10 kg of corn starch and forming the mixture into tablets containing 18 mg of galantamine and 20 mg of trospium chloride by a conventional tableting machine.

EXAMPLE 4

[0182] An oral liquid composition is prepared in a blender equipped with a blade stirrer, wherein 1800 g of galantamine and 5 kg of deionized water are added. The temperature is maintained at 40 C. and the mixture is vigorously stirred until complete solution. The temperature is brought to 25 C., then 20.22 g of potassium sorbate, 44.11 g of sodium metabisulfite and 147 g of commercial strawberry flavoring agent are added. Stirring is continued at room temperature until a clear solution is obtained. The temperature of the obtained solution is brought to 20 C. and added with a previously prepared solution containing 2757 g of xylitol, 2000 g of trospium chloride and 18.38 g of microcrystalline cellulose in 4.41 kg of deionized water. After a gentle stirring to obtain a complete dispersion, the solution thus obtained is passed through a sieve 1.5 mesh. Thus, about 15 kg of a solution are obtained, to be introduced in 1500 unit doses of the following composition

TABLE-US-00003 Galantamine 18.00 mg Trospium chloride 20.00 mg Sodium metabisulfite 4.40 mg Potassium sorbate 2.02 mg Xylitol C 27.57 mg Strawberry flavoring agent 80.00 mg Microcrystalline cellulose 10.00 mg Deionized water to 10,000.00 mg

EXAMPLE 5

[0183] Tablets containing 4 mg of galantamine formulated with a pharmaceutical carrier, tablets containing 12 mg of galantamine formulated with a pharmaceutical carrier and tablets containing 20 mg of trospium chloride formulated with a pharmaceutical carrier are distributed in capsules as described in GB 1,254,580, such that unit dosage forms containing 16 mg of galantamine and 20 mg of trospium are prepared. In the same manner, unit dosage forms containing 8 mg of galantamine formulated with a pharmaceutical carrier, tablets containing 20 mg of galantamine formulated with a pharmaceutical carrier and tablets containing 20 mg of trospium chloride formulated with a pharmaceutical carrier are prepared.

EXAMPLE 6

[0184] By operating as described in Example 1, but using 1.5 Kg of propiverine hydrochloride instead of 2 Kg of trospium chloride, orally disintegrating tablets having the following composition are obtained

TABLE-US-00004 Donepezil hydrochloride 15.00 mg Propiverin hydrochloride 15.00 mg Corn starch 42.00 mg Strawberry flavor powder 6.00 mg Sodium saccharin 2.00 mg Lactose 130.00 mg Microcrystalline cellulose 44.00 mg Sorbitol 29.00 mg Magnesium stearate 1.00 mg