US 20110201597A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0201597 A1 CHASE et al. (43) Pub. Date: Aug. 18, 2011

(54) METHOD AND COMPOSITION FOR Publication Classification TREATING ALZHEIMER-TYPE DEMENTA (51) Int. Cl. (76) Inventors: Thomas N. CHASE, Washington, A6II 3/55 (2006.01) DC (US); Kathleen E. A6II 3/445 (2006.01) CLARENCE-SMITH, A6IP 25/28 (2006.01) Washington, DC (US) (52) U.S. Cl...... 514/215: 514/319 (21) Appl. No.: 13/051,181 (57) ABSTRACT (22) Filed: Mar. 18, 2011 There is described a method for increasing the maximal tol erated dose and thus the efficacy of an acetylcholinesterase Related U.S. Application Data inhibitor (AChEI) in a patient suffering from an Alzheimer type dementia by decreasing concomitant adverse effects by (63) Continuation-in-part of application No. 12/880,395, administration of said AChEI in combination with a non filed on Sep. 13, 2010, Continuation-in-part of appli anticholinergic antiemetic agent, whereby an enhanced ace cation No. PCT/US2010/002475, filed on Sep. 13, tylcholinesterase inhibition in the CNS of said patient is 2010, Continuation-in-part of application No. 12/934, achieved and alleviation of the symptoms of Alzheimer type 140, filed on Sep. 23, 2010, filed as application No. dementia in said patient is thereby improved to a greater PCT/US09/01662 on Mar. 17, 2009. extent. The use of a non-anticholinergic antiemetic agent for (60) Provisional application No. 61/272.382, filed on Sep. the preparation of a pharmaceutical composition for the treat 18, 2009, provisional application No. 61/272.382, ment of Alzheimer type dementia in combination with an acetylcholinesterase inhibitor (AChEI) and pharmaceutical filed on Sep. 18, 2009. compositions comprising (a) a 5HT receptor antagonist, a (30) Foreign Application Priority Data dopamine antagonist, a H1-receptor antagonist, a cannab inoid agonist, aprepitant or casopitant as an antiemetic agent Mar. 27, 2008 (EP) ...... 08005750.8 and (b) an acetylcholinesterase inhibitor are also described. US 2011/02O 1597 A1 Aug. 18, 2011

METHOD AND COMPOSITION FOR central nervous system (CNS) characterized by progressive TREATING ALZHEMER-TYPE DEMENTA cognitive impairment, a variety of neurobehavioral and/or neuropsychiatric disturbances, and restrictions inactivities of CROSS REFERENCE TO RELATED daily living. APPLICATIONS 0005 Alzheimer's disease is the most common form of 0001. This application is a continuation-in-part of U.S. dementia. Prevalence studies indicated that in 2000 there application Ser. No. 12/880,395, filed on Sep. 13, 2010, tak were about 25 million persons with Alzheimer's disease ing benefit from U.S. Provisional Application No. 61/272, worldwide and this number is expected to increase to 114 382, filed on Sep. 18, 2009, which are incorporated herein in million by 2050 unless an effective preventive or neuropro their entirety. This application also is a continuation-in-part tective therapy emerges. Onset usually occurs in those over of the PCT/US2010/002475 Application filed on 13 Sep. age 65. Clinical signs include progressive cognitive loss and 2010, taking benefit from U.S. Provisional Application No. other associated neurobehavioral disabilities together with a 61/272.382 filed on Sep. 18, 2009. This application also is a declining capability of performing the activities of daily liv continuation-in-part of U.S. application Ser. No. 12/934,140 ing. which is the US national phase of PCT/US09/01662 filed on 0006. The basic cause of sporadic Alzheimer's disease is 13 Mar. 2009, taking benefit from EP Application No. not known, probably because the disease is heterogeneous 08005750.8 filed on Mar. 27, 2008. and involves age-related changes together with a complex interaction of genetic and environmental risk factors. Current FIELD OF THE INVENTION hypotheses advanced to explain the pathophysiology of Alzheimer's disease center on the putative deleterious effects 0002 This invention concerns a method for enhancing the of the two misfolded and aggregated proteins, extracellular maximal efficacy and maximal tolerated dose of an acetyl beta amyloid and intracellular tau. Presumably, as a conse cholinesterase inhibitor in a patient Suffering from dementia quence of the selective neurodegenerative process, the Syn of the Alzheimer type by combining said acetylcholinsterase thesis of the neurotransmitter acetylcholine declines. This inhibitor with an antiemetic agent, or the use of an antiemetic reduction undoubtedly interferes with normal synaptic trans agent Substantially devoid of central anticholinergic activity mission in brain. Drugs that act to correct the acetylcholine for the preparation of pharmaceutical compositions for the deficiency thus constitute the mainstay of current therapy. treatment of Alzheimer type dementias in combination with 0007 Dementias of the Alzheimer type also include cog an acetylcholinesterase inhibitor (AChEI). The invention also nitive impairments associated with Parkinson's disease. One concerns pharmaceutical compositions comprising an anti example is Parkinson's disease dementia, also a chronic pro emetic agent, in particular a serotonin 5HT receptor antago gressive CNS degenerative disorder with relatively late life nist compound in association with an acetylcholinesterase onset, Parkinson's disease itself primarily affects motor func inhibitor to allow increasing and prolonging efficacy and tion. But secondary symptoms include cognitive deteriora decreasing toxicity of these conventional cholinomimetic tion, especially deficits in executive function. treatments such as treatments for dementias in diseases of the 0008 Another dementia of the Alzheimer type that is com Alzheimer type. monly linked to Parkinson's disease is known as dementia with Lewy bodies or Lewy body dementia. Although Lewy DEFINITIONS body dementia is now generally regarded as a separate dis ease, differentiation from Alzheimer's disease and from Par “AChEI(s)''': Acetyl Choline Esterase Inhibitor(s). kinson's disease dementia may be clinically challenging. “CNS: Central Nervous System. Lewy body dementia thus tends to be under-diagnosed or “PNS: Peripheral Nervous System. misdiagnosed as Alzheimer's disease or Parkinson's disease 0003 “IR”: Immediate Release of the active ingredient dementia. The clinical presentation of Lewy body dementia is from a composition. typically one of cortical and Subcortical cognitive impair “ER': Extended Release (including slow release) of the ment, with visuospatial and executive dysfunction more pro active ingredient from a composition. nounced than in Alzheimer's disease. Core clinical features of “Non-anticholinergic' refers to antiemetic medications not primarily regarded as anticholinergic agents; they are entirely Lewy body dementia, in addition to parkinsonism, are cog devoid of anticholinergic activity or have an extremely low nitive decline plus fluctuations in attention and recurrent ability to prevent acetylcholine from acting at its cholinergic visual hallucinations. 0009. Both Parkinson's disease dementia and Lewy body receptor sites. dementia are characterized neuropathologically by the pres “MTD': maximum (or maximal) tolerated dose, i.e. the high ence of cortical Lewy body pathology and Synuclein protein est dose of a drug or treatment that does not cause unaccept deposition. Genetic factors appear to play a role in pathogen able side effects. The maximum tolerated dose is determined esis. Not Surprisingly, the pathology of Parkinson's disease in clinical trials by testing increasing doses on different dementia and Lewy body dementia is heterogeneous and groups of people until the highest dose with acceptable side overlapping, often intermixed with changes of the Alzheimer effects is found (NCI Drug Dictionary). and vascular types. A reduction in brain acetylcholine-medi ated neurotransmission has been linked to the primary clini BACKGROUND OF THE INVENTION cal abnormalities found in both these disorders and drugs 0004 Dementias of the Alzheimer type include, but are acting to stimulate cholinergic transmission now constitute not limited to Alzheimer's disease, Parkinson's disease the main approach to therapy. dementia, and related maladies in humans involving cogni 0010. In addition to the aforementioned disorders, the off tive and behavioral dysfunction such as Lewy body dementia. label administration of drugs that augment CNS cholinergic Most are chronic neurodegenerative disorders of the human transmission for various other cognitive disorders is wide US 2011/02O 1597 A1 Aug. 18, 2011

spread. Some of this use involves cognitive disorders for efficacy can be measured by the degree of improvement in which relatively little clear evidence of cholinergic dysfunc cognitive dysfunction and other neurobehavioral abnormali tion currently exists. Nevertheless, an increasing number of ties associated with these disorders using standardized scales. clinical studies now support a rational extension of AChEI 0016. Unfortunately, however, none of the currently avail treatment to various additional disorders of cognitive func able cholinomimetic medications offers more than modest tion, including but not limited to, vascular dementia, Down clinical benefit for some patients suffering from any of the syndrome, traumatic brain injury and mild cognitive impair aforementioned dementing disorders, even when these medi ment. cations are administered at their maximum safe and tolerated 0011. As noted above, reduced levels of neurotransmitters doses. This is the first problem limiting the success of current including acetylcholine have been reported in dementias of AChEI therapy of Alzheimer type dementias. the Alzheimer type and related disorders. In particular, a 0017 Carefully conducted clinical trials of donepezil at a deficit in acetylcholine-mediated transmission is thought to dose of 5 mg to 10 mg per day (Rogers et al., Neurology 1998, contribute to the cognitive and certain of the neurobehavioral 50, 136-45: Winbladet al. Neurology. 2001 Aug. 14: 57(3): abnormalities associated with these disorders. Accordingly, 489-95), rivastigmine at doses of 1 mg to 4 mg and 6 mg to 12 drugs known to augment cholinergic transmission in the CNS mg per day (Rosier et al., Brit. Med. J. 1999, 318, 633-38: are widely used in therapy. Farlow etal. Eur. Neurol., 2000, 44, 236-41) and galantamine 0012 AChEIs are now part of the standard care for at doses ranging between 8 mg to 32 mg per day, usually patients suffering from a dementia of the Alzheimer type and between 16 mg to 24 mg per day (Raskind et al., Neurology, are widely used off label for various other chronic progressive 2000, 54, 2261-68; Tariot et al., Neurology, 2000, 54, 2269 disorders of cognitive function. AChEIs have the enhance 76) in patients with dementias of the Alzheimer type demon ment of acetylcholine-mediated neurotransmission as a gen strated Small, but statistically significant, benefits on cogni eral mechanism of action. All act in the human CNS to tive and global measures relevant to dementia. The magnitude increase and prolong the availability of acetylcholine by of the effect in pivotal clinical trials was on the order of a 2.8 inhibiting its degradatory enzyme acetylcholinesterase. Four point improvement on the 70-point cognitive subscale of the AChEIs have been approved by the U.S. FDA for the treat Alzheimer's Disease Assessment Scale (ADAS-Cog), or ment of Alzheimer's disease and for Parkinson's disease 1-1.5 point improvement on the 30-point Mini-Mental Status dementia: tacrine, donepezil Aricept(R), rivastigmine Ex Examination (MMSE) compared to placebo over six months. elon R and galantamine Razadyne(R). AChEIs are available Differences in global measures assessed by the 7-point Cli in various formulations including immediate release forms nician Interview-Based impression of Change scale (CIBIC) Such as tablets, capsules and Solutions as well as rapid dis were on the order of 0.3-0.5 points in patients receiving an Solving and extended release forms for oral administration as AChEI compared to those receiving placebo. Efficacy was well as those for parenteral (e.g. transdermal) administration. similar for the three commonly used AChEIs. AChEIs also 0013 For example, phenserine is administered in 15 mg appear to have a beneficial effect on the behavioral and neu tablets and is used at a daily dose of 30 mg. tacrine is admin ropsychiatric symptoms in patients with Alzheimer type istered, as hydrochloride, in capsules containing 10, 20, 30 or dementias. More recently, rivastigmine was given open-label 40 mg/capsule and is used at recommended daily dosages of to patients with Parkinson's disease (PD) at an initial dose of from 40 to 160 mg (divided into 4 doses); donepezil is admin 1.5 mg twice a day and the dose was increased after 4 weeks istered, as hydrochloride in IR forms, in tablets containing 5 to 3 mg twice daily, after 8 weeks to 4.5 mg twice daily and or 10 mg/tablet and is used at recommended daily dosages of after 12 weeks to a maximal dose of 6 mg twice daily by from 5 to 10 mg; rivastigmine is administered in capsules trying, between weeks 12 and 26 of the trial, to keep the dose containing the tartrate in amounts corresponding to 1.5, 3, 4.5 of rivastigmine constant at the maximal tolerated dose. or 6 mg of rivastigmine base, as an oral Solution containing According to the Authors, rivastigmine may improve the cog the tartrate corresponding to 2 mg of rivastigmine base and in nitive functions in PD patients with dementia with no wors the form of a transdermal patch releasing rivastigmine at 4.6 ening of motor function. (Giladi et al., Acta Neurol Scand mg/24 hours or 9.5 mg/24 hours, the recommended daily 2003, 108,368-373). dosage for the IR forms being of from 6 to 12 mg. divided into 0018. A second problem limiting the success of current 2 doses and the maximal recommended patch dose being 9.5 AChEI therapy of Alzheimer type dementias is that, even at mg/24 hours; galantamine, as hydrobromide, is administered recommended amounts, all these drugs produce dose limiting in ER capsules containing the equivalent of 8 mg, 16 mg or 24 adverse reactions. These side effects commonly include, for mg of galantamine base, in IR tablets containing 5.126, the aforementioned AChEIS tacrine, donepezil, rivastigmine 10.253, or 15.379 mg of galantamine hydrobromide corre and galantamine: anorexia, nausea, vomiting, diarrhea, sponding to 4 mg., 8 mg and 12 mg, respectively, of galan abdominal pain and weight loss (Physicians Desk Reference tamine base and as a 4 mg/ml oral Solution, the recommended 2008, Thomson PDR, Montvale, N.J.). daily dosage being from 16 mg to 32 mg, although, in the 0019. The most frequently reported adverse effects of United States, the maximum recommended daily dose has rivastigmine, for example, are gastrointestinal, especially been reduced to 24 mg divided into 2 doses; and huperzine A nausea. About half of patients who take this drug in the is administered in 50 Lug IR tablets, the maximum recom recommended therapeutic oral dose range of 6-12 mg/day mended daily dosage being 450 mg. become nauseated and about one-third vomit at least once. 0014. Other AChEIs, in particular tacrine analogs, such as Vomiting was severe in 2% of rivastigmine-treated patients ipidacrine; phenserine analogs; icopezil; and Zanapezil are and was mild or moderate in 14%. Five percent of patients under evaluation. discontinued rivastigmine because of Vomiting, compared to 00.15 Augmentation of cholinergic transmission in the less than 1% on placebo. A loss of appetite was reported by CNS by currently available AChEIs confers therapeutic ben 17% of patients, and weight declined in 25% during rivastig efit to patients with Alzheimer type dementias. Therapeutic mine therapy (averaging 7 to 10 pounds). Presumably, the US 2011/02O 1597 A1 Aug. 18, 2011

drug-induced anorexia, nausea and Vomiting contribute to the antiemetics acting at these or related transmitter receptor sites observed weight loss. These untoward gastrointestinal can thus inhibit vomiting even ifunable to enter the CNS. effects, as well as others occurring with AChEI treatment, make it difficult to increase rivastigmine dosage above 6 mg PRIOR ART daily in most patients. 0020 Adverse events significantly reduce the safety and (0025. A benefit of alleviating the side effects of an AChEI tolerability of AChEI therapy. Attempts to limit them in clini was described in a report of four patients in whom the treat cal practice now rely on initiating treatment with a low dose ment of Alzheimer's disease with the AChEI tacrine was and then escalating the dose slowly. Nevertheless, in current complicated by peripheral cholinergic gastrointestinal side clinical practice, AChEI dosage is guided mainly by side effects, especially cramping, nausea, vomiting and diarrhea effects and not by therapeutic effects in contrast to most drugs (Faberet al. Am J Psychiatry 156:1, 1999, page 156 “Faber used in the treatment of neuropsychiatric disease. The admin 1999). These adverse events were ameliorated by the istration of higher doses than recommended doses tends to adjunctive use of the anticholinergic propantheline (Pro-Ban increase the frequency and severity of these side effects as thine(R) at 7.5 mg to 15 mg taken four times a day. Based on well as introduce additional kinds of adverse reactions. These these results, the authors recommended adjunctive use of include those generally found with high dose administration propantheline in patients with untoward gastrointestinal cho of cholinomimetics. In view of the frequency and potential linergic effects from cholinesterase inhibitors. severity of these high dose adverse effects, maximum recom mended oral doses of AChEIs are rarely intentionally 0026 Several reports of benefiting these GI adverse effects with known antiemetics have been published. For exceeded in clinical practice. example, Jhee SS, ClinNeuropharmacol. 2002 March-April; 0021. It is reported that recommended maximal dose lev els, intended as the recommended maximal daily doses, of 25(2):122-3, "Centrally acting antiemetics mitigate nausea these drugs typically achieve only about 45% acetylcholinest and Vomiting in patients with Alzheimer's disease who erase inhibition in the CNS of Alzheimer disease patients receive rivastigmine'; and Scarzella L., Funct Neurol. 2007 (Brannan Set al. ACNP 46" Annual Meeting, Program No. 4. April-June; 22(2): 101-4. Boca Raton Fla., Dec. 10, 2007 “Brannan 2007) and that 0027 Nevertheless, the aforementioned application of the inhibition of acetylcholinesterase activity and cognitive general concept for improving the treatment of dementias of improvement are significantly correlated (Giacobini et al. J the Alzheimer type provides only limited benefit to patients Neural Transm. 2002 July; 109(7-8): 1053-65) and that, ordi suffering from these disorders. While potentially lessening narily, a higher degree of enzyme blockade must be attained side effects, merely employing the concomitant use of anti for maximum functional effect (Jann et al., Clin Pharmacoki emetics Such as propantheline and domperidone and others net. 2002: 41 (10):719-39 “Jann 2002). falls short of realizing the full therapeutic potential of this 0022. On the other hand, doubling the dose of rivastig acetylcholinesterase approach to the treatment of Alzheimer mine, which became clinically practical when AChEI admin type dementia. There are several major problems regarding istration by immediate release tablets was replaced by skin the anticholinergic selected for use by Faber et al.: (1) the patches, which diminished side effects by blunting peak duration of action of the antiemetic was too short for current blood levels, significantly increased the amount of cognitive practical use in highly non-compliant demented patients; and improvement in patients with Alzheimer's disease without (2) none of these reports disclose or Suggest that, by reducing increasing side effects. adverse events, especially gastrointestinal, it might be pos 0023. By virtue of being dose limiting, these adverse sible to increase AChEI dose and thus improve efficacy. effects also constrain the efficacy of AChEI therapy. Studies 0028. In a Phase II study of rivastigmine in patients with in animal models of human cognitive dysfunction indicate a Alzheimer's Disease (Forette et al., European Journal of Neu direct dose-response relation between the amount of esterase rology, 1999, 6:423-429), during the titration phase the use of inhibition and the degree of cognitive improvement (Bennett an anti-emetic medication enabled 12 of 21 patients (b.i.d.) B Met al., Neuropsychopharmacology. 2007 March; 32(3): and seven of 19 (t.i.d.) patients to take higher doses of 505-13). Similar conclusions have been drawn regarding rivastigmine. According to this document, use of anti-emetic AChEI effects on cognitive and behavioral symptoms in medication allowed most patients who did not initially toler human patients with Alzheimer's disease (Jann 2002: Win ate rivastigmine to reach a higher mean MTD. However, still blad B, Cummings J. Andreasen N. Grossberg G, Onofri M. according to this document, the administered rivastigmine Sadowsky C, Zechner S. Nagel J. Lane R. Int J Geriatr Psy dose was at most 8.8 mg daily, i.e. well below the maximal chiatry. 2007 May; 22(5):456-67). recommended dose (12 mg/day). 0024. The precise causes of the vomiting and related gas 0029. The literature neither mentions nor suggests using trointestinal symptoms induced by AChEI therapy are not an antiemetic with the intent of enabling AChEI dose known. Presumably, they reflect the cholinergic receptor increases beyond recommended maximal dose levels to hyperstimulation attending AChEI administration. Vomiting increase antidementia efficacy. is coordinated in a center located at the base of the brain. The 0030. In summary, the literature neither discloses nor Sug Vomiting center communicates with the nearby chemorecep gests the possibility of taking advantage of the side effect tor trigger Zone, whose stimulation can lead to such com mitigation discovered by Faber 1999, achieved with propan plaints of gastrointestinal distress as anorexia, nausea and theline, or of the nausea/vomiting side effect mitigations Vomiting. The chemoreceptor trigger Zone, which contains achieved with antiemetics, to improve the magnitude and/or numerous serotonin 5-HT3 and dopamine D2 receptors as duration of the otherwise marginal therapeutic response to well as those for acetylcholine, opioids and substance P. lies AChEIs, by allowing an increase in the doses of said AChEIs outside the blood-brain barrier. Systemically administered beyond the recommended maximal dose levels and concur US 2011/02O 1597 A1 Aug. 18, 2011

rently improving neurobehavioral function and quality of life. common adverse events of cholinomimetic treatments of said No attempt was made in this direction heretofore. Alzheimer type dementias that arise as a result of the con comitant stimulation of cholinergic receptors mediating eme SUMMARY OF THE INVENTION sis and emesis-related symptoms at the central vomiting cen ter and chemoreceptor trigger Zone as well as at peripheral 0031 Considering the results of the above-cited previ sites. Non-anticholinergic antiemetic drugs that act to inhibit ously published studies in animal models of human cognitive the nausea/vomiting side effects resulting from cholinomi function indicating a dose-response relation between the metic therapy have the potential to reduce the adverse effects, amount of AChEIs and the degree of cognitive improvement Such that higher cholinomimetic doses can be administered achieved in the clinically relevant dose range, it has been leading to higher and more prolonged antidementia efficacy. assumed, in the present invention, that if dose limiting side By combining an extended release cholinomimetic with a effects of AChEIs could be reduced or eliminated, then the non-anticholinergic antiemetic having an advantageous dura administration of higher doses might provide a much needed tion of pharmacologic action, in a single dosage form, the increase in the size of the therapeutic effect and prolong the benefits to patients of an even longer duration of action is also duration of drug action, while at the same time having no achieved. significant deleterious effect on safety or tolerability. 0038. Thus, it is an object of the present invention to 0032. The therapeutic approach according to the present provide a method for enhancing the maximal tolerated dose invention reverses the approach taught by the prior art, in the and, hence, the therapeutic effect of an AChEI in a patient sense that it provides for an increase of the therapeutic effect Suffering from an Alzheimer type dementia without concur of the AChEIs (i.e., increase in efficacy) by concurrently rent, appreciable adverse effects, which comprises adminis globally counteracting their side effects, as opposed to com tering to said patient said AChEI in combination with a non bating their side effects without appreciably lessening the anticholinergic antiemetic agent. Thereby, an enhanced central activity of AChEIs, but without increasing their effi acetylcholinesterase inhibition in the CNS of said patient is cacy as taught by the whole prior art. achieved and the symptoms of an Alzheimer type dementia in 0033. Thus, it has been found that it is actually possible to said patient are improved. maximize the effects of an AChEI in improving the symptoms 0039. The invention also provides a non-anticholinergic of Alzheimer type dementia in a patient Suffering from said antiemetic agent for use for the treatment of Alzheimer type symptoms by administering to said patient said AChEI in dementias in combination with an AChEI, whereby the maxi combination with a non-anticholinergic antiemetic agent as mal tolerated dose of said AChEI is enhanced, a higher degree defined above. For the purposes of this definition, a non of acetylcholinesterase inhibition in the CNS is achieved and anticholinergic antiemetic drug would have the degree of the symptoms of Alzheimer type dementia are improved to a acetylcholine blockade and the ability to influence the clinical greater extent. effects of cholinergic receptor stimulation of less than 20 0040. The efficacy of non-anticholinergic antiemetic percent of that of atropine and preferably less than 5 percent agents in improving the symptoms of Alzheimer type demen of that of atropine. tia is due to the fact that said antiemetics allow the increase of 0034. In particular, according to the present invention a the therapeutic doses of all the AChEIs up to a factor of 4. non-anticholinergic antiemetic agent, in combination with an Thus, in the combined non-anticholinergic antiemetic/AChEI AChEI, reduces, including to the extent of eliminating, the treatment of Alzheimer type dementias according to the dose limiting side effects of said AChEI thus permitting a present invention, the AChEI therapeutic effect is increased remarkable increase of the AChEI's therapeutic doses, in by administering said AChEI at a dose level that is higher than particular of the AChEI recommended maximal dose levels, the maximal tolerated dose or the recommended maximal and a consequent increase of its therapeutic effect. dose level of said AChEI when administered alone, higher up 0035. It has also surprisingly been found that by a com to a factor of 4 than the therapeutic dose of said AChEI and, in bined antiemetic/AChEI treatment, the maximization of the particular, from 1.5 to 3 times higher than the currently rec cholinomimetic efficacy is achieved with AChEI dose levels ommended AChEI daily dose in the treatment of Alzheimer higher than the currently maximal tolerated or maximal rec type dementia. ommended dose levels and with antiemetic doses equal to or 0041 More particularly, the present invention provides a even lower than those currently used for preventing Vomiting. method for increasing the therapeutic effect of an acetylcho 0036 Finally, it has been found that pharmaceutical com linesterase inhibitor (AChEI) in a patient suffering from an positions comprising a pharmacologically active amount of Alzheimer type dementia, which comprises administering to an AChEI and a pharmacologically active amount of a non said patient said AChEI at a dose level higher than the rec anticholinergic antiemetic agent, in admixture with pharma ommended maximal dose level, in combination with a com ceutical carriers, improve the symptoms of Alzheimer type pound that reduces, including to the extent of eliminating, dementia in patients suffering from said symptoms, even in dose-limiting side effects of said AChEI dose level, said com the case of patients who have been withdrawn or are no longer pound being a non-anticholinergic antiemetic agent. responding to the AChEI therapy because of the severe side 0042. As set forth above, according to the invention, such effects, thus assuring not only an improvement of the quality a remarkable increase of the maximum tolerated dose or of of life of the patients, but also an objective and previously the recommended maximal dose level, inducing a similarly unrealized improvement of their symptoms. remarkable improvement of the conditions of patients suffer ing from Alzheimer type dementia, is attained without con DETAILED DESCRIPTION comitant appreciable adverse effects. 0037. The present invention proposes an improved The AChEIS method to augment the efficacy of conventional cholinergic 0043 Said AChEIs are those currently used or tested for therapies for Alzheimer type dementias by mitigating the this indication, Such as 1,2,3,4-tetrahydro-9-acridinamine US 2011/02O 1597 A1 Aug. 18, 2011

(tacrine) and its pharmaceutically acceptable salts, in particu E=CH-CHs: Z=N CHCHs); thiacymserine (Q-p-iso lar the hydrochloride, 9-amino-2,3,5,6,7,8-hexahydro-1H propylphenyl: E=CH: Z=S); thiatolserine (Q-o-tolyl: cyclopentablquinoline (ipidacrine); (+)-2,3-dihydro-5,6- E=CH: Z=S). dimethoxy-2-1-(phenylmethyl)-4-piperidinyl)methyl)-1H 0045 Donepezil hydrochloride, rivastigmine hydrogen inden-1-one (donepezil) and its pharmaceutically acceptable (2R,3R)-tartrate and galantamine hydrobromide are the most salts, in particular the hydrochloride, 3-2-(1-benzyl-4-pip used AChEIS, phenserine tartrate and huperzine A also being eridyl)ethyl-5,7-dihydro-6H-pyrrolo3.2-f-1,2-benzisox advantageous AChEIS, for improving dementias of Alzhe aZol-6-one (icopezil) and its pharmaceutically acceptable imer's type. salts, in particular the maleate, 3-1-benzylpiperidin-4-yl)-1- 0046 According to the present invention, said AChEI is (2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl)propan-1-one administered at a daily dose that is higher than the maximal (Zanapezil) and its pharmaceutically acceptable salts, in par tolerated dose or recommended maximal dose level of the ticular the fumarate, (S) N-Ethyl-N-methyl-3-1-(dimethy same AChEI when administered alone, in particular at a dose lamino)ethyl-phenyl carbamate (rivastigmine) and its phar up to 4-fold higher than the current therapeutic dose, prefer maceutically acceptable salts, in particular the hydrogen (2R, ably at a daily dose from 1.5 to 3 times higher than the 3R)-tartrate, 4aS,6R,8aS-3-methoxy-11-methyl-4a,5.9.10, maximal recommended AChEI doses presently used in the 11, 12-hexahydroxy-6H-benzofuro3a,3,2-ef benzazepin-6- treatment of Alzheimer type dementia. ol (galantamine) and its pharmaceutically acceptable salts; 0047 Preferably, among the advantageous AChEIs men (1R,9S,13E)-1-amino-13-ethylidene-11-methyl-6-azatricy tioned above, when given in IR preparations, phenserine, as cloT.3.1.0°trideca-2(7),3,10-trien-5-one (huperzine A) tartrate, is administered at a daily dose of from 45 mg to 120 and phenserine and its analogs encompassed by the general mg, advantageously from 60 mg to 90 mg tacrine, as hydro formula I chloride, is administered at daily doses of from 240 mg to 640 mg, advantageously of from 320 mg to 480 mg. donepezil, as hydrochloride, is administered at daily doses of from 15 mg to (I) 40 mg, advantageously from 20 mg to 40 mg; rivastigmine, as HC hydrogen tartrate, is administered at daily doses of from 18 O mg to 48 mg, advantageously from 24 mg to 36 mg; galan tamine, as hydrobromide, is administered at daily doses of from 36 mg to 96 mg, advantageously from 48 mg to 72 mg: huperzine A is administered at a daily dose of from 0.2 mg to 1.2 mg, advantageously from 0.6 mg to 0.8 mg. wherein Q is a phenyl group optionally Substituted with a The Non-anticholinergic Antiemetic Agents (C-C)alkyl or with a methoxy group, Z is an oxygen or 0048. Any antiemetic agent substantially devoid of central sulfur atom or a N-E radical, E and E', independently, are anticholinergic effects may be used according to the present hydrogen or a methyl group optionally Substituted with a invention to improve the efficacy of the AChEIs by allowing phenyl or benzyl group; and pharmaceutical acceptable salts an effective increase of their therapeutic doses. thereof. 0049. Typical non-anticholinergic antiemetic agents are 0044 Exemplary AChEIs of formula (I), described in U.S. 0050 5-HT receptor antagonists (5HT3-antagonists), Pat. No. 6,683,105, are phenserine (Q-phenyl; E=CH: such as 9-methyl-3-(2-methyl-1H-imidazol-1-yl)me Z-N-CH-): (-)-N',N'-bisnorphenserine (Q-phenyl; E-H; thyl-1,2,3,9-tetrahydrocarbazol-4-one (ondansetron) Z=N H); 4'-methoxyphenserine (Q=4'-methoxyphenyl: and pharmaceutically acceptable salts and Solvates E=CH: Z-N CH-): (-)-N',N'-bisbenzylmorphenserine thereof, in particular its hydrochloride dihydrate, (Q-phenyl: E=CH-CHs; Z=N CHCHs); tolserine (Q-o- described in EP 191562; 3S-ondansetron; 3R-ons tolyl; E=CH: Z-N-CH); N-benzylnortolserine (Q-o- dansetron; (3R)-10-oxo-8-azatricyclo[5.3.1.0 undec tolyl; E=CH: Z-N CH, CHs); N-phenethylnor 5-y11H-indole-3-carboxylate (dolasetron) and pharma tolserine (Q-o-tolyl; E=CH: Z=N CH, CH, CHs); ceutically acceptable salts and Solvates thereof, in N'-nortolserine (Q-o-tolyl: E=CH: Z-N-H); N-benzyl particular its monomethanesulfonate (mesylate or mesi nortolserine (Q-o-tolyl; E=N CH, CHs: Z=N CH): late) monohydrate, described in EP 266730; 1-methyl N-phenethylnortolserine (Q-o-tolyl: E=N CH-CH N-(9-methyl-9-azabicyclo[3.3.1 non-3-yl)-indazole-3- CHs: Z-N CHs); N-nortolserine (Q-o-tolyl; E-H; carboxamide (granisetron) and pharmaceutically Z=N CH); N',N'-bisnortolserine (Q-o-tolyl; E=H: acceptable salts and Solvates thereof, in particular its Z-N-H): (-)-N',N'-bisbenzylnortolserine (Q-o-tolyl: hydrochloride, described in EP 200444; (1S,5S)-8-me E=CH-CH: Z=N CHCHs); cymserine (Q-p-isopropy thyl-8-azabicyclo[3.2.1]oct-3-yl 1H-indole-3-carboxy lphenyl; E=CH: Z-N-CH); N-benzylnorcymserine late (tropisetron) and pharmaceutically acceptable salts (Q-p-isopropylphenyl; E=CH: Z=N CH, CHs); and Solvates thereof, in particular its monohydrochlo N'-phenethylnorcymserine (Q-p-isopropylphenyl; E=CH: ride, described in U.S. Pat. No. 4,789,673: 1-phenylm Z-N CH, CH, CHs); N'-norcymserine (Q-p-isopro ethyl-2-piperazinyl-1H-benzimidazole (lerisetron) and pylphenyl: E=CH: Z-N-H); N-benzylnorcymserine pharmaceutically acceptable salts and Solvates thereof, (Q-p-isopropylphenyl; E=N CH, CHs; Z=N CH): in particular its hydrochloride, described in EP 512939: N-phenethylnorcymserine (Q-p-isopropylphenyl: E=N- (R)-5-(1-methyl-3-indolyl)carbonyl-4,5,6,7-tetrahy CHCHCHs: Z=NCH): N-norcymserine dro-1H-benzimidazole (ramosetron) and pharmaceuti (Q-isopropylphenyl; E-H: Z-N-CH); N',N'-bisnorcym cally acceptable salts and Solvates thereof, in particular serine (Q-p-isopropylphenyl; E-H: Z-N-H): (-)-N',N'- its hydrochloride, described in U.S. Pat. No. 5,344,927: bisbenzylmorcymserine (Q-p-isopropylphenyl: (3aR)-2-(3S)-1-azabicyclo[2.2.2]oct-3-yl)-2,3,3a,4,5, US 2011/02O 1597 A1 Aug. 18, 2011

6-hexahydro-1H-benzdeisoquinolin-1-one (pal 0.052 H1 histamine receptor antagonists (“H1-antago onosetron) and pharmaceutically acceptable salts and nists'). Such as 1-(4-chlorophenyl)-phenyl-methyl-4- solvates thereof, in particular its hydrochloride, (3-methylphenyl)methylpiperazine (meclizine or described in U.S. Pat. Nos. 5,202,333: 2,3,4,5-tetrahy meclozine) and pharmaceutically acceptable salts and dro-5-methyl-2-(5-methyl-1H-imidazol-4-yl)methyl solvates thereof, particularly its dihydrochloride mono 1H-pyrido4.3-bindol-1-one (alosetron) and pharma hydrate; dimethyl 1-(10H-phenothiazin-10-yl)propan ceutically acceptable salts and Solvates thereof, in 2-yl)amine (promethazine) and pharmaceutically particular its hydrochloride, described in U.S. Pat. No. acceptable salts and Solvates thereof, particularly its 5,360,800; and (+)-6-chloro-3,4-dihydro-4-methyl-3- hydrochloride: 3-(2-chloro-10H-phenothiazin-10-yl)- oxo-N-(quinuclidinyl)-2H-1,4-benzoxazine-8-carboxa N,N-dimethyl-propan-1-amine (chlorpromazine) or a salt thereof, particularly its hydrochloride: 2-chloro-10 mide (aZasetron) and pharmaceutically acceptable salts 3-(4-methyl-1-piperazinyl)propyl-10H-phenothiaz and solvates thereof, in particular its hydrochloride, ine (prochlorperazine) and pharmaceutically acceptable described in U.S. Pat. No. 4,892,872; which are known salts and Solvates thereof, particularly its dimaleate, to be serotonin receptors blockers in the central nervous dimesylate or 1.2-ethanedisulfonate (1:1) (edisilate); systemand gastrointestinal tract and have been proposed and 2-(2-4-(4-chlorophenyl)(phenyl)methylpiper for use to treat post-operative and cytotoxic drug nausea azin-1-yl)ethoxy)ethanol (hydroxyzine) and pharma and Vomiting: ceutically acceptable salts and Solvates thereof Such as 0051 dopamine antagonists (“DA-antagonists'), such its hydrochloride or 1,1'-methylene-bis(2-hydroxy-3- as 5-chloro-1-(1-3-(2-oxo-2,3-dihydro-1H-benzod naphthalenecarboxylic acid salt (pamoate), which are imidazol-1-yl)propylpiperidin-4-yl)-1H-benzodimi known to be effective in many conditions, including dazol-2(3H)-one (domperidone) and pharmaceutically motion sickness and severe morning sickness in preg acceptable salts and Solvates thereof, particularly its nancy; maleate: 1-1-4-(4-fluorophenyl)-4-oxo-butyl-3,6-di 0.053 cannabinoid receptor agonists (“cannabinoids’), hydro-2H-pyridin-4-yl)-3H-benzoimidazol-2-one (dro such as cannabis; (6aR-trans)-6a,7,8,10a-tetrahydro-6, peridol); 4-4-(4-chlorophenyl)-4-hydroxy-1-pip 6.9-trimethyl-3-pentyl-6H-dibenzob.dpyran-1-ol eridyl-1-(4-fluorophenyl)-butan-1-one (haloperidol); (dronabinol); (6aR,10aR)-rel-3-(1,1-dimethylheptyl)-6, 3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl 6a,7,8,10,10a-hexahydro-1-hydroxy,6,6-dimethyl-9H propan-1-amine (chlorpromazine) and pharmaceuti dibenzob.dpyran-9-one (nabilone); and (-)-cis-3-2- cally acceptable salts and Solvates thereof, particularly hydroxy-4-(1,1-dimethylheptyl)-phenyl-trans-4-(3- its hydrochloride: 2-chloro-10-3-(4-methyl-1-piperazi hydroxypropyl)cyclohexanol (CP 55,940); which are nyl)propyl-10H-phenothiazine (prochlorperazine), and known to be used in patients with cachexia and cytotoxic pharmaceutically acceptable salts and Solvates thereof, nausea and Vomiting: particularly its dimaleate, dimesylate or 1.2-ethanedis 0.054 antagonists of the neurokinin 1 receptor (NK1 ulfonate (1:1) (edisilate); dimethyl 1-(1OH-phenothi antagonists) such as 5-(2R.3S)-2-[(1R)-1-3,5-bis(tri azin-10-yl)propan-2-ylamine (promethazine) and fluoromethyl)phenylethoxy-3-(4-fluorophenyl)-4- pharmaceutically acceptable salts and Solvates thereof, morpholinyl)methyl-1,2-dihydro-3H-1,2,4-triazol-3- particularly its hydrochloride: 4-aminosalicylamide and O (aprepitant); and (2S,4S)-4-(4-Acetyl-1- benzamide derivatives like 4-amino-5-chloro-N-2-(di piperazinyl)-N-(1R)-1-3,5-bis(trifluoromethyl) ethylamino)ethyl-2-methoxybenzamide (metoclopra phenylethyl-2-(4-fluoro-2-methylphenyl)-N-methyl mide) and pharmaceutically acceptable salts and sol 1-piperidinecarboxamide (casopitant); which are vates thereof such as its monohydrochloride known to be neurokinine-1 receptors blockers in both monohydrate, 4-amino-5-bromo-N-2-(diethylamino) the central and peripheral nervous system and have been ethyl-2-methoxybenzamide (bromopride) and pharma proposed for use to treat cytotoxic drug nausea and ceutically acceptable salts and Solvates thereof, particu Vomiting. larly its monohydrochloride and its dihydrochloride 0055 Advantageously, the used non-anticholinergic anti monohydrate, 4-amino-N-(1-benzylpiperidin-4-yl)-5- emetic agents are compounds with a duration of action of at chloro-2-methoxybenzamide (clebopride) and pharma least 6 hours, advantageously from 8 to 24hours, more advan ceutically acceptable salts and Solvates thereof, particu tageously from 10 to 24 hours, preferably from 12 to 24 hours, larly its malate or its hydrochloride monohydrate; N-(1- even though non-anticholinergic antiemetics having an allylpyrrolidin-2-yl)methyl-6-methoxy-1H-benzod appropriate duration of action corresponding to the duration 1.2.3 triazole-5-carboxamide (alizapride) and of action of the concomitantly administered AChEI may be pharmaceutically acceptable salts and Solvates thereof, Successfully used. particularly its hydrochloride: (L)-2-methoxy-N-((1- 0056. According to the present invention, the non-anticho propylpyrrolidin-2-yl)methyl)-5-sulfamoylbenzamide linergic antiemetic agent is administered at doses of from (levosulpiride); N-4-(2-dimethylaminoethoxy)phe 50% to 300% of the currently recommended IR dose in its nyl)methyl-3,4,5-trimethoxy-benzamide (tri antiemetic indication, it being understood that doses of from methobenzamide) and pharmaceutically acceptable 50% to 200% will be used in immediate release unit forms salts and solvates thereof, particularly its hydrochloride: while doses of from 75% to 300% will be used in extended which act in the brain and especially at the chemorecep release or transdermally applicable unit forms. Such a dose tor trigger Zone and are known to be used to treat nausea will allow the maximization of the cholinomimetic efficacy and Vomiting associated with neoplastic disease, radia with AChEI daily doses higher than the currently maximal tion sickness, opioids, cytotoxic drugs and general anes tolerated ones, in particular with doses of AChEIs at least as thetics; high as the currently recommended doses and preferably US 2011/02O 1597 A1 Aug. 18, 2011 higher than said currently recommended doses, in particular aprepitant, at a daily dose of from 40 mg to 375 mg; and of 100% to 300%, and preferably of 150% or 200% up to or casopitant, at a daily dose of from 25 mg to 450 mg. 300% of said recommended dose of AChEI to patients suf 0062 According to an advantageous embodiment of the fering of Alzheimer type dementia without clinically signifi present invention, the non-anticholinergic agent having anti cant symptoms of gastrointestinal distress, particularly anor emetic action to be administered to patients under treatment exia, nausea or vomiting. with an AChEI is granisetron or a pharmaceutically accept 0057 According to an embodiment, the non-anticholin ergic antiemetic agent to be administered to patients under able salt thereof in a transdermal device delivering from 2 treatment with an AChEI is a 5HT3-antagonist selected from mg/24 hours to 6 mg/24 hours of granisetron, manufactured the group consisting of allosetron and pharmaceutically according to known techniques, in particular as described for acceptable salts and Solvates thereof, at a daily dose (in alos example in U.S. Pat. No. 6,562,363 or in WO 2006/028866. etron) of from 0.25 mg to 6 mg. dolasetron and pharmaceu More generally, when the non-anticholinergic antiemetic tically acceptable salts and Solvates thereof, at a daily dose (in agent is available in parenteral forms including patches, Sup dolasetron) of from 50 mg to 300 mg; granisetron and phar positories and preparations for intramuscular or intravenous maceutically acceptable salts and Solvates thereof, at a daily injection, the non-anticholinergic agent having antiemetic dose (in granisetron) of from 1 mg to 6 mg; ondansetron and action to be administered to patients under treatment with an pharmaceutically acceptable salts and Solvates thereof, at a AChEI may also be in Such a parenteral administration form. daily dose (in ondansetron) of from 12 mg to 72 mg; and 0063. The administration of the non-anticholinergic agent tropisetron and pharmaceutically acceptable salts and sol having antiemetic action to a patient Suffering from dementia Vates thereof, at a daily dose (intropisetron) of from 2.5 mg to of Alzheimer type allows the treatment with the maximal 15 mg. recommended doses of an AChEI without clinically signifi 0058 According to another embodiment, the non-anticho cant symptoms of gastrointestinal distress, particularly anor linergic antiemetic agent to be administered to patients under exia, nausea or vomiting and also allows the treatment of said treatment with an AChEI is a dopamine antagonist selected patients with doses higher than the recommended doses, for from the group consisting of domperidone and pharmaceuti example with from 1.1 times to 3 times the recommended cally acceptable salts and Solvates thereof, at a daily dose (in doses, said doses being higher than the maximal AChEI tol domperidone) of from 15 mg to 90 mg; haloperidol, at a daily erated dose when used alone, thus significantly improving the dose of from 0.25 mg to 60 mg; chlorpromazine and pharma symptoms of dementia in said patients. ceutically acceptable salts and solvates thereof, at a daily dose (in chlorpromazine) of from 25 mg to 450 mg; prochlorpera The Clinical Assessment Zine and pharmaceutically acceptable salts and Solvates thereof, at a daily dose (in prochlorperazine) of from 7.5 mg 0064. The fact that non-anticholinergic antiemetic agents to 120-150 mg; the 4-aminosalicylamide derivatives meto allow the increase of the maximal tolerated, therapeutic doses clopramide and pharmaceutically acceptable salts and Sol of the AChEIs results from a randomized, controlled safety, vates thereof, at a daily dose (in metoclopramide) of from 15 tolerability, pharmacokinetic and pharmacodynamic study of mg to 90 mg; bromopride, at a daily dose (in bromopride) of an AChEI agent alone, such as donepezil, rivastigmine or from 10 mg to 180 mg; clebopride and pharmaceutically galantamine, and with a non-anticholinergic antiemetic acceptable salts and Solvates thereof, at a daily dose (in clebo agent, Such as ondansetron, meclizine, prometazine, domp pride) of from 0.75 mg to 4.5 mg; levosulpiride, at a daily dose eridone, metoclopramide or aprepitant, in normal volunteers. of from 37.5 mg to 900 mg; allizapride and pharmaceutically 0065. The protocol is that of a phase 1 study of ascending acceptable salts and Solvates thereof, at a daily dose (inaliza standard doses of rivastigmine alone (as a representative pride) of from 25 mg to 600 mg; and trimethobenzamide and AChEI), and with ascending standard doses of ondansetron pharmaceutically acceptable salts and Solvates thereof, at a (as a representative non-anticholinergic antiemetic agent) in daily dose (in trimethobenzamide) of from 450 mg to 3,600 normal volunteers, to determine the difference between the ng. maximum tolerated dose of rivastigmine as monotherapy and 0059. According to another embodiment, the non-anticho the maximum tolerated dose of rivastigmine coadministered linergic antiemetic agent to be administered to patients under withondansetronas the primary endpoint, the secondary ones treatment with an AChEI is a H1 histamine receptor antago being adverse event profile and drug plasma levels. nist selected from the group consisting of meclizine (also 0.066 Standard approved oral dosage forms of both called meclozine) and pharmaceutically acceptable salts and rivastigmine hydrogen-(2R,3R)-tartrate (simply named solvates thereof, at a daily dose (in meclizine) of from 12.5 rivastigmine in the study) and ondansetron monohydrochlo mg to 300 mg; and promethazine and pharmaceutically ride, dihydrate (simply named ondansetron in the study) are acceptable salts and Solvates thereof, at a daily dose (in used. The objective; to determine the maximum tolerated promethazine) of from 12.5 mg to 112.5 mg. dose (MTD), safety and tolerability as well as the pharmaco 0060 According to another embodiment, the non-anticho kinetic and pharmacodynamic profile of rivastigmine when linergic antiemetic agent to be administered to patients under administered alone at daily oral doses ranging from 3 mg to treatment with an AChEI is a cannabinoid receptor agonist 12 mg and together with ondansetronat daily oral doses of up selected from the group consisting of dronabinol, at a daily to 24 mg. MTD, for the purposes of this protocol, is defined as dose of from 1.25 mg to 60 mg and nabilone, at a daily dose the dose of rivastigmine just preceding the one that produced of from 1 mg to 12 mg. frank Vomiting, or intolerable retching, or that is considered 0061 According to another embodiment, the non-anticho medically inappropriate for readministration by the study linergic agent having antiemetic action to be administered to principal investigator. The ability of any volunteer to with patients under treatment with an AChEI is a neurokinine 1 draw from this study or refuse any medication or procedure is receptor antagonist selected from the group consisting of reiterated on a continuing basis. US 2011/02O 1597 A1 Aug. 18, 2011

0067. The volunteers are males and/or females, who are about 08:00 hours. On study days, subjects will be kept fast considered in good general health, aged 18 to 80 years inclu ing from 00:00 hours (midnight) until at least 4 hours after sive. No concomitant medications are allowed. drug administration (about 12:00 hours). 0068. The study will be a randomized, double-blind, pla 0074 Safety and tolerability are evaluated before, during cebo-controlled, cross-over and parallel groups, dose-rang and after study drug administration by means of reports from ing, non-therapeutic, study conducted on Volunteers at a Subjects as well as by medical staff observations and mea single center. The volunteers are evaluated under blinded Surements. Medical procedures including clinical history and conditions following randomization to either Group A or physical examination, vital signs and laboratory tests are Group B. performed at Screening, and at a follow up visit about 28 days 0069. During the entire study, oral doses of rivastigmine or after the last drug administration. Some medical procedures rivastigmine placebo and ondansetron or ondansetron pla are in addition performed each study day. cebo will be administered simultaneously once daily at about 0075. During each study day, all subjects remain under SAM for up to 10 days. All subjects will be maintained fasting continuous observation from just before drug administration for the preceding 8 hours (nominally midnight) and until 4 until 4 hours after drug administration, or until all medically hours after drug administration (nominally noon). Daily significant study-related abnormalities have subsided. The doses of rivastigmine begin at 3 mg and range up to 12 mg in following tests are performed during each study day: review increments of 3 mg as deemed medically appropriate. Daily of systems (focused on known adverse effects of the drugs dosing continues until a subject Vomits, evidences intolerable used), and vital signs (sitting systolic and diastolic blood retching, refuses further study medications, or the principal pressure and radial pulse rate), just before drug dosing and 2 investigator terminates further dosing for medical reasons. hours thereafter or until any abnormalities have subsided. A Daily doses of ondansetron are 24 mg, given once daily at the 12-lead ECG is obtained on admission and again2 hours after same time as rivastigmine. In the case of ondansetron intol MTD rivastigmine administration. Laboratory tests include erance, in the opinion of the principal investigator, the daily urinalysis and routine evaluations of venous blood samples dose of ondansetron may be reduced to and maintained at 12 (including fasting blood Sugar, blood urea nitrogen, creati ng. nine, liver transaminases, alkaline phosphatase and bilirubin) 0070 Volunteers who are randomized to Group A receive on the first and last study days. single daily doses of rivastigmine starting at 3 mg per day and 0076. The following adverse events are monitored: ascending by 3 mg increments each study day, as tolerated, to 0077 (a) Anorexia or nausea, rated daily during the peak a maximum of 12 mg per day. Once the MTD (as defined for dose period (1 to 2 hours after oral drug administration) in this protocol) for rivastigmine as monotherapy is determined, accordance with responses from study Subjects during the ondansetron co-administration ordinarily begins at a dose of peak dose period (1 to 2 hours after drug administration) on a 24 mg per day and continues each study day at this dose. One numeric scale. day after the introduction of ondansetron, rivastigmine 0078 (b) Retching, rated daily as either absent or present administration resumes at the previously determined MTD during the peak dose period; and rises each study day by increments of 3 mg, as tolerated, to a maximum of 12 mg per day. The study terminates for each 0079 (c) Vomiting, rated daily as either absent or present volunteer once they have reached their MTD for rivastigmine during the peak dose period; and when administered in combination with ondansetron. 0080 (d) Others, rated once daily as either absent or 0071 Volunteers who are randomized to Group B first present in accordance with responses from study subjects: receive ondansetron given once daily at 12 mg and then diarrhea, abdominal pain, coughing or other respiratory dif increased on the second study day to and maintained at 24 mg ficulty, chest pain, palpitations, dysuria or other urinary dis once daily, as tolerated. Then daily doses of simultaneously turbance, blurring of vision, light headedness, Syncope, som administered rivastigmine are introduced, starting at 3 mg and nolence, agitation, confusion. rising in 3 mg increments each study day as tolerated to each I0081 For the pharmacokinetic measurements, venous subjects MID or 12 mg which ever occurs first. blood samples are collected three times from each subject: (1) 0072. During each study day all subjects receive a constant at baseline just prior to the first rivastigmine dose, (2) at number of capsules (rivastigmine or rivastigmine placebo) rivastigmine peak dose 75 minutes after MTD administration and of tablets (ondansetron or ondansetron placebo) once and (3) at 4 hours after MTD rivastigmine administration. All daily. Both study subjects and Center Staff receive no infor specimens are centrifuged, and the serum separated and mation concerning drug type or quantity administered at any stored frozen for Subsequent assay. time during the study. Drugs are administered and compli I0082. The analysis of primary outcome measure is per ance assured by an attendant in accordance with orders from formed both in study completers and in the intent-to-treat a medically qualified investigator. Neither will communicate (ITT) population. The ITT population will include all the with study Subjects nor those having contact with these Sub randomized subjects who have received each of the baseline jects. assessments and at least one post-randomization assessment. 0073 Drug dosing will be in accordance with the protocol I0083. Difference in the MTD of rivastigmine when given description above as considered medically appropriate by the alone and together with ondansetron is analyzed using principal investigator. Standard approved oral dosage forms descriptive statistics both within subjects and between sub of both rivastigmine and ondansetron will be used. Both jects assigned to each of the two treatment order groups. active drugs (rivastigmine capsules and ondansetron tablets) I0084 Safety parameters are analyzed to compare differ and placebo (capsules and tablets) will be administered to ences between the rivastigmine monotherapy and the rivastig blind-folded subjects, who received identical number of cap mine plus ondansetron treatment groups. These parameters sules (active or placebo) and tablets (active or placebo). All include treatment-emergent adverse events, vital signs, rou drugs will be administered orally, once daily in the morning at tine laboratory determinations, and ECG measurements. US 2011/02O 1597 A1 Aug. 18, 2011

0085. In a similar, randomized, single-blind, placebo-con ranging from 75% to 300% of the amount of said non-anti trolled, cross-over or parallel groups, dose-ranging, non cholinergic antiemetic agent contained in the currently therapeutic, study conducted on Volunteers, oral doses of administered unit dosage IR forms for the treatment of the rivastigmine or rivastigmine placebo and ondansetron or above-cited disorders. ondansetron placebo are administered once daily at about 8 0094. An advantageous non-anticholinergic antiemetic AM for up to 20 days, the dose of rivastigmine being agent in said pharmaceutical compositions is selected from increased up to 36 mg. the group consisting of allosetron and pharmaceutically I0086. The Compositions Containing Non-Anticholinergic acceptable salts and Solvates thereof, in an amount (in alos Antiemetic Agents etron) of from 0.25 mg to 3 mg. dolasetron and pharmaceu 0087. For the intended use, the non-anticholinergic anti tically acceptable salts thereof, in an amount (in dolasetron) emetic agent is formulated in pharmaceutical compositions of from 25 mg to 300 mg; granisetron and pharmaceutically comprising, as an active ingredient thereof, said non-anticho acceptable salts thereof, in an amount (in granisetron) of from linergic antiemetic agent in admixture with a pharmaceutical 0.5 mg to 3 mg; ondansetron and pharmaceutically acceptable carrier. salts and Solvates thereof, in an amount (in ondansetron) of 0088 Said composition may beformulated with said phar from 2 mg to 24 mg. tropisetron and pharmaceutically accept maceutical carrier in IR or ER unit forms for oral administra able salts thereof, in an amount (intropisetron) of from 2.5 mg tion or in unit forms for parenteral, i.e. intramuscular, intra to 15 mg. domperidone and pharmaceutically acceptable salts venous, rectal or transdermal, administration. and Solvates thereof, in an amount (in domperidone) of from 0089. The non-anticholinergic antiemetic agent is present 5 mg to 30 mg; haloperidol, in an amount of from 0.5 mg to 30 in an amount that reduces peripherally mediated gastrointes mg; chlorpromazine and pharmaceutically acceptable salts tinal adverse effects that would becaused by the administra and Solvates thereof, in an amount (in chlorpromazine) of tion of a dose of AChEI sufficient to maximally alleviate from 12.5 mg to 300 mg; prochlorperazine and pharmaceu disease-associated dementia and other neurobehavioral tically acceptable salts and Solvates thereof, in an amount of symptoms, beyond the limits heretofore attained. from 2.5 mg to 30 mg; metoclopramide and pharmaceutically 0090 Advantageously, these pharmaceutical composi acceptable salts and Solvates thereof, in an amount (in meto tions comprise the non-anticholinergic antiemetic active clopramide) of from 5 mg to 30 mg, bromopride and phar ingredient in an amount of from 50% to 300% of the dosage maceutically acceptable salts and Solvates thereof, in an used in the compositions currently used for the treatment of amount (in bromopride) of from 5 mg to 30 mg; clebopride disorders such as nausea, Vomiting or motion sickness. The and pharmaceutically acceptable salts thereof, in an amount compositions prepared using the non-anticholinergic anti (in clebopride) of from 0.25 mg to 1.5 mg; levosulpiride, in an emetic agents according to the present invention allow the amount of from 12.5 mg to 300 mg, alizapride and pharma maximization of the cholinomimetic efficacy with AChEI ceutically acceptable salts thereof, in an amount (in aliza doses higher than the currently maximal tolerated ones, in pride) of from 25 mg to 150 mg. trimethobenzamide and particular by administration of from 1.5 up to three times the pharmaceutically acceptable salts and Solvates thereof, in an recommended daily dose of AChEI, to patients suffering of amount (in trimethobenzamide) of from 150 mg to 900 mg: Alzheimer type dementia without clinically significant symp meclizine (also called meclozine) and pharmaceutically toms of gastrointestinal distress particularly anorexia, nausea acceptable salts and Solvates thereof, in an amount (in mecliz or vomiting, thus significantly improving the symptoms of ine) of from 6.25 mg to 150 mg, promethazine and pharma dementia. ceutically acceptable salts thereof, in an amount (in promet 0091. The compositions are preferably formulated in dos hazine) of from 12.5 mg to 150 mg. dronabinol, in an amount age unit forms for oral or parenteral, in particular transder of from 1.25 mg to 30 mg: nabilone, in an amount of from mal, administration, wherein the non-anticholinergic anti 0.25 mg to 3 mg, aprepitant, in an amount of from 20 mg to emetic active ingredient is mixed with a pharmaceutical 375 mg; and casopitant, in an amount of from 25 mg to 150 carrier. ng. 0092. The pharmaceutical compositions prepared using the non-anticholinergic antiemetic agents according to the The Fixed-Dose Combinations present invention are indicated in the treatment of the Symp 0.095 According to an advantageous embodiment, the toms of Alzheimer type dementias in order to improve to a pharmaceutical compositions prepared by using the non-an greater extent said symptoms by also allowing an increase of ticholinergic antiemetics according to the present invention the currently used and also of the maximal tolerated doses of are present in unit forms also containing other active ingre an AChEI, concurrently or sequentially administered there dients, in particular an AChEI which acts as cholinergic agent with, without the side-effects that would hinder said increase in the CNS to improve the symptoms of Alzheimer type of said therapeutic doses. dementia, in a quantity Sufficient to maximally alleviate dis 0093. In said pharmaceutical compositions, the non-anti ease-associated neurobehavioral symptoms, with a minimum cholinergic antiemetic agent is present in an amount of from of treatment-associated adverse effects. 50% to 300% of the amount of said non-anticholinergic anti 0096. Thus, it is another object of the present invention to emetic agent contained in the currently administered IR dos provide a pharmaceutical unit form which comprises age unit forms for the treatment of disorders such as nausea, (a) a non-anticholinergic antiemetic agent; and Vomiting or motion sickness. More particularly, the non anticholinergic antiemetic agentis present, in an IR unit form, (b) an AChEI in an amount ranging from 50% to 200% of the amount of said non-anticholinergic antiemetic agent contained in the cur 0097 in admixture with a pharmaceutical carrier. rently administered IR dosage unit forms for the treatment of 0098. In the pharmaceutical unit form of the present inven the above-cited disorders or, in an ER unit form, in an amount tion, the non-anticholinergic antiemetic agent, Component US 2011/02O 1597 A1 Aug. 18, 2011

(a) is present in an amount of from 50% to 300% of the vates thereof such as the dihydrochloride or the 1,1'-methyl amount of the said non-anticholinergic antiemetic agent con ene bis(2-hydroxy-3-naphthalenecarboxylic acid (pamoate) tained as a sole active ingredient in the currently used brandor salt. generic drugs. 0105 Typical cannabinoids (a4) are nabilone and dronab 0099. According to a preferred embodiment, said Compo inol. nent (a) is a non-anticholinergic antiemetic agent selected 0106 Each of said typical non-anticholinergic antiemetic from the group consisting of (a1) 5HT3-antagonists, (a2) agents is present in the pharmaceutical composition, as Com DA-antagonists, (a3) H1-antagonists, (a4) cannabinoids, (aš) ponent (a), in an amount ranging from 50% of the minimum aprepitant and (a6) casopitant. amount to 300% of the maximum amount of said typical 0100. The pharmaceutical composition to improve the non-anticholinergic antiemetic agent contained in the corre treatment of human dementias of the Alzheimer type accord sponding, currently used generic or brand drug for its anti ing to the present invention may comprise a mixture of a emetic indication in IR form. non-anticholinergic antiemetic agent, Component (a), and of 0107 Advantageous Component (a) is selected from the an AChEI, Component (b), wherein Component (b) is present group consisting of alosetron and pharmaceutically accept in a quantity Sufficient to maximally alleviate disease-associ able salts and solvates thereof, in particular the hydrochlo ated neurobehavioral symptoms and wherein Component (a) ride, in an amount (in alosetron) of from 0.25 mg to 3 mg: is present in a second quantity that reduces adverse effects dolasetron and pharmaceutically acceptable salts and Sol that would be caused by the AChEI if administered without Vates thereof, in particular the mesylate, in an amount (in the accompanying non-anticholinergic antiemetic agent. dolasetron) of from 25 mg to 300 mg; granisetron and phar 0101 Said amount of Component (b) sufficient to maxi maceutically acceptable salts and Solvates thereof, in particu mally alleviate disease-associated cognitive and other neu lar the hydrochloride, in an amount (in granisetron) of from robehavioral symptoms is from 1 time to 3 times, advanta 0.5 mg to 3 mg; ondansetron and pharmaceutically acceptable geously 15 times to 3 times, preferably 2-3 times the maximal salts and solvates thereof, in particular the hydrochloride dose contained in the currently used brand or generic AChEIs. dihydrate, in an amount (in ondansetron) of from 2 mg to 24 0102. As to Component (a), typical 5HT3-antagonist non mg; tropisetron and pharmaceutically acceptable salts and anticholinergic antiemetic agents (al) are the compounds Solvates thereof, in particular the hydrochloride, in an amount described in EP 191562, in particular ondansetron and phar of from 2.5 mg to 15 mg. domperidone and pharmaceutically maceutically acceptable salts and Solvates thereof; the com acceptable salts and Solvates thereof, in an amount (in dom pounds described in EP 200444, in particular granisetron and peridone) of from 5 mg to 30 mg; haloperidol, in an amount of pharmaceutically acceptable salts and Solvates thereof; the from 0.5 mg to 30 mg; chlorpromazine and pharmaceutically compounds described in EP 266730, in particular dolasetron acceptable salts and Solvates thereof, in particular the hydro and pharmaceutically acceptable salts and Solvates thereof. chloride, in an amount (in chlorpromazine) of from 12.5 mg the compounds described in U.S. Pat. No. 4,789,673, in par to 75 mg; prochlorperazine and pharmaceutically acceptable ticular tropisetron and pharmaceutically acceptable salts and salts and Solvates thereof, in particular the dimaleate, in an solvates thereof; and the compounds described in EP 430190. amount (in prochlorperazine) of from 2.5 mg to 30 mg; meto in particular palonosetron and pharmaceutically acceptable clopramide and pharmaceutically acceptable salts and Sol salts and solvates thereof. vates thereof, in particular the monohydrochloride monohy 0103 Typical DA-antagonists (a2) are domperidone and drate, in an amount (in metoclopramide) of from 5 mg to 30 pharmaceutically acceptable salts and Solvates thereof Such mg; bromopride and pharmaceutically acceptable salts and as the maleate; chlorpromazine and pharmaceutically accept solvates, in particular the monohydrochloride and the dihy able salts and solvates thereof such as the hydrochloride: drochloride monohydrate, in an amount (in bromopride) of prochlorperazine and its salts and Solvates, particularly the from 5 mg to 30 mg; clebopride and pharmaceutically accept dimaleate and the dimeSylate; promethazine and pharmaceu able salts and Solvates thereof, in particular the hydrogen tically acceptable salts and solvates thereof such as the hydro malate and the hydrochloride monohydrate, in an amount (in chloride; and 4-aminosalicylamide derivatives Such as meto clebopride) of from 0.25 mg to 1.5 mg; levosulpiride, in an clopramide and pharmaceutically acceptable salts and amount of from 12.5 mg to 300 mg, alizapride and pharma solvates thereof such as the hydrochloride monohydrate, bro ceutically acceptable salts thereof, in particular the hydro mopride and pharmaceutically acceptable salts and Solvates chloride, in an amount (in alizapride) of from 25 mg to 150 thereof such as the monohydrochloride or the dihydrochlo mg; trimethobenzamide and pharmaceutically acceptable ride monohydrate, aliZapride and pharmaceutically accept salts thereofsuch as the monohydrochloride, in an amount (in able salts and solvates thereof such as the hydrochloride, and trimethobenzamide) of from 150 mg to 900 mg; meclizine clebopride and pharmaceutically acceptable salts and Sol (also called meclozine) and pharmaceutically acceptable salts vates thereof such as the malate and the hydrochloride mono and solvates thereof, in an amount (in meclizine) of from 6.25 hydrate. mg to 150 mg; promethazine and pharmaceutically accept 0104 Typical histamine H1 receptor antagonists (a3) are able salts and solvates thereof, in particular the hydrochlo meclizine (meclozine) and pharmaceutically acceptable salts ride, in an amount (in prometazine) of from 12.5 mg to 150 and solvates thereof such as the hydrochloride monohydrate; mg; dronabinol in an amount of from 1.25 mg to 60 mg: promethazine and pharmaceutically acceptable salts and sol nabilone, in an amount of from 1 mg to 12 mg, aprepitant, in vates thereof such as the hydrochloride; chlorpromazine and an amount of from 20 mg to 375 mg; and casopitant, in an pharmaceutically acceptable salts and Solvates thereof Such amount of from 25 mg to 150 mg. as the hydrochloride, prochlorperazine and pharmaceutically 0.108 Preferred Component (a) is selected from the group acceptable salts and Solvates thereof Such as the dimaleate, consisting of ondansetron and pharmaceutically acceptable the dimesylate or the 12-ethanedisulfonate (1:1) (edisilate); salts and Solvates thereof, in an amount (in ondansetron) of hydroxy Zine and pharmaceutically acceptable salts and sol from 2 mg to 24 mg; granisetron and pharmaceutically US 2011/02O 1597 A1 Aug. 18, 2011

acceptable salts and Solvates thereof, in an amount (in gran istered IR dosage unit forms for the treatment of disorders isetron) of from 0.5 mg to 3 mg; domperidone and pharma Such as emesis or motion sickness. ceutically acceptable salts and Solvates thereof, in an amount 0114 More particularly, the non-anticholinergic anti (in domperidone) of from 5 mg to 30 mg; metoclopramide emetic is present, in an IR unit form, in an amount ranging and pharmaceutically acceptable salts and Solvates thereof, in from 50% to 200% of the maximum amount of said anti an amount (in metoclopramide) of from 5 mg to 30 mg: emetic agent contained in the currently administered IR dos dronabinol, in an amount of from 1.25 mg to 30 mg, nabilone, age unit forms for the treatment of the above-cited disorders in an amount of from 0.25 mg to 3 mg: aprepitant, in an or, in an ER unit form, in an amount ranging from 75% to amount of from 20 mg to 375 mg; and casopitant, in an 300% of the currently administered IR dosage unit forms for amount of from 25 mg to 150 mg. the treatment of the above-cited disorders. 0109 As to Component (b), typical AChEIs are 1,2,3,4- tetrahydro-9-acridinamine (tacrine), 9-amino-2,3,5,6,7,8- 0115 For example, among the advantageous non-anticho hexahydro-1H-cyclopentablquinoline (ipidacrine); 2.3-di linergic antiemetic agents used as Component (a), hydro-5,6-dimethoxy-2-1-(phenylmethyl)-4-piperidinyl ondansetron or a pharmaceutically acceptable salt or Solvate methyl)-1H-inden-1-one (donepezil) and its thereof, in particular its hydrochloride dihydrate, is present in pharmaceutically acceptable salts, (S) N-Ethyl-N-methyl an amount (in ondansetron) of from 2 mg to 16 mg per dosage 3-1-(dimethylamino)ethyl-phenyl carbamate (rivastig unit in an IR unit form or in an amount of from 3 mg to 24 mg. mine) and its pharmaceutically acceptable salts, 4aS,6R,8aS preferably from 8 mg to 24 mg, in an ER unit form; alosetron 3-methoxy-11-methyl-4a,5.9,10,11,12-hexahydroxy-6H or a pharmaceutically acceptable salt thereof, in particular its hydrochloride, is present in an amount (in alosetron) of from benzo furo3a,3,2-e.fbenzazepin-6-ol (galantamine) and its 0.25 mg to 2 mg per dosage unit in an IR unit form or in an pharmaceutically acceptable salts: (1R,9 S,13E)-1-amino amount of from 0.375 mg to 3 mg, preferably from 1 mg to 3 13-ethylidene-11-methyl-6-azatricyclo[7.3.1.0°trideca-2 mg, in an ER unit form; tropisetron or a pharmaceutically (7).3,10-trien-5-one (huperzine A) and (3aS,8 aR)-1,2,3,3a, acceptable salt thereof, in particular its hydrochloride, is 8.8a-Hexahydro-13a,8-trimethylpyrrolo2,3-bindol-5-ol present in an amount (intropisetron) of from 2.5 mg to 10 mg 5-(N-phenylcarbamate) and its pharmaceutically acceptable per dosage unit in an IR unit form or in an amount of from salts (phenserine) and its analogs encompassed by the general 3.75 mg to 15 mg, preferably from 5 mg to 15 mg, in an ER formula I. unit form; granisetron or a pharmaceutically acceptable salt 0110 Advantageous AChEIs include those now part of thereof, in particular its hydrochloride, is present in an standard care for patients suffering from a dementia of the amount (in granisetron) of from 0.5 mg to 2 mg per dosage Alzheimer type and that are also widely used off-label for unit in an IR unit form or in an amount of from 0.75 mg to 3 various other chronic progressive disorders of cognitive func mg, preferably from 1 mg to 3 mg, in an ER unit form; tion. AChEIS have as a general mechanism of action the dolasetron, or a pharmaceutically acceptable salt thereof, in enhancement of acetylcholine-mediated neurotransmission. particular its mesilate, is present in an amount (in dolasetron) All act in the human CNS to increase and prolong the avail of from 25 mg to 200 mg per dosage unit in an IR unit form or ability of acetylcholine by inhibiting its degradatory enzyme in an amount of from 37.5 mg to 300 mg, preferably from 100 acetylcholinesterase, Such as tacrine; huperzine A, donepezil; mg to 300 mg, in an ER unit form; domperidone or a phar pharmaceutically acceptable salts of donepezil, especially the maceutically acceptable salt thereof, in particular its maleate, hydrochloride thereof icopezil; pharmaceutically acceptable is present in an amount (in domperidone) of from 5 mg to 20 salts of icopezil, especially the maleate thereof. Zanapezil; mg per dosage unit in an IR unit form or in an amount of from pharmaceutically acceptable salts of Zanapezil, especially the 7.5 mg to 60 mg, preferably from 10 mg to 60 mg, in an ER fumarate thereof rivastigmine; pharmaceutically acceptable unit form; metoclopramide or a pharmaceutically acceptable salts of rivastigmine, especially the hydrogen tartrate thereof; salt or solvate thereof, in particular its monohydrochloride galantamine; pharmaceutically acceptable salts of galan monohydrate, is present in an amount (in metoclopramide) of tamine especially the hydrobromide thereof. from 5 mg to 20 mg per dosage unit in an IR unit form or in an 0111 Preferred Component (b) is an AChEI selected from amount of from 7.5 mg to 30 mg, preferably from 10.0 mg to the group consisting of phenserine and pharmaceutically 30.0 mg, in an ER unit form; allizapride or a pharmaceutically acceptable salts thereof, tacrine; huperzine A, donepezil and acceptable salt thereof, in particular its hydrochloride, is pharmaceutically acceptable salts thereof, in particular its present in an amount (inalizapride) of from 25 mg to 100 mg hydrochloride; rivastigmine and pharmaceutically acceptable per dosage unit in an IR unit form or in an amount of from salts thereof, in particular its hydrogen-(2R,3R)-tartrate (ri 37.5 mg to 300 mg, preferably from 100 mg to 300 mg, in an Vastigmine tartrate); galantamine and pharmaceutically ER unit form; meclizine or a pharmaceutically acceptable salt acceptable salts thereof, in particular its hydrobromide; the thereof, in particularits hydrochloride is present in an amount group consisting of the last three AChEIs and of their phar (in meclizine) of from 6.25 mg to 100 mg per dosage unit in maceutically acceptable salts being particularly preferred. As an IR unit form or in an amount of from 37.5 mg to 150 mg. set forth above, these AChEIs vary in their pharmacological preferably from 50 mg to 150 mg, in an ER unit form; chlo profiles and in their affinities for acetylcholinesterase and rpromazine or a pharmaceutically acceptable salt thereof, in butyrylcholinesterase. particular its hydrochloride is present in an amount (in chlo 0112 The dose of the Component (b) may vary according rpromazine) of from 12.5 mg to 200 mg per dosage unit in an to intrinsic acetylcholinesterase inhibiting potency of said IR unit form or in an amount of from 75 mg to 300 mg. component. preferably from 150 mg to 300 mg, in an ER unit form: 0113. In the unit forms of the present invention, for imme prochlorperazine or a pharmaceutically acceptable salt diate release or extended release, the antiemetic Component thereof, in particular its maleate is present in an amount (in (a) is present in an amount of from 50% to 300% of the prochlorperazine) of from 6.25 mg to 100 mg per dosage unit amount of said antiemetic contained in the currently admin in an IR unit form or in an amount of from 37.5 mg to 150 mg. US 2011/02O 1597 A1 Aug. 18, 2011

preferably from 50 mg to 150 mg, in an ER unit form; dron tered ER unit dosage forms for the treatment of Alzheimer abinol is present in an amount of from 1.25 mg to 20 mg per type dementia, and corresponding to about from 250% to dosage unit in an IR unit form or in an amount of from 1.8 mg 600% of the currently administered IR dosage unit forms. to 60 mg, preferably from 2.5 mg to 60 mg, in an ER unit I0121 For example, among the preferred Components (b), form, nabilone is present in an amount of from 0.25 mg to 2 rivastigmine (as the hydrogen tartrate thereof), is present in a mg per dosage unit in an IR unit form or in an amount of from ER-form as a patch releasing from 10 mg/24 hours to 24 0.75 mg to 3 mg perdosage unit in an ER unit form: aprepitant mg/24 hours, preferably 15 mg/24 hours to 24 mg/24 hours; is present in an amount of from 20 mg to 250 mg per dosage and galantamine (as the hydrobromide thereof), is present in unit in an IR unit form or in an amount of from 30 mg to 750 an ER oral unit form in an amount of from 24 mg to 72 mg, mg, preferably from 125 mg to 500 mg, in an ER unit form: preferably from 48 mg to 72 mg per dosage unit. and casopitant is present in an amount of from 25 mg to 150 I0122) Advantageously, said AChEI can be administered in mg per dosage unit in an IR unit form. a dose level that is higher than the maximal tolerated dose or 0116 Preferred Component (a) is a non-anticholinergic recommended maximal daily dose of the same AChEI when antiemetic agent selected from the group consisting of administered alone and will preferably be from 1.5 to 3 times ondansetron and pharmaceutically acceptable salts and Sol higher than the currently recommended doses in the treatment Vates thereof, in an amount (in ondansetron) of from 2 mg to of Alzheimer type dementia. 24 mg; granisetron and pharmaceutically acceptable salts and Solvates thereof, in an amount (in granisetron) of from 0.5 mg The Formulations to 3 mg; domperidone and pharmaceutically acceptable salts I0123. The unit form of the present invention may be a and Solvates thereof, in an amount (in domperidone) of from tablet, a capsule, a pre-measured Volume of a liquid Solution 5 mg to 30 mg; metoclopramide and pharmaceutically or Suspension for oral administration or a patch for transder acceptable salts and Solvates thereof, in an amount (in meto mal application. In said unit form the antiemetic agent and the clopramide) of from 5 mg to 30 mg. dronabinol, in an amount AChEI may be mixed together or separated according to of from 1.25 mg to 30 mg, nabilone, in an amount of from known technologies in admixture with a pharmaceutical car 0.25 mg to 3 mg, aprepitant, in an amount of from 20 mg to rier in a pharmaceutical composition. 375 mg; and casopitant, in an amount of from 25 mg to 150 0.124 Component (a) and Component (b) are formulated ng. with conventional pharmaceutical carriers in known formu 0117. In unit forms for immediate release or extended lations for oral use wherein said components are mixed release, the AChEI Component (b) is present in an amount of together or separated, for example in two tablets introduced in from 100% to 300% of the amount of said AChEI contained a capsule or in a two-compartment capsule or in a multilayer in the currently administered IR or ER dosage unit forms for (di-layer) tablet wherein the two components are both in IR or the treatment of Alzheimer type dementia. in ER form or one of the two components is in IR form and the 0118 More particularly, the AChEI Component (b) is other is in ER form, according to known technologies. present in an IR unit form, in an amount ranging from about 0.125. The pharmaceutical carriers and vehicles are those 100% to about 300%, preferably from 150% to 300%, of the commonly used for the preparation of compositions for oral, amount of said AChEI contained in the currently adminis buccal and parenteral, in particular transdermal, administra tered IR dosage unit forms for the palliative treatment of tion. Appropriate unit forms comprise the oral forms such as Alzheimer type dementia. tablets, soft or hard gelatin capsules, powders or granulates in 0119 For example, according to the present invention, Sachets and Suitably measured oral Solutions or Suspensions among the preferred Components (b), phenserine or a phar as well as patches for transdermal administration. maceutically acceptable salt thereof, preferably the tartrate, is 0.126 Component (a) and Component (b) may also be present in amount (in phenserine) of from 15 mg to 45 mg. present inform of one of their complexes with a cyclodextrin, advantageously from 22.5 mg to 45 mg, preferably from 30 for example C-cyclodextrin, B-cyclodextrin, Y-cyclodextrin, mg to 45 mg per dosage unit; tacrine is present in amount of 2-hydroxypropyl-3-cyclodextrin or methyl-3-cyclodextrin. from 10 mg to 120 mg, advantageously from 40 mg to 120 I0127 Component (a) and Component (b) may also be mg, preferably from 60 mg to 120 mg per dosage unit; formulated in the form of microcapsules, optionally with one huperzine A is present in an amount of from 50g to 400 mg. or more carriers or additives. advantageously from 100 ug to 150 lug, preferably from 200 I0128. For oral administration, Component (a) and Com ug to 400g per dosage unit, donepezil or a pharmaceutically ponent (b), together or separately, are formulated by mixing acceptable salt thereof, preferably the hydrochloride, is the active ingredient with conventional pharmaceutical present in an amount (in donepezil) of from 5 mg to 30 mg. acceptable carriers enabling said active ingredients to be for advantageously from 10 mg to 30 mg, preferably from 15 mg mulated in tablets, dragees, orally disintegrating tablets, cap to 30 mg, per dosage unit; rivastigmine or a pharmaceutically Sules, liquid solutions or Suspensions, syrups and the like. acceptable salt thereof, preferably the hydrogen tartrate, is I0129 Carriers for IR tablets include for example starches, present in an amount (in rivastigmine) of from 1.5 mg to 18 cellulose and derivatives thereof: lubricants such as talc, mg, advantageously from 6 mg to 18 mg, preferably from 9 Stearic acid or magnesium Stearate; diluents such as talc, mg to 18 mg per dose unit; and galantamine, or a pharmaceu powdered cellulose, lactose, starches such as maize or corn tically acceptable salt thereof, preferably the hydrobromide, Starch, mannitol, Sorbitol, disaggregating agents Such as is present in an amount (in galantamine) of from 4 mg to 36 microcrystalline cellulose or crospovidone; lubricants such mg, advantageously from 12 mg to 36 mg, preferably from 16 as polyethylenglycol or magnesium Stearate; ligands Such as mg to 36 mg per dosage unit. methylcellulose, Sodium carboxymethylcellulose, alginic 0120. The AChEI Component (b) is also present in an ER acid, alginates; Sweeteners, such as saccharose, dextrose, unit form in an amount ranging from 100% to 300% of the mannitol, Saccharin; or flavoring agents such as natural or amount of said AChEI contained in the currently adminis synthetic oils. US 2011/02O 1597 A1 Aug. 18, 2011

0130 Carriers for orally disintegrating tablets include for thereof, in an amount (in domperidone) of from 5 mg to example lubricants, aggregating, Sweetening, flavoring or 30 mg; metoclopramide and the pharmaceutically disaggregating agents as well as agents improving the buccal acceptable salts and Solvates thereof, in an amount (in mucosa absorption of Components (a) and (b) Such as Sorbi metoclopramide) of from 5 mg to 30 mgalizapride and tol, mannitol, lactose and cellulose. the pharmaceutically acceptable salts thereof, in an 0131 Carriers for liquid, normally aqueous, Suspensions amount (in alizapride) of from 25 mg to 150 mg. dron or solutions include for example antioxidants, such as sodium abinol, in an amount of from 1.25 mg to 30 mg per metabisulfite or sodium Sulfite, thickening agents, such as dosage unit; nabilone, in an amount of from 1 mg to 12 microcrystalline cellulose, hydroxypropylcellulose, car mg, aprepitant in an amount of from 20 mg to 375 mg: boxymethylcellulose or polyvinylpyrrolidone, preservatives and casopitant in an amount of from 25 mg to 150 mg, as Such as methyl paraben, ethyl paraben, Sodium ethylenedi Component (a); and aminotetracetate, Sodium benzoate or an alkaline Salt of Sor bic acid, as well as flavoring and Sweetening agents. 0.139 a member selected from the group consisting of 0132) The Sweeteners contained in the orally disintegrat tacrine, in an amount of from 10 mg to 120 mg, advan ing tablets and the liquid Suspensions or Solutions may be tageously of from 40 mg to 120 mg preferably of from 60 natural, optional reduced Sugars such as Sucrose, dextrose, mg to 120 mg, huperzine A, in an amount of from 50 g Xylitol, mannitol or Sorbitol, or synthetic product such as to 400 ug, advantageously of from 100 g to 150 ug, Sodium saccharine or aspartame. preferably from 200 ug to 400 lug; donepezil and phar 0133. The flavoring agents are pharmaceutically accept maceutically acceptable salts thereof, in an amount (in able flavors and tastes of synthetic and natural oils, the latter donepezil) of from 5 mg to 30 mg, advantageously of extracted from plants, leaves, flowers, fruits and their combi from 10 mg to 30 mg, preferably from 15 mg to 30 mg: nations, such as cinnamon, peppermint, anise and citron rivastigmine and its pharmaceutically acceptable salts, leaves, bitter almond, citrus fruits, in particular orange and/or in an amount (in rivastigmine) of from 1.5 mg to 18 mg lemon, linden and grapefruit oils. Also chocolate, Vanilla or advantageously of from 6 mg to 18 mg, preferably from eucalyptus flavor and essences of fruit, in particular apple, 9 mg to 18 mg; and galantamine and its pharmaceuti pear, peach, Strawberry, cherry, apricot, orange, lemon and cally acceptable salts, in an amount, in galantamine, of grapes may be advantageously used. from 4 mg to 36 mgadvantageously of from 12 mg to 36 0134. The composition according to the present invention mg, preferably from 16 mg to 36 mg; as Component (b). may be in form of a capsule containing two tablets as described herein above, one of them comprising Component in admixture with a pharmaceutical carrier. (a) and the other comprising Component (b). 0140 Preferred units forms comprise 0135 The association of a non-anticholinergic antiemetic 0141 (a) a non-anticholinergic antiemetic agent selected and an AChEI may be formulated in tablets in which one or form the group consisting of ondansetron and pharmaceu both of the two components is in controlled-release formula tically acceptable salts and Solvates thereof, in an amount tion, for example as a dispersion of said component in (in ondansetron) of from 2 mg to 16 mg; granisetron and hydroxypropyl methyl cellulose or in a film-coated micro pharmaceutically acceptable salts and Solvates thereof, in granule. Advantageously, the AChEI, in a an ER-formulation an amount (in granisetron) of from 0.5 mg to 2 mg; dom is in the core and the non-anticholinergic antiemetic agent, in peridone and pharmaceutically acceptable salts and Sol IR-formulation, is in the outer layer in multi-layer tablets in Vates thereof, in an amount (in domperidone) of from 5 mg which, for example, both the core and the outer layer are to 20 mg; metoclopramide and pharmaceutically accept coated with a film. Analogously, capsules made of two sepa able salts and Solvates thereof, in an amount (in metoclo rated parts, one containing Component (a), in IR- or ER pramide) of from 5 mg to 20 mg. dronabinol, in an amount formulation and the other containing Component (b), in IR of from 1.25 mg to 20 mg, nabilone, in an amount of from or ER-formulation, may be used 0.25 mg to 2 mg, aprepitant, in an amount of from 20 mg to 0136 Carriers and vehicles for ER tablets include retar 250 mg; and casopitant, in an amount of from 25 mg to 100 dant materials such as is acrylic and methacrylic acid poly mg; and mers and copolymers; cellulose derivatives such as hydrox ypropylmethylcellulose, hydroxyethylcellulose, 0.142 (b) an AChEI selected from the group consisting of hydroxypropylethylcellulose, hydroxypropylcellulose, donepezil and pharmaceutically acceptable salts thereof, in methylcellulose, ethylcellulose, or sodium carboxymethyl an amount (in donepezil) of from 15 mg to 30 mg; rivastig cellulose; gums, waxes; glycerides or aliphatic alcohols or a mine and pharmaceutically acceptable salts thereof, in an mixture thereof. amount (in rivastigmine) of from 9 mg to 18 mg; and 0.137 In particular, the unit forms of the present invention galantamine and pharmaceutically acceptable salts comprise thereof, in an amount (in galantamine) of from 16 mg to 36 0.138 a non-anticholinergic antiemetic agent selected ng from the group consisting of ondansetron and the phar in admixture with a pharmaceutical carrier. maceutically acceptable salts and Solvates thereof, in an 0.143 Such unit forms, formulated as IR oral composi amount (in ondansetron) of from 2 mg to 24 mg; gran tions, are particularly preferred. isetron and the pharmaceutically acceptable salts and 0144. According to an embodiment, the compositions of Solvates thereof, in an amount (in granisetron) of from the present invention are formulated by mixing the Compo 0.5 mg to 3 mg. dolasetron and the pharmaceutically nent (a) and the Component (b) together, in admixture with a acceptable salts and Solvates thereof, in an amount (in pharmaceutical carrier for an immediate or extended release. dolasetron) of from 25 mg to 300 mg; domperidone and An advantageous composition according to this embodiment the pharmaceutically acceptable salts and Solvates comprises an amount of granisetron hydrochloride corre US 2011/02O 1597 A1 Aug. 18, 2011

sponding to from 0.5 mg to 2 mg of granisetron, as Compo in admixture with a pharmaceutical carrier in an IR-formula nent (a); and tion for buccal mucosa absorption, said composition being 0145 from 10 mg to 20 mg, preferably from 15 mg to 20 destined to be administered once or twice per day. mg, of donepezil (as hydrochloride); or 0156 According to another embodiment, the composi 0146 from 6 mg to 18 mg, preferably from 9 mg to 18 tions of the present invention are formulated in solutions for mg, of rivastigmine (as hydrogen tartrate); or oral administration wherein Component (a) and Component 0147 from 12 mg to 24 mg, preferably from 18 mg to 24 (b) are dissolved or suspended in water in admixture with mg, of galantamine (as hydrobromide), conventional carrier or vehicles. Particularly advantageous compositions according to this embodiment are oral Solutions as Component (b), wherein Components (a) and (b) are mixed or Suspensions, each unit form thereof comprising together and with a pharmaceutical carrier in an IR-formula 0157 a Component (a) selected from the group consist tion, said composition being destined to be administered once ing of ondansetron (as hydrochloride dihydrate) in an or twice per day. amount of from 8 mg to 16 mg, preferably from 12 mg to 0148. According to another embodiment, the composi 16 mg: tions of the present invention are formulated by mixing the 0158 domperidone (as maleate) in an amount of from Component (a) with a pharmaceutical carrier for an immedi 10 mg to 20 mg, preferably from 15 mg to 20 mg, and ate or extended release in tablets (Tablet A) and the Compo metoclopramide (as hydrochloride monohydrate) in an nent (b), separately, with a pharmaceutical carrier for an amount of 10 mg to 20 mg, preferably from 15 mg to 20 immediate or extended release in tablets (Tablet B) and intro mg; and ducing Tablet A and Tablet B in a capsule for oral adminis 0159 from 12 mg to 24 mg., preferably from 18 mg to 24 tration as described for example in GB 1204580 or in US mg, of galantamine (as hydrobromide), as Component 2007/0224259. An advantageous composition according to (b), this embodiment consists of soft or hard gelatine capsules in admixture with a pharmaceutical carrier in a liquid IR each containing Tablet A comprising an amount of dolasetron formulation for oral administration, said composition being mesylate hydrate equivalent to from 25 mg to 200 mg of destined to be administered, in said dosage unit form, once or dolasetron, as Component (a), in admixture with a pharma twice per day. ceutical carrier in a IR formulation; and Tablet B, comprising 0160 According to another embodiment, the composi 0149 from 10 mg to 20 mg, preferably from 15 mg to 20 tions of the present invention are formulated in patch for mg, of donepezil (as hydrochloride); or transdermal administration. Particularly advantageous com 0150 from 6 mg to 18 mg, preferably from 9 mg to 18 positions according to this embodiment are transdermal patch mg, of rivastigmine (as hydrogen tartrate); or formulations comprising 0151 from 12 mg to 24 mg, preferably from 18 mg to 24 0.161 from 2 mg/24 hours to 6 mg/24 hours of granis mg, of galantamine (as hydrobromide), etron (as hydrochloride), as Component (a); and as Component (b), with a pharmaceutical carrier in an IR 0162 from 10-15 mg/24 hours to 24 mg/24 hours of formulation, said composition being destined to be adminis rivastigmine (as hydrogen tartrate), as Component (b). tered once or twice per day. with a pharmaceutically acceptable carrier or diluent which is 0152. According to a further embodiment, the composi Suitable for systemic transdermal administration. tions according to the present invention are formulated in a 0163 Another embodiment of the present invention pro di-layer tablet which releases two drug doses, in which the vides units forms consisting of tablets comprising release of a drug from one drug-containing layer does not 0.164 from 10 mg to 20 mg, preferably from 15 mg to 20 interfere with the release of a drug from the other drug mg of metoclopramide (as hydrochloride monohydrate), containing layer as described for example in WO 2006/ as Component (a); and 089493. An advantageous composition according to this 0.165 from 12 mg to 24 mg., preferably from 18 mg to 24 embodiment consists of mg, of galantamine (as hydrobromide), as Component Layer A, comprising an amount of ondansetron hydrochlo (b), ride dihydrate equivalent to from 8 mg to 16 mg, preferably in admixture with a pharmaceutical carrier in a IR-formula from 12 mg to 16 mg, ofondansetron, as Component (a), with tion for oral administration, said composition being destined a pharmaceutical carrier in a IR formulation and to be administered once or twice per day. Layer B, comprising 12 mg to 24 mg, preferably from 18 mg 0166 Another embodiment of the present invention pro to 24 mg of galantamine (as hydrobromide), vides units forms consisting of tablets comprising 0.167 from 10 mg to 20 mg, preferably from 15 mg to 20 as Component (b), in admixture with a pharmaceutical carrier mg, of domperidone (as maleate), as Component (a): in an IR-formulation, said composition being destined to be and administered once or twice per day. 0168 from 6 mg to 18 mg, preferably from 9 mg to 18 0153. According to another embodiment, the composi mg, of rivastigmine (as hydrogen tartrate), as Compo tions of the present invention are formulated in oral disinte nent (b). grable tablets. Particularly advantageous compositions in admixture with a pharmaceutical carrier in a IR-formula according to this embodiment are orally disintegrable tablets tion for oral administration, said composition being destined comprising to be administered once or twice per day. 0154 an amount of ondansetron hydrochloride dihy 0169. A particularly advantageous embodiment of the drate equivalent to from 8 mg to 16 mg, preferably from present invention provides units forms consisting of capsules 12 mg to 16 mg. of ondansetron, as Component (a); and comprising 0155 from 10 mg to 20 mg, preferably from 15 mg to 20 0170 from 40 mg to 250 mg, preferably from 80 mg to mg, of donepezil hydrochloride, as Component (b). 250 mg. of aprepitant, as Component (a); and US 2011/02O 1597 A1 Aug. 18, 2011

0171 from 15 mg to 30 mg, preferably from 20 mg to 30 Example 2 mg, of donepezil (as hydrochloride), as Component (b). 0177 Capsules for IR oral administration are prepared by in admixture with a pharmaceutical carrier in a IR-formula mixing the following ingredients: tion for oral administration, said composition being destined to be administered once a day. 0172. As compared to known drugs of the acetylcholinest Ingredients Parts by weight erase inhibitor type now used alone in the treatment of Alzhe Rivastigmine (as hydrogen tartrate) 900 imer type dementias, the above combined pharmaceutical Domperidone (as maleate) 1,000 compositions show greater and longer efficacy and less Lactose USP 7,350 adverse effects by allowing the safe and tolerable administra Colloidal silicon dioxide 50 tion of larger and thus more therapeutically effective quanti ties of said acetylcholinesterase inhibitor. In particular, the 0.178 After mixing, the mixture is screened through a 40 acetylcholinesterase inhibitor of the pharmaceutical compo mesh screen and introduced in two-piece hard gelatin cap sitions of the present invention is safe and effective, alone or Sules No. 3, each containing 9 mg of rivastigmine and 10 mg in combination with other pharmaceuticals, in treating of domperidone. patients in need of an acetylcholinesterase inhibition, in par ticular dementias of the Alzheimer type on a once or twice Example 3 daily basis. 0179 Tablets for IR oral administration containing 5 mg 0173 The pathologic conditions treated with the compo of donepezil hydrochloride formulated with a pharmaceutical sition of the present invention include, but are not limited to, carrier, tablets containing 10 mg of donepezil hydrochloride Alzheimer's disease, Parkinson's disease dementia, and other formulated with a pharmaceutical carrier and tablets contain disorders of human cognitive and neurobehavioral function ing 10 mg of metoclopramide formulated with a pharmaceu that are treated, in part, by pharmaceuticals intended to aug tical carrier are distributed in capsules as described in GB 1.254.580. Such that unit dosage forms containing 15 mg of ment brain acetylcholine-mediated neurotransmission. donepezil hydrochloride and 10 mg of metoclopramide are 0.174. The therapeutic efficacy is measured by the degree prepared. to which cognitive and other neurobehavioral disabilities associated with dementias of the Alzheimer type, as docu Example 4 mented by the use of standard scales, are reduced. 0180. The calculated amounts of metoclopramimide 0.175. The following examples illustrate the invention. monohydrochloride monohydrate, galantamine hydrobro mide, methyl parahydroxybenzoate, propyl parahydroxyben Example 1 Zoate, Sodium saccharin, sodium Sorbate, hydroxymethylcel lulose, propylene glycol, ethanol, mandarin oil, caramel oil, Orally Disintegrating Tablets Containing 15 Mg of custard oil, Sodium hydroxide and purified water are mixed Donepezil Hydrochloride and 4 Mg of Ondansetron and formulated, according to conventional techniques, to pre pare 100 ml of an oral Solution, containing 10 mg/ml of 0176 One and a halfkilogram of donepezil hydrochloride metoclopramide and 6 mg/ml of galantamine, for a IRadmin and 1.8 kg of corn starch are mixed thoroughly until complete istration, having the following composition homogenizing of the mixture which, after a passage through a 35 mesh sieve, is added with a previously prepared mixture of 400g ofondansetron base, thoroughly stirred together with metoclopramide monohydrochloride monohydrate 105.000 mg 2.4 kg of corn starch and sieved at 35 mesh. The mixture thus galantamine hydrobromide 7.668 mg obtained is added with 0.6 kg of strawberry flavor powder, 0.2 methyl p-hydroxybenzoate 80.000 mg propyl p-hydroxybenzoate 20.000 mg kg of sodium saccharin, 13.08 kg of lactose, 4.4 kg of micro Sodium Sorbate 100.000 mg crystalline cellulose, and 2.9 kg of sorbitol. The mixture is hydroxymethylcellulose 400.000 mg mixed until complete homogenization, then it is added with Sodium saccharin 0.076 mg propylene glycol 0.500 ml 0.1 kg of magnesium Stearate, mixed again and compressed ethanol 1.000 ml with punches of 7 mm to obtain 100,000 orally disintegrating mandarin oil 0.400 ml tablets having the following composition caramel oil 0.500 ml custard oil 0.010 ml Sodium hydroxide to pH 3.0 purified water to 100.000 ml Donepezil hydrochloride 15.00 mg Ondansetron 4.00 mg Corn starch 42.00 mg Strawberry flavor powder 6.00 mg Example 5 Sodium saccharin 2.00 mg Lactose 130.00 mg 0181. The calculated amounts of galantamine hydrobro Microcrystalline cellulose 44.00 mg mide, metoclopramimide monohydrochloride monohydrate, Sorbitol 29.00 mg guar gum, methyl cellulose, ethyl cellulose, silica gel, potato Magnesium Stearate 1.00 mg starch, Sorbitol and pentaerytritol are mixed and formulated, according to conventional techniques, to prepare 150-mg IR tablets having the following composition US 2011/02O 1597 A1 Aug. 18, 2011 16

11. The method of claim 6, wherein said NK1 receptor antagonist is aprepitant or casopitant. Galantamine hydrobromide 23.06 mg 12. The method of claim 6, wherein said AChEI is selected Metoclopramide monohydrochloride monohydrate 10.50 mg from the group consisting of 1.2.3,4-tetrahydro-9-acridi Guar gum 2.00 mg namine (tacrine): (1R,9S.13 E)-1-amino-13-ethylidene-11 Methylcellulose 2.00 mg methyl-6-azatricyclo7.3.1.02.7trideca-2 (7).3,10-trien-5- Ethylcellulose 2.00 mg one (huperzine A); (+)-2,3-dihydro-5,6-dimethoxy-2-1- Silica gel 3.00 mg Potato starch 5.00 mg (phenylmethyl)-4-piperidinyl)methyl)-1H-inden-1-one Sorbitol 2.44 mg (donepezil) and pharmaceutically acceptable salts thereof. Pentaerythritol 97.00 mg (S)- N-Ethyl-N-methyl-3-1-(dimethylamino)ethyl-phe nyl carbamate (rivastigmine) and pharmaceutically accept 1. A method for increasing the therapeutic effect of an able salts thereof; and 4aS,6R,8aS-3-methoxy-11-methyl-4a, acetylcholinesterase inhibitor (AChEI) in a patient suffering 5.9,10,11,12-hexahydroxy-6H-benzofuro3a,3,2-ef from an Alzheimer type dementia, which comprises admin benzazepin-6-ol (galantamine) and its pharmaceutically istering to said patient said AChEI at a dose level which is acceptable salts thereof. higher than the recommended maximal dose level, in combi 13. The method of claim 5, wherein said pharmaceutical nation with a compound that reduces, including to the extent composition containing the non-anticholinergic antiemetic of eliminating, dose-limiting side effects of said AChEI dose agent is in a unit form also containing an AChEI. level, said compound being a non-anticholinergic antiemetic 14. A pharmaceutical unit form which comprises agent. (a) a non-anticholinergic antiemetic agent selected from 2. The method of claim 1, wherein said dose level is the group consisting of 5-HT3 receptor antagonists, increased up to a factor of 4. dopamine antagonists, H1 histamine receptor antago 3. The method of claim 1, wherein said AChEI is admin nists, cannabinoid agonists, aprepitant and casopitant; istered to said patient concurrently or sequentially with said and non-anticholinergic antiemetic agent, whereby an enhanced (b) an AChEI: acetylcholinesterase inhibition in the CNS of said patient is in admixture with a pharmaceutical carrier. achieved and the symptoms of an Alzheimer type dementia in 15. The unit form of claim 14 wherein said non-anticho said patient are improved. linergic antiemetic agent is selected from the group consist 4. The method of claim 1, wherein said AChEI is admin ing of ondansetron and pharmaceutically acceptable salt istered to said patient at a dose level which is from 1.5 to 3 thereof, in an amount (inondansetron) of from 2 mg to 24 mg. times higher than the recommended dose in the treatment of granisetron and pharmaceutically acceptable salt thereof, in Alzheimer type dementia. an amount (in granisetron) of from 0.5 mg to 3 mg; domperi 5. The method of claim 1, wherein the non-anticholinergic done and pharmaceutically acceptable salts thereof, in an antiemetic agent is formulated in a pharmaceutical composi amount (in domperidone) of from 5 mg to 30 mg; metoclo tion, in admixture with a pharmaceutical carrier, in an amount pramide and pharmaceutically acceptable salts and Solvates of from 50% to 300% of the dosage used for preventing thereof, in an amount (in metoclopramide) of from 5 mg to 30 Vomiting. mg; dronabinol, in an amount of from 1.25 mg to 30 mg: 6. The method of claim 1, wherein said non-anticholinergic nabilone, in an amount of from 0.25 mg to 3 mg, aprepitant, antiemetic agent is selected from the group consisting of in an amount of from 20 mg to 375 mg; and casopitant, in an 5-HT3 receptor antagonists, dopamine antagonists, H1 hista amount of from 25 mg to 150 mg. mine receptorantagonists, NK1 receptorantagonists and can 16. The unit form of claim 14, wherein said AChEI is nabinoid agonists. selected from the group consisting of phenserine and phar 7. The method of claim 6, wherein said non-anticholinergic maceutically acceptable salts thereof, in an amount (in antiemetic agent is a 5HT3-antagonist selected from the phenserine) of from 15 to 45 mg. tacrine, in an amount of group consisting of ondansetron, the pharmaceutically from 10 mg to 120 mg; huperzine A, in an amount of from 50 acceptable salts and Solvates of ondansetron, granisetron, the ug to 400 ug; donepeziland pharmaceutically acceptable salts pharmaceutically acceptable salts and Solvates of granisetron, thereof, in an amount (in donepezil) of from 5 mg to 30 mg: tropisetron, the pharmaceutically acceptable salts and sol rivastigmine and pharmaceutically acceptable salts thereof, Vates of tropisetron, lerisetron, the pharmaceutically accept in an amount (in rivastigmine) of from 1.5 mg to 18 mg: able salts and Solvates of lerisetron, ramosetron and the phar galantamine and pharmaceutically acceptable salts thereof, in maceutically acceptable salts and Solvates of ramosetron. an amount (in galantamine) of from 4 mg to 36 mg. 8. The method of claim 6, wherein said dopamine antago 17. The unit form of claim 14, wherein said AChEI is nist is selected from the group consisting of domperidone, the selected from the group consisting of donepezil and pharma pharmaceutically acceptable salts of domperidone, metoclo ceutically acceptable salts thereof, in an amount (in done pramide, the pharmaceutically acceptable salts and Solvates pezil) of from 15 mg to 30 mg; rivastigmine and pharmaceu of metoclopramide, bromopride, the pharmaceutically tically acceptable salts thereof, in an amount (in rivastigmine) acceptable salts of bromopride, clebopride, the pharmaceuti of from 9 mg to 18 mg; and galantamine and pharmaceuti cally acceptable salts of clebopride, alizapride and the phar cally acceptable salts thereof, in an amount (in galantamine) maceutically acceptable salts of alizapride. of from 16 mg to 36 mg. 9. The method of claim 6, wherein said H1 histamine 18. The unit form of claim 14, wherein said AChEI is receptor antagonist is meclizine or a pharmaceutically selected from the group consisting of rivastigmine and phar acceptable salt or solvate thereof. maceutically acceptable salts thereof, in an amount (in 10. The method of claim 6, wherein said cannabinoid ago rivastigmine) of from 10 mg to 24 mg; and galantamine and nist is dronabinol or nabilone. pharmaceutically acceptable salts thereof, in an amount (in US 2011/02O 1597 A1 Aug. 18, 2011 17 galantamine), of from 24 mg to 72 mg; said unit form being mg; dronabinol, in an amount of from 1.25 mg to 20 mg: formulated for ER administration. nabilone, in an amount of from 0.25 mg to 2 mg: aprepi 19. The unit form of claim 14, wherein tant, in an amount of from 20 mg to 250 mg, and caso pitant, in an amount of from 25 mg to 100 mg; and (a) the non-anticholinergic antiemetic agent is selected (b) the AChEI is selected from the group consisting of form the group consisting of ondansetron and pharma- donepezil and pharmaceutically acceptable salts ceutically acceptable salts and Solvates thereof, in an thereof, in an amount (in donepezil) of from 15 mg to 30 amount (in ondansetron) of from 2 mg to 16 mg; gran- mg; rivastigmine and pharmaceutically acceptable salts isetron and pharmaceutically acceptable salts and Sol- thereof, in an amount (in rivastigmine) of from 9 mg to Vates thereof, in an amount (in granisetron) of from 0.5 18 mg; and galantamine and pharmaceutically accept mg to 2 mg; domperidone and pharmaceutically accept- able salts thereof, in an amount (in galantamine) of from able salts and Solvates thereof, in an amount (in domp- 16 mg to 36 mg; eridone) of from 5 mg to 20 mg; metoclopramide and said unit form being formulated as IR oral composition. pharmaceutically acceptable salts and Solvates thereof, in an amount (in metoclopramide) of from 5 mg to 20 ck