AU2004242546B2

AU2004242546B2 - Dosage formulations for acetylcholinesterase inhibitors

Info

Publication number: AU2004242546B2
Application number: AU2004242546A
Authority: AU
Inventors: Bonnie Davis
Original assignee: Individual
Current assignee: Individual
Priority date: 1998-11-23
Filing date: 2004-12-30
Publication date: 2008-05-15
Anticipated expiration: 2019-11-19
Also published as: AU2004242546A1

Description

S&FRef: 557532D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Bonnie Davis, of 160 Cold Spring Road, Syosset, New York, 11791, United States of America Bonnie Davis Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Dosage formulations for acetylcholinesterase inhibitors The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c Dosage Formulations for Acetylcholinesterase Inhibitors 0.

SField of the Invention The present invention relates to dosage forms for cholinesterase inhibitors that will \jO assist in obviating some of the undesirable side effects of use of such drugs and in methods of administering such drugs for this purpose.

Cl- SBackground of the Invention Recently there has been considerable interest in the use of several drugs in this class including tacrine, donepezil, physostigmine, rivastigmine and galanthamine for the treatment of Alzheimer's disease. Cholinergic drugs are known to have an effect on the body's circadian rhythms and in U. S. Patent 5585375, I have claimed the use ofgalanthamine for treatment of jet lag. Although beneficial in some respects, circadian effects ofcholinergic drugs may cause problems for care givers in cases where the patient is unable to take care of his or herself since it can result in the patient becoming active and needing attention during the night.

Summary of the Invention The object of the present invention is to time the release of acetylcholinesteraseinhibiting medication so as to provide it on a suitable physiological schedule, for example to ensure that it can be taken while a patient is awake in the evening and will be acting at the time of expected awakening in the morning and to provide dosage forms suitable for this purpose.

4- From a first aspect, the present invention provides dosage forms of a pharmaceutical composition which comprise an effective amount of an acetylcholinesterase inhibitor wherein the acetylcholinesterase inhibitor is formulated so as to delay its activity for a specified period.. For example in one aspect such delay will be for a period of four to twelve hours so 00 O that a dose may be administered to the patient in the evening and allow a night's sleep N before the acetylcholinesterase inhibitor becomes active in the morning. The duration of a delay chosen will depend upon the exact way in which it is chosen to administer the drug.

For example if it is intended to administer the drug with an evening meal taken at, say 6:30 in the evening a twelve hour delay may be appropriate if one wishes the drug to be active the following morning. If the desired time of administration is bed time, however, a six or seven hour delay may be more useful.

C From a second aspect, the present invention provides a method of treatment of a to patient suffering from a disease or condition in which it is desirable to administer a C centrally acting acetylcholinesterase inhibitor, such as Alzheimer's disease, which comprises administering a dosage form of a pharmaceutical composition which comprises an effective amount of an acetylcholinesterase inhibitor wherein the acetylcholinesterase inhibitor is formulated so as to delay its activity for a specified period prior to acetylcholinesterase inhibition being desired.

According to one embodiment of this invention there is provided a dosage form of a pharmaceutical composition which comprises an effective amount of a centrallyacting acetylcholinesterase inhibitor for the treatment of Alzheimer's disease selected from the group consisting of galanthamine, lycoramine, analogs of galanthamine, analogs of lycoramine and rivastigmine; said compounds having a half life of from one to eleven hours wherein acetylcholinesterase inhibitor is formulated so as to delay its activity for a predetermined period of from four to twelve hours such that acetylcholinesterase inhibition is avoided during such predetermined period.

According to another embodiment of this invention there is provided a method of treatment of a patient suffering from Alzheimer's disease which comprises administering a dosage form of pharmaceutical composition which comprises an effective amount of a centrally acting acetylcholinesterase inhibitor useful in the treatment of Alzheimer's disease selected from the group consisting of galanthamine, lycoramine, analogs of galanthamine and lycoramine and rivastigmine said compounds having a half life of from one to eleven hours wherein the acetylcholinesterase inhibitor is formulated so as to delay its activity for a specified period of from four to twelve hours, such that acetylcholinesterase inhibition is avoided during such predetermined period and wherein said administration is effected at a time prior to a patient's sleeping such that the activity 1201625 1:LNB 1-MAY-2008 12:03 SPRUSON FERGUSON 92615436 NO. 0434 P. 9 2a 00 o of the cholinesterase inhibitor is delayed until after the patient has completed a period of N sleep.

According to a further embodiment of this invention there is provided a method of 0 5 treatment of a patient suffering from Alzheimer's disease which comprises administering a delayed release dosage form of a pharmaceutical composition which comprises an effective amount for treating Alzheimer's disease of a centrally acting acetylcholinesterase inhibitor selected from the group consisting of galanthamine, lycoramine, analogs of galanthamine and analogs oflycoramine and rivastigmine wherein (o 1 said analogs of galanthamine or lycoramine are compounds wherein one or more of the Smethoxy, hydroxy or N-methyl groups is replaced as follows: the methoxy group by 0 another alkoxy group of from two to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group, a carbonate group or a carbamate group; the hydroxy group by an alkoxy group of from one to six carbon atoms, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group; a carbonate group or a carbamate group; the N-methyl group by hydrogen, alkyl, benzyl or a cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group; and wherein said dosage is formulated such that the half life of the activity of the acetylcholinesterase inhibitor and the degree of delayed release are selected such that the 2o formulation may be administered to the patient such that release of acetylcholinesterase inhibitor is avoided for the next anticipated sleep time and wherein administration of the drug is at an appropriate time to achieve such results.

According to yet a further embodiment of this invention there is provided a method of treating Alzheimer's disease comprising administration to a patient suffering therefrom a delayed release composition comprising a centrally acting acetylcholinesterase inhibitor selected from the group consisting of galanthamine, lycoramine, analogs of galanthamine, analogs of lycoramine and rivastigmine wherein said analogs of galanthamine or lycoramine are compounds wherein one or more of the methoxy, hydroxy or N-methyl groups is replaced as follows: the methoxy group by another alkoxy group of from two to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group, a carbonate group or a carbamate group; the hydroxy group by a alkoxy group of from one to six carbon atoms, hydrogen, an alkanoyloxy group, a s3 benzoyloxy or substituted benzoyloxy group; a carbonate group or a carbamate group; the 1221933 1:LNB COMS ID No: ARCS-188846 Received by IP Australia: Time 12:07 Date 2008-05-01 1-MAY-2008 12:04 SPRUSON FERGUSON 92615486 NO. 0)434 P. 2b oO o N-methyl group by hydrogen, alkyl, benzyl or a cyclopropylmethyl group or a substituted or unsubstituted beazoyloxy group; said compounds having a half life of from one to eleven hours wherein the nature of the composition and the time of administration of said composition is such that release of said acetylcholinesterase inhibitor from said Ss composition is minimized prior to and during desired sleep hours so as to allow the patient's central nervous system to become hypocholinergic during the period of desired Ssleep as compared to its cholinergic activity during hours when desired to be awake so as f to avoid sleep disturbance during hours of desired sleep while providing therapeutic activity at other times.

SAccording to a further embodiment there is provided use of a centrally-acting acetylcholinesterase inhibitor selected from the group consisting of galanthamine, lycoramine, analogs of galanthamine, analogs of lycoramine and rivastigmnine; said compounds having a half life of from one to eleven hours in the preparation of a dosage form of a medicament for the treatment of Alzheimer's disease wherein the acetyleholinesterase inhibitor is formulated so as to delay its activity for a predetermined period of from four to twelve hours such that acetylcholinesterase inhibition is avoided during such predetermined period.

Detailed Description of the Invention Acetylcholinesterase inhibitors of use in the present invention are those that have a central effect and have a medium duration of action (typically from 2 to 12 hours) for the treatment of diseases where acetylcholinesterase inhibiting activity in the brain is desired, especially in the treatment of Alzheimer's disease. Suitable acetylcholinesterase inhibitors will typically have a half life in the body of from 1 to 11 hours and once released from the dosage form will pass easily through the blood-brain barrier. The most suitable compounds for this purpose are galanthamine, lycoramine and their analogs wherein at least one of the methoxy, hydroxy or methyl groups of the galanthamine or lycoramine is replaced as follows: the methoxy group by another alkoxy group of from one to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group, a carbonate group or a carbamate group; the hydroxy group by an alkoxy group of from one to six carbon atoms, hydrogen, an 1221933 I:LNB COMS ID No: ARCS-188846 Received by IP Australia: Time 12:07 Date 2008-05-01 alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group, a carbonate group or a

O

O carbamate group; 0 the N-methyl group by hydrogen, alkyl, benzyl, cyclopropylmethyl group or a Ssubstituted or unsubstituted benzoyloxy group.

When reference is made to a substituent group, said group may be selected from alkyl O o0 or alkoxy groups of from 1 to 6 carbon atoms, halo groups, and haloalkyl groups such as Vt) trifluoromethyl.

One or more of the methoxy, hydroxy and methyl groups of galanthamine or Slycoramine may be replaced by the groups noted above.

o Galanthamine and lycoramine have the following formulae: Galanthamine HO 2 13 14 4 12 5 III,., 9 7 SHCO 1 0

N

H

3

C

UI

Lycoramine

H

3

C

Suitable analogs are described for example in International Patent Publication 3 W088/08708 and an article by Bores and Kosley in Drugs of the Future 21: 621-631 (1996).

Other useful pharmacologic agents for such preparations include rivastigmine, and other pharmacologic agents with half lives of 1-11 hours.

Particularly useful analogs of galanthamine and lycoramine that are of use in the present invention include analogs thereof wherein the methoxy group of such compounds is replaced by a hydrogen, hydroxy or alkoxy group of from two to six carbon atoms or an acyloxy group, for example an alkanoyloxy or benzoyl group, of from one to seven carbon atoms or where methoxy group thereof is replaced by a mono or dialkyl carbamate or carbonate group wherein the alkyl groups contain from 1 to 8 carbon atoms, preferably of from 4 to 6 carbon atoms or wherein the methoxy group thereof is replaced by an aryl carbamate or carbonate group wherein said aryl group is selected from phenyl, naphthyl, substituted phenyl and substituted naphthyl groups wherein said substituent is selected from alkyl and alkoxy groups of from 1 to 6 carbon atoms, trifluoro methyl groups and halo 0 groups.

SOther useful analogs include compounds wherein, independently of whether or not the Smethoxy group has been replaced, the hydroxy group is replaced by an alkoxy group of from one to six carbon atoms, hydrogen, an acyloxy group, for example an alkanoyloxy group, S typically of from 1 to 7 carbon atoms, a benzoyloxy or substituted benzoyloxy group wherein n said substituent is selected from alkyl and alkoxy groups of from 1 to 6 carbon atoms, trifluoro methyl groups and halo groups, a carbonate group or a carbamate group which may be a mono or dialkyl or an aryl carbamate or carbonate wherein the alkyl groups contain from S1 to 8 carbon atoms, preferably of from 4 to 6 carbon atoms or said aryl group is selected from phenyl, naphthyl, substituted phenyl and substituted naphthyl groups wherein said substituent is selected from alkyl and alkoxy groups of from 1 to 6 carbon atoms, trifluoro methyl groups and halo groups.

Although a major use of the present invention will be in the treatment of Alzheimer's disease, it is also suitable for treatment of other diseases or conditions in which there is need for increased brain acetyl choline levels after a defined period. Thus it may find use, for example for healthy persons who have need for increased acetyl choline levels some specified time in the future, for example workers changing from a day shift to a night shift or viceversa.

In Alzheimer's disease, the primary and universal neurochemical abnormality is a deficit of acetylcholine. The normal pattern of brain acetylcholine is elevated release just before and during the time of activity, and reduced release during sleep. (Kametani, 1991; Mizuno, 1991) The brain content of acetylcholine exhibits a reciprocal relationship with release patterns, presumably representing stored neurotransmitter. (Saito, 1974) Likewise, acetylcholinesterase activity, which keeps synaptic acetylcholine concentrations low, peaks during the subjective night, and is lowest during activity periods. (Schiebeler, 1974) Consistent with these experimental results is the long-recognized diurnal variation of human bronchial constriction from acetylcholine inhalation, being most sensitive in the evening, Swhen endogenous cholinergic activity would be expected to be low, and least sensitive during 0 waking hours, when cholinergic systems would be expected to be active (Reinberg, 1974 0 Humans are also sensitive to the systemic administration of the acetylcholinesterase dU 5 inhibitors, physostigmine and galanthamine late in the day or at night, when endogenous Scholinergic activity is low. These disturb sleep and produce awakenings. (Sitaram, 1979,

C¢€

Reimann, 1994) 0 Animals who are made hypocholinergic either by disruption of the high affinity choline Suptake system or by being raised on a false cholinergic neurotransmitter have a reduced "t 5 circadian variation of acetylcholine and a disrupted diurnal rhythm of locomotor activity, 0which correlates with the cholinergic hypoactivity. (Morley 1989, Szymusiak, 1993) This same o situation exists in Alzheimer patients who have both cholinergic deficits and disruption of normal sleep-wake cycles. It is of major practical importance because a patient who requires twenty-four hour supervision wears out a single caretaker, requiring multiple shifts of caretakers, or institutionalization, which is expensive, frightening to the patient, and sad for the family. (see New York Times article, July 27, 1998) An additional potential utility of a dosage form which can be taken when convenient, and active when needed, would therefore be the superimposition of a physiological rhythm of cholinergic activity, via a pill, onto a brain in which the cholinergic system is deteriorating.

Preparations for treatment of Alzheimer's disease, containing cholinomimetic agents, may stimulate intestinal peristalsis as they are released, thus promoting their own passage through the gastrointestinal tract. In may therefore be useful to incorporate into the dosage unit, or to manufacture a second, similarly timed tablet, to deliver an anticholinergic agent designed to remain outside the blood brain barrier, in order to reduce gastrointestinal motility.

The anticholinergic tablet might contain, for example, probanthine, 7.5-60 mg, or robinul 1 to 8 mg. A desirable formulation for an Alzheimer patient for whom sleeping hours of 11 pm to 7 am are desirable might be a pill which could be taken at bedtime and begin to release galanthamine at 5 am at a rate of 3 mg (measured as base) per hour for 4 hours, or 2 mg/hour for 6 hours beginning at 4 am. The same pill, taken at 7 am, would cover the daytime hours.

This should allow the central nervous system to become relatively hypocholinergic at the O time of desired sleep, as the half life of galanthamine has been reported to be 4.5-8 hours.

O. (Thomsen, 1990) SAlternatively, a single pill may deliver a full day's medication, although there is some risk of dumping an excessive dose, which could be dangerous in the case of cholinergic medications. The delay before release of active medication could be chosen between one and t' 11 hours depending on whether the pill is to be taken at dinner or bedtime.

(N

Likely pharmacologic agents for such preparations include galanthamine, rivastigmine, S and other pharmacologic agents with half lives of 1-11 hours. Dosage units for twice daily administration should contain from 4-16 mg of galanthamine (as base), or 2-10 mg of rivastigmine, both of which should be doubled in the case of once per day dosage units.

Dosages for other suitable agents can be determined by standard techniques such as those set out for example in Chapter 6 (by Benjamin Calesnick) of Drill's Pharmacology in Medicine (Fourth Edition Joseph R DiPalma ed, McGraw-Hill 1971 or in Chapter 6 by B. E. Rodda et al) of Biopharmaceutical Statistics for Drug Development (ed. Karl E. Peace, Marcel Dekker Inc, 1988). Anticholinergic agents, if needed, could be probanthine, 7.5-60 mg, to be 3 delivered at the same time as the cholinomimetic agents, or robinul (1 to 8 mg) or similar agents incorporated so that a typical dose is delivered within the time frame of the cholinomimetic release.

Delayed action formulations for use in the present invention typically are those used for oral administration and include tablets, capsules, caplets and other convenient devices.

Such dosage units may be prepared by methods well known to those skilled in the art, such as those described in Sustained Release Medications by J.C. Johnson, Noyes Data Corporation, 1980, and an article by Conte et al in Biomaterials 1993 vol 14 pages 1017 to 1023 entitled Press-coated tablets for time-programmed release of drugs; both of which are incorporated herein by reference. For example the active compounds may be coated or incorporated in a matrix which controls the elapse of between administration of the dose and the time at which release is desired.

Claims

29. APR. 2008 12:19 SPRUSON FERGUSON 92615486 NO. 8854 P. 11/15 00 8 SThe claims defining the invention are as follows: 1. A method of treatment of a patient suffering from Alzheimer's disease which Scomprises administering a dosage form of pharmaceutical composition which comprises an effective amount of a centrally acting acetylcholinesterase inhibitor useful in the C s treatment of Alzheimer's disease selected from the group consisting of galanthamine, lycoramine, analogs of galanthamine and lycoramine and rivastigmine said compounds I0 having a half life of from one to eleven hours wherein the acetylcholinesterase inhibitor is lt formulated so as to delay its activity for a specified period of from four to twelve hours, such that acetylcholinesterase inhibition is avoided during such predetermined period and to wherein said administration is effected at a time prior to a patient's sleeping such that the o activity of the cholinesterase inhibitor is delayed until after the patient has completed a c1 period of sleep. 2. A method of treatment as claimed in claim 1 wherein the composition is formulated to delay the activity of the acetylcholinesterase inhibitor for a period of from six to nine hours. 3. A method of treatment as claimed in claim 1 wherein the composition is formulated to delay the activity of the acetylcholinesterase inhibitor for a period of from eight to twelve hours. 4. A method of treatment as claimed in claim 1 wherein said acetylcholinesterase inhibitor has a duration of action of from 2 to 12 hours. A method as claimed in any one of claims 1-4 wherein said acetylcholinesterase inhibitor is an analog of galanthamine or lycoramine and wherein said analog of galanthamine or lycoramine is a compound wherein one or more of the methoxy, hydroxy or N-methyl groups is replaced as follows: the methoxy group by another alkoxy group of from two to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group, a carbonate group or a carbamate group; the hydroxy group by an alkoxy group of from one to six carbon atoms, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group; a carbonate group or a carbamate group; the N-methyl group by hydrogen, alkyl, benzyl or so a cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group. A method of treatment as claimed in any one of claims 1-5 wherein said acetylcholinesterase inhibitor is selected from the group consisting of galanthamine, lycoramine and analogs thereof wherein the methoxy group of such compounds is replaced by a hydrogen, hydroxy or alkoxy group of from two to six carbon atoms or an acyloxy group of from one to seven carbon atoms. 1218271 1 COMS ID No: ARCS-188474 Received by IP Australia: Time 12:22 Date 2008-04-29 29. APR. 2008 12:19 SPRUSON FERGUSON 92615486 NO. 8854 P. 12/15 00 9 0 0 7. A method of treatment as claimed in any one of claims 1-5 wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine or lycoramine wherein the methoxy group thereof is replaced by a mono or dialkyl carbamate or carbonate group wherein the alkyl groups contain from 1 to 8 carbon C s atoms. 8. A method of treatment as claimed in claim 7 wherein the alkyl group or 0groups of said carbonate or carbamate groups comprise from 4 to 6 carbon atoms. t) 9. A method of treatment as claimed in claim 8 wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine or lycoramine wherein the hydroxy group thereof is replaced by a mono or o dialkyl carbamate or carbonate group wherein the alkyl groups contain from 1 to 8 carbon atoms. A method of treatment as claimed in claim 9 wherein the alkyl group or groups of said carbonate or carbamate groups comprise from 4 to 6 carbon atoms. 11. A method of treatment as claimed in any one of claims 1-10 wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine or lycoramine wherein the methoxy group thereof is replaced by an aryl carbamate or carbonate group wherein said aryl group is selected from phenyl, naphthyl, substituted phenyl and substituted naphthyl groups wherein said substituent is selected from alkyl and alkoxy groups of from 1 to 6 carbon atoms, trifluoro methyl groups and halo groups. 12. A method of treatment as claimed in any one of claims 1-11 wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine and lycoramine wherein the hydroxy group thereof is replaced by an aryl carbamate or carbonate group wherein said aryl group is selected from phenyl, naphthyl, substituted phenyl and substituted naphthyl groups wherein said substituent is selected from alkyl and alkoxy groups of from I to 6 carbon atoms, trifluoro methyl groups and halo groups. 13. A method of treatment as claimed in claim 1 wherein said acetylcholinesterase inhibitor is selected from the group consisting of galanthamine, lycoramine and analogs thereof wherein the hydroxy group of such compounds is replaced by a hydrogen or alkoxy group of from one to six carbon atoms or an acyl group of from one to seven carbon atoms. 14. A method of treatment as claimed in claim 1 wherein said acetylcholinesterase inhibitor is galanthamine. 111071 1 COMS ID No: ARCS-188474 Received by IP Australia: Time 12:22 Date 2008-04-29 1-MAY-2008 12:04 SPRUSON FERGUSON 92615436 NO. 0434 P. 11 00 o 15. A method of treatment as claimed in claim 1 wherein said N acetylcholinesterase inhibitor is rivastigmine, S16. A method of treatment as claimed in any one of claims 1-15 wherein said acetylcholinesterase inhibitor is administered in conjunction with a compound that os reduces its peripheral effects. 17. A method of treatment as claimed in claim 16 wherein said Sacetylcholinesterase inhibitor is administered in conjunction with a suitable dose of probanthine or robinul. 18. A method of treatment of a patient suffering from Alzheimer's disease which comprises administering a delayed release dosage form of a pharmaceutical composition o which comprises an effective amount for treating Alzheimer's disease of a centrally Sacting acetylcholinesterase inhibitor selected from the group consisting of galanthamine, lycoramine, analogs of galanthamine and analogs of lycoramine and rivastigmine wherein said analogs of galanthamine or lycoramine are compounds wherein one or more of the is methoxy, hydroxy or N-methyl groups is replaced as follows: the methoxy group by another alkoxy group of from two to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group, a carbonate group or a carbamate group; the hydroxy group by an alkoxy group of from one to six carbon atoms, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group; a carbonate group or a carbamate group; the N-methyl group by hydrogen, alkyl, benzyl or a cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group; and wherein said dosage is formulated such that the half life of the activity of the acetylcholinesterase inhibitor and the degree of delayed release are selected such that the formulation may be administered to the patient such that release of acetylcholinesterase inhibitor is avoided for the next anticipated sleep time and wherein admimstration of the drug is at an appropriate time to achieve such results. 19, A method of treating Alzheimer's disease comprising administration to a patient suffering therefrom a delayed release composition comprising a centrally acting acetylcholinesterase inhibitor selected from the group consisting of galanthamine, lycoramine, analogs of galanthamine, analogs of lycoramine and rivastigmine wherein said analogs of galanthamine or lycoramine are compounds wherein one or more of the methoxy, hydroxy or N-methyl groups is replaced as follows: the methoxy group by another alkoxy group of from two to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group, a carbonate group or a carbamate group; the hydroxy group by a alkoxy group of from one to six carbon atoms, 12-8979 1 COMS ID No: ARCS-188846 Received by IP Australia: Time 12:07 Date 2008-05-01 1-AY-2008 12:04 SPRUSON FERGUSON 92615436 NO. 0)434 P. 12 oo 11 o hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group; a N carbonate group or a carbamate group; the N-methyl group by hydrogen, alkyl, benzyl or a cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group; said compounds having a half life of from one to eleven hours wherein the nature of the o composition and the time of administration of said composition is such that release of said acetyleholinesterase inhibitor from said composition is minimized prior to and during V desired sleep hours so as to allow the patient's central nervous system to become Shypocholinergic during the period of desired sleep as compared to its cholinergic activity during hours when desired to be awake so as to avoid sleep disturbance during hours of to desired sleep while providing therapeutic activity at other times. A method of treatment of Alzheimer's disease in which release of C, acetylcholinesterase is avoided during periods of sleep substantially as hereinbefore described. 21. Use of a centrally-acting acetylcholinesterase inhibitor selected from the group consisting of galanthamine, lycoramine, analogs of galanthamine, analogs of lycoramine and rivastigmine; said compounds having a half life of from one to eleven hours in the preparation of a dosage form of a medicament for the treatment of Alzheimer's disease wherein the acetylcholinesterase inhibitor is formulated so as to delay its activity for a predetermined period of from four to twelve hours such that acetylcholinesterase inhibition is avoided during such predetermined period. 22. Use as claimed in claim 21 wherein the medicament is formulated to delay the activity of the acetylcholinesterase inhibitor for a period of from six to nine hours or from eight to twelve hours and said acetyleholinesterase inhibitor has a duration of action of from 2 to 12 hours and said acetylcholinesterase inhibitor is an analog of galanthamine or an analog of lycoramine wherein said analog of galanthamine or lycoramine is a compound wherein one or more of the methoxy, hydroxy or N-methyl groups is replaced as follows: the methoxy group by another alkoxy group of from two to six carbon atoms, a hydroxy group, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group, a carbonate group or a carbamate group; the hydroxy group by an alkoxy group of from one to six carbon atoms, hydrogen, an alkanoyloxy group, a benzoyloxy or substituted benzoyloxy group; a carbonate group or a carbamate group; the N-methyl group by hydrogen, alkyl, benzyl or a cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group. 23. Use as claimed in claim 21 or 22 wherein said acetylcholinesterase inhibitor is galanthamine or rivastigmine and wherein said dosage form is for twice daily 12a1873 I COMS ID No: ARCS-188846 Received by IP Australia: Time 12:07 Date 2008-05-01 29, APR. 2008 12:21 SPRUSON FERGUSON 92615486 NO. 8854 P. 15/15 00 12 o administration and contains from 4-16 mg of galanthamine or 2-10 mg of rivastigmine or Ssaid dosage form is for once daily administration and contains from 8-32 mg of Sgalanthamine or 4-20 mg of rivastigmine. Dated 29 April, 2008 c s Bonnie Davis d Patent Attorneys for the Applicant/Nominated Person 'f SPRUSON FERGUSON 0 1218271 1 COMS ID No: ARCS-188474 Received by IP Australia: Time 12:22 Date 2008-04-29