AU2004242546A1 - Dosage formulations for acetylcholinesterase inhibitors - Google Patents
Dosage formulations for acetylcholinesterase inhibitors Download PDFInfo
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- AU2004242546A1 AU2004242546A1 AU2004242546A AU2004242546A AU2004242546A1 AU 2004242546 A1 AU2004242546 A1 AU 2004242546A1 AU 2004242546 A AU2004242546 A AU 2004242546A AU 2004242546 A AU2004242546 A AU 2004242546A AU 2004242546 A1 AU2004242546 A1 AU 2004242546A1
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- galanthamine
- lycoramine
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- 239000000544 cholinesterase inhibitor Substances 0.000 title claims description 78
- 239000000203 mixture Substances 0.000 title claims description 15
- 238000009472 formulation Methods 0.000 title claims description 6
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical group O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 118
- IYVSXSLYJLAZAT-NOLJZWGESA-N lycoramine Natural products CN1CC[C@@]23CC[C@H](O)C[C@@H]2Oc4cccc(C1)c34 IYVSXSLYJLAZAT-NOLJZWGESA-N 0.000 claims description 108
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 claims description 71
- 125000004432 carbon atom Chemical group C* 0.000 claims description 63
- HPOIPOPJGBKXIR-UHFFFAOYSA-N 3,6-dimethoxy-10-methyl-galantham-1-ene Natural products O1C(C(=CC=2)OC)=C3C=2CN(C)CCC23C1CC(OC)C=C2 HPOIPOPJGBKXIR-UHFFFAOYSA-N 0.000 claims description 59
- LPCKPBWOSNVCEL-UHFFFAOYSA-N Chlidanthine Natural products O1C(C(=CC=2)O)=C3C=2CN(C)CCC23C1CC(OC)C=C2 LPCKPBWOSNVCEL-UHFFFAOYSA-N 0.000 claims description 59
- 229960003980 galantamine Drugs 0.000 claims description 59
- BGLNUNCBNALFOZ-WMLDXEAASA-N galanthamine Natural products COc1ccc2CCCC[C@@]34C=CCC[C@@H]3Oc1c24 BGLNUNCBNALFOZ-WMLDXEAASA-N 0.000 claims description 59
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 claims description 59
- GJRMHIXYLGOZSE-JDFRZJQESA-N 1,2-Dihydrogalanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)CC2 GJRMHIXYLGOZSE-JDFRZJQESA-N 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 239000002552 dosage form Substances 0.000 claims description 41
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
- 125000005587 carbonate group Chemical group 0.000 claims description 31
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 230000000694 effects Effects 0.000 claims description 23
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 20
- 125000004423 acyloxy group Chemical group 0.000 claims description 20
- 125000001624 naphthyl group Chemical group 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 18
- -1 aryl carbamate Chemical compound 0.000 claims description 15
- 102100033639 Acetylcholinesterase Human genes 0.000 claims description 14
- 108010022752 Acetylcholinesterase Proteins 0.000 claims description 14
- 229940022698 acetylcholinesterase Drugs 0.000 claims description 14
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 10
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical group CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 claims description 9
- 229960004136 rivastigmine Drugs 0.000 claims description 9
- 208000024827 Alzheimer disease Diseases 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 5
- 230000003111 delayed effect Effects 0.000 claims description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 claims description 4
- XLBIBBZXLMYSFF-UHFFFAOYSA-M Propantheline bromide Chemical compound [Br-].C1=CC=C2C(C(=O)OCC[N+](C)(C(C)C)C(C)C)C3=CC=CC=C3OC2=C1 XLBIBBZXLMYSFF-UHFFFAOYSA-M 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229940099209 probanthine Drugs 0.000 claims description 4
- 229940106905 robinul Drugs 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 14
- 125000002252 acyl group Chemical group 0.000 claims 4
- 230000004622 sleep time Effects 0.000 claims 3
- 206010048650 Cholinesterase inhibition Diseases 0.000 claims 2
- 230000002093 peripheral effect Effects 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229940122041 Cholinesterase inhibitor Drugs 0.000 claims 1
- 230000003466 anti-cipated effect Effects 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 229940079593 drug Drugs 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 8
- 229960004373 acetylcholine Drugs 0.000 description 8
- 230000001713 cholinergic effect Effects 0.000 description 8
- 210000004556 brain Anatomy 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- 239000002831 pharmacologic agent Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 230000000718 cholinopositive effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 2
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 230000002060 circadian Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 230000001025 hypocholinergic effect Effects 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 229960001697 physostigmine Drugs 0.000 description 2
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 description 2
- 230000033764 rhythmic process Effects 0.000 description 2
- 208000019888 Circadian rhythm sleep disease Diseases 0.000 description 1
- 206010011953 Decreased activity Diseases 0.000 description 1
- 208000001456 Jet Lag Syndrome Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229940127243 cholinergic drug Drugs 0.000 description 1
- 230000027288 circadian rhythm Effects 0.000 description 1
- 230000002542 deteriorative effect Effects 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000005176 gastrointestinal motility Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 208000033915 jet lag type circadian rhythm sleep disease Diseases 0.000 description 1
- 230000006742 locomotor activity Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000001722 neurochemical effect Effects 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000008454 sleep-wake cycle Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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 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.
l- Background 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 that a dose may be administered to the patient in the evening and allow a night's sleep before Sthe acetyl cholinesterase inhibitor becomes active in the morning. The duration of delay chosen will depend upon-the exact-way in which-it-is -chosen to administerthe drug. For example if it is intended to administer the drug with an evening meal taken at, say 6:30 in the Sevening 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 0 hour delay may be more useful.
From a second aspect, the present invention provides a method of treatment of a patient suffering from a disease or condition in which it is desirable to administer a centrally Sacting 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 bein.g-desired, 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 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 Shydroxy group, hydrogen, an alkanoyloxy group, a benzovloxy 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
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 V) 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
O
O1- 0 0 t"€ Lycoramine
H
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 groups.
Other 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, when 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 U 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 uptake system or by being raised on a false cholinergic neurotransmitter have a reduced 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 S11 hours depending on whether the pill is to be taken at dinner or bedtime.
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 (17)
- 4. A dosage form of a pharmaceutical composition as claimed in claim 2 wherein the composition is formulated to delayithe activity of the acetyl cholinesterase inhibitor for a period of from eight to twelve hours. A dosage form of a pharmaceutical composition as claimed in claim 1 wherein said acetylcholinesterase inhibitor has a duration of action of from 2 to 12 hours.
- 6. -A dosage form of a pharmaceutical composition as claimed in claim 1 wherein-said- acetylcholinesteraseinhibitor has a half life of from one to eleven hours 7 A dosage form of a pharmaceutical composition as claimed in claim 1 wherein said acetylcholinesterase inhibitor is selected from the group consisting of galanthamine, lycoramine and analogs of said compounds wherein the methoxy group thereof is replaced 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.
- 8. A dosage form of a pharmaceutical composition as claimed in claim 1 wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine and lycoramine wherein the hydroxy group of galanthamine or lycoramine is replaced by an alkoxy group of from one to six carbon atoms, hydrogen, an alkanoyloxy S group, a benzoyloxy or substituted benzoyloxy group, a carbonate group or a carbamate group. \O
- 9. A dosage form of a pharmaceutical composition as claimed in claim 1 wherein said i acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine and lycoramine wherein the N-methyl group of galanthamine or lycoramine is N replaced by hydrogen, alkyl, benzyl or a cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group. A dosage form as claimed in claim 7 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. 11 A dosage form as claimed in claim 7 wherein said acetylcholinesterase inhibitor is S 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 atoms
- 12. A dosage from as claimed in claim 11 wherein the alkyl group or groups of said carbonate or carbamate groups comprise from 4 to 6 carbon atoms.
- 13. A dosage form as claimed in claim 7 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 dialkyl carbamate or carbonate group wherein the alkyl groups contain from I to 8 carbon atoms. O U 14. A dosage from as claimed in claim 12 wherein the alkyl group or groups of said carbonate or carbarnate groups comprise from 4 to 6 carbon atoms N 15 A dosage form as claimed in claim 7 wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine or lycoramine wherein the Smethoxy 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 C wherein said substituent is selected from alkyl and alkoxy groups of from 1 to 6 carbon atoms, trifluoro methyl groups and halo groups. 16 A dosage form as claimed in claim 8 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 1 to 6 carbon 3 atoms, trifluoro methyl groups and halo groups. 17 A dosage form as claimed in claim 8 wherein said acetvlcholinesterase 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. 18 A dosage form of a pharmaceutical composition as claimed in claim 7 wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine and lycoramine wherein the hydroxy group of galanthamine or lycoramine is replaced 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.
- 19. A dosage form as claimed in claim 7 wherein said acetylcholinesterase inhibitor is galanthamine. 0 A dosage form as claimed in claim 1 wherein said acetylcholinesterase inhibitor is S rivastigmine.
- 21. A method of treatment of a patient suffering from a disease or condition in which it is S desirable to administer a centrally acting acetylcholinesterase inhibitor which comprises S 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.
- 22. A method of treatment as claimed in claim 21 wherein said patient is suffering from Alzheimer's disease. 23 A method of treatment as claimed in claim 21 wherein the composition is formulated to delay the activity of the acetyl cholinesterase inhibitor for a period of from four to twelve hours. 24 A method of treatment as claimed in claim 23 wherein the composition is formulated to delay the activity of the acetyl cholinesterase inhibitor for a period of from six to nine hours. A method of treatment as claimed in claim 23 wherein the composition is formulated to delay the activity of the acetyl cholinesterase inhibitor for a period of from eight to twelve hours. 26 A method of treatment as claimed in claim 21 wherein said acetylcholinesterase inhibitor has a duration of action of from 2 to 12 hours.
- 27. A method of treatment as claimed in claim 21 wherein said acetylcholinesterase Sinhibitor has a half life of from one to eleven hours S28 A method of treatment as claimed in claim 21 wherein said acetylcholinesterase Sinhibitor is selected from the group consisting of galanthamine, lycoramine and analogs of said compounds wherein at least one of the methoxy, hydroxy or methyl groups of the DO galanthamine or lycoramine is replaced as follows: V) 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; Sthe 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, cyclopropylmethyl or a substituted or unsubstituted benzoyloxy group.
- 29. A method of treatment as claimed in claim 28 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. A method of treatment as claimed in claim 28 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 atoms.
- 31. A method of treatment as claimed in claim 30 wherein the alkyl group or groups of said carbonate or carbamate groups comprise from 4 to 6 carbon atoms
- 32. A method of treatment as claimed in claim 31 wherein said acetylcholinesterase S inhibitor is selected from the group consisting of analogs of galanthamine or lycoramine S wherein the hydroxy group thereof is replaced by a mono or dialkyl carbamate or carbonate group wherein the alkyl groups contain from 1 to 8 carbon atoms.
- 33. A method of treatment as claimed in claim 32 wherein the alkyl group or groups of S said carbonate or carbamate groups comprise from 4 to 6 carbon atoms 34 A method of treatment as claimed in claim 28 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. A method of treatment as claimed in claim 28 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 1 to 6 carbon atoms, trifluoro methyl groups and halo groups. 36 A method of treatment as claimed in claim 28 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.
- 37. A method of treatment as claimed in claim 28 wherein said acetylcholinesterase inhibitor is galanthamine.
- 38. A method of treatment as claimed in claim 21 wherein said acetylcholinesterase Sinhibitor is rivastigmine. 0
- 39. A method of treatment as claimed in claim 21 wherein said acetylcholinesterase inhibitor is administered in conjunction with a compound that reduces its peripheral effects. A method of treatment as claimed in claim 39 wherein said acetylcholinesterase S inhibitor is administered in conjunction with a suitable dose of probanthine or robinul. 0 0 C1 The claims defining the invention are as follows: 1. A dosage form of a pharmaceutical composition which comprises an effective amount of a centrally-acting acetylcholinesterase inhibitor wherein the acetylcholinesterase Sinhibitor has a half life of from one to eleven hours and the composition is formulated so as to delay activity of the acetylcholinesterase inhibitor for a period of from four to twelve Shours. tf 2. A dosage form of a pharmaceutical composition 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. 1 0 3. A dosage form of a pharmaceutical composition 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 dosage form of a pharmaceutical composition as claimed in claim 1 wherein said acetylcholinesterase inhibitor has a duration of action of from two to twelve hours. 5. A dosage form of a pharmaceutical composition as claimed in claim 1 wherein said acetylcholinesterase inhibitor is selected from the group consisting of galanthamine, lycoramine and analogs of said compounds wherein the methoxy group thereof is replaced 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. 6. A dosage form of a pharmaceutical composition as claimed in claim 1 wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine and lycoramine wherein the hydroxy group of galanthamine or lycoramine is replaced 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. 7. A dosage form of a pharmaceutical composition as claimed in claim 1 wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine and lycoramine wherein the N-methyl group of galanthamine or lycoramine is replaced by hydrogen, alkyl, benzyl or a cyclopropylmethyl group or a substituted or unsubstituted benzoyloxy group. 8. A dosage form of a pharmaceutical composition as claimed in claim 5 wherein said acetylcholinesterase inhibitor is selected from the group consisting of galanthamine, [R:\LIBVV]557532_div claim set 2.doc:THR -16- N lycoramine and analogs thereof wherein the methoxy group of such compounds is replaced Sby a hydrogen, hydroxy or alkoxy group of from two to six carbon atoms or an acyloxy Sgroup of from one to seven carbon atoms. 9. A dosage form of a pharmaceutical composition as claimed in claim 5 wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of IO galanthamine or lycoramine wherein the methoxy group thereof is replaced by a mono or l f dialkyl carbamate or carbonate group wherein the alkyl groups contain from 1 to 8 carbon atoms. A dosage form of a pharmaceutical composition as claimed in claim 9 wherein 0 the alkyl group or groups of said carbonate or carbamate groups comprise from 4 to 6 carbon atoms. 11. A dosage form of a pharmaceutical composition as claimed in claim 5 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 dialkyl carbamate or carbonate group wherein the alkyl groups contain from 1 to 8 carbon atoms. 12. A dosage form of a pharmaceutical composition as claimed in claim 11 wherein the alkyl group or groups of said carbonate or carbamate groups comprise from 4 to 6 carbon atoms. 13. A dosage form of a pharmaceutical composition as claimed in claim 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 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. 14. A dosage form of a pharmaceutical composition as claimed in claim 6 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 1 to 6 carbon atoms, trifluoro methyl groups and halo groups. [R:\LIBVV]557532_div claim set 2.doc:THR -17- c 15. A dosage form of a pharmaceutical composition as claimed in claim 6 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. IN 16. A dosage form of a pharmaceutical composition as claimed in claim 5 wherein Ssaid acetylcholinesterase inhibitor is selected from the group consisting of analogs of galanthamine and lycoramine wherein the hydroxy group of galanthamine or lycoramine is replaced 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. 17. A dosage form of a pharmaceutical composition as claimed in claim 5 wherein said acetylcholinesterase inhibitor is galanthamine. 18. A dosage form of a pharmaceutical composition as claimed in claim 1 wherein said acetylcholinesterase inhibitor is rivastigmine. 19. A method of treatment of a patient suffering from a disease or condition in which it is desirable to administer a centrally acting acetylcholinesterase inhibitor, said method comprising 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 period of from four to twelve hours, wherein said administration is effected at a time prior to a patient's sleeping such that the activity of the cholinesterase inhibitor is delayed until after the patient has completed a period of sleep. A method of treatment as claimed in claim 19 wherein said patient is suffering from Alzheimer's disease. 21. A method of treatment as claimed in claim 19 wherein the composition is formulated to delay the activity of the acetyl cholinesterase inhibitor for a period of from six to nine hours. 22. A method of treatment as claimed in claim 19 wherein the composition is formulated to delay the activity of the acetyl cholinesterase inhibitor for a period of from eight to twelve hours. 23. A method of treatment as claimed in claim 19 wherein said acetylcholinesterase inhibitor has a duration of action of from two to twelve hours. [R:\LIBVV]557532_div claim set 2.doc:THR I 18- C1 24. A method of treatment as claimed in claim 19 wherein said acetylcholinesterase inhibitor has a half life of from one to eleven hours. A method of treatment as claimed in claim 19 wherein said c acetylcholinesterase inhibitor is selected from the group consisting of galanthamine, lycoramine and analogs of said compounds wherein at least one of the methoxy, hydroxy or I methyl groups of the galanthamine or lycoramine is replaced as follows: Vt 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; 0 10 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, cyclopropylmethyl or a substituted or unsubstituted benzoyloxy group. 26. A method of treatment as claimed in claim 25 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. 27. A method of treatment as claimed in claim 25 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 I to 8 carbon atoms. 28. A method of treatment as claimed in claim 27 wherein the alkyl group or groups of said carbonate or carbamate groups comprise from 4 to 6 carbon atoms. 29. A method of treatment as claimed in claim 28 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 dialkyl carbamate or carbonate group wherein the alkyl groups contain from 1 to 8 carbon atoms. A method of treatment as claimed in claim 29 wherein the alkyl group or groups of said carbonate or carbamate groups comprise from 4 to 6 carbon atoms. [R:\LIBVV]557532_div claim set 2.doc:THR -19- 1 31. A method of treatment as claimed in claim 25 wherein said a acetylcholinesterase inhibitor is selected from the group consisting of analogs of Sgalanthamine or lycoramine wherein the methoxy group thereof is replaced by an aryl O Cc 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 I alkyl and alkoxy groups of from 1 to 6 carbon atoms, trifluoro methyl groups and halo groups. 32. A method of treatment as claimed in claim 25 wherein said acetylcholinesterase inhibitor is selected from the group consisting of analogs of O io 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 1 to 6 carbon atoms, trifluoro methyl groups and halo groups. 33. A method of treatment as claimed in claim 25 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. 34. A method of treatment as claimed in claim 25 wherein said acetylcholinesterase inhibitor is galanthamine. A method of treatment as claimed in claim 19 wherein said acetylcholinesterase inhibitor is rivastigmine. 36. A method of treatment as claimed in claim 19 wherein said acetylcholinesterase inhibitor is administered in conjunction with a compound that reduces its peripheral effects. 37. A method of treatment as claimed in claim 36 wherein said acetylcholinesterase inhibitor is administered in conjunction with a suitable dose of probanthine or robinul. 38. A method of treatment of a patient suffering from a disease or condition in which it is desirable to administer a centrally acting acetylcholinesterase inhibitor, said method comprising administering a delayed release dosage from of a pharmaceutical composition which comprises an effective amount of a centrally acting acetylcholinesterase [R:\LIBVV]557532_div claim set 2.doc:THR CI inhibitor selected from the group consisting of galanthamine, lycoramine, analogs of galanthamine and lycoramine and rivastigmine wherein said dosage is formulated such that the half life of the activity of the acetyl cholinesterase inhibitor and the degree of delayed release are selected such that the formulation is administered to the patient prior to the start of the patient's normal sleep time, acetyl cholinesterase inhibition is delayed for the I anticipated duration of said sleep time and the acetyl cholinesterase inhibition resulting from V such administration is reduced prior to the patient's next following normal sleep time. 1 Dated 30 December, 2004 SBonnie Davis (M Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [R:\LIBVV]557532_div claim set 2.doc:THR
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2004242546A AU2004242546B2 (en) | 1998-11-23 | 2004-12-30 | Dosage formulations for acetylcholinesterase inhibitors |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60109611 | 1998-11-23 | ||
| AU17388/00A AU1738800A (en) | 1998-11-23 | 1999-11-19 | Dosage formulations for acetylcholinesterase inhibitors |
| AU2004242546A AU2004242546B2 (en) | 1998-11-23 | 2004-12-30 | Dosage formulations for acetylcholinesterase inhibitors |
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| Application Number | Title | Priority Date | Filing Date |
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| AU17388/00A Division AU1738800A (en) | 1998-11-23 | 1999-11-19 | Dosage formulations for acetylcholinesterase inhibitors |
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| AU2004242546A1 true AU2004242546A1 (en) | 2005-01-27 |
| AU2004242546B2 AU2004242546B2 (en) | 2008-05-15 |
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Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4663318A (en) * | 1986-01-15 | 1987-05-05 | Bonnie Davis | Method of treating Alzheimer's disease |
| EP0363415B1 (en) * | 1987-05-04 | 2008-10-15 | Davis, Bonnie | Compounds for the treatment of alzheimer's disease |
| CA1326632C (en) * | 1988-10-26 | 1994-02-01 | Bonnie Davis | Long-active drug formulations comprising galanthamine for treatment of alzheimer's disease |
| US5336675A (en) * | 1991-05-14 | 1994-08-09 | Ernir Snorrason | Method of treating mania in humans |
| US5585375A (en) * | 1994-07-01 | 1996-12-17 | Davis; Bonnie M. | Method for alleviating jet lag |
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