AU2025242171B1 - A Medicament and Method of Treatment of Central Nervous System and/or Neuropsychiatric Disorders - Google Patents

Abstract

28 A xanomeline intranasal medicament for use in treating a central nervous system disorder or a neuropsychiatric disorder in a human subject, wherein the treatment involves intranasal administration of the medicament to deliver a therapeutically effective amount of xanomeline. 28

Description

TITLE 02 Oct 2025

A Medicament and Method of Treatment of Central Nervous System and/or Neuropsychiatric insufficient therapy.

Disorders product with a low enough dose to avoid adverse side effects would at the same time provide

date the pharmaceutical industry has not managed to achieve this, seemingly because a

that a low dose xanomeline medicament with high bioavailability would be beneficial. To

FIELD OF INVENTION Given the side effects associated with a high dose product, the inventors have determined

high enough to give relief against the side effects of xanomeline. 2025242171

This invention relates to intranasal medicaments comprising xanomeline and use of these for hallucinations, dizziness, headache, nausea and others, particularly when taken at doses

treating central nervous system disorders and/or neuropsychiatric disorders. example allergic reactions such as rash, blurred vision, confusion, difficulty urinating,

can help against an overactive bladder, it comes with its own adverse side effects, for

To mitigate the gastrointestinal effects, patients may be given oral trospium. While trospium BACKGROUND trade-off has been a higher incidence of adverse gastric side-affects.

Xanomeline is a muscarinic acetylcholine receptor known for oral use in treating central short half-life and poor bioavailability it has been used in relatively high doses, however the

bioavailability, adverse gastrointestinal side effects, and its short half-life. To address the nervous system (CNS) disorders and neuropsychiatric disorders, particularly Alzheimer’s disease and schizophrenia. However, its clinical development has been limited due to its poor

disease and schizophrenia. However, its clinical development has been limited due to its poor nervous system (CNS) disorders and neuropsychiatric disorders, particularly Alzheimer's

bioavailability, adverse gastrointestinal side effects, and its short half-life. To address the Xanomeline is a muscarinic acetylcholine receptor known for oral use in treating central

short half-life and poor bioavailability it has been used in relatively high doses, however the BACKGROUND trade-off has been a higher incidence of adverse gastric side-affects. treating central nervous system disorders and/or neuropsychiatric disorders.

This invention relates to intranasal medicaments comprising xanomeline and use of these for To mitigate the gastrointestinal effects, patients may be given oral trospium. While trospium FIELDcan help against OF INVENTION an overactive bladder, it comes with its own adverse side effects, for example allergic reactions such as rash, blurred vision, confusion, difficulty urinating, Disorders hallucinations, dizziness, headache, nausea and others, particularly when taken at doses A Medicament and Method of Treatment of Central Nervous System and/or Neuropsychiatric

high enough to give relief against the side effects of xanomeline. TITLE

Given the side effects associated 1 with a high dose product, the inventors have determined that a low dose xanomeline medicament with high bioavailability would be beneficial. To date the pharmaceutical industry has not managed to achieve this, seemingly because a product with a low enough dose to avoid adverse side effects would at the same time provide insufficient therapy.

OBJECT OF THE INVENTION 02 Oct 2025

administration or administration by another person or device.

It is an object of preferred embodiments of the invention to go at least some way towards Any references in this specification to administration to a patient or subject mean self-

addressing the above problem. While this applies for preferred embodiments, the object of mean ± 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of that value. the invention per se is more general, being simply to provide the public with a useful choice. Any references in this document to "about" or "approximately" in relation to a numerical value

Therefore, any objects or benefits applicable to a preferred embodiment should not be taken as a limitation on the scope of claims expressed more broadly. trospium chloride.

tartrate. And 392.5 g of trospium (1 mol) should be taken as equivalent to 428.0 g (1 mol) of 2025242171

281.4 g of xanomeline (1 mol) should be taken as equivalent to 431.5 g (1 mol) of xanomeline

DEFINITIONS salt, solvate or hydrate, to give an equivalent amount of the active component. For example,

active agent, the figure concerned should be taken as adjusted when it is interpreted for the

trospium but also salts thereof, etc. In the event that a claim gives a weight amount for the The term “comprises” or “has”, if/when used in this document in relation to one or more further example, a claim reference to trospium should be taken as embracing not only free

features, should not be seen as excluding the option of additional features that have not been taken as embracing not only free xanomeline but also salts thereof, etc. And by way of

mentioned. The same applies to derivative terms such as “comprising” and “having”. salts, solvates or hydrates thereof. For example, a claim reference to xanomeline should be

pharmaceutically active agent per se should be taken to embrace pharmaceutically active

Unless the context demands otherwise, references in the claims of this specification to a

Unless the context demands otherwise, references in the claims of this specification to a pharmaceutically active agent per se should be taken to embrace pharmaceutically active mentioned. The same applies to derivative terms such as "comprising" and "having".

features, should not be seen as excluding the option of additional features that have not been salts, solvates or hydrates thereof. For example, a claim reference to xanomeline should be The term "comprises" or "has", if/when used in this document in relation to one or more

taken as embracing not only free xanomeline but also salts thereof, etc. And by way of DEFINITIONS further example, a claim reference to trospium should be taken as embracing not only free trospium but also salts thereof, etc. In the event that a claim gives a weight amount for the as a limitation on the scope of claims expressed more broadly.

active agent, the figure concerned should be taken as adjusted when it is interpreted for the Therefore, any objects or benefits applicable to a preferred embodiment should not be taken

salt, solvate or hydrate, to give an equivalent amount of the active component. For example, the invention per se is more general, being simply to provide the public with a useful choice.

addressing the above problem. While this applies for preferred embodiments, the object of 281.4 g of xanomeline (1 mol) should be taken as equivalent to 431.5 g (1 mol) of xanomeline It is an object of preferred embodiments of the invention to go at least some way towards

tartrate. And 392.5 g of trospium (1 mol) should be taken as equivalent to 428.0 g (1 mol) of OBJECT OF THE INVENTION trospium chloride. 2

Any references in this document to “about” or “approximately” in relation to a numerical value mean ± 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of that value.

Any references in this specification to administration to a patient or subject mean self- administration or administration by another person or device.

SUMMARY OF THE INVENTION 02 Oct 2025

Optionally the xanomeline is in the form of a xanomeline salt, solvate or hydrate.

First Aspect Optionally the medicament is a liquid and comprises water as a carrier or solvent.

Medicament for use in Treating a CNS or a Neuropsychiatric Disorder more, to any of the three aspects mentioned above.

The following optional features may be supplemented, alone or in any combination of one or According to one aspect, the invention comprises a xanomeline intranasal medicament for Optional Features use in treating a central nervous system disorder or a neuropsychiatric disorder in a human subject, wherein the treatment involves intranasal administration of the medicament to deliver 2025242171

amount of the xanomeline.

a therapeutically effective amount of xanomeline. administering a medicament comprising xanomeline to the subject to deliver a therapeutically

disorder or a neuropsychiatric disorder in a human subject, comprising intranasally

According to a further aspect, the invention is a method of treating a central nervous system

Second Aspect Method of Treatment

Use of Xanomeline for Producing a Medicament Third Aspect

According to a further aspect, the invention is the use of xanomeline in the production of an administration of the medicament to deliver a therapeutically effective amount of xanomeline.

intranasal medicament for use in treating a central nervous system disorder or a neuropsychiatric disorder in a human subject, wherein the treatment involves intranasal

neuropsychiatric disorder in a human subject, wherein the treatment involves intranasal intranasal medicament for use in treating a central nervous system disorder or a

According to a further aspect, the invention is the use of xanomeline in the production of an administration of the medicament to deliver a therapeutically effective amount of xanomeline. Use of Xanomeline for Producing a Medicament

Second Aspect Third Aspect Method of Treatment a therapeutically effective amount of xanomeline.

subject, wherein the treatment involves intranasal administration of the medicament to deliver

According to a further aspect, the invention is a method of treating a central nervous system use in treating a central nervous system disorder or a neuropsychiatric disorder in a human

According to one aspect, the invention comprises a xanomeline intranasal medicament for disorder or a neuropsychiatric disorder in a human subject, comprising intranasally Medicament for use in Treating a CNS or a Neuropsychiatric Disorder administering a medicament comprising xanomeline to the subject to deliver a therapeutically First Aspect amount of the xanomeline. SUMMARY OF THE INVENTION

Optional Features 3

The following optional features may be supplemented, alone or in any combination of one or more, to any of the three aspects mentioned above.

Optionally the medicament is a liquid and comprises water as a carrier or solvent.

Optionally the xanomeline is in the form of a xanomeline salt, solvate or hydrate.

cocaine, alcohol, methamphetamine, and opioid use disorder) and Huntington's disease.

Optionally the xanomeline salt comprises one or more of xanomeline tartrate, oxalate, sulfate, and Parkinson's disease associated psychosis), substance use disorders (including e.g. 02 Oct 2025

disorder, psychotic depression, Parkinson's disease (including Parkinson's disease dementia phosphate, monohydrogen phosphate, dihydrogenphosphate, chloride, bromide, disorder, a delusional disorder, psychotic depression, a bipolar disorder, a major depressive

hydrobromide, citrate, iodide, hydroiodide, acetate, lactate, maleate, fumarate, succinate, Lewy Body dementia, Frontotemporal dementia), schizophrenia, psychosis, a schizo-affective

nitrate, carbonate, bicarbonate, pyrosulfate, bisulfate, sulfite, bisulfite, metaphosphate, one or more of Alzheimer's disease, Alzheimer's disease psychosis, dementia (including e.g.

Optionally the central nervous system (CNS) disorder or neuropsychiatric disorder comprises pyrophosphate, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, octahydrate, nonahydrate, and decahydrate.

fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, dihydrate, hemihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate,

Optionally the xanomeline hydrate comprises one or more of xanomeline monohydrate, 2025242171

methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, solvate.

methane-sulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene - 2 - sulfonate, dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, or trifluoroacetic acid,

methylcyclohexane, acetonitrile, toluene, benzene, dimethyl sulfoxide, N, N- mandelate, chloride, nitrate, carbonate, bicarbonate, hippurate, benzenesulfonate, adipate, p- tetrahydrofuran, benzyl ether, n-heptane, n-hexane, n-pentane, cyclohexane,

toluenesulfonate, malate, ethanesulfonate, pamoate, gluconate, gluceptate, ascorbate, dioxane, methyl tert butyl ether, cyclopentyl methyl ether, tetrahydrofuran, dimethyl

glucuronate and camsylate. isobutyl ketone, ethyl acetate, isopropyl acetate, dichloromethane, trichloromethane, 1,4-

isopropanol, trifluoroethanol, 1-butanol, 2-butanol, acetone, methyl ethyl ketone, methyl

Optionally the xanomeline solvate comprises one or more of a methanol, ethanol,

Optionally the xanomeline solvate comprises one or more of a methanol, ethanol, isopropanol, trifluoroethanol, 1-butanol, 2-butanol, acetone, methyl ethyl ketone, methyl glucuronate and camsylate.

toluenesulfonate, malate, ethanesulfonate, pamoate, gluconate, gluceptate, ascorbate, isobutyl ketone, ethyl acetate, isopropyl acetate, dichloromethane, trichloromethane, 1,4- mandelate, chloride, nitrate, carbonate, bicarbonate, hippurate, benzenesulfonate, adipate, p-

dioxane, methyl tert butyl ether, cyclopentyl methyl ether, tetrahydrofuran, dimethyl methane-sulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene - 2 - sulfonate,

tetrahydrofuran, benzyl ether, n-heptane, n-hexane, n-pentane, cyclohexane, phenylpropionate, phenylbutyrate, citrate, lactate, y-hydroxybutyrate, glycolate, tartrate,

methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylcyclohexane, acetonitrile, toluene, benzene, dimethyl sulfoxide, N, N- fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate,

dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, or trifluoroacetic acid, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate,

solvate. pyrophosphate, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate,

nitrate, carbonate, bicarbonate, pyrosulfate, bisulfate, sulfite, bisulfite, metaphosphate,

hydrobromide, citrate, iodide, hydroiodide, acetate, lactate, maleate, fumarate, succinate,

Optionally the xanomeline hydrate comprises one or more of xanomeline monohydrate, phosphate, monohydrogen phosphate, dihydrogenphosphate, chloride, bromide,

dihydrate, hemihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, Optionally the xanomeline salt comprises one or more of xanomeline tartrate, oxalate, sulfate,

octahydrate, nonahydrate, and4 decahydrate.

Optionally the central nervous system (CNS) disorder or neuropsychiatric disorder comprises one or more of Alzheimer’s disease, Alzheimer’s disease psychosis, dementia (including e.g. Lewy Body dementia, Frontotemporal dementia), schizophrenia, psychosis, a schizo-affective disorder, a delusional disorder, psychotic depression, a bipolar disorder, a major depressive disorder, psychotic depression, Parkinson’s disease (including Parkinson’s disease dementia and Parkinson’s disease associated psychosis), substance use disorders (including e.g. cocaine, alcohol, methamphetamine, and opioid use disorder) and Huntington's disease.

approximately 20 mg.

Optionally the psychosis is acute psychosis. Optionally the treatment involves administration of a dose of approximately 2.5 mg to

Optionally the psychosis comprises psychosis associated with Alzheimer’s disease, the subject.

Optionally the treatment involves administration of a dose of 2.5 mg - 20 mg xanomeline to

Parkinson’s disease, bi-polar disorder, or psychotic depression. subject.

Optionally the treatment involves administration of a dose of 2 mg - 25 mg xanomeline to the Optionally the medicament is for self-administration, or is self-administered, by the human 2025242171

subject. the subject.

Optionally the treatment involves administration of a dose of 1.5 mg - 30 mg xanomeline to

Optionally the medicament is for administration, or is administered, to the human subject by xanomeline other than said subject. 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 mg

subject, for example approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

Optionally the treatment involves administration of a dose of 1 mg - 40 mg xanomeline to the Optionally the treatment involves administration of a dose of 0.1 mg – 50 mg xanomeline to the subject, for example 0.1, 0.2, 0.3, 0.4 0.5, 0.6, 0.7, 0.8, or 0.9 mg xanomeline, or approximately 1-50, mg xanomeline.

approximately 1-50, mg xanomeline. the subject, for example 0.1, 0.2, 0.3, 0.4 0.5, 0.6, 0.7, 0.8, or 0.9 mg xanomeline, or

Optionally the treatment involves administration of a dose of 0.1 mg - 50 mg xanomeline to

Optionally the treatment involves administration of a dose of 1 mg – 40 mg xanomeline to the other than said subject.

subject, for example approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, Optionally the medicament is for administration, or is administered, to the human subject by

19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 mg subject.

xanomeline . Optionally the medicament is for self-administration, or is self-administered, by the human

Parkinson's disease, bi-polar disorder, or psychotic depression. Optionally the treatment involves administration of a dose of 1.5 mg – 30 mg xanomeline to Optionally the psychosis comprises psychosis associated with Alzheimer's disease,

the subject. Optionally the psychosis is acute psychosis.

Optionally the treatment involves administration of a dose of 2 mg – 25 mg xanomeline to the subject. 5

Optionally the treatment involves administration of a dose of 2.5 mg – 20 mg xanomeline to the subject.

Optionally the treatment involves administration of a dose of approximately 2.5 mg to approximately 20 mg.

Optionally the treatment involves administration of a dose of approximately 2.5 mg to sucroside, decyl sucroside, nonyl sucroside, undecyl sucroside, tridecyl sucroside, 02 Oct 2025

glucoside, and octadecyl--D-glucoside, dodecyl sucroside, tetradecyl sucroside, octyl approximately 20 mg. glucoside, pentadecyl glucoside, hexadecyl glucoside, heptadecyl glucoside, octadecyl--

glucoside, octyl glucoside, decyl glucoside, nonyl glucoside, undecyl glucoside, tridecyl

Optionally the treatment involves administration of a dose of 0.1 mg – 30 mg xanomeline to maltoside, octadecyl-a-maltoside, and octadecyl--D-maltoside dodecyl glucoside, tetradecyl

maltoside, tridecyl maltoside, pentadecyl maltoside, hexadecyl maltoside, heptadecyl the subject. maltoside, tetradecyl maltoside, octyl maltoside, decyl maltoside, nonyl maltoside, undecyl

Optionally the alkylsaccharide absorption enhancer comprises one or more of odecyl

Optionally the treatment involves administration of a dose of 0.1 mg – 30 mg xanomeline absorption enhancer. 2025242171

tartrate to the subject. Optionally the medicament comprises about 0.1 % to about 2.5 % w/v of an alkylsaccharide

Optionally the treatment involves administration of a dose of 20 mg – 30 mg xanomeline to Optionally the medicament comprises an absorption enhancer.

the subject. Optionally the medicament comprises about 0.1 % to about 30% w/v of xanomeline.

Optionally the treatment involves administration of a dose of 20 mg – 30 mg xanomeline period.

Optionally the dose is for administration, or is administered, 1, 2 or 3 times within a 24 hour tartrate to the subject. tartrate to the subject.

Optionally the dose is for administration, or is administered, 1, 2 or 3 times within a 24 hour Optionally the treatment involves administration of a dose of 20 mg - 30 mg xanomeline

period. the subject.

Optionally the treatment involves administration of a dose of 20 mg - 30 mg xanomeline to

Optionally the medicament comprises about 0.1 % to about 30% w/v of xanomeline. tartrate to the subject.

Optionally the treatment involves administration of a dose of 0.1 mg - 30 mg xanomeline

Optionally the medicament comprises an absorption enhancer. the subject.

Optionally the treatment involves administration of a dose of 0.1 mg - 30 mg xanomeline to Optionally the medicament comprises about 0.1 % to about 2.5 % w/v of an alkylsaccharide absorption enhancer. approximately 20 mg.

Optionally the treatment involves administration of a dose of approximately 2.5 mg to

Optionally the alkylsaccharide 6absorption enhancer comprises one or more of odecyl maltoside, tetradecyl maltoside, octyl maltoside, decyl maltoside, nonyl maltoside, undecyl maltoside, tridecyl maltoside, pentadecyl maltoside, hexadecyl maltoside, heptadecyl maltoside, octadecyl-α-maltoside, and octadecyl-β-D-maltoside, dodecyl glucoside, tetradecyl glucoside, octyl glucoside, decyl glucoside, nonyl glucoside, undecyl glucoside, tridecyl glucoside, pentadecyl glucoside, hexadecyl glucoside, heptadecyl glucoside, octadecyl-α- glucoside, and octadecyl-β-D-glucoside, dodecyl sucroside, tetradecyl sucroside, octyl sucroside, decyl sucroside, nonyl sucroside, undecyl sucroside, tridecyl sucroside, maleate, fumarate, succinate, nitrate, carbonate, and bicarbonate.

pentadecyl sucroside, hexadecyl sucroside, heptadecyl sucroside, octadecyl-α-sucroside, bromide, iodide, sulfate, phosphate, dihydrogen phosphate, acetate, citrate, lactate, tartrate, 02 Oct 2025

Optionally the trospium is in the form of a salt, for example one or more of trospium chloride, and octadecyl-β-D-sucroside Optionally the medicament comprises trospium as a further active agent.

Optionally the medicament comprises about 0.2 % to about 1.2 % w/v sodium chloride. simultaneously, or immediately before or after the xanomeline.

Optionally the treatment comprises the human subject also receiving trospium

Optionally the medicament comprises a preservative. edetate.

Optionally the chelating agent comprises about 0.1% (w/v) to about 0.5% (w/v) of disodium 2025242171

Optionally the preservative comprises one or more of Benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium thereof, sodium phosphate, and EDTA (eg sodium or calcium EDTA).

chloride, chlorhexidine, chlorbutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, pharmaceutically acceptable salt thereof, citric acid or a pharmaceutically acceptable salt

Optionally the chelating agent comprises one or more of ethylenediaminetetraacetic acid or a glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben, Optionally the medicament comprises a chelating agent.

propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid, potassium Optionally the preservative is present in an amount of about 0.005% (w/v) to about 1% (w/v). sorbate, EDTA (eg sodium or calcium EDTA), and sodium citrate. . sorbate, EDTA (eg sodium or calcium EDTA), and sodium citrate.

Optionally the preservative is present in an amount of about 0.005% (w/v) to about 1% (w/v). propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid, potassium

nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben,

glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric

Optionally the medicament comprises a chelating agent. chloride, chlorhexidine, chlorbutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol,

chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium

Optionally the preservative comprises one or more of Benzalkonium chloride, benzethonium Optionally the chelating agent comprises one or more of ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof, citric acid or a pharmaceutically acceptable salt Optionally the medicament comprises a preservative.

thereof, sodium phosphate, and EDTA (eg sodium or calcium EDTA). Optionally the medicament comprises about 0.2 % to about 1.2 % w/v sodium chloride.

Optionally the chelating agent comprises about 0.1% (w/v) to about 0.5% (w/v) of disodium and octadecyl--D-sucroside

edetate. pentadecyl sucroside, hexadecyl sucroside, heptadecyl sucroside, octadecyl-a-sucroside,

7

Optionally the treatment comprises the human subject also receiving trospium simultaneously, or immediately before or after the xanomeline.

Optionally the medicament comprises trospium as a further active agent.

Optionally the trospium is in the form of a salt, for example one or more of trospium chloride, bromide, iodide, sulfate, phosphate, dihydrogen phosphate, acetate, citrate, lactate, tartrate, maleate, fumarate, succinate, nitrate, carbonate, and bicarbonate.

about 2 to about 3% w/w trospium. 02 Oct 2025

Optionally the medicament comprises about 8% to 12% w/w xanomeline with or without Optionally the xanomeline and trospium are in a wt/wt ratio of 80: 1 to 4 : 1. about 1 to about 4% w/w trospium.

Optionally the xanomeline is a tartrate salt, the trospium is a chloride salt, and these salt Optionally the medicament comprises about 5% to 15% w/w xanomeline with or without

forms are in a wt/wt ratio of 100 : 1 to 5 : 1. about 0.1 to about 5% w/w trospium.

Optionally the medicament comprises about 1% to 20% w/w xanomeline with or without

Optionally the xanomeline and trospium are in a molar ratio of about 100 : 1 to about 5 : 1 xanomeline with or without about 0.1 mg/mL to about 50 mg/mL trospium. 2025242171

xanomeline to trospium about 0.2 mL medicament, the medicament comprising about 10 mg/mL to about 200 mg/mL

Optionally the treatment comprises the human subject receiving a volume of about 0.1 mL to

Optionally the xanomeline and trospium are in a molar ratio of about 40 : 1 to about 50 : 1 xanomeline and about 2 mg to about 4 mg trospium per dosage event. xanomeline to trospium Optionally the treatment comprises the human subject receiving about 7 mg to about 13 mg

Optionally the treatment comprises the human subject receiving about 1 mg to about 30 mg xanomeline and about 1 mg to about 5 mg trospium per dosage event.

Optionally the treatment comprises the human subject receiving about 5 mg to about 20 mg xanomeline and about 0.01 mg to about 7.5 mg trospium per dosage event. xanomeline and about 0.01 mg to about 7.5 mg trospium per dosage event.

Optionally the treatment comprises the human subject receiving about 5 mg to about 20 mg Optionally the treatment comprises the human subject receiving about 1 mg to about 30 mg

xanomeline and about 1 mg to about 5 mg trospium per dosage event. xanomeline to trospium

Optionally the xanomeline and trospium are in a molar ratio of about 40 : 1 to about 50 : 1

Optionally the treatment comprises the human subject receiving about 7 mg to about 13 mg xanomeline to trospium xanomeline and about 2 mg to about 4 mg trospium per dosage event. Optionally the xanomeline and trospium are in a molar ratio of about 100 : 1 to about 5 : 1

Optionally the treatment comprises the human subject receiving a volume of about 0.1 mL to forms are in a wt/wt ratio of 100 : 1 to 5 : 1.

Optionally the xanomeline is a tartrate salt, the trospium is a chloride salt, and these salt about 0.2 mL medicament, the medicament comprising about 10 mg/mL to about 200 mg/mL xanomeline with or without about 0.1 mg/mL to about 50 mg/mL trospium. Optionally the xanomeline and trospium are in a wt/wt ratio of 80: 1 to 4 : 1.

Optionally the medicament comprises 8 about 1% to 20% w/w xanomeline with or without about 0.1 to about 5% w/w trospium.

Optionally the medicament comprises about 5% to 15% w/w xanomeline with or without about 1 to about 4% w/w trospium.

Optionally the medicament comprises about 8% to 12% w/w xanomeline with or without about 2 to about 3% w/w trospium.

Optionally the medicament and/or the treatment is without any brain penetration enhancer. 02 Oct 2025

psychosis in rats;

Optionally the medicament is for use with intranasal or oral trospium. determine the effect of xanomeline in a D-amphetamine induced model of

Figure 5 provides a schematic overview of a pharmacodynamic experimental design to

intravenously to rats; Optionally Figure 4 the medicament incorporates, or is for use with, one or more muscarinic receptor graphs the pharmacokinetic profile for xanomeline (free base) when delivered

antagonist or a salt or solvate thereof, selected from propantheline (eg propantheline intranasally such that it arrives in the plasma of rats;

bromide), Figure 3 graphsemepronium a pharmacokinetic(eg emepronium profile bromide), for trospium when delivered ipratropium orally and (eg ipratropium bromide), 2025242171

glycopyrrolate (eg glycopyrronium bromide), methylatropine (eg atropine methonitrate), (CSF) of canines;

ethylatropine bromide,such orally and intranasally oxitropium bromide, that it arrives in the plasmaaclidinium bromide, and cerebrospinal fluid and methantheline. Figure 2 graphs a pharmacokinetic profile for xanomeline (free base) when delivered

Optionally in eachin case and intranasally the brain and muscarinic plasma of rats; receptor antagonist, or the salt or solvate thereof, is Figure 1 graphs a pharmacokinetic profile for xanomeline tartrate when delivered orally administered, or is for administration, orally or intranasally. with reference to the accompanying drawings/graphs, of which-

Some preferred embodiments of the invention will now be described by way of example and DRAWINGS / GRAPHS DRAWINGS / GRAPHS

Some preferred embodiments of the invention will now be described by way of example and administered, or is for administration, orally or intranasally. with reference to the accompanying drawings/graphs, of which- Optionally in each case the muscarinic receptor antagonist, or the salt or solvate thereof, is

Figure 1 graphs a pharmacokinetic profile for xanomeline tartrate when delivered orally ethylatropine bromide, oxitropium bromide, aclidinium bromide, and methantheline.

and intranasally in brain and plasma of rats; glycopyrrolate (eg glycopyrronium bromide), methylatropine (eg atropine methonitrate),

bromide), emepronium (eg emepronium bromide), ipratropium (eg ipratropium bromide),

Figure 2 graphs a pharmacokinetic profile for xanomeline (free base) when delivered antagonist or a salt or solvate thereof, selected from propantheline (eg propantheline

orally and intranasally such that it arrives in the plasma and cerebrospinal fluid Optionally the medicament incorporates, or is for use with, one or more muscarinic receptor

(CSF) of canines; Optionally the medicament is for use with intranasal or oral trospium.

Figure 3 graphs a pharmacokinetic profile for trospium when delivered orally and Optionally the medicament and/or the treatment is without any brain penetration enhancer.

intranasally such that it arrives in the plasma of rats; 9

Figure 4 graphs the pharmacokinetic profile for xanomeline (free base) when delivered intravenously to rats;

Figure 5 provides a schematic overview of a pharmacodynamic experimental design to determine the effect of xanomeline in a D-amphetamine induced model of psychosis in rats;

Figure 6 graphs the pharmacodynamic effect of xanomeline (free base) in a D- 02 Oct 2025

amphetamine-induced hyperlocomotion model of psychosis showing the total intranasal use as follows.

distance travelled for control and treated groups; Pharmacokinetic studies were conducted to develop a treatment comprising xanomeline for

Figure 7 graphs a statistical analysis of the hyperlocomotion model showing total receptor agonists such as xanomeline that hinder delivery of the drug to the plasma or brain.

distance travelled over a 120 minute period of open-window recording following administration and because of the known mucous stimulating/creation effects of muscarinic

variability/inconsistency from patient to patient when it comes to intranasal drug administration of xanomeline (free base) by intranasal, subcutaneous and oral to the plasma and brain from patient to patient. This was especially so given the normal

routes; magnitude observed, and also in relation to the consistency of the amount of drug delivered 2025242171

It was surprising that the nasal administration route gave benefits, particularly at the

Figure 8 graphs brain and plasma concentrations of xanomeline (free base) 120 minutes administration. after administration via intranasal, oral, and subcutaneous routes; and dose of xanomeline reduces the risk of the adverse side effects normally associated with oral

Figure 9 graphs a linear pharmacokinetic-pharmacodynamic relationship for intranasally the xanomeline is administered intranasally. This is considered beneficial because a smaller

central nervous system disorder or a neuropsychiatric disorder can be reduced significantly if administered xanomeline (free base) at (A), and the relationship between total The inventors have discovered that the normal oral dosage of xanomeline taken for treating a brain drug exposure the pharmacodynamic effect (hypolocomotion) at (B). DETAILED DESCRIPTION

DETAILED DESCRIPTION brain drug exposure the pharmacodynamic effect (hypolocomotion) at (B).

administered xanomeline (free base) at (A), and the relationship between total

The inventors Figure 9 have graphs a linear discovered that the normal pharmacokinetic-pharmacodynamic oral for relationship dosage of xanomeline taken for treating a intranasally

centralafter nervous system disorder or a neuropsychiatric disorder can be reduced significantly if administration via intranasal, oral, and subcutaneous routes; and

the xanomeline Figure 8 is administered graphs brain and intranasally. plasma concentrations of xanomeline This is considered (free base) 120 minutes beneficial because a smaller

dose of xanomeline reduces the risk of the adverse side effects normally associated with oral routes;

administration. administration of xanomeline (free base) by intranasal, subcutaneous and oral

distance travelled over a 120 minute period of open-window recording following

Figure 7 graphs a statistical analysis of the hyperlocomotion model showing total

It was surprising that the nasal administration route gave benefits, particularly at the distance travelled for control and treated groups;

magnitude observed,hyperlocomotion amphetamine-induced and also inmodel relation to theshowing of psychosis consistency the total of the amount of drug delivered

to the graphs Figure 6 plasma the and brain from pharmacodynamic patient effect to patient. of xanomeline This (free base) in awas D- especially so given the normal

variability/inconsistency from patient 10 to patient when it comes to intranasal drug administration and because of the known mucous stimulating/creation effects of muscarinic receptor agonists such as xanomeline that hinder delivery of the drug to the plasma or brain.

Pharmacokinetic studies were conducted to develop a treatment comprising xanomeline for intranasal use as follows.

Xanomeline in Rodents 02 Oct 2025

Rats (male, Sprague-Dawley, 0.17-0.25 kg) were fasted overnight prior to intranasal or oral dosing of xanomeline, with free access to water. intranasal dosing compared with the oral groups.

indicated, the brain to plasma (B/P) ratio had a two-fold improvement in both instances of For the intranasal group, xanomeline tartrate was dissolved in normal saline and of the active ingredient as 60 mg per kg of xanomeline tartrate when administered orally. As administered intranasally by pipette to rats at a dose volume of 0.1 mL/kg of body weight to tartrate per kg of body weight delivered intranasally gave about an equivalent brain exposure

provide a total dose of 3 mg or 10 mg of xanomeline tartrate per kg of body weight. Blood parameters from the xanomeline tartrate rat experiments. As indicated, 10 mg of xanomeline 2025242171

Figure 1 (annexed) and Table 1 show the drug concentration and other pharmacokinetic samples and brain and nasal mucosa tissue samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post administration (n=3 per timepoint). (half-life) were calculated using Phoenix Winnonlin software.

parameters such as AUC (area under the curve), Cmax (peak plasma concentration) and T ½

determined by LC-MS/MS using carbamazepine as internal standard. The pharmacokinetic For the oral group, xanomeline tartrate was dissolved in normal saline and administered methanol. Concentrations of the intranasal drug in plasma and tissue homogenate were orally by gavage to rats at a dose volume of 10 mL/kg of body weight to provide a total dose For both groups the brain and nasal mucosa tissue of the rats were homogenized with 50%

of 60 mg of xanomeline tartrate per kg of body weight. Blood samples and brain tissue samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post administration (n=3 per timepoint).

samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post administration (n=3 per timepoint). of 60 mg of xanomeline tartrate per kg of body weight. Blood samples and brain tissue

orally by gavage to rats at a dose volume of 10 mL/kg of body weight to provide a total dose

For the oral group, xanomeline tartrate was dissolved in normal saline and administered For both groups the brain and nasal mucosa tissue of the rats were homogenized with 50% methanol. Concentrations of the intranasal drug in plasma and tissue homogenate were 4, 6 and 8 hours post administration (n=3 per timepoint).

determined by LC-MS/MS using carbamazepine as internal standard. The pharmacokinetic samples and brain and nasal mucosa tissue samples were collected at 0.083, 0.25, 0.5, 1, 2,

provide a total dose of 3 mg or 10 mg of xanomeline tartrate per kg of body weight. Blood parameters such as AUC (area under the curve), Cmax (peak plasma concentration) and T ½ administered intranasally by pipette to rats at a dose volume of 0.1 mL/kg of body weight to (half-life) were calculated using Phoenix Winnonlin software. For the intranasal group, xanomeline tartrate was dissolved in normal saline and

dosing of xanomeline, with free access to water. Figure 1 (annexed) and Table 1 show the drug concentration and other pharmacokinetic Rats (male, Sprague-Dawley, 0.17-0.25 kg) were fasted overnight prior to intranasal or oral parameters from the xanomeline tartrate rat experiments. As indicated, 10 mg of xanomeline Xanomeline in Rodents tartrate per kg of body weight delivered intranasally gave about an equivalent brain exposure of the active ingredient as 60 mg 11 per kg of xanomeline tartrate when administered orally. As indicated, the brain to plasma (B/P) ratio had a two-fold improvement in both instances of intranasal dosing compared with the oral groups.

Table 1 02 Oct 2025

xanomeline tartrate per kg of body weight).

Pharmacokinetic parameters of oral and intranasal delivery of xanomeline in rats. sprays) to provide a total dose of 30 mg of xanomeline tartrate per animal (around 3 mg

administered intranasally by syringe sprayer at a dose volume of 0.1 mL per spray (two

Route Sample T1/2 (h) For the intranasal group, xanomeline tartrate was dissolved in normal saline and Cmax (ng/mL) AUC (h*ng/mL)

Plasma xanomeline, with free access to water. 0.7 641 366 PO Beagle dogs (male, 9-12 kg) were fasted overnight prior to intranasal or oral dosing of

Brain 0.9 3928 3225 60 mpk Xanomeline in Canines

B/P Ratio NA 6 9 2025242171

B/P ratio: brain to plasma ratio

mpk: mg per kg Plasma 0.8 421 183 IN: intranasal IN Brain 1 4170 3790 PO: per os

10 mpk Nasal mucosa 0.7 790667 250394 B/P Ratio NA 8.1 21

B/P Ratio NA 10 21 3 mpk

IN Brain Plasma 1.18 12680.58 156 1136 53.6 Plasma 0.58 156 53.6 IN Brain 1.18 1268 1136 B/P Ratio NA 10 21 3 mpk 10 mpk Nasal mucosa 0.7 790667 250394

IN Brain B/P Ratio 1 NA 4170 8.1 3790 21 Plasma 0.8 421 183

NA PO: per os B/P Ratio 6 9 60 mpk 3928 3225 PO IN: intranasal Brain 0.9

Plasma 0.7 641 366 mpk: mg per kg B/P Route ratio: brain to plasma Sample T1/2 (h) ratio Cmax (ng/mL) AUC (h*ng/mL)

Pharmacokinetic parameters of oral and intranasal delivery of xanomeline in rats.

Xanomeline in Canines Table 1

Beagle dogs (male, 9-12 kg) were 12 fasted overnight prior to intranasal or oral dosing of xanomeline, with free access to water.

For the intranasal group, xanomeline tartrate was dissolved in normal saline and administered intranasally by syringe sprayer at a dose volume of 0.1 mL per spray (two sprays) to provide a total dose of 30 mg of xanomeline tartrate per animal (around 3 mg xanomeline tartrate per kg of body weight).

For the oral group, the xanomeline tartrate was dissolved in normal saline and administered 02 Oct 2025

orally to the dogs at a dose volume of 2 mL/kg of body weight to provide a total dose of 20 mg of xanomeline tartrate per kg of body weight. Ratio (CSF/P) 0.00665 3 mpk CSF 1.57 IN For both groups, blood samples were collected at 0.083, 0.17, 0.33, 0.5, 0.75, 1, 2, 4, 6, 8 Plasma 6.34 214 236 and 24 hours post administration, with cerebrospinal fluid (CSF) samples collected at 0.083, Ratio (CSF/P) 0.00138 1 and 4CSF 20 mpk hours post administration (n=3 per timepoint). 0.353 Concentrations of the intranasal drug PO 2025242171

in plasma and CSF 4.54 Plasma were determined 78.5 by LC-MS/MS 255 using carbamazepine as an internal

standard. Route The Sample pharmacokinetic parameters Cmax (ng/mL) suchAUC0-t as AUC, Cmax and T1/2 were calculated (h*ng/mL) T1/2 (h)

using Phoenix Winnonlin software. Pharmacokinetic parameters of oral and intranasal delivery of xanomeline in canines.

Table 2

Figure 2 (annexed) and Table 2 show the drug concentration and other pharmacokinetic parameters for the xanomeline tartrate. As indicated, 3 mg of xanomeline tartrate per kg of significantly improved with intranasal administration.

20 mg of xanomeline tartrate per kg of body weight. The CSF to plasma ratio also body weight delivered intranasally was able to achieve comparable drug concentrations in the plasma, and was four times higher in the CSF, than oral xanomeline tartrate administered at

plasma, and was four times higher in the CSF, than oral xanomeline tartrate administered at body weight delivered intranasally was able to achieve comparable drug concentrations in the

20 mg of xanomeline tartrate per kg of body weight. The CSF to plasma ratio also parameters for the xanomeline tartrate. As indicated, 3 mg of xanomeline tartrate per kg of

Figure 2 (annexed) and Table 2 show the drug concentration and other pharmacokinetic significantly improved with intranasal administration. using Phoenix Winnonlin software.

Table 2 standard. The pharmacokinetic parameters such as AUC, Cmax and T1/2 were calculated

in plasma and CSF were determined by LC-MS/MS using carbamazepine as an internal Pharmacokinetic parameters of oral and intranasal delivery of xanomeline in canines. 1 and 4 hours post administration (n=3 per timepoint). Concentrations of the intranasal drug

and 24 hours post administration, with cerebrospinal fluid (CSF) samples collected at 0.083, Route Sample T1/2 (h) Cmax (ng/mL) For both groups, blood samples were collected at 0.083, 0.17, 0.33, 0.5, 0.75, 1, 2, 4, 6, 8 AUC0-t (h*ng/mL)

Plasma mg of xanomeline tartrate per kg of body weight. 4.54 78.5 255 POthe CSF 0.353 orally to dogs at a dose volume of 2 mL/kg of body weight to provide a total dose of 20

20 mpk For the oral group, the xanomeline tartrate was dissolved in normal saline and administered

Ratio (CSF/P) 0.00138 13 Plasma 6.34 214 236 IN CSF 1.57 3 mpk Ratio (CSF/P) 0.00665

Trospium in Rodents 02 Oct 2025

It was hypothesized that there may be advantages for human patients if trospium is plasma to the oral administration of trospium chloride at 100 mg per kg of body weight.

administered intranasally, simultaneously or immediately before or after, xanomeline. The of 1.5 mg trospium chloride per kg of body weight demonstrated a comparable AUC in

parameters from the trospium chloride for the experiments. As indicated, intranasal delivery reason for this is that trospium can assist against gastrointestinal problems caused by Figure 3 (annexed) and Table 3 show the drug concentration and other pharmacokinetic xanomeline. It was contemplated by the inventors that the nasal administration route may enable patients to get the same benefit from a lower dose of trospium. In view of this, Winnonlin software.

pharmacokinetic parameters such as AUC, Cmax and T1/2 were calculated using Phoenix pharmacokinetic studies were run on rats (male, Sprague-Dawley, 0.17-0.25 kg). They were 2025242171

homogenate were determined by LC-MS/MS using propranolol as internal standard. The fasted overnight prior to intranasal or oral dosing of trospium, with free access to water. methanol. Concentrations of the intranasally administered drug in plasma and tissue

For both groups, brain and nasal mucosa tissue were extracted and homogenized with 50%

For the intranasal group, trospium chloride was dissolved in normal saline and administered 9, 12 and 24 hours post administration, (n=3 per timepoint). intranasally by pipette to the rats at a dose volume of 0.1 mL/kg of body weight to provide a mg trospium chloride per kg of body weight. Blood samples were collected at 0.5, 1, 3, 5, 7,

total dose of 1.5 mg trospium chloride per kg of body weight. Blood samples and brain and rats by gavage at a dose volume of 10 mL/kg of body weight to provide a total dose of 100

For the oral group, trospium chloride was dissolved in water and administered orally to the nasal mucosa tissue samples were collected at 0.083, 0.5, 1, 2, 5 and 10 hours post administration (n=1 per timepoint). administration (n=1 per timepoint).

nasal mucosa tissue samples were collected at 0.083, 0.5, 1, 2, 5 and 10 hours post

total dose of 1.5 mg trospium chloride per kg of body weight. Blood samples and brain and For the oral group, trospium chloride was dissolved in water and administered orally to the intranasally by pipette to the rats at a dose volume of 0.1 mL/kg of body weight to provide a

rats by gavage at a dose volume of 10 mL/kg of body weight to provide a total dose of 100 For the intranasal group, trospium chloride was dissolved in normal saline and administered

mg trospium chloride per kg of body weight. Blood samples were collected at 0.5, 1, 3, 5, 7, 9, 12 and 24 hours post administration, (n=3 per timepoint). fasted overnight prior to intranasal or oral dosing of trospium, with free access to water.

pharmacokinetic studies were run on rats (male, Sprague-Dawley, 0.17-0.25 kg). They were

enable patients to get the same benefit from a lower dose of trospium. In view of this,

For both groups, brain and nasal mucosa tissue were extracted and homogenized with 50% xanomeline. It was contemplated by the inventors that the nasal administration route may

methanol. Concentrations of the intranasally administered drug in plasma and tissue reason for this is that trospium can assist against gastrointestinal problems caused by

administered intranasally, simultaneously or immediately before or after, xanomeline. The homogenate were determined by LC-MS/MS using propranolol as internal standard. The It was hypothesized that there may be advantages for human patients if trospium is

pharmacokinetic parameters such as AUC, Cmax and T1/2 were calculated using Phoenix Trospium in Rodents

Winnonlin software. 14

Figure 3 (annexed) and Table 3 show the drug concentration and other pharmacokinetic parameters from the trospium chloride for the experiments. As indicated, intranasal delivery of 1.5 mg trospium chloride per kg of body weight demonstrated a comparable AUC in plasma to the oral administration of trospium chloride at 100 mg per kg of body weight.

4, 6 and 8 hours post administration (n=3 per timepoint). Table 3 02 Oct 2025

samples and brain and nasal mucosa tissue samples were collected at 0.083, 0.25, 0.5, 1, 2,

Pharmacokinetic parameters of oral and intranasal delivery of trospium in rats. provide a total dose of 2 mg or 6.5 mg pf xanomeline tartrate per kg of body weight. Blood

administered intranasally by pipette to rats at a dose volume of 0.1 mL/kg of body weight, to

Route Sample 1/2 For the intranasal group, xanomeline tartrate was dissolved T (h) in normal saline and Cmax (ng/mL) AUC0-t (h*ng/mL)

PO intranasal, intravenous and oral dosing of xanomeline, with free access to water. Plasma 2.11 15.1 18.1 100 mpk In a further trial, rats (male, Sprague-Dawley, 0.17 - 0.25 kg) were fasted overnight prior to

Plasma 2.11 16.2 25.93 Bioavailability of Xanomeline Administered Intranasally & Orally 2025242171

IN 1.5 mpk compared to oral dosing and yet still deliver an equivalent peripheral exposure of trospium. Nasal 3.00 464000 703215 was surprising and unexpected that such a large dose reduction could be achieved

Ratio (B/P) that trospium is widely known to have very poor permeation across biological membranes, it 0.424 risk of dose-dependent side effects compared to oral administration of these actives. Given

trospium when taken in normal oral doses. It is considered that this significantly mitigates the The above studies suggested to the inventors that trospium is suited for intranasal may be achieved and maintained in patients at a fraction of the dose of both xanomeline and

administration in combination with xanomeline. In this regard it was found to achieve an administration. Based on these findings it is considered that an equivalent therapeutic effect

equivalent peripheral exposure of trospium at a >65 times dose reduction compared with oral approximately 30,000-fold nasal mucosa-to-plasma drug ratio, and also achieved an approximately 30,000-fold nasal mucosa-to-plasma drug ratio, and also achieved an equivalent peripheral exposure of trospium at a >65 times dose reduction compared with oral administration in combination with xanomeline. In this regard it was found to achieve an

administration. Based on these findings it is considered that an equivalent therapeutic effect The above studies suggested to the inventors that trospium is suited for intranasal

may be achieved and maintained in patients at a fraction of the dose of both xanomeline and Ratio (B/P) 0.424

1.5 trospiumNasal mpk when taken3.00 in normal464000 oral doses. 703215 It is considered that this significantly mitigates the IN risk of dose-dependent side effects compared to oral administration of these actives. Given that trospium Plasmais widely known to16.2 2.11 have very poor 25.93 permeation across biological membranes, it

was surprising 100 mpk Plasma and unexpected 2.11 that such a 18.1 15.1 large dose reduction could be achieved PO compared to oral dosing and yet still deliver an equivalent peripheral exposure of trospium. Route Sample T1/2 (h) Cmax (ng/mL) AUC0-t (h*ng/mL)

Pharmacokinetic parameters of oral and intranasal delivery of trospium in rats. Bioavailability of Xanomeline Administered Intranasally & Orally Table 3

In a further trial, rats (male, Sprague-Dawley, 15 0.17 – 0.25 kg) were fasted overnight prior to intranasal, intravenous and oral dosing of xanomeline, with free access to water.

For the intranasal group, xanomeline tartrate was dissolved in normal saline and administered intranasally by pipette to rats at a dose volume of 0.1 mL/kg of body weight, to provide a total dose of 2 mg or 6.5 mg pf xanomeline tartrate per kg of body weight. Blood samples and brain and nasal mucosa tissue samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post administration (n=3 per timepoint).

IN 2 0.6 156 54 / 45% /

For the oral group, xanomeline tartrate was dissolved in normal water and administered orally 02 Oct 2025

IN 6.5 0.8 421 183 46% by gavage to rats at a dose volume of 10 mL/kg of body weight to provide a total dose of 20 / /

PO 20 0.6 60 59 5% mg of xanomeline tartrate per kg of body weight. Blood samples and brain tissue samples / /

IV 0.65mpk 0.5 126 40 11 42 NA were collected at 0.083, 0.25, 0.5, 1, 2, 4 and 6 hours post administration (n=3 per timepoint). (h) (ng/mL) (h*ng/mL) (L/kg) (mL/min/kg) Route Dose F% Cmax/C0 AUC Vdss CI For the intravenous group, xanomeline tartrate was dissolved in normal saline and T1/2

PK Parameters administered to rats intravenously into the tail vein at a dose volume of 5 mL/kg of body Table 4 2025242171

weight to provide a total dose of 0.65 mg of xanomeline tartrate per kg of body weight. Blood samples and brain tissue samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6 ,8 and 24 improvement in drug absorption when xanomeline is administered intranasally.

hours post administration (n=3 per timepoint). nearly 50%) when compared with oral administration (5%), which corresponds to a 10-fold

the 2 mg and 6.5 mg per kg of body weight resulted in significantly higher bioavailability (by

pharmacokinetic parameters. As indicated, intranasal administration of xanomeline for both

For all groups the brain and nasal mucosa tissue of the rats were homogenized with 50% Figure 4 (annexed) and Table 4 below show the resulting drug concentrations and other

methanol. Concentrations of the intranasal drug in plasma and tissue homogenate were concentration) and T ½ (half-life) were calculated using Phoenix Winnonlin software. determined by way of LC-MS/MS, using carbamazepine as an internal standard. The pharmacokinetic parameters such as AUC (area under the curve), Cmax (peak plasma

pharmacokinetic parameters such as AUC (area under the curve), Cmax (peak plasma determined by way of LC-MS/MS, using carbamazepine as an internal standard. The

concentration) and T ½ (half-life) were calculated using Phoenix Winnonlin software. methanol. Concentrations of the intranasal drug in plasma and tissue homogenate were

For all groups the brain and nasal mucosa tissue of the rats were homogenized with 50%

Figure 4 (annexed) and Table 4 below show the resulting drug concentrations and other hours post administration (n=3 per timepoint).

pharmacokinetic parameters. As indicated, intranasal administration of xanomeline for both samples and brain tissue samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6 ,8 and 24

weight to provide a total dose of 0.65 mg of xanomeline tartrate per kg of body weight. Blood the 2 mg and 6.5 mg per kg of body weight resulted in significantly higher bioavailability (by administered to rats intravenously into the tail vein at a dose volume of 5 mL/kg of body

nearly 50%) when compared with oral administration (5%), which corresponds to a 10-fold For the intravenous group, xanomeline tartrate was dissolved in normal saline and

improvement in drug absorption when xanomeline is administered intranasally. were collected at 0.083, 0.25, 0.5, 1, 2, 4 and 6 hours post administration (n=3 per timepoint).

mg of xanomeline tartrate per kg of body weight. Blood samples and brain tissue samples Table 4 by gavage to rats at a dose volume of 10 mL/kg of body weight to provide a total dose of 20

For the oral group, xanomeline tartrate was dissolved in normal water and administered orally

PK Parameters 16 T1/2 Cmax/C0 AUC Vdss Cl Route Dose F% （h） (ng/mL) (h*ng/mL) （L/kg) (mL/min/kg)

IV 0.65mpk 0.5 126 40 11 42 NA

PO 20 0.6 60 59 / / 5%

IN 6.5 0.8 421 183 / / 46%

IN 2 0.6 156 54 / / 45% dose reduction compared with oral administration. Furthermore, administrating xanomeline 02 Oct 2025 that equivalent therapeutic efficacy may be achieved intranasally with an approximately 95% of 39 mg per kg of body weight (human equivalent dose). This suggested to the inventors Pharmacodynamic effects of xanomeline administered intranasally vs orally. equivalent reduction in hyperlocomotion activity to treatment with oral xanomeline at a dose intranasal xanomeline at a dose of 2 mg per kg of body weight produced an approximately

The inventors conducted further studies to evaluate the efficacy of xanomeline administered relative to the vehicle treatment control. Surprisingly, it was observed that treatment with

via intranasal (IN), oral (PO), and subcutaneous (SC) routes in a D-amphetamine-induced Treatment with xanomeline produced a significant reduction in hyperlocomotion activity

hypermocomotion model in male SD rats. The objective was to compare xanomeline’s ability hyperlocomotion activity relative to the control or un-induced group.

to reduce hyperlocomotion, which is a proxy for psychotic activity, across the various delivery As shown in Figure 6 and Figure 7, D-amphetamine induced a significant increase in

routes. 2025242171

pharmacokinetic levels of xanomeline.

plasma was collected after 120 minutes from study initiation, to confirm the respective

Rats were randomised into six groups (n=10 to 12 per group), including vehicle + saline, IN, SC, or PO administration) concurrently with D-amphetamine (intraperitoneally). Blood and

vehicle + D-amphetamine, SC xanomeline (10 mg/kg) + D-amphetamine (n=10), PO phase, followed by testing over two days, with animals receiving xanomeline (or vehicle) (by

Referring to Figure 5, the experiment began with a one-week acclimation and habituation xanomeline (39 mg/kg) + D-amphetamine (n=10), and IN xanomeline (2 mg/kg, n=12; and 6.5 mg/kg, n=11). The oral dose of 39 mg per kg body weight was included as the human route-specific differences.

equivalent dose, e.g. the dose producing approximately equivalent plasma xanomeline minutes in an open-field arena using video tracking, with data analysed via anova to detect

concentrations to that observed in human clinical studies. Locomotion was recorded for 120 concentrations to that observed in human clinical studies. Locomotion was recorded for 120 equivalent dose, e.g. the dose producing approximately equivalent plasma xanomeline

minutes in an open-field arena using video tracking, with data analysed via anova to detect 6.5 mg/kg, n=11). The oral dose of 39 mg per kg body weight was included as the human

route-specific differences. xanomeline (39 mg/kg) + D-amphetamine (n=10), and IN xanomeline (2 mg/kg, n=12; and

vehicle + D-amphetamine, SC xanomeline (10 mg/kg) + D-amphetamine (n=10), PO

Rats were randomised into six groups (n=10 to 12 per group), including vehicle + saline,

Referring to Figure 5, the experiment began with a one-week acclimation and habituation phase, followed by testing over two days, with animals receiving xanomeline (or vehicle) (by routes.

to reduce hyperlocomotion, which is a proxy for psychotic activity, across the various delivery IN, SC, or PO administration) concurrently with D-amphetamine (intraperitoneally). Blood and hypermocomotion model in male SD rats. The objective was to compare xanomeline's ability

plasma was collected after 120 minutes from study initiation, to confirm the respective via intranasal (IN), oral (PO), and subcutaneous (SC) routes in a D-amphetamine-induced

pharmacokinetic levels of xanomeline. The inventors conducted further studies to evaluate the efficacy of xanomeline administered

Pharmacodynamic effects of xanomeline administered intranasally vs orally.

As shown in Figure 6 and Figure 7, D-amphetamine induced a significant increase in hyperlocomotion activity relative 17 to the control or un-induced group.

Treatment with xanomeline produced a significant reduction in hyperlocomotion activity relative to the vehicle treatment control. Surprisingly, it was observed that treatment with intranasal xanomeline at a dose of 2 mg per kg of body weight produced an approximately equivalent reduction in hyperlocomotion activity to treatment with oral xanomeline at a dose of 39 mg per kg of body weight (human equivalent dose). This suggested to the inventors that equivalent therapeutic efficacy may be achieved intranasally with an approximately 95% dose reduction compared with oral administration. Furthermore, administrating xanomeline muscarinic receptor agonism may be beneficial.

intranasally at a higher dose of 6.5 mg per kg of body weight produced an approximately administration routes and may offer an unexpected advantage for treating patients for which 02 Oct 2025

inventors that intranasal administration of xanomeline is surprisingly more effective than other equivalent reduction in hyperlocomotion activity to treatment with subcutaneous xanomeline despite an approximately 33% lower total brain exposure level. These results suggest to the

at a dose of 10 mg per kg body weight. This suggested to the inventors that equivalent behavioural activity to subcutaneously administered xanomeline at 10 mg per kg (circle),

therapeutic efficacy can be achieved intranasally with a significant dose reduction compared Furthermore, intranasally administered xanomeline at 6.5 mg per kg (square) showed similar

to subcutaneous administration. exposure (AUC).

xanomeline at 39 mg per kg (upside-down triangle), but achieved similar levels of total brain

The results of analysis of plasma and brain concentrations of xanomeline after 120 minutes improvement in behavioural activity (hyperlocomotion) compared with orally administered

And intranasally administered xanomeline at 6.5 mg per kg (square) showed a nearly 3-fold 2025242171

after dosing are shown in Figure 8. Similar plasma and brain concentrations were observed down triangle) despite approximately 4-fold less total brain exposure for the intranasal group.

between animals treated with 6.5 mg per kg body weight intranasally and 39 mg per kg body xanomeline intranasally at 2 mg per kg (upright triangle) and orally at 39 mg per kg (upside-

weight orally. However, referring to Figure 7, the intranasally administered 6.5 mg per kg For example, similar levels of behavioural activity (hyperlocomotion) were achieved between

dose resulted in significantly improved efficacy. efficacy (reduction in hyperlocomotion) despite lower brain concentrations (Figure 9B).

was unexpectedly found that intranasal administration of xanomeline may achieve superior

Referring to Figure 9 parts A and B, a linear pharmacokinetic-pharmacodynamic relationship (AUC) to pharmacodynamic effect (hyperlocomotion) for different routes of administration, it

concentration. However, when comparing the relationship between total brain drug exposure was observed with intranasal administration of xanomeline (Figure 9A), where the effect of xanomeline on D-amphetamine-induced hyperlocomotion is approximately proportional to its

xanomeline on D-amphetamine-induced hyperlocomotion is approximately proportional to its was observed with intranasal administration of xanomeline (Figure 9A), where the effect of

concentration. However, when comparing the relationship between total brain drug exposure Referring to Figure 9 parts A and B, a linear pharmacokinetic-pharmacodynamic relationship

(AUC) to pharmacodynamic effect (hyperlocomotion) for different routes of administration, it dose resulted in significantly improved efficacy.

was unexpectedly found that intranasal administration of xanomeline may achieve superior weight orally. However, referring to Figure 7, the intranasally administered 6.5 mg per kg

efficacy (reduction in hyperlocomotion) despite lower brain concentrations (Figure 9B). between animals treated with 6.5 mg per kg body weight intranasally and 39 mg per kg body

after dosing are shown in Figure 8. Similar plasma and brain concentrations were observed

The results of analysis of plasma and brain concentrations of xanomeline after 120 minutes

For example, similar levels of behavioural activity (hyperlocomotion) were achieved between xanomeline intranasally at 2 mg per kg (upright triangle) and orally at 39 mg per kg (upside- to subcutaneous administration.

therapeutic efficacy can be achieved intranasally with a significant dose reduction compared down triangle) despite approximately 4-fold less total brain exposure for the intranasal group. at a dose of 10 mg per kg body weight. This suggested to the inventors that equivalent

And intranasally administered xanomeline at 6.5 mg per kg (square) showed a nearly 3-fold equivalent reduction in hyperlocomotion activity to treatment with subcutaneous xanomeline

improvement in behavioural activity (hyperlocomotion) compared with orally administered intranasally at a higher dose of 6.5 mg per kg of body weight produced an approximately

xanomeline at 39 mg per kg (upside-down 18 triangle), but achieved similar levels of total brain exposure (AUC).

Furthermore, intranasally administered xanomeline at 6.5 mg per kg (square) showed similar behavioural activity to subcutaneously administered xanomeline at 10 mg per kg (circle), despite an approximately 33% lower total brain exposure level. These results suggest to the inventors that intranasal administration of xanomeline is surprisingly more effective than other administration routes and may offer an unexpected advantage for treating patients for which muscarinic receptor agonism may be beneficial.

Water Solvent To volume 02 Oct 2025

Sodium chloride Isotonic agent 0.9 Intranasal Compositions of Xanomeline + Trospium citrate) (0.05 - 0.5 mg) Preferred embodiments of the invention relate to the intranasal administration of xanomeline, or Citric acid (trisodium

acid disodium salt (EDTA) or to the intranasalChelating Ethylenediaminetetraacetic administration agent of both xanomeline and trospium, for treating a central 0.00005 - 0.0005

nervous system (CNS) Benzalkonium chloride disorder or a neuropsychiatric Preservative 0.005 - 0.02 disorder for example of the type noted earlier. 0.1 1 Alkyl maltoside Absorption enhancer 2025242171

Xanomeline tartrate Active ingredient 0.5 30 In preferred Component embodiments the amount of xanomeline administered intranasally at each Function Amount - g/100 mL dosage event for an adult (12 years or older) is optionally in the range of 0.1 – 50 mg, 1 – 40 Intranasal Xanomeline Formulation mg, 1.5 – 30 mg, 2 – 25 mg, 2.5 – 20 mg.

intranasal formulation (a solution) as below:

More preferably, the amount of xanomeline administered intranasally at each dosage event For intranasal treatment of xanomeline only, the medicament may be prepared as an

for an adult is from approximately 2.5 mg to approximately 20 mg. And most preferably the approximately 2.5 mg to approximately 10 mg. amount of xanomeline administered intranasally at each dosage event for an adult is from amount of xanomeline administered intranasally at each dosage event for an adult is from

approximately 2.5 mg to approximately 10 mg. for an adult is from approximately 2.5 mg to approximately 20 mg. And most preferably the

More preferably, the amount of xanomeline administered intranasally at each dosage event

For intranasal treatment of xanomeline only, the medicament may be prepared as an mg, 1.5 - 30 mg, 2 - 25 mg, 2.5 - 20 mg.

intranasal formulation (a solution) as below: dosage event for an adult (12 years or older) is optionally in the range of 0.1 - 50 mg, 1 - 40

In preferred embodiments the amount of xanomeline administered intranasally at each

earlier. Intranasal Xanomeline Formulation nervous system (CNS) disorder or a neuropsychiatric disorder for example of the type noted

Component Function or to the intranasal administration of both xanomeline and trospium, for treating a central Amount - g/100 mL Preferred embodiments of the invention relate to the intranasal administration of xanomeline,

Xanomeline tartrate Active ingredient 0.5 - 30 Intranasal Compositions of Xanomeline + Trospium

Alkyl maltoside Absorption enhancer 0.1 - 1

Benzalkonium chloride Preservative 19 0.005 - 0.02

Ethylenediaminetetraacetic Chelating agent 0.00005 - 0.0005 acid disodium salt (EDTA) or Citric acid (trisodium (0.05 - 0.5 mg) citrate)

Sodium chloride Isotonic agent 0.9

Water Solvent To volume

In other embodiments the xanomeline and trospium may be prepared as a combination 02 Oct 2025

formulation (a solution) as below.

Intranasal Xanomeline + Trospium Formulation feature or features mentioned herein, even if the combination is not claimed below.

Component Function herein in combination with a repeat of itself (eg two or more of the same) and/or any other Amount - g/100 mL In terms of disclosure, this document envisages and hereby posits any feature mentioned

Xanomeline tartrate Active ingredient 0.5 - 30 2025242171

scope of the following claims.

Trospium chloride Active ingredient appreciated that modifications and improvements can be made without departing from the 0.01 - 7.5 While some forms of the invention have been described by way of example, it should be Benzalkonium chloride Preservative 0.005 - 0.02

Ethylenediaminetetraacetic Chelating agent 0.00005 - 0.0005 Water Solvent To volume acid disodium salt (EDTA) Sodium chloride Isotonic agent 0.9 or or citrate) Citric acid (trisodium Citric acid (trisodium (0.05 - 0.5 mg) (0.05 - 0.5 mg) citrate) or or

acid disodium salt (EDTA)

Sodium chloride Ethylenediaminetetraacetio Chelating agent Isotonic agent 0.00005 - 0.0005 0.9

Water Benzalkonium chloride Preservative Solvent 0.005 - 0.02 To volume Trospium chloride Active ingredient 0.01 7.5

Xanomeline tartrate Active ingredient 0.5 30

Component Function Amount - g/100 mL While some forms of the invention have been described by way of example, it should be Intranasal Xanomeline + Trospium Formulation appreciated that modifications and improvements can be made without departing from the scope of the following claims. formulation (a solution) as below.

In other embodiments the xanomeline and trospium may be prepared as a combination

In terms of disclosure, this document envisages and hereby posits any feature mentioned 20 herein in combination with a repeat of itself (eg two or more of the same) and/or any other feature or features mentioned herein, even if the combination is not claimed below.

Claims (20)

21 CLAIMS 13 Nov 2025 2025242171 13 Nov 2025

1. A method of treating a central nervous system disorder or a neuropsychiatric disorder in a human subject, comprising intranasally administering a medicament comprising xanomeline to the subject to deliver a therapeutically amount of the xanomeline.

2. A method according to claim 1, wherein the medicament is a liquid and comprises water 2025242171

as as aa carrier carrierororsolvent. solvent.

3. A method according to claim 1 or 2, wherein the xanomeline is in the form of a xanomeline salt, solvate or hydrate.

4. A method according to claim 3, wherein the xanomeline salt comprises one or more of xanomeline tartrate, oxalate, sulfate, phosphate, monohydrogen phosphate, dihydrogenphosphate, chloride, bromide, hydrobromide, citrate, iodide, hydroiodide, acetate, lactate, maleate, fumarate, succinate, nitrate, carbonate, bicarbonate, pyrosulfate, bisulfate, sulfite, bisulfite, metaphosphate, pyrophosphate, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methane-sulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene - 2 - sulfonate, mandelate, chloride, nitrate, carbonate, bicarbonate, hippurate, benzenesulfonate, adipate, p-toluenesulfonate, malate, ethanesulfonate, pamoate, gluconate, gluceptate, ascorbate, glucuronate and camsylate.

5. A method according to claim 3, wherein the xanomeline solvate comprises one or more of a methanol, ethanol, isopropanol, trifluoroethanol, 1-butanol, 2-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dichloromethane, trichloromethane, 1,4-dioxane, methyl tert butyl ether, cyclopentyl methyl ether, tetrahydrofuran, dimethyl tetrahydrofuran, benzyl ether, n-heptane, n-hexane, n-pentane, cyclohexane, methylcyclohexane, acetonitrile, toluene, benzene, dimethyl sulfoxide, N, N-

22

dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, or trifluoroacetic acid, 13 Nov 2025 2025242171 13 Nov 2025

solvate. solvate.

6. A method according to claim 3, wherein the xanomeline hydrate comprises one or more of xanomeline monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, and decahydrate. 2025242171

7. A method according to any one of the preceding claims, wherein the central nervous system disorder or the neuropsychiatric disorder comprises one or more of Alzheimer’s disease, Alzheimer’s disease psychosis, dementia (including e.g. Lewy Body dementia, Frontotemporal dementia), schizophrenia, psychosis, a schizo-affective disorder, a delusional disorder, psychotic depression, a bipolar disorder, a major depressive disorder, psychotic depression, Parkinson’s disease (including Parkinson’s disease dementia and Parkinson’s disease associated psychosis), substance use disorders (including e.g. cocaine, alcohol, methamphetamine, and opioid use disorder) and Huntington's disease.

8. A method according to claim 7, wherein the psychosis is acute psychosis.

9. A method according to claim 7, wherein the psychosis comprises psychosis associated with Alzheimer’s disease, Parkinson’s disease, bi-polar disorder, or psychotic depression.

10. A method according to any one of the preceding claims, wherein the medicament is self- administered by the human subject.

11. A method according to any one of the preceding claims, wherein the medicament is administered to the human subject by other than said subject.

12. A method according to any one of the preceding claims, comprising administration of a dose of 0.1 mg – 50 mg xanomeline to the subject.

13. A method according to any one of the preceding claims comprising administration of a dose of 1 mg – 40 mg xanomeline to the subject.

23

14. A method according to any one of the preceding claims comprising administration of a 13 Nov 2025 2025242171 13 Nov 2025

dose of 1.5 mg – 30 mg xanomeline to the subject.

15. A method according to any one of the preceding claims comprising administration of a dose of 2 mg – 25 mg xanomeline to the subject.

16. A medicament according to any one of the preceding claims wherein the treatment 2025242171

involves administration of a dose of approximately 2.5 mg to approximately 10 mg.

17. A method according to any one of the preceding claims, wherein the human subject also receives trospium simultaneously, or immediately before or after the xanomeline.

18. A method according to any one of the preceding claims, wherein the treating comprises the human subject receiving about 1 mg to about 30 mg xanomeline and about 0.01 mg to about 7.5 mg trospium per dosage event.

19. A method according to any one of the preceding claims, wherein the treating comprises the human subject receiving about 5 mg to about 20 mg xanomeline and about 1 mg to about 5 mg trospium per dosage event.

20. A method according to any one of the preceding claims, wherein the treating comprises the human subject receiving about 7 mg to about 13 mg xanomeline and about 2 mg to about 4 mg trospium per dosage event.