A medicament and method of treatment of central nervous system and / or neuropsychiatric disorders

Abstract

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.

Description

[0001] TITLE

[0002] A Medicament and Method of Treatment of Central Nervous System and / or Neuropsychiatric Disorders

[0003] FIELD OF INVENTION

[0004] This invention relates to intranasal medicaments comprising xanomeline and use of these for treating central nervous system disorders and / or neuropsychiatric disorders.

[0005] BACKGROUND

[0006] Xanomeline is a muscarinic acetylcholine receptor known for oral use in treating central nervous system (CNS) disorders and neuropsychiatric disorders, particularly Alzheimer’s disease and schizophrenia. However, its clinical development has been limited due to its poor bioavailability, adverse gastrointestinal side effects, and its short half-life. To address the short half-life and poor bioavailability it has been used in relatively high doses, however the trade-off has been a higher incidence of adverse gastric side-affects.

[0007] To mitigate the gastrointestinal effects, patients may be given oral trospium. While trospium can help against an overactive bladder, it comes with its own adverse side effects, for example allergic reactions such as rash, blurred vision, confusion, difficulty urinating, hallucinations, dizziness, headache, nausea and others, particularly when taken at doses high enough to give relief against the side effects of xanomeline.

[0008] Given the side effects associated 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

[0009] It is an object of preferred embodiments of the invention to go at least some way towards addressing the above problem. While this applies for preferred embodiments, the object of the invention per se is more general, being simply to provide the public with a useful choice. 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.

[0010] DEFINITIONS

[0011] The term “comprises” or “has”, if / when used in this document in relation to one or more features, should not be seen as excluding the option of additional features that have not been mentioned. The same applies to derivative terms such as “comprising” and “having”.

[0012] 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 salts, solvates or hydrates thereof. For example, a claim reference to xanomeline should be taken as embracing not only free xanomeline but also salts thereof, etc. And by way of 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 active agent, the figure concerned should be taken as adjusted when it is interpreted for the salt, solvate or hydrate, to give an equivalent amount of the active component. For example, 281.4 g of xanomeline (1 mol) should be taken as equivalent to 431.5 g (1 mol) of xanomeline tartrate. And 392.5 g of trospium (1 mol) should be taken as equivalent to 428.0 g (1 mol) of trospium chloride.

[0013] 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.

[0014] Any references in this specification to administration to a patient or subject mean selfadministration or administration by another person or device.

[0015] References in this specification to “treating” or the like may include but are not limited to overcoming, reducing, preventing the emergence of, or preventing the worsening of, thecondition treated and / or symptoms thereof. For example, to treat pain may include stopping, reducing or preventing the worsening of pain.

[0016] References to a therapeutically effective amount of a medicament or drug component thereof may mean an amount sufficient to meaningfully or materially improve the well-being of a human subject.

[0017] SUMMARY OF THE INVENTION

[0018] First Aspect

[0019] Medicament for use in Treating a CNS or a Neuropsychiatric Disorder

[0020] According to one aspect, the invention is an intranasal medicament comprising xanomeline for use in treating a central nervous system disorder or a neuropsychiatric disorder in a human subject by intranasal administration of the medicament to the subject to deliver a therapeutically effective amount of xanomeline.

[0021] Second Aspect

[0022] Use of Xanomeline for Producing a Medicament

[0023] According to a further aspect, the invention is the use of xanomeline in the production of an intranasal medicament for use in treating a central nervous system disorder or a neuropsychiatric disorder in a human subject by intranasal administration of the medicament to deliver a therapeutically effective amount of xanomeline.

[0024] Third Aspect

[0025] Method of Treatment

[0026] According to a further aspect, the invention is 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.Fourth Aspect

[0027] Treatment for Pain

[0028] According to a further aspect, the invention is an intranasal medicament comprising xanomeline for use in treating pain in a human subject by intranasal administration of the medicament to the subject to deliver a therapeutically effective amount of xanomeline.

[0029] Optional Features

[0030] The following optional features may be supplemented, alone or in any combination of one or more, to any of the three aspects mentioned above.

[0031] Optionally the medicament is a liquid and comprises water as a carrier or solvent.

[0032] Optionally the xanomeline is in the form of a xanomeline salt, solvate or hydrate.

[0033] Optionally 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, y-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.

[0034] Optionally 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-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, or trifluoroacetic acid, solvate.

[0035] Optionally the xanomeline hydrate comprises one or more of xanomeline monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, and decahydrate.

[0036] 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.

[0037] Optionally the psychosis is acute psychosis.

[0038] Optionally the psychosis comprises psychosis associated with Alzheimer’s disease, Parkinson’s disease, bi-polar disorder, or psychotic depression.

[0039] Optionally the medicament is for self-administration, or is self-administered, by the human subject.

[0040] Optionally the medicament is for administration, or is administered, to the human subject by other than said subject.

[0041] 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, 0.40.5, 0.6, 0.7, 0.8, or 0.9 mg xanomeline, or approximately 1-50, mg xanomeline.

[0042] Optionally the treatment involves administration of a dose of 1 mg - 40 mg xanomeline to the subject, for example approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 mg xanomeline .

[0043] Optionally the treatment involves administration of a dose of 1.5 mg - 30 mg xanomeline to the subject.

[0044] Optionally the treatment involves administration of a dose of 2 mg - 25 mg xanomeline to the subject.

[0045] Optionally the treatment involves administration of a dose of 2.5 mg - 20 mg xanomeline to the subject.

[0046] Optionally the treatment involves administration of a dose of approximately 2.5 mg to approximately 20 mg.

[0047] Optionally the treatment involves administration of a dose of approximately 2.5 mg to approximately 20 mg.

[0048] Optionally the treatment involves administration of a dose of 0.1 mg - 30 mg xanomeline to the subject.

[0049] Optionally the treatment involves administration of a dose of 0.1 mg - 30 mg xanomeline tartrate to the subject.

[0050] Optionally the treatment involves administration of a dose of 20 mg - 30 mg xanomeline to the subject.

[0051] Optionally the treatment involves administration of a dose of 20 mg - 30 mg xanomeline tartrate to the subject.

[0052] Optionally the dose is for administration, or is administered, 1 , 2 or 3 times within a 24 hour period.

[0053] Optionally the medicament comprises about 0.1 % to about 30% w / v of xanomeline.Optionally the medicament comprises an absorption enhancer.

[0054] Optionally the medicament comprises about 0.1 % to about 2.5 % w / v of an alkylsaccharide absorption enhancer.

[0055] Optionally the alkylsaccharide absorption 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-a-maltoside, and octadecyl-p-D-maltoside, dodecyl glucoside, tetradecyl glucoside, octyl glucoside, decyl glucoside, nonyl glucoside, undecyl glucoside, tridecyl glucoside, pentadecyl glucoside, hexadecyl glucoside, heptadecyl glucoside, octadecyl-a-glucoside, and octadecyl-p-D-glucoside, dodecyl sucroside, tetradecyl sucroside, octyl sucroside, decyl sucroside, nonyl sucroside, undecyl sucroside, tridecyl sucroside, pentadecyl sucroside, hexadecyl sucroside, heptadecyl sucroside, octadecyl-a-sucroside, and octadecyl-p-D-sucroside

[0056] Optionally the medicament comprises about 0.2 % to about 1.2 % w / v sodium chloride.

[0057] Optionally the medicament comprises a preservative.

[0058] Optionally the preservative comprises one or more of Benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorbutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid, potassium sorbate, EDTA (eg sodium or calcium EDTA), and sodium citrate.

[0059] Optionally the preservative is present in an amount of about 0.005% (w / v) to about 1% (w / v).

[0060] Optionally the medicament comprises a chelating agent.Optionally the chelating agent comprises one or more of ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof, citric acid or a pharmaceutically acceptable salt thereof, sodium phosphate, and EDTA (eg sodium or calcium EDTA).

[0061] Optionally the chelating agent comprises about 0.1% (w / v) to about 0.5% (w / v) of disodium edetate.

[0062] Optionally the treatment comprises the human subject also receiving trospium simultaneously, or immediately before or after the xanomeline.

[0063] Optionally the medicament comprises trospium as a further active agent.

[0064] 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.

[0065] Optionally the xanomeline and trospium are in a wt / wt ratio of 80: 1 to 4 : 1.

[0066] Optionally the xanomeline is a tartrate salt, the trospium is a chloride salt, and these salt forms are in a wt / wt ratio of 100 : 1 to 5 : 1.

[0067] Optionally the xanomeline and trospium are in a molar ratio of about 100 : 1 to about 5 : 1 xanomeline to trospium

[0068] Optionally the xanomeline and trospium are in a molar ratio of about 40 : 1 to about 50 : 1 xanomeline to trospium

[0069] Optionally the treatment 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.

[0070] Optionally the treatment 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.Optionally the treatment 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.

[0071] Optionally the treatment comprises the human subject receiving a volume of about 0.1 mL to 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.

[0072] Optionally the medicament comprises about 1% to 20% w / w xanomeline with or without about 0.1 to about 5% w / w trospium.

[0073] Optionally the medicament comprises about 5% to 15% w / w xanomeline with or without about 1 to about 4% w / w trospium.

[0074] Optionally the medicament comprises about 8% to 12% w / w xanomeline with or without about 2 to about 3% w / w trospium.

[0075] Optionally the medicament and / or the treatment is without any brain penetration enhancer.

[0076] Optionally the medicament is for use with intranasal or oral trospium.

[0077] Optionally the medicament incorporates, or is for use with, one or more muscarinic receptor antagonist or a salt or solvate thereof, selected from propantheline (eg propantheline bromide), emepronium (eg emepronium bromide), ipratropium (eg ipratropium bromide), glycopyrrolate (eg glycopyrronium bromide), methylatropine (eg atropine methonitrate), ethylatropine bromide, oxitropium bromide, aclidinium bromide, and methantheline.

[0078] Optionally in each case the muscarinic receptor antagonist, or the salt or solvate thereof, is administered, or is for administration, orally or intranasally.

[0079] Optionally in relation to the fourth aspect above, the pain comprises one or more of inflammatory pain, neuropathic pain, central pain, central sensitization syndrome pain, nociceptive pain, nociplastic pain, acute pain, chronic pain, musculoskeletal pain and connective tissue pain.DRAWINGS / GRAPHS

[0080] Some preferred embodiments of the invention will now be described by way of example and with reference to the accompanying drawings / graphs, of which- Figure 1 graphs a pharmacokinetic profile for xanomeline tartrate when delivered orally and intranasally in brain and plasma of rats;

[0081] Figure 2 graphs a pharmacokinetic profile for xanomeline (free base) when delivered orally and intranasally such that it arrives in the plasma and cerebrospinal fluid (CSF) of canines;

[0082] Figure 3 graphs a pharmacokinetic profile for trospium when delivered orally and intranasally such that it arrives in the plasma of rats;

[0083] Figure 4 graphs the pharmacokinetic profile for xanomeline (free base) when delivered intravenously to rats;

[0084] 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;

[0085] Figure 6 graphs the pharmacodynamic effect of xanomeline (free base) in a D- amphetamine-induced hyperlocomotion model of psychosis showing the total distance travelled for control and treated groups;

[0086] Figure 7 graphs a statistical analysis of the hyperlocomotion model showing total distance travelled over a 120 minute period of open-window recording following administration of xanomeline (free base) by intranasal, subcutaneous and oral routes;

[0087] Figure 8 graphs brain and plasma concentrations of xanomeline (free base) 120 minutes after administration via intranasal, oral, and subcutaneous routes; and Figure 9 graphs a linear pharmacokinetic-pharmacodynamic relationship for intranasally administered xanomeline (free base) at (A), and the relationship between total brain drug exposure the pharmacodynamic effect (hypolocomotion) at (B).DETAILED DESCRIPTION

[0088] The inventors have discovered that the normal oral dosage of xanomeline taken for treating a central nervous system disorder or a neuropsychiatric disorder can be reduced significantly if the xanomeline is administered intranasally. This is considered beneficial because a smaller dose of xanomeline reduces the risk of the adverse side effects normally associated with oral administration.

[0089] It was surprising that the nasal administration route gave benefits, particularly at the magnitude observed, and also in relation to the consistency of the amount of drug delivered to the plasma and brain from patient to patient. This was especially so given the normal variability / inconsistency from patient 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.

[0090] Pharmacokinetic studies were conducted to develop a treatment comprising xanomeline for intranasal use as follows.

[0091] Xanomeline in Rodents

[0092] 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.

[0093] 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 3 mg or 10 mg of 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).

[0094] For the oral group, xanomeline tartrate was dissolved in normal saline and administered orally by gavage to rats at a dose volume of 10 mL / kg of body weight to provide a total dose 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).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 determined by LC-MS / MS using carbamazepine as internal standard. The pharmacokinetic parameters such as AUC (area under the curve), Cmax (peak plasma concentration) and T 1 (half-life) were calculated using Phoenix Winnonlin software.

[0095] Figure 1 (annexed) and Table 1 show the drug concentration and other pharmacokinetic parameters from the xanomeline tartrate rat experiments. As indicated, 10 mg of xanomeline tartrate per kg of body weight delivered intranasally gave about an equivalent brain exposure of the active ingredient as 60 mg 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.

[0096] Table 1

[0097] Pharmacokinetic parameters of oral and intranasal delivery of xanomeline in rats.

[0098]

[0099] PO: per os

[0100] IN: intranasalmpk: mg per kg

[0101] B / P ratio: brain to plasma ratio

[0102] Xanomeline in Canines

[0103] Beagle dogs (male, 9-12 kg) were fasted overnight prior to intranasal or oral dosing of xanomeline, with free access to water.

[0104] 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).

[0105] For the oral group, the xanomeline tartrate was dissolved in normal saline and administered 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.

[0106] For both groups, blood samples were collected at 0.083, 0.17, 0.33, 0.5, 0.75, 1, 2, 4, 6, 8 and 24 hours post administration, with cerebrospinal fluid (CSF) samples collected at 0.083, 1 and 4 hours post administration (n=3 per timepoint). Concentrations of the intranasal drug in plasma and CSF were determined by LC-MS / MS using carbamazepine as an internal standard. The pharmacokinetic parameters such as AUC, Cmax and T1 / 2 were calculated using Phoenix Winnonlin software.

[0107] 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 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 20 mg of xanomeline tartrate per kg of body weight. The CSF to plasma ratio also significantly improved with intranasal administration.Table 2

[0108] Pharmacokinetic parameters of oral and intranasal delivery of xanomeline in canines.

[0109]

[0110] Trospium in Rodents

[0111] It was hypothesized that there may be advantages for human patients if trospium is administered intranasally, simultaneously or immediately before or after, xanomeline. The reason for this is that trospium can assist against gastrointestinal problems caused by 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, pharmacokinetic studies were run on rats (male, Sprague-Dawley, 0.17-0.25 kg). They were fasted overnight prior to intranasal or oral dosing of trospium, with free access to water.

[0112] For the intranasal group, trospium chloride was dissolved in normal saline and administered intranasally by pipette to the rats at a dose volume of 0.1 mL / kg of body weight to provide a total dose of 1.5 mg trospium chloride per kg of body weight. Blood samples and brain and nasal mucosa tissue samples were collected at 0.083, 0.5, 1, 2, 5 and 10 hours post administration (n=1 per timepoint).

[0113] For the oral group, trospium chloride was dissolved in water and administered orally to the rats by gavage at a dose volume of 10 mL / kg of body weight to provide a total dose of 100 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).For both groups, brain and nasal mucosa tissue were extracted and homogenized with 50% methanol. Concentrations of the intranasally administered drug in plasma and tissue homogenate were determined by LC-MS / MS using propranolol as internal standard. The pharmacokinetic parameters such as AUC, Cmax and T1 / 2 were calculated using Phoenix Winnonlin software.

[0114] 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.

[0115] Table 3

[0116] Pharmacokinetic parameters of oral and intranasal delivery of trospium in rats.

[0117]

[0118] The above studies suggested to the inventors that trospium is suited for intranasal administration in combination with xanomeline. In this regard it was found to achieve 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. Based on these findings it is considered that an equivalent therapeutic effect may be achieved and maintained in patients at a fraction of the dose of both xanomeline and trospium when taken in normal oral doses. It is considered that this significantly mitigates the risk of dose-dependent side effects compared to oral administration of these actives. Given that trospium is widely known to have very poor permeation across biological membranes, it was surprising and unexpected that such a large dose reduction could be achieved compared to oral dosing and yet still deliver an equivalent peripheral exposure of trospium.Bioavailability of Xanomeline Administered Intranasally & Orally

[0119] In a further trial, rats (male, Sprague-Dawley, 0.17 - 0.25 kg) were fasted overnight prior to intranasal, intravenous and oral dosing of xanomeline, with free access to water.

[0120] 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).

[0121] For the oral group, xanomeline tartrate was dissolved in normal water and administered orally by gavage to rats at a dose volume of 10 mL / kg of body weight to provide a total dose of 20 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 and 6 hours post administration (n=3 per timepoint).

[0122] For the intravenous group, xanomeline tartrate was dissolved in normal saline and administered to rats intravenously into the tail vein at a dose volume of 5 mL / kg of body 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 hours post administration (n=3 per timepoint).

[0123] For all 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 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 concentration) and T 1 (half-life) were calculated using Phoenix Winnonlin software.

[0124] Figure 4 (annexed) and Table 4 below show the resulting drug concentrations and other pharmacokinetic parameters. As indicated, intranasal administration of xanomeline for both the 2 mg and 6.5 mg per kg of body weight resulted in significantly higher bioavailability (by nearly 50%) when compared with oral administration (5%), which corresponds to a 10-fold improvement in drug absorption when xanomeline is administered intranasally.Table 4

[0125]

[0126] Pharmacodynamic effects of xanomeline administered intranasally vs orally.

[0127] The inventors conducted further studies to evaluate the efficacy of xanomeline administered via intranasal (IN), oral (PO), and subcutaneous (SC) routes in a D-amphetamine-induced hypermocomotion model in male SD rats. The objective was to compare xanomeline’s ability to reduce hyperlocomotion, which is a proxy for psychotic activity, across the various delivery routes.

[0128] Rats were randomised into six groups (n=10 to 12 per group), including vehicle + saline, vehicle + D-amphetamine, SC xanomeline (10 mg / kg) + D-amphetamine (n=10), PO 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 equivalent dose, e.g. the dose producing approximately equivalent plasma xanomeline concentrations to that observed in human clinical studies. Locomotion was recorded for 120 minutes in an open-field arena using video tracking, with data analysed via anova to detect route-specific differences.

[0129] 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 IN, SC, or PO administration) concurrently with D-amphetamine (intraperitoneally). Blood andplasma was collected after 120 minutes from study initiation, to confirm the respective pharmacokinetic levels of xanomeline.

[0130] As shown in Figure 6 and Figure 7, D-amphetamine induced a significant increase in hyperlocomotion activity relative to the control or un-induced group.

[0131] 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 intranasally at a higher dose of 6.5 mg per kg of body weight produced an approximately equivalent reduction in hyperlocomotion activity to treatment with subcutaneous xanomeline at a dose of 10 mg per kg body weight. This suggested to the inventors that equivalent therapeutic efficacy can be achieved intranasally with a significant dose reduction compared to subcutaneous administration.

[0132] The results of analysis of plasma and brain concentrations of xanomeline after 120 minutes after dosing are shown in Figure 8. Similar plasma and brain concentrations were observed between animals treated with 6.5 mg per kg body weight intranasally and 39 mg per kg body weight orally. However, referring to Figure 7, the intranasally administered 6.5 mg per kg dose resulted in significantly improved efficacy.

[0133] Referring to Figure 9 parts A and B, a linear pharmacokinetic-pharmacodynamic relationship was observed with intranasal administration of xanomeline (Figure 9A), where the effect of xanomeline on D-amphetamine-induced hyperlocomotion is approximately proportional to its concentration. However, when comparing the relationship between total brain drug exposure (AUG) to pharmacodynamic effect (hyperlocomotion) for different routes of administration, it was unexpectedly found that intranasal administration of xanomeline may achieve superior efficacy (reduction in hyperlocomotion) despite lower brain concentrations (Figure 9B).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 (upsidedown triangle) despite approximately 4-fold less total brain exposure for the intranasal group. And intranasally administered xanomeline at 6.5 mg per kg (square) showed a nearly 3-fold improvement in behavioural activity (hyperlocomotion) compared with orally administered xanomeline at 39 mg per kg (upside-down triangle), but achieved similar levels of total brain exposure (AUC).

[0134] 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.

[0135] Intranasal Compositions of Xanomeline + Trospium

[0136] Preferred embodiments of the invention relate to the intranasal administration of xanomeline, or to the intranasal administration of both xanomeline and trospium, for treating a central nervous system (CNS) disorder or a neuropsychiatric disorder for example of the type noted earlier.

[0137] In preferred embodiments the amount of xanomeline administered intranasally at each dosage event for an adult (12 years or older) is optionally in the range of 0.1 - 50 mg, 1 - 40 mg, 1.5 - 30 mg, 2 -25 mg, 2.5 -20 mg.

[0138] More preferably, the amount of xanomeline administered intranasally at each dosage event for an adult is from approximately 2.5 mg to approximately 20 mg. And most preferably the amount of xanomeline administered intranasally at each dosage event for an adult is from approximately 2.5 mg to approximately 10 mg.

[0139] For intranasal treatment of xanomeline only, the medicament may be prepared as an intranasal formulation (a solution) as below:

[0140]

[0141] In other embodiments the xanomeline and trospium may be prepared as a combination formulation (a solution) as below.

[0142]

[0143] While some forms of the invention have been described by way of example, it should be appreciated that modifications and improvements can be made without departing from the scope of the following claims.

[0144] In terms of disclosure, this document envisages and hereby posits any feature mentioned 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

CLAIMS1. Use of xanomeline in the production of an intranasal medicament for use in treating a central nervous system disorder or a neuropsychiatric disorder in a human subject by intranasal administration of the medicament to deliver a therapeutically effective amount of xanomeline.

2. The use according to claim 1 , wherein the medicament a liquid comprising water as a carrier or solvent.

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

4. The use 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, y-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. The use 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 tetra hydrofuran, benzyl ether, n-heptane, n-hexane, n-pentane, cyclohexane, methylcyclohexane, acetonitrile, toluene, benzene, dimethyl sulfoxide, N, IM-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, or trifluoroacetic acid, solvate.

6. The use 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.

7. The use 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. The use according to claim 7, wherein the psychosis is acute psychosis.

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

10. The use according to any one of the preceding claims, wherein the medicament is for self-administration by the human subject.

11. The use according to any one of the preceding claims, wherein the medicament is for administration to the human subject by other than said subject.

12. The use according to any one of the preceding claims, wherein the medicament is for administration in a dose of 0.1 mg - 50 mg xanomeline.

13. The use according to any one of the preceding claims, wherein the medicament is for administration in a dose of 1 mg - 40 mg.

14. The use according to any one of the preceding claims, wherein the medicament is for administration in a dose of 1.5 mg - 30 mg xanomeline.

15. The use according to any one of the preceding claims, wherein the medicament is for administration in a dose of 2 mg - 25 mg xanomeline.

16. The use according to any one of the preceding claim, wherein the medicament is for administration in a dose of approximately 2.5 mg to approximately 10 mg.

17. The use according to any one of the preceding claims, wherein the medicament comprises, or is for use with, trospium.

18. The use according to any one of the preceding claims, wherein the medicament is for administration to deliver about 1 mg to about 30 mg xanomeline and about 0.01 mg to about 7.5 mg trospium per dosage event.

19. The use according to any one of the preceding claims, wherein the medicament is for administration of about 5 mg to about 20 mg xanomeline and about 1 mg to about 5 mg trospium per dosage event.

20. The use according to any one of the preceding claims, wherein the medicament is for administration of about 7 mg to about 13 mg xanomeline and about 2 mg to about 4 mg trospium per dosage event.

21. An intranasal medicament comprising xanomeline for use in treating a central nervous system disorder or a neuropsychiatric disorder in a human subject by intranasal administration of the medicament to the subject to deliver a therapeutically effective amount of xanomeline.

22. An intranasal medicament comprising xanomeline for use in treating pain in a human subject by intranasal administration of the medicament to the subject to deliver a therapeutically effective amount of xanomeline.

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