Compositions and methods for treating neurological disorders

Abstract

A pharmaceutical composition comprises a muscarinic agonist and a pharmacokinetic (PK) modifier that changes the metabolic profile the muscarinic agonist. The pharmaceutical composition may be used for the treatment of a neurological disorder or condition in a subject.

Description

DOCKET NO.: 2046-001 PCTTITLE:COMPOSITIONS AND METHODS FOR TREATING NEUROLOGICAL DISORDERS

[0001] The present application claims priority of United State Provisional Application No. 63 / 719,460, filed on November 12, 2024, which is incorporated herein by references in its entirety.FIELD

[0002] The present application generally relates to pharmaceutical compositions and medical treatments, and in particular to pharmaceutical compositions and medical treatments for muscarinic receptor-related disorders or conditions, such as neurological disorders.BACKGROUND

[0003] The acetylcholine neurotransmitter system plays a significant role in a variety of central nervous system (CNS) and peripheral functions. Acetylcholine signaling occurs through two different families of receptors: nicotinic receptors and muscarinic receptors. Muscarinic cholinergic receptors are G-protein coupled receptors with five different receptor subtypes (M1-M5), each of which are found in the CNS but have different peripheral tissue distributions and functions. Activation of the muscarinic system through use of muscarinic agonists has been suggested to have the potential to treat muscarinic receptor-related neurological disorders. Ml and M4 subtypes have been of particular interest as therapeutic targets for various conditions, such as Alzheimer's disease, Parkinson's disease, schizophrenia, movement disorders and drug addiction.

[0004] Xanomeline, a muscarinic agonist with more potent activity on Ml and M4, has been tested in several clinical trials. Because xanomeline also bound to subtypes of receptors (M2, M3 and M5) other than Ml and M4, a number of various serious side effects were observed including gastrointestinal (GI) side effects and cardiovascular side effects. Xanomeline is an extensively metabolized compound with < 1% bioavailability, resulting in the high oral dose for clinical applications and formation of active metabolites with less selectivity for Ml and M4.

[0005] There is a continued need for development of muscarinic agonist-based medications with improved efficacy and reduced side effects.SUMMARY

[0006] One aspect of the present application relates to a pharmaceutical composition that comprises (1) a muscarinic agonist and (2) a pharmacokinetic (PK) modifier that improves the bioavailability of the muscarinic agonist.

[0007] In some embodiments, the muscarinic agonist is xanomeline, an analog of xanomeline, a derivative of xanomeline, a prodrug of xanomeline, a metabolite of xanomeline, or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the muscarinic agonist is a chemical compound having formula (I)wherein each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and R23is independently chosen from hydrogen (H), deuterium (D) and fluorine (F), and wherein X is oxygen (O) or sulfur (S).

[0009] In some embodiments, the muscarinic agonist is xanomeline (formula II)

[0010] In some embodiments, the PK modifier is a CYP enzyme inhibitor.

[0011] In some embodiments, the CYP enzyme inhibitor is selected from the group consisting of quinidine, cinacalcet, sarpogrelate, chlorpromazine, dihydroquinidine, analogs thereof, derivatives thereof and pharmaceutically acceptable salts thereof.

[0012] In some embodiments, the muscarinic agonist is xanomeline and the PK modifier is quinidine, an analog of quinidine, a derivative of quinidine, a prodrug of quinidine, or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the muscarinic agonist is xanomeline (formula II) and the PK modifier is quinidine (formula III) or dihydroquinidine (formula IV):

[0014] In some embodiments, the pharmaceutical composition comprises (1) xanomeline (X) and quinidine (Q) at a X:Q weight ratio in the range of 0.5:1 to 5: 1, or (2) xanomeline (X) and dihydroquinidine (H) at a X:H weight ratio in the range of 0.5 : 1 to 5 : 1.

[0015] In some embodiments, the pharmaceutical composition is formulated for oral administration.

[0016] Another aspect of the present application relates to a method for treating a neurological disorder or condition in a subject. The method comprises the step of administering to the subject a muscarinic agonist and a PK modifier that improves the bioavailability of the muscarinic agonist.

[0017] In some embodiments, the PK modifier is administered prior to, concurrently with, or subsequent to, the administration of the muscarinic agonist.

[0018] In some embodiments, the muscarinic agonist is xanomeline and the PK modifier is quinidine.

[0019] In some embodiments, the neurological disorder or condition is selected from the group consisting of schizophrenia and schizophreniform diseases, neurodegenerative diseases, ischemic brain diseases, anxiety disorders, autistic disorder, mental retardation, conduct disorder such as extreme aggressiveness, disruptive behavior disorder, attention deficit / hyperactivity disorder, bipolar disorder, drug addiction, non-opioid based therapy for forms of post-operative inflammatory and neuropathic pain, Alzheimer's disease, Down's syndrome, Tourette disease, tardive dyskinesia, Pick's disease, Huntington's chorea,Friedrich's ataxia, Progressive Supranuclear Palsy, Dementia with Lewy Bodies, Parkinson's Disease, sensory abnormalities of the bladder, fronto-temporal dementia vascular diseases, stroke, multi-infarct dementia, subarachnoid hemorrhage, head trauma infections, postencephalitic dementia, syphilis, herpetic encephalitis congenital abnormalities, trisomy 21, toxic brain injuries, Wernike encephalopathy, Krorsakoff psychosis, alcoholic amnesic syndrome and alcoholic dementia.

[0020] In some embodiments, the neurological disorder or condition is schizophrenia or a schizophreniform disease.

[0021] In some embodiments, the neurological disorder or condition is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer's disease or Parkinson's disease.

[0022] In some embodiments, the method for treating a neurological disorder or condition ameliorates one or more neuropsychiatric and / or neuropsychological symptoms of a neurodegenerative disorder. Examples of such symptoms include, but are not limited to, mood changes, psychotic symptoms, behavioral disturbances, cognitive and emotional deficits like memory loss, language problems, and executive dysfunction, which negatively impact a patient's quality of life and can accelerate disease progression. Common symptoms include depression, apathy, agitation, aggression, hallucinations, and delusions. These symptoms arise from the complex interplay of neurobiological changes in the brain and can sometimes manifest before or alongside cognitive symptoms, such as in Alzheimer's or Parkinson's diseases.

[0023] Another aspect of the present application relates to a method for treating a neurological disorder or condition in a subject. The method comprises the step of co-administing an effective amount of a muscarinic agonists with one or more PK modifiers.

[0024] In some embodiments, the one or more PK modifiers change the relative abundance of the muscarinic agonist and metabolites thereof during systemic exposure, as compared to administration of the muscarinic agonist alone.

[0025] In some embodiments, the one or more PK modifiers increase bioavaailability of the muscarinic agonist during systemic exposure, as compared to administration of the muscarinic agonist alone.

[0026] In some embodiments, the one or more PK modifiers alters relative ratio of the muscarinic agonist and metabolites thereof during systemic exposure, as compared to administration of the muscarinic agonist alone.

[0027] Another aspect of the present application relates to a method of reducing side effects caused by metabolite of a compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof. The method comprises the step of coadministering to a subject (1) the compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof and (2) quinidine, a pharmaceutically acceptable salt of quinidine, an analog of quinidine or a derivative of quinidine.

[0028] Another aspect of the present application relates to a method of altering metabolic profile of a compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof. The method compriese the step of co-administering to a subject (1) the compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof and (2) quinidine, a pharmaceutically acceptable salt of quinidine, an analog of quinidine or a derivative of quinidine.

[0029] Another aspect of the present application relates to a method of improving bioavailabililty of a compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof. The method compriese the step of co-administering to a subject (1) the compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof and (2) quinidine, a pharmaceutically acceptable salt of quinidine, an analog of quinidine or a derivative of quinidine.

[0030] A method of reducing Gl-related side effect of a compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof. The method compriese the step of co-administering to a subject (1) the compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof and (2) quinidine, a pharmaceutically acceptable salt of quinidine, an analog of quinidine or a derivative of quinidine.BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIGS. 1A and IB show the chemical structure of xanomeline (FIG. 1A) quinidine (FIG. IB), and dihydroquinidine (FIG. 1C).

[0032] FIGS. 2A-2D show the structural formula of xanomeline analogs and derivatives, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and R23are independently chosen from H, D and F, and wherein X is oxygen (O) or sulfur (S). (FIG. 2A), N-deuterated methyl xanomeline (FIG. 2B), fluorinated xanomeline (FIG. 2C) and tazomeline (FIG. 2D)

[0033] FIG. 3 shows the in vitro metabolites of xanomeline in human hepatocytes.

[0034] FIGS. 4A and 4B show the generation of two major metabolites M9 (FIG. 4A) and Ml 1 (FIG. 4B) in the presence of or without CYP enzyme inhibitor, quinidine.

[0035] FIGS. 5A-5C shows blood concentration-time curves after oral gavage administration in monkeys. FIG. 5A: blood concentration-time curves of xanomeline administered at 5 mg / kg alone or in combination with 100 mg / kg quinidine. FIG. 5B: blood concentration-time curves of xanomeline administered at 10 mg / kg alone or in combination with 100 mg / kg quinidine. FIG. 5C: blood concentration-time curves of quinidine administered at 100 mg / kg alone or in combination with 5 or 10 mg / kg xanomeline.

[0036] FIG. 6 shows a summary of observed gastrointestinal (GI) side effects in monkeys receiving xanomeline with or without quinidine.

[0037] FIG. 7A shows the mean (+ standard deviation) xanomeline plasma concentration vs time following oral administration of X alone or X with quinidine (Q) or dihydroquinidine (H) in monkeys. FIG.7B shows the mean (+ standard deviation) Q / H plasma concentration vs time following oral administration of X alone or X with Q or H. Only positive deviation was shown with the error bar to make a clear illustration. The negative deviation is the same value.

[0038] FIG. 8 shows the mean (+ standard deviation, n=6 subjects) xanomeline pharmacokinetic concentrations on Day 1 for xanomeline alone (10 mg single dose), Day 5 for 1stdose of xanomeline and quinidine (10 mg / 10 mg) BID and Day 9 for 9thdose of xanomeline and quinidine (10 mg / 10 mg) during the 1stcohort. Only positive deviation was shown by the error bar to make a clear illustration, and the negative deviation is the same value.

[0039] FIG. 9 shows the mean (+ standard deviation, n=6 subjects) xanomeline pharmacokinetic concentrations for 0-12 hour on Day 4 for xanomeline alone (10 mg BID), Day 8, DI 1 and D 14 for xanomeline and quinidine (25 mg / 10 mg BID) during the 2ndcohort. Only the positive deviation was shown by the error bar to make a clear illustration, and the negative deviation is the same value.

[0040] FIG. 10 shows the mean (+ standard deviation, n=6 subjects) quinidine plasma concentrations on Day 5 and D 9 for xanomeline and quinidine (10 mg / 10 mg BID) during the 1st cohort and Day 8, DI 1 and D 14 for 0-12 hour for xanomeline and quinidine (25 mg / 10 mg BID) during the 2nd cohort. Only the positive deviation was shown by the error bar to make a clear illustration, and the negative deviation is the same value.

[0041] FIG. 11 shows the mean (+ standard deviation, n=6 subjects) xanomeline plasma concentrations for 0-12 hour on D4 for xanomeline alone (15 mg BID), Day 8, DI 1and D 14 for xanom eline and dihydroquinidine (15 mg / 10 mg BID) during the 3rdcohort. Only positive deviations were shown by the error bar to make a clear illustration, and the negative deviation is the same value.

[0042] FIG. 12 shows the mean (+standard deviation) dihydroquinidine plasma concentrations for 0-12 hour on Day 8, Dll and D14 for xanomeline + hydroquinidine (15 mg / 10 mg BID) during the 3rdcohort. Only the positive deviation was shown by the error bar to make a clear illustration, and the negative deviation is the same value.

[0043] FIG. 13 shows pharmacokinetic concentrations of xanomeline and the major metabolites of xanomeline for 0-12 hours on Day 4 for xanomeline administration alone (25 mg, BID) during the 2ndcohort.

[0044] FIG. 14 shows pharmacokinetic concentrations of xanomeline and the major metabolites of xanomeline for 0-12 hours on D14 for combined xanomeline and quinidine administration (25 mg xanomeline / 10 mg quinidine, BID) during the 2ndcohort.

[0045] While the present disclosure will now be described in detail, and it is done so in connection with the illustrative embodiments, it is not limited by the particular embodiments illustrated in the figures and the appended claims.DETAILED DESCRIPTION

[0046] Reference will be made in detail to certain aspects and exemplary embodiments of the application, illustrating examples in the accompanying structures and figures. The aspects of the application will be described in conjunction with the exemplary embodiments, including methods, materials and examples, such description is non-limiting and the scope of the application is intended to encompass all equivalents, alternatives, and modifications, either generally known, or incorporated here. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. One of skill in the art will recognize many techniques and materials similar or equivalent to those described here, which could be used in the practice of the aspects and embodiments of the present application. The described aspects and embodiments of the application are not limited to the methods and materials described.I. Definitions

[0047] In the specification and in the claims, the terms "including" and "comprising are open-ended terms and should be interpreted to mean "including, but not limited to . . . ."These terms encompass the more restrictive terms “consisting essentially of’ and “consisting of.”

[0048] As used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the content clearly dictates otherwise.

[0049] Ranges may be expressed herein as from "about" one particular value, and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It is also understood that when a value is disclosed that "less than or equal to "the value," greater than or equal to the value" and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "10" is disclosed the "less than or equal to 10" as well as "greater than or equal to 10" is also disclosed.

[0050] It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Further, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein. It is also to be noted that the terms "comprising," "including," “characterized by” and "having" can be used interchangeably. Further, any reactant concentrations described herein should be considered as being described on a weight to weight (w / w) basis, unless otherwise specified to the contrary (e.g., mole to mole, weight to volume (w / v), etc.).

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this application belongs. All publications and patents specifically mentioned herein are incorporated by reference in their entirety for all purposes including describing and disclosing the chemicals, instruments, statistical analyses and methodologies which are reported in the publications which might be used in connection with the application. All references cited in this specification are to be taken as indicative of the level of skill in the art. Nothing herein isto be construed as an admission that the application is not entitled to antedate such disclosure by virtue of prior invention.

[0052] The term "muscarinic agonist", as used herein, is a substance which binds to and activates muscarinic acetylcholine receptors in an in vitro or in vivo setting. Activation of muscarinic acetylcholine receptors can be measured with methods well known in the art (e.g., by Yohn, S. E., et al. (2022). "Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic." Trends in Pharmacological Sciences 43(12): 1098-1112 and by Johnson, C. R., et al. (2022). "Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders." Biomedicines 10(2): 398). Muscarinic agonists are well known in the art.

[0053] When a muscarinic agonist is a chemical compound represented by a chemical formula or structure in the present application, the chemical formula or structure includes all isomers and isotope substituted derivatives of the formula or structure depicted. The formula or structure is also meant to refer to the chemical compound of the present applications regardless of how the chemical compound is produced, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof. All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates. The compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compounds and salts.

[0054] The term "isomer" as used herein, refers to any stereoisomer, enantiomers, mixture of enantiomers, including racemates, mixture of diastereomers, geometric isomers, atropisomers and / or tautomers of the compound that may be present in the structure. Methods for determining and isolating the stereochemistry of such isomers are well known to those skilled in the art.

[0055] The term “isotope substituted derivative” refers to a chemical compound in which one or more of its atoms have been replaced by a different isotope of the same element. Isotopes of an element include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen (H) include tritium (T) and deuterium (D).

[0056] The term "prodrug of a muscarinic agonist" as used herein, refers to a compound that is converted into a muscarinic agonist under physiological conditions in vivo after administration into a subject.

[0057] The term “analog” or “analog compound” as used herein, refers to a molecule / compound with a structure similar to another but with slight differences, such as a different functional group or a substituted atom. These compounds are important in drug development, where a known "lead" compound may be modified to create analogs with improved properties. Analogs share a similar overall structure and geometry, but one or more atoms or functional groups are different.

[0058] The term “derivative,” as used herein, refers to a modified version of an original molecule / compound. A derivative is different from the original molecule / compound in chemical structure, but maintains at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of at least one of the bioactivities of the original molecule / compound.

[0059] phrase “a derivative of a muscarinic agonist”, as used herein, refers to a modified version of the original muscarinic agonist. A derivative of a muscarinic agonist is different from the original muscarinic agonist in chemical structure but maintains at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of the original muscarinic agonist’s ability to activate muscarinic acetylcholine receptor(s).

[0060] The term “systemic exposure” as used hereinafter, refers to the distribution and presence of a substance, such as a drug or chemical, throughout the body's bloodstream and tissues. One or more of the following pharmacokinetic parameters may be used as an indicator of the systemic exposure: Cmax (maximum plasma concentration), tmax(time of maximum measured plasma concentration), AUCo-inf (area under the plasma concentration vs time curve [AUC] from time 0 to infinity), AUCo-t(AUC from time 0 to the time of detection, e.g., AUCo-nis the AUC from time 0 to 12 hours), ti / 2 (terminal phase half-life),C24 (minocycline concentration 24 hours after topical application of minocycline foam 4%), and bioavailability.

[0061] The term “bioavailability” refers to a measurement of what portion of an administered drug reaches the circulatory system when a non-parenteral mode of administration is used to introduce the drug into an animal. The term is used for drugs whose efficacy is related to the blood concentration achieved, even if the drug's ultimate site of action is intracellular. Traditionally, bioavailability studies determine the degree of intestinal absorption of a drug by measuring the change in peripheral blood levels of the drug after an oral dose. The area under the curve (AUCo) is divided by the area under the curve after anintravenous (i.v.) dose (AUCiv) and the quotient is used to calculate the fraction of drug absorbed.

[0062] The terms “side effect” and “adverse effect” are used interchangeably and refers to any unintended, non-therapeutic and undesired response to a drug. A side effect or adverse effect may be mild and predictable, or may be more serious and can even be lifethreatening.

[0063] The term "PK modifier" or “pharmacokinetic modifier” as used herein, refers to any molecule, substance, or chemical compound that changes the pharmacokinetic (PK) profile of another substance, such as a muscarinic agonist, a salt of muscarinic agonist, a analog of muscarinic agonist and a derivative of muscarinic agonist. In some embodiments, the PK modifier of the present application can change the relative abundance of the muscarinic agonist and the metabolites thereof during systemic exposure, as compared to the relative abundance of the muscarinic agonist and the metabolites thereof during systemic exposure when the muscarinic agonist is administered without the administration of the PK modifier. In some embodiments, the PK modifiers of the present application are capable of decreasing the production of undesired metabolites of a muscarinic agonist (such as M283-la) during systemic exposure, thus reducing the adverse effects of the muscarinic agonist.

[0064] The term "prodrug of a PK modifier" as used herein, refers to a molecule, substance, or chemical compound that is converted into a PK modifier under physiological conditions in vivo after administration into a subject

[0065] The phrase “a derivative of a PK modifier”, as used herein, refers to a modified version of the original PK modifier. A derivative of a PK modifier is different from the original PK modifier in chemical formula but maintains at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of the original PK modifier’s ability to modifier the PK of a muscarinic agonist.

[0066] The term “metabolite of a compound”, as used herein, refers to a compound or a class of compounds that may be produced by the metabolic processes from the original compound. It is not intended that the term “metabolite” or “metabolites” requires production of the relevant compound or compounds by a metabolic process in a patient to be treated. Instead, the compound identified as a “metabolite” may be administered directly to the patient in a pharmaceutical composition rather than in a prodrug form that yields the compound as a metabolite in vivo. The term “metabolite” is employed as a broad term that is not intended to limit compounds to be administered to a patient to compounds produced by a particular method of synthesis (in vivo from a prodrug versus ex vivo). Examples ofmetabolite of a compound include metabolites of a muscarinic agonist and metabolites of a PK modifier.

[0067] The term “subject” as used herein, means a human or a non-human mammal, including but not limited to a dog, cat, horse, donkey, mule, cow, domestic buffalo, camel, llama, alpaca, bison, yak, goat, sheep, pig, elk, deer, domestic antelope, or a non-human primate selected for treatment or therapy.

[0068] The phrase “subject suspected of having” means a subject exhibiting one or more clinical indicators of a disease or condition.

[0069] The phrase “subject in need thereof means a subject identified as in need of a therapy or treatment.

[0070] A “therapeutic effect” relieves, ameliorates, attenuates or eliminates one or more of the symptoms of a particular disease or condition or prevents, modifies, or delays the onset of one or more of the symptoms of a particular disease or condition, and includes curing the disease or disorder. “Curing” means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease may exist even after a cure is obtained (such as extensive tissue damage).

[0071] The phrase "effective amount" as used herein refers to an amount of a compound or a combination of compounds that provides a therapeutic effect.

[0072] The terms “treat”, “treatment,” and “treating,” as used herein, refer to administering a pharmaceutical composition for therapeutic purposes.

[0073] The term “prophylactic treatment” refers to treating a patient who does not yet have the relevant disease or disorder, but who is susceptible to, or otherwise at risk of, a particular disease or disorder, whereby the treatment reduces the likelihood that the patient will develop the disease or disorder.

[0074] The term “therapeutic treatment” refers to administering treatment to a patient already having a disease or disorder.

[0075] The term “preventing” or “prevention,” as used herein, refers to delaying or forestalling the onset, development or progression of a condition or disease for a period of time, including weeks, months, or years.

[0076] The term “amelioration,” as used herein, means a lessening of severity of at least one indicator of a condition or disease. In certain embodiments, amelioration includes a delay or slowing in the progression of one or more indicators of a condition or disease. The severity of indicators may be determined by subjective or objective measures which are known to those skilled in the art.

[0077] The term “modulation" means a perturbation of function or activity. In certain embodiments, modulation means an increase in gene expression. In certain embodiments, modulation means a decrease in gene expression. In certain embodiments, modulation means an increase or decrease in total serum levels of a specific protein. In certain embodiments, modulation means an increase or decrease in free serum levels of a specific protein. In certain embodiments, modulation means an increase or decrease in total serum levels of a specific non-protein factor. In certain embodiments, modulation means an increase or decrease in free serum levels of a specific non-protein factor. In certain embodiments, modulation means an increase or decrease in total bioavailability of a specific protein. In certain embodiments, modulation means an increase or decrease in total bioavailability of a specific non-protein factor.

[0078] The term “administering” or “administration” means providing a pharmaceutical agent or composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administering. Administration of the compounds disclosed herein, such as the muscarinic agonists of the present application, pharmaceutically acceptable salts thereof, analogs thereof and derivatives thereof, or the additional therapeutic agents disclosed herein, such as the PK modifiers of the present application, pharmaceutically acceptable salts thereof, analogs thereof and derivatives thereof, can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intraarterially, intranasally, topically, transdermally, intraperitoneally, intramuscularly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.

[0079] The term “parenteral administration,” means administration through injection or infusion. Parenteral administration includes, but is not limited to, subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, and intracranial administration.

[0080] The term “agent” includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to, e.g., protein, polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, and the like. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances.

[0081] The term “in combination” or “combination,” as used herein, refers to a muscarinic agonist and a PK modifier that extends the in vivo half-life of the muscarinicagonist being substantially effective in the body of a subject at a same time. The muscarinic agonist and the PK modifier can be administered to the subject substantially at the same time, or at different times but have effects on the body at the same time. For example, "in combination" includes administering the muscarinic agonist before the administration of the PK modifier, and subsequently administering the PK modifier while functioning of the muscarinic agonist in the body is substantially extant. In addition, "in combination" includes administering the PK modifier before the administration of the muscarinic agonist, and subsequently administering the muscarinic agonist while functioning of the PK modifier in the body is substantially extant. When a pharmaceutical composition is described as containing the muscarinic agonist and the PK modifier in combination, this term refers to both agents being concurrently present in the composition.

[0082] The phrase “pharmaceutically acceptable,” as used herein, indicates that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0083] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient," as used herein, refers to any and all solvents, diluents, emulsifiers, binders, buffers, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like, or any other such compound as is known by those of skill in the art to be useful in preparing pharmaceutical formulations. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, N.J. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

[0084] The term "unit dosage form," as used herein, refers to a composition containing an amount of a compound that is suitable for administration to a subject, in a single dose, according to good medical practice. However, as further described below, the preparation of a single or unit dosage form does not imply that the dosage form is administered once per day or once per course of therapy.

[0085] The phrase "mode of administration" refers to the means by which a compound is administered to a subject. As such, the phrase encompasses the dosage form (for example, a tablet, powder, dissolved liquid, suspension, emulsion, aerosol, etc.) and the mechanism by which the dosage form is applied to the subject (for example, by injection, such as subcutaneously, intramuscularly, intraperitoneally, intravenously, or intraarterially; topically, such as by cream, lotion, or patch; orally, such as by a pill, dissolved liquid, oral suspension, buccal film, or mouth rinse; nasally, such as by a nasal aerosol, powder, or spray; or ocularly, such as by an eye drop). The "mode of administration" may further encompass the dose, dose amount, and dosing schedule by which a compound is administered to a subject. The phrase "duration of the treatment" refers to the time commencing with administration of the first dose and concluding with the administration of the final dose, such length of time being determined by one of ordinary skill in the art of treating a given disease.

[0086] The term “pharmaceutically acceptable salts,” as used herein, refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Examples of pharmaceutically acceptable salts include but are not limited to, hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, and oxalate salts.II. Compositions of the present application

[0087] One aspect of the present application relates to a pharmaceutical composition comprising a muscarinic agonist and a pharmacokinetic (PK) modifier. In some embodiments, the PK modifier changes the metabolic profile of the muscarinic agonist. In some embodiments, the PK modifier improves the bioavailability of the muscarinic agonist. In some embodiments, the PK modifier changes the relative abundance of the muscarinic agonist and metabolites thereof during systemic exposure, as compared to administration of the muscarinic agonist alone. In some embodiments, the PK modifier decreases the percentage of undesired metabolites of the muscarinic agonist, such as M283-la, during systemic exposure and reduces the side effect of the muscarinic agonist. In some embodiments, the PK modifier increases the percentage of the muscarinic agonist and decrease the percentage of undesired metabolites of the muscarinic agonist, such as M283-la, during systemic exposure.

[0088] In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated in a unit dose form.Muscarinic agonist

[0089] The muscarinic agonist can be any muscarinic agonist that may provide a therapeutic effect to a target disease or condition. Examples of muscarinic agonist include, but are not limited to, arecoline, alvameline, bethanechol, BuTAC, cevimeline, carbachol, HTL-9936, milam eline, muscarine, NGX-267, pilocarpine, oxotremorine, RS-86, sabcomeline, SPP1, talsaclidine, tazomeline, WAY-132983, xanomeline, pharmaceutically acceptable salts thereof, prodrugs thereof, isomers thereof and derivatives thereof.

[0090] In some embodiments, the muscarinic agonist is a muscarinic agonist that selectively activates Ml and / or M4 receptors.

[0091] In some embodiments, the muscarinic agonist is xanomeline, a pharmaceutically acceptable salt of xanomeline, a prodrug of xanomeline, an isomer of xanomeline, a derivative of xanomeline or a metabolite of xanomeline. FIGS. 1A and 2A-2D show the exemplary structures of xanomeline and some xanomeline analogs and derivatives. In some embodiments, the muscarinic agonist is xanomeline tartrate.

[0092] In some embodiments, the muscarinic agonist is a pharmacologically active metabolite of xanomeline. Examples of pharmacologically active metabolites of xanomeline include, but are not limited to, N-desmethylxanom eline, hydroxy metabolites, such as 6-hexanol, 5- hexanol, 4-hexanol metabolite, keto metabolites, such as 5-keto and 6-hexanal, oxide metabolites, such as xanomeline N-oxide, 1-butonic and 1-hexanoic metabolites and metabolites from the combination of the aforementioned biotransformation.PK modifiers

[0093] The PK modifier of the present application can be any substance that modifies the bioavailability of the muscarinic agonist in the composition. It is sometimes referred to as PK enhancer or PK booster. In some embodiments, the PK modifier of the present application is capable of (1) changing, attenuating or inhibiting the metabolism of a muscarinic agonist (metabolism inhibitor and / or metabolic profile modifier) such as quinidine; and / or (2) modifying the biodistribution of a muscarinic agonist (biodistribution modifier) by, for example, complexation with cyclodextrin, complexation with counter ions, complexation with permeation / absorption inhibitors / enhancers, such as salcaprozate sodium (SNAC), pegylation, or fatty acid conjugation.

[0094] In some embodiments, the PK modifier of the present application improves the bioavailability of the muscarinic agonist.

[0095] In some embodiments, the PK modifier of the present application changes the relative abundance of the muscarinic agonist and metabolites thereof during systemic exposure, as compared to administration of the muscarinic agonist alone.

[0096] In some embodiments, the PK modifier of the present application decreases the percentage of undesired metabolites of the muscarinic agonist during systemic exposure and reduces the side effect of the muscarinic agonist. In some embodiments, the undesired metabolites of the muscarinic agonist comprise M283-la.

[0097] In some embodiments, the PK modifier of the present application increases the percentage of the muscarinic agonist and decrease the percentage of undesired metabolites of the muscarinic agonist during systemic exposure. In some embodiments, the undesired metabolites of the muscarinic agonist comprise M283-la.

[0098] In some embodiments, the PK modifier of the present application decreases the production of undesired metabolites of a muscarinic agonist during systemic exposure, thus reducing the adverse effects of the muscarinic agonist. In some embodiments, the undesired metabolites of the muscarinic agonist comprise M283-la.

[0099] Examples of PK modifiers include, but are not limited to, probenecid, verapamil, ketoconazole, ritonavir, carbidopa, clavulanic acid, tazobactam, sulbactam, quinidine, bupropion, cobicistat, pharmaceutically acceptable salts thereof, prodrugs thereof, isomers thereof and derivatives thereof.

[0100] In some embodiments, the PK modifier comprises a CYP enzyme inhibitor. In some embodiments, the PK modifier comprises a CYP2D6 enzyme inhibitor. Examples of CYP2D6 enzyme inhibitor include, but are not limited to, abemaciclib, abiraterone, acebutolol, adagrasib, amiodarone, amitriptyline, amlodipine, amodiaquine, amoxapine, artenimol, asunaprevir, asenapine, atorvastatin, azelastine, belumosudil, bepridil, berotralstat, bicalutamide, biperiden, black cohosh, brincidofovir, buprenorphine, bupropion, cannabidiol, cannabinol, cariprazine, celecoxib, cerivastatin, chlorphenamine, chlorpheniramine, chlorpromazine, chloroquine, cholecalciferol, cimetidine, cinacalcet, cisapride, citalopram, clascoterone, clemastine, clinafloxacin, clomipramine, clozapine, cocaine, clobazam, clofazimine, clotrimazole, cobicistat, cobimetinib, curcumin, curcumin sulfate, cyclosporine, dacomitinib, darifenacin, darunavir, delavirdine, deramciclane, desipramine, desvenlafaxine, dexchlorpheniramine, dexchlorpheniramine maleate, dexfenfluramine, dexmedetomidine, dextropropoxyphene, diacerein, dimethyl sulfoxide, diphenhydramine, dosulepin, doxepin,doxorubicin, dronabinol, dronedarone, duloxetine, efavirenz, elexacaftor, eliglustat, enasidenib, encorafenib, entacapone, epinastine,, (lR,2S)-erythro-dihydro bupropion, rac erythro-dihydrobupropion, escitalopram, ethambutol, etoricoxib, everolimus, fedratinib, felodipine, fenfluramine, fexinidazole, flecainide, fluoxetine, fluphenazine, fusidic acid, gefitinib, glycerol phenylbutyrate, halofantrine, haloperidol, hydromethy mirabegron, hydroquinidine, hydroxyurea, hydroxychloroquine, hydroxyzine, imatinib, imipramine, indinavir, indisulam iproniazid, isavuconazole, isavuconazonium, isoniazid, ketoconazole, labetalol, lansoprazole, lasmiditan, lenvatinib, lercanidipine, levomepromazine, lidocaine, lomustine, loratadine, lorcaserin, lumefantrine, manidipine, Mavorixafor, medical cannabis, melperone, Menadione, mepyramine, methadone, methimazole, methotrimeprazine, Methylene blue, metoclopramide, metoprolol, mibefradil, miconazole, midostaurin, mifepristone, mizolastine, moclobemide, nabiximols, naloxegol, nefazodone, nelfinavir, nevirapine, niacin, nicardipine, nicotinamide, nifedipine, nilotinib, nortriptyline, omeprazole, oritavancin, orphenadrine, osilodrostat, ospemifene, oxamniquine, oxprenolol, oxybutynin, oxymetholone, panobinostat, paroxetine, pazopanib, peginterferon alfa-2b, perhexiline, perphenazine, phenelzine, phenylbutyric acid, l-(2-phenylethyl)-4-phenyl-4-acetoxypiperidine, pimozide, pindolol, pipotiazine, pirfenidone pirtobrutinib, pitolisant, planzapine, primaquine, proguanil, promethazine, propafenone, propranolol, (5-(pyridin-3-yl)furan-2-yl) methanamine, quercetin, quinidine, quinine, rabeprazole, ranitidine, ranolazine, reboxetine, resveratrol, rhein, rifamycin, rilpivirine, risperidone, ritanserin, ritonavir, rizatriptan, rolapitant, ropeginterferon alfa-2b, rosiglitazone, rotigotine, rucaparib, safinamide, saquinavir, sarpogrelate, selegiline, sertraline, Sofpironium Sotagliflozin, sorafenib, sparteine, St. John's wort, stiripentol, sulconazole, sulfaphenazole, tamoxifen, tegaserod, telotristat ethyl, temsirolimus, terbinafine, terfenadine, tezacaftor, thioridazine, thiothixene, ticlopidine, tipranavir, tirbanibulin, ubrogepant, tranylcypromine, trazodone, triclabendazole, tripelennamine, trospium, vardenafil, vemurafenib, venlafaxine, verapamil, vemakalant, vilazodone, viloxazine, vinblastine, vinorelbine, zafirlukast and ziprasidone.

[0101] In some embodiments, the muscarinic agonist is xanomeline and the PK modifier is a CYP enzyme inhibitor. In some embodiments, the CYP enzyme inhibitor is selected from the group consisting of inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2C19, CYP2D6 and / or CYP3A4. In some embodiments, the muscarinic agonist is xanomeline and the PK modifier is a CYP2D6 enzyme inhibitor.

[0102] In some embodiments, the muscarinic agonist is xanomeline and the PK modifier is a CYP2D6 enzyme inhibitor selected from the group consisting of quinidine,cinacalcet, terbinafine, fluoxetine, bupropion hydrochloride, paroxetine, and cimetidine, mirabegron, levomepromazine, sarpogrelate, amiodarone, chlorphenamine, chlorpromazine, diphenhydramine, duloxetine, hydroquinidine, (lR,2S)-erythro-Dihydro bupropion and rac erythro-dihydrobupropion.

[0103] In some embodiments, the muscarinic agonist is xanomeline and the PK modifier is selected from the group consisting of quinidine, cinacalcet, sarpogrelate, chlorpromazine, and dihydroquinidine.

[0104] In some embodiments, the muscarinic agonist is xanomeline (formula II)

[0105] In some embodiments, the PK modifier is a CYP enzyme inhibitor.

[0106] In some embodiments, the CYP enzyme inhibitor is selected from the group consisting of quinidine, cinacalcet, sarpogrelate, chlorpromazine, dihydroquinidine, analogs thereof, derivatives thereof and pharmaceutically acceptable salts thereof.

[0107] In some embodiments, the muscarinic agonist is xanomeline and the PK modifier is quinidine, an analog of quinidine, a derivative of quinidine, a prodrug of quinidine, or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the muscarinic agonist is xanomeline (formula II) and the PK modifier is quinidine (formula III) or dihydroquinidine (formula IV):

[0109] In some embodiments, the muscarinic agonist is xanomeline and the PK modifier is quinidine. In some embodiments, the muscarinic agonist is xanomeline tartrate and the PK modifier is quinidine sulfate.Additional therapeutic agents

[0110] In some embodiments, the pharmaceutical composition of the present application comprises an additional therapeutic agent.

[0111] Examples of additional therapeutic agents include, but are not limited to, acetyl-cholinesterase inhibitors, muscarinic antagonists, and antioxidants.

[0112] Examples of acetyl-cholinesterase inhibitors include, but are not limited to, donepezil, galantamine, rivastigmine, tacrine, physostigmine, pyridostigmine, neostigmine, ipidacrine, phenserine, icopezil, zanapezil, ambenonium, edrophonium, huperzine A and ladostigil.

[0113] Examples of muscarinic antagonist include, but are not limited to, darifenacin, fesoterodine, oxybutynin, propiverine, solifenacin, tolterodine, trospium chloride, ipratropium, oxitropium, tiotropium, aclidinium, umeclidinium, glycopyrrolate and revatropate.

[0114] Examples of antioxidant include, but are not limited to, N-acetylcysteine, ascorbic acid, alpha-lipoic acid, scopoletin, forsythin, isoferulic acid, gamma-oryzanol, trans-anethol, thioctic acid, cysteamine, gallic acid, salvianolic acid, vitamin E, lappaconitine, L-sel enomethionine, selenium, coenzyme Q10, vitamin A, catechin, daltro, and salts thereof.Pharmaceutically acceptable carriers

[0115] In some embodiments, the pharmaceutical application further comprises a pharmaceutically acceptable carrier. Exemplary substances, which can serve as pharmaceutically-acceptable carriers or components thereof, include sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, com oil, and theobroma oil; polyols, such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such as sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0116] In some embodiments, the pharmaceutical composition further comprises wetting or emulsifying agents, preservatives or buffering reagents, which enhance the shelf life or effectiveness of therapeutic agents.Formulation and Unit dose

[0117] The pharmaceutical composition of the present application may be formulated for oral administration, parenteral administration, topical administration, intranasal administration, enteral administration, sublingual administration or rectal administration. Parenteral administration includes, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal,subcutaneous, intraneural, intraventricular (subventricular region), intracerebroventricular, and intraperitoneal administration.

[0118] In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as a tablet, a capsule, a granule or a dry suspension. In some embodiments, the pharmaceutical composition is formulated for immediate release. In some embodiments, the pharmaceutical composition is formulated for delayed release. In some embodiments, the pharmaceutical composition is formulated for slow or extended release. In some embodiments, the pharmaceutical composition is formulated for both delayed and extended release.

[0119] As used herein, the term “delayed release” refers to a medication that does not immediately disintegrate and release the active ingredient(s) into the body. In some embodiments, the term “delayed release” is used with reference to a drug formulation having a release profile in which there is a predetermined delay in the release of the drug following administration.

[0120] In some embodiments, the active agents are delivered in a formulation to provide delayed-release at a pre-determined time following administration. The delay may be up to about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, or longer.

[0121] A delayed-release composition may comprise 100% of the total dosage of a given active agent administered in a single unit dose. Alternatively, a delayed-release composition may be included as a component in a combined release profile formulation may provide about 30-95% of the total dosage of the active agent(s) to be delivered by the pharmaceutical formulation. For example, the immediate release component may provide about 5-70%, or about 50% of the total dosage of the active agent(s) to be delivered by the pharmaceutical formulation. In alternate embodiments, the delayed-release component provides about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95% of the total dosage of the active agent(s) to be delivered by the formulation.

[0122] A delayed-release formulation typically comprises a barrier coating that delays the release of the active ingredient(s). The barrier coating may consist of a variety of different materials, depending on the objective. In addition, a formulation may comprise a plurality of barrier coatings to facilitate release in a temporal manner. The coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and / or polyvinylpyrrolidone), or a coating based onmethacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and / or ethylcellulose. Furthermore, the formulation may additionally include a time delay material such as, for example, glyceryl monostearate or glyceryl distearate.

[0123] In some embodiments, the delayed-release formulation includes an enteric coating comprised one or more polymers facilitating release of active agents in proximal or distal regions of the gastrointestinal tract. As used herein, the term “enteric polymer coating” a coating comprising of one or more polymers having a pH dependent or pH-independent release profile. Typically the coating resists dissolution in the acidic medium of the stomach, but dissolves or erodes in more distal regions of the gastrointestinal tract, such as the small intestine or colon. An enteric polymer coating typically resists releases of the active agents until sometime after a gastric emptying lag period of about 3-4 hours after administration.

[0124] In another embodiment, the delay release formulation employs a water-impermeable tablet coating whereby water enters through a controlled aperture in the coating until the core bursts. When the tablet bursts, the drug contents are released immediately or over a longer period of time. These and other techniques may be modified to allow for a predetermined lag period before release of drugs is initiated.

[0125] Various coating techniques may be applied to granules, beads, powders or pellets, tablets, capsules or combinations thereof containing active agents to produce different and distinct release profiles. In some embodiments, the pharmaceutical composition is in a tablet or capsule form containing a single coating layer. In other embodiments, the pharmaceutical composition is in a tablet or capsule form containing multiple coating layers.

[0126] As used herein, the term “extended-release,” also known as sustained-release (SR), sustained-action (SA), time-release (TR), controlled-release (CR), modified release (MR), or continuous-release (CR), is a mechanism used in medicine tablets or capsules to dissolve slowly and release the active ingredient over time. The advantages of extended-release tablets or capsules are that they can often be taken less frequently than immediate-release formulations of the same drug, and that they keep steadier levels of the drug in the bloodstream, thus extending the duration of the drug action and lowering the peak amount of drug in the bloodstream.

[0127] In some embodiments, the pharmaceutical composition of the present application is formulated for extended-release by embedding the active ingredient in a matrix of insoluble substance(s) such as acrylics or chitin. An extended-release form is designed to release the active ingredient(s) of the composition of the present application at a1predetermined rate by maintaining a constant drug level for a specific period of time. This can be achieved through a variety of formulations, including, but not limited to, liposomes and drug-polymer conjugates, such as hydrogels.

[0128] An extended-release formulation can be designed to release the active agents at a predetermined rate so as to maintain a constant drug level for a specified, extended period of time, such as up to about 24 hours, about 20 hours, about 16 hours, about 12 hours, about 10 hours, about 9 hours, about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1 hour following administration or, in the case of a combined delayed / extended release formulation, following a lag period associated with delay ed-release of the drug.

[0129] In some embodiments, the extended-release formulation comprises an active core comprised of one or more inert particles, each in the form of a bead, pellet, pill, granular particle, microcapsule, microsphere, microgranule, nanocapsule, or nanosphere coated on its surfaces with drugs in the form of e.g., a drug-containing coating or film-forming composition using, for example; fluid bed techniques or other methodologies known to those of skill in the art. The inert particle can be of various sizes, so long as it is large enough to remain poorly dissolved. Alternatively, the active core may be prepared by granulating and milling and / or by extrusion and spheronization of a polymer composition containing the drug substance.

[0130] The active agents may be introduced to the inert carrier by techniques known to one skilled in the art, such as drug layering, powder coating, extrusion / spheronization, roller compaction or granulation. The amount of drug in the core will depend on the dose that is required, and typically varies from about 5 to 90 weight %. Generally, the polymeric coating on the active core will be from about 1 to 50% based on the weight of the coated particle, depending on the lag time required and / or the polymers and coating solvents chosen. Those skilled in the art will be able to select an appropriate amount of drug for coating onto or incorporating into the core to achieve the desired dosage. In one embodiment, the inactive core may be a sugar sphere or a buffer crystal or an encapsulated buffer crystal such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. which alters the microenvironment of the drug to facilitate its release.

[0131] The compositions described herein are preferably provided in a unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound that is suitable for administration to a subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not implythat the dosage form is administered once per day or once per course of therapy. A unit dosage form may comprise a single daily dose or a fractional sub-dose wherein several unit dosage forms are to be administered over the course of a day in order to complete a daily dose. According to the present disclosure, a unit dosage form may be given more or less often than once daily, and may be administered more than once during a course of therapy. Such dosage forms may be administered in any manner consistent with their formulation, including orally, parenterally, and may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours). While single administrations are specifically contemplated, the compositions administered according to the methods described herein may also be administered as a continuous infusion or via an implantable infusion pump.

[0132] In some embodiments, the pharmaceutical composition comprises (A) xanomeline, a pharmaceutical salt of xanomeline, an analog of xanomeline or a derivative of xanomeline as the muscarinic agonist and (B) quinidine, a pharmaceutical salt of quinidine, an analog of quinidine or a derivative of quinidine as the PK modifier. In some embodiments, the above-described pharmaceutical composition is formulated for oral administration at a daily dose of 0.1-1000 mg, 0.1-500 mg, 0.1-200 mg, 0.1-100 mg, 0.1-50 mg, 0.1-20 mg, 0.1-10 mg, 0.1-5 mg, 0.1-2 mg, 0.1-1 mg, 0.5-1000 mg, 0.5-500 mg, 0.5-200 mg, 0.5-100 mg, 0.5-50 mg, 0.5-20 mg, 0.5-10 mg, 0.5-5 mg, 0.5-2 mg, 0.5-1 mg, 1-1000 mg, 1-500 mg, 1-200 mg, 1-100 mg, 1-50 mg, 1-20 mg, 1-10 mg, 1-5 mg, 1-2 mg, 2-1000 mg, 2-500 mg, 2-200 mg, 2-100 mg, 2-50 mg, 2-20 mg, 2-10 mg, 2-5 mg, 5-1000 mg, 5-500 mg, 5-200 mg, 5-100 mg, 5-50 mg, 5-20 mg, 5-10 mg, 10-1000 mg, 10-500 mg, 10-200 mg, 10-100 mg, 10-50 mg, 10-20 mg, 20-1000 mg, 20-500 mg, 20-200 mg, 20-100 mg, 20-50 mg, 50-1000 mg, 50-500 mg, 50-200 mg, 50-100 mg, 100-1000 mg, 100-500 mg, 100-200 mg, 200-1000 mg, 200-500 mg, or 500-1000 mg of component A, and 0.5-600 mg, 0.5-300 mg, 0.5-100 mg, 0.5-80 mg, 0.5-60 mg, 0.5-30 mg, 0.5-10 mg, 0.5-3 mg, 2-600 mg, 2-300 mg, 2-100 mg, 2-80 mg, 2-60 mg, 2-30 mg, 2-10 mg, 5-600 mg, 5-300 mg, 5-100 mg, 5-80 mg, 5-60 mg, 5-30 mg, 5-10 mg, 10-600 mg, 10-300 mg, 10-100 mg, 10-80 mg, 10-60 mg, 10-30 mg, 20-600 mg, 20-300 mg, 20-100 mg, 20-80 mg, 20-60 mg, 20-30 mg, 50-600 mg, 50-300 mg, 50-100 mg, 100-600 mg or 100-300 mg of component B.

[0133] In some embodiments, the pharmaceutical composition comprises (A) xanomeline and / or a pharmaceutical salt of xanomeline, and (B) quinidine and / or a pharmaceutical salt of quinidine. In some embodiments, the pharmaceutical composition is formulated for oral administration at a daily dose of 1-100 mg free base equivalent of xanomeline and 5-80 mg free base equivalent of quinidine. In some embodiments, thepharmaceutical composition is formulated for oral administration at a daily dose of 20-80 mg free base equivalent of xanomeline and 20-60 mg free base equivalent of quinidine.

[0134] In some embodiments, the pharmaceutical composition comprises (A) xanomeline, a pharmaceutical salt of xanomeline, an analog of xanomeline or a derivative of xanomeline as the muscarinic agonist and (B) quinidine, a pharmaceutical salt of quinidine, an analog of quinidine or a derivative of quinidine as the PK modifier, wherein component A and component B has a relative molar or weight ratio (A:B molar ratio or A:B weight ratio) in the range of 0.1:1 to 50:1, 0.1:1 to 20:1, 0.1:1 to 10:1, 0.1:1 to 5:1, 0.1:1 to 2:1, 0.1:1 to 1:1, 0.1:1 to 0.3:l, 0.5:1 to 50:1, 0.5:1 to 20:1, 0.5:1 to 10:1, 0.5:1 to 5:1, 0.5:1 to 2:1, 0.5:1 to 1:1, 2:1 to 50:1, 2:1 to 20:1, 2:1 to 10:1 or 2:1 to 5:1. In some embodiments, component A and component B have a A:B molar ratio or A:B weight ratio in the range of 0.5 : 1 to 5 : 1. In some embodiments, component A comprises xanomeline and component B comprises quinidine, wherein component A and component B have a A:B molar ratio or A:B weight ratio in the range of 0.5 : 1 to 5 : 1.

[0135] Another aspect of the present application relates to a pharmaceutical composition that comprises (A) xanomeline, an analog of xanomeline, a derivative of xanomeline or a pharmaceutically acceptable salt thereof; and (B) quinidine, an analog of quinidine, a derivative of quinidine, or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the pharmaceutical composition comprises (A) xanomeline or a pharmaceutically acceptable salt thereof; and (B) quinidine, hydroquinidine, or a pharmaceutically acceptable salt thereof. In some embodiments component A and component B have a component A:component B weight ratio in the range of 0.5:1 to 5:1.III. Methods of the present application

[0137] Another aspect of the present application relates to a method for treatment of a neurological disorder or condition in a subject. The method comprises the step of administering to the subject a muscarinic agonist in combination with a PK modifier that enhances the bioavailability of the muscarinic agonist.

[0127] In some embodiments, the muscarinic agonist is xanomeline and the PK modifier is a CYP2D6 enzyme inhibitor.

[0128] In some embodiments, the muscarinic agonist is xanomeline, a pharmaceutical salt of xanomeline, an analog of xanomeline or a derivative of xanomeline and the PK modifier is quinidine, a pharmaceutical salt of quinidine, an analog of quinidine or a derivative of quinidine.

[0129] In some embodiments, the muscarinic agonist is xanomeline and the PKmodifier is quinidine or dihydroquinidine.

[0130] In some embodiments, the muscarinic agonist and the PK modifier are formulated in the same pharmaceutical composition.

[0131] In some embodiments, the muscarinic agonist and the PK modifier are formulated in different pharmaceutical compositions and are administered separately. The separate administration of the PK modifier may occur prior to, concurrently with, or after the administration of the muscarinic agonist.

[0132] In some embodiments, the neurological disorder or condition is schizophrenia or a schizophreniform disease.

[0133] In some embodiments, the neurological disorder or condition is a neurodegenerative disease. In some embodiments, the neurological disorder or condition is Alzheimer's or Parkinson's diseases.

[0134] In some embodiments, the neurodegenerative disease is Alzheimer's disease or Parkinson's disease. In some embodiments, the method for treating a neurological disorder or condition ameliorates one or more neuropsychiatric and / or neuropsychological symptoms of a neurodegenerative disorder. Examples of such symptoms include, but are not limited to, mood changes, psychotic symptoms, behavioral disturbances, cognitive and emotional deficits like memory loss, language problems, and executive dysfunction, which negatively impact a patient's quality of life and can accelerate disease progression. Common symptoms include depression, apathy, agitation, aggression, hallucinations, and delusions. These symptoms arise from the complex interplay of neurobiological changes in the brain and can sometimes manifest before or alongside cognitive symptoms, such as in Alzheimer's or Parkinson's diseases.

[0135] Another aspect of the present application relates to a method for treatment of a neurological disorder or condition in a subject. The method comprises the step of co-administing an effective amount of a muscarinic agonists with one or more PK modifiers.

[0136] In some embodiments, the one or more PK modifiers change the relative abundance of the muscarinic agonist and metabolites thereof during systemic exposure, as compared to administration of the muscarinic agonist alone.

[0137] In some embodiments, the one or more PK modifiers increase bioavailability of the muscarinic agonist during systemic exposure, as compared to administration of the muscarinic agonist alone.

[0138] In some embodiments, the one or more PK modifiers alters relative ratio of the muscarinic agonist and metabolites thereof during systemic exposure, as compared toadministration of the muscarinic agonist alone.

[0139] Another aspect of the present application relates to a method of reducing side effects caused by metabolite of a compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof. The method comprises the step of coadministering to a subject (1) the compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof and (2) quinidine, a pharmaceutically acceptable salt of quinidine, an analog of quinidine or a derivative of quinidine.

[0140] Another aspect of the present application relates to a method of altering metabolic profile of a compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof. The method compriese the step of co-administering to a subject (1) the compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof and (2) quinidine, a pharmaceutically acceptable salt of quinidine, an analog of quinidine or a derivative of quinidine.

[0141] Another aspect of the present application relates to a method of improving bioavailabililty of a compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof. The method compriese the step of co-administering to a subject (1) the compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof and (2) quinidine, a pharmaceutically acceptable salt of quinidine, an analog of quinidine or a derivative of quinidine.

[0142] A method of reducing Gl-related side effects of a compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof. The method compriese the step of co-administering to a subject (1) the compound of formula I, a pharmaceutically acceptable salt thereof, an analog thereof or a derivative thereof and (2) quinidine, a pharmaceutically acceptable salt of quinidine, an analog of quinidine or a derivative of quinidine.Neurological disorders and conditions

[0143] Neurological disorders or conditions that may be treated with the method of the present application include, but are not limited to, schizophrenia and schizophreniform diseases, neurodegenerative diseases, ischemic brain diseases (cerebrovascular diseases), anxiety disorders, autistic disorder, mental retardation, conduct disorder such as extreme aggressiveness, disruptive behavior disorder, attention deficit / hyperactivity disorder, bipolar disorder, and drug addiction.

[0144] Examples of schizophrenia and schizophreniform diseases include, but are not limited to, schizophrenia (catatonic), schizophrenia (disorganized), schizophrenia(paranoid), schizophrenia (undifferentiated), schizophrenia (residual), schizophreniform disorder, brief reactive psychosis, schizoaffective disorder, induced psychotic disorder, schizotypal personality disorder, schizoid personality disorder, paranoid personality disorder and delusional (paranoid) disorder.

[0145] Examples of neurodegenerative diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, dementia, cognitive dysfunction, progressive supranuclear palsy, multiple system atrophy, olivine nucleus-pony-cerebellar atrophy (OPCA), Shy-Drager syndrome, striatum-nigra degeneration disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), essential tremor, cortical-basal nucleus degeneration, diffuse Lewy body disease, Parkinson's-ALS-dementia complex, Niemann-Pick's disease and Pick's disease.

[0146] Examples of ischemic brain diseases include, but are not limited to, stroke, cerebral hemorrhage, cerebral infarction, head trauma, cerebral circulatory metabolic disorder, vascular dementia, cerebral coma and any pathological abnormality in the blood vessel supplying blood to the brain due to thrombus, embolism, cerebrovascular thickening, cerebrovascular occlusion, and the like.

[0147] Examples of anxiety disorders include, but are not limited to, panic attack, agoraphobia, acute stress disorder, specific phobia, panic disorder, psychoactive substance anxiety disorder, organic anxiety disorder, obsessive-compulsive anxiety disorder, posttraumatic stress disorder, generalized anxiety disorder, and anxiety disorder NOS.Routes, regimen and dosages of administration

[0148] The muscarinic agonist and / or the PK modifier may be administered by oral administration, parenteral administration, topical administration, intranasal administration, enteral administration, sublingual administration or rectal administration. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraneural, intraventricular (subventricular region), intracerebroventricular, intraperitoneal route.

[0149] The muscarinic agonist and the PK modifier that enhances the bioavailability of the muscarinic agonist may be administered simultaneously, separately, or sequentially. It may exhibit disease prophylactic or therapeutic activity. In general, the muscarinic agonist and the PK modifier will generally be administered simultaneously as a composition, but even if each active ingredient is administered to the human body with a time lag, each individually administered active ingredient acts simultaneously in the body. A level of therapeutic activity can be realized.

[0150] As used herein, the term “simultaneous / concurrent administration'” or “administered simultaneously / concurrently” means that the two active ingredients are administered together through the same administration route at substantially the same time.

[0151] As used herein, the term “separate administration” or administered separately” means that the two active ingredients are administered through the same or different administration routes at a predetermined time interval or administered through different administration routes at substantially the same time.

[0152] In some embodiments, the PK modifier is administered prior to the administration of the muscarinic agonist. In some embodiments, the PK modifier is administered 48 hours to 1 minute prior to the administration of the muscarinic agonist. In some embodiments, the PK modifier is administered 48-0.1, 36-0.1, 24-0.1, 16-0.1, 12-0.1, 8-0.1, 4-0.1, 2-0.1, 48-0.5, 36-0.5, 24-0.5, 16-0.5, 12-0.5, 8-0.5, 4-0.5, 2-0.5, 48-1, 36-1, 24-1, 16-1, 12-1, 8-1, 4-1, 2-1, 48-2, 36-2, 24-2, 16-2, 12-2, 8-2, 4-2, 48-4, 36-4, 24-4, 16-4, 12-4 or 8-4 hours prior to the administration of the muscarinic agonist.

[0153] In some embodiments the PK modifier is administered first and the muscarinic agonist is administered within 48, 36, 24, 16, 12, 8, 6 or 4 hours of the administration of the PK modifier. In some embodiments the PK modifier is administered first and the muscarinic agonist is administered within 24 hours of the administration of the PK modifier.

[0154] In some embodiments, the PK modifier is administered concurrently with the administration of the muscarinic agonist.

[0155] In some embodiments, the PK modifier is administered after the administration of the muscarinic agonist. In some embodiments, the PK modifier is administered 24 hours to 1 minute after the administration of the muscarinic agonist. In some embodiments, the PK modifier is administered 48-0.1, 36-0.1, 24-0.1, 16-0.1, 12-0.1, 8-0.1, 4-0.1, 2-0.1, 48-0.5, 36-0.5, 24-0.5, 16-0.5, 12-0.5, 8-0.5, 4-0.5, 2-0.5, 48-1, 36-1, 24-1, 16-1, 12-1, 8-1, 4-1, 2-1, 48-2, 36-2, 24-2, 16-2, 12-2, 8-2, 4-2, 48-4, 36-4, 24-4, 16-4, 12-4 or 8-4 hours after the administration of the muscarinic agonist.

[0156] In some embodiments the muscarinic agonist is administered first and the PK modifier is administered within 48, 36, 24, 16, 12, 8, 6 or 4 hours of the administration of the muscarinic agonist. In some embodiments the muscarinic agonist is administered first and the PK modifier is administered within 24 hours of the administration of the muscarinic agonist.

[0157] In some embodiments, the muscarinic agonist and / or the PK modifier areadministered twice a day, daily, or every 2, 3, 4, 5, 6 or 7 days for a period of 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 20, 25 or 30 weeks.

[0158] In any of the foregoing embodiments, the daily dosing may be administered in one dose per day, or in two or more divided doses administered multiple times per day. For example, the muscarinic agonist and / or the PK modifier may be administered once per day, twice per day, three times per day, or four times per day.

[0159] In some embodiments, the muscarinic agonist is administered at dosages substantially the same as the dosages at which it is administered in the respective monotherapies. In some embodiments, the muscarinic agonist is administered at a dosage which is less than (e.g., less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10%) its monotherapy dosage.

[0160] The actual unit dose of the muscarinic agonist or the PK modifier described herein depends on the specific compound, and on the condition to be treated. In some embodiments, the daily dose of the muscarinic agonist is from 0.003 mg / kg to 30 mg / kg, from 0.01 mg / kg to 30 mg / kg of body weight, from 0.03 mg / kg to 30 mg / kg of body weight, from 0.1 mg / kg to 30 mg / kg of body weight, from 0.3 mg / kg to 30 mg / kg of body weight, from 1 mg / kg to 30 mg / kg of body weight, from 3 mg / kg to 30 mg / kg of body weight, from 10 mg / kg to 30 mg / kg of body weight, from 0.003 mg / kg to 10 mg / kg, from 0.01 mg / kg to 10 mg / kg of body weight, from 0.03 mg / kg to 10 mg / kg of body weight, from 0.1 mg / kg to 10 mg / kg of body weight, from 0.3 mg / kg to 10 mg / kg of body weight, from 1 mg / kg to 10 mg / kg of body weight, from 3 mg / kg to 10 mg / kg of body weight, from 0.003 mg / kg to 3 mg / kg, from 0.01 mg / kg to 3 mg / kg of body weight, from 0.03 mg / kg to 3 mg / kg of body weight, from 0.1 mg / kg to 3 mg / kg of body weight, from 0.3 mg / kg to 3 mg / kg of body weight, from 1 mg / kg to 3 mg / kg of body weight, from 0.003 mg / kg to 1 mg / kg, from 0.01 mg / kg to 1 mg / kg of body weight, from 0.03 mg / kg to 1 mg / kg of body weight, from 0.1 mg / kg to 1 mg / kg of body weight, from 0.3 mg / kg to 1 mg / kg of body weight, from 0.003 mg / kg to 0.3 mg / kg, from 0.01 mg / kg to 0.3 mg / kg of body weight, from 0.03 mg / kg to 0.3 mg / kg of body weight, from 0.1 mg / kg to 0.3 mg / kg of body weight, from 0.003 mg / kg to 0.1 mg / kg, from 0.01 mg / kg to 0.1 mg / kg of body weight, from 0.03 mg / kg to 0.1 mg / kg of body weight, from 0.003 mg / kg to 0.03 mg / kg, from 0.01 mg / kg to 0.03 mg / kg of body weight, or from 0.003 mg / kg to 0.01 mg / kg of body weight.

[0161] In some embodiments, the daily dose of the PK modifier may be from 0.003 mg / kg to 30 mg / kg, from 0.01 mg / kg to 30 mg / kg of body weight, from 0.03 mg / kg to 30 mg / kg of body weight, from 0.1 mg / kg to 30 mg / kg of body weight, from 0.3 mg / kg to 30mg / kg of body weight, from 1 mg / kg to 30 mg / kg of body weight, from 3 mg / kg to 30 mg / kg of body weight, from 10 mg / kg to 30 mg / kg of body weight, from 0.003 mg / kg to 10 mg / kg, from 0.01 mg / kg to 10 mg / kg of body weight, from 0.03 mg / kg to 10 mg / kg of body weight, from 0.1 mg / kg to 10 mg / kg of body weight, from 0.3 mg / kg to 10 mg / kg of body weight, from 1 mg / kg to 10 mg / kg of body weight, from 3 mg / kg to 10 mg / kg of body weight, from 0.003 mg / kg to 3 mg / kg, from 0.01 mg / kg to 3 mg / kg of body weight, from 0.03 mg / kg to 3 mg / kg of body weight, from 0.1 mg / kg to 3 mg / kg of body weight, from 0.3 mg / kg to 3 mg / kg of body weight, from 1 mg / kg to 3 mg / kg of body weight, from 0.003 mg / kg to 1 mg / kg, from 0.01 mg / kg to 1 mg / kg of body weight, from 0.03 mg / kg to 1 mg / kg of body weight, from 0.1 mg / kg to 1 mg / kg of body weight, from 0.3 mg / kg to 1 mg / kg of body weight, from 0.003 mg / kg to 0.3 mg / kg, from 0.01 mg / kg to 0.3 mg / kg of body weight, from 0.03 mg / kg to 0.3 mg / kg of body weight, from 0.1 mg / kg to 0.3 mg / kg of body weight, from 0.003 mg / kg to 0.1 mg / kg, from 0.01 mg / kg to 0.1 mg / kg of body weight, from 0.03 mg / kg to 0.1 mg / kg of body weight, from 0.003 mg / kg to 0.03 mg / kg, from 0.01 mg / kg to 0.03 mg / kg of body weight, or from 0.003 mg / kg to 0.01 mg / kg of body weight.

[0162] In some embodiments, the muscarinic agonist is xanomeline and is administered at a daily dose in the range of 0.5-500 mg, 0.5-200 mg, 0.5-100 mg, 0.5-50 mg, 0.5-20 mg, 0.5-10 mg, 0.5-5 mg, 0.5-2 mg, 1-500 mg, 1-200 mg, 1-100 mg, 1-50 mg, 1-20 mg, 1-10 mg, 1-5 mg, 1-2 mg, 2-500 mg, 2-200 mg, 2-100 mg, 2-50 mg, 2-20 mg, 2-10 mg, 2-5 mg, 5-500 mg, 5-200 mg, 5-100 mg, 5-50 mg, 5-20 mg, 5-10 mg, 10-500 mg, 10-200 mg, 10-100 mg, 10-50 mg, 10-20 mg, 20-500 mg, 20-200 mg, 20-100 mg, 20-50 mg, 50-500 mg, 50-200 mg, 50-100 mg, 100-500 mg, 100-200 mg, or 200-500 mg.

[0163] In some embodiments, the PK modifier is quinidine or hydroquinidine and is administered at a daily dose range of 0.5-300 mg, 0.5-200 mg, 0.5-100 mg, 0.5-50 mg, 0.5-20 mg, 0.5-10 mg, 0.5-5 mg, 0.5-2 mg, 1-300 mg, 1-200 mg, 1-100 mg, 1-50 mg, 1-20 mg, 1-10 mg, 1-5 mg, 1-2 mg, 2-300 mg, 2-200 mg, 2-100 mg, 2-50 mg, 2-20 mg, 2-10 mg, 2-5 mg, 5-300 mg, 5-200 mg, 5-100 mg, 5-50 mg, 5-20 mg, 5-10 mg, 10-300 mg, 10-200 mg, 10-100 mg, 10-50 mg, 10-20 mg, 20-300 mg, 20-200 mg, 20-100 mg, 20-50 mg, 50-300 mg, 50-200 mg, 50-100 mg, 100-300 mg, 100-200 mg, or 200-300 mg.

[0164] In some embodiments, the muscarinic agonist is xanomeline, an analog of xanomeline, a derivative of xanomeline, or a pharmaceutical salt thereof, wherein the xanomeline, the analog of xanomeline, the derivative of xanomeline or the pharmaceutical salt thereof is formulated for oral administration at a daily dose of 0.1-1000 mg, 0.1-500 mg, 0.1-200 mg, 0.1-100 mg, 0.1-50 mg, 0.1-20 mg, 0.1-10 mg, 0.1-5 mg, 0.1-2 mg, 0.1-1 mg,0.5-1000 mg, 0.5-500 mg, 0.5-200 mg, 0.5-100 mg, 0.5-50 mg, 0.5-20 mg, 0.5-10 mg, 0.5-5 mg, 0.5-2 mg, 0.5-1 mg, 1-1000 mg, 1-500 mg, 1-200 mg, 1-100 mg, 1-50 mg, 1-20 mg, 1-10 mg, 1-5 mg, 1-2 mg, 2-1000 mg, 2-500 mg, 2-200 mg, 2-100 mg, 2-50 mg, 2-20 mg, 2-10 mg, 2-5 mg, 5-1000 mg, 5-500 mg, 5-200 mg, 5-100 mg, 5-50 mg, 5-20 mg, 5-10 mg, 10-1000 mg, 10-500 mg, 10-200 mg, 10-100 mg, 10-50 mg, 10-20 mg, 20-1000 mg, 20-500 mg, 20-200 mg, 20-100 mg, 20-50 mg, 50-1000 mg, 50-500 mg, 50-200 mg, 50-100 mg, 100-1000 mg, 100-500 mg, 100-200 mg, 200-1000 mg, 200-500 mg, or 500-1000 mg; and the PK modifier is quinidine, an analog of quinidine, a derivative of quinidine, or a pharmaceutically acceptable salt thereof, wherein the quinidine, the analog of quinidine, the derivative of quinidine, or the pharmaceutically acceptable salt thereof is formulated for oral administration at a daily dose of 0.5-600 mg, 0.5-300 mg, 0.5-100 mg, 0.5-80 mg, 0.5-60 mg, 0.5-30 mg, 0.5-10 mg, 0.5-3 mg, 2-600 mg, 2-300 mg, 2-100 mg, 2-80 mg, 2-60 mg, 2-30 mg, 2-10 mg, 5-600 mg, 5-300 mg, 5-100 mg, 5-80 mg, 5-60 mg, 5-30 mg, 5-10 mg, 10-600 mg, 10-300 mg, 10-100 mg, 10-80 mg, 10-60 mg, 10-30 mg, 20-600 mg, 20-300 mg, 20-100 mg, 20-80 mg, 20-60 mg, 20-30 mg, 50-600 mg, 50-300 mg, 50-100 mg, 100-600 mg or 100-300 mg.

[0165] In some embodiments, the muscarinic agonist is xanomeline and is formulated for oral administration at a daily dose of 10-100 mg free base equivalent of xanomeline and the PK modifier is quinidine and is formulated for oral administration at a daily dose of 20-80 mg free base equivalent of quinidine. In some embodiments, the muscarinic agonist is xanomeline and is formulated for oral administration at a daily dose of 10-100 mg free base equivalent of xanomeline and the PK modifier is hydroquinidine and is formulated for oral administration at a daily dose of 10-80 mg free base equivalent of hydroquinidine.

[0166] In some embodiments, xanomeline (X) and quinidine (Q) are administered at a combined daily dose of 10 mg X / 10 mg Q, 10 mg X / 20 mg Q, 10 mg X / 30 mg Q, 10 mg X / 40 mg Q, 10 mg X / 50 mg Q, 10 mg X / 60 mg Q, 10 mg X / 70 mg Q, 10 mg X / 80 mg Q, 20 mg X / 10 mg Q, 20 mg X / 20 mg Q, 20 mg X / 30 mg Q, 20 mg X / 40 mg Q, 20 mg X / 50 mg Q, 20 mg X / 60 mg Q, 20 mg X / 70 mg Q, 20 mg X / 80 mg Q, 25 mg X / 10 mg Q, 25 mg X / 20 mg Q, 25 mg X / 30 mg Q, 25 mg X / 40 mg Q, 25 mg X / 50 mg Q, 25 mg X / 60 mg Q, 25 mg X / 70 mg Q, 25 mg X / 80 mg Q, 30 mg X / 10 mg Q, 30 mg X / 20 mg Q, 30 mg X / 30 mg Q, 30 mg X / 40 mg Q, 30 mg X / 50 mg Q, 30 mg X / 60 mg Q, 30 mg X / 70 mg Q, 30 mg X / 80 mg Q, 40 mg X / 10 mg Q, 40 mg X / 20 mg Q, 40 mg X / 30 mg Q, 40 mg X / 40 mg Q, 40 mg X / 50 mg Q, 40 mg X / 60 mg Q, 40 mg X / 70 mg Q, 40 mg X / 80 mg Q, 50 mg X / 10 mg Q, 50 mg X / 20 mgQ, 50 mg X / 30 mg Q, 50 mg X / 40 mg Q, 50 mg X / 50 mg Q, 50 mg X / 60 mg Q, 50 mg X / 70 mg Q, 50 mg X / 80 mg Q, 60 mg X / 10 mg Q, 60 mg X / 20 mg Q, 60 mg X / 30 mg Q, 60 mg X / 40 mg Q, 60 mg X / 50 mg Q, 60 mg X / 60 mg Q, 60 mg X / 70 mg Q, 60 mg X / 80 mg Q, 70 mg X / 10 mg Q, 70 mg X / 20 mg Q, 70 mg X / 30 mg Q, 70 mg X / 40 mg Q, 70 mg X / 50 mg Q, 70 mg X / 60 mg Q, 70 mg X / 70 mg Q,70 mg X / 80 mg Q, 80 mg X / 10 mg Q, 80 mg X / 20 mg Q, 80 mg X / 30 mg Q, 80 mg X / 40 mg Q, 80 mg X / 50 mg Q, 80 mg X / 60 mg Q, 80 mg X / 70 mg Q, 80 mg X / 80 mg Q, 90 mg X / 10 mg Q, 90 mg X / 20 mg Q, 90 mg X / 30 mg Q, 90 mg X / 40 mg Q, 90 mg X / 50 mg Q, 90 mg X / 60 mg Q, 90 mg X / 70 mg Q, 90 mg X / 80 mg Q, 100 mg X / 10 mg Q, 100 mg X / 20 mg Q, 100 mg X / 30 mg Q, 100 mg X / 40 mg Q, 100 mg X / 50 mg Q, 100 mg X / 60 mg Q, 100 mg X / 70 mg Q or 100 mg X / 80 mg Q. In some embodiments, the combined daily dose is formulated into a single capsule or tablet. In some embodiments, the capsule or tablet is formulated for immediate release, extended release or delayed release of the X and Q.

[0167] In some embodiments, xanomeline (X) and hydroquinidine (H) are administered at a combined daily dose of 10 mg X / 10 mg H, 10 mg X / 20 mg H, 10 mg X / 30 mg H, 10 mg X / 40 mg H, 10 mg X / 50 mg H, 10 mg X / 60 mg H, 10 mg X / 70 mg H, 10 mg X / 80 mg H, 15 mg X / 10 mg H, 15 mg X / 20 mg H, 15 mg X / 30 mg H, 15 mg X / 40 mg H, 15 mg X / 50 mg H, 15 mg X / 60 mg H, 15 mg X / 70 mg H, 15 mg X / 80 mg H, 20 mg X / 20 mg H, 20 mg X / 30 mg H, 20 mg X / 40 mg H, 20 mg X / 50 mg H, 20 mg X / 60 mg H, 20 mg X / 70 mg H, 20 mg X / 80 mg H, 30 mg X / 20 mg H, 30 mg X / 30 mg H, 30 mg X / 40 mg H, 30 mg X / 50 mg H, 30 mg X / 60 mg H, 30 mg X / 70 mg H, 30 mg X / 80 mg H, 40 mg X / 20 mg H, 40 mg X / 30 mg H, 40 mg X / 40 mg H, 40 mg X / 50 mg H, 40 mg X / 60 mg H, 40 mg X / 70 mg H, 40 mg X / 80 mg H, 50 mg X / 20 mg H, 50 mg X / 30 mg H, 50 mg X / 40 mg H, 50 mg X / 50 mg H, 50 mg X / 60 mg H, 50 mg X / 70 mg H, 50 mg X / 80 mg H, 60 mg X / 20 mg H, 60 mg X / 30 mg H, 60 mg X / 40 mg H, 60 mg X / 50 mg H, 60 mg X / 60 mg H, 60 mg X / 70 mg H, 60 mg X / 80 mg H, 70 mg X / 20 mg H, 70 mg X / 30 mg H, 70 mg X / 40 mg H, 70 mg X / 50 mg H, 70 mg X / 60 mg H, 70 mg X / 70 mg H,70 mg X / 80 mg H, 80 mg X / 20 mg H, 80 mg X / 30 mg H, 80 mg X / 40 mg H, 80 mg X / 50 mg H, 80 mg X / 60 mg H, 80 mg X / 70 mg H, 80 mg X / 80 mg H, 90 mg X / 20 mg H, 90 mg X / 30 mg H, 90 mg X / 40 mg H, 90 mg X / 50 mg H, 90 mg X / 60 mg H, 90 mg X / 70 mg H, 90 mg X / 80 mg H, 100 mg X / 20 mg H, 100 mg X / 30 mg H, 100 mg X / 40 mg H, 100 mg X / 50 mg H, 100 mg X / 60 mg H, 100 mg X / 70 mg H or 100 mg X / 80 mg H. In some embodiments, the combined daily dose is formulated into a single capsule or tablet. In some embodiments, the capsule or tablet is formulated for immediate release, extended release or delayed release of the X and H.

[0168] In some embodiments, xanomeline (X) and quinidine (Q) are administered at a combined daily dose of 20 mg X / 20 mg Q, 30 mg X / 60 mg Q, 40 mg X / 50 mg Q, 50 mg X / 50 mg Q, 60 mg X / 40 mg Q, 70 mg X / 40 mg Q, 80 mg X / 30 mg Q, 90 mg X / 30 mg Q, or 100 mg X / 20 mg Q.

[0169] In some embodiments, xanomeline (X) and quinidine (Q) / hydroquinidine (H) are formulated into one capsule or tablet in a combined dose of 10 mg X / 10 mg Q / H, 10 mg X / 20 mg Q / H, 10 mg X / 30 mg Q / H, 10 mg X / 40 mg Q / H, 20 mg X / 20 mg Q / H, 20 mg X / 30 mg Q / H, 20 mg X / 40 mg Q / H, 30 mg X / 20 mg Q / H, 30 mg X / 30 mg Q / H, 30 mg X / 40 mg Q / H, 40 mg X / 20 mg Q / H, 40 mg X / 30 mg Q / H, 40 mg X / 40 mg Q / H, 50 mg X / 20 mg Q / H, 50 mg X / 30 mg Q / H, or 50 mg X / 40 mg Q / H. The capsule or tablet is administered twice a day (BID). In some embodiments, the capsule or tablet is formulated for immediate release, extended release or delayed release of the X and Q.

[0170] In some embodiments, xanomeline (X) and quinidine (Q) / dihydroquinidin (H) are administered a relative molar or weight ratio (X:Q / H molar ratio or X:Q / H weight ratio) in the range of 0.1: 1 to 50:1, 0.1:1 to 20:1, 0.1:1 to 10:1, 0.1:1 to 5:1, 0.1:1 to 2:1, 0.1:1 to 1:1, 0.1:1 to 0.3:l, 0.5:1 to 50:1, 0.5:1 to 20:1, 0.5:1 to 10:1, 0.5:1 to 5:l, 0.5:1 to 2:1, 0.5:1 to 1:1, 2:1 to 50:1, 2:1 to 20:1, 2:1 to 10:1 or 2:1 to 5:1. In some embodiments, xanomeline (X) and quinidine (Q) / dihydroquinidin (H) have a X:Q / H molar ratio or X:Q / H weight ratio in the range of 0.5 : 1 to 5 : 1.

[0171] The present application is further illustrated by the following examples that should not be construed as limiting. The contents of all references, patents, and published patent applications cited throughout this application, as well as the Figures and Tables, are incorporated herein by reference.EXAMPLES

[0172] Example 1: Metabolism of xanomeline, cytochrome P450 (CYP) enzymes phenotyping evaluation in human liver microsomes (HLM) with chemical inhibitors

[0173] Xanomeline (1.25 pM) was incubated with or without the necessary co-factor NADPH to test the activity of CYP enzymes in human liver microsome (0.5 mg / ml) samples. Xanomeline was quickly metabolized in the presence of NADPH with a very short half life (< 5 min), but it was very stable without NADPH (> 60 min).

[0174] Inhibitors for specific CYP isoforms (see Table 1 A) or corresponding positive control compounds (see Table IB) were tested in a sample solution containing 0.5 mg / ml human liver microsome and 1 pM of xanomeline. Each sample solution was prewarmed at 37 °C for 10 min before the addition of NADPH to initiate the reaction. Forxanomeline, at each time point: 0, 5, 10, 20, 40 min, the reaction was stopped by adding 600 pL internal standard to reaction mixture. The positive controls of CYP isoenzymes were all stopped at 60 min except for the positive control of CYP2C8 enzyme, which was stopped at 5 min (see Table IB).Table 1A. List of inhibitors for CYP enzymes and concentrations

[0175] Table IB. List of substrates for CYP enzymes and concentrations

[0176] As shown in Table 1C, the estimated half-life of xanomeline at 1 pM incubated with human liver microsomes in the absence of any CYP450 inhibitors was 7.55 minutes and in the presence of selected inhibitors, the metabolic half-life of xanomeline showed no significant change except for quinidine, the specific inhibitor for CYP2D6, for which the half-life increased to 14.3 minutes.

[0177] Table 1C. Half-life and % metabolic inhibition of xanomeline with or withoutspecific CYP inhibitors

[0178] Example 2: The metabolic stability of xanomeline in the human hepatocyte with or without CYP2D6 inhibitor

[0179] After a vial of human hepatocytes obtained from liquid nitrogen storage was completely thawed at 37°C water bath incubator, the thawed hepatocyte was immediately added into the pre-warmed cryopreserved hepatocyte recovery medium (CHRM) in a 37°C in the Eppendorf tube (1 mL CHRM per vial of hepatocyte). After the hepatocytes being well suspended in the CHRM, the sample was centrifuged at room temperature (100 x g for 10 minutes) to collect cell pellet before the addition of 1.5 mL of pre-warmed incubation medium (4.0 mM glutamine in Williams E medium). Then the aliquot of cell suspension was counted under a microscope using trypan blue for cell viability and density. The cell suspension with the viability > 70% and the density ~ 8xl05 / ml will be used for the metabolic stability assay of xanomeline. Specifically, the cell suspension (0.4xl06cell / ml) is preincubated for 10 min with or without 2 pM quinidine before xanomeline (2 pM) was added to a final concentration of 1 pM each for quinidine and xanomeline and cell density of 0.2 xlO6cell / ml. The estimated half-life of xanomeline at 1 pM incubated with human hepatocyte (0.2 xlO6cell / ml) was 20.3 minutes, but in the presence of quinidine, the specific inhibitor for CYP2D6, the half-life increased to 42.2 minutes.

[0180] The detailed metabolite profile was also identified using human hepatocyte incubation as shown in FIG. 3. and their relatively abundance was reported in Table 2. As shown in FIGS. 4A-4b, two major potentially active metabolites were significantly inhibited in the presence of quinidine during the hepatocyte incubation with xanomeline.

[0181] Table 2. Observed metabolites of xanomeline in human hepatocytes after 90 min incubation

[0182] Example 3: Monkey liver microsome stability

[0183] In the study of the stability of monkey liver microsomes, it was found that quinidine could inhibit the metabolism of xanomeline in monkey liver microsomes to a certain extent, resulting in a 50% increase in the half-life of xanomeline (see Table 3).

[0184] Table 3. Xanomeline half-life in monkey liver microsomeX:Q = xanomeline: quinidine

[0185] Example 4: In vivo monkey PK study and clinical signs

[0186] Table 4A. Study Design for Monkey PKX: xanomeline; Q: quinidine

[0187] Table 4B. Dose and PK collection day (x)PK timepoints: 0, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours

[0188] The plasma concentration vs time plot and PK parameters for multiple oral administration of xanomeline (X) and quinidine (Q) in monkeys are shown in FIGS. 5A-5C, Table 4C and Table 4D, respectively. Compared with xanomeline alone, co-administration of X and Q increased the Cmax of xanomeline by 2-5 times and the AUC by 2-4 times, and the Tmax of xanomeline was also delayed by 1-2 hours. In addition, at the same dose of quinidine, 5 mg / kg of xanomeline showed a larger increase than 10 mg / kg. Compared with quinidine alone, co-administration of xanomeline at a dose of 10 mg / kg or 20 mg / kg significantlyreduced the Cmax and AUC of 100 mg / kg quinidine.

[0189] Table 4C. PK parameters of xanomeline after multiple oral administration in monkeysote: Cmax ratio = Cmaxof X with Q / Cmaxof X without Q; AUCo-s ratio = AUCo-s of X with Q / AUCo-s of X without Q; bioavailability (%F) is calculated from 0.5 mg / kg IV monkey study vs current oral administration.

[0190] Table 4D. PK parameters of quinidine after multiple oral administration in monkeys

[0191] As shown in FIG. 6, similar or slightly better safety profiles associated with the combination of xanomeline and quinidine were observed at increased systemic exposures of xanomeline.

[0192] Example 5: Inhibition of xanomeline metabolism using a variety of CYP2D6 inhibitors (IpM)

[0193] Xanomeline (IpM) is incubated with 0.25 mg / ml of human liver microsome in the presence of a series of CYP2D6 inhibitors / compounds (1 pM). As shown in Table 5, five inhibitors (quinidine, cinacalcet, sarpogrelate, chlorpromazine and dihydroquinidine) showed strong inhibition of metabolism for xanomeline with the percentage of inhibition > 50%, but other strong CYP2D6 inhibitors (e.g. bupropion, paroxetine, fluoxetine, terbinafine) as defined by the regulatory agency are not as expected. Therefore, the inhibition of metabolism for xanomeline is not predicted based on its CYP phenotyping.

[0194] Table 5: Inhibition of xanomeline metabolism by varies test compounds%inhibition = (1-in vitro CLint with inhibitor / in vitro CLint without)* 100, NA means xanomeline alone without inhibitor.

[0195] Example 6: Human liver microsome stability of xanomeline analogs / derivatives

[0196] Xanomeline and its fluorinated, deuterated analogs and its derivative, tazomeline (IpM) are incubated with 0.25 mg / ml of human liver microsome with or without quinidine (1 pM) for 60 min. As shown in Table 6, inhibition of metabolism is also achieved.

[0197] Table 6. Inhibition of xanomeline analogs by quinidine

[0198] Example 7: Monkey PK study of xanomeline with or without quinidine / dihydroquinidine

[0199] During this study, four Rhesus monkeys (n=2 / sex) were sequentially administrated four different test articles formulated in pH 3.5 water for once a day (see Table for details) via oral gavage at fed state. Food and fruit were provided in amounts right for the size and age of the animals. Tap water was available ad libitum. The animals were restrained manually, and approximate 0.3 mL of blood / time point was collected into pre-cooled EDTA-K2 tubes via cephalic or saphenous veins. Plasma will be obtained within 30 minutes after blood collection by centrifugation at 3500 g and at 4°C for 5 minutes. At least 150 pL plasma will be collected and transferred into a 2 mL Eppendorf LoBind tube, which will be stored upright temporarily in dry ice. Plasma samples were stored at approximately -80°C until analysis. The study design is summarized in Table 7.

[0200] Table 7: Summary of the study design

[0201] PK timepoints: 0 (Pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours

[0202] The plasma concentration vs time plot and the calculated PK parameters of xanomeline (X) and quinidine (Q) / dihydroquinidine (H) in monkeys are shown in FIG. 7A, FIG. 7B, Table 8 and Table 9, respectively. Compared with xanomeline alone, coadministration of X and Q / H increased both the Cmax and AUC of xanomeline and the enhancement can be ranked as X+Q (10+20 mg / kg) > X+H (10+10 mg / kg) > X+Q (10+10 mg / kg).

[0203] The systemic exposure of quinidine in the presence of 10 mg / kg xanomeline is proportional from 10 to 20 mg / kg as shown in FIG. 7B and Table 9. In addition, the systemic exposure of H at 10 mg / kg is very similar to Q at the same dose.

[0204] Table 8. Mean PK parameters of xanomeline in monkey

[0205] Table 9. Mean PK parameters of quinidine and dihydroquinidine in monkey

[0206] All the clinical signs observed in this monkey PK study were consistent with the pharmacologic effects of xanomeline.

[0207] Example 8: An exploratory clinical study of combination of xanomeline and quinidine or dihydroquinidine

[0208] An investigator initiated trial (IIT) was conducted with xanomeline administered alone compared to xanomeline administered with quinidine or dihydroquinidine in normal healthy volunteers. This is a single-center, open-label, fixed-sequence exploratory study in healthy male subjects to evaluate the plasma PK profile of xanomeline when administered alone and in combination with quinidine. The primary objectives of this study were (1) to assess the PK properties of xanomeline with or without quinidine, (2) the PK properties of quinidine or dihydroquinidine co-administered with xanomeline and (3) the safety and tolerability of administering xanomeline alone and with quinidine or dihydroquinidine.

[0209] During the first cohort study, one immediate release (IR) gelatin capsule containing 10 mg of xanomeline was orally administrated to six adult male subjects in the morning at day one, followed by washout from day 2 to day 4. After that, one IR capsule containing 10 mg X and 10 mg Q was administrated twice a day (BID) for 12 hour apart, one in the morning and the other in the evening from day 5 to day 8, followed by a single dose at day 9. The whole blood (4 ml / time point) was collected at day 1, 5 and 9 for PK analysis of both X and Q. A total 12 time points, 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12, 14, 16, 24 hour were collected for day 1 and day 9 and a total of 9 time points, 0 (pre-dose), 0.5, 1, 2, 3, 4, 6, 8, 12 hour for day 5. In addition, two time points, 0 (pre-dose) and 12 (pre-dose) hour, were collected for day 7 and 8 respectively.

[0210] After blood collection at each time point, all samples were immediately sent to the sample processing room for centrifugation to harvest the plasma at 3500 g and at 4°C for 5 minutes. About 1.6 ml plasma was collected and divided into two parts, one for assaytube and the other for backup tube. The cryopreservation tube was allowed to be temporarily stored in a <-20°C refrigerator, then stored in a -80°C ultra-low temperature refrigerator for testing within 24 hours, or directly placed in an ultra-low temperature refrigerator at -80°C within 2 hours until analysis.

[0211] Plasma samples were analyzed by LC-MS / MS with isotope internal standard to determine the concentration of X and Q. The data were analyzed using Phoenix WinNonlin 8.4 software by non-compartmental analysis (NCA) to calculate the PK parameters.Statistical analysis is a t-test based method to compare geometric mean (GM) ratio between test and reference samples at 90% confidence interval (CI) based on a linear mixed-effects model applied to log-transformed AUC and Cmax values. Geometric coefficient of variance (GeoCV%) is calculated by the same software using log-transformed data.

[0212] As shown in FIG. 8, the exposure of X as presented by the plasma concentrations vs time plot significantly increased from day one with X alone to day 5 and day 9 with the combination of X and Q. The calculated PK parameters are listed in Table 10. The results of statistical analysis (see Table 11) show that the geometric mean (GM) of Cmax at day 5 (1stadministration of X+Q combo dose) and day 9 (9thadministration of the combo dose) increases about three and six folds than day 1 and the GM of AUC increases about two and five folds than day 1 respectively. The statistical results in Table 11 also indicate that these enhancements of Cmax and AUCo-t at day 5 and day 9 are statistically significant with a P value < 0.01 at 90% confidence interval (CI). In addition, the enhancement is also significant from day 5 to day 9 with a P value < 0.05 at 90% CI for both Cmax and AUC.

[0213] Table 10. PK parameters of xanomeline for the 1stcohort study presented as GM (GeoCV%)*Median (range)

[0214] Table 11. Statistical analysis of Cmax and AUCo-tfor xanomeline with or without quinidineT : test; R: reference

[0215] During the second cohort study, one IR capsule containing 25 mg of xanomeline was orally administrated to six male adults for BID from day 1 to day 7, followed by one IR capsule containing 25 mg of X and 10 mg of Q for BID (12 hour apart) from day 8 to day 14. The blood sample was collected at days 4, 8, 11 and 14 for plasma concentration analysis of both X and Q. A total seven time points were collected for morning dose each day and they are 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 hr.

[0216] As shown in FIG. 9, the exposure of X as presented by the plasma concentrations vs time significantly increased from day 4 with X alone to day 8, 11 and day 14 with the combination of X and Q. The calculated PK parameters are listed in Table 12 and the statistical analysis is presented in Table 13. The results show that the GM of Cmax from the morning dose at day 8 (1stday administration of X+Q combo dose), day 11 (4thday administration of combo dose), day 14 ( 7thday administration of combo dose) is about 3, 4 and 6 folds than day 4 (4thday administration of X alone to achieve the steady state) and the GM of AUCo-tis about 2, 3 and 4 folds than day 4 respectively. The statistical comparison also indicates that these enhancements of Cmax and AUCo-tat day 8, 11 and 14 compared to day 4 are statistically significant with a P value < 0.001 at 90% CI. In addition, the enhancement of AUC is significant with a P value < 0.05 at 90% CI from day 8 to day 14, but there is no notable change from day 11 to day 14. As for the GM of Cmax among days 8, 11 and 14, there is no notable change observed since the P values are greater than 0.05 at 90% CI.

[0217] Table 12. PK parameters of xanomeline for the 2ndcohort study presented as GM (GeoCV%)*Median (range)

[0218] Table 13. Statistical analysis of Cmax and AUCo-tfor xanomeline with or without quinidine

[0219] As shown in FIG.10, the exposure of Q as presented by the plasma concentratoins singnificantly increased from day 5 (1stadministration of X+Q combo dose) to day 9 (9thadministration of combo dose) during the first cohort study, so did the plasma concentration of Q from day 8 to day 11 and 14 during the second cohort study. The calculated PK parameters are listed in Table 14 and statistical analysis are presented in Table 15. Both the GM values of Cmax and AUC0-12 at day 9 (9thdose administration of X+Q combo dose) is about 2 folds of day 5 (1stdose administration of X+Q combo dose) with a P value < 0.001 at 90% CI. The results also show that both Cmax and AUC0-12 at day 14 (7thday administration of combo dose) and 11 (4thday administration of combo dose) are significantly increased than day 8 (1stday administration of combo dose ) with a P value < 0.0001 at 90% CI. In addition, from day 11 to day 14, a significant increase of Cmax and AUCo-12 are observed with a P value < 0.01 at 90% CI.

[0220] Statistical comparison (see Table 15) of the Cmax and AUCo-tfor day 5 from 1stcohort and day 8 from 2ndcohort shows no notable difference, so are the Cmax and AUCo-t for day 9 from 1stcohort and day 14 from 2ndcohort.

[0221] Table 14. PK parameters of quinidine from both 1stand 2ndcohorts presented as GM (GeoCV%)*Median (range), ND: not determined

[0222] Table 15. Statistical comparison for Cmax and AUC of quinidine for two cohorts

[0223] During the third cohort study, one IR capsule containing 15 mg of xanomeline was orally administrated to six adult male subjects for BID from day 1 to day 7, followed by one IR capsule containing 15 mg of X and 10 mg of Hydorquinidine (H) for BID (12 hour apart) from day 8 to day 14. The blood sample was collected on days 4, 8, 11 and 14 for plasma concentration analysis of both X and H. A total seven time points were collected for morning dose at each day, and they are 0 (pre-dose), 0.5, 1, 2, 4, 8, 12 hour.

[0224] As shown in FIG. 11, the exposure of X as presented by the mean plasma concentratoins clearly increased from day 4 with X alone to day 8, 11 and day 14 with the combination of X and H. The calculated PK parameters are listed in Table 16 and statistical analysis is presented in Table 17. The GM of Cmax at day 8 (1stday administration of X+Hcombo dose), day 11 (4thday administration of combo dose), day 14 (7thday administration of combo dose) is about 2 folds of day 4 (4thday administration of X to achieve the steady state) and the GM of AUC0-12 is about 2 -2.5 folds of day 4, with a P value < 0.0001 at 90% CI. In addition, the enhancement of AUCo-nis significant with a P value < 0.05 at 90% CI from day 8 to day 11 and 14. The GM values of Cmax among day 8, 11 and 14 exhibit no notable change with P > 0.05 at 90% CI, neither are the Cmax and AUo-nfrom day 11 to day 14.

[0225] Table 16. PK parameters of xanomeline for the 3rdcohort study presented as GM (GeoCV%)*Median (range)

[0226] Table 17. Statistical comparison of Cmax and AUC for xanomeline with or without dihydroquinidine

[0227] As shown in FIG. 12, the exposure of H as presented by the plasma concentratoin vs time profile singnificantly increased from day 8 (1stday administration of X+H combo dose) to day 11 (4thday administration of combo dose) and 14 (7thday administration of combo dose) during the 3rd cohort study. The calculated PK parameters are listed in Table 18 and statistical analysis is presented in Table 19. Both Cmax and AUC0-12 on day 14 and 11 are about 2-folds than day 8 with a P value < 0.0001 at 90% CI. However, there is no signficant change of either Cmax or AUC from day 11 to day 14.

[0228] Table 18. PK parameters of dihydroquinidine for the 3rdcohort, GM (GeoCV%)*Median (range)

[0229] Table 19. Statistical comparison for Cmax and AUC of dihydroquinidine for the 3rdcohort

[0230] During this IIT clinical study, combo groups had no gastrointestinal AEs up to the efficacious exposure of xanomeline (Table 20).

[0231] Table 20. Gastrointestinal adverse events in the IIT study (BID x 7 Days)

[0232] Example 9: Metabolite Profiles for the Plasma Samples of the IIT Study

[0233] The plasma samples from D4 and D14 at each time point (0-12 hr) of the six subjects for the second cohort study were mixed at the same time point in equal volumes, and then each mixed sample was pooled together according to Hamilton method (see Table 21). Take 100 pL of the mixed plasma sample, add 3 times the volume (300 pL) of precipitant (ACN / MeOH, 4 / 1, v / v), vortex at 2000 rpm for 5 min, and centrifuge at 4 °C at 20,000 g for10 min. Then, pipette the supernatant (200 pL) into an injection vial to be used for positive ion mode LC-UV-FullMS-ddMS2 analysis.

[0234] Table 21. Plasma pooling plan according to Hamilton method for six subjects

[0235] A total of 33 metabolites related to xanom eline were detected in mixed plasm samples from six subjects in the second cohort study. The biotransfromaton of xanomeline involves both phase I metabolism (oxidation, oxidation to carboxylic acids, hydrolysis, dehydrogenation, and N-demethylation) and phase II metabolism (glucuronide binding and acetylation), as well as multiple combinations of phase I and II metabolism. Table 22 described the representative metabolites, their biotransfomation, relative abundance estimated by mass spectrometry (MS) in the plasma. After oral administration of IR capsules containing 25 mg X alone, the major metabolites with relative abundance > 10% of total MS peak area in the plasma are M283-la (40.74%) and M297-1 (10.8%). In contrast, the relative abundance of the parent xanomeline is only about 2.89%. After oral administration of IR capsules containing 25 mg X + 10 mg Q, the major metabolites were M283-la (20.88%), M265 (10.29%) and M297-l(22.94%). Meanwhile, the relative abundance of the parent Xanomeline significantly increased to about 10.83%. As compared between X alone and X+Q combo, the relative abundance of the major metabolite M283-la decreased by -20% , M297-1 increased by 10%, M265 increased slightly by 2% and the relative abundance of the parent by 8%. Overall, the metabolite M283-la decreased by 50% from X alone to X+Q combo, the metabolite M297-A increased about 100% and the parent increased about 300%.

[0236] FIG. 13 and FIG. 14 present plasma concentration vs time profiles for the major metabolites and parent at D4 with X administration alone and at D14 with X+Q combo administration. Table 23 lists the AUC0-12 determined for pooled plasma of six subjects using reference standards for individual metabolite and confirmed the change of major metabolites M283-la and M297-1 as observed according to the relative abundance by MS. In particular, the metabolite M283-la, which could potentially contribute to the in vivocardiovascular effects (increased heart rate and / or blood pressure), had been reduced about 50% in X+Q combo administration.

[0237] Table 22. Relative MS abundance of xanom eline and its major metabolites*Notes: The % relative MS abundance of each metabolite is the ratio of its MS peak area to the total X-related substances MS peak area; NA: not applicable.

[0238] Table 23. PK Parameters of Metabolites and Parent estimated from the pooled plasma of six subjects.

[0239] While various embodiments have been described above, it should beunderstood that such disclosures have been presented by way of example only and are not limiting. Thus, the breadth and scope of the subject compositions and methods should not be limited by any of the above-described exemplary embodiments but should be defined only in accordance with the following claims and their equivalents.

[0240] The above description is for the purpose of teaching the person of ordinary skill in the art how to practice the present invention, and it is not intended to detail all those obvious modifications and variations of it which will become apparent to the skilled worker upon reading the description. It is intended, however, that all such obvious modifications and variations be included within the scope of the present invention, which is defined by the following claims. The claims are intended to cover the components and steps in any sequence which is effective in meeting the objectives there intended, unless the context specifically indicates the contrary.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition, comprising:a muscarinic agonist; anda pharmacokinetic (PK) modifier that improves the bioavailability of the muscarinic agonist.

2. The pharmaceutical composition of claim 1, wherein the muscarinic agonist is xanomeline, an analog of xanomeline, a derivative of xanomeline, a prodrug of xanomeline, a metabolite of xanomeline, or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition of claim 1 or 2, wherein the muscarinic agonist has a chemical formula ofwherein each of R1to R23is selected from the group consisting of H, D or F, and wherein X is O or S.

4. The pharmaceutical composition of claim 3, wherein the muscarinic agonist is xanomeline having a chemical formula of5. The pharmaceutical composition of any one of claims 1-4, wherein the pharmacokinetic modifier is a CYP enzyme inhibitor.

6. The pharmaceutical composition of claim 5, wherein the pharmacokinetic modifier is a CYP2D6 enzyme inhibitor.

7. The pharmaceutical composition of 6, wherein the pharmacokinetic modifier is a CYP2D6 enzyme inhibitor selected from the group consisting of quinidine, cinacalcet, sarpogrelate, chlorpromazine and dihydroquinidine.

8. The pharmaceutical composition of claim 5, wherein the CYP enzyme inhibitor is quinidine, an analog of quinidine, a derivative of quinidine, a prodrug of quinidine, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition of claim 5, wherein the CYP enzyme inhibitor is dihydroquinidine, an analog of dihydroquinidine, a derivative of dihydroquinidine, a prodrug of dihydroquinidine, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition of claim 5, wherein the CYP enzyme inhibitor is quinidine (formula III) or dihydroquinidine (formula IV):

11. The pharmaceutical composition of claim 10, comprising xanomeline (X) and quinidine (Q) / dihydroquinidine (H) at a X:Q / H weight ratio in the range of 0.5 : 1 to 5 : 1.

12. The pharmaceutical composition of any one of claims 1 to 10, wherein the pharmaceutical composition is formulated for immediate release, delayed release, extended release, or delayed and extended release.

13. A method for treating a neurological disorder in a subject, comprising: administering to the subject an effective amount of the pharmaceutical combination of any one of claims 1-12.

14. A method of treating a neurological disorder in a subject, comprising:administering to the subject an effective amount of a muscarinic agonist; and administering to the subject a pharmacokinetic modifier that improves the bioavailability of the muscarinic agonist.

15. The method of claim 14, wherein the muscarinic agonist is xanomeline.

16. The method of claim 13 or claim 14, wherein the PK modifier is quinidine or dihydroquinidine.

17. The method of any one of claims 14 to 16, wherein the neurological disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, schizophrenia, movement disorders and drug addiction.

18. The method of claim 17, wherein the neurological disorder is schizophrenia.

19. A method of treating neurological disorder in a subject, comprising the step of:co-admini sting an effective amount of a muscarinic agonists with one or more PK modifiers, wherein the one or more PK modifiers change the relative abundance of the muscarinic agonist and metabolites thereof during systemic exposure, as compared to administration of the muscarinic agonist alone.

20. The method of claim 19, wherein one or more PK modifiers increase the perecentage of the muscarinic agonist and decrease the percentage of undesired metabolites of the muscarinic agonist.

21. The mehtod of claim 20, wherein the muscarinic agonist is xanomeline and wherein the undesired metabolites of the muscarinic agonist comprises M283-la.

22. The method of claim 19, wherein the one or more PK modifiers reduce adverse effects of the muscarinic agonist, as compared to administration of the muscarinic agonist alone.

23. The method of claim 22, wherein the one or more PK modifiers reduce gastrointestinal adverse effects of the muscarinic agonist.

24. A pharmaceutical composition, comprising:(A) xanomeline, an analog of xanomeline, a derivative of xanomeline or a pharmaceutically acceptable salt thereof; and(B) quinidine, an analog of quinidine, a derivative of quinidine, or a pharmaceutically acceptable salt thereof.

25. The pharmaceutical composition of claim 24, comprising:(A) xanomeline or a pharmaceutically acceptable salt thereof; and(B) quinidine, dihydroquinidine, or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition of claim 24 or 25, wherein component A and component B have a component A:component B weight ratio in the range of 0.5:1 to 5:1.

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