US20110020423A1 - Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation - Google Patents

Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation Download PDF

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US20110020423A1
US20110020423A1 US12/840,980 US84098010A US2011020423A1 US 20110020423 A1 US20110020423 A1 US 20110020423A1 US 84098010 A US84098010 A US 84098010A US 2011020423 A1 US2011020423 A1 US 2011020423A1
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Prior art keywords
muscarinic
inhibitor
activator
medicament
combination
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US12/840,980
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Eric Elenko
Andrew C. Miller
Philip E. Murray, III
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Puretech Ventures LLC
Puretech Management Inc
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Puretech Ventures LLC
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Priority to US12/840,980 priority Critical patent/US20110020423A1/en
Application filed by Puretech Ventures LLC filed Critical Puretech Ventures LLC
Assigned to PURETECH VENTURES reassignment PURETECH VENTURES ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ELENKO, ERIC, MILLER, ANDREW C., MURRAY, PHILIP E., III
Publication of US20110020423A1 publication Critical patent/US20110020423A1/en
Priority to US13/858,985 priority patent/US20140099356A1/en
Priority to US14/534,698 priority patent/US20150265593A1/en
Priority to US15/378,796 priority patent/US10265311B2/en
Priority to US15/400,108 priority patent/US10238643B2/en
Priority to US16/270,206 priority patent/US10369143B2/en
Priority to US16/289,165 priority patent/US10369144B2/en
Assigned to Puretech Management, Inc. reassignment Puretech Management, Inc. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ELENKO, ERIC
Priority to US16/444,206 priority patent/US10695339B2/en
Priority to US16/880,634 priority patent/US20200323839A1/en
Priority to US18/461,741 priority patent/US20240100039A1/en
Abandoned legal-status Critical Current

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Definitions

  • the present invention relates to: 1) A method of using a combination of one or more muscarinic agonists and one or more muscarinic antagonists for treatment of diseases that are ameliorated by activation of muscarinic receptors (e.g., schizophrenia and related disorders); 2) A medicament comprising one or more muscarinic agonists and one or more muscarinic antagonists.
  • 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) (Raedler et al. American Journal of Psychiatry. 160: 118. 2003), each of which are found in the CNS but have different tissue distributions.
  • M1-M5 G-protein coupled receptors with five different receptor subtypes
  • Activation of the muscarinic system through use of muscarinic agonists has been suggested to have the potential to treat several diseases including Alzheimer's disease, Parkinson's disease, movement disorders and drug addiction.
  • M1 and M4 subtypes have been of particular interest as therapeutic targets for various diseases. For instance, the mood stabilizers lithium and valproic acid, which are used to treat bipolar depression, may exert their effects via the muscarinic system particularly through the M4 subtype receptor. (Bymaster & Felder. Mol Psychiatry. 7 Suppl 1:S57. 2002).
  • antipsychotics are the mainstay of treatment for schizophrenia.
  • the first generation of antipsychotics are generally known as “typical antipsychotics” while newer antipsychotics are generally called “atypical antipsychotics.”
  • Both typical and atypical antipsychotics have limited efficacy and severe side effects.
  • There is little to no difference in efficacy between typical and atypical antipsychotics most likely due to the fact that both classes of drugs achieve their therapeutic effect through the same pharmacological mechanisms (e.g., acting as dopamine receptor antagonists). (Nikam et al. Curr Opin Investig Drugs. 9:37. 2008).
  • Clozapine is an example of an antipsychotic that has major side effects, including sialorrhea (hypersalivation) which occurs in up to 54% of patients. (Davydov and Botts, Ann Pharmacother. 34:662. 2000). The exact mechanism of hypersalivation remains unknown. (Rogers and Shramko. Pharmacotherapy. 20:109. 2000). Clozapine has a complex pharmacological profile with appreciable activity at a variety of receptors, including dopamine receptors, serotonin receptors, adrenergic receptors, muscarinic receptors and possibly others. (Coward. Br J Psychiatry Suppl. 17:5. 1992).
  • Anti-muscarinic drugs such as pirenzepine have shown efficacy in small scale trials (Schneider et al. Pharmacopsychiatry. 37:43. 2004), but other trials with the same agent found no effect. (Liu et al. J Clin Psychopharmacol. 21:608. 2001).
  • Alpha2 adrenergic agonist such as clonidine (Singh et al., J. Psychopharmacol. 19:426. 2005) have also shown efficacy in reducing sialorrhea in small scale trials.
  • Syed et al. reported in a 2008 review that there is inadequate data to guide clinical practice. (Syed et al. Cochrane Database Syst Rev. 16:3. 2008).
  • Muscarinic receptors are G-protein linked receptors that bind the neurotransmitter acetylcholine.
  • M1, M2, M3, M4, and M5 five subtypes of muscarinic receptor have been identified and are generally labeled M1, M2, M3, M4, and M5, respectively.
  • M1, M2, M3, M4, and M5 five subtypes of muscarinic receptor have been identified and are generally labeled M1, M2, M3, M4, and M5, respectively.
  • muscarinic antagonist scopolamine which is used to treat motion sickness, produces cognitive impairment and delusions of the type seen in schizophrenia.
  • M1 agonists More selective M1 agonists have been suggested to potentiate glutamate signaling which could help exert a therapeutic effect.
  • a double-blind placebo controlled trial of schizophrenic patients using xanomeline which has preferential activity at the M1 and M4 receptors, alleviation of schizophrenia was observed.
  • the present invention relates to a method of treating diseases or conditions ameliorated by activation of the muscarinic system by administering one or more muscarinic “Activators” (e.g., agonist, partial agonist, co-agonist, physiological agonist, potentiator, stimulator, allosteric potentiator, positive allosteric modulator or allosteric agonist) and one or more muscarinic “Inhibitors” (e.g., antagonist, partial antagonist, competitive antagonist, non-competitive antagonist, uncompetitive antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible antagonist, inhibitor, reversible inhibitor, irreversible inhibitor, negative allosteric modulator, or allosteric antagonist).
  • Activators e.g., agonist, partial agonist, co-agonist, physiological agonist, potentiator, stimulator, allosteric potentiator, positive allosteric modulator or allosteric agonist
  • such diseases include schizophrenia and related disorders.
  • a single muscarinic Activator and a single muscarinic Inhibitor are used.
  • the combination of the Activator and Inhibitor has a score (“Theta score”) above 230 as determined by in silico testing using a proprietary algorithm as described herein.
  • more than one muscarinic Activator and/or more than one muscarinic Inhibitor are used.
  • the method of treatment can be applied to a mammal.
  • the mammal is a human being.
  • the use of the Inhibitor alleviates the side effects associated with use of the Activator. In another embodiment, use of the Inhibitor allows for a higher maximum tolerated dose of the Activator.
  • the muscarinic Activator may be taken sequentially with the Inhibitor. In another embodiment of the invention, the muscarinic Activator may be taken concurrently with the Inhibitor. In a preferred embodiment of the invention, the Activator and Inhibitor are formulated to be contained in the same dosage form or dosage vehicle. In another embodiment of the invention, the muscarinic Activator and Inhibitor are formulated to be in separate dosage forms or dosage vehicles. In one embodiment, the Activator and Inhibitor are formulated in an immediate release dosage form. In another embodiment, Activator and Inhibitor are formulated in a controlled release dosage form. In another embodiment, either the Activator or the Inhibitor is formulated in an immediate release dosage form, while the other is formulated in a controlled release dosage form.
  • the muscarinic Activator and Inhibitor can be taken orally.
  • the Activator and Inhibitor may be given orally in tablets, troches, liquids, drops, capsules, caplets and gel caps or other such formulations known to one skilled in the art.
  • Other routes of administration can include but are not limited to: parenteral, topical, transdermal, ocular, rectal, sublingual, and vaginal.
  • the muscarinic Activator and Inhibitor are administered either simultaneously or consecutively with other therapies for schizophrenia.
  • the muscarinic Activator and Inhibitor are used simultaneously or sequentially with psychotherapy.
  • the muscarinic Activator and Inhibitor are administered either simultaneously or consecutively with other pharmacological therapies.
  • Pharmacological therapies could include but are not limited to: antipsychotics, anxiolytics, anti-depressants, sedatives, tranquilizers and other pharmacological interventions known to one skilled in the art.
  • a separate embodiment of the invention is a medicament comprising both a muscarinic Activator and a muscarinic Inhibitor.
  • the combination of the Activator and Inhibitor have a theta score above 230 as determined by in silico testing using a proprietary algorithm as described herein.
  • the medicament can be taken orally.
  • the medicament may be given orally in tablets, troches, liquids, drops, capsules, caplets and gel caps or other such formulations known to one skilled in the art.
  • Other routes of administration can include but are not limited to: parenteral, topical, transdermal, ocular, rectal, sublingual, and vaginal.
  • the medicament can be administered in conjunction with other therapies.
  • the medicament is used simultaneously or sequentially with psychotherapy.
  • the medicament is administered either simultaneously or consecutively with other pharmacological therapy.
  • pharmacological therapy could include but is not limited to: antipsychotics, anxiolytics, anti-depressants, sedatives, tranquilizers and other pharmacological interventions known to one skilled in the art.
  • an element means one element or more than one element.
  • controlled release is defined as a prolonged release pattern of one or more drugs, such that the drugs are released over a period of time.
  • a controlled release formation is a formulation with release kinetics that result in measurable serum levels of the drug over a period of time longer than what would be possible following intravenous injection or following administration of an immediate release oral dosage form. Controlled release, slow release, sustained release, extended release, prolonged release, and delayed release have the same definitions for the present invention.
  • mammals include humans, primates, bovines, porcines, canines, felines, and rodents (e.g., mice and rats).
  • parenteral administration and “administered parenterally” are art-recognized and refer to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
  • a “patient,” “subject” or “host” to be treated by the subject method may mean either a human or non-human mammal.
  • pharmaceutically-acceptable carrier refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'
  • salts used interchangeably with “salts,” is art-recognized and refers to salts prepared from relatively non-toxic acids or bases including inorganic acids and bases and organic acids and bases, including, for example, those contained in compositions of the present invention.
  • Suitable non-toxic acids include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, hydrochloric, hydrobromic, phosphoric, and sulfuric acids and the like.
  • inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanes
  • treating is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disorder.
  • therapeutic agent refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject.
  • therapeutic agents also referred to as “drugs,” are described in well-known literature references such as the Merck Index (14 th edition), the Physicians' Desk Reference (64 th edition), and The Pharmacological Basis of Therapeutics (12 th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • psychotherapy refers to use of non-pharmacological therapies in which those skilled in the art use a variety of techniques that involve verbal and other interactions with a patient to affect a positive therapeutic outcome.
  • Such techniques include, but are not limited to, behavior therapy, cognitive therapy, psychodynamic therapy, psychoanalytic therapy, group therapy, family counseling, art therapy, music therapy, vocational therapy, humanistic therapy, existential therapy, transpersonal therapy, client-centered therapy (also called person-centered therapy), Gestalt therapy, biofeedback therapy, rational emotive behavioral therapy, reality therapy, response based therapy, Sandplay therapy, status dynamics therapy, hypnosis and validation therapy.
  • psychotherapy may involve combining two or more techniques and that a therapist can select and adjust the techniques based on the needs of the individual patient and the patient's response.
  • Muscarinic Disorder refers to any disease or condition that is ameliorated by activation of the muscarinic system. Such diseases include ones in which direct activation of muscarinic receptors themselves or inhibition of cholinesterase enzymes has produced a therapeutic effect.
  • Diseases Related To Schizophrenia and “Disorders Related To Schizophrenia” include, but are not limited to, schizo-affective disorder, psychosis, delusional disorders, psychosis associated with Alzheimer's disease, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, bipolar with psychosis or any other disease with psychotic features.
  • Movement Disorders includes, but is not limited to, Gilles de la Tourette's syndrome, Friederich's ataxia, Huntington's chorea, restless leg syndrome and other diseases or disorders whose symptoms include excessive movements, ticks and spasms.
  • Mood Disorders includes major depressive disorder, dysthymia, recurrent brief depression, minor depression disorder, bipolar disorder, mania and anxiety.
  • Cognitive Disorders refers to diseases or disorders that are marked by cognitive deficit (e.g., having abnormal working memory, problem solving abilities, etc.).
  • Diseases include but are not limited to Alzheimer's disease, Parkinson's Disease, dementia (including, but not limited to, AIDS related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies and idiopathic dementia), Pick's disease, confusion, cognitive deficit associated with fatigue, learning disorders, traumatic brain injury, autism, age-related cognitive decline, and Cushing's Disease, a cognitive impairment associated with auto-immune diseases.
  • Attention Disorders refers to diseases or conditions that are marked by having an abnormal or decreased attention span. Diseases include but are not limited to attention hyperactivity deficit disorder, attention deficit disorder, Dubowitz Syndrome, FG Syndrome, Down's Syndrome, growth delay due to insulin-like growth factor I deficiency, hepatic encephalopathy syndrome, and Strauss Syndrome.
  • Addictive Disorders refers to diseases or conditions marked by addiction or substance dependence as defined by the Diagnostic & Statistical Manual IV. Such disorders are characterized by physical dependence, withdrawal and tolerance to a particular substance. Such substances include but are not limited to alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine and cannabis. Addictive Disorders can also encompass behaviors that a patient does in a compulsive, continual manner despite clear negative consequences. For instance, ludomania is recognized by those skilled in the art as being an addictive behavior that often has devastating consequences.
  • Activator means a molecule that can be described as an agonist, partial agonist, co-agonist, physiological agonist, potentiator, stimulator, allosteric potentiator, positive allosteric modulator, allosteric agonist or a molecule that increases the activity or signaling of muscarinic receptors through direct or indirect means.
  • Inhibitor means a molecule that can be described as an antagonist, partial antagonist, competitive antagonist, non-competitive antagonist, uncompetitive antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible antagonist, inhibitor, reversible inhibitor, irreversible inhibitor, negative allosteric modulator, allosteric antagonist or a molecule that decreases the activity or signaling of muscarinic receptors through direct or indirect means.
  • maximum tolerated dose means the highest dose of a drug or therapeutic that can be taken by patients without the patients' experiencing intolerable side effects.
  • the maximum tolerated dose is typically determined empirically in clinical trials.
  • Muscarinic receptors refers to G-protein linked receptors that bind the neurotransmitter acetylcholine, and to date, five subtypes of muscarinic receptor have been identified. “M1” means the subtype one muscarinic receptor. “M2” means the subtype two muscarinic receptor. “M3” means the subtype three muscarinic receptor. “M4” means the subtype four muscarinic receptor. “M5” means the subtype five muscarinic receptor.
  • Antipsychotic refers to a drug that diminishes psychosis, hallucinations or delusions.
  • Antipsychotics can include, but are not limited to: Haloperidol, droperidol, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, periciazine, promazine, triflupromazine, levomepromazine, promethazine, pimozide, chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, zotepine, aripiprazole, bifeprunox, and tetrabenazine.
  • Benzodiazepines e.g., alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, lorazepam
  • buspirone e.g., buspirone
  • barbiturates e.g., amobarbital, pentobarbital, secobarbital, phenobarbitol
  • hydroxyzine e.g., amobarbital, pentobarbital, secobarbital, phenobarbitol
  • Anti-depressants refers to drugs that alleviate depression and related conditions (e.g., dysthymia) and include, but are not limited to: Selective serotonin-reuptake inhibitors (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), serotonin-norepinephrine reuptake inhibitors (e.g., desvenlafaxine, duloxetine, milnacipram, venlafaxine), mianserin, mirtazapin, norepinephrine reuptake inhibitors (e.g., atomoxetine, mazindol, reboxetine, viloxazine), bupropion, tianeptine, agomelatine, trycyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine, trimipramine, desipramine, nortripty
  • “Sedatives” or “tranquilizers” refer to drugs that induce somnolence, promote a feeling of being tired or desire to sleep or promote a state of unconsciousness.
  • Such drugs include but are not limited to benzodiazepines, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbitol), eszopiclone, zaleplon, zolpidem, zopiclone.
  • Theta Score is defined as the numerical value assigned by an in silico algorithm described herein used to predict the overall efficacy and side effects of any given combination of a Muscarinic Activator and a Muscarinic Inhibitor.
  • the present invention relates to the method of use of one or more Activators and Inhibitors of muscarinic receptors in combination for treatment of various disorders that can be ameliorated by activation of the muscarinic system.
  • the present invention also describes a medicament comprising one or more Activators and one or more Inhibitors of muscarinic receptors.
  • Use of muscarinic Activators has previously been hypothesized to be useful for various central nervous system related conditions. In particular, activation of the M1 and M4 receptor subtypes could prove to be of therapeutic value. However, no one has been able to advance M1 and M4 muscarinic Activators through clinical development to receive regulatory approval for CNS indications because of unacceptable side effects.
  • the muscarinic agonist xanomeline had unacceptable GI side effects as well as other side effects primarily linked to binding of muscarinic receptors besides M1 and M4.
  • a muscarinic Activator with an Inhibitor, it is possible to achieve the desired therapeutic effect while diminishing or eliminating the side effects associated with unwanted subtype binding.
  • Muscarinic Inhibitors are used for treatment of overactive bladder and pulmonary disorders and have been suggested for treatment of other disorders. (Witte L P et al. Curr. Opin. Uro 1.1:13. 2009). Groups have outlined use of muscarinic Inhibitors with drugs in other classes to achieve a greater effect for treatment of a disease. For example, WO 2008/121268 suggests a combination for the treatment of lower urinary tract symptoms (LUTS) consisting of a beta-3 adrenergic agonist, which on its own has been investigated for the treatment of LUTS, and a muscarinic antagonist.
  • LUTS lower urinary tract symptoms
  • US 2006/0287294 A1 outlines use of aspartyl protease inhibitors with either an M1 agonist or an M2 antagonist for treatment of various diseases, including improvement of cognitive deficit.
  • M1 Activators and M2 Inhibitors themselves (Carey et al. Eur J Pharmacol 431:198. 2001.) have been suggested to be useful treatments for cognitive deficit, and the rationale for the combination with the aspartyl protease inhibitor was to enhance the effects of the aspartyl protease inhibitor.
  • 5,480,651 discloses use of agents that increase acetylcholine in the synapse or that activate the nicotinic acetylcholine receptors, followed by administration of an acetylcholine receptor antagonist to relieve craving associated with nicotine addiction.
  • the preferred composition uses physostigmine which is an inhibitor of acetylcholinesterase, as opposed to a muscarinic Activator which would not activate the nicotinic acetylcholine receptors.
  • WO 03/092580 discloses compounds that can act simultaneously as muscarinic Activators at certain receptor subtypes and antagonists at others.
  • the Paborji publication also discloses use of a peripherally-acting muscarinic M2/M3 agonist to counteract dry mouth associated with the peripherally-acting M2/M3 muscarinic antagonist.
  • Paborji's approach does not, however, relate to activity at muscarinic receptors in the CNS, which is of critical importance for the work described herein, nor does it pertain to activity at either the M1 or M4 receptor.
  • Paborji's approach is highly limited to a specific muscarinic inhibitor and does not provide any selection criteria to identify preferred or specific combinations of muscarinic Activators with the muscarinic antagonist, in spite of the prohibitively large number of potential combinations for which experimental testing could be done.
  • one or more muscarinic Activators are used in combination with one or more Muscarinic Inhibitors for treatment of Muscarinic Disorders.
  • diseases or disorders include schizophrenia and Diseases Related to Schizophrenia.
  • one or more muscarinic Activators are used in combination with one or more Muscarinic Inhibitors for treatment of Mood Disorders.
  • one or more muscarinic Activators are used with one or more muscarinic Inhibitors to treat Movement Disorders.
  • one or more muscarinic Activators are used with one or more muscarinic Inhibitors to treat Cognitive Disorders, including using the combination to enhance cognitive function not associated with a specific pathology.
  • one or more muscarinic Activators are used with one or more muscarinic Inhibitors to treat Attention Disorders. Outside of disease treatment, enhancement of attention could improve learning and decrease symptoms associated with fatigue due to both lack of sleep and circadian rhythm disturbances such as jet lag. In another embodiment, one or more muscarinic Activators are used with one or more muscarinic Inhibitors to treat Addictive Disorders.
  • the combination of one or more muscarinic Activators with one or more Muscarinic Inhibitors can be used to treat Muscarinic Disorders which are characterized by an amelioration of symptoms in response to inhibitors of cholinesterase enzymes.
  • cholinesterase inhibitors have proven therapeutic for certain diseases (e.g., Alzheimer's disease), the use of such inhibitors is limited due to toxicity.
  • powerful chemical weapons such as sarin gas exert their toxic effects by inhibiting acetylcholinesterase (sarin gas material safety data sheet 103 d Congress, 2 d Session . United States Senate. May 25, 1994. http://www.gulfweb.org/bigdoc/report/appgb.html).
  • muscarinic Activators with one or more Muscarinic Inhibitors represents not only a safer method of treatment of those diseases shown to be response to cholinesterase inhibitors, but also a more effective one given the limitations on current cholinesterase inhibitors.
  • the combination of one or more muscarinic Activators with one or more Muscarinic Inhibitors is used to treat an animal.
  • the animal is a mammal.
  • the mammal is a human being.
  • a single muscarinic Activator and a single muscarinic Inhibitor are used.
  • more than one muscarinic Activator and/or more than one muscarinic Inhibitor is used.
  • use of the Inhibitor decreases the side effects associated with use of the Activator.
  • Such side effects include, but are not limited to, GI side effects, cardiac side effects, excessive sweating and excessive salivation.
  • Use of one or more Inhibitors in combination with one or more Activators may allow the Activators to be used clinically when the Activators may not otherwise be used clinically due to the their side effects.
  • use of the Inhibitor in conjunction with the Activator allows for the Activator to achieve a higher maximum tolerated dose than the Activator would otherwise achieve.
  • animal models have been used to demonstrate the efficacy of new therapeutics for schizophrenia, including both pharmacological models (e.g., ketamine model) and genetic models. (e.g., DISC 1 mouse) (Dawe G S et al. Ann Acad Med Singapore. 38:425. 2009; Desbonnet L. Biochem Soc Trans. 37:308. 2009; Geyer M A. Neurotox Res. 14:71. 2008).
  • animal models including rodents, dogs and non-human primates can be used to demonstrate the side effect profile of pharmacological agents.
  • Standard measures based on patient self-report can be used by those skilled in the art to assess various side effects such as GI discomfort.
  • objective physiological measures e.g., EKGs
  • a set of standard measures has also been developed to assess schizophrenia symptoms including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI). (Mortimer A M. Br J Psychiatry Suppl. 50:s7. 2007).
  • BPRS Brief Psychiatric Rating Scale
  • PANSS Positive and Negative Syndrome Scale
  • CGI Clinical Global Impression
  • the muscarinic Activator is administered concurrently with the muscarinic Inhibitor. In another embodiment, the muscarinic Inhibitor is administered consecutively with the Activator. In further embodiment, the muscarinic Activator is administered prior to administration of the muscarinic Inhibitor. In another embodiment, the muscarinic Inhibitor is administered prior to administration of the muscarinic Activator. In one embodiment, the muscarinic Inhibitor is administered within one hour of administration of the muscarinic Activator. In another embodiment, the muscarinic Inhibitor is administered within 30 minutes of administration of the muscarinic Activator.
  • the muscarinic Inhibitor is administered within 10 minutes of administration of the muscarinic Activator. In another embodiment, the muscarinic Inhibitor is administered within one minute of administration of the muscarinic Activator. In another embodiment, the muscarinic Inhibitor is administered within 30 seconds of administration of the muscarinic Activator.
  • a lead-in period Prior to the start of a drug regimen of the type outlined above, there may be a lead-in period that lasts from one to fourteen days. During this lead-in period, the muscarinic Inhibitor may be given by itself prior to the start of administration of the combination.
  • from 10 micrograms to 10 grams of Activator is used in the combination with the Inhibitor. In another embodiment, from 1 milligram to 1 gram of Activator is used in the combination with the Inhibitor. In a preferred embodiment, from 5 to 500 milligrams of Activator is used. In one embodiment from 10 micrograms to 10 grams of Inhibitor is used in the combination with the Activator. In another embodiment, from 1 milligram to 1 gram of Inhibitor is used in the combination with the Activator. In a preferred embodiment, from 2.5 milligrams and 200 milligrams of Inhibitor is used.
  • the muscarinic Activator and Muscarinic Inhibitor are administered to a patient 6 times during a 24 hour period. In another embodiment, the muscarinic Activator and Muscarinic Inhibitor are administered to a patient 5 times during a 24 hour period. In another embodiment, the muscarinic Activator and Muscarinic Inhibitor are administered to a patient 4 times during a 24 hour period. In a preferred embodiment, the muscarinic Activator and Muscarinic Inhibitor are administered to a patient 3 times during a 24 hour period. In another preferred embodiment, the muscarinic Activator and Muscarinic Inhibitor are administered to a patient 2 times during a 24 hour period. In another preferred embodiment, the muscarinic Activator and Muscarinic Inhibitor are administered to a patient one time during a 24 hour period.
  • each muscarinic Inhibitor based on efficacy data such that, in some cases, low or poor efficacy data was rewarded. Also, contrary to typical approaches, in some cases we rewarded muscarinic Inhibitors for the side effects they exhibited during clinical development. Since most muscarinic Inhibitors were tested for unrelated indications, such as overactive bladder, efficacy for these unrelated indications may be undesirable and may be predictive of a combination with potentially unacceptable side effects. For instance, excessive urination is not a commonly reported side effect of muscarinic Activators. Therefore, having Inhibitors that have the greatest ability to decrease micturition may present the greatest risk of causing urinary retention without providing a benefit in the combination.
  • MCD 386 is a muscarinic Activator for which additional data could result in increased theta scores for muscarinic Activator and Inhibitor combinations that include MCD 386.
  • the scoring system functions by applying a score to each combination based on each property, which we call a p-score.
  • Each p-score contributed to an overall calculation, such that a high p-score signified that a combination has an increased likelihood of being efficacious with acceptable side effects based on a given property.
  • Theta Score a unique overall score
  • scoring methodologies were used to generate p-scores. In all cases, scoring methodologies were consistent within a given property and generated a maximum value of 10, which was then multiplied by a “weight factor.” Weight factors were used to reflect the importance of each property in predicting the probability that a combination is efficacious with acceptable side effects. Some properties, such as those relating to the demonstration of efficacy for an agonist, have a stronger impact in assessing a preferred combination and were thus weighted more heavily. The baseline weight factor for all properties was 1, and the maximum weight factor used was 2.
  • the p-scores applied to each combination were summed to generate three unique Subscores: the Activator Independent Subscore, the Inhibitor Independent Subscore, and the Combination Subscore.
  • the Activator Independent Subscore represents an evaluation of each agonist based on properties that are independent of the antagonist with which it is combined (e.g., the demonstration of efficacy in human trials).
  • the Inhibitor Independent Subscore represents an evaluation of each antagonist based on properties that are independent of the agonist with which it is combined (e.g., level of CNS penetrance).
  • the Combination Subscore in contrast, represents an evaluation based on properties in which characteristics of both the agonist and antagonist are relevant (e.g., similarity of T max based on pharmacokinetic studies).
  • the value was calculated by summing each p-score and then normalizing each score such that the highest ranking entry was given a score of 100. Each lower ranking entry was thus increased or decreased proportionally by the same factor as the highest ranking entry.
  • the same principle was applied; however, the maximum score given was 50.
  • the algorithm generated a final “Theta Score” for each combination such that, as the theta score increased, so did the probability that the combination would produce efficacy with acceptable side effects.
  • Theta Score was calculated by summing the three Subscores.
  • Muscarinic Activators 1 A 72055 2 AF 125 3 AF 150(S) 4 AF 185 5 Alvameline 6 Amifostine 7 Arecoline transdermal-Cogent Pharmaceuticals 8 Cevimeline 9 CI 1017 10 CMI 1145 11 CMI 936 12 CS 932 13 DM 71 14 FPL 14995 15 GSK 1034702 16 Himbacine 17 Itameline 18 KST 2818 19 KST 5410 20 KST 5452 21 L 670548 22 L689660 23 L 696986 24 L 705106 25 LY 316108 26 MCD 386 27 Milameline 28 Muscarinic receptor agonists-ACADIA/Allergan 29 NC 111585 30 Nebracetam 31 NGX 267 32 Norclozapine 33 ORG 20091 34 PD 141606 35 PD 142505 36 PD 151832 37 PDC 008004 38 Pilocarpine 39 Pilocarpine-Controlled Therapeutics 40
  • Muscarinic Inhabitors 1 Aclidinium bromide 2 Aclidinium bromide/formoterol 3 Acotiamide 4 AH 9700 5 Alvameline 6 AQRA 721 7 AQRA 741 8 AZD 9164 9 BIBN 99 10 CEB 1957 11 Clozapine extended release-Azur Pharma 12 Darenzepine 13 Darifenacin 14 Darotropium bromide 15 Dextro-mequitamium iodide 16 Ebeinone 17 Esoxybutynin 18 Espatropate 19 Fesoterodine 20 Glycopyrrolate/indacaterol 21 Glycopyrronium bromide 22 GSK 1160724 23 GSK 202405 24 GSK 573719 25 GSK 656398 26 GSK 961081 27 GYKI 46903 28 Homatropine methylbromide 29 Imidafenacin 30 Inhaled glycopyrrolate-Novartis 31 Ipratropium bromide
  • the algorithm was structured with inputs according to the following 3 tables.
  • the Property, Scoring Methodology, Criteria for a High Score, and Weight columns in each table represent the underlying inputs and mechanics used in calculating each Subscore.
  • stage 4 ROA Route of Administration Unique value assigned to Oral 1 each ROA 5 Pharmacokinetics Tmax Ranked by Tmax value High Tmax 1 6 Pharmacokinetics T(1 ⁇ 2) Ranked by T(1 ⁇ 2) value High T(1 ⁇ 2) 1 7 Efficacy Demonstrated Efficacy Binary scoring Efficacy shown 2 8 Efficacy Demonstrated Efficacy in Binary scoring Efficacy shown 2 Cognition 9 Efficacy Demonstrated Efficacy in Binary scoring Efficacy shown 2 Schizophrenia 10 Receptor Selectivity M2 Agonist? Binary scoring Not M2 Agonist 1 11 Receptor Selectivity M3 Agonist?
  • a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 230 or greater as determined by in silico testing using the above described algorithm is used.
  • a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 200 or greater as determined by in silico testing using the above described algorithm is used.
  • a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 150 or greater as determined by in silico testing using the above described algorithm is used.
  • a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 149 or lower as determined by in silico testing using the above described algorithm is used.
  • xanomeline is used as the muscarinic Activator in combination with the muscarinic Inhibitor.
  • xanomeline is administered to a patient from one time to five times during a 24 hour period.
  • xanomeline is administered from one time to three times during a 24 hour period.
  • from 25 milligrams to 700 milligrams of xanomeline is used during a 24 hour period.
  • from 75 milligrams to 300 milligrams of xanomeline is used during a 24 hour period.
  • sabcomeline is used as the muscarinic Activator in combination with the muscarinic Inhibitor.
  • sabcomeline is administered to a patient from one time to five times during a 24 hour period.
  • sabcomeline is administered from one to three times during a 24 hour period.
  • from 50 micrograms to five milligrams of sabcomeline is used during a 24 hour period.
  • from 150 micrograms to 450 micrograms of sabcomeline is used during a 24 hour period.
  • milameline is used as the muscarinic Activator in combination with the muscarinic Inhibitor.
  • milameline is administered to a patient from one time to five times during a 24 hour period.
  • milameline is administered from one to three times during a 24 hour period.
  • from 0.5 milligrams to 50 milligrams of milameline is used during a 24 hour period.
  • from four milligrams to 16 milligrams of milameline is used during a 24 hour period.
  • talsaclidine is used as the muscarinic Activator in combination with the muscarinic Inhibitor.
  • talsaclidine is administered to a patient from one time to five times during a 24 hour period.
  • talsaclidine is administered from one to three times during a 24 hour period.
  • from five milligrams to 1 gram of talsaclidine is used during a 24 hour period.
  • from 120 milligrams to 480 milligrams of talsaclidine is used during a 24 hour period.
  • cevimeline is used as the muscarinic Activator in combination with the muscarinic Inhibitor.
  • cevimeline is administered to a patient from one time to five times during a 24 hour period.
  • cevimeline is administered from one to three times during a 24 hour period.
  • from 45 milligrams to 750 milligrams of cevimeline is used during a 24 hour period.
  • from 90 milligrams to 360 milligrams of cevimeline is used during a 24 hour period.
  • pilocarpine is used as the muscarinic Activator in combination with the muscarinic Inhibitor.
  • pilocarpine is administered to a patient from one time to five times during a 24 hour period.
  • pilocarpine is administered from one to three times during a 24 hour period.
  • from 7.5 milligrams to 500 milligrams of pilocarpine is used during a 24 hour period.
  • from 30 milligrams to 200 milligrams of pilocarpine is used during a 24 hour period.
  • trospium chloride is used as the muscarinic Inhibitor in combination with the muscarinic Activator.
  • trospium chloride is administered to a patient from one time to five times during a 24 hour period.
  • trospium chloride is administered from one time to three times during a 24 hour period.
  • from five milligrams to 400 milligrams of trospium chloride is used during a 24 hour period.
  • from 20 milligrams to 200 milligrams of trospium chloride is used during a 24 hour period.
  • trospium chloride extended release is used as the muscarinic Inhibitor in combination with the muscarinic Activator.
  • trospium chloride extended release is administered to a patient from one time to five times during a 24 hour period.
  • trospium chloride extended release is administered from one to three times during a 24 hour period.
  • from five milligrams to 400 milligrams of trospium chloride extended release is used during a 24 hour period.
  • from 20 milligrams to 200 milligrams of trospium chloride extended release is used during a 24 hour period.
  • solifenacin is used as the muscarinic Inhibitor in combination with the muscarinic Activator.
  • solifenacin is administered to a patient from one time to five times during a 24 hour period.
  • solifenacin is administered from one time to three times during a 24 hour period.
  • from 0.25 milligrams to 100 milligrams of solifenacin is used during a 24 hour period.
  • from 1 milligram to 30 milligrams of solifenacin is used during a 24 hour period.
  • tolterodine is used as the muscarinic Inhibitor in combination with the muscarinic Activator.
  • tolterodine is administered to a patient from one time to five times during a 24 hour period.
  • tolterodine is administered from one to three times during a 24 hour period.
  • from one milligram to 16 milligrams of tolterodine is used during a 24 hour period.
  • from two milligrams to eight milligrams of tolterodine is used during a 24 hour period.
  • fesoterodine is used as the muscarinic Inhibitor in combination with the muscarinic Activator.
  • fesoterodine is administered to a patient from one time to five times during a 24 hour period.
  • fesoterodine is administered from one to three times during a 24 hour period.
  • from two milligrams to 56 milligrams of fesoterodine is used during a 24 hour period.
  • from four milligrams to 28 milligrams of fesoterodine is used during a 24 hour period.
  • darifenacin is used as the muscarinic Inhibitor in combination with the muscarinic Activator.
  • darifenacin is administered to a patient from one time to five times during a 24 hour period.
  • darifenacin is administered from one to three times during a 24 hour period.
  • from 3.75 milligrams to 150 milligrams of darifenacin is used during a 24 hour period.
  • from 7.5 milligrams to 30 milligrams of darifenacin is used during a 24 hour period.
  • the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period.
  • Treatment including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring.
  • the patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters. Adjustments to the amount(s) of subject composition administered and possibly to the time of administration may be made based on these reevaluations.
  • Treatment may be initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum balance between therapeutic effect and side effects is attained.
  • the muscarinic Activator and muscarinic Inhibitor are in different dosage forms or dosage vehicles. In a preferred embodiment, the muscarinic Activator and muscarinic Inhibitor are in the same dosage form or dosage vehicles.
  • the dosage forms may include one or more pharmaceutically-acceptable carriers.
  • the dosage forms may also include one or more pharmaceutically-acceptable salts.
  • the dosage forms may be administered orally.
  • the Activator and Inhibitor may be delivered orally using tablets, troches, liquids, emulsions, suspensions, drops, capsules, caplets or gel caps and other methods of oral administration known to one skilled in the art.
  • the muscarinic Activator and Inhibitor may also be administered parentally.
  • routes of administration include but are not limited to: topical, transdermal, nasal, ocular, rectal, sublingual, inhalation, and vaginal.
  • the Activator and Inhibitor may be delivered in a cream, gel, ointment, spray, suspension, emulsion, foam, or patch or by other methods known to one skilled in the art.
  • the Activator and Inhibitor may be delivered by sprays, drops, emulsions, foams, creams, ointments or other methods known to one skilled in the art.
  • formulations for inhalation may be prepared as an aerosol, either a solution aerosol in which the active agent is solubilized in a carrier, such as a propellant, or a dispersion aerosol, in which the active agent is suspended or dispersed throughout a carrier and an optional solvent.
  • a carrier such as a propellant
  • a dispersion aerosol in which the active agent is suspended or dispersed throughout a carrier and an optional solvent.
  • the Activator and Inhibitor may be delivered in drops, sprays, injections, solutions, emulsions, suspensions, or ointments, or by other methods known to one skilled in the art.
  • the Activator and Inhibitor may be delivered using suppositories, enemas, creams, foams, gels, or ointments or by other methods known to one skilled in the art.
  • the Activator and Inhibitor may be delivered in tablets, troches, liquids, emulsions, suspensions, drops, capsules, caplets or gel caps and by other methods of oral administration known to one skilled in the art.
  • the Activator and Inhibitor may be delivered in vapor, mist, powder, aerosol, or nebulized form, or by other methods known to one skilled in the art.
  • the Activator and Inhibitor may be delivered in solutions, emulsions, suspensions, ointments, gels, foams, or vaginal rings or by other methods known to one skilled in the art.
  • the muscarinic Activator and Inhibitor may be in a dosage form that immediately releases the drug.
  • the muscarinic Activator and Inhibitor are in a controlled release dosage form.
  • the Activator and Inhibitor have similar release kinetics.
  • the Inhibitor is released prior to the Activator's being released.
  • a three part release profile is used such that the Inhibitor is released immediately, followed by the Activator in a controlled release fashion and then by the Inhibitor in a controlled release fashion.
  • the muscarinic Activator and Inhibitor are packaged in liposomes.
  • the liposome comprises a phospholipid.
  • the phospholipid in the liposome is selected from phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidic acid (PA), egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), egg phosphatidylethanolamine (EPE), egg phosphatidic acid (EPA), soy phosphatidylcholine (SPC), soy phosphatidylglycerol (SPG), soy phosphatidylserine (SPS), soy phosphatidylinositol (SPI), soy phosphatidylethanolamine
  • PC phosphatidyl
  • the controlled release formulation comprises a semi-permeable membrane.
  • the muscarinic Activator and muscarinic Inhibitor may be in different membranes in the same formulation.
  • the muscarinic Activator and muscarinic Inhibitor can be in different membranes in different formulations or dosing vehicles.
  • the semi-permeable membrane comprises a polymer.
  • the controlled release formulation comprises a matrix that suspends the muscarinic Activator(s) and muscarinic Inhibitor(s).
  • the muscarinic Activator and Inhibitor may be in separate matrices within the same medicament.
  • the matrix comprises a polymer.
  • the polymer comprises a water soluble polymer.
  • the water soluble polymer is selected from Eudragit RL, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycol, and mixtures thereof.
  • the polymer comprises a water insoluble polymer.
  • the water insoluble polymer is selected from Eudragit RS, ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(viny
  • the matrix comprises a fatty compound.
  • the fatty compound is a wax or glyceryl tristearate.
  • the polymer comprises a water soluble polymer and a water insoluble polymer.
  • the matrix further comprises a fatty compound.
  • the muscarinic Activator and muscarinic Inhibitor may be in dosage forms that use other methods of controlled release formulation known to one skilled in the art (for example, Dixit & Puthli. J. Control Release. 2:94. 2009; Mizrahi & Domb. Recent Pat Drug Deliv Formul. 2:108. 2008; Forqueri & Singh. Recent Pat Drug Deliv Formul. 3:40. 2009; Kalantzi et al. Recent Pat Drug Deliv Formul. 3:49. 2009; Iconomopoulou et al. Recent Pat Drug Deliv Formul. 2:94. 2008; Panos et al. Curr Drug Discov Technol. 5: 333. 2008; 2008. Wan et al. Nanomed. 2:483. 2007. Wang et al. Drug Delivery: Principles & Applications. Wiley 2005).
  • the combination of the muscarinic Activator and Inhibitor is used in combination with one or more therapies that can include both psychotherapy and drugs.
  • Therapeutic agents include but are not limited to antipsychotics, anxiolytics, anti-depressants, sedatives, tranquilizers and other pharmacological interventions known to one skilled in the art.
  • a therapeutic agent may fall under the category of more than one type of drug. For instance benzodiazepines can be considered anxiolytics, sedatives and tranquilizers.
  • One embodiment of the invention is a medicament comprising one or more muscarinic Activators and one or more muscarinic Inhibitors.
  • from 10 micrograms to 10 grams of Activator is used in the combination with the Inhibitor in the medicament. In another embodiment, from 1 milligram to 1 gram of Activator is used in the combination with the Inhibitor. In another embodiment from 10 micrograms to 10 grams of Inhibitor is used in the combination with the Activator. In another embodiment, from 1 milligram to 1 gram of Inhibitor is used in the combination with the Activator.
  • the medicament is administered to a patient 6 times during a 24 hour period. In another embodiment, the medicament is administered to a patient 5 times during a 24 hour period. In another embodiment, the medicament is administered to a patient 4 times during a 24 hour period. In another embodiment, the medicament is administered to a patient 3 times during a 24 hour period. In another embodiment, the medicament is administered to a patient 2 times during a 24 hour period. In another embodiment, the medicament is administered to a patient one time during a 24 hour period. In a preferred embodiment, the medicament is administered from one to 3 times during a 24 hour period.
  • the medicament contains a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 230 or greater as determined by in silico testing using the above described algorithm. In another embodiment of the invention, the medicament contains a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 200 or greater as determined by in silico testing using the above described algorithm. In another embodiment of the invention, the medicament contains a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 150 or greater as determined by in silico testing using the above described algorithm.
  • the medicament contains a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 149 or lower as determined by in silico testing using the above described algorithm.
  • xanomeline is used as the muscarinic Activator in the medicament.
  • the medicament contains from five milligrams to 700 milligrams of xanomeline. In a preferred embodiment, the medicament contains from 25 milligrams to 300 milligrams of xanomeline.
  • sabcomeline is used as the muscarinic Activator in the medicament.
  • the medicament contains from 10 micrograms to five milligrams of sabcomeline. In a preferred embodiment, the medicament contains from 50 micrograms to 450 micrograms of sabcomeline.
  • milameline is used as the muscarinic Activator in the medicament.
  • the medicament contains from 0.1 milligrams to 50 milligrams of milameline. In a preferred embodiment, the medicament contains from one milligram to 16 milligrams of milameline.
  • talsaclidine is used as the muscarinic Activator in the medicament.
  • the medicament contains from one milligram to one gram of talsaclidine. In a preferred embodiment, the medicament contains from 40 milligrams to 480 milligrams of talsaclidine.
  • cevimeline is used as the muscarinic Activator in the medicament.
  • the medicament contains from nine milligrams to 750 milligrams of cevimeline. In a preferred embodiment, the medicament contains from 30 milligrams to 360 milligrams of cevimeline.
  • pilocarpine is used as the muscarinic Activator in the medicament.
  • the medicament contains from 1.5 milligrams to 500 milligrams of pilocarpine. In a preferred embodiment, the medicament contains from 10 milligrams to 200 milligrams of pilocarpine.
  • trospium chloride is used as the muscarinic Inhibitor in the medicament.
  • the medicament contains from one milligram to 400 milligrams of trospium chloride. In a preferred embodiment, the medicament contains from 6.5 milligrams to 200 milligrams of trospium chloride.
  • trospium chloride extended release is used as the muscarinic Inhibitor in the medicament.
  • the medicament contains from one milligram to 400 milligrams of trospium chloride extended release. In a preferred embodiment, the medicament contains from 6.5 milligrams to 200 milligrams of trospium chloride extended release.
  • solifenacin is used as the muscarinic Inhibitor in the medicament.
  • the medicament contains from 0.25 milligram to 100 milligrams of solifenacin. In a preferred embodiment, the medicament contains from 1 milligrams to 30 milligrams of solifenacin.
  • tolterodine is used as the muscarinic Inhibitor in the medicament.
  • the medicament contains from 0.2 milligrams to 16 milligrams of tolterodine. In a preferred embodiment, the medicament contains from 0.7 milligrams to eight milligrams of tolterodine.
  • fesoterodine is used as the muscarinic Inhibitor in the medicament.
  • the medicament contains from 0.4 milligrams to 56 milligrams of fesoterodine. In a preferred embodiment, the medicament contains between one milligrams to 28 milligrams of fesoterodine.
  • darifenacin is used as the muscarinic Inhibitor in the medicament.
  • the medicament contains from n 0.8 milligrams to 150 milligrams of darifenacin. In a preferred embodiment, the medicament contains from 2.5 milligrams to 30 milligrams of darifenacin.
  • the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period.
  • Treatment including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring.
  • the patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters. Adjustments to the amount(s) of subject composition administered and possibly to the time of administration may be made based on these reevaluations.
  • Treatment may be initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum balance between therapeutic effect and side effects is attained. This principle of drug titration is well understood by those of skill in the art.
  • the medicament may also include one or more pharmaceutically-acceptable salts.
  • the medicament may include one or more pharmaceutically-acceptable carriers.
  • the medicament may be administered orally.
  • the medicament may be delivered orally using tablets, troches, liquids, emulsions, suspensions, drops, capsules, caplets or gel caps and other methods of oral adm inistration known to one skilled in the art.
  • the medicament may also be administered parentally.
  • Other routes of administration include but are not limited to: topical, transdermal, nasal, rectal, ocular, sublingual, inhalation, and vaginal.
  • the medicament may be delivered in a cream, gel, ointment, spray, suspension, emulsion, foam, or patch or by other methods known to one skilled in the art.
  • the medicament may be delivered by sprays, drops, emulsions, foams, creams, or ointments or by other methods known to one skilled in the art.
  • formulations for inhalation may be prepared as an aerosol, either a solution aerosol in which the active agent is solubilized in a carrier, such as a propellant, or a dispersion aerosol, in which the active agent is suspended or dispersed throughout a carrier and an optional solvent.
  • the medicament may be delivered using suppositories, enemas, creams, foams, gels, or ointments or by other methods known to one skilled in the art.
  • the medicament may be delivered in drops, sprays, injections, solutions, emulsions, suspensions, or ointments, or by other methods known to one skilled in the art.
  • the medicament may be delivered in tablets, troches, liquids, emulsions, suspensions, drops, capsules, caplets or gel caps and by other methods of oral administration known to one skilled in the art.
  • the medicament may be delivered in vapor, mist, powder, aerosol, or nebulized form, or by other methods known to one skilled in the art.
  • the medicament may be delivered in solutions, emulsions, suspensions, ointments, gels, foams, or vaginal rings or by other methods known to one skilled in the art.
  • the medicament may be in a dosage form that immediately releases the drug.
  • the medicament may have a controlled release dosage form.
  • the medicament is packaged in liposomes.
  • the liposome comprises a phospholipid.
  • the phospholipid in the liposome is selected from phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidic acid (PA), egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), egg phosphatidylethanolamine (EPE), egg phosphatidic acid (EPA), soy phosphatidylcholine (SPC), soy phosphatidylglycerol (
  • the controlled release formulation comprises a semi-permeable membrane.
  • the muscarinic Activator and muscarinic Inhibitor may be in different membranes in the same formulation.
  • the muscarinic Activator and muscarinic Inhibitor can be in different membranes in different formulations or dosing vehicles.
  • the semi-permeable membrane comprises a polymer.
  • the controlled release formulation comprises a matrix that suspends the muscarinic Activator(s) and Inhibitor(s).
  • the muscarinic Activator and Inhibitor may be in separate matrices within the same medicament.
  • the matrix comprises a polymer.
  • the polymer comprises a water soluble polymer.
  • the water soluble polymer is selected from Eudragit RL, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycol, and mixtures thereof.
  • the polymer comprises a water insoluble polymer.
  • the water insoluble polymer is selected from Eudragit RS, ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(viny
  • the matrix comprises a fatty compound.
  • the fatty compound is a wax or glyceryl tristearate.
  • the polymer comprises a water soluble polymer and a water insoluble polymer.
  • the matrix further comprises a fatty compound.
  • the medicament may be in dosage forms that use other methods of controlled release formulation known to one in the art (for example, Dixit & Puthli. J. Control Release. 2:94. 2009; Mizrahi & Domb. Recent Pat Drug Deliv Formul. 2:108. 2008; Forqueri & Singh. Recent Pat Drug Deliv Formul. 3:40. 2009; Kalantzi et al. Recent Pat Drug Deliv Formul. 3:49. 2009; Iconomopoulou et al. Recent Pat Drug Deliv Formul. 2:94. 2008; Panos et al. Curr Drug Discov Technol. 5: 333. 2008; Wan et al. Nanomed. 2:483. 2007. Wang et al. Drug Delivery: Principles & Applications . Wiley 2005).
  • the medicament is used in combination with one or more therapies that can include both psychotherapy and drugs.
  • Therapeutic agents include but are not limited to antipsychotics, anxiolytics, anti-depressants, sedatives, tranquilizers and other pharmacological interventions known to one skilled in the art.
  • a therapeutic agent may fall under the category of more than one type of drug. For instance benzodiazepines can be considered anxiolytics, sedatives and tranquilizers.
  • the invention is a single capsule formulation containing 75 milligrams of xanomeline and 20 milligrams of trospium chloride.
  • the capsule consists of a gelatin shell surrounding a fill material composed of the active compounds, a vehicle, a surfactant and a modifier.
  • the vehicle is polyethylene glycol with a molecular weight in the range of from 500 to 10,000 Daltons and is 10% of the fill material by weight.
  • the surfactant is polysorbate 80 and represents 0.1% by weight of the fill material.
  • the modifier is fumed silica present at 0.25% by weight of the fill material.
  • the total fill material represents 50% of the total capsule weight and the gelatin shell is 50% of the total capsule weight.
  • a second formulation is the capsule in Example 1 with an additional outer controlled release layer comprising an enteric material (material that is relatively insoluble in the acidic environment of the stomach).
  • enteric material material that is relatively insoluble in the acidic environment of the stomach.
  • enteric materials known to one skilled in the art.
  • hydroxyethylcellulose which would compose 20% of total capsule weight.
  • a third example is a formulation prepared as in Example 2, with the capsule containing 225 mg of xanomeline and 60 milligrams of trospium chloride.
  • the invention is a single capsule formulation containing 75 milligrams of xanomeline and 5 milligrams of solifenacin.
  • the capsule consists of a gelatin shell surrounding a fill material composed of the active compounds, a vehicle, a surfactant and a modifier.
  • the vehicle is polyethylene glycol with a molecular weight in the range of from 500 to 10,000 Daltons and is 10% of the fill material by weight.
  • the surfactant is polysorbate 80 and represents 0.1% by weight of the fill material.
  • the modifier is fumed silica present at 0.25% by weight of the fill material.
  • the total fill material represents 50% of the total capsule weight and the gelatin shell is 50% of the total capsule weight.
  • a second formulation is the capsule in Example 41 with an additional outer controlled release layer comprising an enteric material (material that is relatively insoluble in the acidic environment of the stomach).
  • enteric material material that is relatively insoluble in the acidic environment of the stomach.
  • enteric materials known to one skilled in the art.
  • hydroxyethylcellulose which would compose 20% of total capsule weight.
  • a third example is a formulation prepared as in Example 52, with the capsule containing 225 mg of xanomeline and 10 milligrams of solifenacin.

Abstract

Methods for the treatment of CNS disorders using combinations of muscarinic activators and inhibitors, and medicaments comprising muscarinic activators and inhibitors.

Description

    FIELD OF INVENTION
  • The present invention relates to: 1) A method of using a combination of one or more muscarinic agonists and one or more muscarinic antagonists for treatment of diseases that are ameliorated by activation of muscarinic receptors (e.g., schizophrenia and related disorders); 2) A medicament comprising one or more muscarinic agonists and one or more muscarinic antagonists.
    • BACKGROUND OF THE INVENTION
  • 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) (Raedler et al. American Journal of Psychiatry. 160: 118. 2003), each of which are found in the CNS but have different tissue distributions. Activation of the muscarinic system through use of muscarinic agonists has been suggested to have the potential to treat several diseases including Alzheimer's disease, Parkinson's disease, movement disorders and drug addiction. (US 2005/0085463; Langmead et al. Pharmacology & Experimental Therapeutics. 117: 232:2008). Genetic evidence has suggested a direct link between the muscarinic system and both alcohol addiction (Luo X. Et al. Hum Mol Genet. 14:2421. 2005) and nicotine addiction (Mobascher A et al. Am J Med Genet B Neuropsychiatr Genet. 5:684. 2010). M1 and M4 subtypes have been of particular interest as therapeutic targets for various diseases. For instance, the mood stabilizers lithium and valproic acid, which are used to treat bipolar depression, may exert their effects via the muscarinic system particularly through the M4 subtype receptor. (Bymaster & Felder. Mol Psychiatry. 7 Suppl 1:S57. 2002).
  • Some of the strongest linkages to the muscarinic system have been with schizophrenia, which is a serious mental illness affecting approximately 0.5-1% of the population. (Arehart-Treichel. Psych News. 40:9. 2005). The disease is characterized by a set of symptoms that are generally divided into three categories: 1) Positive symptoms (e.g., hallucinations, delusional thoughts, etc.); 2) Negative symptoms (e.g., social isolation, anhedonia, etc.); and 3) Cognitive symptoms (e.g., inability to process information, poor working memory, etc.). (Schultz. Am Fam Physician. 75:1821. 2007). Patients who suffer from schizophrenia both experience a major decline in quality of life and are at increased risk for mortality due to a number of factors, such as an increased suicide rate. (Brown et al. British Journal of Psychiatry. 177: 212. 2000). The cost of schizophrenia to society is also significant as sufferers of schizophrenia are much more likely to be incarcerated, homeless or unemployed.
  • Today, antipsychotics are the mainstay of treatment for schizophrenia. The first generation of antipsychotics are generally known as “typical antipsychotics” while newer antipsychotics are generally called “atypical antipsychotics.” Both typical and atypical antipsychotics have limited efficacy and severe side effects. There is little to no difference in efficacy between typical and atypical antipsychotics, most likely due to the fact that both classes of drugs achieve their therapeutic effect through the same pharmacological mechanisms (e.g., acting as dopamine receptor antagonists). (Nikam et al. Curr Opin Investig Drugs. 9:37. 2008). Side effects of typical antipsychotics include abnormal movement (e.g., rigidity) whereas atypicals have different but equally significant side effects (e.g., major weight gain, cardiovascular effects, etc.). The side effect profile of current antipsychotics further decreases compliance in a patient population that is already frequently non-compliant. Thus, there exists a clear need for new therapeutics to treat schizophrenia and related disorders (e.g., schizoaffective disorder).
  • Clozapine is an example of an antipsychotic that has major side effects, including sialorrhea (hypersalivation) which occurs in up to 54% of patients. (Davydov and Botts, Ann Pharmacother. 34:662. 2000). The exact mechanism of hypersalivation remains unknown. (Rogers and Shramko. Pharmacotherapy. 20:109. 2000). Clozapine has a complex pharmacological profile with appreciable activity at a variety of receptors, including dopamine receptors, serotonin receptors, adrenergic receptors, muscarinic receptors and possibly others. (Coward. Br J Psychiatry Suppl. 17:5. 1992). Investigators have tried a variety of pharmacological approaches in an attempt to counteract sialorrhea, including botulinum toxin (Kahl et al. Nervenarzt. 76:205. 2005) as well as the antipsychotics amisulpride (Croissant et al. Pharmacopsychiatry. 38:38. 2005) and sulpiride. (Kreinin et al. Isr J Psychiatry Relat Sci. 42:61. 2005). Efforts have focused mostly on alpha2 adrenergic agonists as well as anti-cholinergic drugs due to clozapine's known interaction with these receptors. Anti-muscarinic drugs such as pirenzepine have shown efficacy in small scale trials (Schneider et al. Pharmacopsychiatry. 37:43. 2004), but other trials with the same agent found no effect. (Liu et al. J Clin Psychopharmacol. 21:608. 2001). Alpha2 adrenergic agonist such as clonidine (Singh et al., J. Psychopharmacol. 19:426. 2005) have also shown efficacy in reducing sialorrhea in small scale trials. However, Syed et al. reported in a 2008 review that there is inadequate data to guide clinical practice. (Syed et al. Cochrane Database Syst Rev. 16:3. 2008).
  • Another approach to the treatment of schizophrenia has been use of muscarinic agonists. Muscarinic receptors are G-protein linked receptors that bind the neurotransmitter acetylcholine. (Eglen R M. Auton Autacoid Pharmacol 26: 219. 2006). To date, five subtypes of muscarinic receptor have been identified and are generally labeled M1, M2, M3, M4, and M5, respectively. (Caulfield M P et al. Pharmacol. Rev. 50: 279. 1998). These muscarinic subtypes vary in terms of the affinity of various agonists and antagonists for the receptors. A number of lines of evidence have suggested that the muscarinic system plays a significant role in the pathology of schizophrenia. In particular, decreased expression of M1 and M4 receptor subtypes has been noted in post-mortem studies in deceased schizophrenic patients. (Dean et al. Mol Psych. 1: 54. 1996). Likewise, SPECT imaging studies have shown decreased muscarinic availability in schizophrenia. (Raedler et al. Am J Psych. 160:118. 2003).
  • There is also pharmacological evidence implicating activation of muscarinic receptors as a potential therapeutic approach to schizophrenia. For example, the muscarinic antagonist scopolamine, which is used to treat motion sickness, produces cognitive impairment and delusions of the type seen in schizophrenia. (Ellis et al. Int. J. Neuropsychopharmacol. 9:175. 2006). More selective M1 agonists have been suggested to potentiate glutamate signaling which could help exert a therapeutic effect. (Jones et al. J. Neurosci. 28:10422. 2008). In a double-blind placebo controlled trial of schizophrenic patients using xanomeline, which has preferential activity at the M1 and M4 receptors, alleviation of schizophrenia was observed. (Shekhar et al. Am. J. Psych. 165: 1033. 2008). However, because xanomeline also bound to subtypes of receptors other than M1, a number of various serious side effects were observed including GI side effects, cardiac side effects and problems with hyper-salivation.
  • To date, nobody has been able to harness the approach of employing muscarinic agonists because of the side effects associated with the agents' binding certain muscarinic receptor subtypes. A need exists for a method of using muscarinic agonists and for a medicament employing such muscarinic agonists that would allow for the therapeutic effects associated with activation of muscarinic receptors, but with fewer side effects.
    • SUMMARY OF THE INVENTION
  • In one embodiment, the present invention relates to a method of treating diseases or conditions ameliorated by activation of the muscarinic system by administering one or more muscarinic “Activators” (e.g., agonist, partial agonist, co-agonist, physiological agonist, potentiator, stimulator, allosteric potentiator, positive allosteric modulator or allosteric agonist) and one or more muscarinic “Inhibitors” (e.g., antagonist, partial antagonist, competitive antagonist, non-competitive antagonist, uncompetitive antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible antagonist, inhibitor, reversible inhibitor, irreversible inhibitor, negative allosteric modulator, or allosteric antagonist). In a preferred embodiment, such diseases include schizophrenia and related disorders. In a preferred embodiment, a single muscarinic Activator and a single muscarinic Inhibitor are used. In a preferred embodiment, the combination of the Activator and Inhibitor has a score (“Theta score”) above 230 as determined by in silico testing using a proprietary algorithm as described herein. In another embodiment, more than one muscarinic Activator and/or more than one muscarinic Inhibitor are used.
  • In another embodiment of the invention, the method of treatment can be applied to a mammal. In another embodiment, the mammal is a human being.
  • In one embodiment of the invention, the use of the Inhibitor alleviates the side effects associated with use of the Activator. In another embodiment, use of the Inhibitor allows for a higher maximum tolerated dose of the Activator.
  • In one embodiment, the muscarinic Activator may be taken sequentially with the Inhibitor. In another embodiment of the invention, the muscarinic Activator may be taken concurrently with the Inhibitor. In a preferred embodiment of the invention, the Activator and Inhibitor are formulated to be contained in the same dosage form or dosage vehicle. In another embodiment of the invention, the muscarinic Activator and Inhibitor are formulated to be in separate dosage forms or dosage vehicles. In one embodiment, the Activator and Inhibitor are formulated in an immediate release dosage form. In another embodiment, Activator and Inhibitor are formulated in a controlled release dosage form. In another embodiment, either the Activator or the Inhibitor is formulated in an immediate release dosage form, while the other is formulated in a controlled release dosage form.
  • In another embodiment of the invention, the muscarinic Activator and Inhibitor can be taken orally. The Activator and Inhibitor may be given orally in tablets, troches, liquids, drops, capsules, caplets and gel caps or other such formulations known to one skilled in the art. Other routes of administration can include but are not limited to: parenteral, topical, transdermal, ocular, rectal, sublingual, and vaginal.
  • In another embodiment of the invention, the muscarinic Activator and Inhibitor are administered either simultaneously or consecutively with other therapies for schizophrenia. In one embodiment of the invention, the muscarinic Activator and Inhibitor are used simultaneously or sequentially with psychotherapy. In another embodiment of the invention, the muscarinic Activator and Inhibitor are administered either simultaneously or consecutively with other pharmacological therapies. Pharmacological therapies could include but are not limited to: antipsychotics, anxiolytics, anti-depressants, sedatives, tranquilizers and other pharmacological interventions known to one skilled in the art.
  • A separate embodiment of the invention is a medicament comprising both a muscarinic Activator and a muscarinic Inhibitor. In a preferred embodiment, the combination of the Activator and Inhibitor have a theta score above 230 as determined by in silico testing using a proprietary algorithm as described herein.
  • In another embodiment of the invention, the medicament can be taken orally. The medicament may be given orally in tablets, troches, liquids, drops, capsules, caplets and gel caps or other such formulations known to one skilled in the art. Other routes of administration can include but are not limited to: parenteral, topical, transdermal, ocular, rectal, sublingual, and vaginal.
  • In another embodiment of the invention, the medicament can be administered in conjunction with other therapies. In one embodiment of the invention, the medicament is used simultaneously or sequentially with psychotherapy. In another embodiment of the invention, the medicament is administered either simultaneously or consecutively with other pharmacological therapy. Such pharmacological therapy could include but is not limited to: antipsychotics, anxiolytics, anti-depressants, sedatives, tranquilizers and other pharmacological interventions known to one skilled in the art.
  • These and other embodiments of the invention, and their features and characteristics, will be described in further detail in the description and claims that follow.
    • DETAILED DESCRIPTION OF THE INVENTION Definitions
  • For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as would be understood by a person of ordinary skill in the art.
  • The articles “a” and “an” are used herein to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.
  • The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included.
  • The term “consisting” is used to limit the elements to those specified except for impurities ordinarily associated therewith.
  • The term “consisting essentially of” is used to limit the elements to those specified and those that do not materially affect the basic and novel characteristics of the material or steps.
  • As used herein, unless otherwise specified, the term “controlled release” is defined as a prolonged release pattern of one or more drugs, such that the drugs are released over a period of time. A controlled release formation is a formulation with release kinetics that result in measurable serum levels of the drug over a period of time longer than what would be possible following intravenous injection or following administration of an immediate release oral dosage form. Controlled release, slow release, sustained release, extended release, prolonged release, and delayed release have the same definitions for the present invention.
  • The term “including” is used herein to mean “including but not limited to.” “Including” and “including but not limited to” are used interchangeably.
  • The term “mammal” is known in the art, and exemplary mammals include humans, primates, bovines, porcines, canines, felines, and rodents (e.g., mice and rats).
  • The terms “parenteral administration” and “administered parenterally” are art-recognized and refer to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.
  • A “patient,” “subject” or “host” to be treated by the subject method may mean either a human or non-human mammal.
  • The term “pharmaceutically-acceptable carrier” is art-recognized and refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.
  • The term “pharmaceutically-acceptable salts,” used interchangeably with “salts,” is art-recognized and refers to salts prepared from relatively non-toxic acids or bases including inorganic acids and bases and organic acids and bases, including, for example, those contained in compositions of the present invention. Suitable non-toxic acids include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, hydrochloric, hydrobromic, phosphoric, and sulfuric acids and the like.
  • The term “treating” is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disorder.
  • The term “therapeutic agent” is art-recognized and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject. Examples of therapeutic agents, also referred to as “drugs,” are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • The term “psychotherapy” refers to use of non-pharmacological therapies in which those skilled in the art use a variety of techniques that involve verbal and other interactions with a patient to affect a positive therapeutic outcome. Such techniques include, but are not limited to, behavior therapy, cognitive therapy, psychodynamic therapy, psychoanalytic therapy, group therapy, family counseling, art therapy, music therapy, vocational therapy, humanistic therapy, existential therapy, transpersonal therapy, client-centered therapy (also called person-centered therapy), Gestalt therapy, biofeedback therapy, rational emotive behavioral therapy, reality therapy, response based therapy, Sandplay therapy, status dynamics therapy, hypnosis and validation therapy. It is further understood that psychotherapy may involve combining two or more techniques and that a therapist can select and adjust the techniques based on the needs of the individual patient and the patient's response.
  • The term “Muscarinic Disorder” refers to any disease or condition that is ameliorated by activation of the muscarinic system. Such diseases include ones in which direct activation of muscarinic receptors themselves or inhibition of cholinesterase enzymes has produced a therapeutic effect.
  • The terms “Diseases Related To Schizophrenia” and “Disorders Related To Schizophrenia” include, but are not limited to, schizo-affective disorder, psychosis, delusional disorders, psychosis associated with Alzheimer's disease, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, bipolar with psychosis or any other disease with psychotic features.
  • The term “Movement Disorders” includes, but is not limited to, Gilles de la Tourette's syndrome, Friederich's ataxia, Huntington's chorea, restless leg syndrome and other diseases or disorders whose symptoms include excessive movements, ticks and spasms.
  • The term “Mood Disorders” includes major depressive disorder, dysthymia, recurrent brief depression, minor depression disorder, bipolar disorder, mania and anxiety.
  • The term “Cognitive Disorders” refers to diseases or disorders that are marked by cognitive deficit (e.g., having abnormal working memory, problem solving abilities, etc.). Diseases include but are not limited to Alzheimer's disease, Parkinson's Disease, dementia (including, but not limited to, AIDS related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies and idiopathic dementia), Pick's disease, confusion, cognitive deficit associated with fatigue, learning disorders, traumatic brain injury, autism, age-related cognitive decline, and Cushing's Disease, a cognitive impairment associated with auto-immune diseases.
  • The term “Attention Disorders” refers to diseases or conditions that are marked by having an abnormal or decreased attention span. Diseases include but are not limited to attention hyperactivity deficit disorder, attention deficit disorder, Dubowitz Syndrome, FG Syndrome, Down's Syndrome, growth delay due to insulin-like growth factor I deficiency, hepatic encephalopathy syndrome, and Strauss Syndrome.
  • The term “Addictive Disorders” refers to diseases or conditions marked by addiction or substance dependence as defined by the Diagnostic & Statistical Manual IV. Such disorders are characterized by physical dependence, withdrawal and tolerance to a particular substance. Such substances include but are not limited to alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine and cannabis. Addictive Disorders can also encompass behaviors that a patient does in a compulsive, continual manner despite clear negative consequences. For instance, ludomania is recognized by those skilled in the art as being an addictive behavior that often has devastating consequences.
  • The term “Activator” means a molecule that can be described as an agonist, partial agonist, co-agonist, physiological agonist, potentiator, stimulator, allosteric potentiator, positive allosteric modulator, allosteric agonist or a molecule that increases the activity or signaling of muscarinic receptors through direct or indirect means.
  • The term “Inhibitor” means a molecule that can be described as an antagonist, partial antagonist, competitive antagonist, non-competitive antagonist, uncompetitive antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible antagonist, inhibitor, reversible inhibitor, irreversible inhibitor, negative allosteric modulator, allosteric antagonist or a molecule that decreases the activity or signaling of muscarinic receptors through direct or indirect means.
  • The term “maximum tolerated dose” means the highest dose of a drug or therapeutic that can be taken by patients without the patients' experiencing intolerable side effects. The maximum tolerated dose is typically determined empirically in clinical trials.
  • The term “Muscarinic receptors” refers to G-protein linked receptors that bind the neurotransmitter acetylcholine, and to date, five subtypes of muscarinic receptor have been identified. “M1” means the subtype one muscarinic receptor. “M2” means the subtype two muscarinic receptor. “M3” means the subtype three muscarinic receptor. “M4” means the subtype four muscarinic receptor. “M5” means the subtype five muscarinic receptor.
  • The term “Antipsychotic” refers to a drug that diminishes psychosis, hallucinations or delusions. Antipsychotics can include, but are not limited to: Haloperidol, droperidol, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, periciazine, promazine, triflupromazine, levomepromazine, promethazine, pimozide, chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, zotepine, aripiprazole, bifeprunox, and tetrabenazine.
  • The term “Anxiolytics” refers to drugs that reduce anxiety, fear, panic or related feelings. Such drugs include, but are not limited to: benzodiazepines (e.g., alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, lorazepam), buspirone, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbitol) and hydroxyzine.
  • The term “Anti-depressants” refers to drugs that alleviate depression and related conditions (e.g., dysthymia) and include, but are not limited to: Selective serotonin-reuptake inhibitors (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), serotonin-norepinephrine reuptake inhibitors (e.g., desvenlafaxine, duloxetine, milnacipram, venlafaxine), mianserin, mirtazapin, norepinephrine reuptake inhibitors (e.g., atomoxetine, mazindol, reboxetine, viloxazine), bupropion, tianeptine, agomelatine, trycyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine, trimipramine, desipramine, nortriptyline, protriptyline), monoamine oxidase inhibitors (e.g., isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine).
  • The terms “Sedatives” or “tranquilizers” refer to drugs that induce somnolence, promote a feeling of being tired or desire to sleep or promote a state of unconsciousness. Such drugs include but are not limited to benzodiazepines, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbitol), eszopiclone, zaleplon, zolpidem, zopiclone.
  • The term “Theta Score” is defined as the numerical value assigned by an in silico algorithm described herein used to predict the overall efficacy and side effects of any given combination of a Muscarinic Activator and a Muscarinic Inhibitor.
    • INTRODUCTION
  • The present invention relates to the method of use of one or more Activators and Inhibitors of muscarinic receptors in combination for treatment of various disorders that can be ameliorated by activation of the muscarinic system. The present invention also describes a medicament comprising one or more Activators and one or more Inhibitors of muscarinic receptors. Use of muscarinic Activators has previously been hypothesized to be useful for various central nervous system related conditions. In particular, activation of the M1 and M4 receptor subtypes could prove to be of therapeutic value. However, no one has been able to advance M1 and M4 muscarinic Activators through clinical development to receive regulatory approval for CNS indications because of unacceptable side effects. For instance, while Activators of M1 and M4 muscarinic receptors have been suggested to be efficacious treatments for schizophrenia (Shekhar et al. Am J Psychiatry. 165:1033. 2008; Shirey et el. Nature Chem Biol. 4:41. 2007), the binding by those Activators to subtypes of muscarinic receptors besides M1 and M4 results in side effects which have prevented use of muscarinic Activators in the clinic. (Shekhar et al. Am. J. Psych. 165: 1033.2008). For instance, in both phase I and subsequent trials, the muscarinic agonist xanomeline had unacceptable GI side effects as well as other side effects primarily linked to binding of muscarinic receptors besides M1 and M4. (Sramek et al. The Journal of Clinical Pharmacology. 35:800. 1995), (Cutler & Sramek. Eur. J. Clin. Pharmacol. 48:421-428. 1995), (Bodick et al. Arch Neuro 54:465-473. 1997). By combining a muscarinic Activator with an Inhibitor, it is possible to achieve the desired therapeutic effect while diminishing or eliminating the side effects associated with unwanted subtype binding.
  • Muscarinic Inhibitors are used for treatment of overactive bladder and pulmonary disorders and have been suggested for treatment of other disorders. (Witte L P et al. Curr. Opin. Uro1.1:13. 2009). Groups have outlined use of muscarinic Inhibitors with drugs in other classes to achieve a greater effect for treatment of a disease. For example, WO 2008/121268 suggests a combination for the treatment of lower urinary tract symptoms (LUTS) consisting of a beta-3 adrenergic agonist, which on its own has been investigated for the treatment of LUTS, and a muscarinic antagonist. Others have suggested combining specific muscarinic Activators or Inhibitors with other specific therapeutic agents other than muscarinic agents to further have a therapeutic effect (e.g., WO 2009/037503, WO 2009/036243, WO 2008/104776, WO 2008/096136, WO 2008/096126, WO 2008/096121, WO 2008/096111, WO 2007/127196, WO 2007/125293, EP 2002843, EP 2002844, U.S. Pat. No. 5,744,476, U.S. Pat. No. 7,524,965, US 2005/0267078, US 2006/0189651, and US 2008/0045565). US 2006/0287294 A1 outlines use of aspartyl protease inhibitors with either an M1 agonist or an M2 antagonist for treatment of various diseases, including improvement of cognitive deficit. Both M1 Activators and M2 Inhibitors themselves (Carey et al. Eur J Pharmacol 431:198. 2001.) have been suggested to be useful treatments for cognitive deficit, and the rationale for the combination with the aspartyl protease inhibitor was to enhance the effects of the aspartyl protease inhibitor. No suggestion was made of combining the M1 Activator with the M2 Inhibitor, and both compounds would be capable of reaching and would be active in the central nervous system. U.S. Pat. No. 5,480,651 discloses use of agents that increase acetylcholine in the synapse or that activate the nicotinic acetylcholine receptors, followed by administration of an acetylcholine receptor antagonist to relieve craving associated with nicotine addiction. The preferred composition uses physostigmine which is an inhibitor of acetylcholinesterase, as opposed to a muscarinic Activator which would not activate the nicotinic acetylcholine receptors. WO 03/092580 discloses compounds that can act simultaneously as muscarinic Activators at certain receptor subtypes and antagonists at others. Groups have used various muscarinic Activators with muscarinic Inhibitors in the context of trying to differentiate the role of various muscarinic subtypes in drug pharmacology or normal physiology without suggesting a therapeutic use of the combination. Such studies include use of cellular assays starting from animal materials. (e.g., Iwanaga K. et al. J. Pharmacol. Sci. 110:306. 2009). In US 2009/0318522, Paborji discloses use of a peripherally-acting muscarinic antagonist targeting the M2 and M3 receptors for the treatment of overactive bladder. The Paborji publication also discloses use of a peripherally-acting muscarinic M2/M3 agonist to counteract dry mouth associated with the peripherally-acting M2/M3 muscarinic antagonist. Paborji's approach does not, however, relate to activity at muscarinic receptors in the CNS, which is of critical importance for the work described herein, nor does it pertain to activity at either the M1 or M4 receptor. Paborji's approach is highly limited to a specific muscarinic inhibitor and does not provide any selection criteria to identify preferred or specific combinations of muscarinic Activators with the muscarinic antagonist, in spite of the prohibitively large number of potential combinations for which experimental testing could be done.
  • Method of Using Muscarinic Activators in Combination with Muscarinic Inhibitors
  • In one embodiment of the invention, one or more muscarinic Activators are used in combination with one or more Muscarinic Inhibitors for treatment of Muscarinic Disorders. In a preferred embodiment, such diseases or disorders include schizophrenia and Diseases Related to Schizophrenia. In another embodiment one or more muscarinic Activators are used in combination with one or more Muscarinic Inhibitors for treatment of Mood Disorders. In another embodiment, one or more muscarinic Activators are used with one or more muscarinic Inhibitors to treat Movement Disorders. In another embodiment, one or more muscarinic Activators are used with one or more muscarinic Inhibitors to treat Cognitive Disorders, including using the combination to enhance cognitive function not associated with a specific pathology. For instance, improvement in cognition could be important in undertaking complex tasks. In another embodiment, one or more muscarinic Activators are used with one or more muscarinic Inhibitors to treat Attention Disorders. Outside of disease treatment, enhancement of attention could improve learning and decrease symptoms associated with fatigue due to both lack of sleep and circadian rhythm disturbances such as jet lag. In another embodiment, one or more muscarinic Activators are used with one or more muscarinic Inhibitors to treat Addictive Disorders.
  • In another embodiment, the combination of one or more muscarinic Activators with one or more Muscarinic Inhibitors can be used to treat Muscarinic Disorders which are characterized by an amelioration of symptoms in response to inhibitors of cholinesterase enzymes. While cholinesterase inhibitors have proven therapeutic for certain diseases (e.g., Alzheimer's disease), the use of such inhibitors is limited due to toxicity. In fact, powerful chemical weapons such as sarin gas exert their toxic effects by inhibiting acetylcholinesterase (sarin gas material safety data sheet 103d Congress, 2d Session. United States Senate. May 25, 1994. http://www.gulfweb.org/bigdoc/report/appgb.html). The combination of one or more muscarinic Activators with one or more Muscarinic Inhibitors represents not only a safer method of treatment of those diseases shown to be response to cholinesterase inhibitors, but also a more effective one given the limitations on current cholinesterase inhibitors.
  • In one embodiment, the combination of one or more muscarinic Activators with one or more Muscarinic Inhibitors is used to treat an animal. In a further embodiment, the animal is a mammal. In a preferred embodiment, the mammal is a human being. In one embodiment, a single muscarinic Activator and a single muscarinic Inhibitor are used. In another embodiment more than one muscarinic Activator and/or more than one muscarinic Inhibitor is used.
  • In one embodiment, use of the Inhibitor decreases the side effects associated with use of the Activator. Such side effects include, but are not limited to, GI side effects, cardiac side effects, excessive sweating and excessive salivation. Use of one or more Inhibitors in combination with one or more Activators may allow the Activators to be used clinically when the Activators may not otherwise be used clinically due to the their side effects. In another embodiment, use of the Inhibitor in conjunction with the Activator allows for the Activator to achieve a higher maximum tolerated dose than the Activator would otherwise achieve.
  • Various time and resource intensive methods may be used to demonstrate both the efficacy of combination of the Activator and Inhibitor for the aforementioned embodiments. For example animal models have been used to demonstrate the efficacy of new therapeutics for schizophrenia, including both pharmacological models (e.g., ketamine model) and genetic models. (e.g., DISC 1 mouse) (Dawe G S et al. Ann Acad Med Singapore. 38:425. 2009; Desbonnet L. Biochem Soc Trans. 37:308. 2009; Geyer M A. Neurotox Res. 14:71. 2008). Likewise, animal models including rodents, dogs and non-human primates can be used to demonstrate the side effect profile of pharmacological agents. Animal models serve as an experimental proxy for humans, but may suffer from deficiencies associated with the physiological differences between human and animals and thus may have limited predictive power for translation to human experiments, particularly for central nervous system disorders. Alternatively, the combination can be tried in controlled clinical trials of people. Standard measures based on patient self-report can be used by those skilled in the art to assess various side effects such as GI discomfort. As another example, objective physiological measures (e.g., EKGs) may be used by those skilled in the art. A set of standard measures has also been developed to assess schizophrenia symptoms including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI). (Mortimer A M. Br J Psychiatry Suppl. 50:s7. 2007). Typically, clinical trials are conducted in a double blinded manner in which one group of patients receives an inactive placebo and the other group the active intervention.
  • In one embodiment of the invention, the muscarinic Activator is administered concurrently with the muscarinic Inhibitor. In another embodiment, the muscarinic Inhibitor is administered consecutively with the Activator. In further embodiment, the muscarinic Activator is administered prior to administration of the muscarinic Inhibitor. In another embodiment, the muscarinic Inhibitor is administered prior to administration of the muscarinic Activator. In one embodiment, the muscarinic Inhibitor is administered within one hour of administration of the muscarinic Activator. In another embodiment, the muscarinic Inhibitor is administered within 30 minutes of administration of the muscarinic Activator. In another embodiment, the muscarinic Inhibitor is administered within 10 minutes of administration of the muscarinic Activator. In another embodiment, the muscarinic Inhibitor is administered within one minute of administration of the muscarinic Activator. In another embodiment, the muscarinic Inhibitor is administered within 30 seconds of administration of the muscarinic Activator. Prior to the start of a drug regimen of the type outlined above, there may be a lead-in period that lasts from one to fourteen days. During this lead-in period, the muscarinic Inhibitor may be given by itself prior to the start of administration of the combination.
  • In one embodiment, from 10 micrograms to 10 grams of Activator is used in the combination with the Inhibitor. In another embodiment, from 1 milligram to 1 gram of Activator is used in the combination with the Inhibitor. In a preferred embodiment, from 5 to 500 milligrams of Activator is used. In one embodiment from 10 micrograms to 10 grams of Inhibitor is used in the combination with the Activator. In another embodiment, from 1 milligram to 1 gram of Inhibitor is used in the combination with the Activator. In a preferred embodiment, from 2.5 milligrams and 200 milligrams of Inhibitor is used.
  • In one embodiment, the muscarinic Activator and Muscarinic Inhibitor are administered to a patient 6 times during a 24 hour period. In another embodiment, the muscarinic Activator and Muscarinic Inhibitor are administered to a patient 5 times during a 24 hour period. In another embodiment, the muscarinic Activator and Muscarinic Inhibitor are administered to a patient 4 times during a 24 hour period. In a preferred embodiment, the muscarinic Activator and Muscarinic Inhibitor are administered to a patient 3 times during a 24 hour period. In another preferred embodiment, the muscarinic Activator and Muscarinic Inhibitor are administered to a patient 2 times during a 24 hour period. In another preferred embodiment, the muscarinic Activator and Muscarinic Inhibitor are administered to a patient one time during a 24 hour period.
  • In Silico Testing of Muscarinic Combinations
  • There are 65 unique muscarinic Activators and 114 unique muscarinic Inhibitors that are currently known (Adis R&D Insight™, Pubmed, Web of Science, U.S. FDA Orange Book, U.S. Pat. No. 5,852,029). Therefore, there exist 7,410 potential combinations in which a single muscarinic Activator could be paired with a single muscarinic Inhibitor. If one were to combine more than one muscarinic Activator with one or more muscarinic Inhibitors, then the number of combinations would be even greater. While a number of animal models exist for relevant diseases such as schizophrenia (Dawe G S et al. Ann Acad Med Singapore. 38:425. 2009; Desbonnet L. Biochem Soc Trans. 37:308. 2009; Geyer M A. Neurotox Res. 14:71. 2008), animal models of complex diseases such as schizophrenia are imperfect, and thus the ability to predict human efficacy and side effect burden based on animal data may be limited. Likewise, it is possible to test combinations in humans suffering from a particular disease such as schizophrenia where there exist standard measuring scales (Mortimer A M. Br J Psychiatry Suppl. 50:s7. 2007) for both efficacy of disease treatment as well as side effects. However, testing such a large number of combinations in either animal models of disease or more importantly in human clinical trials is practically impossible as it would be prohibitively expensive, and could take decades due to limitations in the number of existing skilled investigators and required time for patient recruitment.
  • Without a method of testing and predicting the efficacy of a given combination, it is extremely difficult to predict a priori if such a combination will be efficacious. For instance, Medina et al. gave the muscarinic agonist xanomeline and the muscarinic antagonist methscopolamine to investigate whether syncope, which is a side effect observed with xanomeline, can be mediated by muscarinic antagonists (Medina et al. Hypertension. 29: 828. 1997). The group observed no effect on syncope, which may reflect the lack of involvement of the muscarinic system in syncope or, alternatively, may reflect the incorrect selection of a muscarinic combination. Likewise, Maral et al. documented use of the muscarinic agonist RS-86 with the anticholinergic agent glycopyrrolate for treatment of Alzheimer's Disease (Maral et al. Neurology. 38:606. 1988). The approach did not result in any improvement in cognition despite use of escalating amounts of RS-86. US 2006/0194831 discloses use of a derivative of clozapine to activate muscarinic receptors. While US 2006/0194831 discloses that the use of the clozapine derivative can be combined with another therapy selected from a broad list of therapies including use of a muscarinic antagonist, the publication provides no guidance or reasoning, for example, as to why a particular agent should be selected from the broad list for combination with the clozapine derivative, or why such a combination would be useful. U.S. Pat. No. 5,852,029, which discloses a particular muscarinic agonist, mentions potential use of the particular agonist with muscarinic antagonists to help eliminate side effects but does not provide any criteria for selecting an appropriate antagonist.
  • Lack of success by groups such as Maral et al. points to the need to carefully select and ideally test combinations of muscarinic Activators and Inhibitors. Given the impractical nature of physically testing such a large number of combinations, we created an algorithm for in silico testing to perform the extremely difficult task of predicting a priori, without in vivo testing, if a given combination will be efficacious and safe. In order to carry out the in silico testing based on the algorithm, we created an extensive database which captured the known information about muscarinic Activators and Inhibitors. The process by which we created this unique algorithm, as well as the database of muscarinic agents and their properties, was both multi-phased and resource-intensive. First, we created a list of all known muscarinic Activators and Inhibitors. Next, we selected properties of muscarinic agents that are useful in predicting an efficacious and safe combination and determined the relative importance of each property. We then embarked on an exhaustive data-collection process to, wherever possible, gather data related to each property for each muscarinic Activator and Inhibitor. With this data on-hand, we then created a computer-based algorithm, whereby a score is calculated for each property and each combination, such that these scores are then used to generate an overall score for each combination. The scoring system was created such that higher total scores (“Theta Scores”) are applied to combinations with a higher probability to be efficacious with acceptable side effects. Therefore, by testing each combination with the algorithm, we created a prioritized list of combinations whereby combinations with higher scores are more attractive candidates for clinical testing. Given the impracticality of testing every possible combination in vivo, prioritization to select combinations for testing in humans is critical.
  • In order to evaluate different combinations of muscarinic Activator and Inhibitors, we created a proprietary database of all known muscarinic Activators and Inhibitors (see Tables 2 and 3). This database was created through systematic reviews of a variety of resources in search of all current and past programs related to muscarinic Activators and Inhibitors. Our reviews included scholarly literature databases, such as Pubmed and Web of Science, patent databases, such as Delphion, and pharmaceutical research and development databases, such as Adis R&D Insight™. We also reviewed drug package inserts, news databases, company websites, and conference abstracts. In all, we reviewed several thousand journal publications, patents, Adis records, and other documents to generate a comprehensive database of 65 muscarinic Activators and 114 muscarinic Inhibitors.
  • We then selected properties useful in predicting whether a given combination will be efficacious with acceptable side effects. We determined, in other words, the criteria by which each combination may be evaluated in order to generate a quantitative, predictive assessment. This process of selecting relevant properties was driven by rigorous internal analyses and resulted in the identification of several properties that are typically not considered, and/or that are typically thought to be unfavorable, but which we treated as favorable. The combination therapy approach in this application is significantly different from typical combination therapy approaches, which entail looking for synergistic efficacy of two agents. In the present invention, we look for one agent to eliminate the effects of the other agent, which leads to unorthodox criteria for drug selection. For example, we evaluated each muscarinic Inhibitor based on efficacy data such that, in some cases, low or poor efficacy data was rewarded. Also, contrary to typical approaches, in some cases we rewarded muscarinic Inhibitors for the side effects they exhibited during clinical development. Since most muscarinic Inhibitors were tested for unrelated indications, such as overactive bladder, efficacy for these unrelated indications may be undesirable and may be predictive of a combination with potentially unacceptable side effects. For instance, excessive urination is not a commonly reported side effect of muscarinic Activators. Therefore, having Inhibitors that have the greatest ability to decrease micturition may present the greatest risk of causing urinary retention without providing a benefit in the combination.
  • We rewarded certain side effects, particularly those known to be associated with peripheral anticholinergic effects, because they may counteract or lessen the impact of muscarinic Activator side effects. This combination of rewarding side effects and rewarding poor efficacy leads to the selection of a muscarinic Inhibitor that will have physiological effects throughout the periphery, which is desired for the elimination of muscarinic Activator side effects. For example, if a compound demonstrated efficacy for the treatment of overactive bladder without any side effects, this would suggest that the compound was inhibiting muscarinic receptors in the bladder, but not in the gastrointestinal tract or in the salivary glands to a significant degree. Although such as compound would be ideal for a drug whose intended purpose is the treatment of overactive bladder, such a compound would be unfavorable for the uses described herein. A more favorable Inhibitor for the envisioned combination would demonstrate pharmacological effects (i.e., side effects observed when treating overactive bladder) in the same organs where the Activator causes undesired side effects (e.g., the gastrointestinal tract). The rewarding of side effects and penalizing of efficacy stands in contrast to the typical method for selecting pharmaceutical agents.
  • Our intensive selection process resulted in 95 relevant properties, on the basis of which each of the 7,410 combinations of known muscarinic Activators and Inhibitors would be evaluated. The properties fell into three general categories: properties related exclusively to muscarinic Activators; properties related exclusively to muscarinic Inhibitors; and properties that combined attributes of both the Activator and Inhibitor. These classifications are discussed below in detail.
  • To collect data for each muscarinic Activator and Inhibitor based on each property, we embarked on a rigorous data collection process using many of the same resources as those used in generating a database of all known muscarinic Activators and Inhibitors. Again, our review spanned scholarly literature databases, such as Pubmed and Web of Science, patent databases, such as Delphion, pharmaceutical research and development databases, such as Adis R&D Insight™ and the U.S. FDA Orange Book, as well as package inserts and other resources. This process differed, however, in the detailed and often quantitative nature of the information extracted. For example, we gathered and categorized all known efficacy and side effect data for each muscarinic Activator and Inhibitor. We also gathered all known data related to pharmacokinetics and pharmacodynamics. As new data becomes available for compounds currently in our database, or as information regarding potential new entries for our database becomes available, database updates may be made, which would yield new theta scores. For example, MCD 386 is a muscarinic Activator for which additional data could result in increased theta scores for muscarinic Activator and Inhibitor combinations that include MCD 386.
  • Using these data, we then created a computer-based algorithm to quantify the relative probability that each muscarinic Activator and Inhibitor combination will be efficacious with acceptable side effects. The scoring system functions by applying a score to each combination based on each property, which we call a p-score. Each p-score contributed to an overall calculation, such that a high p-score signified that a combination has an increased likelihood of being efficacious with acceptable side effects based on a given property. Since the algorithm tested a total of 7,410 possible combinations, each of which was evaluated based on 95 p-scores, the algorithm summed a total of 703,950 p-scores in calculating a unique overall score (a “Theta Score”) for each combination (see Table 1).
  • Given the varied nature of data from one property to the next, a variety of scoring methodologies were used to generate p-scores. In all cases, scoring methodologies were consistent within a given property and generated a maximum value of 10, which was then multiplied by a “weight factor.” Weight factors were used to reflect the importance of each property in predicting the probability that a combination is efficacious with acceptable side effects. Some properties, such as those relating to the demonstration of efficacy for an agonist, have a stronger impact in assessing a preferred combination and were thus weighted more heavily. The baseline weight factor for all properties was 1, and the maximum weight factor used was 2.
  • The primary methodologies used in generating p-scores were ranking-based scoring, binary scoring, and scoring by value cut-off The mechanics of each of these methodologies are detailed below:
      • Ranking-based p-scores were generated using quantitative data, such as efficacy measurements, and awarding the highest value (e.g., a score of 10) to the most preferable data point, and the lowest value (e.g., a score of 0) to the least preferable data point. The remaining values were then distributed linearly, such that less preferable data points were awarded proportionally lower scores. Finally, a weight factor was applied to each value by multiplying each score by a pre-determined weight that reflected the importance of the given property. Take, for example, the case where three muscarinic Inhibitors (Inhibitor A, Inhibitor B, and Inhibitor C) are evaluated based on the demonstrated reduction in urinary frequency (number of micturitions per 24 hours), such that the minimum reduction, or lowest efficacy, is desired. In this case, Inhibitor A shows a reduction of 1 micturition per 24 hours, while Inhibitors B and C show values of 2 and 4 respectively. To calculate each p-score, since Inhibitor A demonstrated the most desirable results, we first must give Inhibitor A a proportionally higher value than B or C (e.g., Inhibitors A, B, and C are given values of 1, ½, and ¼, respectively). We then linearly distribute these values such that Inhibitor A receives a score of 10, Inhibitor B a score of 5, and Inhibitor C a score of 2.5. Finally, these scores are multiplied by a weight factor, which in this case would be 1, giving final p-scores of 10, 5, and 2.5.
      • Binary p-scores were generated by assigning one of two values relating to a binary property. Take, for example, the case of two muscarinic Activators, A and B, which are evaluated based on whether they have shown efficacy in human trials. Muscarinic Activator A, which has shown efficacy, is awarded a value of 10, while B, which has not, receives a score of 0. Since this important property has a weight factor of 2, muscarinic Activators A and B receive final p-scores of 20 and 0, respectively.
      • Value cut-off p-scores were applied based on the group into which a given value fell. This methodology was used for non-binary cases where a ranking methodology is not preferred or possible (e.g., scoring qualitative data, or scoring quantitative data in which cut-offs are relevant). In these cases, muscarinic Activators or Inhibitors whose values fall into the most desirable category are awarded values of 10 (prior to multiplication by the corresponding weight factor).
  • The p-scores applied to each combination were summed to generate three unique Subscores: the Activator Independent Subscore, the Inhibitor Independent Subscore, and the Combination Subscore. The Activator Independent Subscore represents an evaluation of each agonist based on properties that are independent of the antagonist with which it is combined (e.g., the demonstration of efficacy in human trials). Similarly, the Inhibitor Independent Subscore represents an evaluation of each antagonist based on properties that are independent of the agonist with which it is combined (e.g., level of CNS penetrance). The Combination Subscore, in contrast, represents an evaluation based on properties in which characteristics of both the agonist and antagonist are relevant (e.g., similarity of Tmax based on pharmacokinetic studies). For both the Activator Independent Subscore and the Inhibitor Independent Subscore, the value was calculated by summing each p-score and then normalizing each score such that the highest ranking entry was given a score of 100. Each lower ranking entry was thus increased or decreased proportionally by the same factor as the highest ranking entry. In calculating the Combination Subscore, the same principle was applied; however, the maximum score given was 50.
  • Ultimately, the algorithm generated a final “Theta Score” for each combination such that, as the theta score increased, so did the probability that the combination would produce efficacy with acceptable side effects. The Theta Score was calculated by summing the three Subscores.
  • TABLE 1
    Algorithm Structure
    Figure US20110020423A1-20110127-C00001
  • TABLE 2
    List of Muscarinic Activators
    Muscarinic Activators
    1 A 72055
    2 AF 125
    3 AF 150(S)
    4 AF 185
    5 Alvameline
    6 Amifostine
    7 Arecoline transdermal-Cogent Pharmaceuticals
    8 Cevimeline
    9 CI 1017
    10 CMI 1145
    11 CMI 936
    12 CS 932
    13 DM 71
    14 FPL 14995
    15 GSK 1034702
    16 Himbacine
    17 Itameline
    18 KST 2818
    19 KST 5410
    20 KST 5452
    21 L 670548
    22 L689660
    23 L 696986
    24 L 705106
    25 LY 316108
    26 MCD 386
    27 Milameline
    28 Muscarinic receptor agonists-ACADIA/Allergan
    29 NC 111585
    30 Nebracetam
    31 NGX 267
    32 Norclozapine
    33 ORG 20091
    34 PD 141606
    35 PD 142505
    36 PD 151832
    37 PDC 008004
    38 Pilocarpine
    39 Pilocarpine-Controlled Therapeutics
    40 PTAC
    41 Anavex Life Sciences preclinical muscarinic activator
    42 Eli Lilly preclinical M1 receptor muscarinic activator
    43 Eli Lilly preclinical M4 receptor muscarinic activator
    44 TorryPines Therapeutics preclinical muscarinic activator
    45 Banyu preclinical muscarinic activator
    46 Mithridion preclinical muscarinic activator
    47 ACADIA/Sepracor preclinical muscarinic activator
    48 ACADIA preclinical muscarinic activator
    49 RU 35963
    50 Sabcomeline
    51 SDZ 210086
    52 SR 46559A
    53 SR 96777A
    54 Stacofylline
    55 Talsaclidine
    56 Tazomeline
    57 Thiopilocarpine
    58 Ticalopride
    59 U 80816
    60 Vedaclidine
    61 WAY 131256
    62 WAY 132983
    63 Xanomeline
    64 YM 796
    65 YM 954
  • TABLE 3
    List of Muscarinic Inhibitors
    Muscarinic Inhabitors
    1 Aclidinium bromide
    2 Aclidinium bromide/formoterol
    3 Acotiamide
    4 AH 9700
    5 Alvameline
    6 AQRA 721
    7 AQRA 741
    8 AZD 9164
    9 BIBN 99
    10 CEB 1957
    11 Clozapine extended release-Azur Pharma
    12 Darenzepine
    13 Darifenacin
    14 Darotropium bromide
    15 Dextro-mequitamium iodide
    16 Ebeinone
    17 Esoxybutynin
    18 Espatropate
    19 Fesoterodine
    20 Glycopyrrolate/indacaterol
    21 Glycopyrronium bromide
    22 GSK 1160724
    23 GSK 202405
    24 GSK 573719
    25 GSK 656398
    26 GSK 961081
    27 GYKI 46903
    28 Homatropine methylbromide
    29 Imidafenacin
    30 Inhaled glycopyrrolate-Novartis
    31 Ipratropium bromide dry-powder inhalation-
    Dura/Spiros
    32 Ipratropium bromide dry-powder inhalation-ML
    Laboratories
    33 Ipratroplum bromide hydrofluoroalkane inhalation-
    Boehringer Ingelheim
    34 Ipratropium bromide intranasal-Chiesi
    35 Ipratropium bromide metered solution inhalation-
    Sheffield
    36 Ipratropium bromide/xylometazoline
    37 J 104129
    38 J 106366
    39 L 696986
    40 LAS 35201
    41 Levosalbutamol/Ipratropium inhalation solution-
    Arrow International Limited/Sencacor
    42 Liriodenine
    43 LK 12
    44 Mequitamium iodide
    45 Methantheline
    46 Methantheline bromide
    47 Methscopolamine bromide
    48 N-butylscopolamine
    49 N-methylatropine
    50 NPC 14695
    51 NX 303
    52 Otenzepad
    53 Oxybutynin-Labopharm
    54 Oxybutynin-Penwest Pharmaceuticals
    55 Oxybutynin chloride-ALZA
    56 Oxybutynin intravesical-Situs
    57 Oxybutynin transdermal-Schwarz Pharma
    58 Oxybutynin transdermal-Watson
    59 Oxybutynin transdermal gel-Antares
    60 Oxybutynin transmucosal-Auxilium
    61 Oxybutynin vaginal-Barr Laboratories
    62 PG 1000
    63 Pirenzepine ophthalmic
    64 Pirmenol
    65 PNU 200577
    66 Promethazine/hydrocodone/paracetamol
    Charleston Laboratories
    67 Propantheline
    68 Propantheline bromide
    69 Propiverine
    70 PSD 506
    71 PTAC
    72 QAT 370
    73 Almirall muscarinic Inhibitor
    74 Anavex Life Sciences primary muscarinic inhibitor
    75 Anavex Life Sciences secondary muscarinic inhibitor
    76 FF2-Nuada
    77 GlaxoSmithKline/Theravance
    muscarinic inhibitor
    78 Chiesi Farmaceutici/SALVAT muscarinic inhibitor
    79 UCB muscarinic Inhibitor
    80 Theravance primary muscarinic Inhibitor
    81 Theravance secondary muscarinic Inhibitor
    82 Novartis muscarinic Inhibitor
    83 ACADIA/Sepracor muscarinic Inhibitor
    84 Safetek muscarinic Inhibitor
    85 Revatropate
    86 Rispenzepine
    87 RL 315535
    88 RO 465934
    89 SCH 211803
    90 SCH 57790
    91 Scopolamine intranasal-Nastech
    92 Scopolamine transmucosal-Anestra
    93 Secoverine
    94 S-ET 126
    95 Sintropium bromide
    96 Solifenacin
    97 Solifenacin/tamsulosin
    98 SVT 40776
    99 TD 6301
    100 Telenzepine
    101 Temiverine
    102 Tiotropium bromide
    103 Tolterodine
    104 Tolterodine/tamsulosin
    105 Tropenzilium
    106 Trospium chloride
    107 Trospium chloride controlled release
    108 Trospium chloride inhalation
    109 V 0162
    110 YM 35636
    111 YM 46303
    112 YM 53705
    113 YM 58790
    114 Zamifenacin
  • The algorithm was structured with inputs according to the following 3 tables. The Property, Scoring Methodology, Criteria for a High Score, and Weight columns in each table represent the underlying inputs and mechanics used in calculating each Subscore.
  • TABLE 4
    Mechanics of Activator Independent Subscore
    Activator Subscore Mechanics
    Weight
    Count Property Category Property Scoring Methodology Criteria for a High Score Factor
    1 Development Highest Phase Unique value assigned to High stage of development 1
    each dev. stage
    2 Development Highest Phase CNS Unique value assigned to High stage of development 1
    each dev. stage
    3 Development Highest Phase US Unique value assigned to High stage of development 1
    each dev. stage
    4 ROA Route of Administration Unique value assigned to Oral 1
    each ROA
    5 Pharmacokinetics Tmax Ranked by Tmax value High Tmax 1
    6 Pharmacokinetics T(½) Ranked by T(½) value High T(½) 1
    7 Efficacy Demonstrated Efficacy Binary scoring Efficacy shown 2
    8 Efficacy Demonstrated Efficacy in Binary scoring Efficacy shown 2
    Cognition
    9 Efficacy Demonstrated Efficacy in Binary scoring Efficacy shown 2
    Schizophrenia
    10 Receptor Selectivity M2 Agonist? Binary scoring Not M2 Agonist 1
    11 Receptor Selectivity M3 Agonist? Binary scoring Not M3 agonist 1
    12 Receptor Selectivity M1/M2 ratio Ranked by ratio value High ratio 1
    13 Receptor Selectivity M1/M3 ratio Ranked by ratio value High ratio 1
    14 Receptor Selectivity M1/M5 ratio Ranked by ratio value High ratio 1
    15 Receptor Selectivity M4/M2 ratio Ranked by ratio value High ratio 1
    16 Receptor Selectivity M4/M3 ratio Ranked by ratio value High ratio 1
    17 Receptor Selectivity M4/M5 ratio Ranked by ratio value High ratio 1
    18 Receptor Selectivity M2/M3 ratio Ranked by ratio value Close to 1 1
    19 Receptor Selectivity M5/M2 ratio Ranked by ratio value Close to 1 1
    20 Receptor Selectivity M5/M3 ratio Ranked by ratio value Close to 1 1
  • TABLE 5
    Mechanics of Inhibitor Independent Subscore
    Inhibitor Subscore Mechanics
    Weight
    Count Property Category Property Scoring Methodology Criteria for High Score Factor
    1 Development Highest Phase Unique value assigned to High stage of development 1
    each dev. stage
    2 Development Highest Phase US Unique value assigned to High stage of development 1
    each dev. stage
    3 ROA Route of Administration Unique value assigned to Oral 1
    each ROA
    4 Pharmacokinetics Tmax Ranked by Tmax value High Tmax 1
    5 Pharmacokinetics T(½) Ranked by T(½) value High T(½) 1
    6 CNS Penetrance CNS Penetrance Unique value assigned based Low penetrance 2
    on H, M, L penetrance
    7 Receptor Selectivity M2/M1 ratio Ranked by ratio value High ratio 1
    8 Receptor Selectivity M2/M4 ratio Ranked by ratio value High ratio 1
    9 Receptor Selectivity M3/M1 ratio Ranked by ratio value High ratio 1
    10 Receptor Selectivity M3/M4 ratio Ranked by ratio value High ratio 1
    11 Efficacy Urinary Frequency Ranked by efficacy value Low efficacy 1
    (# Micturitions per 24 hrs) --
    Reduction
    12 Efficacy Urinary Frequency Ranked by efficacy value Low efficacy 1
    (# Micturitions/24 hrs) --
    % Reduction
    13 Efficacy Urinary Frequency Ranked by efficacy value Low efficacy 1
    (# Micturitions/24 hrs) --
    % Reduction over Placebo
    14 Efficacy Urinary Frequency Ranked by efficacy value Low efficacy 1
    (# Micturitions/24 hrs) --
    Reduction over Placebo
    15 Efficacy Volume Voided/micturition Ranked by efficacy value Low efficacy 1
    (mL) -- Reduction
    16 Efficacy Volume Voided/micturition Ranked by efficacy value Low efficacy 1
    (mL) -- % Reduction
    17 Efficacy Volume Voided/micturition Ranked by efficacy value Low efficacy 1
    (mL) -- % Reduction over
    Placebo
    18 Efficacy Volume Voided/micturition Ranked by efficacy value Low efficacy 1
    (mL) -- Reduction over
    Placebo
    19 Efficacy # of Incontinence Eps/24 Ranked by efficacy value Low efficacy 1
    hours -- % Reduction
    20 Efficacy # of Incontinence Eps/24 Ranked by efficacy value Low efficacy 1
    hours -- Reduction
    21 Efficacy # of Incontinence Eps/week -- Ranked by efficacy value Low efficacy 1
    % Reduction
    22 Efficacy # of Incontinence Eps/week -- Ranked by efficacy value Low efficacy 1
    Reduction
    23 Efficacy # Urge incontinence eps/24 Ranked by efficacy value Low efficacy 1
    hrs -- % Reduction
    24 Efficacy # Urge incontinence eps/24 Ranked by efficacy value Low efficacy 1
    hrs -- Reduction
    25 Efficacy # Urge incontinence eps/ Ranked by efficacy value Low efficacy 1
    week -- % Reduction
    26 Efficacy # Urge incontinence eps/ Ranked by efficacy value Low efficacy 1
    week -- Reduction
    27 Adverse Events Dry Mouth -- % increase Ranked by AE value Low AE values 1
    over placebo
    28 Adverse Events Constipation -- % increase Ranked by AE value Low AE values 1
    over placebo
    29 Adverse Events Dyspepsia -- % increase Ranked by AE value Low AE values 1
    over placebo
    30 Adverse Events Abdominal Pain -- % increase Ranked by AE value Low AE values 1
    over placebo
    31 Adverse Events Dry Mouth -- absolute % Ranked by AE value Low AE values 1
    values
    32 Adverse Events Constipation -- absolute % Ranked by AE value Low AE values 1
    values
    33 Adverse Events Dyspepsia -- absolute % Ranked by AE value Low AE values 1
    values
    34 Adverse Events Abdominal Pain -- absolute % Ranked by AE value Low AE values 1
    values
    35 Adverse Events Constipation aggravated Ranked by AE value Low AE values 1
    36 Adverse Events Nausea Ranked by AE value Low AE values 1
    37 Adverse Events Abdominal Distension Ranked by AE value Low AE values 1
    38 Adverse Events Flatulence Ranked by AE value Low AE values 1
    39 Adverse Events Diarrhea Ranked by AE value Low AE values 1
    40 Adverse Events Vomiting Ranked by AE value Low AE values 1
    41 Adverse Events UTI Ranked by AE value Low AE values 1
    42 Adverse Events Upper Respiratory tract Ranked by AE value Low AE values 1
    infection
    43 Adverse Events Influenza Ranked by AE value Low AE values 1
    44 Adverse Events Pharyngitis Ranked by AE value Low AE values 1
    45 Adverse Events Headache Ranked by AE value Low AE values 1
    46 Adverse Events Dizziness Ranked by AE value Low AE values 1
    47 Adverse Events Vision Blurred Ranked by AE value Low AE values 1
    48 Adverse Events Dry Eyes Ranked by AE value Low AE values 1
    49 Adverse Events Urinary Retention Ranked by AE value Low AE values 1
    50 Adverse Events Dysuria Ranked by AE value Low AE values 1
    51 Adverse Events Edema Lower Limb Ranked by AE value Low AE values 1
    52 Adverse Events Edema peripheral Ranked by AE value Low AE values 1
    53 Adverse Events Fatigue Ranked by AE value Low AE values 1
    54 Adverse Events Depression Ranked by AE value Low AE values 1
    55 Adverse Events Insomnia Ranked by AE value Low AE values 1
    56 Adverse Events Cough Ranked by AE value Low AE values 1
    57 Adverse Events Dry Throat Ranked by AE value Low AE values 1
    58 Adverse Events Hypertension Ranked by AE value Low AE values 1
    59 Adverse Events Asthenia Ranked by AE value Low AE values 1
    60 Adverse Events Nasal dryness Ranked by AE value Low AE values 1
    61 Adverse Events Back pain Ranked by AE value Low AE values 1
    62 Adverse Events ALT increased Ranked by AE value Low AE values 1
    63 Adverse Events GGT increased Ranked by AE value Low AE values 1
    64 Adverse Events Rash Ranked by AE value Low AE values 1
    Note:
    ALT = Alanine transaminase; GGT = Gamma-glutamyltransferase
  • TABLE 6
    Mechanics of Combination Subscore
    Combination Subscore Mechanics
    Weight
    Count Property Category Property Scoring Methodology Criteria for High Score Factor
    1 Pharmacokinetics Tmax Unique value given based on Close Tmax values 1
    closeness of Tmax
    2 Pharmacokinetics T(½) Unique value given based on Close T(½) values 1
    closeness of T(½)
    3 Metabolism Drug-drug interaction Unique value assigned based on Low overall risk of drug-drug 1
    potential H, M, or L degree of interaction, interaction
    specifically regarding CYP 450
    4 Receptor Selectivity (M1 Activator selectivity/M1 Ranked by ratio value High ratio value (devalue if 1
    Inhibitor selectivity) ratio Inhibitor acts on M1, Activator
    is weak M1 Activator)
    5 Receptor Selectivity (M4 Activator selectivity/M4 Ranked by ratio value High ratio value (devalue if 1
    Inhibitor selectivity) ratio Inhibitor acts on M4, Activator
    is weak M4 Activator)
    6 Receptor Selectivity (M3 Activator selectivity/M3 Ranked by ratio value Low ratio value (With M3 1
    Inhibitor selectivity) ratio Activator, M3 Inhibitor is
    desired)
    7 Receptor Selectivity (M2 Activator selectivity/M2 Ranked by ratio value Low ratio value (If M2 1
    Inhibitor selectivity) ratio Activator, M2 Inhibitor is
    desired)
    8 Receptor Selectivity (M5 Activator selectivity/M5 Ranked by ratio value High ratio value 1
    Inhibitor selectivity) ratio
    9 Receptor Selectivity M2/M3 ratio comparison Ranked by ratio value Ratio value close to 1 1
    10 Efficacy Reward specific cases of Case specific Case specific 1
    Inhibitor AEs if “offsetting” an
    Activator AE
    11 Adverse Events Reward specific cases of Case specific Case specific 1
    Inhibitor AEs if “offsetting” an
    Activator AE
    Note:
    In cases where Activators inhibits a receptor, or where an Inhibitor activates a receptor, receptor selectivity ratios are changed to equal one divided by the ratio for determining the p-score.
  • TABLE 7
    Top 15 Combinations by Theta Score
    Activator Inhibitor
    Combination Independent Independent Combination
    ID Combination Theta Score Subscore Subscore Subscore
    6355 Xanomeline & Trospium chloride 250 100 100 50
    5003 Sabcomeline & Trospium chloride 245 95 100 50
    2611 Milameline &Trospium chloride 243 98 100 45
    6346 Xanomeline & Tolterodine 241 100 91 50
    2602 Milameline & Tolterodine 239 98 91 50
    5005 Sabcomeline & Trospium chloride 238 95 93 50
    controlled release
    6357 Xanomeline & Trospium chloride 238 100 93 45
    controlled release
    2613 Milameline &Trospium chloride 236 98 93 45
    controlled release
    6347 Xanomeline & Darifenacin 235 100 95 40
    6348 Xanomeline & Solifenacin 234 100 94 40
    4996 Sabcomeline &Solifenacin 229 95 94 40
    5523 Talsaclidine & Trospium chloride 224 94 100 30
    635 Cevimeline & Trospium chloride 219 89 100 30
    5515 Talsaclidine & Darifenacin 219 94 95 30
    5516 Talsaclidine & Solifenacin 218 94 94 30
    5525 Ttalsaclidine & Trospium chloride 217 94 93 30
    controlled release
    5514 Talsaclidine & Tolterodine 215 94 91 30
    6349 Xanomeline & Fesoterodine 215 100 85 30
    627 Cevimeline & Darifenacin 214 89 95 30
    637 Cevimeline & Trospium chloride 212 89 93 30
    controlled release
  • In a preferred embodiment of the invention, a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 230 or greater as determined by in silico testing using the above described algorithm is used. In another embodiment of the invention, a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 200 or greater as determined by in silico testing using the above described algorithm is used. In another embodiment of the invention, a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 150 or greater as determined by in silico testing using the above described algorithm is used. In a further embodiment of the invention, a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 149 or lower as determined by in silico testing using the above described algorithm is used.
  • In one embodiment, xanomeline is used as the muscarinic Activator in combination with the muscarinic Inhibitor. In another embodiment, xanomeline is administered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, xanomeline is administered from one time to three times during a 24 hour period. In another embodiment, from 25 milligrams to 700 milligrams of xanomeline is used during a 24 hour period. In a preferred embodiment, from 75 milligrams to 300 milligrams of xanomeline is used during a 24 hour period.
  • In one embodiment, sabcomeline is used as the muscarinic Activator in combination with the muscarinic Inhibitor. In another embodiment, sabcomeline is administered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, sabcomeline is administered from one to three times during a 24 hour period. In another embodiment, from 50 micrograms to five milligrams of sabcomeline is used during a 24 hour period. In a preferred embodiment, from 150 micrograms to 450 micrograms of sabcomeline is used during a 24 hour period.
  • In one embodiment, milameline is used as the muscarinic Activator in combination with the muscarinic Inhibitor. In another embodiment, milameline is administered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, milameline is administered from one to three times during a 24 hour period. In another embodiment, from 0.5 milligrams to 50 milligrams of milameline is used during a 24 hour period. In a preferred embodiment, from four milligrams to 16 milligrams of milameline is used during a 24 hour period.
  • In one embodiment, talsaclidine is used as the muscarinic Activator in combination with the muscarinic Inhibitor. In another embodiment, talsaclidine is administered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, talsaclidine is administered from one to three times during a 24 hour period. In another embodiment, from five milligrams to 1 gram of talsaclidine is used during a 24 hour period. In a preferred embodiment, from 120 milligrams to 480 milligrams of talsaclidine is used during a 24 hour period.
  • In one embodiment, cevimeline is used as the muscarinic Activator in combination with the muscarinic Inhibitor. In another embodiment, cevimeline is administered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, cevimeline is administered from one to three times during a 24 hour period. In another embodiment, from 45 milligrams to 750 milligrams of cevimeline is used during a 24 hour period. In a preferred embodiment, from 90 milligrams to 360 milligrams of cevimeline is used during a 24 hour period.
  • In one embodiment, pilocarpine is used as the muscarinic Activator in combination with the muscarinic Inhibitor. In another embodiment, pilocarpine is administered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, pilocarpine is administered from one to three times during a 24 hour period. In another embodiment, from 7.5 milligrams to 500 milligrams of pilocarpine is used during a 24 hour period. In a preferred embodiment, from 30 milligrams to 200 milligrams of pilocarpine is used during a 24 hour period.
  • In one embodiment, trospium chloride is used as the muscarinic Inhibitor in combination with the muscarinic Activator. In another embodiment, trospium chloride is administered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, trospium chloride is administered from one time to three times during a 24 hour period. In another embodiment, from five milligrams to 400 milligrams of trospium chloride is used during a 24 hour period. In a preferred embodiment, from 20 milligrams to 200 milligrams of trospium chloride is used during a 24 hour period.
  • In one embodiment, trospium chloride extended release is used as the muscarinic Inhibitor in combination with the muscarinic Activator. In another embodiment, trospium chloride extended release is administered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, trospium chloride extended release is administered from one to three times during a 24 hour period. In another embodiment, from five milligrams to 400 milligrams of trospium chloride extended release is used during a 24 hour period. In a preferred embodiment, from 20 milligrams to 200 milligrams of trospium chloride extended release is used during a 24 hour period.
  • In one embodiment, solifenacin is used as the muscarinic Inhibitor in combination with the muscarinic Activator. In another embodiment, solifenacin is administered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, solifenacin is administered from one time to three times during a 24 hour period. In another embodiment, from 0.25 milligrams to 100 milligrams of solifenacin is used during a 24 hour period. In a preferred embodiment, from 1 milligram to 30 milligrams of solifenacin is used during a 24 hour period.
  • In one embodiment, tolterodine is used as the muscarinic Inhibitor in combination with the muscarinic Activator. In another embodiment, tolterodine is administered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, tolterodine is administered from one to three times during a 24 hour period. In another embodiment, from one milligram to 16 milligrams of tolterodine is used during a 24 hour period. In a preferred embodiment, from two milligrams to eight milligrams of tolterodine is used during a 24 hour period.
  • In one embodiment, fesoterodine is used as the muscarinic Inhibitor in combination with the muscarinic Activator. In another embodiment, fesoterodine is administered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, fesoterodine is administered from one to three times during a 24 hour period. In another embodiment, from two milligrams to 56 milligrams of fesoterodine is used during a 24 hour period. In a preferred embodiment, from four milligrams to 28 milligrams of fesoterodine is used during a 24 hour period.
  • In one embodiment, darifenacin is used as the muscarinic Inhibitor in combination with the muscarinic Activator. In another embodiment, darifenacin is administered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, darifenacin is administered from one to three times during a 24 hour period. In another embodiment, from 3.75 milligrams to 150 milligrams of darifenacin is used during a 24 hour period. In a preferred embodiment, from 7.5 milligrams to 30 milligrams of darifenacin is used during a 24 hour period.
  • While the subject is being treated, the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period. Treatment, including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring. The patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters. Adjustments to the amount(s) of subject composition administered and possibly to the time of administration may be made based on these reevaluations.
  • Treatment may be initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum balance between therapeutic effect and side effects is attained.
  • Dosage Forms of the Combination
  • In one embodiment, the muscarinic Activator and muscarinic Inhibitor are in different dosage forms or dosage vehicles. In a preferred embodiment, the muscarinic Activator and muscarinic Inhibitor are in the same dosage form or dosage vehicles. The dosage forms may include one or more pharmaceutically-acceptable carriers. The dosage forms may also include one or more pharmaceutically-acceptable salts. The dosage forms may be administered orally. The Activator and Inhibitor may be delivered orally using tablets, troches, liquids, emulsions, suspensions, drops, capsules, caplets or gel caps and other methods of oral administration known to one skilled in the art. The muscarinic Activator and Inhibitor may also be administered parentally. Other routes of administration include but are not limited to: topical, transdermal, nasal, ocular, rectal, sublingual, inhalation, and vaginal. For topical and transdermal administration, the Activator and Inhibitor may be delivered in a cream, gel, ointment, spray, suspension, emulsion, foam, or patch or by other methods known to one skilled in the art. For nasal administration, the Activator and Inhibitor may be delivered by sprays, drops, emulsions, foams, creams, ointments or other methods known to one skilled in the art. For nasal administration, formulations for inhalation may be prepared as an aerosol, either a solution aerosol in which the active agent is solubilized in a carrier, such as a propellant, or a dispersion aerosol, in which the active agent is suspended or dispersed throughout a carrier and an optional solvent. For ocular administration, the Activator and Inhibitor may be delivered in drops, sprays, injections, solutions, emulsions, suspensions, or ointments, or by other methods known to one skilled in the art. For rectal administration, the Activator and Inhibitor may be delivered using suppositories, enemas, creams, foams, gels, or ointments or by other methods known to one skilled in the art. For sublingual administration, the Activator and Inhibitor may be delivered in tablets, troches, liquids, emulsions, suspensions, drops, capsules, caplets or gel caps and by other methods of oral administration known to one skilled in the art. For administration by inhalation, the Activator and Inhibitor may be delivered in vapor, mist, powder, aerosol, or nebulized form, or by other methods known to one skilled in the art. For vaginal administration, the Activator and Inhibitor may be delivered in solutions, emulsions, suspensions, ointments, gels, foams, or vaginal rings or by other methods known to one skilled in the art.
  • The muscarinic Activator and Inhibitor may be in a dosage form that immediately releases the drug. In an alternative embodiment, the muscarinic Activator and Inhibitor are in a controlled release dosage form. In one embodiment of the controlled release dosage form, the Activator and Inhibitor have similar release kinetics. In another embodiment, the Inhibitor is released prior to the Activator's being released. In another embodiment, a three part release profile is used such that the Inhibitor is released immediately, followed by the Activator in a controlled release fashion and then by the Inhibitor in a controlled release fashion. In one embodiment, the muscarinic Activator and Inhibitor are packaged in liposomes. In a further embodiment, the liposome comprises a phospholipid. In a further embodiment, the phospholipid in the liposome is selected from phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidic acid (PA), egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), egg phosphatidylethanolamine (EPE), egg phosphatidic acid (EPA), soy phosphatidylcholine (SPC), soy phosphatidylglycerol (SPG), soy phosphatidylserine (SPS), soy phosphatidylinositol (SPI), soy phosphatidylethanolamine (SPE), soy phosphatidic acid (SPA), hydrogenated egg phosphatidylcholine (HEPC), hydrogenated soy phosphatidylcholine (HSPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylcholine (DSPQ), distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidyl-ethanolamine (DOPE), palmitoylstearoylphosphatidyl-choline (PSPC), palmitoylstearolphosphatidylglycerol (PSPG), mono-oleoyl-phosphatidylethanolarnine (MOPE), dilauroyl ethylphosphocholine (DLEP), dimyristoyl ethylphosphocholine (DMEP), dipalmitoyl ethylphosphocholine (DPEP), distearoyl ethylphosphocholine (DSEP), dimyristoylphosphatidic acid (DMPA), dipalmitoylphosphatidic acid (DPPA), distearoylphosphatidic acid (DSPA), dimyristoylphosphatidylinositol (DMPI), dipalmitoylphosphatidylinositol (DPPI), distearoylphosphatidylinositol (DSPI), dimyristoylphosphatidylserine (DMPS), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylserine (DSPS), N-acylated phosphorylethanolamine (NAPE), and combinations thereof.
  • In a further embodiment, the controlled release formulation comprises a semi-permeable membrane. The muscarinic Activator and muscarinic Inhibitor may be in different membranes in the same formulation. In another embodiment, the muscarinic Activator and muscarinic Inhibitor can be in different membranes in different formulations or dosing vehicles. In a further embodiment, the semi-permeable membrane comprises a polymer. In a further embodiment, the controlled release formulation comprises a matrix that suspends the muscarinic Activator(s) and muscarinic Inhibitor(s). The muscarinic Activator and Inhibitor may be in separate matrices within the same medicament. In a further embodiment, the matrix comprises a polymer. In a further embodiment, the polymer comprises a water soluble polymer. In a further embodiment, the water soluble polymer is selected from Eudragit RL, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycol, and mixtures thereof. In a further embodiment, the polymer comprises a water insoluble polymer. In a further embodiment, the water insoluble polymer is selected from Eudragit RS, ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), polyurethane, and mixtures thereof. In a further embodiment, the matrix comprises a fatty compound. In a further embodiment, the fatty compound is a wax or glyceryl tristearate. In a further embodiment, the polymer comprises a water soluble polymer and a water insoluble polymer. In a further embodiment, the matrix further comprises a fatty compound.
  • The muscarinic Activator and muscarinic Inhibitor may be in dosage forms that use other methods of controlled release formulation known to one skilled in the art (for example, Dixit & Puthli. J. Control Release. 2:94. 2009; Mizrahi & Domb. Recent Pat Drug Deliv Formul. 2:108. 2008; Forqueri & Singh. Recent Pat Drug Deliv Formul. 3:40. 2009; Kalantzi et al. Recent Pat Drug Deliv Formul. 3:49. 2009; Iconomopoulou et al. Recent Pat Drug Deliv Formul. 2:94. 2008; Panos et al. Curr Drug Discov Technol. 5: 333. 2008; 2008. Wan et al. Nanomed. 2:483. 2007. Wang et al. Drug Delivery: Principles & Applications. Wiley 2005).
  • In another embodiment, the combination of the muscarinic Activator and Inhibitor is used in combination with one or more therapies that can include both psychotherapy and drugs. Therapeutic agents include but are not limited to antipsychotics, anxiolytics, anti-depressants, sedatives, tranquilizers and other pharmacological interventions known to one skilled in the art. A therapeutic agent may fall under the category of more than one type of drug. For instance benzodiazepines can be considered anxiolytics, sedatives and tranquilizers.
  • Medicament Containing One or More Muscarinic Activators & Muscarinic Inhibitors
  • One embodiment of the invention is a medicament comprising one or more muscarinic Activators and one or more muscarinic Inhibitors.
  • In one embodiment, from 10 micrograms to 10 grams of Activator is used in the combination with the Inhibitor in the medicament. In another embodiment, from 1 milligram to 1 gram of Activator is used in the combination with the Inhibitor. In another embodiment from 10 micrograms to 10 grams of Inhibitor is used in the combination with the Activator. In another embodiment, from 1 milligram to 1 gram of Inhibitor is used in the combination with the Activator.
  • In one embodiment, the medicament is administered to a patient 6 times during a 24 hour period. In another embodiment, the medicament is administered to a patient 5 times during a 24 hour period. In another embodiment, the medicament is administered to a patient 4 times during a 24 hour period. In another embodiment, the medicament is administered to a patient 3 times during a 24 hour period. In another embodiment, the medicament is administered to a patient 2 times during a 24 hour period. In another embodiment, the medicament is administered to a patient one time during a 24 hour period. In a preferred embodiment, the medicament is administered from one to 3 times during a 24 hour period.
  • In one embodiment of the invention, the medicament contains a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 230 or greater as determined by in silico testing using the above described algorithm. In another embodiment of the invention, the medicament contains a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 200 or greater as determined by in silico testing using the above described algorithm. In another embodiment of the invention, the medicament contains a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 150 or greater as determined by in silico testing using the above described algorithm. In a further embodiment of the invention, the medicament contains a combination of a muscarinic Activator and a muscarinic Inhibitor with a theta score of 149 or lower as determined by in silico testing using the above described algorithm. In a further embodiment, xanomeline is used as the muscarinic Activator in the medicament. In another embodiment, the medicament contains from five milligrams to 700 milligrams of xanomeline. In a preferred embodiment, the medicament contains from 25 milligrams to 300 milligrams of xanomeline.
  • In one embodiment, sabcomeline is used as the muscarinic Activator in the medicament. In another embodiment, the medicament contains from 10 micrograms to five milligrams of sabcomeline. In a preferred embodiment, the medicament contains from 50 micrograms to 450 micrograms of sabcomeline.
  • In one embodiment, milameline is used as the muscarinic Activator in the medicament. In another embodiment, the medicament contains from 0.1 milligrams to 50 milligrams of milameline. In a preferred embodiment, the medicament contains from one milligram to 16 milligrams of milameline.
  • In one embodiment, talsaclidine is used as the muscarinic Activator in the medicament. In another embodiment, the medicament contains from one milligram to one gram of talsaclidine. In a preferred embodiment, the medicament contains from 40 milligrams to 480 milligrams of talsaclidine.
  • In one embodiment, cevimeline is used as the muscarinic Activator in the medicament. In another embodiment, the medicament contains from nine milligrams to 750 milligrams of cevimeline. In a preferred embodiment, the medicament contains from 30 milligrams to 360 milligrams of cevimeline.
  • In one embodiment, pilocarpine is used as the muscarinic Activator in the medicament. In another embodiment, the medicament contains from 1.5 milligrams to 500 milligrams of pilocarpine. In a preferred embodiment, the medicament contains from 10 milligrams to 200 milligrams of pilocarpine.
  • In one embodiment, trospium chloride is used as the muscarinic Inhibitor in the medicament. In another embodiment, the medicament contains from one milligram to 400 milligrams of trospium chloride. In a preferred embodiment, the medicament contains from 6.5 milligrams to 200 milligrams of trospium chloride.
  • In one embodiment, trospium chloride extended release is used as the muscarinic Inhibitor in the medicament. In another embodiment, the medicament contains from one milligram to 400 milligrams of trospium chloride extended release. In a preferred embodiment, the medicament contains from 6.5 milligrams to 200 milligrams of trospium chloride extended release.
  • In one embodiment, solifenacin is used as the muscarinic Inhibitor in the medicament. In another embodiment, the medicament contains from 0.25 milligram to 100 milligrams of solifenacin. In a preferred embodiment, the medicament contains from 1 milligrams to 30 milligrams of solifenacin.
  • In one embodiment, tolterodine is used as the muscarinic Inhibitor in the medicament. In another embodiment, the medicament contains from 0.2 milligrams to 16 milligrams of tolterodine. In a preferred embodiment, the medicament contains from 0.7 milligrams to eight milligrams of tolterodine.
  • In one embodiment, fesoterodine is used as the muscarinic Inhibitor in the medicament. In another embodiment, the medicament contains from 0.4 milligrams to 56 milligrams of fesoterodine. In a preferred embodiment, the medicament contains between one milligrams to 28 milligrams of fesoterodine.
  • In one embodiment, darifenacin is used as the muscarinic Inhibitor in the medicament. In another embodiment, the medicament contains from n 0.8 milligrams to 150 milligrams of darifenacin. In a preferred embodiment, the medicament contains from 2.5 milligrams to 30 milligrams of darifenacin.
  • While the subject is being treated, the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period. Treatment, including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring. The patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters. Adjustments to the amount(s) of subject composition administered and possibly to the time of administration may be made based on these reevaluations.
  • Treatment may be initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum balance between therapeutic effect and side effects is attained. This principle of drug titration is well understood by those of skill in the art.
  • The medicament may also include one or more pharmaceutically-acceptable salts. The medicament may include one or more pharmaceutically-acceptable carriers. The medicament may be administered orally. The medicament may be delivered orally using tablets, troches, liquids, emulsions, suspensions, drops, capsules, caplets or gel caps and other methods of oral adm inistration known to one skilled in the art. The medicament may also be administered parentally. Other routes of administration include but are not limited to: topical, transdermal, nasal, rectal, ocular, sublingual, inhalation, and vaginal. For topical and transdermal administration, the medicament may be delivered in a cream, gel, ointment, spray, suspension, emulsion, foam, or patch or by other methods known to one skilled in the art. For nasal administration, the medicament may be delivered by sprays, drops, emulsions, foams, creams, or ointments or by other methods known to one skilled in the art. For nasal administration, formulations for inhalation may be prepared as an aerosol, either a solution aerosol in which the active agent is solubilized in a carrier, such as a propellant, or a dispersion aerosol, in which the active agent is suspended or dispersed throughout a carrier and an optional solvent. For rectal administration, the medicament may be delivered using suppositories, enemas, creams, foams, gels, or ointments or by other methods known to one skilled in the art. For ocular administration, the medicament may be delivered in drops, sprays, injections, solutions, emulsions, suspensions, or ointments, or by other methods known to one skilled in the art. For sublingual administration, the medicament may be delivered in tablets, troches, liquids, emulsions, suspensions, drops, capsules, caplets or gel caps and by other methods of oral administration known to one skilled in the art. For administration by inhalation, the medicament may be delivered in vapor, mist, powder, aerosol, or nebulized form, or by other methods known to one skilled in the art. For vaginal administration, the medicament may be delivered in solutions, emulsions, suspensions, ointments, gels, foams, or vaginal rings or by other methods known to one skilled in the art.
  • The medicament may be in a dosage form that immediately releases the drug. In an alternative embodiment, the medicament may have a controlled release dosage form. In one embodiment, the medicament is packaged in liposomes. In a further embodiment, the liposome comprises a phospholipid. In a further embodiment, the phospholipid in the liposome is selected from phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidic acid (PA), egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), egg phosphatidylethanolamine (EPE), egg phosphatidic acid (EPA), soy phosphatidylcholine (SPC), soy phosphatidylglycerol (SPG), soy phosphatidylserine (SPS), soy phosphatidylinositol (SPI), soy phosphatidylethanolamine (SPE), soy phosphatidic acid (SPA), hydrogenated egg phosphatidylcholine (HEPC), hydrogenated soy phosphatidylcholine (HSPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylcholine (DSPQ), distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidyl-ethanolamine (DOPE), palmitoylstearoylphosphatidyl-choline (PSPC), palmitoylstearolphosphatidylglycerol (PSPG), mono-oleoyl-phosphatidylethanolarnine (MOPE), dilauroyl ethylphosphocholine (DLEP), dimyristoyl ethylphosphocholine (DMEP), dipalmitoyl ethylphosphocholine (DPEP), distearoyl ethylphosphocholine (DSEP), dimyristoylphosphatidic acid (DMPA), dipalmitoylphosphatidic acid (DPPA), distearoylphosphatidic acid (DSPA), dimyristoylphosphatidylinositol (DMPI), dipalmitoylphosphatidylinositol (DPPI), distearoylphosphatidylinositol (DSPI), dimyristoylphosphatidylserine (DMPS), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylserine (DSPS), N-acylated phosphorylethanolamine (NAPE), and combinations thereof.
  • In a further embodiment, the controlled release formulation comprises a semi-permeable membrane. The muscarinic Activator and muscarinic Inhibitor may be in different membranes in the same formulation. In another embodiment, the muscarinic Activator and muscarinic Inhibitor can be in different membranes in different formulations or dosing vehicles. In a further embodiment, the semi-permeable membrane comprises a polymer. In a further embodiment, the controlled release formulation comprises a matrix that suspends the muscarinic Activator(s) and Inhibitor(s). The muscarinic Activator and Inhibitor may be in separate matrices within the same medicament. In a further embodiment, the matrix comprises a polymer. In a further embodiment, the polymer comprises a water soluble polymer. In a further embodiment, the water soluble polymer is selected from Eudragit RL, polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethylene glycol, and mixtures thereof. In a further embodiment, the polymer comprises a water insoluble polymer. In a further embodiment, the water insoluble polymer is selected from Eudragit RS, ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), polyurethane, and a mixtures thereof. In a further embodiment, the matrix comprises a fatty compound. In a further embodiment, the fatty compound is a wax or glyceryl tristearate. In a further embodiment, the polymer comprises a water soluble polymer and a water insoluble polymer. In a further embodiment, the matrix further comprises a fatty compound.
  • The medicament may be in dosage forms that use other methods of controlled release formulation known to one in the art (for example, Dixit & Puthli. J. Control Release. 2:94. 2009; Mizrahi & Domb. Recent Pat Drug Deliv Formul. 2:108. 2008; Forqueri & Singh. Recent Pat Drug Deliv Formul. 3:40. 2009; Kalantzi et al. Recent Pat Drug Deliv Formul. 3:49. 2009; Iconomopoulou et al. Recent Pat Drug Deliv Formul. 2:94. 2008; Panos et al. Curr Drug Discov Technol. 5: 333. 2008; Wan et al. Nanomed. 2:483. 2007. Wang et al. Drug Delivery: Principles & Applications. Wiley 2005).
  • In another embodiment, the medicament is used in combination with one or more therapies that can include both psychotherapy and drugs. Therapeutic agents include but are not limited to antipsychotics, anxiolytics, anti-depressants, sedatives, tranquilizers and other pharmacological interventions known to one skilled in the art. A therapeutic agent may fall under the category of more than one type of drug. For instance benzodiazepines can be considered anxiolytics, sedatives and tranquilizers.
  • The above-described benefits of the novel methods and compositions of the present invention are illustrated by the non-limiting examples that follow.
    • EXAMPLES Example 1
  • In one example, the invention is a single capsule formulation containing 75 milligrams of xanomeline and 20 milligrams of trospium chloride. The capsule consists of a gelatin shell surrounding a fill material composed of the active compounds, a vehicle, a surfactant and a modifier. The vehicle is polyethylene glycol with a molecular weight in the range of from 500 to 10,000 Daltons and is 10% of the fill material by weight. The surfactant is polysorbate 80 and represents 0.1% by weight of the fill material. The modifier is fumed silica present at 0.25% by weight of the fill material. The total fill material represents 50% of the total capsule weight and the gelatin shell is 50% of the total capsule weight.
    • Example 2
  • A second formulation is the capsule in Example 1 with an additional outer controlled release layer comprising an enteric material (material that is relatively insoluble in the acidic environment of the stomach). There are a variety of enteric materials known to one skilled in the art. For this specific formulation we use hydroxyethylcellulose which would compose 20% of total capsule weight.
    • Example 3
  • A third example is a formulation prepared as in Example 2, with the capsule containing 225 mg of xanomeline and 60 milligrams of trospium chloride.
    • Example 4
  • In one example, the invention is a single capsule formulation containing 75 milligrams of xanomeline and 5 milligrams of solifenacin. The capsule consists of a gelatin shell surrounding a fill material composed of the active compounds, a vehicle, a surfactant and a modifier. The vehicle is polyethylene glycol with a molecular weight in the range of from 500 to 10,000 Daltons and is 10% of the fill material by weight. The surfactant is polysorbate 80 and represents 0.1% by weight of the fill material. The modifier is fumed silica present at 0.25% by weight of the fill material. The total fill material represents 50% of the total capsule weight and the gelatin shell is 50% of the total capsule weight.
    • Example 5
  • A second formulation is the capsule in Example 41 with an additional outer controlled release layer comprising an enteric material (material that is relatively insoluble in the acidic environment of the stomach). There are a variety of enteric materials known to one skilled in the art. For this specific formulation we use hydroxyethylcellulose which would compose 20% of total capsule weight.
    • Example 6
  • A third example is a formulation prepared as in Example 52, with the capsule containing 225 mg of xanomeline and 10 milligrams of solifenacin.
    • REFERENCES
  • All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
    • EQUIVALENTS
  • While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.
  • Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

Claims (31)

1. A method of treating a central nervous system disorder comprising:
administering to a patient a muscarinic Activator with a muscarinic Inhibitor, wherein the central nervous system disorder is selected from schizophrenia, Disorders Related To Schizophrenia, Muscarinic Disorder, Movement Disorder, Mood Disorder, Cognitive Disorder, Attention Disorder, and Addictive Disorder.
2. A method of decreasing a side effect induced by a muscarinic Activator in a patient, comprising administering to the patient a muscarinic Inhibitor.
3. The method according to claim 1 or claim 2, wherein the combination of the muscarinic Activator and the muscarinic Inhibitor has a theta score of less than 149.
4. The method according to claim 1 or claim 2, wherein the combination of the muscarinic Activator and the muscarinic Inhibitor has a theta score of greater than 150.
5. The method according to claim 1 or claim 2, wherein the combination of the muscarinic Activator and the muscarinic Inhibitor has a theta score of greater than 200.
6. The method according to claim 1 or claim 2, wherein the combination of the muscarinic Activator and the muscarinic Inhibitor has a theta score of greater than 230.
7. The method according to claim 1 or claim 2, wherein the muscarinic Activator is administered consecutively with the muscarinic Inhibitor.
8. The method according to claim 1 or claim 2, wherein the muscarinic Inhibitor and the muscarinic Activator are administered simultaneously.
9. The method according to claim 1 or claim 2, wherein from 10 micrograms to 10 grams of the muscarinic Activator is administered.
10. The method according to claim 1 or claim 2, wherein from 1 milligram to 1 gram of the muscarinic Activator is administered.
11. The method according to claim 1 or claim 2, wherein from 10 micrograms to 10 grams of the muscarinic Inhibitor is administered.
12. The method according to claim 1 or claim 2, wherein from 1 milligram to 1 gram of the muscarinic Inhibitor is administered.
13. The method according to claim 1 or claim 2, wherein the muscarinic Activator and the muscarinic Inhibitor are packaged in one dosage vehicle.
14. The method of claim 13, wherein the dosage vehicle is selected from a tablet, troche, liquid, emulsion, suspension, drops, capsule, gel cap, cream, gel, ointment, foam, cream, aerosol, suppository, enema, and vaginal ring.
15. The method according to claim 1 or claim 2, wherein the muscarinic Activator and the muscarinic Inhibitor are packaged in separate dosage vehicles independently selected from a tablet, troche, liquid, emulsion, suspension, drops, capsule, gel cap, cream, gel, ointment, foam, cream, aerosol, suppository, enema, and vaginal ring.
16. The method according to claim 1 or claim 2, wherein the muscarinic Activator and the muscarinic Inhibitor are formulated in an immediate release formulation.
17. The method according to claim 1 or claim 2, wherein the muscarinic Activator and the muscarinic Inhibitor are formulated in a controlled release formulation.
18. The method according to claim 1 or claim 2, wherein the muscarinic Activator and the muscarinic Inhibitor are administered in combination with a therapeutic agent.
19. The method of claim 18, wherein the therapeutic agent is selected from an antipsychotic, an anxiolytic, an anti-depressant, a sedative, a tranquilizer, and combinations thereof.
20. A medicament comprising a muscarinic Activator, a muscarinic Inhibitor, and a pharmaceutically acceptable carrier.
21. The medicament of claim 20, wherein the combination of the muscarinic Activator and the muscarinic Inhibitor has a theta score of less than 149.
22. The medicament of claim 20, wherein the combination of the muscarinic Activator and the muscarinic Inhibitor has a theta score of greater than 150.
23. The medicament of claim 20, wherein the combination of the muscarinic Activator and the muscarinic Inhibitor has a theta score of greater than 200.
24. The medicament of claim 20, wherein the combination of the muscarinic Activator and the muscarinic Inhibitor has a theta score of greater than 230.
25. The medicament of claim 20, comprising from 10 micrograms to 10 grams of the muscarinic Activator.
26. The medicament of claim 20, comprising from 1 milligram to 1 gram of the muscarinic Activator.
27. The medicament of claim 20, comprising from 10 micrograms to 10 grams of the muscarinic Inhibitor.
28. The medicament of claim 20, comprising from 1 milligram to 1 gram of the muscarinic Inhibitor.
29. The medicament of claim 20, which is in the form of a tablet, troche, liquid, emulsion, suspension, drops, capsule, gel cap, cream, gel, ointment, foam, cream, aerosol, suppository, enema, or vaginal ring.
30. The medicament of claim 20, which is formulated as an immediate release formulation.
31. The medicament of claim 20, which is formulated as a controlled release formulation.
US12/840,980 2009-07-22 2010-07-21 Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation Abandoned US20110020423A1 (en)

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US12/840,980 US20110020423A1 (en) 2009-07-22 2010-07-21 Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US13/858,985 US20140099356A1 (en) 2009-07-22 2013-04-09 Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US14/534,698 US20150265593A1 (en) 2009-07-22 2014-11-06 Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US15/378,796 US10265311B2 (en) 2009-07-22 2016-12-14 Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US15/400,108 US10238643B2 (en) 2009-07-22 2017-01-06 Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US16/270,206 US10369143B2 (en) 2009-07-22 2019-02-07 Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US16/289,165 US10369144B2 (en) 2009-07-22 2019-02-28 Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US16/444,206 US10695339B2 (en) 2009-07-22 2019-06-18 Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US16/880,634 US20200323839A1 (en) 2009-07-22 2020-05-21 Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation
US18/461,741 US20240100039A1 (en) 2009-07-22 2023-09-06 Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation

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