U.S. patent application number 16/880634 was filed with the patent office on 2020-10-15 for methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation.
The applicant listed for this patent is PureTech Health LLC. Invention is credited to Eric ELENKO, Andrew C. MILLER, Philip E. MURRAY, III.
Application Number | 20200323839 16/880634 |
Document ID | / |
Family ID | 1000004916781 |
Filed Date | 2020-10-15 |
United States Patent
Application |
20200323839 |
Kind Code |
A1 |
ELENKO; Eric ; et
al. |
October 15, 2020 |
METHODS AND COMPOSITIONS FOR TREATMENT OF DISORDERS AMELIORATED BY
MUSCARINIC RECEPTOR ACTIVATION
Abstract
The present disclosure provides a method of treating a central
nervous system disorder in a patient in need thereof. The method
comprises orally administering between 75 mg and 300 mg xanomeline
salt and between 20 mg and 200 mg trospium chloride to the patient
during a 24-hour period, the central nervous system disorder being
selected from schizophrenia, Alzheimer's disease, Huntington's
disease, Parkinson's disease, and Lewy Body dementia, wherein use
of the trospium chloride alleviates a side effect associated with
use of the xanomeline salt.
Inventors: |
ELENKO; Eric; (Boston,
MA) ; MURRAY, III; Philip E.; (Somerville, MA)
; MILLER; Andrew C.; (East Walpole, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PureTech Health LLC |
Boston |
MA |
US |
|
|
Family ID: |
1000004916781 |
Appl. No.: |
16/880634 |
Filed: |
May 21, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16444206 |
Jun 18, 2019 |
10695339 |
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16880634 |
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16270206 |
Feb 7, 2019 |
10369143 |
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16444206 |
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15400108 |
Jan 6, 2017 |
10238643 |
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16270206 |
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15161840 |
May 23, 2016 |
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15400108 |
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14534698 |
Nov 6, 2014 |
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15161840 |
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13858985 |
Apr 9, 2013 |
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14534698 |
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13592480 |
Aug 23, 2012 |
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13858985 |
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13348057 |
Jan 11, 2012 |
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13592480 |
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12840980 |
Jul 21, 2010 |
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13348057 |
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61282658 |
Mar 15, 2010 |
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61213853 |
Jul 22, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/44 20130101;
A61K 31/222 20130101; A61K 31/4178 20130101; A61K 45/06 20130101;
A61K 31/46 20130101; A61K 9/4858 20130101; A61K 9/4866 20130101;
A61K 31/438 20130101; A61K 31/4439 20130101; A61K 9/48 20130101;
A61K 9/4825 20130101; A61K 9/485 20130101; A61K 31/4725 20130101;
A61K 9/4891 20130101; A61K 31/138 20130101; A61K 31/4025
20130101 |
International
Class: |
A61K 31/46 20060101
A61K031/46; A61K 9/48 20060101 A61K009/48; A61K 31/138 20060101
A61K031/138; A61K 31/222 20060101 A61K031/222; A61K 31/4025
20060101 A61K031/4025; A61K 31/4178 20060101 A61K031/4178; A61K
31/438 20060101 A61K031/438; A61K 31/44 20060101 A61K031/44; A61K
45/06 20060101 A61K045/06; A61K 31/4725 20060101 A61K031/4725; A61K
31/4439 20060101 A61K031/4439 |
Claims
1-31. (canceled)
32. A medicament comprising a combination of a muscarinic activator
and a muscarinic inhibitor chosen from: xanomeline and/or a salt
thereof and trospium chloride; sabcomeline and/or a salt thereof
and trospium chloride; milameline and/or a salt thereof and
trospium chloride; xanomeline and/or a salt thereof and tolterodine
and/or a salt thereof; milameline and/or a salt thereof and
tolterodine and/or a salt thereof; sabcomeline and/or a salt
thereof and trospium chloride controlled release; xanomeline and/or
a salt thereof and trospium chloride controlled release; milameline
and/or a salt thereof and trospium chloride controlled release;
xanomeline and/or a salt thereof and darifenacin and/or a salt
thereof; xanomeline and/or a salt thereof and solifenacin and/or a
salt thereof; sabcomeline and/or a salt thereof and solifenacin
and/or a salt thereof; talsaclidine and/or a salt thereof and
trospium chloride; cevimeline and/or a salt thereof and trospium
chloride; talsaclidine and/or a salt thereof and darifenacin and/or
a salt thereof; talsaclidine and/or a salt thereof and solifenacin
and/or a salt thereof; talsaclidine and/or a salt thereof and
trospium chloride controlled release; talsaclidine and/or a salt
thereof and tolterodine and/or a salt thereof; xanomeline and/or a
salt thereof and fesoterodine and/or a salt thereof; cevimeline
and/or a salt thereof and darifenacin and/or a salt thereof; and
cevimeline and/or a salt thereof and trospium chloride controlled
release; and a pharmaceutically acceptable carrier.
33. The medicament of claim 32, wherein use of the muscarinic
inhibitor alleviates a side effect associated with use of the
muscarinic activator.
34. The medicament of claim 32, wherein the combination of a
muscarinic activator and a muscarinic inhibitor is xanomeline
and/or the salt thereof and trospium chloride.
35. The medicament of claim 32, wherein the combination of the
muscarinic activator and the muscarinic inhibitor has a theta score
greater than 230.
36. The medicament of claim 32, comprising from 10 micrograms to 10
grams of the muscarinic activator.
37. The medicament of claim 32, comprising from 1 milligram to 1
gram of the muscarinic activator.
38. The medicament of claim 32, comprising from 10 micrograms to 10
grams of the muscarinic inhibitor.
39. The medicament of claim 32, comprising from 1 milligram to 1
gram of the muscarinic inhibitor.
40. The medicament of claim 32, comprising from 1 milligram to 1
gram of the muscarinic activator and from 1 milligram to 1 gram of
the muscarinic inhibitor.
41. The medicament of claim 32, comprising from 25 to 300
milligrams of xanomeline and/or the salt thereof.
42. The medicament of claim 32, comprising from 6.5 to 200
milligrams of trospium chloride.
43. The medicament of claim 32, 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.
44. The medicament of claim 32, which is formulated as an immediate
release formulation.
45. The medicament of claim 32, which is formulated as a controlled
release formulation.
46. The medicament of claim 32, wherein the muscarinic activator is
formulated as a controlled release formulation and the muscarinic
inhibitor is formulated as an immediate release formulation.
47. A method for treating a central nervous system disorder chosen
from schizophrenia, disorders related to schizophrenia, muscarinic
disorder, movement disorder, mood disorder, cognitive disorder,
attention disorder, and addictive disorder in a patient in need
thereof, comprising administrating the oral medicament of claim 32
to the patient in need thereof
48. The method of claim 47, wherein the central nervous system
disorder is schizophrenia.
49. The method of claim 47, wherein the central nervous system
disorder is Alzheimer's disease.
50. The method of claim 47, wherein the central nervous system
disorder is Huntington's disease.
51. The method of claim 47, wherein the central nervous system
disorder is Parkinson's disease.
52. The method of claim 47, wherein the central nervous system
disorder is Lewy Body dementia
53. The method of claim 47, wherein the muscarinic activator and
the muscarinic inhibitor are in the same dosage vehicle.
54. The method of claim 47, wherein the muscarinic activator and
the muscarinic inhibitor are in different dosage vehicles.
55. The method of claim 47, wherein between 20 mg and 60 mg of
trospium chloride is administered to the patient during the 24-hour
period.
56. The method of claim 47, wherein between 60 and 200 mg trospium
chloride is administered to the patient during the 24-hour
period.
57. The method of claim 47, wherein the xanomeline is the salt of
tartaric acid.
Description
[0001] This application claims the benefit of the filing date as a
continuation of application Ser. No. 16/444,206, filed on Jun. 18,
2019, now allowed, which is a continuation of application Ser. No.
16/270,206, filed on Feb. 7, 2019, now U.S. Pat. No. 10,369,143,
which is a continuation of application Ser. No. 15/400,108, filed
on Jan. 6, 2017, now U.S. Pat. No. 10,238,643, which is
continuation of application Ser. No. 15/161,840 filed on May 23,
2016, now abandoned, which is a continuation of application Ser.
No. 14/534,698 filed on Jun. 11, 2014, now abandoned, which is a
continuation of application Ser. No. 13/358,985 filed on Sep. 4,
2013, now abandoned, which is continuation of application Ser. No.
13/592,480 filed on Aug. 23, 2012, now abandoned, which is a
continuation of application Ser. No. 13/348,057, filed on Jan. 11,
2012, now abandoned, which is a continuation of application Ser.
No. 12/840,980, filed on Jul. 21, 2010, now abandoned, which is a
non-provisional of U.S. Provisional Patent Application Ser. No.
61/213,853 filed Jul. 22, 2009, and a non-provisional of U.S.
Provisional Patent Application Ser. No. 61/282,658 filed Mar. 15,
2010, the disclosures of which are each incorporated by reference
in their entireties for all purposes.
[0002] The present invention relates to: I) 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.
[0003] The acetylcholine neurotransmitter system plays a
significant role in a variety of central nervous system (CNS) and
peripheral functions. Acetylcholine signaling occurs through two
different families of receptors: nicotinic receptors and muscarinic
receptors. Muscarinic cholinergic receptors are G-protein coupled
receptors with five different receptor subtypes (M1-M5) (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 Mal
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. Mal Psychiatry. 7
Suppl I:S57. 2002).
[0004] 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.
[0005] 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).
[0006] 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. (Bai et at. 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).
[0007] 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 MS, 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. Mal Psych.
I: 54. 1996). Likewise, SPECT imaging studies have shown decreased
muscarinic availability in schizophrenia. (Raedler et al. Am J
Psych. 160:118. 2003).
[0008] 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.
[0009] 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
[0010] 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.
[0011] 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.
[0012] 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.
[0013] 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.
[0014] 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.
[0015] 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.
[0016] 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.
[0017] 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.
[0018] 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.
[0019] 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.
BRIEF DESCRIPTION OF THE DRAWING
[0020] FIG. 1 illustrates the relationships among p-Scores,
Subscores, and Theta Scores in accordance with the present
invention.
DETAILED DESCRIPTION
Definitions
[0021] 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.
[0022] 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.
[0023] The terms "comprise" and "comprising" are used in the
inclusive, open sense, meaning that additional elements may be
included.
[0024] The term "consisting" is used to limit the elements to those
specified except for impurities ordinarily associated
therewith.
[0025] 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.
[0026] 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 formulation 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.
[0027] The term "including" is used herein to mean "including but
not limited to." "Including" and "including but not limited to" are
used interchangeably.
[0028] 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).
[0029] 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.
[0030] A "patient," "subject" or "host" to be treated by the
subject method may mean either a human or non-human mammal.
[0031] 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.
[0032] 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.
[0033] The term "treating" is art-recognized and refers to curing
as well as ameliorating at least one symptom of any condition or
disorder.
[0034] 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 (14.sup.th edition), the
Physicians' Desk Reference (64.sup.th edition), and The
Pharmacological Basis of Therapeutics (12.sup.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.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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.
[0039] The term "Mood Disorders" includes major depressive
disorder, dysthymia, recurrent brief depression, minor depression
disorder, bipolar disorder, mania and anxiety.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] 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.
[0046] 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. "MS" means the subtype five muscarinic receptor.
[0047] 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.
[0048] 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,
phenobarbital) and hydroxyzine.
[0049] 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).
[0050] 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, phenobarbital),
eszopiclone, zaleplon, zolpidem, zopiclone.
[0051] 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
[0052] 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.
[0053] 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. Ural.
I: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. Nos. 5,744,476, 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 43 1: 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
[0054] 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.
[0055] 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.
[0056] 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.
[0057] 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.
[0058] 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., DISCl
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.
[0059] 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.
[0060] 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.
[0061] 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
[0062] There are 65 unique muscarinic Activators and 114 unique
muscarinic Inhibitors that are currently known (Adis R&D
Insight.TM., 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.
[0063] 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, Mouradian et al. documented use of the
muscarinic agonist RS-86 with the anticholinergic agent
glycopyrrolate for treatment of Alzheimer's Disease (Mouradian 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.
[0064] Lack of success by groups such as Mouradian 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.
[0065] 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 1 and 2).
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.TM.. 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.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] 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.TM. 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.
[0070] 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
FIG. 1).
[0071] 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.
[0072] 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: [0073] 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 Care given values of 1, 1/2, and 1/4,
respectively). We then linearly distribute these values such that
Inhibitor A receives a score of 10, Inhibitor Ba score of 5, and
Inhibitor Ca 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. [0074] 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. [0075] 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).
[0076] 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 T.sub.max 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.
[0077] 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-US-00001 TABLE 1 List of 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 L 689660 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 Nordozapine 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 Talsadidine 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-US-00002 TABLE 2 List of Muscarinic Inhibitors 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 Dextromequitamium iodide 16
Ebeinone 17 Esoxybutynin 18 Espatropate 19 Fesoterodine 20
Glycopyrrolate/intacaterol 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-M1 Laboratories 33 Ipratropium bromide hydrofluoroalkane
inhalator- 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/S 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 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-Anesta 91 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
[0078] 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-US-00003 TABLE 3 Mechanics of Activator Independent Subscore
Activator Subscore Mechanics Property Scoring Criteria for a Weight
Count Category Property Methodology High Score Factor 1 Develop-
Highest Unique value High stage of 1 ment Phase assigned to each
development dev. stage 2 Develop- Highest Unique value High stage
of 1 ment Phase CNS assigned to each development dev. stage 3
Develop- Highest Unique value High stage of 1 ment Phase US
assigned to each development dev. stage 4 ROA Route of Unique value
Oral 1 Admini- assigned to each stration ROA 5 Pharmaco- Tmax
Ranked by High Tmax 1 kinetics Tmax value 6 Pharmaco- T(1/2) Ranked
by High T(1/2) 1 kinetics T(1/2) value 7 Efficacy Demonstrated
Binary scoring Efficacy 2 Efficacy shown 8 Efficacy Demonstrated
Binary scoring Efficacy 2 Efficacy in shown Cognition 9 Efficacy
Demonstrated Binary scoring Efficacy 2 Efficacy in shown 10
Receptor M2 Agonist? Binary scoring Not M2 1 Selectivity Agonist 11
Receptor M3 Agonist? Binary scoring Not M3 1 Selectivity agonist 12
Receptor M1/M2 ratio Ranked by ratio High ratio 1 Selectivity value
13 Receptor M1/M3 ratio Ranked by ratio High ratio 1 Selectivity
value 14 Receptor M1/M5 ratio Ranked by ratio High ratio 1
Selectivity value 15 Receptor M4/M2 ratio Ranked by ratio Highratio
1 Selectivity value 16 Receptor M4/M3 ratio Ranked by ratio High
ratio 1 Selectivity value 17 Receptor M4/M5 ratio Ranked by ratio
High ratio 1 Selectivity value 18 Receptor M2/M3 ratio Ranked by
ratio Close to 1 1 Selectivity value 19 Receptor M5/M2 ratio Ranked
by ratio Close to 1 1 Selectivity value 20 Receptor M5/M3 ratio
Ranked by ratio Close to 1 1 Selectivity value
TABLE-US-00004 TABLE 4 Mechanics of Inhibitor Independent Subscore
Inhibitor Subscore Mechanics Property Scoring Criteria for Weight
Count Category Property Methodology High Score Factor 1 Development
Highest Phase Unique value High stage of 1 assigned to development
each dev. stage 2 Development Highest Phase US Unique value High
stage of 1 assigned to development each dev. stage 3 ROA Route of
Unique value Oral 1 Administration assigned to each ROA\ 4
Pharmacokinetics Tmax Ranked by High Tmax 1 Tmax value 5
Pharmacokinetics T(1/2) Ranked by High T(1/2) 1 T(1/2) value 6 CNS
Penetrance CNS Penetrance Unique value Low 2 assigned based
penetrance on H, M, L penetrance 7 Receptor M2/M1 ratio Ranked by
High ratio 1 Selectivity ratio value 8 Receptor M2/M4 ratio Ranked
by High ratio 1 Selectivity ratio value 9 Receptor M3/M1 ratio
Ranked by High ratio 1 Selectivity ratio value 10 Receptor M3/M4
ratio Ranked by High ratio 1 Selectivity ratio value 11 Efficacy
Urinary Frequency (# Ranked by Low efficacy 1 Micturitions per 24
efficacy value hrs)-Reduction 12 Efficacy Urinary Frequency (#
Ranked by Low efficacy 1 Micturitions/24 hrs)- efficacy value %
Reduction 13 Efficacy Urinary Frequency (# Ranked by Low efficacy 1
Micturitions/24 hrs)- efficacy value % Reduction over Placebo 14
Efficacy Urinary Frequency (# Ranked by Low efficacy 1
Micturitions/24 hrs)- efficacy value Reduction over Placebo 15
Efficacy Volume Ranked by Low efficacy 1 Voided/micturition
efficacy value (mL)-Reduction 16 Efficacy Volume Ranked by Low
efficacy 1 Voided/micturition efficacy value (mL)-% Reduction 17
Efficacy Volume Ranked by Low efficacy 1 Voided/micturition
efficacy value (mL)-% Reduction over Placebo 18 Efficacy Volume
Ranked by Low efficacy 1 Voided/micturition efficacy value (mL)-%
Reduction over Placebo 19 Efficacy # of Incontinence Ranked by Low
efficacy 1 Eps/24 hours-% efficacy value Reduction 20 Efficacy # of
Incontinence Ranked by Low efficacy 1 Eps/24 hours-% efficacy value
Reduction 21 Efficacy # of Incontinence Ranked by Low efficacy 1
Eps/week-% efficacy value Reduction 22 Efficacy # of Incontinence
Ranked by Low efficacy 1 Eps/week-% efficacy value Reduction 23
Efficacy # Urge incontinence Ranked by Low efficacy 1 eps/24 hrs-%
efficacy value Reduction 24 Efficacy # Urge incontinence Ranked by
Low efficacy 1 eps/24 hrs-% efficacy value Reduction 25 Efficacy #
Urge incontinence Ranked by Low efficacy 1 eps/week-% efficacy
value Reduction 26 Efficacy # Urge incontinence Ranked by Low
efficacy 1 eps/week-% efficacy value Reduction 27 Adverse Events
Dry Mouth-% Ranked by AE Low AE 1 increase over placebo value
values 28 Adverse Events Constipation-% Ranked by AE Low AE 1
increase over placebo value values 29 Adverse Events Dyspepsia-%
Ranked by AE Low AE 1 increase over placebo value values 30 Adverse
Events Abdominal Pain-% Ranked by AE Low AE 1 increase over placebo
value values 31 Adverse Events Dry Mouth-absolute Ranked by AE Low
AE 1 % values value values 32 Adverse Events Constipation- Ranked
by AE Low AE 1 absolute % values value values 33 Adverse Events
Dyspepsia-absolute Ranked by AE Low AE 1 % values value values 34
Adverse Events Abdominal Pain Ranked by AE Low AE 1 absolute %
values value values 35 Adverse Events Constipation Ranked by AE Low
AE 1 aggravated value values 36 Adverse Events Nausea Ranked by AE
Low AE 1 value values 37 Adverse Events Abdominal Ranked by AE Low
AE 1 Distension value values 38 Adverse Events Flatulence Ranked by
AE Low AE 1 value values 39 Adverse Events Diarrhea Ranked by AE
Low AE 1 value values 40 Adverse Events Vomiting Ranked by AE Low
AE value values 41 Adverse Events UTI Ranked by AE Low AE value
values 42 Adverse Events Upper Respiratory Ranked by AE Low AE 1
tract infection value values 43 Adverse Events Influenza Ranked by
AE Low AE 1 value values 44 Adverse Events Pharyngitis Ranked by AE
Low AE 1 value values 45 Adverse Events Headache Ranked by AE Low
AE 1 value values 46 Adverse Events Dizziness Ranked by AE Low AE 1
value values 47 Adverse Events Vision Blurred Ranked by AE Low AE 1
value values 48 Adverse Events Dry Eyes Ranked by AE Low AE 1 value
values 49 Adverse Events Urinary Retention Ranked by AE Low AE 1
value values 50 Adverse Events Dysuria Ranked by AE Low AE 1 value
values 51 Adverse Events Edema Lower Limb Ranked by AE Low AE 1
value values 52 Adverse Events Edema peripheral Ranked by AE Low AE
1 value values 53 Adverse Events Fatigue Ranked by AE Low AE 1
value values 54 Adverse Events Depression Ranked by AE Low AE 1
value values 55 Adverse Events Insomnia Ranked by AE Low AE 1 value
values 56 Adverse Events Cough Ranked by AE Low AE 1 value values
57 Adverse Events Dry Throat Ranked by AE Low AE 1 value values 58
Adverse Events Hypertension Ranked by AE Low AE 1 value values 59
Adverse Events Asthenia Ranked by AE Low AE 1 value values 60
Adverse Events Nasal dryness Ranked by AE Low AE 1 value values 61
Adverse Events Back pain Ranked by AE Low AE 1 value values 62
Adverse Events ALT increased Ranked by AE Low AE 1 value values 63
Adverse Events GGT increased Ranked by AE Low AE 1 value values 64
Adverse Events Rash Ranked by AE Low AE 1 value values Note: ALT =
Alanine transaminase; GGT = Gamma-glutamyltransferase
TABLE-US-00005 TABLE 5 Mechanics of Combination
Subscore-Combination Subscore Mechanics Property Scoring Criteria
for a Weight Count Category Property Methodology High Score Factor
1 Pharmaco- Tmax Unique value given Close Tmax 1 kinetics based on
closeness values of Tmax 2 Pharmaco- T(1/2) Unique value given
Close T(1/2) 1 kinetics based on closeness values of T(1/2) 3
Metabolism Drug-drug Unique value Low overall risk 1 interaction
potential assigned based on of drug-drug H, M, or L degree
interaction of interaction, specifically regarding CYP 450 4
Receptor (M1 Activator Ranked by ratio High ratio value 1
Selectivity selectivity/M1 value (devalue if Inhibitor selectivity)
Inhibitor acts on ratio M1, Activator is weak M1 Activator) 5
Receptor (M4 Activator Ranked by ratio High ratio value 1
Selectivity selectivity/M4 value (devalue if Inhibitor selectivity)
Inhibitor acts on ratio M4, Activator is weak M4 Activator) 6
Receptor (M3 Activator Ranked by ratio Low ratio value 1
Selectivity selectivity/M3 value (With M3 Inhibitor selectivity)
Activator, M3 ratio Inhibitor is desired) 7 Receptor (M2 Activator
Ranked by ratio Low ratio value 1 Selectivity selectivity/M2 value
(If M2 Activator, Inhibitor selectivity) M2 Inhibitor is ratio
desired) 8 Receptor (M5 Activator Ranked by ratio High ratio value
1 Selectivity selectivity/M5 value Inhibitor selectivity) ratio 9
Receptor M2/M3 ratio Ranked by ratio Ratio value close 1
Selectivity comparison value to 1 10 Efficacy Reward specific Case
specific Case specific 1 cases of Inhibitor AEs if "offsetting" an
Activator AE 11 Adverse Reward specific Case specific Case specific
1 Events cases of 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-US-00006 TABLE 6 Top 15 Combinations by Theta Score Combi-
Activator Inhibitor Combi- nation Theta Independent Independent
nation ID Combination Score Subscore Subscore Subscore 6355
Xanomeline & 250 100 100 50 Trospium chloride 5003 Sabcomeline
& 245 95 100 50 Trospium chloride 2611 Milameline & 243 98
100 45 Trospium chloride 6346 Xanomeline & 241 100 91 50
Tolterodine 2602 Milameline & 239 98 91 50 Tolterodine 5005
Sabcomeline & 238 95 93 50 Trospium chloride controlled release
6357 Xanomeline & 238 100 93 45 Trospium chloride controlled
release 2613 Milameline & 236 98 93 45 Trospium chloride
controlled release 6347 Xanomeline & 235 100 95 40 Darifenacin
6348 Xanomeline & 234 100 94 40 Solifenacin 4996 Sabcomeline
& 229 95 94 40 Solifenacin 5523 Talsaclidine & 224 94 100
30 Trospium chloride 635 Cevimeline & 219 89 100 30 Trospium
chloride 5515 Talsaclidine & 219 94 95 30 Darifenacin 5516
Talsaclidine & 218 94 94 30 Solifenacin 5525 Talsaclidine &
217 94 93 30 Trospium chloride controlled release 5514 Talsaclidine
& 215 94 91 30 Tolterodine 6349 Xanomeline & 215 100 85 30
Fesoterodine 627 Cevimeline & 214 89 95 30 Darifenacin 637
Cevimeline & 212 89 93 30 Trospium chloride controlled
release
[0079] 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.
[0080] 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 vperiod. In a preferred
embodiment, from 75 milligrams to 300 milligrams of xanomeline is
used during a 24-hour period.
[0081] 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.
[0082] 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.
[0083] 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.
[0084] 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.
[0085] 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.
[0086] 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.
[0087] 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.
[0088] 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.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] 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
[0094] 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.
[0095] 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-phosphatidylethanolamine (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.
[0096] 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(isobutylmethacrylate), 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.
[0097] 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).
[0098] 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
[0099] One embodiment of the invention is a medicament comprising
one or more muscarinic Activators and one or more muscarinic
Inhibitors.
[0100] 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.
[0101] 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.
[0102] 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.
[0103] 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.
[0104] 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.
[0105] 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.
[0106] 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.
[0107] 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.
[0108] 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.
[0109] 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.
[0110] 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.
[0111] 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.
[0112] 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.
[0113] 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.
[0114] 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.
[0115] 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.
[0116] 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 administration 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.
[0117] 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-phosphatidylethanolamine (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.
[0118] 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.
[0119] 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).
[0120] 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.
[0121] 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
[0122] 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
[0123] 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
[0124] 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
[0125] 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
[0126] 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
[0127] 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
[0128] 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
[0129] 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.
[0130] 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.
* * * * *
References