U.S. patent application number 14/729910 was filed with the patent office on 2015-12-10 for methods of increasing tonic inhibition and treating secondary insomnia.
The applicant listed for this patent is Ovid Therapeutics Inc.. Invention is credited to Matthew During.
Application Number | 20150352085 14/729910 |
Document ID | / |
Family ID | 54767324 |
Filed Date | 2015-12-10 |
United States Patent
Application |
20150352085 |
Kind Code |
A1 |
During; Matthew |
December 10, 2015 |
METHODS OF INCREASING TONIC INHIBITION AND TREATING SECONDARY
INSOMNIA
Abstract
Methods of increasing tonic inhibition in a subject in need
thereof, for example a subject with Fragile X syndrome or Angelman
syndrome are disclosed. Methods of treating secondary insomnia in a
subject with a neurodegenerative disease or disorder are also
disclosed. The methods can include administering the subject an
effective amount of 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol
(THIP) or a derivative thereof, or a pharmaceutically acceptable
salt thereof, increase tonic inhibition in neurons of the subject;
to increase slow wave sleep (SWS) and/or slow wave activity (SWA),
normalize sleep architecture, reduce secondary insomnia, increase
non-rapid eye movement (NREM) sleep, increase sleep continuity,
enhance delta activity within NREM, increase or improve total sleep
time (TST), increase or improve sleep efficiency, reduce total time
awake (TAA), reduce number of awakenings (NWA), reduce latency to
persistent sleep (LPS), or to reduce wake after sleep onset (WASO),
in the subject, or any combination thereof.
Inventors: |
During; Matthew; (Weston,
CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ovid Therapeutics Inc. |
New York |
NY |
US |
|
|
Family ID: |
54767324 |
Appl. No.: |
14/729910 |
Filed: |
June 3, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62008939 |
Jun 6, 2014 |
|
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Current U.S.
Class: |
514/302 |
Current CPC
Class: |
A61K 9/7023 20130101;
A61P 25/00 20180101; A61K 31/437 20130101; A61K 9/0053 20130101;
A61K 9/0019 20130101 |
International
Class: |
A61K 31/437 20060101
A61K031/437 |
Claims
1. A method of increasing tonic inhibition of neurons comprising
administering to a human subject with a neurodegenerative disease,
a neurogenetic disorder, or a central nervous system disorder a
pharmaceutical composition comprising an effective amount of
4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or a
derivative thereof and a pharmaceutically acceptable carrier or
excipient to increase tonic inhibition of neurons of the
subject.
2. The method of claim 1, wherein the subject has Fragile X
syndrome or Fragile X-associated tremor/ataxia syndrome.
3. The method of claim 1, wherein the subject has Angelman
syndrome.
4. The method of any of claim 1, wherein the amount of the THIP or
derivative thereof is not effective to have an adverse effect in
the subject.
5. The method of claim 1, wherein the subject has secondary
insomnia and the pharmaceutical composition is administered in an
effective amount to increase slow wave sleep (SWS) and/or slow wave
activity (SWA), normalize sleep architecture, reduce secondary
insomnia, increase non-rapid eye movement (NREM) sleep, increase
sleep continuity, enhance delta activity within NREM, increase or
improve total sleep time (TST), increase or improve sleep
efficiency, reduce total time awake (TAA), reduce number of
awakenings (NWA), reduce latency to persistent sleep (LPS), reduce
wake after sleep onset (WASO), or any combination thereof in the
subject.
6. The method of claim 1, wherein the neurodegenerative disease is
selected from the group consisting of Parkinson's Disease (PD) and
PD-related disorders, Alzheimer's Disease (AD) and other dementias,
Prion Diseases such as Creutzfeldt-Jakob Disease, Corticobasal
Degeneration, Frontotemporal Dementia, HIV-Related Cognitive
Impairment, Mild Cognitive Impairment, Motor Neuron Diseases (MND),
Spinocerebellar Ataxia (SCA), Spinal Muscular Atrophy (SMA),
Friedreich's Ataxia, Lewy Body Disease, Alpers' Disease, Batten
Disease, Cerebro-Oculo-Facio-Skeletal Syndrome, Corticobasal
Degeneration, Gerstmann-Straussler-Scheinker Disease, Kuru, Leigh's
Disease, Monomelic Amyotrophy, Multiple System Atrophy, Multiple
System Atrophy With Orthostatic Hypotension (Shy-Drager Syndrome),
Multiple Sclerosis (MS), Neurodegeneration with Brain Iron
Accumulation, Opsoclonus Myoclonus, Posterior Cortical Atrophy,
Primary Progressive Aphasia, Progressive Supranuclear Palsy,
Vascular Dementia, Progressive Multifocal Leukoencephalopathy,
Dementia with Lewy Bodies, Lacunar syndromes, Hydrocephalus,
Wernicke-Korsakoff's syndrome, post-encephalitic dementia, cancer
and chemotherapy-associated cognitive impairment and dementia, and
depression-induced dementia and pseudodementia.
7. The method of claim 6, wherein the neurodegenerative disease is
Huntington's disease.
8. The method of claim 6, wherein the neurodegenerative disease is
Parkinson's disease.
9. The method of claim 6, wherein the neurodegenerative disease is
Amyotrophic lateral sclerosis.
10. The method of claim 6, wherein the neurodegenerative disease is
Alzheimer's disease.
11. The method of claim 1, wherein the subject has not been
clinically diagnosed with the neurodegenerative disease.
12. The method of claim 1, wherein the subject has no significant
physical symptoms of the neurodegenerative disease, or the clinical
symptoms are too mild for an affirmative diagnosis of the
neurodegenerative disease.
13. The method of claim 1, wherein the subject has been clinically
diagnosed with the neurodegenerative disease.
14. The method of claim 1, wherein the THIP or derivative thereof
is THIP or a pharmaceutically acceptable salt thereof.
15. The method of claim 1, wherein the THIP or derivative thereof
is the singular active agent in the pharmaceutical composition.
16. The method of claim 1, wherein the pharmaceutical composition
is formulated for extended release.
17. The method claim 1, wherein the pharmaceutical composition is
administered once every 24-48 hours.
18. The method of claim 1, wherein the pharmaceutical composition
is administered transdermally.
19. The method of claim 18, wherein the pharmaceutical composition
is administered by contacting a transdermal patch comprising the
pharmaceutical composition with the skin of the subject.
20. The method of claim 1, wherein the pharmaceutical composition
is administered to the subject in the morning or the evening.
21. The method of claim 1, wherein the daily dosage of the THIP or
derivative thereof is between about 1 mg and 20 mg.
22. The method of claim 1, wherein the composition is administered
to the subject intravenously.
23. The method of claim 22, wherein the subject is administered a
daily dosage of the THIP or derivative thereof is between about
0.001 mg and 30 mg.
24. The method of claim 23, wherein the THIP or derivative thereof
is administered at a rate of 0.001 mg/kg per hour to 1 mg/kg per
hour.
25. A method of treating or preventing Fragile X syndrome or
Fragile X-associated tremor/ataxia syndrome in a subject comprising
administering to a subject with Fragile X syndrome or Fragile
X-associated tremor/ataxia syndrome a pharmaceutical composition
comprising an effective amount of
4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or a
derivative thereof and a pharmaceutically acceptable carrier or
excipient to increase tonic inhibition of neurons in the
subject.
26. A method of treating or preventing Angelman syndrome in a
subject comprising administering to a subject with Angelman
syndrome a pharmaceutical composition comprising an effective
amount of 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or
a derivative thereof and a pharmaceutically acceptable carrier or
excipient to increase tonic inhibition of neurons in the subject.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims benefit of and priority to U.S.
Provisional Application No. 62/008,939, filed Jun. 6, 2014, all of
which is incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The field of the invention generally relates to methods of
using a composition including
4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), a derivative
thereof, or a pharmaceutically acceptable salt thereof for treating
diseases and disorders characterized by secondary insomnia and/or
defects or deficiencies in tonic inhibition.
BACKGROUND OF THE INVENTION
[0003] Although many advances have been made, the treatments for
neurodegenerative diseases and neurogenetic diseases remain largely
inadequate.
[0004] In some cases, neurological diseases are linked by an
underlying pathophysiology, for example, Fragile X syndrome and
Angelman syndrome are linked by loss of tonic inhibition in certain
tissues of the brain. In some cases, neurological diseases are
linked by symptoms. For example, although different
neurodegenerative diseases are characterized by a broad range of
symptoms, many of the diseases and disorders are linked by one or
more sleep-related disorders, such as insomnia, disrupted sleep,
and altered sleep architecture (Jennum, et al., "CHAPTER 39: Sleep
disorders in neurodegenerative disorders and stroke", European
Handbook of Neurological Management, Volume 1, 2nd Edition (Ed.
Gilhus, et al.) Blackwell Publishing Ltd. 2011)).
[0005] For diseases such as Huntington's disease, Parkinson's
disease, Amyotrophic Lateral Sclerosis, Alzheimer's disease,
Fragile X syndrome, and Angelman syndrome, treatments are very
limited and cures do not exist. Therefore, there is a need for
additional therapeutic options for treating neurodegenerative
diseases, neurogenetic, and other central nervous system
disorders.
[0006] Accordingly, it is an object of the invention to provide
methods for treating and preventing secondary insomnia in subjects
with neurological diseases.
[0007] It is another object of the invention to provide methods for
increasing tonic inhibition in a subject in need thereof.
SUMMARY OF THE INVENTION
[0008] Methods of increasing tonic inhibition of neurons in a
subject, particularly subjects with Fragile X syndrome or Angelman
syndrome are provided. Methods of treating secondary insomnia in a
subject with a neurodegenerative disease or a central nervous
system disorder are also provided. The methods typically include
administering to the subject a pharmaceutical composition including
an effective amount of
4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or a
derivative thereof and a pharmaceutically acceptable carrier or
excipient to increase tonic inhibition of neurons in the subject,
to increase slow wave sleep (SWS) and/or slow wave activity (SWA),
normalize sleep architecture, reduce secondary insomnia, increase
non-rapid eye movement (NREM) sleep, increase sleep continuity,
enhance delta activity within NREM, increase or improve total sleep
time (TST), increase or improve sleep efficiency, reduce total time
awake (TAA), reduce number of awakenings (NWA), reduce latency to
persistent sleep (LPS), or reduce wake after sleep onset (WASO) in
the subject, or any combination thereof in the subject.
[0009] In particular embodiments, the subjects suffering from
secondary insomnia have Parkinson's Disease (PD) or a PD-related
disorder, Alzheimer's Disease (AD), Huntington's disease,
Parkinson's disease, Amyotrophic lateral sclerosis, or Alzheimer's
disease.
[0010] In the most preferred embodiments, the THIP or derivative
thereof is THIP or a pharmaceutically acceptable salt thereof. The
THIP or derivative thereof can be the singular active agent or one
of two or more active agents in the pharmaceutical composition. The
pharmaceutical composition is formulated for extended release. The
pharmaceutical composition can be administered transdermally, for
example, by contacting a transdermal patch including the
pharmaceutical composition with the skin of the subject. In a
particular embodiment, the daily dosage of the THIP or derivative
thereof is between about 2.5 mg and 50 mg per day.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions
[0011] As used herein, the term "carrier" or "excipient" refers to
an organic or inorganic ingredient, natural or synthetic inactive
ingredient in a formulation, with which one or more active
ingredients are combined.
[0012] As used herein, the term "pharmaceutically acceptable" means
a non-toxic material that does not interfere with the effectiveness
of the biological activity of the active ingredients.
[0013] As used herein, the terms "effective amount" or
"therapeutically effective amount" means a dosage sufficient to
alleviate one or more symptoms of a disorder, disease, or condition
being treated, or to otherwise provide a desired pharmacologic
and/or physiologic effect. The precise dosage will vary according
to a variety of factors such as subject-dependent variables (e.g.,
age, immune system health, etc.), the disease or disorder being
treated, as well as the route of administration and the
pharmacokinetics of the agent being administered.
[0014] As used herein, the term "prevention" or "preventing" means
to administer a composition to a subject or a system at risk for or
having a predisposition for one or more symptom caused by a disease
or disorder to cause cessation of a particular symptom of the
disease or disorder, a reduction or prevention of one or more
symptoms of the disease or disorder, a reduction in the severity of
the disease or disorder, the complete ablation of the disease or
disorder, stabilization or delay of the development or progression
of the disease or disorder.
II. Compositions Including Gaboxadol or a Derivative Thereof
[0015] Methods of using
4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), a derivative
thereof, or a pharmaceutically acceptable salt thereof for treating
secondary insomnia, disturbed sleep architecture, or a combination
thereof in a subject are disclosed. In some embodiments, the
subject has or is at risk of developing a neurodegenerative disease
or a central nervous system disorder. In the most preferred
embodiments, the subject suffers from secondary insomnia and/or
disturbed sleep architecture due to a neurodegenerative disease or
a central nervous system disorder. As discussed in more detail
below, the methods typically include administering to a subject in
need thereof an effective amount of
4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), a derivative
thereof, or a pharmaceutically acceptable salt thereof to increase
slow wave sleep, normalize sleep architecture, or a combination
thereof a subject. In some embodiments, clinical symptoms of a
neurodegenerative disease or central nervous system disorder are
reduced.
[0016] Methods of using
4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), a derivative
thereof, or a pharmaceutically acceptable salt thereof for
increasing tonic inhibition are also provided. The methods can be
used to increase tonic inhibition in a subject with a disease or
disorder characterized a defect or deficiency in tonic inhibition,
for example Fragile X Syndrome or Angelman Syndrome.
A. 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP)
[0017] The compositions for use in the disclosed methods of
treating secondary insomnia include
4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (also referred to as
THIP and gaboxadol), a derivative thereof, or pharmaceutically
acceptable salt thereof, or a structurally related compound. THIP,
as well as derivatives and structurally related compounds, and
methods of making thereof are known in the art. See, for example,
U.S. Pat. Nos. 4,278,676, 4,362,731, 4,353,910, and WO 2005/094820
each of which is specifically incorporated by reference herein in
its entirety. Particularly preferred compounds are discussed in
more detail below.
[0018] In some embodiments, the compound is of the formula Ia
##STR00001##
or a tautomer, isomer, epimer, or diastereoisomer thereof.
[0019] THIP is well tolerated and is a very potent GABA agonist
having a very specific activity, and being inactive as a
GABA-uptake inhibitor. Gaboxadol is a selective extrasynaptic
GABA.sub.A agonist (SEGA) (Deacon, et al., Sleep, 30(3):281-287
(2007)). The GABA.sub.A receptor is a pentameric transmembrane
protein that has 5 subunits forming a central anion channel.
Gaboxadol binds at the interface between the .alpha. and .beta.
subunits, the same site to which the endogenous GABA ligand binds.
Gaboxadol exerts direct effects on chloride conductance,
independent of GABA and it can directly activate extrasynaptically
located .delta.-containing receptors via interaction with the GABA
binding site. Extrasynaptic .delta.-containing receptors are
predominantly expressed in the thalamus, cerebral cortex, and
limbic system. These regions of the brain have been implicated in
sleep regulation and synchronization of cortical activity.
[0020] It is believed that the selective activity of the compound
Ia is ascribable to the particular position of the nitrogen atom in
the 6-membered ring in relation to the acidic hydroxy group in the
5-membered ring.
[0021] Therefore, compound Ia and derivatives thereof, particularly
derivatives which upon administration will be decomposed in situ to
yield the parent compound Ia, in particular compounds of the
general formula I
##STR00002##
wherein R'' is hydrogen, acetyl or a group of the general formula
II
##STR00003##
wherein R.sub.5 is C.sub.1-8 alkyl; phenyl; phenyl substituted in
the 4-position with halogen, lower alkoxy, or lower alkyl; or
phenylalkyl such as benzyl or phenylethyl in which the phenyl group
may be substituted in the 4-position with halogen, lower alkoxy, or
lower alkyl; and salts thereof.
[0022] It is believed that the groups R'' which are different from
hydrogen may enhance the penetration of the compounds into the
brain in that they may enhance the ability of the compounds to pass
the blood brain barrier, and will thereafter be split off in situ
to yield the parent compound. Also, a prolonged effect of Ia may be
obtained via decomposition in situ of compounds wherein R'' is
different from hydrogen, to yield the parent compound.
[0023] "Lower alkyl", "lower alkoxy", and "lower alkyloxy"
designate such groups containing 1-6 carbon atoms, preferably 1-4
atoms inclusive.
[0024] The compounds of the general formula I may exist in a
tautomeric form, as shown by the formula I'
##STR00004##
Formula I is to be understood as covering also this tautomeric form
(I') and mixtures of the two tautomeric forms.
[0025] Examples of compounds of the general formula I in which R''
is different from hydrogen, are:
6-acetyl-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol, methyl
3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate,
ethyl
3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate,
tert.butyl
3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate,
phenyl
3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate-
, 4-chlorophenyl
3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate,
4-methoxyphenyl
3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate,
benzyl
3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-6-carboxylate-
, and salts thereof with bases.
[0026] Derivatives of THIP are known in the art. See, for examples,
U.S. Pat. No. 4,353,910.
[0027] Preferred derivatives have the formula
##STR00005##
[0028] wherein R is an alkyl group, branched or unbranched, having
from one to seventeen carbon atoms inclusive, a phenyl group
optionally substituted with one or two groups selected from lower
alkyl, lower alkyloxy and halogen, a phenylalkyl group, lower
alkyloxy group or a --NHR.sub.1 group, wherein R.sub.1 is hydrogen,
lower alkyl, phenyl or cyclohexyl, as well as pharmaceutically
acceptable acid addition salts thereof.
[0029] Formula III as well as their pharmaceutically acceptable
acid addition salts show GABA-related activity at the same level as
does the compound THIP, and some of the compounds also show a
prolonged effect compared with THIP. They moreover show pronounced
analgesic and myotonolytic effects.
[0030] As examples of pharmaceutically acceptable salts of the
compounds of the disclosed formulae may be mentioned salts with
inorganic acids. Examples of salts of the compounds of the formulae
are acid addition salts thereof, such as pharmaceutically
acceptable salts with inorganic acids, e.g. hydrochloric,
hydrobromic, nitric, sulfuric, phosphoric acids and the like, or
with organic acids, such as organic carboxylic acids, e.g. acetic,
propionic, glycolic, malonic, succinic, maleic, fumaric, malic,
tartaric, citric, glucuronic, benzoic, pamoic acid and the like, or
organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic,
benzene sulfonic, toluene sulfonic acid and the like, which salts
may be prepared by procedures known per se, e.g. by adding the acid
in question to the base, preferably in a solvent. Compounds of the
formulae can form pharmaceutically acceptable salts with bases,
such as metal salts, e.g. sodium, potassium, calcium or aluminium
salts, and ammonium and substituted ammonium salts, e.g. salts of
amines such as triethylamine, triethanolamine, ethylpiperidine,
procaine, and dibenzylamine.
[0031] Throughout the description "THIP or a derivative thereof" is
intended to include any form of the compound, such as the base
(zwitter ion), pharmaceutically acceptable salts, e.g.,
pharmaceutically acceptable acid addition salts, hydrates or
solvates of the base or salt, as well as anhydrates, and also
amorphous, or crystalline forms.
B. Formulations
[0032] The disclosed compounds can be formulated in a
pharmaceutical composition. Pharmaceutical compositions can be for
administration by parenteral (intramuscular, intraperitoneal,
intravenous (IV) or subcutaneous injection), enteral, transdermal
(either passively or using iontophoresis or electroporation), or
transmucosal (nasal, pulmonary, vaginal, rectal, or sublingual)
routes of administration or using bioerodible inserts and can be
formulated in dosage forms appropriate for each route of
administration.
[0033] The compositions can be administered systemically.
[0034] Drugs can be formulated for immediate release, extended
release, or modified release. A delayed release dosage form is one
that releases a drug (or drugs) at a time other than promptly after
administration. An extended release dosage form is one that allows
at least a twofold reduction in dosing frequency as compared to
that drug presented as a conventional dosage form (e.g. as a
solution or prompt drug-releasing, conventional solid dosage form).
A modified release dosage form is one for which the drug release
characteristics of time course and/or location are chosen to
accomplish therapeutic or convenience objectives not offered by
conventional dosage forms such as solutions, ointments, or promptly
dissolving dosage forms. Delayed release and extended release
dosage forms and their combinations are types of modified release
dosage forms.
[0035] Formulations are prepared using a pharmaceutically
acceptable "carrier" composed of materials that are considered safe
and effective and may be administered to an individual without
causing undesirable biological side effects or unwanted
interactions. The "carrier" is all components present in the
pharmaceutical formulation other than the active ingredient or
ingredients. The term "carrier" includes, but is not limited to,
diluents, binders, lubricants, desintegrators, fillers, and coating
compositions.
[0036] "Carrier" also includes all components of the coating
composition which may include plasticizers, pigments, colorants,
stabilizing agents, and glidants. The delayed release dosage
formulations may be prepared as described in references such as
"Pharmaceutical dosage form tablets", eds. Liberman et. al. (New
York, Marcel Dekker, Inc., 1989), "Remington--The science and
practice of pharmacy", 20th ed., Lippincott Williams & Wilkins,
Baltimore, Md., 2000, and "Pharmaceutical dosage forms and drug
delivery systems", 6.sup.th Edition, Ansel et. al., (Media, Pa.:
Williams and Wilkins, 1995) which provides information on carriers,
materials, equipment and process for preparing tablets and capsules
and delayed release dosage forms of tablets, capsules, and
granules.
[0037] The compound can be administered to a subject with or
without the aid of a delivery vehicle. Appropriate delivery
vehicles for the compounds are known in the art and can be selected
to suit the particular active agent. For example, in some
embodiments, the active agent(s) is incorporated into or
encapsulated by, or bound to, a nanoparticle, microparticle,
micelle, synthetic lipoprotein particle, or carbon nanotube. For
example, the compositions can be incorporated into a vehicle such
as polymeric microparticles which provide controlled release of the
active agent(s). In some embodiments, release of the drug(s) is
controlled by diffusion of the active agent(s) out of the
microparticles and/or degradation of the polymeric particles by
hydrolysis and/or enzymatic degradation.
[0038] Suitable polymers include ethylcellulose and other natural
or synthetic cellulose derivatives. Polymers which are slowly
soluble and form a gel in an aqueous environment, such as
hydroxypropyl methylcellulose or polyethylene oxide, may also be
suitable as materials for drug containing microparticles or
particles. Other polymers include, but are not limited to,
polyanhydrides, poly (ester anhydrides), polyhydroxy acids, such as
polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide)
(PLGA), poly-3-hydroxybut rate (PHB) and copolymers thereof,
poly-4-hydroxybutyrate (P4HB) and copolymers thereof,
polycaprolactone and copolymers thereof, and combinations thereof.
In some embodiments, both agents are incorporated into the same
particles and are formulated for release at different times and/or
over different time periods. For example, in some embodiments, one
of the agents is released entirely from the particles before
release of the second agent begins. In other embodiments, release
of the first agent begins followed by release of the second agent
before the all of the first agent is released. In still other
embodiments, both agents are released at the same time over the
same period of time or over different periods of time.
[0039] 1. Formulations for Parenteral Administration
[0040] Compounds and pharmaceutical compositions thereof can be
administered in an aqueous solution, by parenteral injection. The
formulation may also be in the form of a suspension or emulsion. In
general, pharmaceutical compositions are provided including
effective amounts of the active agent(s) and optionally include
pharmaceutically acceptable diluents, preservatives, solubilizers,
emulsifiers, adjuvants and/or carriers. Such compositions include
diluents sterile water, buffered saline of various buffer content
(e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; and
optionally, additives such as detergents and solubilizing agents
(e.g., TWEEN.RTM. 20, TWEEN.RTM. 80 also referred to as
POLYSORBATE.RTM. 20 or 80), anti-oxidants (e.g., ascorbic acid,
sodium metabisulfite), and preservatives (e.g., Thimersol, benzyl
alcohol) and bulking substances (e.g., lactose, mannitol). Examples
of non-aqueous solvents or vehicles are propylene glycol,
polyethylene glycol, vegetable oils, such as olive oil and corn
oil, gelatin, and injectable organic esters such as ethyl oleate.
The formulations may be lyophilized and redissolved/resuspended
immediately before use. The formulation may be sterilized by, for
example, filtration through a bacteria retaining filter, by
incorporating sterilizing agents into the compositions, by
irradiating the compositions, or by heating the compositions.
[0041] 2. Oral Immediate Release Formulations
[0042] Suitable oral dosage forms include tablets, capsules,
solutions, suspensions, syrups, and lozenges. Tablets can be made
using compression or molding techniques well known in the art.
Gelatin or non-gelatin capsules can prepared as hard or soft
capsule shells, which can encapsulate liquid, solid, and semi-solid
fill materials, using techniques well known in the art.
[0043] Examples of suitable coating materials include, but are not
limited to, cellulose polymers such as cellulose acetate phthalate,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
hydroxypropyl methylcellulose phthalate and hydroxypropyl
methylcellulose acetate succinate; polyvinyl acetate phthalate,
acrylic acid polymers and copolymers, and methacrylic resins that
are commercially available under the trade name Eudragit.RTM. (Roth
Pharma, Westerstadt, Germany), Zein, shellac, and
polysaccharides.
[0044] Additionally, the coating material may contain conventional
carriers such as plasticizers, pigments, colorants, glidants,
stabilization agents, pore formers and surfactants.
[0045] Optional pharmaceutically acceptable excipients present in
the drug-containing tablets, beads, granules or particles include,
but are not limited to, diluents, binders, lubricants,
disintegrants, colorants, stabilizers, and surfactants.
[0046] Diluents, also termed "fillers," are typically necessary to
increase the bulk of a solid dosage form so that a practical size
is provided for compression of tablets or formation of beads and
granules. Suitable diluents include, but are not limited to,
dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose,
mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin,
sodium chloride, dry starch, hydrolyzed starches, pregelatinized
starch, silicone dioxide, titanium oxide, magnesium aluminum
silicate and powder sugar.
[0047] Binders are used to impart cohesive qualities to a solid
dosage formulation, and thus ensure that a tablet or bead or
granule remains intact after the formation of the dosage forms.
Suitable binder materials include, but are not limited to, starch,
pregelatinized starch, gelatin, sugars (including sucrose, glucose,
dextrose, lactose and sorbitol), polyethylene glycol, waxes,
natural and synthetic gums such as acacia, tragacanth, sodium
alginate, cellulose, including hydorxypropylmethylcellulose,
hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic
polymers such as acrylic acid and methacrylic acid copolymers,
methacrylic acid copolymers, methyl methacrylate copolymers,
aminoalkyl methacrylate copolymers, polyacrylic
acid/polymethacrylic acid and polyvinylpyrrolidone.
[0048] Lubricants are used to facilitate tablet manufacture.
Examples of suitable lubricants include, but are not limited to,
magnesium stearate, calcium stearate, stearic acid, glycerol
behenate, polyethylene glycol, talc, and mineral oil.
[0049] Disintegrants are used to facilitate dosage form
disintegration or "breakup" after administration, and generally
include, but are not limited to, starch, sodium starch glycolate,
sodium carboxymethyl starch, sodium carboxymethylcellulose,
hydroxypropyl cellulose, pregelatinized starch, clays, cellulose,
alginine, gums or cross linked polymers, such as cross-linked PVP
(Polyplasdone XL from GAF Chemical Corp).
[0050] Stabilizers are used to inhibit or retard drug decomposition
reactions which include, by way of example, oxidative
reactions.
[0051] Surfactants may be anionic, cationic, amphoteric or nonionic
surface active agents. Suitable anionic surfactants include, but
are not limited to, those containing carboxylate, sulfonate and
sulfate ions. Examples of anionic surfactants include sodium,
potassium, ammonium of long chain alkyl sulfonates and alkyl aryl
sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium
sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl
sodium sulfosuccinates, such as sodium
bis-(2-ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as
sodium lauryl sulfate. Cationic surfactants include, but are not
limited to, quaternary ammonium compounds such as benzalkonium
chloride, benzethonium chloride, cetrimonium bromide, stearyl
dimethylbenzyl ammonium chloride, polyoxyethylene and coconut
amine. Examples of nonionic surfactants include ethylene glycol
monostearate, propylene glycol myristate, glyceryl monostearate,
glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose
acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene
monolaurate, polysorbates, polyoxyethylene octylphenylether,
PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene
glycol butyl ether, POLOXAMER.RTM. 401, stearoyl
monoisopropanolamide, and polyoxyethylene hydrogenated tallow
amide. Examples of amphoteric surfactants include sodium
N-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate,
myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.
[0052] If desired, the tablets, beads granules or particles may
also contain minor amount of nontoxic auxiliary substances such as
wetting or emulsifying agents, dyes, pH buffering agents, and
preservatives.
[0053] 3. Extended Release Dosage Forms
[0054] The extended release formulations are generally prepared as
diffusion or osmotic systems, for example, as described in
"Remington--The science and practice of pharmacy" (20th ed.,
Lippincott Williams & Wilkins, Baltimore, Md., 2000). A
diffusion system typically consists of two types of devices,
reservoir and matrix, and is well known and described in the art.
The matrix devices are generally prepared by compressing the drug
with a slowly dissolving polymer carrier into a tablet form. The
three major types of materials used in the preparation of matrix
devices are insoluble plastics, hydrophilic polymers, and fatty
compounds. Plastic matrices include, but not limited to, methyl
acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene.
Hydrophilic polymers include, but are not limited to,
methylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and
carbopol 934, polyethylene oxides. Fatty compounds include, but are
not limited to, various waxes such as carnauba wax and glyceryl
tristearate.
[0055] Alternatively, extended release formulations can be prepared
using osmotic systems or by applying a semi-permeable coating to
the dosage form. In the latter case, the desired drug release
profile can be achieved by combining low permeable and high
permeable coating materials in suitable proportion.
[0056] The devices with different drug release mechanisms described
above could be combined in a final dosage form comprising single or
multiple units. Examples of multiple units include multilayer
tablets, capsules containing tablets, beads, granules, etc.
[0057] An immediate release portion can be added to the extended
release system by means of either applying an immediate release
layer on top of the extended release core using coating or
compression process or in a multiple unit system such as a capsule
containing extended and immediate release beads.
[0058] Extended release tablets containing hydrophilic polymers are
prepared by techniques commonly known in the art such as direct
compression, wet granulation, or dry granulation processes. Their
formulations usually incorporate polymers, diluents, binders, and
lubricants as well as the active pharmaceutical ingredient. The
usual diluents include inert powdered substances such as any of
many different kinds of starch, powdered cellulose, especially
crystalline and microcrystalline cellulose, sugars such as
fructose, mannitol and sucrose, grain flours and similar edible
powders. Typical diluents include, for example, various types of
starch, lactose, mannitol, kaolin, calcium phosphate or sulfate,
inorganic salts such as sodium chloride and powdered sugar.
Powdered cellulose derivatives are also useful. Typical tablet
binders include substances such as starch, gelatin and sugars such
as lactose, fructose, and glucose. Natural and synthetic gums,
including acacia, alginates, methylcellulose, and
polyvinylpyrrolidine can also be used. Polyethylene glycol,
hydrophilic polymers, ethylcellulose and waxes can also serve as
binders. A lubricant is necessary in a tablet formulation to
prevent the tablet and punches from sticking in the die. The
lubricant is chosen from such slippery solids as talc, magnesium
and calcium stearate, stearic acid and hydrogenated vegetable
oils.
[0059] Extended release tablets containing wax materials are
generally prepared using methods known in the art such as a direct
blend method, a congealing method, and an aqueous dispersion
method. In a congealing method, the drug is mixed with a wax
material and either spray-congealed or congealed and screened and
processed.
[0060] 4. Delayed Release Dosage Forms
[0061] Delayed release formulations are created by coating a solid
dosage form with a film of a polymer which is insoluble in the acid
environment of the stomach, and soluble in the neutral environment
of small intestines.
[0062] The delayed release dosage units can be prepared, for
example, by coating a drug or a drug-containing composition with a
selected coating material. The drug-containing composition may be,
e.g., a tablet for incorporation into a capsule, a tablet for use
as an inner core in a "coated core" dosage form, or a plurality of
drug-containing beads, particles or granules, for incorporation
into either a tablet or capsule. Preferred coating materials
include bioerodible, gradually hydrolyzable, gradually
water-soluble, and/or enzymatically degradable polymers, and may be
conventional "enteric" polymers. Enteric polymers, as will be
appreciated by those skilled in the art, become soluble in the
higher pH environment of the lower gastrointestinal tract or slowly
erode as the dosage form passes through the gastrointestinal tract,
while enzymatically degradable polymers are degraded by bacterial
enzymes present in the lower gastrointestinal tract, particularly
in the colon. Suitable coating materials for effecting delayed
release include, but are not limited to, cellulosic polymers such
as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl
cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl
cellulose acetate succinate, hydroxypropylmethyl cellulose
phthalate, methylcellulose, ethyl cellulose, cellulose acetate,
cellulose acetate phthalate, cellulose acetate trimellitate and
carboxymethylcellulose sodium; acrylic acid polymers and
copolymers, preferably formed from acrylic acid, methacrylic acid,
methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl
methacrylate, and other methacrylic resins that are commercially
available under the tradename EUDRAGIT.RTM.. (Rohm Pharma;
Westerstadt, Germany), including EUDRAGIT.RTM.. L30D-55 and L100-55
(soluble at pH 5.5 and above), EUDRAGIT.RTM.. L-100 (soluble at pH
6.0 and above), EUDRAGIT.RTM.. S (soluble at pH 7.0 and above, as a
result of a higher degree of esterification), and EUDRAGITS.RTM..
NE, RL and RS (water-insoluble polymers having different degrees of
permeability and expandability); vinyl polymers and copolymers such
as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate,
vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate
copolymer; enzymatically degradable polymers such as azo polymers,
pectin, chitosan, amylose and guar gum; zein and shellac.
Combinations of different coating materials may also be used.
Multi-layer coatings using different polymers may also be
applied.
[0063] The preferred coating weights for particular coating
materials may be readily determined by those skilled in the art by
evaluating individual release profiles for tablets, beads and
granules prepared with different quantities of various coating
materials. It is the combination of materials, method and form of
application that produce the desired release characteristics, which
one can determine only from the clinical studies.
[0064] The coating composition may include conventional additives,
such as plasticizers, pigments, colorants, stabilizing agents,
glidants, etc. A plasticizer is normally present to reduce the
fragility of the coating, and will generally represent about 10 wt.
% to 50 wt. % relative to the dry weight of the polymer. Examples
of typical plasticizers include polyethylene glycol, propylene
glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl
phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate,
triethyl acetyl citrate, castor oil and acetylated monoglycerides.
A stabilizing agent is preferably used to stabilize particles in
the dispersion. Typical stabilizing agents are nonionic emulsifiers
such as sorbitan esters, polysorbates and polyvinylpyrrolidone.
Glidants are recommended to reduce sticking effects during film
formation and drying, and will generally represent approximately 25
wt. % to 100 wt. % of the polymer weight in the coating solution.
One effective glidant is talc. Other glidants such as magnesium
stearate and glycerol monostearates may also be used. Pigments such
as titanium dioxide may also be used. Small quantities of an
anti-foaming agent, such as a silicone (e.g., simethicone), may
also be added to the coating composition.
[0065] Methods of Manufacturing
[0066] As will be appreciated by those skilled in the art and as
described in the pertinent texts and literature, a number of
methods are available for preparing drug-containing tablets, beads,
granules or particles that provide a variety of drug release
profiles. Such methods include, but are not limited to, the
following: coating a drug or drug-containing composition with an
appropriate coating material, typically although not necessarily
incorporating a polymeric material, increasing drug particle size,
placing the drug within a matrix, and forming complexes of the drug
with a suitable complexing agent.
[0067] The delayed release dosage units may be coated with the
delayed release polymer coating using conventional techniques,
e.g., using a conventional coating pan, an airless spray technique,
fluidized bed coating equipment (with or without a Wurster insert).
For detailed information concerning materials, equipment and
processes for preparing tablets and delayed release dosage forms,
see Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al.
(New York: Marcel Dekker, Inc., 1989), and Ansel et al.,
Pharmaceutical Dosage Forms and Drug Delivery Systems, 6.sup.th Ed.
(Media, Pa.: Williams & Wilkins, 1995).
[0068] A preferred method for preparing extended release tablets is
by compressing a drug-containing blend, e.g., blend of granules,
prepared using a direct blend, wet-granulation, or dry-granulation
process. Extended release tablets may also be molded rather than
compressed, starting with a moist material containing a suitable
water-soluble lubricant. However, tablets are preferably
manufactured using compression rather than molding. A preferred
method for forming extended release drug-containing blend is to mix
drug particles directly with one or more excipients such as
diluents (or fillers), binders, disintegrants, lubricants,
glidants, and colorants. As an alternative to direct blending, a
drug-containing blend may be prepared by using wet-granulation or
dry-granulation processes. Beads containing the active agent may
also be prepared by any one of a number of conventional techniques,
typically starting from a fluid dispersion. For example, a typical
method for preparing drug-containing beads involves dispersing or
dissolving the active agent in a coating suspension or solution
containing pharmaceutical excipients such as polyvinylpyrrolidone,
methylcellulose, talc, metallic stearates, silicone dioxide,
plasticizers or the like. The admixture is used to coat a bead core
such as a sugar sphere (or so-called "non-pareil") having a size of
approximately 60 to 20 mesh.
[0069] An alternative procedure for preparing drug beads is by
blending drug with one or more pharmaceutically acceptable
excipients, such as microcrystalline cellulose, lactose, cellulose,
polyvinyl pyrrolidone, talc, magnesium stearate, a disintegrant,
etc., extruding the blend, spheronizing the extrudate, drying and
optionally coating to form the immediate release beads.
[0070] 5. Formulations for Mucosal and Pulmonary Administration
[0071] Active agent(s) and compositions thereof can be formulated
for pulmonary or mucosal administration. The administration can
include delivery of the composition to the lungs, nasal, oral
(sublingual, buccal), vaginal, or rectal mucosa. In a particular
embodiment, the composition is formulated for and delivered to the
subject sublingually.
[0072] In one embodiment, the compounds are formulated for
pulmonary delivery, such as intranasal administration or oral
inhalation. The respiratory tract is the structure involved in the
exchange of gases between the atmosphere and the blood stream. The
lungs are branching structures ultimately ending with the alveoli
where the exchange of gases occurs. The alveolar surface area is
the largest in the respiratory system and is where drug absorption
occurs. The alveoli are covered by a thin epithelium without cilia
or a mucus blanket and secrete surfactant phospholipids. The
respiratory tract encompasses the upper airways, including the
oropharynx and larynx, followed by the lower airways, which include
the trachea followed by bifurcations into the bronchi and
bronchioli. The upper and lower airways are called the conducting
airways. The terminal bronchioli then divide into respiratory
bronchiole, which then lead to the ultimate respiratory zone, the
alveoli, or deep lung. The deep lung, or alveoli, is the primary
target of inhaled therapeutic aerosols for systemic drug
delivery.
[0073] Pulmonary administration of therapeutic compositions
comprised of low molecular weight drugs has been observed, for
example, beta-androgenic antagonists to treat asthma. Other
therapeutic agents that are active in the lungs have been
administered systemically and targeted via pulmonary absorption.
Nasal delivery is considered to be a promising technique for
administration of therapeutics for the following reasons: the nose
has a large surface area available for drug absorption due to the
coverage of the epithelial surface by numerous microvilli, the
subepithelial layer is highly vascularized, the venous blood from
the nose passes directly into the systemic circulation and
therefore avoids the loss of drug by first-pass metabolism in the
liver, it offers lower doses, more rapid attainment of therapeutic
blood levels, quicker onset of pharmacological activity, fewer side
effects, high total blood flow per cm.sup.3, porous endothelial
basement membrane, and it is easily accessible.
[0074] The term aerosol as used herein refers to any preparation of
a fine mist of particles, which can be in solution or a suspension,
whether or not it is produced using a propellant. Aerosols can be
produced using standard techniques, such as ultrasonication or
high-pressure treatment.
[0075] Carriers for pulmonary formulations can be divided into
those for dry powder formulations and for administration as
solutions. Aerosols for the delivery of therapeutic agents to the
respiratory tract are known in the art. For administration via the
upper respiratory tract, the formulation can be formulated into a
solution, e.g., water or isotonic saline, buffered or un-buffered,
or as a suspension, for intranasal administration as drops or as a
spray. Preferably, such solutions or suspensions are isotonic
relative to nasal secretions and of about the same pH, ranging
e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7.0.
Buffers should be physiologically compatible and include, simply by
way of example, phosphate buffers. For example, a representative
nasal decongestant is described as being buffered to a pH of about
6.2. One skilled in the art can readily determine a suitable saline
content and pH for an innocuous aqueous solution for nasal and/or
upper respiratory administration.
[0076] Preferably, the aqueous solution is water, physiologically
acceptable aqueous solutions containing salts and/or buffers, such
as phosphate buffered saline (PBS), or any other aqueous solution
acceptable for administration to an animal or human. Such solutions
are well known to a person skilled in the art and include, but are
not limited to, distilled water, de-ionized water, pure or
ultrapure water, saline, phosphate-buffered saline (PBS). Other
suitable aqueous vehicles include, but are not limited to, Ringer's
solution and isotonic sodium chloride. Aqueous suspensions may
include suspending agents such as cellulose derivatives, sodium
alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting
agent such as lecithin. Suitable preservatives for aqueous
suspensions include ethyl and n-propyl p-hydroxybenzoate.
[0077] In another embodiment, solvents that are low toxicity
organic (i.e. nonaqueous) class 3 residual solvents, such as
ethanol, acetone, ethyl acetate, tetrahydrofuran, ethyl ether, and
propanol may be used for the formulations. The solvent is selected
based on its ability to readily aerosolize the formulation. The
solvent should not detrimentally react with the compounds. An
appropriate solvent should be used that dissolves the compounds or
forms a suspension of the compounds. The solvent should be
sufficiently volatile to enable formation of an aerosol of the
solution or suspension. Additional solvents or aerosolizing agents,
such as freons, can be added as desired to increase the volatility
of the solution or suspension.
[0078] In one embodiment, compositions may contain minor amounts of
polymers, surfactants, or other excipients well known to those of
the art. In this context, "minor amounts" means no excipients are
present that might affect or mediate uptake of the compounds in the
lungs and that the excipients that are present are present in
amount that do not adversely affect uptake of compounds in the
lungs.
[0079] Dry lipid powders can be directly dispersed in ethanol
because of their hydrophobic character. For lipids stored in
organic solvents such as chloroform, the desired quantity of
solution is placed in a vial, and the chloroform is evaporated
under a stream of nitrogen to form a dry thin film on the surface
of a glass vial. The film swells easily when reconstituted with
ethanol. To fully disperse the lipid molecules in the organic
solvent, the suspension is sonicated. Nonaqueous suspensions of
lipids can also be prepared in absolute ethanol using a reusable
PARI LC Jet+ nebulizer (PARI Respiratory Equipment, Monterey,
Calif.).
[0080] Dry powder formulations ("DPFs") with large particle size
have improved flowability characteristics, such as less
aggregation, easier aerosolization, and potentially less
phagocytosis. Dry powder aerosols for inhalation therapy are
generally produced with mean diameters primarily in the range of
less than 5 microns, although a preferred range is between one and
ten microns in aerodynamic diameter. Large "carrier" particles
(containing no drug) have been co-delivered with therapeutic
aerosols to aid in achieving efficient aerosolization among other
possible benefits.
[0081] Polymeric particles may be prepared using single and double
emulsion solvent evaporation, spray drying, solvent extraction,
solvent evaporation, phase separation, simple and complex
coacervation, interfacial polymerization, and other methods well
known to those of ordinary skill in the art. Particles may be made
using methods for making microspheres or microcapsules known in the
art. The preferred methods of manufacture are by spray drying and
freeze drying, which entails using a solution containing the
surfactant, spraying to form droplets of the desired size, and
removing the solvent.
[0082] The particles may be fabricated with the appropriate
material, surface roughness, diameter and tap density for localized
delivery to selected regions of the respiratory tract such as the
deep lung or upper airways. For example, higher density or larger
particles may be used for upper airway delivery. Similarly, a
mixture of different sized particles, provided with the same or
different active agents may be administered to target different
regions of the lung in one administration.
[0083] 6. Topical and Transdermal Formulations
[0084] Transdermal formulations may also be prepared. These will
typically be gels, ointments, lotions, sprays, or patches, all of
which can be prepared using standard technology. Transdermal
formulations can include penetration enhancers.
[0085] A "gel" is a colloid in which the dispersed phase has
combined with the continuous phase to produce a semisolid material,
such as jelly.
[0086] An "oil" is a composition containing at least 95% wt of a
lipophilic substance. Examples of lipophilic substances include but
are not limited to naturally occurring and synthetic oils, fats,
fatty acids, lecithins, triglycerides and combinations thereof.
[0087] A "continuous phase" refers to the liquid in which solids
are suspended or droplets of another liquid are dispersed, and is
sometimes called the external phase. This also refers to the fluid
phase of a colloid within which solid or fluid particles are
distributed. If the continuous phase is water (or another
hydrophilic solvent), water-soluble or hydrophilic drugs will
dissolve in the continuous phase (as opposed to being dispersed).
In a multiphase formulation (e.g., an emulsion), the discreet phase
is suspended or dispersed in the continuous phase.
[0088] An "emulsion" is a composition containing a mixture of
non-miscible components homogenously blended together. In
particular embodiments, the non-miscible components include a
lipophilic component and an aqueous component. An emulsion is a
preparation of one liquid distributed in small globules throughout
the body of a second liquid. The dispersed liquid is the
discontinuous phase, and the dispersion medium is the continuous
phase. When oil is the dispersed liquid and an aqueous solution is
the continuous phase, it is known as an oil-in-water emulsion,
whereas when water or aqueous solution is the dispersed phase and
oil or oleaginous substance is the continuous phase, it is known as
a water-in-oil emulsion. Either or both of the oil phase and the
aqueous phase may contain one or more surfactants, emulsifiers,
emulsion stabilizers, buffers, and other excipients. Preferred
excipients include surfactants, especially non-ionic surfactants;
emulsifying agents, especially emulsifying waxes; and liquid
non-volatile non-aqueous materials, particularly glycols such as
propylene glycol. The oil phase may contain other oily
pharmaceutically approved excipients. For example, materials such
as hydroxylated castor oil or sesame oil may be used in the oil
phase as surfactants or emulsifiers.
[0089] "Emollients" are an externally applied agent that softens or
soothes skin and are generally known in the art and listed in
compendia, such as the "Handbook of Pharmaceutical Excipients",
4.sup.th Ed., Pharmaceutical Press, 2003. These include, without
limitation, almond oil, castor oil, ceratonia extract, cetostearoyl
alcohol, cetyl alcohol, cetyl esters wax, cholesterol, cottonseed
oil, cyclomethicone, ethylene glycol palmitostearate, glycerin,
glycerin monostearate, glyceryl monooleate, isopropyl myristate,
isopropyl palmitate, lanolin, lecithin, light mineral oil,
medium-chain triglycerides, mineral oil and lanolin alcohols,
petrolatum, petrolatum and lanolin alcohols, soybean oil, starch,
stearyl alcohol, sunflower oil, xylitol and combinations thereof.
In one embodiment, the emollients are ethylhexylstearate and
ethylhexyl palmitate.
[0090] "Surfactants" are surface-active agents that lower surface
tension and thereby increase the emulsifying, foaming, dispersing,
spreading and wetting properties of a product. Suitable non-ionic
surfactants include emulsifying wax, glyceryl monooleate,
polyoxyethylene alkyl ethers, polyoxyethylene castor oil
derivatives, polysorbate, sorbitan esters, benzyl alcohol, benzyl
benzoate, cyclodextrins, glycerin monostearate, poloxamer, povidone
and combinations thereof. In one embodiment, the non-ionic
surfactant is stearyl alcohol.
[0091] "Emulsifiers" are surface active substances which promote
the suspension of one liquid in another and promote the formation
of a stable mixture, or emulsion, of oil and water. Common
emulsifiers are: metallic soaps, certain animal and vegetable oils,
and various polar compounds. Suitable emulsifiers include acacia,
anionic emulsifying wax, calcium stearate, carbomers, cetostearyl
alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene
glycol palmitostearate, glycerin monostearate, glyceryl monooleate,
hydroxpropyl cellulose, hypromellose, lanolin, hydrous, lanolin
alcohols, lecithin, medium-chain triglycerides, methylcellulose,
mineral oil and lanolin alcohols, monobasic sodium phosphate,
monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer,
poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor
oil derivatives, polyoxyethylene sorbitan fatty acid esters,
polyoxyethylene stearates, propylene glycol alginate,
self-emulsifying glyceryl monostearate, sodium citrate dehydrate,
sodium lauryl sulfate, sorbitan esters, stearic acid, sunflower
oil, tragacanth, triethanolamine, xanthan gum and combinations
thereof. In one embodiment, the emulsifier is glycerol
stearate.
[0092] A "lotion" is a low- to medium-viscosity liquid formulation.
A lotion can contain finely powdered substances that are in soluble
in the dispersion medium through the use of suspending agents and
dispersing agents. Alternatively, lotions can have as the dispersed
phase liquid substances that are immiscible with the vehicle and
are usually dispersed by means of emulsifying agents or other
suitable stabilizers. In one embodiment, the lotion is in the form
of an emulsion having a viscosity of between 100 and 1000
centistokes. The fluidity of lotions permits rapid and uniform
application over a wide surface area. Lotions are typically
intended to dry on the skin leaving a thin coat of their medicinal
components on the skin's surface.
[0093] A "cream" is a viscous liquid or semi-solid emulsion of
either the "oil-in-water" or "water-in-oil type". Creams may
contain emulsifying agents and/or other stabilizing agents. In one
embodiment, the formulation is in the form of a cream having a
viscosity of greater than 1000 centistokes, typically in the range
of 20,000-50,000 centistokes. Creams are often time preferred over
ointments as they are generally easier to spread and easier to
remove.
[0094] An emulsion is a preparation of one liquid distributed in
small globules throughout the body of a second liquid. The
dispersed liquid is the discontinuous phase, and the dispersion
medium is the continuous phase. When oil is the dispersed liquid
and an aqueous solution is the continuous phase, it is known as an
oil-in-water emulsion, whereas when water or aqueous solution is
the dispersed phase and oil or oleaginous substance is the
continuous phase, it is known as a water-in-oil emulsion. The oil
phase may consist at least in part of a propellant, such as an HFA
propellant. Either or both of the oil phase and the aqueous phase
may contain one or more surfactants, emulsifiers, emulsion
stabilizers, buffers, and other excipients. Preferred excipients
include surfactants, especially non-ionic surfactants; emulsifying
agents, especially emulsifying waxes; and liquid non-volatile
non-aqueous materials, particularly glycols such as propylene
glycol. The oil phase may contain other oily pharmaceutically
approved excipients. For example, materials such as hydroxylated
castor oil or sesame oil may be used in the oil phase as
surfactants or emulsifiers.
[0095] A sub-set of emulsions are the self-emulsifying systems.
These drug delivery systems are typically capsules (hard shell or
soft shell) comprised of the drug dispersed or dissolved in a
mixture of surfactant(s) and lipophillic liquids such as oils or
other water immiscible liquids. When the capsule is exposed to an
aqueous environment and the outer gelatin shell dissolves, contact
between the aqueous medium and the capsule contents instantly
generates very small emulsion droplets. These typically are in the
size range of micelles or nanoparticles. No mixing force is
required to generate the emulsion as is typically the case in
emulsion formulation processes.
[0096] The basic difference between a cream and a lotion is the
viscosity, which is dependent on the amount/use of various oils and
the percentage of water used to prepare the formulations. Creams
are typically thicker than lotions, may have various uses and often
one uses more varied oils/butters, depending upon the desired
effect upon the skin. In a cream formulation, the water-base
percentage is about 60-75% and the oil-base is about 20-30% of the
total, with the other percentages being the emulsifier agent,
preservatives and additives for a total of 100%.
[0097] An "ointment" is a semisolid preparation containing an
ointment base and optionally one or more active agents. Examples of
suitable ointment bases include hydrocarbon bases (e.g.,
petrolatum, white petrolatum, yellow ointment, and mineral oil);
absorption bases (hydrophilic petrolatum, anhydrous lanolin,
lanolin, and cold cream); water-removable bases (e.g., hydrophilic
ointment), and water-soluble bases (e.g., polyethylene glycol
ointments). Pastes typically differ from ointments in that they
contain a larger percentage of solids. Pastes are typically more
absorptive and less greasy that ointments prepared with the same
components.
[0098] A "gel" is a semisolid system containing dispersions of
small or large molecules in a liquid vehicle that is rendered
semisolid by the action of a thickening agent or polymeric material
dissolved or suspended in the liquid vehicle. The liquid may
include a lipophilic component, an aqueous component or both. Some
emulsions may be gels or otherwise include a gel component. Some
gels, however, are not emulsions because they do not contain a
homogenized blend of immiscible components.
[0099] Suitable gelling agents include, but are not limited to,
modified celluloses, such as hydroxypropyl cellulose and
hydroxyethyl cellulose; Carbopol homopolymers and copolymers; and
combinations thereof. Suitable solvents in the liquid vehicle
include, but are not limited to, diglycol monoethyl ether; alklene
glycols, such as propylene glycol; dimethyl isosorbide; alcohols,
such as isopropyl alcohol and ethanol. The solvents are typically
selected for their ability to dissolve the drug. Other additives,
which improve the skin feel and/or emolliency of the formulation,
may also be incorporated. Examples of such additives include, but
are not limited, isopropyl myristate, ethyl acetate, C12-C15 alkyl
benzoates, mineral oil, squalane, cyclomethicone, capric/caprylic
triglycerides, and combinations thereof.
[0100] Foams consist of an emulsion in combination with a gaseous
propellant. The gaseous propellant consists primarily of
hydrofluoroalkanes (HFAs). Suitable propellants include HFAs such
as 1,1,1,2-tetrafluoroethane (HFA 134a) and
1,1,1,2,3,3,3-heptafluoropropane (HFA 227), but mixtures and
admixtures of these and other HFAs that are currently approved or
may become approved for medical use are suitable. The propellants
preferably are not hydrocarbon propellant gases which can produce
flammable or explosive vapors during spraying. Furthermore, the
compositions preferably contain no volatile alcohols, which can
produce flammable or explosive vapors during use.
[0101] Buffers are used to control pH of a composition. Preferably,
the buffers buffer the composition from a pH of about 4 to a pH of
about 7.5, more preferably from a pH of about 4 to a pH of about 7,
and most preferably from a pH of about 5 to a pH of about 7. In a
preferred embodiment, the buffer is triethanolamine.
[0102] Preservatives can be used to prevent the growth of fungi and
microorganisms. Suitable antifungal and antimicrobial agents
include, but are not limited to, benzoic acid, butylparaben, ethyl
paraben, methyl paraben, propylparaben, sodium benzoate, sodium
propionate, benzalkonium chloride, benzethonium chloride, benzyl
alcohol, cetylpyridinium chloride, chlorobutanol, phenol,
phenylethyl alcohol, and thimerosal.
[0103] Additional agents that can be added to the formulation
include penetration enhancers. In some embodiments, the penetration
enhancer increases the solubility of the drug, improves transdermal
delivery of the drug across the skin, in particular across the
stratum corneum, or a combination thereof. Some penetration
enhancers cause dermal irritation, dermal toxicity and dermal
allergies. However, the more commonly used ones include urea,
(carbonyldiamide), imidurea, N, N-diethylformamide,
N-methyl-2-pyrrolidone, 1-dodecal-azacyclopheptane-2-one, calcium
thioglycate, 2-pyrrolidone, N,N-diethyl-m-toluamide, oleic acid and
its ester derivatives, such as methyl, ethyl, propyl, isopropyl,
butyl, vinyl and glycerylmonooleate, sorbitan esters, such as
sorbitan monolaurate and sorbitan monooleate, other fatty acid
esters such as isopropyl laurate, isopropyl myristate, isopropyl
palmitate, diisopropyl adipate, propylene glycol monolaurate,
propylene glycol monooleatea and non-ionic detergents such as
BRIJ.RTM. 76 (stearyl poly(10 oxyethylene ether), BRIJ.RTM. 78
(stearyl poly(20)oxyethylene ether), BRIJ.RTM. 96 (oleyl
poly(l0)oxyethylene ether), and BRIJ.RTM. 721 (stearyl poly (21)
oxyethylene ether) (ICI Americas Inc. Corp.). Chemical penetrations
and methods of increasing transdermal drug delivery are described
in Inayat, et al., Tropical Journal of Pharmaceutical Research,
8(2):173-179 (2009) and Fox, et al., Molecules, 16:10507-10540
(2011). In some embodiments, the penetration enhancer is, or
includes, an alcohol such ethanol, or others disclosed herein or
known in the art.
[0104] Delivery of drugs by the transdermal route has been known
for many years. Advantages of a transdermal drug delivery compared
to other types of medication delivery such as oral, intravenous,
intramuscular, etc., include avoidance of hepatic first pass
metabolism, ability to discontinue administration by removal of the
system, the ability to control drug delivery for a longer time than
the usual gastrointestinal transit of oral dosage form, and the
ability to modify the properties of the biological barrier to
absorption.
[0105] Controlled release transdermal devices rely for their effect
on delivery of a known flux of drug to the skin for a prolonged
period of time, generally a day, several days, or a week. Two
mechanisms are used to regulate the drug flux: either the drug is
contained within a drug reservoir, which is separated from the skin
of the wearer by a synthetic membrane, through which the drug
diffuses; or the drug is held dissolved or suspended in a polymer
matrix, through which the drug diffuses to the skin. Devices
incorporating a reservoir will deliver a steady drug flux across
the membrane as long as excess undissolved drug remains in the
reservoir; matrix or monolithic devices are typically characterized
by a falling drug flux with time, as the matrix layers closer to
the skin are depleted of drug. Usually, reservoir patches include a
porous membrane covering the reservoir of medication which can
control release, while heat melting thin layers of medication
embedded in the polymer matrix (e.g., the adhesive layer), can
control release of drug from matrix or monolithic devices.
Accordingly, the active agent can be released from a patch in a
controlled fashion without necessarily being in a controlled
release formulation.
[0106] Patches can include a liner which protects the patch during
storage and is removed prior to use; drug or drug solution in
direct contact with release liner; adhesive which serves to adhere
the components of the patch together along with adhering the patch
to the skin; one or more membranes, which can separate other
layers, control the release of the drug from the reservoir and
multi-layer patches, etc., and backing which protects the patch
from the outer environment.
[0107] Common types of transdermal patches include, but are not
limited to, single-layer drug-in-adhesive patches, wherein the
adhesive layer contains the drug and serves to adhere the various
layers of the patch together, along with the entire system to the
skin, but is also responsible for the releasing of the drug;
multi-layer drug-in-adhesive, wherein which is similar to a
single-layer drug-in-adhesive patch, but contains multiple layers,
for example, a layer for immediate release of the drug and another
layer for control release of drug from the reservoir; reservoir
patches wherein the drug layer is a liquid compartment containing a
drug solution or suspension separated by the adhesive layer; matrix
patches, wherein a drug layer of a semisolid matrix containing a
drug solution or suspension which is surrounded and partially
overlaid by the adhesive layer; and vapor patches, wherein an
adhesive layer not only serves to adhere the various layers
together but also to release vapor. Methods for making transdermal
patches are described in U.S. Pat. Nos. 6,461,644, 6,676,961,
5,985,311, and 5,948,433.
[0108] In a particularly preferred embodiment, THIP or a derivative
thereof, is formulated for transdermal delivery and administered
using a transdermal patch. In some embodiments, the formulation,
the patch, or both are designed for extended release of the THIP or
derivative thereof.
[0109] Exemplary symptoms, pharmacologic, and physiologic effects
are discussed in more detail below.
III. Methods of Treating Secondary Insomnia
[0110] Methods of treating secondary insomnia are provided. The
methods can include administering to the subject an effective
amount of 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP) or
a derivative thereof to decrease sleep disruption, increase slow
wave sleep (SWS) and/or slow wave activity (SWA), normalize sleep
architecture, reduce secondary insomnia, increase non-rapid eye
movement (NREM) sleep, increase sleep continuity, enhance delta
activity within NREM, increase or improve total sleep time (TST),
increase or improve sleep efficiency, reduce total time awake
(TAA), reduce number of awakenings (NWA), reduce latency to
persistent sleep (LPS), reduce wake after sleep onset (WASO), or
any combination thereof. In preferred embodiments, REM sleep is not
substantially reduced. In some embodiments, the methods are
effective to reduce, delay, or prevent one or more other clinical
symptoms of a neurodegenerative disease or central nervous system
disease or disorder.
[0111] A. Treatment Protocol
[0112] It has been discovered that THIP and derivatives thereof can
be used to treat secondary insomnia. Secondary insomnia is the
symptom or side effect of another problem, for example, an
emotional, neurological, or other medical or sleep disorder.
Accordingly, the subject to be treated typically suffers from both
insomnia and an underlying disease, disorder, or condition that is
causing the insomnia.
[0113] Emotional disorders that can cause insomnia include
depression, anxiety, and posttraumatic stress disorder. Conditions
that cause chronic pain, such as arthritis and headache disorders;
conditions that make it hard to breathe, such as asthma and heart
failure; an overactive thyroid; gastrointestinal disorders, such as
heartburn; stroke; sleep disorders, such as restless legs syndrome
and sleep-related breathing problems; menopause and hot flashes;
medication for example asthma medicines, such as theophylline, as
well as some allergy and cold medicines, beta blockers, and
medicines used to treat heart conditions can also cause secondary
insomnia. Use of caffeine and other stimulants, tobacco or other
nicotine products, and alcohol or other sedatives can also lead to
secondary insomnia.
[0114] In a preferred embodiment, the secondary insomnia is caused
by a neurological disease or disorder, such as one those described
in more detail below.
[0115] 1. Sleep Architectur.
[0116] In some embodiments, the subject has or is at risk for
developing reduced slow wave sleep, disrupted sleep architecture,
or would otherwise benefit from increased slow wave sleep.
Therefore, in some embodiments, the compositions are administered
in an effective amount to reduce, alleviate, or prevent one or more
sleep related symptoms. In preferred embodiments, THIP or
derivative thereof is administered to the subject in an effective
amount to decrease sleep disruption, increase slow wave sleep (SWS)
and/or slow wave activity (SWA), normalize sleep architecture,
reduce secondary insomnia, increase non-rapid eye movement (NREM)
sleep, increase sleep continuity, enhance delta activity within
NREM, increase or improve total sleep time (TST), increase or
improve sleep efficiency, reduce total time awake (TAA), reduce
number of awakenings (NWA), reduce latency to persistent sleep
(LPS), reduce wake after sleep onset (WASO), or any combination
thereof. In preferred embodiments, REM sleep is not substantially
reduced.
[0117] Sleep is an active process generated and modulated by a
complex set of neural systems located mainly in the hypothalamus,
brainstem, and thalamus. Sleep is altered in many neurological
diseases due to mechanisms including lesions of the brain areas
that control sleep and wakefulness, lesions or diseases that
produce pain, reduced mobility, and treatments. Excessive daytime
sleepiness (EDS), sleep fragmentation, insomnia, sleep-disordered
breathing (SDB), nocturnal behavioral phenomena such as rapid eye
movement (REM) sleep behavior disorder or nocturnal seizures,
restless legs syndrome, and periodic leg movement syndrome (PLMS)
are common symptoms and findings in neurological disorders (Jennum,
et al., "CHAPTER 39: Sleep disorders in neurodegenerative disorders
and stroke", European Handbook of Neurological Management, Volume
1, 2nd Edition (Ed. Gilhus, et al.) Blackwell Publishing Ltd.
2011). In some cases, sleep disorders precede and influence the
disease course in neurological diseases, particularly those
involving daytime functioning, quality of life, morbidity, and
mortality.
[0118] Evidence is also emerging that subjects with HD can suffer
from abnormalities in both sleep and in the control of daily or
`circadian` rhythms (Morton, "HDBuzz Special Feature: Huntington's
disease and sleep" HDbuzz.net/115, (ed., Wild), Feb. 6, 2013).
Therefore, sleep and circadian dysfunction are symptoms of HD.
Other sleep-related symptoms in patients with Huntington's disease
in the diminishment of involuntary movements tend to diminish
during sleep, sleep disturbances, including disturbed sleep pattern
with an increased sleep onset latency, reduced sleep efficiency,
frequent nocturnal awakenings, and more time spent awake with less
slow wave sleep. These abnormalities can correlate in part with the
duration of illness, severity of clinical symptoms, and degree of
atrophy of the caudate nucleus. The sleep phenotype of Huntington's
disease may also include insomnia, advanced sleep phase, periodic
leg movements, REM sleep behavior disorder (RBD), and reduced REM
sleep. Reduced REM sleep may precede chorea, and mutant huntingtin
may exert an effect on REM sleep and motor control during
sleep.
[0119] Sleep-wake problems are also frequent, although often
unrecognized, complications of amyotrophic lateral sclerosis (ALS).
Sleep disorders such as insomnia, sleep-disordered breathing and
restless legs syndrome have all been reported in patients with ALS,
despite the limited number of studies and the small populations
investigated so far (Lo Coco, et al., Neurodegenerative Disease
Management, 2(3):315-324 (2012)). The prognosis in ALS is closely
related to respiratory muscle strength, and sudden nocturnal death
often occurs during sleep. Respiratory indices such as low
nocturnal oxygen saturation are associated with a poorer prognosis.
Patients with diaphragmatic involvement may have significantly
reduced REM sleep. Patients with dementias often present circadian
disturbances which have been treated with melatonin and light
therapy.
[0120] Sleep and circadian dysfunction may be caused by other
symptoms of the neurodegenerative disease, or may be caused by
factors that are independent of the disease. Sleep and circadian
dysfunction can be caused by personal habits, lifestyle or
environment, for example, staying up too late, getting up too
early, taking drugs that interfere with sleep, and/or
over-stimulation due to late-night activities such as work,
television, etc. Sleep and circadian disturbance in
neurodegenerative disease patients are likely to contribute to
disease symptoms that are worsened by sleep deprivation, such as
irritability and anxiety, and may precede and influence the disease
course involving daytime functioning, quality of life, morbidity,
and mortality. For example, sleep disturbances have been reported
to gradually worsen with disease progression in ALS, indicating a
relationship between the severity of disease and the
neurodegenerative process. Furthermore, subjects with a
neurodegenerative disease may not have the same neurological
reserves to handle sleep deprivation that healthy subjects rely
upon.
[0121] Poor sleep can also be a consequence of several disturbances
such as anxiety, depression, pain, choking, sialorrhea,
fasciculations, cramps, nocturia and the inability to get
comfortable and move freely in bed. Sleep disorders may have many
reflections on patients including excessive daytime somnolence,
fatigue, impaired cognition, reduced quality of life and survival
(Lo Coco, et al., Neurodegenerative Disease Management,
2(3):315-324 (2012)).
[0122] Circadian rhythms and sleep are two different processes,
although the terms are often used interchangeably. Circadian
rhythms are biological processes that change roughly every 24
hours. They are orchestrated by a small part of the brain known as
the suprachiasmatic nucleus or SCN, which regulates the body's
activities including when to get up and when to go to bed. Sleep is
a circadian behavior, but is just one of many circadian behaviors
that are influenced by the SCN. Others include heart rate, hormone
secretion, blood pressure and body temperature.
[0123] During the night, sleep follows a predictable pattern,
moving back and forth between deep restorative sleep (deep sleep)
and more alert stages (collective referred to as Non-REM or NREM)
and dreaming (REM sleep). Specifically, the sleep cycle includes
stages W (wakefulness), N1 (NREM 1), N2 (NREM 2), N3 (NREM3), and R
(REM). Sleep stages can be identified by monitoring a subject's
brain electrical activity (e.g., brain waves). The criteria for
each stage, and methods for determining the stage of a sleeping
subject, and profiling a subject's sleep architecture are described
in Iber, et al., "The AASM Manual for the Scoring of Sleep and
Associated Events, American Academy of Sleep Medicine", pg. 1-57
(2007), which is specifically incorporated by reference herein in
its entirety.
[0124] Together, the stages of REM and non-REM sleep form a
complete sleep cycle. Each cycle typically lasts about 90 minutes
and repeats four to six times over the course of a typical night's
sleep. A normal adult spends approximately 50% of total sleep time
in Stage 2 sleep, 20% in REM sleep, and 30% in the remaining
stages, including deep sleep. For example, a typical first sleep
cycle, N1, is characterized by a low-voltage, mixed-frequency
pattern, and may last for about 1 to about 10 minutes. The second
stage, N2, comes next is characterized by sleep spindles and/or K
complexes in the EEG recording. N2 generally lasts about 10 to
about 25 minutes. As N2 sleep progresses, there is a gradual
appearance of the high-voltage, slow-wave activity characteristic
of N3, the third stage of NREM sleep. This stage, which generally
lasts about 20 to about 40 minutes, is referred to as "slow-wave,"
"delta," or "deep" sleep. Following the N3 stage of sleep, a series
of body movements usually signals an "ascent" to lighter NREM sleep
stages. Typically, a 5 to 10 minute period of N2 precedes the
initial REM sleep episode. REM sleep episodes, the first of which
may last only one to five minutes, generally become longer through
the night. During a typical night, N3 sleep occupies less time in
the second cycle than the first and may disappear altogether from
later cycles. The average length of the first NREM-REM sleep cycle
is between 70 and 100 minutes; the average length of the second and
later cycles is about 90 to 120 minutes. REM sleep makes up about
20 to 25 percent of total sleep in typical healthy adults ("Natural
Patterns of Sleep"
healthysleep.med.harvard.edu/healthy/science/what/sleep-patterns-rem-nrem-
, A resource from the Division of Sleep Medicine at Harvard Medical
School (2007)).
[0125] The duration of the stages of the sleep cycle alone, or in
combination with the cycling of the stages can be referred to as a
subject's sleep architecture. In some embodiments,
neurodegenerative disease subjects have disrupted sleep
architecture, for example, an alteration in the duration of one or
more sleep cycles, an alternation in the duration or number of
sleep cycles, or any combination thereof compared to a control or
reference value. A control or reference value in this case can be,
for example, an average, normal duration for the stage, or average
normal duration or number of cycles in subject or subjects that do
not suffer from disrupted or disturbed sleep architecture (e.g., a
healthy subject).
[0126] Therefore, in some embodiments, THIP or a derivative thereof
is administered to a subject in an effective amount to normalize a
subject's sleep architecture, for example, by bringing one or more
aspects of the subject's sleep architecture into closer alignment
with that of a normal subject.
[0127] Slow-wave sleep (SWS), often referred to as deep sleep,
consists of N3, non-rapid eye movement sleep. The 1968
categorization of the combined Sleep Stages 3-4 was reclassified in
2007 as Stage N3. An epoch (30 seconds of sleep) which consists of
20% or more of slow wave (delta) sleep, is now considered to be
stage 3 (Gazzaniga, Just the Facts 101, e-Study Guide for:
Psychological Science, Content Technologies Inc., 2014). Slow-wave
sleep is believed to be important to consolidate new memories, and
sleep deprivation studies with humans indicate that among other
things, an important function of slow-wave sleep may be to allow
the brain to recover from its daily activities.
[0128] Rapid eye movement (REM) sleep is a stage of sleep
characterized by the rapid and random movement of the eyes and can
be classified into two categories: tonic and phasic. Criteria for
REM sleep includes rapid eye movement, low muscle tone and a rapid,
low-voltage EEG--features which can be identified by polysomnogram.
REM sleep typically occupies 20-25% of total sleep, about 90-120
minutes of a night's sleep.
[0129] In some embodiments THIP or a derivative thereof is
administered to a subject in an effective amount to increase the
length of one or more N3 stages during a subject's sleep, increase
the number of N3 stages during a subject's sleep, or a combination
thereof. In some embodiments, the compositions increase slow wave
sleep by at least 15 minutes, at least 30 minutes, at least 45
minutes, at least 60 minutes, at least 75 minutes, at least 90
minutes, or at least 120 minutes over the course of the sleeping
period (e.g., overnight). In some embodiments the compositions
double or more the amount of slow wave sleep in the subject.
[0130] 2. Dosage and Administratio.
[0131] The disclosed methods of treating secondary insomnia
typically include administering to a subject in need thereof an
effective amount of THIP or a derivative thereof, preferably is a
pharmaceutically acceptable composition such as those discussed in
more detail above.
[0132] The effective amount or therapeutically effective amount is
typically a dosage sufficient to decrease sleep disruption,
increase slow wave sleep (SWS) and/or slow wave activity (SWA),
normalize sleep architecture, reduce secondary insomnia, increase
non-rapid eye movement (NREM) sleep, increase sleep continuity,
enhance delta activity within NREM, increase or improve total sleep
time (TST), increase or improve sleep efficiency, reduce total time
awake (TAA), reduce number of awakenings (NWA), reduce latency to
persistent sleep (LPS), reduce wake after sleep onset (WASO), or
any combination thereof. In preferred embodiments, REM sleep is not
substantially reduced.
[0133] In some embodiment the method reduces or prevents one or
more neuropsychiatric morbidities in a subject with a
neurodegenerative disease or disorder. Therefore, the amount can be
effective to treat or prevent one or more symptoms of a
neurodegenerative disease or central nervous system disorder, or to
otherwise provide a desired pharmacologic and/or physiologic
effect.
[0134] The precise dosage will vary according to a variety of
factors such as subject-dependent variables (e.g., age, immune
system health, clinical symptoms etc.). Exemplary dosages,
symptoms, pharmacologic, and physiologic effects are discussed in
more detail below.
[0135] Studies of the effect of gaboxadol in improving sleep in
subjects are discussed and reviewed in Walsh, et al., Journal of
Clinical Sleep Medicine, 5(2):527-532 (2009) and Deacon, et al.,
Sleep, 30(3):281-287 (2007). For example, 15 mg of gaboxadol
resulted in significantly more stage 4 sleep and SWS (but not stage
3) compared with the placebo group (both p<0.001) in subjects
under sleep-restriction (a mean of 21.8 minutes more SWS was seen
with gaboxadol compared to placebo over four sleep-restriction
nights), Walsh, et al., Journal of Clinical Sleep Medicine,
5(2):527-532 (2009). Gaboxadol also resulted in small but
significant reductions in stage 1 sleep, REM sleep, and shifts to
wake or stage 1 sleep relative to placebo.
[0136] In another dose-response study, 5, 10, or 15 mg gaboxadol
was administered to 109 healthy subjects in whom habitual sleep
time was advanced by 4 hours to produce transient sleep disruption
(Walsh, et al., Sleep, 30:593-602 (2007)). The study results show
that gaboxadol produced a dose-related increase of approximately 5
to 22 minutes in SWS compared with placebo. TST was significantly
increased by approximately 30 minutes (p<0.001) and WASO was
reduced by approximately 17-20 minutes (p<0.05) compared to
placebo at all dosages. Subjective measures of sleep quality also
improved with gaboxadol relative to placebo.
[0137] A dose-related study of 40 primary insomnia subjects
administered 10 and 20 mg of gaboxadol also reported an increase in
SWS compared with placebo (10 mg: p<0.01; 20 mg: p<0.001)
(Lundahl, et al., Psychopharmacology (Berl), 195:139-46 (2007).
Gaboxadol at dosage of 20 mg significantly reduced WASO
(p<0.01), and both doses of gaboxadol significantly reduced NASO
(p<0.001). Gaboxadol at a dosage of 20 mg also significantly
increased TST (p<0.05).
[0138] In another study of the effect of gaboxadol on 26 patients
with primary insomnia, 15 mg was shown to enhance SWS in a study
without significantly affecting stage 1, stage 2, or REM sleep
(Deacon, et al., Sleep, 30(3):281-287 (2007)). Gaboxadol at dosages
5 mg and 15 mg significantly improved TST (p<0.05). The results
also indicate that WASO improved, however, statistical significance
was only achieved with the 5 mg dose. A gaboxadol dosage of 15 mg
also significantly reduced latency to persistent sleep
(p<0.05).
[0139] Furthermore, in pre-clinical studies and in studies in
healthy young and elderly individuals, gaboxadol was found to
increase NREM sleep, sleep continuity, enhances delta activity
within NREM sleep, and increase SWS/SWA without suppressing REM
sleep (Lancel, et al., Neuroreport, 7:2241-5 (1996), Lancel, et
al., Sleep, 20:1099-104 (1997), Faulhaber, et al.,
Psychopharmacology (Berl), 130:285-91 (1997), Lancel, Sleep,
22:33-42 (1999), Lancel, et al., Am J Physiol Endocrinol Metab,
281:E130-7 (2001), Mathias, et al., Psychopharmacology (Berl),
157:299-304 (2001), Mathias, et al., Neuropsychopharmacology,
30:833-41 (2005)).
[0140] In preferred embodiments, THIP or derivative thereof is
administered to a subject in an effective amount to increase slow
wave sleep in the subject.
[0141] Particularly preferred embodiments include formulations for
extended release. For example, the formulation can be suitable for
administration once daily or less. In some embodiments, the
composition is only administered to the subject once every 24-48
hours. In some embodiments, THIP or a derivative thereof is
administered at night before sleep. In other embodiments, THIP or a
derivative thereof is administered in morning, or at least several
hours before sleep.
[0142] The timing of the administration of the composition will
depend on the formulation and/or route of administration used. In
some embodiments, administration of the composition will be given
as a long-term treatment regimen whereby pharmacokinetic steady
state conditions will be reached. Medication for peroral or
parenteral administration may also be given in immediate relation
to a particular sleeping period, for instance 10 minutes to 3 hours
prior to the onset of sleep. Thus, the composition can be
administered in immediate relation to a particular sleeping period,
for example, from 5 minutes to 5 hours prior to onset of sleep, 10
minutes to 3 hours prior to the onset of sleep.
[0143] A preferred route of administration is transdermal, for
example, a transdermal patch or gel that is contacted with the skin
of the subject. In a particular embodiment, the transdermal
formulation is administered to a subject prior to the subject going
to sleep (e.g., at night) using a transdermal patch. In another
particular embodiment, the transdermal formulation is administered
to a subject in the morning using a transdermal patch. As discussed
in more detail below, in some methods a subject with a
neurodegenerative disease or central nervous system disorder is
transdermally administered an amount of THIP or a derivative
thereof effective to decrease sleep disruption or increase slow
wave sleep in the subject.
[0144] In general, by way of example only, dosage forms useful in
the disclosed methods can include doses in the range of 0.1 to
1,000 mg, 1 to 200 mg, 5 to 175 mg, 7.5 to 150 mg, or 10 to 125 mg,
or 12.5 to 150 mg, or 15 to 125 mg, or 17.5 to 100 mg, or 20 to 75
mg, or 22.5 to 60 mg, or 25 to 50 mg, with doses of 1 mg, 5 mg, 10
mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg,
60 mg, 75 mg, and 100 mg being specific examples of preferred
doses. Typically, such dosages are administered once, twice, or
three times daily, or every other day to a human.
[0145] A typical oral dose form preferably includes from about 2.5
mg to about 30 mg THIP. Preferably, the THIP is in a crystalline
form. Further embodiments of the medicament comprises an effective
amount of THIP from 2.5 mg to 20 mg, such as 2.5 mg to 4 mg, 4 mg
to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14
mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg, e.g. 2.5 mg,
5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, or 20 mg. A typical
embodiment is about 5 mg to about 20 mg of crystalline THIP, such
as the hydrochloride of THIP. Typically, such dosages are
administered once, twice, or three times daily, or every other day
to a human. In some embodiments, the total amount administered to a
subject in 24 hour period is 1 mg to 50 mg. In some embodiments,
the subject is started at a low dose and the dosage is escalated in
the drug is well tolerated in the subject.
[0146] When given orally in healthy subjects, gaboxadol is rapidly
absorbed (tmax of 30-60 min) and eliminated (t1/2 of 1.5 h)
(Deacon, et al., Sleep, 30(3):281-287 (2007)). More than 95% of the
dose is excreted in the urine, mostly unchanged, with a glucoronide
conjugate being the only metabolite formed in significant
amounts.
[0147] In some embodiments, the effect of the composition on a
subject is compared to a control. For example, the effect of the
composition on a particular symptom, pharmacologic, or physiologic
indicator can be compared to an untreated subject, or the condition
of the subject prior to treatment. In some embodiments, the
symptom, pharmacologic, or physiologic indicator is measured in a
subject prior to treatment, and again one or more times after
treatment is initiated. In some embodiments, the control is a
reference level, or average determined based on measuring the
symptom, pharmacologic, or physiologic indicator in one or more
subjects that do not have the disease or condition to be treated
(e.g., healthy subjects). In some embodiments, the effect of the
treatment is compared to a conventional treatment that is known the
art, such as one of those discussed herein.
[0148] 3. Intravenous Delivery
[0149] In some embodiments, the composition is administered by
intravenous injection or infusion. When administered orally,
transport of gaboxadol from the intestine into the portal
circulation takes place via the transporter PAT1. Because the amino
acid substrates of the PAT1 transporter, including but not limited
to, proline, tryptophan, alanine, and glycine, are present in food,
their presence during oral administration can influence absorption
of the gaboxadol. More specifically, PAT1 inhibitors such as
L-tryptophan can decrease the absorption rate constant, k.sub.a,
and Cmax, and increase T.sub.max of gaboxadol (see, for example,
Larsen, et al., Br. J. Pharmacol., 157(8):1380-1389 (2009) and WO
2009/056146). Therefore, it is believed that intravenous
administration can improve control of plasma levels (and brain
levels) over oral administration due to significant variability of
gaboxadol uptake via the oral route. Furthermore, high peak
concentrations of gaboxadol in predisposed individuals leads to
hallucinations and has resulted in discontinuation of the drug's
administration to some subjects. Intravenous delivery provides the
ability to titrate dose which ensures that high peak C.sub.max is
not observed, and helps avoid this potential adverse event.
[0150] In some embodiments, the use of intravenous administration
allows for the composition to be delivered in a lower dosage than,
for example, when it is delivered orally. A preferred rate for IV
delivery is 0.001 mg/kg per hour to 1 mg/kg per hour. The treatment
can be administered for the course of minutes, hours, or days.
Dosages, including totally daily dosages, are discussed above. In
particular embodiments, a single treatment includes intravenously
administering to a subject in need thereof a total of between about
0.001 mg and about 30 mg of THIP or derivative thereof. In some
embodiments, the administration is repeated at least once with an
interval of about 3 to about 5 hours. In some embodiments, the
administration is repeated at least six times in a period of
twenty-four hours. In various embodiments, the administration is
repeated three to eight times (e.g., three times, four times, five
times, six times, seven times, or eight times) in a period of
twenty-four hours and between about 0.001 mg and about 30 mg of
THIP or derivative thereof is delivered over the twenty-four hour
period. Dosage regimens are also discussed above. For example, in
some embodiments, a single treatment can be repeated 1, 2, 3, 4, 5,
6, 7, or more days, weeks, or months apart. Intravenous
administration increases the ease with which side effects
associated with dosage escalation can be monitored, improves the
ability to control plasma concentrations, and includes the ability
to titrate dosage. Accordingly, in some embodiments, the
intravenous dosage regimen includes escalation of the dosage from
0.001 mg to about 30 mg of THIP or derivative thereof in a
twenty-four hour period, until the dosage is effective to treat the
subject, and preferably without inducing undesirable side effects.
Intravenous protocols can also be adapted from those known in the
art. See, for example, U.S. Published Application 2009/0143474.
[0151] B. Conditions, Symptoms, Subjects, and Diseases to be
Treated
[0152] The disclosed compositions are typically administered to
subjects with a neurodegenerative disease or disorder or central
nervous system disorder, particularly those leading to secondary
insomnia in the subject. Neurodegeneration refers to the
progressive loss of structure or function of neurons, including
death of neurons. Exemplary diseases and disorders are provided
below. In some embodiments, the compositions are administered to
subjects that do not have a neurodegenerative disease or
disorder.
[0153] Neurodegeneration, and diseases and disorders thereof, can
be caused by a genetic mutation or mutations; protein misfolding;
intracellular mechanisms such as dysregulated protein degradation
pathways, membrane damage, mitochondrial dysfunction, or defects in
axonal transport; defects in programmed cell death mechanisms
including apoptosis, autophagy, cytoplasmic cell death; and
combinations thereof. More specific mechanisms common to
neurodegenerative disorders include, for example, oxidative stress,
mitochondrial dysfunction, excitotoxicity, inflammatory changes,
iron accumulation, and/or protein aggregation.
[0154] 1. Symptoms
[0155] In some embodiments, the disclosed compositions are
administered to a subject in need thereof in an effective amount to
reduce or prevent one or more molecular or clinical symptoms of a
neurodegenerative disease, or one or more mechanisms that cause
neurodegeneration. Symptoms of neurodegenerative diseases are known
in the art and vary from disease to disease. In some embodiments,
the disease exhibits or is characterized by one or any combination
of the following symptoms or diseases: stress, anxiety, seasonal
depression, insomnia and tiredness, schizophrenia, panic attacks,
melancholy, dysfunction in the regulation of appetite, insomnia,
psychotic problems, epilepsy, senile dementia, various disorders
resulting from normal or pathological aging, migraine, memory loss,
disorders of cerebral circulation, cardiovascular pathologies,
pathologies of the digestive system, fatigue due to appetite
disorders, obesity, pain, psychotic disorders, diabetes, senile
dementia, or sexual dysfunction. In some embodiments, the subject
does not exhibit one or more of the preceding symptoms.
[0156] In some embodiments, the subject has been medically
diagnosed as having a neurodegenerative disease or a condition in
need of neuroprotection by exhibiting clinical (e.g., physical)
symptoms of the disease. As discussed above, in some patients the
appearance of sleep-related disorder precedes a clinical diagnosis
of a disease. Therefore, in some embodiments, the compounds or
compositions disclosed herein are administered prior to a clinical
diagnosis of a disease or condition. In some embodiments, a genetic
test indicates that the subject has one or more genetic mutations
associated with a neurodegenerative disease or central nervous
system disorder.
[0157] Neurodegenerative diseases are typically more common in aged
individuals. Therefore in some embodiments, the subject is greater
the 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 years in
age.
[0158] 2. Diseases to be Treated
[0159] The methods disclosed herein can be used to treat subjects
with a neurodegenerative disease or disorder. Exemplary
neurodegenerative diseases include, but are not limited to,
Parkinson's Disease (PD) and PD-related disorders, Huntington's
Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Alzheimer's
Disease (AD) and other dementias, Prion Diseases such as
Creutzfeldt-Jakob Disease, Corticobasal Degeneration,
Frontotemporal Dementia, HIV-Related Cognitive Impairment, Mild
Cognitive Impairment, Motor Neuron Diseases (MND), Spinocerebellar
Ataxia (SCA), Spinal Muscular Atrophy (SMA), Friedreich's Ataxia,
Lewy Body Disease, Alpers' Disease, Batten Disease,
Cerebro-Oculo-Facio-Skeletal Syndrome, Corticobasal Degeneration,
Gerstmann-Straussler-Scheinker Disease, Kuru, Leigh's Disease,
Monomelic Amyotrophy, Multiple System Atrophy, Multiple System
Atrophy With Orthostatic Hypotension (Shy-Drager Syndrome),
Multiple Sclerosis (MS), Neurodegeneration with Brain Iron
Accumulation, Opsoclonus Myoclonus, Posterior Cortical Atrophy,
Primary Progressive Aphasia, Progressive Supranuclear Palsy,
Vascular Dementia, Progressive Multifocal Leukoencephalopathy,
Dementia with Lewy Bodies, Lacunar syndromes, Hydrocephalus,
Wernicke-Korsakoff's syndrome, post-encephalitic dementia, cancer
and chemotherapy-associated cognitive impairment and dementia, and
depression-induced dementia and pseudodementia.
[0160] In some embodiments, the subject has a central nervous
system disorder or is in need of neuroprotection. Exemplary
conditions and/or subjects include, but are not limited to,
subjects having had, subjects with, or subjects likely to develop
or suffer from a stroke, a traumatic brain injury, a spinal cord
injury, Post Traumatic Stress syndrome, or a combination
thereof.
[0161] a. Huntington's Disease
[0162] The methods disclosed herein can be used to treat subjects
with Huntington's disease. Huntington's disease (HD) is a
neurodegenerative genetic disorder that affects muscle coordination
and leads to cognitive decline and psychiatric problems. The
chronic pathology in HD leads to numerous associated troubles
including cognitive dysfunctions, more specifically dysfunction in
thought and mental representations, changes in reasoning, in
judgment. HD is caused by an autosomal dominant mutation in either
of an individual's two copies of the Huntingtin (HTT) gene. Part of
this gene is a repeated section called a trinucleotide repeat,
which varies in length between individuals and may change length
between generations. If the repeat is present in a healthy gene, a
dynamic mutation may increase the repeat count and result in a
defective gene. When the length of this repeated section reaches a
certain threshold, it produces an altered form of the protein,
called mutant Huntingtin protein (mHtt). The differing functions of
these proteins are the cause of pathological changes which in turn
cause the disease symptoms. The Huntington's disease mutation is
genetically dominant and almost fully penetrant. Mutation of either
of a person's HTT genes can cause the disease. Physical symptoms of
Huntington's disease can begin at any age from infancy to old age,
but usually begin between 35 and 44 years of age (Walker, et al.,
Lancet, 369(9557):218-28 (2007)).
[0163] In some embodiments, the subject exhibits one or more of the
HD clinical symptoms, one or more HD molecular symptoms, or a
combination thereof, such as those discussed herein and elsewhere.
Clinical symptoms of HD are known in the art and include behavioral
disturbances including, but not limited to, hallucinations,
irritability, moodiness, restlessness, fidgeting, paranoia,
psychosis, suicidal thoughts, and suicide attempts; abnormal and/or
unusual movements including, but not limited to, chorea, facial
movements such as grimaces, head turning to shift eye position,
quick, sudden, sometimes wild jerking movements of the arms, legs,
face, and other body parts, slow, uncontrolled movements, unsteady
gait, small unintentionally initiated or uncompleted motions, and
lack of coordination; cognitive impairment and/or dementia-related
symptoms including, but not limited to, disorientation and/or
confusion, loss of judgment, loss of memory, personality changes,
and speech changes; and other symptoms including anxiety, stress,
tension, difficulty swallowing, speech impairment, rigidity, slow
movements, tremor, malnutrition, and weight loss. Neuropsychiatric
features are a core component of the disease.
[0164] Mutant Huntingtin is expressed throughout the body and
associated with abnormalities in peripheral tissues that are
directly caused by such expression outside the brain. These
abnormalities include muscle atrophy, cardiac failure, impaired
glucose tolerance, weight loss, osteoporosis and testicular
atrophy.
[0165] A number of studies have examined the prevalence of the
myriad of symptoms in subjects with Huntington's disease. Shiwach,
Acta Psychiatr Scand, 90(4):241-6 (1994) reports the results of a
retrospective study of 110 patients with Huntington disease in 30
families. The study found the minimal lifetime prevalence of
depression to be 39%. The frequency of symptomatic schizophrenia
was 9%, and significant personality change was found in 72% of the
sample. The age at onset was highly variable. Some showed signs in
the first decade and some not until over 60 years of age.
[0166] Rosenberg, et al., J Med Genet., 32(8):600-4 (1995)
describes a double-blind study on 33 persons at risk for HD who had
applied for genetic testing. Significantly inferior cognitive
functioning was disclosed in gene carriers by a battery of
neuropsychologic tests covering attentional, visuospatial,
learning, memory, and planning functions. Primarily, attentional,
learning, and planning functions were affected.
[0167] Bamford, et al., Neurology, 45(10):1867-73 (1995) reports a
prospective analysis of neuropsychologic performance and CT scans
of 60 individuals with Huntington's disease. The study found that
psychomotor skills showed the most significant consistent decline
among cognitive functions assessed.
[0168] Marshall, et al., Arch Neurol., 64(1):116-21 (2007) reports
a study comparing psychiatric manifestations among 29 HD mutation
carriers with no clinical symptoms, 20 HD mutation carriers with
mild motor symptoms, 34 manifesting HD patients, and 171
nonmutation controls. The mild motor symptoms group and the
manifesting HD group showed significantly higher scores for
obsessive-compulsive behavior, interpersonal sensitivity, anxiety,
paranoia, and psychoticism compared to the nonmutation control
group. The mutation carriers without symptoms had higher scores for
anxiety, paranoid ideation, and psychoticism compared to the
nonmutation control group. The results indicated that individuals
in the preclinical stage of HD exhibit specific psychiatric
symptoms, and that additional symptoms may manifest later in the
disease course. Suicidal ideation is a frequent finding in
Huntington disease and physicians should be aware of increased
suicide risk both in asymptomatic at-risk patients and symptomatic
patients (Walker, et al., Lancet, 369(9557):218-28 (2007)).
[0169] The mechanisms underlying HD are explored in Wang, et al.,
Journal of Neuroscience, 31(41):14496-14507 (2011), which is
discussed in more detail below. The study shows that mutant
huntingtin (htt)-mediated toxicity in cells, mice, and humans is
associated with loss of the type 1 melatonin receptor (MT1). High
levels of MT1 receptor were found in mitochondria from the brains
of wild-type mice but much less in brains from HD mice, melatonin
inhibited mutant htt-induced caspase activation and preserved MT1
receptor expression. Therefore, in some embodiments, the compounds
and compositions disclosed herein are administered to a subject
with HD in an effective amount to treat one or more molecular
symptoms of HD, for example, to reduce, delay or inhibit mutant
htt-induced caspase activation; to reduce or prevent loss of MT1
receptor expression, particularly in the mitochondria of cell of
the subject; or a combination thereof.
[0170] In some embodiments, the subject exhibits one or more
symptoms discussed herein, but does not exhibit all of the
symptoms. Therefore, in some embodiments, the subject does not have
one or more of the symptoms disclosed herein or elsewhere.
[0171] In some embodiments, the subject has been medically
diagnosed as having HD by exhibiting clinical (e.g., physical)
symptoms of the disease. Excessive unintentional movements of any
part of the body are often the first clinical symptoms. If these
are abrupt and have random timing and distribution, they suggest a
diagnosis of HD. Cognitive or psychiatric symptoms are rarely the
first diagnosed and are most typically only recognized in hindsight
or when they develop further. Disease progression can be measured
using the unified Huntington's disease rating scale which provides
an overall rating system based on motor, behavioral, cognitive, and
functional assessments (Huntington Study Group, Movement Disorders,
11(2): 136-142 (1996)).
[0172] Medical imaging, such as computerized tomography (CT) and
magnetic resonance imaging (MRI), and functional neuroimaging
techniques, such as fMRI and PET, can supplement analysis of
physical symptoms but are typically not diagnostic alone.
[0173] Genetic testing can be used to confirm a physical diagnosis
if there is no family history of HD. Even before the onset of
symptoms, genetic testing can confirm if an individual or embryo
carries an expanded copy of the trinucleotide repeat in the HTT
gene that causes the disease. The U.S. government sponsored genetic
disease compendium, the Online Mendelian Inheritance in Man (OMIM)
database, gives HD a phenotype number #143100. The gene/locus is
huntingtin (HTT), and is located on Chromosome 4p16.3 with the
Gene/Locus MIM number of 613004. Assignment of the 143100 number to
the OMIM entry is because Huntington disease (HD) is a monogenetic
disorder caused by an expanded trinucleotide repeat (CAG)n,
encoding glutamine, in the gene encoding huntingtin (HTT; 613004)
on chromosome 4p16.3. The genetic test for HD consists of a blood
test which counts the numbers of CAG repeats in each of the HTT
alleles.
[0174] Cutoffs for genetic testing are given as follows according
to De Die-Smulders, et al., Human Reproduction Update,
19(3):304-315 (2013).
[0175] 40 or more CAG repeats: full penetrance allele (FPA). A
"positive test" or "positive result" generally refers to this case.
A person who tests positive for the disease will develop HD
sometime within their lifetime, provided he or she lives long
enough for the disease to appear.
[0176] 36 to 39 repeats: incomplete or reduced penetrance allele
(RPA). It may cause symptoms, usually later in the adult life.
There is a maximum risk of 60% that a person with an RPA will be
symptomatic at the age of 65 years, and a 70% risk of being
symptomatic at the age of 75 years.
[0177] 27 to 35 repeats: intermediate allele (IA), or large normal
allele. It is not associated with symptomatic disease in the tested
individual, but may expand upon further inheritance to give
symptoms in offspring. 26 or less repeats: Not associated with
HD.
[0178] A positive result is considered different than a clinical
diagnosis, since it may be obtained decades before the symptoms
begin. The test can tell a person who originally had a 50 percent
chance of inheriting the disease if their risk goes up to 100
percent or is eliminated.
[0179] Elsewhere, the range of repeat numbers for normal individual
is 9 to 36, and 37 or greater in HD individuals (Duyao et al., Nat
Genet., 4(4):387-92 (1993)).
[0180] Therefore, in some embodiments, the subject has a "positive
result", or is determined to have incomplete or reduced penetrance
allele (RPA), or is determined to have intermediate allele (IA), or
large normal allele by genetic testing, but does not exhibit any of
the clinical symptoms, or the clinical symptoms are too mild for an
affirmative medical diagnosis. In a particular embodiment, the
subject has a "positive result" but does not exhibit any of the
clinical symptoms, or the clinical symptoms are too mild for an
affirmative medical diagnosis. Accordingly, in some embodiments,
the compounds or compositions disclosed herein are administered
prior to a clinical diagnosis of HD.
[0181] b. Parkinson's Disease
[0182] In a particular embodiment, the disclosed compositions are
used to treat a subject with Parkinson's disease or suffering from
parkinsonism or parkinson's syndrome. PD is a degenerative disorder
of the central nervous system. In some embodiments, the subject
exhibits one or more of the PD clinical symptoms, one or more PD
molecular symptoms, or a combination thereof, such as those
discussed herein and elsewhere. Symptoms of PD are well known in
the art and reviewed in Jankovic, et al., J. Neurol. Neurosurg.
Psychiatr., 79(4): 368-76 (2007). The motor symptoms of Parkinson's
disease result from the death of dopamine-generating cells in the
substantia nigra, a region of the midbrain. The cause of the cell
death remains unknown. Early in the course of the disease, the most
obvious symptoms are movement-related and include, but are not
limited to, shaking, rigidity, slowness of movement and difficulty
with walking and gait. In particular, four motor symptoms
considered hallmarks of PD are tremor, rigidity, slowness of
movement, and postural instability. The main motor symptoms are
collectively called parkinsonism, or a "parkinsonian syndrome".
[0183] Later, thinking and behavioral problems may arise and can
range from mild to severe, with dementia commonly occurring in the
advanced stages of the disease, whereas depression is the most
common psychiatric symptom. Other common neuropsychiatric
disturbances include disorders of speech, cognition, mood,
behavior, and thought. Cognitive disturbances, which can occur in
the initial stages of the disease and sometimes prior to diagnosis,
include executive dysfunction, which can include problems with
planning, cognitive flexibility, abstract thinking, rule
acquisition, initiating appropriate actions and inhibiting
inappropriate actions, and selecting relevant sensory information;
fluctuations in attention and slowed cognitive speed; and memory
loss.
[0184] Other symptoms include sensory, sleep and emotional
problems. In fact, disturbances of sleep and wake are among the
most common and disabling non-motor manifestations of PD, affecting
as many as 90% of patients (Videnovic, et al., JAMA Neurol.
doi:10.1001/jamaneuro1.2013.6239, published online Feb. 24,
2014).
[0185] A physician's diagnosis of PD typically comes from a
combination of medical history and neurological examination. Brain
scans of people with PD typically look normal, but can be used to
rule out disorders that could give rise to similar symptoms.
Although no lab test exists for PD, medical organizations have
created diagnostic criteria to facilitate and standardize the
diagnostic process. See, for example, the UK Parkinson's Disease
Society Brain Bank, the U.S. National Institute of Neurological
Disorders and Stroke, and the PD Society Brain Bank which all
provide criteria for diagnosing PD.
[0186] Parkinson's disease is more common in older people, with
most cases occurring after the age of 50. There is no cure for PD,
and the disease is most typically managed using one or a
combination of levodopa (usually combined with a dopa decarboxylase
inhibitor or COMT inhibitor), dopamine agonists and MAO-B
inhibitors. Other common agents include amantadine and
anticholinergics for treating motor symptoms, clozapine for
treating psychosis, cholinesterase inhibitors for treating
dementia, and modafinil for treating daytime sleepiness. Surgery
and deep brain stimulation can be used, most typically when drugs
are no longer effective. Gene therapies, stem cell transplants,
neuroprotective agents, are also being developed as treatment
options for PD.
[0187] In some embodiments, the subject exhibits one or more of the
PD clinical symptoms, one or more ALS molecular symptoms, or a
combination thereof, such as those discussed herein and elsewhere.
In some embodiments, the subject exhibits one or more symptoms
discussed herein, but does not exhibit all of the symptoms.
Therefore, in some embodiments, the subject does not have one or
more of the symptoms disclosed herein or elsewhere.
[0188] In some embodiments, the subject has been medically
diagnosed as having PD by exhibiting clinical (e.g., physical)
symptoms of the disease. In some embodiments, the subject exhibits
one or more symptoms discussed herein, but does not exhibit all of
the symptoms. Therefore, in some embodiments, the subject does not
have one or more of the symptoms disclosed herein or elsewhere.
[0189] In some embodiments, the subject has been medically
diagnosed as having PD by exhibiting clinical (e.g., physical)
symptoms of the disease. In some patients the appearance of a
sleep-related disorder precedes a clinical diagnosis of PD.
Therefore, in some embodiments, the compounds or compositions
disclosed herein are administered prior to a clinical diagnosis of
PD.
[0190] c. Amyotrophic Lateral Sclerosis
[0191] The methods disclosed herein can be used to treat a subject
with amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis
(ALS) is a fatal motor neuron disease, affecting both the first and
second order motor neurons. The progression of ALS is characterized
by a degeneration of motor neurons associated with a demyelination
in the anterior horn of the spinal cord. The etiology is only
partially understood. Of the 5-10% familial cases, 20% carry a
mutation of the superoxide dismutase 1 (SOD1) gene. Such a mutation
is also present in 5% of the sporadic cases (Rowland, et al., New
Engl J Med, 44:1688-1700 (2001)). Three to four percent 3%-4% of
familial cases are due to pathogenic variants in either the TDP-43
or FUS gene (Mackenzie, et al., Lancet Neurol., 9:995-1007
(2010)).
[0192] In some embodiments, the subject exhibits one or more of the
ALS clinical symptoms, one or more ALS molecular symptoms, or a
combination thereof, such as those discussed herein and elsewhere.
Clinical symptoms of ALS are known in the art. For example, the
earliest symptoms of ALS are typically weakness and/or muscle
atrophy. Other early symptoms include trouble swallowing, cramping,
or stiffness of affected muscles; muscle weakness affecting an arm
or a leg; and/or slurred and nasal speech, and in some cases
dementia.
[0193] To be diagnosed with ALS, a patient must have signs and
symptoms of both upper and lower motor neuron damage that cannot be
attributed to other causes. The diagnosis depends on progressive
degeneration of upper (UMN) and lower (LMN) motor neurons findings
by history and examination and is accurate 95% of the time when
made by an experienced clinician (Gordon, Aging and Disease,
4(5):295-310 (2013)). Electromyography can be used to confirm
widespread lower motor neuron disease and exclude other diseases
such as multifocal motor neuropathy with conduction block. Brain
and spinal MRI rule out conditions that affect the UMN, including
cervical spondylosis. Occasionally the brain MRI shows bilateral
signal changes within the corticospinal tracts, a finding that is
pathognomonic of ALS. The El Escorial criteria help standardize
diagnosis for clinical research studies (Brooks, et al., Amyotroph
Lateral Scler Other Motor Neuron Disord, 1:293-299 (2000)).
[0194] Over time, patients experience increasing difficulty moving,
swallowing (dysphagia), and speaking or forming words (dysarthria).
Symptoms of upper motor neuron involvement include tight and stiff
muscles (spasticity) and exaggerated reflexes (hyperreflexia)
including an overactive gag reflex. An abnormal reflex commonly
called Babinski's sign also indicates upper motor neuron damage.
Symptoms of lower motor neuron degeneration include muscle weakness
and atrophy, muscle cramps, and fleeting twitches of muscles that
can be seen under the skin (fasciculations). Degeneration of bulbar
upper motor neurons can cause exaggeration of motor expressions of
emotion.
[0195] Progression is subject-specific, however, eventually most
patients are not able to walk or use their hands and arms. They
also lose the ability to speak and swallow their food, and most end
on a portable ventilator. The rate of progression can be measured
using an outcome measure called the "ALS Functional Rating Scale
Revised (ALSFRS-R)", a 12-item instrument administered as a
clinical interview or patient-reported questionnaire that produces
a score between 48 (normal function) and 0 (severe disability).
[0196] A survey-based study amongst clinicians showed that they
rated a 20% change in the slope of the ALSFRS-R would be clinically
meaningful (Castrillo-Viguera, et al., Amyotroph Lateral Scler,
11(1-2):178-80 (2010)). Therefore, the composition can be
administered to a subject an amount effective to change in the
slope of the ALSFRS-R of a subject 1%, 5%, 10%, 15%, 20%, or
more.
[0197] In some embodiments, the ALSFRS-R score of the subject is
taken prior to, and one or more after initiation of treatment. In
some embodiments, the ALSFRS-R score takes day, weeks, months, or
more to improve.
[0198] In some embodiments, the subject exhibits one or more of the
ALS clinical symptoms, one or more ALS molecular symptoms, or a
combination thereof, such as those discussed herein and elsewhere.
In some embodiments, the subject exhibits one or more symptoms
discussed herein, but does not exhibit all of the symptoms.
Therefore, in some embodiments, the subject does not have one or
more of the symptoms disclosed herein or elsewhere.
[0199] In some embodiments, the subject has been medically
diagnosed as having ALS by exhibiting clinical (e.g., physical)
symptoms of the disease. In some embodiments, the subject exhibits
one or more symptoms discussed herein, but does not exhibit all of
the symptoms. Therefore, in some embodiments, the subject does not
have one or more of the symptoms disclosed herein or elsewhere.
[0200] In some embodiments, the subject has been medically
diagnosed as having ALS by exhibiting clinical (e.g., physical)
symptoms of the disease. In some patients the appearance of
sleep-related disorder precedes a clinical diagnosis of ALS.
Therefore, in some embodiments, the compounds or compositions
disclosed herein are administered prior to a clinical diagnosis of
ALS. In some embodiments, a genetic test indicates that the subject
has one or more genetic mutations associated with ALS.
[0201] d. Alzheimer's Disease
[0202] The methods disclosed herein can be used to treat a subject
with Alzheimer's disease. Alzheimer's disease (AD) is the most
common form of dementia. Although the cause and progression of AD
are not entirely understood, research indicates plaques and tangles
in the brain play a pathophysiological role. Current treatments
only help with the symptoms of the disease and there are no
available treatments that stop or reverse the progression of the
disease.
[0203] In some embodiments, the subject exhibits one or more of the
AD clinical symptoms, one or more AD molecular symptoms, or a
combination thereof, such as those discussed herein and elsewhere.
Clinical symptoms of AD are known in the art. Although Alzheimer's
disease develops differently for every individual, there are many
common symptoms. Early symptoms are often mistakenly thought to be
"age-related" concerns, or manifestations of stress. One of the
most common early symptoms is short term memory loss. Moderate
stage symptoms can include, for example, increased memory loss and
confusion, problems recognizing family and friends, continuously
repeating stories, favorite wants, or motions, difficulty doing
things that have multiple steps, like getting dressed, and/or lack
of concern for hygiene and appearance. Severe stage symptoms can
include, for example, inability to recognize oneself or family,
inability to communicate, lack of control over bowel and bladder,
groaning, moaning, or grunting, and/or needing help with all
activities of daily living. Other common symptoms can include
confusion, irritability, aggression, mood swings, trouble with
language, and long-term memory loss. Gradually, bodily functions
are lost, ultimately leading to death.
[0204] When AD is suspected, the diagnosis is usually confirmed
with tests that evaluate behavior and thinking abilities (e.g.,
cognitive testing), often followed by a brain scan if available.
Assessment of intellectual functioning including memory testing and
neuropsychological tests such as the mini-mental state examination
(MMSE) are widely used to evaluate the cognitive impairments needed
for diagnosis (Waldemar, et al., Eur J Neurol. 14(1):e1-26 (2007)).
Neurological examination in early AD will usually provide normal
results, except for obvious cognitive impairment, which may not
differ from that resulting from other diseases processes, including
other causes of dementia.
[0205] Examination of brain tissue can lead to a definitive
diagnosis. AD develops for an unknown and variable amount of time
before becoming fully apparent, and it can progress undiagnosed for
years.
[0206] In some embodiments, the subject exhibits one or more of the
AD clinical symptoms, one or more ALS molecular symptoms, or a
combination thereof, such as those discussed herein and elsewhere.
In some embodiments, the subject exhibits one or more symptoms
discussed herein, but does not exhibit all of the symptoms.
Therefore, in some embodiments, the subject does not have one or
more of the symptoms disclosed herein or elsewhere.
[0207] In some embodiments, the subject has been medically
diagnosed as having AD by exhibiting clinical (e.g., physical)
symptoms of the disease. In some embodiments, the subject exhibits
one or more symptoms discussed herein, but does not exhibit all of
the symptoms. Therefore, in some embodiments, the subject does not
have one or more of the symptoms disclosed herein or elsewhere.
[0208] In some embodiments, the subject has been medically
diagnosed as having AD by exhibiting clinical (e.g., physical)
symptoms of the disease. In some patients the appearance of
sleep-related disorder precede a clinical diagnosis of AD.
Therefore, in some embodiments, the compounds or compositions
disclosed herein are administered prior to a clinical diagnosis of
AD.
[0209] e. Traumatic Brain Injury
[0210] In another particular embodiment, the disclosed compositions
are used to treat a subject suffering from traumatic brain injury
(TBI). Traumatic brain injury occurs when an external mechanical
force, typically head trauma, causes brain dysfunction.
[0211] Traumatic brain injury can have wide-ranging physical and
psychological effects. Some signs or symptoms may appear
immediately after the traumatic event, while others may not appear
until days or weeks later. Symptoms of TBI include, but are not
limited to, loss of consciousness; a state of being dazed, confused
or disoriented; memory or concentration problems; headache,
dizziness or loss of balance; nausea or vomiting; sensory problems
such as blurred vision, ringing in the ears or a bad taste in the
mouth; sensitivity to light or sound; mood changes or mood swings;
feeling depressed or anxious; fatigue or drowsiness; difficulty
sleeping; sleeping more than usual, agitation, combativeness or
other unusual behavior; slurred speech; inability to awaken from
sleep; weakness or numbness in fingers and toes; loss of
coordination; convulsions or seizures, dilation of one or both
pupils of the eyes; and/or clear fluids draining from the nose or
ears. In children, additional symptoms include change in eating or
nursing habits; persistent crying and inability to be consoled;
unusual or easy irritability; change in ability to pay attention;
change in sleep habits; sad or depressed mood; and/or loss of
interest in favorite toys or activities.
[0212] TBI can be diagnosed using the Glasgow Coma Scale, a
15-point test that helps a doctor or other emergency medical
personnel assess the initial severity of a brain injury by checking
a person's ability to follow directions and move their eyes and
limbs. The coherence of speech also provides important clues.
Abilities are scored numerically with higher scores indicating more
mild injury. Imaging such as computerized tomography (CT) and
magnetic resonance imaging (MRI), as well as intracranial pressure
monitoring can also be used to assist in the diagnoses by helping
to identify the local(s) and extent of the trauma.
[0213] Conventional treatments for TBI include administration of
agents such as diuretics, anti-seizure drugs, and coma-inducing
drugs; surgery to remove clotted blood, repair skull fractures,
and/or relieve pressure inside the skull.
IV. Methods of Increasing Tonic Inhibition
[0214] Method of using
4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), a derivative
thereof, or a pharmaceutically acceptable salt thereof for
increasing tonic inhibition are also provided. The methods can be
used to increase tonic inhibition in a subject with a disease or
disorder characterized by a defect or deficiency in tonic
inhibition. Exemplary diseases include neurogenetic diseases such
as Fragile X syndrome or Angelman syndrome.
[0215] A. Treatment Protocol
[0216] 1. Tonic Inhibition
[0217] The disclosed methods for increasing tonic inhibition in a
subject typically include administering to a subject in need
thereof an effective amount of THIP or a derivative thereof to
increase tonic inhibition in the brain of the subject.
[0218] Neural inhibition in the mammalian brain is mediated by two
fast transmitters, glycine and gamma-aminobutyric acid (GABA)
(Jonas and Buzaki, Scholarpedia, 2(9):3286 (2007)). Glycine is the
major inhibitory transmitter in the spinal cord, while GABA is the
major transmitter in higher brain regions. GABA released from
presynaptic terminals can activate three different types of
receptors: GABA receptors (GABARs) type A, B, and C. Neural
inhibition can be "phasic" or "tonic". Phasic inhibition is a
short-lasting inhibition most often generated by the activation of
GABAA receptors following action potentials in a presynaptic
interneuron. Among several long-lasting forms of inhibition is
tonic GABAA conductance activated by ambient GABA in the
extracellular space. Tonic inhibition is mediated by molecularly
and functionally specialized GABAA receptors containing alpha6 or
delta subunits, and which display a high affinity for GABA binding.
THIP, is a superagonist of the 6-subunit-containing presynaptic and
extrasynaptic GABA A receptors that mediates strong tonic
inhibitory conductance in the CNS (Brown, et al., Br. J.
Pharmacol., 136:965-974 (2002), Glykys, et al., J Physiol.,
582:1163-1178 (2007), Brown, et al., Cell, 107:477-487 (2001).
[0219] Therefore, THIP can be used to increase tonic inhibition is
a subject in need thereof.
[0220] In vitro and animal model studies show that reduced tonic
inhibition can be an underlying cause of some neurogenetic
diseases. For example, studies show that decreased concentrations
of GABA can lead to decreased tonic inhibition of cerebellar
granule cells which is the underlying cause of cerebellar ataxia in
Angelman syndrome (Egawa, et al., Science Translational Medicine,
4:163ra157 (2012)). Treatment with THIP (500 nM) increased tonic
holding currents and reduced the excitability of cerecellar ganule
cells from a mouse model of Angelman syndrome rescuing the defect.
Doses of THIP (1.25 mg/kg and 2.5 mg/kg) were effective to rescue
cerebellar dysfunction in vivo (reduced hind paw abduction without
effective width or stride), while low effective doses (e.g., 1.25
mg/kg) were effective to rescue cerebellar dysfunction without
adverse effects (reduced time on rotarod).
[0221] Studies also show that impaired GABAergic transmission in
different brain regions such as the amygdala, striatum, or cerebral
cortex contributes to neuron excitability deficits and behavioral
abnormalities in Fragile X syndrome (Olmos-Serrano, et al., Dev.
Neurosci., 33:395-403 (2011), Olmos-Serrano, et al., J. Neurosci.,
30(29):9929-9938 (2010), Braat and Kooy, Drug Discovery Today,
19(4):510-519 (2014)). In vitro experiments reveled that
augmentation of tonic inhibitory tone using THIP rescued the
decreased bioavailability of GABA and reduced tonic currents of
principal neurons of the BL amygdala of Fmrl knockout mice.
Furthermore, THIP treatment improved a number of Fragile X
phenotypes in Fmrl knockout mice in vivo, including, reduction or
dampening of hyperactivity (e.g., measured by travel and velocity),
and reduction of hypersensitivity to auditory stimuli.
[0222] 2. Dosage and Administration
[0223] The disclosed methods of increasing tonic inhibition
typically include administering a subject in need thereof an
effective amount of THIP or a derivative thereof, preferably is a
pharmaceutically acceptable composition such as those discussed in
more detail above.
[0224] The effective amount or therapeutically effective amount is
typically a dosage sufficient to increase tonic inhibition of
neurons in the brain of the subject. In some embodiment the method
reduces or prevents one or more neuropsychiatric morbidities or
phenotypes in a subject with a neurogenetic disease or disorder as
discussed in more detail below. Therefore, the amount can be
effective to treat or prevent one or more symptoms of a
neurogenetic disease, or to otherwise provide a desired
pharmacologic and/or physiologic effect, for example.
[0225] The precise dosage will vary according to a variety of
factors such as subject-dependent variables (e.g., age, immune
system health, clinical symptoms etc.). Exemplary dosages,
symptoms, pharmacologic, and physiologic effects are discussed in
more detail below.
[0226] Particularly preferred embodiments include formulations for
extended release. For example, the formulation can suitable for
administration once daily or less. In some embodiments, the
composition is only administered to the subject once every 24-48
hours.
[0227] The timing of the administration of the composition will
depend on the formulation and/or route of administration used. In
some embodiments, administration of the composition will be given
as a long-term treatment regimen whereby pharmacokinetic steady
state conditions will be reached.
[0228] A preferred route of administration is transdermal, for
example, a transdermal patch that is contacted with the skin of the
subject.
[0229] In general, by way of example only, dosage forms useful in
the disclosed methods can include doses in the range of 0.1 to
1,000 mg, 1 to 200 mg, 5 to 175 mg, 7.5 to 150 mg, or 10 to 125 mg,
or 12.5 to 150 mg, or 15 to 125 mg, or 17.5 to 100 mg, or 20 to 75
mg, or 22.5 to 60 mg, or 25 to 50 mg, with doses of 1 mg, 5 mg, 10
mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg,
60 mg, 75 mg, and 100 mg being specific examples of preferred
doses. Typically, such dosages are administered once, twice, or
three times daily, or every other day to a human.
[0230] A typical oral dose form preferably includes from about 2.5
mg to about 30 mg THIP. Preferably, the THIP is in a crystalline
form. Further embodiments of the medicament comprises an effective
amount of THIP from 2.5 mg to 20 mg, such as 2.5 mg to 4 mg, 4 mg
to 6 mg, 6 mg to 8 mg, 8 mg to 10 mg, 10 mg to 12 mg, 12 mg to 14
mg, 14 mg to 16 mg, 16 mg to 18 mg, or 18 mg to 20 mg, e.g. 2.5 mg,
5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, or 20 mg. A typical
embodiment is about 5 mg to about 20 mg of crystalline THIP, such
as the hydrochloride of THIP. Typically, such dosages are
administered once, twice, or three times daily, or every other day
to a human. In some embodiments, the total amount administered to a
subject in 24 hour period is 1 mg to 50 mg. In some embodiments,
the subject is started at a low dose and the dosage is escalated in
the drug is well tolerated in the subject.
[0231] In the most preferred embodiments, the dosage is effective
to increase tonic inhibition without causing an adverse effect in
the subject. Adverse effects can include, for example, induced
neuronal dysfunction and negative effects on the function of
thalamo-cortical network, such as increased frequency of seizures
or excessive drowsiness or daytime somnolence. The animals models
discussed above utilize a dosage of 1.25 mg/kg to 3 mg/kg in mice.
In a particular animal model, a dosage of 1.25 mg/kg was preferred
over a dosage of 2.5 mg/kg because there were fewer adverse
effects. Therefore in some embodiments, the dosage is about 0.1
mg/kg to about 5 mg/kg, preferably wherein there are few or no
adverse effects. Dosages can be scaled from mouse to human using
conversions that are known in the art. Because this therapy
typically includes administration during a time when the subject is
active, the dosage also preferably does not induce a sedative
effect in the subject.
[0232] In some embodiments, the effect of the composition on a
subject is compared to a control. For example, the effect of the
composition on a particular symptom, pharmacologic, or physiologic
indicator can be compared to an untreated subject, or the condition
of the subject prior to treatment. In some embodiments, the
symptom, pharmacologic, or physiologic indicator is measured in a
subject prior to treatment, and again one or more times after
treatment is initiated. In some embodiments, the control is a
reference level, or average determined based on measuring the
symptom, pharmacologic, or physiologic indicator in one or more
subjects that do not have the disease or condition to be treated
(e.g., healthy subjects). In some embodiments, the effect of the
treatment is compared to a conventional treatment that is known the
art, such as one of those discussed herein.
[0233] B. Conditions, Symptoms, Subjects, and Diseases to be
Treated
[0234] In some embodiments, subjects in need of tonic inhibition
are subjects with a neurogenetic disease. In some embodiments, the
composition is administered in an effective amount to reduce or
prevent one or more symptoms or phenotypes of the disease. Diseases
and symptoms thereof are discussed in more detail below.
[0235] 1. Angelman Syndrome
[0236] In some embodiments, the composition is used to treat a
subject with Angelman syndrome. Angelman syndrome is a neurogenetic
disorder caused by deletion or inactivation of genes on the
maternally inherited chromosome 15 while the paternal copy, which
may be of normal sequence, is imprinted and silenced. Prader-Willi
syndrome, is caused by a similar loss of paternally inherited genes
and maternal imprinting.
[0237] Symptoms of Angelman syndrome include: consistent symptoms
which are exhibited in 100% of cases, frequent symptoms which occur
in more than 80% of cases, and associated which occur in 20-80% of
cases. Consistent symptoms include developmental delay; speech
impairment, no or minimal use of words; receptive and non-verbal
communication skills higher than verbal ones; movement or balance
disorder; usually ataxia of gait and/or tremulous movement of
limbs; and behavioral uniqueness such as frequent laughter/smiling,
apparent happy demeanor, easily excitable personality, often with
hand flapping movements, hypermotoric behavior, short attention
span, or any combination thereof. Frequent symptoms include
delayed, disproportionate growth in head circumference, usually
resulting in microcephaly (absolute or relative) by age 2;
seizures, onset usually <3 years of age; and abnormal EEG having
a characteristic pattern with large amplitude slow-spike waves.
[0238] Associated symptoms include strabismus; hypopigmented skin
and eyes; tongue thrusting; suck/swallowing disorders; hyperactive
tendon reflexes; feeding problems during infancy; uplifted, flexed
arms during walking; prominent mandible; increased sensitivity to
heat; wide mouth, wide-spaced teeth; sleep disturbance; frequent
drooling, protruding tongue; attraction to/fascination with water;
excessive chewing/mouthing behaviors; flat back of head; smooth
palms; attraction to/fascination with water; fascination with
crinkly items such as certain papers and plastics; abnormal food
related behaviors; obesity (in the older child); scoliosis; and
constipation.
[0239] Other common symptoms of Angelman syndrome as well as
methods of diagnoses are discussed in Williams, et al., American
Journal of Medical Genetics, 140A:413-418 (2006), which is
specifically incorporated by referenced herein in its entirety.
[0240] 2. Fragile X Syndrome
[0241] In some embodiments, the composition is used to treat a
subject with Fragile X syndrome (FXS). Fragile X syndrome is a
neurogenetic disorder. It is the most common single-gene cause of
autism and an inherited cause of intellectual disability especially
among boys. FXS is related to the expansion of the CGG
trinucleotide repeat affecting the Fragile X mental retardation 1
(FMR1) gene on the X chromosome. In normal individuals, this DNA
segment is repeated from 5 to about 40 times. In people with
fragile X syndrome, the CGG segment is repeated more than 200
times, which leads to silencing of the gene. Loss or a shortage
(deficiency) of FMR1 disrupts nervous system functions and leads to
the signs and symptoms of fragile X syndrome. In addition to
intellectual disability, prominent characteristics and symptoms of
the syndrome can include an elongated face, large or protruding
ears, flat feet, larger testes (macroorchidism), and low muscle
tone; recurrent otitis media (middle ear infection) and sinusitis
is common during early childhood; speech may be cluttered or
nervous; stereotypic movements (e.g., hand-flapping) and atypical
social development, particularly shyness, limited eye contact,
memory problems, and difficulty with face encoding; psychiatric
problems including attention deficit hyperactive disorder,
obsessive-compulsive disorder, mood disorders, dementia, and
anxiety disorders; hypersensitivity and repetitive behavior
including very short attention spans, hyperactivity, and
hypersensitivity to visual, auditory, tactile, and olfactory
stimuli, and perseveration; ophthalmologic problems such as
strabismus and amblyopia; neurological complications such as
seizures; problems in performing tasks that require the central
executive of working memory; and premature menopause. Some
individuals with fragile X syndrome also meet the diagnostic
criteria for autism.
[0242] Diagnosis of fragile X syndrome is made through genetic
testing to determine the number of CGG repeats. Although at least
200 repeats are needed for a diagnosis of FXS, males and females
with 55 to 200 repeats of the CGG segment are said to have an FMR1
gene premutation. Most people with a premutation are intellectually
normal, however, some individuals with a premutation have lower
than normal amounts of FMRP. As a result, they may have mild
versions of the physical symptoms of the disease and may experience
emotional problems such as anxiety or depression.
[0243] In some embodiments, the subject has Fragile X-associated
tremor/ataxia syndrome (FXTAS).
[0244] 3. Rett Syndrome
[0245] In some embodiments, the composition is used to treat a
subject with Rett Syndrome, also referred to as cerebroatrophic
hyperammonemia. Rett syndrome is a neurodevelopmenal disorder that
most often affects females. Genetically, Rett syndrome is most
typically caused by a mutation in the gene MECP2 located on the X
chromosome. The mutation can arise sporadically or from germline
mutations, but is not typically inherited. In less than 10% of Rett
syndrome cases, mutations in the genes CDKL5 or FOXG1 have also
been found. Rett syndrome is initially diagnosed by clinical
observation, but the diagnosis is definitive when there is a
genetic defect in the MECP2 gene.
[0246] The onset and severity of Rett syndrome vary from subject to
subject. Before the onset of symptoms, the child generally appears
to grow and develop normally. Early subtle abnormalities even in
early infancy, can include loss of muscle tone (hypotonia),
difficulty feeding, and jerkiness in limb movements. Next,
gradually, mental and physical symptoms begin to manifest. The
subject loses purposeful use of her hands and the ability to speak,
and can experience other early symptoms including problems crawling
or walking and diminished eye contact. The loss of functional use
of the hands is followed by compulsive hand movements such as
wringing and washing. Apraxia, the inability to perform motor
functions, can interfere with all body movements, including eye
gaze and speech.
[0247] Children with Rett syndrome can also exhibit autistic-like
behaviors such as incontinence, screaming fits, inconsolable
crying, breath holding, hyperventilation & air swallowing,
avoidance of eye contact, lack of social/emotional reciprocity,
markedly impaired use of nonverbal behaviors to regulate social
interaction, loss of speech, and sensory problems. Other symptoms
include walking on the toes, sleep problems, a wide-based gait,
teeth grinding and difficulty chewing, slowed growth, seizures,
cognitive disabilities, and apnea (breath holding), possible short
stature, sometimes with unusual body proportions because of
difficulty walking or malnutrition caused by difficulty swallowing,
hypotonia, delayed or absent ability to walk, ataxia, microcephaly,
gastrointestinal problems, some forms of spasticity, chorea, and
dystonia.
[0248] There is currently no cure for Rett syndrome, but
restoration of MECP2, for example using Insulin-like Growth
Factor-1 (IGF-1) has shown promise in a mouse model (Tropea, et
al., Proc Natl Acad Sci USA., 106(6): 2029-2034 (2009)). NMDA
receptor antagonists have also shown promise. Symptoms can also be
treated using, for example, sleep aids, selective serotonin
reuptake inhibitors (SSRIs), anti-psychotics (for self-harming
behaviors), beta-blockers (for long QT syndrome), and agents to
manage gastrointestinal dysfunction and malnutrition.
[0249] 4. Autism Spectrum Disorders
[0250] In some embodiments, the composition is used to treat a
subject with Asperger's syndrome, pervasive developmental disorder,
not otherwise specified (PDD-NOS), autistic disorder, or another
autism spectrum disorder.
[0251] Autism spectrum disorder (ASD) is a range of
neurodevelopment disorders, generally characterized by social
impairments, communication difficulties, and restricted,
repetitive, and stereotyped patterns of behavior. Autistic
disorder, also referred to as autism or classical ASD, is the most
severe form of ASD. Children with classic ASD exhibit impairments
involving social and language function as well as repetitive
behaviors that are typically more severe than in children with
other spectrum disorders. Often, they also have mental retardation
and/or seizures.
[0252] Other conditions along the autism spectrum include Asperger
syndrome, and PDD-NOS. Asperger's syndrome (AS) is the mildest form
of autism. Children with AS become obsessively interested in a
single object or subject. They often learn all about their
preferred subject and discuss it continuously. Social skills are
typically markedly impaired in AS children, and they are often
awkward and uncoordinated.
[0253] Symptoms of PDD-NOS can vary widely from one child to the
next. Overall, child with PDD-NOS can be characterized as having
impaired social interaction, better language skills than kids with
autistic disorder but not as good as those with Asperger's
syndrome, fewer repetitive behaviors than children with Asperger's
syndrome or autistic disorder, and a later age of onset. There are
no agreed-upon criteria for diagnosing a subject with PDD-NOS. A
child can be diagnosed with PDD-NOS if the child seems autistic to
professional evaluators but does not meet all the criteria for
autistic disorder.
[0254] Pharmaceutical interventions typically limited to treatment
of specific autism-related symptoms, such as anxiety, depression,
or obsessive-compulsive disorder. Antipsychotic medications can be
used to treat behavioral problems. Seizures can be treated with one
or more anticonvulsant drugs. Medication used to treat attention
deficit disorder can be used reduce impulsivity and hyperactivity
in autism spectrum subjects.
V. Combination Therapies
[0255] In some embodiments, THIP or a derivative thereof is
administered in combination with one or more additional active
agents. The combination therapies can include administration of the
active agents together in the same admixture, or in separate
admixtures. Therefore, in some embodiments, the pharmaceutical
composition includes two, three, or more active agents. Such
formulations typically include an effective amount of THIP or a
derivative. The different active agents can have the same, or
different mechanisms of action. In some embodiments, the
combination results in an additive effect on the treatment of the
disease or disorder. In some embodiments, the combinations results
in a more than additive effect on the treatment of the disease or
disorder.
[0256] The pharmaceutical compositions can be formulated as a
pharmaceutical dosage unit, also referred to as a unit dosage
form.
[0257] A THIP or a derivative can be the singular active agent
administered to increase slow wave sleep, to increase tonic
inhibition, to treat a neurogenetic disorder, a neurodegenerative
disease, a central nervous system disorder, or a symptom or
pathology thereof or THIP or a derivative thereof can be
administered in combination with another agent increase slow wave
sleep, to reduce or prevent cognitive impairment, to treat a
neurodegenerative disease, a central nervous system disorder, or a
symptom or pathology thereof.
[0258] In particular embodiments, a combination therapy includes
THIP or a derivative thereof and one or more conventional
treatments for neurodegeneration, or for increasing or enhancing
neuroprotection, such as those discussed herein. Exemplary
neuroprotective agents are known in the art and include, for
example, glutamate antagonists, antioxidants, and NMDA receptor
stimulants. Other neuroprotective agents and treatments include
caspase inhibitors, trophic factors, anti-protein aggregation
agents, therapeutic hypothermia, and erythropoietin. In some
embodiments, THIP or derivative thereof is administered to a
subject in combination with a treatment that increase nerve
regeneration.
[0259] In a particular embodiment, THIP or a derivative thereof is
administered to a subject in combination with a conventional
treatment for Huntington's disease, such as a dopamine blocker to
help reduce abnormal behaviors and movements, or a drug such as
amantadine and tetrabenazine to control movement, etc. Other drugs
that help to reduce chorea include neuroleptics and
benzodiazepines. Compounds such as amantadine or remacemide have
shown preliminary positive results. Hypokinesia and rigidity,
especially in juvenile cases, can be treated with antiparkinsonian
drugs, and myoclonic hyperkinesia can be treated with valproic
acid. Psychiatric symptoms can be treated with medications similar
to those used in the general population. Selective serotonin
reuptake inhibitors and mirtazapine have been recommended for
depression, while atypical antipsychotic drugs are recommended for
psychosis and behavioral problems.
[0260] In another particular embodiment, THIP or a derivative
thereof is administered to a subject in combination with a
conventional treatment for Parkinson's disease, such as levodopa
(usually combined with a dopa decarboxylase inhibitor or COMT
inhibitor), a dopamine agonist, or an MAO-B inhibitor. Other common
agents that can be used in combination the disclosed combinations
include amantadine and anticholinergics for treating motor
symptoms, clozapine for treating psychosis, cholinesterase
inhibitors for treating dementia, and modafinil for treating
daytime sleepiness.
[0261] In another particular embodiment, THIP or a derivative
thereof is administered to a subject in combination with a
conventional treatment for ALS such as the antiexcitotoxin riluzole
(RILUTEK.RTM.) (2-amino-6-(trifluoromethoxy)benzothiazole). Other
medications, most used off-label, and interventions can reduce
symptoms due to ALS. Some treatments improve quality of life and a
few appear to extend life. Common ALS-related therapies are
reviewed in Gordon, Aging and Disease, 4(5):295-310 (2013), which
is specifically incorporated by reference herein in its entirety.
Exemplary ALS treatments and interventions are provided in Table 1,
below, which is adapted from Gordon, Aging and Disease,
4(5):295-310 (2013).
TABLE-US-00001 TABLE 1 Treatments for ALS Treatment Administration
Indication *Riluzole 50 mg bid ALS *Multidisciplinary care Every
three monthly All symptoms of ALS visits *Non-invasive ventilation
Nighttime and during Respiratory insufficiency symptoms at least 4
hours/day Gastrostomy Daily calorie supplements Dysphagia and
malnutrition *Dextromethorphan/quinidine 20 mg/10 mg bid
Pseudobulbar affect Diaphragm Pacing Up to 24 hours/day Respiratory
insufficiency Brain-computer interface Experimental Communication
Amitriptyline 12.5-125 mg qhs Anxiety SSRI antidepressants 20-100
mg qd Mirtazapine 15-30 mg qhs Buspirone 10 mg tid Diazepam 2-10 mg
tid Lorazepam 0.5-2 mg tid Mirtazapine 15-30 mg qhs SSRI
antidepressants 10-100 mg qd Diazepam 2-10 mg tid Cramps Phenytoin
100-300 mg qhs Vitamin E 400 IU tid Mirtazapine 15-30 mg qhs
Depression SSRI antidepressants 20-100 mg qd Tricyclic
antidepressants 12.5-150 mg qhs Venlafaxine 37.5-75 mg qd
Amantadine 100 mg qAM, qnoon Fatigue Bupropion SR 150-450 mg qd
Fluoxetine 20-80 mg qd Pemoline 18.75-93.75 mg qd Pyridostigmine 60
mg tid Venlafaxine 75-225 mg qd Amitriptyline 12.5-125 mg qhs
Sialorrhea Atropine sulphate 0.4 mg q4-6h 1-2 ophthalmic drops SL
q4-6h Diphenhydramine 25-50 mg tid Hyoscyamine sulfate 0.125-0.25
mg q4h Scopolamine transdermal patch 0.5 mg q72h Baclofen 10-60 mg
tid Spasticity Benzodiazepines 2-10 mg tid Dantrolene 25-100 mg tid
Tizanidine 2-8 mg tid Amitriptyline 12.5-75 mg qhs Urinary urgency
Oxybutynin 2.5-5 mg bid 3.9 mg patch qd Tolterodine 1-2 mg bid Bid
= twice daily; IU = international units; qAM = every morning; qd =
daily; qhs = every day; qt = bedtime; qid = four times daily; qnoon
= every day at noon; qxh = every x hours; SL = sublingual; SR =
slow release; SSRI = serotonin-specific reuptake inhibitor; tid =
three times daily. *shown to have a beneficial effect in ALS
[0262] A number of other agents have been tested in one or more
clinical trials with efficacies ranging from non-efficacious to
promising. Exemplary agents are reviewed in Carlesi, et al.,
Archives Italiennes de Biologie, 149:151-167 (2011). For example,
in some embodiments, THIP or a derivative thereof, is administered
to a subject in combination with an agent that reduces
excitotoxicity such as talampanel
(8-methyl-7H-1,3-dioxolo(2,3)benzodiazepine), a cephalosporin such
as ceftriaxone, or memantine; an agent that reduces oxidative
stress such as coenzyme Q10, manganoporphyrins, KNS-760704
[(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine
dihydrochloride, RPPX], or edaravone
(3-methyl-1-phenyl-2-pyrazolin-5-one, MCI-186); an agent that
reduces apoptosis such as histone deacetylase (HDAC) inhibitors
including valproic acid, TCH346
(Dibenzo(b,f)oxepin-10-ylmethyl-methylprop-2-ynylamine),
minocycline, or tauroursodeoxycholic Acid (TUDCA); an agent that
reduces neuroinflammation such as thalidomide and celastol; a
neurotropic agent such as insulin-like growth factor 1 (IGF-1) or
vascular endothelial growth factor (VEGF); a heat shock protein
inducer such as arimoclomol; or an autophagy inducer such as
rapamycin or lithium.
[0263] In another particular embodiment, THIP or a derivative
thereof is administered to a subject in combination with a
conventional treatment for AD, for example, acetylcholinesterase
inhibitor such as tacrine, rivastigmine, galantamine or donepezil;
or an NMDA receptor antagonist such as memantine, or an
antipsychotic drug.
[0264] In some embodiments, the active agent(s) is administered in
combination with a co-therapy such as dietary changes with or
without dietary supplements, exercise, psychological and/or
psychosocial counseling, physical therapy, occupational therapy,
and speech therapy.
[0265] Unless defined otherwise, all technical and scientific terms
used herein have the same meanings as commonly understood by one of
skill in the art to which the disclosed invention belongs.
Publications cited herein and the materials for which they are
cited are specifically incorporated by reference.
[0266] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims.
* * * * *