U.S. patent application number 13/627185 was filed with the patent office on 2013-07-25 for enteric-coated ht-2157 compositions and methods of their use.
This patent application is currently assigned to DART NEUROSCIENCE (CAYMAN) LTD.. The applicant listed for this patent is Dart Neuroscience (Cayman) Ltd.. Invention is credited to Alan P Kaplan.
Application Number | 20130189314 13/627185 |
Document ID | / |
Family ID | 46924697 |
Filed Date | 2013-07-25 |
United States Patent
Application |
20130189314 |
Kind Code |
A1 |
Kaplan; Alan P |
July 25, 2013 |
ENTERIC-COATED HT-2157 COMPOSITIONS AND METHODS OF THEIR USE
Abstract
Drug compositions comprising the compound HT-2157 and their
therapeutic uses, including the treatment of CNS disorders and
cognitive impairments and the modulation of cognitive function, are
disclosed. More particularly, the present invention relates to
enteric-coated formulations comprising HT-2157 that reduce the
appearance of clinically relevant methemoglobinemia relative to
administration of non-enteric-coated formulations comprising
HT-2157.
Inventors: |
Kaplan; Alan P; (San Diego,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Dart Neuroscience (Cayman) Ltd.; |
Grand Cayman |
|
KY |
|
|
Assignee: |
DART NEUROSCIENCE (CAYMAN)
LTD.
Grand Cayman
KY
|
Family ID: |
46924697 |
Appl. No.: |
13/627185 |
Filed: |
September 26, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13354428 |
Jan 20, 2012 |
8277842 |
|
|
13627185 |
|
|
|
|
Current U.S.
Class: |
424/400 ;
514/418 |
Current CPC
Class: |
A61K 9/2846 20130101;
A61P 25/22 20180101; A61P 25/28 20180101; A61P 25/00 20180101; A61P
25/24 20180101; A61K 9/4891 20130101 |
Class at
Publication: |
424/400 ;
514/418 |
International
Class: |
A61K 31/404 20060101
A61K031/404; A61P 25/28 20060101 A61P025/28; A61P 25/24 20060101
A61P025/24; A61P 25/22 20060101 A61P025/22; A61K 9/00 20060101
A61K009/00; A61P 25/00 20060101 A61P025/00 |
Claims
1. A composition comprising a solid-dosage form, wherein said
solid-dosage form comprises: (a) a therapeutically effective amount
of HT-2157, which has the following structure: ##STR00004## and (b)
an enteric coating.
2. The composition of claim 1, wherein said administration of the
enteric-coated composition to a subject reduces appearance of
clinically relevant methemoglobinemia, relative to administration
of a non-enteric coated composition comprising the same amount of
HT-2157.
3. The composition of claim 1, wherein said administration of the
enteric-coated composition to a subject results in a lower increase
in percent of methemoglobin, relative to administration of a
non-enteric coated composition comprising the same amount of
HT-2157.
4. The composition of claim 3, wherein said administration of the
enteric-coated composition increases methemoglobin levels to less
than about 3 percent.
5. The composition of claim 3, wherein said administration of the
enteric-coated composition increases methemoglobin levels to less
than about 1.5 percent.
6. The composition of claim 1, wherein the enteric coating
comprises a methacrylic polymer
7. The composition of claim 1, further comprising one or more
excipients selected from the following: a diluent, a binder, a
surfactant, a glidant, and a lubricant.
8. The composition of claim 1, wherein the composition remains
stable after about 1 year of storage at 25.degree. C./60% RH or
after about 6 months of storage at 40.degree. C./75% RH.
9. A method comprising: (a) administering the composition of claim
1 to a subject; (b) reducing appearance of clinically relevant
methemoglobinemia, relative to administration of a non-enteric
coated composition comprising the same amount of HT-2157.
10. A method comprising: administering the composition of claim 1
to a subject, wherein said administering results in a lower
increase in percent of methemoglobin, relative to administration of
a non-enteric coated composition comprising the same amount of
HT-2157.
11. The method of claim 10, wherein said administration of the
enteric coated composition increases methemoglobin levels to less
than about 3 percent.
12. The method of claim 10, wherein said administration of the
enteric coated composition increases methemoglobin levels to less
than about 1.5 percent.
13. The method of claim 9, wherein the enteric coating of the
composition administered in step (a) comprises a methacrylic
polymer.
14. The method of claim 9, wherein the composition administered in
step (a) further comprises one or more excipients selected from the
following: a diluent, a binder, a surfactant, a glidant, and a
lubricant.
15. The method of claim 9, wherein the composition administered in
step (a) remains stable after about 1 year of storage at 25.degree.
C./60% R.H or after about 6 months of storage at 40.degree. C./75%
R.H.
16. A method of treating a CNS disorder comprising administering
the composition of claim 1 to a subject in need thereof.
17. The method of claim 16, wherein the CNS disorder is depression
or anxiety.
18. A method comprising the steps of: (a) providing cognitive
training to an animal in need of treatment of a cognitive
impairment under conditions sufficient to produce an improvement in
performance by said animal of a cognitive function whose deficit is
associated with said cognitive impairment; (b) administering the
composition of claim 1 to said animal in conjunction with said
cognitive training; (c) repeating said providing and said
administering of steps (a) and (b) one or more times; and (d)
reducing the number of training sessions sufficient to produce said
improvement in performance, relative to the improvement in
performance produced by cognitive training alone.
19. The method of claim 18, wherein said administering reduces
appearance of clinically relevant methemoglobinemia or results in a
lower increase in percent of methemoglobin, relative to
administration of a non-enteric coated composition comprising the
same amount of HT-2157.
20. The method of claim 18, wherein the cognitive impairment
includes a memory impairment.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to drug compositions
comprising the compound HT-2157 and their therapeutic uses,
specifically in subjects, and more specifically in humans,
including the treatment of CNS disorders and cognitive impairments
and the modulation of cognitive function. More particularly, the
present invention relates to enteric-coated formulations comprising
HT-2157 that reduce appearance of clinically relevant
methemoglobinemia relative to administration of non-enteric-coated
formulations comprising HT-2157.
BACKGROUND OF THE INVENTION
[0002] HT-2157 (also called SNAP 37889 or SNEC-2) is an
indolone-derived compound
(1,3-dihydro-1-phenyl-3[[3-trifluoromethyl)phenyl]imino]-2H-indo-
l-2-one) having the following structure:
##STR00001##
[0003] In laboratory studies, HT-2157 has been found to be a highly
potent and selective antagonist of the Galanin 3 receptor (GalR3).
See, e.g., Swanson et al., Proc. Natl. Acad. Sci. USA, 102,
17489-1494, 2005. GalR3 is one of three G-protein-coupled
receptors--the other two being GalR1 and GalR2--that bind the
peptide galanin. By inhibiting adenylate cyclase, galanin binding
to GalR3 can reduce cAMP levels--a decrease that can be antagonized
by HT-2157. See, e.g., Kolakowski et al., J. Neurochem. 71,
2239-2251, 1998.
[0004] Galanin is a neurotransmitter involved in a variety of
peripheral and central physiological and pathophysiological
processes, including gastrointestinal motility, cardiovascular
contraction, neuroendocrine function, feeding behavior, pain
perception, learning, memory, anxiety, and depression. For a
review, see Mitsukawa et al., EXS 102, 7-23, 2010. The three
galanin receptors are distributed in numerous areas of the CNS,
including those associated with mood, memory, emotion, and pain.
Consistent with these observations, studies of HT-2157 in cellular
and animal models have shown multiple effects of this compound on
function and pathology of the nervous system:
[0005] WO 09/086,532 relates to the use of neurite outgrowth assays
as a general screen for compounds, including HT-2157, which can
enhance and improve memory function.
[0006] US 2008/003946 relates to the administration of GalR3
antagonists to modulate neurite outgrowth. Such antagonists include
HT-2157 and the E/Z isomers or mixtures thereof. The antagonists
can be administered in single or divided doses or in sustained
release forms, depending on numerous factors, including the
particular symptoms and effect desired.
[0007] U.S. 2004/0110821 and WO 04014376 each relate to pyrimidine
and indolone derivatives (including HT-2157) that are selective
antagonists for the GAL3 receptor. Each describes a method of
treating an affective disorder with compositions that can include a
pharmaceutically acceptable carrier and a therapeutically effective
amount of the selective antagonist. The composition may be in solid
form and include lubricants, glidants, and binders.
[0008] U.S. 2005/0192337 relates to processes for preparing the
HT-2157 compound.
[0009] WO 10/009,453 relates to methods and systems of evaluating,
identifying, or assessing the effectiveness of memory agents and
training protocols in subjects, including macaques and humans. The
memory agents can be formulated as a solution, suspension,
emulsion, or lyophilized powder, in association with a
pharmaceutically acceptable parenteral vehicle.
[0010] U.S. 2007/0135509 and U.S. 2007/0135510 each relate to
treating cognitive impairments with several different categories of
compounds, including HT-2157. Solid forms of compositions suitable
for oral administration include pills, capsules, granules, tablets,
and powders.
[0011] US 2004/0102507 relates to methods for treating depressive
and anxiety disorders with indolone compounds, including HT-2157.
It further relates to pharmaceutical compositions, including solid
forms or liquid forms, which combine such antagonists with a
pharmaceutically acceptable carrier.
[0012] WO 04/014307 relates to GalR3 antagonists in the treatment
of neuropathic pain and cognitive disorders. Such antagonists
comprise indolones, including HT-2157. Solid carriers for use with
such antagonists can include endogenous carriers (e.g. nutrient or
micronutrient carriers), flavoring agents, lubricants,
solubilizers, suspending agents, fillers, glidants, and compression
aids
[0013] U.S. Pat. No. 7,642,281 relates to methods for treating
cognitive impairments with various compounds, including the
indolone compound HT-2157. The indolone compounds can be formulated
as capsules, including powder-filled hard gel capsules, as well as
suppositories, creams, inhalants, or transdermal patches.
[0014] WO 04/014855 relates to crystalline and amorphous forms of
HT-2157 and processes for their preparation. It is further directed
to pharmaceutical compositions, including those comprising HT-2157,
which are useful in treating depression, anxiety, and other CNS
disorders. Solid carriers for use in such compositions include
endogenous carriers (e.g. nutrient or micronutrient carriers),
flavoring agents, lubricants, suspending agents, fillers, glidants,
compression aids, binders or tablet-disintegrating agents.
[0015] WO 04/014854 and U.S. 2004/0082615 each relate to treating
depression or anxiety with various categories of compounds,
including the indolone compound HT-2157. Corresponding
pharmaceutical compositions can include HT-2157, along with solid
carriers, such as endogenous carriers, encapsulating materials, and
powder mixtures.
[0016] Ash et al. (Regul. Pept. 166, 59-67, 2010) relates to
behavioral studies in rats treated with HT-2157 (SNAP 37889) to
evaluate a possible association between galanin and alcohol. Such
studies included tests for anxiety and operant self-administration
of ethanol.
[0017] Konkel et al. (J. Med. Chem. 49, 3757-3758, 2006) relates to
a series of 3-imino-2-indolones as high-affinity antagonists of the
galanin GAL3 receptor. The antagonists, which include HT-2157,
showed high selectivity for GalR3 over a broad panel of targets,
including GAL1 and GAL2.
[0018] Oegren et al. (CNS Drugs 20, 633-654, 2006) relates
generally to the pathophysiology of mood disorders, including the
observation that GalR3 receptor antagonists, such as HT-2157, can
cross the blood-brain barrier after systemic administration and
show antidepressant-like activity in several animal models.
[0019] Swanson et al. (Proc. Natl. Acad. Sci. USA 102, 17489-17494,
2005) relates to the use of behavioral, neurochemical, and
electrophysiological approaches to investigate anxiolytic- and
antidepressant-like effects following acute administration of
GalR3-selective antagonists, including HT-2157 (SNAP 37889).
[0020] In summary, numerous studies have uncovered a role of GalR3
in modulating function and dysfunction in the nervous system, and
they have uniformly disclosed and relied upon the HT-2157 compound
itself or conventional HT-2157 formulations. As disclosed in the
instant application, however, such conventional formulations have
proven unsuitable for therapeutic use in humans, giving rise to
significant and previously unreported safety issues. The present
application discloses alternative HT-2157 compositions, which
utilize an enteric coating, that overcome these safety issues.
SUMMARY OF THE INVENTION
[0021] In one aspect, the present disclosure relates to a
composition that includes a solid dosage form comprising a
therapeutically effective amount of HT-2157 and an enteric coating,
wherein HT-2157 has the following structure:
##STR00002##
[0022] In some embodiments, administration of the composition to a
subject reduces appearance of clinically relevant methemoglobinemia
or results in a lower increase in percent of methemoglobin,
relative to administration of a non-enteric coated composition
comprising the same amount of HT-2157. In a specific aspect,
administration of the compositions of the present invention
increases methemoglobin levels to less than about 3 percent, or to
less than about 1.5 percent. In some embodiments, the composition
with an enteric coating provides greater bioavailability of
HT-2157, compared to the composition without an enteric
coating.
[0023] The enteric coating of the composition may, in one
embodiment, comprise a methacrylic polymer, and the composition may
further comprise one or more excipients, such as a diluent, binder,
surfactant, glidant, or lubricant.
[0024] In certain embodiments, the composition remains stable after
1 year of storage at 25.degree. C./60% R.H or after 6 months of
storage at 40.degree. C./75% R.H
[0025] The present disclosure also relates to a method comprising
administration of any of the compositions of the present invention,
wherein the administration reduces appearance of clinically
relevant methemoglobinemia or results in a lower increase in
percent of methemoglobin, relative to administration of a
non-enteric coated composition comprising the same amount of
HT-2157.
[0026] In still another aspect, the present disclosure relates to a
method of administering any of the compositions of the present
invention to treat neuropathic pain or a CNS disorder in a subject
in need thereof. In specific embodiments, the CNS disorder is
depression or anxiety.
[0027] In yet another aspect, the present disclosure relates to a
method of treating a cognitive impairment. In a specific
embodiment, the method comprises the steps of: providing cognitive
training to an animal in need of treatment of a cognitive
impairment under conditions sufficient to produce an improvement in
performance of a cognitive function whose deficit is associated
with the cognitive impairment; administering a compositions of the
present invention to the animal in conjunction with cognitive
training; repeating the providing and administering steps one or
more times; and (d) reducing the number of training sessions
sufficient to produce the improvement in performance, relative to
improvement in performance produced by cognitive training
alone.
[0028] In a specific aspect of the methods, administering the
compositions of the present invention reduces appearance of
clinically relevant methemoglobinemia or results in a lower
increase in percent of methemoglobin, relative to administration of
a non-enteric coated composition comprising the same amount of
HT-2157. In another aspect, the cognitive impairment includes a
memory impairment.
[0029] Other features and advantages of the invention will become
apparent from the following detailed description. It should be
understood, however, that the detailed description and the specific
examples, while indicating specific embodiments of the invention,
are given by way of illustration only, because various changes and
modifications within the spirit and scope of the invention will
become apparent to those skilled in the art from this detailed
description.
DETAILED DESCRIPTION OF THE INVENTION
[0030] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the pharmaceutical arts. Although methods and
materials similar or equivalent to those described herein can be
used in the practice or testing of the present invention, suitable
methods and materials are described herein. All publications,
patent applications, patents, and other references, including
product descriptions, clinical studies, and protocols, mentioned in
this application are incorporated by reference in their entirety.
In addition, the materials, methods, and examples are illustrative
only and are not intended to be limiting.
[0031] Reference is made to standard textbooks of molecular biology
and pharmaceutics that contain definitions and methods and means
for carrying out basic techniques, which may be encompassed by the
present invention. See, e.g., Current Protocols in Pharmacology,
Enna et al. (eds.), John Wiley and Sons, Inc., Hoboken, N.J.
(2011), Current Protocols in Molecular Biology, Ausubel et al.
(eds.), John Wiley & Sons, Inc., Hoboken, N.J. (2011), Current
Protocols in Cell Biology, Bonifacino et al. (eds.), John Wiley
& Sons, Inc.: Hoboken, N.J. (2011); Current Protocols in
Neuroscience, Gerfen et al. (eds.), John Wiley & Sons, Inc.,
Hoboken, N.J. (2011); and the various references cited therein.
DEFINITIONS
[0032] The terms "comprising" and "including" are used herein in
their open, non-limiting sense.
[0033] As used herein, the terms "a," "an," and "the" are to be
understood as meaning both singular and plural, unless explicitly
stated otherwise. Thus, "a," "an," and "the" (and grammatical
variations thereof where appropriate) refer to one or more.
[0034] As used herein, the term "about" or "approximately" means
within an acceptable range for a particular value as determined by
one skilled in the art, and may depend in part on how the value is
measured or determined, e.g., the limitations of the measurement
system or technique. As used herein, the term "about," when located
before a dosage amount or dosage range of a specific ingredient,
refers to an amount or range closely above or closely below the
stated amount or range that does not manifestly alter the
therapeutic effect of the specific ingredient from the stated
amount or range and is meant to encompass at least all equivalents
of that amount. For example, "about" can mean a range of up to 20%,
up to 10%, up to 5%, or up to 1% or less of a given value.
Alternatively, with respect to biological systems or processes, the
term "about" can mean within an order of magnitude, within 5-fold,
or within 2-fold of a value. Numerical quantities given herein are
approximate unless stated otherwise, meaning that the term "about"
or "approximately" can be inferred when not expressly stated
[0035] The term "HT-2157" is synonymous with "SNAP 37889" and
"SNEC-2."
[0036] The term "HT-2800" is synonymous with "SNAP 68582" and
refers to an active metabolite of HT-2157 that is formed in humans
and some animals and has the following structure:
##STR00003##
[0037] As used herein, a "subject" may be a vertebrate, in
particular, a mammal, and more particularly, a human. A subject can
also include a laboratory animal in the context of a clinical trial
or screening or activity experiment. Thus, as can be readily
appreciated by one of ordinary skill in the art, the compositions
and methods of the present invention are particularly suited to
administration to any vertebrate, particularly a mammal, and more
particularly, a human.
[0038] As used in the present disclosure, the term "therapeutically
effective amount" means an amount or dose of HT-2157 (or HT-2800)
that is effective to ameliorate, delay, minimize, or prevent any
symptom, behavior, or other event associated with a cognitive
disorder, disease, or condition, or any other nervous system
disorder, disease, or condition specified herein. Alternatively, a
therapeutically effective amount is the amount of HT-2157 that is
effective to improve one or more symptoms of a clinically
significant disorder, disease, or condition in the individual.
[0039] As used herein, the terms "treat," "treatment," "treating"
include: [0040] (i) prophylactic treatment, which includes
preventing and/or reducing the incidence of and/or ameliorating the
effect and/or duration of a disease, disorder, or condition from
occurring in subjects that may get, be exposed to and/or be
predisposed to the disease, disorder or condition, but may not yet
have been diagnosed as having it; or are diagnosed as having the
disease, disease, or condition; or are at risk of developing such
disease, disorder, or condition; [0041] (ii) inhibiting the
disease, disorder, or condition, i.e., delaying the onset of a
disease, disorder, or condition; arresting further development or
progression of a disease, disorder, or condition in a subject
already suffering from or having one or more symptoms of the
disease, disorder, or condition; or reducing the risk of a disease,
disorder, or condition worsening; [0042] (iii) relieving the
disease, disorder, or condition, i.e., causing regression of the
disease, disorder, or condition, or one or more of its
symptoms.
[0043] As used herein, the phrase "pharmaceutically acceptable"
refers to molecular entities and compositions that are generally
regarded as "safe," e.g., that are physiologically tolerable and do
not typically produce an allergic or similar untoward reaction,
such as gastric upset, dizziness and the like, or other significant
adverse events, when administered to a human. Preferably, as used
herein, the term "pharmaceutically acceptable" means approved by a
regulatory agency of the Federal or a state government of listed in
the U.S. Pharmacopeia or other generally recognized pharmacopeia
for use in animals, and more particularly in humans.
[0044] The term "carrier" refers to a diluent, adjuvant, excipient,
or vehicle with which the compound is administered. In preferred
embodiments of this invention, the carrier is a solid carrier.
Suitable pharmaceutical carriers include those described in
Remington: The Science and Practice of Pharmacy, 21st Ed.,
Lippincott Williams & Wilkins (2005).
[0045] The term "dosage form," as used herein, is the form in which
the dose is to be administered to the subject or patient. The drug
or supplement is generally administered as part of a formulation
that includes nonmedical agents. The dosage form has unique
physical and pharmaceutical characteristics. Dosage forms, for
example, may be solid, liquid or gaseous. "Dosage forms," may
include for example, a capsule, tablet, caplet, gel caplet
(gelcap), syrup, a liquid composition, a powder, a concentrated
powder, a concentrated powder admixed with a liquid, a chewable
form, a swallowable form, a dissolvable form, an effervescent, a
granulated form, and an oral liquid solution. In a specific
embodiment, the dosage form is a solid dosage form, and more
specifically, comprises a tablet or capsule.
[0046] As used herein, the terms "inactive," "inert," and
"excipient" refer to any compound that is an inactive ingredient of
a described composition. The definition of "inactive ingredient" as
used herein follows that of the U.S. Food and Drug Administration,
as defined in 21 C.F.R. 201.3(b)(8), which is any component of a
drug product other than the active ingredient.
[0047] A "stable" composition is one in which the amount of active
ingredient is not decreased by more than about 10% after about 1
year of storage at 25.degree. C./60% RH or after about 6 months of
storage at 40.degree. C./75% RH.
[0048] The phrase "reduce the appearance of clinically relevant
methemoglobinemia" means that methemoglobin levels in the blood are
not increased to levels that cause significant health complications
associated with the condition methemoglobinemia. In some
embodiments, the phrase "reduce the appearance of clinically
relevant methemoglobinemia" means methemoglobin levels in the blood
are increased to less than about 3%, and in some embodiments to
less than about 1.5%.
Pharmaceutical Compositions
[0049] The present invention is based partly upon the discovery
that administration of the compound HT-2157 or conventional HT-2157
pharmaceutical compositions can result in methemoglobinemia. This
previously unreported observation presents a significant safety
issue that must be addressed in order to utilize HT-2157 in
therapeutic applications.
[0050] Accordingly, the present invention discloses alternative
HT-2157 compositions with an enteric coating that reduce clinically
relevant methemoglobin in a subject or result in a lower increase
in percent of methemoglobin, relative to administration of a
conventional, i.e., non-enteric coated, composition comprising the
same amount of HT-2157.
[0051] In addition to an enteric coating, compositions of the
present invention may also comprise one or more pharmaceutically
acceptable carriers, including excipients, such as a diluent,
binder, surfactant, glidant, or lubricant. The solid dosage forms
disclosed herein may also be formulated with other pharmaceutically
inactive components, including, but not limited to, disintegrants,
colorants, flavoring agents, preservatives, and sorbents. The
excipients of the present invention are well known to those of
ordinary skill in the art, and details can be found, for example,
in Handbook of Pharmaceutical Excipients, 5.sup.th Ed., Rowe et al.
(eds.), Pharmaceutical Press (2005); Remington: The Science and
Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins
(2005); Current Protocols in Pharmacology, Enna et al. (eds.), John
Wiley and Sons, Inc., Hoboken, N.J. (2011).
[0052] In a specific embodiment, the solid dosage forms are for
oral administration. In preparing the composition in oral dosage
form, any of the usual media may be utilized. Pharmaceutical
acceptable carriers such as diluents, fillers, binders,
surfactants, granulating agents, lubricants, disintegrating agents
and the like may be used to prepare oral solids (e.g., powders,
caplets, pills, tablets, capsules) and determination of workable
proportions in any particular instance will generally be within the
capability of the person skilled in the art. Fillers and
excipients, for example, are commercially available from companies
such as Aldrich Chemical Co., FMC Corp, Bayer, BASF, Alexi Fres,
Witco, Mallinckrodt, Rhodia, ISP, and others. Controlled release
forms may also be used. Given their ease in administration,
caplets, tablets, pills, and capsules represent the most
advantageous oral dosage unit form, in which case solid carriers
are employed. If desired, tablets may be sugar coated.
[0053] In a specific mode of administration, the dosage forms may
be swallowable, chewable or dissolvable. Swallowable compositions
are well known in the art and are those that do not readily
dissolve when placed in the mouth and may be swallowed whole
without any chewing or discomfort. In a specific embodiment of the
present invention, the swallowable compositions may have a shape
containing no sharp edges and a smooth, uniform and substantially
bubble free outer coating. The compositions of the present
invention may be prepared using conventional methods and materials
known in the pharmaceutical arts.
[0054] Enteric Polymers and Coatings
[0055] Enteric polymers used to coat pharmaceutical dosage forms
include cellulose, vinyl, and acrylic derivatives. Enteric
polymeric materials are primarily weak acids containing acidic
functional groups, which are capable of ionization at elevated
pH.
[0056] In some embodiments, the enteric coating coats a core of a
solid dosage form disclosed herein and controls the location in the
digestive tract where the active agent contained in the solid
dosage form's core is released and absorbed. In certain
embodiments, the enteric coating is in the form of one or more
components selected from the group including polymers, fatty acids,
waxes, shellac, plastics, and plant fibers.
[0057] In certain embodiments, the enteric coating comprises one or
more of the following: acrylates and acrylate copolymers, including
methacrylic acid/methacrylic acid methylester copolymer and
methacrylic acid/ethyl acrylate copolymer; cellulose esters,
including cellulose acetate phthalate, cellulose acetate
trimellitate, and cellulose acetate succinate; hydroxypropyl
methylcellulose phthalate; hydroxypropyl methylcellulose acetate
succinate; polyvinyl derivatives, including polyvinyl acetate
phthalate; and carboxymethyl ethyl cellulose. In some specific
embodiments, the enteric coating includes one or more components
sold under trade names, for example EMCOAT 120 N, MARCOAT 125,
AQUACOAT CPD.RTM., SEPIFILM.TM., AQUACOAT.RTM. ECD, METOLOSE.RTM.,
SURETERIC.RTM., AND EUDRAGIT.RTM.. In certain embodiments, the
enteric coating may comprise colorants. In a specific embodiment,
the enteric coating comprises a EUDRAGIT.RTM. polymer and a
colorant, and is sold under the trade name ACRYL-EZE
ORANGE.RTM..
[0058] In some embodiments, the enteric coating may further
comprise a plasticizer. In some embodiments, the plasticizer will
influence, i.e., increase or decrease, the rate of dissolution of
the enteric coating. In some embodiments, the plasticizer may be
lipophilic. In other embodiments, the plasticizer may be
hydrophilic.
[0059] In other embodiments, the plasticizer comprises one or more
of the group including cetanol, triacetin, citric acid esters such
as triethyl citrate, phthalic acid esters such as diethyl phthalate
and dibutyl phthalate, dibutyl succinate, propylene glycol,
polyethylene glycol (PEG), and oils and glycerides such as
fractional coconut oil.
[0060] In still other embodiments, the dosage forms disclosed
herein comprise pharmacologically inactive components or
excipients. Acceptable pharmacologically inactive components or
excipients will be recognized by those of skill in the art, and
include diluents, binders or fillers, surfactants, glidants,
lubricants, disintegrants, colorants, flavoring agents,
preservatives, and sorbents.
[0061] Diluents and Fillers
[0062] In certain embodiments, the dosage form is a solid dosage
form, which can include one or more diluents or fillers. In some
embodiments, the diluents or fillers comprise one or more selected
from the group consisting of microcrystalline cellulose, colloidal
silicon dioxide, starches such as pregelatanized starch, calcium
carbonate, confectioner sugar, calcium phosphate, calcium hydrogen
phosphate dihydrate, ethyl cellulose, mannitol, magnesium
carbonate, magnesium oxide, and sodium chloride.
[0063] Binders
[0064] In specific embodiments, solid dosage forms disclosed herein
comprise one or more binders. In some embodiments, the binders
comprise one or more selected from the group consisting of
hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sucrose,
lactose, starches, cellulose, microcrystalline cellulose, cellulose
ethers, methyl cellulose, xylitol, sorbitol, and maltitol, gelatin,
polyvinylpyrrolidone, polyethylene glycol, acacia, alginate, sodium
alginate, alginic acid, candelilla wax, carnuba wax, corn starch,
copolyvidone, povidone, and polyethylene oxide.
[0065] Surfactants
[0066] In certain embodiments, solid dosage forms disclosed herein
comprise one or more surfactants. In some embodiments, the
surfactants comprise one or more selected from the group consisting
of sodium lauryl sulfate and glyceryl monosterate
[0067] Glidants
[0068] In particular embodiments, solid dosage forms disclosed
herein comprise one or more glidants. In some embodiments, the
glidants comprise one or more selected from the group consisting of
colloidal silicon dioxide, fumed silica, talc, and magnesium
carbonate.
[0069] Lubricants
[0070] In certain embodiments, solid dosage forms disclosed herein
comprise one or more lubricants. In some embodiments, the
lubricants comprise one or more selected from the group consisting
of minerals, such as talc and silica, and fats and fatty acids,
such as vegetable stearin, magnesium stearate, stearic acid,
calcium stearate, castor oil, glyceryl behenate, mineral oil,
poloxamers, sodium lauryl sulfate, and sodium stearyl fumarate.
[0071] Moisture Barriers
[0072] In some embodiments, the dosage forms may include a moisture
barrier coating. For example, granules may be coated with a
moisture barrier film to impede, retard, or protect against the
absorption of environmental moisture or vapor. Suitable moisture
barrier coatings may include wax components or other compounds
known to one skilled in the art, such as ethyl cellulose,
hypromellose (hydroxypropyl methylcellulose), polyvinyl alcohol,
acrylic polymers, or other polymers. Thus, in one aspect of the
invention, the moisture barrier substantially impedes or retards
the absorption of moisture into the solid dosage form, thereby
increasing the stability of HT-2157.
[0073] Processes
[0074] The dosage forms disclosed herein may be manufactured by any
acceptable or art-recognized method including but not limited to:
granulation of the core components to form a tablet mix prior to
core formation using dry granulation, wet granulation, low shear
wet granulation, high shear wet granulation, and fluid bed
granulation; granule lubrication; compression of the tablet mix in
a tablet press to form the core; coating of the core with an
enteric coating using coating pans, spray coating, fluid-bed
coating, dry coating, and the like.
[0075] Application of the enteric coating to an HT-2157 composition
can be accomplished by any method known in the art for applying
enteric coatings. For example, but not by way of limitation, the
enteric polymers can be applied using organic solvent based
solutions contain from about 5 to 10% w/w for spray applications
and up to about 30% 1/1 polymer for pan coatings. Solvents that are
commonly in use include, but are not limited to, acetone,
acetone/ethyl acetate mixtures, methylene chloride/methanol
mixtures, and tertiary mixtures containing these solvents. In
addition, some enteric polymers, such as methacrylic
acid-methacrylyic acid ester copolymers can be applied using water
as a dispersant. The volatility of the solvent system must be
tailored to present sticking due to tackiness and to prevent high
porosity of the coating due to premature spray drying or
precipitation of the polymer as the solvent evaporates.
[0076] Solid Dosage Forms
[0077] Solid dosage forms may include granules, pellets, beads,
spheroids, a tablet, a minitablet, a microtablet, a capsule,
granules in a capsule, pellets in a capsule, microtablets in a
capsule, and minitablets in a capsule, each of which may be enteric
coated.
[0078] In specific embodiments, the dosage form comprises beads of
HT-2157. In one aspect, the beads of HT-2157 or a salt may be
prepared by spraying inactive cores with a slurry or a solution of
HT-2157 or a salt thereof optionally along with other
pharmaceutically acceptable excipients and optionally coating the
beads of HT-2157 or a salt thereof thus obtained with a moisture
barrier, followed by enteric coating with pharmaceutically
acceptable enteric polymers.
[0079] In another aspect, the beads of HT-2157 or a salt thereof
may also be prepared by a process of extrusion-spheronization or
marumerization and optionally coating the beads of HT-2157 or a
salt thereof thus obtained with a moisture barrier followed by
enteric coating with pharmaceutically acceptable enteric
polymers.
[0080] In still another aspect, the beads of HT-2157 or a salt
thereof may be prepared by adsorbing HT-2157 or a salt thereof on
pharmaceutically acceptable adsorbent, processing the adsorbate
into beads of HT-2157 or a salt thereof and optionally coating the
beads of HT-2157 or a salt thereof thus obtained with a moisture
barrier followed by enteric coating with pharmaceutically
acceptable enteric polymers.
[0081] Spraying or adsorption can be carried out by a fluidized bed
processor, glatt, spray dryer or by any other suitable coating
techniques known in the art.
[0082] The inactive cores can be made up of one or more of
saccharides or derivatives thereof such as polysaccharides, sugars
such as mannitol, sorbitol, lactose, sucrose, maltodextrin,
starches such as maize starch, rice starch, celluloses such as
microcrystalline cellulose, sodium carboxymethyl cellulose,
vegetable gums, waxes, and the like.
[0083] The adsorbate of HT-257 or a salt thereof can be processed
into beads of HT-2157 or a salt thereof by extrusion-spheronization
or marumerization or any other suitable technique known in the
art.
[0084] The pharmaceutically acceptable adsorbents may be one or
more of colloidal silicon dioxide, calcium silicate, magnesium
aluminum silicate, porous ceramics, polypropylene foams, cellulose,
cellulose derivatives, polyols, starches, pre-gelatinized starches,
starch derivatives, modified starches, dextrins, maltodextrins,
polydextroses, dextroses, calcium carbonate, calcium phosphate, or
calcium sulfate.
[0085] The slurry or solution of HT-2157 or a salt thereof may
include HT-2157 or a salt thereof suspended or dissolved in water,
optionally along with other pharmaceutically acceptable excipients,
such as hypromellose, hydroxypropyl cellulose, polyvinyl
pyrrolidone, methacrylates and the like, and optionally with other
pharmaceutically acceptable excipients. The slurry of HT-2157 or a
salt thereof may be milled through a machine adapted for grinding
suspensions in order to reduce the particle size of HT-2157. See
Remington: The Science and Practice of Pharmacy, 21st Ed.,
Lippincott Williams & Wilkins (2005).
Methods
[0086] The present invention provides various methods relying on
administration of HT-2157 compositions of the present invention to
treat a central nervous system ("CNS") disorder. The term
"disorder" is used interchangeably with "condition" or "disease."
The present invention also provides methods to treat a cognitive
deficit, such as an impairment in memory. In some embodiments,
administration of a composition of the present invention is carried
out in conjunction with a cognitive training protocol, as discussed
below. In a specific aspect, these methods reduce the appearance of
clinically relevant methemoglobinemia or result in a lower increase
in the percent methemoglobin, relative to non-enteric compositions
comprising the same amount of HT-2157.
[0087] Dosages
[0088] Optimal dosages to be administered may be determined by
those skilled in the art and will depend on multiple factors,
including the particular composition in use, the strength of the
preparation, the mode and time of administration, and the
advancement of the disease or condition. Additional factors may
include characteristics on the subject being treated, such as age,
weight, gender, and diet.
[0089] When used according to the compositions and methods of the
present invention, the effective dose may be in the range of about
0.01 to 100 mg/kg, specifically about 0.01 to 10 mg/kg, more
specifically, about 0.01 to 5 mg/kg, and even more specifically,
about 0.5 to 5 mg/kg.
[0090] CNS and Cognitive Disorders
[0091] In certain embodiments, compositions of the present
invention are used in methods for treating various disorders,
including neuropathic pain and other CNS disorders. In specific
embodiments, the CNS disorder is depression or anxiety.
[0092] In other embodiments, compositions of the instant invention
are used in methods for treating a cognitive disorder. For the
purposes of the present invention, the terms "cognitive impairment"
and "cognitive disorder" are deemed to cover the same therapeutic
indications, and are used interchangeably throughout this
application.
[0093] Cognitive disorders reflect problems in cognition, i.e., the
general processes by which knowledge is acquired, retained and
used. Accordingly, cognitive disorders can encompass impairments in
functions such as concentration, perception, attention, information
processing, learning, memory, and/or language. Cognitive disorders
can also encompass impairments in psychomotor learning, which
include physical skills such as movement and coordination;
disruptions in fine motor skills such as the use of precision
instruments or tools; and deficits in gross motor skills, such as
those engaged in dance, musical, and/or athletic performance.
[0094] Cognitive disorders can also encompass impairments in
executive functions, which include abilities underlying the
planning and execution of goal-oriented behaviors. Such abilities
include flexibility, i.e., the capacity for quickly switching to
the appropriate mental mode; anticipation and prediction based on
pattern recognition; reasoning and problem-solving; decision
making; working memory, i.e., the capacity to hold and manipulate
internally or externally-derived information in real time;
emotional self-regulation, including the ability to recognize and
manage one's emotions for good performance; sequencing, such as the
ability to dissect complex actions into manageable units and
prioritize them in the right order; and self-inhibition, i.e., the
ability to withstand distraction and internal urges.
[0095] Cognitive disorders commonly occur in association with CNS
disorders (also referred to as CNS conditions or CNS diseases). CNS
disorders include, but are not limited to, the following categories
(which need not be mutually exclusive): (1) dementias, for example,
those associated with Alzheimer's disease, Parkinson's disease,
Huntington's disease, and other neurodegenerative diseases; (2)
anxiety disorders, such as phobias, panic disorders,
obsessive-compulsive disorder, generalized anxiety disorder, eating
disorders, and posttraumatic stress disorder; (3) mood disorders,
such as depression and bipolar disorder; (4) psychotic disorders,
such as schizophrenia and delusional disorder; (5) developmental
and genetic conditions affecting cognitive functions, such as
autism spectrum disorders and mental retardation; (6)
trauma-dependent losses of cognitive functions, such as memory,
language, and motor impairments resulting from head trauma, stroke,
hypoxia, viral infection (e.g., encephalitis), and alcohol abuse;
(7) age-associated memory impairments, including mild cognitive
impairment (MCI); and (8) learning disabilities, such as perceptual
handicaps, dyslexia, and attention disorders.
[0096] In some cases, cognitive impairments can be a direct result
of a CNS disorder. For example, impairments in speech and language
may be a direct result of a stroke or head-injury that damages the
brain regions controlling speech and language, as in aphasia. In
other cases, cognitive impairments may be associated with a complex
developmental or genetic syndrome, such as deficits in executive
control that accompany autism or mental retardation.
[0097] Cognitive disorders can significantly impair social and
occupational functioning, adversely impacting the autonomy and
quality of life of the affected individual. An estimated four to
five million Americans (about 2% of all ages and 15% of those older
than 65) have some form and degree of cognitive impairment. Abrams
et al., Merck Manual of Geriatrics, Whitehouse Station (NJ),
Medical Services, 1995.
[0098] Cognitive Training
[0099] In some embodiments, the compositions of the instant
invention are used in conjunction with cognitive training Cognitive
training protocols and the underlying principles are well known in
the art. See, e.g., U.S. Pat. No. 7,868,015 (and references cited
therein); Klingberg et al., J. Am. Acad. Child. Adolesc. Psychiatry
44, 177-186, 2005; Belleville et al., Dement. Geriatr. Cogn.
Disord. 22, 486-499, 2006; Jaeggi et al., Proc. Natl. Acad. Sci.
USA 105, 6829-6833, 2008; Lustig et al., Neuropsychol. Rev. 19,
504-522, 2009; Park and Reuter-Lorenz, Ann. Rev. Psych. 60,
173-196, 2009; Chein et al., Psychon. Bull. Rev. 17, 193-199, 2010;
Klingberg, Trends Cogn. Sci. 14, 317-324, 2010; Owen et al., Nature
465, 775-778, 2010; Jaeggi et al., Proc. Natl. Acad. Sci. USA 108,
10081-10086, 2011.
[0100] Cognitive training protocols are directed to numerous
cognitive dimensions, including memory, concentration and
attention, perception, learning, planning, sequencing, and
judgment. One or more protocols (or modules) underling a cognitive
training program can be provided to a subject.
[0101] In some embodiments, the protocols can be used to treat, or
rehabilitate, cognitive impairments in afflicted subjects. Such
protocols may be restorative or remedial, intended to reestablish
prior skills and cognitive functions, while other protocols may be
focused on delaying or slowing cognitive decline due to
neurological disease. Other protocols may be compensatory,
providing a means to adapt to a cognitive deficit by enhancing
function of related and uninvolved cognitive domains. In other
embodiments, the protocols can be used to improve particular skills
or cognitive functions in otherwise healthy individuals. For
example, a cognitive training program might include modules focused
on delaying or preventing cognitive decline that normally
accompanies aging; here the program is designed to maintain or
improve cognitive health.
[0102] In general, a cognitive training protocol (or module)
comprises a set of distinct exercises that can be process-specific
or skill-based: Process-specific training focuses on improving a
particular cognitive domain such as attention, memory, language, or
executive functions. Here the goal of cognitive training is to
obtain a general improvement that transfers from the trained
activities to untrained activities associated with the same
cognitive function or domain. For example, an auditory cognitive
training protocol can be used to treat a student with impaired
auditory attention. At the end of training, the student should show
a generalized improvement in auditory attention, manifested by an
increased ability to attend to and concentrate on verbal
information presented in class--and therefore to remember to write
down and complete homework assignments.
[0103] Similarly, a cognitive training protocol may be directed to
impaired executive function in an autistic subject, preventing the
subject from carrying out instructions to complete an activity,
such as making a meal, cleaning one's room, or preparing for school
in the morning. Cognitive training allows the subject to focus his
attention and concentration and as a result, complete the sequence
of tasks required for such activities.
[0104] Skill-based cognitive training is aimed at improving
performance of a particular activity or ability. Here the goal of
cognitive training is to obtain a general improvement in the skill
or ability. For example, a training protocol may focus on learning
a new language, performing a musical instrument, or improving
memory. The different exercises within such a protocol will focus
on core components underlying skill. Modules for increasing memory,
for example, may include tasks directed to the recognition and use
of fact, and the acquisition and comprehension of explicit
knowledge rules.
[0105] Some cognitive rehabilitation programs may rely on a single
strategy (such as computer-assisted cognitive training) targeting
either an isolated cognitive function or multiple functions
concurrently. For example, the CogState testing method comprises a
customizable range of computerized cognitive tasks able to measure
baseline and change in cognitive domains underlying attention,
memory, executive function, as well as language and
social-emotional cognition. See, e.g., Yoshida et al., PLoS ONE 6,
e20469, 2011; Frederickson et al., Neuroepidemiology 34, 65-75,
2010. Other cognitive rehabilitation programs may use an integrated
or interdisciplinary approach. Cognitive training programs may
involve computer games, handheld game devices, interactive
exercises, and may employ feedback and adaptive models.
[0106] Augmented Cognitive Training
[0107] Cognitive training protocols generally require multiple
training sessions to attain the desired benefits. This can be
costly and time-consuming, deterring subject compliance and the
realization of real world benefits that endure. These deficits
underscore the need for methods to improve the efficiency of
cognitive training
[0108] The efficiency of cognitive training can be improved by
administering certain agents (known as augmenting agents) in
conjunction with cognitive training. Such augmenting agents have
the ability to enhance CREB pathway function. More particularly,
this method (known as augmented cognitive training or ACT) can
decrease the number of training sessions required to improve
performance of a cognitive function, relative to the improvement
observed by cognitive training alone. (See, e.g., U.S. Pat. No.
7,868,015; U.S. Pat. No. 7,947,731; U.S. 2008/0051437).
[0109] In this regard, several recent investigations indicate that
HT-2157 is such an augmenting agent. For example, injection or oral
administration of HT-2157 has been shown to enhance 24-hour memory
(long-term memory) in a standardized contextual fear conditioning
task. See U.S. Pat. No. 7,642,281. In addition, intraperitoneal
administration of HT-2157 has been shown to enhance 24 hour memory
(long-term memory) in an object recognition task. See U.S. Pat. No.
7,642,281. In each of these tasks, the cyclic AMP response element
binding protein (CREB) pathway is required for long-term memory
formation. Indeed, the fear conditioning task was originally
developed for evaluation of memory in CREB knock-out mice.
Bourtchouladze et al., Cell 79, 59-68, 1994.
[0110] The enhancing effect of HT-2157 in these two tasks indicates
that this compound enhances CREB pathway function and therefore can
augment cognitive training. Accordingly, in certain embodiments,
the methods of the present invention comprise administering an
HT-2157 composition of the instant invention in conjunction with a
cognitive training protocol. The phrase "in conjunction" means that
HT-2157 enhances CREB pathway function during cognitive
training
[0111] In a particular embodiment, the method comprises the steps
of: (a) providing cognitive training to a subject in need of
treatment of a cognitive deficit under conditions sufficient to
produce an improvement in performance by said animal of a cognitive
function whose impairment is associated with said cognitive
deficit; (b) administering an enteric-coated composition of the
present invention to the animal in conjunction with said cognitive
training; repeating steps (a) and (b) one or more times; and (d)
reducing the number of training sessions sufficient to produce the
improvement in performance, relative to the same improvement in
performance produced by cognitive training alone.
[0112] In other embodiments, this method reduces appearance of
clinically relevant methemoglobinemia or results in a lower
increase in percent of methemoglobin in a subject, relative to
administration of a non-enteric coated composition comprising the
same amount of HT-2157.
[0113] In a specific aspect, the cognitive deficit treated by these
methods is or includes a memory impairment, and more particularly,
a defect in long-term memory.
EXAMPLES
[0114] The present disclosure will be further illustrated by the
following non-limiting Examples. These Examples are understood to
be exemplary only, and they are not to be construed as limiting the
scope of the invention as defined by the appended claims.
Example 1
HT-2157 and Methemoglobinemia
[0115] Background
[0116] Methemoglobinemia is a disorder characterized by the
presence of a higher than normal level of methemoglobin (metHb) in
the blood. For a review, see Lee and Taraber, Medscape Emergency
Medicine, Apr. 11, 2011; Lee and Ferguson, Medscape Emergency
Medicine, Apr. 11, 2011. Methemoglobin is an oxidized form of
hemoglobin that has a decreased affinity for oxygen, leading to an
increased affinity of oxygen to other heme sites that results in an
overall reduced ability to release oxygen to tissue. In healthy
humans, the protective enzyme systems normally present in red blood
cells maintain methemoglobin levels at less than 1 to 1.5 percent
of the total hemoglobin. When methemoglobin levels are too high,
tissue hypoxia can occur. Levels above 30% can result in multiple
adverse consequences, including dyspnea, nausea, and tachycardia.
Moreover, there is no known safe level of methemoglobin exposure
above about 1 to 1.5 percent.
[0117] Methemoglobinemia can occur as either a hereditary or
acquired condition. For a review, see Ashurst and Wasson, Del. Med.
83, 203-208, 2011. Hereditary methemoglobinemia has multiple
causes, including congenital deficiencies in diaphorase 1 (NADH
methemoglobin reductase) or pyruvate kinase--an essential cofactor
for diaphorase 1; or the presence of an abnormal hemoglobin variant
not amenable to reduction, such as hemoglobin M or hemoglobin H.
Such hereditary forms are often associated with methemoglobin
levels of 20-40 percent of total hemoglobin.
[0118] Acquired methemoglobinemia can result from exposure to
certain drugs, metabolites, and toxins, which may accelerate the
rate of formation of methemoglobin up to 1000-fold, overwhelming
the protective enzyme systems and acutely increasing methemoglobin
levels. Such exposure is typically associated with methemoglobin
levels of about 5 to about 15%. Substances that may be associated
with acquired methemoglobinemia include drugs and toxic substances,
such as sodium nitrite, amyl nitrite, nitroglycerin, nitroprusside,
silver nitrate, aniline dyes, acetanilid, phenacetin, sulfonamides,
lidocaine, topical benzocaine, chlorate paraquat, and
phenazopyridine.
[0119] Animal Studies
[0120] Numerous animal studies, including the following, show that
administering HT-2157 (without an enteric coating) can increase the
formation of methemoglobin in red blood cells, limiting its
therapeutic potential. Such HT-2157 administration studies were
carried out in several animal models, including rats, dogs (as well
as mice). In this regard, the major human metabolite of HT-2157,
HT-2800, was found in human, mouse, and monkey microsomes following
incubation with the HT-2157 compound, but it was not detected in
rat or dog microsomes or in plasma collected from dogs dosed with
HT-2157.
[0121] Consequently, separate toxicokinetic studies directed to
HT-2800 (without an enteric coating) were performed in rat and in
dog, which is considered the more sensitive species. These studies
demonstrated two types of hematological abnormalities: hemolytic
anemia and methemoglobinemia, which appeared to be dose-dependent
effects. In these studies, the non-toxic dose level for oral
administration of HT-2157 over 28 days was 30 mg/kg/day for female
rats, 100 mg/kg/day for male rats and 50 mg/kg/day for dogs (both
sexes). Table 1 lists the mean C.sub.max and AUC values of HT-2157
in the plasma associated with these dosages:
TABLE-US-00001 TABLE 1 28-Day Oral Toxicity Studies with
Non-enteric Coated HT-2157 Duration of Dosing C.sub.max
AUC.sub.0-24 Species Ref # NOEL NOEL (days) (ng/ml) (ng h/ml)
Rat-Male 5 100 590 1 252 1376 28 442 1445 Rat-Female 5 30 177 1
77.8 235 28 109 283 Dog-Male 6 50 1000 1 99.0 676 28 87.1 550
Dog-Female 6 50 1000 1 162.2 571 28 103.7 799 NOEL: No effect
level
[0122] Hemolytic anemia was observed in these studies, and there
were decreases of approximately 4 to 21% in the following
hematologic parameters: red blood cells (RBC), hemoglobin,
hematocrit, and mean corpuscular hemoglobin concentration (MCHC).
There were also increases of between 6 and 110% in the following
parameters: platelet count, mean corpuscular volume (MCV) and red
cell distribution width.
[0123] These findings indicate that a process of hemolytic anemia
and compensatory hematopoietic response to anemia occurred in the
animals. The hemolytic anemia was reversible upon discontinuation
of drug treatment. In animals at high doses, there were also
increases in methemoglobin of between 30 and 40% in treatment as
compared to control animals. These increases resolved 1 to 2 weeks
after discontinuation of dosing. Ninety-day studies with HT-2157
revealed statistically significant methemoglobin formation at 750
mg/kg/day for mice, 150 mg/kg/day for rats, and 30 mg/kg/day and
higher for dogs.
[0124] Drug-related findings in repeat-dose animal toxicology
studies conducted with non-enteric coated HT-2157 administered PO
in mice for up to 3 months, rats for up to 1 year, and dogs for up
to 9 months, and with non-enteric coated HT-2800 administered PO in
rats for up to 6 months and in dogs for 9 months were restricted to
dose-dependent shifts in hemoglobin fractions (methemoglobin,
carboxyhemoglobin, oxyhemoglobin) and mild to moderate reversible
hemolytic anemia with associated compensatory responses.
Example 2
Clinical Studies of HT-2157 Formulations
[0125] Uncoated Solid-Dosage Capsules
[0126] Subjects were administered single and repeated doses of a
conventional non-enteric coated HT-2157 formulation, namely
uncoated powder-filled capsules. Following administration of the
HT-2157 powder capsules, elevated methemoglobin levels were seen in
several subjects at dose levels ranging from 150 to 600 mg.
[0127] Enteric-Coated and Uncoated Liquid Gel Capsules
[0128] Compositions and Administration
[0129] The results described here were based on oral administration
of standard (uncoated) and enteric-coated formulations described in
Table 2 and 3, respectively:
TABLE-US-00002 TABLE 2 Composition of HT-2157 (20 mg) Uncoated
Liquid Capsules Weight Component Purpose Percentage (mg/capsule)
HT-2157 API 3 20 Cremophor RH 40 Excipient 32.3 215.4 Vitamin E
TPGS Excipient 64.7 431.6 Capsugel .RTM. Swedish Orange Capsule N/A
N/A opaque Licaps size 0 capsules Total 100 667 N/A = not
applicable
TABLE-US-00003 TABLE 3 Composition of HT-2157 (30 mg)
Enteric-Coated Liquid Capsules Weight Component Purpose Percentage
(mg/capsule) HT-2157 API 3.1 30.1 Cremophor RH 40 Excipient 32.27
313 Vitamin E TPGS Excipient 64.63 626.9 Capsugel .RTM. Swedish
Orange Capsule N/A N/A opaque Licaps size 00EL capsules Total 100
667 Enteric-coat composition: Eudragit FCC D55 (95.24%) + Triethyl
citrate (4.76%) N/A = not applicable
[0130] Two groups of subjects received a 120 mg dose of HT-2157
once-a-day for three days under fed conditions: One group received
20 mg standard (uncoated) HT-2157 gel capsules in an amount
totaling 120 mg. The other group received 30 mg enteric-coated gel
capsules in an amount totaling 120 mg.
[0131] Pharmacokinetics
[0132] Table 4 summarizes the accumulation of HT-2157 and HT-2800
in the two groups at the first and third day of dosing. After
one-day and three days of dosing, exposures to HT-2157 and HT-2800
were much higher in the enteric capsule group than the uncoated
capsule group. The bioavailability of HT-2157 in the gel capsules
was therefore significantly increased in the presence of an
enteric-coating.
TABLE-US-00004 TABLE 4 HT-2157 and HT-2800 Levels in Groups
Receiving Uncoated and Enteric-Coated Gel Capsules (120 mg) Mean
AUC Uncoated Enteric-Coated (hr ng/ml) HT-2157 HT-2800 HT-2157
HT-2800 0-24 h 10.2 30.9 85.4 91.8 48-72 h 13.4 42.2 180.3
211.6
[0133] Methemoglobin
[0134] Table 5 shows the methemoglobin responses associated with
administration of the uncoated and enteric-coated HT-2157 gel
capsules.
TABLE-US-00005 TABLE 5 Methemoglobin Levels Reached in Groups
Receiving Uncoated and Enteric-Coated Capsules (120 mg) Uncoated
Enteric-Coated Mean Peak Levels of 2.53 0.58 Methemoglobin (%)
[0135] The mean peak level of methemoglobin in the uncoated group
was 2.53%--above the normal upper limit of 1.5%. On an individual
basis, 3 out of 4 subjects in the uncoated group had methemoglobin
levels above the normal upper limit (1.5%).
[0136] In contrast, the mean peak level of methemoglobin in the
enteric coated group was only 0.58%--well below the normal upper
limit. Moreover, this group showed very little variation in
methemoglobin values after a small rise between the 0 and 12 hour
time points, and no individual in this group showed methemoglobin
levels above the normal range (0 to 1.5%).
[0137] In sum, these results indicate that enteric-coating of oral
formulations of HT-2157 may mitigate or prevent the formation of
clinically relevant levels of methemoglobin caused by HT-2157.
Indeed, even though exposures to HT-2157 and HT-21800 were much
higher in the enteric coated group than the uncoated group (Table
4), the subjects in the enteric coated group showed no unsafe
(clinically relevant) levels of methemoglobin (Table 5).
[0138] Enteric-Coated, Solid-Dosage Tablets
[0139] Twenty normal, healthy female volunteers were enrolled in a
double-blind, single center, placebo-controlled, randomized, study
to evaluate the pharmacokinetic and safety profiles of single doses
(25, 50, 150, and 200 mg) of an enteric-coated tablet formulation
of HT-2157.
[0140] Compositions and Administration
[0141] Tables 6 and 7 list the components of enteric-coated HT-2157
tablets and enteric-coated placebo tablets, respectively.
TABLE-US-00006 TABLE 6 Composition of Enteric-Coated HT-2157
Tablets Weight Component Purpose (mg/tablet) HT-2157 (milled) API
25.0 Microcrystalline Cellulose and Diluent 191.0 Colloidal Silicon
Dioxide (Prosolv SMCC 90LM) Pregelatinized Starch, Starch 1500
Diluent 60.0 Hydroxypropyl Cellulose, Klucel EF Binder 15.0 Sodium
Lauryl Sulfate, Stepanol .RTM. Surfactant 6.0 Colloidal Silicon
Dioxide (Cab-o-Sil Glidant 1.5 M-5P) Magnesium Stearate (HyQual
.RTM.) Lubricant 1.5 Acryl-eze Orange Enteric coating 25.0
TABLE-US-00007 TABLE 7 Quantitative Composition of Enteric-Coated
Placebo Tablets Component Weight (mg/tablet) Microcrystalline
Cellulose and 208.4 Colloidal Silicon Dioxide (Prosolv SMCC 90 LM)
Pregelatinized Starch, Starch 1500 65.5 Hydroxypropyl Cellulose,
Klucel 16.4 EF Sodium Lauryl Sulfate, Stepanol .RTM. 6.5 Colloidal
Silicon Dioxide 1.6 (Cab-o-Sil M-5P) Magnesium Stearate (HyQual
.RTM.) 1.6 Acryl-eze Orange (Enteric 48.0 Coating) Total 348
[0142] The subjects were divided into 4 cohorts. Each cohort had
five members, four receiving the HT-2157 tablet and one receiving a
placebo. The subjects in each cohort were randomized to receive 25
mg enteric-coated tablets of HT-2157 (or matching placebo tablets)
in amounts totaling 25, 50, 150, and 200 mg, respectively, under
fasting conditions.
[0143] Pharmacokinetics
[0144] In the 25 mg and 50 mg groups, HT-2157 plasma concentrations
were generally below the limit of quantification. In the 150 mg and
200 mg dose groups, comparable mean AUC, CL/F and T.sub.1/2 values
for HT-2157 were observed. The mean C.sub.max values for HT-2157
were greater in the 200 mg group than in the 150 mg group (5.03 vs.
2.71 ng/ml), and mean T.sub.max values occurred later in the 200 mg
group than in the 150 mg group (8.75 vs. 6.0 hours).
[0145] Mean plasma exposures of HT-2800 were comparable in the 25
and 50 mg dose groups. Although formal linear regression analysis
was not performed, visual comparisons of mean AUC and C.sub.max
data for HT-2800 suggest that plasma exposures increase
proportionally with the HT-2157 dose across the dose range of 50 to
200 mg. The mean T.sub.112 values for HT-2800 varied, ranging from
approximately 11 hours (200 mg group) to 31 hours (50 mg group). At
the two highest dose levels, the mean T.sub.max values for HT-2800
were comparable to those of the parent.
[0146] Table 8 summarizes the accumulation of HT-2157 and HT-2800
in the tablet cohorts at 3 days following a single dose:
TABLE-US-00008 TABLE 8 HT-2157 and HT-2800 Levels in Enteric-Coated
Tablet Cohorts Single Dose HT-2157 HT-2800 (mg) Mean AUC.sub.0-72
(hr ng/ml) 25 0 23.7 50 1.21 23.6 150 53.9 97.28 200 48.8
124.84
[0147] Methemoglobin
[0148] All of the individual methemoglobin values were below 1.5%
in the active and placebo groups. No subjects developed
methemoglobinemia.
[0149] In sum, the results from this study indicate that the plasma
levels of drug were comparable with what had been seen using
non-enteric coated formulations, but there was no indication of
methemoglobinemia in any of the trial participants.
[0150] Stability
[0151] The 12-month stability results for 25 mg enteric-coated
tablets stored under standard and accelerated conditions are listed
in Tables 9 and 10, respectively:
TABLE-US-00009 TABLE 9 Stability Results for 25 mg HT-2157 Enteric
Coated Tablets: 25.degree. C./60% RH Initial 1 Month 3 Months 6
Months 12 Months HPLC Assay 97.1 95.1 95.4 93.7 95.9 (90.0%-100.0%)
Total Impurities 2.7 2.9 2.8 3.0 3.4 TFMA 0.96 1.06 0.99 1.06 1.22
PIT 1.67 1.80 1.74 1.76 1.96 DPA <0.1 <0.01 <0.01 <0.01
<0.01 HT-2860 <0.1 <0.01 <0.01 <0.01 0.09 Unknown
0.09 0.07 0.10 0.17 0.12 .sup.3TFMA = m-trifluoromethylaniline
.sup.2PIT = 1-phenylisatin .sup.3DPA = diphenylamine
TABLE-US-00010 TABLE 10 Stability Results for 25 mg HT-2157 Enteric
Coated Tablets: 40.degree. C./75% RH Initial 1 Month 3 Months 6
Months HPLC Assay 97.1 93.5 93.6 92.1 (90.0%-100.0%) Total
Impurities 2.7 3.7 3.4 3.6 TFMA.sup.1 0.96 1.39 1.32 1.50 PIT.sup.2
1.67 2.17 1.81 1.61 DPA.sup.3 <0.1 <0.01 <0.01 <0.1
HT-2860 <0.1 0.05 0.18 <0.38 Unknown 0.09 0.07 0.10 0.15
.sup.3TFMA = m-trifluoromethylaniline .sup.2PIT = 1-phenylisatin
.sup.3DPA = diphenylamine
[0152] These data show that the 25 mg enteric-coated tablets meet
the HPLC Assay specifications (90.0%-100.0%) at 25.degree. C./60%
RH and 40.degree. C./75% RH. At the end of each set of storage
conditions, the amount of HT-2157 was not decreased by more than
10%.
Example 3
Pharmacokinetic and Safety Data Following Administration of
Enteric-Coated Versus Non-Enteric Coated HT-2157 Formulations
[0153] This study is a randomized double-blind, placebo-controlled,
multiple dose evaluation of the safety, tolerability, and
pharmacokinetics of orally-administered, enteric-coated versus
non-enteric coated HT-2157 solid-dosage formulation in healthy
volunteers.
[0154] The study comprises two cohorts: Group I and Group II. Each
cohort has ten members, eight receiving a HT-2157 solid-dosage
formulation and two receiving a placebo tablet. Subjects in cohort
1 are randomized to receive an enteric-coated, solid-dosage HT-2157
(or matching placebo) tablet in single doses for 21 days. Subjects
in cohort 2 are randomized to receive a non-enteric coated HT-2157
(or matching placebo) tablet in single doses for 21 days. Following
administration of the enteric-coated and non-enteric coated
formulations, multiple parameters, including pharmacokinetics (PK)
and safety data are evaluated.
[0155] Pharmacokinetics and Methemoglobin
[0156] The results include the observation that at the same dosage
(125 mg), the C.sub.MAX is higher in subjects receiving the
enteric-coated HT-2157 formulation versus the non-enteric coated
HT-2157 formulation. However, despite their higher exposure to
HT-2157, subjects in the enteric coated group show no clinically
relevant methemoglobinemia. In all subjects receiving the
enteric-coated formulation, the levels of methemoglobin remain
below 1.5%.
Example 4
Therapeutic Administration of Enteric-Coated HT-2157
Formulations
[0157] This trial comprises a randomized, double-blind,
placebo-controlled, multiple (21-day) ascending-dose study in
twenty otherwise-healthy male and female patients with
mild-to-moderate major depressive disorder (as defined by the
American Psychiatry Association Diagnostic and Statistical Manual
of Mental Disorders--4th edition [DSM-IV-TR] and confirmed by the
Mini International Neuropsychiatric Interview [MINI]) of mild to
moderate severity (as assessed by the Montgomery-.ANG.sberg
Depression Rating Scale [MADRS]).
[0158] Compositions and Administration
[0159] The patients are divided into 2 cohorts. Each cohort has ten
members, eight receiving HT-2157 and two receiving a placebo.
Patients in cohort 1 are randomized to receive a 125 mg
enteric-coated, solid dosage HT-2157 formulation (or matching
placebo) on days 1-21 in a fed state, and multiple parameters,
including pharmacokinetics (PK), safety, and pharmacodynamics (PD)
data are evaluated. Procedures for Cohort 2 are identical to those
for Cohort 1, except that patients in Cohort 2 will receive single
doses of 250 mg HT-2157 for 21 days.
[0160] Cognitive function in Cohorts 1 and 2 is assessed using the
CogState testing method, which comprises a customizable range of
computerized cognitive tasks able to measure baseline and change in
all cognitive domains. Specialized tasks in CogState can assess
attention, memory, executive function, as well as language and
social-emotional cognition.
[0161] Mean blood methemoglobin levels in each Cohort do not
increase substantially and do not exceed 1.5% in any single patient
as measured daily--even after 21 days of dosing. There is no
evidence of hemolytic processes or significant cardiovascular
findings. Under the dosing duration of 3 weeks (21 days), there is
evidence of HT-2157-induced changes on PD endpoints that indicate
an antidepressant effect.
[0162] While certain embodiments are described herein, it will be
understood that the described embodiments are not intended to limit
the scope of the invention as defined by the appended claims. On
the contrary, the present disclosure is intended to cover
alternatives, modifications and equivalents that may be included
within the spirit and scope of the invention as defined by the
appended claims. Furthermore, certain details in the present
disclosure are provided to convey a thorough understanding of the
invention defined by the appended claims. However, it will be
apparent to those skilled in the art that certain embodiments may
be practiced without these details. In certain instances,
well-known methods, procedures, or other specific details have not
been described to avoid unnecessarily obscuring aspects of the
invention defined by the appended claims.
* * * * *