U.S. patent application number 15/213341 was filed with the patent office on 2017-06-15 for methods and compositions employing bicifadine for treating disability or functional impairment associated with acute pain, chronic pain, or neuropathic disorders.
The applicant listed for this patent is EBI Life Sciences, Inc.. Invention is credited to Johnson Lim, Arnold S. Lippa, Warren Stern.
Application Number | 20170165228 15/213341 |
Document ID | / |
Family ID | 39261819 |
Filed Date | 2017-06-15 |
United States Patent
Application |
20170165228 |
Kind Code |
A1 |
Lippa; Arnold S. ; et
al. |
June 15, 2017 |
METHODS AND COMPOSITIONS EMPLOYING BICIFADINE FOR TREATING
DISABILITY OR FUNCTIONAL IMPAIRMENT ASSOCIATED WITH ACUTE PAIN,
CHRONIC PAIN, OR NEUROPATHIC DISORDERS
Abstract
Methods and compositions are provided for formulating and
administering bicifadine and related compounds to treat or prevent
functional impairment and disabilities associated with acute pain,
chronic pain, and neuropathic disorders.
Inventors: |
Lippa; Arnold S.;
(Ridgewood, NJ) ; Stern; Warren; (Plymouth,
MA) ; Lim; Johnson; (Edison, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
EBI Life Sciences, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
39261819 |
Appl. No.: |
15/213341 |
Filed: |
July 18, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13907920 |
Jun 2, 2013 |
9393204 |
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15213341 |
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13742335 |
Jan 15, 2013 |
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13907920 |
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13488341 |
Jun 4, 2012 |
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13742335 |
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13297439 |
Nov 16, 2011 |
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13488341 |
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11708951 |
Feb 20, 2007 |
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13297439 |
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11438909 |
May 22, 2006 |
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11708951 |
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11260887 |
Oct 26, 2005 |
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11438909 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/403 20130101;
A61P 43/00 20180101; A61P 25/00 20180101; A61K 9/2054 20130101 |
International
Class: |
A61K 31/403 20060101
A61K031/403 |
Claims
1-70. (canceled)
71. A method for treating chronic pain and/or neuropathic pain in a
mammalian subject comprising administering to the mammalian subject
a sustained release pharmaceutical composition comprising a
therapeutically effective amount of a compound of Formula I
##STR00003## or a pharmaceutically acceptable salt thereof combined
with a sustained release vehicle, matrix, binder, or coating
material.
72. The method of claim 71, wherein the sustained release
pharmaceutical composition comprises a therapeutically effective
amount of 1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane
hydrochloride.
73. The method of claim 71, wherein the sustained release
pharmaceutical composition comprises a therapeutically effective
amount of (+)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane or a
pharmaceutically acceptable salt thereof.
74. The method of claim 71, wherein the sustained release
pharmaceutical composition comprises a therapeutically effective
amount of (-)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane or a
pharmaceutically acceptable salt thereof.
75. The method of claim 71, wherein the sustained release
pharmaceutical composition comprises polymorph form B of
1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
76. The method of claim 71, wherein the sustained release
pharmaceutical composition comprises polymorph form A of
1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
77. A method for treating chronic pain in a mammalian subject
comprising administering to the mammalian subject a therapeutically
effective amount of a compound of Formula I ##STR00004## or a
pharmaceutically acceptable salt thereof in a daily dosing regimen
consisting of one or two doses of Formula I per day.
78. The method of claim 77 comprising administering
1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
79. The method of claim 77 comprising administering
(+)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane or a
pharmaceutically acceptable salt thereof.
80. The method of claim 77 comprising administering
(+1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane or a
pharmaceutically acceptable salt thereof.
81. The method of claim 77 comprising administering polymorph form
B of 1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane
hydrochloride.
82. The method of claim 77 comprising administering polymorph form
A of 1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit as a
continuation-in-part of U.S. patent application Ser. No.
11/260,887, filed Oct. 26, 2005, which is a continuation-in-part of
U.S. patent application Ser. No. 10/621,435, filed Jul. 17, 2003,
which is entitled to priority from U.S. Provisional Application No.
60/399,852, filed Jul. 31, 2002. The present application claims all
priority rights from the foregoing priority applications, the
disclosures of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Compounds of Formula I, below
##STR00001##
including bicifadine, and salts and other forms of these compounds,
are analgesics that are not narcotics (that is, are not
morphine-like in action). See U.S. Pat. No. 4,231,935 and U.S. Pat.
No. 4,196,120.
[0003] In administering a compound of Formula I to produce
analgesia, it is important that the compound be administered in an
effective manner to provide prompt and sustained activity through
the presence of the compound in the blood system to effectively
alleviate pain in the patient. There remains a significant, unmet
need in the art for effective compositions and methods for
delivering a compound of Formula I that will provide rapid relief
of moderate and severe pain when administered and will maintain
this relief for long periods of time.
SUMMARY OF EXEMPLARY EMBODIMENTS OF THE INVENTION
[0004] It is therefore an object of the present invention to
provide novel and improved compositions, dosage forms, and methods
employing a compound of Formula I, for example a bicifadine
compound, to treat pain and improve functioning in mammalian
subjects.
[0005] It is a further object of the invention to provide novel and
improved compositions, dosage forms, and methods employing a
compound of Formula I to treat or prevent one or more conditions of
acute pain (e.g., pain resulting after major surgery and during
recovery), chronic pain (e.g., chronic low back pain), and/or pain
and other symptoms associated with neuropathic disorders, in
mammalian subjects, and/or to approve functioning in subjects
presenting with these conditions.
[0006] The invention achieves these objects and satisfies
additional objects and advantages by providing new and surprisingly
effective compositions, dosage forms, and methods employing a
compound of Formula I in an effective formulation for treating
acute pain, chronic pain, and/or pain or other symptoms associated
with neuropathic disorders in mammals.
[0007] In one embodiment, the invention provides pharmaceutical
compositions comprising a pre-determined dosage amount of an active
compound of Formula I, which may be selected from, for example,
bicifadine and pharmaceutically acceptable salts, enantiomers,
polymorphs, solvates, hydrates, and prodrugs of bicifadine, and
combinations thereof, in combination with a sustained release
vehicle, matrix, binder or coating material. Following
administration of this pharmaceutical composition to a mammalian
treatment subject, the composition provides a mean maximum plasma
concentration (Cmax) of the active compound in the treatment
subject which is less than about 80% of a Cmax provided in a
control subject after administration of the same amount of the
active compound in an immediate release (IR) formulation.
[0008] In other embodiments of the invention, a composition
comprising an active compound of Formula I (as used herein for
shorthand, this reference to compounds of Formula I is intended to
include all pharmaceutically acceptable salts, enantiomers,
polymorphs, solvates, hydrates, and prodrugs of compounds that
satisfy this formula) in combination with a sustained release
vehicle, matrix, binder or coating material will provide, following
administration of the composition to a mammalian treatment subject,
a summated plasma concentration over time (referred to by those
skilled in the art as Area Under the Curve (AUC)) of the active
compound in the treatment subject which is less than about 80% of
an AUC provided in a control subject following administration of
the same amount of the active compound in an immediate release (IR)
formulation.
[0009] In determining and comparing pharmacokinetic values
according to the present description and examples below, including
comparative AUC and Cmax values for SR and IR bicifadine
formulations, standard procedures and statistical methods are
employed. These standard procedures and statistical methods are
well known in the art and may be found, for example, in FDA
Guidance for Industry, Bioavailability and Bioequivalence Studies
for Orally Administered Drug Products--General Considerations,
CDER. October 2000; and FDA Guidance for Industry, Statistical
Approaches to Establishing Bioequivalence
(http://www.fda.gov/cder/guidance/index.htm;
http://www.fda.gov/cder/guidance/3616fnl.htm); and Fundamentals of
Clinical Pharmacokinetics. J. G. Wagner, Drug Intelligence
Publications, Inc., Hamilton, Ill., 1975 (each incorporated herein
by reference). For example, in comparative pharmacokinetic studies
presented herein, immediate-release (IR) oral dosage formulations
of bicifadine are compared with exemplary sustained release (SR)
oral dosage formulations using two-treatment, two-sequence,
two-period crossover studies in healthy adult male and female human
subjects. Metrics of peak (Cmax) and total (AUCt, AUCf) exposure
are compared between bicifadine IR-dosed and SR-dosed subjects by
analysis of variance (ANOVA) with effects for sequence, subject
nested within sequence, period, and treatment. Confidence intervals
(90%) are estimated around ratios (IR/SR) of least squares means
derived from logarithmic-transformed metrics. Comparative Cmax
and/or AUC value(s) produced in subjects after administration of an
SR bicifadine formulation compared to the value(s) produced in
subjects after administration of an IR bicifadine formulation
is/are determined to be less than about 0.80 when the comparative
data are evidenced by at least 90% confidence intervals.
[0010] Within additional embodiments of the invention, a
composition comprising an active compound of Formula I in
combination with a sustained release vehicle, matrix, binder, or
coating material will provide, following administration of the
composition to a mammalian treatment subject, a Cmax and an AUC of
the active compound in the treatment subject which are each,
respectively, less than about 80% of a Cmax and an AUC provided in
a control subject following administration of the same amount of
the active compound in an immediate release formulation.
[0011] The instant invention further provides novel methods for
preventing or treating a condition or symptom of acute pain,
chronic pain, and/or a neuropathic disorder in mammalian subjects.
These methods involve administering to a treatment subject a
pharmaceutical composition comprising a therapeutically effective
amount of an active compound of Formula I (e.g., selected from
bicifadine and pharmaceutically acceptable salts, enantiomers,
polymorphs, solvates, hydrates, and prodrugs of bicifadine, and
combinations thereof) combined with a sustained release vehicle,
matrix, binder, or coating material. Following administration of
this pharmaceutical composition to the treatment subject, a mean
maximum plasma concentration (Cmax) of the active compound is
obtained in the treatment subject which is less than about 80% of a
Cmax obtained in a control subject after administration of the same
amount of the active agent in an immediate release formulation.
These methods surprisingly provide for prompt, long-lasting relief
or prevention of the targeted condition or symptom of acute pain,
chronic pain, or a neuropathic disorder in the subject without
attendant, unacceptable adverse side effects. Within certain
exemplary embodiments of the invention, the sustained release
compositions and dosage forms described herein reduce the incidence
and/or severity of one or more adverse side effects in treatment
subjects compared to an incidence and/or severity of the same side
effect(s) observed in subjects after administration of an
equivalent amount of the active agent in an immediate release
formulation.
[0012] Within additional embodiments of the invention, distinct
methods for preventing or treating a condition or symptom of
chronic pain in mammalian subjects are provided. These chronic pain
treatment methods involve administering to the subject an active
compound of Formula I (e.g., selected from bicifadine and
pharmaceutically acceptable salts, enantiomers, polymorphs,
solvates, hydrates, and prodrugs of bicifadine, and combinations
thereof), in a daily dosing regimen consisting of only one or two
doses of the active compound per day, which is surprisingly
effective to alleviate or prevent the targeted chronic pain
condition or symptom in the subject, without attendant,
unacceptable adverse side effects, over an extended period, e.g.,
up to a 24 hour period. Within alternate embodiments of this aspect
of the invention, a once daily or twice daily dosing protocol is
provided which employs either an immediate release, controlled
release, or sustained release formulation, which is effective for
treating the chronic pain over an extended period. Within certain
exemplary embodiments, a sustained release composition or dosage
form as described herein is employed in a method for treating
chronic pain involving a limited dosing schedule of once or twice
daily administration, wherein an incidence and/or severity of one
or more adverse side effects is reduced in treatment subjects
compared to an incidence and/or severity of the same side effect(s)
observed in subjects after administration of an equivalent amount
of the active agent in an immediate release formulation.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 illustrates plasma concentration time course data for
exemplary bicifadine immediate release (IR) and sustained release
(SR) formulations.
[0014] FIG. 2 illustrates mean plasma concentration time course
data following administration of 200 mg BID, 200 mg TID, and 400 mg
BID (multiple dose, steady-state profiles) of an exemplary
bicifadine SR formulation according to the invention administered
to subjects in an acute dental pain clinical trial.
[0015] FIG. 3 illustrates the dose-response relationship for
analgesic effects of bicifadine and tramadol relative to placebo in
an acute dental pain study.
[0016] FIG. 4 presents Pain Severity Rating (PSR) data based on a
100 mm visual analogue scale (VAS) developed from long-term
clinical studies using bi-daily dosing of bicifadine to treat
chronic lower back pain (CLBP).
[0017] FIG. 5 demonstrates that bicifadine significantly treats
pain-associated disability, by enhancing function/activity
performance, in Chronic Low Back Pain (CLBP) subjects. In a poorly
functional cohort of patients having a baseline Roland-Morris
Disability Questionnaire (RDQ) score of greater than 17, bicifadine
showed significant activity for reversing disabilities and
enhancing functional/activity performance in treated subjects
compared to placebo-treated subjects (LOCF="last observation
carried forward" calculation method).
[0018] FIG. 6 demonstrates that pain-relief results for bicifadine
are also significant and substantial among a moderate to severely
disabled cohort of CLBP patients. VAS pain scores in moderate to
severely disabled CLBP patients (presenting with a baseline RDQ
score greater than 17) were reduced by 50% or more in at least
three times as many bicifadine-treated as placebo-treated
patients.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS OF THE INVENTION
[0019] The instant invention provides novel compositions, dosage
forms and methods for treating symptoms of acute pain, chronic
pain, and/or a neuropathic disorder in mammalian subjects. The
compositions and methods of the invention employ a pre-determined,
therapeutically effective dosage amount of an active therapeutic
compound of Formula I, below, formulated in a sustained release
composition or dosage form.
##STR00002##
In exemplary embodiments, the compound of Formula I is selected
from bicifadine (e.g., a free base form of bicifadine) and
pharmaceutically acceptable salts, enantiomers, polymorphs,
solvates, hydrates, and prodrugs of bicifadine, and combinations
thereof.
[0020] Within exemplary compositions and dosage forms of the
invention, the compound of Formula I is combined with a sustained
release vehicle, matrix, binder, or coating material. As used
herein, the term "sustained release vehicle, matrix, binder, or
coating material" refers to any vehicle, matrix, binder, or coating
material that effectively, significantly delays dissolution of the
active compound in vitro, and/or delays, modifies, or extends
delivery of the active compound into the blood stream (or other in
vivo target site of activity) of a subject following administration
(e.g., oral administration), in comparison to dissolution and/or
delivery provided by an "immediate release" formulation, as
described herein, of the same dosage amount of the active compound.
Accordingly, the term "sustained release vehicle, matrix, binder,
or coating material" as used herein is intended to include all such
vehicles, matrices, binders and coating materials known in the art
as "sustained release", "delayed release", "slow release",
"extended release", "controlled release", "modified release", and
"pulsatile release" vehicles, matrices, binders and coatings.
[0021] In one aspect, the current invention comprises an oral
sustained release dosage composition for administering an active
compound of Formula I. In a related aspect, the invention comprises
a method of reducing one or more side effects that attend
administration of an oral dosage forms of a compound of Formula I.
Within these methods, the compound of Formula I is provided in a
sustained release oral dosage form and the dosage form is
introduced into a gastrointestinal tract of a mammalian subject
presenting with acute pain, chronic pain, or a neuropathic
disorder, by having the subject swallow the dosage form. The method
further includes releasing the active compound of Formula I in a
sustained, delayed, gradual or modified release delivery mode into
the gastrointestinal tract (e.g., the intestinal lumen) of the
subject over a period of hours, during which the active compound
reaches, and is sustained at, a therapeutic concentration in a
blood plasma, tissue, organ or other target site of activity (e.g.,
a central nervous system (CNS) tissue, fluid or compartment) in the
patient. When following this method, the side effect profile of the
active compound is less than a side effect profile of an equivalent
dose of the active compound administered in an immediate release
oral dosage form.
[0022] In certain embodiments, the active compound of Formula I is
released from the sustained release compositions and dosage forms
of the invention and delivered into the blood plasma or other
target site of activity in the subject at a sustained therapeutic
level over a period of at least about 6 hours, often over a period
of at least about 8 hours, at least about 12 hours, or at least
about 18 hours, and in other embodiments over a period of about 24
hours or greater. By sustained therapeutic level is meant a plasma
concentration level of at least about 400-500 ng/ml or greater. In
more detailed embodiments of the invention, the sustained release
compositions and dosage forms will yield a therapeutic level of a
compound of Formula I following administration to a mammalian
subject in a desired dosage amount (e.g., 200, 400, 600, or 800 mg)
that yields a minimum plasma concentration of greater than 500
ng/ml over a period of at least about 6 hours, at least about 8
hours, at least about 12 hours, at least about 18 hours, or up to
24 hours or longer. In alternate embodiments of the invention, the
sustained release compositions and dosage forms will yield a
therapeutic level of a compound of Formula I following
administration to a mammalian subject in a desired dosage amount
(e.g., 200, 400, 600, or 800 mg) that yields a minimum plasma
concentration of greater than 600 ng/ml, greater than 700 ng/ml,
greater than 800 ng/ml, or greater than 900 ng/ml over a period of
at least about 6 hours, at least about 8 hours, at least about 12
hours, at least about 18 hours, or up to 24 hours or longer.
[0023] In certain embodiments, the active compound of Formula I is
released from the compositions and dosage forms of the invention
and delivered into the blood plasma or other target site of
activity in the subject in a sustained release profile
characterized in that from about 0% to 20% of the active compound
is released and delivered (as determined, e.g., by measuring blood
plasma levels) within in 0 to 2 hours, from 20% to 50% of the
active compound is released and delivered within about 2 to 12
hours, from 50% to 85% of the active compound is released and
delivered within about 3 to 20 hours, and greater than 75% of the
active compound is released and delivered within about 5 to 18
hours.
[0024] In more detailed embodiments of the invention, compositions
and oral dosage forms of a compound of Formula I are provided,
wherein the compositions and dosage forms, after ingestion, provide
a curve of concentration of the active compound over time, the
curve having an area under the curve (AUC) which is approximately
proportional to the dose of the active compound administered, and a
maximum concentration (Cmax) that is proportional to the dose of
the active compound administered.
[0025] In other detailed embodiments, the Cmax of the active
compound of Formula I provided after oral delivery of a composition
or dosage form of the invention is less than about 80%, often less
than about 75%, in some embodiments less than about 60%, or 50%, of
a Cmax obtained after administering an equivalent dose of the
active compound in an immediate release oral dosage form.
[0026] In other detailed embodiments, the AUC of the active
compound of Formula I provided after oral delivery of a composition
or dosage form of the invention is less than about 80%, often less
than about 75%, in some embodiments less than about 60%, or 50%, of
a AUC obtained after administering an equivalent dose of the active
compound in an immediate release oral dosage form.
[0027] In other detailed embodiments, each of the Cmax and AUC of
the active compound of Formula I provided after oral delivery of a
composition or dosage form of the invention is less than about 80%,
often less than about 75%, in some embodiments less than about 60%,
or 50%, of a Cmax and AUC obtained after administering an
equivalent dose of the active compound in an immediate release oral
dosage form.
[0028] Within exemplary embodiments of the invention, the
compositions and dosage forms containing the active compound of
Formula I and a sustained release vehicle, matrix, binder, or
coating will yield sustained delivery of the active compound such
that, following administration of the composition or dosage form to
a mammalian treatment subject, the Cmax of the active compound in
the treatment subject is less than about 80% of a Cmax provided in
a control subject after administration of the same amount of the
active agent in an immediate release formulation.
[0029] Within other exemplary embodiments of the invention, the
compositions and dosage forms containing the active compound of
Formula I and a sustained release vehicle, matrix, binder, or
coating will yield sustained delivery of the active compound such
that, following administration of the composition or dosage form to
a mammalian treatment subject, the AUC of the active compound in
the treatment subject is less than about 80% of a AUC provided in a
control subject after administration of the same amount of the
active agent in an immediate release formulation.
[0030] Within additional exemplary embodiments, the compositions
and dosage forms containing the active compound of Formula I and a
sustained release vehicle, matrix, binder, or coating will yield
sustained delivery of the active compound such that, following
administration of the composition or dosage form to a mammalian
treatment subject, the Cmax and AUC of the active compound in the
treatment subject are, respectively, less than about 80% of a Cmax
and a AUC provided in a control subject after administration of the
same amount of the active agent in an immediate release
formulation.
[0031] As used herein, the term "immediate release dosage form"
refers to a dosage form of an active compound of Formula I wherein
the active compound readily dissolves upon contact with a liquid
physiological medium, for example phosphate buffered saline (PBS)
or natural or artificial gastric fluid. In certain embodiments, an
IR formulation will be characterized in that at least 70% of the
active compound will be dissolved within a half hour after the
dosage form is contacted with a liquid physiological medium. For
example, at least 70% of the active compound in an IR bicifadine
dosage form will dissolve within a half hour following contact of
the dosage form with a liquid physiological medium in an
art-accepted in vitro dissolution assay (e.g., using a USP 1
Apparatus, 20 mesh baskets, 75 rpm, and a dissolution medium
comprised of 900 ml 0.01 N HCl at 37.degree. C..+-.0.5.degree. C.;
or following an alternate USP basket method at 100 rpm in 700 ml
Simulated Gastric Fluid (SGF) at 37.degree. C. for 1 hour and
thereafter switching to 900 ml with phosphate buffer to a pH of 7.5
at 37.degree. C.). In alternate embodiments, at least 80%, 85%, 90%
or more, or up to 100%, of the active compound in an IR bicifadine
dosage form will dissolve within a half hour following contact of
the dosage form with a liquid physiological medium in an
art-accepted in vitro dissolution assay. These general
characteristics of an IR dosage form will often relate to powdered
or granulated compositions of a compound of Formula I in a
capsulated dosage form, for example in a gelatin-encapsulated
dosage form, where dissolution will often be relatively immediate
after dissolution/failure of the gelatin capsule. In alternate
embodiments, the IR dosage form may be provided in the form of a
compressed tablet, granular preparation, powder, or even liquid
dosage form, in which cases the dissolution profile will often be
even more immediate (e.g., wherein at least 85%-95% of the active
compound is dissolved within a half hour).
[0032] In additional embodiments of the invention, an IR dosage
form will include compositions wherein the active compound is not
admixed, bound, coated or otherwise associated with a formulation
component that substantially impedes in vitro or in vivo
dissolution and/or in vivo bioavailability of the active compound.
Within certain embodiments, the active compound will be provided in
an immediate release dosage form that does not contain significant
amounts of a sustained release vehicle, matrix, binder or coating
material. In this context, the term "significant amounts of a
sustained release vehicle, matrix, binder or coating material" is
not intended to exclude any amount of such materials, but an amount
sufficient to impede in vitro or in vivo dissolution of an active
compound in a formulation containing such materials by at least 5%,
often at least 10%, and up to at least 15%-20% compared to
dissolution of the active compound when provided in a composition
that is essentially free of such materials.
[0033] In alternate embodiments of the invention, an IR dosage form
of a compound of Formula I may be any dosage form comprising the
active compound which fits the FDA Biopharmaceutics Classification
System (BCS) Guidance definition (see, e.g.,
http://www.fda.gov/cder/OPS/BCS_guidance.htm) of a "high solubility
substance in a rapidly dissolving formulation". In exemplary
embodiments, an IR bicifadine formulation according to this aspect
of the invention will exhibit rapid dissolution characteristics
according to BCS Guidance parameters, such that at least
approximately 85% of the bicifadine in the formulation will go into
a test solution within about 30 minutes at pH 1, pH 4.5, and pH
6.8.
[0034] In yet additional embodiments of the invention, an IR dosage
form of a compound of Formula I may be any of the IR dosage forms
specifically described herein.
[0035] The compositions, dosage forms and methods of the invention
are thus characterized and distinguished as novel tools for
treatment of pain and neuropathic disorders by virtue that they
provide for sustained release and/or sustained delivery of the
active compounds of Formula I. As used herein, "sustained release"
and "sustained delivery" are evinced by a sustained, delayed,
extended, or modified, in vitro or in vivo dissolution rate, in
vivo release and/or delivery rate, and/or in vivo pharmacokinetic
value(s) or profile. Within exemplary embodiments of the invention,
the sustained release and sustained delivery compositions and
dosage forms of the invention will exhibit less than about 80% of
one or more release/delivery property(ies) value(s) or range(s)
selected from i) an in vitro dissolution rate, ii) in vivo
dissolution or release rate, and/or iii) plasma Cmax, AUC, and/or
Cmax and AUC, exhibited by an otherwise comparable, immediate
release composition or dosage form of the active compound. Often,
the one or more release/delivery property(ies) selected from i) an
in vitro dissolution rate, ii) in vivo dissolution or release rate,
and/or iii) plasma Cmax, AUC, and/or Cmax and AUC of the sustained
release compositions and dosage forms of the invention will be less
than about 75%, in some embodiments less than about 60%, or 50%, of
the respective release/delivery property(ies) of an otherwise
comparable, immediate release dosage form of the active compound.
The terms "sustained release" and "sustained delivery" are intended
herein to encompass release and delivery properties conventionally
known in the art as "sustained", "delayed", "slow", "extended",
"controlled", "modified", and "pulsatile" release and delivery.
[0036] The sustained release dosage forms of the present invention
can take any form as long as one or more of the dissolution,
release, delivery and/or pharmacokinetic property(ies) identified
above are satisfied. Within illustrative embodiments, the
composition or dosage form can comprise the active compound of
Formula I combined with any one or combination of: a drug-releasing
polymer, matrix, bead, microcapsule, or other solid drug-releasing
vehicle; drug-releasing tiny timed-release pills or mini-tablets;
compressed solid drug delivery vehicle; controlled release binder;
multi-layer tablet or other multi-layer or multi-component dosage
form; drug-releasing lipid; drug-releasing wax; and a variety of
other sustained drug release materials as contemplated herein, or
formulated in an osmotic dosage form.
[0037] The present invention thus provides a broad range of
sustained release compositions and dosage forms comprising an
active compound of Formula I, which in certain embodiments are
adapted for providing sustained release of the active compound
following, e.g., oral administration. Sustained release vehicles,
matrices, binders and coatings for use in accordance with the
invention include any biocompatible sustained release material
which is inert to the active agent and which is capable of being
physically combined, admixed, or incorporated with the active
compound. Useful sustained release materials may be dissolved,
degraded, disintegrated, and/or metabolized slowly under
physiological conditions following delivery (e.g., into a
gastrointestinal tract of a subject, or following contact with
gastric fluids or other bodily fluids). Useful sustained release
materials are typically non-toxic and inert when contacted with
fluids and tissues of mammalian subjects, and do not trigger
significant adverse side effects such as irritation, immune
response, inflammation, or the like. They are typically metabolized
into metabolic products which are biocompatible and easily
eliminated from the body.
[0038] In certain embodiments, sustained release polymeric
materials are employed as the sustained release vehicle, matrix,
binder, or coating (see, e.g., "Medical Applications of Controlled
Release," Langer and Wise (eds.), CRC Press., Boca Raton, Fla.
(1974); "Controlled Drug Bioavailability," Drug Product Design and
Performance, Smolen and Ball (eds.), Wiley, N.Y. (1984); Ranger and
Peppas, 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61; see also
Levy et al., 1985, Science 228: 190; During et al., 1989, Ann.
Neurol. 25:351; Howard et al, 1989, J. Neurosurg. 71:105, each
incorporated herein by reference). Within exemplary embodiments,
useful polymers for co-formulating with the active compound of
Formula Ito yield a sustained release composition or dosage form
include, but are not limited to, ethylcellulose, hydroxyethyl
cellulose; hydroxyethylmethyl cellulose; hydroxypropyl cellulose;
hydroxypropylmethyl cellulose; hydroxypropylmethyl cellulose
phthalate; hydroxypropylmethylcellulose acetate succinate;
hydroxypropylmethylcellulose acetate phthalate; sodium
carboxymethylcellulose; cellulose acetate phthalate; cellulose
acetate trimellitate; polyoxyethylene stearates; polyvinyl
pyrrolidone; polyvinyl alcohol; copolymers of polyvinyl pyrrolidone
and polyvinyl alcohol; polymethacrylate copolymers; and mixtures
thereof.
[0039] Additional polymeric materials for use as sustained release
vehicles, matrices, binders, or coatings within the compositions
and dosage forms of the invention include, but are not limited to,
additional cellulose ethers, e.g., as described in Alderman, Int.
J. Pharm. Tech. & Prod. Mfr., 1984, 5(3) 1-9 (incorporated
herein by reference). Other useful polymeric materials and matrices
are derived from copolymeric and homopolymeric polyesters having
hydrolysable ester linkages. A number of these are known in the art
to be biodegradable and to lead to degradation products having no
or low toxicity. Exemplary polymers in this context include
polyglycolic acids (PGAs) and polylactic acids (PLAs),
poly(DL-lactic acid-co-glycolic acid)(DL PLGA), poly(D-lactic
acid-coglycolic acid)(D PLGA) and poly(L-lactic acid-co-glycolic
acid)(L PLGA). Other biodegradable or bioerodable polymers for use
within the invention include such polymers as
poly(.epsilon.-caprolactone), poly(.epsilon.-aprolactone-CO-lactic
acid), poly(.epsilon.-aprolactone-CO-glycolic acid),
poly(.beta.-hydroxy butyric acid), poly(alkyl-2-cyanoacrilate),
hydrogels such as poly(hydroxyethyl methacrylate), polyamides,
poly-amino acids (e.g., poly-L-leucine, poly-glutamic acid,
poly-L-aspartic acid, and the like), poly (ester ureas), poly
(2-hydroxyethyl DL-aspartamide), polyacetal polymers,
polyorthoesters, polycarbonates, polymaleamides, polysaccharides,
and copolymers thereof. Methods for preparing pharmaceutical
formulations using these polymeric materials are generally known to
those skilled in the art (see, e.g., Sustained and Controlled
Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker,
Inc., New York, 1978, incorporated herein by reference).
[0040] In other embodiments of the invention, the compositions and
dosage forms comprise an active compound of Formula I coated on a
polymer substrate. The polymer can be an erodible or a nonerodible
polymer. The coated substrate may be folded onto itself to provide
a bilayer polymer drug dosage form. For example an active compound
of Formula I can be coated onto a polymer such as a polypeptide,
collagen, gelatin, polyvinyl alcohol, polyorthoester, polyacetyl,
or a polyorthocarbonate, and the coated polymer folded onto itself
to provide a bilaminated dosage form. In operation, the bioerodible
dosage form erodes at a controlled rate to dispense the active
compound over a sustained release period. Representative
biodegradable polymers for use in this and other aspects of the
invention can be selected from, for example, biodegradable
poly(amides), poly (amino acids), poly(esters), poly(lactic acid),
poly(glycolic acid), poly(carbohydrate), poly(orthoester), poly
(orthocarbonate), poly(acetyl), poly(anhydrides), biodegradable
poly(dehydropyrans), and poly(dioxinones) which are known in the
art (see, e.g., Rosoff, Controlled Release of Drugs, Chap. 2, pp.
53-95 (1989); and U.S. Pat. Nos. 3,811,444; 3,962,414; 4,066,747,
4,070,347; 4,079,038; and 4,093,709, each incorporated herein by
reference).
[0041] In another embodiment of the invention, the dosage form
comprises an active compound of Formula I loaded into a polymer
that releases the prodrug by diffusion through a polymer, or by
flux through pores or by rupture of a polymer matrix. The drug
delivery polymeric dosage form comprises the active compound
contained in or on the polymer. The dosage form comprises at least
one exposed surface at the beginning of dose delivery. The
non-exposed surface, when present, can be coated with a
pharmaceutically acceptable material impermeable to the passage of
a drug. The dosage form may be manufactured by procedures known in
the art, for example by blending a pharmaceutically acceptable
carrier like polyethylene glycol, with a pre-determined dose of the
active compound at an elevated temperature (e.g., 37.degree. C.),
and adding it to a silastic medical grade elastomer with a
cross-linking agent, for example, octanoate, followed by casting in
a mold. The step is repeated for each optional successive layer.
The system is allowed to set for 1 hour, to provide the dosage
form. Representative polymers for manufacturing such sustained
release dosage forms include, but are not limited to, olefin, and
vinyl polymers, addition polymers, condensation polymers,
carbohydrate polymers, and silicon polymers as represented by
polyethylene, polypropylene, polyvinyl acetate, polymethylacrylate,
polyisobutylmethacrylate, poly alginate, polyamide and polysilicon.
These polymers and procedures for manufacturing them have been
described in the art (see, e.g., Coleman et al., Polymers 1990, 31,
1187-1231; Roerdink et al., Drug Carrier Systems 1989, 9, 57-10;
Leong et al., Adv. Drug Delivery Rev. 1987, 1, 199-233; and Roff et
al., Handbook of Common Polymers 1971, CRC Press; U.S. Pat. No.
3,992,518).
[0042] In other embodiments of the invention, the compositions and
dosage forms comprise an active compound of Formula I incorporated
with or contained in beads that on dissolution or diffusion release
the active compound over an extended period of hours, for example
over a period of at least 6 hours, over a period of at least 8
hours, over a period of at least 12 hours, or over a period of up
to 24 hours or longer. The drug-releasing beads may have a central
composition or core comprising an active compound of Formula I and
a pharmaceutically acceptable carrier, along with one or more
optional excipients such as a lubricants, antioxidants,
dispersants, and buffers. The beads may be medical preparations
with a diameter of about 1 to 2 mm. In exemplary embodiments the
are formed of non-cross-linked materials to enhance their discharge
from the gastrointestinal tract. The beads may be coated with a
release rate-controlling polymer that gives a timed release
pharmacokinetic profile. In alternate embodiments the beads may be
manufactured into a tablet for therapeutically effective drug
administration. The beads can be made into matrix tablets by direct
compression of a plurality of beads coated with, for example, an
acrylic resin and blended with excipients such as
hydroxypropylmethyl cellulose. The manufacture and processing of
beads for use within the invention is described in the art (see,
e.g., Lu, Int. J. Pharm., 1994, 112, 117-124; Pharmaceutical
Sciences by Remington, 14.sup.th ed, pp 1626-1628 (1970); Fincher,
J. Pharm. Sci. 1968, 57, 1825-1835; and U.S. Pat. No. 4,083,949,
each incorporated by reference) as has the manufacture of tablets
(Pharmaceutical Sciences, by Remington, 17.sup.th Ed, Ch. 90,
pp1603-1625, 1985, incorporated herein by reference).
[0043] In another embodiment of the invention, the dosage from
comprises a plurality of tiny pills or mini-tablets. The tiny pills
or mini-tablets provide a number of individual doses for providing
various time doses for achieving a sustained-release drug delivery
profile over an extended period of time up to 24 hours. The tiny
pills or mini-tablets may comprise a hydrophilic polymer selected
from the group consisting of a polysaccharide, agar, agarose,
natural gum, alkali alginate including sodium alginate,
carrageenan, fucoidan, furcellaran, laminaran, hypnea, gum arabic,
gum ghatti, gum karaya, grum tragacanth, locust bean gum, pectin,
amylopectin, gelatin, and a hydrophilic colloid. The hydrophilic
polymer may be formed into a plurality (e.g., 4 to 50) tiny pills
or mini-tablet, wherein each tiny pill or mini-tablet comprises a
pre-determined dose of the active compound of Formula I, e.g., a
dose of about 10 ng, 0.5 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 5.0 mg
etc. The tiny pills and mini-tablets may further comprise a release
rate-controlling wall of 0.001 up to 10 mm thickness to provide for
timed release of the active compound. Representative wall forming
materials include a triglyceryl ester selected from the group
consisting of glyceryl tristearate, glyceryl monostearate, glyceryl
dipalmitate, glyceryl laureate, glyceryl didecenoate and glyceryl
tridenoate. Other wall forming materials comprise polyvinyl
acetate, phthalate, methylcellulose phthalate and microporous
olefins. Procedures for manufacturing tiny pills and mini-tablets
are known in the art (see, e.g., U.S. Pat. Nos. 4,434,153;
4,721,613; 4,853,229; 2,996,431; 3,139,383 and 4,752,470, each
incorporated herein by reference). The tiny pills and mini-tablets
may further comprise a blend of particles, which may include
particles of different sizes and/or release properties, and the
particles may be contained in a hard gelatin or non-gelatin capsule
or soft gelatin capsule.
[0044] In yet another embodiment of the invention, drug-releasing
lipid matrices can be used to formulate therapeutic compositions
and dosage forms comprising an active compound of Formula I. In one
exemplary embodiment, solid microparticles of the active compound
are coated with a thin controlled release layer of a lipid (e.g.,
glyceryl behenate and/or glyceryl palmitostearate) as disclosed in
Farah et al., U.S. Pat. No. 6,375,987 and Joachim et al., U.S. Pat.
No. 6,379,700 (each incorporated herein by reference). The
lipid-coated particles can optionally be compressed to form a
tablet. Another controlled release lipid-based matrix material
which is suitable for use in the sustained release compositions and
dosage forms of the invention comprises polyglycolized glycerides,
e.g., as described in Roussin et al., U.S. Pat. No. 6,171,615
(incorporated herein by reference).
[0045] In other embodiments of the invention, drug-releasing waxes
can be used for producing sustained release compositions and dosage
forms comprising an active compound of Formula I. Examples of
suitable sustained drug-releasing waxes include, but are not
limited to, carnauba wax, candedilla wax, esparto wax, ouricury
wax, hydrogenated vegetable oil, bees wax, paraffin, ozokerite,
castor wax, and mixtures thereof (see, e.g., Cain et al., U.S. Pat.
No. 3,402,240; Shtohryn et al. U.S. Pat. No. 4,820,523; and
Walters, U.S. Pat. No. 4,421,736, each incorporated herein by
reference).
[0046] In still another embodiment, osmotic delivery systems are
used for sustained release delivery of an active compound of
Formula I (see, e.g., Verma et al., Drug Dev. Ind. Pharm., 2000,
26:695-708, incorporated herein by reference). In one exemplary
embodiment, the osmotic delivery system is an OROS.RTM. system
(Alza Corporation, Mountain View, Calif.) and is adapted for oral
sustained release delivery of drugs (see, e.g., U.S. Pat. No.
3,845,770; and U.S. Pat. No. 3,916,899, each incorporated herein by
reference).
[0047] In another embodiment of the invention, the dosage form
comprises an osmotic dosage form, which comprises a semipermeable
wall that surrounds a therapeutic composition comprising the
prodrug. In use within a patient, the osmotic dosage form
comprising a homogenous composition imbibes fluid through the
semipermeable wall into the dosage form in response to the
concentration gradient across the semipermeable wall. The
therapeutic composition in the dosage form develops osmotic energy
that causes the therapeutic composition to be administered through
an exit from the dosage form over a prolonged period of time up to
24 hours (or even in some cases up to 30 hours) to provide
controlled and sustained prodrug release. These delivery platforms
can provide an essentially zero order delivery profile as opposed
to the spiked profiles of immediate release formulations.
[0048] In alternate embodiments of the invention, the dosage form
comprises another osmotic dosage form comprising a wall surrounding
a compartment, the wall comprising a semipermeable polymeric
composition permeable to the passage of fluid and substantially
impermeable to the passage of the active compound present in the
compartment, a drug-containing layer composition in the
compartment, a hydrogel push layer composition in the compartment
comprising an osmotic formulation for imbibing and absorbing fluid
for expanding in size for pushing the prodrug composition layer
from the dosage form, and at least one passageway in the wall for
releasing the prodrug composition. This osmotic system delivers the
active compound by imbibing fluid through the semipermeable wall at
a fluid imbibing rate determined by the permeability of the
semipermeable wall and the osmotic pressure across the
semipermeable wall causing the push layer to expand, thereby
delivering the active compound through the exit passageway to a
patient over a prolonged period of time (up to 24 or even 30
hours). The hydrogel layer composition may comprise 10 mg to 1000
mg of a hydrogel such as a member selected from the group
consisting of a polyalkylene oxide of 1,000,000 to 8,000,000 which
are selected from the group consisting of a polyethylene oxide of
1,000,000 weight-average molecular weight, a polyethylene oxide of
2,000,000 molecular weight, a polyethylene oxide of 4,000,000
molecular weight, a polyethylene oxide of 5,000,000 molecular
weight, a polyethylene oxide of 7,000,000 molecular weight and a
polypropylene oxide of the 1,000,000 to 8,000,000 weight-average
molecular weight; or 10 mg to 1000 mg of an alkali
carboxymethylcellulose of 10,000 to 6,000,000 weight average
molecular weight, such as sodium carboxymethylcellulose or
potassium carboxymethylcellulose. The hydrogel expansion layer may
comprise a hydroxyalkylcellulose of 7,500 to 4,500,00
weight-average molecular weight (e.g., hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxybutylcellulose or hydroxypentylcellulose), an osmagent,
e.g., selected from the group consisting of sodium chloride,
potassium chloride, potassium acid phosphate, tartaric acid, citric
acid, raffinose, magnesium sulfate, magnesium chloride, urea,
inositol, sucrose, glucose and sorbitol, and other agents such a
hydroxypropylalkylcellulose of 9,000 to 225,000 average-number
molecular weight (e.g., hydroxypropylethylcellulose,
hydroxypropypentylcellulose, hydroxypropylmethylcellulose, or
hydropropylbutylcellulose), ferric oxide, antioxidants (e.g.,
ascorbic acid, butylated hydroxyanisole, butylated hydroxyquinone,
butylhydroxyanisol, hydroxycomarin, butylated hydroxytoluene,
cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl
gallate, propyl-hydroxybenzoate, trihydroxybutylrophenone,
dimethylphenol, dibutylphenol, vitamin E, lecithin and
ethanolamine), and/or lubricants (e.g., calcium stearate, magnesium
stearate, zinc stearate, magnesium oleate, calcium palmitate,
sodium suberate, potassium laureate, salts of fatty acids, salts of
alicyclic acids, salts of aromatic acids, stearic acid, oleic acid,
palmitic acid, a mixture of a salt of a fatty, alicyclic or
aromatic acid, and a fatty, alicyclic, or aromatic acid).
[0049] In the osmotic dosage forms, the semipermeable wall
comprises a composition that is permeable to the passage of fluid
and impermeable to passage of the active compound of Formula I. The
wall is nontoxic and comprises a polymer selected from the group
consisting of a cellulose acylate, cellulose diacylate, cellulose
triacylate, cellulose acetate, cellulose diacetate and cellulose
triacetate. The wall typically comprises 75 wt % (weight percent)
to 100 wt % of the cellulosic wall-forming polymer; or, the wall
can comprise additionally 0.01 wt % to 80 wt % of polyethylene
glycol, or 1 wt % to 25 wt % of a cellulose ether (e.g.,
hydroxypropylcellulose or a hydroxypropylalkycellulose such as
hydroxypropylmethylcellulose). The total weight percent of all
components comprising the wall is equal to 100 wt %. The internal
compartment comprises the drug-containing composition alone or in
layered position with an expandable hydrogel composition. The
expandable hydrogel composition in the compartment increases in
dimension by imbibing the fluid through the semipermeable wall,
causing the hydrogel to expand and occupy space in the compartment,
whereby the drug composition is pushed from the dosage form. The
therapeutic layer and the expandable layer act together during the
operation of the dosage form for the release of prodrug to a
patient over time. The dosage form comprises a passageway in the
wall that connects the exterior of the dosage form with the
internal compartment. The osmotic powered dosage form delivers the
active compound of Formula I from the dosage form to the patient at
a zero order rate of release over a period of up to about 24 hours.
As used herein, the expression "passageway" comprises means and
methods suitable for the metered release of an active compound of
Formula I from the compartment of an osmotic dosage form. The exit
means comprises at least one passageway, including orifice, bore,
aperture, pore, porous element, hollow fiber, capillary tube,
channel, porous overlay, or porous element that provides for the
osmotic controlled release of the active compound. The passageway
includes a material that erodes or is leached from the wall in a
fluid environment of use to produce at least one controlled-release
dimensioned passageway. Representative materials suitable for
forming a passageway, or a multiplicity of passageways comprise a
leachable poly(glycolic) acid or poly(lactic) acid polymer in the
wall, a gelatinous filament, poly(vinyl alcohol), leach-able
polysaccharides, salts, and oxides. A pore passageway, or more than
one pore passageway, can be formed by leaching a leachable
compound, such as sorbitol, from the wall. The passageway possesses
controlled-release dimensions, such as round, triangular, square
and elliptical, for the metered release of prodrug from the dosage
form. The dosage form can be constructed with one or more
passageways in spaced apart relationship on a single surface or on
more than one surface of the wall. The expression "fluid
environment" denotes an aqueous or biological fluid as in a human
patient, including the gastrointestinal tract. Passageways and
equipment for forming passageways are disclosed in U.S. Pat. Nos.
3,845,770; 3,916,899; 4,063,064; 4,088,864; 4,816,263; 4,200,098;
and 4,285,987 (each incorporated herein by reference).
[0050] Within other aspects of the invention, microparticle,
microcapsule, and/or microsphere drug delivery technologies can be
employed to provide sustained release delivery of an active
compound of Formula I within the compositions, dosage forms and
methods of the invention. A variety of methods is known by which an
active compound of Formula I can be encapuslated in the form of
microparticles, for example using by encapsulating the active
compound within a biocompatible, biodegradable wall-forming
material (e.g., a polymer)--to provide sustained or delayed release
of the active compound. In these methods, the active compound is
typically dissolved, dispersed, or emulsified in a solvent
containing the wall forming material. Solvent is then removed from
the microparticles to form the finished microparticle product.
Examples of conventional microencapsulation processes are
disclosed, e.g., in U.S. Pat. Nos. 3,737,337; 4,389,330; 4,652,441;
4,917,893; 4,677,191; 4,728,721; 5,407,609; 5,650,173; 5,654,008;
and 6,544,559 (each incorporated herein by reference). These
documents disclose methods that can be readily implemented to
prepare microparticles containing an active compound of Formula I
in a sustained release formulation according to the invention. As
explained, for example, in U.S. Pat. No. 5,650,173, by
appropriately selecting the polymeric materials, a microparticle
formulation can be made in which the resulting microparticles
exhibit both diffusional release and biodegradation release
properties. For a diffusional mechanism of release, the active
agent is released from the microparticles prior to substantial
degradation of the polymer. The active agent can also be released
from the microparticles as the polymeric excipient erodes. In
addition, U.S. Pat. No. 6,596,316 (incorporated herein by
reference) discloses methods for preparing microparticles having a
selected release profile for fine tuning a release profile of an
active agent from the microparticles.
[0051] In another embodiment of the invention, enteric-coated
preparations can be used for oral sustained release administration.
Preferred coating materials include polymers with a pH-dependent
solubility (i.e., pH-controlled release), polymers with a slow or
pH-dependent rate of swelling, dissolution or erosion (i.e.,
time-controlled release), polymers that are degraded by enzymes
(i.e., enzyme-controlled release) and polymers that form firm
layers that are destroyed by an increase in pressure (i.e.,
pressure-controlled release). Enteric coatings may function as a
means for mediating sustained release of the active compound of
Formula I by providing one or more barrier layers, which may be
located entirely surrounding the active compound, between layers of
a multi-layer solid dosage form (see below), and/or on one or more
outer surfaces of one or multiple layers of a multi-layer solid
dosage form (e.g., on end faces of layers of a substantially
cylindrical tablet). Such barrier layers may, for example, be
composed of polymers which are either substantially or completely
impermeable to water or aqueous media, or are slowly erodible in
water or aqueous media or biological liquids and/or which swell in
contact with water or aqueous media. Suitable polymers for use as a
barrier layer include acrylates, methacrylates, copolymers of
acrylic acid, celluloses and derivatives thereof such as
ethylcelluloses, cellulose acetate propionate, polyethylenes and
polyvinyl alcohols etc. Barrier layers comprising polymers which
swell in contact with water or aqueous media may swell to such an
extent that the swollen layer forms a relatively large swollen
mass, the size of which delays its immediate discharge from the
stomach into the intestine. The barrier layer may itself contain
active material content, for example the barrier layer may be a
slow or delayed release layer. Barrier layers may typically have an
individual thickness of 10 microns up to 2 mm. Suitable polymers
for barrier layers which are relatively impermeable to water
include the Methocel.TM. series of polymers, used singly or
combined, and Ethocel.TM. polymers. Such polymers may suitably be
used in combination with a plasticiser such as hydrogenated castor
oil. The barrier layer may also include conventional binders,
fillers, lubricants and compression acids etc such as Polyvidon K30
(trade mark), magnesium stearate, and silicon dioxide.
[0052] Additional enteric coating materials for mediating sustained
release of an active compound of Formula I include coatings in the
form of polymeric membranes, which may be semipermeable, porous, or
asymmetric membranes (see, e.g., U.S. Pat. No. 6,706,283,
incorporated herein by reference). Coatings of these and other
types for use within the invention may also comprise at least one
delivery port, or pores, in the coating, e.g., formed by laser
drilling or erosion of a plug of water-soluble material. Other
useful coatings within the invention including coatings that
rupture in an environment of use (e.g., a gastrointestinal
compartment) to form a site of release or delivery port. Exemplar
coatings within these and other embodiments of the invention
include poly(acrylic) acids and esters; poly(methacrylic) acids and
esters; copolymers of poly(acrylic) and poly(methacrylic) acids and
esters; cellulose esters; cellulose ethers; and cellulose
ester/ethers.
[0053] Additional coating materials for use in constructing solid
dosage forms to mediate sustained release of an active compound of
Formula I include, but are not limited to, polyethylene glycol,
polypropylene glycol, copolymers of polyethylene glycol and
polypropylene glycol, poly(vinylpyrrolidone), ethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl
cellulose, carboxymethylethyl cellulose, starch, dextran, dextrin,
chitosan, collagen, gelatin, bromelain, cellulose acetate,
unplasticized cellulose acetate, plasticized cellulose acetate,
reinforced cellulose acetate, cellulose acetate phthalate,
cellulose acetate trimellitate, hydroxypropylmethylcellulose,
hydroxypropylmethyl-cellulose phthalate,
hydroxypropylmethylcellulose acetate succinate,
hydroxypropylmethylcellulose acetate trimellitate, cellulose
nitrate, cellulose diacetate, cellulose triacetate, agar acetate,
amylose triacetate, beta glucan acetate, beta glucan triacetate,
acetaldehyde dimethyl acetate, cellulose acetate ethyl carbamate,
cellulose acetate phthalate, cellulose acetate methyl carbamate,
cellulose acetate succinate, cellulose acetate dimethaminoacetate,
cellulose acetate ethyl carbonate, cellulose acetate chloroacetate,
cellulose acetate ethyl oxalate, cellulose acetate methyl
sulfonate, cellulose acetate butyl sulfonate, cellulose acetate
propionate, cellulose acetate p-toluene sulfonate, triacetate of
locust gum bean, cellulose acetate with acetylated hydroxyethyl
cellulose, hydroxlated ethylene-vinylacetate, cellulose acetate
butyrate, polyalkenes, polyethers, polysulfones, polyethersulfones,
polystyrenes, polyvinyl halides, polyvinyl esters and ethers,
natural waxes and synthetic waxes.
[0054] In additional embodiments of the invention, sustained
release of the active compound of Formula I is provided by
formulating the active compound in a dosage form comprising a
multi-layer tablet or other multi-layer or multi-component dosage
form. In exemplary embodiments, the active compound is formulated
in layered tablets, for example having a first layer which is an
immediate release layer and a second layer which is a slow release
layer. Other multi-layered dosage forms of the invention may
comprise a plurality of layers of compressed active ingredient
having variable (i.e., selectable) release properties selected from
immediate, extended and/or delayed release mechanisms.
Multi-layered tablet technologies useful to produce sustained
release dosage forms of an active compound of Formula I are
described, for example, in International Publications WO 95/20946;
WO 94/06416; and WO 98/05305 (each incorporated herein by
reference). Other multi-component dosage forms for providing
sustained delivery of an active compound of Formula I include
tablet formulations having a core containing the active compound
clavulanate coated with a release retarding agent and surrounded by
an outer casing layer (optionally containing the active compound)
(see, e.g., International Publication WO 95/28148, incorporated
herein by reference). The release retarding agent is an enteric
coating, so that there is an immediate release of the contents of
the outer core, followed by a second phase from the core which is
delayed until the core reaches the intestine. Additionally,
International Publication WO 96/04908 (incorporated herein by
reference) describes tablet formulations which comprise an active
agent in a matrix, for immediate release, and granules in a delayed
release form comprising the active agent. Such granules are coated
with an enteric coating, so release is delayed until the granules
reach the intestine. International Publication WO 96/04908
(incorporated herein by reference) describes delayed or sustained
release formulations formed from granules which have a core
comprising an active agent, surrounded by a layer comprising the
active agent.
[0055] Another useful multi-component (bi-layer tablet) dosage form
for sustained delivery of active compounds of Formula I is
described in U.S. Pat. No. 6,878,386 (incorporated herein by
reference). Briefly, the bilayer tablet comprises an immediate
release and a slow release layer, optionally with a coating layer.
The immediate release layer may be, for example, a layer which
disintegrates immediately or rapidly and has a composition similar
to that of known tablets which disintegrate immediately or rapidly.
An alternative type of immediate release layer may be a swellable
layer having a composition which incorporates polymeric materials
which swell immediately and extensively in contact with water or
aqueous media, to form a water permeable but relatively large
swollen mass. Active material content may be immediately leached
out of this mass. The slow release layer may have a composition
comprising the active compound of Formula I with a release
retarding vehicle, matrix, binder, coating, or excipient which
allows for slow release of the active compound. Suitable release
retarding excipients include pH sensitive polymers, for instance
polymers based upon methacrylic acid copolymers, which may be used
either alone or with a plasticiser; release-retarding polymers
which have a high degree of swelling in contact with water or
aqueous media such as the stomach contents; polymeric materials
which form a gel on contact with water or aqueous media; and
polymeric materials which have both swelling and gelling
characteristics in contact with water or aqueous media. Release
retarding polymers which have a high degree of swelling include,
inter alia, cross-linked sodium carboxymethylcellulose,
cross-linked hydroxypropylcellulose, high-molecular weight
hydroxypropylmethylcellulose, carboxymethylamide, potassium
methacrylatedivinylbenzene co-polymer, polymethylmethacrylate,
cross-linked polyvinylpyrrolidone, high-molecular weight
polyvinylalcohols etc. Release retarding gellable polymers include
methylcellulose, carboxymethylcellulose, low-molecular weight
hydroxypropylmethylcellulose, low-molecular weight
polyvinylalcohols, polyoxyethyleneglycols, non-cross linked
polyvinylpyrrolidone, xanthan gum etc. Release retarding polymers
simultaneously possessing swelling and gelling properties include
medium-viscosity hydroxypropylmethylcellulose and medium-viscosity
polyvinylalcohols. An exemplary release-retarding polymer is
xanthan gum, in particular a fine mesh grade of xanthan gum,
preferably pharmaceutical grade xanthan gum, 200 mesh, for instance
the product Xantural 75 (also known as Keltrol CR.TM. Monsanto, 800
N Lindbergh Blvd, St Louis, Mo. 63167, USA). Xanthan gum is a
polysaccharide which upon hydration forms a viscous gel layer
around the tablet through which the active has) to diffuse. It has
been shown that the smaller the particle size, the slower the
release rate. In addition, the rate of release of active compound
is dependent upon the amount of xanthan gum used and can be
adjusted to give the desired profile. Examples of other polymers
which may be used within these aspects of the invention include
Methocel K4M.TM., Methocel E5.TM., Methocel E5O.TM., Methocel
E4M.TM., Methocel K15M.TM. and Methocel K100M.TM.. Other known
release-retarding polymers which may be incorporated within this
and other embodiments of the invention to provide a sustained
release composition or dosage form of an active compound of Formula
I include, hydrocolloids such as natural or synthetic gums,
cellulose derivatives other than those listed above,
carbohydrate-based substances such as acacia, gum tragacanth,
locust bean gum, guar gum, agar, pectin, carageenin, soluble and
insoluble alginates, carboxypolymethylene, casein, zein, and the
like, and proteinaceous substances such as gelatin.
[0056] Within other embodiments of the invention, a sustained
release delivery device or system is placed in the subject in
proximity of the target of the active compound of Formula I, thus
requiring only a fraction of the systemic dose (see, e.g., Goodson,
in "Medical Applications of Controlled Release," supra, vol. 2, pp.
115-138, 1984; and Langer, 1990, Science 249:1527-1533, each
incorporated herein by reference). In other embodiments, an oral
sustained release pump may be used (see, e.g., Langer, supra;
Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201; and Saudek et
al., 1989, N. Engl. J. Med. 321:574, each incorporated herein by
reference).
[0057] Pharmaceutical compositions and dosage forms comprising
active compounds of Formula I may further include one or more
carriers, excipients or additives, including, without limitation,
binders, fillers, compression aides, lubricants, film-forming
agents, glidants, anti-tacking agents, emulsifiers, suspending
agents, flavors, flavor enhancers, sweeteners, flavorings,
preservatives, buffers, wetting agents, disintegrants, effervescent
agents and other conventional excipients and additives. Within
exemplary embodiments, the compositions and dosage forms of the
invention for treating acute pain, chronic pain, and/or symptoms of
neuropathic disorders may include any one or combination of the
following: a pharmaceutically acceptable carrier or excipient;
other medicinal agent(s); pharmaceutical agent(s); adjuvants;
buffers; preservatives; diluents; and various other pharmaceutical
additives and agents known to those skilled in the art. These
additional formulation additives and agents will often be
biologically inactive and can be administered to patients without
causing deleterious side effects or interactions with the active
agent.
[0058] In accordance with this invention, the compositions in the
oral unit dosage forms comprising an active compound of Formula I
will often contain a carrier. Suitable carriers include, for
example, microcrystalline cellulose, lactose, sucrose, fructose,
glucose dextrose, or other sugars, dibasic calcium phosphate,
calcium sulfate, cellulose, methylcellulose, cellulose derivatives,
kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, or other
sugar alcohols, dry starch, dextrin, maltodextrin or other
polysaccharides, inositol or mixtures thereof. In exemplary
embodiments, the carrier dibasic calcium phosphate is employed. In
other exemplary embodiments, a diluent or carrier is present in the
composition in an amount of about 40% to 60% by weight of the
composition.
[0059] Suitable lubricants include, for example, stearic acid,
magnesium stearate, talc, calcium stearate, hydrogenated vegetable
oils, sodium benzoate, sodium chloride, leucine carbowax, magnesium
lauryl sulfate, colloidal silicon dioxide and glyceryl
monostearate. Suitable glidants include, for example, colloidal
silica, fumed silicon dioxide, silica, talc, fumed silica, gypsum
and glyceryl monostearate. A variety of effervescent and
disintegrant agents may be employed, which are well known in the
art for their uses in the formulation of rapidly disintegrating
tablets. By effervescent agent is meant a couple, typically an
organic acid and a carbonate or bicarbonate.
[0060] Within exemplary embodiments of the invention, the
pharmaceutical compositions and dosage forms comprise a unit oral
dosage form, for example a capsule, lozenge, or tablet. Any
conventional method of preparing pharmaceutical oral unit dosage
forms can be utilized in preparing the unit dosage forms of this
invention. In forming tablets, the composition will often be
compressed by conventional means. The term "tablet" as used herein
is intended to encompass powdered, compressed, granulated,
microencapsulated, and all other pharmaceutical oral dosage
formulations, of all sizes and shapes, whether coated or uncoated.
These pharmaceutical oral unit dosage forms, will contain one or
more of the conventional additional formulation ingredients noted
above. In alternate embodiments, the oral dosage forms of the
invention may contain any number of these additives and other
ingredients (e.g., glidants, compression aides, disintegrants,
lubricants, binders, flavors, flavor enhancers, sweeteners and
preservatives), selected alone or in any combination for their
known uses in preparing such dosage forms as tablets.
[0061] Additional compositions and methods of the invention
comprise an active compound of Formula I formulated and
administered in any of a variety of inhalation or nasal delivery
forms known in the art. Devices capable of depositing aerosolized
drug formulations in the sinus cavity or pulmonary alveoli of a
patient include metered dose inhalers, nebulizers, dry powder
generators, sprayers, and the like. Methods and compositions
suitable for pulmonary delivery of drugs for systemic effect are
well known in the art. Suitable formulations, wherein the carrier
is often a liquid or gel, for administration, as for example, a
nasal spray, nasal drops or a nasal gel, may include aqueous or
oily solutions of an active compound of Formula I and any
additional active or inactive ingredient(s) useful for nasal or
pulmonary drug formulation. Intranasal and intrapulmonary delivery
permits the passage of the active compound of Formula I to the
blood stream directly after administering an effective amount of
the compound to the nasal or pulmonary mucosal or alveolar surface.
In addition, intranasal delivery can achieve direct, or enhanced,
delivery of the active compound to the central nervous system
(CNS). For intranasal and pulmonary administration, a liquid
aerosol formulation will often contain an active compound of
Formula I combined with a dispersing agent and/or a physiologically
acceptable diluent. Alternative, dry powder aerosol formulations
may contain a finely divided solid form of the active compound of
Formula I and an optional dispersing agent allowing for the ready
dispersal of the dry powder particles. With either liquid or dry
powder aerosol formulations, the formulation will often be
aerosolized into small, liquid or solid particles in order to
ensure that the aerosolized dose reaches the mucous membranes of
the nasal passages or the lung. The term "aerosol particle" is used
herein to describe a liquid or solid particle suitable of a
sufficiently small particle diameter, e.g., in a range of from
about 2-5 microns, for nasal or pulmonary distribution to targeted
mucosal or alveolar surfaces. These formulations may also include a
sustained release vehicle, matrix, or binder for extended release
of the active compound following administration, and may be
provided in unit-dose or multi-dose containers, often containing or
adapted for dispensing) a daily unit dose, or unit daily sub-dose,
as described herein, or an appropriate fraction thereof, of the
active compound. Other considerations include the construction of
the delivery device, additional components in the formulation, and
particle characteristics. These aspects of nasal or pulmonary
administration of drugs are well known in the art, and optimization
of these formulations, aerosolization means, and of delivery
devices for effective administration of an active compound of
Formula I is within the level of ordinary skill in the art.
[0062] Yet additional compositions and methods of the invention are
provided for topical administration of an active compound of
Formula I for the treatment of acute pain, chronic pain, and/or
symptoms of a neuropathic disorder in mammals. Topical compositions
may comprise an active compound of Formula I and any other active
or inactive component(s) incorporated in a dermatological or
mucosal acceptable carrier, including in the form of aerosol
sprays, powders, dermal patches, sticks, granules, creams, pastes,
gels, lotions, syrups, ointments, impregnated sponges, cotton
applicators, or as a solution or suspension in an aqueous liquid,
non-aqueous liquid, oil-in-water emulsion, or water-in-oil liquid
emulsion. These topical compositions may feature the active
compound of Formula I dissolved or dispersed in a portion of water
or other solvent or liquid to be incorporated in the topical
composition or delivery device. Transdermal administration may be
enhanced by the addition of a dermal penetration enhancer known to
those skilled in the art. Alternatively, these formulations and
devices may include a sustained release vehicle, matrix, or binder
for extended release of the active compound following
administration, and will be adapted to deliver a daily unit dose,
or unit daily sub-dose, as described herein, or an appropriate
fraction thereof, of the active compound. Formulations suitable for
such topical dosage forms incorporate commonly utilized excipients,
including means (e.g. a structure or matrix), for sustaining the
absorption of drug over an extended period of time, for example up
to 8, 12, 18, or 24 hours.
[0063] Yet additional compositions and dosage forms for
administering an active compound of Formula I for treating acute
pain, chronic pain, and/or a symptom of a neuropathic disorder in
mammals are provided for parenteral administration, including
aqueous and non-aqueous sterile injectable solutions which may
optionally contain such know useful additives and other ingredients
as anti-oxidants, buffers, bacteriostats, suspending agents,
thickening agents, and/or solutes to render the formulation
isotonic with the blood of the subject. These formulations may also
include polymers and other sustained release vehicles, matrices, or
binders for extended release following parenteral administration,
and may be provided in unit-dose or multi-dose containers.
Extemporaneous injection solutions, emulsions and suspensions may
be prepared from sterile powders, granules and tablets of the kind
previously described. Exemplary unit dosage formulations are those
containing a daily unit dose, or unit daily sub-dose, as described
herein, or an appropriate fraction thereof, of the active
compound.
[0064] The pharmaceutical compositions and dosage forms of the
current invention will typically be provided for administration in
a sterile or readily sterilizable, biologically inert, and easily
administered form.
[0065] Within exemplary embodiments of the invention, it has been
found that the beneficial results for oral delivery of an active
compound of Formula I are achieved through the use of hydrophilic
slow release polymers, for example hydroxypropyl methyl cellulose.
Within these exemplary embodiments, the hydrophilic polymer
mediates relatively immediate onset of relief followed by continued
maintenance of the active ingredient in the blood stream of the
patient. The illustrative slow release polymer hydroxypropyl methyl
cellulose used in accordance with this invention will often have a
viscosity in the range of about 100 cps to about 100,000 cps, and
in more detailed embodiments in the range of from about 15,000 cps
to about 100,000 cps. On exposure to aqueous fluids such as in the
body of the patient (e.g., when the oral dosage form such as a
tablet is swallowed), these exemplary dosage forms become wet, and
the polymer starts to hydrate to form a gel layer. The soluble
nature of the active ingredient causes an initial burst from the
external layer of the tablet. Thereafter an expansion of the gel
layer occurs when water permeates into the tablet increasing the
thickness of the gel layer. The soluble drug diffuses through the
gel layer. Concomitantly, the outer layers become fully hydrated
and dissolves, a process generally referred to as erosion. Water
continues to permeate towards the tablet core until it has
dissolved. This initial burst release of the active compound should
be sufficient to provide a fast onset of action, often without the
need for separate inclusion of an immediate release portion in the
dosage form. This exemplary polymeric sustained release vehicle
provides a release which constitutes an) initial burst followed by
a continued sustained release of the active compound of formula I
or its salt. In accordance with these exemplary embodiments, the
composition containing the compound of formula I or its salt and a
slow release polymer mediates release of the active compound so
that not less than 10% of this active ingredient is released within
15 minutes and not less than 50% of this active ingredient is
released within 4 hours a and not less than 85% by weight of this
active ingredient is released within 12 hours. Other sustained
release profiles as contemplated herein can be obtained using this
and other sustained release polymers, or any other sustained
release vehicle, matrix, binder, or coating as described
herein.
[0066] For use within the methods and compositions of the instant
invention, compounds of Formula I include the compound bicifadine,
in pure form or in various mixtures, optical and geometric isomers
of bicifadine, and all other compounds contemplated according to
Formula I. In certain exemplary embodiments, the compositions and
methods of the invention employ
(.+-.)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride
(bicifadine HCl), enantiomers of bicifadine, pharmaceutically
acceptable, active salts of bicifadine, prodrugs of bicifadine,
polymorphs, hydrates, and solvates of bicifadine, or any
combination of the foregoing forms of bicifadine. In more detailed
embodiments, bicifadine hydrochloride is employed within
therapeutic formulations, dosage forms, and methods of the
invention.
[0067] Bicifadine HCl exists in at least two polymorphic
crystalline forms, designated polymorph forms A and B (e.g., as
described in U.S. patent application Ser. No. 10/702,397,
corresponding to US Patent Publication 20040102638 A1, published
May 27, 2004, incorporated herein by reference). Other polymorphic
forms of bicifadine hydrochloride may exist and are likewise
candidates for use within the methods and compositions of the
invention for treating a neuropathic disorder and/or related
symptom(s).
[0068] Polymorphs include compounds with identical chemical
structure but different internal structures. Additionally, many
pharmacologically active organic compounds regularly crystallize
incorporating second, foreign molecules, especially solvent
molecules, into the crystal structure of the principal
pharmacologically active compound forming pseudopolymorphs. When
the second molecule is a solvent molecule, the pseudopolymorphs can
also be referred to as solvates. All of these additional forms of
bicifadine are likewise useful within the methods and formulations
of the invention.
[0069] Polymorph form A of bicifadine HCl can be formed, for
example, by methods disclosed in U.S. Pat. No. 4,231,935 and U.S.
Pat. No. 4,196,120 (each of which is incorporated herein by
reference). Polymorph form B can be formed, for example, by methods
disclosed in U.S. patent application Ser. No. 10/702,397, related
international application PCT/US2003/035099 (Intl. Pub. No.
WO04/043920), and priority U.S. Provisional Patent Application No.
60/424,982 (each incorporated by reference). For example, polymorph
B can be formed from polymorph form A through the application of
kinetic energy and through crystallization techniques. In one
embodiment, kinetic energy in the form of agitating, stirring,
grinding or milling can be applied to a pure composition of
polymorph form A, or a mixture of forms A and B, particularly at
selected temperatures, for example from about -200.degree. C. to
about 50.degree. C., in another embodiment from about -200.degree.
C. to about 35.degree. C., in a further embodiment from about
-200.degree. C. to about 0.degree. C. In another embodiment,
polymorph B can be crystallized from a solution of polymorph A that
is heated and allowed to cool under defined conditions of
temperature and time to form polymorph B. Under selected
conditions, preparations of pure polymorph A of bicifadine, or
mixtures of polymorph A and B of bicifadine, can be processed to
yield desired compositions for use within the invention containing
enriched quantities of polymorph B, for example ranging from
approximately at least 10%, to about 10-20%, 20-35%, 35-50%,
50-70%, 70-85%, 85-95%, and up to 95-99% or greater (by weight)
bicifadine polymorph B in the composition.
[0070] Polymorphs of bicifadine HCl may be characterized by their
infrared spectra and/or their x-ray powder diffraction pattern. As
described in U.S. patent application Ser. No. 10/702,397
incorporated above, X-ray powder diffraction (XRPD) analyses of
polymorph forms A and B of racemic bicifadine hydrochloride were
performed with a Shimadzu XRD-6000 X-ray powder diffractometer
using Cu Ka radiation. The bicifadine was loaded onto the machine
as a crystalline powder. The instrument was equipped with a fine
focus X-ray tube. The tube voltage and amperage were set to 40 kV
and 40 mA, respectively. The divergence and scattering slits were
set at 1.degree. and the receiving slit was set at 0.15 mm.
Diffracted radiation was detected by a NaI scintillation detector.
A theta-to theta continuous scan at 3/min (0.4 sec/0.02.degree.
step) from 2.5 to 40.degree. 2.theta. was used. A silicon standard
was analyzed to check the instrument alignment. Data were collected
and analyzed using XRD-6000 v.4.1.
[0071] The X-ray powder diffraction pattern of polymorph form A of
racemic bicifadine hydrochloride is given in terms of "d" spacing
and relative intensities (I) is as follows (s=strong, m=medium,
w=weak, v=very, d=diffuse) and these terms are set forth in 1
below, and the X-ray powder diffraction pattern of form B of
bicifadine hydrochloride is set forth in Table 2 below:
TABLE-US-00001 TABLE 1 Peak Positions, d-Spacings, and Intensities
for Polymorph Form A Bicifadine Hydrochloride 2.theta. (deg) d
(.ANG.) I.sup.a 5.35 16.50 Vs 10.61 8.33 Vs 11.45 7.72 W 15.22 5.82
W 15.93 5.56 W 16.97 5.22 W 18.37 4.83 W 20.04 4.43 Md 20.26 4.38
Md 21.22 4.18 M 21.89 4.06 S 23.12 3.84 Md 23.54 3.78 Wd 26.63 3.34
M 27.83 3.20 Wd 28.32 3.15 Wd 30.67 2.91 Wd 32.03 2.79 S 37.57 2.39
W 38.20 2.35 W .sup.as = strong, m = medium, w = weak, v = very, d
= diffuse
TABLE-US-00002 TABLE 2 Peak Positions, d-Spacings, and Intensities
for Polymorph Form B Bicifadine Hydrochloride 2.theta. (deg) d
(.ANG.) I.sup.a 5.08 17.39 Vs 10.07 8.77 S 15.19 5.83 S 16.83 5.27
S 18.64 4.76 Md 18.76 4.73 Md 19.64 4.52 W 20.16 4.40 M 21.96 4.05
M 22.37 3.97 S 23.16 3.84 W 24.00 3.70 W 25.27 3.52 D 27.33 3.26 Md
27.74 3.21 M 29.00 3.08 M 30.43 2.93 Md 31.84 2.80 Wd 32.29 2.77 W
35.27 2.54 Wd 35.64 2.52 W .sup.as = strong, m = medium, w = weak,
v = very, d = diffuse
[0072] Table 1 and Table 2 represent the XRPD pattern of the peak
positions of bicifadine hydrochloride form A and form B,
respectively. The results in these tables demonstrate the
difference between the XRPD patterns of form A and form B. However,
there are key peaks at given angles in this pattern which identify
polymorph form B of bicifadine hydrochloride and are typically
present in the XRPD pattern of polymorph form B irrespective of its
particle size. These angles, expressed as 2.theta. (deg), locating
these major peaks, which alone or in any distinguishing
combination, distinguish bicifadine polymorph form B from form A,
using Cu Ka radiation, are: 5.08; 10.07; 20.16; 25.17; and
30.43.
[0073] The infrared spectra were obtained for each of the samples
using a Magna-IR 860.RTM. Fourier transform infrared (FT-IR)
spectrophotometer (Thomas Nicolet) equipped with an Ever-Glo
mid/far IR source, an extended range potassium bromide (KBr)
beamsplitter, and a deuterated triglycine sulfate (DTGS) detector.
The spectrophotometer measured the intensity of infrared light
bands of each of the samples at given wavelengths. A diffuse
reflectance accessory (the Collector.TM., Thermo Spectra-Tech) was
used for sampling. Each spectrum represents 256 co-added scans
collected from 400-4000 cm.sup.-1 at a spectral resolution of 4
cm.sup.-1. Sample preparation consisted of placing the sample of
powder containing crystals in either polymorph form A or form B
into a 13-mm diameter cup and leveling the material with a frosted
glass slide. A background data set was acquired with an alignment
mirror in place. The reflectance R is the ratio, at a given
wavenumber, of the light intensity of the sample/light intensity of
the background set. A Log 1/R(R=reflectance) spectrum acquired by
taking a ratio of these two data sets (the sample and the
background light intensities) against each other. The infrared
spectrum of polymorph A or racemic bicifadine hydrochloride as a
dry crystalline powder, as provided in Table 3, showed the
indicated main peaks which characterized this polymorph. The
infrared spectrum of polymorph B of racemic bicifadine
hydrochloride in dry crystalline powder, as provided in Table 4,
showed the indicated main peaks which characterize this
polymorph.
TABLE-US-00003 TABLE 3 Infrared Peak Positions For Polymorph Form A
Bicifadine Hydrochloride. All values in wavenumbers (cm.sup.-1)
3949 2923 2431 2280 2091 1895 1790 1595 1522 1430 1376 1233 1130
1088 1068 1050 900 825 781 714 689 652 574 533 437
TABLE-US-00004 TABLE 4 Infrared Peak Positions for Polymorph Form B
Bicifadine Hydrochloride. All values in wavenumbers (cm.sup.-1)
3185 2769 2437 2276 2108 1908 1804 1658 1596 1518 1453 1403 1343
1305 1274 1209 1131 1111 1022 963 904 891 856 818 783 719 684 660
637 580 532 475 422
[0074] Table 3 and Table 4 provide the complete patterns of the
infrared peak positions with respect to polymorph form A and
polymorph form B of bicifadine hydrochloride respectively. However,
there are certain key peaks, within this pattern, which are
associated with polymorph form B of bicifadine hydrochloride and
are sufficient to characterize this polymorph, individually or in
any distinguishing combination. These peaks, expressed in
wavenumbers (cm .sup.-1), are: 2108; 891; 856; 719; and 660.
[0075] Bicifadine compositions for use within the invention may
comprise any crystalline polymorphic or amorphous form of the
compound, or mixture(s) thereof. In exemplary embodiments,
effective therapeutic formulations and dosage forms will comprise
substantially pure bicifadine HCl polymorph "form A" (i.e., having
a concentration of about 95%-98% or greater by weight of total
bicifadine present), substantially pure "form B", or any mixture of
polymorph forms A and B. In certain embodiments, the formulation or
dosage form of the invention may contain from about 10% to 98%
polymorph form B. In other embodiments there may be present in the
formulation or dosage form greater than about 50% polymorph form B,
greater than about 75% polymorph B, greater than about 90%
polymorph B, greater than about 98% polymorph B, or essentially
pure polymorph B (i.e., where any levels of polymorph A, or any
other form of bicifadine other than the B polymorph, that may be
present are below a level of detection).
[0076] In additional embodiments, one or more isolated (+) or (-)
enantiomers of bicifadine are employed within the methods and
compositions of the invention. The (+) and (-) enantiomers of
bicifadine, and methods for resolving these enantiomers to yield
essentially pure compositions of the respective enantiomers, are
reported by Epstein et al. (J. Med. Chem. 24(5):481, 1981; NIDA
Res. Monogr. pp. 93-98, 1982). See, also U.S. Pat. No. 4,131,611;
U.S. Pat. No. 4,118,417; U.S. Pat. No. 4,196,120; U.S. Pat. No.
4,231,935; and U.S. Pat. No. 4,435,419, each incorporated herein by
reference). In exemplary embodiments, effective therapeutic dosage
forms for treating mammalian subjects presenting with acute pain,
chronic pain, or a neuropathic disorder will comprise essentially
pure (+) bicifadine (i.e., having a concentration of 90-95% of the
(+) enantiomer by weight of total bicifadine present), essentially
pure (-) bicifadine, or any racemic mixture of the (+) and (-)
enantiomeric forms of bicifadine. In certain embodiments, the
formulation or dosage form may contain from about 10% to 98% (+) or
(-) bicifadine. In other embodiments there may be present in the
formulation or dosage form greater than about 50% (+) or (-)
bicifadine, greater than about 75% (+) or (-) bicifadine, or
greater than about 90% (+) or (-) bicifadine.
[0077] As noted above, in certain embodiments the methods and
compositions of the invention employ pharmaceutically acceptable
acid addition and/or base salts of a compound of Formula I. The
term "pharmaceutically acceptable salts" refers to those salts of
the parent compound which do not significantly adversely affect the
pharmaceutical properties (e.g., toxicity, effectiveness, etc.) of
the parent compound such as are conventionally used in the
pharmaceutical art. Acid-addition salts may be prepared by
treatment of the parent compound with the appropriate organic or
inorganic acid in a manner well-known to those skilled in the art.
It is to be understood that for the purposes of this invention, the
acid-addition salts are equivalent to the parent free base.
[0078] Suitable acid addition salts are formed from acids, which
form non-toxic salts. Examples include inorganic and organic acid
addition salts, including but not limited to, hydrochloride,
hydrobromide, hydroiodide, sulfate, hydrogen sulphate, nitrate,
phosphate, hydrogen phosphate, citrate, fumarate, maleate,
succinate, and pamoate salts. In other embodiments, useful
pharmaceutically acceptable salts of compounds of Formula I
include, but are not limited to, metal salts such as sodium salt,
potassium salt, cesium salt and the like; alkaline earth metals
such as calcium salt, magnesium salt and the like; organic amine
salts such as triethylamine salt, pyridine salt, picoline salt,
ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt and the like; organic acid salts
such as acetate, citrate, lactate, succinate, tartrate, maleate,
fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate,
oxalate, formate and the like; sulfonates such as methanesulfonate,
benzenesulfonate, p-toluenesulfonate and the like; and amino acid
salts such as arginate, asparginate, glutamate, tartrate, gluconate
and the like. Suitable base salts are formed from bases, which form
non-toxic salts and examples are the aluminum, calcium, lithium,
magnesium, potassium, sodium, zinc and diethanolamine salts.
[0079] In other detailed embodiments, the methods and compositions
of the invention employ a prodrug of a compound of Formula I.
Prodrugs are considered to be any covalently bonded carriers which
release the active parent drug in vivo. Examples of prodrugs useful
within the invention include esters or amides with hydroxyalkyl or
aminoalkyl as a substituent, and these may be prepared by reacting
such compounds as described above with anhydrides such as succinic
anhydride.
[0080] The invention disclosed herein will also be understood to
encompass methods and compositions using in vivo metabolic products
of a compound of Formula I (either generated in vivo after
administration of the subject precursor compound, or directly
administered in the form of the metabolic product itself). Such
products may result for example from the oxidation, reduction,
hydrolysis, amidation, esterification and the like of the
administered compound, primarily due to enzymatic processes.
Accordingly, the invention includes methods and compositions of the
invention employing compounds produced by a process comprising
contacting a compound of Formula I with a mammalian subject (e.g.,
a mammalian cell, tissue, organ or individual) for a period of time
sufficient to yield a metabolic product thereof. Such products
typically are identified by preparing a radiolabelled compound of
the invention, administering it parenterally in a detectable dose
to an animal such as rat, mouse, guinea pig, monkey, or to man,
allowing sufficient time for metabolism to occur and isolating its
conversion products from the urine, blood or other biological
samples.
[0081] The invention disclosed herein will also be understood to
encompass the methods and compositions of the invention employing a
compound of Formula I isotopically-labelled by having one or more
atoms replaced by an atom having a different atomic mass or mass
number. Examples of isotopes that can be incorporated into the
compounds of Formula I include isotopes of hydrogen, carbon,
nitrogen, and oxygen, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C,
.sup.15N, .sup.18O, and .sup.17O, respectively. Other useful
labeling moieties in this context may include any detectable
chemical moiety, for example conventional fluorophores,
chemiluminescers, and enzymes.
[0082] Within related aspects of the invention, novel
pharmaceutical compositions and unit dosage forms containing a
compound of formula I, and methods for administering these
compositions and dosage forms, are provided which are effective to
alleviate or prevent acute pain, chronic pain, and/or pain or other
symptoms associated with a neuropathic disorder in mammalian
patients. The methods of the invention produce a strong, rapid
onset of relief of targeted symptoms followed by a sustained
maintenance of this relief for a long period of time.
[0083] Exemplifying compounds of Formula I, Bicifadine HCl,
((.+-.)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexane hydrochloride
(also referred to as racemic 1-(p-toyl)-3-azabicyclo[3.1.0]hexane
hydrochloride), is known as an effective, non-narcotic analgesic
(see, e.g., U.S. Pat. Nos. 4,231,935; and 4,196,120, each
incorporated herein by reference). Bicifadine HCl has been reported
to be potent and active in the "Randall-Selitto" test, an animal
model of acute inflammatory pain (see, e.g., Epstein et al., J.
Med. Chem. 24(5):481, 1981; and Epstein et al., NIDA Res. Monogr.
pp. 93-98, 1982, each incorporated herein by reference). Both
opiates (e.g., morphine and codeine) and non-steroidal
anti-inflammatory drugs (NSAIDs; e.g., aspirin) used to treat acute
pain are also active in this model of acute, nociceptive pain. In
addition, bicifadine has been reported to be as effective as
codeine and tramadol, two commonly used analgesics for treating
acute, nociceptive pain following dental surgery (Czobor P., et
al., Stark J., Beer G., Petti S., Lippa A., Brown J., Beer B.: A
Double-Blind, Placebo Controlled Randomized Study of DOV220,075
(bicifadine) SR and Codeine 60 mg in the Treatment of
Post-Operative Dental Pain. Presented at the 2nd Annual Scientific
Meeting Mar. 20-23, 2003 Chicago, Ill. American Pain Society
Abstract Database at
http://www.ampainsoc.org/abstract/2003/data/index.html. (Poster
#915)); Czobor P., Stark J., Beer G., Brown J., Sunshine A., Konery
S., Turpin M., Olson N., Otero A., Lippa A., Beer B.: A two center
double-blind, placebo-controlled randomized study of DOV 220,075
(bicifadine) SR and Tramadol 100 mg in the treatment of
post-operative dental pain. The Journal of Pain, 2004: 5(1),
Supplement 1, p59. Presented at the Joint APS and Canadian Pain
Society Annual Meeting (23rd APS Annual Scientific Meeting) May
6-9, 2004, Vancouver, BC Canada. American Pain Society Abstract
Database at http://www.ampainsoc.org/abstract/2004/data/index.html
(Poster #801); each incorporated herein by reference).
[0084] By employing the novel, sustained release compositions and
dosage forms of the invention comprising an active compound of
Formula I, including bicifadine, the invention provides effective
tools and methods to treat and/or prevent acute pain in mammalian
subjects. The pharmaceutical compositions and dosage forms of the
invention effectively treat a wide variety of acute pain conditions
and symptoms, including those associated with trauma and other
injuries, for example burns; cuts; wounds; trauma; surgery;
headaches; sprains; bone fractures; fibromyalgia; acute lower back
pain; dorsopathy; dysmenorrhea; infection; dysfunction of the
liver, pancreas, endocrine glands, kidney, bladder, gall bladder,
spleen, hematopoetic system, vasculature or other body organ or
tissue; torn or injured muscle, ligament, or tendon; acute
exacerbation of a chronic or intermittent pain condition, including
arthritic flare, migraine attack, and acute worsening of chronic
lower back pain or chronic neuropathic pain. As used herein, the
term "acute pain" will further be understood to encompass either an
initial phase of a painful condition, which either largely resolves
within several hours, days or months (typically lasting no more
than about 3 months), or progresses on to a subacute pain (e.g.,
lasting 3-6 months) or chronic pain (e.g., persisting, in some
cases intermittently, for more than 3 months, and often more than 6
months) condition. Acute pain also refers to a transient
exacerbation or flare up of a chronic pain condition in which pain
intensity worsens substantially, whereby supplemental treatment
and/or upwards dose adjustment is indicated, provided that such
treatment would be tolerated adequately.
[0085] The novel compositions and dosage forms of the invention
comprising bicifadine or another active compound of Formula I also
provide surprisingly effective tools and methods to treat and/or
prevent chronic pain in mammalian subjects. The pharmaceutical
compositions and dosage forms of the invention effectively treat a
wide variety of chronic pain conditions and symptoms, including,
for example; osteoarthritis pain; rheumatoid arthritis pain; cancer
pain; and various other chronic pain conditions of non-neuropathic
origin, including chronic low back pain, chronic lumbar and
cervical pain, chronic fibromyalgia pain, chronic pain from
arteriovenuous malformation, arachnoiditis, chronic pain from root
avulsion, chronic postthoracotomy pain, and chronic postmastectomy
pain of non-neuropathic origin.
[0086] Within a distinct embodiment of the invention, it has been
surprisingly found that conditions and symptoms of chronic pain in
mammalian subjects can be effectively treated by administering to
the subject a therapeutically effective amount of an active
therapeutic agent selected from a compound of Formula I, or a
pharmaceutically acceptable salt, enantiomer, polymorph, solvate,
hydrate, or prodrugs thereof, in a daily dosing regimen consisting
of only one or two doses of the active agent per day. Based on
findings from extensive studies employing bicifadine HCl for
treating acute pain (for example acute dental pain and bunionectomy
pain studies), exemplary unit doses (e.g., in the range of about
200 mg, 400 mg, or 600 mg) of bicifadine, yielding acceptable side
effect levels, were found to have a period of analgesic efficacy
for effectively treating acute pain of approximately 6 hours or
even less. According to Czobor et al., supra, 2003, 2004, a
duration of analgesic efficacy of bicifadine in acute dental pain
studies was suggested using a distinct, "last observation carried
forward" (LOCF) statistical method, and was projected to last up to
6 hours, or even up to 12 hours. However, these findings did not
correlate directly to an actual period of analgesic efficacy of
bicifadine for treating acute dental pain. On the contrary, the
data relied upon by Czobor et al. to suggest a 6 hour or 12 hour
efficacy period for bicifadine in acute pain studies were
principally comprised of pain ratings assessed much earlier, at 1-4
hours post-dose. In contrast, actual periods of therapeutic
efficacy of bicifadine for treating acute pain require direct
assessment of pharmacokinetic and pain data throughout a full test
period to reliably determine efficacy, and such determinations are
further refined by analysis of rescue medication use by study
subjects.
[0087] When these methods were applied to assess the duration of
efficacy of bicifadine for treating acute pain, it was determined
that patients administered bicifadine SR tablets in standard test
dosage amounts (e.g., 200 mg, or 400 mg bicifadine SR tablets) did
not show sustained, therapeutically-effective plasma levels of the
drug for periods substantially longer than about six hours, or at
most about eight hours (see, e.g., Stern et al., "Relationship
Between Plasma Bicifadine Levels and Analgesic Effect in a Dental
Pain Model, Abstract #314-P291 presented at the 11.sup.th World
Congress on Pain, Sydney, Australia, Aug. 21-26, 2005, incorporated
herein by reference). As described in further detail in the
Examples below, these findings correlated with a positive
dose-dependent relationship for both the pharmacokinetics (AUC,
Cmax) of bicifadine and the pharmacodynamic measures of efficacy of
bicifadine for treating acute dental pain. Plasma bicifadine levels
>1000 ng/ml were associated with the greatest pain relief, and
drug levels between 500-1000 ng/ml were associated with significant
analgesic efficacy. However, lower plasma drug levels of 500 ng/ml
or less were not associated with significant analgesic effects.
These data strongly indicated that effective treatment acute or
chronic pain using a compound of Formula I would require at least
three times daily. (tid) dosing, or four times daily (qid) dosing,
to effectively treat subjects.
[0088] These conclusions are further substantiated by the use of
rescue medication by subjects in the Stern et al. acute dental pain
studies. Table 5 below summarizes information on the use of rescue
medication for patients who took rescue medication among the
various treatment groups in the clinical trial reported by Stern et
al. (id.) A nonparametric analysis (Median Test) was conducted to
evaluate the median latency to rescue medication. The Median Test
showed that the difference among the five treatment groups (single
dose of 200 mg, 400 mg or 600 mg bicifadine SR tablet, Tramadol 100
mg, or Placebo) did not reach statistical significance
(Chi-square=4.7, df=4, P=0.32).
[0089] Survival analysis (Kaplan-Meier method, 95% confidence) was
performed to compare the treatment groups with regard to
time-to-rescue medication. For the purpose of this analysis,
patients who did not take rescue medication until the end of the
follow-up period were treated as censored observations. The
analysis yielded a statistically significant difference among the
treatment groups (Log-Rank test, Chi-square=26.9, df=4, P=0.0001).
Subsequent pair-wise comparisons indicated that subjects receiving
the bicifadine SR 400-mg (Log-Rank test, Chi-square=9.3, df=1,
P=0.002), bicifadine SR 600-mg (Log-Rank test, Chi-square=12.4,
df=1, P=0.0004), and tramadol 100-mg treatments (Log-Rank test,
Chi-square=18.7, df=1, P=0.0001) were significantly less likely to
use rescue medication than study subjects receiving placebo.
[0090] In view of the foregoing evidence, the present disclosure
documenting efficacy of a reduced, bi-daily or less frequent dosing
regimen of bicifadine to yield effective treatment of chronic pain
are unexpected. The extended duration of treatment efficacy of
preferred dosage amounts of bicifadine identified herein does not
accord with the findings from the previously-published acute pain
studies, nor with the pharmacokinetic data generated from these and
related studies. It is a surprising benefit, therefore, that a
dosing regimen consisting of only one or two doses of an active
compound of Formula I effectively alleviates symptoms of chronic
pain over an extended period. The extended period of efficacy of
the novel compositions and dosage forms of the invention provide
significant relief of chronic pain symptoms over a period of at
least 8 hours, or at least 12 hours, often at least 18 hours, and
up to 24 hours or longer.
[0091] The novel dosing methods of the invention for treating
chronic pain are not limited to sustained release formulations of
active compounds of Formula I. Rather, within this distinct aspect
of the invention it is contemplated that all delivery modalities
can be enlisted to achieve the unexpected therapeutic benefits
identified herein attending a reduced dosing regimen for chronic
pain. Thus, in certain embodiments, immediate release formulations
of active compounds of Formula I may be employed within the subject
dosing methods to achieve an unexpected duration of activity for
alleviating symptoms of chronic pain.
[0092] Within these distinct aspects of the invention, methods for
treating chronic pain comprising once daily or twice daily dosing
of subjects will employ a once daily or twice daily effective
amount of the active compound of Formula I, which will often be
formulated for oral administration. Effective dosage amounts in
this context will typically be between about 25 to 1800 mg, often
between about 50 to 1200 mg, more often between about 75 to 1000
mg, or 100 to 600 mg, and in exemplary embodiments between about
200 to 400 mg, or 100 to 200 mg.
[0093] Although the novel methods of the invention providing
effective treatments for chronic pain using bi-daily or less
frequent dosing of a compound of Formula I are not dependent on use
of the sustained release (SR) compositions and dosage forms
described herein, it will often he advantageous to formulate the
active therapeutic agent in such an SR dosage form using a
sustained release vehicle, matrix, binder or coating material
according to the teachings herein. Thus, in certain aspects of the
invention, methods for treating chronic pain involving bi-daily or
less frequent dosing of a compound of Formula I will employ a
sustained release dosage forms as described herein, which in
related embodiments will often yield desired results, e.g., by
extending the release kinetics and lowering a side effect profile
of the active therapeutic agent, as presently described.
[0094] Within exemplary embodiments, sustained release dosage forms
useful for treating chronic pain on a once or twice daily dosing
schedule will provide a mean maximum plasma concentration (Cmax) of
the active therapeutic agent in a treatment subject which is less
than about 80% of a Cmax provided in a control subject after
administering the same amount of the active agent in an immediate
release formulation. In related embodiments the sustained release
dosage forms for treating chronic pain yield an Area Under the
Curve (AUC) of the active therapeutic agent in a treatment subject
which is less than about 80% of an AUC provided in a control
subject administered the same amount of the active agent in an
immediate release formulation. In additional related embodiments
for treating chronic pain, a sustained release dosage form as
contemplated herein will yields a Cmax and an AUC of the active
therapeutic agent in a treatment subject which are each,
respectively, less than about 80% of a Cmax and an AUC provided in
a control subject following administration of the same amount of
the active agent in an immediate release formulation.
[0095] In yet additional embodiments, sustained release dosage
forms useful for treating chronic pain on a once or twice daily
dosing schedule will exhibit an in vitro dissolution profile
wherein about 5% to about 35% of the compound of Formula I is
dissolved within 30 minutes, measured in a <711> dissolution
test, Apparatus 1, USP 28, 2005, at 37.0.degree. C..+-.0.5.degree.
C., using 900 ml 0.05M potassium phosphate monobasic buffer pH 6.8
and a basket or paddle speed of 75 rpm. In related embodiments, the
sustained release dosage form will exhibit an in vitro dissolution
profile wherein about 15% to about 40% of the compound of Formula I
is dissolved within 1 hour according to the foregoing test
parameters. In other related embodiments the sustained release
dosage form will exhibit an in vitro dissolution profile wherein
about 25% to about 60% of the compound of Formula I is dissolved
within 2 hours according to these test parameters. In additional
embodiments the sustained release dosage form will exhibit an in
vitro dissolution profile wherein about 50% to about 80% of the
compound of Formula I is dissolved within 4 hours. In yet
additional embodiments the sustained release dosage form will
exhibit an in vitro dissolution profile wherein about 70% to about
90-100% of the compound of Formula I is dissolved within 8 hours.
In still other embodiments, the sustained release dosage form will
exhibit an in vitro dissolution profile wherein about 75% to about
100% of the compound of Formula I is dissolved within 12 hours. In
alternate embodiments, the sustained release dosage form will
exhibit an in vitro dissolution profile wherein about 80% to about
100% of the compound of Formula I is dissolved within 24 hours. In
this context, SR formulations which have a more extended
dissolution profile will yield more extended in vivo release
kinetics, such that extended in vivo release will provide effective
therapeutic levels achieved by only once daily dosing that is
sustained for a period of at least about 18 hours, and up to 24
hours, or longer. Exemplary formulations in this context include
the long term sustained release formulations described below in
Examples 2 and 3. The dissolution profiles/parameters of sustained
release compositions and dosage forms of a compound of Formula I
can be obtained or adjusted for any of the sustained release
formulations and methods contemplated herein, including all
contemplated compositions, dosage forms and treatment methods for
acute pain, chronic pain and neuropathic disorders.
[0096] In more detailed embodiments of the invention for treating
chronic pain using a once daily or twice daily dosing regimen,
where a sustained release dosage form is selected, the sustained
release vehicle, matrix, binder, or coating material, will often
comprise a sustained release polymer. Exemplary sustained release
polymers in this context include, but are not limited to,
ethylcellulose, hydroxyethyl cellulose; hydroxyethylmethyl
cellulose; hydroxypropyl cellulose; hydroxypropylmethyl cellulose;
hydroxypropylmethyl cellulose phthalate;
hydroxypropylmethylcellulose acetate succinate;
hydroxypropylmethylcellulose acetate phthalate; sodium
carboxymethylcellulose; cellulose acetate phthalate; cellulose
acetate trimellitate; polyoxyethylene stearates; polyvinyl
pyrrolidone; polyvinyl alcohol; copolymers of polyvinyl pyrrolidone
and polyvinyl alcohol; polymethacrylate copolymers; and mixtures
thereof.
[0097] Within additional embodiments of the invention, sustained
release pharmaceutical compositions, dosage forms, and methods are
provided that effectively treat and/or prevent neuropathic pain and
related symptoms associated with neuropathic disorders in mammalian
patients. Neuropathies and related symptoms attendant to
neuropathic disorders include, but are not limited to,
paraesthesias, allodynia, hyperalgesia and other sensory symptoms
of neuropathies often referred to as "neuropathic pain", in
mammals. Conventional analgesics, including NSAIDs and opiates,
which are effective for treating general nociceptive pain, are
rarely effective for neuropathic pain (The Lancet, 353:1959-1966,
1999). For example, morphine has a strong analgesic effect on
nociceptive pain, but does not exhibit remarkable/sufficient
activity for alleviating neuropathic pain. In fact, resistance to
morphine therapy will provide a useful diagnostic index to
differentiate subjects with neuropathy-associated pain amenable to
treatment using the methods and compositions of the invention (see,
e.g., Crosby et al., J. Pain Symptom Manage.) 19(1):35-9, 2000;
Chen et al., J. Neurophysiol. 87:2726-2733, 2002; Shir et al.,
Harefuah 118(8):452-4, 1990, each incorporated herein by
reference). Accordingly, in certain aspects of the invention the
compositions and methods herein are directed toward treatment of
symptoms of a neuropathic disorder in individuals whose pain
symptoms are insufficiently relieved by opioid treatment, and/or to
treatment using other classes of analgesic drugs effective for
treating nociceptive pain, such as NSAIDs. In this context,
patients presenting with neuropathic disorders who will be amenable
for treatment using the compositions and methods of the invention
will often show less than a 50% reduction in the severity or
frequency of their pain symptoms following administration of a
nociceptive pain therapeutic agent (e.g., an opiate or NSAID)
compared to placebo-treated or other suitable control subjects. In
certain cases, the subject patients will show less than a 30%, 20%,
or 10% reduction, or no measurable reduction, in the severity or
frequency of pain symptoms after receiving the nociceptive pain
drug, compared to control subjects exhibiting similar pain
symptoms.
[0098] The compositions, dosage forms and methods effectively treat
or prevent a wide variety of symptoms and conditions associated
with neuropathies, including, for example, neuropathic pain and
related symptoms associated with diabetic neuropathy; peripheral
neuropathy; distal symmetrical polyneuropathy; post-herpetic
neuralgia; trigeminal neuralgia; alcoholism-related neuropathy; HIV
sensory neuropathy; sciatica; spinal cord injury; post-stroke
neuropathy; multiple sclerosis; Parkinson's disease; idiopathic or
post-traumatic neuropathy; mononeuritis; cancer-associated
neuropathy; peripheral nerve trauma; nerve transection; carpal
tunnel injury; neuropathy associated with Fabry's disease;
vasculitic neuropathy; neuropathy associated with Guillain-Barre
syndrome; entrapment neuropathy; phantom limb syndrome; and various
additional neuropathic conditions that may be associated with,
e.g., fibromyalgia, Wallenberg's syndrome, connective tissue
disease, plexus irradiation, ischemic irradiation, hematomyelia,
dyscraphism, tumor compression, arteriovenuous malformation,
syphilitic myelitis, commissural myelotomy, arachnoiditis, root
avulsion, certain chronic lower back pain syndromes of neuropathic
origin, and reflex sympathic dystrophy.
[0099] The methods of the invention for treating acute pain,
chronic pain, and/or neuropathic pain in mammalian subjects
collectively comprise administering to a treatment subject a
sustained release pharmaceutical composition or dosage form
comprising a therapeutically effective amount (for a selected,
acute pain, chronic pain, and/or neuropathic pain indication) of an
active therapeutic agent comprising an active compound of Formula I
(e.g., selected from bicifadine and pharmaceutically acceptable
salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs of
bicifadine, and combinations thereof) combined with a sustained
release vehicle, matrix, binder, or coating, as described herein.
Following administration of the pharmaceutical composition or
dosage form to the treatment subject, the active compound is
released into the subject (e.g., into a gastrointestinal tract of
the subject) and allowed to transit to a target site for delivery
(e.g., a blood plasma or other tissue or compartment in the
subject). In certain embodiments of the invention, this method
results in a mean maximum plasma concentration (Cmax) of the active
compound in the treatment subject which is less than about 80% of a
Cmax obtained in a control subject after administration of the same
amount of the active compound in an immediate release formulation.
In other embodiments, the method results in an Area Under the Curve
(AUC) of the active compound in the treatment subject which is less
than about 80% of an AUC obtained in a control subject after
administration of the same amount of the active compound in an
immediate release formulation. In other embodiments, the method
results in a Cmax and an AUC of the active compound in the
treatment subject which are each, respectively, less than about 80%
of a Cmax and an AUC obtained in a control subject after
administration of the same amount of the active agent in an
immediate release formulation.
[0100] According to these methods of the invention, targeted
conditions or symptoms of acute pain, chronic pain, and/or a
neuropathic disorder are substantially alleviated or prevented in
the treatment subject, without attendant, unacceptable adverse side
effects. Typically, subjects treated using the pharmaceutical
compositions and dosage forms of the invention will exhibit an
occurrence and/or severity of one or more targeted conditions or
symptoms of acute pain, chronic pain, and/or a neuropathic disorder
that is reduced by at least 10%, 20%, 30%, 50% or greater, up to a
75-90%, and even 95% or greater, compared to the occurrence and/or
severity of the same one or more side effect(s) observed in
placebo-treated control subjects under otherwise equivalent or
comparable conditions.
[0101] Various animal and human models, assays and scoring systems
are widely known in the art for determining therapeutic efficacy of
the compositions, dosage forms and methods of the invention for
treating conditions or symptoms of acute pain. As noted above, the
analgesic efficacy of bicifadine HCl for treating acute pain has
been previously established in animal models, for example in the
"Randall-Selitto" test, an animal model of acute inflammatory pain
(see, e.g., Epstein et al., J. Med. Chem. 24(5):481, 1981; and
Epstein et al., NIDA Res. Monogr. pp. 93-98, 1982).
[0102] For determining therapeutic efficacy of the compositions,
dosage forms and methods of the invention for treating conditions
or symptoms of acute and/or chronic pain in human subjects, there
is a variety of useful pain assessment models, assays and scoring
systems known in the art. Exemplary methods and tools for assessing
efficacy of compositions and methods of the invention for treating
acute pain and/or chronic low back pain include the Pain Severity
Rating (PSR), test; the Short-Form McGill Pain Questionnaire
(SF-MPQ); and the Roland-Morris Disability Questionnaire. An
exemplary PSR test uses a 100 mm visual analogue scale (VAS) to
provide a patient pain severity rating, wherein patients are
instructed to draw a vertical line on the scale to indicate the
amount of low back pain they have experienced over the past 48
hours, from "no pain" to "worst pain imaginable". Study
professionals measure the distance in mm (0-100) from the left side
of the scale to the patient's vertical mark and record this number
as the PSR value. The SF-MPQ rates the intensity of 15 sensory and
affective components of pain and includes VAS and categorical
scales to rate present overall pain intensity (see, e.g., Melzack
R. The short-form McGill Pain Questionnaire. Pain 30:191-197,
1987). The SF-36 Health Survey is a generic quality of life
instrument which has 36 items covering eight domains: physical
functioning, role-physical, bodily pain, general health, vitality,
social functioning, role-emotional, and mental health (see, e.g.,
Ware J E, Snow K K, Kosinski M, Gandek B. SF-36.RTM. Health Survey
Manual and Interpretation Guide. Boston, Mass.: New England Medical
Center, The Health Institute, 1993). For additional pain assessment
methods and tools useful for determining efficacy of the
compositions, dosage forms and methods of the invention, see, e.g.,
Strand et al., Back Performance Scale for the assessment of
mobility-related activities in people with back pain. Phys Ther.
82:1213-1223, 2002; Linton et al., Int. J. Beh. Med. 7(4):291-304,
2000; and Hsieh et al., J. Manipulative Physiol. Ther. 15(1):4-9,
1992 (each incorporated herein by reference). Using such methods,
the efficacy of bicifadine for treating acute pain has been
demonstrated in human clinical trials to assess efficacy of
bicifadine for treating acute, nociceptive pain following dental
surgery--including trials testing activity of bicifadine HCl in
side-by-side comparisons against, for example, opiates (see, e.g.,
Czobor P., et al., supra, 2003; Czobor P., et al., supra, 2004; and
U.S. Pat. Nos. 4,231,935 and 4,196,120, each incorporated herein by
reference).
[0103] In certain embodiments of the invention, subjects treated
effectively using the methods and compositions described herein
will exhibit an improvement, decreased occurrence, remission, or
enhancement in a functional or activity-based, disability or
quality of life measure or score associated with a targeted
condition or symptom of acute pain, chronic pain, and/or a
neuropathic disorder. In exemplary embodiments, one or more
functional indices of impairment, or disability measures, in
treated patients will be reduced by at least 10%, 20%, 30%, 50% or
greater, up to a 75-90%, and even 95% or greater, compared to the
occurrence and/or severity of the same one or more functional
indices of impairment, or disability measures, in placebo-treated
control subjects under otherwise equivalent or comparable
conditions. For example, patients treated for acute pain, chronic
pain, and/or a neuropathic disorder who exhibit a "baseline"
functional disability index or score prior to treatment will
exhibit an improvement (in terms of increased function, decreased
disability, improved activity and/or other functional/quality of
life measures) of at least 10%, 20%, 30%, 50% or greater, up to a
75-90%, and even 95% or greater improvement in the subject
disability index or score. In more detailed embodiments, patients
treated according to the methods and compositions of the invention
will show at least a 10%, 20%, 30%, 50% or greater, up to a 75-90%,
and even 95% or greater, improvement in a disability rating based
on functional/activity measures, for example as embodied in the
well-known Roland-Morris Disability Questionnaire, and/or SF-36
Health Survey. Any one or more disability indices may be reduced
(corresponding to one or more enhanced functional/activity
measures) in different patient populations or using different
formulations or treatment protocols according to the) invention.
Typically, multiple disability indices will be reduced,
corresponding to enhancement of one or more functional/activity
measures, in treated patients. In illustrative embodiments,
subjects treated for acute pain, chronic pain, and/or a neuropathic
disorder according to the methods and compositions of the invention
will exhibit an improvement or decreased occurrence of one or more
disability indices, corresponding to enhancement or reversal of one
or more functional/activity measures, by at least 10%, 20%, 30%,
50% or greater, up to a 75-90%, and even 95% or greater, identified
in the Roland-Morris Disability Questionnaire (RDQ) compared to the
occurrence and/or severity of the same one or more functional
indices of impairment, or disability measures, in placebo-treated
control subjects under otherwise equivalent or comparable
conditions. In certain embodiments, improvement in a comprehensive
disability or functional/activity measure (e.g., an overall RDQ
score) will be observed, for example a 10%, 20%, 30%, 50% or
greater, up to a 75-90%, and even 95% or greater reduction in an
RDQ score based on the following RDQ format.
Roland-Morris Disability Questionnaire
[0104] Because of My Back Pain Today: (Mark each numbered item YES
or NO)
[0105] 1. I stay at home most the time because of my back.
[0106] 2. I change position frequently to try to get my back
comfortable.
[0107] 3. I walk more slowly than usual because of my back.
[0108] 4. Because of my back, I am not doing any of the jobs that I
usually do around the house.
[0109] 5. Because of my back, I use a handrail to get upstairs.
[0110] 6. Because of my back, I lie down to rest more often.
[0111] 7. Because of my back, I have to hold on to something to get
out of an easy chair.
[0112] 8. Because of my back, I try to get other people to do
things for me.
[0113] 9. I get dressed more slowly that usual because of my
back.
[0114] 10. I only stand up for short periods of time because of my
back.
[0115] 11. Because of my back, I try not to bend or kneel down.
[0116] 12. I find it difficult to get out of a chair because of my
back.
[0117] 13. My back is painful almost all the time.
[0118] 14. I find it difficult to turn over in bed because of my
back.
[0119] 15. My appetite is not very good because of my back
pain.
[0120] 16. I have trouble putting on my socks (or stockings)
because of the pain in my back.
[0121] 17. I only walk short distances because of my back pain.
[0122] 18. I sleep less well because of my back.
[0123] 19. Because of my back pain, I get dressed with help from
someone else.
[0124] 20. I sit down for most the day because of my back.
[0125] 21. I avoid heavy jobs around the house because of my
back.
[0126] 22. Because of my back pain, 1 am more irritable and bad
tempered with people than usual.
[0127] 23. Because of my back, I go upstairs more slowly than
usual.
[0128] 24. I stay in bed most of the time because of my back.
[0129] The foregoing methods and compositions of the invention that
treat subjects with acute, chronic, and/or neuropathic pain by
eliciting an improvement in, or reduced occurrence of, one or more
disability indices, or by enhancing one or more functional/activity
measures, may yield a corresponding decrease in pain symptoms in
treated patients, but they may alternatively achieve the indicated
therapeutic benefit indirectly without a direct, or at least
directly proportionate, effect of alleviating pain in treated
subjects. Thus, the subject methods and compositions may or may not
correlate directly, or in all subjects, with a commensurate
therapeutic benefit expressed in terms of reduced pain symptoms
(e.g., as evinced by VAS or SF-MPQ scores).
[0130] For determining therapeutic efficacy of the compositions,
dosage forms and methods of the invention for treating pain
conditions and other symptoms of neuropathic disorders, there are
also several useful animal and human models, assays and scoring
systems known in the art. In this context, bicifadine HCl has now
been tested and demonstrated to be effective in the spinal nerve
ligation (Chung) model (see, e.g., Bennett, G. J., Chung, J. M.,
Honore, M., and Seltzer, Z. "Models of Neuropathic Pain. In:
Current Protocols in Neuroscience" (J. N. Crawley, C. R. Gerfen, M.
A. Rogawski, D. R. Sibley, P. Skolnick, and S. Wray, eds.) pp.
9.14.1-9.14.16. John Wiley & Sons, New York (2003); Morrow, T.
J. "Animal Models of Painful Diabetic Neuropathy: The STZ rat
model." In: Current Protocols in Neuroscience (J. N. Crawley, C. R.
Gerfen, M. A. Rogawski, D. R. Sibley, P. Skolnick, and S. Wray,
eds.) pp. 9.18.1-9.18.11. John Wiley & Sons, New York (2004),
each incorporated herein by reference). These findings based on
widely accepted models of neuropathic pain (i.e., the spinal nerve
ligation model and STZ diabetes induced model), using well accepted
endpoints modeling the symptoms associated with neuropathy,
including thermal and mechanical-hyperalgesia, comprise the first
report of efficacy for bicifadine in the treatment of neuropathic
pain and other conditions and symptoms associated with neuropathic
disorders (see, U.S. Provisional Patent Application No. 60/702,800,
entitled Methods and Compositions For The Treatment of Neuropathies
and Related Disorders, filed Jul. 26, 2005, incorporated herein by
reference).
[0131] Surprisingly, the novel compositions, dosage forms and
methods of the invention employing an active compound of Formula I
effectively treat targeted symptoms of acute pain, chronic pain,
and neuropathic pain and other symptoms associated with
neuropathies, with a satisfactorily rapid onset of relief and over
an extended period of time, without eliciting unacceptable, adverse
side effects in subjects receiving the treatment. More
specifically, the sustained release compositions and dosage forms
of the invention for delivering active compounds of Formula I
unexpectedly yield a significant reduction in one or more adverse
side effects associated with delivery of the active compound in an
"immediate release" formulation in a comparable dose. In more
detailed embodiments, the compositions, dosage forms and methods of
the invention yield effective treatment and/or prevention of acute
pain, chronic pain, and/or neuropathy symptoms in a treatment
subject, while exhibiting a significant reduction in the occurrence
and/or severity of one or more adverse side effect(s) selected from
euphoria, sedation, dizziness, headache, mydriasis, drowsiness,
sleep impairment, disorientation, memory loss or other cognitive
impairment, mood disorders, respiratory impairment, loss of motor
function, nausea, constipation, dry mouth, low blood pressure,
weight gain, eruption, dyspepsia, problems with cardiac function,
dependence and/or withdrawal in the treatment subject--as compared
to the occurrence and/or severity of the same one or more side
effect(s) observed in control subjects over a similar time period
following administration of the same amount of the active compound
in an immediate release formulation.
[0132] Typically, subjects treated using the pharmaceutical
compositions and dosage forms of the invention will exhibit an
occurrence and/or severity of one or more of the foregoing adverse
side effect(s) that is reduced by at least 10%, 20%, 30%, 50% or
greater, up to a 75-90%, and even 95% or greater, compared to the
occurrence and/or severity of the same one or more side effect(s)
observed in control subjects receiving the same or comparable dose
of the active compound of Formula I in an immediate release
formulation under otherwise equivalent or comparable conditions.
Within exemplary embodiments, the occurrence and/or severity of one
or more adverse side effects selected from euphoria; dizziness;
headache; mydriasis; sleepiness; drowsiness; and nausea in
treatment subjects will be reduced by at least 10%, 20%, 30%, 50%,
75% or greater compared to the occurrence and/or severity of the
same one or more side effect(s) observed in control subjects.
[0133] In a related aspect, the invention comprises a method of
reducing one or more side effects that attend administration of an
oral dosage form of a compound of Formula I. Within these methods,
the compound of Formula I is provided in a sustained release oral
dosage form and the dosage form is introduced into a
gastrointestinal tract of a mammalian subject presenting with acute
pain, chronic pain, or a neuropathic disorder. The method further
includes releasing the active compound of Formula I in a sustained
release (i.e., sustained release, delayed release, slow release,
extended release, gradual release, controlled release, modified
release, or pulsatile release) delivery mode into the
gastrointesinal tract (e.g., the intestinal lumen) of the subject
over a period of hours, during which the active compound reaches,
and is sustained at, a therapeutic concentration in a blood plasma,
tissue, organ or other target site of activity (e.g., a central
nervous system (CNS) tissue, fluid or compartment) in the subject.
When following this method, the side effect profile of the active
compound is less than a side effect profile of an equivalent dose
of the active compound administered in an immediate release oral
dosage form. In more detailed embodiments, subjects treated using
the methods of the invention for reducing side effects associated
with administration of an oral dosage form of a compound of Formula
I will exhibit an occurrence and/or severity of one or more of the
foregoing adverse side effect(s) that is reduced by at least 10%,
20%, 30%, 50% or greater, up to a 75-90%, and even 95% or greater,
compared to the occurrence and/or severity of the same one or more
side effect(s) observed in control subjects as described above.
Within exemplary embodiments, the occurrence and/or severity of one
or more adverse side effects selected from euphoria; dizziness;
headache; mydriasis; sleepiness; drowsiness; and nausea in
treatment subjects will be reduced by at least 10%, 20%, 30%, 50%,
75% or greater compared to the occurrence and/or severity of the
same one or more side effect(s) observed in control subjects.
[0134] The compositions, dosage forms and methods of the invention
for treating or preventing acute pain, chronic pain, and/or
neuropathic disorders or related symptoms generally employ a
therapeutically effective amount or dose of a compound of Formula I
(including all active derivatives, enantiomers, salts, polymorphs,
solvates, hydrates, and/or prodrugs of these compounds), optionally
formulated with one or more additional components, such as
physiologically-compatible carriers, additives, buffers,
excipients, preservatives, and the like. The formulations, dosage
forms and methods of the invention will be therapeutically
effective and well tolerated among mammalian subjects, in useful
and commercially feasible dosage amounts as indicated herein, and
without unacceptable adverse side effects. As used herein, the
terms "therapeutically effective amount" and "therapeutically
effective dose" refer to effective amount or dose of an active
compound of Formula I that is sufficient to elicit a desired
pharmacological or therapeutic effect in a mammalian
subject--typically resulting in a measurable reduction in an
occurrence, frequency, or severity of acute pain, chronic pain, or
symptom(s) associated with a neuropathic disorder in the subject.
In certain embodiments, when a compound of the invention is
administered to treat one of these indications, an effective amount
of the compound will be an amount sufficient in vivo to delay or
eliminate onset of one or more symptoms associated with the
targeted indication. Therapeutically-effective amounts,
formulations and dosages can alternatively be determined by an
administered formulation/dosage that yields a decrease in the
occurrence, frequency or severity of one or more symptoms of acute
pain, chronic pain, or a neuropathic disorder. In other
embodiments, a therapeutically-effective amount, formulation or
dose will yield a detectable, therapeutic reduction in the nature
or severity, occurrence, frequency, and/or duration of one or more
symptom(s) associated with the targeted condition or disorder.
Therapeutically effective amounts and dosage regimens will be
readily determinable by those of ordinary skill in the art, often
based on routine clinical or patient-specific factors.
[0135] In exemplary embodiments of the invention, the compound of
formula I is administered in an effective unit dosage amount of
from about 25 mg to about 600 mg. Within these exemplary
embodiments, the compound of Formula I may be provided in a
sustained release, unit oral dosage composition comprising about
40% to 60%, by weight of the composition, of a pharmaceutically
acceptable carrier, and from about 15% to 50% by weight of the
composition of a slow release matrix, such as polymeric slow
release matrix (e.g., hydroxypropyl methyl cellulose), with the
carrier and the active ingredient dispersed in the slow release
matrix. In more detailed embodiments, these exemplary formulations
and methods employ a unit dosage composition comprising about 20%
to 25% by weight, based upon the total weight of the composition,
of a slow release matrix, which produces a controlled release
formulation of the active compound of formula I causing an initial
rapid release of the active compound in the blood system of the
patient to provide an immediate relief of pain and thereafter
maintaining a relatively constant slow release of the active
compound for an extended period. In accordance with these exemplary
embodiments, the compound of formula I or its salts are
administered in an effective amount to alleviate pain. In general
oral dosages of from about 0.5 mg/kg to about 20 mg/kg per day are
used. However the amount of the compound of formula I or its salt
in the oral unit dose to be administered will depend to a large
extent on the amount of pain and the weight of the patient and of
course be subject to the physician's judgment. For example, for
patients of from about 60 kg to about 80 kg unit oral dosage forms
containing from about 100 mg to about 600 mg will often be
utilized, with dosages of about 200 to 400 mg being generally
preferred.
[0136] In other embodiments of the invention, suitable effective
unit dosage amounts of the active compound of Formula I may range
from about 1 to 1200 mg, 50 to 1000 mg, 75 to 900 mg, 100 to 800
mg, or 150 to 600 mg. In certain embodiments, the effective unit
dosage will be selected within narrower ranges of, for example, 10
to 25 mg, 30 to 50 mg, 75 to 100 mg, 100 to 150 mg, 150 to 250 mg,
200-400 mg, 250 to 500 mg, or 400-600 mg. These and other effective
unit dosage amounts may be administered in a single dose, or in the
form of multiple daily, weekly or monthly doses, for example in a
dosing regimen comprising from 1 to 5, or 2-3, doses administered
per day, per week, or per month. In exemplary embodiments, dosages
of 10 to 25 mg, 30 to 50 mg, 75 to 100 mg, 100 to 200 mg, or 250 to
500 mg, are administered one, two, three, or four times per day. In
more detailed embodiments, dosages of 50-75 mg, 100-150 mg, 150-200
mg, 250-400 mg, or 400-600 mg are administered once daily, twice
daily, or three times daily. In alternate embodiments, dosages are
calculated based on body weight, and may be administered, for
example, in amounts from about 0.5 mg/kg to about 30 mg/kg per day,
1 mg/kg to about 15 mg/kg per day, 1 mg/kg to about 10 mg/kg per
day, 2 mg/kg to about 20 mg/kg per day, 2 mg/kg to about 10 mg/kg
per day or 3 mg/kg to about 15 mg/kg per day.
[0137] The amount, timing and mode of delivery of the active
compound of Formula I will be routinely adjusted on an individual
basis, depending on such factors as weight, age, gender, and
condition of the individual, symptom presentation pattern, whether
the administration is prophylactic or therapeutic, and on the basis
of other factors known to effect drug delivery, absorption,
pharmacokinetics, including half-life, and efficacy. An effective
dose or multi-dose treatment regimen for the compounds of the
invention will ordinarily be selected to approximate a minimal
dosing regimen that is necessary and sufficient to substantially
prevent or alleviate the targeted pain condition or symptom(s) in
the subject, as described herein.
[0138] Suitable routes of administration for the active compounds
of Formula I to treat or prevent acute pain, chronic pain, or
symptoms of a neuropathic disorder include, but are not limited to,
oral, buccal, nasal, aerosol, topical, transdermal, mucosal,
injectable, slow release, controlled release, although various
other known delivery routes, devices and methods can likewise be
employed.
[0139] Within additional aspects of the invention, combinatorial
formulations and methods are provided which employ an active
compound of Formula I and one or more additional active agents,
that are combinatorially formulated or coordinately administered
with the compound of Formula I. These combinatorial formulations
and coordinate treatment methods employ an effective amount of an
active compound of Formula I (including pharmaceutically effective
enantiomers, salts, solvates, hydrates, polymorphs or prodrugs
thereof), and one or more secondary or adjunctive active agent(s)
that is/are combinatorially formulated or coordinately administered
with the compound of Formula I. These combinatorial formulations
and coordinate treatment methods are effective to modulate,
alleviate, treat or prevent one or more symptom(s) of a targeted
condition or symptom of acute pain, chronic pain, or a neuropathic
disorder in a mammalian subject. Exemplary combinatorial
formulations and coordinate treatment methods in this context
employ an active compound of Formula I in combination with one or
more known, secondary or adjunctive treatment agents effective for
treating pain and/or symptoms of neuropathic disorders.
Contemplated useful secondary or adjunctive therapeutic agents in
this context include, but are not limited to, NSAIDs (e.g., aspirin
and ibuprofen); COX-2 inhibitors; synthetic and natural opiates
(e.g., oxycodone, meperidine, morphine, and codeine); mexiletine;
baclofen; tramadol; antiarrhythmics; anticonvulsants (e.g.,
lamotrigine, gabapentin, valproic acid, topiramate, famotodine,
phenobarbital, diphenylhydantoin, phenytoin, mephenytoin, ethotoin,
mephobarbital, primidone, carbamazepine, ethosuximide,
methsuximide, phensuximide, trimethadione, benzodiazepines such as
diazepam, phenacemide, acetazolamide, progabide, clonazepam,
divalproex sodium, magnesium sulfate injection, metharbital,
paramethadione, phenytoin sodium, valproate sodium, clobazam,
sulthiame, dilantin, diphenylan; capsaicin cream;
membrane-stabilizing drugs (e.g., lidocaine); N-methyl-D-aspartate
receptor (NMDA) antagonists such as ketamine; as well as all other
known analgesic drugs and drugs useful for treating symptoms of
neuropathies, such as pregabalin, harkoseride, amitriptiline,
desipramine and other related tricyclic antidepressants.
[0140] To practice a coordinate treatment method of the invention,
an active compound of Formula I is administered, simultaneously or
sequentially, in a coordinate treatment protocol with one or more
of the secondary or adjunctive therapeutic agents or methods
described above. The coordinate administration may be done
simultaneously or sequentially in either order, and there may be a
time period while only one or both (or all) active therapeutic
agents, individually and/or collectively, exert their biological
activities. A distinguishing aspect of all such coordinate
treatment methods is that the active compound of Formula I exerts
at least some detectable therapeutic activity as described herein,
and/or elicits a favorable clinical response, which may or may not
be in conjunction with a secondary clinical response provided by
the secondary or adjunctive therapeutic agent. Often, the
coordinate administration of an active compound of Formula I with a
secondary or adjunctive therapeutic agent as contemplated herein
will yield an enhanced therapeutic response, and/or will yield a
reduced side effect profile, compared to the therapeutic response
and side effect profile elicited by either or both the compound of
Formula I and secondary or adjunctive agent, alone.
[0141] The following examples illustrate certain embodiments of the
present invention, and are not to be construed as limiting the
present disclosure.
IN THE EXAMPLES
[0142] Bicifadine HCl is the hydrochloric acid salt of the compound
of formula I.
[0143] Emcompress is the carrier dibasic calcium phosphate.
[0144] Methocel K100M is the hydrophilic polymeric hydroxypropyl
methyl cellulose having a viscosity of 100,000 cps for a 2%
solution in water [HPMC].
[0145] Methocel K100LV is the hydrophilic polymeric hydroxypropyl
methyl cellulose having a viscosity of 100 cps for a 2% solution in
water [HPMC].
[0146] Carbopol 971P is a polyacrylic acid polymer having a
viscosity of 4,000 to 12,000 cps for a 0.5% solution at pH
7.5[PAA].
[0147] Aerosil 200 is colloidal silicon dioxide.
[0148] A vicel PH101 is microcrystalline cellulose.
[0149] The content of the active ingredient of formula I in the
sample as reported in the dissolution tables was determined by
HPLC.
Example 1
Preparation of 200 mg. Bicifadine HCl Tablet
[0150] A first example of a bicifadine HCl 200 mg sustained release
(SR) tablet (referred to below as "formulation F" or "treatment F")
was prepared using the following ingredients. In the table below
the "% composition" is the % by weight of the ingredient based upon
the total weight of the composition.
[0151] (i) Bicifadine HCl 200 mg SR Tablets
[0152] Batch Size: 5.2 kg
TABLE-US-00005 Material % Composition Mg/tablet Bicifadine HCl
31.25 200.0 Methocel K100M 20.00 128.0 Emcompress 47.75 305.6
Magnesium Stearate 0.50 3.2 Aerosil 200 0.50 3.2
[0153] The tablets were prepared from the above ingredients
according to the procedure set forth below.
[0154] (1) Sieve the Bicifadine HCl through a 1 mm screen, and
collect in a polyethylene lined container. Weigh the exact quantity
required.
[0155] (2) Add the Aerosil 200 to a portion of the Emcompress. Bag
blend for 2 minutes and pass through a 600 micron screen.
[0156] (3) Add the Magnesium Stearate to a portion of the
Emcompress. Bag blend for 2 minutes and pass through a 600 micron
screen.
[0157] (4) Transfer the components to a V cone blender (Pharmatech
Mobile Multi-Blend Blender, equipped with 25 L V cone), and blend
for 20 minutes at 18 rpm.
[0158] Order of addition: [0159] Half of Emcompress [0160] Sieved
Emcompress/Aerosil mix [0161] Sieved Bicifadine HCl [0162] Methocel
K100M [0163] Remaining Emcompress
[0164] (5) Add the Sieved Emcompress I Magnesium Stearate mix, and
blend for a further 3 minutes at 18 rpm.
[0165] (6) Tablet the blend using a rotary tablet press (Piccola
Tablet Press)
[0166] Tabletting Parameters [0167] Press Speed Setting: 6 [0168]
Punch Description: 18.times.8 mm oval normal concave [0169] No of
punches: 5 [0170] Main Compression Force Setting: 2.5 [0171]
Filomatic Speed Setting 4 [0172] Target Tablet Weight: 0.640 g
(Range: 0.595-0.685 g) [0173] Target Tablet Hardness 150N (Range:
105-195N)
Example 2
Preparation of 200 mg Bicifadine HCl SR Tablet
[0174] A second example of a Bicifadine HCl 200 mg SR tablet
(referred to herein below as "formulation B" or "treatment B") was
prepared using the following ingredients. In the table below the "%
composition" is the % by weight of the ingredient based upon the
total weight of the composition.
TABLE-US-00006 Material % Composition Mg/tablet Bicifadine HCl
31.25 200.0 Methocel K100M 40.00 256.0 Emcompress 27.25 174.4
Magnesium Stearate 01.00 006.4 Aerosil 200 00.50 003.2
[0175] These Bicifadine HCl SR tablets were manufactured similarly
to those in Example 1.
Example 3
Preparation of 200 mg Bicifadine HCl SR Tablet
[0176] A third example of bicifadine HCl 200 mg SR tablet (referred
to herein below as "formulation C" or "treatment C") was prepared
using the following ingredients. In the table below the "%
composition" is the % by weight of the ingredient based upon the
total weight of the composition.
TABLE-US-00007 Material % Composition Mg/tablet Bicifadine HCl
31.25 200.0 Methocel K100M 60.00 384.0 Emcompress 07.25 046.4
Aerosil 200 00.50 003.2 Magnesium Stearate 01.00 006.4
[0177] These Bicifadine HCl SR tablets were manufactured similarly
to those of Example 1.
Example 4
Dissolution of 200 mg Bicifadine HCl Tablets
[0178] Dissolution Testing of the bicifadine SR tablets from
examples 1, 2 and 3 (formulations F, B, and C, respectively) was
performed using USP 1 Apparatus, 20 mesh baskets, 75 rpm, 900 ml
phosphate buffer pH 6.8.+-.0.05, 37.degree. C..+-.0.5.degree.
C.
TABLE-US-00008 Time Formula F Formula B Formula C (Hrs.) (Ex. 1)
(Ex. 2) (Ex. 3) 0.25 14.6 11.2 9.2 0.5 22.9 16.8 13.1 1 33.5 24.0
21.1 2 48.4 37.3 33.2 4 69.1 54.4 48.4 8 89.7 76.8 69.7 12 99.9
88.4 82.7 22 -- 100.6 95.5
[0179] For these SR tablets, a substantial amount of the active
ingredient is released at the early timepoints. For formulation F,
for example, a significant portion of the total amount of active
ingredient (approximately 15%) is released within the first 15
minutes, with the remainder released in a slow and continuous
manner over the remaining 12 hrs.
Example 5
Preparation of 200 mg Bicifadine SR HCl Tablet
[0180] A fourth example of a bicifadine HCl 200 mg SR tablet was
prepared using the following ingredients. In the table below the "%
composition" is the % by weight of the ingredient based upon the
total weight of the composition.
TABLE-US-00009 Material % Composition Mg/tablet Bicifadine HCl
31.25 200.00 Methocel K100M 30.00 192.00 Emcompress 37.75 241.60
Aerosil 200 00.50 003.20 Magnesium Stearate 00.50 003.20
[0181] These Bicifadine HCl SR tablets were manufactured similarly
to those in Example 1.
Example 6
Preparation of 200 mg SR Bicifadine HCl Tablet
[0182] A fifth example of a bicifadine HCl 200 mg SR tablet was
prepared using the following ingredients. In the table below the "%
composition" is the % by weight of the ingredient based upon the
total weight of the composition.
TABLE-US-00010 Material % Composition Mg/tablet Bicifadine HCl
31.25 200.00 Methocel K100M 13.60 087.04 Methocel K100LV 26.40
168.96 Emcompress 27.75 177.60 Aerosil 200 00.50 003.20 Magnesium
Stearate 00.50 003.20
[0183] These Bicifadine HCl SR tablets were manufactured similarly
to those in Example 1.
Example 7
Dissolution of 200 mg SR Bicifadine HCl Tablets
[0184] Dissolution Testing of the bicifadine tablets produced in
Examples 5 and 6 was performed using USP 1 Apparatus, 20 mesh
baskets, 75 rpm, 900 ml phosphate buffer pH 6.8.+-.0.05, 37.degree.
C..+-.0.5.degree. C.
TABLE-US-00011 Example 5 Example 6 Time (Hrs) Mean % Released 0.25
13.9 13.3 0.5 21.6 19.2 1 28.3 27.7 2 41.8 41.4 4 60.7 60.4 8 85.3
85.5 12 96.1 97.4 22 104.1 101.0
Example 8
Preparation of 180 mg Bicifadine HCl SR Tablet
[0185] Additional exemplary bicifadine HCl (180 mg) SR tablets were
prepared according to the following table ("% composition" is the %
by weight of the ingredient based upon the total weight of the
composition).
TABLE-US-00012 G H I J K L Material % Composition Bicifadine 30.0
30.0 30.0 30.0 40.0 40.0 HCl Methocel 30.0 -- 30.0 -- 30.0 40.0
K100M Methocel -- 30.0 -- 30.0 -- -- K15M Emcompress -- -- 38.5
38.5 -- -- Pharmatose 38.5 38.5 -- -- -- -- DCL 11 Mannitol -- --
-- 23.5 18.5 Aerosil 200 00.5 00.5 00.5 00.5 00.5 00.5 Magnesium
01.0 01.0 01.0 01.0 01.0 01.0 Stearate Tablet 600 mg 600 mg 600 mg
600 mg 450 mg 450 mg Weight
[0186] These blends were manufactured using manual blending. The
tablets were compressed manually using 300 bar pressure and an
Enerpac single station tablet press using 13 mm normal concave
tooling.
Example 9
Dissolution of 180 mg Bicifadine HCl SR Tablets
[0187] Dissolution Testing of the exemplary bicifadine SR tablets
produced in Example 8 was performed using USP 2 Apparatus, 50 rpm,
900 ml phosphate buffer pH 6.8.+-.0.05, 37.degree.
C..+-.0.5.degree. C.)
TABLE-US-00013 Time G H I J K L (Hrs) Mean % Released 0.25 17.7
17.2 16.8 21.0 18.9 17.8 1 25.5 24.9 24.4 30.7 27.1 22.7 4 52.3
51.0 48.7 57.4 54.1 54.3 8 74.3 70.3 66.0 73.2 74.3 75.0 12 88.6
84.4 77.2 84.1 87.8 89.0 22 101.4 99.3 91.1 96.5 99.8 100.8
Example 10
Preparation of 200 mg Bicifadine HCl SR Tablet
[0188] This example is directed to the preparation of 200 mg
Bicifadine HCl SR tablets which contain another exemplary slow
release component, such as a polyacrylic acid polymer alone
(formulation D), or polyacrylic acid polymer combined with
hydroxypropylmethyl cellulose (formulation E).
[0189] These bicifadine HCl 200 mg SR tablets were prepared using
the following ingredients. In the table below, the "% composition"
is the % by weight of the ingredient based upon the total weight of
the composition.
TABLE-US-00014 Formula D Formula E % Amount % Amount Material
Composition mg/tab Composition mg/tab Bicifadine HCl 31.25 200
31.25 200 Carbopol 971P 15.0 96 10.0 64 Methocel K100M -- -- 40.0
256 Emcompress 52.25 334.4 17.25 110.4 Aerosil 0.5 3.2 0.5 3.2
Magnesium Stearatc 1.0 6.4 1.0 6.4
[0190] The Bicifadine HCl SR tablets were manufactured similarly to
those in Example I, with Carbopol 971P substituting Methocel K100M
as required. The target tablet hardness was 200N (Range:
140-260N).
Example 11
Dissolution of 200 mg Bicifadine HCl SR Tablets of Example 10
[0191] Dissolution Testing of the tablets produced in example 10
above was performed using USP 1 Apparatus, 20 mesh baskets, 75 rpm.
The dissolution medium used was 900 ml 0.01N HCl for the first two
hours, followed by 900 ml phosphate buffer pH 6.8.+-.0.05,
37.degree. C..+-.0.5.degree. C. for the remaining time.
TABLE-US-00015 Formula D Formula E Time (hrs) Mean % Released 0.25
17.6 12.0 0.5 23.6 16.7 1 31.2 22.9 2 42.9 32.8 4 49.9 42.9 8 59.7
58.1 12 65.7 67.4 22 74.2 81.2
Example 12
Preparation of 100 mg Bicifadine HCl IR Tablet
[0192] This example is directed to the preparation of exemplary
bicifadine HCl 100 mg immediate release (IR) tablets (referred to
herein below as "formulation A" or "treatment A") which do not
contain any hydrophilic slow release polymer matrix. These
bicifadine HCl 100 mg IR tablets were prepared using the following
ingredients ("% composition" is the % by weight of the ingredient
based upon the total weight of the composition).
TABLE-US-00016 Material % Composition Mg/tab Bicifadine 15.625 100
Avicel PHlOl 72.875 466.4 Polyplasdone 10.0 64 Aerosil 0.5 6.4
Magnesium Stearate 1.0 3.2
[0193] The IR tablets were prepared from these ingredients as set
forth below:
[0194] (1) Blend Avicel PH101 with Aerosil 200 in a ratio of ca.
1:40 for two minutes, then pass through a screen of aperture 600
Tm.
[0195] (2) Blend Avicel PH101 with Magnesium Stearate in a ratio of
ca. 1:20 for two minutes, then pass through a screen of aperture
600 Tm.
[0196] (3) Pass Bicifadine raw material through a 1 mm screen.
Weigh the exact amount required.
[0197] (4) Transfer the components to a V cone blender (Pharmatech
Mobil Multi-Blend Blender),
[0198] Order with 25 L cone, and blend for ten minutes at 18
rpm
[0199] Approximately half of the remaining Avicel PH101
[0200] Polyplasdone
[0201] Screened Avicel/Aerosil blend to blender.
[0202] Remaining Avicel to the blender.
[0203] (5) Add the screened Avicel Magnesium Stearate to the
blender and blend for three minutes at 18 rpm. Tablet the blend
using a rotary tablet press (Piccola Tablet Press), using
18.times.8 mm oval normal concave tooling to a target tablet weight
of 0.640 g (Range:0.595-0.685 g).
Example 13
Dissolution of 100 mg Bicifadine HCl IR Tablets of Example 12
[0204] Dissolution Testing of the exemplary IR bicifadine HCl
tablets produced in Example 12 was performed using USP 1 Apparatus,
20 mesh baskets, 75 rpm. The dissolution medium used was 900 ml
0.01N HCl, 37.degree. C..+-.0.5.degree. C.
TABLE-US-00017 Formulation A Time (hrs) % Released 0.083 95.6 0.5
101.1
Example 14
In Vivo Pharmacokinetic Study
[0205] This example demonstrates that the use of exemplary
bicifadine sustained release (SR) oral dosage forms, e.g., having
from about 20-50% by weight of hydroxypropylmethyl cellulose
hydrophilic slow release polymer matrix produces a sustained
maintenance of bicifadine in the blood for longer periods of time
than utilizing comparable matrix systems which contain greater than
50% hydroxypropylmethyl cellulose as well as systems which contain
other sustained release polymer matrixes. In addition, this example
compares the various indicated SR bicifadine formulations against
an exemplary Immediate Release (IR) bicifadine formulation.
[0206] In this study the following treatments were evaluated: 1)
Treatment A=IR Tablets of Example 12; 2) Treatment B=SR Tablets of
Example 2 (40% HPMC); 3) Treatment C=SR Tablets of Example 3 (60%
HPMC); 4) Treatment D=SR Tablets of Example 10 (40% HPMC and 10%
PAA); and 5) Treatment E=SR Tablets of Example 10 (PAA).
[0207] A five treatment, randomized balanced crossover study in 15
healthy volunteers examining the absorption of bicifadine HCl
sustained release tablets relative to absorption of bicifadine HCl
immediate release tablets was performed. Objectives of this study
included: [0208] To evaluate the effect of different types/levels
of matrix-forming polymers within bicifadine SR tablets. [0209] To
evaluate the release of bicifadine from exemplary SR and IR dosage
forms. [0210] To evaluate safety and tolerability of SR and IR
bicifadine oral dosage forms. Methodology:
[0211] Five-Treatment, 5-period, fasted, balanced crossover study
with a three to four day washout between each dose.
[0212] Number of Subjects:
[0213] Fifteen (15) healthy volunteers.
[0214] Diagnosis and Main Criteria for Inclusion:
[0215] Healthy male volunteers, aged greater than 18 and less than
40 years, and within .+-.10% of ideal body weight.
[0216] Duration of Treatment:
[0217] The test treatment was administered as a single oral dose.
In each treatment period the duration of stay in the clinic was
approximately 12 hours prior to dosing and 24 hours after dosing.
There were 5 treatment periods. There was a 3-4 day washout period
between each dose administration (for example, a Monday/Thursday or
equivalent dosing schedule).
[0218] The total duration of the study was approximately 28 days.
Total confinement during the study was 10 days and 10 nights.
[0219] During each day of the 28 day period the blood of each of
the patients was extracted and the concentration of bicifadine in
the blood was evaluated and analyzed and reported in ng/ml.
[0220] A sensitive and specific assay was developed and validated
for the determination of bicifadine in human plasma. Bicifadine and
an internal standard were separated from plasma by solid-liquid
extraction and the samples were analyzed by Liquid
Chromatography/Mass Spectrometry/Mass Spectrometry (LC/MS/MS) in
the APCI positive mode according to well known methods. The assays
were carried out using a 0.5 mL sampling volume of human plasma and
the validated quantitation limit of the method was 5.0 ng-mL.sup.-1
of bicifadine. A plasma standard curve was daily elaborated between
5 to 2000 ngmL.sup.-1 of bicifadine. A 11X2 weighted quadratic
regression analysis was used to determine the b coefficient,
intercept and determination coefficient. The calibration lines were
plotted on the basis of chromatographic peak area ratios
(analyte/internal standard) versus the corresponding plasma
concentrations. The concentrations are expressed as ng of
bicifadine per millilitre of plasma. Samples collected during the
study were assayed in runs composed of a calibration curve and a
batch of six quality control samples. The low relative standard
deviation and bias calculated during the within-run and between-run
assays of the validation demonstrated the fidelity of this method
for routine measurement of bicifadine in human plasma samples
collected during pharmacokinetic studies.
[0221] Heparinized plasma was obtained from non-infectious
subjects. Following selectivity testing, as a lack of any
interference has been demonstrated, plasma samples were pooled in
order to get a sufficient volume of the same matrix to spike
calibration standards and quality control samples. A sufficient
volume of drug-free heparinized control plasma was prepared for the
whole study. Calibration standards were prepared and a plasma
standard curve was performed each run of the assay. The daily
calibration curves were obtained, throughout the assay, by plotting
the chromatographic peak area ratios (compound/internal standard)
versus the known concentrations of bicifadine. A 1/X2 weighted
quadratic regression analysis was used to determine the b
coefficient, intercept and determination coefficient. These
parameters were used to calculate the concentrations of bicifadine
in quality control samples and in the biological samples collected
during the study. The plasma calibration curves realized during the
analysis of the study samples were straight lines over the studied
range of concentrations.
[0222] Liquid chromatography was performed using an ALLIANCE system
from Waters. The analytical column (50 mm.times.4.6 mm ID) was
packed with an Hypersil BDS C-18 stationary phase. The mobile phase
was a mixture of 30% acetonitrile, 35% methanol, 0.5% formic acid
filled up to 100% with water. The HPLC was connected to a PE SCIEX
API 3000 system operating in the APCI positive mode with the
following parameters: Nebulizer gas: Nitrogen (3 bar) Auxiliary
gas: Air (4 bar) Curtain gas: Nitrogen (6 bar). The API 3000 MS/MS
system was remotely controlled by a PC using NT rev 4.0 US
Operating System, and running Applied Biosystem Analyst software
rev 1.1. The MS/MS system was focused in the Multiple Reaction
Monitoring (MRM) mode to monitor the following ion transitions:
-174.2 133.1 for bicifadine; 227.9 187.2 for internal standard.
[0223] The concentration of ng/ml of drug in the plasma was plotted
against time and various features of the resulting curve were
measured and reported in table 6 as follows:
[0224] Abbreviations:
[0225] Area under the drug plasma concentration versus time
curve=AUC.sub.t
[0226] Area under the drug plasma concentration versus time curve
extrapolated to infinity=AUCO.sub.inf
[0227] The maximum measured concentration of the drug in the
plasma=Cmax.
[0228] The time at which the Cmax was measured=tmax.
[0229] Terminal elimination rate=Lamda,
[0230] Apparent half life=t1/2.
TABLE-US-00018 TABLE 6 Pharmacokinetic Comparison of Bicifadine SR
and IR Formulations TrtD- 200 mg TrtB- TrtC- Bicifadine 200 mg 200
mg SR (40% TrtE- TrtA- Bicifadine Bicifadine Methocel 200 mg 100 mg
SR (40% SR (60% K100M Bicifadine Bicifadine Methocel Methocel and
10% SR (15% PK IR tablet K100M) K100M) Carbopol) Carbopol)
Parameters N = 15 N = 15 N = 15 N = 15 N = 15 AUC.sub.inf 2621.81
.+-. 4837.19 .+-. 3506.81 .+-. 3764.95 .+-. 3160.12 .+-. (nglmLh)
838.33 1801.19t 1819.09* 1538.40 2071.62t CV % 32.0 37.2 51.9 40.9
65.6 AUC.sub.last 2578.75 .+-. 4460.36 .+-. 3293.94 .+-. 3273.54
.+-. 3308.39 .+-. (ng/mLh) 805.08 1390.56 1372.03 995.39 1573.14 CV
% 31.2 31.2 41.7 30.4 47.6 Cmax 1485.93 .+-. 546.36 .+-. 440.35
.+-. 545.58 .+-. 398.82 .+-. (ng/mL) 495.32 103.69 81.74 165.75
125.89 CV % 33.3 19.0 18.6 30.4 31.6 Tmax (h) 0.53 .+-. 1.47 .+-.
1.50 .+-. 0.80 .+-. 1.52 .+-. 0.26 0.90 0.93 0.44 0.91 CV % 47.9
61.1 61.7 55.4 59.8 Lambda.sub.z 0.41 .+-. 0.16 .+-. 0.22 .+-. 0.11
.+-. 0.20 .+-. (h.sup.-1) 0.13 0.09t 0.13* 0.08t 0.10t CV % 31.1
54.0 61.8 73.1 51.3 t.sub.1/2 (h) 1.84 .+-. 5.55 .+-. 4.74 .+-.
9.36 .+-. 4.96 .+-. 0.56 2.49t 3.38* 4.63t 3.36t CV % 30.8 44.8
71.2 49.5 67.8 * n = 14 t n = 12 tt n = 9
[0231] From the plotted plasma profiles for each of the treatments,
and the pharmacokinetic parameters reported in the table, the
tablets which contained 40% by weight hydroxymethyl cellulose had a
higher concentration of drug in the blood stream for longer periods
of time than those produced from tablets containing 60%
hydroxypropyl methylcellulose slow release polymer matrix. This was
clearly observed by comparing Treatment B with Treatment C. In
addition, Treatment B which contained 40% by weight of
hydroxypropylmethyl cellulose hydrophilic slow release polymer
matrix produced superior results with regard to the maintenance of
bicifadine in the blood stream for longer periods of time than that
produced in Treatment E by the tablets containing either
polyacrylic acid alone as the slow release polymer matrix or in a
mixture with hydroxypropyl methyl cellulose (Treatment D).
[0232] According to these findings, those skilled in the art will
readily appreciate that a wide range of alternative SR formulations
are operative within the invention, and these formulations can be
adjusted to achieve specific pharmacokinetic results that will be
desired in different embodiments of the invention, e.g., to
optimize the formulations according to such variables as pain type
(acute, chronic, or neuropathic), nature of injury/condition being
treated, and patient-specific variables such as age, weight,
condition, treatment history and response, etc.
Example 15
Preparation of Exemplary 200mg Bicifadine HCl SR Tablets
Quantitative Composition of Tablet Formulations
TABLE-US-00019 [0233] Bicifadine HCl Tablets Product 200 mg SR
Ingredients mg/tab %/tab Bicifadine HCl 200.00 44.44 Hypromellose,
USP 110.00 24.44 Bibasic calcium phosphate dihydrate, USP 135.50
30.11 Colloidal silicon dioxide, NF 2.25 0.50 Magnesium stearate
vegetable grade, NF 2.25 0.50 Total 450.00 100.00 Opadry II blue
85F90631 (3% w/w) 13.5 3.00 Purified water, USP* 54.0 --
*Evaporates during coating process
[0234] The above table details another exemplary bicifadine HCl SR
tablet formulation (hereafter referred to as "formulation M"). In
this example, bicifadine HCl is used "as is" and the potency is
based on the salt. Hypromellose (hydroxypropymethylcellulose), acts
as a rate controlling hydrophilic polymer for sustained release.
Dibasic calcium phosphate dihydrate is a carrier. Colloidal silicon
dioxide is a glidant, and magnesium stearate is a lubricant.
[0235] The tablets were manufactured using a slugging/roller
compaction (chilsonation) process. The process involves blending
the bicifadine with a portion of the colloidal silicon dioxide and
magnesium stearate and then slugging/roller compacting
(chilsonating) and milling the compacted material. It is then
blended with the remaining ingredients, compressed and film-coated
with a 20% opadry II blue suspension. The resulting tablets have a
hardness ranging from about 8 Kp to about 12 Kp.
Example 16
In Vivo Pharmacokinetic Comparison of Sustained Release (SR) and
Immediate Release (IR) Bicifadine Formulations
[0236] The present study provides an in vivo pharmacokinetic
comparison for exemplary SR and IR bicifadine formulations, based
on plasma concentration time-course analysis following
administration of the exemplary bicifadine SR and IR oral tablets
to human subjects. The data for IR pharmacokinetics were obtained
from a single-dose, balanced, crossover, placebo-controlled, study
in healthy adult male subjects administered one 100 mg immediate
release (IR) tablet (Formulation A; Example 12).
[0237] The data for SR pharmacokinetics were obtained from a
randomized, single dose, open-label, two-period, two-sequence,
two-treatment crossover bioequivalence study in 24 healthy adult
male human subjects administered two exemplary bicifadine 200 mg SR
formulations (formulation M from example 15, and a second 200 mg SR
tablet, "formulation N"). Formulation N was produced as above,
using 110 mg hydroxypropylmethylcellulose, 135.5 mg dibasic calcium
phosphate, 2.25 mg colloidal silicon dioxide, 2.25 mg magnesium
stearate, 13.5 mg Opadry II blue, and 54 mg purified water USP
(evaporates during coating process). Table 7 below provides the
comparative pharmacokinetic metrics for the IR formulation and
formulation M. FIG. 1, below, graphically depicts the
pharmacokinetic metrics for the IR formulation (triangles) in
comparison to both SR formulations (diamonds indicate formulation M
data, squared indicate formulation N data), which were shown to be
essentially bioequivalent).
TABLE-US-00020 TABLE 7 Pharmacokinetic Metrics [mean (SD)] for IR
and SR Bicifadine Formulations IR SR (Formula M) Dose Formulation
100 mg 200 mg AUC.sub.t (ng/mL*h) 5158* 4586 C.sub.max (ng/mL)
2972* 721 t.sub.max (h) 0.53 1.63 t.sub.1/2 (h) 1.84 3.74
*Dose-adjusted to 200 mg
Example 17
Analgesic Efficacy and In Vivo Pharmacokinetics of Bicifadine SR
Tablets in Acute Dental Pain Studies
[0238] A two-center, double-blind, placebo-controlled, randomized
study of subjects administered an exemplary bicifadine SR
formulation (Formulation F; Example 1) in 200 mg, 400 mg (two
tablets), and 600 mg (three tablets), or Tramadol 100 mg in the
treatment of post-operative dental pain was conducted. Healthy
adult male and female human subjects who underwent surgical
extraction of two or more impacted third molars were enrolled in
the study. Following cessation of the local anesthetic effect and
onset of pain of at least 40 mm intensity on the 100 mm VAS,
patients were randomized to into 1 of the 5 treatment arms
(n.about.108 per arm) and remained in the clinic for the subsequent
12 hours of the study. The study subjects were randomized to
receive either a single dose of: 200 mg, 400 mg or 600 mg
bicifadine SR tablets, Tramadol 100 mg, or Placebo. Analgesia
ratings were obtained over a 12 h post-dosing period. Rescue
medication (acetaminophen) was available, but no analgesia measures
were taken after the use of rescue medication by a given patient. A
subset of 150 patients provided blood samples at 0.5 hr and hourly
intervals following dosing with study medication for the purpose of
determining bicifadine levels (n=90). Bicifadine was measured with
a validated LC/MS/MS assay that had a lower limit of quantization
of 4 ng/mL and a range of 4 to 1652 ng/mL.
[0239] The main efficacy endpoints utilized in the overall study
(n.about.540) were the individual assessment of Pain Severity and
Pain Relief scores at a given time point; the derived scores (PID,
PRID, SPID, SPRID, TOTPAR), and the global improvement. The last
observation carried forward (LOCF) approach was used to estimate
change over time for those patients who used rescue medication. For
the full study efficacy evaluations, one-way analysis of covariance
with baseline pain severity as a covariate was applied. The global
tests which included all treatment arms were followed by post-hoc
comparisons of the individual treatment arms vs. placebo.
[0240] Plasma time course profiles were determined in a subset of
30 subjects (15 male/15 female) from each treatment group. These
pharmacokinetic results are presented in Table 8.
TABLE-US-00021 TABLE 8 Pharmacokinetics [mean (SD)] Dose (mg) 200
400 600 C.sub.max (ng/mL) 572 (248) 1284 (594) 1908 (476) t.sub.max
(h) 2.90 (1.56) 3.55 (1.91) 3.77 (1.55) AUC.sub..infin. (ng/mL*h)
4292 (2286) 9027 (4740) 14167 (5711) t.sub.1/2 (h) 4.44 (1.44) 4.07
(1.55) 3.57 (1.06)
[0241] Pharmacokinetic linearity of peak and total exposure was
apparent across the single dose range of 200 to 600 mg. Times to
peak exposure (t.sub.max=2.90 to 3.77 h) were slightly longer than
in previous studies, where observed t.sub.max values for a
bicifadine SR formulation ranged between 1.0-2.3 hours, although
apparent terminal half-lives were similar. This delay of t.sub.max
appears to relate to the effects of dental surgery, possibly due to
delayed gastric emptying, as a similar post-surgery t.sub.max delay
has been reported in ibuprofen-treated dental surgery patients (F.
Jamali, C. Kunz-Dober, Pain-mediated altered absorption and
metabolism of ibuprofen: An explanation for decreased serum
enantiomer concentration after dental surgery, Br. J. Clin.
Pharmacol. 47:391-396, 1999). Pain severity ratings at t.sub.max
correlated significantly with C.sub.max. Subjects with
C.sub.max>1000 ng/mL had a significantly higher odds ratio of
having a lower pain severity rating at t.sub.max. No differences in
peak (C.sub.max) or total (AUC) exposure were observed between
genders.
[0242] FIG. 2 graphically depicts mean plasma concentration time
course data on Day 4 following administration of 200 mg BID, 200 mg
TID, and 400 mg BID (multiple dose, steady-state profiles within a
dosing interval at steady state) in this acute dental pain
study.
[0243] FIG. 3 illustrates the dose-response relationship for
analgesic effects of bicifadine and tramadol relative to placebo in
this acute dental pain study.
[0244] The results of this study demonstrate a clear, statistically
significant (P<0.001) dose-response relation for SPRID-6 and
other derived analgesia scores in patients with pain following
third molar surgery. The magnitude of the effects at 400 mg and 600
mg of bicifadine were numerically comparable to that of 100 mg
tramadol and were statistically superior to placebo. Bicifadine at
200 mg was better than placebo on some measures, but on all
analgesia measures the effects were lower than that of 400 mg or
600 mg, and, as such 200 mg represented a minimally effective dose
in this study.
[0245] The relationship between mean pain relief ratings (PRR) and
mean plasma bicifadine levels was determined at three exemplary
plasma level ranges: between 0-500 ng/ml, 500-1000 ng/ml, and
>1000 ng/ml, respectively. A clear positive relationship was
observed across 3 ranges of bicifadine levels. In particular,
bicifadine plasma concentrations in the >1000 ng/ml range were
associated with a PR score approximately 3 times as high as plasma
concentrations in the 0-500 ng/ml range (p<0.001, Hierarchical
Linear Model analysis).
[0246] The probability of treatment response as a function of
bicifadine blood concentration levels was also determined.
Association between the probability of treatment response and
bicifadine blood concentration levels was investigated with the
widely known Generalized Estimating Equation (GEE) approach. For
the purpose of the GEE analyses described here, bicifadine blood
concentration was treated as a continuous independent (predictor)
variable. Treatment (analgesic) response served as a dichotomous
(yes, no) dependent variable in the GEE model. In particular,
treatment response for each individual patient for each of the time
points was defined as a Pain Relief Rating of 3 or more (range
0-4). Results of the GEE analyses indicated that the association
between bicifadine plasma levels and the likelihood of treatment
response reached significance (p=0.006; Odds Ratio of Response for
an increase of 500 ng/ml in bicifadine blood levels was 1.59).
[0247] In the pharmacokinetic portion of this study that employed
90 patients, there was a clear dose proportional relationship
between bicifadine dose and AUC, a relationship demonstrated in
prior pharmacokinetic studies conducted in smaller numbers of
normal volunteers.
[0248] The foregoing studies demonstrate a positive dose-dependent
relationship for both the pharmacokinetics (AUC, Cmax) of
bicifadine and the pharmacodynamic measures of efficacy for
treating acute dental pain. Plasma bicifadine levels >1000 ng/ml
were associated with the greatest pain relief. Drug levels between
500-1000 ng/ml were associated with significant analgesic efficacy.
Lower plasma drug levels of 500 ng/ml or less were not associated
with significant analgesic effects in this acute dental pain study.
In respect to analyses performed on individual patients identified
as responders or nonresponders to bicifadine, these distinct
categories of subjects also showed a significant relationship with
plasma drug levels, with responders exhibiting significantly higher
blood levels of bicifadine than nonresponders.
Example 18
Comparative Side Effect Profiles of Sustained Release and Immediate
Release Bicifadine Formulations
[0249] A side-by side comparison of side effect profiles of
sustained release SR bicifadine formulations (side effect data from
studies using SR formulations F and M from examples 1 and 15 were
pooled) and an exemplary immediate release (IR) bicifadine
formulation (Formulation A; example 12) was conducted. These
comparisons were performed using 5 bicifadine dose levels (0-149
mg/day, 150-399 mg/day, 400-599 mg/day, 600-799 mg/day and >=800
mg/day) on 7 parameters (Euphoria, Dizziness, Headache, Mydriasis,
Nausea, Sleepiness/Drowsiness, and Vomiting) using the Fisher exact
test, according to generally known methods.
[0250] The results of the IR vs SR comparisons for different dose
ranges of bicifadine are shown in Table 9 below.
TABLE-US-00022 TABLE 9 Side Effect Profiles of Bicifadine SR and IR
Formulations Event Dosage Form Placebo 400-599 mg 600-799 mg
.gtoreq.800 mg Euphoria IR (1.7%) (80.0%) (63.6%) (90.0%) SR (0.0%)
(1.3%) (4.6%) (2.0%) p-Value 0.217 <0.001 <0.001 Dizziness IR
(0.0%) (60.0%) (60.0%) (70.0%) SR (7.3%) (1.3%) (11.7%) (7.0%)
p-Value <0.001 <0.001 0.0119 <0.001 Sleepiness/ IR (0.0%)
(80.0%) (9.1%) (10.0%) Drowsiness SR (5.3%) (4.2%) (10.7%) (3.3%)
p-Value <0.001 <0.001 1.0000 0.3075 Nausea IR (0.0%) (20.0%)
(18.2%) (80.0%) SR (14.9%) (24.7%) (32.5%) (10.2%) p-Value
<0.001 1.0000 0.5119 <0.001 Mydriasis IR (0.0%) (90.0%)
(30.0%) (100%) SR (0.3%) (4.9%) (11.8%) (0.4%) p-Value 1.0000
<0.001 0.1142 <0.001 Headache IR (0.0%) (20.0%) (27.3%) SR
(8.5%) (10.9%) (13.2%) p-Value <0.001 0.3082 0.1810
[0251] The data presented in Table 9 clearly demonstrate that for
similar daily doses of bicifadine SR and IR formulations, there is
a marked and unexpected decrease in the occurrence of specific
adverse events elicited by the SR formulation in comparison to the
IR formulation.
Example 19
Therapeutic Efficacy of a Reduced Bicifadine Dosing Regimen to
Treat Chronic Pain
[0252] The present study evaluated the therapeutic efficacy of a
reduced dosing regimen employing bicifadine in a bi-daily (BID)
dosing protocol to treat chronic low back pain (CLBP). More than
800 study subjects were recruited in this study, and a subset of
these subjects was administered 400 mg of a sustained release oral
dosage form (formula M; example 15) of bicifadine BID to evaluate
the long-term analgesic efficacy of bicifadine for treating CLBP.
As an efficacy comparator for these studies, a second subset of the
study subjects was treated according to the standard of care (SOC)
for CLBP treatment, which provided a concurrent control for
efficacy as well as spontaneous occurrence of serious adverse
events. The following outcome measures were assessed in the
study:
[0253] 1. Pain Severity Rating (VAS);
[0254] 2. SF-McGill Pain Questionnaire (SF-MPQ);
[0255] 3. Roland-Morris Disability Rating;
[0256] 4. Short-Form 36 (SF-36) Health Survey
[0257] 5. Incidence of Discontinuation due to lack of efficacy;
and
[0258] 6. Time to Discontinuation due to lack of efficacy.
[0259] Inclusion criteria for study subjects, as selected for other
studies herein, included the following: Subjects were at least 18
years of age. If subject was female and of childbearing potential,
the subject had to have a negative serum pregnancy test during the
screening period. Subjects were required to have drug and alcohol
toxicology screening results during the screening period. Subjects
exhibited lower back pain that was either localized to the lower
back, or radiating into the lower extremity (assessed as Class 1,
Class 2, or Class 3 according to the widely known and practiced,
Quebec Task Force Classification for Spinal Disorders. Quebec
Classes 4, 5 and 8 were exclusionary, i.e., study subjects were
without detectable weakness by neurological examination, and
without spinal instability or acute fracture. Subjects had on
average required daily analgesic medication for low back pain for
at least 3 months immediately prior to the screening period, and
had a score of at least 10 on the 24-point Roland-Morris Disability
Questionnaire, and a Pain Severity Rating (PSR) of at least 40 mm
on a 100 mm Visual Analog Scale (VAS), at the baseline visit.
[0260] Other exclusionary criteria in this study included: Low back
pain due to acute fracture, infection, severe osteoporosis,
malignancy, marked scoliosis, or severe congenital malformation
such as spina bifida; Receipt of an epidural injection of
corticosteroid in the lower back within 1 month prior to the
baseline visit; Use of any antidepressant for pain or sleep
(including SSRIs or SNRIs), anti-epileptic, or muscle relaxant, or
receipt of transcutaneous electrical nerve stimulation,
chiropractic adjustment, or acupuncture within 3 weeks prior to the
baseline visit; Use of any antidepressant (including SSRIs or
SNRIs) for depression within 3 months prior to the baseline visit;
Use of any opioid analgesic or benzodiazepine (or other
sedative-hypnotic) within 2 weeks prior to the baseline visit; Use
of any NSAID (except aspirin <81 mg per day or <325 mg every
other day for cardiac prophylaxis and except ibuprofen) or any
non-opioid analgesic (except acetaminophen) within 1 week, or
acetaminophen or ibuprofen within 60 hours, prior to the baseline
visit; Active malignancy of any type or history of a malignancy
within 5 years prior to the first dose of study medication
(patients with treated localized basal or squamous cell carcinoma
of the skin within 5 years are permitted); Active GI disease
(including any GI surgery that, in the Investigator's opinion,
would interfere with the absorption of the study medication), or a
chronic or acute renal or hepatic disorder; Mental instability,
known substance abuse, history of clinically significant depression
or alcoholism, or incapacity of being compliant with the
requirements of the study; Any clinically significant
cardiovascular, renal, endocrine, hepatic, immunologic,
respiratory, neurologic, gastrointestinal, psychiatric, or
hematologic disease, or any underlying serious medical condition
that would preclude patient's participation in the study; and,
other standard, relevant exclusion criteria.
[0261] Patients who qualified for enrollment into the study
completed the PSR test, Roland-Morris Disability Questionnaire,
Short Form McGill Pain Questionnaire (SF-MPQ) and the SF-36 quality
of life survey at the baseline visit and at various time points
throughout the study.
[0262] Study subjects were randomized on a 25:6 basis to receive
either bicifadine 400 mg BID or SOC treatment, respectively. SOC
treatment was provided as any appropriate pharmacological analgesic
treatment selected by the investigator based on the subjects'
baseline and ongoing presentation. Subjects were permitted to
reduce the dose for tolerability reasons, first to bicifadine 300
mg BID, and then, if necessary, to bicifadine 200 mg BID.
[0263] Summary statistics, including observed means and standard
deviations along with mean change from baseline were summarized by
visit for each outcome measure. Incidence of discontinuation due to
lack of efficacy and its 95% confidence interval were likewise
calculated. The median and its 95% confidence interval and a
Kaplan-Meier plot were provided for Time to Discontinuation due to
lack of efficacy and other reasons. In addition, analyses for the
mean change from baseline at each visit were carried out using
paired t-test. All statistical comparisons were made at a
comparison-wise error rate of 0.05% (two-sided).
[0264] FIG. 4 presents the VAS pain score results from the
foregoing CLBP studies. These data show that bicifadine is
surprisingly effective in a reduced, bi-daily (BID) dosing regimen
to achieve sustained relief of chronic pain exemplified by CLBP.
The therapeutic efficacy of BID-dosed bicifadine in these CLBP
clinical studies as determined from pain relief data was comparable
to that of standard of care (SOC) treatment over the 4.5 month
period of the study. In addition, the therapeutic efficacy of
BID-dosed bicifadine in these CLBP clinical studies was
demonstrated on the basis of improved functional/activity results,
which were also comparable to those observed among SOC-treated
subjects in the study.
Example 20
Therapeutic Efficacy of Bicifadine for Treating Functional
Disabilities in Human Subjects Associated with Pain
[0265] The present study evaluated the therapeutic efficacy of
bicifadine to treat and/or reduce disability and enhance functional
and activity performance in human subjects presenting with
pain-associated disability. The study followed the foregoing study
design described in Example 19 involving administration of
bicifadine to patients presenting with Chronic Low Back Pain
(CLBP). In the instant example, the efficacy of bicifadine to treat
disability and enhance functional and activity performance in these
bicifadine-treated CLBP subjects was particularly pronounced in a
subset of patients presenting with more severe disability
associated with their CLBP.
[0266] In a more highly disabled, poorly functional cohort of
patients, characterized by having an initial Roland-Morris
Disability Questionnaire (RDQ) score of greater than 17, the
effects of bicifadine for reversing disabilities and enhancing
functional/activity performance in treated subjects compared to
placebo-treated subjects were significant and substantial.
[0267] As shown in FIG. 5, for patients with moderate to severe
impairment at baseline (i.e., subjects presenting with an RDQ>17
at baseline), receiving 400-800 mg/day (i.e., 200, 300 or 400 mg
twice daily) disability scores on the RDQ were significantly
decreased compared to similarly qualified, placebo-treated
subjects. As the data are presented in FIG. 5, patients in the
bicifadine-treated and placebo-treated populations were identified
as "responders" if their RDQ score showed a 50% or greater
improvement from baseline (e.g., a reduction in RDQ from a baseline
of 18, to a last observed datum of 9). In the placebo-treated
subjects, less than 15% of the patients were classified as
"responders", whereas roughly twice this percentage of
bicifadine-treated subjects exhibited a 50% or greater reduction in
RDQ scores compared to baseline.
[0268] Additional analyses identified another major subgroup of
patients (in addition to the moderate to severely impaired subgroup
noted above) in which the effectiveness of bicifadine was
substantial--patients with chronic low back pain along with pain
radiating down the leg (sciatica). Patients with low back pain who
also had pain radiating down the leg showed a placebo pain response
rate that was approximately half of that in patients with low back
pain alone. Patients with low back pain and radiating pain were two
times more responsive to treatment with bicifadine than patients
with only localized back pain and showed an 11 mm improvement in
VAS pain score compared to placebo.
[0269] The efficacy of bicifadine for reducing pain-related
disability and enhancing functionality in CLBP subjects illustrates
a separate and distinct therapeutic indication for this drug.
Patients with moderate to severe disability due to their back pain
(e.g. limited ability to walk up stairs, bend over, lift objects,
etc.) had only about one third of the placebo response of patients
with mild to moderate disability. The patients with moderate to
severe disability also were substantially more responsive to
treatment with bicifadine, as described above.
[0270] Although the disability-reversing and function-enhancing
effects of bicifadine are distinct from pain-relief results for the
drug, these pain relief results were also substantial and
significant for the moderate to severely disabled cohort of CLBP
patients. As shown in FIG. 6, the VAS pain scores in moderate to
severely disabled CLBP patients (presenting with a baseline RDQ
score greater than 17) were also significantly reduced by
bicifadine treatment compared to placebo. In fact, the percentage
of bicifadine-treated subjects in the moderate to severely disabled
cohort that showed at least a 50% reduction in VAS scores was
roughly three times the percentage of placebo-treated subjects in
the moderate to severely disabled cohort that reported this level
of reduction in VAS scores (FIG. 6).
[0271] Although the foregoing invention has been described in
detail by way of example for purposes of clarity of understanding,
persons of ordinary skill in the art will understand that certain
changes and modifications may be practiced within the scope of the
appended claims which are presented by way of illustration not
limitation. In this context, the invention is not limited to the
particular formulations, processes, and materials disclosed herein,
as such formulations, process steps, and materials may vary
somewhat. Also, the terminology employed herein is used for
describing particular embodiments only, and is not intended to be
limiting of the invention embodied in the claims. Various
publications and other reference information have been cited within
the foregoing disclosure for economy of description. Each of these
references is incorporated herein by reference in its entirety for
all purposes. It is noted, however, that the various publications
discussed herein are incorporated solely for their disclosure prior
to the filing date of the present application, and the inventors
reserve the right to antedate such disclosure by virtue of prior
invention.
* * * * *
References