Note: Descriptions are shown in the official language in which they were submitted.
CA 02530904 2012-12-12
72859-361
-1-
PHARMACEUTICAL AGENTS FOR THE TREATMENT OF PAIN ASSOCIATED
WITH SPINAL CORD INJURY
=
This invention relates to a method of treating
pain associated with spinal cord injury with (S)-(+)-3-
(aminomethyl)-5-methylhexanoic acid (pregabalin).
BACKGROUND OF THE INVENTION
Pregabalin US)-(+)-3-(aminomethyl)-5-
methylhexanoic acid) is a compound that exhibits activity as
an alpha2delta,ligand (a28 ligand). As such, it has
affinity for the a25 subunit of a calcium channel.
Pregabalin and methods of synthesizing it are
referred to in U.S. Patent 6,197,819, which issued on
March 6, 2001. Methods of treating pain using pregabalin
are referred to in U.S. Patent 6,001,876, which issued on
December 14, 1999. Other pharmaceutical uses for pregabalin
and methods for synthesizing pregabalin, as well as
pharmaceutical formulations of pregabalin, are referred to
in the following patents and patent applications: World
Patent Application WO 99/59572, which was published on
November 25, 1999; World Patent Application WO 99/59573,
which was published on November 25, 1999; World patent
Application WO 01/55090, which was published on
August 2, 2001; World Patent Application WO 04/054559, which
was published on July 1, 2004; U.S. Patent 5,629,447, which
issued on May 13, 1997; U.S. Patent 5,616,793, which issued
on April 1, 1997; U.S. Patent 5,637,767, which issued on
June 10, 1997; U.S. Patent 6,046,353, which issued on
April 4, 2000; and U.S. Patent 5,840,956, which issued on
November 24, 1998.
CA 02530904 2005-12-20
50190-174
-2-
Pregabalin is structural analogue of the mammalian
neurotransmitter, GABA, that is being investigated for
various indications, including neuropathic pain. Pregabalin
is an alpha-2delta (a28) ligand that has analgesic,
anxiolytic, and antiepileptic activity. Alpha-2-delta is an
auxiliary protein associated with voltage-gated calcium
channels. Pregabalin binds potently to the a23 subunit of
such calcium channels. Potent binding at this site reduces
stimulus induced calcium influx at nerve terminals and
reduces the release of several neurotransmitters, including
glutamate, noradrenaline, and substance P. Binding to the
alpha-2-delta is required for the full pharmacologic
activity in animal models of neuropathic pain, epilepsy and
anxiety. Pregabalin is inactive at GABAA and GABAB
receptors, it is not converted metabolically into GABA or a
GABA antagonist, and it does not alter GABA uptake or
degradation.
SUMMARY OF THE INVENTION
Pregabalin has been demonstrated to have
particular efficacy in treating pain associated with spinal
cord injury.
This invention relates to a method of treating
pain associated with spinal cord injury in a mammal,
comprising administering to a mammal, preferably a human, in
need of such treatment a therapeutically effective amount of
pregabalin or a pharmaceutically acceptable salt thereof.
This invention also relates to a pharmaceutical
composition for treating pain associated with spinal cord
injury in a mammal, preferably a human, comprising a
therapeutically effective amount of pregabalin, or a
CA 02530904 2005-12-20
50190-174
-3-
pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier.
This invention also relates to the use of
pregabalin, or a pharmaceutically acceptable salt thereof,
in the manufacture of a medicament for the treatment of pain
associated with spinal cord injury in a mammal, preferably a
human.
The term "treating", as used herein, refers to
reversing, alleviating, inhibiting the progress of, or
preventing the disorder or condition to which such term
applies, or preventing one or more symptoms of such
condition or disorder. The term "treatment", as used
herein, refers to the act of treating, as "treating" is
defined immediately above.
The term "therapeutically effective amount", as
used herein, refers to an amount of pregabalin that is
effective, when administered in a treatment regimen as
described in this document, in treating pain associated with
spinal cord injury.
Pregabalin is an amino acid and is therefore
capable of forming a wide variety of both base and acid
addition salts. Pregabalin is capable of forming salts with
various inorganic and organic acids. Although such salts
must be pharmaceutically acceptable for administration to
animals, it is often desirable in practice to initially
isolate pregabalin from the reaction mixture in which it was
synthesized as a pharmaceutically unacceptable salt and then
simply convert such salt to the free base compound by
treatment with an alkaline reagent, and then convert the
pregabalin free base to a pharmaceutically acceptable acid
addition salt. The acid addition salts of pregabalin are
readily prepared by treating pregabalin with a substantially
CA 02530904 2005-12-20
50190-174
-4-
equivalent amount of the chosen mineral or organic acid in
an aqueous solvent or in a suitable organic solvent, such as
methanol or ethanol. Upon careful evaporation of the
solvent, the desired solid salt is readily obtained. The
acids which are used to prepare the pharmaceutically
acceptable acid addition salts pregabalin are those that
form nontoxic salts derived from inorganic acids such as he
following salts: sulfate, pyrosulfate, bisulfate, sulfite,
bisulfite, nitrate, phosphate, monohydrogenphosphate,
dihydrogenphosphate, metaphosphate, pyrophosphate, chloride,
bromide, iodide, acetate, trifluoroacetate, propionate,
caprylate, isobutyrate, oxalate, malonate, succinate,
suberate, sebacate, fumarate, maleate, mandelate, benzoate,
chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,
benzenesulfonate, toluenesulfonate, phenylacetate, citrate,
lactate, malate, tartrate, methanesulfonate, and the like.
Also contemplated are salts of amino acids such as arginate
and the like and gluconate, galacturonate (see, for example,
Berge S.M. et al., "Pharmaceutical Salts," J. of Pharma.
Sci., 1977;66:1).
Pregabalin is also capable of forming
pharmaceutically acceptable base addition salts. Such salts
can be prepared by contacting the free acid form of the
compound with a nontoxic metal cation such as an alkali or
alkaline earth metal cation, or an amine, especially an
organic amine. Examples of suitable metal cations include
sodium cation (Na+), potassium cation (K+), magnesium cation
(Mg2+), calcium cation (Ca2+), and the like. Examples of
suitable amines are N,W-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, dicyclohexylamine,
ethylenediamine, N-methylglucamine, and procaine (see, for
example, Berge, supra., 1977).
CA 02530904 2005-12-20
50190-174
-5-
DETAILED DESCRIPTION OF THE INVENTION
The method of this invention is practiced by
administering pregabalin, or a pharmaceutically acceptable
salt thereof, in an amount that is therapeutically effective
to treat pain associated with spinal cord injury. Typical
dosages will range from about 10 to about 5000 mg/day for an
adult subject of normal weight. A daily dosage of about
1 mg/kg to about 50 mg/kg is preferred. In a clinical
setting, regulatory agencies such as, for example, the Food
and Drug Administration ("FDA") in the U.S. may require a
particular therapeutically effective amount.
In determining what constitutes an effective
amount, i.e., a therapeutically effective amount, of
pregabalin, or a pharmaceutically acceptable salt thereof,
for treating pain associated with spinal cord injury, a
number of factors will generally be considered by the
medical practitioner or veterinarian in view of the
experience of the medical practitioner or veterinarian,
published clinical studies, the subject's age, sex, weight
and general condition, as well as the severity of the spinal
cord injury pain being treated, and the use of other
medications, if any, by the subject. As such, the
administered dose may fall within the ranges or
concentrations recited above, or may vary outside, i.e.,
either below or above, those ranges depending upon the
requirements of the individual subject, the severity of the
condition being treated, and the particular therapeutic
formulation being employed. Determination of a proper dose
for a particular situation is within the skill of the
medical or veterinary arts. Generally, treatment may be
initiated using smaller dosages of pregabalin, or a
pharmaceutically acceptable salt thereof, that are less than
optimum for a particular subject. Thereafter, the dosage
CA 02530904 2005-12-20
50190-174
-6-
can be increased by small increments until the optimum
effect under the circumstance is reached. For convenience,
the total daily dosage may be divided and administered in
portions during the day, if desired.
Pharmaceutical compositions of pregabalin, or a
pharmaceutically acceptable salt thereof, are produced by
formulating the active compound in dosage unit form with a
pharmaceutical carrier. Some examples of dosage unit forms
are tablets, capsules, pills, powders, aqueous and
nonaqueous oral solutions and suspensions, and parenteral
solutions packaged in containers containing either one or
some larger number of dosage units and capable of being
subdivided into individual doses.
Some examples of suitable pharmaceutical carriers,
including pharmaceutical diluents, are gelatin capsules;
sugars such as lactose and sucrose; starches such as corn
starch and potato starch; cellulose derivatives such as
sodium carboxymethyl cellulose, ethyl cellulose, methyl
cellulose, and cellulose acetate phthalate; gelatin; talc;
stearic acid; magnesium stearate; vegetable oils such as
peanut oil, cottonseed oil, sesame oil, olive oil, corn oil,
and oil of theobroma; propylene glycol, glycerin; sorbitol;
polyethylene glycol; water; agar; alginic acid; isotonic
saline, and phosphate buffer solutions; as well as other
compatible substances normally used in pharmaceutical
formulations.
The compositions to be employed in the invention
can also contain other components such as coloring agents,
flavoring agents, and/or preservatives. These materials, if
present, are usually used in relatively small amounts. The
compositions can, if desired, also contain other therapeutic
CA 02530904 2005-12-20
50190-174
-7-
agents commonly employed to treat the disorder or condition
being treated.
The percentage of pregabalin in the foregoing
compositions can be varied within wide limits, but for
practical purposes it is preferably present in a
concentration of at least 10% in a solid composition and at
least 2% in a primary liquid composition. The most
satisfactory compositions are those in which a much higher
proportion of pregabalin is present, for example, up to
about 95%.
Preferred routes of administration of pregabalin
and its pharmaceutically acceptable salt are oral routes or
parenteral routes such as intravenous, intramuscular, or
subcutaneous injection as a liquid formulation.
For example, a useful intravenous dose is
between 5 and 50 mg, and a useful oral dosage is
between 20 and 800 mg.
A clinical study was conducted to evaluate the
efficacy of pregabalin relative to placebo for the treatment
of spinal cord injury pain in men and women with a diagnosis
of nonprogressive spinal cord injury (paraplegia or
tetrapiegia) and chronic central neuropathic pain.
Study Design
The study was a randomized, double-blind, placebo-
controlled, parallel-group, multicenter study with 2 phases:
(1) a 1-week baseline phase, and (2) a 12-week double-blind
treatment phase. Eligible subjects completed a 1-week
baseline phase and then were randomly assigned to 1 of 2
treatment groups in a 1:1 ratio: (1) escalating doses of
pregabalin 150, 300, and 600 mg/day administered BID which
CA 02530904 2005-12-20
50190-174
-8-
were adjusted based on subject response and tolerability at
weekly intervals; or (2) placebo administered BID, following
the same blinded adjustment schedule as the pregabalin
group, for the 12-week double-blind treatment. The daily
dosage of study medication was adjusted for the first 3
weeks, and then remained stable for the rest of the study.
Dosage and Administration
Subjects were to take 150 mg/day (75 mg BID) of
pregabalin or the placebo equivalent during Days 1-7. The
daily dosage was to be adjusted (based on response and
tolerability) to 300 mg/day (150 mg BID) during Days 8-14.
From Days 15-84, the target daily dosage was 600 mg/day
(300 mg BID). Subjects who could not tolerate the target
dosage were allowed to have their dosage reduced. The
details regarding dosage reductions are described below.
During Week 2, subjects who experienced
intolerable adverse events were allowed to reduce the target
daily dosage from 300 mg/day to 150 mg/day as directed by
the investigator. During Week 3, subjects who experienced
intolerable adverse events during the week the dose was
increased were allowed to reduce their target dose
by 1 level (e.g., 600 mg/day to 300 mg/day, or 300 mg/day
to 150 mg/day) as directed by the investigator. Subjects
with dosage reductions were to be maintained on the reduced
dosage for the remainder of the study.
Beginning at Visit 3 (end of Week 1), subject
whose pain was reduced by at least 50% during the preceding
week could have been maintained on the same dosage of study
medication for the remainder of the study or could have been
further adjusted to achieve further pain reduction as
directed by the investigator. The same applied to Visit 4
CA 02530904 2005-12-20
50190-174
-9-
(end of Week 2). The subject's daily dosage was to have
been stabilized by no later than Visit 5 (end of Week 3).
Efficacy Results
A total of 136 subjects were randomly assigned to
a double-blind treatment group, took at least 1 does of
study medication, and had at least 1 post-randomization
efficacy evaluation on any efficacy scale. These 136
subjects (67 in the placebo group and 69 in the pregabalin
group) were included in the intent-to-treat population for
efficacy analyses (one subject in the pregabalin group
discontinued due to an adverse event after 3 days of double-
blind treatment, had no post-baseline efficacy data, and was
excluded from the intent-to-treat population).
Pain was reported in this study on a 0 to 10
numerical scale (0 indicating no pain, 10 indicating worst
possible pain). Pain scores for each week (7 days) were
averaged to obtain the mean pain scores. Endpoint mean pain
scores were computed based on the last 7 days (or fewer if 7
postbaseline entries were not available) of treatment
regardless of when the subject exited the study. A negative
change in mean pain score at each week and at endpoint
indicates a reduction (i.e., improvement) in mean pain
score.
Table I presents the results of the ANCOVA to
compare the endpoint mean pain scores of the placebo and
pregabalin groups. At baseline, the LS mean pain scores
were comparable (6.615 in the placebo group vs. 6/430 in the
pregabalin group). At endpoint, the pregabalin group had a
larger reduction from baseline in mean pain score than the
placebo group (LS mean change, -0.433) in the placebo group
vs. -1.967 in the pregabalin group). Results of the
analysis of covariance (ANCOVA) model showed that the
CA 02530904 2005-12-20
50190-174
-10-
treatment difference (1.533 [S.E. 0.312], 95% CI [0.916,
2.150] was statistically significant in favor of pregabalin
(p<0.001).
Table I. Primary Efficacy Analysis: Mean Pain Score at
Baseline and Endpoint Intent-to-Treat Population
Treatment Difference (Placebo-Pregabalin)a
Placebo Pregabalin Estimate (S.E.) 95% Cl
p-value
Baseline
67 69
Mean (SD) 6.727 (1.446) 6.540 (1.253)
LS Mean (S.E.) 6.615 (0.174) 6.430 (0.170) .185
(0.230) -0.27, 0.641 0.423
Endpoint
67 69
Mean Change -0.454 -1.917
LS Mean (S.E.) 6.199 (0.235) 4.665 (0.231)
LS Mean Change -0.433 -1.967 1.533 (0.312) 0.916,
2.150 <0.001
LS Mean = Least squares mean; S.E. Standard error; LS Mean Change = Least
square mean of change from baseline;
SD=Standard deviation; Mean Change = Mean change from baseline, 95% Cl = 95%
Confidence Interval.
a Placebo - Pregabalin difference in LS Means from the ANCOVA Model with
Treatment, Center, and Baseline (Baseline not
included at baseline time point) as factors.
Pregabalin was shown to be superior to placebo
with respect to pain reduction in subjects with central
neuropathic pain based on the subjects' mean weekly pain
scores. The differences between groups were apparent as
early as Week 1 (at a daily dosage of 150 mg/day) and were
sustained for the duration of the study. These findings
were consistently supported by other measures of pain
reduction. Pregabalin was also shown to be superior to
placebo with respect to alleviating sleep interference due
to pain. Supporting data are listed below.
= At endpoint, the pregabalin group had a
significantly greater reduction in mean pain score from
baseline (LS mean change, -0.433 in the placebo group
vs. -1.967 in the pregabalin group). Treatment differences
with respect to reductions in mean pain scores were apparent
CA 02530904 2005-12-20
50190-174
-11-
as early as Week 1 and a statistically significant treatment
difference was maintained at each week, through Week 12 of
double-blind treatment.
= The proportion of subjects who had a..30%
reduction in mean pain score from baseline to endpoint was
significantly higher in the pregabalin group (42.0%)
compared to the placebo group (16.4%). Similarly, the
proportion of subjects who had a ?_50% reduction in mean pain
score from baseline to endpoint was significantly higher in
the pregabalin group (21.7%) compared to the placebo
group (7.5%).
= Significantly greater reductions in pain-related
sleep interference scores occurred in the pregabalin group
than in the placebo group (-1.478 versus -0.109). The
treatment difference in favor of pregabalin was apparent at
Week 1 and remain statistically significant at each week,
through Week 12 of treatment.
= At endpoint, there were statistically
significant treatment differences in favor of pregabalin
with respect to the sensory, affective, and total scores of
the Short Form McGill Pain Questionaire (SF-MPQ).
= Greater improvements in the SF-MPQ PPI index and
Visual Analog Scale (VAS) of the SF-MPQ scores were apparent
in the pregabalin group compared to the placebo group at
endpoint. Statistically significant treatment differences
in favor of pregabalin were apparent at all but 1 time point
(Week 12) measured for the PPI index.
= At endpoint, the change from baseline in the
Medical Outcomes Study (MOS) Sleep Questionaire sleep
disturbance score (-3.937 in the placebo group and -17.218
in the pregabalin group), overall sleep problems score
CA 02530904 2005-12-20
50190-174
-12-
(-3.001 in the placebo group and -9.405 in the pregabalin
group), and sleep quantity (0.017 in the placebo group and
0.582 in the pregabalin group) were statistically
significant in favor of pregabalin. The treatment
differences at endpoint with respect to the MOS measures of
snoring, awaken short of breath, sleep adequacy, and
somnolence were not statistically significant.
