U.S. patent application number 15/290676 was filed with the patent office on 2017-04-06 for pharmaceutical compositions of spiro-oxindole compound for topical administration and their use as therapeutic agents.
The applicant listed for this patent is Xenon Pharmaceuticals Inc.. Invention is credited to Haigang Chen, Conrad Stewart Winters, Meidong Yang.
Application Number | 20170095449 15/290676 |
Document ID | / |
Family ID | 43981337 |
Filed Date | 2017-04-06 |
United States Patent
Application |
20170095449 |
Kind Code |
A1 |
Winters; Conrad Stewart ; et
al. |
April 6, 2017 |
PHARMACEUTICAL COMPOSITIONS OF SPIRO-OXINDOLE COMPOUND FOR TOPICAL
ADMINISTRATION AND THEIR USE AS THERAPEUTIC AGENTS
Abstract
This invention is directed to pharmaceutical compositions for
topical administration to a mammal, wherein the pharmaceutical
compositions comprise a spiro-oxindole compound, as an enantiomer,
a racemate or a non-racemic mixture, or a pharmaceutically
acceptable salt thereof. These pharmaceutical compositions are
useful for the treatment and/or prevention of sodium
channel-mediated diseases or conditions.
Inventors: |
Winters; Conrad Stewart;
(Vancouver, CA) ; Yang; Meidong; (Playa Del Rey,
CA) ; Chen; Haigang; (Edina, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Xenon Pharmaceuticals Inc. |
Burnaby |
|
CA |
|
|
Family ID: |
43981337 |
Appl. No.: |
15/290676 |
Filed: |
October 11, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13580129 |
Oct 30, 2012 |
9504671 |
|
|
PCT/US11/26359 |
Feb 25, 2011 |
|
|
|
15290676 |
|
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|
61308759 |
Feb 26, 2010 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/407 20130101;
A61P 19/02 20180101; A61K 9/0014 20130101; A61K 47/10 20130101;
A61P 1/04 20180101; A61P 43/00 20180101; A61K 9/06 20130101; A61P
13/10 20180101; A61P 25/02 20180101; A61P 25/06 20180101; A61P
17/04 20180101; A61P 29/00 20180101; A61P 25/00 20180101; A61K
47/14 20130101; A61P 25/04 20180101 |
International
Class: |
A61K 31/407 20060101
A61K031/407; A61K 47/14 20060101 A61K047/14; A61K 47/10 20060101
A61K047/10; A61K 9/00 20060101 A61K009/00; A61K 9/06 20060101
A61K009/06 |
Claims
1.-20. (canceled)
21. A method of treating, preventing or ameliorating a sodium
channel-mediated disease or a condition in a mammal, wherein the
method comprises topically administering to the mammal in need
thereof a therapeutically effective amount of a pharmaceutical
composition comprising two or more pharmaceutically acceptable
excipients and a therapeutically effective amount of a
spiro-oxindole compound having the following formula: ##STR00007##
or a pharmaceutically acceptable salt thereof, wherein each
pharmaceutically acceptable excipient is present in a concentration
of from about 0.01% w/w to about 99% w/w, wherein the
pharmaceutically acceptable excipients are selected from one or
more solvents, one or more penetration enhancing agents, one or
more stiffening agents, one or more ointment bases and, optionally,
one or more antioxidants, and wherein a solvent is selected from
PEG 400 or PEG 3350, a penetration enhancing agent is selected from
diethylene glycol monoethyl ether, oleyl alcohol, or isopropyl
myristate, a stiffening agent is stearyl alcohol, an ointment base
is selected from PEG 400 or PEG 3350, and the antioxidant, if
present, is butylated hydroxytoluene (BHT), and wherein said
disease or condition is selected from the group consisting of
neuropathic pain, inflammatory pain, visceral pain, post-herpetic
neuralgia, cancer pain, chemotherapy pain, trauma pain, surgical
pain, post-operative pain, pruritis, trigeminal neuralgia, familial
erythromelalgia, primary erythromelalgia, familial rectal pain,
childbirth pain, labor pain, neurogenic bladder, ulcerative
colitis, chronic pain, persistent pain, peripherally mediated pain,
centrally mediated pain, chronic headache, migraine headache, sinus
headache, tension headache, phantom limb pain, peripheral nerve
injury, and combinations thereof.
22. The method of claim 21, wherein said disease or condition is
selected from the group consisting of neuropathic pain,
inflammatory pain, post-herpetic neuralgia, trigeminal neuralgia,
familial erythromelalgia, primary erythromelalgia and combinations
thereof.
23. The method of claim 21, wherein the mammal is a human.
24. A method of treating pain through inhibition of ion flux
through a voltage-dependent sodium channel in a mammal, wherein the
method comprises topically administering to the mammal in need
thereof a therapeutically effective amount of a pharmaceutical
composition comprising two or more pharmaceutically acceptable
excipients and a therapeutically effective amount of a
spiro-oxindole compound having the following formula: ##STR00008##
or a pharmaceutically acceptable salt thereof, wherein each
pharmaceutically acceptable excipient is present in a concentration
of from about 0.01% w/w to about 99% w/w, wherein the
pharmaceutically acceptable excipients are selected from one or
more solvents, one or more penetration enhancing agents, one or
more stiffening agents, one or more ointment bases and, optionally,
one or more antioxidants, and wherein a solvent is selected from
PEG 400 or PEG 3350, a penetration enhancing agent is selected from
diethylene glycol monoethyl ether, oleyl alcohol, or isopropyl
myristate, a stiffening agent is stearyl alcohol, an ointment base
is selected from PEG 400 or PEG 3350, and the antioxidant, if
present, is butylated hydroxytoluene (BHT).
25. The method of claim 24, wherein the mammal is a human.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
application Ser. No. 13/580,129, filed Oct. 30, 2012, now allowed;
which is a national stage application, filed under 35 U.S.C.
.sctn.371, of International Application No. PCT/US2011/026359,
accorded an international filing date of Feb. 25, 2011; which
claims the benefit under 35 U.S.C. .sctn.119(e) of U.S. Provisional
Patent Application No. 61/308,759, filed Feb. 26, 2010.
FIELD OF THE INVENTION
[0002] The present invention relates to a pharmaceutical
composition for topical administration to a mammal, preferably a
human, comprising one or more pharmaceutically acceptable
excipients and a therapeutically effective amount of a
spiro-oxindole compound that is a sodium channel blocker,
preferably a neuronal voltage-gated sodium channel antagonist. In
particular, the present invention relates to pharmaceutical
compositions for treating diseases or conditions, such as pain,
preferably post-herpetic neuralgia (PHN), osteoarthritis, and
persistent post-operative pain, which is alleviated by the
inhibition of a sodium channel, preferably a neuronal voltage-gated
sodium channel. However, other neurological disorders unrelated to
pain could similarly be treated as part of this invention, for
example, alleviation of symptoms of myotonia and multiple
sclerosis.
BACKGROUND OF THE INVENTION
[0003] Diseases and conditions which are alleviated by the
inhibition (or "blocking") of sodium channels, particularly
neuronal voltage-gated sodium channels, include acute and chronic
pain, particularly neuropathic and inflammatory pain. Persistent
(chronic) neuropathic pain occurs in a wide range of clinical
conditions, including post-herpetic neuralgia (PHN), trigeminal
neuralgia, painful diabetic neuropathy (PDN), lower back pain,
post-operative pain, chemotherapy-related and HIV infection.
Estimates of the prevalence of chronic neuropathic pain vary
greatly by geographical region, ranging from approximately 11% of
the population of the U.S. to estimates that 20% of all European
adults suffer with moderate to severe chronic pain (see, for
example, Hall, G. C. et al., "Primary Care Incidence and Treatment
of Four Neuropathic Pain Conditions: A Descriptive Study,
2002-2005," BMC Fam. Pract. (2008); Vol. 9, No. 26; and Hardt, J.
et al., "Prevalence of Chronic Pain in a Representative Sample in
the United States," Pain Medicine (2008), Vol. 9, No. 7, pp.
803-812). In the U.S., the most common chronic neuropathic pain
conditions, PHN and PDN, are thought to affect 1 million and 3
million people, respectively (see, for example, Dworkin, R. H. et
al., "Advances in Neuropathic Pain Diagnosis, Mechanism, and
Treatment Recommendations," Arch. Neurol. (2003), Vol. 60, pp.
1524-1534).
[0004] Numerous pharmacological agents are available for the
treatment of neuropathic pain, including tricyclic antidepressants,
serotonin noradrenaline reuptake inhibitors, anticonvulsants (e.g.,
gabapentin and pregabalin), local anaesthetics and opioids (e.g.,
morphine). However, these treatments offer sub-optimal efficacy
and/or have unacceptable side effects in a chronic setting, with
adequate relief of neuropathic pain reported in only approximately
50% of patients (see, for example, Moulin, D. E., "The Clinical
Management of Neuropathic Pain," Pain Res. Manag. (2006), Vol. 11
(Supplement A), pp. 30A-36A). Frequently, multiple drug therapy
with tricyclic antidepressants, anticonvulsants and local
anaesthetics is necessary for relief of neuropathic pain.
[0005] The Lidoderm.RTM. patch (5% lidocaine) belongs to a class of
local and topical anaesthetic medications and is approved for the
treatment of PHN. However, while lidocaine may have local effects,
it is systemically absorbed and must be used with extreme caution
when administered topically, as applying to too large a surface
area can result in severe systemic toxicity and death.
[0006] Voltaren.RTM. (diclofenac sodium gel) is a non-steroidal
anti-inflammatory agent (NSAID) in a topical formulation. It is a
marketed treatment option for osteoarthritis patients. While the
risk of gastrointestinal side effects for NSAID topical use is
lower than it is for NSAID oral use, these serious side effects
remain a concern for topical diclofenac. Furthermore, meaningful
elevation of hepatic enzymes has recently been reported in some
patients on long-term topical diclofenac, necessitating regular
monitoring for hepatotoxicity in this patient population (see, FDA
website, MedWatch, 2009; Volteren Gel (diclofenac sodium) 1%
topical gel; Safety Labeling Changes Approved by FDA Center for
Drug Evaluation and Research--September 2009).
[0007] Neuronal voltage-gated sodium channels (Na.sub.v's) are
well-known to modulate the transmission of pain signals. For
example, loss-of-function mutations of Na.sub.v1.7, which is
expressed primarily in sensory neurons of the peripheral nervous
system and is upregulated by both nerve injury and inflammation,
cause a human condition known as congenital indifference to pain,
which is characterized by an inability to sense pain (see, for
example, Goldberg, Y. P. et al., Clin. Genet. (2007), Vol. 71, No.
4, pp. 311-119). Lidocaine and other local anaesthetics act mainly
by inhibiting Na.sub.v's.
[0008] PCT Published Patent Application No. WO 06/110917 is
directed to spiro-oxindole compounds which are disclosed as being
useful as sodium channel blockers. These compounds, inter alia,
inhibit sodium ion flux through sodium channels. As such, the
compounds are considered to be sodium channel blockers and are
therefore useful for treating diseases and conditions in mammals,
preferably humans, which are the result of aberrant
voltage-dependent sodium channel biological activity or which may
be ameliorated by modulation of the biological activity of sodium
channels.
[0009] There exists, therefore, a need for a topical pharmaceutical
composition comprising a compound that is a sodium channel blocker,
preferably a neuronal voltage-gated sodium channel antagonist, for
the treatment of pain having minimal systemic exposure of the
compound and that is cosmetically and pharmaceutically acceptable
for chronic application of the compound to the skin (i.e.,
non-irritating, non-stinging and non-sensitizing).
SUMMARY OF THE INVENTION
[0010] The present invention is directed to pharmaceutical
compositions comprising one or more pharmaceutically acceptable
excipients and a therapeutically effective amount of a
spiro-oxindole compound, or a pharmaceutically acceptable salt
thereof. In particular, the present invention is directed to
pharmaceutical compositions comprising one or more pharmaceutically
acceptable excipients and a therapeutically effective amount of a
spiro-oxindole compound that is a sodium channel blocker. Such
pharmaceutical compositions are useful in the treatment and/or
prevention of diseases or conditions mediated by sodium channels
and are topically administered to a mammal, preferably a human, in
need thereof, with minimal systemic exposure of the spiro-oxindole
compound.
[0011] Accordingly, in one aspect, the invention is directed to a
pharmaceutical composition for topical administration to a mammal,
wherein the pharmaceutical composition comprises one or more
pharmaceutically acceptable excipients and a therapeutically
effective amount of a spiro-oxindole compound having the following
formula:
##STR00001##
as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof.
[0012] In another aspect, the invention provides a method for the
treatment of pain in a mammal, preferably a human, wherein the
method comprises administering to the mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the invention as set forth above.
[0013] In another aspect, the present invention provides a method
for treating or lessening the severity of a disease, condition, or
disorder where activation or hyperactivity of one or more of
neuronal voltage-gated sodium channels selected from Na.sub.v1.1,
Na.sub.v1.2, Na.sub.v1.3, Na.sub.v1.4, Na.sub.v1.5, Na.sub.v1.6,
Na.sub.v1.7, Na.sub.v1.8, or Na.sub.v1.9 is implicated in the
disease, condition or disorder, wherein the methods comprise
administering to the mammal in need thereof a therapeutically
effective amount of a pharmaceutical composition of the invention
as set forth above.
[0014] In another aspect, the invention provides a method of
treating a range of sodium channel-mediated diseases or conditions,
preferably neuronal voltage-gated sodium channel-mediated diseases
or conditions, wherein the diseases or conditions are selected
from, but are not limited to, pain associated with HIV, HIV
treatment induced neuropathy, trigeminal neuralgia, post-herpetic
neuralgia (PHN), familial erythromelalgia, primary erythromelalgia,
familial rectal pain, eudynia, heat sensitivity, pain associated
with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS),
painful diabetic neuropathy, peripheral neuropathy, arthritis,
rheumatoid arthritis, osteoarthritis, tendonitis, bursitis,
musculoskeletal sprains, tenosinovitis, chondromalacia patellae,
myositis, myotonia (including but not limited to SCN4A-related
myotonia), paramyotonia, rhabdomyolysis, paroxysmal dystonia,
myasthenia syndromes, malignant hyperthermia, sodium channel toxin
related illnesses, cancer pain, restless leg syndrome,
fibromyalgia, and neurodegenerative disease, as well as other
neurological disorders including multiple sclerosis, wherein the
method comprises administering to the mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the invention as set forth above.
[0015] In another aspect, the invention provides a method of
treating a range of sodium channel-mediated diseases or condition,
preferably neuronal voltage-gated sodium channel-mediated diseases
or condition, in a mammal, preferably a human, wherein the diseases
or conditions are selected from, but are not limited to,
neuroprotection under ischaemic conditions caused by stroke or
neural trauma, neurodegenerative disease, as well as other
neurological disorders including multiple sclerosis, wherein the
method comprises administering to the mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the invention as set forth above.
[0016] In another aspect, the invention provides a method of
treating a range of sodium channel-mediated diseases or conditions,
preferably neuronal voltage-gated sodium channel-mediated diseases
or conditions, in a mammal, preferably a human, wherein the
diseases or conditions are selected from, but are not limited to,
pruritis (itch), dermatitis, contact dermatitis, allergic
dermatitis, eczema, acne, and inflammatory skin disorders, wherein
the method comprises administering to the mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the invention as set forth above.
[0017] In another aspect, the invention provides a method of
treating a range of sodium channel-mediated diseases or condition,
preferably neuronal voltage-gated sodium channel-mediate diseases
or condition, in a mammal, preferably a human, through inhibition
of ion flux through a voltage-dependent sodium channel in the
mammal, preferably a neuronal voltage-gated sodium channel, wherein
the method comprises administering to the mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the invention as set forth above.
[0018] A further aspect of this invention is a process for the
preparation of the pharmaceutical composition of this
invention.
[0019] Specific embodiments of these aspects of the invention are
described in more detail below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] The following drawings form part of the present
specification and are included to further demonstrate certain
aspects of the present invention. The invention may be better
understood by reference to one or more of these drawings in
combination with the detailed description of specific embodiments
presented herein.
[0021] FIG. 1 is a graph showing the mean percent change from
baseline (CFB) for each dosage group described in the CFA-induced
chronic inflammatory pain study in Example 1. Data are expressed as
Mean.+-.SD change from baseline values.
[0022] FIG. 2 is a graph showing the mean paw withdrawal threshold
expressed as percent change from baseline (CFB) for each treatment
group described in the neuropathic pain model study in Example 2.
Data are plotted as Mean.+-.SEM.
[0023] FIG. 3 is a graph showing 30-minute post-dosing von Frey
Change from Baseline (CFB) for treated paw from the diabetic
neuropathy study in Example 4.
[0024] FIG. 4 is a graph showing the mean percent change from
baseline (CFB) for each dosage group described in the CCI model for
neuropathic pain study in Example 5. Data are expressed as
Mean.+-.SD change from baseline values.
[0025] FIG. 5 is a graph showing the mean plasma concentration of
COMPOUND A for each treatment group described in the CCI model
study in Example 5.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0026] Unless defined otherwise in the specification, the following
terms and phrases shall have the following meaning:
[0027] "Spiro-oxindole compound" refers to a compound having the
following formula:
##STR00002##
or a pharmaceutically acceptable salt thereof. This compound is
disclosed in PCT Published Patent Application No. WO 06/110917,
which is incorporated in full by reference herein. The
spiro-oxindole compound may exist as a single enantiomer, a
racemate or as a non-racemic mixture of enantiomers. One of the
enantiomers of the spiro-oxindole compound has the following
formula:
##STR00003##
and is named herein as
(S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzo-
dioxole-7,3'-indol]-2'(1'H)-one. This enantiomer is also identified
herein as "COMPOUND A". The use of the "COMPOUND A" identifier
herein is intended to include the enantiomer as a free base or as a
pharmaceutically acceptable salt.
[0028] The term "about" when placed before a numerical value "X"
herein refers to an interval extending from X minus 10% of X to X
plus 10% of X and preferably to an interval extending from X minus
5% of X to X plus 5% of X.
[0029] The expression "% w/w" refers to a percentage by weight
compared to the total weight of the composition being
considered.
[0030] The expression "% w/v" refers to a weight of a solute in a
given volume of solvent. For example, 50% w/v of PEG is 50 grams of
PEG in 100 mL solvent
[0031] "Clathrates" refers to substances which fix gases, liquids
or compounds as inclusion complexes so that the complex may be
handled in solid form and the included constituent (or "guest"
molecule) subsequently releases by the action of a solvent or by
melting. The term "clathrate" can be used interchangeably with the
phrase "inclusion molecule" or with the phrase "inclusion complex".
Clathrates contemplated for use in the instant invention are
prepared from cyclodextrins. Cyclodextrins are widely known as
having the ability to form clathrates (i.e., inclusion compounds)
with a variety of molecules. See, for example, Inclusion Compounds,
edited by J. L. Atwood, J. E. D. Davies, and D. D. MacNicol,
London, Orlando, Academic Press, 1984; Goldberg, I., "The
Significance of Molecular Type, Shape and Complementarity in
Clathrate Inclusion", Topics in Current Chemistry (1988), Vol. 149,
pp. 2-44; Weber, E. et al., "Functional Group Assisted Clathrate
Formation--Scissor-Like and Roof-Shaped Host Molecules", Topics in
Current Chemistry (1988), Vol. 149, pp. 45-135; and MacNicol, D. D.
et al., "Clathrates and Molecular Inclusion Phenomena", Chemical
Society Reviews (1978), Vol. 7, No. 1, pp. 65-87. Conversion into
cyclodextrin clathrates is known to increase the stability and
solubility of certain compounds, thereby facilitating their use as
pharmaceutical agents. See, for example, Saenger, W., "Cyclodextrin
Inclusion Compounds in Research and Industry", Angew. Chem. Int.
Ed. Engl. (1980), Vol. 19, pp. 344-362; U.S. Pat. No. 4,886,788
(Schering AG); U.S. Pat. No. 6,355,627 (Takasago); U.S. Pat. No.
6,288,119 (Ono Pharmaceuticals); U.S. Pat. No. 614,969 (Ono
Pharmaceuticals); U.S. Pat. No. 6,235,780 (Ono Pharmaceuticals);
U.S. Pat. No. 6,262,293 (Ono Pharmaceuticals); U.S. Pat. No.
6,225,347 (Ono Pharmaceuticals); and U.S. Pat. No. 4,935,446 (Ono
Pharmaceuticals).
[0032] "Mammal" includes humans and both domestic animals such as
laboratory animals and household pets, (e.g., cats, dogs, swine,
cattle, sheep, goats, horses, and rabbits), and non-domestic
animals such as wildlife and the like.
[0033] "Pharmaceutically acceptable excipient" or "excipient"
includes without limitation any inactive material that is combined
with a spiro-oxindole compound of the invention in order to produce
a drug dosage form for topical administration. The term
"pharmaceutically acceptable excipient" is intended to include, but
is not limited to, any solvents, penetration enhancing agents,
antioxidants, stiffening agents (i.e., thickeners), ointment bases,
protectives, adsorbents, demulcents, emollients, preservatives,
moisturizers, buffers, adjuvants, bioavailability enhancers,
carriers, glidants, sweetening agents, diluents, dye/colorants,
flavor enhancers, solubilizers (including surfactants), wetting
agents, dispersing agents, suspending agents, stabilizers and
isotonic agents, which have been approved by a regulatory agency,
such as for example, but is not limited to, the United States Food
and Drug Administration, the European Medicines Agency or Health
Canada, as being acceptable for use in a formulation for the
topical administration of a pharmacologically active ingredient,
and/or are considered as Generally Recognized As Safe materials
(GRAS materials), and/or are listed in the Inactive Ingredients
Guide published by the United States Food and Drug Administration.
"Pharmaceutically acceptable excipient" can also comprise the
acceptable excipients listed in Remington: The Science and Practice
of Pharmacy, Fox, 21.sup.st ed. 2005. Exemplary pharmaceutically
acceptable excipients include, but are not limited to, the
following: [0034] ascorbic acid and esters; [0035] benzyl alcohol;
[0036] benzyl benzoate; [0037] butylated hydroxytoluene ("BHT");
[0038] butylated hydroxyanisole ("BHA"); [0039] caprylic/capric
triglyceride; [0040] cetyl alcohol; [0041] chelating agents (e.g.,
EDTA and citric acid); [0042] cholesterol; [0043] cross-linked
acrylic acid based polymers (e.g., Carbopol.RTM.); [0044] decyl
methyl sulfoxide; [0045] diethyl sebacate; [0046] dimethylamine
("DMA"); [0047] dimethicone; [0048] dimethyl sulfoxide; [0049]
diethylene glycol mono ether (e.g., Transcutol.RTM. P); [0050]
diisopropyl adipate (e.g., Ceraphyl.RTM. 230); [0051] ethanol;
[0052] flavinoid; [0053] glutathione; [0054] glycerine; [0055]
glycerol oleate/propylene glycol (e.g., Arlacel 186); [0056]
glycerol monooleate; [0057] glyceryl caprylate/caprate and PEG-8
(polyethylene glycol) caprylate/caprate complex; carpylocaproyl
macrogolglycerides (e.g., Labrasol.RTM.); [0058] glyceryl
monocaprylate (e.g., Capmul.RTM. MCM C8); [0059] glyceryl
monolinoleate (e.g., Maisine.TM. 35-1); [0060] glyceryl monooleate
(e.g., Peceol.TM.); [0061] glyceryl monostearate; [0062] hexylene
glycol; [0063] hydroxypropyl-.beta.-cyclodextrin (HP-.beta.-CD);
[0064] isopropyl alcohol; [0065] isopropyl myristate; [0066]
laurocapram; (e.g., Azone.RTM.); [0067] lauroyl macrogol-32
glycerides (e.g. Gelucire.RTM. 44/14); [0068] macrogol-15
hydroxystearate (e.g., Solutol.RTM. HS15); [0069] medium chain
triglycerides (e.g., Miglyol.RTM. 810, Miglyol.RTM. 840 or
Miglyol.RTM. 812); [0070] methyl laurate; [0071]
N-methyl-2-pyrrolidine (e.g., Pharmasolve.RTM.); [0072] mineral
oil; [0073] mono diglycerides (e.g., Capmul.RTM. MCM); [0074]
octyldodecanol; [0075] oleic acid; [0076] oleyl alcohol; [0077]
peanut oil; [0078] 1,2-pentanediol; [0079] polysorbates (e.g.,
Tween.RTM. 80); [0080] polyethylene glycol (e.g., PEG-8, PEG 400,
PEG1000, PEG 3350, PEG 6000, or Lutrol.RTM. E 400); [0081] polyoxyl
35 castor oil (e.g., Cremophor.RTM. EL); [0082] polyoxyl 40
hydrogenated castor oil (e.g., Cremophor.RTM. RH 40); [0083]
propylene glycol; [0084] propylene glycol diacetate; [0085]
propylene glycol monocaprylate (e.g., Capmul PG-8, Capryol 90);
[0086] propylene glycol monolaurate (e.g., Capmul PG-12); [0087]
propylene glycol monooleate; [0088] 2-pyrrolidone; [0089] soybean
oil; [0090] stearyl alcohol; [0091]
sulfobutylether-.beta.-cyclodextrin (e.g., Capitsol.RTM.); [0092]
tocopherols (e.g., Vitamin E acetate); [0093] .alpha.-tocopherol
polyethylene glycol succinate (TPGS); [0094] water; and [0095]
white petrolatum.
[0096] Additional pharmaceutically acceptable excipients are
disclosed herein.
[0097] "Solvents" refer to substances that readily dissolve other
substances, such as a spiro-oxindole compound of the invention, in
order to form a solution. Suitable solvents for the purposes of
this invention include polyethylene glycol (e.g., PEG 400, PEG 100,
and PEG 3350), diethylene glycol monoethyl ether (e.g.,
Transcutol.RTM.), Tween 80, alcohols (e.g., oleyl alcohol, and
stearyl alcohol), Labrasol.RTM., caprylic/capric triglyceride,
fatty acid esters (e.g., isopropyl myristate, and diisopropyl
adipate (e.g., Ceraphyl.RTM. 230)), diethyl sebacate, propylene
glycol monocaprylate (e.g., Capmul.RTM. PG-8), propylene glycol
laurate (e.g., Capmul.RTM. PG-12), mono diglycerides (e.g.,
Capmul.RTM. MCM), glyceryl monocaprylate (e.g., Capmul.RTM. MCM
C8), medium chain triglycerides, hexylene glycol, glyceryl
mono-oleate (e.g., Peceol.TM.), 1,2-pentanediol, octyldodecanol,
glyceryl mono-linoleate (e.g., Maisine.TM. 35-1), isopropyl
alcohol, glycerol oleate/propylene glycol (e.g., Arlacel.RTM. 186),
mineral oil, water, and glycerine.
[0098] "Penetration enhancing agents" refer to substances that
increase the permeability of the skin or mucosa to a
pharmacologically active ingredient, preferably a spiro-oxindole
compound of the invention, so as to increase the rate at which the
active ingredient permeates through the skin or mucosa of a mammal,
preferably a human. Suitable penetration enhancing agents for the
purposes of this invention include, but are not limited to,
dimethyl sulfoxide (DMSO), decylmethylsulfoxide, laurocapram (e.g.,
Azone.RTM.), pyrrolidones (e.g., 2-pyrrolidone, and
N-methyl-2-pyrrolidine (Pharmasolve.RTM.)), surfactants, alcohols
(e.g., oleyl alcohol), oleic acid, polyethylene glycol (e.g., PEG
400), diethylene glycol monoethyl ether (e.g., Transcutol.RTM.),
and fatty acid esters (e.g., isopropyl myristate, methyl laurate,
glycerol monooleate, and propylene glycol monooleate). A
penetration enhancing agent may be used independently or more than
one may be used in a pharmaceutical composition of the
invention.
[0099] "Ointment bases" refers to substances that function as a
carrier and enhance penetration into the skin in order to deliver a
pharmacologically active ingredient, preferably a spiro-oxindole
compound of the invention, to the area to be treated in the mammal,
preferably a human. Suitable "ointment bases" for the purposes of
this invention include, but are not limited to, polyethylene
glycols (e.g., PEG 400 and PEG 3350). An ointment base may be used
independently or more than one may be used in a pharmaceutical
composition of the invention.
[0100] "Stiffening agents" refers to substances which increase the
viscosity and/or physical stability of a pharmaceutical composition
of the invention. Suitable "stiffening agents" for the purposes of
this invention include, but are not limited to, stearyl alcohol,
carbopols, dimethicone and polymers. A stiffening agent may be used
independently or more than one may be used in a pharmaceutical
composition of the invention.
[0101] "Antioxidants" refers to substances which are capable of
preventing the oxidation of another molecule. Suitable
"antioxidants" for the purposes of this invention include, but are
not limited to, butylated hydroxytoluene (BHT), butylated
hydroxyanisole (BHA), tocopherols (e.g., Vitamin E acetate),
flavinoid, glutathione, ascorbic acid and its esters, DMSO, and
chelating agents (e.g., EDTA and citric acid).
[0102] "Pharmaceutically acceptable salt" includes both acid and
base addition salts.
[0103] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as, but are not limited to, hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid and the like, and
organic acids such as, but not limited to, acetic acid,
2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid,
aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,
capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic
acid, citric acid, cyclamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic
acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric
acid, lactic acid, lactobionic acid, lauric acid, maleic acid,
malic acid, malonic acid, mandelic acid, methanesulfonic acid,
mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic
acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid,
orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic
acid, pyroglutamic acid, pyruvic acid, salicylic acid,
4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,
tartaric acid, thiocyanic acid, p-toluenesulfonic acid,
trifluoroacetic acid, undecylenic acid, and the like.
[0104] "Pharmaceutically acceptable base addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free acids, which are not biologically or
otherwise undesirable. These salts are prepared from addition of an
inorganic base or an organic base to the free acid. Salts derived
from inorganic bases include, but are not limited to, the sodium,
potassium, lithium, ammonium, calcium, magnesium, iron, zinc,
copper, manganese, aluminum salts and the like. Preferred inorganic
salts are the ammonium, sodium, potassium, calcium, and magnesium
salts. Salts derived from organic bases include, but are not
limited to, salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins, such as
ammonia, isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, diethanolamine, ethanolamine,
deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, benethamine, benzathine,
ethylenediamine, glucosamine, methylglucamine, theobromine,
triethanolamine, tromethamine, purines, piperazine, piperidine,
N-ethylpiperidine, polyamine resins and the like. Particularly
preferred organic bases are isopropylamine, diethylamine,
ethanolamine, trimethylamine, dicyclohexylamine, choline and
caffeine.
[0105] A "pharmaceutical composition" refers to a formulation of a
spiro-oxindole compound of the invention and a medium generally
accepted in the art for the topical administration of the
spiro-oxindole compound to mammals, e.g., humans. Such a medium
includes all pharmaceutically acceptable excipients. For purposes
of this disclosure, the phrase "pharmaceutical composition" is
interchangeable with the phrase "pharmaceutical formulation".
[0106] "Sodium channel-mediated disease or condition" refers to a
disease or condition which is ameliorated or alleviated upon
modulation of the sodium channel and includes, but is not limited
to, pain, or post-herpetic neuralgia. Further examples of sodium
channel-mediated diseases or conditions are disclosed below.
[0107] "Therapeutically effective amount" refers to that amount of
a spiro-oxindole compound of the invention or a pharmaceutical
composition of the invention which, when administered to a mammal,
preferably a human, is sufficient to effect treatment, as defined
below, of the indicated disease or condition in the mammal,
preferably a human. The amount of the spiro-oxindole compound or
the pharmaceutical composition which constitutes a "therapeutically
effective amount" will vary depending on the spiro-oxindole
compound, the pharmaceutical composition, the nature of the disease
or condition and its severity, other conditions (e.g., age, weight,
general health) affecting the health of the mammal to be treated,
and the manner of administration, as well as upon the potency,
bioavailability and in vivo half-life of the components of the
pharmaceutical composition used, but can be determined routinely by
one of ordinary skill in the art having regard to his own knowledge
and to this disclosure.
[0108] "Treating" or "treatment" as used herein covers the
treatment of the disease or condition of interest in a mammal,
preferably a human, having the disease or condition of interest,
and includes: [0109] (i) preventing the disease or condition from
occurring in a mammal, in particular, when such mammal is
predisposed to the condition but has not yet been diagnosed as
having it; [0110] (ii) inhibiting the disease or condition, i.e.,
arresting its development; [0111] (iii) relieving the disease or
condition, i.e., causing regression of the disease or condition; or
[0112] (iv) relieving the symptoms resulting from the disease or
condition.
[0113] As used herein, the terms "disease" and "condition" may be
used interchangeably or may be different in that the particular
malady or condition may not have a known causative agent (so that
etiology has not yet been worked out) and it is therefore not yet
recognized as a disease but only as an undesirable condition or
syndrome, wherein a more or less specific set of symptoms have been
identified by clinicians.
[0114] "Analgesia" refers to an absence of pain in response to a
stimulus that would normally be painful.
[0115] "Allodynia" refers to a condition in which a normally
innocuous sensation, such as pressure or light touch, is perceived
as being extremely painful.
Embodiments of the Invention
[0116] Of the various aspects of the invention set forth above in
the Summary of the Invention, certain embodiments are
preferred.
[0117] Of the pharmaceutical compositions of the invention, as set
forth above in the Summary of the Invention, one embodiment is a
pharmaceutical composition comprising a therapeutically effective
amount of the spiro-oxindole compound, as an enantiomer, a racemate
or a non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof, and one or more pharmaceutically
acceptable excipients selected from the exemplary list of
pharmaceutically acceptable excipients as set forth above in the
Definitions.
[0118] Another embodiment is a pharmaceutical composition
comprising a therapeutically effective amount of the spiro-oxindole
compound, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable excipients, wherein the
pharmaceutically acceptable excipients are selected from one or
more solvents, optionally from one or more penetration enhancing
agents, optionally from one or more stiffening agents, optionally
from one or more ointment bases, and optionally from one or more
antioxidants.
[0119] Another embodiment is a pharmaceutical composition
comprising a therapeutically effective amount of the spiro-oxindole
compound, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof, and two
or more pharmaceutically acceptable excipients, wherein the
pharmaceutically acceptable excipients are selected from one or
more solvents, optionally from one or more penetration enhancing
agents, optionally from one or more stiffening agents, optionally
from one or more ointment bases, and optionally from one or more
antioxidants.
[0120] Another embodiment is a pharmaceutical composition
comprising a therapeutically effective amount of the spiro-oxindole
compound, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof, and two
or more pharmaceutically acceptable excipients, wherein the
pharmaceutically acceptable excipients are selected from one or
more solvents, from one or more penetration enhancing agents, from
one or more stiffening agents, from one or more ointment bases, and
optionally from one or more antioxidants.
[0121] Another embodiment is a pharmaceutical composition
comprising a therapeutically effective amount of the spiro-oxindole
compound, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable excipients, wherein one of the
pharmaceutically acceptable excipients is a solvent selected from
polyethylene glycol, diethylene glycol monoethyl ether,
polysorbates, alcohols, carpylocaproyl macrogolglycerides,
caprylic/capric triglyceride, fatty acid esters, diethyl sebacate,
propylene glycol monocaprylate, propylene glycol laurate, mono
diglycerides, glyceryl monocaprylate, medium chain triglycerides,
hexylene glycol, glyceryl monooleate, 1,2-pentanediol,
octyldodecanol, glyceryl mono-linoleate, glycerol oleate/propylene
glycol, mineral oil, water, or glycerine.
[0122] Another embodiment is a pharmaceutical composition
comprising a therapeutically effective amount of the spiro-oxindole
compound, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable excipients, wherein one of the
pharmaceutically acceptable excipients is a penetration enhancing
agent selected from dimethyl sulfoxide, decylmethylsulfoxide,
laurocapram, pyrrolidones, surfactants, alcohols, oleic acid,
polyethylene glycol, diethylene glycol monoethyl ether, or fatty
acid esters.
[0123] Another embodiment is a pharmaceutical composition
comprising a therapeutically effective amount of the spiro-oxindole
compound, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable excipients, wherein one of the
pharmaceutically acceptable excipients is a stiffening agent
selected from stearyl alcohol, carbopols, dimethicone or
polymers.
[0124] Another embodiment is a pharmaceutical composition
comprising a therapeutically effective amount of the spiro-oxindole
compound, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable excipients, wherein one of the
pharmaceutically acceptable excipients is an ointment base selected
from polyethylene glycols.
[0125] Another embodiment is a pharmaceutical composition
comprising a therapeutically effective amount of the spiro-oxindole
compound, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable excipients, wherein one of the
pharmaceutically acceptable excipients is an antioxidant selected
from butylated hydroxytoluene, butylated hydroxyanisole,
tocopherols, flavinoid, glutathione, ascorbic acid and esters,
dimethyl sulfoxide, or chelating agents.
[0126] Another embodiment is a pharmaceutical composition
comprising a therapeutically effective amount of the spiro-oxindole
compound, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable excipients, wherein each
pharmaceutically acceptable excipient is present in a concentration
of from about 0.01% w/w to about 99% w/w.
[0127] Another embodiment is a pharmaceutical composition
comprising a therapeutically effective amount of the spiro-oxindole
compound, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable excipients, wherein a first
pharmaceutically acceptable excipient is a solvent present at a
concentration of from about 30% w/w to about 70% w/w, a second
pharmaceutically acceptable excipient is a penetration enhancing
agent present in a concentration of from about 2% w/w to about 25%
w/w, a third pharmaceutically acceptable excipient is a penetration
enhancing agent present in a concentration of from about 1% w/w to
about 10% w/w, a fourth pharmaceutically acceptable excipient is a
penetration enhancing agent present in a concentration of from
about 1% w/w to about 25% w/w, a fifth pharmaceutically acceptable
excipient is a stiffening agent present in a concentration of from
about 0.1% w/w to about 10% w/w, a sixth pharmaceutically
acceptable excipient is an antioxidant present in a concentration
of from about 0.01% w/w to about 2% w/w, and a seventh
pharmaceutically acceptable excipient is an ointment base present
in a concentration of from about 10% w/w to about 50% w/w.
[0128] Another embodiment is a pharmaceutical composition
comprising a therapeutically effective amount of the spiro-oxindole
compound, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable excipients, wherein a first
pharmaceutically acceptable excipient is a solvent present at a
concentration of from about 45% w/w to about 55% w/w, a second
pharmaceutically acceptable excipient is a penetration enhancing
agent present in a concentration of from about 5% w/w to about 15%
w/w, a third pharmaceutically acceptable excipient is a penetration
enhancing agent present in a concentration of from about 2.5% w/w
to about 7.5% w/w, a fourth pharmaceutically acceptable excipient
is a penetration enhancing agent present in a concentration of from
about 2.5% w/w to about 7.5% w/w, a fifth pharmaceutically
acceptable excipient is a stiffening agent present in a
concentration of from about 0.1% w/w to about 7.5% w/w, a sixth
pharmaceutically acceptable excipient is an antioxidant present in
a concentration of from about 0.05% w/w/to about 1% w/w, and a
seventh pharmaceutically acceptable excipient is an ointment base
present in a concentration of from about 15% w/w to about 30%
w/w.
[0129] Another embodiment is a pharmaceutical composition
comprising a therapeutically effective amount of the spiro-oxindole
compound, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, or a pharmaceutically acceptable salt thereof, and one
or more pharmaceutically acceptable excipients selected from a
solvent selected from PEG 400 or PEG 3350; one or more penetration
enhancing agents selected from Transcutol.RTM. P, oleyl alcohol or
isopropyl myristate; a stiffening agent selected from stearyl
alcohol; an ointment base selected from PEG 400 or PEG 3350; and an
antioxidant selected from butylated hydroxytoluene.
[0130] Of this embodiment, a further embodiment is a pharmaceutical
composition comprising a therapeutically effective amount of the
spiro-oxindole compound, as an enantiomer, a racemate or a
non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof, wherein PEG 400 is present in a
concentration of from about 30% w/w to about 70% w/w,
Transcutol.RTM. P is present in a concentration of from about 2%
w/w to about 25% w/w, oleyl alcohol is present in a concentration
of from about 1% w/w to about 10% w/w, isopropyl myristate is
present in a concentration of from about 1% w/w to about 25% w/w,
stearyl alcohol is present in a concentration of from about 0.1%
w/w to about 10% w/w, BHT is present in a concentration of from
about 0.01% w/w to about 2% w/w, and PEG 3350 is present in a
concentration of from about 10% w/w to about 50% w/w.
[0131] Of this embodiment, a further embodiment is a pharmaceutical
composition comprising a therapeutically effective amount of the
spiro-oxindole compound, as an enantiomer, a racemate or a
non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof, wherein PEG 400 is present in a
concentration of from about 45% w/w to about 55% w/w,
Transcutol.RTM. P is present in a concentration of from about 5%
w/w to about 15% w/w, oleyl alcohol is present in a concentration
of from about 2.5% w/w to about 7.5% w/w, isopropyl is myristate
present in a concentration of from about 2.5% w/w to about 7.5%
w/w, stearyl alcohol is present in a concentration of from about
0.1% w/w to about 7.5% w/w, BHT is present in a concentration of
from about 0.05% w/w to about 1% w/w, and PEG 3350 is present in a
concentration of from about 15% w/w to about 30% w/w.
[0132] Of all of the above embodiments, a further embodiment is
wherein the spiro-oxindole compound is present in a concentration
of from about 0.1% w/w to about 10% w/w.
[0133] Of this embodiment, a further embodiment is wherein the
spiro-oxindole compound is present in a concentration of from about
2% w/w to about 8% w/w.
[0134] Of all of the above embodiments, a further embodiment is
wherein the pharmaceutical composition comprises the spiro-oxindole
compound at a concentration of 2.0% w/w; PEG 400 at a concentration
of 52.9% w/w; Transcutol.RTM. P at a concentration of 10% w/w;
oleyl alcohol at a concentration of 5% w/w; isopropyl myristate at
a concentration of 5% w/w; stearyl alcohol at a concentration of 5%
w/w;
[0135] butylated hydroxytoluene at a concentration of 0.1% w/w; and
PEG 3350 at a concentration of 20% w/w of the pharmaceutical
composition.
[0136] Of all of the above embodiments, another further embodiment
is wherein the pharmaceutical composition comprises the
spiro-oxindole compound at a concentration of 4% w/w; PEG 400 at a
concentration of 50.9% w/w; Transcutol.RTM. P at a concentration of
10% w/w; oleyl alcohol at a concentration of 5% w/w; isopropyl
myristate at a concentration of 5% w/w; stearyl alcohol at a
concentration of 5% w/w; butylated hydroxytoluene at a
concentration of 0.1% w/w; and PEG 3350 at a concentration of 20%
w/w of the pharmaceutical composition.
[0137] Of all of the above embodiments, another further embodiment
is wherein the pharmaceutical composition comprises the
spiro-oxindole compound at a concentration of 4% w/w; PEG 400 at a
concentration of 50.9% w/w; Transcutol.RTM. P at a concentration of
5% w/w; oleyl alcohol at a concentration of 5% w/w; isopropyl
myristate at a concentration of 5% w/w; stearyl alcohol at a
concentration of 10% w/w; butylated hydroxytoluene at a
concentration of 0.1% w/w; and PEG 3350 at a concentration of 20%
w/w of the pharmaceutical composition.
[0138] Of all of the above embodiments, another further embodiment
is wherein the pharmaceutical composition comprises the
spiro-oxindole compound at a concentration of 8% w/w; PEG 400 at a
concentration of 46.9% w/w; Transcutol.RTM. P at a concentration of
10% w/w; oleyl alcohol at a concentration of 5% w/w; isopropyl
myristate at a concentration of 5% w/w; stearyl alcohol at a
concentration of 5% w/w; butylated hydroxytoluene at a
concentration of 0.1% w/w; and PEG 3350 at a concentration of 20%
w/w of the pharmaceutical composition.
[0139] Of all of the above embodiments, a further embodiment is
wherein the spiro-oxindole compound is a compound of the following
formula:
##STR00004##
or a pharmaceutically acceptable salt thereof.
[0140] Of the methods of treating, preventing or ameliorating a
sodium channel-mediated disease or a condition in a mammal, as set
forth above in the Summary of the Invention, one embodiment
comprises topically administering to the mammal, preferably a
human, in need thereof a therapeutically effective amount of the
pharmaceutical composition of any of the above embodiments of
pharmaceutical compositions of the invention.
[0141] Of this embodiment, a further embodiment is wherein the
wherein said disease or condition is selected from the group
consisting of neuropathic pain, inflammatory pain, visceral pain,
post-herpetic neuralgia, cancer pain, chemotherapy pain, trauma
pain, surgical pain, post-operative pain, pruritis, osteoarthritis,
trigeminal neuralgia, familial erythromelalgia, primary
erythromelalgia, familial rectal pain, childbirth pain, labor pain,
neurogenic bladder, ulcerative colitis, chronic pain, persistent
pain, peripherally mediated pain, centrally mediated pain, chronic
headache, migraine headache, sinus headache, tension headache,
phantom limb pain, peripheral nerve injury, and combinations
thereof.
[0142] Specific embodiments of the pharmaceutical compositions of
the invention and methods of using the pharmaceutical compositions
of the invention are described in more detail below.
Utility of the Pharmaceutical Compositions of the Invention
[0143] This invention is directed to pharmaceutical compositions
comprising one or more pharmaceutically acceptable excipients and a
therapeutically effective amount of the spiro-oxindole compound, or
a pharmaceutically acceptable salt thereof, for use in the
treatment of sodium channel-mediated diseases or conditions,
preferably diseases or conditions related to pain, such as for
example, post-herpetic neuralgia, osteoarthritis, and persistent
post-operative pain, in a mammal by topically administering a
therapeutically effective amount of the pharmaceutical composition
to the mammal, preferably a human, in need thereof.
[0144] Sodium channel-mediated diseases or conditions of particular
interest to the invention are those disease or conditions which are
ameliorated or alleviated by the modulation, preferably the
inhibition (or blocking), of the sodium channel. Preferably the
sodium channel-mediated diseases or conditions of the invention are
those diseases or conditions which are ameliorated or alleviated by
the modulation, preferably the inhibition (or blocking) of neuronal
voltage-gated sodium channels (Na.sub.v's), including, but not
limited to, pain or post-herpetic neuralgia.
[0145] Accordingly, the invention provides a method of treating a
range of sodium channel-mediated diseases or conditions in a
mammal, preferably a human, wherein the diseases or conditions are
selected from, but are not limited to, pain, post-herpetic
neuralgia (PHN), post-operative pain, pruritis, pain associated
with HIV, HIV treatment induced neuropathy, trigeminal neuralgia,
familial erythromelalgia, primary erythromelalgia, familial rectal
pain, eudynia, heat sensitivity, pain associated with multiple
sclerosis (MS), amyotrophic lateral sclerosis (ALS), painful
diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid
arthritis, osteoarthritis, tendonitis, bursitis, musculoskeletal
sprains, tenosinovitis, chondromalacia patellae, myositis, myotonia
(including but not limited to SCN4A-related myotonia),
paramyotonia, rhabdomyolysis, paroxysmal dystonia, myasthenia
syndromes, malignant hyperthermia, sodium channel toxin related
illnesses, cancer pain, restless leg syndrome, fibromyalgia, and
neurodegenerative disease, as well as other neurological disorders
including multiple sclerosis, by administering to the mammal a
therapeutically effective amount of a pharmaceutical composition of
the invention.
[0146] For purposes of this invention and unless otherwise
specifically defined herein, the term "pain" refers to all
categories of pain and is recognized to include, but is not limited
to, neuropathic pain, inflammatory pain, nociceptive pain,
idiopathic pain, neuralgic pain, orofacial pain, burn pain, somatic
pain, visceral pain, myofacial pain, dental pain, cancer pain,
chemotherapy pain, trauma pain, surgical pain, post-surgical pain,
childbirth pain, labor pain, reflex sympathetic dystrophy, brachial
plexus avulsion, acute pain (e.g., musculoskeletal and
post-operative pain), chronic pain, persistent pain, peripherally
mediated pain, centrally mediated pain, conditions associated with
cephalic pain, phantom limb pain, peripheral nerve injury, pain
following stroke, thalamic lesions, radiculopathy, HIV pain,
post-herpetic pain, and combinations thereof.
[0147] Pruritis, commonly known as itch and also known as pruritus,
is a common dermatological condition. While the exact causes of
pruritis are complex and poorly understood, there has long been
acknowledged to be mediated by sensory neurons some of which also
mediate pain responses. In particular, it is believed that sodium
channels likely communicate or propagate along the nerve axon the
itch signals along the skin. Transmission of the itch impulses
results in the unpleasant sensation that elicits the desire or
reflex to scratch.
[0148] From a neurobiology level, it is believed that there is a
shared complexity of specific mediators, related neuronal pathways
and the central processes of itch and pain and recent data suggest
that there is a broad overlap between pain- and itch-related
peripheral mediators and/or receptors (Ikoma et al., Nature Reviews
Neuroscience, 7:535-547, 2006). Remarkably, pain and itch have
similar mechanisms of neuronal sensitization in the peripheral
nervous system and the central nervous system but exhibits
intriguing differences as well.
[0149] For example, the mildly painful stimuli from scratching are
effective in abolishing the itch sensation. In contrast, analgesics
such as opioids can generate severe pruritis. The antagonistic
interaction between pain and itch can be exploited in pruritis
therapy, and current research concentrates on the identification of
common targets for future analgesic and antipruritis therapy.
COMPOUND A, or a pharmaceutically acceptable salt thereof, has been
shown to have analgesic effects in a number of animal models at
oral doses ranging from 1 mg/Kg to 100 mg/Kg. Accordingly, COMPOUND
A, as an enantiomer or a pharmaceutically acceptable salt thereof,
can also be useful for treating pruritis.
[0150] The types of pruritis, include, but are not limited to:
[0151] a) psoriatic pruritis, itch due to hemodialysis, and itching
caused by skin disorders (e.g., dermatitis), systemic disorders,
neuropathy, psychogenic factors or a mixture thereof; [0152] b)
itch caused by allergic reactions, insect bites, hypersensitivity
(e.g., dry skin, eczema, psoriasis), acne, inflammatory conditions
or injury; [0153] c) skin irritation or inflammatory effect from
administration of another therapeutic such as, for example,
antibiotics, antivirals and antihistamines; and [0154] d) itch
caused by viral infections, such as itch associated with
post-herpetic neuralgias.
[0155] The general utility of the spiro-oxindole compound, or a
pharmaceutically acceptable salt thereof, of the invention as a
sodium channel blocker is described in PCT Published Patent
Application No. WO 06/110917. In particular, the general utility of
the spiro-oxindole compound, or a pharmaceutically acceptable salt
thereof, used in the pharmaceutical compositions of the invention
in mediating, especially inhibiting, the sodium channel ion flux
has been determined using the assays described in PCT Published
Patent Application No. WO 06/110917. The general utility of
COMPOUND A, or a pharmaceutically acceptable salt, used in the
pharmaceutical compositions of the invention in treating
sodium-channel mediated diseases or conditions may be established
in industry standard animal models and in the animal models
disclosed in PCT Published Patent Application No. WO 06/110917 for
demonstrating the efficacy of the spiro-oxindole compound, or a
pharmaceutically acceptable salt thereof, in treating such diseases
and conditions.
[0156] Accordingly, this invention provides a method of treating a
range of sodium channel-mediated diseases or condition, preferably
neuronal voltage-gated sodium channel-mediate diseases or
condition, in a mammal, preferably a human, through inhibition of
ion flux through a voltage-dependent sodium channel in the mammal,
preferably a neuronal voltage-gated sodium channel, wherein the
method comprises administering to the mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the invention as set forth above.
[0157] As noted above, the pharmaceutical compositions of the
invention are useful in treating sodium channel-mediated diseases
or conditions, preferably neuronal voltage-gated sodium
channel-mediated diseases or conditions. In particular, the
pharmaceutical compositions of the invention are useful in treating
or lessening the severity of a disease or condition where
activation or hyperactivity of one or more of neuronal
voltage-gated sodium channels selected from Na.sub.v1.1,
Na.sub.v1.2, Na.sub.v1.3, Na.sub.v1.4, Na.sub.v1.5, Na.sub.v1.6,
Na.sub.v1.7, Na.sub.v1.8, or Na.sub.v1.9 is implicated in the
disease or condition. Preferably, the pharmaceutical compositions
of the invention are useful in treating or lessening the severity
of a disease or condition where activation or hyperactivity of
Na.sub.v1.7 is implicated in the disease or condition, such as pain
or post-herpetic neuralgia.
[0158] Accordingly, the invention provides a method for treating or
lessening the severity of a disease, condition, or disorder where
activation or hyperactivity of one or more of neuronal
voltage-gated sodium channels selected from Na.sub.v1.1,
Na.sub.v1.2, Na.sub.v1.3, Na.sub.v1.4, Na.sub.v1.5, Na.sub.v1.6,
Na.sub.v1.7, Na.sub.v1.8, or Na.sub.v1.9 is implicated in the
disease, condition or disorder, wherein the methods comprise
administering to the mammal in need thereof a therapeutically
effective amount of a pharmaceutical composition of the invention
as set forth above.
[0159] Further disclosure of the utility of the pharmaceutical
compositions of the invention is set forth below.
Preparation of the Spiro-Oxindole Compound of the Invention
[0160] The spiro-oxindole compound, as an enantiomer, a racemate or
a non-racemic mixture of enantiomers, or a pharmaceutically
acceptable salt thereof, used in the pharmaceutical compositions of
the invention can be prepared by the methods disclosed in PCT
Published Patent Application No. WO 06/110917, or by methods known
to one skilled in the art. COMPOUND A and its corresponding
(R)-enantiomer, and their pharmaceutically acceptable salts, can be
prepared by the methods disclosed in PCT Published Patent
Application No. WO 2011/002708, the relevant disclosure of which is
disclosed herein in its entiretly, or by methods known to one
skilled in the art.
[0161] COMPOUND A, or a pharmaceutically acceptable salt thereof,
and its corresponding (R)-enantiomer can be prepared by the
resolution of the spiro-oxindole compound using either chiral high
pressure liquid chromatography methods or by simulated moving bed
chromatography methods, as described below in the following
Reaction Scheme wherein "chiral HPLC" refers to chiral high
pressure liquid chromatography and "SMB" refers to simulated moving
bed chromatography:
##STR00005##
[0162] One of ordinary skill in the art would recognize variations
in the above Reaction Scheme which are appropriate for the
resolution of the individual enantiomers.
[0163] Alternatively, COMPOUND A and its corresponding
(R)-enantiomer can be synthesized from chiral starting materials
which are known or readily prepared using process analogous to
those which are known.
[0164] Preferably, COMPOUND A obtained by the resolution methods
disclosed herein is substantially free of the (R)-enantiomer or
contains only traces of the (R)-enantiomer.
[0165] The following Synthetic Examples serve to illustrate the
resolution methods disclosed by the above Reaction Scheme and are
not intended to limit the scope of the invention.
Synthetic Example 1
Synthesis of
1'-{[5-(trifluoromethyhfuran-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxo-
le-7,3'-indol]-2'(1'H)-one (Spiro-Oxindole Compound)
##STR00006##
[0167] To a suspension of
spiro[furo[2,3-f][1,3]benzodioxole-7,3'-indol]-2'(1'H)-one (1.0 g,
3.6 mmol), which can be prepared according to the methods disclosed
in PCT Published Patent Application No. WO 06/110917, and cesium
carbonate (3.52 g, 11 mmol) in acetone (50 mL) was added
2-bromomethyl-5-trifluoromethylfuran (1.13 g, 3.9 mmol) in one
portion and the reaction mixture was stirred at 55-60.degree. C.
for 16 hours. Upon cooling to ambient temperature, the reaction
mixture was filtered and the filtrate was evaporated under reduced
pressure. The residue was subjected to column chromatography,
eluting with ethyl acetate/hexane (1/9-1/1) to afford
1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]benzodiox-
ole-7,3'-indol]-2'(1'H)-one, i.e., the Spiro-oxindole compound,
(1.17 g, 76%) as a white solid: mp 139-141.degree. C.; .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.32-6.97 (m, 5H), 6.72 (d, J=3.24
Hz, 1H), 6.66 (s, 1H), 6.07 (s, 1H), 5.90-5.88 (m, 2H), 5.04 (ABq,
2H), 4.74 (ABq, 2H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.
176.9, 155.7, 153.5, 148.8, 142.2, 141.9, 140.8, 140.2, 139.7,
139.1, 132.1, 129.2, 124.7, 124.1, 123.7, 121.1, 120.1, 117.6,
114.5, 114.4, 110.3, 109.7, 103.0, 101.9, 93.8, 80.0, 57.8, 36.9;
MS (ES+) m/z 430.2 (M+1), 452.2 (M+23); Cal'd for
C.sub.22H.sub.14F.sub.3NO.sub.5: C, 61.54%; H, 3.29%; N, 3.26%.
Found: C, 61.51%; H, 3.29%; N, 3.26%.
Synthetic Example 2
Resolution of the Spiro-Oxindole Compound by Chiral HPLC
[0168] The spiro-oxindole compound was resolved into COMPOUND A and
the corresponding (R)-enantiomer by chiral HPLC under the following
conditions: [0169] Column: Chiralcel.RTM. OJ-RH; 20 mm
I.D..times.250 mm, 5 mic; Lot: OJRH CJ-EH001 (Daicel Chemical
Industries, Ltd) [0170] Eluent: Acetonitrile/Water (60/40, v/v,
isocratic) [0171] Flow rate: 10 mL/min [0172] Run time: 60 min
[0173] Loading: 100 mg of compound of formula (I) in 1 mL of
acetonitrile [0174] Temperature: Ambient
[0175] Under the above chiral HPLC conditions, the (R)-enantiomer,
i.e.,
(R)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]-benz-
odioxole-7,3'-indol]-2'(1'H)-one, was isolated as the first
fraction as a white solid; ee (enantiomeric excess)>99%
(analytical OJRH, 55% acetonitrile in water); mp 103-105.degree.
C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.32-6.99 (m, 5H),
6.71 (d, J=3.35 Hz, 1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (ABq,
2H), 5.03 (ABq, 2H), 4.73 (ABq, 2H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 177.2, 155.9, 152.0, 149.0, 142.4, 142.0,
141.3, 132.0, 129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3,
108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9; MS (ES+) m/z 430.2
(M+1), [.alpha.].sub.D-17.46 (c 0.99, DMSO). COMPOUND A, i.e.,
(S)-1'-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro-[furo[2,3-f][1,3]benz-
odioxole-7,3'-indol]-2'(1'H)-one, was isolated as the second
fraction as a white solid; ee>99% (analytical OJRH, 55%
acetonitrile in water); mp 100-102.degree. C.; .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 7.32-6.99 (m, 5H), 6.71 (d, J=3.43 Hz,
1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (ABq, 2H), 5.03 (ABq, 2H),
4.73 (ABq, 2H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 177.2,
155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9,
120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3,
58.2, 36.9; MS (ES+) m/z 430.2 (M+1), [.alpha.].sub.D+14.04 (c
0.99, DMSO).
Synthetic Example 3
Resolution of the Spiro-Oxindole Compound by SMB Chromatography
[0176] The spiro-oxindole compound was resolved into COMPOUND A and
the corresponding (R)-enantiomer by SMB chromatography under the
following conditions: [0177] Extract: 147.05 mL/min [0178]
Raffinate: 76.13 mL/min [0179] Eluent: 183.18 mL/min [0180] Feed:
40 mL/min [0181] Recycling: 407.88 mL/min [0182] Run Time: 0.57 min
[0183] Temperature: 25.degree. C. [0184] Pressure: 46 bar
[0185] The feed solution (25 g of compound of formula (I) in 1.0 L
of mobile phase (25:75:0.1 (v:v:v) mixture of
acetonitrile/methanol/trifluoroacetic acid)) was injected
continuously into the SMB system (Novasep Licosep Lab Unit), which
was equipped with eight identical columns in 2-2-2-2 configuration
containing 110 g (per column, 9.6 cm, 4.8 cm I.D.) of chiralpack AD
as stationary phase. The first eluting enantiomer (the
(R)-enantiomer) was contained in the raffinate stream and the
second eluting enantiomer (COMPOUND A) was contained in the extract
stream. The characterization data of COMPOUND A and the
(R)-enantiomer obtained from the SMB resolution were identical to
those obtained above utilizing chiral HPLC.
Preparation of the Pharmaceutical Compositions of the Invention
[0186] The preparation of the pharmaceutical compositions of the
invention employs conventional techniques of pharmaceutical
formulation, medicinal chemistry and the like, which are within the
skill of one ordinarily skilled in the art. Such techniques are
explained fully in the literature. Preparation of pharmaceutical
compositions are described, for example, in Remington: The Science
and Practice of Pharmacy, 21.sup.st edition (Lippincott Williams
& Wilkins, (2005) and Ansel et al., Pharmaceutical Dosage Forms
and Drug Delivery Systems, 8.sup.th Ed. (Med, P A: Williams &
Wilkins, 2005), hereby incorporated by reference.
[0187] The pharmaceutical compositions of the invention are
preferably in ointment form. Ointments are semisolids that contain
little if any water and are typically prepared by mixing the active
ingredient with a greasy or non-greasy base with the aid of
suitable machinery.
[0188] The pharmaceutical compositions of the invention comprise
one or more pharmaceutically acceptable excipients.
[0189] It is understood that the pharmaceutically acceptable
excipients used in any of the topical pharmaceutical compositions
of the invention are preferably sterile and/or preferably have been
approved by the United States Food and Drug Administration, the
European Medicines Agency or Health Canada as being acceptable for
use in topical formulations to be administered to humans and
animals.
[0190] In the preparation of pharmaceutical compositions of the
invention, extensive studies, such as solubility and stability,
were conducted to provide pharmaceutical compositions which allowed
for the desired therapeutically effective amount of the active
ingredient, i.e., the spiro-oxindole compound, as an enantiomer, a
racemate or a non-racemic mixture of enantiomers, or a
pharmaceutically acceptable salt thereof, preferably COMPOUND A, or
a pharmaceutically acceptable salt thereof, to be dissolved in one
or more pharmaceutically acceptable excipients and which allowed
for the active ingredient to be readily solubilized in the
pharmaceutical composition, and well-preserved for multiple
applications. Furthermore, the pharmaceutical compositions need to
be physically and chemically stable at ambient temperature over a
suitable period of time, preferably for a period of time from about
1 month to about 5 years, more preferably for a period of time from
about 1 year to about 3 years.
[0191] The spiro-oxindole compound of the invention, particularly,
COMPOUND A, is relatively lipophilic and has poor water solubility.
COMPOUND As water solubility is less than 5 .mu.g/mL. Furthermore,
COMPOUND A has a calculated Log P of about 3.07, and does not
contain functional groups that can be ionised by pH alteration and
consequently varying the pH of a solution to 2, 7.4 and 12 does not
change the solubility of COMPOUND A, which remains at <5
.mu.g/mL.
[0192] Attempts to improve the solubility of COMPOUND A for use in
a topical pharmaceutical composition, preferably as an ointment,
were undertaken using a variety of solubilization techniques. The
aim was to conduct a thorough investigation of the use of various
pharmaceutically acceptable excipients to maximize the solubility
of COMPOUND A. A series of solubility studies, which were performed
using standard solubility testing techniques, was therefore carried
out to identify proper excipient(s) and/or excipient combinations
for achieving the target dosage strength for COMPOUND A. The
solubility of COMPOUND A in these studies was determined by UV
spectrophotometry using COMPOUND As UV absorbance wavelength at 312
nm.
[0193] In addition to the solubility studies undertaken, a series
of stability studies were conducted to determine the physical and
chemical stability of the pharmaceutical compositions prepared.
[0194] Based on the results obtained from the solubility and
stability studies and the results obtain from in vivo efficacy
studies, the following representative pharmaceutical compositions
of the invention were prepared:
TABLE-US-00001 TABLE 1 Component Function % (w/w) % (w/w) % (w/w) %
(w/w) % (w/w) COMPOUND A Active 1.0 2.0 4.0 4.0 8.0 Ingredient PEG
400 Solvent and 53.9 52.9 50.9 50.9 46.9 ointment base Transcutol
.RTM. P Penetration 10.0 10.0 5.0 10.0 10.0 enhancer Oleyl alcohol
Penetration 5.0 5.0 5.0 5.0 5.0 enhancer Isopropyl Penetration 5.0
5.0 5.0 5.0 5.0 myristate enhancer Stearyl alcohol Stiffening 5.0
5.0 10.0 5.0 5.0 agent Butylated Antioxidant 01 0.1 0.1 0.1 0.1
hydroxytoluene (BHT) PEG 3350 Ointment 20.0 20.0 20.0 20.0 20.0
base Total 100.0 100.0 100.0 100.0 100.0
[0195] In general, each pharmaceutically acceptable excipient may
be present in a pharmaceutical composition of the invention in a
concentration of from about 0.5% w/w to about 99.0% w/w. More
preferred, each pharmaceutically acceptable excipient may be
present in a pharmaceutical composition of the invention in a
concentration of from about 1% w/w to about 90% w/w. Even more
preferred, each pharmaceutically acceptable excipient may be
present in a pharmaceutical composition of the invention in a
concentration of from about 10% w/w to about 80.0% w/w.
[0196] Preferably, in a pharmaceutical composition of the
invention, PEG 400 is present in a concentration of from about 30%
w/w to about 70% w/w, Transcutol.RTM. P is present in a
concentration of from about 2% w/w to about 25% w/w, oleyl alcohol
is present in a concentration of from about 1% w/w to about 10%
w/w, isopropyl myristate is present in a concentration of from
about 1% w/w to about 25% w/w, stearyl alcohol is present in a
concentration of from about 0.1% w/w to about 10% w/w, BHT is
present in a concentration of from about 0.01% w/w to about 2% w/w,
and PEG 3350 is present in a concentration of from about 10% w/w to
about 50% w/w.
[0197] More preferably, in a pharmaceutical composition of the
invention, PEG 400 is present in a concentration of from about 45%
w/w to about 55% w/w, Transcutol.RTM. P is present in a
concentration of from about 5% w/w to about 15% w/w, oleyl alcohol
is present in a concentration of from about 2.5% w/w to about 7.5%
w/w, isopropyl myristate is present in a concentration of from
about 2.5% w/w to about 7.5% w/w, stearyl alcohol is present in a
concentration of from about 0.1% w/w to about 7.5% w/w, BHT is
present in a concentration of from about 0.05% w/w to about 1% w/w,
and PEG 3350 is present in a concentration of from about 15% w/w to
about 30% w/w.
[0198] Preferably, in a pharmaceutical composition of the
invention, the spiro-oxindole compound, as an enantiomer, a
racemate or a non-racemic mixture of enantiomers, or a
pharmaceutically acceptable salt thereof, is present in a
concentration of from about 0.1% w/w to about 10% w/w, and
preferably from about 2% w/w to about 8% w/w.
[0199] The stability of the pharmaceutical compositions disclosed
herein may be tested in conventional manner, e.g., by measurement
of COMPOUND A, or a pharmaceutically acceptable salt thereof, and
its degradation products, dissolution, friability, disintegration
time, microbial content, appearance and/or microscopy, for defined
periods of time.
[0200] Preferably, the pharmaceutical compositions of this
invention will be stable for a time period of between about 1 month
and about 5 years when kept at a temperature between about
5.degree. C. and about 50.degree. C. More preferably, the
pharmaceutical compositions of this invention will be stable for a
time period of between about 6 months and about 4 years when kept
at a temperature between about 15.degree. C. and about 45.degree.
C. Even more preferably, the pharmaceutical compositions of this
invention will be stable for a time period of between about 6
months and about 3 years when kept at a temperature between about
25.degree. C. and about 40.degree. C. In a more preferred
embodiment, the pharmaceutical compositions are stable when kept at
a temperature of between about 25.degree. C. and about 40.degree.
C. over a period of time such as a year, and preferably 2 years.
More preferably, the pharmaceutical compositions are stable for 3
years.
[0201] The pharmaceutical compositions of the invention set forth
above in Table 1 may be prepared as set forth in the following
PREPARATION EXAMPLE 1. It is understood, however, that that one
skilled in the art would be able to prepare the pharmaceutical
compositions by similar methods or by methods known to one skilled
in the art. It is also understood that one skilled in the art would
be able to prepare in a similar manner as described below other
pharmaceutical compositions of the invention not specifically
illustrated below by using the appropriate components and modifying
the parameters of the preparation as needed.
Preparation Example 1
[0202] A standard manufacturing vessel with a propeller/shaft is
tared and the tare weight recorded. With continuous propeller
mixing, oleyl alcohol, isopropyl myristate, Transcutol.RTM. P, PEG
3350, stearyl alcohol, PEG 400 and butylated hydroxytoluene (BHT)
are added to the vessel in the amounts listed above in Table 1, one
excipient at a time until a homogenous solution is obtained before
the addition of the next excipient, at preferably 60.degree. C. to
70.degree. C. To the resultant mixture is added the desired amount
of COMPOUND A, or a pharmaceutically acceptable salt thereof, in
the amount listed above in Table 1 at preferably 60.degree. C. to
70.degree. C. The resultant mixture is mixed for a suitable period
of time, preferably for a period of time of between about 30
minutes and about 1 hour. Upon completion (when COMPOUND A, or a
pharmaceutically acceptable salt thereof, is completely dissolved),
the propeller mixer is removed and the homogenization process is
started. A Silverson Mixer (Model No. L4RT) is used for the
homogenization, where the homogenization is carried out for 10
minutes and the rotor speed is kept at 6000 rpm. During the
homogenization process, the temperature of the solution is
constantly monitored and is kept at preferably between about
60.degree. C. and about 70.degree. C. After the homogenization is
completed, the heat source is removed to cool the mixture, and
quickly switched to propeller mixing until an ointment is formed
and the temperature reaches a suitable temperature, preferably
35.degree. C. or below. The sides of the vessel are continuously
scraped down during the cooling and mixing stage to ensure the
ointment is homogenous. The resulting ointment is then transferred
to an appropriate container.
[0203] The process described above can be carried out utilizing
conventional equipment and under conventional conditions known to
those skilled in the art. All of the raw materials were used as
obtained from the various manufactures with the following exception
of COMPOUND A, which is obtained as described herein.
Administration of the Pharmaceutical Compositions of the
Invention
[0204] The pharmaceutical compositions of the invention are to be
topically administered to a mammal, preferably a human. The
pharmaceutical composition is applied topically to a site at or
adjacent to a region where the treatment is desired. Typically, one
to four applications per day of a pharmaceutical composition of the
invention are recommended during the treatment period, or it can be
reapplied as often as necessary. Relief is typically obtained
within minutes and lasts for periods of variable duration ranging
from minutes to hours to even, in some cases, days. Generally, the
amount of the pharmaceutical formulation of the invention applied
to the affected skin area ranges from about 0.02 g/cm.sup.2 of skin
surface area to about 0.5 g/cm.sup.2, preferably, 0.1 g/cm.sup.2 to
about 0.30 g/cm.sup.2 of skin surface area.
[0205] In some embodiments, the pharmaceutical composition of the
invention, when topically administered to the skin of a mammal in
need thereof, exerts only a local effect. In other embodiments, the
pharmaceutical composition of the invention, when topically
administered to the skin of a mammal in need thereof, additionally
has a systemic effect.
[0206] Application of the pharmaceutical composition of the
invention may be performed by a medical professional or by the
patient. In certain embodiments, for maximum effectiveness and
increased absorption, the area to which the pharmaceutical
composition of the invention is to be administered is first
cleansed, for example using an astringent, such as a standard
commercial antiseptic or alcohol. The area is then allowed to dry,
and the pharmaceutical composition of the invention is applied onto
the target area and rubbed until all the pharmaceutical composition
has been absorbed or no residue remains on the skin.
[0207] Typically, a successful therapeutic effective amount of a
pharmaceutical composition of the invention will meet some or all
of the following criteria. As will be appreciated by one skilled in
the art, the therapeutically effective dosage of a spiro-oxindole
compound of the invention, as an enantiomer, a racemate or a
non-racemic mixture of enantiomers, preferably as COMPOUND A, or a
pharmaceutically acceptable salt thereof, will be such that it is
effective for its intended purpose (e.g., prevent, reduce or
alleviate pain). In general, a spiro-oxindole compound of the
invention, as an enantiomer, a racemate or a non-racemic mixture of
enantiomers, preferably as COMPOUND A, or a pharmaceutically
acceptable salt thereof, is present in a pharmaceutical composition
of the invention in an amount of from about 2% to about 10% of the
total weight of the composition, preferably in an amount of from
about 4% to about 8% of the total weight of the composition, more
preferably, of from about 4% to about 6% of the total weight of the
composition.
[0208] The potency (as expressed by IC.sub.50 value) of COMPOUND A,
or a pharmaceutically acceptable salt thereof, should be less than
10 .mu.M, preferably below 1 .mu.M and most preferably below 50 nM.
The IC.sub.50 ("Inhibitory Concentration--50%") is a measure of the
amount of compound required to achieve 50% inhibition of ion flux
through a sodium channel, over a specific time period, in an assay
of the invention. For example, COMPOUND A, or a pharmaceutically
acceptable salt thereof, when tested in the guanidine influx assay
disclosed in PCT Published Patent Application No. WO 06/110917,
demonstrated an IC.sub.50 of less than 1 .mu.M concentration.
[0209] The recipients of administration of the pharmaceutical
compositions of the invention can be any vertebrate animal, such as
mammals. Among mammals, the preferred recipients are mammals of the
Orders Primate (including humans, apes and monkeys), Arteriodactyla
(including horses, goats, cows, sheep, and pigs), Rodenta
(including mice, rats, rabbits, and hamsters), and Carnivora
(including cats, and dogs). Among birds, the preferred recipients
are turkeys, chickens and other members of the same order. The most
preferred recipients are humans.
Combination Therapy
[0210] The pharmaceutical compositions of the invention may be
usefully combined with one or more other therapeutic agent or as
any combination thereof, in the treatment of sodium
channel-mediated diseases and conditions. For example, the
pharmaceutical composition of the invention may be administered
simultaneously, sequentially or separately in combination with
other therapeutic agents, including, but not limited to: [0211]
opiates analgesics, e.g., morphine, heroin, cocaine, oxymorphine,
levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine,
propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone,
meripidine, methadone, nalorphine, naloxone, naltrexone,
buprenorphine, butorphanol, nalbuphine and pentazocine; [0212]
non-opiate analgesics, e.g., acetomeniphen, and salicylates (e.g.,
aspirin); [0213] nonsteroidal antiinflammatory drugs (NSAIDs),
e.g., ibuprofen (Advil.RTM.), naproxen, fenoprofen, ketoprofen,
diclofenac, diflusinal, etodolac, fenbufen, flufenisal,
flurbiprofen, indomethacin, ketorolac, meclofenamic acid, mefenamic
acid, meloxicam, nabumetone, nimesulide, nitroflurbiprofen,
olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine,
sulindac, tolmetin and zomepirac; [0214] anticonvulsants, e.g.,
carbamazepine, oxcarbazepine, lamotrigine, gabapentin and
pregabalin; [0215] antidepressants such as tricyclic
antidepressants, e.g., amitriptyline, clomipramine, despramine,
imipramine, duloxetine and nortriptyline; [0216] COX-2 selective
inhibitors, e.g., celecoxib, rofecoxib, parecoxib, valdecoxib,
deracoxib, etoricoxib, and lumiracoxib; [0217] alpha-adrenergics,
e.g., doxazosin, tamsulosin, clonidine, guanfacine,
dexmetatomidine, modafinil, and 4-amino-6,7-dimethoxy-2-(5-methane
sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)
quinazoline; [0218] barbiturate sedatives, e.g., amobarbital,
aprobarbital, butabarbital, butabital, mephobarbital, metharbital,
methohexital, pentobarbital, phenobartital, secobarbital, talbutal,
theamylal and thiopental; [0219] tachykinin (NK) antagonist,
particularly an NK-3, NK-2 or NK-1 antagonist, e.g.,
(.alpha.R,9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9--
methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-
-dione (TAK-637),
5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophe-
nyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one
(MK-869), aprepitant, lanepitant, dapitant or
3-[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine
(2S,3S); [0220] paracetamol; [0221] metabotropic glutamate receptor
(mGluR) antagonists; [0222] local anaesthetic such as mexiletine
and lidocaine; [0223] corticosteroid such as dexamethasone; [0224]
muscarinic antagonists, e.g., tolterodine, propiverine, tropsium t
chloride, darifenacin, solifenacin, temiverine and ipratropium;
[0225] cannabinoids; [0226] vanilloid receptor agonists (e.g.,
resinferatoxin) or antagonists (e.g., capsazepine); [0227] topical
agents (e.g., lidocaine, capsacin and resiniferotoxin); [0228]
muscle relaxants such as benzodiazepines, baclofen, carisoprodol,
chlorzoxazone, cyclobenzaprine, methocarbamol and orphrenadine;
[0229] anti-histamines or H1 antagonists; [0230] NMDA receptor
antagonists; [0231] PDEV inhibitors; [0232] Tramadol.RTM.; [0233]
cholinergic (nicotinc) analgesics; [0234] alpha-2-delta ligands;
[0235] prostaglandin E2 subtype antagonists; [0236] leukotriene B4
antagonists; and [0237] 5-lipoxygenase inhibitors
[0238] Sodium channel-mediated diseases and conditions that may be
treated and/or prevented using such combinations include but not
limited to, pain, post-herpetic neuralgia (PHN), post-operative
pain, pruritis, pain associated with HIV, HIV treatment induced
neuropathy, trigeminal neuralgia, familial erythromelalgia, primary
erythromelalgia, familial rectal pain, eudynia, heat sensitivity,
pain associated with multiple sclerosis (MS), amyotrophic lateral
sclerosis (ALS), painful diabetic neuropathy, peripheral
neuropathy, arthritis, rheumatoid arthritis, osteoarthritis,
tendonitis, bursitis, musculoskeletal sprains, tenosinovitis,
chondromalacia patellae, myositis, myotonia (including but not
limited to SCN4A-related myotonia), paramyotonia, rhabdomyolysis,
paroxysmal dystonia, myasthenia syndromes, malignant hyperthermia,
cystic fibrosis, sodium channel toxin related illnesses, cancer
pain, restless leg syndrome, fibromyalgia, and neurodegenerative
disease, as well as other neurological disorders including multiple
sclerosis.
[0239] As used herein "combination" refers to any mixture or
permutation of a pharmaceutical composition of the invention with
one or more additional therapeutic agent. Unless the context makes
clear otherwise, "combination" may include simultaneous or
sequentially delivery of a pharmaceutical composition of the
invention with one or more therapeutic agents. Unless the context
makes clear otherwise, "combination" may include dosage forms of a
pharmaceutical composition of the invention with another
therapeutic agent. Unless the context makes clear otherwise,
"combination" may include different routes of administration of a
pharmaceutical composition of the invention with another
therapeutic agent. For example, the pharmaceutical composition of
the invention is administered topically in combination with another
therapeutic agent that is administered orally. Unless the context
makes clear otherwise, "combination" may include formulations of a
pharmaceutical composition of the invention with another
therapeutic agent. Dosage forms, routes of administration and
pharmaceutical compositions include, but are not limited to, those
described herein.
Article of Manufacture
[0240] The present invention also provides kits that contain a
pharmaceutical composition of the invention. The kit also includes
instructions for the use of the pharmaceutical composition for
modulating the activity of sodium channels, for the treatment of
pain, as well as other utilities as disclosed herein. Preferably, a
commercial package will contain one or more unit doses of the
pharmaceutical composition. It will be evident to those of ordinary
skill in the art that such compositions which are light and/or air
sensitive may require special packaging and/or formulation. For
example, packaging may be used which is opaque to light, and/or
sealed from contact with ambient air, and/or formulated with
suitable coatings or excipients.
[0241] The invention may be even better understood by way of the
following non-limiting Biological Examples which describe assays
which can be performed to demonstrate the utility of the
invention.
Biological Example 1
Dose Proportionality in CFA Induced Chronic Inflammatory Pain
[0242] In this test, mechanical hyperalgesia is assessed with
electronic von Frey filament by means of Electrovonfrey
anesthesiometer (Model 2290, IITC Life Science, Woodland Hills,
Calif.). Following a full week of acclimatization to the vivarium
facility, 150 .mu.L of the "Complete Freund's Adjuvant" (CFA)
emulsion (CFA suspended in an oil/saline (1:1) emulsion at a final
concentration of 0.5 mg/mL) was injected subcutaneously into the
plantar surface of the left hind ankle joint of rats under light
isoflurane anaesthesia. Animals were allowed to recover from the
anaesthesia and the baseline mechanical nociceptive thresholds of
all animals were assessed one week after the administration of CFA.
All animals were habituated to the experimental chambers for 20
minutes on the day of the experiment. The animals were then
randomly assigned to 5 different test groups including a vehicle
control group and 4 pharmaceutical compositions with COMPOUND A at
1%, 2%, 4% and 8% (w/w) groups. After baseline measurements,
animals were anaesthetized under isoflurane, shaved at the site of
application, and then dosed by application of 50 mg test
compositions on the entire ipsilateral hind ankle and foot. Animals
were then placed in Plexiglas tubes for 30 minutes to prevent early
removal/ingestion of drug. Test compositions were applied twice a
day for 3 days. On the fourth day, immediately after application,
animals were placed in tubes for 15 minutes and then removed and
placed in Plexiglas enclosures for 15 minutes prior to making paw
withdrawal measurements. Von Frey withdrawal thresholds were
measured as the mean of several independent determinations made
within 1-2 minutes of each other on the affected paw of each animal
30 minutes post-dosing. The time point used was previously
determined to show the highest analgesic effect for each test
composition.
[0243] The response thresholds of animals to tactile stimuli were
measured using the Model 2290 Electrovonfrey anesthesiometer (IITC
Life Science, Woodland Hills, Calif.). Animals were placed in an
elevated Plexiglas enclosure set on a mire mesh surface. After 15
minutes of accommodation, a von Frey hair was applied
perpendicularly to the plantar surface of the ipsilateral hind paws
of the animals with sufficient force, measured in grams, to elicit
a crisp response of the paw. The response indicated a withdrawal
from the painful stimulus and constituted the efficacy
endpoint.
Results
[0244] At baseline, there were no significant differences between
the means of the von Frey paw withdrawal measurements for the 5
test groups. On the fourth day of dosing at 30 minutes post-dosing,
the groups treated with pharmaceutical compositions of COMPOUND A
at 2%, 4%, and 8% (w/w) all showed statistically significant
increases in the von Frey mechanical paw withdrawal thresholds as
expressed by percent change from baseline (CFB) to indicate an
analgesic effect (see FIG. 1). The analgesic effect for the
compositions with COMPOUND A increased with increasing doses up to
the highest dose tested of 8% (w/w), which showed the maximum
percent CFB at +45.1%. The 1% (w/w) dosage group, however, did not
demonstrate an observable increase in von Frey mechanical paw
withdrawal threshold. The results, as set forth in FIG. 1, indicate
that compositions of COMPOUND A have analgesic effects in the
CFA-induced inflammatory pain model in the range of 2% to 8%
(w/v).
Biological Example 2
Time Course of Efficacy in the Neuropathic Pain Model; Chronic
Constriction Injury
[0245] Neuropathic pain is characterized by spontaneous pain and
stimulus-evoked allodynia and hyperalgesia. Pharmaceutical
compositions of the invention were evaluated in Chronic
Constriction Injury model using Sprague-Dawley rats as described
below.
[0246] An approximately 3 cm incision was made through the skin and
the fascia at the mid thigh level of a rat's left hind leg using a
no. 10 scalpel blade. The left sciatic nerve was exposed via blunt
dissection through the biceps femoris with care to minimize
haemorrhagia. Four loose ligatures were tied along the sciatic
nerve using four chromic gut sutures at intervals of 1 mm to 2 mm
apart. The tension of the loose ligatures was tight enough to
induce slight constriction of the sciatic nerve when viewed under a
dissection microscope at a magnification of 4 fold. As sham
controls, the right sciatic nerve was exposed and manipulated in
the same manner as described above, except sutures were not tied
onto the nerve. Antibacterial ointment was applied directly into
the wound, and the muscle was closed using sterilized sutures.
Betadine.RTM. was applied onto the muscle and its surroundings,
followed by skin closure with surgical clips.
[0247] A painful neuropathy was allowed to develop for at least 14
days in the ipsilateral leg as determined by lower paw withdrawal
thresholds to a mechanical stimulus. Only those with significant
hyperalgesia, as determined by reduced threshold of paw withdrawal
to the von Frey filament, measured in grams, were enrolled in the
study. All animals enrolled in the study showed paw withdrawal
thresholds of <12 g.
[0248] The response thresholds of animals to tactile stimuli were
measured using the Model 2290 Electrovonfrey anesthesiometer (IITC
Life Science, Woodland Hills, Calif.). Animals were placed in an
elevated Plexiglass enclosure set on a mire mesh surface. After 15
minutes of accommodation, a von Frey hair was applied
perpendicularly to the plantar surface of the ipsilateral hind paws
of the animals with sufficient force, measured in grams, to elicit
a crisp response of the paw. The response indicated a withdrawal
from the painful stimulus and constituted the efficacy endpoint.
The force (in grams) required to elicit a crisp withdrawal response
was recorded before dosing as a baseline measurement, and at
multiple time points post-dosing.
[0249] Three days prior to baseline measurement, animals were
anaesthetized under isoflurane and the whole of the ipsilateral
hind legs, including the upper sciatic notch thigh area, ankle and
foot, was shaved. The animals were then randomly assigned to one of
4 different test groups including a vehicle control group, a 5%
(w/v) Lidocaine (Xylocaine.RTM.), and 2 pharmaceutical compositions
of the invention comprising COMPOUND A at 4% (w/w) containing
either 5% or 10% Transcutol.RTM. P. After baseline measurement, 100
mg of the test composition was applied on the entire shaved area.
The animals were then placed in plastic tubes for at least 15
minutes, to prevent early removal/ingestion of drug. Subsequently,
animals were placed in the Plexiglas enclosure 15 minutes before
von Frey measurement at the respective time points. Von Frey
withdrawal thresholds were measured as the mean of several
independent determinations made within 1-2 minutes of each other on
the affected paw of each animal at 0.5, 1 and 2 hours post
dosing.
Results
[0250] The percent mean change from baseline (CFB) for each groups'
paw withdrawal thresholds is shown in FIG. 2. Observations of
+23.1%, +26.3%, and +33.8% CFB were made for the 5% (w/v) lidocaine
group and 4% (w/w) COMPOUND A in 5% and 10% Transcutol.RTM. P test
groups at 0.5 hours post-dosing, respectively. At 1 hour
post-dosing, +18.1% and +26.7% CFB were observed for 4% (w/w)
COMPOUND A in 5% and 10% Transcutol.RTM. P treatment groups
respectively. No significant changes (p>0.05) were observed for
the 5% (w/v) lidocaine treatment group at any time points later
than 0.5 hours post-dosing. The 4% (w/w) COMPOUND A in 10%
transcutol group exhibited analgesic effects from 0.5 hour up to 2
hours post-dosing, with improved efficacy and longer duration of
analgesia as compared to the 4% (w/w) COMPOUND A in 5% transcutol
group. Both groups of 4% (w/w) COMPOUND A exhibited a longer
lasting analgesic effect when compared with the 5% lidocaine group,
which exhibited analgesic effects only up to 0.5 hours post-dosing
in the CCI-induced neuropathic pain model.
Biological Example 3
STZ Model of Diabetic Neuropathy
[0251] This study evaluates the efficacy of a pharmaceutical
composition of the invention in the STZ-induced neuropathic pain
model in male Sprague-Dawley rats, following acute dosing, as
compared with a 5% (w/v) topical Lidocaine (Xylocaine.RTM.) and a
1.16% (w/v) topical Diclofenac (Voltaren.RTM.). A rodent model of
painful peripheral diabetic neuropathy (PDN) that mimics human
condition was created by inducing a diabetic state in the rat
through the ablation of the insulin producing pancreatic beta
cells. A single streptozotocin (STZ) injection destroys beta cells
in rats and produces a diabetic state that over time progresses to
painful Peripheral Diabetic Neuropathy (PDN).
[0252] Streptozotocin (STZ) was dissolved in citrate buffer (20 mM,
pH 4.5) and administered at a dose of 60 mg/Kg, intraperitoneal, to
induce pancreatic beta-cell death. Blood glucose level was measured
once a week following injection, using the AccuSoft Blood Glucose
Monitoring System. A booster injection was administered two weeks
post-initial injection to animals that did not display elevated
blood glucose levels following the first injection. Animals with
plasma glucose concentrations above 16 mmol/L were considered
diabetic and included in the study. Hyperalgesia and allodynia,
which are signs of diabetic neuropathic pain, were monitored using
the von Frey test as described below. Von Frey measurements were
recorded from both left and right paws. Only those with significant
hyperalgesia as determined by reduced threshold, measured in grams,
of paw withdrawal to the von Frey filament were enrolled in the
study. The study was executed during the 8th week following STZ
injection. During this time their health status was closely
monitored.
[0253] The animals were randomly divided into 4 test groups (n=7
animals/group) including a vehicle control, a 5% (w/v) Lidocaine
(Xylocaine.RTM.), a 1.16% (w/v) Diclofenac (Voltaren.RTM.), and a
pharmaceutical composition with 4% (w/w) COMPOUND A. After baseline
measurement, 50 mg of the test composition was applied on the
entire left foot. Animals were then placed in Plexiglas tubes for
15 minutes to prevent early removal/ingestion of drug, and then
moved to the Plexiglas enclosure for von Frey measurement. The paw
withdrawal thresholds of animals from mechanical tactile stimuli
were measured using the Electrovonfrey anesthesiometer (Model 2290,
IITC Life Science, Woodland Hills, Calif.). Animals were placed in
an elevated acrylic enclosure set on a wire mesh surface. After 15
minutes of accommodation, a flexible von Frey hair (tip #15) was
applied perpendicularly to the plantar surface of the ipsilateral
hind paws of the animals, with sufficient force to elicit a crisp
response of the paw. The response indicated a withdrawal from the
painful stimulus and constitutes the efficacy endpoint. The force
(g) required to elicit a crisp withdrawal response was recorded
before dosing as a baseline measurement, and at 30 minutes
post-dosing.
[0254] Withdrawal measurements were recorded from both the treated
(left) and un-treated (right) paws. The von Frey paw withdrawal
data were analyzed using GraphPad Prism 5 statistical analysis
software. One-way ANOVA was used for multivariate analysis with
Bonferroni adjustment. Unpaired t-test was used for univariate
analysis. Results are expressed as mean.+-.SEM. Values that reached
a p<0.05 level of significance were considered statistically
significant.
Results
[0255] At baseline, there were no significant differences between
the four test groups in the von Frey paw withdrawal measurements
for treated paws, nor were there differences between the left and
right hind paw measurements.
[0256] At 30 minutes post-dosing, the percent mean change from
baseline (CFB) for each groups' paw withdrawal thresholds (of
treated paws) is provided in FIG. 3. The change from baseline
reached 44.9% for the 4% (w/w) COMPOUND A dosage group (p<0.05),
substantially above the 25.9% change from baseline observed in the
5% (w/v) Lidocaine group. No significant CFB was observed in the
1.16% (w/v) Diclofenac group.
[0257] Therefore, a local analgesic effect was observed for
composition containing 4% (w/w) COMPOUND A in the STZ-induced
neuropathic pain model at 30 minutes post-dosing, manifesting as a
44.9% change from baseline, greater than the local efficacy
observed with the reference compounds.
Biological Example 4
Relationship Between Efficacy and Systemic Exposure for Topical and
Oral Administration; Chronic Constriction Injury
[0258] The Chronic Constriction Injury (CCI) model, an established
neuropathic pain model in the rat, is used in this study to compare
the levels of efficacy and systemic exposure of COMPOUND A between
the topical and oral administration in male rats.
[0259] A peripheral neuropathy was induced in rats by placing loose
constrictive ligatures around the common sciatic nerve as described
by Bennett G J, and Xie Y-K., Pain, (1988) 33: pp. 87-107.
Eight-week old male Sprague Dawley rats were anaesthetized with
3.5% isoflurane, and a 3 cm incision was made through the skin and
fascia at the mid-thigh level of the animal's left hind leg using a
no. 10 scalpel blade. The left sciatic nerve was exposed via blunt
dissection through the biceps femoris, with care taken to minimize
haemorrhagia. Four loose ligatures were tied along the sciatic
nerve using four chromic gut sutures at intervals of 1 mm to 2 mm
apart. The tension of the loose ligatures was tight enough to
induce slight constriction of the sciatic nerve when viewed under a
dissection microscope at a magnification of 4 fold. Antibacterial
ointment was applied directly into the wound, and the muscle was
closed using sterilized sutures. Betadine.RTM. was applied onto the
muscle and its surroundings, followed by skin closure with surgical
clips.
[0260] A painful neuropathy was allowed to develop in the
ipsilateral leg as determined by lower paw withdrawal thresholds to
a mechanical stimulus. Only those with significant hyperalgesia as
determined by reduced threshold, measured in grams, to paw
withdrawal to the von Frey filament were enrolled in the study. All
animals enrolled in the study showed paw withdrawal thresholds of
<12 g.
[0261] The paw withdrawal thresholds of animals from mechanical
tactile stimuli were measured using the Model 2290 Electrovonfrey
anesthesiometer (IITC Life Science, Woodland Hills, Calif.).
Animals were placed in an elevated Plexiglass enclosure set on a
wire mesh surface. After 15 minutes of accommodation in this
enclosure, a von Frey hair was applied perpendicularly to the
plantar surface of the ipsilateral hind paws of the animals, with
sufficient force, measured in grams, to elicit a crisp response of
the paw. The response indicated a withdrawal from the painful
stimulus and constituted the efficacy endpoint.
[0262] Following paw withdrawal baseline measurements, animals were
randomly divided into 4 different test groups (N=8 animals/group),
including a vehicle control group for oral dosage, a vehicle
control group for topical dosage, and two treatment groups. For the
oral dosage groups, animals were dosed by oral gavages after
baseline measurement. Doses of COMPOUND A were chosen based on
previous studies indicating that the oral dose of 25 mg/Kg of
COMPOUND A produces an approximately half-maximal reversal of pain
response and a level of efficacy comparable to that of the
pharmaceutical composition of the invention comprising COMPOUND A
at 8% (w/w). For the topical dosage groups, 50 mg of the test
composition was applied on the ipsilateral ankle and foot. Animals
were then placed in plastic tubes for 15 minutes, to prevent early
removal/ingestion of drug. Subsequently, animals were placed in the
Plexiglass enclosure for 15 minutes prior to paw withdrawal
measurement. Von Frey withdrawal thresholds were measured as the
mean of several independent determinations made within 1-2 minutes
of each other on the affected paw of each animal. Withdrawal
measurements were taken 60 minutes post dosing for the oral dosage
group and 30 minutes post-dosing for the topical dosage group,
representing their respective peak efficacy time points as
determined in previous studies.
[0263] Blood samples were taken from the same animals immediately
after withdrawal threshold measurements using the following
procedure at approximately 10-15 minutes after their respective
efficacy time points. The rats were bled by jugular vein puncture
while under anaesthesia. The time at which each blood sample was
drawn, relative to the time of dosing, was recorded. Each blood
sample (.about.150 .mu.L) was collected into a heparin-coated,
labelled microvette tube containing 10 .mu.L of heparin (100 Units)
and placed on ice immediately. The blood samples were centrifuged
at 4.degree. C. to separate the plasma. The plasma was transferred
to labelled tubes and snap-frozen in liquid nitrogen for storage at
-80.degree. C. At the time of analysis, the plasma was thawed and
extracted using solid phase extraction, and the plasma drug
concentration was quantified by HPLC/MS/MS.
[0264] The von Frey paw withdrawal data were analyzed using
GraphPad Prism 5 statistical analysis software. One-way ANOVA was
used for multivariate analysis with Bonferroni adjustment. Unpaired
t-test was used for univariate analysis. Results are expressed as
mean.+-.SEM. Values that reached a p<0.05 level of significance
were considered statistically significant.
Results
[0265] At baseline, there were no significant differences between
the means of the von Frey paw withdrawal measurements for the four
test groups.
[0266] The percent mean Change From Baseline (CFB) for each groups'
paw withdrawal thresholds is shown in FIG. 4. At 60 and 30-minute
post-dosing, the CFB reached 44.3% for the 25 mg/Kg COMPOUND A oral
dosage group and 47.1% for the 8% (w/w) COMPOUND A topical dosage
group respectively, which was statistical significance (p<0.001)
when compared to the vehicle groups and indicated an analgesic
effect. No statistical significance was observed between the CFB of
the oral and topical dosage groups (p=0.742).
[0267] Plasma samples were collected from the animals immediately
after von Frey testing. The systemic plasma concentration of
COMPOUND A for the oral and topical dosage groups is shown in FIG.
5. The plasma level of COMPOUND A in the topical dosage group was
significantly lower (.about.20.times.) than the level in the oral
dosage group (p<0.0001).
[0268] 8% (w/w) COMPOUND A by topical administration exhibited a
degree of efficacy (47% CFB) that is comparable to 25 mg/kg
COMPOUND A (44% CFB) by oral administration in the CCI neuropathic
pain model. Systemic plasma exposure of COMPOUND A was
significantly lower (.about.20.times.) in the topical dosage group
than the oral dosage group. Therefore, COMPOUND A given by topical
administration in the CCI neuropathic pain model provides efficacy
comparable to COMPOUND A by oral administration with minimal
systemic exposure.
[0269] Unless indicated otherwise, any U.S. patent, U.S. patent
application publication, or PCT published patent application
referred to in this specification is incorporated herein by
reference in its entirety, including U.S. Provisional Patent
Application No. 61/308,759.
[0270] Although the foregoing invention has been described in some
detail to facilitate understanding, it will be apparent that
certain changes and modifications may be practiced within the scope
of the appended claims. Accordingly, the described embodiments are
to be considered as illustrative and not restrictive, and the
invention is not to be limited to the details given herein, but may
be modified within the scope and equivalents of the appended
claims.
* * * * *