U.S. patent application number 12/871860 was filed with the patent office on 2010-12-23 for combinations of retigabine and sodium channel inhibitors or sodium channel-influencing active compounds for treating pains.
This patent application is currently assigned to Valeant Pharmaceuticals North America. Invention is credited to Kay BRUNE, Robert HERMANN, Mathias LOCHER, Istvan SZELENYI.
Application Number | 20100323987 12/871860 |
Document ID | / |
Family ID | 46149049 |
Filed Date | 2010-12-23 |
United States Patent
Application |
20100323987 |
Kind Code |
A1 |
SZELENYI; Istvan ; et
al. |
December 23, 2010 |
COMBINATIONS OF RETIGABINE AND SODIUM CHANNEL INHIBITORS OR SODIUM
CHANNEL-INFLUENCING ACTIVE COMPOUNDS FOR TREATING PAINS
Abstract
The invention relates to pharmaceutical combinations of
retigabine and sodium channel inhibitors for treating, pains which
are accompanied by an increase in muscle tone.
Inventors: |
SZELENYI; Istvan; (Schwaig,
DE) ; BRUNE; Kay; (Marloffstein, DE) ;
HERMANN; Robert; (Hanau, DE) ; LOCHER; Mathias;
(Ronneburg, DE) |
Correspondence
Address: |
MCDERMOTT, WILL & EMERY LLP
600 13th Street, NW
Washington
DC
20005-3096
US
|
Assignee: |
Valeant Pharmaceuticals North
America
Aliso Viejo
CA
|
Family ID: |
46149049 |
Appl. No.: |
12/871860 |
Filed: |
August 30, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10727655 |
Dec 5, 2003 |
7799832 |
|
|
12871860 |
|
|
|
|
Current U.S.
Class: |
514/63 ; 514/162;
514/317; 514/324; 514/367; 514/479 |
Current CPC
Class: |
A61K 31/44 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61P 19/02 20180101;
A61P 25/02 20180101; A61P 25/08 20180101; A61P 21/00 20180101; A61P
25/04 20180101; A61P 29/00 20180101; A61P 25/00 20180101; A61P
25/06 20180101; A61P 25/16 20180101; A61K 31/44 20130101; A61K
31/27 20130101; A61K 31/27 20130101 |
Class at
Publication: |
514/63 ; 514/479;
514/317; 514/367; 514/162; 514/324 |
International
Class: |
A61K 31/695 20060101
A61K031/695; A61K 31/27 20060101 A61K031/27; A61K 31/4453 20060101
A61K031/4453; A61K 31/428 20060101 A61K031/428; A61K 31/625
20060101 A61K031/625; A61K 31/4535 20060101 A61K031/4535; A61P
19/02 20060101 A61P019/02; A61P 25/04 20060101 A61P025/04; A61P
25/00 20060101 A61P025/00; A61P 29/00 20060101 A61P029/00 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 3, 2003 |
DE |
DE 10349729.3 |
Claims
1. The use of retigabine or its pharmaceutically utilizable salts
in combination with sodium channel-inhibiting or -influencing
substances, or of their therapeutically utilizable salts, for
treating pains which are accompanied by an increase in muscle
tone.
2. The use as claimed in claim 1, wherein the sodium
channel-inhibiting or -influencing substances employed are
tolperisone or its analogs eperisone or silperisone, or riluzole,
propafenone, lidocaine, flecainide or metixen, or their
pharmaceutically utilizable salts.
3. The use as claimed in claim 1, wherein the sodium
channel-inhibiting or -influencing substances employed are
tolperisone or its analogs, such as eperisone or silperisone, or
their pharmaceutically utilizable salts.
4. The use of retigabine in combination with tolperisone or its
analogs, such as eperisone or silperisone, or their
pharmaceutically utilizable salts, for treating pains which are
accompanied by an increase in muscle tone.
5. The use as claimed in claim 1, for treating pains associated
with neuralgias.
6. The use as claimed in claim 1, for treating pains associated
with arthritis and arthrosis.
7. The use as claimed in claim 1, for treating pains associated
with chronic or episodic tension headache.
8. The use as claimed in claim 1, for treating pains associated
with lower spastic paraparesis syndrome (e.g. lower paraspasm,
transverse myelitis, multiple sclerosis, heritable inferior spastic
paraplegia (Stuempel paraplegia), disturbances of the spinal blood
circulation and cerebral paralysis involving lower spastic
paresis).
9. The use as claimed in claim 1, for treating pains associated
with tetraparesis in connection with cervical myelopathy, cervical
brachialgia or vertebral dysplasia.
10. The use as claimed in claim 1, for treating pains associated
with Parkinson's disease.
11. The use of retigabine or its pharmaceutically utilizable salts
in combination with sodium channel-inhibiting or -influencing
substances, and of their therapeutically utilizable salts, for
producing a medicament for oral, rectal, intravenous, transdermal
or subcutaneous or intracutaneous administration for treating pains
which are accompanied by an increase in muscle tone.
Description
[0001] This application is a continuation of U.S. application Ser.
No. 10/727,655, filed Dec. 5, 2003, which claims priority to German
Application Serial No. DE 10349729.3, filed Oct. 3, 2003, each of
which the entire contents are incorporated herein by reference.
[0002] The invention relates to pharmaceutical combinations of
retigabine and sodium channel inhibitors for treating pains which
are accompanied by an increase in muscle tone.
[0003] A number of different painful diseases are accompanied by an
increase in skeletal muscle tone. In some cases, the pain
generation is elicited by joint inflammations, and a painful body
posture, which is frequently accompanied by painful muscle spasms,
develops as a consequence. The treatment of these diseases includes
benzodiazepines, for example; however, these compounds possess a
marked potential for addiction and this limits their use.
Frequently, treating the basic disease, e.g. the rheumatoid
inflammation, does not result in corresponding, satisfactory
therapeutic successes. For this reason, the additional
administration of analgesics and/or skeletal muscle relaxants is
often indicated.
[0004] In clinical practice, centrally acting muscle relaxants are
used for alleviating abnormally elevated muscle tone in patients
who are suffering from painful muscle spasms and/or rigidity in
association with rheumatoid diseases or spasms in connection with
neurological diseases. While a number of appropriate active
compounds are available on the market, their clinical efficacy is
frequently questionable or else limited by undesirable side
effects.
[0005] The Na.sup.+ channel-inhibiting substances constitute one
class of these active compounds. Evidence exists that these
substances are able to relieve an increase in muscle tone. It has
been shown that, in clinically relevant concentration, propofol has
a marked inhibitory effect on the sarcolemma sodium channels. This
mechanism could contribute to reducing muscle tone (Haeseler et
al., Anesth Analg 2001; 92:1192-8). It has also been shown that
inhibiting the Na.sup.+ channels inhibits neurotransmitter release
from the presynaptic termini (Obrenovitch, Int Rev Neurobiol 1997;
40:109-35). The neuroprotective active compound riluzole is a
sodium channel inhibitor and an antiexcitotoxic substance which is
used for treating amyotrophic lateral sclerosis. Kennel et al. (J
Neurol Sci 2000; 180:55-61) have recently shown that riluzole
significantly delays the onset of the paralysis, and retards the
progress of the functional parameters connected to muscle strength,
in a mouse model of motoneuron disease. In a mouse model of
heritable myotonia (De Luca et al., J Pharmacol Exp Ther 1997;
282:93-100), metilexin, an antiarrhythmic and antimyotonic
substance, blocks the skeletal muscle sodium channels (Duranti et
al., Eur J Med Chem 2000; 35:147-56) and relieves the
hyperexcitability of the skeletal muscles. That the function of the
skeletal muscle sodium channels is important in maintaining normal
tone is supported by the fact that it has been possible to connect
mutations in the gene for the .alpha.-subunit of the
voltage-induced Na.sup.+ channel (SCN4A) with inherited,
nondystrophic myotonia. Interestingly, the myotonia resolved
dramatically on administration of the Na.sup.+ channel-inhibiting
substance flecainide (Rosenfeld et al., Ann Neurol 1997;
42:811-4).
[0006] Tolperisone is a centrally acting muscle relaxant which is
relatively well tolerated clinically. To date, relatively few
publications have dealt with the mechanism of action of
tolperisone-like compounds. Tolperisone suppresses transmission of
the spinal segment reflex and effectively reduces C fiber-induced
transmission in the afferent nerves both in vivo and in vitro
(Farkas et al., Neurobiology 1997; 5:57-58). As compared with
lidocaine, a local anesthetic, the substance has less of a blocking
effect on transmission in the A fibers. It characteristic effect is
that of strongly inhibiting the monosynaptic and polysynaptic
spinal reflexes (Farkas et al. Neurobiology 1997; 5:57-58, Kocsis
et al., Acta Pharm Hung 2002; 72(1):49-61, Okada et al., Jpn J
Pharmacol 2001; 86:134-136). In rats, Ono et al. (J Pharmacobio
Dynam 1984; 7:171-178) showed that tolperisone exhibits an effect
like that of a local anesthetic ("membrane-stabilizing") both in
motor neurons and in primary afferents in vivo as well as on the
peripheral nerves in vitro. The effect of tolperisone appears to be
similar to that of lidocaine, which is known to act as an inhibitor
of voltage-dependent sodium channels (Strathmann 2002,
www.ifap-index.de/bda/hausarzt/19-2002/6483.pdf). It has been shown
that tolperisone, like lidocaine, blocks the tetrodotoxin
(TTX)-sensitive and TTX-resistant currents and in this way gives
rise to an inhibitory effect on both types of voltage-dependent
sodium channels (Bastigkeit, MMW-Forschr Med 2000; 142:50-51,
Farkas et al., 2000,
http://www.asso.univparis5.fr/ewcbr/Francais/EWCBR2000/Abstracts/ABST126.-
htm; Kocsis et al., Acta Pharm Hung 2002; 72(1):49-61). It is
probable that the mechanism of action of tolperisone in this
connection differs somewhat from that of lidocaine. In addition,
evidence exists that tolperisone lowers sodium permeability. This
effect could be responsible for the excitability-reducing effect of
tolperisone and consequently for the antispastic effect which has
been recorded in clinical observations (Hinck and Koppenhofer, Gen
Physiol Biophys 2001; 20:413-29). In addition, voltage-clamp
experiments performed on snail neurons showed that tolperisone and
its analogs inhibit voltage-dependent calcium flows (Novalies-Li et
al., Eur J Pharmacol 1989; 168:299-305). Tolperisone analogs such
as eperisone and silperisone exhibited similar behavior in
electrophysiological experiments. Thus, it has been shown, for
example, that silperisone reduces sodium permeability (During and
Koppenhofer, Gen Physiol Biophys 2001; 20:157-73). It can be
concluded from this that these substances might be able to reduce
spastic skeletal muscle tone.
[0007] It has furthermore been shown, in clinical studies, that
these substances are able to alleviate painful spasms which are
associated with neurological or rheumatoid diseases. The effective
employment of tolperisone in treating muscle spasms has been
reported (Pratzel et al., Pain 1996; 67:417-25). Some derivatives
of tolperisone, e.g. eperisone, also exhibited efficacy in the
treatment of painful muscle spasms (Bose, Methods Find Exp Clin
Pharmacol 1999; 21:209-13). Under certain pathological conditions,
neurons are in a state of continuous depolarization, resulting in
their sodium channels reacting more sensitively to the inhibitory
effects of particular substances. This provides the possibility of
alleviating muscle spasms and pain while preserving a favorable
side-effect profile. More recent data indicate that tolperisone and
its analogs exert selectively inhibitory effects on
voltage-dependent sodium channels. This mechanism could be
responsible for their spinal reflex-suppressing and muscle-relaxing
effect. In addition, this property could produce the
pain-alleviating effect which, because of the small differences
which have been observed, could, in contrast to lidocaine, be free
of side effects.
[0008] The potassium channel openers constitute another class of
muscle-relaxing substances.
[0009] The substances include retigabine, for example. In in vitro
analyses, it was shown that retigabine exerts multiple effects on
sites which are connected with neurotransmission and membrane
excitability. The primary mechanism of action appears to be based
on a potassium channel opening which leads to marked stabilization
of slightly depolarized, i.e. hyperexcitable cells and can result
in an elevated skeletal muscle tone being reduced (Rundfeldt and
Netzer, Neurosci Letters 2000, 282:73-6).
[0010] Flupirtine is another representative of this substance
class, which belongs to a class of triaminopyridines and which is
used as a nonopioid analgesic possessing muscle-relaxing
properties. It has been shown that flupirtine reduces skeletal
muscle tone when it is used in doses which are comparable to those
of the antinociceptive effect (Nickel et al., Arzn Forsch/Drug Res
1990a; 40:909-11).
[0011] More recent investigations demonstrate that flupirtine
activates voltage-independent potassium channels (Kornhuber et al.,
J Neural Transm 1999; 106:857-67). This potassium channel-opening
effect of flupirtine could be responsible for its analgesic and
skeletal muscle-relaxing effect.
[0012] The prior art which has been described shows clearly that,
while there are a number of substances which are used for treating
pain conditions involving an increase in muscle tone, undesirable
side effects frequently set limitations to their use. For example,
at higher doses, flupirtine exhibits neurotoxic effects such as
drowsiness and coordination disturbance. While tolperisone does not
exhibit any severe undesirable side effects, its activity and the
duration of its effect in connection with muscle relaxation are not
satisfactory, possibly due to its relatively low bioavailability
and its short half-life in humans (Ito et al., Arch Int Pharmacodyn
Ther 1985; 275:105-22), Matsunaga et al., Jpn J Pharmacol 1997;
73:215-20).
[0013] The object of this invention is therefore that of providing
a pharmaceutical for treating pains which are accompanied by an
increase in muscle tone, which pharmaceutical exhibits less serious
side effects while having a comparable efficacy or else exhibits a
higher activity at the same dose.
[0014] According to the invention, it was possible to achieve this
by means of the novel combination of retigabine and a sodium
channel inhibitor.
[0015] It was possible to show that the combination of sodium
channel-inhibiting or -influencing active compounds and potassium
channel openers increases the muscle-relaxing effect.
[0016] The following may, for example, be employed as Na.sup.+
channel-inhibiting or -influencing substances: tolperisone and its
analogs eperisone and silperisone, riluzole, propafenone,
lidocaine, flecainide and metixen, as well as their
pharmaceutically utilizable salts.
[0017] Particular preference is given, in this connection; to the
combination of tolperisone, or its analogs, and retigabine, or
their pharmaceutically utilizable salts. The combination according
to the invention makes the treatment of pains which are accompanied
by an increase in muscle tone more effective and more reliable. The
combination of Na-channel inhibiting or -influencing substances and
retigabine leads either to an increase in the therapeutic effect or
an improvement in tolerability. For example, it has been shown that
Na channel-inhibiting or -influencing active compounds such as
tolperisone can amplify the muscle-relaxing effect of retigabine,
and vice versa. However, what is surprising, and unexpected for the
skilled person, is, in particular, the effect that tolperisone
superadditively amplifies the skeletal muscle-relaxing effect of
retigabine and vice versa. By contrast, tolperisone does not
amplify the side effects of retigabine.
[0018] The combination of the two substances can be used for
treating pains in connection with diseases of the skeletal
musculature which are accompanied by hypermyotonia and restricted
mobility, in particular those which are elicited by injuries to the
spinal cord, osteoporosis, arthritis and ankylosis/spastic
conditions. It is also effective in connection with pains of the
following origin: lumboischial pains, neurolathyrism, arthritis,
diseases of the peripheral circulatory system, climacteric muscular
and vascular complaints, trismus, myogenic headaches, rheumatic
diseases which are accompanied by muscle hypertonia, spasms, pain,
inflammatory symptoms and restricted mobility, and multiple
sclerosis, and in the postoperative treatment of traumatic patients
and for treating lower spastic paraparesis syndrome: lower
paraspasm, transverse myelitis, multiple sclerosis, heritable
inferior spastic paraplegia (Stuempel paraplegia), disturbances of
the spinal blood circulation, cerebral paralysis involving lower
spastic paresis, tetraparesis in connection with cervical
myelopathy, vertebral dysplasia, tension headache and cervical
brachialgia.
[0019] The combinations of Na.sup.+ channel-inhibiting or
-influencing active compounds and retigabine, and of their
pharmaceutically utilizable salts, can be administered in all oral,
enteral, rectal, lingual, intravenous, intramuscular,
intraperitoneal, transdermal, subcutaneous or intracutaneous
administration forms. Examples of preferred oral administration
forms are tablets, film-coated tablets, sugar-coated tablets, hard
gelatin capsules, soft gelatin capsules, chewing tablets, sucking
tablets, syrup, controlled release preparations (for example dual
formulation, delayed-release formulation), pellets, chewing tablets
or soluble granules. Examples of other suitable administration
forms are: solutions for injection, suspensions, suppositories,
creams, ointments, gels, transdermal administration forms and
subcutaneous or intracutaneous implants.
[0020] The substances can be administered simultaneously,
consecutively or in a fixed combination. They can be administered
together in one administration form or in two administration forms
which can be identical or different. They can be administered
simultaneously or consecutively, either briefly one after the other
or at longer time intervals, for example retigabine in the evening
and tolperisone in the morning.
[0021] The active compounds can be administered between 1 and 8
times daily, in an adequate quantity to achieve the desired affect.
The active compounds are preferably administered from once to four
times daily.
[0022] The daily dose should correspond to the approved quantities
of the substances which are in each case employed in the
combination.
* * * * *
References