Note: Descriptions are shown in the official language in which they were submitted.
CA 02710318 2010-06-21
PAZ 6334 PCT
Drugs as well as their production and use in the treatment of pain-
associated neuropathies
[0001] The present invention is related to drugs which contain tarenflurbil
(proposed INN name; previous name R-flurbiprofen) in pure form or enriched
with
respect to the racemate as active ingredient, to the production and use of
said
drugs in pharmaceutical preparation for systemic or topical application as
rapid- or
modified-release formulations for the treatment of pain-associated
neuropathies or
neuropathic pain in mammals, in particular in man.
Background of the invention
[0002] Neuropathies are diseased conditions of the nerves that can be related
to
two very different types of disease. One type of disease is the disease due to
nerve damage in terms of a somatic disease. The other type of disease is
related
to the nerve system in terms of an irritable weakness (e.g. nervousness,
neurasthenia, neurosis). The latter meaning is to be seen more in a historic
context; the term, mental disease, is used more commonly nowadays.
[0003] Somatic neuropathies can have various causes, e.g. severing of the
nerve due to amputation or accident, blood circulation disorder upon
manifestation
of arterial occlusive disease or diabetes mellitus, mechanically damaging
influences (traumata) acting on the nerve, tumors, metabolic (metabolism-
related)
disorder or nerve damage due to diabetes mellitus, vitamin deficiency, hepatic
or
renal disease, infectious diseases such as Herpes zoster, toxic diseases due
to
alcohol, heavy metals, medications, cyclic hydrocarbons, autoimmune diseases,
mainly in the case of Guillain-Barre syndrome, and central nervous disorders
or
damage affecting the spinal cord or brain.
[0004] There are numerous options for the treatment of neuropathy depending
on the cause of the disease. Therapeutic algorithms currently in use take into
CA 02710318 2010-06-21
2
account the therapy of the underlying cause, the pharmacological and non-
pharmacological therapy of disease symptoms as well as supportive
psychological
therapy.
[0005] Since the pain conduction system itself is disturbed or damaged in
somatic neuropathies, inherent nerve pain, so-called neuropathic pain, occurs
often. This type of pain is characterized by burning, lightning-like
spontaneous
pain, shooting pain attacks, and evoked pain (allodynia, hyperalgesia), but
also by
paresthesia and hypesthesia.
[0006] Neuropathic pain is completely different from nociceptor pain since the
causes are different and the etiology is different. In contrast to neuropathic
pain,
nociceptor pain occurs after tissue damage or inflammation, in which the
peripheral and central nerve structures are intact. Therefore, the triggering,
conduction, and central processing of the pain impulses by the peripheral and
central nervous system, i.e. so-called nociception, is fully functional in
nociceptor
pain. Nociceptor pain includes, e.g., all chronic inflammation pain, visceral
pain,
many components of chronic back pain, and most of the components of tumor
pain.
[0007] Because of the difference in the cause of disease, course of disease,
and
medication therapy, the Committee for Proprietary Medicinal Products (CPMP) of
the European Agency for the Evaluation of Medicinal Products (EMEA) issued
different official guidelines for the clinical development of drugs for the
treatment of
neuropathy-related pain [Guideline on Clinical Medicinal Products intended for
the
Treatment of Neuropathic Pain, CPMP/EWP/252/03 Rev.1, 24 January 2007] and
nociceptive pain [Note for Guidance on Clinical Investigation of Medicinal
Products
for Treatment of Nociceptive Pain, CPMP/EWP/612/00, 21 November 2002].
CA 02710318 2010-06-21
3
[0008] Pain-associated neuropathies impair the quality of life of the patient
significantly and are a major health-economy problem. The point prevalence of
pain-associated neuropathies in the general population is estimated to be
approx.
5% according to a survey in six European countries [McDermott AM, Tolle TR,
Rowbotham DJ, Schaefer CP, Dukes EM: The burden of neuropathic pain: results
from a cross-sectional survey. Eur J Pain 2006; 10(2): 127-135.]. During the
"Second International Congress on Neuropathic Pain" of the International
Association for the Study of Pain (IASP) held 7-10 June 2007 in Berlin, it was
noted that neuropathic pain becomes manifest in 8% of the brain infarction
patients, 20% of the diabetics, 28% of the multiple sclerosis patients,
approx. 33%
of the patient with tumor pain, 37% of the patients with back pain, and 67% of
the
patients with spinal cord injuries in Germany.
[0009] Pain as a consequence of a neuropathy requires a different medicinal
therapy than nociceptor pain. It is therefore essential to diagnose the
manifestation
of neuropathic pain and differentiate this from nociceptor pain, which is more
common in medical practice, before initiating any treatment. Several validated
procedures are available for safe diagnosis of neuropathic pain [overview in:
Baron, R: Diagnostik and Therapie neuropathischer Schmerzen (Detection of
neuropathic pain syndromes), Deutsches Arzteblatt 103, issue 41, 2006, 2720-
30].
The diagnostic options range from clinically-oriented diagnoses [Dworkin RH,
Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ et al.: Advances in
neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch
Neurol 2003; 60(11): 1524-34. Cruccu G, Anand P, Attal N, Garcia-Larrea L,
Haanpaa M, Jorum E et al.: EFNS guidelines on neuropathic pain assessment.
Eur J Neurol 2004; 11(3): 153-62. Jensen IS, Baron R: Translation of symptoms
and signs into mechanisms in neuropathic pain. Pain 2003; 102(1-2):1-8] up to
simple questionnaires [Freynhagen R, Baron R, Gockel U, Tolle TR: painDETECT
- a new screening questionnaire to identify neuropathic components in patients
with back pain. Curr Med Res Opin 2006; 22(10): 1911-20].
CA 02710318 2010-06-21
4
[00010] In accordance with current therapeutic guidelines [Baron R, Ludwig J,
Binder A: Therapie Tabellen Neurologie/Psychiatrie no. 29, May 2006,
Neuropathische Schmerzen, Westermayer Verlag, Pentenried], the following drugs
are available for pharmacotherapy of neuropathic pain: antidepressants (e.g.
amitriptyline, nortriptyline; desipramine, maprotiline, venlafaxine,
duloxetine,
bupropion), anticonvulsants (e.g. carbamazepine, oxcarbazepine, lamotrigine,
gabapentin, pregabalin), opioids (e.g. tramadol, morphine, oxycodone),
cannabinoids (e.g. tetrahydro-cannabinol), myotonolytics (e.g. baclofen), and
NMDA (= N-Methyl-D-aspartate) antagonists (e.g. dextromethorphan, ketamine,
memantine), radical scavengers (e.g. alpha-lipoic acid). Topical drugs to be
considered include local analgesics and local anesthetics (e.g. capsaicin,
lidocaine, and benzocaine).
[00011] Both opioid analgesics and non-opioid analgesics are in use for
pharmacotherapy of nociceptive pain. The non-opioid analgesics include the non-
steroidal antiinflammatory drugs (NSAIDs) including the COX-2-selective
inhibitors
which have an analgesic, antiphlogistic, and antipyretic effect. NSAIDs have
not
been included in the current therapeutic recommendations and official
guidelines
of EMEA for the treatment of pain-associated neuropathies because they have
proven to be ineffective and would therefore only cause side effects. This
applies,
e.g., to ibuprofen [Baron, R: Diagnostik and Therapie neuropatischer Schmerzen
(Detection of neuropathic pain syndromes), Deutsches Arzteblatt 103, issue 41,
2006, 2720-30. Max, MB et al.: Association of pain relief with drug side
effects in
postherpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen,
and
placebo, Clin Pharmacol Ther. 1988;43(4), 363-71] as well as diclofenac, indo-
methacin and aspirin [Hempenstall, K et al.: Analgesic therapy in postherpetic
neuralgia: A quantitative systematic review. PLoS Med. 2005; 2(7),1-27].
CA 02710318 2010-06-21
[00012] Therefore, according to the current therapeutic recommendations, of
the
pain medications currently available, only opioid analgesics are well-suited
for the
treatment of both pain-associated neuropathies and for the treatment of
nociceptive pain. All other agents are well-suited only for either the
treatment of
pain-associated neuropathies or only for the treatment of nociceptive pain due
to
the difference in the cause of pain and due to their mechanism of action.
Accordingly, mixed pain syndromes, consisting of neuropathic and nociceptive
pain, must usually be treated individually using the agents that are well-
suited for
the corresponding type of pain.
[00013] Some of the well-known NSAIDs contain an asymmetric carbon atom
and therefore form an R-enantiomer and an S-enantiomer. This includes the
agent
class of the 2-aryl propionic acids, which includes well-known substances such
as,
e.g., ibuprofen, flurbiprofen, ketoprofen, naproxen and tiaprofenic acid. Both
ibuprofen and ketoprofen are used for therapy both in the form of the racemate
(50% S-enantiomer, 50% R-enantiomer) and in the form of the pure S-enantiomer,
whereby only the S-enantiomer is considered to be effective. Naproxen is used
in
drugs exclusively in the form of the S-enantiomer. Flurbiprofen and
tiaprofenic acid
are thus far being used for therapy only in the form of the racemate.
[00014] According to the prior art and contrary to previous scientific
insight, some
2-aryl propionic acids are now known to be pharmacologically effective not
only in
the form of the S-enantiomer, but also show desired pharmacological effects,
in
particular an analgesic effect, in the form of the R-enantiomer, see, e.g., DE
40 28
906, EP 0 607 128, US 5,200,198, and US 5,206,029. These documents relate to
nociceptive pain exclusively.
[00015] WO 00/13684 describes that some R-(2)-aryl propionic acids,
preferably,
tarenflurbil, have antinflammatory effects at doses exceeding the effective
doses
CA 02710318 2010-06-21
6
for analgesia, whereby the mechanism of action is stated to be an inhibition
of the
induction of COX-2 at mRNA level.
[00016] EP 1 154 766 claims the use of R-(2) aryl propionic acids, preferably
tarenflurbil, for the production of drugs for fighting rheumatic diseases,
asthma,
shock, inflammatory bowel diseases, radiation damage, arteriosclerosis, and
rejection reactions after tissue or organ transplantations, whereby the effect
in
these diseases is said to be based on the inhibition of transcription factor
NF-
kappaB activation.
[00017] Further applications of R-(2) aryl propionic acids, preferably of
tarenflurbil, as chemo-preventative agents for the treatment of neoplastic
diseases
(colorectal cancer) as well as for the treatment of cystic fibrosis and
Alzheimer's
disease are described in WO 98/09603.
[00018] EP 1 322 305 claims the use of R-(2) aryl propionic acids, preferably
of
tarenflurbil, for the treatment of chronic-destructive cartilage and articular
diseases
in the presence of rheumatism.
[00019] Ketoprofen has been described to trigger an inhibitory effect on
tactile
allodynia in rats after spinal application of R-ketoprofen or of mixtures of
morphine
and S-ketoprofen. This is taken to conclude that spinal application of these
substances may be well-suited for the treatment of neuropathic pain [Ossipov
MH,
Jerussi TP, Ren K, Sun H, Porreca F: Differential effects of spinal (R)-
ketoprofen
and (S)-ketoprofen against signs of neuropathic pain and tonic nociception:
evidence for a novel mechanism of action of (R)-ketoprofen against tactile
allodynia. Pain. 2000 Aug;87(2):193-9]. The pain model used suggests that not
just neuropathic pain was addressed, but rather nociceptive pain or mixed pain
consisting of nociceptive and neuropathic pain. The spinal application
selected in
the animal model is limited in its clinical applicability due to the extensive
effort
CA 02710318 2010-06-21
7
involved. This type of application would only permit the treatment of central
neuropathic pain, whereas treatment of peripheral neuropathic pain would not
be
feasible. The continuous use of this type of application is feasible with
extensive
technical effort only, e.g. with implantable pumps. A pharmacological effect
in
other types of applications as are common in the practice of long-term therapy
has
not been described for this substance. The results of this scientific
publication are
the basis of US 6,620,851 B2, in which procedures for the treatment of
neuropathic pain and other disorders through the use of R(-)-ketoprofen are
claimed. Oral types of administration are mentioned, but no evidence of their
efficacy is provided. The efficacy of pure, orally-administered R-ketoprofen
cannot
be demonstrated either in rats or humans, since R-ketoprofen is converted to S-
ketoprofen to a significant extent after oral application in both species. As
a result,
any possibly existing effect of R-ketoprofen cannot be distinguished from the
stronger effect of S-ketoprofen. Moreover, bioinversion of R-ketoprofen to S-
ketoprofen after oral administration would also lead to the well-known adverse
effects of S-ketoprofen and thus might ruin any better tolerability of R-
ketoprofen.
[00020] The expert cannot assume that the effect found with R-ketoprofen is
applicable to other R-aryl propionic acids due to the very different effects
and/or
effective dosages and, mainly, the strongly different degree of inversion
varying
from species to species and from aryl propionic acid to aryl propionic acid
found in
the studies carried out thus far. As such, unlike the S-enantiomers, the R-
aryl
propionic acids cannot be considered to be one uniform class of agents.
[00021] There continues to be a need for therapeutic procedures and/or drugs
that are well-suited for the treatment of pain-associated neuropathies.
Summary of the invention
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8
[00022] It has been found surprisingly that the application of tarenflurbil in
pharmacological models of neuropathic pain in rats leads to a significant
reduction
of the evoked neuropathic pain.
[00023] As expected, S-flurbiprofen, which is very effective against
nociceptive
pain, did not show this effect. According to current insights, rats are the
only
established species of laboratory animals that almost not invert tarenflurbil
to S-
flurbiprofen under in vivo conditions. For this reason, this species is well-
suited for
selective determination of the effects of tarenflurbil, whereby the effects
found are
applicable to humans.
[00024] For this reason, the present invention relates to a procedure for the
treatment of pain-associated neuropathy; of pain-associated neuropathy
accompanied by states of nociceptive pain; of peripheral and/or predominantly
peripheral neuropathic pain; or of central and/or predominantly central
neuropathic
pain in a mammal, in particular in man.
[00025] In particular, the invention relates to a procedure for the treatment
of the
following types of neuropathic pain and/or neuropathic pain due to a cause
that is
selected from the group of the following causes: systemic diseases, e.g.
diabetic
neuropathy; drug-induced lesions, e.g. neuropathy due to chemotherapy;
traumatic syndrome and entrapment syndrome; lesions in nerve roots and
posterior ganglia; neuropathies after HIV infections; neuralgia after Herpes
infections; nerve root avulsions; cranial nerve lesions; cranial neuralgias,
e.g., tri-
geminal neuralgia; neuropathic cancer pain; phantom pain; compression of
peripheral nerves, neuroplexus and nerve roots; paraneoplastic peripheral
neuropathy and ganglionopathy; complications of cancer therapies, e.g.
chemotherapy, irradiation, and surgical interventions; complex regional pain
syndrome; type I lesions (previously known as sympathetic reflex dystrophy);
and
type II lesions (corresponding approximately to causalgia).
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9
[00026] Moreover, the invention relates to a procedure for the treatment of
neuropathic pain due to a cause that is selected from the following group of
causes: cerebral lesions that are predominantly thalamic; infarction, e.g.
thalamic
infarction or brain stem infarction; cerebral tumors or abscesses compressing
the
thalamus or brain stem; multiple sclerosis; brain operations, e.g. thalamotomy
in
cases of motoric disorders; spinal cord lesions; spinal cord injuries; spinal
cord
operations, e.g. anterolateral cordotomy; ischemic lesions; anterior spinal
artery
syndrome; Wallenberg's syndrome; and syringomyelia.
[00027] According to the invention, enantiomerically-pure or essentially
enantiomerically-pure tarenflurbil and/or a pharmaceutically tolerable salt or
derivative thereof, or tarenflurbil and/or pharmacologically tolerable
tarenflurbil
derivative or salt that is enriched with respect to flurbiprofen racemate
and/or a
racemate of said salt or derivative is administered to a mammal, in particular
to a
human, who is afflicted by said pain-associated neuropathies or neuropathic
pain.
[00028] Moreover, the present invention relates to the use of tarenflurbil
and/or a
pharmaceutically tolerable salt or derivative thereof in enantiomerically-pure
or
essentially enantiomerically-pure form or in a form that is enriched with
respect to
flurbiprofen racemate and/or a racemate of said salt or derivative, for the
production of a drug for the treatment of said pain-associated neuropathies or
neuropathic pain in a mammal, in particular in a human.
[00029] Moreover, the invention relates to tarenflurbil and/or a
pharmaceutically
tolerable salt or derivative thereof in enantiomerically-pure or essentially
enantiomerically-pure form or in a form that is enriched with respect to
flurbiprofen
racemate and/or a racemate of said salt or derivative, and drugs and/or drug
compositions containing these for use for the treatment of said pain-
associated
neuropathies or neuropathic pain in a mammal, in particular in a human.
CA 02710318 2010-06-21
Short description of the figures
[00030] Figures 1 a, 1 b, and 1 c show the dose-dependent effects of
tarenflurbil
R-flurbiprofen; RF) in the spared nerve injury model (SNI model, graphs on the
left) and in the chronic constriction injury model (CCI model; graphs on the
right) of
peripheral neuropathic pain as compared to the effects of S-flurbiprofen (SF),
gabapentin (Gaba) and vehicle (vehicle).
[00031] Figure 2 shows the effects of a treatment, from the first
postoperative
day, with tarenflurbil (= R flurbiprofen; RF), by administration of a dose of
9 mg/kg
twice daily i.p., as compared to vehicle in the spared nerve injury model of
peripheral neuropathic pain.
[00032] Figure 3 shows the effects of tarenflurbil (single i.p. dose of 9
mg/kg) as
compared to vehicle in untreated rats.
Detailed description of the invention
[00033] Although NSAIDs are applied broadly in the treatment of nociceptive
pain
and inflammatory diseases, they have proven ineffective for the treatment of
pain-
associated neuropathies in the studies that have been carried out thus far and
are
therefore not included in the therapeutic algorithms for the treatment of pain
in
association with neuropathies.
[00034] In the context of the present invention, tarenflurbil, the R-
enantiomer of
the NSAID, flurbiprofen, which is commercially available in the form of the
racemate, was surprisingly found to be effective in terms of pain relief in
the
treatment of pain-associated neuropathies. The effect of tarenflurbil in pain-
associated neuropathies is selective and is not elicited by the S-enantiomer
of
flurbiprofen.
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11
[00035] The pharmacological investigations that have been carried out in the
context of the present invention show the dose-dependent effect of
tarenflurbil in
pharmacologically accepted models of pain-associated neuropathies. If dosed
sufficiently, the efficacy is in the range of the efficacy of 25 mg/kg body
weight
gabapentin as reference substance. S-flurbiprofen does not show a significant
effect in these models.
[00036] Tarenflurbil (and/or a pharmaceutically tolerable salt or derivative
thereof)-containing drugs can therefore be used in the scope of the invention
in all
forms of pain-associated neuropathies or neuropathic pain described above as
mono-therapy or in combination with other drugs or treatment procedures. The
dosing should follow the current therapeutic guidelines for the known agents.
This
means that the dosing should be designed individually, depending on both the
efficacy and adverse effects.
[00037] In the context of the treatment of pain-associated neuropathies and/or
neuropathic pain, efficacy is understood to be a reduction of pain by at least
30 to
50%. This should preferably be evaluated only after a treatment period of two
to
four weeks on high daily doses. After this period, the dose can be adjusted
upwards or downwards or a combination therapy including the known agents can
be initiated.
[00038] Since the adverse drug effects of flurbiprofen racemate are
essentially
caused by the S-enantiomer, it is particularly advantageous in the scope of
the
invention to use and/or administer tarenflurbil and/or its pharmaceutically
tolerable
salts or derivatives in enantiomerically-pure or essentially enantiomerically-
pure
form. Forms of tarenflurbil and/or its pharmaceutically tolerable salts or
derivatives,
in which tarenflurbil and/or the pharmaceutically tolerable salt or derivative
is
enriched with respect to the corresponding racemic form consisting of 50%
tarenflurbil or pharmaceutically tolerable salt or derivative and 50% S-
flurbiprofen
CA 02710318 2010-06-21
12
and/or pharmaceutically tolerable salt or derivative thereof are also well-
suited for
this purpose. The higher the enantiomeric excess of tarenflurbil and/or
pharmaceutically tolerable salt or derivative with respect to the
corresponding S-
enantiomer, the higher the drugs made therefrom can be dosed, e.g., in order
to
attain the desired analgesic effect in the treatment of pain-associated
neuropathies
in combination with an incidence and severity of the adverse drug effects as
low
as possible.
[00039] Particularly well-suited for this purpose are forms of tarenflurbil
and/or
forms of the pharmaceutically tolerable salt or derivative thereof, in which
tarenflurbil and/or its pharmaceutically tolerable salt or derivative is
present at a
molar ratio of larger than or equal to 60:40 with respect to S-flurbiprofen
and/or the
corresponding pharmaceutically tolerable salt or derivative of S-flurbiprofen.
It is
particularly preferred for the molar ratio to be larger than or equal to 95:5,
whereby
a molar ratio from 95:5 is "essentially enantiomerically-pure" in the scope of
the
invention. It is even more particularly preferred for the molar ratio to be
larger than
or equal to 98:2, >_ 99.5:0.5 or >_ 99.9:0.1, whereby a molar ratio from 98:2
is
"enantiomerically-pure" in the scope of the invention.
[00040] The drugs and drug compositions made in accordance with the use
according to the invention and/or the drugs and drug compositions for use
according to the invention preferably contain tarenflurbil and/or its
pharmaceutically tolerable salt or derivative in said well-suited forms of
enantiomeric purity or enrichment.
[000411 If reasonable on technological grounds during the production of the
tarenflurbil agent, pure tarenflurbil and/or its pharmaceutically tolerable
salt or
derivative, in which no S-flurbiprofen and/or corresponding S-flurbiprofen
salt or
derivative can be detected with modern analytical methods, should be used in
the
CA 02710318 2010-06-21
13
procedures according to the invention and/or for the production of the drugs
and/or
drug compositions according to the invention.
[00042] Unlike most of the other R-NSAIDs, tarenflurbil shows no or no more
than extremely minor inversion of the R-form to the S-form under in vivo
conditions
when applying it in humans. For this reason, even after the application of
high
therapeutic doses, there is no risk of toxic concentrations of S-flurbiprofen
occurring in the human organism due to the inversion of tarenflurbil to S-
flurbiprofen. Due to the high enantiomeric stability of tarenflurbil under-in
vivo
conditions in man, drugs should be produced to contain the agent as
enantiomerically-pure as possible in order to obtain a particularly favorable
benefit-
risk relationship in the treatment of pain-associated neuropathies or
neuropathic
pain according to the invention. Enantiomerically-pure or essentially
enantiomerically-pure tarenflurbil is available in a form produced by several
commercial agent producers in compliance with the international Good
Manufacturing Practices (GMP) for pharmaceutical agents.
[00043] All specifications of well-suited daily doses, single doses, and agent
concentrations made in the present description of the invention and the claims
refer to tarenflurbil and/or its corresponding pharmaceutically tolerable salt
or
derivative including the fraction of S-flurbiprofen and/or S-enantiomer of the
corresponding pharmaceutically tolerable salt or derivative that may also be
present in addition in accordance with the degree of enantiomeric purity or
enrichment of the form of tarenflurbil or its pharmaceutically tolerable salt
or
derivative that is used.
[00044] Because of the low toxicity, the administered daily dose can be
adjusted
widely to the individual situation of the patient. Upon systemic application,
i.e. if the
administered dose is to be made available by means of the blood circulation in
the
organism, the daily dose should be at least 1 mg/kg body weight and can be
CA 02710318 2010-06-21
14
increased up to 50 mg/kg or higher. A preferred dosage for systemic
application is
a daily dose of 2 to 30 mg/kg body weight, 3 to 25 mg/kg body weight is
particularly preferred, 5 to 20 mg/kg body weight is even more particularly
preferred, and 10 to 20 mg/kg body weight is most preferred.
[00045] Depending on the release kinetics of the pharmaceutical preparation
and
the form of application, the daily dose should be split into one to five,
preferably
one to four units such that an application is made once to five times,
preferably
four times, daily.
[00046] All known application routes in which the known pharmaceutical
formulations can be used, such as oral, peroral, intramuscular, intravenous,
intraperitoneal, buccal, sublingual, nasal, transdermal, by inhalation, and
rectal,
can be used for application.
[00047] Oral or rectal formulations that are administered in the form of a
solid
preferably contain as single dose form 30 mg to 1800 mg, more preferably 50 mg
to 1200 mg, particularly preferably 100-1000 mg, and more particularly
preferably
200-800 mg tarenflurbil and/or a pharmaceutically tolerable salt or derivative
thereof. For suppositories, single doses are split similarly to solid oral
formulations.
[00048] Solutions or suspensions for parenteral administration preferably
contain
the entire daily dose in a single dose form, but can also be prepared as lower-
dosed single dose forms for multiple daily application according to
therapeutic
need.
[00049] In the case of oral drink preparations, the entire daily dose can be
taken
at once, even if it exceeds 1800 mg. Solutions or suspensions for oral
application
can contain the requisite quantity for a typical therapeutic period, such as,
e.g.,
CA 02710318 2010-06-21
one or several weeks or one or several months, whereby in this case a daily
dose
or a single dose is obtained by measuring an aliquot.
[00050] Aside from systemic application, tarenflurbil and/or a
pharmaceutically
tolerable salt or derivative thereof can be used for local therapy of pain-
associated
neuropathies or neuropathic pain. For this purpose, a pharmaceutical
formulation
for topical application is applied to the skin on the site of the body
afflicted by the
disease. All pharmaceutical formulations known for topical agents are well-
suited
for this application route, such as, e.g., ointments, cremes, emulsions, gels,
patches.
[00051] Formulations with concentrations of tarenflurbil or its
pharmaceutically
tolerable salt or derivative of 0.5 g/100 g to 25 g/100 g of preparation,
preferably of
1 g/100 g to 20 g/100 g of preparation, particularly preferably of 1 g/100 g
to
15 g/100 g of preparation, more particularly preferably of 1.5 g/1 00 g to 10
g/1 00 g
of preparation, and most preferably of 5 g/100 g to 10 g/100 g of preparation
are
well-suited for topical applications.
[00052] The pharmaceutical formulation of the drugs and/or drug compositions
according to the invention can be produced in any form that is desired and
known
in pharmaceutical technology. This includes, e.g., tablets, capsules, coated
tablets, granulates, non-sterile solutions and suspensions for oral
application,
nanopellets, sterile solutions and suspensions for parenteral administration,
suppositories, aerosols, ointments, cremes, emulsions, and liposome
preparations.
[00053] The oral pharmaceutical preparations and preparations for
intramuscular
or intraperitoneal application according to the invention can be produced and
used
therapeutically in the form of both rapid-release and modified-release
formulations.
In particular in the case of the oral preparations, it is advisable to provide
CA 02710318 2010-06-21
16
pharmaceutical preparations with delayed release in order to reduce the
frequency
of intake, for improving the patient compliance, and for improving the
tolerability.
The release can be controlled continuously or in pulses via several individual
releases that are staggered over time. In order to reduce the frequency of
application of formulations for intramuscular or intraperitoneal application,
the
preparations for delayed agent release that are known in pharmaceutical
technology, such as, e.g., crystal suspensions and biodegradable excipients,
can
be used.
[00054] According to a preferred embodiment of the invention, tarenflurbil or
its
pharmaceutically tolerable salt or derivative is applied and/or administered
in the
procedures, uses, and drugs and/or drug compositions according to the
invention
over an extended period of time, preferably over several weeks or several
months,
e.g. over more than 3 months, more than 6 months or more than 12 months.
[00055] Aside from tarenflurbil and/or its pharmaceutically tolerable salt or
derivative, drugs and/or drug compositions according to the invention can
comprise other agents as agent as well as one or several pharmaceutically
tolerable excipient(s).
[00056] The term pharmaceutically tolerable derivatives refers to derivatives
made from tarenflurbil and pharmaceutically tolerable inorganic or organic
bases
for salt formation, alcoholic and phenolic compounds for ester formation or
amines
for amide formation. This includes, in particular, metal salts, e.g.
containing
aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc or organic
salts, e.g. containing lysine, N,N'-dibenzylethylene diamine, choline,
diethanolamine, ethylene diamine, meglumine, trometamine, arginine, and
alkylamines with 1 to 6 C-atoms, or esters, e.g. containing aliphatic or
isoaliphatic
alcohols with 1 to 8 C-atoms. It is also included in the scope of the
invention to use
tarenflurbil in the form of the free acid.
CA 02710318 2010-06-21
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[00057] According to the invention, tarenflurbil and/or the pharmaceutically
tolerable salt or derivative thereof can be used advantageously in free or
fixed
combination with other agents that are well-suited for the treatment of pain-
associated neuropathies or neuropathic pain.
[00058] For medicinal combination therapy of pain-associated neuropathies or
neuropathic pain, tarenflurbil and/or a pharmaceutically tolerable salt or
derivative
thereof can be used in fixed combinations with other substances that are
effective
in this indication. For systemic combination therapy, substances from the
agent
groups of the antidepressants, anticonvulsants, opioids, cannabinoids, and
myotonolytics are preferable. For topical combination therapy, combinations of
tarenflurbil and topical analgesics or local anesthetics can be used. In the
production of drugs containing fixed combinations of tarenflurbil and/or a
pharmaceutically tolerable salt or derivative thereof and other agents, the
doses
are selected such that tarenflurbil (and/or the pharmaceutically tolerable
salt or
derivative thereof that is used) is used at the doses described above and the
combination agent is used at the common therapeutic dose of the corresponding
mono-agent.
[00059] According to the invention, tarenflurbil is therefore well-suited not
only for
the therapy of pain-associated neuropathies, but also for the treatment of
pain that
is composed of pain-associated neuropathies and nociceptor pain due to the
manifest damage. Mixed pain of this type occurs when pain-associated tissue
traumata and pain-associated peripheral or central nerve damage occur in close
proximity in the body. Especially this type of pain is often inadequately
treated in
the practice of medicine, since the known non-opioid analgesics are effective
only
in the case of nociceptor pain, but not in pain-associated neuropathies,
whereas
most of the agents used for the treatment of pain-associated neuropathies are
effective only in this type of pain, but not against nociceptor pain.
Tarenflurbil
CA 02710318 2010-06-21
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and/or a pharmaceutically tolerable salt or derivative is effective against
mixed
pain simultaneously via the known pain-relieving effect against nociceptor
pain as
well as via the effect against pain-associated neuropathies that has been
found
according to the invention. Tarenflurbil and its pharmaceutically tolerable
salts and
derivatives therefore have a known nociceptive pain potential and a previously
unknown neuropathic pain potential similar to the opioid agents, but without
their
well-known addictive potential and respiratory depressive potential. This
combination of pain has never before been described for any other non-opioid
substance and provides therefore a major, previously unknown, therapeutic
benefit. Due to its excellent tolerability, tarenflurbil (and/or its
pharmaceutically
tolerable salts and derivatives) can be used against mixed pain at high doses
from
the very beginning. A comparably broad action spectrum against pain-associated
neuropathies and nociceptor pain is present, at best, in the opioid
analgesics, but
these should only be used if strongly indicated because of their adverse
effect
profile. Back pain and tumor pain are commonly occurring types of mixed pain
for
the treatment of which tarenflurbil (and/or its pharmaceutically tolerable
salts and
derivatives) would be a preferable drug independent of a differential
diagnosis.
[00060] All agents that are used for the therapy of pain-associated
neuropathies, such as, e.g., antidepressants (amitriptyline, nortriptyline;
desipramine, maprotiline, venlafaxine, duloxetine, bupropion), anticonvulsants
(carbamazepine, oxcarbazepine, lamotrigine, gabapentin, pregabalin), opioids
(tramadol, morphine, oxycodon), cannabinoids (tetrahydro-cannabinol),
myotonolytics (baclofen), NMDA antagonists (dextromethorphane, ketamine,
memantine) or radical scavengers (alpha-lipoic acid), are well-suited as
further
agents that can be produced in combination with tarenflurbil (and/or its
pharmaceutically tolerable salts or derivatives), e.g., as drugs for systemic
application, and used for medical purposes as fixed combination. For drugs for
topical application, local anesthetics (e.g. capsaicin, lidocaine, and
benzocaine)
CA 02710318 2010-06-21
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can be considered as agents for combination with tarenflurbil and/or its
pharmaceutically tolerable salts or derivatives.
[00061] According to the invention, pharmaceutically tolerable excipients are
to
be understood to be carrier substances, such as starch, sugar,
microcrystaIline
cellulose, diluents, granulation aids, lubricants, binding agents, tablet
disintegrants, and alike, depending on the formulation. Particularly
advantageous
pharmaceutical formulations for tarenflurbil-containing drugs are described in
EP 0 607 128, EP 0 641 200, and EP 0 615 440.
The examples described in the following are meant to illustrate the invention
in
more detail without limiting it to the actual embodiments described. Unless
specified otherwise, all part and % specifications in the scope of the present
invention refer to the weight and/or the total weight of the
composition/mixture.
Example 1
[00062] The Chronic Constriction Injury model (CCI model) [Bennet GJ, Xie YK:
A peripheral mononeuropathy in rat that produces disorders of pain sensation
like
those seen in man. Pain 1988, 33:87-107] and the Spared Nerve Injury model
(SNI model) [Decosterd I, Woolf CJ: Spared Nerve injury: an animal model of
persistent peripheral neuropathic pain. Pain 2000, 87:149-158] were used as
animal models that show essential elements of the clinical pain syndromes in
the
presence of neuropathies. In both models, the animals sustain defined nerve
damage by surgical means. The pain behavior of the animals can be used to
quantitatively measure the efficacy of substances in pain-associated
neuropathies.
The investigations were carried out on rats according to the published models.
In
rats, it is possible to measure the effect of tarenflurbil exclusively, since
they, like
man, basically do not invert tarenflurbil to S-flurbiprofen. The same is not
true of
most other species of laboratory animals.
CA 02710318 2010-06-21
[00063] In a first series of experiments, the animals sustained a nerve lesion
by
surgical means according to the SNI model and according to the CCI model. From
day 10 to day 21 postoperatively, groups of 12 animals each received
intraperitoneal administrations of the test substances twice daily. In tests
according to the SNI model, in each application, 2.5, 4.5 or 9 mg tarenflurbil
(referred to as RF2.5, RF4.5, and RF9), 4.5 mg S-flurbiprofen (SF4.5), pure
vehicle (vehicle - as control) or 25 mg gabapentin (Gaba25 - as reference
substance), each per kg of body weight, were administered. The behavioral
parameters that are typical of pain-associated neuropathies were measured,
namely mechanical allodynia using Frey's aestesiometer, cold allodynia using
the
acetone test, and cold hyperalgesia using the cold plate at 2 C. In tests
according
to the CCI model, 4.5 or 9 mg/kg body weight of tarenflurbil (RF4.5 and RF9),
9 mg/kg body weight S-flurbiprofen (SF9) or vehicle (vehicle) were
administered
per group. As before, mechanical/static allodynia, cold allodynia and cold
hyperalgesia were measured using Frey's hair test, the acetone test, and the
cold
plate at 2 C, respectively.
[00064] The results of the series' of experiments are shown in Figures 1 a, 1
b,
and 1 c. A significant reduction of allodynia was attained with 4.5 and 9
mg/kg
tarenflurbil twice daily. S-flurbiprofen showed no significant effect. No
testing of
S-flurbiprofen doses in excess of 4.5 mg/kg twice daily was feasible due to
the
manifestation of gastrointestinal bleeding in some animals starting after
approx.
1 week of treatment. Gabapentin used in neuropathies and here as a positive
control showed no significant difference from tarenflurbil.
Example 2
[00065] In another series of experiments, animals having sustained nerve
damage according to the SNI model were treated twice daily with
intraperitoneal
doses of 9 mg/kg body weight tarenflurbil or vehicle from the first
postoperative
day and for a period of two weeks. Both the mechanical dynamic allodynia (on
the
CA 02710318 2010-06-21
21
ipsilateral and on the contralateral side) and the cold allodynia (ipsilateral
only)
were measured by means of Frey's aesthesiometer and the cold plate at 10 C,
respectively.
[00066] The results of this series of experiments are summarized in Figure 2.
Tarenflurbil (RF9-ipsi) shows a significantly different effect from vehicle
(vehicle-
ipsi) on the ipsilateral side with regard to mechanical allodynia and cold
allodynia
during the entire treatment period of two weeks. On the contralateral side,
there is
no difference between tarenflurbil (RF9-contra) and vehicle (vehicle-contra).
After
completion of treatment, the pain-relieving effect decreases slowly in the
group
treated with tarenflurbil and reaches the pain intensity of the vehicle group
eight
days after the end of treatment.
Example 3
[00067] For qualification of the series' of experiments mentioned above, a
single
dose of 9 mg/kg body weight tarenflurbil (RF9) or vehicle (vehicle) was
applied
intraperitoneally in another series of experiments on rats that had not
sustained
damage and the mechanical allodynia and the heat sensitivity were measured for
up to 6 hours after the application using Frey's aesthesiometer and the
Hargreaves model, respectively. The results shown in Figure 3 evidence no
significant differences between the groups treated with tarenflurbil versus
vehicle.
This means that the effects measured for tarenflurbil in Examples 1 and 2 are
exclusively related to the effect in pain-associated neuropathies.
