Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Use of ambroxol in the treatment of chronic pains, cerebral
excitotoxicity -related disorders and cardiac arrhythmias
The invention relates to the use of ambroxol and the pharmacologically
acceptable salts thereof for preparing a pharmaceutical composition for the
treatment of diseases which are based on powerful activation of voltage-
dependent sodium channels, particularly for the treatment of chronic pain.
Background to the invention
The active substance ambroxol (trans-4-(2-amino-3,5-dibrombenzylamino)-
cyclohexanol) is a known antitussive and expectorant. In addition, the
activity
of ambroxol as a sodium channel blocker has been described in the literature
(Society for Neuroscience Abstracts, 2000, Vol.26, No. 1-2).
The potential activity of sodium channel blockers as analgesics is also known
from the prior art (Mao and Chen(2000), Pain 87, 7-17). However, known
sodium channel blockers are unsuitable for the treatment of chronic pain and
for treating diseases caused by excessive activation of voltage-dependent
sodium channels, as they preferentially inhibit those sodium channels which
play a minor part in the development and transmission of noxic signals in
sensory neurones, i.e. those which may be inhibited by tetrodotoxin, in
contrast to tetrodotoxin-resistant neuronal sodium channels (Rush and Elliott
ters 226, 95-98; Scholz et al. (1998); Journal of
(1997), Neuroscience Let1. I
Neurophysiology 79, 1746-1754;Song et al. (1997), Journal of Pharmacology
and Experimental Therapeutics, 282, 707-714).
Diseases connected with chronic or chronically recurrent pain include, inter
a/ia, migraine, neuralgia, muscle pain and inflammatory pain. They share the
same mechanisms as chronically recurrent pain [Dray, A. Urban L. and
Dickenson, A. Trends in Pharmacological Sciences 1994; 15:190-197].
.The chronic neuronal pains include inter a/ia postoperative pain, shingles,
phantom pain, diabetic neuropathy, pain after chronic nerve compression as
well as the final stages of Aids and cancer.
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The aim of the present invention is to prepare an active substance for the
treatment of diseases caused by excessively powerful activation of voltage-
dependent sodium channels.
In particular, the aim of the present invention is to provide an active
substance for the treatment of chronic pain, especially chronic neuronal or
neuropathic pain, with good bioavailability and a strong antinociceptive
activity.
Description of the invention
Surprisingly, ambroxol exhibits a very good activity in the treatment of
chronic
pain and neurological diseases, which is based on blocking excessively
strongly activated voltage-dependent sodium channels, particularly
excessively strongly activated voltage-dependent neuronal sodium channels.
The invention therefore relates to the use of ambroxol or one of the
pharmacologically acceptable salts thereof for preparing a pharmaceutical
composition for the treatment of diseases which are based on a powerful
activation of voltage-dependent sodium channels.
Ambroxol or one of the pharmacologically acceptable salts thereof is
preferably used to prepare a pharmaceutical composition for the treatment of
chronic and/or neuropathic pain, preferably in diabetic neuropathy,
postherpetic neuralgia, chronic back pain, migraine, trigeminai neuralgia or
tumour pain, most preferably in diabetic neuropathy, postherpetic neuralgia,
chronic back pain or migraine, most preferably in diabetic neuropathy or
postherpetic neuralgia.
Most preferably, ambroxol or one of the pharmacologically acceptable salts
thereof is used to prepare a pharmaceutical composition for the treatment of
cerebral excitotoxicity-induced disorders, preferably epilepsy, brain trauma
or
cerebral stroke, more preferably epilepsy or brain trauma, most preferably
epilepsy.
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It is also particularly preferred to use ambroxol or one of the
pharmacologically acceptable salts thereof to prepare a pharmaceutical
composition for the treatment of cardiac arrhythmias.
The invention further relates to a pharmaceutical composition containing
ambroxol and one or more active substances selected from among the
analgesics, the anticonvulsants, for example barbiturates, preferably
phenobarbital,
hydantoins, succinimides, oxazolidines, benzodiazepines, neuroprotective
substances, for example NMDA receptor antagonists, and antiarrhythmics,
preferably lidocaine, verapamil or gallopamil.
it is particularly preferable to use ambroxol or one of the pharmacologically
acceptable salts thereof in combination with one or more other active
substances, selected from among the analgesics, the anticonvulsants, for
example
barbiturates, hydantoins, succinimides, oxazolidines, benzodiazepines,
preferably phenobarbital, neuroprotective substances, for example NMDA
receptor antagonists, or antiarrhythmics, preferably lidocaine, verapamil or
gallopamil.
The invention further relates to a pharmaceutical composition containing
ambroxol and one or more active substances selected from among the
opiates, preferably morphine, buprenorphine, levomethadone, codeine,
tramadol or tilidine, non-steroidal analgesics, for example acetylsalicylic
acid,
paracetamol, diclofenac, meloxicam, ibuprofen, ibuprofen lysinate, ibuprofen
in extruded form (as described in WO 99/06038), gabapentine and
antidepressants, preferably imipramine, maprotiline, mianserine, fluoxetine,
viloxazine, tranylcypromine or moclobemide, and alpha-adrenergic agonists
such as clonidine, for example.
It is also particularly preferred to use ambroxol or one of the
pharmacologically acceptable salts thereof in combination with one or more
other pain relievers selected from among the opiates, preferably morphine,
buprenorphine, levomethadone, codeine, tramadol or tilidine, non-steroidal
analgesics, for example acetylsalicylic acid, paracetamol, diclofenac,
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meloxicam, ibuprofen, ibuprofen lysinate, ibuprofen in extruded form (as
described
in WO 99/06038), gabapentine or antidepressants, preferably imipramine,
maprotiline, mianserine, fluoxetine, viloxazine, tranylcypromine or
moclobemide.
It is also preferable to use ambroxol for the treatment of patients
suffering pain or patients with tumoral diseases.
The present invention further relates to a pharmaceutical formulation
comprising ambroxol or one of the pharmacologically acceptable salts thereof
and an
acceptable excipient, carrier or diluent for a use in treatment as described
herein.
The present invention further relates to a use of ambroxol or one of
the pharmacologically acceptable salts thereof for a treatment as described
herein.
Suitable acids for forming salts of ambroxol are for example
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric
acid,
oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, citric
acid,
ascorbic acid and methanesulphonic acid, preferably hydrochloric acid.
The activity of ambroxol according to the invention is to be illustrated
by the following Examples. These are intended solely as an illustration of the
invention and are not to be regarded as limiting.
Ambroxol exhibits an antinociceptive activity which is based on the
blocking of voltage-dependent sodium channels. In contrast to the sodium
channel blockers described which are used clinically, ambroxol preferentially
inhibits tetrodotoxin-resistant sodium channels in nociceptive C-fibre
neurones.
Their special relevance to inflammatory and chronic pain has been demonstrated
in vivo (Waxman et al. (1999) Proceedings of the National Academy of Science
96, 7635-7639; Khasar et al. (1998), Neuroscience Letters 256, 17-20).
In neurone cultures from the posterior root ganglions of adult rats,
tetrodotoxin-resistant sodium channels were semi-maximally inhibited by 35 M
of
ambroxol. Tetrodotoxin-sensitive currents were inhibited much less strongly by
this concentration and here the IC50 was higher than 100 [M.
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The powerful analgesic effect of blocking the channels was
demonstrated inter alia by animal experimentation using the formalin paw test
on
rats. The test is described below.
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Formalin Paw Test (Ref: Carlton S M and Zhou S: Attenuation of formalin-
induced nociceptive behaviors following local peripheral injection of
gabapeptin. Pain 76, 201-207, 1998).
Male rats (Chbb: THOM) weighing 250-300 grams are used. 20 pl of a 2%
formaldehyde solution is injected into the plantar region of the right hind
paw.
Immediately after, the number of flinches (twitches of the affected hind paw)
and the length of time spent licking the affected paw are recorded over a
period of one hour. After 5 minutes in each case the values are grouped
together into epochs. From the epoch values, time-effect curves for flinches
and licking are plotted. Typically, two phases of formalin effect are observed
(flinches, licking). A first phase lasting 0-10 minutes and a second phase
lasting 10-60 minutes. Between the two phases the number of flinches and
duration of licking fall towards 0 (interphase). From the time-effect curves
the
areas under the curve for the first phase and for the second phase are
determined. Usually, 5 animals are used for each control, placebo and dose of
substance. The results of the doses of substance are compared with those of
the controls and ED50 values are calculated. The ED50 is the dose at which
the control values are inhibited by 50%.
The ED50 value for ambroxol hydrochloride is 70 mg/kg p.o.
In other test models for neuropathic pain in the rat (1),(2) ambroxol reduced
the
tactile allodynia, as well as the thermal al hyper algesia.
(1) Bennett GJ and Xie Y-K. A peripheral mononeuropathy in rat that produces
disorders of pain sensation like those seen in man. Pain 33, 87-107, 19883.
(2) Seltzer, Z., Dubner R. and Shir, Y. A novel behavioral model of
neuropathic
pain disorder. Pain 43, 205-218, 1990.
Ambroxol may be used on its own or in conjunction with other
pharmacologically active substances. Suitable preparations include for
example tablets, capsules, suppositories, solutions, elixirs, emulsions or
dispersible powders. Suitable tablets may be obtained, for example, by
mixing the active substance(s) with known excipients, for example inert
diluents such as calcium carbonate, calcium phosphate or lactose,
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disintegrants such as corn starch or alginic acid, binders such as starch nr
geatine, lubricants such as magnesium stearate or talc and/or agents for
delaying release, such as carboxymethyl cellulose, cellulose acetate
phthalate, or polyvinyl acetate. The tablets may also comprise several layers-
Coated tablets may be prepared accordingly by coating cores produced
analogously to the tablets with substances normally used for tablet coatings,
for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
To achieve delayed release or prevent incompatibilities the core may also
consist of a number of layers. Similarly the tablet coating may consist of a
number of layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations thereof
according to the invention may additionally contain a sweetener such as
saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a
flavouring such as vanillin or orange extract. They may also contain
suspension adjuvants or thickeners such as sodium carboxymethyl cellulose,
wetting agents such as, for example, condensation products of fatty alcohols
with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Solutions for injection are prepared in the usual way, e.g. with the addition
of
preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal
salts of ethylenediamine tetraacetic acid, and transferred into injection
vials
or ampoules.
Capsules containing one or more active substances or combinations of active
substances may for example be prepared by mixing the active substances
with inert carriers such as lactose or sorbitol and packing them into gelatine
capsules.
Suitable suppositories may be made for example by mixing with carriers
provided for this purpose, such as neutral fats or polyethyleneglycol or the
derivatives thereof.
A therapeutically effective daily dose is between 30 and 4000 mg, preferably
100 to 2000 mg in adults.
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The Examples which follow illustrate the present invention without restricting
its scope:
Examples of pharmaceutical formulations
A) Tablets per tablet
active substance 800 mg
lactose 140 mg
corn starch 240 mg
polyvinylpyrrolidone 20 mg
magnesium stearate 10 mg
Ambroxol, lactose and some of the corn starch are mixed together. The
mixture is screened, then moistened with a solution of polyvinylpyrrolidone in
water, kneaded, wet-granulated and dried. The granules, the remaining corn
starch and the magnesium stearate are screened and mixed together. The
mixture is compressed to produce tablets of suitable shape and size.
B) Tablets per tablet
ambroxol 800 mg
corn starch 190 mg
lactose 55 mg
microcrystalline cellulose 35 mg
polyvinylpyrrolidone 20 mg
sodium-carboxymethyl starch 30 mg
-magnesium stearate 10 mg
The ambroxol, some of the corn starch, lactose, microcrystalline cellulose and
polyvinylpyrrolidone are mixed together, the mixture is screened and worked
with the remaining corn starch and water to form a granulate which is dried
and screened. The sodium-carboxymethyl starch and the magnesium stearate
are added and mixed in and the mixture is compressed to form tablets of a
suitable size.
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C) Coated tablets per coated tablet
Ambroxol 500 mg
Corn starch 45 mg
Lactose 30 mg
Polyvinylpyrrolidone 5 mg
Magnesium stearate 5 mg
The ambroxol, corn starch, lactose and polyvinylpyrrolidone are thoroughly
mixed and moistened with water. The moist mass is pushed through a screen
with a 1 mm mesh size, dried at about 45 C and the granules are then passed
through the same screen. After the magnesium stearate has been mixed in,
convex tablet cores with a diameter of 11 mm are compressed in a tablet-
making machine. The tablet cores thus produced are coated in known
manner with a covering consisting essentially of sugar and talc. The finished
coated tablets are polished with wax.
D) Capsules per capsule
Ambroxol 250 mg
Corn starch 268.5 mg
Magnesium stearate 1.5 mg
The ambroxol and corn starch are mixed and moistened with water. The
moist mass is screened and dried. The dry granules are screened and mixed
with magnesium stearate. The finished mixture is packed into size 1 hard
gelatine capsules.
E) Parenteral solution
ambroxol 500 mg
citric acid monohydrate 100 mg
sodium hydroxide 35 mg
mannitol 1500 mg
water for inj. 50 ml
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The ambroxol is dissolved in water at its own pH or optionally at pH 4.5 to
5.5
and mannitol is added to make it isotonic. The solution obtained is filtered
free
from pyrogens and the filtrate is transferred under aseptic conditions into
injection bottles which are then sealed with rubber stoppers and autoclaved.
F) Suppositories
Ambroxol 450 mg
Solid fat 1650 mg
The hard fat is melted. At 40 C the ambroxol is homogeneously dispersed. It
is cooled to 38 C and poured into slightly chilled suppository moulds.
G) Oral solution
ambroxol 150 mg
hydroxyethylceIlulose 50 mg
sorbic acid 5 mg
sorbitol (70%) 600 mg
glycerol 200 mg
flavouring 15 mg
water ad 10 MI
Distilled water is heated to 70 C . Hydroxyethylcellulose is dissolved therein
with stirring. After the sorbitol solution and glycerol have been added the
mixture is cooled to ambient temperature. At ambient temperature sorbic acid,
flavouring and ambroxol are added. To remove air from the suspension it is
evacuated with stirring.
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H) Ointment
composition g/100 g ointment:
ambroxol 20 g
sodium disulphite 0.1 g
cetylalcohol 10 g
stearylalcohol 10 g
white Vaseline 5 g
perfume oil q.s_
distilled water ad 100 g
The ingredients are processed in the usual way to form an ointment.
