Note: Descriptions are shown in the official language in which they were submitted.
ease a i.suz-rt Boehringer Ingelheim Pharma KG
CA 02477105 2004-08-25
78903pct.210
Ambroxol for the treatment of painful conditions in the mouth and pharyngeal
cavity.
The invention relates to the use of ambroxol and the pharmacologically
acceptable
salts thereof for preparing a pharmaceutical composition for the treatment of
painful
conditions in the oral and pharyngeal cavity.
Io Backctround to the invention
Painkillers for relieving pain in the oral and pharyngeal cavity often have
the
drawback of side effects, e.g. in the form of local irritations.
is The active substance ambroxol ( traps-4-(2-amino-3,5-dibromobenzyfamino)-
cyclohexanol) is a known expectorant and mucolytic. It is used in oral
preparations
such as syrups, capsules, tablets, inhalable solutions, drops or suckable
pastilles.
The aim of the present invention is to prepare a well-tolerated active
substance for
2o the treatment of pain in the oral and pharyngeal cavities.
Description of the invention
Surprisingly, it has been found that, when administered locally in suitable
doses or
2s concentrations, ambroxol has a very good pain-relieving effect in the oral
and
pharyngeal cavity in addition to being very well tolerated.
The invention therefore relates to the use of ambroxol or one of the
pharmacologically acceptable salts thereof for preparing a pharmaceutical
3o composition for the treatment of pain in the oral and/or pharyngeal cavity,
selected
from among acute sore throat, aphthae, gingivitis, parodontopathies, pressure
points
caused by prostheses, pain after oro-pharyngeal interventions, lesions on the
mucous membrane in the oral and pharyngeal cavity and herpes simplex in the
oral
and pharyngeal cavity, particularly aphthae, gingivitis, parodontopathies,
pressure
CA 02477105 2004-08-25
2
points caused by prostheses, pain after oro-pharyngeal interventions, lesions
on the
mucous membrane in the oral and pharyngeal cavity and herpes simplex in the
oral
and pharyngeal cavity, most particularly for the treatment of acute sore
throats. By
acute sore throats are meant severe sore throats, for example inflamed throats
with
s difficulty swallowing or with burning in the throat.
The invention further relates to a pharmaceutical composition containing
ambroxol or
one of the pharmacologically acceptable salts thereof and one or more active
substances selected from among the antiseptics, vitamins, corticoids,
to antiinflammatories, virostatics, antibiotics, antimycotics and proteolytic
enzymes.
Suitable antiseptics are for example cetylpyridinium-CI, dequalinium-CI,
chlorhexidine-digluconate, benzalkonium-CI or ethacridine-lactate.
Suitable vitamins are for example dexpanthenol (pantothenic acid) or ascorbic
acid.
Suitable corticoids are for example triamcinolone or prednisolone-acetate.
is Suitable antiinflammatories are for example benzydamine-CI or choline
salicylate.
Suitable virostatics are for example acyclovir or idoxuridine.
Suitable antibiotics are for example thyrotricin or bacitracin.
Suitable antimycotics are for example amphotericin B or nystatin.
An example of a suitable proteolytic enzyme is lysozyme.
zo Suitable ethereal oils are for example peppermint oil, thyme or sage oils.
The invention further relates to a pharmaceutical composition containing
ambroxol or
one of the pharmacologically acceptable salts thereof and one or more active
substances, selected from the group consisting of lysozyme hydrochloride,
2s dipotassium glycyrrhizinate, ammonium glycyrrhizinate, cetylpyridinium
chloride,
chlorpheniramine maleate, noscapine, dequalinium chloride, dextromethorphan,
phenolphthalinate, potassium guaiacolsulphonate, dl-methylephedrine
hydrochloride,
chlorhexidine hydrochloride, and potassium cresolsulphonate.
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3
Ambroxol is a metabolite of the secretolytic bromhexine. The two active
substances
represent a very well tolerated combination of active substances which
positively
influences the dual effect of ambroxol.
s The invention therefore also relates to a pharmaceutical composition
consisting of
ambroxol, bromhexine or the pharmacologically acceptable salts thereof and
pharmaceutical excipients, preferably with a ratio of ambroxol to bromhexine
in the
range from 4:1 to 6:1, more preferably 5:1.
to A particularly preferred pharmaceutical composition is one wherein the
single dose
contains 15 to 50 mg of ambroxol, preferably 20 mg of ambroxol.
The invention further relates to a solid, suckable or slowly dissolving form
of a
pharmaceutical composition containing ambroxol and one or more active
substances
Is selected from among the antiseptics, vitamins, corticoids,
antiinflammatories,
antibiotics, antimycotics and proteolytic enzymes.
The invention further relates to the use of a pharmaceutical composition as
described
above for preparing a medicament for the treatment of pain in the oral and/or
2o pharyngeal cavity, selected from among acute sore throat, aphthae,
gingivitis,
parodontopathies, pressure points caused by prostheses, pain after oro-
pharyngeal
interventions, lesions on the mucous membrane in the oral and pharyngeal
cavity
and herpes simplex in the oral and pharyngeal cavity, most preferably for
treating
acute sore throats.
The invention further relates to the use of a pharmaceutical composition
consisting of
ambroxol hydrochloride, a flavouring, a lubricant, a matrix material, a
sweetening
agent and a polyethyleneglycol for preparing a pharmaceutical composition for
the
treatment of pain in the oral and/or pharyngeal cavity, selected from among
acute
3o sore throat, aphthae, gingivitis, parodontopathies, pressure points caused
by
prostheses, pain after oro-pharyngeal interventions, lesions on the mucous
membrane in the oral and pharyngeal cavity and herpes simplex in the oral and
pharyngeal cavity, most preferably for treating acute sore throats.
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4
Suitable flavourings may be, for example, peppermint, eucalyptus or lemon,
preferably peppermint flavouring.
Suitable matrix materials may be, for example, calcium carbonate, calcium
phosphate or sorbitol, preferably sorbitol.
s Suitable sweetening agents may be, for example, saccharin, saccharin sodium,
cyclamate, glycerol or sugar, preferably saccharin sodium.
Suitable tablet lubricants may be, for example, polyethyleneglycols,
preferably
Macrogol 6000.
Suitable lubricants may be for example talcum or magnesium stearate,
preferably
io talc.
The invention further relates to the use of a suckable tablet containing
ambroxol
based on sugar alcohols as the matrix material, characterised in that it
contains a
pharmaceutically acceptable layered silicate and a polyethyleneglycol,
optionally
Is together with other pharmaceutical excipients, taste or flavouring agents
to prepare a
pharmaceutical composition for treating pain in the oral and/or pharyngeal
cavity,
selected from among acute sore throat, aphthae, gingivitis, parodontopathies,
pressure points caused by prostheses, pain after oro-pharyngeal interventions,
lesions on the mucous membrane in the oral and pharyngeal cavity and herpes
2o simplex in the oral and pharyngeal cavity, most preferably for the
treatment of acute
sore throats.
The invention further relates to the use of ambroxol for preparing a
pharmaceutical
composition with a pain-relieving effect lasting for a period of at least 3
hours,
2s preferably more than 3 hours, after administration.
The invention also relates to the use of a pharmaceutical composition
containing
ambroxol for preparing a pharmaceutical composition with a pain-relieving
effect
lasting for a period of at least 3 hours, preferably more than 3 hours, after
3o administration.
The pharmaceutical composition according to the invention is preferably
administered 1 to 6 times, preferably 2 to 4 times a day.
CA 02477105 2004-08-25
Acids suitable for forming salts of ambroxol include for example hydrochloric
acid,
hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, oxalic acid,
malonic
acid, fumaric acid, malefic acid, tartaric acid, citric acid, ascorbic acid
and
methanesulphonic acid, preferably hydrochloric acid.
5
The activity of ambroxol according to the invention is intended to be
illustrated by the
following examples of clinical trials which investigate the effectiveness of
different
strengths of suckable tablets containing ambroxol. These are intended solely
to
illustrate the invention and are not to be regarded as limiting.
io
Example 1
Investigation of the activity and tolerance of suckable tablets containing 20
mg
of ambroxol hydrochloride (traps-4-((2-amino-3,5-dibromo-
benzyl)amino]cyclohexano hydrochloride, CAS Reg. No. 18683-91-5) compared
is with a placebo in treating acute sore throats
A multi-centred, prospective, placebo-controlled, randomised double-blind
trial was
carried out over two days' treatment with up to 6 suckable tablets containing
ambroxol hydrochloride per day.
2o Patients: 218 patients (97 men, 121 women) with an average age of 39.4 ~ 15
years
(range from 17-81 years) were recruited; of these 215 patients were treated:
107 with
20 mg of ambroxol and 108 with placebo. 26 patients stopped the treatment
early (13
in each treatment group). The intent-to-treat (ITT) population consisted of
208
patients (105 treated with ambroxol and 103 given the placebo); 196 patients
formed
2s the per-protocol (PP) population (97 with test substance and 99 with
placebo). For
the drug safety analysis, all the patients treated were studied.
Treatments: Double-blind treatment with up to s suckable tablets per day,
which
either contained 20 mg of ambroxol or constituted a placebo (suckable tablet
without
the active substance, but with a marked flavour of peppermint similar to the
test
3o substance)
End points: the average pain reduction, weighted for time, during the first 3
hours
after administration of the first suckable tablet, standardised to the degree
of initial
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6
pain (SPIDnorm)~ moreover, the assessment of effectiveness and tolerance by
the
patient at the end of each day of treatment
Results: In both treatment groups there was a reduction in the intensity of
pain; the
average SPIDnorm (~ SD) after the first suckable tablet was 0.39 t 0.27 for 20
mg
s ambroxol hydrochloride and 0.28 ~ 0.25 for placebo.
The superiority of the ambroxol over the placebo was apparent from a
statistically
significant treatment effect (p=0.0029; - 95% confidence interval for the
average
difference between the ambroxol treatment groups minus placebo: 0.04 to 0.18).
At
the end of each successive day of ambulant treatment with up to 6 suckable
tablets a
io statistically significantly larger number of patients reported a higher
degree of
effectiveness for the active treatment with ambroxol hydrochloride than for
the
administration of the placebo. The test substance was found to be tolerated
just as
well as the placebo.
Conclusion: The administration of suckable tablets containing 20 mg of
ambroxol
Is hydrochloride to patients with acute sore throat has an effective pain-
relieving effect
which is superior to the inherently beneficial effect of sucking a placebo.
Figure 1 shows the course, over time, of the average change in pain intensity
(PID)
for the period before taking the tablet (base line) up to 3 hours after taking
the first
suckable tablet containing 20 mg of ambroxol hydrochloride and placebo.
Example 2
Investigation of the activity and tolerance of suckable tablets containing 20
or
mg of ambroxol hydrochloride (trans-4-((2-amino-3,5-dibromo-
benzyl)amino]cyclohexano hydrochloride, CAS Reg. No. 18683-91-5) compared
2s with a placebo in treating acute sore throats
A multi-centred, prospective, placebo-controlled, randomised double-blind
trial was
carried out over three days' treatment with up to 6 suckable tablets
containing
ambroxol hydrochloride per day.
3o Patients: 331 ambulant patients with acute uncomplicated sore throats of at
least
moderate severity but with no bacterial pharyngitis were investigated.
Treatments: Double-blind treatment with up to 6 suckable tablets per day
containing
either 20 mg or 30 mg of ambroxol hydrochloride or constituting a placebo
(suckable
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tablet without the active substance, but again with a marked flavour of
peppermint
similar to the test substance)
End points: the average pain reduction, weighted for time, during the first 3
hours
after administration of the first suckable tablet, standardised to the degree
of initial
pain (SPIDnorm)~ moreover, the assessment of effectiveness and tolerance by
the
patient at the end of each day of treatment
Results: All the treatments led to a reduction in the intensity of pain; the
average
SPIDnorm (~ SD) after the first suckable tablet was taken was 0.53 t 0.28 or
0.50 ~
0.30 for 20 mg and 30 mg ambroxol hydrochloride, respectively, and 0.38 t 0.28
for
to placebo. The effect of the treatment was statistically significant. The
superiority of
the active treatments over the placebo could be clearly demonstrated (95%
confidence interval (CI) for the average differences between the groups
treated with
suckable tablets containing 20 or 30 mg of ambroxol minus placebo: 0.08 to
0.23 or
0.05 to 0.20). At the end of each successive day of ambulant treatment with up
to 6
is suckable tablets per day a statistically significantly larger number of
patients reported
a higher degree of effectiveness for the active treatments with ambroxol
hydrochloride than for the administration of the placebo. The test substance
was
found to be tolerated just as well as the placebo in all dosages.
Conclusion: The administration of suckable tablets containing 20 or 30 mg of
2o ambroxol hydrochloride to patients with acute sore throat has a markedly
effective
pain-relieving effect which is superior to the inherently beneficial effect of
sucking a
placebo. Both doses were tolerated equally well.
Figure 2 shows the course, over time, of the average change in pain intensity
(PID)
2s for the period before taking the tablet (base line) up to 3 hours after
taking the first
suckable tablet containing 20 mg or 30 mg of ambroxol hydrochloride and
placebo.
Ambroxol may be used on its own or combined with other pharmacologically
active
substances. It may be applied in any of the preparation forms which are
suitable for
30 local use. Preparations suitable for sucking or dissolving slowly in the
mouth include,
for example, tablets or sweets based on sugar or sugar substitutes or pastille-
like
products with a gum arabic or gelatine base.
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g
Examples of semisolid preparations for application to the oral mucosa include
gels,
for example, especially gels based on cellulose or acrylate.
Suitable solutions for spraying, gargling and rinsing include aqueous
preparations,
advantageously with the addition of viscosity-increasing substances such as
modified
celluloses, acrylic acid derivatives or polyvinyl compounds.
In addition, the semisolid and liquid forms in particular may contain
sweetening
agents and moisture retainers such as glycols and sugar alcohols, for example.
All the forms are flavoured in the conventional way, e.g. by the addition of
ethereal
oils.
to
The preparations may be produced by methods known in pharmacy.
The following examples of pharmaceutical formulations illustrate the present
invention without restricting its scope:
Example 1 )
Suckable pastille per pastille
ambroxol hydrochloride 20.0 mg
2o peppermint flavouring 16.0 mg
sorbitol 1373.5 mg
saccharin sodium 0.5 mg
Macrogol 6000 30 mg
talc 60 mg
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Example 2)
Suckablepastille per tablet
Ambroxol hydrochloride 20.0 mg
s Lysozyme hydrochloride 5.0 mg
Dipotassium glycyrrhizinate 2.5 mg
Cetylpyridinium Chloride 1.0 mg
Chlorpheniramine Maleate 1.0 mg
Xylitol 920.5 mg
io D-Mannitol 9.5 mg
Polyvinylpyrrolidone 21.0 mg
Stearic acid 10.0 mg
Peppermint oil 6.0 mg
light anhydrous silicic acid 1.0 mg
is talc 1.0 mg
magnesium stearate 1.5 mg
Example 3)
2o Suckable pastille
per tablet
Ambroxol hydrochloride 20.0 mg
Noscapine 5.0 mg
Dequalinium Chloride 0.125 mg
Sucrose (purified) 908.675 mg
2s I-Menthol 1.0 mg
Peppermint oil 0.6 mg
Lemon flavour 3.6 mg
Corn starch 30.0 mg
Polyvinylpyrrolidone 21.0 mg
so Magnesium Stearate 10.0 mg
CA 02477105 2004-08-25
Example 4)
Suckable pastille
per tablet
Ambroxol hydrochloride 20.0 mg
5 Dextromethorphan phenolphthalinate 10.0 mg
Potassium guaiacolsulphonate 23.3 mg
Cetylpyridinium Chloride 1.0 mg
Sucrose (purified) 869.7 mg
Peppermint flavour 16.0 mg
to Corn starch 30.0 mg
Polyvinylpyrrolidone 20.0 mg
Magnesium Stearate 10.0 mg
Example 5)
Suckable pastille per tablet
Ambroxol hydrochloride 20.0 mg
dl-Methylephedrine Hydrochloride 6.25 mg
Chlorhexidine Hydrochloride 5.0 mg
2o Lactose 905.25 mg
Low-substituted Hydroxypropylcellulose 25.0 mg
Hydroxypropylcellulose 20.0 mg
Peppermint flavour 16.0 mg
Magnesium Stearate 2.5 mg
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Example 6)
Suckable pastille per tablet
Ambroxol hydrochloride 20.0 mg
s Ammonium glycyrrhizate 1.67 mg
Potassium Cresolsulphonate 30.0 mg
Lactose 884.83 mg
Low-substituted Hydroxypropylcellulose 25.0 mg
Hydroxypropylcellulose 20.0 mg
io Peppermint flavour 16.0 mg
Magnesium Stearate 2.5 mg
