Note: Descriptions are shown in the official language in which they were submitted.
WO 2011/058373 PCT/GB2010/051895
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DRUG COMBINATION WITH THEOBROMINE AND ITS USE IN THERAPY
Field of the Invention
This invention relates to a drug combination, its composition and its use
in the therapy of cough.
Background of the Invention
Cough is a protective reflex. Persistent cough can be distressing. Over-
the-counter remedies are available but their effectiveness is doubtful.
W098/42322 discloses the use of theobromine for the treatment of
cough, to be given orally. Usmeni et al., FASEB J. express acticle 10.1096,
discloses that theobromine inhibits sensory nerve action and cough. Data are
provided, showing effects following oral dosing in citric-acid induced cough
in the
guinea pig, and in the capsaicin cough challenge in humans, and following
bathing of isolated guinea pig vagus nerve preparations.
A number of non-opiate antitussive drugs have been developed for cough
therapies. A number of these antitussive drugs are NMDA antagonists.
Dextromethorphan is one such drug that has been developed specifically for use
as a cough therapy. However, its efficacy and suitability as a treatment for
cough has already been brought into question. In J. Ramsey et al., British
Journal of Clinical Pharmacology, the authors report that the apparent success
of dextromethorphan as a clinical treatment for cough is in fact just a
placebo
effect, and that it has no efficacy in cough.
Summary of the Invention
The invention is based at least in part on data showing a synergistic anti-
tussive effect for theobromine combined with the non-opiate antitussive drug,
dextromethorphan, in a citric acid-induced cough model. The data show that
when theobromine is combined with dextromethorphan, the effect is surprisingly
potent and greater than the sum of the individual drugs, revealing that the
combination has a substantially improved effect.
Consequently, a considerably reduced dose of both drugs can be given
for an equivalent effect for each individual drug, so reducing side-effects
and
drug burden. One such side-effect of dextromethorphan, and many other non-
opiate antitussives is sedation. It has surprisingly been found that
theobromine
counteracts the sedative properties of such drugs.
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Therefore, according to the present invention, an agent comprises
theobromine and another non-opiate antitussive, as a combined preparation for
simultaneous, sequential or separate use in therapy.
It is believed that this synergistic relationship will be exhibited by all non-
opiate antitussives. Without wishing to be bound by theory, this may be
because
non-opiate antitussives act via a similar mechanism, which may be NMDA
antagonism.
Description of the Drawing
Figure 1 shows the effect of theobromine, and a combination of
theobromine and dextromethorphan, on citric acid-induced cough in guinea-pig.
Description of the Invention
Any suitable form of theobromine can be chosen. These include salts,
prodrugs and active metabolites. Theobromine may also be in the form of cocoa
or chocolate. Suitable dose ranges for theobromine are known in the art,
although the synergistic effect of the combination means that the effective
dose
may be reduced.
The additional agent (a different non-opiate antitussive drug, i.e. not
theobromine) may be used in an amount that is already known for its use,
although combination according to this invention means that a reduced dose
may be effective. Preferably, the dose of the non -opiate antitussive that is
administered with the theobromine is greater than 0.1, e.g. more than 5, and
typically up to 30 mg/kg/day.
The non-opiate antitussive drug is preferably selected from
dextromethorphan, isoaminile, benzonate, zipeprol, morclofone, prenoxdiazine,
dropropizine, piperidione, pentoxyverine, oxolamine, oxeladin, nepinalone,
meprotixol, indantadol, dimemorfan, dibunate, cloperastine, clofedanol,
butamirate, bibenzonium, benproperine and fedrilate. Dextromethorphan is the
most preferred antitussive drug, e.g. at a dose of 0.1 to 6 mg/kg/day.
The non-opiate antitussive drug is preferably an NMDA antagonist.
The compounds of the invention may be administered by any available
route, such as via the oral, inhaled, intranasal, sublingual, intravenous,
rectal
and vaginal routes. The oral route is the preferred route of administration.
The compounds of the invention are preferably as combinations to be
administered orally, for example as tables, troches, lozenges, aqueous or oral
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suspensions, dispersible powders or granules. Preferred pharmaceutical
compositions of the invention are tablets and capsules. Liquid dispersions for
oral administration may be syrups, emulsions and suspensions. More
preferably, the pharmaceutical composition of the combination is a pressed
tablet or capsule with conventional excipients, examples of which are given
below.
Compositions of the combination intended for oral use may be prepared
according to any method known to the art for the manufacture of pharmaceutical
compositions, and such compositions may contain one or more agents selected
from the group consisting of sweetening agents, flavouring agents, colouring
agents and preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets contain the combined active ingredients in
admixture with non-toxic pharmaceutically acceptable excipients which are
suitable for the manufacture of tablets. These excipients may be, for example,
inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium
phosphate or sodium phosphate; granulating and disintegrating agents, for
example corn starch or alginic acid; binding agents, for example starch
gelatin,
acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating
agents,
for example magnesium stearate, stearic acid or talc. The tablets may be
uncoated or they may be coated by known techniques to delay disintegration
and absorption in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material such as
glyceryl
monostearate or glyceryl distearate may be employed.
Aqueous suspensions contain the combined active materials in admixture
with excipients suitable for the manufacture of aqueous suspensions. Such
excipients are suspending agents, for example sodium carboxymethylcellulose,
methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl
pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may
be a naturally occurring phosphatide, for example lecithin, or condensation
products of an alkylene oxide with fatty acids, for example polyoxyethylene
stearate, or condensation products of ethylene oxide with long-chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation products
of ethylene oxide with partial esters derived from fatty acids, for example
polyoxyethylene sorbitan monooleate. The aqueous suspensions may also
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contain one or more preservatives, for example ethyl or n-propyl p-
hydroxybenzoate, one or more colouring agents, one or more flavouring agents,
and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient
in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut
oil,
polyoxyethylene hydrogenated castor oil, fatty acids such as oleic acid, or in
a
mineral oil such as liquid paraffin or in other surfactants or detergents. The
oily
suspensions may contain a thickening agent, for example beeswax, hard
paraffin or cetyl alcohol. Sweetening agents, such as those set forth above,
and
flavouring agents may be added to provide a palatable oral preparation. These
compositions may be preserved by the addition of an antioxidant such as
ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by the addition of water provide the combined active ingredients in
admixture with a dispersing or wetting agent, suspending agent and one or more
preservatives. Suitable sweetening, flavouring and colouring agents may also
be present.
The combined pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a vegetable oil,
for
example olive oil or arachis oil, or a mineral oil, for example liquid
paraffin, or
mixtures of these. Suitable emulsifying agents may be naturally occurring
gums,
for example gum acacia or gum tragacanth, naturally occurring phosphatides,
for
example soya bean, lecithin, and esters or partial esters derived from fatty
acids
and hexitol anhydrides, for example sorbitan monooleate and condensation
products of the said partial esters with ethylene oxide, for example
polyoxyethylene sorbitan monooleate. The emulsions may also contain
sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for
example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may
also contain a demulcent, a preservative, flavouring and colouring agents.
Suspensions and emulsions may contain a carrier, for example a natural
gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose,
or
polyvinyl alcohol.
WO 2011/058373 PCT/GB2010/051895
In a preferred embodiment, theobromine in combination with an
antitussive drug is to be administered via the oral route. Combined
compositions
according to the invention may be produced using conventional formulation
techniques. In particular, spray-drying may be used to produce microparticles
5 comprising the active agent dispersed or suspended within a material that
provides the controlled release properties.
The process of milling, for example jet milling, may also be used to
formulate the therapeutic composition. The manufacture of fine particles by
milling can be achieved using conventional techniques. The term "milling" is
used herein to refer to any mechanical process which applies sufficient force
to
the particles of active material to break or grind the particles down into
fine
particles. Various milling devices and conditions are suitable for use in the
production of the compositions of the invention. The selection of appropriate
milling conditions, for example, intensity of milling and duration, to provide
the
required degree of force, will be within the ability of the skilled person.
Ball
milling is a preferred method. Alternatively, a high pressure homogeniser may
be used, in which a fluid containing the particles is forced through a valve
at high
pressure, producing conditions of high shear and turbulence. Shear forces on
the particles, impacts between the particles and machine surfaces or other
particles, and cavitation due to acceleration of the fluid, may all contribute
to the
fracture of the particles. Suitable homogenisers include the EmulsiFlex high
pressure homogeniser, the Niro Soavi high pressure homogeniser and the
Microfluidics Microfluidiser. The milling process can be used to provide the
microparticles with mass median aerodynamic diameters as specified above. If
hygroscopic, the active agent may be milled with a hydrophobic material, as
stated above.
If it is required, the microparticles produced by the milling step can then
be formulated with an additional excipient. This may be achieved by a spray-
drying process, e.g. co-spray-drying. In this embodiment, the particles are
suspended in a solvent and co-spray-dried with a solution or suspension of the
additional excipient. Preferred additional excipients include polysaccharides.
Additional pharmaceutically effective excipients may also be used.
Compositions of the combination intended for inhaled, topical, intranasal,
intravenous, sublingual, rectal and vaginal use may be prepared according to
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any method known to the art for the manufacture of pharmaceutical
compositions.
Therapy according to the invention may be conducted in generally known
manner, depending on various factors, such as the sex, age or condition of the
patient, and the existence or otherwise of one or more concomitant therapies.
The patient population may be important.
The present invention is based at least in part on the following study.
Study
Cough was induced in guinea pigs by the use of citric acid. One group of
guinea pigs was administered 10 mg/kg of theobromine, and a second group
was administered 10 mg/kg of theobromine in combination with 30 mg/kg of
dextromethorphan. A third group was used as a control, receiving only vehicle.
Administration was via the oral route.
The results are shown in Figure 1. The data show that a combination of
theobromine and dextromethorphan has improved efficacy in cough therapy
when compared to theobromine monotherapy (shown in the Figure) and
dextromethorphan monotherapy (recently reported to have no effect in cough).
