COMBINAISON DE MEDICAMENT AVEC LA THEOBROMINE ET SON UTILISATION EN THERAPIE

DRUG COMBINATION WITH THEOBROMINE AND ITS USE IN THERAPY

Abrégé français

La présente invention concerne un agent comprenant de la théobromine et un opiacé, pour utilisation simultanée, séquentielle ou séparée en thérapie. De préférence, la thérapie est celle de la toux.

Abrégé anglais

An agent comprises theobromine and an opiate, for simultaneous, sequential or separate use in therapy. Preferably, the therapy is of cough.

Revendications

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We Claim:
1. A composition consisting of theobromine and an opiate, as a combined
preparation for
treatment of cough of a subject.
2. The composition according to claim 1, wherein the opiate is codeine,
morphine,
diamorphine, thebaine, oripavine, fentanyl, alphamethylfentanyl, alfentanil,
sufentanil,
remifentanil, carfentanyl, propoxyphene, oxymorphone, oxycodone,
hydromorphone,
pethidine, dihydrocodeine, buprenorphine, etorphine, ethylmorphine,
loperamide,
hydrocodone, pentazocine, tramadol, tipepidine or noscapine.
3. The composition according to claim 1 or claim 2, wherein the opiate is
codeine.
4. The composition according to claim 1 or claim 2, wherein the opiate is in a
dose of 0.1
mg/kg/day to 30 mg/kg/day.
5. The composition according to claim 2 or claim 3, wherein the codeine is in
a dose of up to 3
mg/kg/day.
6. The composition according to any one of claims 1-5, wherein the composition
is formulated
for oral administration.
7. The composition according to any one of claims 1-6, wherein the composition
is prepared as
a tablet, capsule, troche, lozenge, powder, granule, suspension, syrup or
emulsion.
8. A pharmaceutical composition comprising the composition defined in any one
of claims 1-
5and a carrier.
9. The pharmaceutical composition according to claim 8, further comprising one
or more
excipients, and optionally one or more of sweetening agents, flavoring agents,
coloring
agents and/or preserving agents.
10. The pharmaceutical composition according to claim 8 or claim 9, wherein
the pharmaceutical

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composition is formulated for oral administration.
11. The pharmaceutical composition according to any one of claims 8-10,
wherein the
composition is prepared as a tablet, capsule, troche, lozenge, powder,
granule, suspension,
syrup or emulsion.
12. Use of a composition as defined in any one of claims 1-7 or a
pharmaceutical composition
as defined in any one of claims 8-11 in the manufacture of a medicament for
treatment of
cough of a subject.
13. Use of a composition in the manufacture of a medicament for treatment of
cough of a
subject, wherein the composition consists of theobromine and an opiate as a
combined
preparation.
14. The use according to claim 13, wherein the opiate is codeine, morphine,
diamorphine,
thebaine, oripavine, fentanyl, alphamethylfentanyl, alfentanil, sufentanil,
remifentanil,
carfentanyl, propoxyphene, oxymorphone, oxycodone, hydromorphone, pethidine,
dihydrocodeine, buprenorphine, etorphine, ethylmorphine, loperamide,
hydrocodone,
pentazocine, tramadol, tipepidine or noscapine.
15. The use according to claim 13, wherein the opiate is codeine.
16. The use according to claim 13 or claim 14, wherein the opiate is in a dose
of 0.1 mg/kg/day
to 30 mg/kg/day.
17. The use according to claim 14 or claim 15, wherein the codeine is in a
dose of up to 3
mg/kg/day.
18. The use according to any one of claims 13-17, wherein the medicament is
formulated for
oral administration.
19. The use according to any one of claims 13-18, wherein the medicament is
prepared as a
tablet, capsule, troche, lozenge, powder, granule, suspension, syrup or
emulsion.

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20. Use of a composition for a treatment of cough, wherein the composition
consists of
theobromine and an opiate as a combined preparation.
21. The use according to claim 20, wherein the opiate is codeine, morphine,
diamorphine,
thebaine, oripavine, fentanyl, alphamethylfentanyl, alfentanil, sufentanil,
remifentanil,
carfentanyl, propoxyphene, oxymorphone, oxycodone, hydromorphone, pethidine,
dihydrocodeine, buprenorphine, etorphine, ethylmorphine, loperamide,
hydrocodone,
pentazocine, tramadol, tipepidine or noscapine.
22. The use according to claim 20, wherein the opiate is codeine.
23. The use according to claim 20 or claim 21, wherein the opiate is in a dose
of 0.1 mg/kg/day
to 30 mg/kg/day.
24. The use according to claim 21 or claim 22, wherein the codeine is in a
dose of up to 3
mg/kg/day.

Description

WO 2011/058374 PCT/GB2010/051896
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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 article 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 opiate drugs have been developed for cough therapies.
Codeine is an example of one such drug, and it is widely used as an
antitussive.
However due to the addictive properties of codeine and other opiates, there is
a
need for replacement cough therapies. Also, as recent evidence suggest, the
therapeutic index for certain patient populations is very low.
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 opiate drug, codeine, in a
citric
acid-induced cough model. The data show that when theobromine is combined
with codeine, the effect is surprisingly potent and greater than the sum of
the
individual drugs, revealing that the combination has a substantially improved
effect. One advantage of lowering the minimum effective dose of codeine is
that
there is less chance of codeine overdose, as described above.
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 codeine, and many other opiate drugs is
sedation. It has surprisingly been found that theobromine counteracts the
sedative properties of opiates.

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Therefore, according to the present invention, an agent comprises
theobromine and an opiate, as a combined preparation for simultaneous,
sequential or separate use in therapy.
It is believed that this synergistic relationship will be exhibited by all
opiates. Without wishing to be bound by theory, this may be due to the
structural similarity of the members of the opiate family.
Description of the Drawing
Figure 1 shows the effect of theobromine, and a combination of
theobromine and codeine, on citric acid-induced cough in guinea-pig.
Description of the Invention
As used herein, the term "opiate" describes any of the narcotic opioid
alkaloids found as natural products in the opium poppy plant, as well as many
chemical derivatives of such alkaloids. The term "opiate" describes a defined
class of drugs, and will be understood by the person skilled in the art.
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 opiate 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. The dose of the opiate that is administered with the
theobromine will of course depend on the usual factors, including its potency,
but
is preferably at least 0.1, e.g. at least 5, and may be up to 30 mg/kg/day.
The opiate is preferably selected from codeine, morphine, diamorphine,
thebaine, papaverine, noscapine, oripavine, fentanyl, alphamethylfentanyl,
alfentanil, sufentanil, remifentanil, carfentanyl, propoxyphene, oxymorphone,
oxycodone, hydromorphone, pethidine, dihydrocodeine, buprenorphine,
etorphine, ethylmorphine, loperamide and hydrocodone, pentazocine and
tramadol, tipepidine and noscapine. Codeine is the most preferred opiate drug,
e.g. at a dose of 3 mg/kg/day.
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.

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The compounds of the invention are preferably as combinations to be
administered orally, for example as tables, troches, lozenges, aqueous or oral
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

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of ethylene oxide with partial esters derived from fatty acids, for example
polyoxyethylene sorbitan monooleate. The aqueous suspensions may also
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

WO 2011/058374 PCT/GB2010/051896
gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose,
or
polyvinyl alcohol.
In a preferred embodiment, theobromine in combination with an
antitussive drug is to be administered via the oral route. Combined
compositions
5 according to the invention may be produced using conventional formulation
techniques. In particular, spray-drying may be used to produce microparticles
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.

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Compositions of the combination intended for inhaled, topical, intranasal,
intravenous, sublingual, rectal and vaginal use may be prepared according to
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 7 mg/kg of theobromine, and two groups were
administered theobromine in combination with 8 or 16 mg/kg of codeine. A
fourth group was given codeine and, as a control, a fifth group received only
vehicle. Administration was via the oral route.
The results are shown in Figure 1. The data show that combinations of
theobromine and codeine have a significant, improved efficacy in cough therapy
when compared to theobromine monotherapy and codeine monotherapy.