WO2011058373A2 - Drug combination with theobromine and its use in therapy - Google Patents

Drug combination with theobromine and its use in therapy Download PDF

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Publication number
WO2011058373A2
WO2011058373A2 PCT/GB2010/051895 GB2010051895W WO2011058373A2 WO 2011058373 A2 WO2011058373 A2 WO 2011058373A2 GB 2010051895 W GB2010051895 W GB 2010051895W WO 2011058373 A2 WO2011058373 A2 WO 2011058373A2
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WO
WIPO (PCT)
Prior art keywords
theobromine
therapy
cough
agent
dextromethorphan
Prior art date
Application number
PCT/GB2010/051895
Other languages
French (fr)
Other versions
WO2011058373A3 (en
Inventor
John Brew
Robin Mark Bannister
Original Assignee
Biocopea Limited
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Publication date
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Priority to CA2780703A priority Critical patent/CA2780703A1/en
Priority to MX2012005532A priority patent/MX2012005532A/en
Priority to JP2012538415A priority patent/JP2013510841A/en
Priority to AU2010317667A priority patent/AU2010317667B2/en
Priority to CN2010800516299A priority patent/CN102753174A/en
Priority to RU2012124038/15A priority patent/RU2519086C2/en
Priority to BR112012011227A priority patent/BR112012011227A2/en
Priority to NZ599949A priority patent/NZ599949A/en
Priority to EP10825831A priority patent/EP2498777A2/en
Application filed by Biocopea Limited filed Critical Biocopea Limited
Priority to UAA201207164A priority patent/UA108993C2/en
Publication of WO2011058373A2 publication Critical patent/WO2011058373A2/en
Publication of WO2011058373A3 publication Critical patent/WO2011058373A3/en
Priority to US13/446,217 priority patent/US20120252824A1/en
Priority to IL219768A priority patent/IL219768A0/en
Priority to ZA2012/04248A priority patent/ZA201204248B/en
Priority to US14/287,017 priority patent/US10016437B2/en
Priority to US14/287,015 priority patent/US9308211B2/en
Priority to US14/287,014 priority patent/US9314465B2/en
Priority to US14/488,215 priority patent/US20150005325A1/en
Priority to US14/687,393 priority patent/US20150216869A1/en
Priority to US14/991,892 priority patent/US20160120899A1/en
Priority to US15/061,656 priority patent/US9700561B2/en
Priority to US15/063,465 priority patent/US9675618B2/en
Priority to US15/144,798 priority patent/US20160271136A1/en
Priority to US15/144,800 priority patent/US20160271197A1/en
Priority to US16/042,670 priority patent/US10420812B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a drug combination, its composition and its use in the therapy of cough.
  • Cough is a protective reflex. Persistent cough can be distressing. Over- the-counter remedies are available but their effectiveness is doubtful.
  • WO98/42322 discloses the use of theobromine for the treatment of cough, to be given orally.
  • 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.
  • its efficacy and suitability as a treatment for cough has already been brought into question.
  • 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.
  • 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.
  • an agent comprises theobromine and another non-opiate antitussive, as a combined preparation for simultaneous, sequential or separate use in therapy.
  • Figure 1 shows the effect of theobromine, and a combination of theobromine and dextromethorphan, on citric acid-induced cough in guinea-pig.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum
  • 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.
  • preservatives for example ethyl or n-propyl p- hydroxybenzoate
  • colouring agents for example ethyl or n-propyl p- hydroxybenzoate
  • flavouring agents such as sucrose or saccharin.
  • 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.
  • 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.
  • a carrier for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • 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.
  • 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 may also be used to formulate the therapeutic composition.
  • the manufacture of fine particles by milling can be achieved using conventional techniques.
  • 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.
  • 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.
  • 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.
  • the microparticles produced by the milling step can then be formulated with an additional excipient.
  • an additional excipient This may be achieved by a spray- drying process, e.g. co-spray-drying.
  • 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 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.
  • 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.

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Abstract

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

Description

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.
WO98/42322 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. 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 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 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. 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 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 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).

Claims

1. An agent comprising theobromine and another non-opiate antitussive, as a combined preparation for simultaneous, sequential or separate use in therapy.
2. An agent according to claim 1 , wherein the therapy is of cough.
3. Theobromine for the therapy of cough, wherein the subject to be treated has also been administered another non-opiate antitussive.
4. An agent according to claim 1 or claim 2, or theobromine according to claim 3, wherein the another non-opiate antitussive is 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.
5. An agent or theobromine according to any preceding claim, wherein the another non-opiate antitussive is dextromethorphan.
6. An agent or theobromine according to any preceding claim, wherein the another non-opiate antitussive is to be administered in a dose of 0.1 to 30 mg/kg/day.
7. An agent or theobromine according to claim 5, wherein the dextromethorphan is to be administered in a dose of 0.1 to 6 mg/kg/day.
PCT/GB2010/051895 2009-06-16 2010-11-12 Drug combination with theobromine and its use in therapy WO2011058373A2 (en)

Priority Applications (24)

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NZ599949A NZ599949A (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy
BR112012011227A BR112012011227A2 (en) 2009-11-13 2010-11-12 theobromine and agent combined with another non-opioid antitussive and its therapeutic use
JP2012538415A JP2013510841A (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy
AU2010317667A AU2010317667B2 (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy
EP10825831A EP2498777A2 (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy
RU2012124038/15A RU2519086C2 (en) 2009-11-13 2010-11-12 Medical combination with theobromine and using it in treatment
MX2012005532A MX2012005532A (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy.
CA2780703A CA2780703A1 (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy
CN2010800516299A CN102753174A (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy
UAA201207164A UA108993C2 (en) 2009-11-13 2010-12-11 MEDICINAL COMBINATION WITH THEOBROMINE AND ITS APPLICATION IN Cough
US13/446,217 US20120252824A1 (en) 2009-06-16 2012-04-13 Drug Combinations and Uses in Treating a Coughing Condition
IL219768A IL219768A0 (en) 2009-11-13 2012-05-13 Drug combination with thebromine and its use in therapy
ZA2012/04248A ZA201204248B (en) 2009-11-13 2012-06-11 Drug combination with theobromine and its use in therapy
US14/287,017 US10016437B2 (en) 2009-06-16 2014-05-24 Drug combinations and uses in treating a coughing condition
US14/287,014 US9314465B2 (en) 2009-06-16 2014-05-24 Drug combinations and uses in treating a coughing condition
US14/287,015 US9308211B2 (en) 2009-06-16 2014-05-24 Drug combinations and uses in treating a coughing condition
US14/488,215 US20150005325A1 (en) 2009-06-16 2014-09-16 Drug Combinations and Uses in Treating a Coughing Condition
US14/687,393 US20150216869A1 (en) 2009-06-16 2015-04-15 Drug Combinations and Uses in Treating a Coughing Condition
US14/991,892 US20160120899A1 (en) 2009-06-16 2016-01-08 Drug Combinations and Uses in Treating a Coughing Condition
US15/061,656 US9700561B2 (en) 2009-06-16 2016-03-04 Drug combinations and uses in treating a coughing condition
US15/063,465 US9675618B2 (en) 2009-06-16 2016-03-07 Drug combinations and uses in treating a coughing condition
US15/144,798 US20160271136A1 (en) 2009-06-16 2016-05-02 Drug Combinations and Uses in Treating a Coughing Condition
US15/144,800 US20160271197A1 (en) 2009-06-16 2016-05-02 Drug Combinations and Uses in Treating a Coughing Condition
US16/042,670 US10420812B2 (en) 2009-06-16 2018-07-23 Drug combinations and uses in treating a coughing condition

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GBGB0919889.6A GB0919889D0 (en) 2009-11-13 2009-11-13 Drug composition and its use in therapy
GB0919889.6 2009-11-13

Related Parent Applications (2)

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PCT/GB2010/050997 Continuation-In-Part WO2010146394A1 (en) 2009-06-16 2010-06-15 Theobromine for the treatment of cough
PCT/GB2010/051896 Continuation-In-Part WO2011058374A1 (en) 2009-06-16 2010-11-12 Drug combination with theobromine and its use in therapy

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PCT/GB2010/051896 Continuation-In-Part WO2011058374A1 (en) 2009-06-16 2010-11-12 Drug combination with theobromine and its use in therapy
PCT/GB2010/052056 Continuation-In-Part WO2011070363A1 (en) 2009-06-16 2010-12-09 Carbon and its use in blood cleansing applications
PCT/GB2010/052086 Continuation-In-Part WO2011073647A1 (en) 2009-06-16 2010-12-14 Therapeutic combinations of theobromine and an antihistamine

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WO2011058373A3 WO2011058373A3 (en) 2011-07-07

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CN (1) CN102753174A (en)
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CA (1) CA2780703A1 (en)
CO (1) CO6551744A2 (en)
GB (1) GB0919889D0 (en)
IL (1) IL219768A0 (en)
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NZ (1) NZ599949A (en)
PE (1) PE20130147A1 (en)
RU (1) RU2519086C2 (en)
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US9314465B2 (en) 2009-06-16 2016-04-19 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
US9675618B2 (en) 2009-06-16 2017-06-13 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
US10016437B2 (en) 2009-06-16 2018-07-10 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
US8703158B2 (en) 2009-06-16 2014-04-22 Biocopea Limited Theobromine for the treatment of cough
US9700561B2 (en) 2009-06-16 2017-07-11 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
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ZA201204248B (en) 2013-02-27
GB0919889D0 (en) 2009-12-30
JP2016128439A (en) 2016-07-14
NZ599949A (en) 2013-08-30
RU2519086C2 (en) 2014-06-10
AU2010317667A1 (en) 2012-06-07
CN102753174A (en) 2012-10-24
RU2012124038A (en) 2013-12-20
BR112012011227A2 (en) 2017-06-13
CO6551744A2 (en) 2012-10-31
JP6118919B2 (en) 2017-04-19
CA2780703A1 (en) 2011-05-19
EP2498777A2 (en) 2012-09-19
PE20130147A1 (en) 2013-03-13
UA108993C2 (en) 2015-07-10
WO2011058373A3 (en) 2011-07-07
MX2012005532A (en) 2012-09-28
AU2010317667B2 (en) 2014-05-29
IL219768A0 (en) 2012-07-31

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