WO2011058374A1 - 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
WO2011058374A1
WO2011058374A1 PCT/GB2010/051896 GB2010051896W WO2011058374A1 WO 2011058374 A1 WO2011058374 A1 WO 2011058374A1 GB 2010051896 W GB2010051896 W GB 2010051896W WO 2011058374 A1 WO2011058374 A1 WO 2011058374A1
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WO
WIPO (PCT)
Prior art keywords
theobromine
opiate
therapy
codeine
agent
Prior art date
Application number
PCT/GB2010/051896
Other languages
French (fr)
Inventor
John Brew
Robin Mark Bannister
Original Assignee
Biocopea Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP10778715A priority Critical patent/EP2498776A1/en
Priority to RU2012124063/15A priority patent/RU2587329C2/en
Priority to UAA201207163A priority patent/UA105940C2/en
Priority to CA2780704A priority patent/CA2780704C/en
Priority to NZ599957A priority patent/NZ599957A/en
Priority to MX2012005538A priority patent/MX2012005538A/en
Priority to CN201080051628.4A priority patent/CN102740853B/en
Priority to JP2012538416A priority patent/JP2013510842A/en
Application filed by Biocopea Limited filed Critical Biocopea Limited
Priority to BR112012011224A priority patent/BR112012011224A2/en
Priority to AU2010317668A priority patent/AU2010317668C1/en
Publication of WO2011058374A1 publication Critical patent/WO2011058374A1/en
Priority to US13/446,217 priority patent/US20120252824A1/en
Priority to ECSP12011893 priority patent/ECSP12011893A/en
Priority to ECSP12011892 priority patent/ECSP12011892A/en
Priority to IL219769A priority patent/IL219769A0/en
Priority to ZA2012/04247A priority patent/ZA201204247B/en
Priority to US14/287,015 priority patent/US9308211B2/en
Priority to US14/287,017 priority patent/US10016437B2/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 US15/144,800 priority patent/US20160271197A1/en
Priority to US15/144,798 priority patent/US20160271136A1/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
    • 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.
  • 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.
  • the invention is based at least in part on data showing a synergistic antitussive 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.
  • an agent comprises theobromine and an opiate, 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 codeine, on citric acid-induced cough in guinea-pig.
  • opioid 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.
  • opioid 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.
  • 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.
  • 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. 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 receiv ed only vehicle. Administration was via the oral route.

Abstract

An agent comprises theobromine and an opiate, 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 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 antitussive 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. 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. 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 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 receiv ed 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.

Claims

1. An agent comprising theobromine an opiate, 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 an opiate.
4. An agent according to claim 1 or claim 2, or theobromine according to claim 3, wherein the opiate is 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, hydrocodone, pentazocine, tramadol, tipepidine and noscapine.
5. An agent or theobromine according to any preceding claim, wherein the opiate is codeine.
6. An agent or theobromine according to any preceding claim, wherein the opiate 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 codeine is to be administered in a dose of up to 3 mg/kg/day.
PCT/GB2010/051896 2009-06-16 2010-11-12 Drug combination with theobromine and its use in therapy WO2011058374A1 (en)

Priority Applications (26)

Application Number Priority Date Filing Date Title
CN201080051628.4A CN102740853B (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy
UAA201207163A UA105940C2 (en) 2009-11-13 2010-11-12 Drug formulation with theobromine and opiate for treatment of cough
CA2780704A CA2780704C (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy
NZ599957A NZ599957A (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy
MX2012005538A MX2012005538A (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy.
EP10778715A EP2498776A1 (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy
JP2012538416A JP2013510842A (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy
RU2012124063/15A RU2587329C2 (en) 2009-11-13 2010-11-12 Drug combination with theobromine and use thereof in treatment
BR112012011224A BR112012011224A2 (en) 2009-11-13 2010-11-12 theobromine and agent combined with an antitussive opioid and its therapeutic use
AU2010317668A AU2010317668C1 (en) 2009-11-13 2010-11-12 Drug combination with theobromine and its use in therapy
US13/446,217 US20120252824A1 (en) 2009-06-16 2012-04-13 Drug Combinations and Uses in Treating a Coughing Condition
ECSP12011893 ECSP12011893A (en) 2009-11-13 2012-05-11 COMBINATION OF DRUGS WITH THEOBROMINE AND ITS USE IN THERAPY
ECSP12011892 ECSP12011892A (en) 2009-11-13 2012-05-11 COMBINATION OF DRUGS WITH THEOBROMINE AND ITS USE IN THERAPY
IL219769A IL219769A0 (en) 2009-11-13 2012-05-13 Drug combination with theromine and its use in therapy
ZA2012/04247A ZA201204247B (en) 2009-11-13 2012-06-11 Drug combination with theobromine and its use in therapy
US14/287,015 US9308211B2 (en) 2009-06-16 2014-05-24 Drug combinations and uses in treating a coughing condition
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
US14/488,215 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
US15/144,800 US20160271197A1 (en) 2009-06-16 2016-05-02 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
US16/042,670 US10420812B2 (en) 2009-06-16 2018-07-23 Drug combinations and uses in treating a coughing condition

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0919893.8 2009-11-13
GBGB0919893.8A GB0919893D0 (en) 2009-11-13 2009-11-13 Drug composition and its use in therapy

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/GB2010/051895 Continuation-In-Part WO2011058373A2 (en) 2009-06-16 2010-11-12 Drug combination with theobromine and its use in therapy

Related Child Applications (2)

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PCT/GB2010/051895 Continuation-In-Part WO2011058373A2 (en) 2009-06-16 2010-11-12 Drug combination with theobromine and its use in therapy
PCT/GB2010/052085 Continuation-In-Part WO2011073646A1 (en) 2009-06-16 2010-12-14 Combination of theobromine with a decongestant and its use for the treatment of cough

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JP (2) JP2013510842A (en)
CN (1) CN102740853B (en)
AU (1) AU2010317668C1 (en)
BR (1) BR112012011224A2 (en)
CA (1) CA2780704C (en)
CO (1) CO6551745A2 (en)
EC (2) ECSP12011892A (en)
GB (1) GB0919893D0 (en)
IL (1) IL219769A0 (en)
MX (1) MX2012005538A (en)
NZ (1) NZ599957A (en)
PE (1) PE20121472A1 (en)
RU (1) RU2587329C2 (en)
SG (1) SG10201407496SA (en)
UA (1) UA105940C2 (en)
WO (1) WO2011058374A1 (en)
ZA (1) ZA201204247B (en)

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US8703158B2 (en) 2009-06-16 2014-04-22 Biocopea Limited Theobromine for the treatment of cough
JP2014518252A (en) * 2011-07-05 2014-07-28 バイオコピア リミテッド Combinations of drugs and use in the treatment of cough conditions
US9308211B2 (en) 2009-06-16 2016-04-12 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
US9314465B2 (en) 2009-06-16 2016-04-19 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

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Publication number Priority date Publication date Assignee Title
US8703158B2 (en) 2009-06-16 2014-04-22 Biocopea Limited Theobromine for the treatment of cough
US9308211B2 (en) 2009-06-16 2016-04-12 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
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
US9700561B2 (en) 2009-06-16 2017-07-11 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
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ECSP12011892A (en) 2012-09-28
CO6551745A2 (en) 2012-10-31
EP2498776A1 (en) 2012-09-19
RU2012124063A (en) 2013-12-20
JP2013510842A (en) 2013-03-28
AU2010317668B2 (en) 2015-01-22
CN102740853A (en) 2012-10-17
NZ599957A (en) 2014-05-30
CN102740853B (en) 2015-04-08
JP2016041748A (en) 2016-03-31
MX2012005538A (en) 2012-09-28
UA105940C2 (en) 2014-07-10
IL219769A0 (en) 2012-07-31
ECSP12011893A (en) 2012-10-30
CA2780704A1 (en) 2011-05-19
SG10201407496SA (en) 2015-02-27
CA2780704C (en) 2018-07-17
ZA201204247B (en) 2013-02-27
BR112012011224A2 (en) 2017-03-01
AU2010317668C1 (en) 2016-02-11
AU2010317668A1 (en) 2012-06-07
GB0919893D0 (en) 2009-12-30
PE20121472A1 (en) 2012-11-30
RU2587329C2 (en) 2016-06-20

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