WO2011073647A1 - Therapeutic combinations of theobromine and an antihistamine - Google Patents

Therapeutic combinations of theobromine and an antihistamine Download PDF

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Publication number
WO2011073647A1
WO2011073647A1 PCT/GB2010/052086 GB2010052086W WO2011073647A1 WO 2011073647 A1 WO2011073647 A1 WO 2011073647A1 GB 2010052086 W GB2010052086 W GB 2010052086W WO 2011073647 A1 WO2011073647 A1 WO 2011073647A1
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WO
WIPO (PCT)
Prior art keywords
antihistamine
theobromine
agent
cough
agents
Prior art date
Application number
PCT/GB2010/052086
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 EP10796123A priority Critical patent/EP2512472A1/en
Priority to AU2010332495A priority patent/AU2010332495C1/en
Priority to CN2010800570274A priority patent/CN102802625A/en
Priority to CA2784215A priority patent/CA2784215A1/en
Priority to SG2012042495A priority patent/SG181603A1/en
Priority to MX2012006624A priority patent/MX2012006624A/en
Priority to JP2012543903A priority patent/JP2013513652A/en
Priority to BR112012014159A priority patent/BR112012014159A8/en
Priority to RU2012129675/15A priority patent/RU2012129675A/en
Priority to UAA201208623A priority patent/UA105827C2/en
Application filed by Biocopea Limited filed Critical Biocopea Limited
Publication of WO2011073647A1 publication Critical patent/WO2011073647A1/en
Priority to US13/446,217 priority patent/US20120252824A1/en
Priority to ZA2012/04294A priority patent/ZA201204294B/en
Priority to IL220384A priority patent/IL220384A0/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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • 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 therapy, particularly 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.
  • W098/42322 discloses the use of theobromine for the treatment of cough, to be given orally.
  • Antihistamines namely diphenhydramine have been to shown to have efficacy in the citric acid-induced cough model in healthy human volunteers (Packman et. al., Int J Clin Pharmacol Ther Toxicol, 1991 ). However, a recent review article, Bjornsdottir et al. 2007 Dec, 29(6): 577-83 reports that presumptions about efficacy of diphenhydramine against cough in humans are not univocally substantiated in literature. In other words, there is no strong evidence that antihistamines have any efficacy in cough.
  • the invention is based at least in part on data showing a synergistic antitussive effect for theobromine combined with the antihistamine chlorpheniramine, in a citric acid-induced cough model. Given the recent literature suggesting that antihistamines have no efficacy in cough, it was therefore surprising to find that a combination of theobromine and chlorpheniramine has an improved antitussive effect, compared to theobromine alone.
  • an agent comprises theobromine and an antihistamine , as a combined preparation for simultaneous, sequential or separate use in therapy.
  • a pharmaceutical composition comprises theobromine and an antihistamine.
  • Figure 1 shows the effect of theobromine, and of a combination of theobromine and chlorpheniramine, on citric acid-induced cough in guinea-pig.
  • antihistamine means an agent that inhibits the action of histamine via histamine receptors. This term represents a well-defined class of drugs that is well known to the skilled person.
  • the antihistamine is an H-i-receptor antihistamine. Any suitable form of the antihistamine agent may be chosen. These include salts, prodrugs and active metabolites.
  • the treatment of cough means any therapy that reduces the number and/or the severity of cough. Preferably, it means a reduction in the number of coughs, i.e. a direct antitussive effect that reduces the body's urge to cough. Therefore, according to a preferred embodiment of the invention, an agent comprises theobromine and an antihistamine, for use as an antitussive pharmaceutical composition.
  • An agent of the invention is useful as an antitussive in the control of cough. Preferably, it is used in the control of nonproductive cough.
  • the antihistamine 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 antihistamine 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 50 mg/kg/day. Preferably, it is dosed in a range of 0.1 to 30 mg/kg/day.
  • 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 and will depend on the usual factors (age etc); although the synergistic effect of the combination means that the effective dose may be reduced.
  • a combination according to the invention may be provided in a single formulation or in separate formulations, for combined, simultaneous or sequential administration.
  • This antihistamine may be chosen from the following drugs: diphenhydramine, loratadine, desloratadine, alimemazine, dimenhydrinate, doxylamine, meclizine, quetiapine, fexofenadine, pheniramine, cetirizine, promethazine, clemastine, chlorpheniramine, dexchlorpheniramine, levocetirizine, hydroxyzine, alimemazine, acrivastine, cyproheptadine, astemizole, fexofenadine, loratadine, cetirizine, levocetirizine, brompheniramine, dextrobrompheniramine, promethazine, mizolastine and triprolidine.
  • the antihistamine is chlorpheniramine.
  • 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 compounds of the invention are preferably as combinations to be administered orally, for example as tables, troches, lozenges, aqueous or oily 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 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.
  • compositions according to the invention may be produced using conventional formulation techniques.
  • spray-drying may be used to produce micro particles comprising the active agent dispersed or suspended within a material that provides the controlled release properties.
  • milling for example jet milling
  • the process of milling may also be used to formulate the therapeutic composition. This applies particularly to particles intended for administration by inhalation.
  • 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.
  • 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. 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.
  • 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, sublingual, intravenous, 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 two groups were administered theobromine in combination with 10 or 30 mg/kg of chlorpheniramine.
  • a fourth group received only vehicle. Administration was via the oral route.

Abstract

An agent comprises theobromine and an antihistamine, as a combined preparation for simultaneous, sequential or separate use in therapy, particularly in the therapy of cough.

Description

THERAPEUTIC COMBINATIONS OF THEOBROMINE AND AN ANTIHISTAMINE
Field of the Invention
This invention relates to a drug combination, its composition and its use in therapy, particularly 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.
Antihistamines namely diphenhydramine have been to shown to have efficacy in the citric acid-induced cough model in healthy human volunteers (Packman et. al., Int J Clin Pharmacol Ther Toxicol, 1991 ). However, a recent review article, Bjornsdottir et al. 2007 Dec, 29(6): 577-83 reports that presumptions about efficacy of diphenhydramine against cough in humans are not univocally substantiated in literature. In other words, there is no strong evidence that antihistamines have any efficacy in cough.
Summary of the Invention
The invention is based at least in part on data showing a synergistic antitussive effect for theobromine combined with the antihistamine chlorpheniramine, in a citric acid-induced cough model. Given the recent literature suggesting that antihistamines have no efficacy in cough, it was therefore surprising to find that a combination of theobromine and chlorpheniramine has an improved antitussive effect, compared to theobromine alone.
Consequently, when theobromine is used in combination with an antihistamine, a considerably reduced dose of theobromine can be given for an equivalent antitussive effect for theobromine alone, so reducing side-effects and drug burden. Therefore, according to a first aspect of, the present invention, an agent comprises theobromine and an antihistamine , as a combined preparation for simultaneous, sequential or separate use in therapy.
According to a second aspect, a pharmaceutical composition comprises theobromine and an antihistamine.
It is believed that this synergistic relationship will be exhibited by all antihistamines. Without wishing to be bound by theory, this may be due to the structural similarity of the members of the antihistamine class of drugs.
Description of the Drawing
Figure 1 shows the effect of theobromine, and of a combination of theobromine and chlorpheniramine, on citric acid-induced cough in guinea-pig. Description of the Invention
As used herein, the term "antihistamine" means an agent that inhibits the action of histamine via histamine receptors. This term represents a well-defined class of drugs that is well known to the skilled person. In a preferred embodiment, the antihistamine is an H-i-receptor antihistamine. Any suitable form of the antihistamine agent may be chosen. These include salts, prodrugs and active metabolites.
As used herein, the treatment of cough means any therapy that reduces the number and/or the severity of cough. Preferably, it means a reduction in the number of coughs, i.e. a direct antitussive effect that reduces the body's urge to cough. Therefore, according to a preferred embodiment of the invention, an agent comprises theobromine and an antihistamine, for use as an antitussive pharmaceutical composition. An agent of the invention is useful as an antitussive in the control of cough. Preferably, it is used in the control of nonproductive cough.
The antihistamine 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 antihistamine 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 50 mg/kg/day. Preferably, it is dosed in a range of 0.1 to 30 mg/kg/day.
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 and will depend on the usual factors (age etc); although the synergistic effect of the combination means that the effective dose may be reduced.
A combination according to the invention may be provided in a single formulation or in separate formulations, for combined, simultaneous or sequential administration.
This antihistamine may be chosen from the following drugs: diphenhydramine, loratadine, desloratadine, alimemazine, dimenhydrinate, doxylamine, meclizine, quetiapine, fexofenadine, pheniramine, cetirizine, promethazine, clemastine, chlorpheniramine, dexchlorpheniramine, levocetirizine, hydroxyzine, alimemazine, acrivastine, cyproheptadine, astemizole, fexofenadine, loratadine, cetirizine, levocetirizine, brompheniramine, dextrobrompheniramine, promethazine, mizolastine and triprolidine. Preferably, the antihistamine is chlorpheniramine.
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 compounds of the invention are preferably as combinations to be administered orally, for example as tables, troches, lozenges, aqueous or oily 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 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.
Combined compositions according to the invention may be produced using conventional formulation techniques. In particular, spray-drying may be used to produce micro particles 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. This applies particularly to particles intended for administration by inhalation. 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, sublingual, intravenous, 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 two groups were administered theobromine in combination with 10 or 30 mg/kg of chlorpheniramine. As a control, a fourth 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 chlorpheniramine have a significant, improved efficacy in cough therapy when compared to theobromine monotherapy.

Claims

1. An agent comprising theobromine and an antihistamine, 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. A pharmaceutical composition comprising theobromine and an antihistamine.
4. An agent or composition according to any preceding claim, wherein the antihistamine is selected from diphenhydramine, loratadine, desloratadine, alimemazine, dimenhydrinate, doxylamine, meclizine, quetiapine, fexofenadine, pheniramine, cetihzine, promethazine, clemastine, chlorpheniramine, dexchlorpheniramine, levocetihzine, hydroxyzine, alimemazine, acrivastine, cyproheptadine, astemizole, fexofenadine, loratadine, cetihzine, levocetihzine, brompheniramine, dextrobrompheniramine, promethazine, mizolastine, and triprolidine.
5. An agent or composition according to claim 4 , wherein the antihistamine is chlorpheniramine.
6. An agent or composition according to any preceding claim, wherein the antihistamine is to be administered in a dose of 0.1 to 30 mg/kg/day.
PCT/GB2010/052086 2009-06-16 2010-12-14 Therapeutic combinations of theobromine and an antihistamine WO2011073647A1 (en)

Priority Applications (24)

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AU2010332495A AU2010332495C1 (en) 2009-12-14 2010-12-14 Therapeutic combinations of theobromine and an antihistamine
CN2010800570274A CN102802625A (en) 2009-12-14 2010-12-14 Therapeutic combinations of theobromine and an antihistamine
CA2784215A CA2784215A1 (en) 2009-12-14 2010-12-14 Therapeutic combinations of theobromine and an antihistamine
SG2012042495A SG181603A1 (en) 2009-12-14 2010-12-14 Therapeutic combinations of theobromine and an antihistamine
MX2012006624A MX2012006624A (en) 2009-12-14 2010-12-14 Therapeutic combinations of theobromine and an antihistamine.
EP10796123A EP2512472A1 (en) 2009-12-14 2010-12-14 Therapeutic combinations of theobromine and an antihistamine
JP2012543903A JP2013513652A (en) 2009-12-14 2010-12-14 A therapeutic combination of theobromine and antihistamines
BR112012014159A BR112012014159A8 (en) 2009-12-14 2010-12-14 therapeutic combinations of theobromine and an antihistamine
RU2012129675/15A RU2012129675A (en) 2009-12-14 2010-12-14 THERAPEUTIC COMBINATIONS OF THEOBROMIN AND ANTIHISTAMINE
UAA201208623A UA105827C2 (en) 2009-12-14 2010-12-14 Normal;heading 1;heading 2;heading 3;HERAPEUTIC COMBINATION OF THEOBROMINE AND AN ANTIHISTAMINE ACTING ON H1-RECEPTOR
US13/446,217 US20120252824A1 (en) 2009-06-16 2012-04-13 Drug Combinations and Uses in Treating a Coughing Condition
ZA2012/04294A ZA201204294B (en) 2009-12-14 2012-06-12 Therapeutic combinations of theobromine and an antihistamine
IL220384A IL220384A0 (en) 2009-12-14 2012-06-13 Therapeutic combinations of theobromine and an antihistamine
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

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GBGB0921803.3A GB0921803D0 (en) 2009-12-14 2009-12-14 Drug composition and its use in therapy
GB0921803.3 2009-12-14

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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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PCT/GB2011/051610 Continuation-In-Part WO2012025761A1 (en) 2009-06-16 2011-08-25 Theobromine in combination with an expectorant or a mucolytic for use in therapy

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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
US10016437B2 (en) 2009-06-16 2018-07-10 Infirst Healthcare Limited Drug combinations and uses in treating a coughing condition
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MX2012006624A (en) 2012-10-05
BR112012014159A2 (en) 2017-08-29
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JP2013513652A (en) 2013-04-22
GB0921803D0 (en) 2010-01-27
SG10201408374WA (en) 2015-01-29
IL220384A0 (en) 2012-08-30
BR112012014159A8 (en) 2017-12-26
UA105827C2 (en) 2014-06-25
JP2016040280A (en) 2016-03-24
SG181603A1 (en) 2012-07-30
PE20121538A1 (en) 2012-12-21
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JP6078605B2 (en) 2017-02-08

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