AU2010332495A1 - Therapeutic combinations of theobromine and an antihistamine - Google Patents

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

WO 2011/073647 PCT/GB2010/052086 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. 5 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. 10 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. 15 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, Bj6rnsd6ttir et al. 2007 Dec, 29(6): 577-83 reports that presumptions about efficacy of diphenhydramine against cough in humans are 20 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 25 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. 30 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.

WO 2011/073647 PCT/GB2010/052086 2 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 5 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 10 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 15 class of drugs that is well known to the skilled person. In a preferred embodiment, the antihistamine is an H-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 20 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 25 antitussive in the control of cough. Preferably, it is used in the control of non productive 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 30 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 35 or chocolate. Suitable dose ranges for theobromine are known in the art and will WO 2011/073647 PCT/GB2010/052086 3 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 5 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, 10 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 15 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 20 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. 25 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 30 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 35 starch or alginic acid; binding agents, for example starch gelatin, acacia, WO 2011/073647 PCT/GB2010/052086 4 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 5 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, 10 methylcel lu lose, hydroxypropyl methylcel lu lose, 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 15 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, 20 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 25 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. 30 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.

WO 2011/073647 PCT/GB2010/052086 5 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, 5 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 10 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 15 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 microparticles comprising the active agent dispersed or 20 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 25 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 30 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 WO 2011/073647 PCT/GB2010/052086 6 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 5 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 10 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, 15 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 20 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 25 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 30 theobromine and chlorpheniramine have a significant, improved efficacy in cough therapy when compared to theobromine monotherapy.

Claims (6)

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. 5

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, 10 pheniramine, cetirizine, promethazine, clemastine, chlorpheniramine, dexchlorpheniramine, levocetirizine, hydroxyzine, alimemazine, acrivastine, cyproheptadine, astemizole, fexofenadine, loratadine, cetirizine, levocetirizine, brompheniramine, dextrobrompheniramine, promethazine, mizolastine, and triprolidine. 15

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.