JP6078605B2 - A therapeutic combination of theobromine and antihistamines - Google Patents

Description

  The present invention relates to drug combinations, compositions thereof, and their use, particularly in the treatment of cough.

  Cough is a defensive reflex. Persistent cough can be painful. Non-prescription treatments are available, but their effectiveness is questionable.

  WO 98/42322 discloses the use of theobromine for the treatment of cough given orally.

  Usmeni et al., FASEB J. et al. express article 10.1096 discloses that theobromine inhibits sensory nerve action and cough. Data are provided to show the effect of citrate-induced cough in guinea pigs and in capsaicin cough tests in humans after oral dosing and after bathing of isolated guinea pig vagus nerve preparations.

  An antihistamine or diphenhydramine has been shown to have efficacy in a citric acid-induced cough model in healthy human volunteers (Packman et al., Int J Clin Pharmacol The Toxicol, 1991). However, a recent review paper, Bjornsdotir et al., December 2007, 29 (6): 577-83, suggests that estimates of the effectiveness of diphenhydramine against cough in humans have not been uniquely established in the literature. Reporting. In other words, there is no strong evidence that antihistamines have any efficacy in coughing.

  The present invention is based at least in part on data showing a synergistic antitussive effect for theobromine in combination with the antihistamine chlorpheniramine in a citric acid-induced cough model. Therefore, given that recent literature suggests that antihistamines have no efficacy in cough, theobromine and chlorpheniramine combination has improved cough suppression compared to theobromine alone. It was surprising to find that it had an effect.

  As a result, when theobromine is used in combination with an antihistamine, the dose of theobromine can be significantly reduced due to the antitussive effect equivalent to theobromine alone, reducing side effects and drug burden.

  Thus, according to the first aspect of the invention, the medicament comprises theobromine and antihistamine as a combined preparation for simultaneous, sequential or separate use in therapy.

  According to a second aspect, the pharmaceutical composition comprises theobromine and an antihistamine.

  This synergistic relationship is believed to be demonstrated by all antihistamines. While not wishing to be bound by theory, this may be due to the structural similarity of the antihistamine drug members.

FIG. 1 shows the effect of theobromine and the combination of theobromine and chlorpheniramine on citric acid-induced cough in guinea pigs.

(Description of the invention)
As used herein, the term “antihistamine” means an agent that inhibits the action of histamine via a histamine receptor. The term represents a well-defined type of drug that is well known to those skilled in the art. In a preferred embodiment, the antihistamine is a H ₁ -receptor antihistamine. Any suitable form of antihistamine can be selected. These include salts, prodrugs, and active metabolites.

  As used herein, treatment of cough means any treatment that reduces the number and / or severity of cough. Treatment of cough preferably means a direct antitussive effect that reduces the number of coughs, i.e. reduces the urge to cough the body. Thus, according to a preferred embodiment of the invention, the medicament comprises theobromine and an antihistamine for use as an antitussive pharmaceutical composition. The agent of the present invention is useful as an antitussive agent in the management of cough. It is preferably used in the management of dry cough.

  The antihistamine may be used in an amount already known for its use, but the combination according to the invention means that a reduced dose is effective. The dose of antihistamine administered with theobromine will, of course, depend on normal factors including its efficacy, but should be at least 0.1 mg / kg / day, for example at least 5 mg / kg / day. Preferably, it may be up to 50 mg / kg / day. The antihistamine is preferably administered in the range of 0.1 to 30 mg / kg / day.

  Any suitable form of theobromine can be selected. These include salts, prodrugs, and active metabolites. Theobromine may also be in the form of cocoa or chocolate. Suitable dosage ranges for theobromine are known in the art and depend on normal factors (such as age), but the synergistic effect of the combination means that the effective dosage can be reduced. ing.

  The combinations according to the invention can be provided in a single formulation or in separate formulations for combined, simultaneous or sequential administration.

  The antihistamine can be selected from the following drugs: diphenhydramine, loratadine, desloratadine, alimemazine, dimenhydrinate, doxylamine, meclizine, quetiapine, fexofenadine, pheniramine, cetirizine, promethazine, clemastine, chlorpheniramine, dex Chlorpheniramine, levocetirizine, hydroxyzine, alimemazine, acribastine, cyproheptadine, astemizole, fexofenadine, loratadine, cetirizine, levocetirizine, brompheniramine, dextrobrompheniramine, promethazine, mizolastine, and triprolidine. The antihistamine is preferably chlorpheniramine.

  The compounds of the present invention can be administered by any available route, such as via the oral, inhalation, intranasal, sublingual, intravenous, rectal and vaginal routes.

  The compound of the present invention is preferably administered as a combination orally, for example, as a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granule. Preferred pharmaceutical compositions of the present invention are tablets and capsules. Liquid dispersions for oral administration may be syrups, emulsions and suspensions. More preferably, the combined pharmaceutical composition is a compressed tablet or capsule using conventional excipients, examples of which are described below.

  Compositions intended for oral use can be prepared according to any method known in the art for producing pharmaceutical compositions, such compositions are pharmaceutically refined and One or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives can be included to provide a palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch And gelatin, gum arabic, microcrystalline cellulose, or polyvinylpyrrolidone; and lubricants such as 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 can be employed.

  Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic; naturally occurring phospholipids such as lecithin, or alkylene A product derived from a condensation product of an oxide with a fatty acid (eg, polyoxyethylene stearate), or a condensation product of an ethylene oxide with a long-chain aliphatic alcohol (eg, heptadecaethyleneoxycetanol), or a portion derived from an ethylene oxide fatty acid A dispersing or wetting agent that may be a condensation product with an ester (eg, polyoxyethylene sorbitan monooleate). Aqueous suspensions also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one such as sucrose or saccharin. One or more sweeteners can also be included.

  Oily suspensions may be vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, polyoxyethylene hydrogenated castor oil, fatty acids such as oleic acid, or mineral oils such as liquid paraffin, or other surfactants or It can be formulated by suspending the active ingredient in a cleaning agent. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

  Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water are combined in a mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. Active ingredient. Suitable sweetening, flavoring and coloring agents can also be present.

  The combined pharmaceutical composition of the present invention may be in the form of an oil-in-water emulsion. 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 emulsifiers include naturally occurring gums such as gum arabic or tragacanth, naturally occurring phospholipids such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides such as monooleic acid. It may be sorbitan and the condensation product of the above partial ester with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. Emulsions can also contain sweetening and flavoring 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 and flavoring and coloring agents.

  Suspensions and emulsions can contain carriers such as natural rubber, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

  A combination composition according to the present invention can be produced using conventional formulation techniques. In particular, spray drying methods can be used to produce microparticles containing active agents dispersed or suspended in a material that provides controlled release properties.

  Milling methods, such as jet milling methods, can also be used to formulate therapeutic compositions. This is especially true for particles intended for administration by inhalation. Production of fine particles by milling can be accomplished using conventional techniques. The term “milling” is used herein to refer to any mechanical process that applies sufficient force to the particles of active material to break or break the particles into fine particles. A variety of milling equipment and conditions are suitable for use in making the compositions of the present invention.

  The selection of appropriate milling conditions, such as milling strength and time, to provide the required degree of force will be within the ability of one skilled in the art. Ball milling is a preferred method. As an alternative, a high pressure homogenizer can be used that forces the fluid containing the particles through the valve at high pressure, creating high shear and turbulent conditions. Cavitation due to shear forces on the particles, impacts between the particles and the machine surface or other particles, and fluid acceleration can all contribute to particle crushing.

  Suitable homogenizers include EmulsiFlex high pressure homogenizers, Niro Soavi high pressure homogenizers, and Microfluidics Microfluidizer. A milling method can be used to provide microparticles with mass median aerodynamic diameter as defined above. If hygroscopic, the active agent can be milled with a hydrophobic material, as described above.

  If required, the microparticles produced by the milling process can then be formulated with additional excipients. This formulation can be achieved by spray drying methods, for example, co-spray drying methods. In this embodiment, the particles are suspended in a solvent and co-spray dried with a solution or suspension of additional excipients. Preferred additional excipients include polysaccharides. Additional pharmaceutically effective excipients can also be used.

  A combination composition intended for inhalation, topical, intranasal, sublingual, intravenous, rectal, and vaginal use is any method known in the art for producing pharmaceutical compositions. Can be prepared according to

  Treatment according to the present invention can be performed in a generally known manner depending on various factors such as the patient's sex, age, or health status, and the presence or absence of one or more combination treatments. The patient population may be important.

  The present invention is based at least in part on the following tests.

(test)
Cough was induced in guinea pigs by using citric acid. One group of guinea pigs was administered 10 mg / kg theobromine and two groups were administered theobromine in combination with 10 or 30 mg / kg chlorpheniramine. As a control, the fourth group received only vehicle. Administration was via the oral route.

  The results are shown in FIG. The data show that the combination of theobromine and chlorpheniramine has significantly improved efficacy in treating cough when compared to theobromine monotherapy.

Claims (4)

Consisting of theobromine , and chlorpheniramine or diphenhydramine , one or more excipients, and optionally one or more sweeteners, flavoring agents, colorants, and / or preservatives, of chlorpheniramine or diphenhydramine A pharmaceutical composition for treating cough , wherein the dose is 0.1 to 30 mg / kg / day.   The pharmaceutical composition according to claim 1, which is produced for oral administration.   The pharmaceutical composition according to claim 1 or 2, which is prepared as a tablet, capsule, troche, lozenge, powder, granule, suspension, syrup, or emulsion.   Use of the pharmaceutical composition according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of cough.

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