JP2016128439A - Drug combination with theobromine and its use in therapy - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a drug and a pharmaceutical composition for treating cough.SOLUTION: The invention provides a drug consisting of theobromine and dextromethorphan; and a pharmaceutical composition for oral administration consisting of the drug, one or more vehicles, and optionally one or more of an edulcorant, taste-masking agent, coloring agent, and/or preservative, wherein the dosage of dextromethorphan is 0.1-6 mg/kg/day, the pharmaceutical composition being prepared as a tablet, capsule, troche, lozenge, powder, granule, suspension, syrup, or emulsion.SELECTED DRAWING: None

Description

  The present invention relates to drug combinations, compositions thereof, and their use 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.

  Many non-opiate antitussives have been developed for the treatment of cough. Many of these antitussives are NMDA antagonists. Dextromethorphan is one such drug that has been developed specifically for use as a cough treatment. However, its efficacy and suitability as a treatment for cough has long been questioned. J. et al. In Ramsey et al., British Journal of Clinical Pharmacology, the authors show that the apparent success of dextromethorphan as a clinical treatment for cough is actually only a placebo effect and has no efficacy in cough. Reporting.

  The present invention is based at least in part on data showing the synergistic antitussive effect for theobromine in combination with dextromethorphan, a non-opiate antitussive, in a citric acid-induced cough model. The data show that when theobromine is combined with dextromethorphan, the effect is surprisingly strong and exceeds the sum of the individual drugs, and the combination has a substantially improved effect It is made clear.

  As a result, both drug doses can be significantly reduced for the same effect as each individual drug, reducing side effects and drug burden. One such side effect of dextromethorphan and many other non-opiate antitussives is sedation. Surprisingly, theobromine has been found to offset the sedative properties of such drugs.

  Thus, according to the present invention, the medicament comprises theobromine and another non-opiate antitussive as a combined preparation for simultaneous, sequential or separate use in therapy.

  This synergistic relationship is believed to be demonstrated by all non-opiate antitussives. While not wishing to be bound by theory, this may be because non-opiate antitussives act through a similar mechanism that may be NMDA antagonism.

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

(Description of the invention)
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. While suitable dosage ranges for theobromine are known in the art, the synergistic effect of the combination means that the effective dosage is reduced.

  Additional drugs (different non-opiate antitussives, i.e. not theobromine) may be used in amounts already known for their use, but the combination according to the present invention is effective at reduced doses. Means. The dosage of the non-opiate antitussive administered with theobromine is preferably greater than 0.1 mg / kg / day, such as greater than 5 mg / kg / day, typically up to 30 mg / kg / day.

  Non-opiate antitussive drugs include dextromethorphan, isoaminyl, benzonate, dipeprol, molclophone, plenoxdiazine, dropropidine, piperidione, pentoxyberine, oxolamine, oxerazine, nepinalone, meprothixol, indantadol, dimemorphan, Preferably, it is selected from dibutate, cloperastine, clofedanol, butyramylate, bibenzonium, benproperin, and fedrylate. Dextromethorphan is the most preferred antitussive, for example, at a dosage of 0.1-6 mg / kg / day.

  The non-opiate antitussive is preferably an NMDA antagonist.

  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 oral route is the preferred route of administration.

  The compounds of the invention can preferably be administered orally as a combination, for example as tablets, troches, lozenges, aqueous or oral suspensions, dispersible powders or granules. 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.

  Combination compositions intended for oral use can be prepared according to any method known in the art for producing pharmaceutical compositions, such compositions being pharmaceutically refined. And may contain one or more substances selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives 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, tragacanth gum, 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 ethylene oxide with a long-chain aliphatic alcohol (eg, heptadecaethyleneoxycetanol), or a portion derived from a fatty acid of ethylene oxide A condensation product with an ester (eg, a dispersing or wetting agent that may be polyoxyethylene sorbitan monooleate. An aqueous suspension may also contain one or more preservatives, such as Chill or n- propyl p- hydroxybenzoate, one or more coloring agents, can also contain one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

  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 combination 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 monoolein. It may be an acid sorbitan and a condensation product of the partial ester with ethylene oxide, such as 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, flavoring and coloring agents.

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

  In a preferred embodiment, theobromine in combination with an antitussive is administered via the oral route. The combination composition according to the present invention can be manufactured 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. 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.

  Combination compositions intended for inhalation, topical, intranasal, intravenous, sublingual, rectal, and vaginal use can be 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 the second group was administered 10 mg / kg theobromine in combination with 30 mg / kg dextromethorphan. A third group receiving vehicle only was used as a control. Administration was via the oral route.

  The results are shown in FIG. Data have been reported that theobromine and dextromethorphan combination has no effect on cough with theobromine monotherapy (shown in the figure) and dextromethorphan monotherapy (recently, The improved efficacy in the treatment of cough.

Claims (7)

  A drug comprising theobromine and another non-opiate antitussive as a combined preparation for simultaneous, sequential or separate use in therapy.   The medicament according to claim 1, wherein the treatment is treatment of cough.   Theobromine for treating cough, in which the subject being treated has also been administered another non-opiate antitussive.   Other non-opiate antitussives are dextromethorphan, isoaminyl, benzoate, dipeprol, morcrophone, plenoxdiazine, dropropidine, piperidione, pentoxyberine, oxolamine, oxerazine, nepinalone, meprothixol, indantadol, dimemorphan, dibunato, cloperastine, 4. The agent according to claim 1 or claim 2, or theobromine according to claim 3, which is selected from danol, butamylate, bibenzonium, benproperin, and fedrylate.   5. The agent according to any one of claims 1, 2, and 4, or theobromine according to claim 3 or 4, wherein another non-opiate antitussive is dextromethorphan.   6. The medicament according to any one of claims 1, 2, 4, and 5, or another 3-5, wherein another non-opiate antitussive is administered at a dosage of 0.1-30 mg / kg / day. Theobromine according to any one of the above.   6. The medicament or theobromine according to claim 5, wherein dextromethorphan is administered at a dosage of 0.1-6 mg / kg / day.

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