RU2587329C2 - Drug combination with theobromine and use thereof in treatment - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: proposed is a group of 7 inventions for the treatment of cough. It includes means for combined treatment of cough, comprising theobromine and codeine to codeine administration at a dose of 3 mg/kg/day, a pharmaceutical composition containing said combination agent application means or formulation for the treatment of cough; means or applying the composition to obtain a medicament for the treatment of cough, a method of treating cough, the use of theobromine in combination with Codeine for a preparation for the treatment of cough (variants) and the use of theobromine in combination with codeine for the treatment of cough (variants).

EFFECT: technical result is to increase the effectiveness of the combination of the claimed anti monotherapy with theobromine and codeine alone.

14 cl, 1 dwg

Description

FIELD OF THE INVENTION

This invention relates to a medicinal combination, its composition and its use in the treatment of cough.

BACKGROUND

Coughing is a protective reflex. A persistent cough can be tiring. Over-the-counter medicines are publicly available, but their effectiveness is questionable.

WO 98/42322 discloses the use of theobromine for the treatment of oral cough. Usmeni et al., FASEB J. express article 10.1096, discloses that theobromine inhibits sensory nerve stimulation and coughing. Data are presented demonstrating the effects after oral administration in citric acid-induced cough in a guinea pig and capsaicin-induced cough in humans and after washing preparations of the vagus nerve guinea pig.

Many opiate medicines have been developed to treat cough. Codeine is an example of one of these medicines, and it is widely used as an antitussive. However, due to the addictive properties of codeine and other opiates, there is a need for substitute drugs for treating cough. In addition, recent data show that the therapeutic index for certain patient groups is very low.

SUMMARY OF THE INVENTION

The invention is based, at least in part, on data showing the synergistic antitussive effect of theobromine in combination with opiate drugs, codeine in a citric acid-induced cough model. The data show that when theobromine is combined with codeine, the effect becomes unexpectedly stronger and longer than the sum of the individual drugs, demonstrating that the combination has a significantly improved effect. One of the benefits of reducing the minimum effective dose of codeine is the reduced chance of an overdose of codeine, as described above.

Therefore, in order to achieve an effect equivalent to the individual drugs, the dose of both drugs can be significantly reduced, thereby reducing the side effects of the drug and possible complications. One of the side effects of codeine and many other opiate medicines is sedation. It has been unexpectedly discovered that theobromine counteracts the sedative properties of opiates.

Thus, in accordance with the present invention, the drug contains theobromine and opiate in the form of a combined preparation for simultaneous, sequential or separate use in therapy.

It is believed that this synergistic interaction will be demonstrated by all opiates. Not wanting to be bound by theory, this may be due to the structural similarity of members of the opiate family.

DESCRIPTION OF FIGURES

The figure 1 shows the effect of theobromine, as well as a combination of theobromine and codeine on citric acid-induced cough in a guinea pig.

DESCRIPTION OF THE INVENTION

As used herein, the term “opiate” describes any of the narcotic opioid alkaloids found as natural products in opium poppy plants, as well as many chemical derivatives of such alkaloids. The term "opiate" describes a particular class of drugs and will be understood by a person skilled in the art.

Any suitable form of theobromine may be selected. These include salts, prodrugs, and active metabolites. Theobromine can also be in the form of cocoa or chocolate. A suitable dose range for theobromine is known in the art, however, the synergistic effect of the combination means that the effective dose can be reduced.

The opiate can be used in an amount that is already known due to its use, although the combination in accordance with the present invention means that a dose reduction can be effective. The dose of opiate that is administered with theobromine, of course, depends on common factors, including its effectiveness, but preferably at least 0.1, for example at least 5, and may be up to 30 mg / kg / day.

Opiate preferably selected from codeine, morphine, diamorphine, thebaine, papaverine, noscapine, oripavine, fentanyl alfametilfentanila, alfentanil, sufentanil, remifentanil, carfentanil, propoxyphene, oxymorphone, oxycodone, hydromorphone, pethidine, dihydrocodeine, buprenorphine, etorphine, ethylmorphine, loperamide and hydrocodone, pentazocine and tramadol, tipepidine and noscapine. Codeine is the most preferred opiate, for example, at a dose of 3 mg / kg / day.

The compounds of the invention can be administered by any available route, such as oral, inhalation, intranasal, sublingual, intravenous, rectal and vaginal methods. The oral route is the most preferred route of administration.

The compounds of the invention are preferably presented as combinations for oral administration, for example, in the form of tablets, lozenges, lozenges, aqueous or oral suspensions, soluble powders or granules. Preferred pharmaceutical compositions of the invention are in tablets and capsules. Liquid dispersions for oral administration may be syrups, emulsions and suspensions. More preferably, the pharmaceutical compositions of this combination are compressed tablets or capsules with conventional excipients, examples of which are given below.

Compositions of this combination intended for oral use can be obtained by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more substances selected from the group consisting of sweeteners, flavorings, colorings and preservatives to obtain pharmaceutically suitable and palatable preparations. Tablets contain combined active ingredients in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can 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, binders, for example gelatinized starch, acacia, microcrystalline cellulose or polyvinylpyrrolidone, and lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known methods to slow down the breakdown and absorption in the gastrointestinal tract, and thereby provide continuous exposure over a longer period of time. For example, retarding agents such as glyceryl monostearate or glyceryl distearate can be used.

Aqueous suspensions contain combined active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such auxiliary substances are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and Arabian gum; dispersing or wetting agents can be naturally occurring phosphatides, for example lecithin, or condensation products of alkylene oxide with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, such as heptadecaethylenoxetethenol, monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl-p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

Oily suspensions may be prepared by suspending the active ingredient in vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, polyoxyethylene hydrogenated castor oil, fatty acids such as oleic acid, or in 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. Sweeteners such as those mentioned above and flavoring agents may be added to make the oral preparation taste good. These compositions may be protected by the addition of an antioxidant such as ascorbic acid.

Soluble powders and granules suitable for preparing an aqueous suspension by adding water are combined active ingredients in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavoring and coloring agents may also be present.

The combined pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or mineral oil, for example liquid paraffin, or mixtures thereof. Suitable emulsifying agents can be gums of natural origin, for example, gum arabic or tragacanth gum, natural phosphatides, for example soybeans, lecithin, as well as esters or partial esters of derivatives of fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of these partial complex esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. Emulsions may also contain sweeteners and flavorings.

Syrups and elixirs may contain sweeteners, for example glycerin, propylene glycol, sorbitol or sucrose. Such formulations may also contain an emollient, preservative, flavoring and coloring agents.

Suspensions and emulsions may contain a carrier, for example, natural gum, agar, sodium alginate, pectin, methyl cellulose, carboxymethyl cellulose or polyvinyl alcohol.

In a preferred embodiment, theobromine in combination with an antitussive drug is administered orally. Combined compositions according to the invention can be obtained using traditional manufacturing methods. In particular, a spray drying method can be used to produce microparticles containing an active substance dispersed or suspended in a material that provides controlled release.

The grinding process, for example, jet grinding, can be used to create a therapeutic composition. The production of fine particles by grinding can be achieved using conventional methods. The term "grinding" is used in this description to refer to any mechanical process that is applied with sufficient force directed at the particles of the active substance to crush or grind these particles before turning them into small particles. Various grinding devices and conditions are suitable for the manufacture of compositions of the present invention. To ensure the necessary degree of impact, the specialist is able to select the appropriate grinding conditions, for example, the intensity and duration of grinding. Ball grinding is the preferred method. In another embodiment, a high pressure homogenizer may be used in which a fluid containing particles is passed through a valve under high pressure to provide high shear rate and turbulence. The shear force applied to the particles, the impact between the particles and the surface of the machine or other particles, and cavitation due to the acceleration of the liquid, all this can contribute to the destruction of the particles. Suitable homogenizers include EmulsiFlex high pressure homogenizer, Niro Soavi high pressure homogenizer and Microfluidics Microfluidiser. The grinding process can be used to obtain microparticles with an average aerodynamic diameter of mass, as described above. If the active substance is hygroscopic, it can be ground with a hydrophobic material, as described above.

If necessary, the microparticles obtained in the grinding step can then be combined with additional excipients. This can be achieved by spray drying, for example, co-spray drying. In this embodiment, the particles are suspended in a solvent and spray dried together with a solution or suspension of an additional excipient. Preferred additional excipients include polysaccharides. Additional pharmaceutically effective excipients may also be used.

Compositions of the claimed combinations, intended for inhalation, local, intranasal, intravenous, sublingual, rectal and vaginal use, can be obtained by any method known in the art for the manufacture of pharmaceutical compositions.

The treatment in accordance with the invention can be carried out in a well-known manner, depending on various factors, such as gender, age or condition of the patient, as well as on the presence or absence of one or more concomitant therapies. Composition of patients may be important.

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

STUDY

Guinea pigs cough was caused by citric acid. 7 mg / kg of theobromine was administered to one group of guinea pigs, and theobromine was administered to two groups in combination with 8 or 16 mg / kg of codeine. The fourth group received codeine, and the fifth group received only the vehicle as a control. The introduction was carried out by oral route.

The results are presented in Figure 1. The data show that the combination of theobromine and codeine have a significant increase in the effectiveness of cough treatment compared to theobromine monotherapy and codeine monotherapy.

Claims (14)

1. A combined cough treatment product containing theobromine and codeine for the administration of codeine at a dose of up to 3 mg / kg / day. 2. The tool according to claim 1, made in the form for oral administration. 3. The tool according to claim 2 in the form of tablets, lozenges, lozenges, syrups, emulsions, suspensions, capsules, powders or granules. 4. A pharmaceutical composition for treating cough, comprising an agent according to any one of claims. 1-3. 5. The pharmaceutical composition according to claim 4, further comprising excipients and optionally containing one or more sweeteners, flavorings, colorings and preservatives. 6. The pharmaceutical composition according to claim 4 or claim 5, made in the form for oral administration. 7. The pharmaceutical composition according to paragraphs. 4-6, made in the form of tablets, capsules, troches, lozenges, powders, syrups, emulsions, suspensions or granules. 8. The use of funds according to any one of paragraphs. 1-3 or composition according to paragraphs. 4-6 to obtain a drug for the treatment of cough. 9. The use of funds according to any one of paragraphs. 1-3 or composition according to paragraphs. 4-6 for the treatment of cough. 10. A method of treating cough by administering to a patient an agent according to any one of paragraphs. 1-3 or a pharmaceutical composition according to any one of paragraphs. 4-6. 11. The use of theobromine in combination with codeine for the treatment of cough, where codeine is administered at a dose of up to 3 mg / kg / day. 12. The use of theobromine in combination with codeine to obtain a drug for the treatment of cough by introducing codeine at a dose of up to 3 mg / kg / day. 13. The use of claim 12, wherein the preparation for treating cough is prepared in an oral form. 14. The use of claim 12 or claim 13, wherein the preparation is obtained in the form of tablets, capsules, troches, lozenges, powders, syrups, emulsions, suspensions or granules.

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