Classifications

• • 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
  • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • 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
  • 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 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.
• WO98/42322 discloses the use of theobromine for the treatment of cough, to be given orally.
• non-opiate antitussive drugs have been developed for cough therapies.
• a number of these antitussive drugs are NMDA antagonists.
• Dextromethorphan is one such drug that has been developed specifically for use as a cough therapy.
• its efficacy and suitability as a treatment for cough has already been brought into question.
• J. Ramsey et al. British Journal of Clinical Pharmacology, the authors report that the apparent success of dextromethorphan as a clinical treatment for cough is in fact just a placebo effect, and that it has no efficacy in cough.
• the invention is based at least in part on data showing a synergistic anti- tussive effect for theobromine combined with the non-opiate antitussive drug, dextromethorphan, in a citric acid-induced cough model.
• the data show that when theobromine is combined with dextromethorphan , the effect is surprisingly potent and greater than the sum of the individual drugs, revealing that the combination has a substantially improved effect.
• an agent comprises theobromine and another non-opiate antitussive, as a combined preparation for simultaneous, sequential or separate use in therapy.
• Figure 1 shows the effect of theobromine, and a combination of theobromine and dextromethorphan, on citric acid-induced cough in guinea-pig.
• 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, although the synergistic effect of the combination means that the effective dose may be reduced.
• the additional agent (a different non-opiate antitussive drug, i.e. not theobromine) 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 non -opiate antitussive that is administered with the theobromine is greater than 0.1 , e.g. more than 5, and typically up to 30 mg/kg/day.
• the non-opiate antitussive drug is preferably selected from dextromethorphan, isoaminile, benzonate, zipeprol, morclofone, prenoxdiazine, dropropizine, piperidione, pentoxyverine, oxolamine, oxeladin, nepinalone, meprotixol, indantadol, dimemorfan, dibunate, cloperastine, clofedanol, butamirate, bibenzonium, benproperine and fedrilate.
• Dextromethorphan is the most preferred antitussive drug, e.g. at a dose of 0.1 to 6 mg/kg/day.
• the non-opiate antitussive drug is preferably an NMDA antagonist.
• 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 oral route is the preferred route of administration.
• the compounds of the invention are preferably as combinations to be administered orally, for example as tables, troches, lozenges, aqueous or oral 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.
• the pharmaceutical composition of the combination is a pressed tablet or capsule with conventional excipients, examples of which are given below.
• compositions of the combination 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.
• theobromine in combination with an antitussive drug is to be administered via the oral route.
• Combined compositions according to the invention may be produced using conventional formulation techniques.
• spray-drying may be used to produce microparticles comprising the active agent dispersed or suspended within a material that provides the controlled release properties.
• the process of milling may also be used to formulate the therapeutic composition.
• the 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.
• 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.
• 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.
• 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, intravenous, sublingual, 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 a second group was administered 10 mg/kg of theobromine in combination with 30 mg/kg of dextromethorphan.
• a third group was used as a control, receiving only vehicle. Administration was via the oral route.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pulmonology (AREA)
• Emergency Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2009
  • 2009-11-13 GB GBGB0919889.6A patent/GB0919889D0/en not_active Ceased
• 2010
  • 2010-11-12 CA CA2780703A patent/CA2780703A1/en not_active Abandoned
  • 2010-11-12 AU AU2010317667A patent/AU2010317667B2/en not_active Ceased
  • 2010-11-12 EP EP10825831A patent/EP2498777A2/de not_active Ceased
  • 2010-11-12 NZ NZ599949A patent/NZ599949A/xx not_active IP Right Cessation
  • 2010-11-12 JP JP2012538415A patent/JP2013510841A/ja active Pending
  • 2010-11-12 RU RU2012124038/15A patent/RU2519086C2/ru not_active IP Right Cessation
  • 2010-11-12 WO PCT/GB2010/051895 patent/WO2011058373A2/en active Application Filing
  • 2010-11-12 BR BR112012011227A patent/BR112012011227A2/pt not_active IP Right Cessation
  • 2010-11-12 MX MX2012005532A patent/MX2012005532A/es active IP Right Grant
  • 2010-11-12 PE PE2012000649A patent/PE20130147A1/es not_active Application Discontinuation
  • 2010-11-12 CN CN2010800516299A patent/CN102753174A/zh active Pending
  • 2010-12-11 UA UAA201207164A patent/UA108993C2/en unknown
• 2012
  • 2012-05-11 CO CO12078027A patent/CO6551744A2/es not_active Application Discontinuation
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  • 2012-06-11 ZA ZA2012/04248A patent/ZA201204248B/en unknown
• 2016
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