WO2005037245A2 - A multiple route medication for the treatment of rhinitis and asthma - Google Patents

A multiple route medication for the treatment of rhinitis and asthma Download PDF

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Publication number
WO2005037245A2
WO2005037245A2 PCT/DK2004/000718 DK2004000718W WO2005037245A2 WO 2005037245 A2 WO2005037245 A2 WO 2005037245A2 DK 2004000718 W DK2004000718 W DK 2004000718W WO 2005037245 A2 WO2005037245 A2 WO 2005037245A2
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active composition
daily dose
route
day
preset amount
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PCT/DK2004/000718
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French (fr)
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WO2005037245A3 (en
Inventor
Troels Keldmann
Erik Keldmann
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Direct-Haler A/S
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Priority to EP04762937A priority Critical patent/EP1680084A2/en
Publication of WO2005037245A2 publication Critical patent/WO2005037245A2/en
Publication of WO2005037245A3 publication Critical patent/WO2005037245A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy

Definitions

  • the present invention relates to a multiple route medication for the . prophylactic and/or therapeutic treatment of conditions in the respiratory system including rhinitis and asthma; the use of a first active composition in a form suitable for an oral administration, a second active composition in a form suitable for the nasal inhalation route and optionally a third active composition in a form suitable for the pulmonary inhalation route for the preparation of a multiple route medication for the prophylac- tic and/or therapeutic treatment of conditions in the respiratory system including rhinitis and asthma; the prophylactic and/or therapeutic treatment of conditions in the respiratory system including rhinitis and asthma of an individual having such condition to be treated or having an increased risk of developing such condition; and a kit to be used thereby.
  • Especially the invention relates to two or three route medication for the treatment of rhinitis and asthma ensuring a prophylactic prevention or postponement of the development of asthma in individuals having a risk factor such as allergic rhinitis based on the concept of "one airway - one disease".
  • inflammation is regarded as a key element and antin- flammatory corticosteroids have been locally applied pulmonarily for asthma and nasally for rhinitis.
  • the inflamed tissues, both nasal and pulmonary, will have a reduced threshold for additional affects both from antigens and from non-allergic irritants, and such inflamed tissues are susceptible to invasion by bacteria and viruses. Therefore, a reduction of inflammation is a key feature to prevent increased severity of the disease and to prevent further infections.
  • Rhinitis is a disease of increasing occurrence.
  • the current therapy of rhinitis is mainly based on two classes of drugs.
  • Antihistamines such as loratidine, de- sloratidine, fexofenatidine and cetericine which are administered orally using tablets
  • nasal corticosteroids such as budesonide, fluticasone propionate, be- clomethasone, mometasone, flunisolide and triamcinolone acetonide, which are delivered by nasal spray.
  • the antihistamines remove the rhinitis symptoms including runny nose, itching, sneezing and nasal congestion. It is generally acknowledged that antihistamines are most effective when taken before development of the symptoms.
  • the nasal corticosteroids reduce and prevent the underlying inflammation in the up- per airways. It is important that the corticosteroids are administered locally by nasal delivery because this minimizes systemic absorption of the corticosteroids. Such systemic absorption has potential side effects.
  • the medications for the treatment of rhinitis are generally available without prescrip- tion as so called over the counter (OTC) preparations.
  • OTC over the counter
  • the current practice allows patients to diagnose themselves and require such OTC-drugs for the treatment of rhinitis by self-medication without consultation of a physician.
  • nasal steroids may require a prescription from a medical physician.
  • Rhinitis often is intermittent or has varying intensity. If patients are self-medicated based on OTC-drugs only - without consulting a physician - the patients may experience a relief from the symptoms. However, no treatment strategy for the medication is established to prevent an escalation of the disease. Such strategy is very important because a regular treatment is more effective than a medication only taken when needed. Without a preventive medication the rhinitis may increase in severity with increased risk for the development of asthma.
  • Asthma is also a disease of increasing occurrence. Being a severe and even life- threatening disease it is very important to identify patients with undiagnosed or untreated asthma, or asthma which is not optimally controlled. However, once the asthma has been diagnosed the risk of severe attacks may necessitate a continued treatment with corticosteroids. It is important that these are administered locally to the lungs because this minimizes systemic absorption. Such systemic absorption has potential side effects.
  • rhinitis asthma is solely treated with medication prescribed by medical professionals on the basis of a thorough examination of the patient. Asthma can develop to a severe and life-threatening disease due to occurrence of asthma attacks, during which the patient cannot breathe in sufficient oxygen.
  • inhalation preparations of short-acting bronchodilators are available. This type of bronchodilators are categorized as "short-acting /3 2 -agonists" and can be exemplified by salbutamol. /3 2 -agonists having a longer time of action are also available, such as formoterol and salmeterol.
  • Medication of asthma by a fixed pulmonary combination therapy has been known since 1991 (salmeterol + fluticasone) and later (formoterol + budesonide; mome- tasone + formoterol).
  • the medication is based on the combination of inhaled corticosteroid with inhaled long-acting /5 2 -agonist.
  • the rationale has been to improve patient compliance.
  • prophylactic dosing of corticosteroids has a low patient compliance as the patient may feel no need for the dose and will not perceive any difference after dosing. In comparison the patient will be able to perceive a breathing enhancement after inhalation of a /3 2 -agonist.
  • a fixed combination dose of a ⁇ 2 - agonist and a corticosteroid would ensure motivation from the patient providing an immediate improvement together with a prophylactic effect.
  • oral antileukotrienes have been introduced in asthma therapy.
  • examples are montelukast, pranlukast and zafir- lukast. These agents modulate the inflammation and are for preventive treatment only.
  • the prior art discloses several combination preparations in the field of therapeutic treatment of respiratory diseases.
  • EP-A-416 951 discloses pharmaceutical compositions comprising salmeterol and flu- ticasone propionate as a combined preparation for simultaneous, sequential or separate administration by inhalation in the treatment of respiratory disorders.
  • the phar- maceutical compositions may be provided in the form of a metered spray composition or a dry powder composition for administration on a twice daily basis.
  • WO 99/00134 discloses a therapeutic composition of formoterol and rofleponide and a kit comprising a vessel containing the formoterol, a vessel containing the rofleponide and instructions for the sequential or simultaneous administration of the formoterol and the rofleponide by inhalation.
  • US-P-5,972,919 discloses the combination of a bronchodilator and a steroidal anti-inflammatory drug for the treatment of respiratory disorders, whereby formoterol and budesonide are used in combination for simultaneous, sequential or separate administration by inhalation in the treatment of respiratory disorder.
  • WO 97/28797 discloses a method of treating asthma, allergy and inflammation by the oral administration of loratadine and a leukotriene antagonist selected from: (A) montelukast sodium; (B) sodium l-(((R)-(3-(2-(6,7-difluror-2- quinolinyl)ethenyl)phenyl)-3 (2-(2-hydroxy-2-propyl)phenyl)thio)methyl)cyclopropaneactate; (C) l-(((l-(R)-(3- (2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl) ⁇ henyl)-3-(2-(l-hydroxy-l- methylethyl)-phenyl)propyl)thio)methyl)cyclopropaneacetic acid or a sodium salt thereof; (D) pranlukast; and (E) zafirluk
  • US Patent Application Publication 2002/0061902 discloses a method of treating and/or preventing a cardiovascular disease in a human suffering from an allergic and/or inflammatory condition of the skin or upper airway passages or cardiovascular disease by administrating an antihistamine, preferably desloratadine, alone, or in admixture with at least one leukotriene antagonist, preferably, montelu- kast, for such reducing and/or preventing. Oral administration is preferred.
  • US-P-5,580,490 discloses a method and device for organizing, storing, instructing, and coordinating the combined use of aerosol and oral medications for the treatment of disorders including respiratory tract disorders for the purpose of reducing medication error and increasing therapeutic compliance.
  • Appropri- ate combinations of doses of the active drugs are not detailed in the disclosure and according to the examples a four times a day protecol is contemplated.
  • WO 98/06394 (Schering; Kreutner) relates to a combination of a histamine HI receptor antagonist (including cetirizine, fexofenadine and loratadine) and a histamine H3 receptor antagonist.
  • the active components can be combined in a single dosage formulation, or in separate dosage forms by inhalation or by other means. A combination with a nasal corticosteroid is not disclosed.
  • US patent application publication No US 2002/0162769 A 1 discloses a prepackaged, therapeutic regimen comprising a first dosage unit of a nasal deconges- tant to be administered in the morning and a second dosage unit of an antihistamin and a nasal decongestant to be given at bedtime.
  • the decongestant is exemplified by pseudophedrine which is an - and /3-receptor stimulation agent.
  • pseudophedrine is an - and /3-receptor stimulation agent.
  • a combination with a nasal corticosteroid is not disclosed.
  • Such treatment could be an effective multiple route treatment of respiratory conditions affecting both the upper and the lower respiration tract, including asthma and rhinitis, in a well controlled way using a pre-selected combination with a pre-selected ratio of a medication given by nasal inhalation, a medication given orally, and in case of diagnosed moderate or severe asthma a medication given by pulmonary inhalation.
  • This pulmonary inhalation may also be given in case of mild asthma.
  • the object of the present invention is to improve the medication for the treatment of rhinitis and asthma.
  • a further object is to find an optimisation of the medication for the rhinitis and asthma treatment in order to lower the incidences of severe asthma conditions. This would allow a reduction of health care expenses and can reduce mortality.
  • rhinitis is a risk factor in development of asthma
  • - rhinitis is a first step in the development of asthma
  • - more than 80% of asthma patients have also rhinitis and need treatment of both conditions
  • - effective and continuous treatment of rhinitis can prevent development of asthma
  • - effective treatment of rhinitis in asthma patients can reduce their risk of hospitalisation and asthma attacks.
  • the object of the present invention is to improve the treatment of rhinitis and asthma. Accordingly the present invention relates to a multiple route medication for the prophylactic and/or therapeutic treatment of conditions in the respiratory system including rhinitis and asthma, wherein the medication comprises - a first active composition in a form suitable for an administration by the oral route, which first active composition includes an antihistamine in a daily dose of
  • a second active composition in a form suitable for the nasal inhalation route which second active composition includes a corticosteroid in a daily dose of 20 - 800 ⁇ g budesonide, 30 - 600 ⁇ g fiuticasone propionate, 50 - 600 ⁇ g be- clomethasone, 50 - 600 ⁇ g momethasone, 20 - 800 ⁇ g flunisolide, 50 - 600 ⁇ g tri- amcinolone acetonide or 50 - 600 ⁇ g ciclesonide, - and optionally a third active composition in a form suitable for the pulmonary inhalation route.
  • the present invention further provides a multiple route medication based on a unit comprising a preset amount of the first active composition, a preset amount of the second active composition, and optionally a preset amount of the third active composition, wherein the preset amounts are doses to be given once or twice a day as well as a package containing one or more of such units.
  • the present invention relates to the use of - a first active composition in a form suitable for an administration of an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebas- tine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine, by the oral route; - a second active composition in a form suitable for an administration of a corticosteroid in a daily dose of 20 - 800 ⁇ g budesonide, 30 - 600 ⁇ g fiuticasone propionate, 50 - 600 ⁇ g beclomethasone, 50 - 600 ⁇ g momethasone, 20 - 800 ⁇ g flunisolide, 50 - 600 ⁇ g triamcinolone acetonide or 50 - 600 ⁇ g ciclesonide for the nasal inhalation
  • kits for prophylactic and/or therapeutic treatment of rhinitis and asthma of an individual having such condition to be treated or having an increased risk of developing such condition comprising a) an oral preparation containing preset amount of a first active composition including an antihistamine, an antileukotriene or a combination thereof in the form of a dose unit, b) a first inhaler for nasal inhalation of a preset amount of a corticosteroid, c) optionally a second inhaler for pulmonary inhalation of a preset amount of a corticosteroid, a /52-agonist or a combination thereof, together with instructions for the intake of the oral preparation, the nasal inhalation and optionally the pulmonary inhalation in accordance with a pre-selected schedule.
  • a first active composition including an antihistamine, an antileukotriene or a combination thereof in the form of a dose unit
  • the inventive two or three route medication represent an optimisation of the rhinitis and asthma treatment and will lower the incidences of severe asthma conditions. This allows a reduction of health care expenses and can reduce mortality.
  • the present invention is based on the understanding of rhinitis and asthma as two expressions of the same underlying disease in the respiratory system. This under- standing can also be referred to as the concept of "one airway - one disease".
  • the present medication ensures a well balanced treatment of asthma and/or rhinitis, especially conditions requiring a long term treatment on regular basis. By such treatment it is important to avoid overdosing resulting in severe side effects. This is ensured by administering a preset amount of each of the active compounds or agents by a pre-determined route selected among the oral route, the nasal route and the pulmonary route.
  • the medication ensures an oral administration of a composition including one or more active agents, a selective topical administration of a composition including one or more active agents to the nasal cavity, and optionally a selective topical administration of a composition including one or more active agents to the trachea, bronchi and lungs.
  • the present invention provides one fixed daily dosing of a combination of specific drugs to be taken in sequence by specific delivery route administration within a specific time frame in order to obtain relief from rhinitis symptoms and prevent escalation of the rhinitis and hence significantly reduce the risk of asthma development.
  • a rhinitis medication comprises a daily dose of an oral antihistamine combined with a daily dose of a nasal corticosteroid.
  • An oral antihistamine tablet may further include an anti-leukotriene agent. This medication will include relief and control of the symptoms twice or preferably once daily and additional a preventive dose controlling inflammation.
  • the invention extends the medication to include also a pulmonary dose for patients suffering both from rhinitis and from asthma.
  • a corticosteroid dose to the lungs is provided for reducing and preventing a local inflammatory condition in the lungs.
  • the pulmonary medication dose may be extended to include a long-acting 3 2 -agonist for symptom relief.
  • An integrated medication comprising local treatment of the mucosa of the respiratory system and systemic treatment of inflammation is important to acquire an improved control of inflammatory diseases in the respiratory system.
  • the present invention provides a fixed daily combined medication, which is easy to follow by the patients and improves patient compliance.
  • the medications and medication systems according to the invention preferably depend on a suitable drug delivery system, which facilitates the correct delivery sequence according to the dose-time protocol.
  • the drug delivery system can be a system for dispensing and delivery of multiple doses, for example comprising the medication for one month.
  • the system may include means for inhalation such as the conventional elements of inhalation devices known and marketed for either nasal or pulmonary delivery.
  • nasal administration can be carried out in any conventional way using conventional devices for nasal delivery such as liquid spray devices, pressurized me- tered dose inhalers and nasal insufflators.
  • Other means for nasal administration include a simple drop pipette or a rhinyl.
  • Pre-compression metered-dose spray pumps with typical dose volumes from 25 ⁇ l to 150 ⁇ l can be used, whereby the concentration of corticosteroid in the suspension is adjusted to give the desired unit dose.
  • monospray or a bispray pump can be used; for the latter, the recommended unit dose is sequentially delivered into each nostril.
  • the twice or preferably once daily medication is delivered in a unit-dose two or three route format. This further supports the compliance and fulfil the requirement of easy use.
  • the nasal steroid dose is preferably delivered by a device which prevents any inhala- tion and immediate swallowing of the nasal steroid dose.
  • a device which prevents any inhala- tion and immediate swallowing of the nasal steroid dose.
  • the patient exhales through a mouth piece with airflow resistance - forcing the soft pal- ate to close the connecting passage between the nasal cavity and the oral cavity.
  • This closure during the delivery of the nasal steroid dose will prevent any inhalation to the lungs and/or immediate swallowing of the specific nasal steroid dose, hence exclude any pulmonary deposition of the steroid.
  • Such inhaler device to be used only once is described in US 2002 0165482 Al and WO 98/53869 (corresponding to US 6 648 848)
  • the third active composition to be delivered by the pulmonary route can be administered by any conventional pulmonary inhaler such as dry powder inhalers, pressur- ized metered dose inhalers and nebulisers.
  • any conventional pulmonary inhaler such as dry powder inhalers, pressur- ized metered dose inhalers and nebulisers.
  • the third active composition is conveniently delivered by conventional means, e.g. in the form of a metered dose inhaler prepared in a conventional manner or in combination with a spacer device.
  • a me- tering valve is provided to deliver a metered amount of the composition.
  • Spray compositions may for example be formulated as aqueous solutions or suspensions and may be administered by a nebuliser. Aerosol spray formulations, for example in which the active ingredients are suspended, optionally together with one or more stabilisers, in a propellant, e.g.
  • a halogenated hydrocarbon such as trichlorofluoro- methane, dichlorodifluoromethane, 1,2-dichlorotetrafluoroethane, trichlorotrifluoro- ethane, monochloropentafluoroethane, chloroform or methylene chloride, may also be employed.
  • the third active composition may take the form of a dry powder composition, for example a powder mix of the active ingredients and a suitable carrier such as lactose.
  • the powder compositions may be presented in unit dosage form in, for example, capsules, cartridges or blister packs from which the powder may be administered with the aid of an inhaler.
  • the multiple route medication may in a preferred embodiment be a unit comprising a preset amount of the first active composition, a preset amount of the second active composition, and optionally a preset amount of the third active composition, wherein the preset amounts are doses to be given once a day.
  • a medication unit may be based on a combination of the above inhaler devices to be used once only disclosed in WO 98/53869 and US 5 797 392 respectively together with a pill or tablet for oral administration.
  • a further convenient device combining the nasal inhaler and the pulmonary inhaler is described in applicants simultaneous DK patent application No PA 2003 01547.
  • the present two or three route medication is usable for a prophylactic and/or therapeutic regular long lasting treatment of rhinitis to avoid or postpone the development of asthma or in case of diagnosed asthma to reduce the risk of asthmatic attacks and postpone the further progress of the disease.
  • the inventive multiple route medication may be used as a convenient daily treatment depending on the development and severity of the condition to be treated.
  • the medication can be a two route medica- tion, preferably given once a day within the same short period of time, wherein the first active composition for an administration by the oral route includes an antihistamine selected from the group consisting of loratidine, desloratidine, fexofenadine,HCl, ebastine, mizolastine, mequitazine and ceterizine, and the second active composition for the nasal inhalation route includes a corticosteroid selected from the group consisting of budesonide, fluticasone propionate, beclomethasone, momethasone, flunisolide, triamcinolone acetonide and ciclesonide.
  • the medication can be a three route medication wherein the first active composition for an admini- stration by the oral route includes an antihistamine selected from the group consisting of loratidine, desloratidine, fexofenadine,HCl, ebastine, mizolastine, mequitazine and ceterizine; the second active composition for the nasal inhalation route includes a corticosteroid selected from the group consisting of budesonide, fluticasone propionate, beclomethasone, momethasone, flunisolide, triamcinolone acetonide and ciclesonide; and the third active composition for the pulmonary inhalation route a corti- costeroid selected from the group consisting of budesonide, fluticasone propionate, beclomethasone, momethasone, flunisolide, triamcinolone acetonide and ciclesonide.
  • the first active composition for an admini- stration by the oral route includes
  • the above medication can be supplemented by the inclusion of a 5 2 -agonist selected from the group consisting of salmeterol and formoterol in combination with the corticosteroid in the third active composition for the pulmonary route.
  • an anti-leukotriene selected from the group consisting of montelukast, zafirlukast and pranlukast thogether with the antihistamine in the first active composition for oral administration.
  • an anti-leukotriene selected from the group consisting of montelukast, zafirlukast and pranlukast thogether with the antihistamine in the first active composition for oral administration.
  • the medication for moderate persistent asthma may include an antihistamine and an anti-leukotriene for the oral route, a corticosteroid for the nasal route and a low dose corticosteroid and a /3 2 -agonist for the pulmonary route
  • the medication for mild asthma may include an antihistamine and an anti-leukotriene for the oral route and a corticosteroid for the nasal route.
  • the above mentioned active compounds or agents may be the actual mentioned compounds or active derivatives thereof.
  • the mometasone is suitable used as mometasone furoate
  • beclomethasone may be used as beclomethasone dipropionate
  • formoterol may be used as formoterol fumarate.
  • any derivative including but not limited to pharmaceutically acceptable esters, solvates or salts with an acid or base provided such derivatives have the desired activity combined with acceptable low side effects if any.
  • each type of the active compounds such as the antihistamines
  • the inventive medication is also intended to cover the use of two or more antihistamines together, in which case the doses of each single compound should be adjusted to give an activity corresponding to the activity obtained by a single antihistamine.
  • Such adjusting is an obvious routine for the skilled person.
  • the other types of active compounds including the corticosteroids, the anti-leukotrienes and the 3 2 -agonists.
  • the multiple route medication according to the invention is further illustrated by the following examples wherein the proposed doses for the relevant active compounds are stated. These doses are the daily dose to an adult patient.
  • the daily doses can be given once a day or divided in two doses for a twice a day protocol, but preferably a once a day protocol is used.
  • the precise dose will of course depend on the age, weight and condition of the patient and thus in case of children, such as children up to 12 years, the doses may be in the lower end of the stated scope or in some cases even below the lower limit.
  • the clinician will determine the suitable dose and composition of each of the first, second and third compositions of the inventive medication considering the age and weight of the patient and the severity of the condition starting in the low end and stepwise increasing the doses if necessary.
  • the inventive medication in the form of a two route medication usable for a first step condition of the disease with rhinitis and only intermittent asthma.
  • Such condition can be treated by a two route medication using the oral and the nasal route.
  • the medication comprises an oral antihistamine and a nasal corticosteroid as further described below.
  • An oral medication is given as the first active composition, which includes an anti- histamine given once a day. Examples are:
  • Loratidine 3 - 30 mg/day, preferably 5 - 20 mg/day, such as 10 mg/day.
  • Desloratidine 1 - 20 mg/day, preferably 2 - 10 mg/day, such as 5 mg/day.
  • Fexofenadine, HC1 50 - 400 mg/day, preferably 100 - 200 mg/day, more preferred 110 - 190 mg/day.
  • Ceterizine 2 - 20 mg/day, preferably 5 - 15 mg/day, more preferred 9 - 11 mg/day.
  • Ebastine 3 - 30 mg/day, preferably 5 - 20 mg/day, such as 10 mg/day.
  • Mizolastine 3 - 30 mg/day, preferably 5 - 20 mg/day, such as 10 mg/day.
  • Mequitazine 3 - 30 mg/day, preferably 5 - 20 mg/day, such as 10 mg/day.
  • the second composition is given by the nasal route. For practical reasons this is done within the same short period of time.
  • This second composition for nasal inhalation is preferably dosed with a half dose in each of the nostrils.
  • the doses of the corticosteroids given below are the total doses for both nostrils. Examples of nasal corticosteroids included in the second composition and the total doses to be given once a day for rhinitis medication are:
  • Budesonide 20 - 800 ⁇ g/day, preferably 30 - 700 ⁇ g/day, more preferred 50 - 400 ⁇ g/day.
  • Fluticasone propionate 30 - 600 ⁇ g/day, preferably 40 - 400 ⁇ g/day, more preferred 50 - 300 ⁇ g/day.
  • Beclomethasone 50 - 600 ⁇ g/day, preferably 60 - 300 ⁇ g/day, more preferred 70 - 350 ⁇ g/day.
  • Momethasone 50 - 600 ⁇ g/day, preferably 60 - 500 ⁇ g/day, more preferred 80 - 300 ⁇ g/day.
  • Triamcinolone acetonide 50 — 600 ⁇ g/day, preferably 70 - 500 ⁇ g/day, more preferred 90 - 300 ⁇ g/day.
  • Ciclesonide 50 - 600 ⁇ g/day, preferably 70 - 500 ⁇ g/day, more preferred 90 - 300 ⁇ g/day.
  • Flunisolide 20 - 800 ⁇ g/day, preferably 30 - 700 ⁇ g/day, more preferred 50 - 400 ⁇ g/day.
  • the inventive medication in the form of a three route medication usable for a second step condition of the disease with rhinitis and mild persistent asthma.
  • Such condition can be treated by a three route medication using the oral route, the nasal route and the pulmonary route.
  • the medication comprises an oral antihistamine, a nasal corticosteroid and a pulmonary corticosteroid as further described below.
  • the third active composition can include a pulmonary corticosteroid given preferably once a day in following doses:
  • Budesonide 50 - 2100 ⁇ g/day, preferably 80 - 1900 ⁇ g/day, more preferred 100 - 1600 ⁇ g/day.
  • Fluticasone propionate 30 - 1800 ⁇ g/day, preferably 40 - 1400 ⁇ g/day, more preferred 50 - 1000 ⁇ g/day.
  • Beclomethasone 50 - 2100 ⁇ g/day, preferably 80 - 1900 ⁇ g/day, more preferred 100 - 1600 ⁇ g/day.
  • Momethasone 50 - 2100 ⁇ g/day, preferably 80 - 1900 ⁇ g/day, more pre- ferred 100 - 1600 ⁇ g/day.
  • Triamcinolone acetonide 50 - 2100 ⁇ g/day, preferably 80 - 1900 ⁇ g/day, more preferred 100 - 1600 ⁇ g/day.
  • Ciclesonide 50 - 2100 ⁇ g/day, preferably 80 - 1900 ⁇ g/day, more preferred 100 - 1600 ⁇ g/day.
  • Flunisolide 50 - 3000 ⁇ g/day, preferably 100 - 2500 ⁇ g/day, more preferred 150 - 2000 ⁇ g/day.
  • This medication comprises an oral combination of antihistamine and anti-leukotriene and a nasal corticosteroid as further described below.
  • the second composition given by the nasal route is similar to that given according to example 1, whereas the first composition to be given orally is a combination of an antihistamine in a daily dose similar to that in example 1 together with an anti-leukotriene.
  • anti-leukotrienes and usable daily doses thereof are:
  • 3 - 30 mg/day preferably 5 - 20 mg/day, such as 10 mg/day of montelukast; 6 - 60 mg/day, preferably 10 - 50 mg/day, such as 40 mg/day of zafirlukast; or
  • 150 - 1400 mg/day preferably 300 - 800 g/day, such as 450 mg/day of pranlukast.
  • the inventive medication in the form of a three route medica- tion usable for a third step condition of the disease with rhinitis and moderate persistent asthma.
  • Such condition can be treated by a three route medication using the oral route, the nasal route and the pulmonary route.
  • the medication comprises an oral antihistamine, a nasal corticosteroid and a pulmonary combination of corticosteroid and /? 2 -agonist as further described below.
  • the medication in this situation is similar to that disclosed in example 2 using a similar dose of an antihistamine given orally, a similar dose of a corticosteroid given nasally as well as a dose similar to that in example 2 of a pulmonary administered corticosteroid.
  • the third active composition includes further to the corticoster- oid as disclosed in example 2 a long-acting /3 2 -agonist. Examples of such combined third active compositions for the pulmonary route are:
  • Example 4a Fluticasone propionate 50 - 1000 ⁇ g/day Salmeterol 25 - 200 ⁇ g/day
  • Example 4b Budesonide 100 - 1600 ⁇ g/day Formoterol 3 - 40 ⁇ g/day
  • Example 4c Mometasone 100 - 1600 ⁇ g/day Formoterol 3 - 40 ⁇ g/day
  • Example 5 This is an alternative example of the inventive medication in the form of a tliree route medication usable for a third step condition of the disease with rhinitis and moderate persistent asthma.
  • Such condition can be treated by a three route medication using the oral route, the nasal route and the pulmonary route.
  • the medication comprises an oral combination of antihistamine and anti-leukotriene, a nasal cor- ticosteroid and a pulmonary combination of corticosteroid and 3 2 -agonist as fiurther described below.
  • the first composition to be given orally is a combination of an antihistamine in a daily dose similar to that in example 1 together with an anti- leukotriene.
  • anti-leukotrienes and usable daily doses thereof are: 3 - 30 mg/day, preferably 5 - 20 mg/day, such as 10 mg/day of montelukast; 6 - 60 mg/day, preferably 10 - 50 mg/day, such as 40 mg/day of zafirlukast; or 150 - 1400 mg/day, preferably 300 - 800 g/day, such as 450 mg/day of pranlukast.
  • the first active oral composition may include 3
  • the second composition given by the nasal route is similar to that given according to example 1.
  • the third composition given by the pulmonary route is a combination of a corticosteroid and a long-acting /3 2 -agonist.
  • the dose of the long-acting ⁇ -agonist may be similar to that used in example 4, but the dose of the corticosteroid can be reduced due to the additional anti-leukotriene in the first oral composition.
  • pulmonary corticosteroid is typically:
  • Budesonide 25 - 1000 ⁇ g/day, preferably 40 - 1000 ⁇ g/day, more preferred 50 - 800 ⁇ g/day.
  • Fluticasone propionate 15 - 900 ⁇ g/day, preferably 20 - 700 ⁇ g/day, more preferred 25 - 500 ⁇ g/day.
  • Beclomethasone 25 - 1000 ⁇ g/day, preferably 40 - 900 ⁇ g/day, more preferred 50 - 800 ⁇ g/day.
  • Momethasone 25 - 1000 ⁇ g/day, preferably 40 - 900 ⁇ g/day, more pre- ferred 50 - 800 ⁇ g/day.
  • Triamcinolone acetonide 25 - 1000 ⁇ g/day, preferably 40 - 900 ⁇ g/day, more preferred 50 - 800 ⁇ g/day.
  • Ciclesonide 25 - 1000 ⁇ g/day, preferably 40 - 900 ⁇ g/day, more preferred 50 - 800 ⁇ g/day.
  • Flunisolide 25 - 1500 ⁇ g/day, preferably 50 - 1200 ⁇ g/day, more preferred 75 - 1000 ⁇ g/day. Examples of such combined third active compositions for the pulmonary route are:
  • Example 5a Fluticasone propionate 25 - 500 ⁇ g/day Salmeterol 25 - 200 ⁇ g/day
  • Example 5b Budesonide 50 - 800 ⁇ g/day Formoterol 3 - 40 ⁇ g/day
  • the combined two or three route medication prescribes preset doses of each of the three active compositions to be given once a day.
  • all three compositions are given within the same short period of time.
  • the use of all three compositions once a day at the same time each day will be more easy for the patient compliance and to ensure that the pa- tient really follows the prescribed medication protocol, which is very important if the development of a more severe condition is to be prevented or postponed.
  • the first, second and/or third active composition including the doses stated in the above examples may alternatively be given in divided doses according to a twice a day protocol, provided the protocol will be followed correctly. However, due to the easier patient compliance and safer fulfilment of the medication protocol the once a day protocol is preferred in the most cases.

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Abstract

A multiple route medication for the prophylactic and/or therapeutic treatment of rhinitis and asthma based on the concept of “one airway-one disease”. A first preset amount of an active composition for the oral route is given together with preset amount of a second active composition for the nasal route and optionally also with a third preset amount of a third active composition for the pulmonary route. The first active composition can include an antihistamine, such as loratidine, desloratidine, fexofenadine, HCI, ebastine, mizolastine, mequitazine or ceterizine, an anti-leukotriene, such as montelukast, zafirlukast or pranlukast or a combination of an- antihistamine and a anti-leukotriene. The second active composition can include a coticosteroid such as budesonide, fluticasone propionate, beclomethasone, momethasone, flunisolide, triamcinolone acetonide or ciclesonide. The third active composition can include a corticosteroid of the same type or a combination of such corticosteroid with a β2-agonist, such as salmeterol and formoterol. The invention provides a fixed daily dosing of a combination of specific drugs to be taken in sequence by specific delivery route administration within a specific time frame in order to obtain relief from rhinitis and asthma symptoms and prevention or postponing the escalation of asthma from intermittent through mild, moderate to severe persistent asthma. Preferably the fixed daily doses are to be given once a day or as subdivided doses to be given twice a day.

Description

Title: A Multiple Route Medication for the Treatment of Rhinitis and Asthma
Technical Field
The present invention relates to a multiple route medication for the . prophylactic and/or therapeutic treatment of conditions in the respiratory system including rhinitis and asthma; the use of a first active composition in a form suitable for an oral administration, a second active composition in a form suitable for the nasal inhalation route and optionally a third active composition in a form suitable for the pulmonary inhalation route for the preparation of a multiple route medication for the prophylac- tic and/or therapeutic treatment of conditions in the respiratory system including rhinitis and asthma; the prophylactic and/or therapeutic treatment of conditions in the respiratory system including rhinitis and asthma of an individual having such condition to be treated or having an increased risk of developing such condition; and a kit to be used thereby. Especially the invention relates to two or three route medication for the treatment of rhinitis and asthma ensuring a prophylactic prevention or postponement of the development of asthma in individuals having a risk factor such as allergic rhinitis based on the concept of "one airway - one disease".
Background Art Respiratory diseases of asthma and rhinitis have been subject to research and development of medications and therapies for decades. The relationship between the two diseases is complex. It has been observed repeatedly in the past 50 years that there is a link between the upper and lower respiratory tracts, but this link has only been studied more carefully in the past decade.
Traditionally the scientific investigation and treatment of the respiratory system has been divided between the upper part (nasal and throat ) and the lower part (lungs) as each part has its own characteristics. Thus rhinitis and the airways from the nostril to the vocal cords is the domain of the otorhinolaryngologist, whereas asthma and the airways below the vocal cords is the domain of the pulmonologist. Each separate part of the airways is a target for the development of specific therapeutic agents usable for a one route local treatment of diseases in the part in question.
Also the current regulatory practice tends to maintain this separation due to the sepa- rate approval of an active substance either for the indication rhinitis or for the indication asthma. The same separation of the two diseases is seen in the diagnosis and prescription of separate medications for the two diseases.
However, in both diseases inflammation is regarded as a key element and antin- flammatory corticosteroids have been locally applied pulmonarily for asthma and nasally for rhinitis. The inflamed tissues, both nasal and pulmonary, will have a reduced threshold for additional affects both from antigens and from non-allergic irritants, and such inflamed tissues are susceptible to invasion by bacteria and viruses. Therefore, a reduction of inflammation is a key feature to prevent increased severity of the disease and to prevent further infections.
Current treatment of rhinitis
Rhinitis is a disease of increasing occurrence. The current therapy of rhinitis is mainly based on two classes of drugs. Antihistamines such as loratidine, de- sloratidine, fexofenatidine and cetericine which are administered orally using tablets, and nasal corticosteroids such as budesonide, fluticasone propionate, be- clomethasone, mometasone, flunisolide and triamcinolone acetonide, which are delivered by nasal spray.
The antihistamines remove the rhinitis symptoms including runny nose, itching, sneezing and nasal congestion. It is generally acknowledged that antihistamines are most effective when taken before development of the symptoms.
The nasal corticosteroids reduce and prevent the underlying inflammation in the up- per airways. It is important that the corticosteroids are administered locally by nasal delivery because this minimizes systemic absorption of the corticosteroids. Such systemic absorption has potential side effects.
The medications for the treatment of rhinitis are generally available without prescrip- tion as so called over the counter (OTC) preparations. Thus the current practice allows patients to diagnose themselves and require such OTC-drugs for the treatment of rhinitis by self-medication without consultation of a physician. However in some countries nasal steroids may require a prescription from a medical physician.
Rhinitis often is intermittent or has varying intensity. If patients are self-medicated based on OTC-drugs only - without consulting a physician - the patients may experience a relief from the symptoms. However, no treatment strategy for the medication is established to prevent an escalation of the disease. Such strategy is very important because a regular treatment is more effective than a medication only taken when needed. Without a preventive medication the rhinitis may increase in severity with increased risk for the development of asthma.
Current treatment of asthma
Asthma is also a disease of increasing occurrence. Being a severe and even life- threatening disease it is very important to identify patients with undiagnosed or untreated asthma, or asthma which is not optimally controlled. However, once the asthma has been diagnosed the risk of severe attacks may necessitate a continued treatment with corticosteroids. It is important that these are administered locally to the lungs because this minimizes systemic absorption. Such systemic absorption has potential side effects.
Unlike rhinitis asthma is solely treated with medication prescribed by medical professionals on the basis of a thorough examination of the patient. Asthma can develop to a severe and life-threatening disease due to occurrence of asthma attacks, during which the patient cannot breathe in sufficient oxygen. For immediate relief under asthma attacks inhalation preparations of short-acting bronchodilators are available. This type of bronchodilators are categorized as "short-acting /32-agonists" and can be exemplified by salbutamol. /32-agonists having a longer time of action are also available, such as formoterol and salmeterol.
Medication of asthma by a fixed pulmonary combination therapy has been known since 1991 (salmeterol + fluticasone) and later (formoterol + budesonide; mome- tasone + formoterol). The medication is based on the combination of inhaled corticosteroid with inhaled long-acting /52-agonist. The rationale has been to improve patient compliance. Usually prophylactic dosing of corticosteroids has a low patient compliance as the patient may feel no need for the dose and will not perceive any difference after dosing. In comparison the patient will be able to perceive a breathing enhancement after inhalation of a /32-agonist. A fixed combination dose of a β2- agonist and a corticosteroid would ensure motivation from the patient providing an immediate improvement together with a prophylactic effect.
For many years the two inhaled agents were given in combination but with separate pulmonary inhalers. Later it was proposed to make fixed combination doses from the same pulmonary inhalation device. Examples thereof are the above mentioned combination of corticosteroid and long-acting /32-agonist.
In addition to the locally delivered asthma medications oral antileukotrienes have been introduced in asthma therapy. Examples are montelukast, pranlukast and zafir- lukast. These agents modulate the inflammation and are for preventive treatment only.
The prior art discloses several combination preparations in the field of therapeutic treatment of respiratory diseases.
EP-A-416 951 discloses pharmaceutical compositions comprising salmeterol and flu- ticasone propionate as a combined preparation for simultaneous, sequential or separate administration by inhalation in the treatment of respiratory disorders. The phar- maceutical compositions may be provided in the form of a metered spray composition or a dry powder composition for administration on a twice daily basis.
WO 99/00134 discloses a therapeutic composition of formoterol and rofleponide and a kit comprising a vessel containing the formoterol, a vessel containing the rofleponide and instructions for the sequential or simultaneous administration of the formoterol and the rofleponide by inhalation.
US-P-5,972,919 (Carling, et al.) discloses the combination of a bronchodilator and a steroidal anti-inflammatory drug for the treatment of respiratory disorders, whereby formoterol and budesonide are used in combination for simultaneous, sequential or separate administration by inhalation in the treatment of respiratory disorder.
US Patent Application Publication 2003/0050290 (Hassan et al.) discloses a me- dicament containing, separately or together, (A) formoterol or a pharmaceutically acceptable salt thereof or a solvate of formoterol or a solvate of the salt and (B) mome- tasone furoate, for simultaneous, sequential or separate administration in the treatment of an inflammatory or obstructive airways disease.
WO 97/28797 discloses a method of treating asthma, allergy and inflammation by the oral administration of loratadine and a leukotriene antagonist selected from: (A) montelukast sodium; (B) sodium l-(((R)-(3-(2-(6,7-difluror-2- quinolinyl)ethenyl)phenyl)-3 (2-(2-hydroxy-2-propyl)phenyl)thio)methyl)cyclopropaneactate; (C) l-(((l-(R)-(3- (2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)ρhenyl)-3-(2-(l-hydroxy-l- methylethyl)-phenyl)propyl)thio)methyl)cyclopropaneacetic acid or a sodium salt thereof; (D) pranlukast; and (E) zafirlukast; either substantially concurrently in separate dosage forms or combined in the single pharmaceutical formulation.
US Patent Application Publication 2002/0061902 (Harris et al.) discloses a method of treating and/or preventing a cardiovascular disease in a human suffering from an allergic and/or inflammatory condition of the skin or upper airway passages or cardiovascular disease by administrating an antihistamine, preferably desloratadine, alone, or in admixture with at least one leukotriene antagonist, preferably, montelu- kast, for such reducing and/or preventing. Oral administration is preferred.
US-P-5,580,490 (Weinstein et al.) discloses a method and device for organizing, storing, instructing, and coordinating the combined use of aerosol and oral medications for the treatment of disorders including respiratory tract disorders for the purpose of reducing medication error and increasing therapeutic compliance. Appropri- ate combinations of doses of the active drugs are not detailed in the disclosure and according to the examples a four times a day protecol is contemplated.
WO 98/06394 (Schering; Kreutner) relates to a combination of a histamine HI receptor antagonist (including cetirizine, fexofenadine and loratadine) and a histamine H3 receptor antagonist. The active components can be combined in a single dosage formulation, or in separate dosage forms by inhalation or by other means. A combination with a nasal corticosteroid is not disclosed.
US patent application publication No US 2002/0162769 A 1 (Weinstein) discloses a prepackaged, therapeutic regimen comprising a first dosage unit of a nasal deconges- tant to be administered in the morning and a second dosage unit of an antihistamin and a nasal decongestant to be given at bedtime. The decongestant is exemplified by pseudophedrine which is an - and /3-receptor stimulation agent. A combination with a nasal corticosteroid is not disclosed.
The above publications disclose improvements by combinations of some well established drugs. Some of these combinations are intended to be given orally whereas others are given by inhalation, but most of them are intended as one route medication. Even the prior art proposals for multiple route medications lack sufficient de- tails for an appropriate combination for an improved prophylactic and/or therapeutic treatment of the respiratory diseases of asthma and rhinitis. The currently available fixed-combination products intended to the local treatment of the respiratory system only target the lower respiratory system, the lungs. However, this is only half of the "one airway" system. There is still a need for an integrated treatment for a disease present in and affecting the overall respiratory system (i.e. based on the concept of "one airway - one disease") for further improving control of rhinitis and asthma. Such treatment could be an effective multiple route treatment of respiratory conditions affecting both the upper and the lower respiration tract, including asthma and rhinitis, in a well controlled way using a pre-selected combination with a pre-selected ratio of a medication given by nasal inhalation, a medication given orally, and in case of diagnosed moderate or severe asthma a medication given by pulmonary inhalation. This pulmonary inhalation may also be given in case of mild asthma.
The object of the present invention is to improve the medication for the treatment of rhinitis and asthma. A further object is to find an optimisation of the medication for the rhinitis and asthma treatment in order to lower the incidences of severe asthma conditions. This would allow a reduction of health care expenses and can reduce mortality.
Since 1997 it has been scientifically supported to regard asthma and rhinitis as two separate expressions for the same disease in the overall respiratory system. The research shows correlation between good management of rhinitis and a subsequent development and severity of asthma.
Research shows that - rhinitis is a risk factor in development of asthma, - rhinitis is a first step in the development of asthma, - more than 80% of asthma patients have also rhinitis and need treatment of both conditions, - effective and continuous treatment of rhinitis can prevent development of asthma, and - effective treatment of rhinitis in asthma patients can reduce their risk of hospitalisation and asthma attacks.
Despite the above factual knowledge it has apparently not been obvious to the providers and developers of medications for rhinitis and asthma therapy to provide such integrated medications and medication systems. In fact the providers have introduced completely different delivery technologies for rhinitis treatment and asthma treat- ment. Thus the rhinitis therapy involves liquid nasal spray devices and formulations with corticosteroids, whereas asthma treatment is realised with dry powder inhalers and by pressurized metered dose inhalers. In this way the separation of rhinitis versus asthma treatment is maintained by the providers.
In this way the current practice does not - in spite of the common knowledge on "one airway - one disease" - lead in the direction of integrated medications of fixed combinations of drug doses to be taken at regular intervals in accordance with a fixed protocol.
A further factor, which has discouraged such innovation, is the currently applied regulatory categorizations of diseases making it more complicated to obtain a marketing authorisation for a combination medication for the treatment of two indications, which from a legal point of view are considered as "different" indications.
Concerning the present general knowledge reference can be made to a recent report "ARIA in the Pharmacy", Paris, October 23, 2002 and San Antonio, November 17, 2002, available on http ://www. whiar. com/pharmguide/pharm.pdf.
Disclosure of Invention The object of the present invention is to improve the treatment of rhinitis and asthma. Accordingly the present invention relates to a multiple route medication for the prophylactic and/or therapeutic treatment of conditions in the respiratory system including rhinitis and asthma, wherein the medication comprises - a first active composition in a form suitable for an administration by the oral route, which first active composition includes an antihistamine in a daily dose of
3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine, - a second active composition in a form suitable for the nasal inhalation route, which second active composition includes a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fiuticasone propionate, 50 - 600 μg be- clomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg tri- amcinolone acetonide or 50 - 600 μg ciclesonide, - and optionally a third active composition in a form suitable for the pulmonary inhalation route.
The present invention further provides a multiple route medication based on a unit comprising a preset amount of the first active composition, a preset amount of the second active composition, and optionally a preset amount of the third active composition, wherein the preset amounts are doses to be given once or twice a day as well as a package containing one or more of such units.
Furthermore the present invention relates to the use of - a first active composition in a form suitable for an administration of an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebas- tine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine, by the oral route; - a second active composition in a form suitable for an administration of a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fiuticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide for the nasal inhalation route and - optionally a third active composition in a form suitable for the pulmonary inhalation route for the preparation of a multiple route medication for the prophylactic and/or therapeutic treatment of conditions in the respiratory system including rhinitis and asthma.
Moreover the present invention provides a kit for prophylactic and/or therapeutic treatment of rhinitis and asthma of an individual having such condition to be treated or having an increased risk of developing such condition comprising a) an oral preparation containing preset amount of a first active composition including an antihistamine, an antileukotriene or a combination thereof in the form of a dose unit, b) a first inhaler for nasal inhalation of a preset amount of a corticosteroid, c) optionally a second inhaler for pulmonary inhalation of a preset amount of a corticosteroid, a /52-agonist or a combination thereof, together with instructions for the intake of the oral preparation, the nasal inhalation and optionally the pulmonary inhalation in accordance with a pre-selected schedule.
The inventive two or three route medication represent an optimisation of the rhinitis and asthma treatment and will lower the incidences of severe asthma conditions. This allows a reduction of health care expenses and can reduce mortality.
The extent of applicability of the invention appears from the following detailed description. It should, however, be understood that the detailed description and the specific examples are merely included to illustrate the preferred embodiments, and that various alterations and modifications within the scope of protection will be obvious to persons skilled in the art on the basis of the detailed description.
Detailed description of the invention
The present invention is based on the understanding of rhinitis and asthma as two expressions of the same underlying disease in the respiratory system. This under- standing can also be referred to as the concept of "one airway - one disease". The present medication ensures a well balanced treatment of asthma and/or rhinitis, especially conditions requiring a long term treatment on regular basis. By such treatment it is important to avoid overdosing resulting in severe side effects. This is ensured by administering a preset amount of each of the active compounds or agents by a pre-determined route selected among the oral route, the nasal route and the pulmonary route.
Thus the medication ensures an oral administration of a composition including one or more active agents, a selective topical administration of a composition including one or more active agents to the nasal cavity, and optionally a selective topical administration of a composition including one or more active agents to the trachea, bronchi and lungs.
The present invention provides one fixed daily dosing of a combination of specific drugs to be taken in sequence by specific delivery route administration within a specific time frame in order to obtain relief from rhinitis symptoms and prevent escalation of the rhinitis and hence significantly reduce the risk of asthma development.
In a preferable embodiment of the invention a rhinitis medication comprises a daily dose of an oral antihistamine combined with a daily dose of a nasal corticosteroid. An oral antihistamine tablet may further include an anti-leukotriene agent. This medication will include relief and control of the symptoms twice or preferably once daily and additional a preventive dose controlling inflammation.
The invention extends the medication to include also a pulmonary dose for patients suffering both from rhinitis and from asthma. Thus a corticosteroid dose to the lungs is provided for reducing and preventing a local inflammatory condition in the lungs. In case of diagnosed moderate to severe asthma the pulmonary medication dose may be extended to include a long-acting 32-agonist for symptom relief. An integrated medication comprising local treatment of the mucosa of the respiratory system and systemic treatment of inflammation is important to acquire an improved control of inflammatory diseases in the respiratory system. To this end the present invention provides a fixed daily combined medication, which is easy to follow by the patients and improves patient compliance.
The medications and medication systems according to the invention preferably depend on a suitable drug delivery system, which facilitates the correct delivery sequence according to the dose-time protocol.
In an embodiment the drug delivery system can be a system for dispensing and delivery of multiple doses, for example comprising the medication for one month. The system may include means for inhalation such as the conventional elements of inhalation devices known and marketed for either nasal or pulmonary delivery.
In general the nasal administration can be carried out in any conventional way using conventional devices for nasal delivery such as liquid spray devices, pressurized me- tered dose inhalers and nasal insufflators. Other means for nasal administration include a simple drop pipette or a rhinyl. Pre-compression metered-dose spray pumps with typical dose volumes from 25 μl to 150 μl can be used, whereby the concentration of corticosteroid in the suspension is adjusted to give the desired unit dose. Also monospray or a bispray pump can be used; for the latter, the recommended unit dose is sequentially delivered into each nostril.
According to an alternative and preferred embodiment the twice or preferably once daily medication is delivered in a unit-dose two or three route format. This further supports the compliance and fulfil the requirement of easy use.
The nasal steroid dose is preferably delivered by a device which prevents any inhala- tion and immediate swallowing of the nasal steroid dose. When using such device the patient exhales through a mouth piece with airflow resistance - forcing the soft pal- ate to close the connecting passage between the nasal cavity and the oral cavity. This closure during the delivery of the nasal steroid dose will prevent any inhalation to the lungs and/or immediate swallowing of the specific nasal steroid dose, hence exclude any pulmonary deposition of the steroid. Such inhaler device to be used only once is described in US 2002 0165482 Al and WO 98/53869 (corresponding to US 6 648 848)
The third active composition to be delivered by the pulmonary route can be administered by any conventional pulmonary inhaler such as dry powder inhalers, pressur- ized metered dose inhalers and nebulisers.
Accordingly the third active composition is conveniently delivered by conventional means, e.g. in the form of a metered dose inhaler prepared in a conventional manner or in combination with a spacer device. In the case of a metered dose inhaler, a me- tering valve is provided to deliver a metered amount of the composition. Spray compositions may for example be formulated as aqueous solutions or suspensions and may be administered by a nebuliser. Aerosol spray formulations, for example in which the active ingredients are suspended, optionally together with one or more stabilisers, in a propellant, e.g. a halogenated hydrocarbon such as trichlorofluoro- methane, dichlorodifluoromethane, 1,2-dichlorotetrafluoroethane, trichlorotrifluoro- ethane, monochloropentafluoroethane, chloroform or methylene chloride, may also be employed.
Alternatively, for pulmonary administration by inhalation or insufflation, the third active composition may take the form of a dry powder composition, for example a powder mix of the active ingredients and a suitable carrier such as lactose. The powder compositions may be presented in unit dosage form in, for example, capsules, cartridges or blister packs from which the powder may be administered with the aid of an inhaler.
A useful inhaler to be used only once is disclosed in US 5 797 392. The multiple route medication may in a preferred embodiment be a unit comprising a preset amount of the first active composition, a preset amount of the second active composition, and optionally a preset amount of the third active composition, wherein the preset amounts are doses to be given once a day. Such a medication unit may be based on a combination of the above inhaler devices to be used once only disclosed in WO 98/53869 and US 5 797 392 respectively together with a pill or tablet for oral administration. A further convenient device combining the nasal inhaler and the pulmonary inhaler is described in applicants simultaneous DK patent application No PA 2003 01547.
The present two or three route medication is usable for a prophylactic and/or therapeutic regular long lasting treatment of rhinitis to avoid or postpone the development of asthma or in case of diagnosed asthma to reduce the risk of asthmatic attacks and postpone the further progress of the disease.
The inventive multiple route medication may be used as a convenient daily treatment depending on the development and severity of the condition to be treated. Thus in case of rhinitis only intermittent asthma the medication can be a two route medica- tion, preferably given once a day within the same short period of time, wherein the first active composition for an administration by the oral route includes an antihistamine selected from the group consisting of loratidine, desloratidine, fexofenadine,HCl, ebastine, mizolastine, mequitazine and ceterizine, and the second active composition for the nasal inhalation route includes a corticosteroid selected from the group consisting of budesonide, fluticasone propionate, beclomethasone, momethasone, flunisolide, triamcinolone acetonide and ciclesonide.
In case of rhinitis together with a mild persistent asthma condition the medication can be a three route medication wherein the first active composition for an admini- stration by the oral route includes an antihistamine selected from the group consisting of loratidine, desloratidine, fexofenadine,HCl, ebastine, mizolastine, mequitazine and ceterizine; the second active composition for the nasal inhalation route includes a corticosteroid selected from the group consisting of budesonide, fluticasone propionate, beclomethasone, momethasone, flunisolide, triamcinolone acetonide and ciclesonide; and the third active composition for the pulmonary inhalation route a corti- costeroid selected from the group consisting of budesonide, fluticasone propionate, beclomethasone, momethasone, flunisolide, triamcinolone acetonide and ciclesonide. Alternatively the above two route medication can be used wherein the oral antihistamine is combined with an anti-leukotriene of the type disclosed below.
In case of a moderate to severe persistent asthma the above medication can be supplemented by the inclusion of a 52-agonist selected from the group consisting of salmeterol and formoterol in combination with the corticosteroid in the third active composition for the pulmonary route.
In case of a mild to moderate asthma it is possible to include an anti-leukotriene selected from the group consisting of montelukast, zafirlukast and pranlukast thogether with the antihistamine in the first active composition for oral administration. By use of this anti-leukotriene the dose of pulmonary corticosteroid can be reduced and in case of mild persistent asthma even omitted.
Thus the medication for moderate persistent asthma may include an antihistamine and an anti-leukotriene for the oral route, a corticosteroid for the nasal route and a low dose corticosteroid and a /32-agonist for the pulmonary route, Whereas the medication for mild asthma may include an antihistamine and an anti-leukotriene for the oral route and a corticosteroid for the nasal route.
The above mentioned active compounds or agents may be the actual mentioned compounds or active derivatives thereof. Thus as examples the mometasone is suitable used as mometasone furoate, beclomethasone may be used as beclomethasone dipropionate and formoterol may be used as formoterol fumarate. Generally use can be made of any derivative including but not limited to pharmaceutically acceptable esters, solvates or salts with an acid or base provided such derivatives have the desired activity combined with acceptable low side effects if any.
In the present specification and claims the proposed doses of each type of the active compounds, such as the antihistamines, are for practical reasons referred to as the particular doses of a number of alternative compounds. This refers to a usual embodiment wherein only one antihistamine, such as loratidine, is used as the antihistamine by the inventive medication. However, the inventive medication is also intended to cover the use of two or more antihistamines together, in which case the doses of each single compound should be adjusted to give an activity corresponding to the activity obtained by a single antihistamine. Such adjusting is an obvious routine for the skilled person. The same apply to the other types of active compounds including the corticosteroids, the anti-leukotrienes and the 32-agonists.
The multiple route medication according to the invention is further illustrated by the following examples wherein the proposed doses for the relevant active compounds are stated. These doses are the daily dose to an adult patient. The daily doses can be given once a day or divided in two doses for a twice a day protocol, but preferably a once a day protocol is used. As it is well known in the art the precise dose will of course depend on the age, weight and condition of the patient and thus in case of children, such as children up to 12 years, the doses may be in the lower end of the stated scope or in some cases even below the lower limit. In practice the clinician will determine the suitable dose and composition of each of the first, second and third compositions of the inventive medication considering the age and weight of the patient and the severity of the condition starting in the low end and stepwise increasing the doses if necessary.
Example 1
This is an example of the inventive medication in the form of a two route medication usable for a first step condition of the disease with rhinitis and only intermittent asthma. Such condition can be treated by a two route medication using the oral and the nasal route. Thus the medication comprises an oral antihistamine and a nasal corticosteroid as further described below.
An oral medication is given as the first active composition, which includes an anti- histamine given once a day. Examples are:
Loratidine: 3 - 30 mg/day, preferably 5 - 20 mg/day, such as 10 mg/day.
Desloratidine: 1 - 20 mg/day, preferably 2 - 10 mg/day, such as 5 mg/day. Fexofenadine, HC1: 50 - 400 mg/day, preferably 100 - 200 mg/day, more preferred 110 - 190 mg/day.
Ceterizine: 2 - 20 mg/day, preferably 5 - 15 mg/day, more preferred 9 - 11 mg/day.
Ebastine: 3 - 30 mg/day, preferably 5 - 20 mg/day, such as 10 mg/day. Mizolastine: 3 - 30 mg/day, preferably 5 - 20 mg/day, such as 10 mg/day.
Mequitazine: 3 - 30 mg/day, preferably 5 - 20 mg/day, such as 10 mg/day.
Together with the oral dose the second composition is given by the nasal route. For practical reasons this is done within the same short period of time. This second composition for nasal inhalation is preferably dosed with a half dose in each of the nostrils. The doses of the corticosteroids given below are the total doses for both nostrils. Examples of nasal corticosteroids included in the second composition and the total doses to be given once a day for rhinitis medication are:
Budesonide: 20 - 800 μg/day, preferably 30 - 700 μg/day, more preferred 50 - 400 μg/day. Fluticasone propionate: 30 - 600 μg/day, preferably 40 - 400 μg/day, more preferred 50 - 300 μg/day. Beclomethasone: 50 - 600 μg/day, preferably 60 - 300 μg/day, more preferred 70 - 350 μg/day. Momethasone: 50 - 600 μg/day, preferably 60 - 500 μg/day, more preferred 80 - 300 μg/day.
Triamcinolone acetonide: 50 — 600 μg/day, preferably 70 - 500 μg/day, more preferred 90 - 300 μg/day. Ciclesonide: 50 - 600 μg/day, preferably 70 - 500 μg/day, more preferred 90 - 300 μg/day.
Flunisolide: 20 - 800 μg/day, preferably 30 - 700 μg/day, more preferred 50 - 400 μg/day.
Example 2
This is an example of the inventive medication in the form of a three route medication usable for a second step condition of the disease with rhinitis and mild persistent asthma. Such condition can be treated by a three route medication using the oral route, the nasal route and the pulmonary route. Thus the medication comprises an oral antihistamine, a nasal corticosteroid and a pulmonary corticosteroid as further described below.
Together with the medication through the oral and the nasal routes similar to that disclosed in example 1 a further dose is given by the pulmonary route. For practical rea- sons this is also given within the same short period of time. The third active composition can include a pulmonary corticosteroid given preferably once a day in following doses:
Budesonide: 50 - 2100 μg/day, preferably 80 - 1900 μg/day, more preferred 100 - 1600 μg/day. Fluticasone propionate: 30 - 1800 μg/day, preferably 40 - 1400 μg/day, more preferred 50 - 1000 μg/day. Beclomethasone: 50 - 2100 μg/day, preferably 80 - 1900 μg/day, more preferred 100 - 1600 μg/day. Momethasone: 50 - 2100 μg/day, preferably 80 - 1900 μg/day, more pre- ferred 100 - 1600 μg/day. Triamcinolone acetonide: 50 - 2100 μg/day, preferably 80 - 1900 μg/day, more preferred 100 - 1600 μg/day.
Ciclesonide: 50 - 2100 μg/day, preferably 80 - 1900 μg/day, more preferred 100 - 1600 μg/day. Flunisolide: 50 - 3000 μg/day, preferably 100 - 2500 μg/day, more preferred 150 - 2000 μg/day.
Example 3
This is an alternative example of the inventive medication in the form of a two route medication usable for a second step condition of the disease with rhinitis and mild persistent asthma. This medication comprises an oral combination of antihistamine and anti-leukotriene and a nasal corticosteroid as further described below.
By this treatment the second composition given by the nasal route is similar to that given according to example 1, whereas the first composition to be given orally is a combination of an antihistamine in a daily dose similar to that in example 1 together with an anti-leukotriene. Examples of anti-leukotrienes and usable daily doses thereof are:
3 - 30 mg/day, preferably 5 - 20 mg/day, such as 10 mg/day of montelukast; 6 - 60 mg/day, preferably 10 - 50 mg/day, such as 40 mg/day of zafirlukast; or
150 - 1400 mg/day, preferably 300 - 800 g/day, such as 450 mg/day of pranlukast.
Example 4
This is an example of the inventive medication in the form of a three route medica- tion usable for a third step condition of the disease with rhinitis and moderate persistent asthma. Such condition can be treated by a three route medication using the oral route, the nasal route and the pulmonary route. Thus the medication comprises an oral antihistamine, a nasal corticosteroid and a pulmonary combination of corticosteroid and /?2-agonist as further described below. The medication in this situation is similar to that disclosed in example 2 using a similar dose of an antihistamine given orally, a similar dose of a corticosteroid given nasally as well as a dose similar to that in example 2 of a pulmonary administered corticosteroid. However, the third active composition includes further to the corticoster- oid as disclosed in example 2 a long-acting /32-agonist. Examples of such combined third active compositions for the pulmonary route are:
Example 4a Fluticasone propionate 50 - 1000 μg/day Salmeterol 25 - 200 μg/day
Example 4b Budesonide 100 - 1600 μg/day Formoterol 3 - 40 μg/day
Example 4c Mometasone 100 - 1600 μg/day Formoterol 3 - 40 μg/day
Example 5 This is an alternative example of the inventive medication in the form of a tliree route medication usable for a third step condition of the disease with rhinitis and moderate persistent asthma. Such condition can be treated by a three route medication using the oral route, the nasal route and the pulmonary route. Thus the medication comprises an oral combination of antihistamine and anti-leukotriene, a nasal cor- ticosteroid and a pulmonary combination of corticosteroid and 32-agonist as fiurther described below.
By this treatment the first composition to be given orally is a combination of an antihistamine in a daily dose similar to that in example 1 together with an anti- leukotriene. Examples of anti-leukotrienes and usable daily doses thereof are: 3 - 30 mg/day, preferably 5 - 20 mg/day, such as 10 mg/day of montelukast; 6 - 60 mg/day, preferably 10 - 50 mg/day, such as 40 mg/day of zafirlukast; or 150 - 1400 mg/day, preferably 300 - 800 g/day, such as 450 mg/day of pranlukast. According to a preferred embodiment the first active oral composition may include 3
- 30 mg/day, preferably 5 - 20 mg/day, such as 10 mg/day of an antihistamine and 3
- 60 mg/day, preferably 5 - 40 mg/day, more preferred 10 - 20 mg/day of an antileukotriene. An example is
Loratidine 10 mg/day
Montelukast 10 mg/day.
The second composition given by the nasal route is similar to that given according to example 1.
The third composition given by the pulmonary route is a combination of a corticosteroid and a long-acting /32-agonist. The dose of the long-acting ^-agonist may be similar to that used in example 4, but the dose of the corticosteroid can be reduced due to the additional anti-leukotriene in the first oral composition.
Accordingly the dose of pulmonary corticosteroid is typically:
Budesonide: 25 - 1000 μg/day, preferably 40 - 1000 μg/day, more preferred 50 - 800 μg/day. Fluticasone propionate: 15 - 900 μg/day, preferably 20 - 700 μg/day, more preferred 25 - 500 μg/day.
Beclomethasone: 25 - 1000 μg/day, preferably 40 - 900 μg/day, more preferred 50 - 800 μg/day.
Momethasone: 25 - 1000 μg/day, preferably 40 - 900 μg/day, more pre- ferred 50 - 800 μg/day.
Triamcinolone acetonide: 25 - 1000 μg/day, preferably 40 - 900 μg/day, more preferred 50 - 800 μg/day.
Ciclesonide: 25 - 1000 μg/day, preferably 40 - 900 μg/day, more preferred 50 - 800 μg/day. Flunisolide: 25 - 1500 μg/day, preferably 50 - 1200 μg/day, more preferred 75 - 1000 μg/day. Examples of such combined third active compositions for the pulmonary route are:
Example 5a Fluticasone propionate 25 - 500 μg/day Salmeterol 25 - 200 μg/day
Example 5b Budesonide 50 - 800 μg/day Formoterol 3 - 40 μg/day
Example 5 c Mometasone 50 - 800 μg/day Formoterol 3 - 40 μg/day
Example 6
In case of the fourth step condition of the disease involving rhinitis and a severe persistent asthma the oral anti-leukotriene is not usable. In this case a three route medi- cation is used with an oral antihistamine, a nasal corticosteroid and a pulmonary combination of corticosteroid and a long-acting ?2-agonist. Thus this medication is very similar to that in example 4, but where necessary doses will be in the upper range, especially the dose of pulmonary corticosteroid.
The combined two or three route medication prescribes preset doses of each of the three active compositions to be given once a day. Of course it is not necessary for the effect of the medication that all three compositions are given within the same short period of time. However, the use of all three compositions once a day at the same time each day will be more easy for the patient compliance and to ensure that the pa- tient really follows the prescribed medication protocol, which is very important if the development of a more severe condition is to be prevented or postponed.
If appropriate and in case of special circumstances the first, second and/or third active composition including the doses stated in the above examples may alternatively be given in divided doses according to a twice a day protocol, provided the protocol will be followed correctly. However, due to the easier patient compliance and safer fulfilment of the medication protocol the once a day protocol is preferred in the most cases.
The above description of the invention reveals that it is obvious that it can be varied in many ways. Such variations are not to be considered a deviation from the scope of the invention, and all such modifications which are obvious to persons skilled in the art are also to be considered comprised by the scope of the succeeding claims.

Claims

Claims
1. A multiple route medication for the prophylactic and/or therapeutic treatment of conditions in the respiratory system including rhinitis and asthma, characterised in, that the medication comprises - a first active composition in a form suitable for an administration by the oral route, which first active composition includes an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine, - a second active composition in a form suitable for the nasal inhalation route, which second active composition includes a corticosteroid in a daily dose of
20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide, - and optionally a third active composition in a form suitable for the pulmo- nary inhalation route.
2. A medication as claimed in claim 1, characterised in, that the medication is a two route medication wherein - the first active composition in a form suitable for an administration by the oral route includes an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine, and - the second active composition in a form suitable for the nasal inhalation route includes a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide.
3. A medication as claimed in claim 1, characterised in, that the medication is a three route medication wherein - the first active composition in a form suitable for an administration by the oral route includes an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine; - the second active composition in a form suitable for the nasal inhalation route includes a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide; and - the third active composition in a form suitable for the pulmonary inhalation route includes a corticosteroid in a daily dose of 50 - 2100 μg budesonide, 30 - 1800 μg fluticasone propionate, 50 - 2100 μg beclomethasone, 50 -2100 μg momethasone, 50 - 3000 μg flunisolide, 50 -2100 μg triamcinolone acetonide or 50 -2100 μg ciclesonide.
4. A tliree route medication as claimed in claim 3, characterised in, that the third active composition for the pulmonary route is a combination of a corticosteroid in a daily dose of 50 - 2100 μg budesonide, 30 - 1800 μg fluticasone propionate, 50 - 2100 μg beclomethasone, 50 -2100 μg momethasone, 50 - 3000 μg flunisolide, 50 - 2100 μg triamcinolone acetonide or 50 -2100 μg ciclesonide, and a /32-agonist in a daily dose of 25 - 200 μg salmeterol or 3 - 40 μg formoterol.
5. A medication as claimed in any one of the preceding claims, characterised in, that the first active composition for the oral route is a combination of an antihis- tamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine and an anti-leukotriene in a daily dose of 3 - 30 mg mon- telukast, 6 - 60 mg zafϊrlukast or 125 - 1400 mg pranlukast;
6. A three route medication as claimed in claim 1, characterised in, that - the first composition for the oral route is a combination of an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine and an anti-leukotriene in a daily dose of 3 - 30 mg mon- telukast, 6 - 60 mg zafϊrlukast or 125 - 1400 mg pranlukast; - the second composition for the nasal route is a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide; and - the third composition for the pulmonary route is a combination of a corticosteroid in a daily dose of 25 - 1000 μg/day budesonide, 15 - 900 μg/day fluticasone propionate, 25 - 1000 μg/day beclomethasone, 25 - 1000 μg/day momethasone, 25 - 1500 μg flunisolide, 25 - 1000 μg/day triamcinolone acetonide, 25 - 1000 μg/day ciclesonide, and a /32-agonist in a daily dose of 25 - 200 μg salmeterol or 3 - 40 μg formoterol.
7. A multiple route medication according to any one of the preceding claims, characterised in, that the medication is a unit comprising a preset amount of the first active composition, a preset amount of the second active composition, and op- tionally a preset amount of the third active composition, wherein the preset amounts are doses to be given once or twice a day.
8. A multiple route medication according to any one of the preceding claims, characterised in, that the medication is a unit comprising a preset amount of the first active composition, a preset amount of the second active composition, and optionally a preset amount of the third active composition, wherein the preset amounts are doses to be given once a day.
9. A package containing one or more of the units according to claim 7.
10. The use of - a first active composition in a form suitable for an administration of an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine, by the oral route; - a second active composition in a form suitable for an administration of a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 50 - 600 μg 20 - 800 μg flunisolide, triamcinolone acetonide or 50 - 600 μg ciclesonide for the nasal inhalation route and - optionally a third active composition in a form suitable for the pulmonary inhalation route for the preparation of a multiple route medication for the prophylactic and/or therapeutic treatment of conditions in the respiratory system including rhinitis and asthma.
11. The use according to claim 10 of - a first active composition in a form suitable for an administration of an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequi- tazine or 2 - 20 mg ceterizine, by the oral route; and - a second active composition in a form suitable for an administration of a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide for the nasal inhalation route for the preparation of a two route medication for the treatment of a condition of rhinitis and intermittent asthma.
12. The use according to claim 10 of - a first active composition in a form suitable for an administration by the oral route including an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine; - a second active composition in a form suitable for the nasal inhalation route including a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide; and - a third active composition in a form suitable for the pulmonary inhalation route including a corticosteroid in a daily dose of 50 - 2100 μg budesonide, 30 - 1800 μg fluticasone propionate, 50 - 2100 μg beclomethasone, 50 -2100 μg momethasone, 50 - 3000 μg flunisolide, 50 -2100 μg triamcinolone acetonide or 50 -2100 μg ciclesonide for the preparation of a three route medication for the treatment of a condition of rhinitis and mild persistent asthma.
13. The use according to claim 10 of - a first active composition in a form suitable for an administration by the oral route including a combination of an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebas- tine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine and an anti-leukotriene in a daily dose of 3 - 30 mg montelukast, 6 - 60 mg zafirlukast or 125 - 1400 mg pranlukast; and - a second active composition in a form suitable for the nasal inhalation route including a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 — 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide; for the preparation of a two route medication for the treatment of a condition of rhinitis and mild persistent asthma.
14. The use according to claim 10 of - a first active composition in a form suitable for an administration by the oral route including an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine; - a second active composition in a form suitable for the nasal inhalation route including a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide; and - a third active composition in a form suitable for the pulmonary inhalation route including a combination of a corticosteroid in a daily dose of 50 - 2100 μg budesonide, 30 - 1800 μg fluticasone propionate, 50 - 2100 μg beclomethasone, 50 - 2100 μg momethasone, 50 - 3000 μg flunisolide, 50 -2100 μg triamcinolone acetonide or 50 -2100 μg ciclesonide and a /52-agonist in a daily dose of 25 - 200 μg sal- meterol or 3 - 40 μg formoterol, for the preparation of a three route medication for the treatment of a condition of rhinitis and moderate to severe persistent asthma.
15. The use according to claim 10 of - a first active composition in a form suitable for an administration by the oral route including a combination of an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine and an anti-leukotriene in a daily dose of 3 - 30 mg montelukast, 6 - 60 mg zafirlukast or 125 - 1400 mg pranlukast; - a second active composition in a form suitable for the nasal inhalation route including a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg cicle- sonide; and - a third active composition in a form suitable for the pulmonary inhalation route including a combination of a corticosteroid in a daily dose of 25 - 1000 μg/day budesonide, 15 - 900 μg/day fluticasone propionate, 25 - 1000 μg/day beclomethasone, 25 - 1000 μg/day momethasone, 25 - 1500 μg flunisolide, 25 - 1000 μg/day triamcinolone acetonide, 25 - 1000 μg/day ciclesonide, and a /32-agonist in a daily dose of 25 - 200 μg salmeterol or 3 - 40 μg formoterol, for the preparation of a three route medication for the treatment of a condition of rhinitis and moderate persistent asthma.
16. A method of prophylactic and/or therapeutic treatment of rhinitis and asthma of an individual having such condition to be treated or having an increased risk of developing such condition wherein - a preset amount of a first active composition including an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine is given to the individual by oral administration; - a preset amount of a second active composition including a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide is given to the individual by nasal inhalation and - optionally a preset amount of a third active composition is given to the individual by pulmonary inhalation.
17. A method according to claim 16, for the treatment of an individual having a condition of rhinitis and intermittent asthma wherein - a preset amount of a first active composition including an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitaz- ine or 2 - 20 mg ceterizine is given to the individual by oral administration; and - a preset amount of a second active composition including a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide is given to the individual by nasal inhalation.
18. A method according to claim 16, for the treatment of an individual having a condition of rhinitis and mild persistent asthma wherein - a preset amount of a first active composition including an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine is given to the individual by oral administration; - a preset amount of a second active composition including a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide is given to the individual by nasal inhalation; and - a preset amount of a third active composition including a corticosteroid in a daily dose of 50 - 2100 μg budesonide, 30 - 1800 μg fluticasone propionate, 50 - 2100 μg beclomethasone, 50 -2100 μg momethasone, 50 - 3000 μg flunisolide, 50 - 2100 μg triamcinolone acetonide or 50 -2100 μg ciclesonide is given to the individual by pulmonary inhalation.
19. A method according to claim 16, for the treatment of an individual having a condition of rhinitis and mild persistent asthma wherein - a preset amount of a first active composition including a combination of a preset amount of an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine, and a preset amount of an anti-leukotriene in a daily dose of 3 - 30 mg montelukast, 6 - 60 mg zafirlukast or 125 - 1400 mg pranlukast is given to the individual by oral administration; and - a preset amount of a second active composition including a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide is given to the individual by nasal inhalation.
20. A method according to claim 16, for the treatment of an individual having a condition of rhinitis and moderate to severe persistent asthma wherein - a preset amount of a first active composition including an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine is given to the individual by oral administration; - a preset amount of a second active composition including a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide is given to the individual by nasal inhalation; and - a preset amount of a third active composition including a combination of a preset amount of a corticosteroid in a daily dose of 50 - 2100 μg budesonide, 30 - 1800 μg fluticasone propionate, 50 - 2100 μg beclomethasone, 50 -2100 μg momethasone, 50 - 3000 μg flunisolide, 50 -2100 μg triamcinolone acetonide or 50 - 2100 μg ciclesonide and a preset amount of a /32-agonist in a daily dose of 25 - 200 μg salmeterol or 3 - 40 μg formoterol is given to the individual by pulmonary inhalation.
21. A method according to claim 16, for the treatment of an individual having a condition of rhinitis and moderate persistent asthma wherein - a preset amount of a first active composition including a combination of a preset amount of an antihistamine in a daily dose of 3 - 30 mg loratidine, 1 - 20 mg desloratidine, 50 - 400 mg fexofenadine,HCl, 3 - 30 mg ebastine, 3 - 30 mg mizolastine, 3 - 30 mg mequitazine or 2 - 20 mg ceterizine and a preset amount of an anti-leukotriene in a daily dose of 3 - 30 mg montelukast, 6 - 60 mg zafirlukast or 125 - 1400 mg pranlukast is given to the individual by oral administration; - a preset amount of a second active composition including a corticosteroid in a daily dose of 20 - 800 μg budesonide, 30 - 600 μg fluticasone propionate, 50 - 600 μg beclomethasone, 50 - 600 μg momethasone, 20 - 800 μg flunisolide, 50 - 600 μg triamcinolone acetonide or 50 - 600 μg ciclesonide is given to the individual by nasal inhalation; and - a preset amount of a third active composition including a combination of a preset amount of a corticosteroid in a daily dose of 25 - 1000 μg/day budesonide, 15 - 900 μg/day fluticasone propionate, 25 - 1000 μg/day beclomethasone, 25 - 1000 μg/day momethasone, 25 - 1500 μg flunisolide, 25 - 1000 μg/day triamcinolone acetonide, 25 - 1000 μg/day ciclesonide, and a preset amount of a /32-agonist in a daily dose of 25 - 200 μg salmeterol or 3 - 40 μg formoterol is given to the individual by pulmonary inhalation.
22. A method according to any one of the claims 16 - 21, wherein the daily dose of said first, second and optional third active compositions each are given in a preset amount once or twice a day.
23. A method according to claim 22, wherein the daily dose of said first, second and optional third active compositions each are given in a preset amount once a day.
24. A kit for prophylactic and/or therapeutic treatment of rhinitis and asthma of an individual having such condition to be treated or having an increased risk of de- veloping such condition comprising a) an oral preparation containing preset amount of a first active composition including an antihistamine, an antileukotriene or a combination thereof in the form of a dose unit, b) a first inhaler for nasal inhalation of a preset amount of a corticosteroid, c) optionally a second inhaler for pulmonary inhalation of a preset amount of a corticosteroid, a 52-agonist or a combination thereof, together with instructions for the intake of the oral preparation, the nasal inhalation and optionally the pulmonary inhalation in accordance with a pre-selected schedule.
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