Classifications

• • 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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