Title of Invention

COMBINATION OF CICLESONIDE AND ANTIHISTAMINES FOR THE TREATMENT OF ALLERGIC RHINITIS

Abstract

Pharmaceutical composition for the treatment of allergic rhinitis and/or allergic conjunctivitis for application to the mucosa, which is an aqueous composition comprising as the active ingredients a combination of at least one antihistamine, a stereoisomer, a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof and ciclesonide, pharmaceutically acceptable salts of ciclesonide, epimers of ciclesonide optionally in any mixing ratio with ciclesonide, solvates of ciclesonide, physiologically functional derivatives of ciclesonide or solvates thereof and a pharmaceutically acceptable carrier and/or one or more excipients, wherein the composition having an osmotic pressure of less than 290 mOsm.

Full Text

FORM 2 THE PATENT ACT 197 0 (39 of 1970) The Patents Rules, 2003 COMPLETE SPECIFICATION (See Section 10, and rule 13) TITLE OF INVENTION COMBINATION OF CICLESONIDE AND ANTIHISTAMINES FOR THE TREATMENT OF ALLERGIC RHINITIS APPLICANT(S) a) Name b) Nationality c) Address NYCOMED GMBH GERMAN Company BYK-GULDEN-STRASSE 2' D-78467 KONSTANZ, GERMANY PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed : - Technical Field of the Invention The present invention is related to a novel combination of ciclesonide and antihistamines for use in drug therapy in particular in the treatment of allergic rhinitis. In particular the novel combination is adminis¬tered in the form of an aqueous pharmaceutical composition that contains ciclesonide and antihista¬mine and having an osmotic pressure of less than 290 mOsm. Background Art Allergic rhinitis is a common disorder and the number of patients is steadily increasing. The disease is caused by ambient airborne allergens, which cause an allergic inflammation within the nasal mucosa and it is often accompanied by conjunctivitis. According to the allergen, the allergic rhinitis is subdivided into seasonal allergic rhinitis (allergens like grass pollen, cedar pollen) and perennial allergic rhinitis (indoor allergens like mould, allergens from animals and house dust mite). Allergic rhinitis has a great impact on the quality of life. The patients suffer from an itchy and running nose, nasal blockage, head¬ache and fatigue. Allergic conjunctivitis is often linked to allergic rhinitis and requires co-treatment. The major symptoms of conjunctivitis are burning and itching eyes and lacrimation. The basic mechanisms involved in this disease are the same as for allergic rhinitis. The current treatment of allergic rhinitis is mainly focused on symptomatic relief. Oral and to a lesser extent topical antihistamines are the most widely used remedies. Oral antihistamines alleviate the his¬tamine driven symptoms only. Allergen contact causes degranulation of mucosal mast cells and hista¬mine is released. Histamine is responsible for the itching and sneezing and the increase in nasal secre¬tion. Antihistamines block the binding of histamine to the histamine-H1-receptor and thereof the hista¬mine mediated symptoms. Beside this obvious pathway, the allergens cause an eosinophilic inflamma¬tion of the nasal mucosa, which is mainly responsible for symptoms like nasal hyperreactivity, nasal blockage and the fear of the so called change of floors, which means that an untreated allergic rhinitis can develop to sinusitis and asthma bronchiale. Treatment with glucocorticoids is currently the only one therapy, which targets the underlying allergic inflammation. To avoid systemic side effects typically for glucocorticoids, e.g. immunosuppression, reduced protein synthesis, impaired growth in children, topical treatment with glucocorticoids is the pre¬ferred way of administration. A disadvantage of nasal steroids is the slow onset of action and the need for continuous treatment. It takes 4-6 days of continuous treatment before a symptom relief can be observed. Therefore, the pa- tients are recommended to begin to take glucocorticoids before the pollen season starts. The slow on¬set of action, the need of consequent treatment and the fear of steroid induced side effects have a negative impact on the use of intranasal steroids and patient's compliance. Other medications available for the treatment are just for symptomatic relief, for example intranasal muscarinic antagonists (ipratropium to reduce nasal secretion), adrenoreceptor agonists (xylometha-zoline to reduce nasal congestion). WO 97/01337 describes a nasal spray or nasal drops formulation comprising beclomethasone, flunisol-ide, triamcinolone, dexamethasone or budesonide in combination with the antihistamines levocabas-tine, azelastine or azatadine and sterile water, WO 97/46243 is related to a nasal spray containing an intranasal steroid and an antihistamine. WO 98/48839 is related to topically applicable nasal compositions comprising a therapeutically effective amount of an antiinflammatory agent and a therapeutically effective amount of at least one agent se¬lected from the group consisting of a vasoconstrictor, a neuraminidase inhibitor, a leukotriene inhibitor, an antihistamine, an antiallergic agent, an anticholinergic agent, an anesthetic and a mucolytic agent. WO 01/22955 is related to a novel combination of loteprednol, a so-called soft steroid with antihista¬mines. WO 03/049770 discloses compositions and methods for treating rhinitis with H1 antago-nists/antiallergics and safe steroids. US 5164194 is related to nasal formulations for azelastine. Detailed Description of the invention Surprisingly it has now been found that combined administration of ciclesonide and at least one antihis¬tamine results in a very effective and safe treatment of symptoms accompanied with allergic rhinitis and/or allergic conjunctivitis. In particular by combined administration of the ciclesonide and the antihis¬tamine as hypotonic aqueous pharmaceutical formulation a rapid onset of action and quick symptom relief is observed without the fear of glucocorticoid like side effects. By administering such hypotonic aqueous pharmaceutical composition according to the invention to the nasal mucosa the active ingredi¬ents rapidly enter the nasal mucosa and have a very long retention time. Therefore very low doses of ciclesonide and a once-daily, maximal twice-daily treatment is necessary to achieve aneffective treat¬ment. In one aspect the present invention therefore relates to the combined administration of ciclesonide and at least one antihistamine for the treatment of allergic rhinitis and/or allergic conjunctivitis. Another sub¬ject of the invention therefore is a pharmaceutical composition for the treatment of allergic rhinitis and/or allergic conjunctivitis comprising as active ingredients a combination of at least one antihistami¬ne, a pharmaceutically acceptable salt and/or a solvate or physiologically functional derivative thereof and ciclesonide, pharmaceutically acceptable salts of ciclesonide, epimers of ciclesonide in any mixing ratio with ciclesonide, solvates of ciclesonide, physiologically functional derivatives of ciclesonide or solvates thereof and a pharmaceutically acceptable carrier and/or one or more excipients. It will be appreciated that the compounds of the combination may be administered simultaneously, ei¬ther in the same pharmaceutical formulation (hereinafter also referred to as fixed combination) or in different pharmaceutical formulations (hereinafter also referred to as free combination)'or sequentially in any order. If there is sequential administration, the delay in administering the second compound should not be such as to lose the beneficial therapeutic effect of the combination. As an example, both drugs may be provided separately as oral formulations, or one may be an oral preparation and the other an inhalant, or both may be provided in a form suitable for application to mucosa (nasal application). Administration may be at the same time. Or they may be administered either close in time or remotely, such as where one drug is administered in the morning and the second drug is administered in the eve¬ning. Accordingly, the present invention also provides a method for the prophylaxis or treatment of allergic rhinitis and/or allergic conjunctivitis in a mammal, such as a human, which comprises administration of a therapeutically effective amount of a pharmaceutical formulation comprising at least one antihista¬mine or a pharmaceutical acceptable salt, solvate, or physiologically functional derivative thereof and ciclesonide or a pharmaceutical acceptable salt, solvate, or physiologically functional derivative thereof, and a pharmaceutical acceptable carrier and/or one or more excipients. In a preferred aspect, there is provided such a method, which comprises administration of a therapeutically effective amount of a combination comprising at least one antihistamine and ciclesonide, and a pharmaceutical acceptable carrier and/or one or more excipients. The formulations include those suitable for oral, parenteral including subcutaneous, intradermal, intra¬muscular, intravenous and intraarticular, intranasal, inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulisers or insufflators), rectal and topical (including dermal, buccal, sublingual and intraocular administration) although the most suitable route may depend upon for example the condition and disorder of the recipi¬ent. In a preferred embodiment according to the invention the formulation is suitable for topical admini¬stration. In a preferred embodiment the formulation according to the invention is a formulation suitable for application to mucosa in the case of treatment of allergic rhinitis. In the case of treatment of allergic conjunctivitis a preferred formulation is a formulation suitable for conjunctival administration (application to the conjunctival sac). The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredients into association with the carrier, which constitutes one or more accessory ingredienls/excipients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. In a preferred embodiment the present invention relates to an aqueous pharmaceutical composition for the treatment of allergic rhinitis for application to the mucosa, comprising as active ingredients a combi¬nation of at least one antihistamine and ciclesonide. In particular the aqueous pharmaceutical composi¬tion is a sterile aqueous pharmaceutical composition. The present invention further relates to an aqueous pharmaceutical composition for the treatment of allergic rhinitis for application to the mucosa comprising as active ingredients a combination of at least one antihistamine and ciclesonide together with one or more water-insoluble and/or water-low soluble substance and having an osmotic pressure of less than 290 mOsm. Preferably the osmotic pressure is 150 mOsm or lower, more preferably 72 mOsm or lower, more preferably 60 mOsm or lower, more pre¬ferably 40 mOsm or lower, more preferably 30 mOsm or lower and still more preferably 20 mOsm (e.g. 10 mOsm or lower). According to the present invention it is not particularly required to add a substance for controlling osmo¬tic pressure (osmotic pressure-controlling agent) but when it is added any substance can be used. In the present invention, a substance for controlling osmotic pressure (osmotic pressure controlling agent) can be added to control osmotic pressure, specific examples of which include salts such as sodium chloride and water-soluble sugars such as glucose, with glucose being a particularly preferable exam¬ple. In a preferred embodiment the pharmaceutical composition is a pharmaceutical composition as de¬scribed for ciclesonide in WO 01/28562 or WO 01/28563. Thus in one aspect the present invention relates to an aqueous pharmaceutical composition for the treatment of allergic rhinitis for application to the mucosa, comprising as active ingredients a combina¬tion of at least one antihistamine and ciclesonide together with one or more water-insoluble and/or wa¬ter-low soluble substance and having an osmotic pressure of less than 290 mOsm. The water-insoluble or water-low soluble substance may be any substance, and preferred examples include celluloses, more preferably crystalline celluloses and particularly preferred microcrystalline cel¬luloses. According to the present invention, the concentration of water-insoluble and/or water-low solu¬ble substance present in form of solid particles in an aqueous medium is preferably 0.3% w/w and above, and particularly preferably 0.5% w/w to 5% w/w, relative to the total amount of the composition. In addition, an aqueous polymer substance can also be added in the present pharmaceutical composi¬tion. Specific examples of such include propylene glycol alginate, pectin, low methoxyl pectin, gua gum, gum Arabic, carrageenan, methyl cellulose, carboxymethyl cellulose sodium, xanthan gum hydroxypro¬pylmethyl cellulose and hydroxypropyl cellulose, while particularly preferable examples include carbox¬ymethyl cellulose sodium, polyethylene glycol and hydroxypropyl cellulose. Carboxymethyl cellulose so¬dium blended with microcrystalline cellulose, is an example of a combination of these water-soluble substance and water-insoluble substance that can be used in the present invention. Furthermore, in the case of adding these water-soluble polymer substances, the concentration of said substance is pref¬erably 1% w/w to 30 % w/w relative to the water-insoluble substance and/or water-low soluble sub¬stance. In a preferred embodiment of the invention hydroxypropylmethyl cellulose is contained in the pharma¬ceutical compositions according to the invention. The hydroxypropylmethyl cellulose may be any grade, a specific example is hydroxypropylmethyl cellulose 2910. Although said hydroxypropylmethyl cellulose may be present at any concentration, its concentration is preferably from 0.001 % w/w to 30 % w/w, particularly preferably form 0.01 % w/w to 5 % w/w, more particularly preferably from 0.01 % w/w to 1 % w/w, and most preferably from 0.01 % w/w to 0.5 % w/w, relative to the total amount of composition. A surfactant and/or wetting agent, although not essential in the present invention, can be added, spe¬cific examples of which include Polysorbate 80, glycerin monosterarate, polyoxyl stearate, lauro-macrogol, sorbitan oleate and sucrose fatty acid esters. An effective amount of ciclesonide and the topical antihistamine used in the present invention can be determined according to the type and degree of the respective disease, as well as the age and body weight of the patient, and so forth. Preferably the pharmaceutical composition according to the inven¬tion is administered as one to four sprays per nostril once or twice a day. The dose of ciclesonide per actuation is expediently from 10 ug to 400 ug, preferably 20 ug to 200 ug. The dose of the antihistami¬ne per actuation will depend on the type of antihistamine and the route of administration. Expediently the dose is from 10 ug to 500 ug, preferably 25 ug to 250 ug per actuation. In case of azelastin the dose preferably is within the ranges described in US 5164194. Ciclesonide (hereinafter also referred to as active ingredient) is the INN for a compound with the che¬mical name[11β,16ά(R)]-16,17-[(Cyclohexylmethylen)bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxoprop-oxy)pregna-1,4-dien-3,20-dion. Ciclesonide and its preparation are disclosed in DE 4129535. Cicleson¬ide as used herein also includes, pharmaceutically acceptable salts of ciclesonide, epimers of cicleson¬ide (e.g. [11β,16a(S)]-16,17-[(Cyclohexylmethylen)bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)-pregna-1,4-dien-3,20-dion) in any mixing ratio with ciclesonide, solvates of ciclesonide, physiologically functional derivatives of ciclesonide or solvates thereof. By the term "physiologically functional deriva¬tive" is meant a chemical derivative of ciclesonide having the same physiological function as cicleson¬ide, for example, by being convertible in the body thereto or by being an active metabolite of cideson- ide. Physiological functional derivatives of ciclesonide which may be mentioned in connection with the invention are for example the 21-hydroxy derivative of ciclesonide with the chemical name 16ά ,17-(22R,S)-Cyclohexylmethylendioxy-11 β,21 -dihydroxypregna-1,4-dien-3,20-dion, 16ά, 17-(22S)-Cyclo- hexylmethylendioxy-11β,21-dihydroxypregna-1,4-dien-3,20-dion and in particular 16ά ,17-(22R)-Cyclohexylmethylendioxy-11 β,21-dihydroxypregna-1,4-dien-3,20-dion. This compound and its preparation are disclosed in WO 9422899. Preferably ciclesonide is dispersed in the aqueous medium in form of solid particles. The concentration of ciclesonide of the present invention is preferably from 0.01 % w/w to 1 % w/w, and particularly preferably from 0.05 w/w to 0.5 % w/w, relative to the total amount of the composition. Although the ciclesonide particles that can be used in the present invention may be of any size, they are preferably within the range of 10 nm to 100 urn, and particularly preferably within the range of 100 nm to 10 μm. Antihistamines, which may be mentioned in connection with the invention, can be any antihistamine suitable for the treatment of allergic rhinitis and/or allergic conjunctivitis. Examples which may be men¬tioned are (E)-6-[(E)-3-(1-pyrrolidinyl)-1-p-tolylpropenyl]-2-pyridineacrylic acid [INN: ACRIVASTINE], 6,11-Dihydro-11-(1-methyl-4-piperidyliden)-5H-benzo[5,6Jcyclohepta-[1,2-b]pyridin[INN: AZATADINE], 4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-1(2H)phthalazinone [INN: AZELA-STINE], (+)-(S)-4-[4-[1-(4-chlorophenyl)-1-(2-pyridyl)methoxy]piperidin-1-yl]-butanoic acid [INN: BEPO-TASTINE], (plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-acetic acid [INN: CETIRI2INE],(+)-2-{2-[(p-Chlor-alpha-methyl-alphaphenylbenzyl)oxy]ethyl}-1-methylpyrrolidin[INN: CLEMASTINE], 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine [INN: DESLORATADINE], [3-(4-Chlorophenyl)-3-pyridin-2-yl-propyl]-dimethylamine [INN: DEXCHLOR-PHENIRAMINE], 4'-tert-butyl-4-[4-(diphenytmethoxy)piperidino]butyrophenone [INN: EBASTINE], [2-[4-[bis(p-fluorophenyl)methyl]-1-piperazinyt]ethoxy]acetic acid [INN: EFLETIRIZINE], 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-benzimidazole [INN: EMEDASTINE], 3-amino-9,13b-di-hydro-1H-dibenz[c,f]imidazo[1,5-a]azepine[INN: EPINASTINE], (plus/minus)-p-[1-hydroxy-4-[4-(hydro-xydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropic acid [INN: FEXOFENADINE], 3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)-piperidin-1-yl]propionic acid [Research Code: HSR-609], (-)-(3S,4R)-1-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylis'onipecotic acid [INN: LEVOCABASTINE], [2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-piperazinyl]ethoxy]-acetic acid [INN: LEVOCETIRIZINE], ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate[INN:LORATADINE],2-[N-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methyl-amino]pyrimidin-4(3H)-one [INN: MIZOLASTINE], 1-(4-fluorobenzyi)-2-(piperidin-4-ylamino)-1H-benzimidazole [INN: NORASTEMiZOLE], 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine [INN: NORTRIPTYLINE], 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyri-do[1,2-a]pyrimidin-4-one [INN: PEMIROLAST], 8-chloro-11-[1-(5-methylpyridin-3-ylmethyl)piperidin-4-yl- idene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine[INN:RUPATADINE], 1-[2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1H-azepine [INN: SETASTINE], S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yt)-S-methylsulfoximine [INN: SUDEXANOX], 1-(p-tert-butylpheny!)-4-[4'-(alpha-hydro-xydiphenylmethyl)-1'-piperidy1]-butanol [INN: TERFENADINE], N-benzy1-N,N,-dimethyl-N-(2-pyridyl)-ethylenediamine [INN: TRIPELENAMINE] and 1-{4-fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzim-idazole [INN: TECASTEMIZOLE] and mixtures thereof. The antihistamine may also be present in form of a pharmaceutically acceptable salt and/or a solvate. Depending on the chemical structure the antihis¬tamine may exist in different stereoisomeric forms. The term antihistamine includes the pure stereoi¬somers (eg. pure epimer, diastereoisomer or enantiomer) and their mixtures in any mixing ratio, Suit¬able pharmacologically acceptable salts of antihistamines are in particular water-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phos¬phoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydro-xybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methane-sulfonic acid or 1-hydroxy-2-naphthoic acid, the acids being employed in salt preparation - depending on whether it is a mono- or polybasic acid and depending on which salt is desired - in an equimolar quantitative ratio or one differing therefrom. By the term "physiologically functional derivative" is meant a chemical derivative of an antihistamine having the same physiological function as the antihistamine, for example, by being convertible in the body thereto or by being an active metabolite of the antihistamine. In a preferred embodiment the antihistamine is an antihistamine with long acting topical activity. Azatadine, azelastin, levocabastin and pharmaceutically acceptable salts thereof are particularly pre¬ferred. Azatadine is known e.g. from US 3326924. Preferred salts of azatadine include its maleate, sulfate, succinate and acetate salts. Azelastine is known from US 3813384 and from US 5164194. Pre¬ferred are acid addition salts, such as, the hydrohalogen salt and salts with organic acids. Preferred salts include the hydrochloride, hydrobromide, salts with embonic acid, maleic acid, citric acid and tar¬taric acid. Levocabastine is known from US 4369184. Suitable salts include the hydrochloride, hydro-bromide and salts with sulphuric acid, nitric acid, acetic acid and propionic acid. In case of water soluble antihistamines such as azelastin hydrochloride, the antihistamine will be dis¬solved in the pharmaceutical compositions according to the invention. The concentration of the topical antihistamine is preferably from 0.01 % w/w to 0.5 % w/w, and particu¬larly preferably from 0.05 w/w to 0.2 % w/w, relative to the total amount of the composition. Any method for dispersing a water-insoluble substance and/or water-low soluble substance in an aque¬ous medium may be used for the production of the aqueous pharmaceutical composition according to the invention, a specific example of which is a method that uses a homomixer. Known antiseptics, pH controlling agents, preservatives, buffers, colorants, smell corrigents and so forth may be added as necessary to the compositions of the present invention to improve its physical properties, stability, appearance or odor and so forth of the formulation. Examples of antiseptics include benzalkonium chloride, examples of pH controlling agents include hy¬drochloric acid and sodium hydroxide, examples of preservatives include potassium sorbate, examples of buffers include phosphoric acid and its salt, examples of colorants include red dye no. 2, and exam¬ples of smell corrigents include menthol. Due to the unique galenic formulation, ciclesonide rapidly enters the nasal mucosa and has a very long retention time. Therefore, very low doses of ciclesonide and the once daily, maximal twice-daily treat¬ment is necessary to achieve an effective treatment. A low dose of ciclesonide in a hypotonic watery suspension in combination with a topical antihistamine (e.g. azelastine or levocabastine) results in a very effective and safe treatment of all symptoms accompanied with allergic rhinitis. A clear advantage of this combination is the rapid onset of action and quick symptom relief without the fear of glucocorti¬coid like side effects. In another embodiment the present invention relates to a combination of ciclesonide with azelasine and ciclesonide is applied in a pharmaceutical composition as described for ciclesonide in WO 01/28562 or WO 01/28563 and azelastine is applied in a pharmaceutical formulation according to US 5164194. When given to the nasal mucosa the formulation according to the present invention may be filled into plastic squeeze bottles or plastic or glass bottles, which are fitted with a metering atomising pump and a nasal adapter or with a suitable dropper. When given to the eye the formulation according to the pre¬sent invention may be filled into plastic squeeze bottles or plastic or glass bottles, which are fitted with a suitable dropper. Examples Ciclesonide aqueous pharmaceutical compositons containing the components indicated below are pre¬pared by processing with a homomixer. Homomixer processing is performed, e.g., at 6000 rpm for 30 minutes. Example 1: Combination of Ciclesonide and Azelastine Hydrochloride Ciclesonide: 0.05% Azelastine hydrochloride 0.14% Microcrystalline cellulose and carboxymethyl cellulose sodium 1.7% Hydroxypropylmethyl cellulose 2910 0.1 % Each 100 mg spray delivered by a nasal applicator delivers 50 ug of ciclesonide and 140 ug of aze¬lastine hydrochloride. Example 2: Combination of Ciclesonide and Levocabastine Hydrochloride Ciclesonide: 0.05% Levocabastine hydrochloride 0.054% Microcrystalline cellulose and carboxymethyl cellulose sodium 1.7% Hydroxypropylmethyl cellulose 2910 0.1% Each 100 mg spray delivered by a nasal applicator delivers 50 ug of ciclesonide and 54 ug of levoca¬bastine hydrochloride (equivalent to 50 ug levocabastine). WE CLAIM:- 1. Pharmaceutical composition for the treatment of allergic rhinitis and/or allergic conjunctivitis for application to the mucosa, which is an aqueous composition comprising as the active ingredients a combination of at least one antihistamine, a stereoisomer, a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof and ciclesonide, pharmaceutically acceptable salts of ciclesonide, epimers of ciclesonide optionally in any mixing ratio with ciclesonide, solvates of ciclesonide, physiologically functional derivatives of ciclesonide or solvates thereof and a pharmaceutically acceptable carrier and/or one or more excipients, wherein the composition having an osmotic pressure of less than 290 mOsm. 2. The pharmaceutical composition for application to the mucosa according to claim 1, wherein said osmotic pressure is 150 mOsm or less. 3. The pharmaceutical composition for application to the mucosa according to claim 1, wherein said osmotic pressure is 60 mOsm or less. 4. The pharmaceutical composition for application to the mucosa according to claim 1, wherein said osmotic pressure is 40 mOsm or less. 5. The pharmaceutical composition for application to the mucosa according to claim 1, wherein said osmotic pressure is 20 mOsm or less. 6. The pharmaceutical composition for application to the mucosa according to claim 1, further comprising an osmotic pressure-controlling agent. 7. The pharmaceutical composition for application to the mucosa according to claim 1, further comprising a water-insoluble and/or water-low soluble substance, wherein said water-insoluble and/or water-low soluble substance is a cellulose. 8. The pharmaceutical composition for application to the mucosa according to claim 7, wherein said cellulose is microcrystalline cellulose. 9. The pharmaceutical composition for application to the mucosa according to claim 7, wherein said one or more water-insoluble and/ or water-low soluble substance is present as solid particles in an aqueous medium. 10. The pharmaceutical composition for application to the mucosa according to claim 7, further comprising a water-soluble polymer substance. 11. Pharmaceutical composition for application to the mucosa according to claim 10, wherein a combination of said water-insoluble substance and water-soluble polymer is present which is microcrystalline cellulose and carboxymethyl cellulose sodium. 12. The pharmaceutical composition for application to the mucosa according to claim 1, further comprising a surfactant and / or a wetting agent. 13. The pharmaceutical composition for application to the mucosa according to claim 1, wherein said mucosa is nasal mucosa. 14. Pharmaceutical composition according to claims 1 through 13, wherein the antihistamine is selected from the group of (E)-6-[(E)-3-(l-pyrrolidinyl)-l-p- tolylpropenyl]-2-pyridineacrylic acid [INN:ACRrVASTINE],6,ll-Dihydro-ll-(l- merhy 1-4-piperidy liden)-5H-benzo [5,6] cyclohepta- [1,2-b] py ridin [INN: AZATADINE],4-[(4-chlorophenyl)methyl]-2-(hexahydro-l-methyl-lHazepin-4-yl)- 1(2H) phthalazinone [INN:AZELASTINE], (+)-(S)-4-[4-[l-(4-chlorophenyl)-l-(2- pyridyl)methoxy]piperidin-l-yl]-butanoic acid [INN: BEPOTASTINE],(plus/minus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-l- piperazinyl]ethoxy]-acetic acid [INN: CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha- methyl-alpha phenyl benzyl) oxy] ethyl} -1-methylpyrrolidin [INN: CLEMASTINE], 8 -chloro -6, 11 -dihydro -11 -(4-piperidylidene) -5H-benzo[5,6]cyc lohepta-[l,2- b]pyridine[INN: DESLORATADINE], [3-(4-Chlorophenyl) -3- pyridrn-2-yl-propyl]- dimethylamine [INN: DEXCHLORPHENIRAMINE], 4'-tert-butyl-4-[4- (diphenylmethoxy)piperidino]butyrophenone [INN: EBASTINE], [2-[4-[bis(p-fluoro- phenyl)methyl]-l-piperazinyl]ethoxy]acetic acid [INN: EFLETIRIZINE], l-(2-ethoxyethyl)-2-(hexahydro-4-methyl-lH-l,4-diazepin-l-yl)- benzimidazole [INN: EMEDASTINE], 3-amino-9,13b-dihydro-lH- dibenz[c,f]imidazo[l,5-a]azepine [INN: EPINASTINE], (plus/minus)-p-[l-hydroxy- 4-[4-(hydroxydiphenylmethyl)piperidino]-butyl]-alpha-methylhydratropic acid [INN: FEXOFENADINE], 3-[4-(8-fluoro-5,ll-dihydrobenz[b]oxepino[4,3-b]pyridin-ll-ylidene)-piperidrn-l-yl]propionic acid [Research Code: HSR-609], (-)-(3S,4R)-l-[cis-4-cyano-4-(p-fluorophenyl)cyclohexyl)- 3-methyl-4-phenylisonipecotic acid [INN: LEVOCABASTINE], [2-[4-[(R)-p-chloro- alpha-phenylbenzyl)-l-piperazinyl]ethoxy]-acetic acid [INN: LEVOCETIRIZINE], ethyl 4-(8-chloro-5,6-dihydro-ll H-benzo[5,6]cyclohepta[l,2-b]pyridin-ll-ylidene)-l- piperidinecarboxylate [INN: LORATADINE], 2-[N-[l-(4"fluorobenzyl)-lH- benzimidazol-2-yl]-4-piperidmyl]-N-memyl-amino]pyrimidin-4(3H)-one [INN:MIZOLASTINE], l-(4-fluorobenzyl)-2-(piperidin-4-ylamino)-lH- benzimidazole [INN:NORASTEMIZOLE],3-(10,ll-dihydro-5H- dibenzo[a/d]cyclohepten-5-ylidene)-N-methyl-l-propanamine [INN: NORTRIPTYLINE], 9-methyl-3-(l H-tetrazol-5-yl)-4H-pyrido[l,2-a]pyrimidin-4-one [INN: PEMIROLAST), 8-chloro-ll-[l-(5-methylpyridin-3-ylmethyl)piperidin-4- ylidene]-6,ll-dihydro-5H-benzo[5,6]cyclohepta[l,2-b]pyridine[INN: RUPATADINE]. l-[2-[(p-chloro-alpha-methyl-alpha- phenylbenzyl)oxy]ethyl]hexahydro-lH-azepine [INN: SETASTINE], S-(7-carboxy-4- hexyl-9-oxoxanmen-2-yl)-S-memylsulfoximine [INN: SUDEXANOX], l-(p-tert- butylphenyl)-4-[4'-(alpha-hydroxydiphenylmethyl)-l'-piperidyl]-butanol [INN: TERFENADINE], N-benzyl-N,N'-dimethyl-N-(2-pyridyl)-ethylenediamine [INN: TRIPELENAMINE] and l-(4-fluorobenzyl)-2-(piperidin-4-ylamino)- 1 H-benzimidazole [INN; TECASTEMIZOLE] and mixtures, stereoisomers thereof, pharmaceutically acceptable salts and/or solvates thereof, IS.Pharmaceutical composition according to claims 1 through 14, wherein the antihistamine is azelastine, levocabastine, a salt or solvate thereof. Dated this 24th Day of January, 2005 HIRAL CHANDRAKANT JOSHI AGENT FOR NYCOMED GmbH

Documents:

97-mumnp-2005-cancelled pages(26-12-2007).pdf

97-mumnp-2005-claims(granted)-(20-12-2007).doc

97-mumnp-2005-claims(granted)-(20-12-2007).pdf

97-mumnp-2005-correspondence(ipo)-(07-02-2008).pdf

97-mumnp-2005-correspondence1(26-12-2007).pdf

97-mumnp-2005-correspondence2(14-01-2008).pdf

97-mumnp-2005-correspondence3(04-04-2008).pdf

97-mumnp-2005-form 1(11-09-2007).pdf

97-mumnp-2005-form 13(29-08-2007).pdf

97-mumnp-2005-form 18(03-02-2006).pdf

97-mumnp-2005-form 2(granted)-(20-12-2007).doc

97-mumnp-2005-form 2(granted)-(20-12-2007).pdf

97-mumnp-2005-form 3(11-09-2007).pdf

97-mumnp-2005-form-pct-ipea-409(29-12-2006).pdf

97-mumnp-2005-form-pct-isa-210(29-12-2006).pdf