WO2004019955A1

WO2004019955A1 - The use of the combination of ciclesonide and antihistamines for the treatment of allergic rhinitis

Info

Publication number: WO2004019955A1
Application number: PCT/EP2003/009622
Authority: WO
Inventors: Degenhard Marx; Helgert MÜLLER
Original assignee: Altana Pharma Ag
Priority date: 2002-08-30
Filing date: 2003-08-29
Publication date: 2004-03-11
Also published as: KR101067795B1; JP2005539044A; JP2011021043A; EP2295062A1; BRPI0313611B1; CN1674916A; IL166483A0; SI1545548T1; ES2348034T3; EP2295062B1; NO20051521D0; ES2393864T3; CA2495830C; AU2003273396A1; EP1545548B1; ATE472329T1; NO20051521L; DK1545548T3; EP1545548A1; CA2495830A1

Abstract

The present invention relates to a combination of ciclesonide with antihistamines.

Description

THE USE OF THE COMBINATION OF CICLESONIDE AND ANTIHISTAMINES FOR THE TREATMENT OF ALLERGIC RHINITIS

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 administered 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, headache 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 lacπmation 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 Histamme is responsible for the itching and sneezing and the increase in nasal secretion Antihistamines block the binding of histamine to the hιstamιne-H1 -receptor and thereof the histamme mediated symptoms Beside this obvious pathway, the allergens cause an eosinophihc inflammation 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 preferred 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 onset 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 muscaπnic antagonists (ipratropium to reduce nasal secretion), adrenoreceptor agonists (xylometha- zohne to reduce nasal congestion)

WO 97/01337 describes a nasal spray or nasal drops formulation comprising beciomethasone, flunisol- ide, tπamcinolone, dexamethasone or budesonide in combination with the antihistamines levocabas- tine, azelastine or azatadme 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 antnnflammatory agent and a therapeutically effective amount of at least one agent selected from the group consisting of a vasoconstrictor, a neuraminidase inhibitor, a leukotπene inhibitor, an antihistamine, an antiallergic agent, an anticho nergic agent, an anesthetic and a mucolytic agent

WO 01/22955 is related to a novel combination of loteprednol, a so-called soft steroid with antihistamines

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 antihistamine 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 antihistamine 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 ingredients 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 an effective treatment 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 subject 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 antihistamine, 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, either 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¬

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 antihistamine 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, intramuscular, intravenous and intraaarticular, intranasal, inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebu sers or insufflators), rectal and topical (including dermal, buccal, subhngual and intraocular administration) although the most suitable route may depend upon for example the condition and disorder of the recipient In a preferred embodiment according to the invention the formulation is suitable for topical administration 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 ingredients/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 combination of at least one antihistamine and ciclesonide In particular the aqueous pharmaceutical composition 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 preferably 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 osmotic 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 example

In a preferred embodiment the pharmaceutical composition is a pharmaceutical composition as described 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 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

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 celluloses According to the present invention, the concentration of water-insoluble and/or water-low soluble 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 composition Specific examples of such include propylene glycol algmate, pectin, low methoxyl pectin, gua gum, gum Arabic, carrageenan, methyl cellulose, carboxymethyl cellulose sodium, xanthan gum hydroxypropylmethyl cellulose and hydroxypropyl cellulose, while particularly preferable examples include carboxymethyl cellulose sodium, polyethylene glycol and hydroxypropyl cellulose Carboxymethyl cellulose sodium blended with microcrystalhne 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 preferably 1% w/w to 30 % w/w relative to the water-insoluble substance and/or water-low soluble substance

In a preferred embodiment of the invention hydroxypropylmethyl cellulose is contained in the pharmaceutical 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, specific 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 invention is administered as one to four sprays per nostril once or twice a day The dose of ciclesonide per actuation is expediently from 10 μg to 400 μg, preferably 20 μg to 200 μg The dose of the antihistamine per actuation will depend on the type of antihistamine and the route of administration Expediently the dose is from 10 μg to 500 μg, preferably 25 μg to 250 μg 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 chemical name t11 β,16α(R)]-16,17-[(Cyclohexylmethylen)bιs(oxy)]-11-hydroxy-21-(2-methyl-1 -oxoprop- oxy)pregna-1 ,4-dιen-3,20-dιon Ciclesonide and its preparation are disclosed in DE 4129535 Ciclesonide as used herein also includes, pharmaceutically acceptable salts of ciclesonide, epimers of ciclesonide (e g [11 β, 16α(S)]-16,17-[(Cyclohexylmethylen)bιs(oxy)]-11 -hydroxy-21 -(2-methyl-1 -oxopropoxy)- pregna-1 ,4-dιen-3,20-dιon) in any mixing ratio with ciclesonide, solvates of ciclesonide, physiologically functional derivatives of ciclesonide or solvates thereof By the term "physiologically functional derivative" is meant a chemical derivative of ciclesonide having the same physiological function as ciclesonide, for example, by being convertible in the body thereto or by being an active metabolite of cicleson- 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 16α ,17-(22R,S)-Cyclohexylmethylendιoxy-11 β,21-dιhydroxypregna-1 ,4-dιen-3,20-dιon, 16α,17-(22S)-Cyclo- hexylmethylendιoxy-11 β,21-dιhydroxypregna-1 ,4-dιen-3,20-dιon and in particular 16α ,17-(22R)-Cyclohexylmethylendιoxy-11 β,21-dιhydroxypregna-1 ,4-dιen-3,20-dιon 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 μm, 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 mentioned are (E)-6-[(E)-3-(1-pyrrolιdιnyl)-1-p-tolylpropenyl]-2-pyrιdιneacrylιc acid [INN ACRIVASTINE], 6,11-Dιhydro-11-(1-methyl-4-pιperιdylιden)-5H-benzo[5,6]cyclohepta-[1 ,2-b]pyπdιn [INN AZATADINE], 4-[(4-chlorophenyl)methyl]-2-(hexahydro-1 -methyl-1 H-azepιn-4-yl)-1 (2H)phthalazιnone [INN AZELASTINE], (+)-(S)-4-[4-[1-(4-chlorophenyl)-1 -(2-pyπdyl)methoxy]pιperιdιn-1-yl]-butanoιc acid [INN BEPO- TASTINE], (plus/mιnus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-pιperazιnyl]ethoxy]-acetιc acid [INN CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alpha phenylbenzyl)oxy]ethyl}-1-methylpyrrolιdιn [INN CLEMASTINE], 8-chloro-6,11-dιhydro-11 -(4-pιpeπdylιdene)-5H-benzo[5,6]cyclohepta-[1 ,2-b]pyrιdιne [INN DESLORATADINE], [3-(4-Chlorophenyl)-3-ρyπdιn-2-yl-propyl]-dιmethylamιne [INN DEXCHLOR- PHENIRAMINE], 4'-tert-butyl-4-[4-(dιphenylmethoxy)pιperιdιno]butyrophenone [INN EBASTINE], [2-[4- [bιs(p-fluorophenyl)methyl]-1-pιperazιnyl]ethoxy]acetιc acid [INN EFLETIRIZINE], 1-(2-ethoxyethyl)-2- (hexahydro-4-methyl-1 H-1 ,4-dιazepιn-1 -yl)-benzιmιdazole [INN EMEDASTINE], 3-amιno-9,13b-dι- hydro-1 H-dιbenz[c,f]ιmιdazo[1 ,5-a]azepιne [INN EPINASTINE], (plus/mιnus)-p-[1 -hydroxy-4-[4-(hydro- xydιphenylmethyl)pιperιdιno]-butyl]-alpha-methylhydratropιc acid [INN FEXOFENADINE], 3-[4-(8-fluoro- 5,11 -dιhydrobenz[b]oxepιno[4,3-b]pyπdιn-11-ylιdene)-pιpeπdιn-1-yl]propιonιc acid [Research Code HSR-609], (-)-(3S,4R)-1-[cιs-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylιsonιpecotιc acid [INN LEVOCABASTINE], [2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1-pιperazιnyl]ethoxy]-acetιc acid [INN LEVOCETIRIZINE], ethyl 4-(8-chloro-5,6-dιhydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyπdιn-11- ylιdene)-1-pιperιdιnecarboxylate [INN LORATADINE], 2-[N-[1-(4-fluorobenzyl)-1 H-benzιmιdazol-2-yl]-4- pιperιdιnyl]-N-methyl-amιno]pyπmιdιn-4(3H)-one [INN IZOLASTINE], 1-(4-fluorobenzyl)-2-(pιperιdιn- 4-ylamιno)-1 H-benzιmιdazole [INN NORASTEMIZOLE], 3-(10,11-dιhydro-5H-dιbenzo[a,d]cyclohepten- 5-ylιdene)-N-methyl-1-propanamιne [INN NORTRIPTYLINE], 9-methyl-3-(1 H-tetrazol-5-yl)-4H-pyrι- do[1 ,2-a]pyrιmιdιn-4-one [INN PEMIRO AST], 8-chloro-11-[1-(5-methylpyrιdιn-3-ylmethyl)pιperιdιn-4-yl- ιdene]-6,11 -dιhydro-5H-benzo[5,6]cyclohepta[1 ,2-b]pyrιdιne [INN RUPATADINE], 1-[2-[(p-chloro-alpha- methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1 H-azepιne [INN SETASTINE], S-(7-carboxy-4-hexyl- 9-oxoxanthen-2-yl)-S-methylsulfoxιmιne [INN SUDEXANOX], 1 -(p-tert-butylphenyl)-4-[4'-(alpha-hydro- xydιphenylmethyl)-1'-pιperιdyl]-butanol [INN TERFENADINE], N-benzyl-N,N'-dιmethyl-N-(2-pyrιdyl)- ethylenediamine [INN TRIPELENAMINE] and 1-(4-fluorobenzyl)-2-(pιperιdιn-4-ylamιno)-1 H-benzιm- 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 antihistamine may exist in different stereoisomeπc forms The term antihistamine includes the pure stereoi- somers (eg pure epimer, diastereoisomer or enantiomer) and their mixtures in any mixing ratio Suitable 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, phosphoric acid, nitric acid, sulfuπc acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydro- xybenzoyl)-benzoιc acid, butyric acid, sulfosalicy c acid, maleic acid, lauric acid, malic acid, fumaπc acid, succinic acid, oxalic acid, tartanc acid, embonic acid, steaπc acid, toluenesulfonic acid, methane- sulfonic acid or 1-hydroxy-2-naphthoιc 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 preferred 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 Preferred are acid addition salts, such as, the hydrohalogen salt and salts with organic acids Preferred salts include the hydrochloπde, hydrobromide, salts with embonic acid, maleic acid, citric acid and tartanc acid Levocabastine is known from US 4369184 Suitable salts include the hydrochloπde, hydro- bromide and salts with sulphuric acid, nitric acid, acetic acid and propionic acid

In case of water soluble antihistamines such as azelastin hydrochloπde, the antihistamine will be dissolved 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 particularly 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 aqueous 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 corπgents 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 benzalkomum chloride, examples of pH controlling agents include hydrochloric 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 examples of smell comgents 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 treatment 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 levocabastme) 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 present 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 prepared 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 μg of ciclesonide and 140 μg of azelastine 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 μg of ciclesonide and 54 μg of levocabastine hydrochloride (equivalent to 50 μg levocabastine)

Claims

Patent Claims

1 Pharmaceutical composition for the treatment of allergic rhinitis and/or allergic conjunctivitis comprising as 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

2 Pharmaceutical composition according to claim 1 for the treatment of allergic rhinitis for application to the mucosa, which is an aqueous pharmaceutical composition comprising the active ingredients together with one or more water-insoluble and/or water-low soluble substance and having an osmotic pressure of less than 290 mOsm

3 The pharmaceutical composition for application to the mucosa according to claim 2, wherein said osmotic pressure is 150 mOsm or less

4 The pharmaceutical composition for application to the mucosa according to claim 2, wherein said osmotic pressure is 60 mOsm or less

5 The pharmaceutical composition for application to the mucosa according to claim 2, wherein said osmotic pressure is 40 mOsm or less

6 The pharmaceutical composition for application to the mucosa according to claim 2, wherein said osmotic pressure is 20 mOsm or less

7 The pharmaceutical composition for application to the mucosa according to claim 2, further comprising an osmotic pressure-controlling agent

8 The pharmaceutical composition for application to the mucosa according to claim 2, wherein said water-insoluble and/or water-low soluble substance is a cellulose

The pharmaceutical composition for application to the mucosa according to claim 8, wherein said cellulose is microcrystalline cellulose

10 The pharmaceutical composition for application to the mucosa according to claim 2, wherein said one or more water-insoluble and/or water-low soluble substance is present as solid particles in an aqueous medium The pharmaceutical composition for application to the mucosa according to claim 2, further comprising a water-soluble polymer substance

Pharmaceutical composition for application to the mucosa according to claim 11 , wherein a combination of said water-insoluble substance and water-soluble polymer is present which is microcrystalline cellulose and carboxymethyl cellulose sodium

The pharmaceutical composition for application to the mucosa according to claim 2, further comprising a surfactant and/or a wetting agent

The pharmaceutical composition for application to the mucosa according to claim 2, wherein said mucosa is nasal mucosa

Pharmaceutical composition according to claims 1 through 14, wherein the antihistamine is selected from the group of (E)-6-[(E)-3-(1-pyrrolιdιnyl)-1-p-tolylpropenyl]-2-pyrιdιneacrylιc acid [INN ACRIVASTINE], 6,11-Dιhydro-11-(1 -methyl-4-pιperιdylιden)-5H-benzo[5,6]cyclohepta-[1 ,2-b]pyπdιn [INN AZATADINE], 4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1 H-azepιn-4-yl)-1(2H)phthal- azmone [INN AZELASTINE], (+)-(S)-4-[4-[1 -(4-chlorophenyl)-1 -(2-pyrιdyl)methoxy]pιperιdιn-1 -yl]- butanoic acid [INN BEPOTASTINE], (plus/mιnus)-[2-[4-(p-chloro-alpha-phenylbenzyl)-1-pιperazι- nyl]ethoxy]-acetιc acid [INN CETIRIZINE], (+)-2-{2-[(p-Chlor-alpha-methyl-alpha phenylbenzyl)oxy]- ethyl}-1-methylpyrrolιdιn [INN CLEMASTINE], 8-chloro-6,11 -dιhydro-11-(4-pιperιdylιdene)-5H- benzo[5,6]cyclohepta-[1 ,2-b]pyrιdιne [INN DESLORATADINE], [3-(4-Chlorophenyl)-3-pyrιdιn-2-yl- propyl]-dιmethylamιne [INN DEXCHLORPHENIRAMINE], 4'-tert-butyl-4-[4-(dιphenylmethoxy)- pιperιdιno]butyrophenone [INN EBASTINE], [2-[4-[bιs(p-fluorophenyl)methyl]-1 -pιperazιnyl]ethoxy]- acetic acid [INN EFLETIRIZINE], 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1 H-1 ,4-dιazepιn-1-yl)- benzimidazole [INN EMEDASTINE], 3-amιno-9,13b-dιhydro-1 H-dιbenz[c,f]ιmιdazo[1 ,5-a]azepιne [INN EPINASTINE], (plus/mιnus)-p-[1 -hydroxy-4-[4-(hydroxydιphenylmethyl)pιperιdιno]-butyl]- alpha-methylhydratropic acid [INN FEXOFENADINE], 3-[4-(8-fluoro-5,11 -dιhydrobenz[b]oxe- pιno[4,3-b]pyrιdιn-11-ylιdene)-pιpeπdιn-1 -yl]propιonιc acid [Research Code HSR-609], (-)-(3S,4R)- 1-[cιs-4-cyano-4-(p-fluorophenyl)cyclohexyl]-3-methyl-4-phenylιsonιpecotιc acid [INN LEVOCABASTINE], [2-[4-[(R)-p-chloro-alpha-phenylbenzyl)-1 -pιperazιnyl]ethoxy]-acetιc acιd [INN LEVO- CETIRIZINE], ethyl 4-(8-chloro-5,6-dιhydro-11 H-benzo[5,6]cyclohepta[1 ,2-b]pyrιdιn-11-ylιdene)-1- pipeπdinecarboxylate [INN LORATADINE], 2-[N-[1 -(4-fluorobenzyl)-1 H-benzιmιdazol-2-yl]-4-pιper- ιdιnyl]-N-methyl-amιno]pyrιmιdιn-4(3H)-one [INN MIZOLASTINE], 1-(4-fluorobenzyl)-2-(pιperιdιn-4- ylamιno)-1 H-benzιmιdazole [INN NORASTEMIZOLE], 3-(10,11-dιhydro-5H-dιbenzo[a,d]cyclo- hepten-5-yhdene)-N-methyl-1-propanamιne [INN NORTRIPTYLINE], 9-methyl-3-(1 H-tetrazol-5-yl)- 4H-pyrιdo[1 ,2-a]pyrιmιdιn-4-one [INN PEMIROLAST], 8-chloro-11-[1-(5-methylpyrιdιn-3-ylmethyl)- pιperιdιn-4-ylιdene]-6,11-dιhydro-5H-benzo[5,6]cyclohepta[1 ,2-b]pyrιdιne [INN RUPATADINE], 1- [2-[(p-chloro-alpha-methyl-alpha-phenylbenzyl)oxy]ethyl]hexahydro-1 H-azepine [INN SETASTINE], S-(7-carboxy-4-hexyl-9-oxoxanthen-2-yl)-S-methylsulfoxιmιne [INN SUDEXANOX], 1-(p-tert-butyl- phenyl)-4-[4'-(alpha-hydroxydιphenylmethyl)-r-pιperιdyl]-butanol [INN TERFENADINE], N-benzyl- N,N'-dιmethyl-N-(2-pyrιdyl)-ethylenedιamιne [INN TRIPELENAMINE] and 1-(4-fluorobenzyl)-2- (pιperιdιn-4-ylamιno)-1 H-benzιmιdazole [INN TECASTEMIZOLE] and mixtures, stereoisomers thereof, pharmaceutically acceptable salts and/or solvates thereof

Pharmaceutical composition according to claims 1 through 14, wherein the antihistamine is azelastine, levocabastine, a salt or solvate thereof

Use of ciclesonide in combination with at least one antihistamine for the manufacture of a pharmaceutical composition for the treatment of allergic rhinitis and/or allergic conjunctivitis

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 antihistamine 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