WO2011135585A2

WO2011135585A2 - Aqueous pharmaceutical solution of ciclesonide

Info

Publication number: WO2011135585A2
Application number: PCT/IN2011/000288
Authority: WO
Inventors: Sunilendu Bhushan Roy; Kapileswar Swain; Shailesh Arvindbhai Patel; Ravindra Nandlal Purohit
Original assignee: Cadila Healthcare Limited
Priority date: 2010-04-28
Filing date: 2011-04-28
Publication date: 2011-11-03
Also published as: WO2011135585A3

Abstract

The present invention relates to an aqueous pharmaceutical solution of ciclesonide or pharmaceutically acceptable salts thereof. In particular, the present invention relates to a stable aqueous nasal spray solution comprising ciclesonide or its pharmaceutically acceptable salts and process of manufacturing thereof. The aqueous solution is particularly suitable for topical administration into the nose for the treatment of inflammatory conditions.

Description

AQUEOUS PHARMACEUTICAL SOLUTION OF CICLESONIDE

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Ciclesonide is a new candidate from the class of lipophilic corticosteroids. Chemically, ciclesonide is Pregna-l,4-diene-3,20-dione,16,17-[[(R)- cyclohexylmethylene]bis(oxy)]- 1 1 -hydroxy-21 -(2-methyl- 1 -oxopropoxy)- (11 [beta], 16 [alpha] )-(9CI), havin the structural formula as represented below:

Ciclosonide was first disclosed in U.S. Patent No. 5,733,901. Ciclesonide is a non- halogenated glucocorticoid with high local anti-inflammatory properties that is inhaled in the treatment of asthma. It is an ester prodrug essentially devoid of oral bioavailability, which is activated upon cleavage by endogenous esterases.

Ciclesonide has undergone evaluation as an antiasthmatic and pharmacokinetic studies show that it will be useful in an inhaler formulation. Ciclesonide is only moderately absorbed after oral administration and has low systemic activity. The concentration of the drug in the lungs is high and metabolism by liver oxidases is very high, giving the drug a low plasma half-life. The systemic activity of ciclesonide is three times lower than that of budesonide, but anti-inflammatory activity is higher for the former.

Due to its bioactivity, a commercially available ciclesonide containing pharmaceutical preparation for topical (mucosal) or systemic diseases is preferred.

The nasal administration of drugs allows for their deposition to the nose, sinuses, and other nasal cavities. Intranasal administration of drugs such as corticosteroids or their combinations with antihistaminics are frequently used to treat nasal symptoms including seasonal allergic rhinitis, perennial allergic rhinitis, perennial non-allergic rhinitis, nasal polyps, as well as prevention of post surgical polyps, chronic sinusitis, recurrent sinusitis, asthma, grass pollen rhinitis, hay fever, snoring, cluster headache, and other diseases and disorders.

Suitable formulations for pressurized metered dose inhalers (MDls) for inhalation for ciclesonide are disclosed for example, in U.S. Patent Nos. 6,264,923 and 6,120,752.

International (PCT) Publication No. WO2009/003199 discloses methods for treating an allergic symptom or disorder by nasal administration.

European Patent Application No. EP 1894559 discloses aqueous pharmaceutical compositions of corticosteroid suitable for administration as an aerosol.

US Patent Publication No. US2007/0020299 discloses an aqueous liquid formulation comprising a therapeutically effective amount of corticosteroid dissolved therein, SAE-CD, and an aqueous liquid carrier.

U.S. Patent No. 6,767,901 discloses an aqueous pharmaceutical suspension for application to the mucosa, comprising one or more water insoluble and/or water-low soluble substance, and ciclesonide, and having an osmotic pressure of 150 mOsm or less. .

U.S. Patent No. 6,939,559 discloses an aqueous pharmaceutical suspension for application to the mucosa, comprising one or more water insoluble and/or water- low soluble substance, and one or more medicament, and having an osmotic pressure of 72 mOsm or less.

U.S. Patent No. 7,235,247 discloses an aqueous pharmaceutical suspension for application to the mucosa, comprising one or more water insoluble and/or water-low soluble substance, and one or more medicament, and having an osmotic pressure of 150 mOsm or less. For developing suitable nasal formulation of drugs having limited aqueous solubility, such as ciclesonide, it is usually developed in the form of suspension product. Currently, ciclesonide is commercially sold by Nycomed under the trademark OMNARIS^® which is in the form of hypotonic aqueous suspension.

However, because suspension product has limitations of systemic absorption, bioavailability, poor physical stability, dose variation with each administration and need dispersing or shaking the product before dose administration to avail dose homogeny. Moreover, there are more issues in scaling up suspension products as compared to the solution products. It is also challenging to devise an aqueous formulation of ciclesonide in the form of solution which also renders stability to the formulation over the storage period.

Hence, there exists a need to develop a stable ready to deliver aqueous nasal solution formulation of ciclesonide.

SUMMARY OF THE INVENTION

In one general aspect there is provided a stable aqueous nasal spray solution for topical administration comprising ciclesonide or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally, one or more surfactants.

In another general aspect there is provided a stable aqueous nasal spray solution for topical administration comprising ciclesonide or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally, one or more surfactants, wherein the solution retains at least 80% potency of ciclesonide or pharmaceutically acceptable salts thereof after storage for one month at stress stability conditions.

In another general aspect there is provided a stable aqueous nasal spray solution for topical administration comprising ciclesonide or pharmaceutically acceptable salts thereof; one or more water soluble polymers, surfactants, chelating agents preservatives, pH adjusting agents, taste masking agents and optionally one or more pharmaceutically acceptable excipients.

In another general aspect, there is provided a stable aqueous nasal spray solution for topical administration comprising ciclesonide or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients wherein the pH of the solution ranges from about 3.5 to about 7.5. Embodiments of the aqueous nasal spray solution may include one or more of the following features. For example, the aqueous nasal spray solution may include one or more pharmaceutically acceptable excipients selected from water soluble polymers, surfactant, preservatives, chelating agents, pH adjusting agents, sweetener/taste masking agents, and the like.

In another general aspect there is provided a stable aqueous nasal spray solution for topical administration comprising ciclesonide or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients wherein the solution is in the form of nasal spray.

In another aspect there is provided a stable aqueous nasal spray solution for topical administration comprising combination of ciclesonide or pharmaceutically acceptable salts thereof and at least one active agent selected from the therapeutic category of corticosteroids, non- steroidal anti-inflammatory agents, antihistaminic agents, decongestants, antiallergic agents; and one or more pharmaceutically acceptable excipients.

Embodiments of the aqueous nasal spray solution may include one or more of the following features. For example, the aqueous nasal spray solution may include one or more pharmaceutically acceptable excipients selected from water soluble polymers, surfactant, preservatives, chelating agents, pH adjusting agents, sweetener/taste masking agents and the like.

In another general aspect there is provided a process for preparing a stable aqueous nasal spray solution for topical administration comprising preparing the solution of ciclesonide or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients.

In another general aspect there is provided a process for preparing a stable aqueous nasal spray solution for topical administration, the process comprising preparing the solution of ciclesonide or pharmaceutically acceptable salts thereof using one or more water soluble polymers and one or more surfactants and optionally with one or more pharmaceutically acceptable excipients. In another general aspect there is provided a process for preparing a stable aqueous nasal spray solution for topical administration of ciclesonide or pharmaceutically acceptable salts thereof, the process comprising the steps of- (a) preparing a solution of polymers;

(b) dispersing surfactant with ciclesonide or pharmaceutically acceptable salts thereof and adding to the solution of step (a);

(c) preparing a solution of other pharmaceutically acceptable excipients by sequentially dissolving in water;

(d) adding the solution of step (b) into solution (c);

(e) providing the solution of preservative in water;

(f) adding the solution of step (e) to solution of step (d); and

(g) filling the solution of step (f) into suitable containers.

Embodiments of the aqueous nasal spray solution may include one or more of the following features. For example, the aqueous nasal spray solution may include one or more pharmaceutically acceptable excipients selected from water soluble polymers, surfactant, preservatives, chelating agents, pH adjusting agents, sweetener/taste masking agents and the like:

In another general aspect, there is provided a stable aqueous nasal spray solution for topical administration comprising ciclesonide or pharmaceutically acceptable salts thereof for use in preparation of medicament for treatment of inflammatory disorders comprising administering the said solution to the patient in need thereof.

In another general aspect, there is provided method for treating an allergic and/or inflammatory symptom or disorder in a subject in need thereof, comprising nasally administering said subject an aqueous nasal spray solution comprising ciclesonide or pharmaceutically acceptable salts thereof and one or more water soluble polymers optionally with one or more surfactants.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description. Embodiments of the aqueous nasal spray solution may include one or more of the following features. For example, the aqueous nasal spray solution may include one or more pharmaceutically acceptable excipients selected from water soluble polymers, surfactant, preservatives, chelating agents, pH adjusting agents, sweetener/taste masking agents and the like.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the present invention have surprisingly found that it is possible to develop a stable aqueous nasal spray solution for topical administration of ciclesonide by using judicial combination of pharmaceutically acceptable excipients.

In particular, the present inventors have found that a stable aqueous nasal spray solution of ciclesonide can be obtained by using pharmaceutically acceptable excipients comprising one or more water soluble polymer. Further, the inventors of the present invention have found that that the resulting pharmaceutical aqueous solution of ciclesonide may remain stable for at least one month when stored at stress stability conditions (temperatures (in 10°C increments (e.g., 40°C, 50°C, 60°C, etc.) above that for accelerated testing), humidity (e.g., 75% RH or greater)).

Thus, the present invention provides a stable aqueous nasal spray solution comprising ciclesonide or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients.

The present invention further provides a stable aqueous nasal spray solution comprising ciclesonide or pharmaceutically acceptable salts thereof; and one or more pharmaceutically acceptable excipients, which retains at least 80% potency of ciclesonide or pharmaceutically acceptable salts thereof after subjecting to storage at stressed stability conditions.

The present invention further provides a stable aqueous nasal spray solution comprising ciclesonide or pharmaceutically acceptable salts thereof; at least one water soluble polymer with one or more pharmaceutically acceptable excipients.

In an embodiment, the ratio of amount of ciclesonide to the amount of water soluble polymer present in the aqueous nasal spray solution according to the present invention ranges from about 1 :2 to about 1 :80. It will be appreciated that ciclesonide, for the purpose of the present invention, may be provided as the free base, or in the form of an appropriate pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a pharmaceutically acceptable enantiomer, a pharmaceutically acceptable derivative, a pharmaceutically acceptable polymorph or a pharmaceutically acceptable prodrug thereof.

The present invention provides a stable aqueous nasal spray solution comprising ciclesonide or pharmaceutically acceptable salts thereof; at least one water soluble polymer; at least one surfactant with one or more pharmaceutically acceptable excipients.

In an embodiment, the ratio of amount of surfactant to the amount of water soluble polymer in the aqueous solution of ciclesonide ranges from about 1:0.01 to about 1 :6.

The aqueous nasal spray solution is preferably water or aqueous based solutions. Further solvent constituents that may be present are all solvents which are suitable for nasal administration, in particular alcohols, such as, for example, ethanol, propanol, propanediol or glycerol. The aqueous nasal spray solution preferably comprises water or ethanol/water mixtures as solvent, the solvent more preferably consists of water.

In a further embodiment, there is provided a stable aqueous nasal spray solution comprising ciclesonide or pharmaceutically acceptable salts thereof; at least one water soluble polymer; at least one surfactant; at least one chelating agent; at least one preservative; at least one pH adjusting agent; at least one sweetener/taste masking agent and optionally with one or more pharmaceutically acceptable excipients.

Examples of suitable water soluble polymers which can be employed in the aqueous nasal spray solution of ciclesonide according to the present invention may be selected from, but not limited to polyhydroxy alcohols such as glycerin, polyethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 2- methyl -2,4-pentanediol, 1,2,6-hexanetriol and thioglycol, alginic acid, polyoxyethylene polyoxypropylene glycol, pectin, low methoxyl pectin, guar gum, gum arabic, carrageenan, cellulose derivatives such as- methyl cellulose, carboxymethyl cellulose sodium, xanthan gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or mixtures thereof. The above polyoxyethylene polyoxypropylene glycol is a series of polymers in which ethylene oxide has been addition-polymerized to a polypropylene glycol obtained by polymerization of propylene oxide, and are classified into several types by the difference in the mean degree of polymerization of propylene oxide and ethylene oxide. Particularly preferred water soluble polymers are polyhydroxy alcohols such as polyethylene glycol, propylene glycol, glycerol and cellulose derivatives such as hydroxylpropyl methyl cellulose. The amount of water soluble polymer may ranges from about 0.001% to about 30% w/w relative to the total weight of the solution.

Suitable "surfactants" which can be used for preparing aqueous nasal spray solution of ciclesonide may include one or more of anionic, cationic, non-ionic or zwitterionic surfactants or mixtures thereof.

Examples of suitable surfactants which can be employed in the aqueous nasal spray solution of ciclesonide according to the present invention may be selected from, but not limited to polyethoxylated sorbitan derivatives such as polysorbates, their ether ethoxylates, produced by reaction of sorbitan esters with ethylene oxide, polyoxyethylene alkyl phenol, polyoxyethylene cetyl ether, polyoxyethylene alkyl-aryl ether, polyoxyethylene monolaurate, polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene esters or mixed fatty and resin acids, polyoxyethylene sorbitol lanolin derivative, polyoxyethylene tridecylether, polyoxyethylene sorbitan esters of mixed fatty and resin acids, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene monostearate, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene tridecyl ether, polyoxyethylene fatty alcohol, polyoxyethylene alkyl amine, polyoxyethylene glycol monopalmitate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene cetyl ether, polyoxyethylene oxypropylene stearate, polyoxyethylene lauryl ether, polyoxyethylene lanolin derivative, sodium oleate, quaternary ammonium derivative, potassium oleate, N-cetyl N-ethyl morpholinium ethosulfate, sodium lauryl sulfate or mixtures thereof. Particularly preferred surfactants are polyethoxylated sorbitan derivatives.

The amount of surfactant may range from about bout 1% to about 20% w/w relative to the total weight of the solution.

In an embodiment, the HLB value of the surfactant employed in the aqueous nasal spray solution is approximately 10 or greater. In order to improve the ability of the aqueous nasal solution to be tolerated on administration to the nasal mucous membrane, it is advantageous to formulate it as isotonic solution. The osmolality can be set by variation of the amounts of the dissolved substances present in the aqueous solution besides ciclesonide and any further substances present, and/or by addition of an iso tonicity agent, preferably a physiologically tolerated salt, such as, for example, sodium chloride or potassium chloride, or a physiologically tolerated polyol, such as, for example, a sugar alcohol, in particular sorbitol or glycerol, in the concentration necessary for rendering isotonic.

In an embodiment, the osmolality of the aqueous nasal spray solution of ciclesonide has an osmolality of about less than 350 mOsm/kg.

Examples suitable of the preservatives which can be employed in the aqueous nasal spray solution may be selected from, but not limited to benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, disodium edetate. Quaternary ammonium halide preservatives are preferred. Suitable quaternary ammonium halide preservatives include polyquaternium-1 and benzalkonium halides. Preferred benzalkonium halides are benzalkonium chloride and benzalkonium bromide. The amount of the preservative present in the aqueous nasal spray solution of the present invention may range from about 0.005 to about 0.05% w/w relative to the total weight of the solution. Preferably, the preservative is present at a concentration of 0.01 % relative to the final weight of the solution.

Examples of suitable antioxidants which can be employed in the aqueous nasal spray solution may be selected from, but not limited to ascorbic acid, alpha-tocopherol (vitamin-E), butylated hydroxyanisole, butylated hydroxytoluene, glutathione and the like. The amount of the antioxidant present in the aqueous nasal spray solution may ranges from about 0.0002 to about 0.5% w/w relative to the total weight of the solution.

Examples of suitable chelating agents which can be employed in the aqueous nasal spray solution may be selected from, but not limited to edetate disodium (EDTA); edetate trisodium; edetate tetrasodium; and diethyleneamine pentaacetate, preferably EDTA. The amount of the chelating agent present in the aqueous nasal spray solution of the present invention may range from about 0.0002% to about 0.5% w/w relative to the total weight of the solution. Examples of suitable pH adjusting agents which can be employed in the aqueous nasal spray solution may be selected from, but not limited, to citric acid, acetic acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, or combinations thereof.

The solution of the present invention comprises an amount of a pH adjusting agent sufficient to adjust the pH of the solution to from about 3.5 to about 7.5, preferably from about 4.5 to about 6.5 and more preferably from about 3.5 to about 6.5. Preferably, the amount of pH adjusting agent ranges from about 0.005% to about 1% w/w relative to the total weight of the solution.

Examples of suitable sweetener/taste masking agents which can be employed in the aqueous nasal spray solution may be selected from, but not limited to sucralose, thaumatin (e.g., Talin^(R)) sucrose, saccharin (including the salt forms: sodium, calcium, etc.), fructose, glucose, dextrose, corn syrup, aspartame, acesulfame- , xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, eucalyptus oil, camphor, and natural or artificial flavors or flavoring agents (for example menthol, mints, vanilla, orange, etc.), or combinations of two or more of such agents. Particularly preferred taste masking agent is sucralose. The amount of the sweetener/taste masking agent present in the aqueous nasal spray solution of the present invention may range from about 0.05 to about 0.1% w/w relative to the total weight of the solution.

Alternatively, the aqueous nasal spray solution further may include a crystallization inhibitor. Examples of suitable crystallization inhibitors that can be used may include, but not limited to hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, poly(2-propenoic acid), and other cellulose derivatives, and combinations of these cellulose derivatives with low viscosity grades. The amount of crystallization inhibitor that can be used may ranges from about 0.01% to about 10.0% w/w relative to the total weight of the solution.

It will also be appreciated to the skilled artisan that in order to improve the physical properties, appearances, or smells of the solution of the present invention, one or more further pharmaceutically acceptable excipients may be added as desired.

The stable aqueous nasal spray solution of ciclesonide may comprise one or more additional pharmaceutical active agent/s selected from the therapeutic category of, but not limited to, corticosteroids, non- steroidal anti-inflammatory agents, antihistaminic agents, decongestants, antiallergic agents and the like.

Suitable corticosteroid, may be selected from, but not limited to beclomethasone, flunisolide, triamcinolone, fluticasone, mometasone, budesonide, pharmaceutically acceptable salts thereof and mixtures thereof. Other corticosteroids may be also be selected from aldosterone, beclomethasone, betamethasone, budesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocoitolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, tixocortol or pharmaceutically-acceptable salts, optically active racemates and mixtures thereof.

Suitable non-steroidal anti-inflammatory agents may be selected from, but not limited to acetaminophen, acetylsalicylic acid, ibuprofen, etodolac, fenbuprofen, fenoprofen, flurbiprofen, indomethacin, ketoprofen, naproxen, oxaprozin, sulindac,. etodolac, droxicam, lornoxicam, licofelone pharmaceutically-acceptable salts thereof, optically active racemates thereof and mixtures thereof.

Suitable antihistaminic agents may be selected from, but not limited to drug belonging from class of piperazines, phenothiazines, piperidines such as azelastine, cetirizine, loratadine, azelastine, olopatadine, chlorpheniramine, fexofenadine, desloratadine, loratadine, astemizole, cyclizine, bepotastine, promethazine, diphenhydramine, dimenhydrinate, pheniramine, ebastine, levocetirizine, quetiapine, meclizine, ciproxifan, clobenpropit, thioperamide pharmaceutically acceptable salts or mixtures thereof

Suitable decongestants may be selected from, but not limited to pseudoephedrine, desoxyephedrine, propylhexedrine, phenylpropanolamine, xylometazoline, phenylephrine, tetrahydrozoline, naphazoline, oxymetazoline, tramazoline and pharmaceutically acceptable salts or mixtures thereof.

Suitable antiallergic agents, may be selected from but not limited to cromolyn, ketotifen, N-allyl-(dichloro-3, 4-benzyl)-2-methylamino-2-propanol-l, Andolast, oxatamide, nedocromil, emedastine, pyrilamine, levocabastine, and pharmaceutically- acceptable salts or mixtures thereof.

The aqueous nasal spray solution can be administered as a drop or solution or any other form suitable for topical administration. The solution may also be administered using a nasal tampon or a nasal sponge.

In a preferred embodiment, the aqueous nasal spray solution is provided in the form of nasal spray.

Other means for delivering the nasal spray, such as inhalation via a metered dose inhaler (MDI), may also be used. Several types of MDIs are regularly used for administration by inhalation. These types of devices can include breath-actuated MDI, spacer/holding chambers in combination with MDI, and nebulizers. The term "MDI" as used herein refers to an inhalation delivery system comprising, for example, a canister containing mixture of active agent and a propellant optionally with one or more excipients, a metered dose valve, an actuator, and a mouthpiece. The canister is usually filled with a solution of an active agent, such as the nasal spray solution, and a propellant, such as one or more hydrofluoroalkanes [e.g. 1,1,1,2-tetrafluoroethane (HFA-134a) and 1,1,1,2,3,3,3- heptafluoropropane (HFA-227)]; chlorofluorocarbons; and alcohols such as ethanol, isopropanol, butanol, propanol or mixtures thereof. When the actuator is depressed a metered dose of the solution is aerosolized for inhalation. Particles comprising the active agent are propelled toward the mouthpiece where they may then be inhaled by a subject.

The amount of ciclesonide is a therapeutically effective amount and can be determined depending on the type and the degree of the disease, the age and the weight of the patient, and the like. It is usually from the same to 20 times as much as the amount of each drug commonly used for injection, more preferably from the same to 10 times as much..

The concentration of ciclesonide is preferably 0.01% w/w to 1% w/w, and most preferably 0.01% w/w to 0.5% w/w relative to the total weight of the solution.

However, it will be appreciated that the above dosing regime should be tailored according to the individual patient's age, body weight and/or symptom severity. In an embodiment, the process of preparing the stable aqueous nasal spray solution comprises step of preparing solution of ciclesonide or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients.

In a further embodiment, the process of preparing the stable aqueous nasal spray solution comprises step of preparing solution of ciclesonide or pharmaceutically acceptable salts thereof with at least one water soluble polymer and further addition of one or more pharmaceutically acceptable excipients to the said solution.

In a still further embodiment, there is provided a process of preparing the stable aqueous nasal spray solution comprising ciclesonide or pharmaceutically acceptable salts thereof comprises steps of-

(a) preparing the of solution of polymers;

(b) dispersing surfactant with ciclesonide and adding to the solution of step (a);

(c) preparing the solution of other pharmaceutically acceptable excipients by sequentially dissolving in water;

(d) adding the solution of step (b) into solution (c);

(e) providing the solution of preservative in water;

(f) adding the solution of step (e) to solution of step (d); and

(g) Filling the solution of step (f) into suitable containers.

The clear solution formulations are filled in to commercially available bottles and fit with metered dose pumps for nasal delivery of the drug products.

The aqueous nasal spray solution can, for nasal administration, be applied in all medicament forms which are suitable for nasal administration, such as, for example, nasal drops, by means of dispensing devices suitable for this purpose, such as bottles with drop device or nasal spray pumps.

In an embodiment, the invention provides a stable aqueous nasal spray solution for topical administration comprising ciclesonide or pharmaceutically acceptable salts thereof for use in preparation of medicament for treatment of inflammatory disorders comprising administering the said solution to the patient in need thereof.

In a further embodiment, the invention provides a method for treating an allergic and/inflammatory symptom or disorder in a subject in need thereof, comprising: nasally administering to the subject a stable aqueous nasal spray solution comprising a therapeutically effective amount of ciclesonide and a pharmaceutically acceptable aqueous liquid carrier.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1

Table 1

Procedure:

A solution of hydroxypropyl methylcellulose was prepared in water. Polyethylene Glycol was added to a solution of Ciclesonide and Polysorbate 80 to prepare drug solution. A bulk solution containing Edetate disodium, Citric acid monohydrate, Sodium Citrate dehydrate and Sucralose was prepared with purified water and added to the HPMC solution followed by addition of drug solution and benzalkonium Chloride solution to the same. Finally, the solution was filled into suitable containers. Example 2

Table 2

Procedure:

A solution of Propylene Glycol and Polyethylene Glycol was prepared. Separately, Ciclesonide and Polysorbate 80 were dispersed to prepare drug solution. A bulk solution containing Edetate disodium, Citric acid monohydrate, Sodium Citrate dehydrate and Sucralose was prepared with purified water and added to the solution of propylene glycol and polyethylene glycol followed by addition of the drug solution. A solution of benzalkonium Chloride was prepared separately and addend to the above bulk solution. Finally, the solution was filled into suitable containers.

While the invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims

We Claim:

1. A stable aqueous nasal spray solution for topical administration comprising ciclesonide or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally, one or more surfactants.

2. The stable aqueous nasal spray solution as claimed in claim 1, wherein the water soluble polymer comprises one or more of glycerin, polyethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 2-methyl-2,4-pentanediol, 1,2,6- hexanetriol, thioglycol, alginic acid, polyoxyethylene polyoxypropylene glycol, pectin, low methoxyl pectin, guar gum, gum arabic, carrageenan, methyl cellulose, carboxymethyl cellulose sodium, xanthan gum, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.

3. The stable aqueous nasal spray solution as claimed in claim 1, wherein the ratio of the amount of ciclesonide, or pharmaceutically acceptable salts thereof to the amount of water soluble polymer is in the range of from about 1 :2 to about 1 :80.

4. The stable aqueous nasal spray solution as claimed in claim 1 , wherein the surfactant comprises one or more of anionic, cationic and non-ionic surfactants.

5. The stable aqueous nasal spray solution as claimed in claim 4, wherein the surfactant comprises one or more of non-ionic surfactants.

6. The stable aqueous nasal spray solution as claimed in claim 5, wherein the non-ionic surfactant is a polyethoxylated sorbitan derivative.

7. The stable aqueous nasal spray solution as claimed in claim 1 , wherein the ratio of the amount of surfactant to the amount of water soluble polymer is in the range of from about 1 :0.01 to about 1:6.

8. The stable aqueous nasal spray solution as claimed in claim 1, further comprising one or more pharmaceutically acceptable excipients comprising one or more chelating agents, preservatives, pH adjusting agents, and taste masking agents.

9. The stable aqueous nasal spray solution as claimed in claim 8, wherein the chelating agent comprises one or more of edetate disodium, edetate trisodium, edetate tetrasodium, and diethyleneamine pentaacetate.

10. The stable aqueous nasal spray solution as claimed in claim 8, wherein the preservative comprises one or more of benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, and disodium edetate.

11. The stable aqueous nasal spray solution as claimed in claim 8, wherein the pH adjusting agent comprises one or more of citric acid, acetic acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, and phosphate salts.

12. The stable aqueous nasal spray solution as claimed in claim 8, wherein the taste masking agent comprises one or more of sucralose, thaumatin, sucrose, saccharin, fructose, glucose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, eucalyptus oil, and camphor.

13. The stable aqueous nasal spray solution as claimed in claim 1, wherein pH of the solution ranges from about 3.5 to about,7.5.

14. The stable aqueous nasal spray solution as claimed in claim 1, wherein the osmolality of the solution is less than about 350 mOsm/kg.

15. The stable aqueous nasal spray solution as claimed in claim 1, further comprising at least one active agent selected from corticosteroids, non- steroidal anti-inflammatory agents, antihistamine agents, decongestants and antiallergic agents.

16. The stable aqueous nasal spray solution as claimed in claim 15, wherein the active agent is an antihistaminic agent.

17. The stable aqueous nasal spray solution as claimed in claim 16, wherein the antihistaminic agent is azelastine or pharmaceutically acceptable salts thereof.

18. A stable aqueous nasal spray solution for topical administration comprising:

(a) ciclesonide, or pharmaceutically acceptable salts thereof;

(b) about 0.005% to about 0.05% w/w of one or more preservatives;

(c) about 0.005% to about 1% w/w of one or more pH adjusting agents;

(d) about 0.0002%) to about 0.5% w/w of one or more chelating agents;

(e) about 0.001% to about 30% w/w of one or more water soluble polymers;

(f) about 1% to about 20% w/w of one or more surfactants; and

(g) water in quantity sufficient to make volume.

19. The stable aqueous nasal spray solution as claimed in claim 18, further comprising about 0.05% to about 0.1% w/w of one or more sweetening agents.

20. A stable aqueous nasal spray solution for topical administration comprising ciclesonide or pharmaceutically acceptable salts thereof, one or more water soluble polymers, and optionally, one or more surfactants, wherein the solution retains at least 80% potency of ciclesonide or pharmaceutically acceptable salts thereof after storage for one month at stress stability conditions.

21. A process for preparing a stable aqueous nasal spray solution for topical administration, the process comprising preparing the solution of ciclesonide or pharmaceutically acceptable salts thereof using one or more water soluble polymers and one or more surfactants and optionally with one or more pharmaceutically acceptable excipients.

22. A method for treating an allergic and/or inflammatory symptom or disorder in a subject in need thereof, comprising nasally administering said subject an aqueous nasal spray solution comprising xiclesonide or pharmaceutically acceptable salts thereof and one or more water soluble polymers optionally with one or more surfactants.