Indian Patents. 257031:A PHARMACEUTICAL FORMULATION

Title of Invention	A PHARMACEUTICAL FORMULATION
Abstract	The instant invention discloses a pharmaceutical formulation which comprises azelastine, or a phannaceutically acceptable salt, solvate or physiologically functional derivative thereof, and mometasone or a phannaceutically acceptable ester thereof.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See Section 10; Rule 13) TITLE A PHARMACEUTICAL FORMULATION APPLICANT CIPLA LIMITED AN INDIAN COMPANY OF 289 BELLASIS ROAD, MUMBAI CENTRAL, MUMBAI 400 008 INDIA The following specification particularly describes the nature of the invention and the manner in which it is performed. - 1A- This application is divided out of the Indian Patent Application no. : 733/MUMNP/2004 The present invention relates to pharmaceutical products and formulations. More particularly the present invention relates to pharmaceutical products and formulations useful for preventing or minimising allergic reactions. More particularly, but not exclusively, the present invention relates to pharmaceutical products and formulations for nasal and ocular use. Such allergic reactions commonly comprise the allergy-related and vasomotor-related symptoms and the rhinovirus-related symptoms. It is known to use antihistamines in nasal sprays and eye drops to treat allergy-related conditions. Thus, for example, it is known to use the antihistamine azelastine (usually as the hydrochloride salt) as a nasal spray against seasonal or perennial allergic rhinitis, or as eye drops against seasonal and perennial allergic conjunctivitis. It is also known to treat these conditions using a corticosteroid, which will suppress nasal and ocular inflammatory conditions. Among the corticosteroids known for nasal use are, for example, beclomethasone, mometasone, fluticasone, budesonide and cyclosenide. Corticosteroids known for ocular anti-inflammatory use include betamethasone sodium, dexamethasone sodium and prednisolone acetate, for example. It would be highly desirable, however, to provide a treatment that combines the effects of anti-histamine treatments and steroid treatments, in a phartnaceutically acceptable formulation, which is tolerated in situ, without significantly disrupting the potency of the constituent pharmaceuticals. We have now found that, very surprisingly, azelastine (4-[(4-Chlorophenyl)methyl]-2-(hexahydro-l-methyl-lH-azepin-4-yl)-l(2H)-phthalazinone), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, preferably in salt form and even more preferably in the form of the hydrochloride salt, can advantageously be combined with a steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, to provide a stable, very effective combination product or formulation preferably for nasal or ocular treatment. The combination can provide, in a single administration or dosing regime, the antihistaminic properties of azelastine and the anti- 2 inflammatory (and / or other) properties of the steroid, without any significant interference between the two, or adverse reaction in situ. In one aspect the invention provides a pharmaceutical formulation comprising azelastine or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and a steroid, preferably a corticosteroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, the formulation preferably being in a form suitable for administration nasally or ocularly. The term "physiologically functional derivative" as used herein denotes a chemical derivative of any of the specific therapeutic agents described herein having the same or similar physiological function as the free base therapeutic agent and, for example, being convertible in the body thereto. According to the present invention, examples of physiologically functional derivatives include esters. The preferred forms of formulations of the invention are nasal drops, eye drops, nasal sprays, nasal inhalation solutions or aerosols or insufflation powders. Preferred embodiments of the invention can comprise stable aqueous solutions of azelastine or one or more of its salts, in combination with steroids which may be beclomethasone, mometasone, fluticasone, budesonide or cyclosenide, which can be used in the form of inhalation solution, pressurized aerosoL eye drops or nasal drops, and in a particular preferred embodiment, in the form of a spray (preferably a nasal spray). The spray can, for example, be formed by the use of a conventional spray-squeeze bottle or a pump vaporizer. In addition, it is also possible to use compressed gas aerosols. In a preferred embodiment, 0.03 to 3 mg of azelastine base and 0.05 to 0.15 mg of the steroid should be released per individual actuation. The formulations preferably contain a preservative and/or stabilizer. These include, for example: ethylene diamine tetra-acetic acid (edetic acid) and its alkali salts (for example dialkali salts such as disodium salt, calcium salt, calcium-sodium salt), lower alkyl p-hydroxybenzoates, chlorhexidine (for example in the form of the acetate or gluconate) and phenyl mercury borate. Other suitable preservatives are: pharmaceutically useful quaternary ammonium compounds, for example cetylpyridinium chloride, tetradecyltrimethyl ammonium bromide, generally known as "cetrimide", benzyldimethyl-[2-[2-[p-(l,l,3,3-tetramethyl-butyl)phenoxy]ethoxy]-ammonium chloride, generally known as "benzethonium chloride" and myristyl picolrnium chloride. Each of these compounds may be used in a 3 concentration of 0.002 to 0.05%, for example 0,02% (weight/volume in liquid formulations, otherwise weight/weight). Preferred preservatives among the quaternary ammonium compounds are, however, alkylbenzyl dimethyl ammonium chloride and mixtures thereof, for example the compounds generally known as "benzalkonium chloride". The total amount of preservatives in the formulations (solutions, ointments, etc.) is preferably from 0.001 to O.lOg, preferably O.Olg per 100ml of solution/suspension or lOOg of formulation. In the case of preservatives, the following amounts of individual substances can, for example, be used: thimero sal 0.002-0.02%; benzalkonium chloride 0.002 to 0.02% (in combination with thimero sal the amount of thimero sal is, for example =0.002 to 0.005%;); chlorhexidine acetate or gluconate 0.01 to 0.02%; phenyl mercuric/nitrate, borate, acetate 0.002-0.004%; p-hydroxybenzoic acid ester (for example, a mixture of the methyl ester and propyl ester in the ratio 7:3): preferably 0.05-0.15, more preferably 0.1%. The preservative used is preferably a combination of edetic acid (for example, as the disodium salt) and benzalkonium chloride. In this combination, the edetic acid is preferably used in a concentration of 0.05 to 0.1%, benzalkonium chloride preferably being used in a concentration of 0.005 to 0.05%, more preferably 0.01%. In the case of solutions/suspensions reference is always made to percent by weight/volume, in the case of sohd or semi-solid formulations to percent by weight/weight of the formulation. Further auxiliary substances which may, for example, be used for the formulations of the invention are: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, polyethoxylated sorbitan fatty acid esters (for example polyefhoxylated sorbitan trioleate), sorbimacrogol oleate, synthetic amphotensides (tritons), ethylene oxide ethers of octylphenolformaldehyde condensation products, phosphatides such as lecithin, polyethoxylated fats, polyethoxylated oleotriglycerides and polyethoxylated fatty alcohols. In this context, polyethoxylated means that the relevant substances contain polyoxyethylene chains, the degree of polymerisation of which is generally between 2 to 40, in particular between 10 to 20. These substances are preferably used to improve the solubility of the azelastine component. It is optionally possible to use additional isotonization agents. Isotonization agents which may, for example, be used are: saccharose, glucose, glycerine, sorbitol, 1,2-propylene 4 glycol and NaCl. The isotonization agents adjust the osmotic pressure of the formulations to the same osmotic pressure as nasal secretion. For this purpose these substances are in each case to be used in such amount that, for example, in the case of a solution, a reduction in the freezing point of 0.50 to 0.56 degree C is attained in comparison to pure water. In Example 1, it is possible to use instead of NaCl per 100 ml of solution, for example: Glucose 1H20 3.81g; saccharose 635%; glycerine 2.2g; 1,2-propylene glycol 1.617g; sorbitol 3.84g (in the case of mixtures of these substances correspondingly less may optionally be used). Moreover, it is possible to add thickening agents to solutions according to the present invention to prevent the solution from flowing out of the nose too quickly and to give the solution a viscosity of about 1.5 to 3, preferably 2 mPa. Such thickening agents may, for example, be: cellulose derivatives (for example cellulose ether) in which the cellulose-hydroxy groups are partially etherified with lower unsaturated aliphatic alcohols and/or lower unsaturated aliphatic oxyalcohols (for example methyl cellulose, carboxymethyl cellulose, hydroxypropylmethylcellulose), gelatin, polyvinylpyrrolidone, tragacanth, ethoxose (water soluble binding and thickening agents on the basis of ethyl cellulose), alginic acid, polyvinyl alcohol, polyacrylic acid, pectin and equivalent agents. Should these substances contain acid groups, the corresponding physio logically acceptable salts may also be used. In the event of the use of hydroxypropyl cellulose, 0.1% by weight of the formulation, for example, is used for this purpose. In the event of the use of Avicel RC 591 or CL11, 0.65-3.0% by weight of the formulation, for example, is used for the purpose. It is also possible to add to the formulations buffer substances such as citric acid/sodium hydrogensulphate borate buffer, phosphates (sodium hydrogenorthophosphate, disodium hydrogenphosphate), trometamol or equivalent conventional buffers in order, for example, to adjust the formulations to a pH value of 3 to 7, preferably 4.5 to 6.5. The amount of citric acid is, for example, 0.01 to 0.14g, preferably 0.04 to 0.05g, the amount of disodium hydrogenphosphate 0.1 to 0.5g, preferably 0.2 to 0.3g per 100 ml of solution. The weights given relate in each case to the anhydrous substances. 5 In the case of solutions and suspensions, the maximum total concentration of active agent and buffer is preferably less than 5%, in particular less than 2% (weight/volume). For the nasal application, a solution or suspension can preferably be used which is applied as an aerosol, i.e. in the form of a fine dispersion in air or in another conventional carrier gas, for example by means of a conventional pump vaporizer. Application as a dosage aerosol is, however, also possible. Dosage aerosols are defined as being pressure packings which contain the azelastine or its salts in combination with steroid, in the form of a solution or suspension in a so-called propellant The propellant may be a pressurized liquid chlorinated, fluorinated hydrocarbon or mixtures of various chlorinated, fluorinated hydrocarbons as well as propane, butane, isobutene or mixtures of these among themselves or with chlorinated, fluorinated hydrocarbons which are gaseous at atmospheric pressure and room temperature. Hydrofluorocarbons (HFCs), such as HFC 134a, and HFC 227a can also be used, and are preferred for environmental reasons. The pressure packing has a dosage or metering valve which, on actuation, releases a defined amount of the solution or suspension of the medicament. The subsequent very sudden vaporization of the propellant tears the solution or suspension of azelastine into the finest droplets or minute particles which can be sprayed in the nose or which are available for inspiration into the nose. Certain plastic applicators may be used to actuate the valve and to convey the sprayed suspension into the nose. In the case of application as an aerosol, it is also possible to use a conventional adapter. Particularly preferred embodiments of the present invention are hereinafter described and it will of course be appreciated that any of the previous description of suitable ingredients and formulation characteristics can also be applicable to the following products and formulations as provided by the present invention. It will be appreciated, therefore, that the present invention further provides a pharmaceutical product comprising (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, provided in an aerosol formulation preferably together with a propellant typically suitable for MDI delivery, and (ii) at least one steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, provided in an aerosol formulation preferably together with a propellant typically suitable for MDI delivery, as a combined preparation for simultaneous, separate or sequential 6 use in the treatment of conditions for which administration of one or more anti-histamine and / or one or more steroid is indicated. The present invention also provides an aerosol formulation preferably suitable for MDI delivery comprising (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) at least one steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, together with a propellant. It will also be appreciated from the above, that the respective therapeutic agents of the combined preparation can be administered simultaneously, either in the same or different pharmaceutical formulations, or separately or sequentially. If there is separate or sequential administration, it will also be appreciated that the subsequently administered therapeutic agents should be administered to a patient within a time scale so as to achieve, or more particularly optimise, the above referred to advantageous synergistic therapeutic effect of a combined preparation as present in a pharmaceutical product according to the present invention. Suitable propellants for use in pharmaceutical products of formulations as provided by the present invention include 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3,-heptafluoropropane (HFA 227), or a combination of both, or mono-fluoro trichloromethane and dichloro difiuoromethane, in particular 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), with HFA 134a being preferred. A pharmaceutical aerosol formulation according to the present invention preferably further comprises a polar cosolvent such as C2^ aliphatic alcohols and polyols, for example ethanol, isopropanol and propylene glycol, with ethanol often being preferred. Preferably, the concentration of the cosolvent is in the range of about 2 to 10% by weight, typically up to about 5%, of the total formulation. A pharmaceutical aerosol formulation according to the present invention may further comprise one or more surfactants. Such surfactants can be included to stabilise the formulations and for lubrication of a valve system. Some of the most commonly used surfactants in aerosol formulations are oils derived from natural sources, such as corn oil, olive oil, cottonseed oil and sunflower seed oil, and also phospholipids. Suitable surfactants can include lecithin, oleic acid or sorbitan oleate. A further preferred embodiment of the present invention can be where a formulation 7 or product is provided in the form of insuffiatable powder, where preferably the maximum particle size of the substance suitably does not exceed 10am. Azelastine or its salts and the steroid may be mixed with inert carrier substances or drawn up onto inert carrier substances. Carrier substances which may, for example, be used are: sugars such as glucose, saccharose, lactose and fructose. Also starches or starch derivatives, oligosaccharides such as dextrins, cyclodextrins and their derivatives, polyvinylpyrrolidone, alginic acid, tylose, silicic acid, cellulose, cellulose derivatives (for example cellulose ether), sugar alcohols such as mannitol or sorbitol, calcium carbonate, calcium phosphate, etc. In one embodiment, the therapeutic agents employed have a particle size of less than about 10 urn, preferably less than 5 urn The use of insufflation powders can represent a preferred embodiment of the present invention and there is provided by the present invention a pharmaceutical product comprising (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, provided as an insufflation powder, and (ii) at least one steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, provided as an insufflation powder, as a combined preparation for simultaneous, separate or sequential use in the treatment of conditions for which administration of one or more anti¬histamine and / or one or more steroid is indicated. It will be appreciated from the above, that the respective therapeutic agents of the combined preparation can be administered simultaneously, either in the same or different insufflation powder formulations, or separately or sequentially. If there is separate or sequential administration as discussed above, it will also be appreciated that the subsequently administered therapeutic agents should be administered to a patient within a time scale so as to achieve, or more particularly optimise, the above referred to advantageous synergistic therapeutic effect of a combined preparation as present in a pharmaceutical product according to the present invention The present invention also provides an insufflation powder formulation comprising (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) at least one steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, together with a pharmaceutically acceptable carrier or excipient therefor. Dry insufflation powder formulations as provided by the present invention can be 8 beneficial where it is required that therapeutic agents as employed according to the present invention are retained in the nasal cavity, and systemic side effects can be minimised or eliminated. Furthermore, insufflation powder formulations as employed in the present invention can. be beneficial whereby retention of azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, at the nasal mucosa is improved, and the bitter aftertaste associated with liquid antihistamine formulations significantly reduced, whilst also exhibiting the synergistic therapeutic effect associated with the azelastine / steroid combinations provided by the present invention. By providing a dry insufflation powder formulation of azelastine, together with a steroid, having an average particle size of less than about 10 urn, the therapeutic agents can be restricted primarily to the desired target organ, the nasal mucosa. A dry powder insufflation formulation according to the present invention can be administered by the use of an insufflator, which can produce a finely divided cloud of the dry powder. The insufflator preferably is provided with means to ensure administration of a substantially pre-determined amount of a formulation or product as provided by the present invention. The powder may be used directly with an insufflator which is provided with a bottle or container for the powder, or the powder may be rilled into a capsule or cartridge, such as a gelatin capsule, or other single dose device adapted for administration. The insufflator preferably has means to open the capsule or other dose device. Preferred combinations of therapeutic agents employed in pharmaceutical products and formulations according to the present invention (in particular nasal sprays or drops, aerosol or insufflation products and formulations as described above) comprise any one of the following combinations. The present invention further provides, therefore, a pharmaceutical product comprising (i) azelastine, or a pharmaceutically acceptable salt thereof, and (ii) at least one steroid selected from the group consisting of beclomethasone, fluticasone, mometasone and pharmaceutically acceptable esters thereof, as a combined preparation for simultaneous, separate or sequential use in the treatment of conditions for which administration of one or more anti-mstamine and / or one or more steroid is indicated. Suitably the esters can be selected from beclomethasone dipropionate, fluticasone propionate, fluticasone valerate, mometasone furoate and mometasone furoate monohydrate. 9 The present invention also provides a pharmaceutical formulation comprising (i) azelastine, or a pharmaceutically acceptable salt thereof, and (ii) at least one steroid selected from the group consisting of beclomethasone, fluticasone, mometasone and pharmaceutically acceptable esters thereof, together with a pharmaceutically acceptable carrier or excipient therefor. Suitably the esters can be selected from beclomethasone dipropionate, fluticasone propionate, fluticasone valerate, mometasone furoate and mometasone furoate monohydrate. In the case of a nasal spray, a particularly preferred formulation as provided by the present invention is a nasal spray comprising azelastine, or a pharmaceutically acceptable salt thereof (preferably azelastine hydrochloride), together with mometasone either as the free base or in ester form, preferably as mometasone furoate. Specific combinations of therapeutic agents employed in pharmaceutical products and formulations according to the present invention comprise any one of the following combinations: azelastine hydrochloride and beclomethasone dipropionate; azelastine hydrochloride and fluticasone propionate; azelastine hydrochloride and fluticasone valerate; azelastine hydrochloride and mometasone furoate; and azelastine hydrochloride and mometasone furoate monohydrate. There is also provided by the present invention a method for the prophylaxis or treatment in a mammal, such as a human, of conditions for which administration of one or more anti-histamine and / or one or more steroid is indicated, which method comprises administration of a therapeutically effective amount of a pharmaceutical product substantially as hereinbefore described, as a combined preparation for simultaneous, separate or sequential use in the treatment of such conditions. The present invention also provides a method for the prophylaxis or treatment in a mammal, such as a human, of conditions for which administration of one or more anti¬histamine and / or one or more steroid is indicated, which method comprises administration of a therapeutically effective amount of a pharmaceutical formulation substantially as hereinbefore described. There is also provided by the present invention for use in the manufacture of a medicament for the prophylaxis or treatment in a mammal, such as a human, of conditions for which administration of one or more anti-histamine and / or one or more steroid is indicated, 10 a pharmaceutical product, as a combined preparation for simultaneous, separate or sequential use in the treatment of such conditions. There is further provided by the present invention, therefore, a process of preparing a pharmaceutical product substantially as hereinbefore described, which process comprises providing as a combined preparation for simultaneous, separate or sequential use in the treatment of conditions for which administration of one or more anti-histamine and / or one or more steroid is indicated: (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) at least one steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. The present invention also provides a process of preparing a pharmaceutical formulation substantially as hereinbefore described, which process comprises admixing a pharmaceutically acceptable carrier or excipient with: (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) at least one steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Preferably pharmaceutical formulations according to the present invention can comprise insufflation powder formulations, nasal sprays, nasal inhalation solutions or aerosols substantially as hereinbefore described. The present invention is now illustrated by the following Examples, which do not limit the scope of the invention in any way. In Examples where only the ingredients of formulations according to the present invention are listed, these formulations are prepared by techniques well known in the art. Example 1 Nasal spray or nasal drops with 0.1% azelastine hydrochloride as active ingredient and steroid 0.1% Sr.No Ingredients Quantity %w/v 1. Azelastine hydrochloride 0.1% 2. Steroid 0.1% 3. Disodium edetate 0.005% 11 4. Sodium chloride 0.9% 5. Benzalkonium chloride 0.001% 6. AvicelRC591 1.2% 7. Citric acid monohydrate 0.2% 8. Disodium hydrogen phosphate dodecahydrate 0.1% 9. Purified water Example 2 Dosage aerosol giving off 0.5 mg of azelastine hydrochloride and 50 micrograms of beclomethasone dipropionate fireon solvate per stroke. About 8.0 kg of a mixture of 70 parts by weight of difluorodichloromethane and 30 parts by weight of l,2dichlorotetrafluoroethane are cooled to about -55 degree C in an appropriate cooling vessel. A mixture of 0.086 kg of pre-cooled sorbitantrioleate and 0.8600 kg of pre-cooled trichlorofluoromethane are dissolved with stirring into the mixture at -55 degrees C, 0.0688 kg of micronized azelastine hydrochloride, 0.00688 kg of beclomethasone dipropionate fireon solvate and 0.0688 kg of micronized lactose are then incorporated in portions into the solution thereby obtained with intensive stirring. The total weight of the suspension thereby obtained is made up to 9.547 kg through addition of more of the mixture of 70 parts by weight of difluorodichloromethane and 30 parts by weight of 1,2-dichlorotetrafluoroethane cooled to about -55 degree C. Following closure of the cooling vessel the suspension is again cooled to about -55 degrees C under intensive stirring. It is then ready to be filled. Example 3 Nasal spray or nasal drops with Azelastine and steroid* Sr. No. Ingredients Quantity (% w/w) Azelastine Hydrochloride 0.10 12 1 Fluticasone propionate 0.0357 Glycerin 2.60 AvicelRC591 1.35 Polysorbate 80 0.025 Benzalkonium chloride 0.01 Phenyl ethyl alcohol 0.25 Purified water q.s. Each spray delivers Azelastine Hydrochloride (140 meg) and Fluticasone propionate (50 meg). Example 4 Nasal spray or nasal drops with Azelastine and steroid Sr. No. Ingredients Quantity (% w/w) Azelastine Hydrochloride 0.10 Fluticasone valerate 0.0357 Glycerin 2.60 AviceIRC591 1.20 Polysorbate 80 0.030 Benzalkonium chloride 0.01 Phenyl ethyl alcohol 0.25 Purified water q.s. Each spray delivers Azelastine Hydrochloride (140 meg) and Fluticasone valerate (50 meg). 13 Example 5 Nasal spray or nasal drops with Azelastine and steroid* Sr. No. Ingredients Quantity (% w/w) Azelastine Hydrochloride 0.10 Fluticasone propionate 0.0714 Glycerin 2.60 AvicelRC581 1.35 Polysorbate 80 0.025 Benzalkonium chloride 0.01 Phenyl ethyl alcohol 0.25 Purified water q-s- 1 Each spray delivers Azelastine Hydrochloride (140 meg) and Fluticasone propionate (50 meg). Example 6 Nasal spray or nasal drops with Azelastine and steroid Sr. No. Ingredients Quantity (% w/w) Azelastine Hydrochloride 0.10 Mometasone Furoate 0.05173 Glycerin 2.30 Disodium edetate 0.005 Polysorbate 80 0.0125 AvicelRC581 1.35 Benzalkonium chloride 0.01 Citric acid monohydrate 0.20 Disodium hydrogen phosphate 0.10 14 dodecahydrate Purified water q.s. Example 7 Nasal spray or nasal drops with Azelastine and steroid Sr. No. Ingredients Quantity (% w/w) Azelastine Hydrochloride 0.10 Mometasone Furoate monohydrate 0.05173 Glycerin 2.60 AvicelCL611 2.295 Polysorbate SO 0.0125 Benzalkonium chloride 0.01 Phenyl ethyl alcohol 0.25 Purified water q.s. *Each spray delivers Azelastine Hydrochloride (140 meg) and Mometasone furoate (50 meg). Example 8 Nasal MDI with Azelastine and steroid Sr. No. Ingredients Quantity in meg Azelastine Hydrochloride 140 Mometasone Furoate monohydrate 50 HFA 134a q.s. Lecithin 0.1% Alcohol (up to 5%) 15 Example 9 Nasal MDI with Azelastine and steroid Sr. No. Ingredients Quantity in meg Azelastine Hydrochloride 140 Fluticasone propionate 50 HFA 134a q.s. Sorbitan trioleate 0.1% Alcohol (up to 5%) Example 10 Nasal MDI with Azelastine and steroid Sr. No. Ingredients Quantity in meg Azelastine Hydrochloride 140 Fluticasone propionate 100 HFA134a q.s. Oleic acid 0.1% Example 11 Nasal MDI with Azelastine and steroid Sr. No. Ingredients Quantity in meg Azelastine Hydrochloride 140 Fluticasone Valerate 50 HFA 134a q.s. Alcohol (up to 5%) Imufflatable powders containing Azelastine and Steroid: 16 Example 12 Sr. NO. Ingredients Quantity (% w/w) Azelastine Hydrochloride (Micronized) 140 meg Fluticasone propionate 50 meg Lactose q.s. (up to 25 meg) Example 13 Sr. No. Ingredients Quantity (% w/w) Azelastine Hydrochloride (Micronized) 140 meg Fluticasone propionate 100 meg . Mannitol q.s. (up to 30 meg) Example 14 Sr. No. Ingredients Quantity (% w/w) Azelastine Hydrochloride (Micronized) 140 meg Fluticasone propionate 250 meg Lactose q.s. (up to 30 meg) »7 WE CLAIM; 1. A pharmaceutical formulation which comprises azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and mometasone or a pharmaceutically acceptable ester thereof. 2. A pharmaceutical formulation according to claim 1, wherein said azelastine is present as azelastine hydrochloride. 3. A formulation according to claim 1 or 2, wherein the steroid is mometasone furoate or mometasone furoate monohydrate. 4. A formulation according to any of claims 1 to 3, which contains mometasone or a pharmaceutically acceptable ester thereof in an amount from about 50 micrograms/ml to about 5 mg/ml of the formulation. 5. A formulation according to any of claims 1 to 4, wherein the formulation has a particle size of less than about 10 urn, preferably less than 5 urn. 6. A formulation according to any of claims 1 to 5, which is a suspension containing 0.0005 to 2% (weight/weight of the formulation) of azelastine or a pharmaceutically acceptable salt of azelastine, and from 0.5 to 1.5% (weight/weight of the formulation) of mometasone or a pharmaceutically acceptable ester thereof. 7. A formulation according to claim 6, which contains from 0.001 to 1% (weight/weight of the formulation) azelastine, or salt thereof, and from 0.5% to 1.5% (weight/weight of the formulation) mometasone or a pharmaceutically acceptable ester thereof. 8. A formulation according to any of claims 1 to 7, which also contains a surfactant, comprising a polysorbate or poloxamer surfactant. 9. A formulation according to claim 8, which contains from about 50 micrograms to & about 1 milligram of surfactant per ml of the formulation. 10. A formulation according to any of claims 1 to 9, which also contains an isotonic agent comprising sodium chloride, saccharose, glucose, glycerine, sorbitol or 1,2-propylene glycol. 11. A formulation according to any of claims 1 to 10, which also contains at least one of a buffer, a preservative and a suspending or thickening agent, wherein said preservative is selected from edetic acid and its alkali salts, lower alkyl p-hydroxybenzoates, chlorhexidine, phenyl mercury borate, or benzoic acid or a salt, a quaternary ammonium compound, or sorbic acid or a salt thereof, the suspending agent or thickening agent is selected from cellulose derivatives, gelatin, polyvinylpyrrolidone, tragacanth, ethoxose (water soluble binding and thickening agents on the basis of ethyl cellulose), alginic acid, polyvinyl alcohol, polyacrylic acid, or pectin, and the buffer comprises a citric acid-citrate buffer. 12. A formulation according to claim 11, wherein the buffer maintains the pH of the aqueous phase at from 3 to 7, preferably 4.5 to about 6.5. 13. A formulation according to any preceding claim, which comprises azelastine hydrochloride and mometasone furoate. 14. A formulation according to any preceding claim, which comprises azelastine hydrochloride and and mometasone furoate monohydrate. 15. A formulation according to any of claims 1 to 14, which is in the form of an insufflation powder. 16. A formulation according to any of claims 1 to 15, which is an aqueous suspension or solution. 17. A formulation according to claim 16, which is in the form of an aerosol, an ointment, eye drops, nasal drops, a nasal spray or an inhalation solution. 18. A formulation according to claim 17, which is in the form of nasal drops or nasal spray. 19. A formulation according to claim 17, which is in the form of an aerosol. 20. A pharmaceutical product comprising (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) mometasone or a pharmaceutically acceptable ester thereof, as a combined preparation for simultaneous, separate or sequential use in medicine, said (i) azelastine and (ii) mometasone being in the form of an aerosol formulation for MDI delivery, in the form of an insufflation powder, or in the form of a nasal spray. 21. A pharmaceutical product according to claim 20, which comprises azelastine hydrochloride and mometasone furoate. 22. A pharmaceutical product according to claim 20, which comprises azelastine hydrochloride and and mometasone furoate monohydrate. 23. A pharmaceutical product according to claim 20, 21 or 22, for use as a nasal spray in the treatment of seasonal allergic rhinitius, perennial allergic rhinitis. 24. A pharmaceutical product according to claim 20, 21 or 22, for use as eye drops in the treatment of seasonal allergic conjunctivitis, perennial allergic conjunctivitis.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See Section 10; Rule 13)
TITLE A PHARMACEUTICAL FORMULATION

APPLICANT
CIPLA LIMITED
AN INDIAN COMPANY
OF 289 BELLASIS ROAD, MUMBAI CENTRAL, MUMBAI 400 008
INDIA
The following specification particularly describes the nature of the invention and the manner in which it is performed.

- 1A-
This application is divided out of the Indian Patent Application no. : 733/MUMNP/2004
The present invention relates to pharmaceutical products and formulations. More particularly the present invention relates to pharmaceutical products and formulations useful for preventing or minimising allergic reactions. More particularly, but not exclusively, the present invention relates to pharmaceutical products and formulations for nasal and ocular use.
Such allergic reactions commonly comprise the allergy-related and vasomotor-related symptoms and the rhinovirus-related symptoms.
It is known to use antihistamines in nasal sprays and eye drops to treat allergy-related conditions. Thus, for example, it is known to use the antihistamine azelastine (usually as the hydrochloride salt) as a nasal spray against seasonal or perennial allergic rhinitis, or as eye drops against seasonal and perennial allergic conjunctivitis.
It is also known to treat these conditions using a corticosteroid, which will suppress nasal and ocular inflammatory conditions. Among the corticosteroids known for nasal use are, for example, beclomethasone, mometasone, fluticasone, budesonide and cyclosenide. Corticosteroids known for ocular anti-inflammatory use include betamethasone sodium, dexamethasone sodium and prednisolone acetate, for example.
It would be highly desirable, however, to provide a treatment that combines the effects of anti-histamine treatments and steroid treatments, in a phartnaceutically acceptable formulation, which is tolerated in situ, without significantly disrupting the potency of the constituent pharmaceuticals.
We have now found that, very surprisingly, azelastine (4-[(4-Chlorophenyl)methyl]-2-(hexahydro-l-methyl-lH-azepin-4-yl)-l(2H)-phthalazinone), or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, preferably in salt form and even more preferably in the form of the hydrochloride salt, can advantageously be combined with a steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, to provide a stable, very effective combination product or formulation preferably for nasal or ocular treatment. The combination can provide, in a single administration or dosing regime, the antihistaminic properties of azelastine and the anti-

2
inflammatory (and / or other) properties of the steroid, without any significant interference between the two, or adverse reaction in situ.
In one aspect the invention provides a pharmaceutical formulation comprising azelastine or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and a steroid, preferably a corticosteroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, the formulation preferably being in a form suitable for administration nasally or ocularly.
The term "physiologically functional derivative" as used herein denotes a chemical derivative of any of the specific therapeutic agents described herein having the same or similar physiological function as the free base therapeutic agent and, for example, being convertible in the body thereto. According to the present invention, examples of physiologically functional derivatives include esters.
The preferred forms of formulations of the invention are nasal drops, eye drops, nasal sprays, nasal inhalation solutions or aerosols or insufflation powders.
Preferred embodiments of the invention can comprise stable aqueous solutions of azelastine or one or more of its salts, in combination with steroids which may be beclomethasone, mometasone, fluticasone, budesonide or cyclosenide, which can be used in the form of inhalation solution, pressurized aerosoL eye drops or nasal drops, and in a particular preferred embodiment, in the form of a spray (preferably a nasal spray). The spray can, for example, be formed by the use of a conventional spray-squeeze bottle or a pump vaporizer. In addition, it is also possible to use compressed gas aerosols. In a preferred embodiment, 0.03 to 3 mg of azelastine base and 0.05 to 0.15 mg of the steroid should be released per individual actuation.
The formulations preferably contain a preservative and/or stabilizer. These include, for example: ethylene diamine tetra-acetic acid (edetic acid) and its alkali salts (for example dialkali salts such as disodium salt, calcium salt, calcium-sodium salt), lower alkyl p-hydroxybenzoates, chlorhexidine (for example in the form of the acetate or gluconate) and phenyl mercury borate. Other suitable preservatives are: pharmaceutically useful quaternary ammonium compounds, for example cetylpyridinium chloride, tetradecyltrimethyl ammonium bromide, generally known as "cetrimide", benzyldimethyl-[2-[2-[p-(l,l,3,3-tetramethyl-butyl)phenoxy]ethoxy]-ammonium chloride, generally known as "benzethonium chloride" and myristyl picolrnium chloride. Each of these compounds may be used in a

3
concentration of 0.002 to 0.05%, for example 0,02% (weight/volume in liquid formulations, otherwise weight/weight). Preferred preservatives among the quaternary ammonium compounds are, however, alkylbenzyl dimethyl ammonium chloride and mixtures thereof, for example the compounds generally known as "benzalkonium chloride".
The total amount of preservatives in the formulations (solutions, ointments, etc.) is preferably from 0.001 to O.lOg, preferably O.Olg per 100ml of solution/suspension or lOOg of formulation.
In the case of preservatives, the following amounts of individual substances can, for example, be used: thimero sal 0.002-0.02%; benzalkonium chloride 0.002 to 0.02% (in combination with thimero sal the amount of thimero sal is, for example =0.002 to 0.005%;); chlorhexidine acetate or gluconate 0.01 to 0.02%; phenyl mercuric/nitrate, borate, acetate 0.002-0.004%; p-hydroxybenzoic acid ester (for example, a mixture of the methyl ester and propyl ester in the ratio 7:3): preferably 0.05-0.15, more preferably 0.1%.
The preservative used is preferably a combination of edetic acid (for example, as the disodium salt) and benzalkonium chloride. In this combination, the edetic acid is preferably used in a concentration of 0.05 to 0.1%, benzalkonium chloride preferably being used in a concentration of 0.005 to 0.05%, more preferably 0.01%.
In the case of solutions/suspensions reference is always made to percent by weight/volume, in the case of sohd or semi-solid formulations to percent by weight/weight of the formulation.
Further auxiliary substances which may, for example, be used for the formulations of the invention are: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, polyethoxylated sorbitan fatty acid esters (for example polyefhoxylated sorbitan trioleate), sorbimacrogol oleate, synthetic amphotensides (tritons), ethylene oxide ethers of octylphenolformaldehyde condensation products, phosphatides such as lecithin, polyethoxylated fats, polyethoxylated oleotriglycerides and polyethoxylated fatty alcohols. In this context, polyethoxylated means that the relevant substances contain polyoxyethylene chains, the degree of polymerisation of which is generally between 2 to 40, in particular between 10 to 20. These substances are preferably used to improve the solubility of the azelastine component.
It is optionally possible to use additional isotonization agents. Isotonization agents which may, for example, be used are: saccharose, glucose, glycerine, sorbitol, 1,2-propylene

4
glycol and NaCl.
The isotonization agents adjust the osmotic pressure of the formulations to the same osmotic pressure as nasal secretion. For this purpose these substances are in each case to be used in such amount that, for example, in the case of a solution, a reduction in the freezing point of 0.50 to 0.56 degree C is attained in comparison to pure water.
In Example 1, it is possible to use instead of NaCl per 100 ml of solution, for example: Glucose 1H20 3.81g; saccharose 635%; glycerine 2.2g; 1,2-propylene glycol 1.617g; sorbitol 3.84g (in the case of mixtures of these substances correspondingly less may optionally be used).
Moreover, it is possible to add thickening agents to solutions according to the present invention to prevent the solution from flowing out of the nose too quickly and to give the solution a viscosity of about 1.5 to 3, preferably 2 mPa.
Such thickening agents may, for example, be: cellulose derivatives (for example cellulose ether) in which the cellulose-hydroxy groups are partially etherified with lower unsaturated aliphatic alcohols and/or lower unsaturated aliphatic oxyalcohols (for example methyl cellulose, carboxymethyl cellulose, hydroxypropylmethylcellulose), gelatin, polyvinylpyrrolidone, tragacanth, ethoxose (water soluble binding and thickening agents on the basis of ethyl cellulose), alginic acid, polyvinyl alcohol, polyacrylic acid, pectin and equivalent agents. Should these substances contain acid groups, the corresponding physio logically acceptable salts may also be used.
In the event of the use of hydroxypropyl cellulose, 0.1% by weight of the formulation, for example, is used for this purpose.
In the event of the use of Avicel RC 591 or CL11, 0.65-3.0% by weight of the formulation, for example, is used for the purpose.
It is also possible to add to the formulations buffer substances such as citric
acid/sodium hydrogensulphate borate buffer, phosphates (sodium
hydrogenorthophosphate, disodium hydrogenphosphate), trometamol or equivalent conventional buffers in order, for example, to adjust the formulations to a pH value of 3 to 7, preferably 4.5 to 6.5.
The amount of citric acid is, for example, 0.01 to 0.14g, preferably 0.04 to 0.05g, the amount of disodium hydrogenphosphate 0.1 to 0.5g, preferably 0.2 to 0.3g per 100 ml of solution. The weights given relate in each case to the anhydrous substances.

5
In the case of solutions and suspensions, the maximum total concentration of active agent and buffer is preferably less than 5%, in particular less than 2% (weight/volume).
For the nasal application, a solution or suspension can preferably be used which is applied as an aerosol, i.e. in the form of a fine dispersion in air or in another conventional carrier gas, for example by means of a conventional pump vaporizer.
Application as a dosage aerosol is, however, also possible. Dosage aerosols are defined as being pressure packings which contain the azelastine or its salts in combination with steroid, in the form of a solution or suspension in a so-called propellant The propellant may be a pressurized liquid chlorinated, fluorinated hydrocarbon or mixtures of various chlorinated, fluorinated hydrocarbons as well as propane, butane, isobutene or mixtures of these among themselves or with chlorinated, fluorinated hydrocarbons which are gaseous at atmospheric pressure and room temperature. Hydrofluorocarbons (HFCs), such as HFC 134a, and HFC 227a can also be used, and are preferred for environmental reasons. The pressure packing has a dosage or metering valve which, on actuation, releases a defined amount of the solution or suspension of the medicament. The subsequent very sudden vaporization of the propellant tears the solution or suspension of azelastine into the finest droplets or minute particles which can be sprayed in the nose or which are available for inspiration into the nose. Certain plastic applicators may be used to actuate the valve and to convey the sprayed suspension into the nose.
In the case of application as an aerosol, it is also possible to use a conventional adapter.
Particularly preferred embodiments of the present invention are hereinafter described and it will of course be appreciated that any of the previous description of suitable ingredients and formulation characteristics can also be applicable to the following products and formulations as provided by the present invention.
It will be appreciated, therefore, that the present invention further provides a pharmaceutical product comprising (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, provided in an aerosol formulation preferably together with a propellant typically suitable for MDI delivery, and (ii) at least one steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, provided in an aerosol formulation preferably together with a propellant typically suitable for MDI delivery, as a combined preparation for simultaneous, separate or sequential

6
use in the treatment of conditions for which administration of one or more anti-histamine and / or one or more steroid is indicated.
The present invention also provides an aerosol formulation preferably suitable for MDI delivery comprising (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) at least one steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, together with a propellant.
It will also be appreciated from the above, that the respective therapeutic agents of the combined preparation can be administered simultaneously, either in the same or different pharmaceutical formulations, or separately or sequentially. If there is separate or sequential administration, it will also be appreciated that the subsequently administered therapeutic agents should be administered to a patient within a time scale so as to achieve, or more particularly optimise, the above referred to advantageous synergistic therapeutic effect of a combined preparation as present in a pharmaceutical product according to the present invention.
Suitable propellants for use in pharmaceutical products of formulations as provided by the present invention include 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3,-heptafluoropropane (HFA 227), or a combination of both, or mono-fluoro trichloromethane and dichloro difiuoromethane, in particular 1,1,1,2-tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), with HFA 134a being preferred.
A pharmaceutical aerosol formulation according to the present invention preferably further comprises a polar cosolvent such as C2^ aliphatic alcohols and polyols, for example ethanol, isopropanol and propylene glycol, with ethanol often being preferred. Preferably, the concentration of the cosolvent is in the range of about 2 to 10% by weight, typically up to about 5%, of the total formulation.
A pharmaceutical aerosol formulation according to the present invention may further comprise one or more surfactants. Such surfactants can be included to stabilise the formulations and for lubrication of a valve system. Some of the most commonly used surfactants in aerosol formulations are oils derived from natural sources, such as corn oil, olive oil, cottonseed oil and sunflower seed oil, and also phospholipids. Suitable surfactants can include lecithin, oleic acid or sorbitan oleate.
A further preferred embodiment of the present invention can be where a formulation

7
or product is provided in the form of insuffiatable powder, where preferably the maximum particle size of the substance suitably does not exceed 10am. Azelastine or its salts and the steroid may be mixed with inert carrier substances or drawn up onto inert carrier substances. Carrier substances which may, for example, be used are: sugars such as glucose, saccharose, lactose and fructose. Also starches or starch derivatives, oligosaccharides such as dextrins, cyclodextrins and their derivatives, polyvinylpyrrolidone, alginic acid, tylose, silicic acid, cellulose, cellulose derivatives (for example cellulose ether), sugar alcohols such as mannitol or sorbitol, calcium carbonate, calcium phosphate, etc.
In one embodiment, the therapeutic agents employed have a particle size of less than about 10 urn, preferably less than 5 urn
The use of insufflation powders can represent a preferred embodiment of the present invention and there is provided by the present invention a pharmaceutical product comprising (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, provided as an insufflation powder, and (ii) at least one steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, provided as an insufflation powder, as a combined preparation for simultaneous, separate or sequential use in the treatment of conditions for which administration of one or more anti¬histamine and / or one or more steroid is indicated.
It will be appreciated from the above, that the respective therapeutic agents of the combined preparation can be administered simultaneously, either in the same or different insufflation powder formulations, or separately or sequentially. If there is separate or sequential administration as discussed above, it will also be appreciated that the subsequently administered therapeutic agents should be administered to a patient within a time scale so as to achieve, or more particularly optimise, the above referred to advantageous synergistic therapeutic effect of a combined preparation as present in a pharmaceutical product according to the present invention
The present invention also provides an insufflation powder formulation comprising (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) at least one steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, together with a pharmaceutically acceptable carrier or excipient therefor.
Dry insufflation powder formulations as provided by the present invention can be

8
beneficial where it is required that therapeutic agents as employed according to the present invention are retained in the nasal cavity, and systemic side effects can be minimised or eliminated. Furthermore, insufflation powder formulations as employed in the present invention can. be beneficial whereby retention of azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, at the nasal mucosa is improved, and the bitter aftertaste associated with liquid antihistamine formulations significantly reduced, whilst also exhibiting the synergistic therapeutic effect associated with the azelastine / steroid combinations provided by the present invention. By providing a dry insufflation powder formulation of azelastine, together with a steroid, having an average particle size of less than about 10 urn, the therapeutic agents can be restricted primarily to the desired target organ, the nasal mucosa.
A dry powder insufflation formulation according to the present invention can be administered by the use of an insufflator, which can produce a finely divided cloud of the dry powder. The insufflator preferably is provided with means to ensure administration of a substantially pre-determined amount of a formulation or product as provided by the present invention. The powder may be used directly with an insufflator which is provided with a bottle or container for the powder, or the powder may be rilled into a capsule or cartridge, such as a gelatin capsule, or other single dose device adapted for administration. The insufflator preferably has means to open the capsule or other dose device.
Preferred combinations of therapeutic agents employed in pharmaceutical products and formulations according to the present invention (in particular nasal sprays or drops, aerosol or insufflation products and formulations as described above) comprise any one of the following combinations.
The present invention further provides, therefore, a pharmaceutical product comprising (i) azelastine, or a pharmaceutically acceptable salt thereof, and (ii) at least one steroid selected from the group consisting of beclomethasone, fluticasone, mometasone and pharmaceutically acceptable esters thereof, as a combined preparation for simultaneous, separate or sequential use in the treatment of conditions for which administration of one or more anti-mstamine and / or one or more steroid is indicated. Suitably the esters can be selected from beclomethasone dipropionate, fluticasone propionate, fluticasone valerate, mometasone furoate and mometasone furoate monohydrate.

9
The present invention also provides a pharmaceutical formulation comprising (i) azelastine, or a pharmaceutically acceptable salt thereof, and (ii) at least one steroid selected from the group consisting of beclomethasone, fluticasone, mometasone and pharmaceutically acceptable esters thereof, together with a pharmaceutically acceptable carrier or excipient therefor. Suitably the esters can be selected from beclomethasone dipropionate, fluticasone propionate, fluticasone valerate, mometasone furoate and mometasone furoate monohydrate.
In the case of a nasal spray, a particularly preferred formulation as provided by the present invention is a nasal spray comprising azelastine, or a pharmaceutically acceptable salt thereof (preferably azelastine hydrochloride), together with mometasone either as the free base or in ester form, preferably as mometasone furoate.
Specific combinations of therapeutic agents employed in pharmaceutical products and formulations according to the present invention comprise any one of the following combinations:
azelastine hydrochloride and beclomethasone dipropionate; azelastine hydrochloride and fluticasone propionate; azelastine hydrochloride and fluticasone valerate; azelastine hydrochloride and mometasone furoate; and azelastine hydrochloride and mometasone furoate monohydrate. There is also provided by the present invention a method for the prophylaxis or treatment in a mammal, such as a human, of conditions for which administration of one or more anti-histamine and / or one or more steroid is indicated, which method comprises administration of a therapeutically effective amount of a pharmaceutical product substantially as hereinbefore described, as a combined preparation for simultaneous, separate or sequential use in the treatment of such conditions.
The present invention also provides a method for the prophylaxis or treatment in a mammal, such as a human, of conditions for which administration of one or more anti¬histamine and / or one or more steroid is indicated, which method comprises administration of a therapeutically effective amount of a pharmaceutical formulation substantially as hereinbefore described.
There is also provided by the present invention for use in the manufacture of a medicament for the prophylaxis or treatment in a mammal, such as a human, of conditions for which administration of one or more anti-histamine and / or one or more steroid is indicated,

10
a pharmaceutical product, as a combined preparation for simultaneous, separate or sequential
use in the treatment of such conditions.
There is further provided by the present invention, therefore, a process of preparing a
pharmaceutical product substantially as hereinbefore described, which process comprises
providing as a combined preparation for simultaneous, separate or sequential use in the treatment of conditions for which administration of one or more anti-histamine and / or one or more steroid is indicated: (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) at least one steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
The present invention also provides a process of preparing a pharmaceutical formulation substantially as hereinbefore described, which process comprises admixing a pharmaceutically acceptable carrier or excipient with: (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) at least one steroid, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof. Preferably pharmaceutical formulations according to the present invention can comprise insufflation powder formulations, nasal sprays, nasal inhalation solutions or aerosols substantially as hereinbefore described.
The present invention is now illustrated by the following Examples, which do not limit the scope of the invention in any way. In Examples where only the ingredients of formulations according to the present invention are listed, these formulations are prepared by techniques well known in the art.
Example 1
Nasal spray or nasal drops with 0.1% azelastine hydrochloride as active ingredient and steroid 0.1%

Sr.No Ingredients Quantity %w/v
1. Azelastine hydrochloride 0.1%
2. Steroid 0.1%
3. Disodium edetate 0.005%

11

4. Sodium chloride 0.9%
5. Benzalkonium chloride 0.001%
6. AvicelRC591 1.2%
7. Citric acid monohydrate 0.2%
8. Disodium hydrogen phosphate dodecahydrate 0.1%
9. Purified water
Example 2
Dosage aerosol giving off 0.5 mg of azelastine hydrochloride and 50 micrograms of beclomethasone dipropionate fireon solvate per stroke.
About 8.0 kg of a mixture of 70 parts by weight of difluorodichloromethane and 30 parts by weight of l,2dichlorotetrafluoroethane are cooled to about -55 degree C in an appropriate cooling vessel. A mixture of 0.086 kg of pre-cooled sorbitantrioleate and 0.8600 kg of pre-cooled trichlorofluoromethane are dissolved with stirring into the mixture at -55 degrees C, 0.0688 kg of micronized azelastine hydrochloride, 0.00688 kg of beclomethasone dipropionate fireon solvate and 0.0688 kg of micronized lactose are then incorporated in portions into the solution thereby obtained with intensive stirring. The total weight of the suspension thereby obtained is made up to 9.547 kg through addition of more of the mixture of 70 parts by weight of difluorodichloromethane and 30 parts by weight of 1,2-dichlorotetrafluoroethane cooled to about -55 degree C.
Following closure of the cooling vessel the suspension is again cooled to about -55 degrees C under intensive stirring. It is then ready to be filled.
Example 3
Nasal spray or nasal drops with Azelastine and steroid*

Sr. No. Ingredients Quantity (% w/w)
Azelastine Hydrochloride 0.10

12

1 Fluticasone propionate 0.0357
Glycerin 2.60
AvicelRC591 1.35
Polysorbate 80 0.025
Benzalkonium chloride 0.01
Phenyl ethyl alcohol 0.25
Purified water q.s.
*Each spray delivers Azelastine Hydrochloride (140 meg) and Fluticasone propionate (50 meg).
Example 4
Nasal spray or nasal drops with Azelastine and steroid*

Sr. No. Ingredients Quantity (% w/w)
Azelastine Hydrochloride 0.10
Fluticasone valerate 0.0357
Glycerin 2.60
AviceIRC591 1.20
Polysorbate 80 0.030
Benzalkonium chloride 0.01
Phenyl ethyl alcohol 0.25
Purified water q.s.
Each spray delivers Azelastine Hydrochloride (140 meg) and Fluticasone valerate (50 meg).

13 Example 5
Nasal spray or nasal drops with Azelastine and steroid*

Sr. No. Ingredients Quantity (% w/w)
Azelastine Hydrochloride 0.10
Fluticasone propionate 0.0714
Glycerin 2.60
AvicelRC581 1.35
Polysorbate 80 0.025
Benzalkonium chloride 0.01
Phenyl ethyl alcohol 0.25
Purified water q-s- 1
*Each spray delivers Azelastine Hydrochloride (140 meg) and Fluticasone propionate (50 meg).
Example 6
Nasal spray or nasal drops with Azelastine and steroid

Sr. No. Ingredients Quantity (% w/w)
Azelastine Hydrochloride 0.10
Mometasone Furoate 0.05173
Glycerin 2.30
Disodium edetate 0.005
Polysorbate 80 0.0125
AvicelRC581 1.35
Benzalkonium chloride 0.01
Citric acid monohydrate 0.20
Disodium hydrogen phosphate 0.10

14

dodecahydrate
Purified water q.s.
Example 7
Nasal spray or nasal drops with Azelastine and steroid*

Sr. No. Ingredients Quantity (% w/w)
Azelastine Hydrochloride 0.10
Mometasone Furoate monohydrate 0.05173
Glycerin 2.60
AvicelCL611 2.295
Polysorbate SO 0.0125
Benzalkonium chloride 0.01
Phenyl ethyl alcohol 0.25
Purified water q.s.
*Each spray delivers Azelastine Hydrochloride (140 meg) and Mometasone furoate (50 meg).
Example 8
Nasal MDI with Azelastine and steroid

Sr. No. Ingredients Quantity in meg
Azelastine Hydrochloride 140
Mometasone Furoate monohydrate 50
HFA 134a q.s.
Lecithin 0.1%
Alcohol (up to 5%)

15
Example 9
Nasal MDI with Azelastine and steroid

Sr. No. Ingredients Quantity in meg
Azelastine Hydrochloride 140
Fluticasone propionate 50
HFA 134a q.s.
Sorbitan trioleate 0.1%
Alcohol (up to 5%)
Example 10
Nasal MDI with Azelastine and steroid

Sr. No. Ingredients Quantity in meg
Azelastine Hydrochloride 140
Fluticasone propionate 100
HFA134a q.s.
Oleic acid 0.1%
Example 11
Nasal MDI with Azelastine and steroid

Sr. No. Ingredients Quantity in meg
Azelastine Hydrochloride 140
Fluticasone Valerate 50
HFA 134a q.s.
Alcohol (up to 5%)
Imufflatable powders containing Azelastine and Steroid:

16
Example 12

Sr. NO. Ingredients Quantity (% w/w)
Azelastine
Hydrochloride
(Micronized) 140 meg
Fluticasone propionate 50 meg
Lactose q.s. (up to 25 meg)
Example 13

Sr. No. Ingredients Quantity (% w/w)
Azelastine
Hydrochloride
(Micronized) 140 meg
Fluticasone propionate 100 meg
. Mannitol q.s. (up to 30 meg)
Example 14

Sr. No. Ingredients Quantity (% w/w)
Azelastine
Hydrochloride
(Micronized) 140 meg
Fluticasone propionate 250 meg
Lactose q.s. (up to 30 meg)

»7
WE CLAIM;
1. A pharmaceutical formulation which comprises azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and mometasone or a pharmaceutically acceptable ester thereof.
2. A pharmaceutical formulation according to claim 1, wherein said azelastine is present as azelastine hydrochloride.
3. A formulation according to claim 1 or 2, wherein the steroid is mometasone furoate or mometasone furoate monohydrate.
4. A formulation according to any of claims 1 to 3, which contains mometasone or a pharmaceutically acceptable ester thereof in an amount from about 50 micrograms/ml to about 5 mg/ml of the formulation.
5. A formulation according to any of claims 1 to 4, wherein the formulation has a particle size of less than about 10 urn, preferably less than 5 urn.
6. A formulation according to any of claims 1 to 5, which is a suspension containing 0.0005 to 2% (weight/weight of the formulation) of azelastine or a pharmaceutically acceptable salt of azelastine, and from 0.5 to 1.5% (weight/weight of the formulation) of mometasone or a pharmaceutically acceptable ester thereof.
7. A formulation according to claim 6, which contains from 0.001 to 1% (weight/weight of the formulation) azelastine, or salt thereof, and from 0.5% to 1.5% (weight/weight of the formulation) mometasone or a pharmaceutically acceptable ester thereof.
8. A formulation according to any of claims 1 to 7, which also contains a surfactant, comprising a polysorbate or poloxamer surfactant.
9. A formulation according to claim 8, which contains from about 50 micrograms to

&
about 1 milligram of surfactant per ml of the formulation.
10. A formulation according to any of claims 1 to 9, which also contains an isotonic agent comprising sodium chloride, saccharose, glucose, glycerine, sorbitol or 1,2-propylene glycol.
11. A formulation according to any of claims 1 to 10, which also contains at least one of a buffer, a preservative and a suspending or thickening agent, wherein said preservative is selected from edetic acid and its alkali salts, lower alkyl p-hydroxybenzoates, chlorhexidine, phenyl mercury borate, or benzoic acid or a salt, a quaternary ammonium compound, or sorbic acid or a salt thereof, the suspending agent or thickening agent is selected from cellulose derivatives, gelatin, polyvinylpyrrolidone, tragacanth, ethoxose (water soluble binding and thickening agents on the basis of ethyl cellulose), alginic acid, polyvinyl alcohol, polyacrylic acid, or pectin, and the buffer comprises a citric acid-citrate buffer.
12. A formulation according to claim 11, wherein the buffer maintains the pH of the aqueous phase at from 3 to 7, preferably 4.5 to about 6.5.
13. A formulation according to any preceding claim, which comprises azelastine hydrochloride and mometasone furoate.
14. A formulation according to any preceding claim, which comprises azelastine hydrochloride and and mometasone furoate monohydrate.
15. A formulation according to any of claims 1 to 14, which is in the form of an insufflation powder.
16. A formulation according to any of claims 1 to 15, which is an aqueous suspension or solution.
17. A formulation according to claim 16, which is in the form of an aerosol, an ointment, eye drops, nasal drops, a nasal spray or an inhalation solution.

18. A formulation according to claim 17, which is in the form of nasal drops or nasal spray.
19. A formulation according to claim 17, which is in the form of an aerosol.
20. A pharmaceutical product comprising (i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) mometasone or a pharmaceutically acceptable ester thereof, as a combined preparation for simultaneous, separate or sequential use in medicine, said (i) azelastine and (ii) mometasone being in the form of an aerosol formulation for MDI delivery, in the form of an insufflation powder, or in the form of a nasal spray.
21. A pharmaceutical product according to claim 20, which comprises azelastine hydrochloride and mometasone furoate.
22. A pharmaceutical product according to claim 20, which comprises azelastine hydrochloride and and mometasone furoate monohydrate.
23. A pharmaceutical product according to claim 20, 21 or 22, for use as a nasal spray in the treatment of seasonal allergic rhinitius, perennial allergic rhinitis.
24. A pharmaceutical product according to claim 20, 21 or 22, for use as eye drops in the treatment of seasonal allergic conjunctivitis, perennial allergic conjunctivitis.

A PHARMACEUTICAL FORMULATION

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