(19)
`
`(12)
`
`(cid:6)(cid:27)&(cid:11)(cid:11)(cid:12)(cid:16)(cid:12)(cid:20)(cid:18)(cid:14)(cid:12)(cid:24)(cid:12)(cid:6)
`EP 1 519 731 B1
`
`(11)
`
`A61K31/56(2006.01)
`A61K31/58(2006.01)
`A61P37/08(2006.01)
`A61P11/06(2006.01)
`
`(45) Date of publication and mention
`of the grant of the patent:
`15.04.2009 Bulletin 2009/16
`
`(21) Application number: 03738280.1
`
`EUROPEAN PATENT SPECIFICATION
`(51) Int Cl.:(cid:3)
`A61K31/55(2006.01)
`A61K31/57(2006.01)
`A61K9/00(2006.01)
`A61P27/14(2006.01)
`
`(22) Date of filing: 13.06.2003
`
`(86) International application number:
`PCT/GB2003/002557
`
`(87) International publication number:
`WO 2003/105856 (24.12.2003 Gazette 2003/52)(cid:3)
`
`(54) COMBINATION OF AZELASTINE AND FLUTICASONE
`
`KOMBINATION VON AZELASTINE UND FLUTICASONE
`
`ASSOCIATION D’AZELASTINE ET DE FLUTICASONE
`
`(84) Designated Contracting States:
`AT BE BG CH CY CZ DE DK EE ES FI FR GB GR
`HU IE IT LI LU MC NL PT RO SE SI SK TR
`Designated Extension States:
`LT LV MK
`
`(30) Priority: 14.06.2002 GB 0213739
`
`(43) Date of publication of application:
`06.04.2005 Bulletin 2005/14
`(73) Proprietor: Cipla Ltd.(cid:3)
`Mumbai 400 008 (IN)(cid:3)
`
`(72) Inventors:
`• LULLA, Amar
`Mumbai 400 005 (IN)(cid:3)
`• MALHOTRA, Geena
`Mumbai 400 010 (IN)(cid:3)
`
`(74) Representative: Curtis, Philip Anthony et al
`A.A. Thornton & Co.
`235 High Holborn
`London WC1V 7LE (GB)(cid:3)
`
`(56) References cited:
`EP-(cid:3)A- 0 780 127
`
`WO-(cid:3)A-(cid:3)97/01337
`
`• DATABASE MEDLINE [Online] US NATIONAL
`LIBRARY OF MEDICINE (NLM), BETHESDA, MD,
`US; 2000 PORTMANN D ET AL: "[Acceptability of
`local treatment of allergic rhinitis with a
`combination of a corticoid (beclomethasone) and
`an antihistaminic (azelastine)]" Database
`accession no. NLM11233712 XP002252974 &
`REVUE DE LARYNGOLOGIE - OTOLOGIE -
`RHINOLOGIE. FRANCE 2000, vol. 121, no. 4, 2000,
`pages 273-279, ISSN: 0035-1334
`• BUSSE W W ET AL: "CORTICOSTEROID-(cid:3)
`SPARING EFFECT OF AZELASTINE IN THE
`MANAGEMENT OF BRONCHIAL ASTHMA"
`AMERICAN JOURNAL OF RESPIRATORY AND
`CRITICAL CARE MEDICINE, AMERICAN LUNG
`ASSOCIATION, NEW YORK, NY, US, vol. 153, no.
`1, 1996, pages 122-127, XP000604179 ISSN:
`1073-449X
`
`Remarks:
`The file contains technical information submitted after
`the application was filed and not included in this
`specification
`
`Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent
`Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the
`Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been
`paid. (Art. 99(1) European Patent Convention).
`
`Printed by Jouve, 75001 PARIS (FR)
`
`EP1 519 731B1
`
`CIPLA LTD. EXHIBIT 2030 PAGE 1
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`

`

`EP 1 519 731 B1
`
`Description
`(cid:3)[0001] The present invention relates to pharmaceutical products according to claim 20 and formulations according to
`claim 1. More particularly the present invention relates to said pharmaceutical products and formulations useful for
`preventing or minimising allergic reactions. More particularly, but not exclusively, the present invention relates to said
`pharmaceutical products and formulations for nasal and ocular use.
`(cid:3)[0002] Such allergic reactions commonly comprise the allergy-(cid:3)related and vasomotor-(cid:3)related symptoms and the rhi-
`novirus-(cid:3)related symptoms.
`(cid:3)[0003]
`It is known to use antihistamines in nasal sprays and eye drops to treat allergy-(cid:3)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.
`(cid:3)[0004]
`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-(cid:3)inflammatory use include betamethasone sodium,
`dexamethasone sodium and prednisolone acetate, for example.
`(cid:3)[0005]
`It would be highly desirable, however, to provide a treatment that combines the effects of anti-(cid:3)histamine treat-
`ments and steroid treatments, in a pharmaceutically acceptable formulation, which is tolerated in situ, without significantly
`disrupting the potency of the constituent pharmaceuticals.
`(cid:3)[0006] We have now found that, very surprisingly, azelastine (4-[(4-(cid:3)Chlorophenyl)(cid:3)methyl]-(cid:3)2-(hexahydro-(cid:3)1-(cid:3)methyl-(cid:3)1H-
`azepin-(cid:3)4-(cid:3)yl)-(cid:3)1(cid:3)(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 the steroid fluticasone, or a pharmaceutically acceptable ester 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-(cid:3)inflammatory (and/or other)
`properties of the steroid fluticasone, without any significant interference between the two, or adverse reaction in situ.
`(cid:3)[0007]
`In one aspect the invention provides a pharmaceutical formulation which comprises azelastine, or a pharma-
`ceutically acceptable salt, solvate or physiologically functional derivative thereof, and fluticasone or a pharmaceutically
`acceptable ester thereof.
`(cid:3)[0008] 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 physio-
`logically functional derivatives include esters.
`(cid:3)[0009] The preferred forms of formulations of the invention are nasal drops, eye drops, nasal sprays, nasal inhalation
`solutions or aerosols or insufflation powders.
`(cid:3)[0010] Preferred embodiments of the invention can comprise stable aqueous solutions of azelastine or one or more
`of its salts, in combination with Fluticasone, 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-(cid:3)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 fluticasone or ester thereof should be released per individual actuation.
`(cid:3)[0011] The formulations preferably contain a preservative and/or stabilizer. These include, for example: ethylene
`diamine tetra-(cid:3)acetic acid (edetic acid) and its alkali salts (for example dialkali salts such as disodium salt, calcium salt,
`calcium-(cid:3)sodium salt), lower alkyl phydroxybenzoates, 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" benzyldir-
`nethyl-[2-[2-[p-(1,1,3,3-(cid:3)tetramethyl-(cid:3)butyl)(cid:3)phenoxy](cid:3)ethoxy]-ammonium chloride, generally known as "benzethonium chlo-
`ride" and myristyl picolinium chloride. Each of these compounds may be used in a concentration of 0.002 to 0.05%, for
`example 0.02% (weight/(cid:3)volume in liquid formulations, otherwise weight/(cid:3)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".
`(cid:3)[0012] The total amount of preservatives in the formulations (solutions, ointments, etc.) is preferably from 0.001 to 0.
`10g, preferably 0.01g per 100ml of solution/(cid:3)suspension or 100g of formulation.
`(cid:3)[0013]
`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/(cid:3)nitrate, borate,
`acetate 0.002-0.004%; p-(cid:3)hydroxybenzoic acid ester (for example, a mixture of the methyl ester and propyl ester in the
`ratio 7:(cid:3)3): preferably 0.05-0.15, more preferably 0.1 %.
`(cid:3)[0014] The preservative used is preferably a combination of edetic acid (for example, as the disodium salt) and
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`EP 1 519 731 B1
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`benzalkonium chloride. In this combination, the edetic acid is preferably used in a concentration of 0.05 to 0.1%, ben-
`zalkonium chloride preferably being used in a concentration of 0.005 to 0.05%, more preferably 0.01%.
`(cid:3)[0015]
`In the case of solutions/(cid:3)suspensions reference is always made to percent by weight/(cid:3)volume, in the case of
`solid or semi-(cid:3)solid formulations to percent by weight/(cid:3)weight of the formulation.
`(cid:3)[0016] 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
`polyethoxylated 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
`(cid:3)[0017]
`It is optionally possible to use additional isotonization agents. Isotonization agents which may, for example, be
`used are: saccharose, glucose, glycerine, sorbitol, 1,2-(cid:3)propylene glycol and NaCl.
`(cid:3)[0018] 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.
`(cid:3)[0019]
`In Example 1, it is possible to use instead of NaCl per 100 ml of solution, for example: Glucose 1H2O 3.81g;
`saccharose 6.35g; glycerine 2.2g; 1,2-(cid:3)propylene glycol 1.617g; sorbitol 3.84g (in the case of mixtures of these substances
`correspondingly less may optionally be used).
`(cid:3)[0020] 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.
`(cid:3)[0021] Such thickening agents may, for example, be: cellulose derivatives (for example cellulose ether) in which the
`cellulose-(cid:3)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 physiologically acceptable salts may also be used.
`(cid:3)[0022]
`In the event of the use of hydroxypropyl cellulose, 0.1% by weight of the formulation, for example, is used for
`this purpose.
`(cid:3)[0023]
`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.
`(cid:3)[0024]
`It is also possible to add to the formulations buffer substances such as citric acid/(cid:3)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.
`(cid:3)[0025] 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.
`(cid:3)[0026]
`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/(cid:3)volume).
`(cid:3)[0027] 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.
`(cid:3)[0028] 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-(cid:3)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 them-
`selves 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.
`(cid:3)[0029]
`In the case of application as an aerosol, it is also possible to use a conventional adapter.
`(cid:3)[0030] 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.
`(cid:3)[0031]
`It will be appreciated, therefore, that the present invention further provides a pharmaceutical product comprising
`
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`EP 1 519 731 B1
`
`(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) the steroid fluti-
`casone, or a pharmaceutically acceptable ester 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 use
`in the treatment of conditions for which administration of one or more anti-(cid:3)histamine and/or one or more steroid is indicated.
`(cid:3)[0032]
`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 se-
`quentially. 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 pharma-
`ceutical product according to the present invention.
`(cid:3)[0033] Suitable propellants for use in pharmaceutical products of formulations as provided by the present invention
`include 1,1,1,2-(cid:3)tetrafluoroethane (HFA 134a) or 1,1,1,2,3,3,3,-heptafluoropropane (HFA 227), or a combination of both,
`or mono-(cid:3)fluoro trichloromethane and dichloro difluoromethane, in particular 1,1,1,2-(cid:3)tetrafluoroethane (HFA 134a) or
`1,1,1,2,3,3,3-(cid:3)heptafluoropropane (HFA 227), with HFA 134a being preferred.
`(cid:3)[0034] A pharmaceutical aerosol formulation according to the present invention preferably further comprises a polar
`cosolvent such as C2-6 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.
`(cid:3)[0035] 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.
`(cid:3)[0036] A further preferred embodiment of the present invention can be where a formulation or product is provided in
`the form of insufflatable powder, where preferably the maximum particle size of the substance suitably does not exceed
`10Pm. Azelastine or its salts and the fluticasone or its esters 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, sac-
`charose, 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 cel-
`lulose ether), sugar alcohols such as mannitol or sorbitol, calcium carbonate, calcium phosphate, etc.
`(cid:3)[0037]
`In one embodiment, the therapeutic agents employed have a particle size of less than about 10 Pm, preferably
`less than 5 Pm.
`(cid:3)[0038]
`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 se-
`quentially. 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.
`(cid:3)[0039] Dry insufflation powder formulations as provided by the present invention can be 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 physiolog-
`ically 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/(cid:3)fluticasone combinations provided by the present invention. By providing a dry insufflation powder for-
`mulation of azelastine, together with fluticasone,(cid:3) having an average particle size of less than about 10 Pm, the therapeutic
`agents can be restricted primarily to the desired target organ, the nasal mucosa.
`(cid:3)[0040] 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-(cid:3)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 filled 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.
`(cid:3)[0041] 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.
`(cid:3)[0042] Thus, in another aspect of the present invention, there is provided a pharmaceutical product comprising (i)
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`azelastine, or a pharmaceutically acceptable salt thereof, and (ii) fluticasone or a pharmaceutically acceptable ester
`thereof, as a combined preparation for simultaneous, separate or sequential use in the treatment of conditions for which
`administration of one or more anti-(cid:3)histamine and/or one or more steroid is indicated. Suitably the esters can be selected
`from fluticasone propionate and fluticasone valerate.
`(cid:3)[0043] Specific combinations of therapeutic agents employed in pharmaceutical products and formulations according
`to the present invention comprise any one of the following combinations:(cid:3)
`
`azelastine hydrochloride and fluticasone propionate; and
`azelastine hydrochloride and fluticasone valerate.
`(cid:3)[0044] The pharmaceutical products herein described may be used in methods for the prophylaxis or treatment in a
`mammal, such as a human, of conditions for which administration of one or more anti-(cid:3)histamine and/or one or more
`steroid is indicated, the methods comprising administrating 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.
`(cid:3)[0045] The pharmaceutical formulations of the present invention may also be used in a method for the prophylaxis or
`treatment in a mammal, such as a human, of conditions for which administration of one or more anti-(cid:3)histamine and/or
`one or more steroid is indicated, the methods comprising administrating a therapeutically effective amount of a phar-
`maceutical formulation substantially as hereinbefore described.
`(cid:3)[0046]
`In another aspect of the present invention, there is provided the 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, of a pharmaceutical product, as a combined preparation for simulta-
`neous, separate or sequential use in the treatment of such conditions.
`(cid:3)[0047] The pharmaceutical products substantially as hereinbefore described, may be prepared by a process which
`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-(cid:3)histamine and/or one or more steroid is indicated: (i) azelastine, or a
`pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) fluticasone, or a phar-
`maceutically acceptable ester thereof.
`(cid:3)[0048] The pharmaceutical formulations substantially as hereinbefore described, may be prepared by a process which
`comprises admixing a pharmaceutically acceptable carrier or excipient with: (i) azelastine, or a pharmaceutically accept-
`able salt, solvate or physiologically functional derivative thereof and (ii) fluticasone or a pharmaceutically acceptable
`ester 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.
`(cid:3)[0049] The present invention is now illustrated by the following Examples, which do not limit the scope of the invention
`in any way. Examples 2, 6, 7 and 8 are comparative examples. 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
`(cid:3)[0050] Nasal spray or nasal drops with 0.1% azelastine hydrochloride as active ingredient and steroid 0.1%
`
`Sr. No
`
`Ingredients
`
`Quantity %w/v
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`Azelastine hydrochloride
`
`Steroid
`
`Disodium edetate
`
`Sodium chloride
`
`Benzalkonium chloride
`
`Avicel RC 591
`
`Citric acid monohydrate
`
`0.1%
`
`0.1%
`
`0.005%
`
`0.9%
`
`0.001%
`
`1.2%
`
`0.2%
`
`Disodium hydrogen phosphate dodecahydrate
`
`0.1%
`
`Purified water
`
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`EP 1 519 731 B1
`
`Example 2
`(cid:3)[0051] Dosage aerosol giving off 0.5 mg of azelastine hydrochloride and 50 micrograms of beclomethasone dipropi-
`onate freon solvate per stroke.
`(cid:3)[0052] About 8.0 kg of a mixture of 70 parts by weight of difluorodichloromethane and 30 parts by weight of
`1,2dicblorotetufluoroethane are cooled to about -55 degree C in an appropriate cooling vessel. A mixture of 0.086 kg of
`pre-(cid:3)cooled sorbitantrioleate and 0.8600 kg of pre-(cid:3)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 freon
`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-(cid:3)dichlorotetrafluoroethane
`cooled to about -55 degree C.
`(cid:3)[0053] 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
`(cid:3)[0054]
`
`Example 4
`(cid:3)[0055]
`
`Nasal spray or nasal drops with Azelastine and steroid*
`
`Sr. No.
`
`Ingredients
`
`Quantity (% w/w)
`
`Azelastine Hydrochloride
`
`0.10
`
`Fluticasone propionate
`
`0.0357
`
`Glycerin
`
`Avicel RC 591
`
`Polysorbate 80
`
`Benzalkonium chloride
`
`Phenyl ethyl alcohol
`
`Purified water
`
`2.60
`
`1.35
`
`0.025
`
`0.01
`
`0.25
`
`q. s.
`
`*Each spray delivers Azelastine Hydrochloride (140 mcg)
`and Fluticasone propionate (50 mcg).
`
`Nasal spray or nasal drops with Azelastine and steroid*
`
`Sr. No.
`
`Ingredients
`
`Quantity (% w/w)
`
`Azelastine Hydrochloride
`
`0.10
`
`Fluticasone valerate
`
`0.0357
`
`Glycerin
`
`Avicel RC 591
`
`Polysorbate 80
`
`Benzalkonium chloride
`
`Phenyl ethyl alcohol
`
`2.60
`
`1.20
`
`0.030
`
`0.01
`
`0.25
`
`6
`
`CIPLA LTD. EXHIBIT 2030 PAGE 6
`
`CIPLA LTD. EXHIBIT 2030 PAGE 6
`
`

`

`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Example 5
`(cid:3)[0056]
`
`Example 6
`(cid:3)[0057]
`
`Example 7
`(cid:3)[0058]
`
`EP 1 519 731 B1
`
`(continued)
`
`Sr. No.
`
`Ingredients
`
`Quantity (% w/w)
`
`Purified water
`
`q. s.
`
`*Each spray delivers Azelastine Hydrochloride (140 mcg)
`and Fluticasone valerate (50 mcg).
`
`Nasal spray or nasal drops with Azelastine and steroid*
`
`Sr. No.
`
`Ingredients
`
`Quantity (% w/w)
`
`Azelastine Hydrochloride
`
`0.10
`
`Fluticasone propionate
`
`0.0714
`
`Glycerin
`
`Avicel RC 581
`
`Polysorbate 80
`
`Benzalkonium chloride
`
`Phenyl ethyl alcohol
`
`Purified water
`
`2.60
`
`1.35
`
`0.025
`
`0.01
`
`0.25
`
`q. s.
`
`*Each spray delivers Azelastine Hydrochloride (140 mcg)
`and Fluticasone propionate (50 mcg).
`
`Nasal spray or nasal drops with Azelastine and steroid
`
`Sr. No.
`
`Ingredients
`
`Quantity (% w/w)
`
`Azelastine Hydrochloride
`
`0.10
`
`Mometasone Furoate
`
`Glycerin
`
`Disodium edetate
`
`Polysorbate 80
`
`Avicel RC 581
`
`Benzalkonium chloride
`
`Citric acid monohydrate
`
`Disodium hydrogen phosphate
`
`dodecahydrate
`
`Purified water
`
`0.05173
`
`2.30
`
`0.005
`
`0.0125
`
`1.35
`
`0.01
`
`0.20
`
`0.10
`
`q. s.
`
`7
`
`CIPLA LTD. EXHIBIT 2030 PAGE 7
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`CIPLA LTD. EXHIBIT 2030 PAGE 7
`
`

`

`5
`
`10
`
`15
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`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Examples 8
`(cid:3)[0059]
`
`Example 9
`(cid:3)[0060]
`
`Example 10
`(cid:3)[0061]
`
`EP 1 519 731 B1
`
`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
`
`Avicel CL 611
`
`Polysorbate 80
`
`Benzalkonium chloride
`
`Phenyl ethyl alcohol
`
`Purified water
`
`2.60
`
`2.295
`
`0.0125
`
`0.01
`
`0.25
`
`q. s.
`
`*Each spray delivers Azelastine Hydrochloride (140 mcg) and
`Mometasone furoate (50 mcg).
`
`Nasal MDI with Azelastine and steroid
`
`Sr. No.
`
`Ingredients
`
`Quantity in mcg
`
`Azelastine Hydrochloride
`
`Mometasone Furoate monohydrate
`
`HFA 134a
`
`Lecithin
`
`Alcohol
`
`140
`
`50
`
`q.s.
`
`0.1%
`
`(up to 5%)
`
`Nasal MDI with Azelastine and steroid
`
`Sr. No.
`
`Ingredients
`
`Quantity in mcg
`
`Azelastine Hydrochloride
`
`Fluticasone propionate
`
`HFA 134a
`
`Sorbitan trioleate
`
`Alcohol
`
`140
`
`50
`
`q.s.
`
`0.1%
`
`(up to 5%)
`
`Nasal MDI with Azelastine and steroid
`
`Sr. No.
`
`Ingredients
`
`Quantity in mcg
`
`Azelastine Hydrochloride
`
`140
`
`8
`
`CIPLA LTD. EXHIBIT 2030 PAGE 8
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`CIPLA LTD. EXHIBIT 2030 PAGE 8
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`

`

`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Example 11
`(cid:3)[0062]
`
`EP 1 519 731 B1
`
`(continued)
`
`Sr. No.
`
`Ingredients
`
`Quantity in mcg
`
`Fluticasone propionate
`
`HFA 134a
`
`Oleic acid
`
`100
`
`q.s.
`
`0.1%
`
`Nasal MDI with Azelastine and steroid
`
`Sr. No.
`
`Ingredients
`
`Quantity in mcg
`
`Azelastine Hydrochloride
`
`Fluticasone Valerate
`
`HFA 134a
`
`Alcohol
`
`140
`
`50
`
`q.s.
`
`(up to 5%)
`
`(cid:3)[0063]
`
`Insufflatable powders containing Azelastine and Steroid:
`
`Example 12
`(cid:3)[0064]
`
`Example 13
`(cid:3)[0065]
`
`Example 14
`(cid:3)[0066]
`
`Sr. No.
`
`Ingredients
`
`Quantity (% w/w)
`
`Azelastine Hydrochloride (Micronized)
`
`140 mcg
`
`Fluticasone propionate
`
`50 mcg
`
`Lactose
`
`q.s. (up to 25 mcg)
`
`Sr. No.
`
`Ingredients
`
`Quantity (% w/w)
`
`Azelastine Hydrochloride (Micronized)
`
`140 mcg
`
`Fluticasone propionate
`
`100 mcg
`
`Mannitol
`
`q.s. (up to 30 mcg)
`
`Sr. No.
`
`Ingredients
`
`Quantity (% w/w)
`
`Azelastine Hydrochloride (Micronized)
`
`140 mcg
`
`Fluticasone propionate
`
`250 mcg
`
`Lactose
`
`q.s. (up to 30 mcg)
`
`9
`
`CIPLA LTD. EXHIBIT 2030 PAGE 9
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`CIPLA LTD. EXHIBIT 2030 PAGE 9
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`

`

`Claims
`
`EP 1 519 731 B1
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`1. A pharmaceutical formulation which comprises azelastine, or a pharmaceutically acceptable salt, solvate or physi-
`ologically functional derivatives thereof, and fluticasone 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 fluticasone propionate or fluticasone valerate,
`
`4. A formulation according to any of claims 1 to 3, which contains fluticasone 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
`Pm, preferably less than 5 Pm.
`6. A formulation according to any of claims 1 to 5, which is a suspension containing 0.0005 to 2% (weight/(cid:3)weight o