(121UK Patent Application (19)GB (11)2 389 530 (13)A
`
`(43) Date of A Publication
`
`17.12.2003
`
`(21) Application No:
`
`(22) Date of Filing:
`
`0213739.6
`
`14.06.2002
`
`(51) INT CL7:
`A61K31/573 31/ 55, A61P11/00
`
`(71) Applicant(s):
`Clpla Limited
`(Incorporated In lndla)
`289 Bellasls Road, Mumbai Central,
`Mumbai 400 008, lndla
`
`(72) lnventor(s):
`Amar Lulla
`Geena Malhotra
`
`(74) Agent and/or Address for Service:
`A A Thornton & Co
`235 High Holborn, LONDON, WC1V 7LE,
`United Kingdom
`
`(52) UK CL (Edition V ):
`A5B BJA 824Y 8241 8244 8246 8247 848Y 8480
`850Y 8503 854Y 8541 855Y 8552 856Y 8567
`857Y 8576 B58Y 8586 B61Y 8616 865Y 8651
`867Y 8670
`
`(56) Documents Cited:
`EP 0780127 A1
`WO 1997/001337 A1
`
`WO 1998/048839 A1
`DE 019947234 A1
`
`(58) Field of Search:
`UK CL (Edition T ) A5B
`INT CL7 A61K31/55 31/573, A61P11/00
`Other: Online: CAS·ONUNE, EPODOC, WPI, PAJ
`
`(54) Abstract Title: Pharmaceutical composition comprising azelastine and steroid
`
`(57) A pharmaceutical composition comprises azelastine or a salt thereof, and a steroid, the composition
`being in a form suitable for nasal or ocular administration.
`Preferred steroids include beclomethasone, mometazone, fluticasone, budesonide and cyclosenide and
`preferred formulations include aerosols, ointments, eye drops, nasal drops or sprays, inhalation solutions
`or insufflation powders.
`Also provided is a method of treating irritation or disorders of the nose and eye comprising applying
`directly to nasal tissues or to the conjunctiva I sac of the eyes, a medicament which contains a member
`selected from the group consisting of azelastine and its pharmaceutically acceptable salts, in combination
`with a steroid.
`
`G)
`OJ
`l\J
`w
`~
`<.Tl w
`0
`
`Exhibit 1006
`IPR2017-00807
`ARGENTUM
`
`000001
`
`

`

`2389530
`
`-1-
`
`PHARMACEUTICAL COMPOSITIONS
`
`This invention relates to pharmaceutical compositions. More particularly this
`
`invention relates to pharmaceutical compositions useful for preventing or minimising
`
`allergic reactions. More particularly, but not exclusively, this invention relates to
`
`pharmaceutical compositions for nasal and ocular use.
`
`Such allergic reactions commonly comprise the allergy-related and vasomotor(cid:173)
`
`related symptoms and the rhinovirus-related symptoms.
`
`It is known to use antihistamines in nasal sprays and eye drops to treat allergy(cid:173)
`
`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
`
`eye 1 osenide.
`
`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 phannaceutically
`
`acceptable composition, 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-IH-azepin-4-yl)-1(2H)-phthalazinone) , or
`
`a salt thereof, can advantageously be combined with a steroid to provide a stable, very
`
`effective combination composition for nasal or ocular treatment. The combination
`
`provides, in a single administration, the antihistaminic properties of azelastine and the
`
`anti-inflammatory (and/or other) properties of the steroid, without any significant
`
`interference between the two, or adverse reaction in situ.
`
`000002
`
`

`

`-2-
`
`In one aspect the invention provides a pharmaceutical composition comprising
`azelastine or a salt thereof and a steroid, preferably a corticosteroid, the composition
`
`being in a form suitable for administration nasally or ocularly.
`
`The pref erred forms of compositions of the invention are nasal drops, eye drops,
`
`nasal sprays, nasal inhalation solutions or aerosols or insufflation powders.
`
`Preferred embodiments of the invention 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 compositions 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, chlorohexidine (for example in the form of the acetate
`
`or gluconate ), 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-( 1, 1,3,3-tetramethyl-butyl)phenoxy ]ethoxy ]-ammonium
`
`chloride, generally known as "benzethonium chloride" 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/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 amounts of preservatives in the formulations (solutions, ointments, etc.)
`is preferably from 0.001 to O.lOg, preferably O.Olg per IOOml of solution/suspension or
`
`1 OOg of formulation.
`
`000003
`
`

`

`-3-
`
`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 solid 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 polyethoxylated sorbitan
`
`trioleate), sorbimacrogol oleate, synthetic amphotensides (tritons), ethylene oxide ethers
`
`of octylphenolformaldehyde condensation products, phosphatides such as
`
`lecithin,
`
`polyethoxylated fats, polyethoxylated oleotriglycerides, 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 I 0 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 glycol, 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.
`
`000004
`
`

`

`-4-
`
`In Example 1, it is possible to use instead of NaCl per 100 ml of solution, for
`
`example: Glucose 1H20 3.81g; saccharose 6.35g; 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 the solutions 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 physiologically 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 CLll, 0.65-3.0% by weight of the
`
`composition, 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 O.Sg, preferably 0.2 to 0.3g per l 00 ml
`
`of solution. The weights given relate in each case to the anhydrous substances.
`
`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).
`
`000005
`
`

`

`-5-
`
`For the nasal application a solution or suspension is preferably 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 l 34a, can also be used, if desired. The pressure packing has a dosage 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.
`
`In the case of insufflatable powder, the maximum particle size of the substance
`
`preferably does not exceed 1 Oµm. 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 steroid has a particle size of less than about 1 Oµm,
`
`preferably less than 5 µm.
`
`000006
`
`

`

`-6-
`
`DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
`
`The invention is illustrated by the following examples.
`
`EXAMPLE 1
`
`Nasal spray or nasal drops with 0.1 % azelastine hydrochloride as active ingredient and
`
`steroid 0 .1 %
`
`S.NO.
`
`NAME OF INGREDIENTS
`
`OUANTITY
`%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
`
`Disodium hydrogen phosphate dodecahydrate
`
`Purified water
`
`0.1%
`
`0.1%
`
`0.005%
`
`0.9%
`
`0.001%
`
`1.2%
`
`0.2%
`
`0.1%
`
`EXAMPLE 2
`
`Dosage aerosol giving off 0.5 mg of azelastine hydrochloride and 50 micrograms of
`
`Beclomethasone dipropionate freon solvate per stroke.
`
`000007
`
`

`

`-7-
`
`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 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-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.
`
`000008
`
`

`

`-8-
`
`CLAIMS:
`
`A pharmaceutical composition which comprises azelastine or a salt thereof, and a
`
`steroid, the composition being in a form suitable for nasal or ocular administration.
`
`2
`
`A composition according to claim 1, which is an aqueous suspension or solution.
`
`3
`
`A composition according to claim 1 or 2, which is in the form of an aerosol, an
`ointment, eye drops, nasal drops, a nasal spray or an inhalation solution.
`
`4
`
`A composition according to claim 1, which ts in the form of an insufflation
`
`powder.
`
`5
`
`A composition according to any of claims 1 to 4, wherein the steroid is
`
`beclomethasone or an ester thereof, mometasone or an ester thereof, fluticasone or an
`
`ester thereof, budesonide or cyclosenide, in any chiral form or mixture.
`
`6
`
`A composition according to claim 5, wherein the steroid 1s beclomethasone
`
`propionate, mometasone furoate or fluticasone propionate.
`
`7
`
`An composition according to any of claims I to 6, which contains the steroid in an
`
`amount from about 50 micrograms/ml to about 5 mg/ml of the composition.
`
`8
`
`· A composition according to any of claims I to 7, which is a suspension containing
`
`0.0005 to 2% (weight/weight of the composition) of azelastine or a pharmaceutically
`
`acceptable salt of azelastine, and from 0.5 to 1.5% (weight/weight of t~e composition) of
`
`said steroid.
`
`000009
`
`

`

`-9-
`
`9
`
`A composition according to claim 8, which contains from 0.001
`
`to I%
`
`(weight/weight of the composition) azelastine, or salt thereof, and from 0.5% to 1.5%
`
`(weight/weight of the composition) steroid.
`
`10
`
`A composition according to any of claims l to 9, wherein the composition has a
`
`particle size of less than about 1 Oµm, preferably less than 5 µm.
`
`11
`
`A composition according to any of claims I to 10, which also contains a
`
`surfactant.
`
`12
`
`A composition according to claim 11, wherein the surfactant comprises a
`
`polysorbate or poloxamer surfactant.
`
`13
`
`A composition according to claim 10 or 11, which contains from about 50
`
`micrograms to about 1 milligram of surfactant per ml of the composition.
`
`14
`
`A composition according to any of claims 1 to 13, which also contains an isotonic
`
`agent.
`
`15
`
`A composition according to claim 14, wherein the isotonic agent comprises
`
`sodium chloride, saccharose, glucose, glycerine, sorbitol or 1,2-propylene glycol.
`
`16
`
`A composition according to any of claims 1 to 15, which also contains at least one
`
`of a buffer, a preservative and a suspending or thickening agent.
`
`17
`
`A composition according to claim 16, wherein said preservative is selected from
`
`edetic acid and its alkali salts, lower alkyl p-hydroxybenzoates, chlorohexidine, phenyl
`
`mercury borate, or benzoic acid or a salt, a quaternary ammonium compound, or sorbic
`
`acid or a salt thereof.
`
`000010
`
`

`

`-10-
`
`18
`
`A composition according to claim 16 or 17, wherein the suspending agent or
`
`thickening agent is selected from cellulose derivatives, gelatine, polyvinylpyrrolidone,
`
`tragacanth, ethoxose (water soluble binding and thickening agents on the basis of ethyl
`
`cellulose), alginic acid, polyvinyl alcohol, polyacrylic acid, or pectin.
`
`19
`
`A composition according to claim 16, 1 7 or 18, wherein the buffer comprises a
`
`citric acid-citrate buffer.
`
`20
`
`A composition according to claim 16, 17, 18 or 19, wherein the buffer maintains
`
`the pH of the aqueous phase at from 3 to 7, preferably 4.5 to about 6.5.
`
`21
`
`An aqueous pharmaceutical composition substantially as herein described m
`
`Example 1 or 2.
`
`22
`
`A method of treating irritation or disorders of the nose and eye which comprises
`
`applying directly to nasal tissues or to the conjunctiva! sac of the eyes, a medicament
`
`which contains a member selected from the group consisting of azelastine and its
`
`pharmaceutically acceptable salts, in combination with a steroid.
`
`23
`
`A method according to claim 22, in which the medicament is a composition as
`
`claimed in any of claims 1 to 21.
`
`24
`
`A method of treating airway disorders, comprising administering by nebulization
`
`to surfaces of the airway a treatment-effective amount of a composition as claimed in any
`
`of claims 1to21.
`
`000011
`
`

`

`a
`
`.
`..... •
`
`()
`
`~--cP
`11\\'l!S fOH 11\ l'hOPLE
`
`Application No:
`Claims searched:
`
`GB 0213739.6
`1-24
`
`Examiner:
`Date of search:
`
`Lee Ellison
`22 November 2002
`
`Patents Act 1977
`Search Report under Section 17
`
`Databases searched:
`
`UK Patent Office collections, including GB, EP, WO & US patent specifications, in:
`
`UK Cl (Ed.T): ASB
`
`Int Cl (Ed.7): A61K 31/55; A61K 31/573; A61P 11100
`
`Other: CAS-ONLINE, EPODOC, WPI, P AJ
`
`Documents considered to be rele'\lant:
`
`Category Identity of document and relevant passage
`
`x
`
`EP 0780127 Al
`
`x WO 98/48839 Al
`
`x WO 97101337 Al
`
`x
`
`DE 19947234 Al
`
`(PROCTER & GAMBLE CO.) See pp. 3 lines 5-30,
`34-41 & 45-50; pp. 3 line 59 - pp. 4 line 2; pp. 4 line
`56 - pp. 5 line 22; & Example I & III, especially
`Example III.
`
`(WARNER-LAMBERT COMPANY) See pp. 1
`lines 4-11; pp. 2 line 18 - pp. 3 line 12; pp. 3 lines
`19-20; pp. 3 lines 29-31; & pp. 4 lines 4-14 & 20-28.
`
`(McNEIL-PPC, INC) See pp. 1 Jines 3-7; pp. 2 lines
`8-17, 20-25 & 29-31; pp. 3 lines 4-7 & 19-22; pp. 3
`line 35 - 7; pp. 4 lines 11-16 & 31-36; pp. 5 lines 9-
`27; pp.6 lines 12-15; pp. 7 lmes 14-16; & pp 7 line
`22 - pp. 8 line 5.
`
`(AST A MEDI CA AG) See EPODOC abstract and
`WPI abstract Acc. No. 2001-274582 (29]. See also
`patent specification, especially Tabelle I or 2.
`
`Relevant
`to claims
`
`1-24
`
`1-24
`
`1-24
`
`1-24
`
`x
`y
`
`Document md1catmg lack of novelty or mvent1ve step
`Document mdtcatmg lack of inventive step 1f combmed
`with one or more other documents of same category
`
`& Member of the same patent family
`
`A Document md1catmg technolog1cal background and/or state of the art
`P Document pubhshed on or after the decla1ed pnomydate but before the
`filing date ofth1s mvent1on
`E Patent document pubhshed on or afier, but with pnorny date earlter
`than, the filmg date of this apphcat1on
`
`An Execut 1 vc Agency of the Department of Trade and Indu'>ll)'
`
`000012
`
`