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`
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`EXHIBIT 6
`
`EXHIBIT 6
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`
`
`

`
`l
`Case 1:14-cv-01453-LPS Document 43-3 Filed 10/22/15 Page 2 of 43 PageID #: 278
`US. PATEl\'l‘ AND TRADEMARK OFFICE: U.S. DEPARTME.t\'1' OF COMMERCE
`FORM PTO-1390 (Modified)
`A1'roRN£Y's;>ocKE NUMBER
`r
`\
`(REV. 07-2004)
`TPP3l753
`
`TRANSMITTAL LET'Er{ TO THE UNITED STATES
`
`DESIGNATED/ELECTED OFFICE (DO/EO/US)
`
`5
`-
`
`CONCERNING A SUBMISSION UNDER 35 U.S.C. 371
`INTERNATIONAL APPLICATION No.
`-
`PCT/GBO3/02557
`TITLE or INVENTION
`COMBINATION OF AZELASTINE AND STEROIDS
`
`13 June 2003
`
`U.S. APPLICATION NO. (If known, see 37 CFR 1.5)
`1 0/ 518 U 16
`
`14 June 2002
`
`APPL1CANT(SILIfOR DO/E0/US
`Amar LULLA
`Geena MALHORTRA
`
`Applicant herewith submits to the United States Designated/Elected Office (DO/E07/U S) the following items and other information:
`
`This is a FIRST submission of items concerning a submission under 35 U.S.C. 371.
`
`This is a SECOND or SUBSEQUENT submission of items concerning a submission under 35 USC. 371.
`This is an express request to begin national examination procedures (35 U.S.C. 371(t)). The submission must include items (5),
`(6), (9) and (24) indicated below.
`The US has been elected (Article 31).
`A copy ofthe Intemational Application as filed (35 U.S.C. 371 (c) (2))
`a.
`'14
`is attached hereto (required only if not communicated by the International Bureau).
`b. Ci
`has been communicated by the lntemational Bureau.
`C.
`1:1
`is not required, as the application was tiled in the United States Receiving Office (RO/US).
`An English language translation of the International Application as filed (35 U.S.C. 371(c)(2)).
`a. E]
`is attached hereto.
`
`b. Ci
`
`has been previously submitted under 35 U.S.C. l54(d)(4).
`
`Amendments to the claims ofthe International Application under PCT Article 19 (35 U.S.C. 371 (c)(3))
`a. Cl
`are attached hereto (required only if not communicated by the International Bureau). '
`b. D
`have been communicated by the lntemational Bureau.
`c. C]
`have not been made; however, the time limit for making such amendments has NOT expired.
`have not been made and will not be made.
`d. El
`
`An English language translation ofthe amendments to the claims under PCT Article 19 (35 U.S.C. 371(c)(3)).
`An oath or declaration of the inventor(s) (35 U.S.C. 371 (c)(4)).
`
`An English language translation ofthe annexes to the International Preliminary Examination Report under PCT
`Article 36 (35 U.S.C. 371 (c)(5)).
`
`A copy ofthe International Preliminary Examination Report (PCT/lPEA!409).
`A copy ofthe International Search Report (PCT/ISA/210).
`
`NIXl’ll‘|Fl
`
`Items 13 to 23 below concern document(s) or information included:
`An Information Disclosure Statement under 37 CFR 1.97 and 1.98.
`
`Ei‘|Vl|‘|l—ll7||‘||_llZ|—|l7
`
`An assignment document for recording. A separate cover sheet in compliance with 37 CFR 3.28 and 3.31 is included.
`A FIRST preliminary amendment.
`A SECOND or SUBSEQUENT preliminary amendment.
`A substitute specification.
`A power of attorney and/or change of address letter.
`
`A computer-readable form ofthe sequence listing in accordance with PCT Rule l3ter.2 and 37 CFR 1.821 - 1.825.
`A second copy ofthe published lntemational Application under 35 U.S.C. l54(d)(4).
`
`A second copy ofthe English language translation ofthe International Application under 35 U.S.C. l54(d)(4).
`Express Mail Label No.
`Other items or information:
`
`12.
`
`13.
`14.
`15.
`16.
`17.
`18.
`19.
`20.
`21.
`22.
`23.
`
`Notice of Claim for Priority
`Cover Sheet of WO 0311005856
`
`Application Data Sheet
`
`Page I of 2
`
`Pcrust/Revo4
`
`M ED_DYM_0O000002
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`

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`t
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`Case 1:14-cv-01453-LPS Document 43-3 Filed 10/22/15 Page 3 of 43 PageID #: 279
`ALL _
`’
`A
`83
`-
`‘N '
`INTERNATIONAL APPLICATION NO.
`ATTORNEYS DOCKET NUMBER
`PCT/GB03/02557
`TPP3l753
`
`24,
`
`‘The following fees are submitted:
`a) Basic
`
`b)
`
`5:1
`
`TOTAL OF ABOVE CALCULATIONS =
`
`$300.00
`
`$200.00
`
`$1000.00
`
`D Additional fee for specification and drawings filed in paper over 100 sheets (excluding sequence
`listing or computer program listing filed in an electronic medium). The fee is $250 for each
`additional 50 sheets of aer or fraction thereof.
`
`CALCULATIONS no use ONLY
`
`x $250.00
`
`E
`
`El 8.
`
`$0.00
`
`RATE —
`$50.00
`$1,550.0
`$200.00
`$0.0 —
`$0-0 —
`$2,550.0
`
`‘
`
`%6 ¢G@960
`
`Surcharge of $130.00 for fumishing the oath or declaration later than
`months from the earliest claimed priority date (37 CFR !.492(e)).
`CLAIMS
`NUMBER FILED
`—
`NUMBER EXTRA
`
`Total claims
`Inde endent claims
`
`51
`3
`
`— 20 =
`0
`||
`9-)
`
`x
`x
`
`Multi le Deendent Claims (check if 3 - licable).
`TOTAL OF ABOVE CALCULATIONS
`
`=
`
`[:1 Applicant claims small entity status. See 37 CFR 1.27. The fees indicated above are
`reduced by 1/2.
`
`Processing fee of $130.00 for furnishing the English translation later than
`months from the earliest claimed priority date (37 CFR 1.492(0).
`
`SUBTOTAL 7.
`D 20
`
`-
`
`.
`
`$2,550.00
`
`.
`
`$0_()()
`
`Fee for recording the enclosed assignment (37 CFR l.2l(h)). The assignment must be
`accompanied by an appropriate cover sheet (37 CFR 3.28, 3.31) (check if applicable).
`
`TOTAL FEES ENCLOSED .
`
`. =
`
`$2,550.00—
`
`$0 00
`
`$2,550.00
`Amount to be:
`refunded
`
`'
`
`charged
`
`a.
`
`A check in the amount of $2550. 00
`
`to cover the above fees is enclosed.
`
`'
`
`_
`
`'
`
`Please charge my Deposit Account No.
`
`in the amount of
`
`to cover the above fees.
`
`’
`
`The Director is hereby authorized to charge any additional fees which may be required, or credit any overpayment
`to Deposit Account No.
`19-4375
`'
`-
`
`Fees are to be charged to a credit card. WARNING: Infonnation on this form-may become public. Credit card
`information should not be included on this form. Provide credit card information and authorization on PTO—2038.
`
`NOTE: Where an appropriate time limit under.37 CFR 1.494 or 1.495 has not been met, a petition to revive (37 CFR
`I.l37(a) or (b)) must be filed and granted to restore the International Application to-pending status.
`’
`
`SEND ALL CORRESPONDENCE TO:
`
`Thomas P. Pavelko
`
`STEVENS, DAVIS, 'MILI_.ER & MOSHER, LLP
`1615 L Street N.W., Suite 850
`Washington, D.C. 20036
`Tel: 202-785-0100
`Fax: 202-785-0200
`
`SIGNATURE
`
`Thomas P. Pavelko
`NAME
`
`31,689
`
`REGISTRATION NUMBER
`
`December‘l4, 2004
`DATE
`
`Page 2 of2
`
`M ED_DYM_00000003
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`

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`Case 1:14-cv-01453-LPS Document 43-3 Filed 10/22/15 Page 4 of 43 PageID #: 280
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`W0 03/105856
`PCT/GB03/02557
`10/518 016
`
`QOMBINATION OF AZE_I_3_§§ElLl§ $2 SIEROIDS
`
`The present invention relates to pharmaceutical products and formulations. More
`
`particularly the present invention relates to pharmaceutical products and formulations usefiil
`
`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, rnometasone, 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
`
`elfects of anti-histamine treatments and steroid treatments, in a pharmaceutically 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-
`
`4
`
`(l1exahydro-l-methyl-lH-azepin-4-yl)-l(2H)-phthalazinone), or a pharmaceutically acceptable
`
`salt, solvate or physiologically fimctional 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
`
`in a single
`treatment The combination can provide,
`preferably for nasal or ocular
`administration or dosing regime, the antihistaminic properties of azelastine and the anti-
`
`M ED_DYM_0O000004
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`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-(1,l,3,3—
`
`tetramethyl-buty1)phenoxy]ethoxy]-ammonium chloride, generally known as “benzethonium
`
`chloride” and myristyl picolinium chloride. Each of these compounds may be used in a
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`M ED_DYM_0O000005
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`3
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`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 0.10g, preferably 0.01 g per 100ml of solution/suspension or 100g of
`
`formulation.
`
`V
`
`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
`9
`
`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-hydroxybnenzoic 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 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, l,2—propylene
`
`M ED_DYM_0O000006
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`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 II-I20 3.81 g; 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 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,
`
`hydroxypropyhnethylcellulose),
`
`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
`
`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 buflers 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.
`
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`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, ‘Le. 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
`
`M ED_DYM_0O000008
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`6
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`use in the treatment of conditions for which administration of one or more anti-histamine and
`
`I 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 diflerent
`
`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
`invention
`V
`
`in a pharmaceutical product according to the present
`
`Suitable propellants for use in pharmaceutical products of formulations as provided
`
`by the present
`
`invention include 1,1,1,2—tetrafluoroethane (I-IFA 134a) or l,1,l,2,3,3,3,-
`
`heptafluoropropane (I-IFA 227), or a combination of both, or mono~fluoro trichloromethane
`
`and dichloro difluoromethane,
`
`in particular 1,l,1,2-tetrafluoroethane (HFA 134a) or
`
`1,1,1,2,3,3,3-heptafluoropropane (I-IFA 227), with HFA 134a being preferred.
`
`A pharmaceutical aerosol formulation according to the present invention preferably
`further comprises a polar cosolvent such as Q4; aliphatic alcohols and polyols, for example
`
`ethanol, isopropanol and propylene glycol, with ethanol ofien 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,
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`olive oil, cottonseed oil and sunflower seed oil, and also phospholipids. Suitable surfactants
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`can include lecithin, oleic acid or sorbitan oleate.
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`A further preferred embodiment of the present invention can be where a formulation
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`or product is provided in the form of insufilatable powder, where preferably the maximum
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`particle size of the substance suitably does not exceed 10p.m Azelastine or its salts and the
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`steroid may be mixed with inert carrier substances or drawn up onto inert carrier substances.
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`Carrier substances which may, for example, be used are: sugars such as glucose, saccharose,
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`lactose and fiuctose. Also starches or starch derivatives, oligosaccharides such as dextrins,
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`cyclodextrins and their derivatives, polyvinylpyrrolidone, alginic acid, tylose, silicic acid,
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`cellulose, cellulose derivatives (for example cellulose ether), sugar alcohols such as mannitol
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`or sorbitol, calcium carbonate, calcium phosphate, etc.
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`In one embodiment, the therapeutic agents employed have a particle size of less than
`
`about 10 um, preferably less than 5 urn,
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`The use of insufflation powders can represent a preferred embodiment of the present
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`invention and there is provided by the present invention a pharmaceutical product comprising
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`(i) azelastine, or a pharmaceutically acceptable salt, solvate or physiologically fimctional
`
`derivative thereof, provided as an insufilation powder, and (ii) at least one steroid, or a
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`pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof,
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`provided as an insufilation powder, as a combined preparation for simultaneous, separate or
`sequential use in the treatment of conditions for which administration of one or more anti-
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`histamine and / or one or more steroid is indicated.
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`It will be appreciated from the above, that the respective therapeutic agents of the
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`combined preparation can be administered simultaneously, either in the same or difierent
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`insufilation powder formulations, or separately or sequentially.
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`If there is separate or
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`sequential administration as discussed above, it will also be appreciated that the subsequently
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`administered therapeutic agents should be administered to a patient within a time scale so as
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`to achieve, or more particularly optimise, the above referred to advantageous synergistic
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`therapeutic effect of a combined preparation as present in a pharmaceutical product according
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`to the present invention
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`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
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`or physiologically functional derivative thereof, together with a pharmaceutically acceptable
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`carrier or excipient therefor.
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`Dry insufiflation powder formulations as provided by the present invention can be
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`beneficial where it is required that therapeutic agents as employed according to the present
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`invention are retained in the nasal cavity, and systemic side effects can be minimised or
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`eliminated
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`Furthermore,
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`insufiilation 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,
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`and the bitter afiertaste associated with liquid antihistamine formulations significantly
`
`reduced, whilst also exhibiting the synergistic therapeutic efi'ect associated with the azelastine
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`/ steroid combinations provided by the present invention By providing a dry insufflation
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`powder formulation of azelastine, together with a steroid, having an average particle size of
`
`less than about 10 um, the therapeutic agents can be restricted primarily to the desired target
`
`organ, the nasal mucosa.
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`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
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`powder. The insufflator preferably is provided with means to ensure administration of a
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`substantially pre-deterrnined amount of a formulation or product as provided by the present
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`invention. The powder may be used directly with an insufflator which is provided with a
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`bottle or container for the powder, or the powder may be filled into a capsule or cartridge,
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`such as a gelatin capsule, or other single dose device adapted for administration. The .
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`insufflator preferably has means to open the capsule or other dose device.
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`Preferred combinations of therapeutic agents employed in pharmaceutical products
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`and formulations according to the present invention (in particular nasal sprays or drops,
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`aerosol or insufflation products and formulations as described above) comprise any one of the
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`following combinations.
`
`The present
`
`invention further provides,
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`therefore, a pharmaceutical product
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`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
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`pharmaceutically acceptable esters thereof, as a combined preparation for simultaneous,
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`separate or sequential use in the treatment of conditions for which administration of one or
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`more anti-histamine and / or one or more steroid is indicated Suitably the esters can be
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`selected from beclomethasone dipropionate, fluticasone propionate, fluticasone valerate,
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`mometasone furoate and mometasone furoate monohydrate.
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`The present invention also provides a pharmaceutical formulation comprising (i)
`
`azelastine, or a pharmaceutically acceptable salt thereof, and (ii) at least one steroid selected
`
`fiom 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;
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`azelastine hydrochloride and fluticasone propionate;
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`azelastine hydrochloride and fluticasone valerate;
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`azelastine hydrochloride and mometasone furoate; and
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`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
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`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,
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`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 ftmctional derivative thereof, and (ii) at
`
`least one steroid, or
`
`a
`
`pharmaceutically acceptable salt, solvate or physiologically ftmctional 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 acceptab