(19)
`
`(12)
`
`Europaisches Patentamt
`
`European Patent Office
`
`Office europeen des brevets
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`EP0780127A1
`
`(11)
`
`EUROPEAN PATENT APPLICATION
`
`(43) Date of publication:
`25.06.1997 Bulletin 1997/26
`
`(21) Application number: 96308852.1
`
`(22) Date of filing: 05.12.1996
`
`(51) Int Cl. 6: A61 K 31/57, A61 K 31/58,
`A61 K 31/56, A61 K 31/495,
`A61 K 31/445, A61 K 31/55
`// (A61 K31/56, 31 :495),
`(A61 K31/56, 31 :445),
`(A61 K31/56, 31 :55),
`(A61 K31/57, 31 :495),
`(A61 K31/57, 31 :445),
`(A61 K31/57, 31 :55),
`(A61 K31/58, 31 :495),
`(A61 K31/58, 31 :445)
`
`(84) Designated Contracting States:
`AT BE CH DE DK ES Fl FR GB GR IE IT LI LU NL
`PTSE
`
`(72) Inventor: Cramer, Ronald Dean
`Cincinnati, Ohio 45215 (US)
`
`(30) Priority: 19.12.1995 US 574791
`
`(71) Applicant: THE PROCTER & GAMBLE COMPANY
`Cincinnati, Ohio 45202 (US)
`
`(74) Representative: Woof, Victoria
`Procter & Gamble Pharmaceuticals Ltd.,
`Patent Department,
`Lovett House,
`Lovett Road
`Staines, Middlesex TW18 3AZ (GB)
`
`(54)
`
`A nasal spray containing a steroid and a antihistamine
`
`(57)
`The present invention relates to novel nasal
`spray compositions comprising a safe and effective
`
`amount of a glucocorticosteroid and an antihistamine
`possessing leukotriene inhibiting properties.
`
`T"'"
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`Printed by Jouve. 75001 PARIS (FR)
`
`

`

`EP O 780 127 A1
`
`Description
`
`TECHNICAL FIELD
`
`5
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`The present invention relates to novel nasal spray compositions comprising a safe and effective amount of a
`glucocorticosteroid and an antihistamine.
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`BACKGROUND OF THE INVENTION
`
`Allergic disorders remain a leading cause of both acute and chronic illnesses the world over. These illnesses are
`often times present in the form of acute or chronic rhinoconjunctivitis. The symptoms of allergic rhinoconjunctivitis are
`reddening of the eyes, ocular secretions, nasal congestion, ocular and palatial irritation, sneezing and hypersecretion.
`These symptoms occur following exposure to allergens. The most common allergens are grass and/or tree pollens,
`hence, allergic rhinoconjunctivitis is most common during the spring and summer months.
`The symptoms of allergic rhinoconjunctivitis are believed to be due primarily to the stimulation of H-1 receptors by
`histamine, followed by reflexive activation of parasympathetic nerves causing increases in nasal secretion and ob(cid:173)
`struction. Histamine is initially released from the tissue mast cells upon sensitization of the mast cells. This sensitization
`results when airborne allergens combine with specific lgE antibodies attached to mast cell membranes.
`Antihistamines and/or decongestants have traditionally been the drugs of choice in treating allergic rhinoconjunc-
`tivitis. Other forms of therapy include the use of cromolyn sodium, hypertonic salt solutions or immunotherapy.
`In addition, Hagen et al., U.S. Patent 4,767,612, discloses nasal corticosteroid therapy as an effective means of
`treating allergic rhinoconjunctivitis; and is herein incorporated by reference in its entirety. Notwithstanding the many
`disclosures in the area of allergic rhinoconjunctivitis, there is still a need for additional formulations which provide
`improved symptomatic relief with increased user acceptance and compliance.
`The present inventor has found that by combining a nasal corticosteroid with a leukotriene inhibiting antihistamine,
`improved intranasal compositions result, providing improved relief of symptoms generally associated with either sea(cid:173)
`sonal or perennial allergic rhinoconjunctivitis.
`It is, therefore, an object of the present invention to provide pharmaceutical compositions having improved effec(cid:173)
`tiveness in the treatment of symptoms generally associated with either seasonal or perennial allergic rhinoconjunctivitis.
`A further object of the present invention is to provide a safe and effective method for treating the symptoms of
`seasonal or perennial allergic rhinoconjunctivitis.
`These objects and other objects will become more apparent from the detailed description that follows.
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to pharmaceutical compositions for nasal administration comprising:
`
`a) a safe and effective amount of a glucocorticoid selected from the group consisting of beclomethasone, flunisolide,
`triamcinolone, fluticasone, mometasone, budesonide, pharmaceutically acceptable salts thereof and mixtures
`thereof;
`b) a safe and effective amount of a leukotriene inhibiting antihistamine selected from the group consisting of ceti(cid:173)
`rizine, loratadine, azelastine, pharmaceutically acceptable salts thereof, optically active racemates thereof and
`mixtures thereof; and
`c.) an intranasal carrier.
`
`The intranasal carrier of the present invention is preferably aqueous.
`The present invention also relates to a method for the treatment of symptoms associated with seasonal or perennial
`allergic rhinoconjunctivitis comprising the administration of a safe and effective amount of the intranasal pharmaceutical
`compositions of the present invention. By "symptoms of seasonal or perennial allergic rhinoconjunctivitis" or "symptoms
`associated with seasonal or perennial allergic rhinoconjunctivitis," is meant ocular and palatial irritation, ocular secre(cid:173)
`tions, reddening of the eyes, sneezing, mucoid hypersecretion, nasal congestion and itching.
`By "safe and effective amount," as used herein, is an amount that is effective to mitigate and/or treat the symptoms
`for which the active ingredient is indicated in a human without undue adverse side effects commensurate with a rea(cid:173)
`sonable risk/benefit ratio.
`By "leukotriene inhibiting antihistamine, "as used herein, is meant an antihistamine effective in inhibiting or reducing
`in vivo the biosynthesis of and/or cellular release of leukotrienes or otherwise modulating mammalian leukotriene levels.
`The pH of the compositions is preferably from about 4.5 to about 9, more preferably from about 6 to about 7.
`All percentages and ratios herein are by weight unless otherwise specified. Additionally, all measurements are
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`EP O 780 127 A1
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`made at 25°C unless otherwise specified.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The compositions of the present invention contain the essential components as well as various optional compo-
`nents as indicated below.
`More specifically, the compositions of the instant invention are for nasal administration and contain a therapeutically
`effective amount of the herein described pharmaceutical agents. They are preferably provided as isotonic aqueous
`solutions, suspensions or viscous compositions which may be buffered to a selected pH.
`
`Essential Ingredients
`
`Glucocorticoid Agents
`
`Agents within this class have potent glucocorticoid activity and weak mineralocorticoid activity. Glucocorticoid
`agents most useful to the present invention include those selected from the group consisting of beclomethasone,
`flunisolide, triamcinolone, fluticasone, mometasone, budesonide, pharmaceutically acceptable salts thereof and mix(cid:173)
`tures thereof.
`When used in the compositions of the present invention, the glucocorticoid component is preferably present at a
`concentration of from about 0.001 % to about 0.2%, more preferably from about 0.01 % to about 0.1 %.
`
`Leukotriene Inhibiting, Antihistaminic Agents
`
`Antihistamines useful to the present invention are histamine H-1 receptor antagonists which also reduce mamma-
`lian leukotriene levels. Such H-1 receptor antihistamines may be selected from among the following groups of antihis(cid:173)
`tamines: piperazines, phenothiazines, piperidines.
`Examples of useful leukotriene inhibiting antihistamines include cetirizine, loratadine, azelastine and the like, op(cid:173)
`tically active racemates thereof, pharmaceutically acceptable salts thereof and mixtures thereof. When used in the
`compositions of the present invention, the antihistamine component is preferably present at a concentration of from
`about 0.01 % to about 4.0%, more preferably from about 0.01 % to about 1 %.
`
`Pharmaceutically-Acceptable Aqueous Nasal Carrier.
`
`One other essential component of the present invention is a pharmaceutically-acceptable intranasal carrier. Pre-
`ferred for use herein are aqueous saline solution carriers. These solutions which generally contain sodium chloride as
`the salt are fully described in Remington's Pharmaceutical Sciences, 17th edition (1985) p. 835, which is herein incor(cid:173)
`porated by reference. The salt is present in the solution at a level of about 0.01 % to about 2%, preferably from about
`0.5% to about 1.0%.
`The combination of any of the above described antihistamines and glucocorticoids can be conveniently adminis-
`tered nasally to warm-blooded animals to elicit the desired therapeutic response by formulating it into a nasal dosage
`form, together with a nontoxic pharmaceutically-acceptable nasal carrier. Suitable nontoxic pharmaceutically-accept(cid:173)
`able nasal carriers are known to those skilled in the art and are also fully disclosed in Remington's Pharmaceutical
`Sciences, 17th edition, 1985. Obviously, the choice of suitable carrier forms will depend on the exact nature of the
`particular nasal dosage form required, e.g., whether the drug(s) is to be formulated into a nasal solution (for use as
`drops or as a spray), a nasal suspension, a nasal ointment, a nasal gel or another nasal form. Preferred nasal dosage
`forms are solutions, suspensions and gels, which normally contain sodium chloride in a major amount of water (pref(cid:173)
`erably purified water) in addition to the antihistamine and glucocorticoid. Minor amounts of other ingredients such as
`pH adjusters (e.g., an acid such as HCI), emulsifiers or dispersing agents, buffering agents, preservatives, wetting
`agents and jelling agents (e.g., methylcellulose) may also be present. Most preferably, the nasal composition is isotonic,
`i.e., it has the same osmotic pressure as blood and lacrimal fluid.
`Preferably the composition is applied to the nasal mucosa via topical application of a safe and effective amount
`of the composition to treat nasal symptoms. The amount of the antihistamine and glucocorticoid combination and
`frequency of topical application to the nasal mucosa may vary, depending upon personal or medical needs, but it is
`suggested, as an example, that topical application range from about once per day to about four times daily, preferably
`twice daily, most preferably once daily. As a practical matter the selected therapeutic compositions will normally be
`prepared in unit dosage forms or actuations to contain therapeutically effective amounts of the selected antihistamine
`and glucocorticoid combination. In specific instances fractions of these dosage units or multiple dosage units will be
`employed. Typically, dosage units may be prepared to deliver from about 0.5 mcg to about 100 mcg of the glucocorticoid
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`EP O 780 127 A1
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`agent and from about 5 mcg to about 1000 mcg of the antihistaminic agent per spray actuation (e.g., 50 mg to about
`200 mg of the spray composition). A typical dose contains one to four sprays per nostril.
`
`Optional Ingredients
`
`Optional ingredients useful in the present invention include decongestants. Decongestants useful to the present
`invention may be selected from among the class of sympathomimetic agents; examples of which include pseudoephe(cid:173)
`drine, desoxyephedrine, propylhexedrine, phenylpropanolamine, xylometazoline, phenylephrine, tetrahydrozoline,
`naphazoline, oxymetazoline, tramazoline and pharmaceutically acceptable salts thereof. Also useful as decongestants
`are the 5-(2-imidazolinylamino)benzimedazole compounds. Mixtures of these decongestants can also be used.
`When used in the compositions of the present invention, the sympathomimetic agents may be incorporated at
`concentrations, preferably, of from about 0.01 % to about 0.5%, more preferably from about 0.05% to about 0.1 %.
`The compositions of the present invention may also contain antiallergics. Suitable antiallergics include, but are
`not limited to, cromolyn, ketotifen, N-allyl-(dichloro-3, 4-benzyl)-2-methylamino-2-propanol-1, AP-582 (Pharmaprojects
`No. 3055-under investigation by Ariad Pharmaceuticals), Andolast, oxatamide and pharmaceutically-acceptable salts
`thereof. Mixtures of these antiallergics may also be used.
`Similarly, mucolytics such as acetylcysteine and anticholinergics such as ipratropium bromide may also be used
`in the compositions of the present invention.
`Also of optional use in the compositions of the present invention are nonopiate analgesics such as oxaprozin. The
`intranasal use of oxaprozin is described in Namiki et al., Studies on improvement of pharmaceutical preparations
`prescribed in hospitals. VI. oxaprozin nasal spray, Drug Design and Delivery 1988;2: pp. 311-321, herein incorporated
`by reference. Further examples of preferred nonopiate analgesics include, but are not limited to, acetaminophen, ace(cid:173)
`tylsalicylic acid, ibuprofen, etodolac, fenbuprofen, fenoprofen, flurbiprofen, indomethacin, ketoprofen, naproxen, phar(cid:173)
`maceutically-acceptable salts thereof, optically active racemates thereof and mixtures thereof. Still further examples
`of such drugs are disclosed in U.S. Patent No. 4,522,828, to Sunshine et al., issued June 11, 1985; this patent being
`incorporated herein by reference in its entirety.
`Synthetic opiate analgesics such as butorphanol may also be incorporated into the compositions of the present
`invention. The intranasal use of butorphanol is described in Baumel, Migraine: A pharmacologic review with newer
`options and delivery modalities, Neurology 1994;44(supp):pp. s13-s17, herein incorporated by reference. Further ex(cid:173)
`amples of preferred synthetic opioid analgesics include alfentanil, buprenorphine, fentanyl, meperidine, methadone,
`nalbuphine, natrexone, propoxyphene, pentazocine, sufenanil, pharmaceutically-acceptable salts thereof and mixtures
`thereof.
`Compounds commonly known as lipoxygenase inhibitors and receptor antagonists are also optionally useful in
`the compositions of the present invention. Suitable lipoxygenase inhibitors are described in U.S. Patent 4,873,259, to
`Summers et al., issued October 10 1989 and European Patent Application 318093, both of which are herein incorpo(cid:173)
`rated by reference. Lipoxygenase antagonists suitable for use in the present invention include Zafirlukast (Accolate,
`Zeneca).
`Leukotriene receptor antagonists may also be incorporated into the compositions of the present invention. Suitable
`examples include, but are not limited to, experimental agents such as LY171883, Wy-45,911, LY163443, ONO-RS-
`411 and ONO-RS-347 and ICI 198,615. A more detailed discussion of leukotriene receptor antagonists is found in
`Fleisch, J. H., Development of Cysteinyl Leukotriene Receptor Antagonists, Vol. 12 Advances in Inflammation Research
`173-189 (A. Lewis et al. ed. 1988), herein incorporated by reference in its entirety.
`Various aromatic components (e.g., aldehydes and esters) may also be used. These aromatics include, for exam(cid:173)
`ple, menthol, camphor, eucalyptol, benzaldehyde (cherry, almond); citral (lemon, lime); neral; decanal (orange, lemon);
`aldehyde C-8, aldehyde C-9 and aldehyde C-12 (citrus fruits); tolyl aldehyde (cherry, almond); 2,6-dimethyl-octanal
`(green fruit); and 2-dodecenal (citrus, mandarin). Additional aromatic components suitable for use in the present in(cid:173)
`vention include those described in U.S. Patent 4,136,163 to Watson et al., U.S. Patent 4,459,425 to Amano et al., and
`U.S. Patent 4,230,688 to Rowsell et al.; all of which are herein incorporated by reference. Mixtures of these aromatics
`can also be used.
`The desired isotonicity of the compositions of this invention may be accomplished using, for example, the sodium
`chloride already present, or other pharmaceutically-acceptable agents such as dextrose, boric acid, citric acid, sodium
`tartrate, sodium phosphate, potassium phosphate, propylene glycol or other inorganic or organic solutes or mixtures
`thereof. Sodium chloride is preferred particularly for buffers containing sodium ions. Further examples of sodium chlo(cid:173)
`ride equivalents are disclosed in Remington's Pharmaceutical Sciences pp. 1491-1497 (Alfonso Gennaro 18th ed.
`1990).
`Viscosity of the compositions may be maintained at the selected level using a pharmaceutically-acceptable thick(cid:173)
`ening agent. Methyl cellulose is preferred because it is readily and economically available and is easy to work with.
`Other suitable thickening agents include, for example, xanthan gum, microcrystalline cellulose, carboxymethyl cellu-
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`EP O 780 127 A1
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`lose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, car(cid:173)
`boxyvinyl polymer, carbomer, and the like or pharmaceutical salts thereof. Mixtures of such thickening agents may also
`be used. The preferred concentration of the thickener will depend upon the agent selected. The important point is to
`use an amount which will achieve the selected viscosity. Viscous compositions are normally prepared from solutions
`by the addition of such thickening agents.
`Preferred compositions within the scope of this invention will contain from about 0.01 % to about 5% of a humectant
`to inhibit drying of the mucous membrane and to prevent irritation. Any of a variety of pharmaceutically-acceptable
`humectants can be employed including, for example sorbitol, propylene glycol, polyethylene glycol, glycerol or mixtures
`thereof. As with the thickeners, the concentration will vary with the selected agent, although the presence or absence
`of these agents, or their concentration is not an essential feature of the invention.
`Enhanced absorption across the nasal membrane can be accomplished employing a therapeutically acceptable
`surfactant. Typical useful surfactants for these therapeutic compositions include polyoxyethylene derivatives of fatty
`acid partial esters of sorbitol anhydrides such as Polysorbate 80, Polyoxyl 40 Stearate, Polyoxylethylene 50 Stearate
`and Octoxynol, as well as Oxyethylated tertiary octyl phenol formaldehyde polymer (available from Sterling Organics
`as tyloxapol) or mixtures thereof. The usual concentration is from 0.5% to 10% based on the total weight.
`A pharmaceutically-acceptable preservative is generally employed to increase the shelf life of the compositions
`of the present invention. Benzyl alcohol is suitable, although a variety of preservatives including, for example, parabens,
`phenylethyl alcohol, thimerosal, chlorobutanol, phenylmecuric acetate or benzalkonium chloride may also be employed.
`The most preferred preservative system for use herein comprises a combination of benzalkonium chloride, chlorhex-
`idine gluconate and disodium EDTA. A suitable concentration of the preservative will be from 0.001 % to 2% based on
`the total weight, although there may be appreciable variation depending upon the agent selected Mixtures of these
`preservatives may also be used.
`Other Optional Components. A variety of additional ingredients may be added to the emulsion compositions of the
`present invention. These additional ingredients include various polymers for aiding the film-forming properties and
`substantivity of the formulation, antioxidants, and agents suitable for aesthetic purposes such as fragrances, pigments,
`and colorings.
`The compositions can also contain low levels of insoluble ingredients added, for example for visual effect purposes,
`e.g. thermochromic liquid crystalline materials such as the microencapsulated cholesteryl esters and chiral nematic
`(nonsterol) based chemicals such as the (2-methylbutyl) phenyl 4-alkyl(oxy)benzoates available from Hallcrest, Glen-
`view, Illinois 60025, U.S.A. Mixtures of these ingredients may also be used.
`
`EXAMPLES
`
`The following examples further describe and demonstrate embodiments within the scope of the present invention.
`The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present
`invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
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`Example I
`
`40
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`The intranasally administered pharmaceutical composition of the present invention is prepared by combining the
`following components utilizing conventional mixing techniques similar to that described below.
`
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`Component
`
`Wgt%
`
`0.042
`beclomethasone diproprionate, monohydrate
`0.200
`loratadine
`avicel RC - 591 1
`1.200
`5.100
`dextrose
`0.025
`polysorbate 80
`0.040
`benzalkonium chloride
`0.250
`phenylethyl alcohol
`q.s. to vol.
`distilled water
`I m,crocrystalline cellulose and sodium carboxymethyl cellulose, supplied by FMC corporation.
`
`In an appropriately sized vessel, the dextrose, polysorbate 80 and benzalkonium chloride are added one at a time
`to water with mixing, allowing each to dissolve or completely disperse before adding the next. To this is added, with
`mixing, a premixed slurry of the avicel and water. Upon forming a uniform solution, the beclomethasone, loratadine
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`

`EP O 780 127 A1
`
`and phenylethyl alcohol are added. After all the ingredients are added, purified water is used to bring the batch to the
`appropriate weight.
`Administration of approximately 0.4 grams of the composition is used for topical nasal application to provide relief
`from allergy or allergy-like symptoms.
`
`Example II
`
`The intranasally administered pharmaceutical composition of the present invention is prepared by combining the
`following components utilizing conventional mixing techniques similar to that described in Example I.
`
`Component
`
`flunisolide
`cetirizine
`propylene glycol
`polyethylene glycol
`sodium chloride
`ethylenediamine tetraacetic acid
`benzalkonium chloride
`distilled water
`
`Wgt%
`
`0.025
`0.200
`2.000
`1.000
`0.900
`0.050
`0.010
`q.s. to vol.
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`Administration of approximately 0.4 grams of the composition is used for topical nasal application to provide relief
`from allergy or allergy-like symptoms.
`
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`Example Ill
`
`The intranasally administered pharmaceutical composition of the present invention is prepared by combining the
`following components utilizing conventional mixing techniques similar to that described in Example I.
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`Component
`
`triamcinolone acetonide
`azelastine HCI
`polysorbate 80
`glycerin
`hydroxypropyl methyl cellulose
`sodium chloride
`ethylenediamine tetraacetic acid
`benzalkonium chloride
`distilled water
`
`Wgt%
`
`0.050
`0.070
`0.050
`2.000
`1.000
`0.900
`0.050
`0.020
`q.s. to vol.
`
`Administration of approximately 0.4 grams of the composition is used for topical nasal application to provide relief
`from allergy or allergy-like symptoms. Additionally, substantially similar results are also obtained using, in whole or in
`part, equivalent amounts of other glucocorticoid agents such as fluticasone, mometasone, budesonide, pharmaceuti(cid:173)
`cally acceptable salts thereof and mixtures thereof. Furthermore, the above described compositions may also contain
`a decongestant such as pseudoephedrine, phenylpropanolamine, phenylephrine, tetrahydrozoline, naphazoline,
`oxymetazoline, tramazoline, 5-(2-imidazolinylamino)benzimedazoles, optically active racemates thereof, pharmaceu(cid:173)
`tically acceptable salts thereof and mixtures thereof. Those skilled in the art will quickly realize other suitable ingredients,
`diluents and dosage forms (or readily ascertain such using routine experimentation) which may further be incorporated
`into the above compositions without departing from the scope and spirit of the present invention.
`
`Claims
`
`1. A pharmaceutical composition comprising:
`
`a) a safe and effective amount of a glucocorticoid selected from the group consisting of beclomethasone,
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`

`EP O 780 127 A1
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`flunisolide, triamcinolone, fluticasone, mometasone, budesonide, pharmaceutically acceptable salts thereof
`and mixtures thereof;
`b) a safe and effective amount of a leukotriene inhibiting antihistamine selected from the group consisting of
`cetirizine, loratadine, azelastine, pharmaceutically acceptable salts thereof, optically active racemates thereof
`and mixtures thereof; and
`c.) an intranasal carrier.
`
`2. A composition according to Claim 1 in the form of an isotonic aqueous solution
`
`3. A composition according to Claim 1 or 2 wherein the glucocorticoid is selected from the group consisting
`of beclomethasone, budesonide, fluticasone and mixtures thereof.
`4. A pharmaceutical composition according to any of Claims 1-3, which further comprises a sympathomimetic
`amine selected from the group consisting of pseudoephedrine, desoxyephedrine, propylhexedrine, phenyl(cid:173)
`propanolamine, xylometazoline, phenylephrine, tetrahydrozoline, naphazoline, oxymetazoline, tramazoline,
`5-(2-imidazolinylamino)benzimedazoles, pharmaceutically acceptable salts thereof, optically active race(cid:173)
`mates thereof and mixtures thereof.
`5. A pharmaceutical composition according to any of Claims 1-4, which further comprises a non-steroidal anti
`inflammatory agent, or optically active racemates thereof and mixtures thereof.
`6. A pharmaceutical composition according to any of Claims 1-5, which further comprises a lipoxygenase
`inhibitor or antagonist, a leukotriene receptor antagonist, a nonopiate analgesic, a mucolytic, an antiallergic,
`and pharmaceutically acceptable salts thereof and mixtures thereof.
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`EP O 780 127 A1
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`European Patent
`
`Otlice
`
`EUROPEAN SEARCH REPORT
`
`Application Number
`
`EP 96 30 8852
`
`CLASSIHCATION OF lHt:
`APPUCATION (lnt.Cl.6)
`
`A61K31/57
`A61K31/58
`A61K31/56
`A61K31/495
`A61K31/445
`A61K31/55
`//(A61K31/56,
`A61K31:495),
`(A61K31/56,
`A61K31:445),
`(A61K31/56,
`A61K31:55),
`(A61K31/57,
`A61K31:495),
`(A61K31/57,
`A61K31:445),
`(A61K31/57,
`A61K31:55),
`
`TECHNICAL FIELDS
`SEARCHED
`(Int.Cl.bl
`A61K
`
`Category
`
`X,Y
`
`X,Y
`
`X,Y
`
`D,Y
`
`y
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`Citation or document with indication, where appropriate,
`or relevant passages
`ADVANCES IN THERAPY,
`vol. 12, no. 6, November 1995 - December
`1995, USA,
`pages 340-349, XP000651473
`DROUIN ET AL:
`"ADDING LORATADINE TO
`TOPICAL NASAL STEROID THERAPY IMPROVES
`MODERATELY SEVERE SEASONAL ALLERGIC
`RHINOCONJUNCTIVITIS"
`* the whole document*
`
`Relevant
`lo claim
`1-6
`
`1-6
`
`1-6
`
`CLINICAL AND EXPERIMENTAL ALLERGY,
`vol. 22, no. 10, October 1992, UK,
`pages 916-922, XP000651660
`ARMITAGE ET AL :
`"INVESTICATION OF THE
`TENDENCY TO WHEEZE IN POLLEN SENSITIVE
`PATIENTS"
`* the whole document*
`
`DRUG INVESTIGATION,
`vol. 8, no. 4, 1994, UK,
`pages 225-233, XP000651434
`BENINCASA ET AL:
`"EVALUATION OF
`FLUTICASONE PROPIONATE AQUEOUS NASAL SPRAY
`TAKEN ALONE AND IN COMBINATION WITH
`CETIRIZINE IN THE PROPHYLACTIC TREATMENT
`OF SEASONAL ALLERGIC RHINITIS"
`* the whole document*
`
`US 4 767 612 A (HAGEN NICHOLAS S ET AL)
`30 August 1988
`*abstract*
`
`1,2,4-6
`
`"MARTINDALE THE
`JAMES E.F. REYNOLDS:
`EXTRA PHARMACOPOEIA, 13TH EDITION"
`1993 , THE PHARMACEUTICAL PRESS , LONDON
`XP002028542
`PAGE 931: AZELASTINE
`
`1-6
`
`-/--
`
`The present search report has been drawn up for all claims
`
`Place of ,ean::h
`
`Date of co~lelion of lhe ~arch
`
`F,xamirer
`
`MUNICH
`I
`CATEGORY OF CITED IJOC:t'MENTS
`
`X : particularly relevant if taken alone
`Y : particularly relevant if combined with another
`document of the same category
`A : technological background
`0 : nun-written disdosure
`P : intermediate document
`
`Herrera, S
`1 Apri 1 1997
`l : theory or principle underlying the invention
`E : earlier patent document, but published on, or
`after the filing date
`D : document cited in the application
`l. : document cited for other reasons
`
`& : member of the same patent family, corresponding
`documenr
`
`8
`
`

`

`EP O 780 127 A1
`
`European Patent
`
`Office
`
`EUROPEAN SEARCH REPORT
`
`Application Number
`
`EP 96 30 8852
`
`DOCUMENTS CONSIDERED TO BE RELEVANT
`Citation of document with indication, where appropriate,
`of relevant passages
`
`Category
`
`Relevant
`to claim
`
`CLASSIFICATION OF THE
`APPLICATION (Int.Cl.6)
`
`y
`
`EP 0 605 203 A (SENJU PHARMA CO) 6 July
`1994
`* the whole document*
`
`1-6
`
`(A61K31/58,
`A61K31:495),
`(A61K31/58,
`A61K31:445)
`
`TECHNICAL HELDS
`SEARCHED
`(lnt.Cl.6)
`
`The present search report has been drawn up fur all claims
`
`I
`I
`i f----M_U_N_I C_H _____ ..J..__ ___ l_Ap_r_i_l_l9_9_7 __ ---J. __ H_er_r_e_r_a_, _s ____ -----1
`
`Pl~ce of search
`
`D;de of completion of the sear-ch
`
`F:nminer
`
`CATt:GORY OF CITF.D IJOCU\1EI\TS
`
`X : particularly relevant if taken alone
`Y : particularly relevant if combined with another
`document of the same caregory
`A : technological back~round
`0 : nonMwritten disclosure
`P : intermediate document
`
`:;;
`:!
`~
`
`~ ~ - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - '
`
`T : theory or principle underlying the invention
`E; earlier patent document 1 but published on, or
`after the filing date
`D : document cited in the application
`L: ducument cited for other reasons
`
`& : member of the same patent family. correspondinK
`document
`
`9
`
`