NZ620005B2 - Pharmaceutical composition comprising ebastine and fluticasone - Google Patents

Abstract

Provided are pharmaceutical compositions comprising the combination of the antihistamine ebastine and the corticosteroid fluticasone. The compositions are for ophthalmic or nasal use. The compositions may be useful in the treatment of allergic rhinitis, uritcaria and nasal polyps.

Description

TITLE: PHARMACEUTICAL COMPOSITION COMPRISING EBASTINE AND FLUTICASONE' FIELD OF ION: The present invention relates to pharmaceuticalcompositions for nasal and ocular use.

There is also provided a process for preparing the said compositions and their .use in the treatment and / or prevention of allergic disorders.

BACKGROUND OF INVENTION: Allergic rhinitis (AR) is an extremely common health m, affecting approXimater -25% of the pOpulation worldwide. ic rhinitis is characterized by inflammation of the upper airway mucus membranes mediated by binding of ns cific immunoglobulin E (IgE) antibodies. The symptoms of allergic rhinitis include congestion, runny‘noserpostnasal drip, red itchy eyes1 headaches, sneezing, pru‘ritis of'the nasal mucosa and orOpharynx, allergic s, ation, and fatigue which are most bothersome for patients.

Nasal congestion is one of the most prevalent symptoms of Allergic rhinitis and occurs in. approximately 90% ofppatie'nts. In fact, nasal'congestion is the symptom that is most closely associated with Allergic is related sleep problems. Other nasal and ‘ symptoms such as nasal itching also play an important role in awakening patients..The effect of nasal congestion on sleep increases as the severity of congestion intensifies.

Another important aspect of ic rhinitis (AR) associated nasal congestion is its negative impaCt on the patient’s quality of life.

Nasal congestion aggravates in supine position, thus worsening its effects during sleep. In addition, nasal congestion, rhinorrhoea and sneezing exhibit circadian rhythms, with the greatest intensity in the early morning, thusexacerbating their negative effects onsleep.

Allergic rhinitis d inflammatory mediators also exhibit a ian pattern, with SUBSTITUTE SHEET (RULE 26) WO 17821 peak levels in early morning. In addition, sympathetic tone decreases at night, resulting in a relative parasympathetic excess, which is ated with nasal congestion and reduCed bronchial dilation. ’ The daytime tiredness experienced by the vast majority of Allergic rhinitis (AR) sufferers is directly'related to the fact that patients with Allergic rhinitis experience disrupted sleep at. night. In addition to this daytime fatigue and somnolence, nal sleep impairment is associated with sion, irritability, memory deficits, inability to concentrate, decreased alertness and which overall leads to decreased y of life. Consequently, many of the sequelae of Allergic rhinitis, such as fatigue, decreased ive functioning and work performanceand reduced quality of life may be caused or worsened byAllergic rhinitis related sleep impairment.

Abnormal sleep is one such factor that classifies the severity of ic rhinitis from mild to te/severe. Thus, achievement of unimpaired sleep therefore is the primary goal of Allergic rhinitis treatment. ic rhinitis associated nasal congestion results from dilation of venous capacitance vessels in the nasal sub mucosa and increased vascular permeability, mucosal oedema with influx of inflammatory cells and excess secretions. This allergic response is composed of two phases: the early phase and late phase. During the early'phase, nasal allergic response antigen depositionon the mucosal surface s in binding of IgE antibodies to atory mucosal mast cells and peripheral blood basophils. Consequent mast cell degranulation and release 'of chemical mediators Such'as histamine, leukotrienes and pro-inflammatory cytokines are primarily responsible for ng, itching and rhinorrhea. Nasal congestion- the predominant late phase symptom results from the infiltration of inflammatory cells such as eosinophils and T cells into tissue and consequent prolonged release mediators such as histamine, leukotrienes and glandins.

SUBSTITUTE SHEET (RULE 26) Treatment of Allergic rhinitis is commonly based on the type and severity of the individual patient’s symptoms and should ideally reduce nasal congestion, sneezing and rhinorrhea over the course of entire day and night.

Antihistamines are the mainstay of therapy for Allergic rhinitis and are effective in reducing us, sneezing and watery rhinorrhea. These drugs act primarily by blocking the H 1-histamine receptor. Antihistamines also interfere with mediator release from mast— cells bylinhibiting either ctalcium'iion influx across mast cell and basophil plasma membrane or intracellular calcium ion release within the cells. Further, antihistamines may also inhibit the late phase allergic reaction by acting on rienes or prostaglandins or by producing an anti—platelet activating factor (PAF) effect. However they S1gn1fcantly do not reduce nasal obstruction as compared to that of intranasal corticosteroids.

Corticosteroids such as intranasal and intraocular corticosteroids are considered as the first line therapy for te to severe seaSOnal and perennial Allergic rhinitis.

Corticosteroids known for intranasal use include beclomethasone, mometasone, fluticasone, budesonide and ciclesonide. osteroids known for ocular anti—inflammatory use e betamethasone sodium, dexamethasone sodium and prednisolone acetate.

Intranasal corticosteroids prevent both the early phaSe (cytokine release) and late phase (migration of mast cells, ils and eo'sinophils to the nasal ) allergic reaction.

Intranasal corticosteroids also decrease microvascular permeability, edema and mucus ion Intranasal osteroids suppress many of the atory mediators implicated in the allergic reaction and effectively reduce nasal symptoms including' congestion, rhinorrhea sneezing, pruritus, ocular itching, redness and tears. Onset of SUBSTITUTE SHEET (RULE 26) effect of intranasal corticosteroids occurs after 6—12 hours and maximum benefit is achieved after a week'or more of regular use.

Intranasal corticosteroids are generally considered safe in adults and en due to their topicaladministration and low ic bioavailability. Intranasal corticosteroids are one of the most effective agents for COntrolling nasal ction, and thus reduce sleep problems and associated daytime somnolence. 243 discloses a nasal spray composition of a safe and effective amount of a glucocorticoid such as beclomethasone, flunisolide, fluticasone, mometasone, budesonide and a safe effective amount of a fast acting antihistamine such as acrivastine, carbinoxamine, diphenhydramine, chloropheniramine, brompheniramine, dexchloropheniramine, doxylarnine, tine, promethazine, rocastine,_trimeprazine, methdilazine, hydroxyzine, pyrilamine, tripelennarnine, meclizine, triprolidine, azatadine, cyproheptadine, phenindamine and an aqueous intranasal carrier and the composition is free of eapsaicin.

USZOO90324699 discloses a liposomal delivery of a pharmaceutical composition comprising an antihistamine a osteroid and a pharmaceutically acceptable aqueous carrier. However, such compositions involve use’of a complex process for manufacturing such liposomes‘. ation therapy of an antihistamine and an intranasal or intraocular corticosteroid es instant relief from the -allergic symptoms and ls progression of the disease. Further, selection of a‘specific antihistamine and an intranasal or intraocular corticosteroid plays a very ant role in formulation of such combinations.

Additionally it simplifies the therapy, reduces the cost and also provides control of both‘ early phase and late phase symptoms of Allergic rhinitis. , SUBSTITUTE SHEET (RULE 26) Hence, there still remains a need to formulate a ceutical composition which is efficacious, and exhibits potent topical activity for the treatment and / or prevention of allergic disorders.

OBJECT'OF THE INVENTION: ' The object of the present invention is to provide a pharmaceutical composition sing an antihistamine and a corticosteroid for administration in treatment and / or - tion of allergic disorders.

Another object of the present invention is to provide a process for preparing a pharmaceutical‘ composition comprising an antihistamine and a osteroid for administration in treatment and / or prevention of allergic disorders, -Yet another object of the present invention is to provide a method for tion and /or ent of allergic disorders which method comprises stering a pharmaceutical composition sing an stamine and a corticosteroid.

, SUMMARY OF THE INVENTION: According to one aSpect of the present invention, there is provided a pharmaceutical ' composition comprising at least one antihistamine and at least one corticosteroid.

According to another aspect of the present. invention, there is provided a process for ing the pharmaceutical composition comprising at least one antihistamine and at least one corticosteroid! According to yet another aspect of the invention there is provided a pharmaceutical composition comprising at least one antihistamine, at least One corticosteroid, and at least one pharmaceutically acceptable excipients‘, wherein at least one antihistamine comprises ebastine or its pharmaceutically acceptable salt, solvate, ester or physiologically SUBSTITUTE SHEET (RULE 26) WO 17821 functional derivative thereof, and wherein" at least one corticosteroid comprises flut-icasone or its pharmaceutically acceptable ester thereof.

According to another aspect of the invention, there is provided a pharmaceutical ition of the invention for use in treating disorders or conditions that respond to, or are prevented, rated or eliminated by the stration of an antihistamine and a corticosteroid.

According to another aspect of the invention, there is provided a method for the prevention and/or ent of a er or condition that responds to, is prevented, ameliorated or eliminated by the administration of an stamine and a corticostercid, which method comprises administering to a patient in need thereof, a therapeutically effective amount of a pharmaceutical composition of the invention.

According to another aspect of the invention, there is provided a processtfor the preparation of a pharmaceutical composition according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION: As discussed r it is highly desirable to provide a treatment for allergic disorders that 'combines the effects of antihistamine and a corticosteroid, in a pharmaceutically able composition which is tolerated in situ, without significantly disrupting the potency of the tuent pharmaceuticals.

Our inventors have found that antihistamine such as ebastine can advantageously be combined with a corticosteroid such as fluticasone to provide a stable and effective combination product or composition for the treatment of allergic disorders.

Eba’stine is not very soluble in water and exhibits low bioavailability'in the commercially ble dosage forms. Further since this a nasal preparation; there is a very limited choice of excipients/solvents available.‘ SUBSTITUTE SHEET (RULE 26) Surprisingly, our'inventors have developed a nasal dosage form wherein ebastine has been formulated in a nasal dosage form inspite of the limitations as stated above.

The terms “ebastine” and "fluticasone’f are used in broad sense to include, not only “ebastine” and "fluticasone” per se, but also their pharmaceutically acceptable salts, pharmaceutically able solvates, pharmaceutically acceptable esters. pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceuticall’y acceptable polymorphs, etc.

The term “derivative” includes; but is not limited to, pharmacologically active metabolites and gs. ably the asal corticosteroid used in the compositions of the present invention is fluticasone.

Any ester of fluticasone can be used in the pharmaceutical compositions of the present invention. Preferably, the esters of fluticasone are selected from the group Comprising fluticasone propionate, fluticasone furoate, fluticasone valerate.

Fluticasone is currently cially available in the form of fluticasone e and fluticasone propionate.

Fluticasone ‘propionate is a synthetic rinated osteroid having the‘chemical name S-(fluoromethyl) 6o, 9-difluoro-1 lBdihydroxy-l6d-methyloxoandrosta-1, >diene-17B-carbothioate, 17-propionate. Fluticasone propionate is a lly active corticosteroid with efficacy in seasonal and perennial Allergic rhinitis. Fluticasone propionate also exhibits high lipOphilicity, high selectivity and affinity for the glucocorticoid receptor, low oral systemic absorption,.and rapid metabolic clearance.

SUBSTITUTE SHEET (RULE 26) Fluticasone furoate is a synthetic, lipophilic, orinated glucocorticoid receptor agonist containing a ‘17-alpha-furoate ester having the chemical name (6a,llB,16a,17a)—6,9~ difluoro-17—{[(fluoro-methyl)thio]carbonyl}-1 l-hydroxymethyl~3-oxoandrosta—1,4- dienyl 2-furancarboxylate. Further, fluticasone furoate is a novel corticosteroid which , ntially overcomes the ial sideeffects that are generally produced by the use - of conventional corticosteroids.

Preferably the antihistamine used in compositions of the present invention is ebastine.

Ebastine, (4—diphenylmethoxy_[3-(4-terbutylbenzoyl) - } piperidine), is a long- acting and selective Hl-histamine receptor antagonist. .Ebastine is converted to the pharmacologically active acid metabolite, carebastine. Ebastine is indicated for the symptomatic treatment of seasonal and perennial allergic rhinitis and idiopathic c urticaria Ebastineis commercially available as ated 10mg oral tablets and1n the form of pediatric syrup. Ebastine is lly administered once daily1n strengths of 10mg, and is a nonsedating antihistamine for the treatment of symptoms associated with seasonal~ and perennial ic rhinitis. Ebastine is also highly effective in the therapy- and treatment of seasonal and perennial ic rhinitis and related diseases. ne' is not very soluble in water and as a result of which it does not ‘ However, become readily bioavailable when given orally. Thus, it would also be desirable to formulate a more soluble and more bioavailable form'of antihistamine such as ebastine.

Such a formulation would be fast acting, thereby providing immediate relief to a subject suffering from rhinitis, urticaria and such related disorders much more quickly.» Thus, the present invention provides a ceutical composition sing ebastine and fluticasone for administration via nasal and ocular route.

Fluticasone is preferably present in an amount from about 10 mcg to 70 meg, and more preferably from about 20mcg to about SOmcg.

SUBSTITUTE SHEET (RULE 26) Preferably, fluticasone propionate is present in the amount of about 50mcg, and fluticasone furoate is present in the amount of about 27.5mcg. , Ebastine may be present in the inthe amount of about 25 mcg to about 2 Preferably, the pharmaceutical compositions of the invention are free of liposomes.

Preferably, the pharmaceutical compositions of the invention are free 'of fast'acting antihistamines. Preferably, the compositions of the invention e of antihistamines wherein the onset of action occurs within one hour of administration. Preferably, the pharmaceutical compositions of the invention are free of acrivastine, carbinoxamine, diphenylhydramine, chloropheniramine, brompheniramine, oropheniramine, doxylamine, clemastine, promethazine, trimeprazine, methdilazine, hydroxyzine, pyrilamine, rocastine, tripelennamine, ine, triprolidine, ine, cyproheptadine, phenindamine, and pharmaceutically acceptable salts thereof.

The ceutical compositions of the present invention may be administered by suitable methods used for delivery of the drugs to the respiratory tract.

The pharmaceutical compositions of the invention can be formulated for Simultaneous, separate or sequential stration.

The pharmaceutical composition of the present invention can be formulated in a suitable nasal dosage form.

The pharmaceutical compositions, of ' the present invention, preferably comprise pharmaceutically acceptable excipients suitable for nasal ry, and the at least one stamine and at least corticosteroid are t in a dosage form suitable for nasal delivery.

SUBSTITUTE SHEET (RULE 26) 2012/000631 Preferably, the pharmaceutical compositions of the present invention are formulated in a form suitable for nasal delivery such as but not limited to nasal spray, nasal solutions, nasal suspensions, nasal ointments, nasal drops and nasal gels.

The pharmaceutical composition of the present invention may comprise ebastine and fluticasone in a suitable nasal dosage form with one or more pharmaceutically acceptable excipients.

The preferred dosage forms, suitable for nasal delivery, according to the present invention may se carriers/excipients suitable‘for formulating the same such as, but not limited to, pH ers, osmotic agents, emulsifiers or dispersing agents, surfactants, lizers, buffering agents, preservatives, wetting agents, gelling agents, tency ' agents, ciliary stimulant, mucus thinning agent and es thereof.

The buffer or the pH adjusting agent may comprise one or more of organic or inorganic acids such as, but not limited to, citric acid, citric acid drate, sodium citrate dehydrate, sodium hydrogen te borate .bufi‘er, 'phOSphates (sodium hydrogen disodium , orthophosphate, hydrogen phosphate, Sodium dihydrogen phosphate), trometamol, acetate buffer, citrate buffer and their hydrates, or lent conventional buffers, for example, to adjust the formulations to a pH value of about 3.0 to about 7.5.

Suitable preservatives may also be ed in the pharmaceutical composition of the present invention to protect the formulation fromcontamination with pathogenic bacteria.

The preservative may se one or more of, but is not limited to, benzalkonium de, benzoic acid or a salt, sodium benzoate, potassium sorbate, sorbic acid or a salt, ~edetic acid and its alkali salts, lower alkyl p-hydroxybenzoates, chlorhexidine, phenyl mercury borate, quaternary ammonium compound or mixtures thereof.

SUBSTITUTE SHEET (RULE 26) According to the present invention, preservative is present in an amount of from about . 0.005 to 2%.

Osmotic agents refer to agents that are specifically added to the composition to se the solute level .in the composition and contribute to achieving isotonicity of the pharmaceutical composition.

Tonicity is the ‘effective osmolality' and is equal'to the sum of the trations of the solutes which have the capacity to exert an osmotic force across the membrane.

Isotonic ions are required for ophthalmic, nasal, most olyte and other preparations. Hypertonic solution will cause’water to leave the intracellular compartment with consequent cell shrinkage while hypotonic'solution will cause the cell to imbibe water which produces swelling, distention and finally rupture of the cells.

Osmotic agents, that may be used, comprise, but are not limited to, sodium chloride, potasSium chloride, zinc chloride, calcium chloride, mannitol, ol, and boric acid, citric acid, sodium tartrate, sodium phosphate, potassium phosphate, propyleneglycol other nic or organic solutes, dextrose/ anhydrous glucose and mixtures thereof.

Further as per common general knowledge known to one skilled in the art, 0.9% w/v sodium chloride solution is said to be ic(308 mOsm/ kg) with body fluids while glycerin at 2.6% w/v concentration is iso-osmotic with 0.9% w/v saline on.

Chelating agents according to the present invention may comprise, but arevnot d to, editic acid (EDTA) or one of the known salts thereof, e.g. sodiumrEDTA or disodium EDTA dihydrate (sodium edetate) and mixtures thereof.

According to the present invention, Chelating agents may be present‘in an amount of from about 0.01 to 5%.

SUBSTITUTE SHEET (RULE 26) Suitable surfactants or wetting agents may also be used in the pharmaceutical compositions 'of the present invention. According to the t invention, suitable amphoteric, non-ionic, cationic or anionic tants may be included in the pharmaceutical composition of the present invention. tant may comprise one or more, but are not limited to, Polysorbates such as‘ polysorbate 20, rbate 40, polysorbate 60, polysorbate 80, polysorbate 65, polysorbate. 85, sorbitan-fatty acid esters s Span 20, Span 40, Span 60 Span 80, Span 120; sodium Ilauryl sulfate; hoxylated castor oil; polyethoxylated hydrogenated caster oil, sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide, Docusate sodium, Cetyl trimethyl ammonium, bromide (CTAB) Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N, , N— dimethyldodecylamine—N—oxide, Hexadecyltrimethyiammonium e, Polyoxyl 10 lauryl ether, Brij, Bile salts (sodium holate, sodium cholate), Polyoxyl castor oil, Nonylphenol ethoxylate, Cyclodextrins, Lecithin, Methylbenzethonium chloride.

Carboxylates, Petroleum , ,Sulphonates, sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin'sulphonates, Alkyl sulphates, Sulphates, 'Sulphated natural oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated & sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters Polyethylene glycol esters,” Anhydrosorbitol ester & it's ethoxylated tives, Glycol esters of fatty acids, Garboxylic amides, Monoalkanolamine condensates, Poiyoxyethylene fatty acid amides, Quatemary ammonium salts, Amines with amide " linkages, yethylene alkyl & alicyclic amines, N,N,N,N tetrakis substituted ethylenediamines 2- alkyl 1- hydroxyethyl 2-imidazolines, N -coco 3-am-inopropionic acid/ sodium salt, N-tallow 3 -iminodipropionate um salt, N-carboxymethyl n dimethyl n-9 octadecen-yi ammonium hydroxide, n-cocoamidethyi n—hydroixyethylglycine sodium salt etc and mixtures thereof. tants maybe present in an amount of from abottt 0.005 to 0.2% w/w.

SUBSTITUTE SHEET (RULE 26) Suitable suspending or thickening agents may also be used in the pharmaceutical composition of the present invention, include, but are not limited to, cellulose derivatives (for example ose ether) in which the ose-hydroxy groups are partially etherified with lower unsaturated aliphatic alcohols and/or lower unsaturated tic oxyalcohols' (for example methyl cellulose, carboxymethyl cellulose, ypropylmethylcellulose), gelatin, polyvinylpyrrolidone, tragacanth, se - (water soluble binding and thickening agents on the basis of ethyl cellulose), alginic acid, polyvinyl alcohol, polyacrylic acid, pectin, microcrystalline cellulose, and equivalent agents or es thereof. Should these substances contain acid groups, the , corresponding logically able salts may also be used.

According to the present invention, thickening agents can be present in an amount of from about 05 to 5% nSistency aids may provide enhanced physical ity as - well as proper consistency to the pharmaceutical composition prior to stration so that an optimal degree of spreading over the mucosa is achieved after administration.

Consistency aids may reduce or delay the rate at which the active agents in the nasal spray composition are adsorbed by the mucin of the mucosa .which permits the pharmaceutical composition to have a better spread and coat the nasal mucosa.

Consistency aids that are used in compositions of the present invention may comprise, but are not limited to, low molecular weight mono and polyols selected from the. group consisting of monosaccharides, disaccharides and other Sugars, ribose, ine/glycerol, sorbitol, xylitol, inositol, propylene glycol, galactose, mannose, xylose, rhamnose,’ glutaraldehyde, invert sugars, ethanol, honey, mannitol, polyethylene glycol, and mixtures thereof.

Cilia along the inside of the nasal cavity keep the nasal passagesclear of mucus. If cilia function is subnormal, mucus will build up and contribute to congestion Iof the nasal passages.

Ciliary stimulants that are used in cdmpositions of the present invention may comprise saline solutions. ‘ SUBSTITUTE SHEET (RULE 26) Mucus thinning agent lowers the viscosity of the mucus y making it more susceptible, to transport by the cilia. . < Mucus thinning agents that are used in compositions of the present invention may se alkaline agent/s but are not d to sodium bicarbonate.

Suitable rizers and lubricants can also be" incorporated in the pharmaceutical ition of the present invention such as, but not limited to, glycerin which prevents cracking and scaling within the inside of the nose.

The pharmaceutical composition according to the present invention is dispensed in suitable containers provided with means for enabling the application of the pharmaceutical ition to the respiratory tract.

For example, pharmaceutical composition can be administrated into the nasal passages of a t by_ means of a dropper (or pipette) that includes a glass, plastic or metal dispensing tube. Fine droplets and sprays can be provided by an intranasal pump dispenser or squeeze bottle as well known in the art.

According to a preferred embodiment, the pharmaceutical composition may be present in (a container sing an elongated discharge member formed for insertion into a nasal cavity. A reservoir is coupled to the discharge member with spray actuation being achieved by squeezing the discharge member towards the reservoir.

The pharmaceutical composition, according to the present ion, may be applied to the nasal mucosa from about once a day to about three times a day and may also vary depending upon individual needs.

Preferably, the pharmaceutical composition of the invention when formulated in a way suitable for nasal administration, comprises at least onekor more of a surfactant, a thickening agent, an osmotic agent, a preservative, a chelating agent or water.

SUBSTITUTE SHEET (RULE 26) Even more ably, the ceutical composition of the invention when formulated in a Way suitbale for nasal administration, comprises at least one or more of dispersible cellulose, rbate 80, anhydrous e, benzalkonium chloride, phenyl ethyl alcohol, disodium edetate, or purified water. ably, the compositions comprise a surfactant in an amount of from about 0.005 to 0/ 1% w/w.

Preferably, the compositions comprise a thickener in an amount of from abbut 1.5 to 2% w/w.

Preferably, the compositions comprise an c agent in an amount of from about 3 to . 6%.

Preferably, the compositions comprise preservatives in an amount of from about 0.01 to 0.4% of vatives Preferably, the compositions comprise a chelating agent in an amount of from 0.01 to 5% w/w.

Preferably, the compositioncomprises from 0.005 to 0.1% w/w of a surfactant, from 1.5 to 2% w/w of a thickener, from 3 to, 6% of anhydrous glucose, from 0.01to 0.4% w/w of preservatives, and/or from 0.01 to 5% w/w of a chelating agent.

In another embodiment the pharmaceutical composition of the present invention can be formulated in a suitable ocular dosage form.

The composition of the present invention can thus be administered as but not limited to, ophthalmic drops, suspension, solution, gel, ointment, in situ gel, occusert, emulsion.

SUBSTITUTE SHEET (RULE 26) The pharmaceutical composition of the t ion may comprise ebastine and fluticasone in a suitable ocular dosage form with one or more phamnaceutically acceptable excipients such as but not limited to such as tonicity~adjusting , pH— adjusting agents, buffering agents, preservatives, comfort enhancing agents, viscosity modifying agents, stabilizing agents, antioxidants, wetting eading agents.

The pharmaceutical composition, according to the present invention, may be applied to the eyes from about once a day to a few times a day and may also vary depending upon dual needs.

The pharri1aceutical composition of the present invention can also be delivered by the use of other means Such as, but not limited to, nasal spray, metered dose inhalers (MDI), dry powder inhalers (DPI), nebuliser, and insufflation powders.

Several types of MDIs are regularly used for administration by inhalation. These types of devices comprise but are not limited to breath—actuated MDI, dry powder r (DPI), spacer/holding chambers in combination with MDI, and nebulizers.

The metered dose rs according to the present invention may se one or more pharmaceutically acceptable excipients as HFC/HFA propellants, co-s-olvents, bulking agents, non volatile component, butters/pH adjusting agents, surface active agents, preservatives, chelating agents, or combinations thereof. lants arethose which, when mixed with the cosolvent(s), form a homogeneous propellant system in which a therapeutically effective amount of the medicament can be dissolved. The HFC/HFA lant must be toxicologically safe and must have a vapor pressure which is suitable to enable the medicament to be administered via a pressurized MDI, According to the present invention the HFC/HFA propellants may comprise, one or more, but not limited to, 1,1,1,2-tetrafluoroethane ’ (HFA-134(a)) and 1,],1,2,3,3,3,- uoropropane (HFA-227), HFC-32 (difluoromethane), HFC—il43(a) (l, l, l- SUBSTITUTE SHEET (RULE 26) trifluoroethane), HFC-l34 (1,1,2,2-tetrafluoroethane), and HFC-lSZa (1,1- difluoroethane) and such other propellants which may be known to the person having a skill in the art and mixtures thereof.

Co-solvent is any solvent which is miscible in the formulation in the amount desired and which, when added provides a formulation in which the medicament can be dissolved.‘ The function of the cosolvent is to increase the solubility of the medicament and the excipients in the formulation.

According to the present invention the co-Solvent may comprise one or more of, C2- C5 aliphatic alcohols, such as, but not limited to, ethyl alcohol and isopropyl alcohol; s such as but not limited to ene glycol, polyethylene glycols, polypropylene glycols, glycol , and block mers of oxyethylene and oxypropylene; and other substances, such as, but not limited to, glycerol, polyoxyethylene alcohols, and polyoxyethylene fatty acid esters; arbons such as, but not limited to, n-propane, n— butane, isobutane, n-pentane, iso-pentane, neo—pentane, and n-hexane; and ethers such as, but not limited to, diethyl ether or mixtures thereof.

' Suitable tants may be employed in the aerosol solution composition of the present invention Which may serve to stabilize the solution formulation and improve the performance of valve systems of the metered dose r.

According to the present invention the surfactant may comprise one or more ionic and/or non- ionic surfactant, such as, but not d to oleic acid, an tribleate, lecithin, isopropylmyristate, tyloxapol, polyvinylpyrrolidone, polysOrbates such as polysorbate 80, vitamin E-TPGS, and macrogol hydroxystearates such as macrogol-l5-hydroxystearate or mixtures thereof. - Non— volatile component is all the ded or dissolvedconstituents that would be left after evaporation of the solvent.

SUBSTITUTE SHEET (RULE 26) According to the t invention, the non-volatile component may comprise one or more of ccharides such as, but not limited to, glucose, arabinose; disaccharides such as lactose, maltose; oligosaccharides and polysaccharides such as but not limited to dextrans; polyalcohol such as but not limited to glycerol, sorbitol, mannitol, xylitol; salts such as but not limited to potassitim chloride, ium chloride, magnesium sulphate, sodium chloride, sOdium citrate, sodium phosphate, sodium hydrogen‘phosphate, sodium hydrogen carbonate, potassium citrate, potassium phosphate, potassium hydrogen phosphate, potassium hydrogen carbonate, calcium carbonate and calcium chloride or mixtures thereof.

Suitable bulking agents maybe employed in metered dose inhalation composition of the present ion.

According to the t invention, the bulking agent may comprise one or more, but not d to, saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, terhalose, lactose, maltose, starches, dextran or mannitol or mixtures thereof.

Suitable buffers or pH adjusting agents may be employed in the metered dose inhalation composition of the present invention.

The buffer or the pH adjusting agent may se one or more of, but not d to, ', organic or inorganic acids such' as but not limited to citric acid, ascorbic acid, hydrochloric acid, sulfuric acid, nitric acid, or oric acid or mixtures thereof.

Suitable preservatives may be employed in the aerosol on composition of the present invention to protect the formulation from contamination with pathogenic bacteria.

The preservative may comprise one or more, but not limited to, benzalkonium chloride, benzoic acid, benzoates such as sodium benzoate and such other vatives which may be known to the person having a n the art or mixtures f.

SUBSTITUTE SHEET (RULE 26) Suitable ing agents may be employed in the aerosol solution composition of the present invention which is e offorming complex bonds.

The chelating agent may comprise one or more but not limited to, sodium EDTA or disodium EDTA or mixtures thereof.

The pharmaceutical composition of the present invention may be administered by: a dry powder inhaler (DPT).

The pharmaceutically acceptable excipients suitable for 'dry powder inhalation according to the present inventidn may be selected from le carriers which include, but are not limited to, sugars such cose, saccharose, lactose and fructose, 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 ate, m phosphate, etc. lactose, lactitol, dextrates, saccharides , dextrose, maltodextrin,‘ including monosaccharides, harides, polysaccharides; sugar alcohols such as arabinose, ribose, mannoSe, sucrose, trehalose, maltose, n or mixtures thereof.

The pharmaceutical composition of the present invention may be administered. by nebulizer. Such nebulizers include, but are not limited to,~a jet nebulizer, ultraSOnic nebulizer and breath actuated nebulizer. Preferably, the nebulizer is a jet nebulizer connected to an air compressor with adequate air flow. The zer being ed with a iece or suitable face mask. Specifically, a nebulizer (with face mask or mouthpiece) connected to a compressor may be used to deliver the inhalation liquid of the present invention to a patient.

Nebulisation therapy has an advantage over other inhalation, y, since it is easy to use and does not e co-ordination or much effort .It also works much more rapidly than medicines taken by mouth.

SUBSTITUTE SHEET (RULE 26) For nebulizers, the composition according to the present ion may comprise suitable excipients such as tonicity agents, pH regulators, chelating agents in a suitable vehicle. lsotonicity-adjusting agents, which may be used, comprise sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other isotonicity-adjusting agents may also include, but are not limited to, mannitol,‘ glycerol, and dextrose and . mixtures thereof.

The pH may be adjusted by the addition of pharmacologically able acids.

Pharmacologically acceptable inorganic acids or organic acids may be used for this purpose. Examples of preferred inorganic acids are selected from the group comprising hydrochloric acid, bromic acid, nitric acid, Sulphuric acid and phOSphoric acid. suitable organic acids are ed from the group comprising _ Examples of particularly ascorbic acid, citric acid, malic' acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid or es thereof.

Chelating agents, that may be used, according to the present invention may comprise editic acid (EDTA) or one of the known salts thereof, e.g. sodium EDTA or disodium EDTA dihydrate (sodium edetate) or mixtures thereof, - Anti-microbial preservative agent may be added for multi-dose packages.

The ition according to the present invention may be included in suitable. containers provided with means enabling the ation of the phamiaceutical composition to the atory tract. When the compositions of the present invention are formulated for nasal or ocular delivery, the ners are preferably adapted for » introduction of the pharmaceutical composition to the nasal passages or eyes.

The powder for inhalation intended to be used for DPI may either be encapsulated in capsules of' gelatin or HPMC ’ or in blisters or alternatively, the dry powder may be contained as a reservoir either in a single dose or multi-dose dry powder inhalation device.

SUBSTITUTE SHEET (RULE 26) Alternatively, the powder for inhalation intended to be used for DPI may be suspended in a suitable liquid vehicle and packed in an aerosol container along with suitable propellants or mixtures thereof.

Further, the powder for inhalation intended to be used for DPI may also be 'diSpersed in a suitable gas stream to form an aerosol composition.

The MDI composition according to the present invention may be packed in plain aluminium cans or SS (stainless steel) cans. Some aerosol drugs tend to adhere to the inner surfaces, i.e., walls of the cans and valves, of the MDI-{This can lead to the patient g significantly less than the prescribed amount of the active agent upon each. tion of the MDl Coating the inner surface of the container with a suitable polymer can reduce this adhesion‘problem. Suitable coatings include fluorocarbon copolymers » such as FEP-PES (fluorinated ethylene prOpylene and polyethersulphone) and P’FA-PES (perfluoroalkoxyalkane and polyethersulphone), epoxy and ethylene. Alternatively, the inner surfaces of the-cans may be anodized, plasma treated or plasma coated, The pharmaceutical compositions of the present invention may also comprise the s in micronized form.

Poorly water-soluble drugs ofienrequire-high doses in order to reach therapeutic plasma concentrations after oral administration. ement in the extent and rate of dissolution is highly ble for such compounds, as this can lead to an increased and more reproducible oral ilability and subsequently. to clinically relevant dose ion and more reliable therapy.

Physical modifications of the drug les such as micronization aim to. increase the surface area, solubility and/or wettability of the powder particles. micronization is used to raise drug activity by increasing le specific surface, or by allowing active substances to reach their site of action by reducing particle size.

SUBSTITUTE SHEET (RULE 26) The actives in micronized form can be obtained by any of the process such as but not d to ball milling, jet milling, sonication, homogenization and solvent precipitation.

The pharmaceutical compositions of the present invention may also comprise the actives in nanosize form.

Nanonization of hydrophobic or poorly water-soluble drugs generally involves the production of drug .nanocrystals through either chemical precipitation (bottom-up technology) or disintegration (top-down technology). Different methods may be utilized to reduce the particle. size of the hydrophobic or poorly water soluble drugs. [Huabing‘ Chen et al., discusses the s methods to develop rmulations in ization strategies for poorly water-soluble drugs,” 'Drug Discovery Todayg Volume 00, Number . 00, March 2010].

Nanosizing leads to se in the exposure of surface area of particles leading to an increase in the rate‘of dissolution.

The nanoparticles of the present invention can be obtained by any of the process such as but not limited to milling, precipitation and homogenization.

Accordingly, the process of g comprises. dispersing drug particles in a liquid dispersion medium in which the drug is poorly soluble, followed by ng mechanical means in the presence of grinding media to reduce the particle size of drug to the desired effective average particle size. ,1 Accordingly, the s of precipitation involves the formation of crystalline or semi- crystalline drug nanoparticles by nucleation and the grth of drug crystals. In a typical procedure, drug molecules-are first dissolved in an appropriate organic solvent such as e, tetrahydrofuran or N~methyl-Z-pyrrolidone at a super saturation concentration to allow for the tion of drug seeds. Drug nanocrystals are then formed by adding the organic mixture to an antisolvent like water in the ce of stabilizers such surfactants.

SUBSTITUTE SHEET (RULE 26) WO 17821 The choice of solvents and izers and the mixing process are key factors to control the size and stability of the drug nanocrystals.

Accordingly, the process of nization involves g a suspension of crystalline drug and stabilizers through the narrow gap of a homogenizer at high pressure (500—2000 bar). The pressure creates powerful tive forces such 'as cavitation, collision and shearing, which disintegrate coarse particles to nanoparticles.

‘ Accordingly, the process of high pressure homogenization comprises drug presuspension (containing drug in the micrometer range) by subjecting the drug to airjet milling in the presence of an aqueous surfactant solution. The "presuspension is then ted to high— pressure homogenization in which it passes through a very small homogenizer gap of ~25 pm which leads-to a high ing velocity. High-pressure hemogenization is based on the principle ofl'cavitations (i.e., the formation, growth, and implosive collapse of vapor bubbles in a liquid).

Accordingly, the process of spray-freeze drying es the atomization of an aqueous drug solution intOwa spray chamber filled with a cryogenic liquid (liquid nitrogen) or halocarbon refrigerant such as chlorofluorocarbon or fluorocarbon. The water is removed by sublimation after the liquid droplets solidify.

Accordingly, the process of supercritical fluid technology involves controlled crystallization of drug from dispersion in supercritical fluids, carbon dioxide.

Accordingly, the process of double emulsion/solvent evaporation technique involves preparation of oil/water (o/w) emulsions with subsequent removal of the oil phase through evaporation. The emulsions are ed by emulsifying the organic phase containing drug, r and organic solvent in an aqueous solution; containing emulsifier. The organic solvent diffuses out of the polymer phase and into the aqueous phase, and is then evaporated, forming oaded polymeric nanoparticles.

SUBSTITUTE SHEET (RULE 26) Accordingly, the process of PRINT (Particle replication in non-wetting templates) involves utilization of a low surface energy fluoropolymeric mold that enables high- resolution to fabricate 'a variety of organic particles. PRINT can } imprint lithography, precisely manipulate particle size of drug ranging from 20 nm to more than 100 nm.

Accordingly, the process of l condensation involves use of capillary aerosol tor (CAG) to e high concentration condensation submicron to micron sized aerosols from drug solutions.

Accordingly, the process of ultrasonication es ation of ultrasound during, particle. synthesis or precipitation, which leads to smaller particles of drug and sed size mity.

Accordingly, the process of spray drying involves supplying the feed solution at room temperature and pumping it through the nozzle where it is atomized by the nozzle gas.

The atomized on is then dried by preheated drying gas. in a special chamber to remove water moistur‘efrom the system, thus forming dry particles of drug.

The pharmaceutical compositions of the invention can be manufactured by any of the types of ses as described above.

It may be well acknowledged to a person skilled in the art that the said pharmaceutical composition, according to the present invention, may further comprise one or more (s), but not limited to and selected from antichol’inergics, antiallergics, leukotriene' antagonist, decongestants, sympathomimetic agents, mucolytics, opiate analgesics, lipoxygenase inhibiting compounds or their pharmaceutically acceptable salts, solvates, ‘ tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.

The present invention also provides a, process/s to manufacture the compositions according to the present invention.

SUBSTITUTE SHEET (RULE 26) The present ion provides a process of preparing an inhalation liquid which process comprises ving the drugs, optionally chelating agents, osmotic/isotonicity adjusting agents and any other suitable ingredients in the vehicle and adjusting the pH using a suitable pH adjusting agent.

There is also ed a process of preparing a metered dose inhalation composition which process comprises admixing a pharmaceutically acceptable r or excipient with the actives and the propellant and providing the composition in precrimped cans.

There is also provided a process of preparing a dry powder inhalation composition which process comprises admixing of a ceutically acceptable’carrier or excipient With the actives and providing the composition suitable; to be administered as a dry powder inhaler with a suitable device.

The present ion alsoprovides a method for the treatment and/or prevention of allergic disorders, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention.

The t invention further provides a method for the treatment of nasal polyps, which method comprises stration of a eutically effective amount of a pharmaceutical composition according to the present invention.

The present invention further provides a method for the treatment of urticaria, which method comprises administration of a therapeutically effective amount of a pharmaceutical compositiOn according to the present invention.

The t invention also provides-a use of the pharmaceutical composition ing to . the present invention, in the manufacture of a medicament for the treatment of nasal polyps.

SUBSTITUTE SHEET (RULE 26) The present invention also provides a use of the pharmaceutical composition ing to the present invention, in the manufacture of a ment for the treatment of urticaria.

The present invention es a pharmaceutical composition comprising at least one antihistamine and atleast one corticosteroid for use in treating and preventing disorders or. conditions that respond to, or are prevented, ameliorated or eliminated ' by, the administration of atleast one antihistamine and atleast one corticosteroid.

The t invention preferably relates to s ‘for the ent and / or prevention of allergic disorders, characterized in that ebastine and fluticasone are administered in therapeutically effective amounts.

The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

Example 1 -—-3. ' _-4.

Process: 1) Anhydrous glucose was added to Purified water.

SUBSTITUTE SHEET (RULE 26) 2) Dispersible cellulose was diSpersed in filtered Glucose solution ed from step (1) to 'produce the main bulk. 3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasone Propionate and Ebastine were added to the solution obtained in step (3) to produce uniform slurry.

) The slurry obtained in step (4) was added to the main bulk obtained in step (2) and homogenized. were added to the 6) Benzalkonium chloride, Phenyl ethyl alcohol and Disodium edetate main bulk obtained in step (2). 7) Weight was made up with Purified water EXample 2 Fluticasone Propionate . SOmcg/spray 3 Polysorbate 80 - 0.005- 0.10 % , w/w sible ose 1.5: 2 % w/w ‘ 5 % w/w .-Anhydrous e Benzalkonium chloride ‘ 1 0.02 % w/w ~ Phenyl ethyl alcohol 0.25 % w/w Process: 1) Anhydrous glucose was added to Purified water. 2) DiSpersible cellulose was dispersed in filtered Glucose~ solution obtained from step (1) to ce the main bulk. 3) Polysorbate '80 was dissolved in Purified water. , ' 4) Fluticasone Propionate and Ebastine were added to the solution ed in step (3) to' produce uniform slurry.

SUBSTITUTE SHEET (RULE 26) S) The slurry ed in step (4) was added to the main- bulk obtained in step (2) and homogenized. i 6) Benzalkonium chloride and Phenyl ethyl l were added to the main bulk obtained in step (2).~ 7) Weight was made up with Purified water. _ Example ' Fluticasone Propionate V 50mcg/Spray 3. Polysorbate 80 , 0.005- 0.10 °/o w/w ’ Dispersible cellulose ' 1.5 2 %.w/w _Benzalkonium de 0.02 % w/w Phenyl ethyl alcohol . 0.75 % w/w~ Disodium e'detate 0.01 0.5 % w/w Purified water ' q.s.

Process; 1) Anhydrous glucose was added to Purified water. 2) Dispersible cellulose was dispersed in filtered Glucose solution obtained from step (1) to produce the main bulk. 3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasone nate and Ebastine were added to the solution obtained in step (3) to produce uniform .

) The slurry obtained in step (4) was added to the main bulk obtained in step (2) and homogenized. 6) Benzalkonium chloride and Phenyl ethyl alcohol were added to the main bulk obtained i. i ’ 1 instep (2). ‘ ‘ - 7) Weight was made up with Purified water.

SUBSTITUTE SHEET (RULE 26) Example 4 Fluticasone Propionate spray 3. Polysorbate 80 0.005- 0.10 %’> . w/w Dispersible cellulose ‘ - 71.5- 2 % w/w _Benzalkonium de 0.02 % w/w' Phenyl ethyl alcohol , 0.25 % w/w Process: 1) Anhydrous glucose was added to Purified waterf 2) Dispersible cellulose was dispersed in filtered Glucose solution obtained from step (1) to produce themain bulk. 3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasone Propionate and Ebastine wereadded to the on obtained in step (3) to produce uniform .

)) The slurry obtained in step (4) was added to the main bulk obtained in Step (2) and homogenized. 6) Benzalkonium chloride and Phenyl ethyl alcohol were added to the main bulk obtained in step (2). 7) Weight was made up with Purified water.

Example 5 Fluticasone Propionate , 50mcg/spray SUBSTITUTE SHEET (RULE 26) :- Dispersible cellulosePolysorbate 80 0.005: 0.10 % 1 5-2 % w/w _Benzalkonium chloride 0.02 % w/w 1 Phenyl ethyl alcohol 0.25 % w/w Disodium e 0.01- 0.5 % w/w -——4 1) Anhydrous glucose was added to Purified water. 2) sible cellulose was dispersed in filtered Glucose solution obtained from step (1) to e the main bulk. 3) Polysorbate 80’_was ved in Purified water. 4) Fluticasone Propionate and Ebastine were added to the solution obtained in step (3) under magnetic stirring to produce uniform slurry.

) The slurry obtained in step (4) was added to the main bulk obtained in step (2) and homogenized. 6) Benzalkonium chloride, Phenyl ethyl alcohol and Disodium edetate were added to the main bulk obtained in step (2). 7) Weight Was made up with Purified water.

Example 6 Ebastine Z—OOmcg/spray Fluticasone Propionate SOmcg/Spray :- Dispersible cellulosePolysorbate 80 O.005- O 10 % ‘ 1 5- 2 % w/w _Benzalkonium chloride 0.02 % w/w .

SUBSTITUTE SHEET (RULE 26) Phenyl ethyl alcohol 0.25 % w/w Purified water Process: 1) Anhydrous glucose was added to d water. i 2) sible cellulose was dispersed in filtered Glucose solution obtained from step (I) to produce the main bulk. 3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasone nate and Ebastine were added to the solution obtained in Step (3) under magnetic stirring to produce uniform slurry.

) The slurry obtained in step (4) was added to the main bulk obtained in step (2) and homogenized. 6) Benzalkonium chloride and Phenyl ethyl alcohol were added to the main bulk obtained in step (2). 7) Weight was made. up with Purified water. le 7 —1z: SOng/spray ' Polysorbate 8O ' t , 0.005— 0.10 % sible cellulose . 1.5- 2 % w/w _Benzalkonium chloride 0.02 % w/w Phenyl ethyl alcohol ' 0.25 % w/w Disodium edetate ‘ 0.01- 0.5 % w/w Purified water - q.s.

Process: SUBSTITUTE SHEET (RULE 26) l) Anhydrous glucose was added to Purified water. 2) Dispersible cellulose was dispersed in filtered Glucose solution obtained. from step (1) to produce the main bulk. 3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasone Propionate and Ebastine were added to the solution ed in step (3) to v produce uniform slurry.

) The slurry obtained in step (4) was added to the main bulk obtained in step (2) and homogenized. . 6) Benzalkonium chloride,Phenyl ethyl alcohol and Disoidium edetate were added to the main bulk obtained in step (2). .7) Weight was made up with Purified water.

Example 8 Fluticasone Propionate SOmcg/spray :- sible cellulosePolysorbate 80 0005-0 10 % l .-5 2 % w/w rous glucose 5% w/w Benzalkonium chloride 0.02 "/0 w/w Phenyl ethyl alcohol 1 0.25 % w/w Process: 1) Anhydrous glucose was added to d water. 2) sible cellulose was dispersed in filtered Glucose solution obtained from step (1) to produce the main bulk. ' ' 3) Polysorbate 80 was dissolved in Purified water. ' 4) Fluticasone nate and Ebastine were added to the solution obtained in step (3) to produce uniform slurry.

SUBSTITUTE SHEET (RULE 26) WO 17821 ) The slurry obtained in step (4) was added to the main bulk obtained in step (2) and homogenized. 6) Benzalkonium chloride and Phenyl ethyl alcohol were added to the main bulk obtained in step (2). 7) Weight was made up with Purified water.

Example 9 ientsEbastine 2mg/spray . 2. Fluticasone nate SOmcg/spray 3. Polysorbate 80 0.005— 0.10 % . w/w 4. Dispersible cellulose . 1.5- 2_ % w/w . g . Anhydrous glucose , 5 % w/w 6. Benzalkonium 'chloride . 0.02 % w/w IPhenyl ethyl alcohol 0.25 "/0 w/w‘ ’ 99° Disodium edetate 0.01- 0.5 % w/w Process: 1) Anhydrous glucose was added to Purified water. 2) Dispersible cellulose was dispersed in filtered Glucose solution obtained from step (1) to produce the main bulk. 3) Polysorbate 80 was ved in Purified water. 4) Fluticasone Propionate and 'Ebastine were added to the on obtained in step (3) to produce uniform slurry. V ) The slurry obtained in step (4) was added to the main bulk obtained in step (2) and homogenized. 6) Benzalkonium chloride, Phenyl ethyl alcohol and Disodium edetate were added to the main bulk obtained in step (2). 7) Weight was made up with d water.

SUBSTITUTE SHEET (RULE 26) Example 10 Ingredients 1. Ebastine 2mg/spray Fluticasone Propionate SOmcg/spray 3. Polysorbate 80 0.005- 0.10 % Dispersible cellulose - 1.5- 2 % w/w Benzalkonium chloride ' 0.02 % w/w Phenyl ethyl alcohol 0 25 % W/w Purified water ‘ ' q.s Process: 1) Anhydrous glucose was added to Purified water 2) Dispersible. cellulose was dispérsed in filtered e solution obtained frOm step (1) to produce the main bulk. 3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasone Propionate and Ebastine were added to the solution ed in step (3) to e uniform . ' 5) The slurry obtained in'step (4) was added tothe main bulk obtained in step (2) and homogenized. 6) Benzalkonium chloride and Phenyl ethyl alcohol were added to the main bulk ed in step (2). 7) Weight was made up with Purified water.

A Example SUBSTITUTE SHEET (RULE 26) 3. Polysorbate 80 0.005- 0.10 % » w/w Dispersible cellulose 1.5— 2 % w/w ous glucose 5 % w/w _Benzalkonium chloride 0.02 % w/w Phenyl ethyl alcohol 0.25 % w/w Purified water q.s.

Process: 1) Anhydrous glucose was added to Purified water 2) Dispersible cellulose was dispersed in filtered Glucose on obtained from step (1) tq produce the main bulk; 3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasonc e and Ebastine were added to the solution obtained in step (3) to produce uniform slurry. 4 ) The slurry obtained in step (4) was added to the main bulk obtained in step (2) and homogenized. 6) Benzalkoniurn chloride, Phenyl ethyl alcohol and Disodium edetate were added to the main bulk obtained in step (2). l 7) Weight was made up with d water Example 12 ients *' Qt» Ebastine - SOng/spray Polysorbate 80 0.005- 0.10 % - - w/w 4. Dispersible cellulose 1.5- 2 % w/w . Anhydrous glucOse SUBSTITUTE SHEET (RULE 26) WO 17821 n‘Benzalkonium chloride 0.02 % w/w Phenyl ethyl alcohol ' 0.25 % w/w Process: 1) Anhydrous glucose was added to Purified water. 2) Dispersible cellulose was diSpersed in filtered Glucose solution obtained from step (1) to produce the main bulk. 3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasone Furoate and Ebastine were added to the solution ed in step (3) to produce uniform slurry.

) The slurry obtained in step (4) was added to the main bulk obtained in step (2) and homogenized. 6,) Benzalkonium de and Phenyl ethyl alcohol'were added to the main bulk obtained: in step (2). 7) Weight was made up with Purified water.

Exa‘m ple 13 Ingredients Qty Ebastine ‘ lODmcg/spray Fluticasone Furoate 27.5mcg/spray Polysorbate 80 0.005- 0.10 % DiSpersible cellulose 1.5- 2 % w/w Anhydrous glucose _ 5%w/w konium chloride 0.02 % w/w Phenyl ethyl alcohol 0.25 % w/w Disodium edetate 0.01- 0.5 % w/w d water q.s.

SUBSTITUTE SHEET (RULE 26) Process: 1) Anhydrous glucose was added to Purified water. 2) Dispersible cellulose was dispersed in filtered Glucose solution obtained from step (1) to produce the main bulk. 3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasone Furoate and Ebastine were added to the solution obtained in step (3) to produce uniform .

) The slurry obtained in step (4) was added to the main bulk obtained in step (2) and homogenized. . 6) Benzalkonium chloride, Phenyl ethyl alcohol and Disodium edetate were added to the rnain bulk obtained in step (2). V 7).Volume was made up with Purified water e 14 3 Polysorbate 80 ‘ 0.005- 0.10 % Dispersible‘cellulose 1.5- 2 % w/w Anhydrous glucose 5 % w/w _Benzalkonium chloride 0.02 % w/w Phenyl ethyl alcohol , 0.25 % w/w Process: 1) Anhydrous glucose was added to d water. 2) Dispersible ose was dispersed in filtered Glucose solution obtained from step (1) to produce the main bulk. 4 3) Polysorbate 80 was ved in Purified water.

SUBSTITUTE SHEET (RULE 26) 4) Fluticasone Furoate and ne were added to the solution obtained in step (3) to produce uniform slurry.

) The slurry Obtained in step (4) was added to the main bulk obtained in step (2) and homogenized. 6) Benzalkonium de and Phenyl ethyl alcohol were added to the main bulk obtained in step (2). 7) Weight was made up with Purified water ' Example 15 -Polysorbate 80 0005- 0.10 % -Dispersible cellulose 2% w/w Anhydrous e 5% w/w '_ Benzalkonium chloride ‘0.02 % w/w -Phenyl ethyl alcohol 0.25 % w/w Process: 1) Anhydrous glucose was added to Purified water. 2) Dispersible cellulose was dispersed in filtered Glucose solution obtained from step (I) to produce the main bulk. 3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasone Furoate and Ebastine were added to the solution obtained in step (3) to produce m slurry.- ) The slurry obtained in step (4) was added to the main bulk obtained in step (2) and homogenized.

SUBSTITUTE SHEET (RULE 26) 4 6) Benzalkonium de, Phenyl ethyl alcoholand Disodium edetate were added to the main bulk obtained in step (2). 7) Weight was made up with Purified water Example 16 200mcg/spray ' h 27.5mcg/spray 0.005- 0.10 % 1.5—2 %w/w 0.02 % w/w 0.25 % w/w Purified water Process: 1) ous glucose was added to Purified water. 2) Dispersible cellulose was diSpersed in d Glucose solution obtained from step (1) to produce the main bulk. 3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasone Furoate and Ebastine were added to the solution obtained in step (3) under magnetic stirring to produce uniform slurry.

) The slurry obtained in step '(4) was added to the main bulk obtained in step (2) and homogenized. 6) Benzalkonium chloride and Phenyl ethyl alcohol were added to the main bulk obtained in step (2). ' 7) Weight was made up with Purified water Example 17 SUBSTITUTE SHEET (RULE 26) Ingredients -l IE01mg/spray 27.5mcg/spray Polysorbate 80 0.005- 0.10 % Dispersible cellulose 1.5- 2 % w/w Anhydrous glucose ' % w/w~—_fl n—0.02 % w/w -—7 0.25 % w/w Ii.—0.01- 0.5 % w/w 'n Purified water q‘.s.

Process: 1) Anhydrous e was added to Purified water. 2) Sifted Dispersible cellulose was diSpersed in filtered Glucose solution obtained from - step (1) to produce the main bulk. 3) Polysorbate 80 was dissolved in Purified Water 4) asone Furoate and Ebastine were added to the solution obtained in step (3) to produce uniform slurry.

) The slurry ed in step (4) was added tothe main bulk obtained in step (2) and homogenized. 6) Benzalkonium chloride, Phenyl ethyl alcohol and Disodium edetate'were added to the main bulk obtained in step (2). 7) Weight was made up with d water Example 18 Polysorbate 80 0.005— 0.10 % ‘ - w/w SUBSTITUTE SHEET (RULE 26) m——.

Process: 1) Anhydrous glucose was added to Purified water. 2) Dispersible‘cellulose was dispersed in d Glucose solution obtained from step (1) to produce the main bulk. 3) Polysorbate 80 was dissolved in ed» water. 4) ,Fluticasone Furoate and Ebastine were added to the solution obtained in step (3) Under magnetic stirring to produce uniform slurry. . _5) The slurry-obtained in step (4) was added to the main bulk obtained in step (2) and homogenized; 6) Benzalkonium de and Phenyl ethyl alcohol were added to the main bulk obtained in step (2). . 7) Weight was made up with Purified water Example 19 Fluticasone Furoate 27.5mcg/spray Polysorbate 80 0.005- 0.10 % w/w A , Anhydrous glucose 6. Benzalkonium chloride 0.02 % w/w Phenyl ethyl alcohol SUBSTITUTE SHEET (RULE 26) 2012/000631 Process: 1) Anhydrous glucose was added to Purified water. 2) sible cellulose was dispersed in filtered Glucose solution obtained from step (1) to produce the main bulk. 3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasone Furoate and Eb‘astine were added to the solution obtained in step (3) under magnetic stirring to produce uniform slurry.

) The "slurry obtained in step (4) was added to the main bulk obtained. in step (2) and homogenized. 6) Benzalkonium chloride, Phenyl ethyl alcohol and Disodium edetate were added to. the main bulk obtained in step (2). 7) Weight was made up with Purified water Example 20 :- sible cellulosePolysorbate 80 0.005- 0.10 % 1. 5- 2 % w/w _Benzalkonium chloride_Phenyl ethyl alcohol 0.02 % w/w 025 % w/w Purified water Process: 1) Anhydrous glucose was added to Purified water. 2) sible cellulose was dispersed in filtered Glucose solution obtained from step ( 1) to e the mairi bulk.

SUBSTITUTE SHEET (RULE 26) WO 17821 _3) Polysorbate 80 was dissolved in Purified water. 4) Fluticasone Furoate and Ebastine were added to the solution obtained in step (3) under magnetic stirring to produce uniform .

) The slurry obtained in step (4) was addedto the main bulk obtained in step (2) and nized. 6) Benzalkonium chloride and Phenyl ethyl alcohol were added to the main bulk obtained in step (2). ' 7) Weight wasmade up with Purified water It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made 'to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed, by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered‘to fall within the scope of the ion.

It is to be understood that the ology and terminology used herein is for the purpose of description 'and should not be regarded as limiting. The use of ding,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

It must be noted that, as used in this specification and the appended claims, the singular forms “a," "an" and "the" include plural references unless the context clearly dictates ise. Thus, for example, reference to ”an excipient" es a single excipient as well as two or more ent excipients, and the like.

SUBSTITUTE SHEET (RULE 26)

Claims (20)

1. A pharmaceutical composition comprising at least one antihistamine, at least one corticosteroid, and at least one pharmaceutical excipient, wherein the at least one antihistamine comprises ne or its pharmaceutically acceptable salt, solvate, or ester, and wherein the at least one corticosteroid comprises fluticasone or its pharmaceutically acceptable ester thereof wherein the composition further comprises ceutically acceptable excipients formulated for nasal delivery, and wherein at least one antihistamine and at least one corticosteroid are t in a dosage form formulated for nasal delivery, optionally wherein the composition is in the form of a nasal spray, nasal solution, a nasal suspension, a nasal ointment, nasal drops or a nasal gel.

2. A pharmaceutical composition according to claim 1, wherein the fluticasone comprises fluticasone propionate, fluticasone furoate or fluticasone te.

3. A pharmaceutical composition according to any one of the preceding , wherein the fluticasone is present in an amount of from 20mcg to 50 mcg and/or wherein ebastine is present in an amount of from 25 mcg to 2g.

4. A pharmaceutical composition according to any one of claims 1, 2 or 3, wherein the pharmaceutically acceptable ents are selected from the group comprising at least one of pH adjusters, osmotic agents, emulsifiers, dispersing agents, surfactants, solubilizers, buffering agents, preservatives, wetting , gelling agents, consistency agents, chelating agents, ciliary stimulants, mucus thinning agents, suspending , thickening agents, or ations thereof.

5. A pharmaceutical composition according to claim 4, wherein the pH adjuster is citric acid, sodium citrate, sodium hydrogen sulphate, borate , sodium hydrogen orthophosphate, disodium hydrogen phosphate, Sodium dihydrogen phosphate, trometamol, e buffer, citrate buffer and their hydrous, anhydrous forms or mixtures thereof and/or n the c agent is sodium chloride, potassium chloride, zinc chloride, calcium chloride, mannitol, glycerol, and boric acid, citric acid, sodium tartrate, sodium phosphate, potassium phosphate, propylene glycol or other nic or organic solutes, dextrose, anhydrous glucose or mixtures thereof.

6. A pharmaceutical composition according to claim 4 or 5, wherein the surfactant is an amphoteric, non-ionic, cationic or anionic or combinations f, and/or wherein the preservative is benzalkonium chloride, benzoic acid or a salt, sodium benzoate, potassium sorbate, sorbic acid or a salt, edetic acid and its alkali salts, lower alkyl p-hydroxybenzoates, chlorhexidine, phenyl mercury borate, quaternary ammonium compound or mixtures thereof.

7. A ceutical composition according to any one of claims 4 to 7, wherein the consistency agents are monosaccharides, disaccharides and other sugars, , glycerine/glycerol, sorbitol, xylitol, inositol, propylene glycol, ose, mannose, xylose, rhamnose, glutaraldehyde, invert sugars, ethanol, honey, mannitol, polyethylene glycol or mixtures thereof, and/or wherein the chelating agent is sodium EDTA or um EDTA or mixtures thereof.

8. A pharmaceutical composition according to any one of the preceding claims, n said composition has a pH of from 3.0 to 7.5.

9. A pharmaceutical composition according to any one of the preceding claims, wherein the at least one antihistamine and/or at least one corticosteroid are in ized form or wherein the at least one antihistamine and/or at least one corticosteroid are in nanosize form.

10. A pharmaceutical composition according to any one of the preceding claims, further comprising at least one or more of an anticholinergic, antiallergic, leukotriene antagonist, decongestant, sympathomimetic agent, mucolytic, opiate analgesic, a lipoxygenase inhibiting compound, or a pharmaceutically acceptable salt, e, tautomer, enantiomer, isomer, hydrate, or polymorph f.

11. A nasal spray comprising a ceutical composition according to any one of the preceding claims.

12. A container comprising a pharmaceutical composition according to claim 8, optionally wherein the container is adapted for introduction of the pharmaceutical ition to the nasal passages.

13. A pharmaceutical composition according to any one of claims 1 to 10, wherein ne, fluticasone and at least one pharmaceutically acceptable ent are formulated for aneous, separate or sequential administration.

14. A pharmaceutical composition according to any one of claims 1 to 10 or 13 for use in treating disorders or conditions that respond to, or are prevented, ameliorated or eliminated by the administration of an antihistamine and a corticosteroid.

15. A pharmaceutical composition according to claim 14, wherein the disorder or condition is allergic is.

16. A process for the preparation of a pharmaceutical ition according to any one of claims 1 to 10, or 13, wherein the process comprises formulating at least one corticosteroid with at least one antihistamine and at least one pharmaceutical excipient, so as to form the pharmaceutical composition of any one of claims 1 to 10 or 13.

17. A process according to claim 16, wherein the pharmaceutical composition is according to claim 9, and the s comprises any of ball milling, jet g, sonication, homogenisation or solvent precipitation, or wherein the process comprises any of milling, precipitation, high pressure homogenisation, spray-freeze drying, double emulsion/solvent evaporation, particle ation in non-wetting templates, thermal condensation, or ultrasonication.

18. A s according to any one of claims 16 or 17, wherein the pharmaceutical composition is according to any one of claims 1 to 5, and wherein the process comprises dissolving at least one corticosteroid and at least one antihistamine, optionally adding other le pharmaceutically acceptable excipients, and adjusting the pH using a suitable pH adjusting agent.

19. Use of the pharmaceutical composition according to any one of claims 1 to 10, in the manufacture of a medicament for the treatment of nasal polyps or ria.

20. Use of the pharmaceutical composition according to any one of claims 1 to 10, in the manufacture of a medicament for the treatment of disorders or conditions that respond to, or are ted, ameliorated or eliminated by the administration of an antihistamine and a corticosteroid.