Alcaftadine and corticosteroid combination

Abstract

The present invention relates to a topical pharmaceutical composition comprising alcaftadine or a pharmaceutically acceptable salt thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof, a method for treating allergic rhinitis, allergic rhinitis-conjunctivitis, or symptoms thereof (e.g., nasal congestion) using a combination of alcaftadine or a pharmaceutically acceptable salt thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof, and a method for making the topical composition.

Description

[Technical Field]

[0001] This application claims the benefit of Indian Patent Application No. 201921053286, filed on June 15, 2020, which is incorporated herein by reference.

[0002] The present invention relates to a topical pharmaceutical composition comprising alcaftadine or a pharmaceutically acceptable salt thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof, a method for treating allergic rhinitis, allergic rhinitis-conjunctivitis, or symptoms thereof (e.g., nasal congestion) using a combination of alcaftadine or a pharmaceutically acceptable salt thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof, and a method for making the topical composition. [Background technology]

[0003] Allergic rhinitis is one of the most common diseases worldwide. It persists throughout life. The self-reported prevalence of allergic rhinitis ranges from 2% to 25% in children and from 1% to over 40% in adults. Symptoms of allergic rhinitis include sneezing, rhinorrhea, nasal itching, and nasal congestion. Ocular symptoms are also common. Rhino-conjunctivitis is characterized by itchy, red, and watery eyes.

[0004] Allergic rhinitis is characterized by inflammation of the nasal mucosa due to a complex response to nasal allergen exposure. Histamine levels are elevated in allergic rhinitis. Allergic rhinitis is characterized by two types of inflammation, immediate and delayed, following sensitization and antigen-specific IgE expression. Mast cells are thought to be activated during the immediate response, while basophils are activated during the delayed response. The immediate response appears and resolves within 30 minutes and is characterized by sneezing and rhinorrhea. The immediate response involves crosslinking of IgE molecules followed by mast cell degranulation and the release of mediators such as histamine, tryptase, prostaglandins, chymase, kinins, heparin, and leukotrienes. The delayed response is inflammatory, resulting in nasal congestion approximately 6 hours after allergen exposure and slowly subsiding. The delayed response is characterized by the influx of inflammatory cells, including T lymphocytes, basophils, and eosinophils. The delayed response involves the release of mediators from cells, including leukotrienes, kinins, histamine, cytokines, and chemokines, which produce the symptoms of rhinorhea, nasal congestion, sneezing, itching, nasal redness, watery eyes, swelling of the nasopharyngeal region, increased intraocular pressure, and postnasal drip.

[0005] Nasal congestion is one of the most common symptoms encountered in primary care and specialty practice and is also one of the most bothersome symptoms for patients. Mucosal inflammation contributes to many of the distinct correlates of nasal congestion, including increased venous congestion, increased nasal secretions, and tissue swelling and edema.

[0006] Studies have shown that over 60% of allergic rhinitis patients are dissatisfied with their current treatments, particularly those that are ineffective (Bousquet et al., J Allergy Clin Immunol., 2009 September, 124(3):428-33).

[0007] US 5,468,743 discloses alcaftadine and methods for treating allergic conditions.

[0008] US 8664215 discloses ophthalmic alcaftadine compositions and methods for treating or preventing ocular allergies.

[0009] CN 102283849 discloses a combination of alcaftadine and pseudoephedrine, and a combination of alcaftadine, pseudoephedrine, and acetaminophen for the relief of symptoms associated with allergic rhinitis and allergic conjunctivitis.

[0010] US Pat. No. 5,164,194 discloses a pharmaceutical product for nasal and ophthalmic use containing azelastine as the active ingredient.

[0011] US 2009 / 0324699 discloses pharmaceutical compositions comprising a corticosteroid and an antihistamine, polar lipid liposomes, and a pharmaceutically acceptable aqueous carrier, but such compositions involve the use of complex processes to prepare such liposomes.

[0012] WO 2019 / 022225 describes a preservative-free aqueous pharmaceutical composition containing alcaftadine or a salt thereof in a concentration greater than 0.15% w / v. Summary of the Invention [Problem to be solved by the invention]

[0013] There is a need for intranasal compositions that provide improved relief, including a faster onset of action compared to currently available treatments. [Means for solving the problem]

[0014] The present invention relates to a topical pharmaceutical composition useful for treating allergic rhinitis, allergic rhinoconjunctivitis, and nasal congestion, comprising alcaftadine or a pharmaceutically acceptable salt thereof and a corticosteroid or a pharmaceutically acceptable salt thereof. The topical composition is preferably suitable for intranasal or ocular administration. The topical composition optionally contains one or more pharmaceutically acceptable excipients. The composition provides enhanced mucoadhesion to the nasal mucosa, optimal penetration through the nasal mucosa, and minimal nasal irritation. The topical composition also has improved organoleptic properties, resulting in better patient compliance and better treatment outcomes than other unpleasant-tasting antihistamine products, such as azelastine products. In one embodiment, the topical composition provides a rapid onset of relief compared to other nasally administered antihistamines, such as olopatadine and corticosteroids. In one embodiment, the topical composition provides an onset of action in less than 15 minutes or 10 minutes when administered intranasally. In another embodiment, the composition does not have an unpleasant taste.

[0015] In one embodiment, the topical pharmaceutical composition (e.g., intranasal pharmaceutical composition) comprises: (i) about 0.05 to about 5% w / w of alcaftadine or a pharmaceutically acceptable salt thereof (e.g., alcaftadine) (e.g., about 0.125 to about 0.75% w / w of alcaftadine, such as 0.125, 0.25, 0.35, 0.45, 0.5, 0.6, and 0.75% w / w); (ii) about 0.01 to about 5% w / w of fluticasone furoate or fluticasone propionate (e.g., about 0.036% w / w of fluticasone propionate or about 0.02% w / w of fluticasone furoate); (iii) optionally, about 0.01 to about 1.0% (v) about 0.0019 to about 0.19% w / w monobasic sodium phosphate; (v) about 0.005 to about 0.5% w / w edetate disodium (e.g., edetate disodium dihydrate); (vi) about 0.0025 to about 0.25% w / w benzalkonium chloride; (vii) about 0.001 to about 0.5% w / w polysorbate 80; and (viii) about 0.5 to about 15% w / w co-spray dried combination of microcrystalline cellulose and sodium carboxymethylcellulose (e.g., the combination includes 11.3 to 18.8% sodium carboxymethylcellulose). The composition may include sodium hydroxide and / or hydrochloric acid in an amount to provide a desired pH, such as, for example, 6.0 to 7.5, 6.5 to 7.0, or 6.3 to 7.3 (eg, 6.7 to 7.3).

[0016] In another embodiment, the topical pharmaceutical composition (e.g., intranasal pharmaceutical composition) comprises (i) about 0.125 w / w alcaftadine, (ii) about 0.036% w / w fluticasone propionate or about 0.02% w / w fluticasone furoate, (iii) optionally, about 0.1% w / w suspending agent (e.g., hydroxypropylmethylcellulose, povidone, sodium carboxymethylcellulose, or hydroxyethylcellulose), (iv) about 0.068 to about 6.8% w / w sodium chloride, (v) about 0.0019 to about 0.19% w / w sodium phosphate monobasic, (vi) about 0.005 to about 0.5% w / w sodium phosphate monobasic, (vii) about 0.005 to about 0.5% w / w sodium phosphate monobasic, (viii) about 0.036% w / w fluticasone propionate or about 0.02% w / w fluticasone furoate, (viiii) optionally, about 0.1% w / w suspending agent (e.g., hydroxypropylmethylcellulose, povidone, sodium carboxymethylcellulose, or hydroxyethylcellulose), (iv) about 0.068 to about 6.8% w / w sodium chloride, (v) about 0.0019 to about 0.19% w / w sodium phosphate monobasic, (viii) about 0.005 to about 0.5% w / w sodium phosphate monobasic, (viiii ... An aqueous pharmaceutical composition comprising (w / w) edetate disodium (e.g., edetate disodium dihydrate), (vii) about 0.0025 to about 0.25% benzalkonium chloride, (viii) about 0.001 to about 0.5% w / w polysorbate 80, and (ix) about 0.5 to about 15% w / w co-spray-dried combination of microcrystalline cellulose and sodium carboxymethylcellulose (e.g., the combination includes 11.3 to 18.8% sodium carboxymethylcellulose). The composition may contain sodium hydroxide and / or hydrochloric acid in amounts to achieve a desired pH, e.g., 6.0 to 7.5, 6.5 to 7.0, or 6.3 to 7.3 (e.g., 6.7 to 7.3).

[0017] In yet another embodiment, the topical pharmaceutical composition (e.g., intranasal pharmaceutical composition) comprises (i) about 0.125 w / w alcaftadine, (ii) about 0.036% w / w fluticasone propionate or about 0.02% w / w fluticasone furoate, (iii) about 0.68% w / w sodium chloride, (iv) about 0.019% w / w monobasic sodium phosphate, (v) about 0.05% w / w edetate disodium (e.g., edetate disodium dihydrate), (vi) about 0.0125% benzalkonium chloride, (vii) about 2.1% glycerin, (viii) about 0.003% w / w polysorbate 80, and (ix) about 3.64% co-spray dried fluticasone furoate. An aqueous pharmaceutical composition comprising a w / w combination of microcrystalline cellulose and sodium carboxymethylcellulose (e.g., the combination includes 11.3-18.8% sodium carboxymethylcellulose). The composition may contain sodium hydroxide and / or hydrochloric acid in amounts to achieve a desired pH, e.g., 6.0-7.5, 6.5-7.0, or 6.3-7.3 (e.g., 6.7-7.3).

[0018] The topical pharmaceutical compositions described herein are stable. In one embodiment, after storage at 25°C and 60% relative humidity, or at 40°C and 75% relative humidity for 24 hours, 3 months, or 6 months, the topical composition contains at least 90, 95, or 98% of the initial amount of each active ingredient present. In another embodiment, the amount of any one individual impurity (of the active ingredient) is 0.5%, 0.2%, 0.1%, or 0.05% by weight or less, based on the amount of active ingredient present. In yet another embodiment, the amount of total impurities (of the active ingredient) is 3%, 2%, 1%, 0.5%, 0.3%, or 0.2% by weight or less, based on the amount of active ingredient present.

[0019] Another embodiment is a method of treating allergic rhinitis, allergic rhinitis-conjunctivitis, or a symptom thereof (e.g., nasal congestion) in a patient in need thereof by topically administering an effective amount of alcaftadine or a pharmaceutically acceptable salt thereof and a corticosteroid or a pharmaceutically acceptable salt thereof. In one embodiment, the alcaftadine and the corticosteroid are administered intranasally. In another embodiment, the alcaftadine and the corticosteroid are administered ophthalmically. In one preferred embodiment, the method includes administering (e.g., intranasally) a topical composition of the invention. In one embodiment, the patient is suffering from allergic rhinitis. In another embodiment, the patient is suffering from seasonal allergic rhinitis. In yet another embodiment, the patient is suffering from perennial allergic rhinitis. In yet another embodiment, the patient is suffering from moderate to severe seasonal allergic rhinitis. In yet another embodiment, the patient is suffering from moderate to severe perennial allergic rhinitis.

[0020] Yet another embodiment is a method of treating allergic rhinitis, allergic rhinitis conjunctivitis, or symptoms thereof (e.g., nasal congestion) in a patient in need thereof by topically administering an effective amount of a topical composition of the present invention. In one embodiment, the topical composition is administered intranasally. In another embodiment, the topical composition is administered ophthalmically. In one embodiment, the patient is suffering from allergic rhinitis. In another embodiment, the patient is suffering from seasonal allergic rhinitis. In yet another embodiment, the patient is suffering from perennial allergic rhinitis. In yet another embodiment, the patient is suffering from moderate to severe seasonal allergic rhinitis. In yet another embodiment, the patient is suffering from moderate to severe perennial allergic rhinitis.

[0021] Yet another embodiment is a method of reducing nasal decongestant use by topically administering effective amounts of alcaftadine, or a pharmaceutically acceptable salt thereof, and a corticosteroid, or a pharmaceutically acceptable salt thereof. The topical pharmaceutical compositions of the present invention are preferably administered intranasally.

[0022] Yet another embodiment is a method of inhibiting, suppressing, or preventing the formation of nasal polyps in a patient in need thereof by topically administering an effective amount of alcaftadine or a pharmaceutically acceptable salt thereof and a corticosteroid or a pharmaceutically acceptable salt thereof. In one embodiment, the alcaftadine and corticosteroid are administered intranasally. In another embodiment, the alcaftadine and corticosteroid are administered ophthalmically. In one preferred embodiment, the method includes administering (e.g., intranasally) a topical composition of the invention.

[0023] In the methods described herein, the alcaftadine and the corticosteroid may be administered simultaneously, separately, or sequentially.

[0024] The inventors have found that when administered intranasally, alcaftadine does not produce an unpleasant taste like the antihistamine azelastine, which may result in better patient compliance with the methods and topical compositions described herein than other treatments for allergic rhinitis.

[0025] Yet another embodiment includes the steps of: (i) dissolving a pH adjuster (e.g., hydrochloric acid), a tonicity adjuster (e.g., sodium chloride), and alcaftadine in water to form a first active phase solution; (ii) mixing a surfactant and co-solvent (e.g., glycerin) with a corticosteroid (e.g., fluticasone propionate or fluticasone furoate) in water to form a first dispersion; (iii) dispersing (and optionally homogenizing) a suspending agent (e.g., a combination of co-spray dried microcrystalline cellulose and sodium carboxymethylcellulose) in water to form a second dispersion; (iv) adding the first dispersion to the second dispersion to form a second active phase solution; (v) mixing a chelating agent (e.g., edetate disodium dihydrate, etc.) with a corticosteroid (e.g., fluticasone propionate or fluticasone furoate) in water to form a first dispersion; (iv) adding (with stirring) the first active phase solution and the third solution of step (v) to the second active phase solution to obtain a dispersion; (vii) adding a preservative (e.g., benzalkonium chloride) to the solution prepared in step (vi); (viii) optionally adjusting the pH of the solution of step (vii) using sodium hydroxide (e.g., to 6.0-7.5, 6.5-7.0, or 6.3-7.3); and (ix) optionally adding water (e.g., purified water) to the solution of step (viii) to obtain a desired amount and / or concentration of each component. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present inventors have discovered that combining alcaftadine, or a pharmaceutically acceptable salt thereof, with a corticosteroid, or a pharmaceutically acceptable salt thereof, provides a composition useful for treating allergic rhinitis, allergic rhinitis-related conjunctivitis, and their symptoms (e.g., nasal congestion). Without being bound by any particular theory, it is believed that alcaftadine, through its H4 receptor antagonist activity, which is predicted to upregulate lipocortin-1, enhances the activity of the corticosteroid, resulting in a synergistic combination that allows the dose of the corticosteroid to be reduced without a decrease in clinical activity, or that allows for increased clinical activity with co-administration.

[0027] Topical compositions for intranasal administration (e.g., a combination of alcaftadine and fluticasone or their esters) have a rapid onset of action, e.g., within 0.15, 0.1, 0.08, or 0.05 hours. Topical compositions for intranasal administration provide improved relief of nasal itching and nasal decongestion. Furthermore, topical compositions have fewer side effects. Other antihistamines have adverse central nervous system effects, including inverse agonism at H1 receptors, inhibiting neurotransmission in histaminergic neurons, and impairing wakefulness, cognition, learning, and memory functions (not necessarily associated with sedation, drowsiness, fatigue, or lethargy). Intranasal administration of alcaftadine exerts a local effect without systemic absorption and, therefore, without CNS side effects. For example, intranasal compositions of alcaftadine and a corticosteroid (eg, fluticasone or its esters) cause fewer adverse reactions, such as headaches and nosebleeds, compared with olapatadine and azelastine nasal sprays.

[0028] One embodiment is a nasal composition of alcaftadine in combination with fluticasone or its esters (e.g., fluticasone propionate or fluticasone furoate), which is characterized by a rapid onset of relief compared to combinations of other antihistamines (e.g., azelastine and olopatadine) with corticosteroids. In a preferred embodiment, the composition has a rapid onset of action and is effective in reducing the T of alcaftadine. max is about 0.25 hours or less (e.g., 0.2, 0.15, 0.1, 0.08, or 0.05 hours).

[0029] In a further embodiment, the present invention provides a pharmaceutical composition of alcaftadine in combination with fluticasone or its esters (e.g., fluticasone propionate or fluticasone furoate) for the treatment of symptoms associated with allergic rhinitis, such as sneezing, nasal itching, nasal inflammation, nasal irritation, rhinorrhea, nasal pruritus, and nasal congestion. The composition is an effective nasal decongestant. As a result, patients can reduce the concomitant use of other nasal decongestants.

[0030] The topical compositions of the present invention can be administered intranasally or ophthalmically once or twice daily.

[0031] Alcaftadine Alcaftadine (6,11-dihydro-11-(l-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine-3-carboxaldehyde) is an antiallergic therapeutic agent with inverse agonist effects on H1, H2, and H4 receptors, as well as cytostabilizing effects on mast cells. [ka]

[0032] H2 receptors play an important role in nasal congestion. H4 receptors affect inflammatory responses (eosinophils, T cells, dendritic cells, basophils, mast cells, and sensory neurons). Alcaftadine has higher binding affinity for H1 and H2 receptors than other antihistamines, azelastine and olapatadine, and is therefore more effective in controlling comprehensive nasal symptoms, including nasal congestion. H1 and H2 receptor signaling contributes to pruritus, nasal redness, cytokine secretion, fibroblast proliferation, adhesion molecule expression, microvascular permeability, and procollagen production. Estelle et al., J Allergy Clin Immunol, 2011, 128:1139-50. H4 receptor signaling has been shown to affect cytokine and chemokine release, chemotaxis, and adhesion molecule expression in experimental models of allergic rhinitis. Hanuskova et al.,Open Journal of Molecular and Integrative Physiology,2013,3:6-14.

[0033] Corticosteroids The methods and compositions described herein include one or more corticosteroids. Suitable corticosteroids include, but are not limited to, alclometasone, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, deflazacort, deprodone, dexamethasone, diflucortolone, fluocinolone, etiprednol, flunisolide, fluocinonide ... fluocinonide, fluocortolone, fluprednidene, flurometholone, fluticasone, halcinonide, hydrocortisone, KSR-592, loteprednol, methylprednisolone, mometasone, prednisolone, rimexolone, triamcinolone, esters thereof, and pharmaceutically acceptable salts thereof. In one embodiment, the corticosteroid is selected from beclomethasone, mometasone and its esters (e.g., mometasone furoate), fluticasone and its esters (e.g., fluticasone furoate and fluticasone propionate), budesonide, ciclesonide, and pharmaceutically acceptable salts thereof. In yet another embodiment, the corticosteroid is a glucocorticoid.

[0034] In one preferred embodiment, when the topical composition is a nasal composition or when the corticosteroid is administered intranasally, the corticosteroid is selected from beclomethasone, mometasone and its esters (e.g., mometasone furoate), fluticasone and its esters (e.g., fluticasone furoate and fluticasone propionate), budesonide, ciclesonide, and pharmaceutically acceptable salts thereof.

[0035] In a more preferred embodiment, the corticosteroid is fluticasone, its ester (e.g., fluticasone furoate, fluticasone propionate, and fluticasone valerate) or a pharmaceutically acceptable salt thereof. Any ester of fluticasone can be used in the topical compositions and methods of the present invention. Preferably, the ester of fluticasone is selected from fluticasone propionate, fluticasone furoate, and fluticasone valerate. Fluticasone is currently commercially available in the form of fluticasone furoate and fluticasone propionate.

[0036] Fluticasone propionate is a corticosteroid with the chemical name S-(fluoromethyl)6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, 17-propionate. Fluticasone propionate exhibits high lipid solubility, high selectivity and affinity for the glucocorticoid receptor, low oral systemic absorption, and rapid metabolic clearance. Fluticasone propionate has the following chemical formula (I): [ka]

[0037] Fluticasone furoate has the following chemical formula (II): [ka]

[0038] Dosage form The present invention provides alcaftadine and corticosteroids (e.g., fluticasone propionate or fluticasone furoate) that are deionized at the site of action, thereby improving permeability through the nasal mucosa. Sprays can be formed, for example, by using conventional spray-squeeze bottles or pump-type inhalers. Additionally, compressed gas aerosols can be used.

[0039] The topical composition may provide simultaneous or sequential release of alcaftadine and the corticosteroid. The topical composition may be a nasal composition such as a nasal solution, nasal suspension, nasal powder, nasal spray, nasal aerosol, nasal drops, nasal ointment, nasal inhalation, or nasal gel.

[0040] In one embodiment, the topical composition comprises an effective amount of alcaftadine in the range of 0.05% to 5% w / w in combination with an effective amount of fluticasone or an ester thereof (e.g., fluticasone propionate or fluticasone furoate) in the range of 0.01% to 5% w / w. For example, the topical composition may comprise 0.1% to 4% w / w, e.g., 0.1% to 3% w / w, 0.1% to 2% w / w, or 0.1% to 1% w / w (e.g., 0.125% w / w, 0.25% w / w, or 0.50% w / w) of alcaftadine, based on 100% total composition weight. In one embodiment, the alcaftadine is present in the composition in dissolved form. The composition may comprise 0.01 to 0.1% w / w of a corticosteroid (e.g., fluticasone propionate or fluticasone furoate), for example about 0.036% w / w fluticasone propionate or about 0.02% w / w fluticasone furoate.

[0041] In one embodiment, alcaftadine or a pharmaceutically acceptable salt thereof (e.g., free alcaftadine) and fluticasone propionate are present in a weight ratio of about 5:1 to about 1:200 or about 1:1 to about 1:150, preferably about 1:2 to about 1:110.

[0042] In one embodiment, alcaftadine or a pharmaceutically acceptable salt thereof (e.g., free alcaftadine) and fluticasone furoate are present in a weight ratio of about 5:1 to about 1:300 or about 3:1 to about 1:250, preferably about 1:1 to about 1:200.

[0043] In another embodiment, alcaftadine or a pharmaceutically acceptable salt thereof (e.g., free alcaftadine) and fluticasone propionate are present in a molar ratio of about 5:1 to about 1:250 or about 3:1 to about 1:200, preferably about 1:1 to about 1:180.

[0044] In one embodiment, alcaftadine or a pharmaceutically acceptable salt thereof (e.g., free alcaftadine) and fluticasone furoate are present in a molar ratio of about 5:1 to about 1:500, or about 2:1 to about 1:400, preferably about 1:0.7 to about 1:360.

[0045] In one embodiment, the topical composition is a suspension. For example, in the topical composition, alcaftadine is in dissolved form and the corticosteroid (e.g., fluticasone or its esters, such as fluticasone propionate or fluticasone furoate) is in particulate form. The corticosteroid (e.g., fluticasone propionate or fluticasone furoate) can have a d50 of about 1 to about 100 μm, e.g., about 1 to about 10 μm. In one embodiment, the corticosteroid can have a d90 of about 1 to about 100 μm, e.g., about 3 to about 15 μm.

[0046] The topical composition may comprise one or more pharmaceutically acceptable excipients. Suitable excipients include, but are not limited to, mucoadhesives, buffers, osmotic or tonicity adjusting agents, chelating agents, permeation enhancers, surfactants, pH adjusters, suspending agents, thickening agents (or viscosity adjusters), preservatives, solubilizing agents, and vehicles (e.g., solvents and cosolvents).

[0047] Topical compositions for intranasal administration may contain a mucoadhesive agent that provides better adhesion to the nasal mucosa and improves retention of alcaftadine and the corticosteroid on the nasal mucosa. Suitable mucoadhesives include, but are not limited to, cellulose derivatives (such as hydroxypropylmethylcellulose, hydroxyethylcellulose, and sodium carboxymethylcellulose), povidone, chitosan, poloxamer (Pluronic®), and natural gums (e.g., guar gum and xanthan gum). Mucoadhesives are often temperature-dependent and form a gel on the nasal mucosa when applied or sprayed into the nasal cavity. The gel prolongs the contact and retention time of alcaftadine and the corticosteroid on the nasal mucosa, thereby prolonging the relief of nasal congestion. The mucoadhesive may be used in an amount of 0.01% to 10% by weight of the total composition, preferably 0.01% to 1% by weight (based on the composition), e.g., 0.01% to 0.9% by weight, 0.01% to 0.7% by weight, 0.01% to 0.5% by weight, 0.01% to 0.3% by weight, or 0.01% to 0.1% by weight. The mucoadhesive may be temperature-dependent, forming a gel on the nasal mucosa upon application or spraying into the nasal cavity. The gel prolongs the contact and retention time of alcaftadine and the corticosteroid on the nasal mucosa, thereby prolonging the duration of nasal congestion relief.

[0048] In one embodiment, the composition has a sufficient amount of mucoadhesiveness to provide the composition with a contact angle of less than 109°, 108°, 107°, 106°, 105°, 104°, or 103°.

[0049] Suitable buffering agents include, but are not limited to, sodium phosphate monobasic, disodium hydrogen phosphate, sodium phosphate dibasic, sodium phosphate tribasic, and potassium phosphate dibasic. Buffering agents may be used in an amount of 0.005% to 2% by weight of the total composition, e.g., 0.0009% to 0.19% w / w, 0.0009% to 0.1% w / w, 0.009% to 0.1% w / w, 0.007% to 0.1% w / w, or 0.005% to 0.1% w / w.

[0050] Osmotic agents or tonicity adjusters refer to agents specifically added to a topical composition to increase the solute level in the composition and achieve isotonicity in the composition. Tonicity is the "effective osmolality" and is equal to the total concentration of solutes capable of exerting an osmotic force across a membrane. Suitable tonicity adjusters include, but are not limited to, sodium chloride, dextrose (e.g., dextrose USP), glycerin (e.g., glycerin USP), mannitol (e.g., mannitol USP), and potassium chloride (e.g., potassium chloride USP). In one embodiment, a topical composition for intranasal administration contains sodium chloride in an amount sufficient to provide the composition with a nasally acceptable osmolality, preferably 50 to 700 mOsmol / kg. Tonicity adjusters may be used in an amount of 0.050% to 7% by weight of the total composition. In a preferred embodiment, the nasal pharmaceutical composition contains 0.068% w / w to 6.8% w / w of sodium chloride, for example, 0.068% w / w to 5.8% w / w, 0.068% w / w to 4.8% w / w, 0.058% w / w to 3.8% w / w, 0.058% w / w to 2.8% w / w, or 0.058% w / w to 1.8% w / w of sodium chloride, based on the composition.

[0051] Suitable chelating agents include, but are not limited to, edetate disodium, diethylene-triamine-pentaacetic acid (DTPA), iminodisuccinic acid, and ethylenediaminedisuccinic acid. Chelating agents may be used in an amount of 0.005% to 0.5% by weight of the total composition. In one embodiment, the composition contains edetate disodium dihydrate in a range of 0.005% to 0.5% w / w, e.g., 0.005% to 0.4% w / w, 0.005% to 0.3% w / w, 0.005% to 0.2% w / w, or 0.005% to 0.1% w / w, based on the composition.

[0052] The permeation enhancer can enhance the permeation of alcaftadine and / or the corticosteroid through the nasal mucosa. The permeation enhancer can be a hydroxyl group-containing compound. Non-limiting examples of hydroxyl group-containing compounds that can be used as permeation enhancers include alcohols (e.g., ethanol), diols (e.g., propylene glycol (also known as 1,2-propanediol), 1,3-propanediol, butylene glycol (including 1,3-butanediol, 1,2-butanediol, 2,3-butanediol, and 1,4 butanediol), hexylene glycol, dipropylene glycol, 1,5-pentanediol, 1,2-pentanediol, 1,8-octanediol, ethoxyhexadiol, p-menthane-3,8-diol, and 2,4-butanediol). -methyl-2,4-pentanediol), triols (e.g., glycerin), polyols (e.g., suitable polymers containing multiple hydroxyl groups) (including polyethylene glycol (PEG), polypropylene glycol, polysorbates, and sorbitan esters, as well as suitable sugar alcohols), cyclitols (e.g., pinitol, inositol), cyclic diols (e.g., cyclohexanediol), aromatic diols (e.g., hydroquinone, bisphenol A, resorcinol, and catechol), or any combination thereof. Other permeation enhancers include, but are not limited to, bile salts, vitamin E TPGS, alkyl maltosides, nonionic, anionic, or amphoteric surfactants having an HLB value of 8 to 14, or combinations thereof. Non-limiting examples of such permeation enhancers are sodium glycocholate, sodium taurocholate, dodecyl maltoside, tridecyl maltoside, or tetradecyl maltoside, or any combination thereof. In one embodiment, the permeation enhancer may be present in the topical pharmaceutical composition in an amount of 0.5% to 50% by weight of the total composition, for example, 2% w / w, 5% w / w, 7.5% w / w, 10% w / w, 20% w / w, and 40% w / w.

[0053] Suitable surfactants (or wetting agents) include nonionic, cationic, amphoteric, and anionic surfactants. Suitable surfactants include, but are not limited to, sodium lauryl sulfate; polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydride, such as polysorbates selected from polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85, including sorbitan monolaurate (Span® 20), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), and sorbitan octanoate. Examples of surfactants include sorbitan fatty acid esters such as sorbitan isostearate (Span® 80) and sorbitan isostearate (Span® 120); polyethoxylated castor oil; polyethoxylated hydrogenated castor oil, sodium dodecyl sulfate (sodium lauryl sulfate), polyoxyethylene sorbitan, octoxynol, polyoxyl 10 lauryl ether, polyoxyl castor oil, cyclodextrin, lecithin, carboxylates, sulfonates, polygluconates (single-chain starch), and lignin sulfonates. In preferred embodiments, surfactants may be used in amounts of 0.001 or 0.5% to 60% by weight (e.g., 0.001 to 0.1% w / w) of the total composition. Surfactants affect the surface tension of droplets in the delivered nasal spray plume, producing spherical or substantially spherical particles with a narrow droplet size distribution (DSD), as well as affecting the viscosity of the liquid formulation.

[0054] Suitable pH adjusters include, but are not limited to, hydrochloric acid, sodium hydroxide, ammonium hydroxide, magnesium hydroxide, sulfuric acid, phosphoric acid, citric acid, malic acid, and tartaric acid. The pH adjuster may be used in an amount sufficient to obtain a pH of about 3 to about 11, e.g., about 5 to about 9, about 6 to about 8, about 6 to about 7.5, about 6.3 to about 7.3, or about 6.7 to about 7.3.

[0055] Suitable suspending and thickening agents include, but are not limited to, cellulose derivatives (e.g., cellulose ethers) in which cellulose hydroxy groups are partially etherified with lower unsaturated aliphatic alcohols and / or lower unsaturated aliphatic oxyalcohols (e.g., methylcellulose, carboxymethylcellulose (e.g., sodium carboxymethylcellulose), hydroxypropylmethylcellulose, and hydroxyethylcellulose), gelatin, polyvinylpyrrolidone (povidone), tragacanth, alginic acid, polyvinyl alcohol, polyacrylic acid, pectin, microcrystalline cellulose (with or without treatment with sodium carboxymethylcellulose), and mixtures thereof. When these substances contain acid groups, the corresponding physiologically acceptable salts may be used. Thickening and suspending agents can be added to the solutions of the present invention to prevent topical compositions (e.g., nasal solutions) from rapidly flowing out of the nose and to impart a viscosity of about 100 to about 400 cP to the solution. In preferred embodiments, thickening and suspending agents may be used in amounts of 0.1, 0.2, or 0.5% to 50% by weight of the total composition (e.g., 0.1 or 0.2% to 5% w / w).

[0056] Suitable preservatives include, but are not limited to, benzalkonium chloride, potassium sorbate, methylparaben, propylparaben, chlorbutol, chlorocresol, chlorhexidine, sodium benzoate, benzyl alcohol, and propylene glycol. In a preferred embodiment, the preservative may be used in an amount of 0.0025% to 3% by weight of the total composition. In one embodiment, the preservative may be used in an amount of 0.0025% to 2.5% by weight of the total composition. In another embodiment, the composition contains 0.0025% to 0.25% by weight of the preservative, e.g., 0.0025% to 0.15% by weight, 0.0025% to 0.1% by weight, or 0.0025% to 0.05% by weight of the preservative, based on the weight of the composition. In one preferred embodiment, the composition includes benzalkonium chloride. In one embodiment, the composition comprises between 0.0025% w / w and 2.5% w / w benzalkonium chloride by weight of the composition.

[0057] In another embodiment, the topical composition is preservative-free.

[0058] Suitable vehicles (e.g., solvents and cosolvents) and solubilizers include, but are not limited to, purified water, glycols such as propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol (glycerin), polyoxyethylene alcohols, and polyoxyethylene fatty acid esters. The vehicle or stabilizer may be present in the composition in an amount of 5% w / w to 20% w / w, for example, 5% w / w to 15% w / w, 5% w / w to 10% w / w, or 5% w / w to 7% w / w, based on the weight of the composition. Propylene glycol and polyethylene glycol may be used in an amount of 5% w / w to 20% w / w of the total composition. Purified water may be used in an amount that brings the formulation to 100% by weight of the total composition.

[0059] In one embodiment, the topical composition is a stable suspension, in which alcaftadine or a pharmaceutically acceptable salt thereof is in dissolved form, the corticosteroid is in particulate form, and the composition comprises glycerin, a polysorbate (such as polysorbate 80), and a mixture of microcrystalline cellulose and sodium carboxymethylcellulose. The topical composition may comprise: (a) 0.050% to 7% by weight (e.g., 0.5 to 4% w / w) glycerin, (b) 0.001 to 0.5% by weight (e.g., 0.001 to 0.1% w / w) polysorbate (e.g., polysorbate 80), and (c) 0.1 to 5% by weight (or 0.2 to 5% by weight) of the mixture of microcrystalline cellulose and sodium carboxymethylcellulose. In one preferred embodiment, the mixture of microcrystalline cellulose and sodium carboxymethylcellulose has a viscosity of 50-118 cps (2.6% solids, 120 seconds) and contains 11.3-18.8% sodium carboxymethylcellulose.

[0060] In one embodiment, the topical composition has an osmolality of 50-700 mOsmol / kg, for example, 100-600 mOsmol / kg or 100-500 mOsmol / kg.

[0061] In one embodiment, the topical composition (e.g., nasal solution) has a viscosity of about 100 to about 400 cPs. Viscosity can be measured using a Brookfield (DV II+Pro) AD-VS-02 with a ULA spindle, 10 mL of sample, at 100 rpm, ambient temperature, and a 60-second measurement time. Viscosity measurements can be the average of three measurements.

[0062] In one embodiment, the pH of the topical composition ranges from about 3 to about 11. In another embodiment, the pH of the topical composition ranges from about 6 to about 8, e.g., from about 6 to about 7.5, or from about 6.7 to 7.3 (e.g., 6.8, 6.9, 7.0, 7.1, or 7.2). The topical composition may include a buffering agent in an amount effective to maintain a pH of from about 3 to about 11, from about 6 to about 8, from about 6 to about 7.5, or from about 6.7 to 7.3 (e.g., 6.8, 6.9, 7.0, 7.1, or 7.2).

[0063] In one embodiment, the composition has a contact angle of less than 109°, 108°, 107°, 106°, 105°, 104°, or 103°.

[0064] Spray pump performance can be characterized in terms of the emitted spray pattern, plume shape, and / or droplet size distribution. These parameters have been found to be affected by nozzle size and shape, pump design, metering chamber size, and formulation characteristics. Droplet size is affected by device operating parameters and the composition being administered. Typical droplet median sizes can be about 30 to about 200 μm. Spray characteristics of the plume delivered after spraying (e.g., plume shape, spray pattern, pump delivery, and droplet size distribution (DSD)) can be measured under specified experimental and instrumental conditions by suitable, validated, and / or calibrated analytical procedures known in the art. Such analytical procedures include photography, laser diffraction, and impact systems (e.g., cascade impact and next generation impact).

[0065] In one embodiment, the topical pharmaceutical compositions described herein have a droplet size distribution, at 3 cm, in which D10 is 40 μm or less (e.g., about 5 to about 30 μm), D50 is 80 μm or less (e.g., about 30 to about 200 μm or about 10 to about 50 μm), D90 is 180 μm or less (e.g., about 40 to about 100 μm), and / or SPAN is 3 or less (e.g., about 1.0 to about 3.0). In one embodiment, the spray content uniformity is about 85 to about 115%.

[0066] In another embodiment, the topical pharmaceutical compositions described herein have a droplet size distribution at 6 cm, where D10 is 40 μm or less (e.g., about 5 to about 30 μm), D50 is 80 μm or less (e.g., about 30 to about 200 μm or about 10 to about 50 μm), D90 is 180 μm or less (e.g., about 40 to about 100 μm), and / or SPAN is 3 or less (e.g., about 1.0 to about 3.0). In one embodiment, the spray content uniformity is about 85 to about 115%.

[0067] The evaluation of the spray pattern, spray distance between the nozzle and the collecting surface, number of sprays per spray pattern, position and orientation of the collecting surface relative to the nozzle, and visualization procedure were performed using the ellipticity and D max In one embodiment, the topical pharmaceutical composition of the present invention is 3 cm long and D max is 100 mm or less (e.g., about 20 to about 100 mm), or 50 mm or less (e.g., about 20 to about 50 mm), and D min is 75 mm or less (e.g., about 15 to about 75 mm), or 25 mm or less, the ellipticity is 2.0 or less (e.g., about 0.5 to about 2.0), and the area is 2000 mm 2 In yet another embodiment, the nasal pharmaceutical composition of the present invention has the following spray pattern: max is 100 mm or less (for example, about 30 to about 100 mm), D min The diameter is 75 mm or less (for example, about 25 to about 75 mm), the ellipticity is 2.0 or less (for example, about 0.5 to about 2.0), and the area is 5000 mm 2 It has the following spray pattern:

[0068] In yet another embodiment, the topical pharmaceutical composition provides a droplet size distribution characterized by one or more of the following: (i) D10 is in the range of 40 μm or less (e.g., 5-25 μm), and 10% of the droplets in the plume have a size less than D10; (ii) D50 is 80 μm or less (e.g., 10-70 μm), and 50% of the droplets in the plume have a size less than D50; (iii) D90 is less than 200 μm, or less than 120 μm, and 90% of the droplets in the plume have a size less than D90; (iv) SPAN is 1-6, for example, 3 or less, and SPAN is calculated according to (D90-D10) / D50, or any combination of the foregoing.

[0069] In further embodiments of the present invention, the topical composition is in the form of an aerosol or solution and is contained in a delivery system such as a nasal spray pump, a metered dose pump, an inhaler, a bottle with a dropper or other structure for intranasal use, or a pump delivery container, or a high-density polyethylene container, or a PET (polyethylene terephthalate) container, or a glass container. The composition may be delivered as a mist of spray droplets or fine droplets to coat the nasal mucosa upon administration. A preferred pump for use in the products of the present invention is a metered multi-dose pump. The choice of pump is based on the desired dose per spray volume and a spray pattern appropriate for topical delivery to the nasal mucosa. The dose per spray may range from 1 ml to 100 ml, and each spray may deliver 100 μl to 400 μl per spray.

[0070] The topical composition may be in the form of an aerosol and may contain a propellant. The propellant may be a pressurized liquid chlorinated hydrocarbon, fluorinated hydrocarbon, or mixture of various chlorinated and fluorinated hydrocarbons, as well as propane, butane, isobutene, or mixtures thereof, or mixtures thereof with chlorinated and fluorinated hydrocarbons that are gaseous at atmospheric pressure and room temperature. Hydrofluorocarbons (HFCs), such as HFC 134a and HFC 227a, can also be used as propellants and are preferred for environmental reasons. The topical composition may be stored under pressure. The aerosol container may have a dosage or metering valve that, upon actuation, releases a predetermined amount of the topical composition (e.g., solution or suspension). Subsequent very rapid vaporization of the propellant breaks up the alcaftadine solution or suspension into fine droplets or extremely small particles that can be sprayed into the nose or taken up by nasal inspiration. A specific plastic applicator may be used to actuate the valve and deliver the atomized topical composition to the nose.

[0071] In another embodiment, the topical composition is in the form of an inhalable powder, for example, the maximum particle size of the composition does not exceed 10 μm. Alcaftadine or its salt and corticosteroid may be mixed with one or more inert carrier substances or absorbed onto one or more inert carrier substances. Carrier substances that can be used include sugars (e.g., glucose, sucrose, lactose, and fructose), starch or starch derivatives, oligosaccharides (e.g., dextrin), cyclodextrin and its derivatives, polyvinylpyrrolidone, alginic acid, tylose, silicic acid, cellulose, cellulose derivatives (e.g., cellulose ethers), sugar alcohols (e.g., mannitol or sorbitol), calcium carbonate, calcium phosphate, and any combination of any of the above.

[0072] Preparation method One embodiment includes the steps of: (i) dissolving a pH adjusting agent (e.g., hydrochloric acid), a tonicity adjusting agent (e.g., sodium chloride), and alcaftadine in water to form a first active phase solution; (ii) mixing a suspending agent, a tonicity adjusting agent (e.g., glycerin), and a corticosteroid (e.g., fluticasone propionate or fluticasone furoate) in water to form a first dispersion; (iii) dispersing (and optionally homogenizing) a suspending agent (e.g., a combination of co-spray dried microcrystalline cellulose and sodium carboxymethylcellulose) in water to form a second dispersion; (iv) adding the first dispersion to the second dispersion to form a second active phase solution; (v) mixing a chelating agent (e.g., an edetate disodium dihydrate, etc.) in water to form a second dispersion; (iv) adding (with stirring) the first active phase solution and the third solution of step (v) to the second active phase solution to obtain a dispersion; (vii) adding a preservative (e.g., benzalkonium chloride) to the solution prepared in step (vi); (viii) optionally adjusting the pH of the solution of step (vii) using sodium hydroxide (e.g., to 6.0-7.5, 6.5-7.0, or 6.3-7.3); and (ix) optionally adding water (e.g., purified water) to the solution of step (viii) to obtain a desired amount and / or concentration of each component.

[0073] The final formulation may be characterized for droplet size distribution by Spraytec and particle size distribution by Copley.

[0074] The compositions prepared by the methods described herein are capable of withstanding accelerated stability conditions of temperature and relative humidity and maintaining their physical and chemical integrity at the accelerated stability conditions.

[0075] Treatment method Another embodiment is a method of treating allergic rhinitis, allergic rhinitis-conjunctivitis, or a symptom thereof (e.g., nasal congestion) in a patient in need thereof by intranasally administering an effective amount of alcaftadine or a pharmaceutically acceptable salt thereof and a corticosteroid (e.g., a topical pharmaceutical composition comprising alcaftadine or a pharmaceutically acceptable salt thereof and a corticosteroid). The topical pharmaceutical composition of the present invention is preferably administered intranasally. In one embodiment, the patient is suffering from allergic rhinitis. In another embodiment, the patient is suffering from seasonal allergic rhinitis. In yet another embodiment, the patient is suffering from perennial allergic rhinitis. In yet another embodiment, the patient is suffering from moderate to severe seasonal allergic rhinitis. In yet another embodiment, the patient is suffering from moderate to severe perennial allergic rhinitis. In one embodiment, the topical pharmaceutical composition is administered intranasally as one or two sprays per nostril of the patient once daily. In another embodiment, the topical pharmaceutical composition is administered intranasally as one or two sprays per nostril of a patient twice daily. Each spray of the topical pharmaceutical composition may contain (i) about 171.25 mcg, about 342.5 mcg, or about 685 mcg of alcaftadine, and (ii) about 49.9 mcg of fluticasone propionate or about 27.4 mcg of fluticasone furoate.

[0076] The topical pharmaceutical compositions of the present invention can be administered intranasally or ophthalmically once or twice daily. In one embodiment, about 340 to about 5500 mcg of alcaftadine and about 80 to about 400 mcg of fluticasone propionate are administered daily (e.g., once daily in one dose or twice daily in two equally divided doses). For example, about 170 to about 2740 mcg of alcaftadine and about 40 to about 200 mcg of fluticasone propionate may be administered daily in each nostril. In another embodiment, about 340 to about 5500 mcg of alcaftadine and about 50 to about 250 mcg of fluticasone furoate are administered daily (e.g., once daily in one dose or twice daily in two equally divided doses). For example, about 170 to about 2740 mcg of alcaftadine and about 25 to about 125 mcg of fluticasone propionate may be administered daily in each nostril.

[0077] In one embodiment, one spray of a topical pharmaceutical composition containing alcaftadine and a corticosteroid (eg, as described herein) is administered per nostril once daily.

[0078] In another embodiment, two sprays of a topical pharmaceutical composition containing alcaftadine and a corticosteroid (eg, as described herein) are administered per nostril once daily.

[0079] In yet another embodiment, one spray of a topical pharmaceutical composition containing alcaftadine and a corticosteroid (eg, as described herein) is administered per nostril twice daily.

[0080] In yet another embodiment, two sprays of a topical pharmaceutical composition described herein are administered per nostril twice daily.

[0081] Each spray of the topical pharmaceutical composition may provide about 170 to about 685 mcg of alcaftadine (free base basis), e.g., about 171.25, 342.5, or 685 mcg of alcaftadine. Each spray of the topical pharmaceutical composition may provide 49 to 51 mcg of fluticasone propionate (e.g., about 49.9 mcg of fluticasone propionate). Each spray of the topical pharmaceutical composition may provide 26 to 29 mcg of fluticasone furoate (e.g., about 27.4 mcg of fluticasone furoate).

[0082] In one embodiment, about 170 to about 1370 mcg of alcaftadine and about 40 to about 100 mcg of fluticasone propionate are administered once or twice daily in each nostril. In another embodiment, about 171.25, 342.5, 685, or 1370 mcg of alcaftadine and about 49.9 mcg of fluticasone propionate are administered once daily in each nostril. In yet another embodiment, about 171.25, 342.5, 685, or 1370 mcg of alcaftadine and about 49.9 mcg of fluticasone propionate are administered twice daily in each nostril.

[0083] In another embodiment, about 170 to about 1370 mcg of alcaftadine and about 25 to about 60 mcg of fluticasone furoate are administered into each nostril once or twice daily. In another embodiment, about 171.25, 342.5, 685, or 1370 mcg of alcaftadine and about 27.4 mcg of fluticasone furoate are administered into each nostril once daily. In yet another embodiment, about 171.25, 342.5, 685, or 1370 mcg of alcaftadine and about 27.4 mcg of fluticasone propionate are administered into each nostril twice daily.

[0084] In one embodiment of the methods described herein, about 340 to about 5480 mcg of alcaftadine and about 90 to about 400 mcg of fluticasone propionate are administered daily to a patient in need thereof. In another embodiment, about 340 to about 1370 mcg of alcaftadine and about 90 to about 200 mcg of fluticasone propionate are administered daily to a patient in need thereof. In yet another embodiment, about 340 to about 690 mcg of alcaftadine and about 90 to about 200 mcg of fluticasone propionate are administered daily to a patient in need thereof.

[0085] In one embodiment of the methods described herein, about 340 to about 5480 mcg of alcaftadine and about 90 to about 420 mcg of fluticasone propionate are administered daily to a patient in need thereof. In another embodiment, about 685 to about 2740 mcg of alcaftadine and about 90 to about 210 mcg of fluticasone propionate are administered daily to a patient in need thereof. In yet another embodiment, about 685 to about 1370 mcg of alcaftadine and about 90 to about 210 mcg of fluticasone propionate are administered daily to a patient in need thereof. In yet another embodiment, about 5000 to about 5480 mcg (eg, 5280 mcg) of alcaftadine and about 380 to about 420 mcg (eg, 399.2 mcg) of fluticasone propionate are administered daily to a patient in need thereof.

[0086] In another embodiment of the methods described herein, about 340 to about 5480 mcg of alcaftadine and about 50 to about 220 mcg of fluticasone furoate are administered daily to a patient in need thereof. In another embodiment, about 340 to about 1370 mcg of alcaftadine and about 50 to about 110 mcg of fluticasone furoate are administered daily to a patient in need thereof. In yet another embodiment, about 340 to about 690 mcg of alcaftadine and about 50 to about 110 mcg of fluticasone furoate are administered daily to a patient in need thereof.

[0087] In one embodiment, the patient is between 6 and 17 years of age. In another embodiment, the patient is 17 or 18 years of age or older.

[0088] definition "Pharmaceutically acceptable excipient" means any component of a pharmaceutical composition, other than an active ingredient, that has been approved by a regulatory agency or is generally regarded as safe for use in humans or animals.

[0089] As used herein, the term "mucoadhesion" refers to the adhesion or attachment of a substance to the mucous membrane within the nasal mucosa. In the context of the present invention, mucoadhesion is intended to mean the delivery of a substance that is capable of adhering to the nasal mucous membrane when placed in contact with the surface of the nasal mucosa, thereby adhering the composition of the present invention to said surface. Such substances are hereinafter collectively referred to as "mucoadhesive substances" or "mucoadhesive agents."

[0090] The term "allergic rhinitis" includes allergic reactions of the nasal mucosa and includes hay fever, seasonal allergic rhinitis, and perennial rhinitis (non-seasonal allergic rhinitis), which are characterized by seasonal or perennial sneezing, rhinorrhea, nasal congestion, pruritus, and itchy, red, and watery eyes.

[0091] The term "patient" or "subject" refers to a human patient unless otherwise indicated. A patient may be 12 years of age or older, or 18 years of age or older. A patient may also be 6-17 years of age.

[0092] In the context of administering treatment to a patient, the terms "treat," "treatment," and "treating" refer to the reduction or inhibition of the progression and / or duration of a disease or condition, the reduction or amelioration of the severity of a disease or condition, and / or the amelioration of one or more symptoms that results from administering one or more treatments.

[0093] An "effective amount" is an amount of a compound sufficient to achieve a specified purpose (e.g., reducing one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, delay, inhibition, suppression, or reduction of one or more symptoms of a disease or disorder, which may also be referred to as a "therapeutically effective amount." A "reduction" (and grammatical equivalents of such terms) of one or more symptoms refers to a decrease in the severity or frequency of the symptoms, or the elimination of the symptoms. An "effective amount" of a drug can be the amount of drug that, when administered to a subject, has an intended prophylactic effect, such as preventing or delaying the occurrence (or recurrence) of an injury, disease, condition, or condition, or reducing the likelihood of the occurrence (or recurrence) of an injury, disease, condition, or condition, or a symptom thereof. The precise amount will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). Dosages may vary depending on the needs of the patient and the compound being used. In the context of the present disclosure, the dosage administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over the long term. Dosage levels may also vary based on experience and the nature and extent of any adverse side effects. Determination of the proper dosage for a particular situation is within the skill of one of ordinary skill in the art.

[0094] As used herein, unless otherwise indicated, the term "stable" refers to a pharmaceutical composition of the invention where at least 90, 95, or 98% of the initial amount of each active ingredient is present after 3 or 6 months of storage at 25°C and 60% relative humidity, 30°C and 60% relative humidity, or 40°C and 75% relative humidity.

[0095] As used herein, the term "salt" or "pharmaceutically acceptable salt" refers to salts, solvates, and esters that are suitable for use in contact with the tissues of humans and lower animals, within the scope of sound medical judgment, without undue toxicity, irritation, or allergic reaction, commensurate with a reasonable benefit-to-risk ratio, and effective for the intended use. Representative acid addition salts include hydrochloride, furoate, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulfate. Representative alkali metal or alkaline earth metal salts include sodium, calcium, potassium, and magnesium salts.

[0096] The transitional term "comprising," which is synonymous with "containing," "including," or "characterized by," is inclusive and open-ended and does not exclude additional, unrecited elements or method steps. The specification is understood to include embodiments having the transitional phrase "consisting of" or "consisting essentially of" in place of the transitional phrase "comprising." The transitional phrase "consisting of" excludes all unspecified elements, steps, or ingredients in the claim, except for their associated contaminants. The transitional phrase "consisting essentially of" limits the claim to the specified materials or steps, "and those that do not materially affect the basic and novel characteristics of the claimed invention."

[0097] The present invention is further illustrated by reference to the following examples, which are for illustrative purposes only and are not intended to limit the scope of the invention in any way. [Example]

[0098] Examples 1A and 1B

[0099] The aqueous compositions shown in Table 1A below were prepared. [Table 1]

[0100] ** - In Examples 1A and 1B, benzalkonium chloride is incorporated into the composition in the form of a 50% benzalkonium chloride solution, and therefore contains 0.0125% w / w benzalkonium chloride.

[0101] Avicel CL611 (available from FMC Corporation, Philadelphia, PA) is a co-spray dried combination of microcrystalline cellulose and 11.3-18.8% sodium carboxymethylcellulose.

[0102] Examples 1A and 1B were prepared as follows: a) Preparation of alcaftadine phase solutions : Hydrochloric acid, sodium chloride, and alcaftadine were added to an appropriate amount of purified water and stirred to obtain a clear alcaftadine phase solution. b) Preparation of fluticasone phase solution Polysorbate 80, glycerin, and fluticasone propionate or fluticasone furoate were added to an appropriate amount of purified water and homogenized to obtain a first uniform dispersion. Separately, microcrystalline cellulose and sodium carboxymethylcellulose were dispersed in water and homogenized to obtain a second uniform dispersion. The first uniform dispersion was added to the second uniform dispersion to obtain a fluticasone phase solution. c) Edetate disodium and sodium phosphate monobasic were added to purified water and stirred to obtain a clear third solution. d) The alcaftadine phase solution from step (a) and the third solution from step (c) were added to the fluticasone phase solution from step (b) with stirring to obtain a uniform dispersion. e) Benzalkonium chloride was added to the dispersion prepared in step (d) and stirred to obtain a uniform dispersion. f) The pH of the dispersion prepared in step (e) was adjusted to 6.0-7.5 using sodium hydroxide (1M). g) Purified water was added to the dispersion from step (f) to obtain the desired concentration and volume.

[0103] Each spray of Examples 1A and 1B can provide 123.3 to 150.7 mg (e.g., 137 μL) of composition, which provides 171.25 mcg of alcaftadine for a composition containing 0.125% w / w alcaftadine. Each spray of Example 1A provides 49.9 mcg of fluticasone propionate. Each spray of Example 1B provides 27.4 mcg of fluticasone furoate.

[0104] The stability of Examples 1A and 1B was evaluated by measuring the amount of impurities, pH, viscosity, shot weight, and spray pattern initially and after 3 and 6 months (3M and 6M) of storage at (a) 25°C and 60% relative humidity (RH), (b) 30°C and 75% RH, or (c) 40°C and 75% RH. The results are shown in Tables 1B-1G below. [Table 2]

[0105] [Table 3]

[0106] [Table 4]

[0107] [Table 5]

[0108] [Table 6]

[0109] [Table 7]

[0110] Example 2

[0111] Aqueous Compositions 2A-2H shown in Tables 2A and 2B were prepared according to the procedure described in Example 1.

[0112] [Table 8]

[0113] [Table 9]

[0114] Example 3: Bitter taste of intranasal alcaftadine

[0115] The alcaftadine formulations shown in the table below were evaluated for bitterness and compared to a similar formulation without alcaftadine (placebo formulation) and three commercially available intranasal products (Astelin®, Patanase®, and Azep®).

[0116] [Table 10]

[0117] Alcaftadine formulations were prepared as follows:

[0118] a) Preparation of active phase solution: A suitable amount of purified water and benzalkonium chloride were dissolved under stirring. Alcaftadine was added to the solution and stirred to obtain a uniform dispersion. Hydrochloric acid and sodium chloride were added to obtain a clear solution.

[0119] b) Preparation of bulk solution: Add appropriate amount of purified water and hydroxypropyl methylcellulose (Hypromellose 2910) and stir to obtain a clear solution. Add edetate disodium and sodium phosphate monobasic and stir to obtain a clear solution.

[0120] c) Addition phase: The active phase solution prepared in step a) was added to the bulk solution prepared in step b) with stirring to obtain a clear solution. The container of the active phase solution was rinsed with purified water and added to the bulk solution. The bulk solution was stirred to obtain a clear solution.

[0121] d) pH adjustment: The pH of the solution prepared in step c) was adjusted to 6.0-8.0 using sodium hydroxide.

[0122] e) Batch volumes were made up using purified water.

[0123] The formulations were evaluated in 20 volunteers according to the following evaluation criteria:

[0124] [Table 11]

[0125] The results are shown in the table below.

[0126] [Table 12]

[0127] Alcaftadine was found to have a well-tolerated taste compared with azelastine hydrochloride and olopatadine hydrochloride.

[0128] Example 4: Pharmacokinetics of intranasal alcaftadine

[0129] The nasal formulations of Examples 4A, 4B and 4C shown below were prepared by the method described in Example 3 for the alcaftadine formulation.

[0130] [Table 13]

[0131] The pharmacokinetic profiles of the test alcaftadine formulations 4A, 4B, and 4C and the olapatdine nasal formulation were determined in six male New Zealand White rabbits. The olopatadine nasal formulation (0.6% w / v) was prepared from 0.7% w / v Olopat Max®. Olopat Max® was diluted to 0.6% w / v using purified water.

[0132] A total of 24 male New Zealand White rabbits were used in the study. The rabbits were divided into four groups (G1-G4, 6 rabbits per group). Mild anesthesia was induced in all rabbits by inhalation of 2% isoflurane. Three groups of anesthetized rabbits (G1-G3) were intranasally administered 250 μL of alcaftadine once daily using the formulations of Examples 10A, 10B, and 10C. 250 μL of the comparative substance, olopatadine, at a concentration of 0.6% w / v, was intranasally administered once daily to the fourth group of anesthetized rabbits (G4).

[0133] Sampling details for test and reference products: From each rabbit, approximately 0.5 mL blood samples were drawn from the marginal ear vein and collected in labeled Eppendorf tubes containing 10% EDTA as an anticoagulant. Blood samples were collected at 0, 5, 10, 15, 30, 60, 120, 240, 480, and 1440 minutes after administration of the test and reference products.

[0134] Sample preparation procedure: Collected blood samples were gently mixed and kept on crushed ice. Plasma samples were separated after centrifugation at 3500 rpm for 10 minutes at 4°C. Plasma separation was performed within 30 minutes of sample collection and stored at -70 ± 10°C. Animals were euthanized by intravenous overdose of sodium thiopental, and nasal epithelium was harvested. Half of the nasal epithelial tissue was homogenized using phosphate buffered saline (20% homogenization) and assayed for alcaftadine and olopatidine. The remaining half of the tissue was stored in 10% neutral formalin and underwent detailed gross histopathological examination during necropsy for signs of necrosis, inflammation, or any other changes.

[0135] Concentrations of alcaftadine or olopatadine in rabbit plasma and nasal epithelial tissue were determined using a fit-for-purpose LC-MS / MS method with LLOQs of 0.500 ng / mL or 0.250 ng / mL, respectively. Pharmacokinetic parameters were assessed by noncompartmental analysis using Phoenix WinNonlin® Ent-Version 8.0.

[0136] Results: The time to peak concentration after administration of 1.5 mg olopatadine to New Zealand rabbits was 0.38 hours after a single dose. The time to peak concentration (T) after single intranasal instillation of alcaftadine at doses of 0.312 mg, 0.625 mg, and 1.25 mg was 0.38 hours. max ) was found to be 0.08 hours in all three groups. max was achieved much more rapidly than with olopatadine at the 1.5 mg dose. Thus, intranasal alcaftadine exhibited a faster onset of action than intranasal olopatadine.

[0137] Area under the curve (AUC) after single administration of alcaftadine at doses of 0.625 to 1.25 mg 0~24時 ) and peak plasma concentration (C max ) was proportional to the dose.

[0138] After intranasal administration of alcaftadine at doses of 0.312 mg, 0.625 mg, and 1.25 mg to rabbits, no signs or symptoms of inflammation or irritation were observed in any of the three groups. Histopathological examination revealed mild to moderate inflammatory cell (lymphocyte / heterophil) infiltration of the nasal epithelium and increased mucous secretion in several animals in the test and reference formulation groups.

[0139] Alcaftadine plasma concentrations were found to be dose-proportional, and systemic exposure was overall low.

[0140] All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. A topical composition for intranasal administration comprising alcaftadine or a pharmaceutically acceptable salt thereof, and a corticosteroid or a pharmaceutically acceptable salt thereof.

2. 10. The topical composition of claim 1, wherein the alcaftadine is in free form.

3. 3. The topical composition of claim 1 or 2, wherein the corticosteroid is selected from alclometasone, beclomethasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, deflazacort, deprodone, dexamethasone, diflucortolone, fluocinolone, etiprednol, flunisolide, fluocinonide, fluocortolone, fluprednidene, flurometholone, fluticasone, halcinonide, hydrocortisone, loteprednol, methylprednisolone, mometasone, prednisolone, rimexolone, triamcinolone, esters thereof, and pharmaceutically acceptable salts thereof.

4. 3. The topical composition of claim 1, wherein the corticosteroid is selected from beclomethasone, mometasone and its esters, fluticasone and its esters, budesonide, ciclesonide, and pharmaceutically acceptable salts thereof.

5. 3. The topical composition of claim 1 or 2, wherein the corticosteroid is fluticasone furoate.

6. 3. The topical composition of claim 1, wherein the corticosteroid is fluticasone propionate.

7. The topical composition of any of claims 1 to 6, further comprising a suspending agent.

8. The topical composition of any of claims 1 to 7, further comprising a preservative.

9. 9. The topical composition of any of claims 1 to 8, further comprising at least 0.0125% w / w benzalkonium chloride, based on the total weight of the composition.

10. 10. The topical composition of any of claims 1-9, further comprising a buffering agent, a tonicity adjusting agent, a chelating agent, or any combination of any of the foregoing.

11. 11. The topical composition of claim 10, wherein the buffering agent is sodium phosphate monobasic.

12. 12. The topical composition of claim 10 or 11, wherein the tonicity adjusting agent is sodium chloride.

13. 13. The topical composition of any one of claims 10 to 12, wherein the chelating agent is edetate disodium.

14. (i) about 0.05 to about 5% w / w of alcaftadine or a pharmaceutically acceptable salt thereof, (ii) about 0.01 to about 5% w / w of fluticasone furoate or fluticasone propionate, (iii) about 0.01 to about 1.0% w / w of a suspending agent, (iv) about 0.068 to about 6.8% w / w of sodium chloride, (v) about 0.0019 to about 0.19% w / w of sodium phosphate monobasic, (v) about 0.005 to about 0.5% w / w of edetate disodium, (vi) about 0.0025 to about 0.25% w / w of benzalkonium chloride, (vii) about 0.001 to about 0.5% w / w of polysorbate 80, and (viii) about 0.5 to about 15% 1. An aqueous nasal pharmaceutical composition comprising a w / w combination of microcrystalline cellulose and sodium carboxymethylcellulose, wherein the pH of said composition is 6.0 to 7.

5.

15. (i) about 0.125% w / w alcaftadine, (ii) about 0.036% w / w fluticasone propionate or about 0.02% w / w fluticasone furoate, (iii) about 0.068 to about 6.8% w / w sodium chloride, (iv) about 0.0019 to about 0.19% w / w sodium phosphate monobasic, (v) about 0.005 to about 0.5% w / w edetate disodium, (vi) about 0.0025 to about 0.25% w / w benzalkonium chloride, (vii) about 0.001 to about 0.5% w / w polysorbate 80, and (viii) about 0.5 to about 15% 1. An aqueous nasal pharmaceutical composition comprising a w / w combination of microcrystalline cellulose and sodium carboxymethylcellulose, wherein the pH of said composition is 6.0 to 7.

5.

16. (i) about 0.125% w / w alcaftadine, (ii) about 0.036% w / w fluticasone propionate or about 0.02% w / w fluticasone furoate, (iii) about 0.68% w / w sodium chloride, (iv) about 0.019% w / w sodium phosphate monobasic, (v) about 0.05% w / w edetate disodium, (vi) about 0.0125% w / w benzalkonium chloride, (vii) about 2.1% glycerin, (viii) about 0.003% w / w polysorbate 80, and (ix) about 3.64% w / w 1. An aqueous nasal pharmaceutical composition comprising a w / w combination of microcrystalline cellulose and sodium carboxymethylcellulose, wherein the pH of said composition is 6.0 to 7.

5.

17. The composition of any of claims 1 to 16, wherein the composition has a viscosity of about 100 to about 400 cPs.

18. The composition of any one of claims 1 to 17, wherein the pH of the composition is from about 6.0 to about 7.

5.

19. A composition according to any one of claims 1 to 18 for the treatment of allergic rhinitis or one or more symptoms thereof in a subject.

20. A composition according to any one of claims 1 to 19 for the treatment of nasal congestion in a subject.

21. A composition described in any one of claims 1 to 20, which (i) has an onset of action in less than 15 minutes, (ii) has a T max of alcaftadine of about 0.25 hours or less, or is both (i) and (ii).

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