RU2798030C2 - Treatment of allergic rhinitis in pediatric category using a combination of mometasone and olopatadine - Google Patents

Abstract

FIELD: medicine; pediatrics.

SUBSTANCE: invention can be used to treat allergic rhinitis in children aged 6–11 years. The method includes administering to the subject a pharmaceutical composition for nasal administration twice a day in the form of a single injection in each nostril. The pharmaceutical composition contains 0.025% wt./wt. mometasone furoate, 0.665% w/w olopatadine hydrochloride and hydrocolloid at a concentration of 0.1% wt./wt. up to 3% w/w and provides onset of action within 15 minutes. Each injection of the pharmaceutical composition contains 25 μg of mometasone furoate in the form of particles and 665 μg of olopatadine hydrochloride.

EFFECT: use of the invention makes it possible to achieve a rapid onset of action in terms of alleviating the symptoms associated with allergic rhinitis due to the combined action.

4 cl, 6 tbl, 6 ex

Description

This patent application is a division of US Patent Application No. 15/903,597, filed Feb. 23, 2018, which is incorporated herein by reference in its entirety.

FIELD OF TECHNOLOGY

This patent application relates to a method for treating allergic rhinitis in a pediatric subject by administering a combination of mometasone or a salt thereof and olopatadine or a salt thereof.

BACKGROUND OF THE INVENTION

Allergic rhinitis is a medical term referring to inflammation and irritation of the nasal mucosa. Allergic rhinitis typically occurs when an allergen, such as pollen, dust, or animal dander (particles of exfoliated skin and hair), is inhaled by a subject with a sensitized immune system. Allergic rhinitis can cause additional symptoms such as runny nose (profuse nasal discharge), sneezing, nasal itching, nasal congestion and obstruction, cough, headache, fatigue, and malaise. Symptoms may vary in severity in different individuals.

Many treatment options are available for the treatment of allergic rhinitis, such as, for example, antihistamines (eg, cetirizine and loratadine), steroids (eg, triamcinolone), decongestants, and leukotriene receptor antagonists (eg, montelukast). These treatments are typically administered orally or nasally and some are associated with an unpleasant taste and odor (eg ^Dymista® nasal spray, which is a combination of azelastine and fluticasone propionate).

Olopatadine hydrochloride, an antihistamine that is chemically described as (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride, and described in US Patent No. 4,871,865 and 4923892. In the US it is commercially available as a nasal spray PATANASE ^® , which contains 0.6% wt./about. olopatadine (base) in non-sterile aqueous solution. It is indicated for the relief of symptoms of seasonal allergic rhinitis (SAR) in adults and children 6 years of age and older. ^PATANASE® has been found to start working in 30 minutes post-dose in the Environmental Exposure Unit (See USFDA Approved Patanase Label)

Mometasone furoate is a glucocorticosteroid used topically to reduce skin or airway inflammation. Mometasone furoate monohydrate is commercially available in the United States as ^NASONEX® , a nasal spray indicated for (i) the treatment of nasal symptoms of allergic rhinitis in patients ≥2 years of age, (ii) the treatment of nasal congestion associated with seasonal allergic rhinitis in patients ≥2 years of age. 2 years, (iii) prevention of seasonal allergic rhinitis in patients ≥12 years of age, and (iv) treatment of nasal polyps in patients ≥18 years of age. It is available as 50 µg in a manual pump metered spray device containing an aqueous suspension of mometasone furoate monohydrate equivalent to 0.05% w/w. mometasone furoate (in terms of an anhydrous basis).

International publication WO 2011/141929 describes an aqueous nasal aerosol solution containing fluticasone and olopatadine.

US Pat. No. 6,127,353 describes the pharmaceutical composition mometasone furoate monohydrate.

US Pat. Nos. 7,977,376 and 8,399,508 describe a formulation of olopatadine for topical

International Publication No. WO 2011/008923 describes a regimen for the use of a nasal spray containing olopatadine in children.

International Publication No. WO 1995/020393 describes the use of mometasone furoate for the treatment of diseases of the respiratory tract and lungs.

International Publication No. WO 2010/025236 describes a combination of a nasal steroid and a nasal antihistamine for the treatment of upper respiratory viral infections, upper respiratory infections and the common cold.

SUMMARY OF THE INVENTION

The present invention relates to a fixed dose combination of mometasone or a salt thereof and olopatadine or a salt thereof, and its use for the treatment of rhinitis in a pediatric subject in need thereof. The inventors have surprisingly found that mometasone furoate and olopatadine hydrochloride act synergistically in the treatment of allergic rhinitis and the combination is more effective and provides better therapeutic value in pediatric subjects than treatment with either of the active ingredients alone. The fixed-dose combination of mometasone furoate and olopatadine hydrochloride, administered as a single injection twice daily, each injection containing 25 µg mometasone furoate and 665 µg olopatadine hydrochloride, results in a significant improvement in the quality of life of pediatric subjects, including a significant reduction in allergic symptoms. rhinitis.

The inventors have also surprisingly found that nasal administration of a pharmaceutical composition of mometasone or a salt thereof (eg mometasone furoate) and olopatadine or a salt thereof (eg olopatadine hydrochloride) provides a more rapid onset of action in terms of alleviating symptoms associated with allergic rhinitis, such as seasonal allergic rhinitis or perennial allergic rhinitis compared with olopatadine hydrochloride monotherapy or mometasone furoate monotherapy. In particular, the pharmaceutical composition provides more rapid relief of nasal symptoms such as nasal congestion, rhinorrhea, itching and sneezing. The pharmaceutical composition may also provide a faster onset of action with respect to ocular symptoms such as ocular itching, lacrimation/watery eyes, and redness of the eyes. The onset of action may be less than 30 minutes, such as within about 15 minutes, such as within about 10 minutes. In one embodiment, the invention relates to a method of treating allergic rhinitis in a pediatric human subject in need thereof, comprising nasally administering to the subject an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof. Preferably, the composition is administered nasally as 1 spray into each nostril of the subject twice daily. Each injection preferably contains mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of from about 1:5 to about 1:60, for example, in a weight ratio of from about 1:12 to about 1:53, from about 1:13.3 to about 1:50 or from about 1:18 to about 1:40 (based on the equivalent weight of olopatadine free base). In one embodiment, each injection contains about 665 micrograms of olopatadine hydrochloride and about 25 micrograms of mometasone furoate. In one embodiment, the fixed dose pharmaceutical composition is a suspension in which mometasone or a salt thereof is present in particulate form and olopatadine or a salt thereof is present in dissolved form.

In another embodiment, the invention relates to a method of treating allergic rhinitis in a pediatric human subject in need thereof, comprising nasally administering to the subject an effective amount of a fixed dose pharmaceutical composition comprising mometasone furoate monohydrate and olopatadine hydrochloride. In one preferred embodiment, the composition is administered nasally as 1 spray into each nostril of the subject twice daily. Each injection of the pharmaceutical composition may contain olopatadine hydrochloride equivalent to about 300 µg, about 450 µg, about 600 µg, about 750 µg or about 900 µg of olopatadine and about 12.5 µg, about 25 µg, about 37.5 µg, about 50 µg , or about 62.5 mcg of mometasone furoate. In one embodiment, each injection contains olopatadine hydrochloride equivalent to about 600 µg of olopatadine and about 25 µg of mometasone furoate.

Allergic rhinitis in the context of this invention includes, but is not limited to, inflammation and irritation of the nasal mucosa and associated nasal and/or non-nasal symptoms. It includes, for example, persistent allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, chronic rhinitis, drug rhinitis, vasomotor rhinitis, infectious rhinitis, autonomic rhinitis, hormonal rhinitis, drug rhinitis, atrophic rhinitis, and gustatory rhinitis. Preferably, allergic rhinitis is selected from perennial allergic rhinitis, persistent allergic rhinitis, seasonal allergic rhinitis, and associated nasal and/or non-nasal symptoms.

In the context of this invention, symptoms associated with rhinitis include rhinorrhea, nasal congestion, nasal itching, sneezing, itchy/burning eyes, watery/watery eyes, red eyes, itchy ears or palate, cough, itchy eyes, excessive watery eyes, headache, fatigue and malaise.

In another embodiment, the invention relates to a method of treating allergic rhinitis in a pediatric human subject in need thereof, the method comprising nasally administering to the subject an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof by weight. in a ratio of about 1:5 to about 1:60, or about 1:12 to about 1:53, wherein (i) the composition is administered nasally as 1 spray in each nostril twice daily, and (ii) each spray contains olopatadine hydrochloride equivalent to about 600 micrograms of olopatadine and about 25 micrograms of mometasone furoate. In one embodiment, the composition is administered over about 1 week. In another embodiment, the composition is administered over a period of about 2 weeks.

In one embodiment, the overall rhinitis symptom severity scale (TNSS) score for the human subject is reduced by at least 40%, preferably by at least 50%, from study entry after 1 or 2 weeks of treatment. In another embodiment, the human subject's total eye symptom score (TOSS) score is reduced by at least 30%, preferably by at least 40%, from study entry after 1 or 2 weeks of treatment. In one aspect of the invention, the Global Rhinitis Symptom Severity Scale (TNSS) and the Total Ocular Symptoms Scale (TOSS) scores can be defined as instantaneous, or retrospective, or both.

Another embodiment is a method of treating symptoms associated with allergic rhinitis in a pediatric human subject in need thereof, comprising nasal administration twice daily as one injection into each nostril of a fixed dose pharmaceutical composition containing mometasone or its salt (eg mometasone furoate) and olopatadine or its salt (eg olopatadine hydrochloride). Each injection may contain mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of about 1:5 to about 1:60 (e.g., a weight ratio of about 1:12 to about 1:53, about 1:13.3 to about 1:50 or about 1:18 to about 1:40) (based on the equivalent weight of olopatadine free base) (e.g., each spray contains about 12.5 µg, about 25 µg, about 37.5 µg, about 50 mcg or about 62.5 mcg of mometasone or a salt thereof (e.g., about 50 mcg of mometasone furoate) and olopatadine hydrochloride equivalent to about 300 mcg, about 450 mcg, about 600 mcg, about 750 mcg, or about 900 mcg of olopatadine (e.g., about 665 mcg of olopatadine hydrochloride). In one embodiment, each injection contains about 665 micrograms of olopatadine hydrochloride and about 25 micrograms of mometasone furoate. Administration can provide relief from one or more symptoms of allergic rhinitis (such as nasal symptoms or ocular symptoms) faster (eg onset of action in less than 30 minutes, eg within about 15 minutes, eg within 10 minutes) than nasal administration mometasone or its salt, or olopatadine or its salt in monotherapy. In another embodiment, the administration may provide relief from one or more symptoms of allergic rhinitis (such as nasal symptoms) in a subject exposed to an environmental exposure chamber (EEC) (such as ragweed pollen at a concentration of 3500 ± 500 particles/m ³ for 6 hours) faster (eg onset of action in less than 15 minutes, eg within about 10 minutes) than nasal mometasone or a salt thereof, or olopatadine or a salt thereof alone.

Another embodiment is a method of providing a more rapid onset of relief of symptoms associated with allergic rhinitis in a pediatric human subject in need thereof, comprising nasal administration twice a day as one injection in each nostril of a fixed dose pharmaceutical composition. containing mometasone or its salt (for example, mometasone furoate) and olopatadine or its salt (for example, olopatadine hydrochloride). This method may provide more rapid relief of one or more symptoms than administration of mometasone alone or a salt thereof, or olopatadine alone or a salt thereof. Each injection may contain mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of about 1:5 to about 1:60 (e.g., a weight ratio of about 1:12 to about 1:53, about 1:13.3 to about 1:50 or about 1:18 to about 1:40) (based on the equivalent weight of olopatadine free base) (e.g., each spray contains about 12.5 µg, about 25 µg, about 37.5 µg, about 50 mcg or about 62.5 mcg of mometasone or a salt thereof (e.g., about 50 mcg of mometasone furoate) and olopatadine hydrochloride equivalent to about 300 mcg, about 450 mcg, about 600 mcg, about 750 mcg, or about 900 mcg of olopatadine (e.g., about 665 mcg of olopatadine hydrochloride). In one embodiment, each injection contains about 665 micrograms of olopatadine hydrochloride and about 25 micrograms of mometasone furoate. Administration may provide relief from one or more symptoms within 30 minutes, such as within 15 minutes or 10 minutes. In another embodiment, the administration may provide relief from one or more symptoms of allergic rhinitis (such as nasal symptoms) in a subject exposed to an environmental exposure chamber (EEC) (such as ragweed pollen at a concentration of 3500±500 particles/m3 for 6 hours) less than 15 minutes, for example, for about 10 minutes.

A human subject in the pediatric age category may be pre-treated with mometasone alone or a salt thereof, or olopatadine alone or a salt thereof. For such human subjects, the methods described herein may include the step of stopping treatment with mometasone or salt or olopatadine or salt monotherapy prior to initiating nasal administration of the fixed dose pharmaceutical composition of mometasone or salt and olopatadine or salt thereof.

In one embodiment, the methods herein provide a faster onset of action to relieve nasal symptoms in a subject. In another embodiment, the methods herein provide a faster onset of action to relieve ocular symptoms in a patient.

In one preferred embodiment, the method comprises nasal administration to a human subject twice daily as a single injection into each nostril of a fixed dose pharmaceutical composition containing 25 μg of mometasone furoate and 665 μg of olopatadine hydrochloride.

In one embodiment, the pharmaceutical composition provides a faster onset of action to relieve nasal symptoms in a patient. In yet another embodiment, the pharmaceutical composition provides a faster onset of action to relieve eye symptoms in a patient.

Another embodiment is a method of treating a pediatric human subject suffering from allergic rhinitis, comprising the step of administering to the subject a nasal pharmaceutical composition twice a day as a single injection in each nostril, wherein (i) the pharmaceutical composition provides onset of action for 15 minutes to treat allergic rhinitis; and (ii) each injection of the pharmaceutical composition contains about 25 µg of mometasone furoate and about 665 µg of olopatadine hydrochloride.

Another embodiment is a method of treating a pediatric human subject suffering from allergic rhinitis, comprising the steps of:

(a) administering to a pediatric human subject a fixed dose nasal pharmaceutical composition twice daily as a single injection into each nostril, the fixed dose pharmaceutical composition comprising mometasone or a salt thereof (such as mometasone furoate) and olopatadine, or its salt (such as olopatadine hydrochloride), and each injection contains mometasone or its salt and olopatadine or its salt in a weight ratio of from about 1:5 to about 1:60 (for example, in a weight ratio of from about 1:12 to about 1: 53, about 1:13.3 to about 1:50, or about 1:18 to about 1:40) (based on the equivalent weight of olopatadine free base) (e.g., each injection contains about 12.5 micrograms, about 25 mcg, about 37.5 mcg, about 50 mcg, or about 62.5 mcg mometasone or a salt thereof (e.g., about 50 mcg mometasone furoate) and olopatadine hydrochloride equivalent to about 300 mcg, about 450 mcg, about 600 mcg, about 750 mcg or about 900 micrograms of olopatadine (for example, about 665 micrograms of olopatadine hydrochloride)) (preferably each injection contains about 665 micrograms of olopatadine hydrochloride and about 25 micrograms of mometasone furoate),

wherein the administration is in accordance with (i) marketing the pharmaceutical composition as (A) providing a faster onset of action (e.g., onset of action in less than 30 minutes, e.g., within 15 minutes, e.g., within 10 minutes) to facilitate one or more symptoms (eg, nasal symptoms) of allergic rhinitis than nasal mometasone or its salt (eg, 25 mcg mometasone furoate), or olopatadine or its salt (eg, 665 mcg olopatadine hydrochloride) alone, (B) providing relief to one or more symptoms of allergic rhinitis within 15 minutes (or 30 minutes), and (ii) a diagnosis of a human subject suffering from allergic rhinitis, or (C) providing a faster onset of action (e.g., within 15 minutes, e.g., within about 10 minutes) to relieve one or more symptoms (eg, nasal symptoms) of allergic rhinitis in subjects exposed in an environmental exposure chamber (EEC) (eg, ragweed pollen at 3500±500 particles/m ³ for 6 hours ) than nasal administration of mometasone or its salt, or olopatadine or its salt in monotherapy. (D) providing relief from one or more symptoms of allergic rhinitis (eg, nasal symptoms) in subjects exposed in an environmental exposure chamber (EEC) (eg, ragweed pollen at 3500±500 particles/m ³ for 6 hours) within 15 minutes, for example within about 10 minutes; And

(b) administering the designated pharmaceutical composition to the subject. In one preferred embodiment, each injection of the fixed dose pharmaceutical composition provides 25 μg of mometasone furoate and 665 μg of olopatadine hydrochloride.

Another embodiment is a method of treating a pediatric human subject suffering from allergic rhinitis (e.g., seasonal allergic rhinitis or perennial allergic rhinitis) comprising the step of administering to the subject a fixed dose nasal fixed dose pharmaceutical composition twice daily at as a single injection into each nostril, the fixed dose pharmaceutical composition comprising mometasone or a salt thereof (e.g. mometasone furoate) and olopatadine or a salt thereof (e.g. olopatadine hydrochloride) and each injection containing mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of about 1:5 to about 1:60 (e.g., a weight ratio of about 1:12 to about 1:53, about 1:13.3 to about 1:50, or about 1:18 to about 1: 40) (based on the equivalent weight of olopatadine free base) (for example, each injection contains about 12.5 micrograms, about 25 micrograms, about 37.5 micrograms, about 50 micrograms, or about 62.5 micrograms of mometasone or its salt (for example, about 50 µg mometasone furoate) and olopatadine hydrochloride equivalent to about 300 µg, about 450 µg, about 600 µg, about 750 µg, or about 900 µg olopatadine (e.g., about 665 µg olopatadine hydrochloride)). In one embodiment, each injection contains about 665 micrograms of olopatadine hydrochloride and about 25 micrograms of mometasone furoate. The pharmaceutical composition is administered in accordance with (a) marketing the pharmaceutical composition as (A) providing a faster onset of action (e.g., onset of action in less than 30 minutes, e.g., within 15 minutes, e.g., within 10 minutes) to relieve symptoms ( nasal symptoms) of allergic rhinitis than nasal mometasone or its salt (eg, 50 mcg mometasone furoate) or olopatadine or its salt (eg, 665 mcg olopatadine hydrochloride) alone, or (B) providing relief from one or more symptoms allergic rhinitis within 15 minutes (or 30 minutes); and (b) diagnosing a subject suffering from allergic rhinitis. In one preferred embodiment, each injection of the fixed dose pharmaceutical composition provides 25 μg of mometasone furoate and 665 μg of olopatadine hydrochloride.

In one embodiment, in accordance with any of the methods described herein, allergic rhinitis is selected from perennial allergic rhinitis, persistent allergic rhinitis, seasonal allergic rhinitis, and associated nasal and/or non-nasal symptoms. In one preferred embodiment, according to any of the methods described herein, the allergic rhinitis is seasonal allergic rhinitis. In another preferred embodiment according to any of the methods described herein, the allergic rhinitis is perennial allergic rhinitis.

In one embodiment, the subject suffers from persistent allergic rhinitis and is treated for 4 or 6 weeks.

In another embodiment, the subject shows a positive skin prick test for the allergen. Alternatively, the subject may have positive blood tests indicative of an allergy.

In yet another embodiment, the method does not cause significant treatment-related adverse events in the subject after 1 or 2 weeks of treatment.

In another embodiment, the invention relates to a method of treating seasonal allergic rhinitis and/or nasal symptoms associated with seasonal allergic rhinitis in a pediatric subject in need thereof, comprising nasal administration to the subject of a combination (e.g., a synergistic combination) containing mometasone furoate and olopatadine hydrochloride, the combination being in the form of a pharmaceutical composition containing mometasone furoate and olopatadine hydrochloride in a weight ratio of from about 1:5 to about 1:60, or from about 1:13.3 to about 1:53.2 (in terms of equivalent weight of olopatadine free base). In one embodiment, the invention relates to a method of treating allergic rhinitis in a human in need thereof, comprising nasally administering to a human an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof, wherein (i) the composition is administered nasally into as 1 injection into each human nostril twice daily, and (ii) each injection contains mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of from about 1:5 to about 1:60, or from about 1:13.3 to about 1:53.2 (based on the equivalent weight of the free base of olopatadine). In one embodiment, each injection contains about 665 micrograms of olopatadine hydrochloride and about 25 micrograms of mometasone furoate. The method may provide a reduction in at least one treatment-related adverse event (eg, epistaxis and drowsiness) compared with mometasone or olopatadine alone. For example, the method may provide effective treatment of seasonal allergic rhinitis and/or nasal symptoms associated with seasonal allergic rhinitis in a subject with a reduction in the incidence of drowsiness and epistaxis. In another embodiment, the method may provide effective treatment of seasonal allergic rhinitis and/or nasal symptoms associated with seasonal allergic rhinitis in a subject without significant drowsiness and/or inducing epistaxis.

In another embodiment, the invention relates to a method of treating perennial allergic rhinitis and/or nasal symptoms associated with perennial allergic rhinitis in a pediatric subject in need thereof, comprising nasal administration to the subject of a combination (e.g., a synergistic combination) containing mometasone furoate and olopatadine hydrochloride, the combination being in the form of a pharmaceutical composition containing mometasone furoate and olopatadine hydrochloride in a weight ratio of from about 1:5 to about 1:60, or from about 1:13.3 to about 1:53.2 (in terms of equivalent weight of olopatadine free base). In one embodiment, each injection contains about 665 micrograms of olopatadine hydrochloride and about 25 micrograms of mometasone furoate.

In one aspect of this embodiment, each injection contains about 25 micrograms of mometasone furoate and olopatadine hydrochloride, equivalent to about 600 micrograms of olopatadine. In one aspect of this embodiment, the pharmaceutical composition is a suspension containing mometasone or a salt thereof in particulate form and olopatadine or a salt thereof in solution. In one aspect of this embodiment, the composition is administered for at least 1 week as 1 spray in each nostril twice daily. In yet another aspect of this embodiment, allergic rhinitis is selected from perennial allergic rhinitis, persistent allergic rhinitis, seasonal allergic rhinitis, and associated nasal and/or non-nasal symptoms. In a preferred aspect, the allergic rhinitis is seasonal allergic rhinitis and/or associated nasal symptoms. In yet another aspect of this embodiment, (i) a person's rhinitis symptom severity score (TNSS) score is reduced by at least 50% from study entry after 2 weeks of treatment, and/or (ii) a person's overall ocular symptom score symptoms (TOSS) in the individual is reduced by at least 40% from the time of entry into the study after 2 weeks of treatment, and/or (iii) the individual does not experience significant treatment-related adverse events after 2 weeks of treatment. In one aspect of said embodiment, the individual exhibits a positive skin prick test for the allergen. In one embodiment, treatment-related adverse events include drowsiness or epistaxis, or a combination thereof.

A fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof may be administered nasally to a pediatric human subject as 1 spray in each nostril twice daily for a period of at least 1 week or 2 weeks.

In another embodiment of any of the methods described herein, the subject is a subject in the pediatric age category (e.g., ≥2 to <12 years of age, e.g., ≥6 to <12 years of age, or ≥6 months to <6 years) and the fixed dose pharmaceutical composition is administered nasally as 1 spray in each nostril twice daily. In one embodiment, each injection of a fixed dose pharmaceutical composition contains 665 μg of olopatadine hydrochloride and 25 μg of mometasone furoate (eg, with the formulation of Example 9). In yet another embodiment, the composition is administered nasally for at least 1 week, such as for at least 2 weeks, for at least 4 weeks, for at least 8 weeks, or for at least 12 weeks. In one embodiment, the age of the subject is from 2 to 11 years. In another embodiment, the age of the subject is from 6 to 11 years. In another embodiment, the age of the subject is from 2 to 5 years.

Yet another embodiment is a method of treating symptoms associated with allergic rhinitis in a pediatric human subject in need thereof (e.g., ≥2 to <12 years of age, e.g., ≥6 to <12 years of age). years or aged ≥6 months to <6 years), comprising nasal administration twice daily of a single dose of a pharmaceutical composition containing mometasone furoate and olopatadine hydrochloride, and a single dose of the composition provides about 1330 μg of olopatadine hydrochloride and about 50 μg of mometasone furoate. In one preferred embodiment, one dose comprises one injection into each nostril of the pharmaceutical composition, with each injection providing 665 μg of olopatadine hydrochloride and 25 μg of mometasone furoate (eg, with the formulation of Example 9). Allergic rhinitis may be, for example, seasonal allergic rhinitis or perennial allergic rhinitis. In one embodiment, the age of the subject is between 2 and 11 years old. In another embodiment, the age of the subject is from 6 to 11 years. In another embodiment, the age of the subject is from 2 to 5 years.

Yet another embodiment is a method of treating symptoms associated with allergic rhinitis in a pediatric human subject in need thereof (e.g., ≥2 to <12 years of age, e.g., ≥6 to <12 years of age). years or aged ≥6 months to <6 years) involves nasal administration twice a day as a single injection in each nostril of a fixed dose pharmaceutical composition containing mometasone furoate and olopatadine hydrochloride, with each injection providing 665 mcg of olopatadine hydrochloride and 25 µg of mometasone furoate (for example, with the composition of example 9). Allergic rhinitis may be, for example, seasonal allergic rhinitis or perennial allergic rhinitis. In one embodiment, the age of the subject is from 2 to 11 years. In another embodiment, the age of the subject is from 6 to 11 years. In another embodiment, the age of the subject is from 2 to 5 years.

In another embodiment, the invention relates to a method of treating seasonal allergic rhinitis and/or nasal symptoms associated with seasonal allergic rhinitis in a pediatric human in need thereof, comprising nasally administering to a human a combination (e.g., a synergistic combination) containing mometasone furoate and olopatadine hydrochloride, the combination being in the form of a pharmaceutical composition containing particulate mometasone furoate and olopatadine hydrochloride in solution in a weight ratio of from about 1:13.3 to about 1:53.2 (based on the equivalent weight of olopatadine free base) wherein the composition is administered as 1 spray into each human nostril twice a day for at least 1 week, the method providing a reduction in at least one treatment-related adverse event.

In one aspect of this implementation, the composition is administered twice a day for 2 weeks. In another aspect of this embodiment, each injection contains about 25 µg of mometasone furoate and about 665 µg of olopatadine hydrochloride. In yet another aspect of this embodiment, (i) a person's rhinitis symptom severity score (TNSS) score is reduced by at least 50% from study entry after 2 weeks of treatment, and/or (ii) a person's overall ocular symptom score symptoms (TOSS) in the individual is reduced by at least 40% from the time of entry into the study after 2 weeks of treatment, and/or (iii) the individual does not experience significant treatment-related adverse events after 2 weeks of treatment. In one aspect of said embodiment, the individual exhibits a positive skin prick test for the allergen. Preferably, treatment-related adverse events include drowsiness or epistaxis, or a combination thereof.

In one aspect of the invention, the fixed dose pharmaceutical composition may be administered for about 1 week, 2 weeks, 4 weeks, 6 weeks, or 8 weeks. Preferably, the fixed dose pharmaceutical composition is administered as 1 spray into each nostril of a pediatric human subject twice daily for 1 week or 2 weeks. In another embodiment, each injection of the composition contains olopatadine hydrochloride equivalent to about 600 micrograms of olopatadine and about 25 micrograms of mometasone furoate. Preferably, each injection of the composition contains about 665 micrograms of olopatadine hydrochloride (equivalent to about 600 micrograms of olopatadine) and about 25 micrograms of mometasone furoate. In yet another aspect, the composition is odor and taste free. In yet another embodiment, the overall rhinitis symptom severity scale (TNSS) score in a human subject is reduced by at least 40% or at least 50% from study entry after 1 or 2 weeks of treatment. In yet another embodiment, a person's Total Ocular Symptom Score (TOSS) score is reduced by at least 30% or at least 40% from study entry after 1 or 2 weeks of treatment. In yet another embodiment, said method provides for the reduction of one or more treatment-related adverse events. Preferably, treatment-related adverse events include drowsiness or epistaxis, or a combination thereof. In yet another embodiment, the human subject is a patient who exhibits a positive skin prick test for an allergen.

In one aspect, the invention relates to the use of mometasone, or a salt thereof, and olopatadine, or a salt thereof, in a weight ratio of about 1:5 to about 1:60, or about 1:12 to about 1:53, in the manufacture of a fixed dose pharmaceutical composition of the invention. for the treatment of allergic rhinitis in a pediatric human subject in need thereof. In one aspect, the fixed dose pharmaceutical composition is a suspension in which mometasone or a salt thereof is present in particulate form (e.g., with an average particle size of about 1 to about 20 microns, or about 1 to about 15 microns) and olopatadine or a salt thereof present in dissolved form. In yet another aspect, the composition is odorless and tasteless.

In a separate embodiment, this invention relates to a method for reducing symptoms associated with rhinitis in a pediatric human subject in need thereof, the method comprising nasally administering to the subject an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or its salt in a weight ratio of from about 1:5 to about 1:60 or from about 1:12 to about 1:53 for about 1 or 2 weeks.

In yet another embodiment, the invention relates to a method for reducing symptoms associated with allergic rhinitis in a pediatric human in need thereof, comprising nasally administering to a human an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof. wherein (i) the composition is administered nasally as 1 injection into each human nostril twice daily, and (ii) each injection contains mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of from about 1:5 to about 1:60 or from about 1:12 to 1:53 for about 1 or 2 weeks (based on the equivalent weight of olopatadine free base) and the composition is administered as 1 spray into each human nostril twice a day for at least 1 weeks, while the method provides a reduction in at least one undesirable phenomenon. In one aspect of this embodiment, each injection contains about 25 micrograms of mometasone furoate and olopatadine hydrochloride, equivalent to about 600 micrograms of olopatadine. In one aspect of this embodiment, the pharmaceutical composition is a suspension containing mometasone or a salt thereof in particulate form and olopatadine or a salt thereof in solution. In one aspect of this embodiment, the composition is administered for at least 1 week as 1 spray in each nostril twice daily. In yet another aspect of this embodiment, allergic rhinitis is selected from perennial allergic rhinitis, persistent allergic rhinitis, seasonal allergic rhinitis, and associated nasal and/or non-nasal symptoms. In a preferred aspect, the allergic rhinitis is seasonal allergic rhinitis and/or associated nasal symptoms. In yet another aspect of this embodiment, (i) a person's rhinitis symptom severity score (TNSS) score is reduced by at least 50% from study entry after 2 weeks of treatment, and/or (ii) a person's overall ocular symptom score symptoms (TOSS) in the individual is reduced by at least 40% from the time of entry into the study after 2 weeks of treatment, and/or (iii) the individual does not experience significant treatment-related adverse events after 2 weeks of treatment. In one aspect of said embodiment, the individual exhibits a positive skin prick test for the allergen. In one aspect of said embodiment, the symptoms include rhinorrhea, nasal congestion, itchy nose, sneezing, itchy/burning eyes, watery/watery eyes, red eyes, itchy ears or palate, cough, itchy eyes, excessive watery eyes, headache, fatigue and malaise. In yet another embodiment, treatment-related adverse events include drowsiness or epistaxis, or a combination thereof.

Another embodiment relates to a method of reducing the amount of eosinophils in a subject's nasal lavage by nasally administering an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of from about 1:5 to about 1:60 (in terms of per equivalent weight of olopatadine free base), the method providing a greater reduction in eosinophils than that provided by mometasone or its salt or olopatadine or its salt when used as monotherapy. The number of eosinophils can be determined by any known method, for example, using a hemocytometer.

Another embodiment relates to a method for reducing the total number of cells in nasal lavage by nasally administering an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of from about 1:5 to about 1:60 (in equivalent weight of olopatadine free base), the method providing a greater reduction in total cell count than that provided by mometasone or its salt, or olopatadine or its salt when used as monotherapy.

In another aspect, the present invention relates to a fixed dose stable aqueous pharmaceutical composition for nasal administration to a pediatric human. The composition contains mometasone or a salt thereof and olopatadine or a salt thereof. The pharmaceutical composition may be contained in a container suitable for nasal administration. In one embodiment, the pharmaceutical composition is contained in a spray bottle (such as an atomizer). The spray bottle may include a container for storing the pharmaceutical composition and a pump for intranasal spraying of the pharmaceutical composition. In one embodiment, the container is capable of storing 30, 56, 60, 120, or 240 doses. For example, a container containing 120 doses can provide a 1 month supply of pharmaceutical composition (1 spray in each nostril twice a day (4 sprays per day) for 30 days). A 28 dose container can provide a 1 week supply of pharmaceutical composition (1 spray in each nostril twice daily (4 sprays per day) for 7 days). In one embodiment, the container may be sized to hold 4-5 ml (e.g. 4.5 ml or 28 doses), 9-10 ml of a pharmaceutical composition (e.g. 9 ml or 60 doses) or 18-19 ml (e.g. 18 ml or 120 doses) of a pharmaceutical composition.

One embodiment is a stable, fixed-dose, aqueous pharmaceutical composition (eg, contained in a container) for nasal administration to a pediatric human, wherein the composition contains from about 0.001% w/w. up to about 0.075% wt./wt. mometasone or its salt and from about 0.5% wt./wt. up to about 0.8% w/w of olopatadine or a salt thereof. The pharmaceutical composition may be in the form of a solution or suspension, but preferably the composition is in the form of a suspension (more preferably a single phase suspension) in which mometasone or a salt thereof is present in particulate form and olopatadine or a salt thereof is present in dissolved form. In one aspect, mometasone or a salt thereof and olopatadine or a salt thereof are present in a weight ratio of about 1:3 to about 1:106, or about 1:5 to about 1:53, or preferably about 1:5 to about 1 :36.

The composition preferably also contains a hydrocolloid. In one embodiment, the composition is a suspension and contains a sufficient amount of hydrocolloid to prevent or inhibit phase separation (i.e., separation of particles and solution) after 3 or 6 months of storage at 25±2°C and 60%±RH. 5%, or at 40±2°C and RH 75%±5%. In one embodiment, the aqueous pharmaceutical composition is a single phase suspension that remains a single phase suspension even after 3 or 6 months of storage at 25±2°C and 60%±5% RH, or at 40±2°C and 75% RH ±5%.

Another embodiment is a fixed dose stable aqueous pharmaceutical composition (e.g. contained in a container) for nasal administration to a pediatric human subject, wherein the composition contains from about 0.001% w/w to about 0.075% w/w. mometasone furoate monohydrate and from about 0.5% wt./wt. to about 0.8% w/w olopatadine hydrochloride.

Another embodiment is a stable, fixed-dose, aqueous suspension pharmaceutical composition (eg, contained in a container) for nasal administration to a human, wherein the composition contains from about 0.025% w/w. up to about 0.05% wt./wt. mometasone or its salts, from about 0.6% wt./wt. up to about 0.7% wt./wt. olopatadine or its salts and hydrocolloid.

Another embodiment is a stable, fixed-dose, aqueous suspension pharmaceutical composition (e.g., contained in a container) for nasal administration to a pediatric human, wherein the composition contains from about 0.025% w/w. up to about 0.05% wt./wt. mometasone or its salts, from about 0.6% wt./wt. up to about 0.7% wt./wt. olopatadine or salts thereof; and a hydrocolloid which includes sodium carboxymethyl cellulose and xanthan gum. The hydrocolloid may be present at a concentration of at least about 0.1% w/w. compositions.

One embodiment is a stable, fixed-dose, aqueous suspension pharmaceutical composition (eg, contained in a container) for nasal administration to a pediatric human, containing from about 0.025% w/w. up to about 0.05% wt./wt. mometasone furoate, from about 0.6% wt./wt. up to about 0.7% wt./wt. olopatadine hydrochloride; and a hydrocolloid, the hydrocolloid being xanthan gum. Xanthan gum may be present in a concentration of at least about 0.1% w/w. or preferably from about 0.1% wt./wt. up to about 3% wt./wt. compositions.

One embodiment is a stable, fixed-dose, aqueous suspension pharmaceutical composition (eg, contained in a container) for nasal administration to a pediatric human, containing from about 0.025% w/w. up to about 0.05% wt./wt. mometasone furoate, from about 0.6% wt./wt. up to about 0.7% wt./wt. olopatadine hydrochloride; and a hydrocolloid, wherein the hydrocolloid contains sodium carboxymethylcellulose. Sodium carboxymethylcellulose may be present at a concentration of at least about 0.1% w/w. or preferably from about 0.1% wt./wt. up to about 3% wt./wt. compositions.

Another embodiment is a stable, fixed-dose, aqueous pharmaceutical composition in the form of a suspension (e.g., contained in a container) for nasal administration to a human, comprising mometasone or a pharmaceutically acceptable salt thereof, olopatadine or a pharmaceutically acceptable salt thereof, a hydrocolloid at a concentration of at least about 0.1% w/w and a pharmaceutically acceptable excipient.

Suitable pharmaceutically acceptable excipients include, but are not limited to, chelating agents, preservatives, buffers, surfactants, isotonic agents, taste masking agents, antioxidants, humectants, pH adjusting agents, and mixtures thereof.

In one embodiment, the pharmaceutical composition has a pH of about 3.3 to about 4.1, or about 3.5 to about 3.9, or about 3.5 to about 3.7. The inventors have found that olopatadine hydrochloride crystallizes from the fixed dose combination aqueous suspension at pH 5 to 5.5. However, olopatadine hydrochloride remains dissolved in the aqueous suspension at a pH of about 3.3 to about 4.1.

The aqueous pharmaceutical composition is preferably substantially free of olopatadine hydrochloride crystals. In one embodiment, the aqueous pharmaceutical composition contains less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% crystalline olopatadine hydrochloride, based on 100% of the total weight of olopatadine hydrochloride in the composition. In another embodiment, the aqueous pharmaceutical composition is substantially free of olopatadine hydrochloride crystals after 3 or 6 months of storage at 25±2°C and 60%±5% RH or at 40±2°C and 75%±5% RH. humidity. In yet another embodiment, the aqueous pharmaceutical composition contains less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% of crystalline olopatadine hydrochloride, based on 100% of the total weight of olopatadine hydrochloride in the composition after 3 or 6 months storage at 25±2°C and RH 60%±5% or at 40±2°C and RH 75%±5%.

The osmolality of the pharmaceutical composition may range from about 200 mOsm/kg to about 400 mOsm/kg, or from about 250 mOsm/kg to about 350 mOsm/kg.

The viscosity of the pharmaceutical composition may range from about 10 centipoise to about 200 centipoise, or preferably from about 20 centipoise to about 150 centipoise. In one embodiment, the composition has a viscosity of about 60 to about 150 centipoise, such as about 90 to about 150 centipoise, or about 100 to about 150 centipoise. In another embodiment, the composition has a viscosity of about 20 to about 60 centipoise.

In yet another aspect, the pharmaceutical composition is in the form of a suspension and contains mometasone furoate in particles having an average particle size in the range of about 1 µm to about 20 µm, or preferably about 1 µm to about 15 µm. In one aspect, the suspension pharmaceutical composition according to this invention has an average particle size of less than 15 microns, as determined by microscopy.

In yet another aspect, the pharmaceutical composition, when administered nasally (e.g., as a nasal spray) at a dose equivalent to 200 μg of mometasone or its salt in humans, results in (a) an area under the pharmacokinetic curve (AUC) _{of 0-∞} for mometasone or its salt from about 50 pg h/mL to about 140 pg h/mL, preferably from about 68 pg h/mL to about 124 pg h/mL, (b) C _max for mometasone or a salt thereof from about 6.5 pg /ml to about 16 pg/ml, preferably from about 8.6 pg/ml to about 12.9 pg/ml, (c) T _max for mometasone or its salt from about 15 minutes to about 120 minutes, or (d) any combination of any of the above. In yet another aspect, the pharmaceutical composition, when administered nasally (e.g., as a nasal spray) at a dose equivalent to 2400 μg of olopatadine or a salt thereof in humans, results in (a) an AUC _0-∞ for olopatadine or a salt thereof of about 42.5 ng ⋅h/ml to about 116.5 ng⋅h/ml, preferably from about 56.7 ng⋅h/ml to about 99.8 ng*h/ml, (b) C _max for olopatadine or its salt from about 10 3 ng/mL to about 24.1 ng/mL, preferably from about 13.8 ng/mL to about 20.7 ng/mL, (c) T _max from about 15 minutes to about 120 minutes, or (d) any combinations of any of the above.

In yet another aspect, the pharmaceutical composition, when administered nasally (e.g., as a nasal spray) at a dose equivalent to 100 μg of mometasone or a salt thereof (e.g., mometasone furoate), to a human for the first time, results in (a) the area under the pharmacokinetic curve (AUC) _{of tau} mometasone or its salt from about 12 pg h/ml to about 73 pg h/ml, preferably from about 20 pg h/ml to about 36 pg h/ml, (b) C _max for mometasone or its salt from about 3 pg/ml to about 13 pg/ml, preferably from about 5 pg/ml to about 9 pg/ml, (c) T _max for mometasone or a salt thereof from about 15 minutes to about 120 minutes, or (d) any combinations of any of the above. In yet another aspect, the pharmaceutical composition, when administered nasally (e.g., as a nasal spray) at a dose equivalent to 100 μg of mometasone or a salt thereof (e.g., mometasone furoate) to a human at steady state (e.g., 8 days after administration of 100 μg of mometasone or its salt twice a day) results in (a) an area under the pharmacokinetic curve (AUC) _{of tau} for mometasone or its salt from about 26 pg h/mL to about 124 pg h/mL, preferably from about 40 pg h/mL. ml to about 80 pg h/ml, (b) C _max for mometasone or a salt thereof from about 4 to about 16 pg/ml, preferably from about 8 pg/ml to about 12 pg/ml, (c) T _max mometasone or its salt from about 15 minutes to about 120 minutes, or (d) any combination of any of the above.

In yet another aspect, the pharmaceutical composition, when delivered as a nasal spray, has spray characteristics comprising a spray pattern having a longest axis of about 15-75 mm, a shortest axis of about 10-65 mm, and an ellipticity of about 1-2.

Another embodiment is a stable fixed dose pharmaceutical composition in the form of a suspension (e.g., contained in a container) for nasal administration to a pediatric human, comprising mometasone furoate monohydrate, olopatadine hydrochloride, and a hydrocolloid that includes xanthan gum at a concentration of about 0.3% wt./wt. compositions, and the composition has a pH of from about 3.5 to about 3.9.

Another embodiment is a stable fixed dose pharmaceutical composition in the form of a suspension (e.g., contained in a container) for nasal administration to a pediatric human, comprising mometasone furoate monohydrate, olopatadine hydrochloride, and a hydrocolloid that contains sodium carboxymethylcellulose at a concentration of about 0. 5% w/w compositions, and the composition has a pH of from about 3.5 to about 3.9.

In a further embodiment, the fixed dose stable aqueous pharmaceutical composition is contained in a nebulizer, and when the composition is sprayed into the human nose, a spray pattern is obtained having a longest axis of 15-75 mm, a shortest axis of 10-65 mm, and an ellipticity of 1-2.

One embodiment is a fixed dose stable aqueous pharmaceutical composition comprising mometasone furoate monohydrate, olopatadine hydrochloride and optionally a hydrocolloid contained in a nebulizer, with each spray of the aqueous pharmaceutical composition providing (i) mometasone furoate monohydrate equivalent to about 50 μg of mometasone furoate , and (ii) olopatadine hydrochloride equivalent to about 600 micrograms of olopatadine.

Another embodiment is a fixed dose stable aqueous pharmaceutical composition comprising mometasone furoate monohydrate, olopatadine hydrochloride and optionally a hydrocolloid contained in a nebulizer, with each spray of the aqueous pharmaceutical composition providing (i) mometasone furoate monohydrate equivalent to about 25 μg of mometasone furoate, and (ii) olopatadine hydrochloride equivalent to about 600 µg of olopatadine.

In one embodiment, this invention relates to a stable aqueous suspension pharmaceutical composition with a fixed dose (for example, contained in a container) for nasal administration to a child of the pediatric age category, and the composition contains (1) about 0.025% w/w. mometasone furoate monohydrate, (2) about 0.665% w/w. olopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3% wt./wt. xanthan gum and about 0.5% wt./wt. sodium carboxymethylcellulose, (4) about 0.02% wt./wt. benzalkonium chloride, (5) about 0.4% wt./wt. sodium chloride, (6) about 0.01% wt./wt. disodium edetate, (7) about 0.94% wt./wt. sodium phosphate heptahydrate and (8) about 0.01% wt./wt. polysorbate 80.

Another embodiment is a fixed dose stable aqueous suspension pharmaceutical composition (e.g., contained in a container) for nasal administration to a pediatric human, wherein the composition contains (1) about 0.050% w/w. mometasone furoate monohydrate, (2) about 0.665% w/w. olopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3% wt./wt. xanthan gum and about 0.5% wt./wt. sodium carboxymethylcellulose, (4) about 0.02% wt./wt. benzalkonium chloride, (5) about 0.4% wt./wt. sodium chloride, (6) about 0.01% wt./wt. disodium edetate, (7) about 0.94% wt./wt. sodium phosphate heptahydrate and (8) about 0.01% wt./wt. polysorbate 80.

Another embodiment is a stable fixed dose aqueous suspension pharmaceutical composition (e.g., contained in a container) for nasal administration to a pediatric human, wherein the composition contains (1) about 0.025% w/w. mometasone furoate monohydrate, (2) about 0.665% w/w. olopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3% wt./wt. xanthan gum and about 0.5% wt./wt. sodium carboxymethylcellulose, (4) from about 1% wt./mass. up to about 1.2% wt./wt. a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, (5) about 0.02% wt./wt. benzalkonium chloride, (6) about 0.4% wt./wt. sodium chloride, (7) about 0.01% wt./wt. disodium edetate, (8) about 0.94% wt./wt. sodium phosphate heptahydrate and (9) about 0.01% wt./wt. polysorbate 80.

Another embodiment is a stable fixed dose aqueous suspension pharmaceutical composition (e.g., contained in a container) for nasal administration to a pediatric human, wherein the composition contains (1) about 0.050% w/w. mometasone furoate monohydrate, (2) about 0.665% w/w. olopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3% wt./wt. xanthan gum and about 0.5% wt./wt. sodium carboxymethylcellulose, (4) from about 1% wt./mass. up to about 1.2% wt./wt. a mixture of microcrystalline cellulose and sodium carboxymethylcellulose, (5) about 0.02% wt./wt. benzalkonium chloride, (6) about 0.4% wt./wt. sodium chloride, (7) about 0.01% wt./wt. disodium edetate, (8) about 0.94% wt./wt. sodium phosphate heptahydrate and (9) about 0.01% wt./wt. polysorbate 80.

Another embodiment is a stable suspension suitable for nasal administration to a pediatric human comprising (a) an aqueous solvent, (b) particles of mometasone furoate suspended in a solvent, wherein the particles have an average particle size of about 1 to about 20 microns, ( c) olopatadine hydrochloride dissolved in a solvent; and (d) a hydrocolloid, wherein the suspension has a viscosity in the range of about 20 centipoise to about 150 centipoise. In one preferred embodiment, the suspension has a pH of about 3.5-3.9 and an osmolality in the range of about 250 mOsm/kg to about 350 mOsm/kg. In one embodiment, the suspension further comprises a chelating agent, a preservative, a buffer, a surfactant, an isotonic agent, and optionally a pH adjusting agent.

Preferably the suspensions according to the present invention have only one phase (ie they are preferably a single phase suspension).

In an additional embodiment, this invention relates to a stable aqueous pharmaceutical composition with a fixed dose (for example, contained in a container) for nasal administration, containing from about 0.025% wt./wt. up to about 0.05% wt./wt. mometasone or its salt and from about 0.5% wt./wt. up to about 0.8% wt./wt. olopatadine or its salt for the treatment of rhinitis in a person in need thereof.

Any of the above pharmaceutical compositions containing mometasone or a salt thereof and olopatadine (or a salt thereof) can be used in the above methods such as a method for treating allergic rhinitis.

In another embodiment, the invention relates to a kit containing a stable, fixed-dose aqueous pharmaceutical composition contained in a container for nasal administration and a leaflet containing instructions for use of the pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The terms used in this document are defined as follows. If the definition set forth in this application and the definition set forth earlier in the provisional application on which these applications claim priority conflict, the definition in this application shall prevail.

The term “onset of action” is the point at which patients can reasonably expect a significant reduction in their allergic rhinitis symptoms (e.g., a significant reduction in the Retrospective General Rhinitis Symptoms Scale (rTNSS), Instantaneous Generalized Rhinitis Symptoms Scale (iTNSS), or Retrospective Common Eye Symptoms Scale (rTOSS)). Statistically, this is the first time point after treatment initiation that a drug shows a change greater than placebo treatment from entry into the study in the primary efficacy endpoint. This statistically significant difference between drug and placebo is maintained for a period (eg, 4 hours) from this point forward. See "Guidance for Industry, Allergic Rhinitis: Clinical Development Programs for Drug Products", U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), April 2000.

The term "faster onset of action" refers, in one embodiment, to a statistically significant faster decrease in one or more parameters associated with the treatment of allergic rhinitis in a subject, such as a statistically significant faster decrease in the Retrospective General Rhinitis Symptoms Scale (rTNSS) score, instantaneous a general rhinitis symptom score (iTNSS) or a retrospective general ocular symptom score (rTOSS) score for the subject.

The term "advertising" refers to the notification, informing and/or notification of one or more persons about information (for example, about the effectiveness or time of onset of action of a pharmaceutical product for the treatment or reduction of symptoms), for example, by the mass media, including, but not limited to, newspaper, magazine and online advertising, commercials and billboards. In the context of this document, the term "advertising" also includes a statement in the labeling of a pharmaceutical product that a pharmaceutical product can treat or relieve symptoms.

The term "marketing" refers to the act or process of selling a product, including, but not limited to, any offer to sell or sell a product, and advertising.

The term "effective amount" or "therapeutically effective amount" means the amount of the active ingredient which, when administered to a subject for the treatment of allergic rhinitis, produces the intended therapeutic effect in the subject. As used herein, the term "active ingredient" (used interchangeably with "active" or "active pharmaceutical ingredient" or "drug") includes mometasone or a salt thereof and olopatadine or a salt thereof.

The terms "salt" or "pharmaceutically acceptable salt" are understood to mean those salts and esters which are medically suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic reactions, and a reasonable benefit/risk ratio. and are also effective for their intended application. Exemplary acid-formed salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate , maleate, fumarate, fuorate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate and lauryl sulfate salts. Exemplary alkali or alkaline earth metal salts include, but are not limited to, sodium, calcium, potassium, and magnesium salts. Preferably, the mometasone salt is mometasone furoate (eg, mometasone furoate monohydrate) and the olopatadine salt is olopatadine hydrochloride.

In the context of this document, the term "mometasone and its salt" also includes hydrates of mometasone and its salts, such as monohydrate, for example, mometasone furoate monohydrate.

All references to weight or weight ratio, including "olopatadine or salt thereof" or "olopatadine or salt thereof", are based on the equivalent weight of olopatadine free base, unless otherwise indicated.

In the context of this document, the term "treatment process" or "treatment" also encompasses the prevention, mitigation, avoidance, amelioration, or suppression of a disorder.

In the context of this document, the term "synergistic" or "synergism" refers to a combination exhibiting an effect greater than would be expected from the sum of the effects of the individual components of the combination in monotherapy. The term "synergistic" or "synergism" in relation to the combination of mometasone or its salt with olopatadine or its salt, which is used in the treatment of allergic rhinitis (for example, in the form of a pharmaceutical composition, combination product or kit according to the invention) refers to the effectiveness of the treatment of allergic rhinitis, which higher than would be expected based on the sum of their individual effects. The advantages of the synergistic combinations of this invention include, but are not limited to, the demonstration of increased efficacy compared to each of the ingredients when used separately, a reduction in the required dose of one or more active ingredients from the combination, a reduction in the undesirable effects of one or more active compounds from the combination, and/ or increasing the tolerability of one or more active ingredients to a subject in need of allergic rhinitis treatment.

The term "pharmaceutically acceptable excipients" refers to any of the components of a pharmaceutical composition, other than active substances, and which are approved by regulatory authorities or are generally considered safe for medical or veterinary use.

Unless otherwise noted, "subject", "child age category subject", "child age category human" or "child age category human subject" refers to a human subject under the age of seventeen (17) years. In one embodiment, the subject is an infant (between one month and two years of age). In another embodiment, the subject is a child (between two and twelve years of age). In yet another embodiment, the subject is a teenager (twelve to sixteen years of age). In yet another embodiment, the subject is a subject between the ages of two and less than twelve years of age. In yet another embodiment, the subject is a subject between the ages of six and less than twelve years of age. In yet another embodiment, the subject is a subject under the age of sixteen.

As used herein, the term "allergic rhinitis" refers to an allergic and/or inflammatory disease of the nasal mucosa and includes, but is not limited to, inflammation and irritation of the nasal mucosa, and associated nasal and/or non-nasal symptoms. Generally, allergic rhinitis includes persistent allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, chronic rhinitis, drug rhinitis, vasomotor rhinitis, infectious rhinitis, autonomic rhinitis, hormonal rhinitis, drug rhinitis, atrophic rhinitis, and gustatory rhinitis. Preferably, allergic rhinitis includes perennial allergic rhinitis, persistent allergic rhinitis, seasonal allergic rhinitis, and associated nasal and/or non-nasal symptoms. More preferably, allergic rhinitis includes seasonal allergic rhinitis and associated nasal and/or non-nasal symptoms.

In the context of this invention, nasal and/or non-nasal symptoms associated with allergic rhinitis include, for example, sneezing, nasal itching, rhinorrhea (runny nose or runny nose), nasal congestion, cough, itchy eyes, excessive watery eyes, headache, fatigue and malaise.

Methods of treatment

The present invention relates to the use of a fixed dose combination of mometasone or a salt thereof and olopatadine or a salt thereof for the treatment of allergic rhinitis in a pediatric subject in need thereof. The inventors have surprisingly found that mometasone furoate and olopatadine hydrochloride act synergistically in the treatment of allergic rhinitis and their combination is more effective and provides better therapeutic value than treatment with the active ingredients alone.

In one embodiment, the invention relates to a method of treating allergic rhinitis in a pediatric subject in need thereof, comprising nasally administering to the subject an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof. Preferably, the composition is administered nasally as 1 spray into each nostril of the subject twice daily. Each injection may contain mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of about 1:5 to about 1:60, about 1:10 to about 1:55, or about 1:12 to about 1:53, or about 1:13.3 to about 1:50. Preferably, the weight ratio of mometasone or a salt thereof to olopatadine or a salt thereof is in the range of about 1:18 to about 1:40, or about 1:24 to about 1:26.6. In an embodiment, the fixed dose pharmaceutical composition is a suspension in which mometasone or a salt thereof is present in particulate form and olopatadine or a salt thereof is present in dissolved form.

Another embodiment relates to a method of treating allergic rhinitis in a pediatric subject in need thereof, comprising nasally administering to the subject an effective amount of a fixed dose pharmaceutical composition comprising mometasone furoate monohydrate and olopatadine hydrochloride. The composition can be administered nasally as 1 spray into each nostril of the subject twice daily. Each injection of the pharmaceutical composition may contain olopatadine hydrochloride equivalent to about 300 µg, about 450 µg, about 600 µg, about 750 µg or about 900 µg of olopatadine and about 12.5 µg, about 25 µg, about 37.5 µg, about 50 µg , or about 62.5 mcg of mometasone furoate. In one embodiment, each injection contains olopatadine hydrochloride equivalent to about 600 µg of olopatadine and about 25 µg of mometasone furoate. In another embodiment, each injection contains olopatadine hydrochloride equivalent to about 600 μg of olopatadine. and about 50 mcg of mometasone furoate. Preferably, each injection contains about 665 micrograms of olopatadine hydrochloride (equivalent to about 600 micrograms of olopatadine) and about 25 micrograms of mometasone furoate.

Allergic rhinitis in the context of this invention includes, but is not limited to, inflammation and irritation of the nasal mucosa and associated nasal and/or non-nasal symptoms. It includes, for example, persistent allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, chronic rhinitis, drug rhinitis, vasomotor rhinitis, infectious rhinitis, autonomic rhinitis, hormonal rhinitis, drug rhinitis, atrophic rhinitis, and gustatory rhinitis. Preferably, allergic rhinitis is selected from perennial allergic rhinitis, persistent allergic rhinitis, seasonal allergic rhinitis, and associated nasal and/or non-nasal symptoms.

In the context of this invention, symptoms associated with rhinitis include rhinorrhea, nasal congestion, nasal itching, sneezing, itchy/burning eyes, watery/watery eyes, red eyes, itchy ears or palate, cough, itchy eyes, excessive watery eyes, headache, fatigue and malaise.

In another embodiment, the invention relates to a method of treating allergic rhinitis in a pediatric human subject in need thereof, comprising nasally administering to a human a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of about 1 :5 to about 1:60, or about 1:12 to about 1:53, or about 1:13.3 to about 1:50, or about 1:18 to about 1:40, wherein the composition is administered nasally in the form of 1 injection into each nostril twice a day. Each injection may contain olopatadine hydrochloride equivalent to about 600 micrograms of olopatadine and about 25 micrograms of mometasone furoate. In an embodiment, the composition is administered over about 1 week. In another embodiment, the composition is administered over a period of about 2 weeks.

In one embodiment, the overall rhinitis symptom severity scale (TNSS) score for the human subject is reduced by at least 40%, preferably by at least 50%, from study entry after 1 or 2 weeks of treatment. In another embodiment, the human subject's total eye symptom score (TOSS) score is reduced by at least 30%, preferably by at least 40%, from study entry after 1 or 2 weeks of treatment. In one aspect of the invention, the Global Rhinitis Symptom Severity Scale (TNSS) and the Total Ocular Symptoms Scale (TOSS) scores can be defined as instantaneous, or retrospective, or both.

In the context of the present invention, the rhinitis symptom severity scale (TNSS) scores include the sum of nasal congestion, rhinorrhea, pruritus, and sneezing scores from entry into the study to the end of treatment (eg, 1 or 2 weeks). Further assessment on the Total Eye Symptom Scale (TOSS) includes itchy eyes, watery/watery eyes, and redness of the eyes from entry into the study to the end of treatment.

In one embodiment, the subject suffers from persistent allergic rhinitis and is treated for 4 or 6 weeks.

In another embodiment, the subject shows a positive skin prick test for the allergen. Alternatively, the subject may have positive blood tests indicative of an allergy.

In yet another embodiment, the method does not cause significant treatment-related adverse events in the subject after 1 or 2 weeks of treatment.

In another embodiment, this invention relates to a method of treating seasonal allergic rhinitis and/or nasal symptoms associated with seasonal allergic rhinitis in a pediatric subject in need thereof, comprising nasal administration to the subject of a synergistic combination containing mometasone furoate and olopatadine hydrochloride, wherein the combination is in the form of a pharmaceutical composition containing mometasone furoate and olopatadine hydrochloride in a weight ratio of from about 1:5 to about 1:60, or from about 1:13.3 to about 1:53.2 (based on the equivalent weight of the free base of olopatadine ).

In one embodiment, the invention relates to a method of treating allergic rhinitis in a human in need thereof, comprising nasally administering to a human in a pediatric age group an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof, wherein (i) the composition is administered nasally as 1 spray into each human nostril twice daily, and (ii) each spray contains mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of from about 1:5 to about 1:60 or from about 1:13 .3 to about 1:53.2 (based on the equivalent weight of olopatadine free base). In one embodiment, each injection contains about 665 micrograms of olopatadine hydrochloride and about 25 micrograms of mometasone furoate. The method may provide a reduction in at least one treatment-related adverse event (eg, epistaxis and drowsiness) compared to using mometasone or olopatadine alone. For example, the method may provide effective treatment of seasonal allergic rhinitis and/or nasal symptoms associated with seasonal allergic rhinitis in a subject with a reduction in the incidence of drowsiness and epistaxis. In another embodiment, the method may provide effective treatment of seasonal allergic rhinitis and/or nasal symptoms associated with seasonal allergic rhinitis in a subject without significant drowsiness and/or inducing epistaxis.

In another embodiment, the invention relates to a method of treating perennial allergic rhinitis and/or nasal symptoms associated with perennial allergic rhinitis in a pediatric subject in need thereof, comprising nasal administration to the subject of a combination (e.g., a synergistic combination) containing mometasone furoate and olopatadine hydrochloride, the combination being in the form of a pharmaceutical composition containing mometasone furoate and olopatadine hydrochloride in a weight ratio of from about 1:5 to about 1:60, or from about 1:13.3 to about 1:53.2 (in terms of equivalent weight of olopatadine free base). In one embodiment, each injection of the pharmaceutical composition provides about 665 micrograms of olopatadine hydrochloride and about 25 micrograms of mometasone furoate.

In one aspect of this embodiment, each injection contains about 25 micrograms of mometasone furoate and olopatadine hydrochloride, equivalent to about 600 micrograms of olopatadine. In one aspect of this embodiment, the pharmaceutical composition is a suspension containing mometasone or a salt thereof in particulate form and olopatadine or a salt thereof in solution. In one aspect of this embodiment, the composition is administered for at least 1 week as 1 spray in each nostril twice daily. In yet another aspect of this embodiment, allergic rhinitis is selected from perennial allergic rhinitis, persistent allergic rhinitis, seasonal allergic rhinitis, and associated nasal and/or non-nasal symptoms. In a preferred aspect, the allergic rhinitis is seasonal allergic rhinitis and/or associated nasal symptoms. In yet another aspect of this embodiment, (i) a person's rhinitis symptom severity score (TNSS) score is reduced by at least 50% from study entry after 2 weeks of treatment, and/or (ii) a person's overall ocular symptom score symptoms (TOSS) in the individual is reduced by at least 40% from the time of entry into the study after 2 weeks of treatment, and/or (iii) the individual does not experience significant treatment-related adverse events after 2 weeks of treatment. In one aspect of said embodiment, the individual exhibits a positive skin prick test for the allergen. In one aspect of said embodiment, treatment-related adverse events include drowsiness or epistaxis, or a combination thereof.

Another embodiment is a method of treating allergic rhinitis in a subject of a pediatric age group, wherein the subject shows a positive skin prick test for an allergen. A skin prick test can be performed by pricking the skin with a needle or pin containing a small amount of the ragweed allergen. In one embodiment, prior to administration of the combination of olopatadine and mometasone as described herein, a skin prick test was performed on the subject resulting in an allergic papule diameter at least 3 mm larger than that of a negative control such as saline.

The methods of treatment described herein can be applied to a subject in the pediatric age category without the subject exhibiting any significant treatment-related adverse events associated with treatment, for example, after 1 or 2 weeks of treatment.

In the context of this invention, treatment-related adverse events may include, but are not limited to, eye disease (e.g., conjunctivitis), gastrointestinal disorders (e.g., bloating, diarrhea, dyspepsia, dysphagia and stomach ulcers, hemorrhoidal bleeding, hyperchlorhydria, nausea and vomiting and toothache), general disorders (eg, fatigue, local edema, peripheral edema, pain, and pyrexia), infections and parasitic diseases (eg, oral herpes and upper respiratory infections), trauma, poisoning, and complications caused by research procedures, musculoskeletal and connective tissue disorders (eg, arthralgia), nervous system disorders (eg, impaired attention, dizziness, dysgeusia, drowsiness, and headache), reproductive system and breast disorders (eg, dysmenorrhea ), respiratory, thoracic, and mediastinal disorders (eg, epistaxis, dry throat, dyspnea, epistaxis, nasal congestion, nasal discomfort, respiratory bleeding, rhinorrhea, throat irritation, and upper respiratory tract cough syndrome) , disorders of the skin and subcutaneous tissues (for example, rash and urticaria).

In another embodiment, this invention relates to a method of treating seasonal allergic rhinitis and/or nasal symptoms associated with seasonal allergic rhinitis in a pediatric subject in need thereof, comprising nasal administration to the subject of a synergistic combination containing mometasone furoate and olopatadine hydrochloride, wherein the combination is in the form of a pharmaceutical composition containing mometasone furoate and olopatadine hydrochloride in a weight ratio of from about 1:5 to about 1:60, or from about 1:13.3 to about 1:53.2 (based on the equivalent weight of the free base of olopatadine ). In one embodiment, each injection of the pharmaceutical composition provides about 665 micrograms of olopatadine hydrochloride and about 25 micrograms of mometasone furoate.

a) A fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof may be administered nasally to a pediatric subject as 1 spray in each nostril twice daily for a period of at least 1 week or 2 weeks.

In another embodiment, the present invention relates to a method of treating seasonal allergic rhinitis and/or nasal symptoms associated with seasonal allergic rhinitis in a pediatric human in need thereof, comprising nasal administration to a human of a synergistic combination comprising mometasone furoate and olopatadine hydrochloride, wherein the combination is in the form of a pharmaceutical composition comprising particulate mometasone furoate and olopatadine hydrochloride in solution in a weight ratio of from about 1:13.3 to about 1:53.2 (based on the equivalent weight of olopatadine free base), and wherein the composition administered as 1 injection into each human nostril twice a day for at least 1 week, the method providing a reduction in at least one adverse event. In one aspect of this implementation, the composition is administered twice a day for 2 weeks. In another aspect of this embodiment, each injection contains about 25 µg of mometasone furoate and about 665 µg of olopatadine hydrochloride. In yet another aspect of this embodiment, (i) a person's rhinitis symptom severity score (TNSS) score is reduced by at least 50% from study entry after 2 weeks of treatment, and/or (ii) a person's overall ocular symptom score symptoms (TOSS) in the individual is reduced by at least 40% from the time of entry into the study after 2 weeks of treatment, and/or (iii) the individual does not experience significant treatment-related adverse events after 2 weeks of treatment. In one aspect of said embodiment, the individual exhibits a positive skin prick test for the allergen. Preferably, treatment-related adverse events include drowsiness or epistaxis, or a combination thereof.

In one aspect of the invention, the fixed dose pharmaceutical composition may be administered for about 1 week, 2 weeks, 4 weeks, 6 weeks, or 8 weeks. Preferably, the fixed dose pharmaceutical composition is administered as 1 spray into each nostril of a pediatric subject twice daily for 1 week to 2 weeks. In another embodiment, each injection of the composition contains olopatadine hydrochloride equivalent to about 600 micrograms of olopatadine and about 25 micrograms of mometasone furoate. Preferably, each injection of the composition contains about 665 micrograms of olopatadine hydrochloride (equivalent to about 600 micrograms of olopatadine) and about 25 micrograms of mometasone furoate. In yet another aspect, the composition is odor and taste free. In yet another embodiment, the overall rhinitis symptom severity scale (TNSS) score in a human subject is reduced by at least 40% or at least 50% from study entry after 1 or 2 weeks of treatment. In yet another embodiment, a person's Total Ocular Symptom Score (TOSS) score is reduced by at least 30% or at least 40% from study entry after 1 or 2 weeks of treatment. In yet another embodiment, said method provides for a reduction in treatment-related adverse events. Preferably, treatment-related adverse events include drowsiness or epistaxis, or a combination thereof. In yet another embodiment, the human subject is a patient who exhibits a positive skin prick test for an allergen.

In one aspect, this invention relates to the use of mometasone, or a salt thereof, and olopatadine, or a salt thereof, in a weight ratio of about 1:5 to about 1:60, or about 1:12 to about 1:53, in the manufacture of a fixed dose pharmaceutical composition of the invention. for the treatment of allergic rhinitis in a pediatric subject in need thereof. In one aspect, the fixed dose pharmaceutical composition is a suspension in which mometasone or a salt thereof is present in particulate form (e.g., with an average particle size of about 1 to about 20 microns, or about 1 to about 15 microns) and olopatadine or a salt thereof present in dissolved form. In yet another aspect, the composition is odor and taste free. In one embodiment, each injection of the pharmaceutical composition provides about 665 micrograms of olopatadine hydrochloride and about 25 micrograms of mometasone furoate.

In a separate embodiment, this invention relates to a method for reducing symptoms associated with rhinitis in a pediatric subject in need thereof, which method comprises nasally administering to the subject an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or its salt in a weight ratio of from about 1:5 to about 1:60 or from about 1:12 to about 1:53 for about 1 or 2 weeks.

In another embodiment, the invention relates to a method for reducing symptoms associated with allergic rhinitis in a pediatric human in need thereof, comprising nasally administering to a human an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof. wherein (i) the composition is administered nasally as 1 injection into each human nostril twice daily, and (ii) each injection contains mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of from about 1:5 to about 1:60 or from about 1:12 to about 1:53 for about 1 or 2 weeks. (in terms of the equivalent weight of the free base of olopatadine) and the composition is administered as 1 injection into each nostril of a person twice a day for at least 1 week, and the method provides a reduction in at least one undesirable phenomenon. In one aspect of this embodiment, each injection contains about 25 micrograms of mometasone furoate and olopatadine hydrochloride, equivalent to about 600 micrograms of olopatadine. In one aspect of this embodiment, the pharmaceutical composition is a suspension containing mometasone or a salt thereof in particulate form and olopatadine or a salt thereof in solution. In one aspect of this embodiment, the composition is administered for at least 1 week as 1 spray in each nostril twice daily. In yet another aspect of this embodiment, allergic rhinitis is selected from perennial allergic rhinitis, persistent allergic rhinitis, seasonal allergic rhinitis, and associated nasal and/or non-nasal symptoms. In a preferred aspect, the allergic rhinitis is seasonal allergic rhinitis and/or associated nasal symptoms. In yet another aspect of this embodiment, (i) a person's rhinitis symptom severity score (TNSS) score is reduced by at least 50% from study entry after 2 weeks of treatment, and/or (ii) a person's overall ocular symptom score symptoms (TOSS) in the individual is reduced by at least 40% from the time of entry into the study after 2 weeks of treatment, and/or (iii) the individual does not experience significant treatment-related adverse events after 2 weeks of treatment. In one aspect of said embodiment, the individual exhibits a positive skin prick test for the allergen. In one aspect of said embodiment, the symptoms include rhinorrhea, nasal congestion, itchy nose, sneezing, itchy/burning eyes, watery/watery eyes, red eyes, itchy ears or palate, cough, itchy eyes, excessive watery eyes, headache, fatigue and malaise. In yet another embodiment, treatment-related adverse events include drowsiness or epistaxis, or a combination thereof.

Administration of a pharmaceutical composition may provide relief from one or more symptoms of allergic rhinitis (such as nasal symptoms or ocular symptoms) in a pediatric subject faster (e.g., onset of action in less than 30 minutes, e.g., within about 15 minutes, e.g., within 10 minutes) than nasal administration of mometasone or its salt, or olopatadine or its salt in monotherapy. In another embodiment, the administration may provide relief from one or more symptoms of allergic rhinitis (such as nasal symptoms) in a subject exposed to an environmental exposure chamber (EEC) (such as ragweed pollen at a concentration of 3500 ± 500 particles/m ³ for 6 hours) faster (eg onset of action in less than 15 minutes, eg within about 10 minutes) than nasal mometasone or a salt thereof, or olopatadine or a salt thereof alone.

Another embodiment is a method of providing a more rapid onset of relief of symptoms associated with allergic rhinitis in a pediatric human subject in need thereof, comprising nasal administration twice a day as one injection in each nostril of a fixed dose pharmaceutical composition. containing mometasone or its salt (for example, mometasone furoate) and olopatadine or its salt (for example, olopatadine hydrochloride). This method may provide more rapid relief of one or more symptoms than administration of mometasone alone or a salt thereof, or olopatadine alone or a salt thereof. Each injection may contain mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of about 1:5 to about 1:60 (e.g., a weight ratio of about 1:12 to about 1:53, about 1:13.3 to about 1:50 or about 1:18 to about 1:40) (based on the equivalent weight of olopatadine free base) (e.g., each spray contains about 12.5 µg, about 25 µg, about 37.5 µg, about 50 mcg or about 62.5 mcg of mometasone or a salt thereof (e.g., about 50 mcg of mometasone furoate) and olopatadine hydrochloride equivalent to about 300 mcg, about 450 mcg, about 600 mcg, about 750 mcg, or about 900 mcg of olopatadine (e.g., about 665 mcg of olopatadine hydrochloride). In one embodiment, each injection of the pharmaceutical composition provides about 665 micrograms of olopatadine hydrochloride and about 25 micrograms of mometasone furoate. Administration may provide relief of one or more symptoms within 30 minutes, such as within 15 minutes or within 10 minutes. In another embodiment, the administration may provide relief from one or more symptoms of allergic rhinitis (such as nasal symptoms) in a subject exposed to an environmental exposure chamber (EEC) (such as ragweed pollen at a concentration of 3500 ± 500 particles/m ³ in for 6 hours) less than 15 minutes, for example, for about 10 minutes.

Another embodiment is a method of treating a pediatric human subject suffering from allergic rhinitis, comprising the step of administering to the subject a nasal pharmaceutical composition twice a day as a single injection in each nostril, wherein (i) the pharmaceutical composition provides onset of action for 15 minutes to treat allergic rhinitis; and (ii) each injection of the pharmaceutical composition contains about 25 µg of mometasone furoate and about 665 µg of olopatadine hydrochloride.

Another embodiment is a method of treating a pediatric human subject suffering from allergic rhinitis, comprising the steps of:

(a) administering to a pediatric subject a fixed-dose nasal pharmaceutical composition twice daily as a single injection into each nostril, the fixed-dose pharmaceutical composition comprising mometasone or a salt thereof (such as mometasone furoate) and olopatadine or a salt thereof (such as olopatadine hydrochloride) and each injection contains mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of about 1:5 to about 1:60 (e.g., a weight ratio of about 1:12 to about 1:53, about 1:13.3 to about 1:50 or about 1:18 to about 1:40) (based on the equivalent weight of olopatadine free base) (e.g., each injection contains about 12.5 micrograms, about 25 micrograms, about 37.5 micrograms, about 50 micrograms, or about 62.5 micrograms of mometasone or a salt thereof (e.g., about 50 micrograms of mometasone furoate) and olopatadine hydrochloride equivalent to about 300 micrograms, about 450 micrograms, about 600 micrograms, about 750 micrograms, or about 900 micrograms of olopatadine (for example, about 665 micrograms of olopatadine hydrochloride)),

wherein the administration is in accordance with (i) marketing the pharmaceutical composition as (A) providing a faster onset of action (e.g., onset of action in less than 30 minutes, e.g., within 15 minutes, e.g., within 10 minutes) to facilitate one or more symptoms (eg, nasal symptoms) of allergic rhinitis than nasal mometasone or its salt (eg, 25 mcg mometasone furoate), or olopatadine or its salt (eg, 665 mcg olopatadine hydrochloride) alone, (B) providing relief to one or more symptoms of allergic rhinitis within 15 minutes (or 30 minutes), and (ii) a diagnosis of a human subject suffering from allergic rhinitis, or (C) providing a faster onset of action (e.g., within 15 minutes, e.g., within about 10 minutes) to relieve one or more symptoms (eg, nasal symptoms) of allergic rhinitis in subjects exposed in an environmental exposure chamber (EEC) (eg, ragweed pollen at 3500±500 particles/m ³ for 6 hours ) than nasal administration of mometasone or its salt, or olopatadine or its salt in monotherapy. (D) providing relief from one or more symptoms of allergic rhinitis (eg, nasal symptoms) in subjects exposed in an environmental exposure chamber (EEC) (eg, ragweed pollen at 3500±500 particles/m ³ for 6 hours) within 15 minutes, for example within about 10 minutes; And

(b) administering the designated pharmaceutical composition to the subject. In one preferred embodiment, each injection of the fixed dose pharmaceutical composition provides 25 μg of mometasone furoate and 665 μg of olopatadine hydrochloride.

Another embodiment is a method of treating a pediatric human subject suffering from allergic rhinitis (e.g., seasonal allergic rhinitis or perennial allergic rhinitis) comprising the step of administering to the subject a fixed dose nasal fixed dose pharmaceutical composition twice daily at as a single injection into each nostril, the fixed dose pharmaceutical composition comprising mometasone or a salt thereof (e.g. mometasone furoate) and olopatadine or a salt thereof (e.g. olopatadine hydrochloride) and each injection containing mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of about 1:5 to about 1:60 (e.g., a weight ratio of about 1:12 to about 1:53, about 1:13.3 to about 1:50, or about 1:18 to about 1: 40) (based on the equivalent weight of olopatadine free base) (for example, each injection contains about 12.5 micrograms, about 25 micrograms, about 37.5 micrograms, about 50 micrograms, or about 62.5 micrograms of mometasone or its salt (for example, about 50 µg mometasone furoate) and olopatadine hydrochloride equivalent to about 300 µg, about 450 µg, about 600 µg, about 750 µg, or about 900 µg olopatadine (e.g., about 665 µg olopatadine hydrochloride)). The pharmaceutical composition is administered in accordance with (a) marketing the pharmaceutical composition as (A) providing a faster onset of action (e.g., onset of action in less than 30 minutes, e.g., within 15 minutes, e.g., within 10 minutes) to relieve symptoms ( nasal symptoms) of allergic rhinitis than nasal mometasone or its salt (eg, 50 mcg mometasone furoate) or olopatadine or its salt (eg, 665 mcg olopatadine hydrochloride) alone, or (B) providing relief from one or more symptoms allergic rhinitis within 15 minutes (or 30 minutes); and (b) diagnosing a subject suffering from allergic rhinitis. In one preferred embodiment, each injection of the fixed dose pharmaceutical composition provides 25 μg of mometasone furoate and 665 μg of olopatadine hydrochloride.

Another embodiment relates to a method of reducing the number of eosinophils in the nasal lavage of a pediatric subject by nasal administration of an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of from about 1:5 to about 1:60 (in terms of the equivalent weight of the free base of olopatadine), while the method provides a greater reduction in the number of eosinophils than that provided by mometasone or its salt or olopatadine or its salt when used as monotherapy. The number of eosinophils can be determined by any known method, for example, with using a hemocytometer. In one embodiment, the method comprises nasal administration as a single injection of the pharmaceutical composition into each nostril twice daily, each injection containing 25 μg of mometasone furoate and 665 μg of olopatadine hydrochloride.

Another embodiment relates to a method of reducing the total number of cells in nasal lavage by nasally administering to a pediatric subject an effective amount of a fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of from about 1:5 to about 1 :60 (based on the equivalent weight of the free base of olopatadine), while the method provides a greater reduction in the total number of cells than that provided by mometasone or its salt, or olopatadine or its salt when used as monotherapy. In one embodiment, the method comprises nasal administration as a single injection of the pharmaceutical composition into each nostril twice daily, each injection containing 25 μg of mometasone furoate and 665 μg of olopatadine hydrochloride.

In the context of this invention, the number of eosinophils and the total number of cells can be measured using various instruments such as a hemocytometer. The response to a sneeze can be determined using tools such as whole body plethysmography (Buxco Research Systems, Wilmington, NC, USA).

In the context of the present invention, a fixed dose pharmaceutical composition comprising mometasone or a salt thereof, olopatadine or a salt thereof is preferably supplied in the form of a nasal spray with one or more pharmaceutically acceptable excipients (e.g. chelating agents, preservatives, buffer, surfactants, isotonic agent, taste-masking agents, suspending agents, humectants, antioxidants and diluents) in a container and kit containing instructions for its use and administration. The pharmaceutical composition may, for example, have any of the formulations that are described in International Patent Application No. PCT/IB2014/064251, filed September 4, 2014, US Patent Application No. 14/483837, filed September 11, 2014, in the application U.S. Patent Application No. 14/662,128, filed March 18, 2015, U.S. Patent Application No. 15/183,534, filed June 15, 2016, and U.S. Patent Application No. 15/210,692, filed July 14, 2016, each of which are incorporated herein by reference in their entirety.

The pharmaceutical composition may be administered nasally via a nasal spray device (eg, a device capable of delivering an aerosol into a subject's nostrils for topical application to the nasal mucosa).

Pharmaceutical compositions

The pharmaceutical composition may contain an effective amount of mometasone or a salt thereof and olopatadine or a salt thereof. An effective amount of mometasone or a salt thereof may range from about 0.01 mg to about 10 mg, or preferably from about 0.02 mg to about 5 mg. An effective amount of olopatadine or a salt thereof in the pharmaceutical composition may range from about 0.05 mg to about 20 mg, or preferably from about 0.1 mg to about 15 mg.

For daily nasal administration, an effective amount of mometasone or a salt thereof in a pharmaceutical composition may range from about 10 μg to about 500 μg, or preferably from about 20 μg to about 400 μg, and for olopatadine or a salt thereof, may range from about 50 micrograms to about 7000 micrograms, or preferably from about 100 micrograms to about 5400 micrograms.

In the context of this document, the term "average particle size" (or used as a synonym for the term "average particle size") refers to the distribution of particles, where about 50%. all measured particles have a size smaller than the specified average value of the particle size, and about 50% vol. of all measured particles have a particle size greater than the predetermined average value of the particle size. This can be defined by the term "D ₅₀ " or "d _(0.5) ". The average particle size can be measured using various techniques such as microscopy, laser diffraction, photon correlation spectroscopy (PCS) and the Coulter method.

The term "C _max " means the maximum concentration of the drug (for example, mometasone or olopatadine) in blood plasma.

The term "T _max " means the time at which the peak (maximum) concentration of the drug in the blood plasma is reached.

The term "AUC _0-∞ " is the mean area under the plasma concentration-time curve extrapolated to infinity. It is calculated as the arithmetic mean of the area under the concentration-time curve versus time 0, extrapolated to infinity.

The term "AUC _tau " is the area under the curve of plasma, serum or blood concentration of a drug versus time reached by a given dose during a single dose interval at steady state. The area under the curve is measured over time tau at steady state, where tau is the interval between drug injections.

The term "hydrocolloid" refers to a colloidal system in which hydrophilic colloidal particles (eg, hydrophilic polymers) are dispersed in water. The hydrocolloid system can exist in a gel state or in an ash (liquid) state. In suspension formulations, hydrocolloids act as thickening, stabilizing and suspending agents. Non-limiting examples of hydrocolloids include xanthan gum, gum arabic, guar gum, locust bean gum, alginate, starch, agar-agar, carrageenan, gelatin, a mixture of microcrystalline cellulose (MCC) and sodium carboxymethyl cellulose (sodium CMC) (for example, Avicel RC591 ^® (available from FMC Biopolymer, Philadelphia, PA), a mixture of MCC and sodium CMC with 8.3-13.8% MCC sodium, and cellulose derivatives (eg, sodium carboxymethyl cellulose). Preferably the hydrocolloid contains xanthan gum or sodium carboxymethyl cellulose.

Some embodiments of this invention provide compositions containing sodium carboxymethyl cellulose. In some embodiments, the compositions contain from about 0.08% to about 2% sodium carboxymethyl cellulose. In some embodiments, the implementation of the composition contains from about 0.1% wt./wt. up to about 1.5% wt./wt. sodium carboxymethyl cellulose. In some embodiments, the implementation of the composition contains from about 0.12% wt./wt. up to about 1% wt./wt. sodium carboxymethyl cellulose. In some embodiments, the implementation of the composition contains from about 0.15% wt./wt. up to about 0.75% wt./wt. sodium carboxymethyl cellulose. In some embodiments, the implementation of the composition contains about 0.083% wt./wt. sodium carboxymethyl cellulose. In some embodiments, the compositions contain 0.0830% wt./wt. sodium carboxymethyl cellulose. In some embodiments, the implementation of the composition contains about 0.1% wt./wt. sodium carboxymethyl cellulose. In some embodiments, the compositions contain 0.0996% wt./wt. sodium carboxymethyl cellulose. In some embodiments, the implementation of the composition contains about 0.7% wt./wt. sodium carboxymethyl cellulose. In some embodiments, the compositions contain 0.6656% wt./wt. sodium carboxymethyl cellulose.

The term "container" refers to a single dose container or a multi-dose container. Suitable single-dose or multi-dose containers include, but are not limited to, glass, aluminum, polypropylene, or high density polyethylene, such as high density polyethylene containers made using blow-fill-seal manufacturing techniques. In one embodiment, the container is a nebulizer that delivers the pharmaceutical composition in the form of a fine mist. The nebulizer typically includes a container containing the pharmaceutical composition, a pump sealed (eg, hermetically connected) to the container, a removable drive receiving the top of the pump, and a removable cap connected to the container and the drive.

One embodiment is a stable, fixed-dose, aqueous pharmaceutical composition (eg, contained in a container) for nasal administration to a human, wherein the composition contains from about 0.001% w/w. up to about 0.075% wt./wt. mometasone or its salts and from about 0.5% wt./wt. up to about 0.8% w/w of olopatadine or a salt thereof.

The pharmaceutical composition may be in the form of a solution or suspension, but preferably the composition is in the form of a suspension (more preferably a single phase suspension) in which mometasone or a salt thereof is present in particulate form and olopatadine or a salt thereof is present in dissolved form. Mometasone or a salt thereof and olopatadine or a salt thereof may be present in a weight ratio of from about 1:3 to about 1:106, or from about 1:5 to about 1:53, or preferably from about 1:5 to about 1:36. In one embodiment, the weight ratio of mometasone or a salt thereof and olopatadine or a salt thereof in the composition is from about 1:10 to about 1:53, or from about 1:12 to about 1:30.

The composition preferably also contains a hydrocolloid. In one embodiment of the invention, the composition is a suspension and contains a hydrocolloid in sufficient quantity to prevent phase separation (i.e. separation of particles and solution) after 3 or 6 months of storage at a temperature of 25±2°C and a relative humidity (RH) of 60%±5 %, or at a temperature of 40±2°C and RH 75%±5%. In one embodiment, the aqueous pharmaceutical composition is a single phase suspension that remains a single phase suspension even after 3 or 6 months of storage at 25±2°C and 60%±5% RH, or at 40±2°C and 75% RH ±5%.

Another embodiment is an aqueous pharmaceutical composition comprising (a) mometasone or a salt thereof, (b) olopatadine or a salt thereof, and (c) a fibrillar network containing cellulose material. The fibrillar network may have interfibrillar spaces. In one embodiment, the interfibrillar spaces contain one or more mometasone particles. In some embodiments, mometasone or a salt thereof is present in the form of particles having an average particle size of less than about 15 microns. In additional embodiments, the mometasone particles are equidistantly spaced or substantially equidistantly spaced within the fibrillar network. The average distance between adjacent particles of mometasone can be large enough to ensure consistent delivery of a fixed amount (or effective amount) of both mometasone (or a salt thereof) and olopatadine (or a salt thereof), for example, for 30, 56, 60, 120 or 240 doses (eg via nasal spray). In some embodiments, the fibrillar network is at least partially responsible for the ability of the compositions of this invention to provide a stable dosage of a fixed amount or an effective amount of active ingredients to a target site. In such compositions, olopatadine or a salt thereof may be in dissolved form.

The term "stable", as used in connection with aqueous suspensions, refers to a composition that, when shaken and then stored for at least 24 hours at ambient conditions, does not show phase separation upon visual inspection. Preferably, such a stable composition does not show phase separation for at least 3 days, or at least 5 days, or at least 7 days. In one aspect of the invention, a "stable" composition according to the invention demonstrates, after shaking (e.g., for 1 minute) and visual inspection, no clumping and a total impurity content of no more than 1.0% after storage at ambient conditions (at about 25 °C and relative humidity about 60%) for at least 6 months.

In the context of this invention, drug content and impurities can be determined using various analytical methods such as HPLC, LC-MS, TLC, and the like.

It has been noted that when various pharmaceutical compositions for nasal administration are made containing mometasone or a salt thereof and olopatadine or a salt thereof, such compositions generally exhibit physical separation in the suspension composition. This physical instability further leads to a lack of dose uniformity. Surprisingly, it has been found that the addition of hydrocolloid at certain concentrations (eg, at a concentration of at least about 0.1% w/w) to the suspension composition provides a physically stable composition (no separation) that is suitable for nasal administration.

Another embodiment is a stable, fixed-dose, aqueous suspension pharmaceutical composition (eg, contained in a container) for nasal administration to a human, wherein the composition contains from about 0.025% w/w. up to about 0.05% wt./wt. mometasone or its salts, from about 0.6% wt./wt. up to about 0.7% wt./wt. olopatadine or its salts and hydrocolloid.

Another embodiment is a stable, fixed-dose, aqueous suspension pharmaceutical composition (eg, contained in a container) for nasal administration to a human, wherein the composition contains from about 0.025% w/w. up to about 0.05% wt./wt. mometasone or its salts, from about 0.6% wt./wt. up to about 0.7% wt./wt. olopatadine or salts thereof; and a hydrocolloid which includes sodium carboxymethyl cellulose and xanthan gum. The hydrocolloid may be present at a concentration of at least about 0.1% w/w. compositions.

Another embodiment is a stable fixed dose aqueous suspension pharmaceutical composition (eg, contained in a container) for nasal administration to a human, containing from about 0.025% w/w. up to about 0.05% wt./wt. mometasone furoate, from about 0.6% wt./wt. up to about 0.7% wt./wt. olopatadine hydrochloride and a hydrocolloid that contains xanthan gum. Xanthan gum may be present in a concentration of at least about 0.1% by weight, or preferably from about 0.3% w/w. up to about 3% wt./wt. compositions.

Another embodiment is a stable fixed dose aqueous suspension pharmaceutical composition (eg, contained in a container) for nasal administration to a human, containing from about 0.025% w/w. up to about 0.05% wt./wt. mometasone furoate, from about 0.6% wt./wt. up to about 0.7% wt./wt. olopatadine hydrochloride and a hydrocolloid that contains sodium carboxymethylcellulose. Sodium carboxymethylcellulose may be present at a concentration of at least about 0.1% w/w. or preferably from about 0.1% wt./wt. up to about 3% wt./wt. compositions.

Another embodiment is a stable, fixed-dose, aqueous pharmaceutical composition in the form of a suspension (e.g., contained in a container) for nasal administration to a human, comprising mometasone or a pharmaceutically acceptable salt thereof, olopatadine or a pharmaceutically acceptable salt thereof, a hydrocolloid (e.g., at a concentration of at least about 0.1% w/w) and a pharmaceutically acceptable excipient.

One skilled in the art will also appreciate that one or more additional pharmaceutically acceptable excipients may be added as needed to improve the physical properties, appearance or odors of the composition of the present invention. Suitable pharmaceutically acceptable excipients include, but are not limited to, chelating agents, preservatives, buffers, surfactants, isotonic agents, taste masking agents, antioxidants, humectants, pH adjusting agents, and any combination of any of the above.

Suitable surfactants that can be used to form an aqueous nasal spray composition may include one or more anionic, cationic, nonionic, or zwitterionic surfactants.

Examples of suitable surfactants that can be used in an aqueous nasal spray suspension can be selected from, but not limited to, the following: , polyoxyethylene cetyl ether, polyoxyethylene alkylaryl ether, polyoxyethylene monolaurate, polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene esters or mixed fatty and resin acids, polyoxyethylene sorbitan lanolin derivative, polyoxyethylene tridecyl ether, polyoxyethylene sorbitan esters of mixed fatty and resin acids, polyoxyethylene sorbitanmon stearate, polyoxyethylene sorbitan monooleate, polyoxyethylene monostearate, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene tridecyl ether, polyoxyethylene fatty alcohol, polyoxyethylene alkylamine, polyoxyethylene glycol monopalmitate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene cetyl ether, polyoxyethyleneoxypropylene stearate, polyoxyethylene lauryl ether, polyoxyethylenelanolin derivative, sodium oleate, quaternary ammonium derivative, potassium oleate, N-cetyl N -ethylmorpholinium ethosulfate, sodium lauryl sulfate or their mixtures. Preferred surfactants are polyethoxylated sorbitan derivatives (such as polysorbate 80). The amount of surfactant may vary from about 0.001% wt./wt. up to about 1% wt./wt. relative to the total weight of the composition.

In order to improve the tolerability of the aqueous suspension for nasal spray when applied to the nasal mucosa, it is advisable to formulate it isotonic. The osmolality can be determined by changing the amount of substances present in the aqueous nasal spray suspension other than mometasone, olopatadine and any other substances present and/or by adding an isotonic substance, preferably a physiologically acceptable salt such as, for example, sodium chloride or potassium chloride, or a physiologically tolerable polyol, such as, for example, a sugar alcohol, in particular sorbitol or glycerol, at a concentration necessary to obtain isotonicity.

Examples of suitable preservatives that can be used in the aqueous nasal spray suspension include, but are not limited to, benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, and disodium edetate. Quaternary ammonium halides are preferred. Suitable quaternary ammonium halides preservatives include polyquaternium-1 and benzalkonium halides. Preferred benzalkonium halides include benzalkonium chloride and benzalkonium bromide. The amount of preservative present in the aqueous nasal spray suspension may vary from about 0.005 to about 0.2% w/w. relative to the total weight of the composition. Preferably, the preservative is present at a concentration of about 0.02% w/w. relative to the total weight of the composition.

Examples of suitable chelating agents that can be used in the aqueous nasal spray suspension include, but are not limited to, disodium edetate (EDTA), trisodium edetate, tetrasodium edetate, and diethylamine pentaacetate, preferably EDTA. The amount of chelating agent present in the aqueous nasal spray suspension may vary from about 0.0002 to about 0.5% w/w. relative to the total weight of the composition.

Examples of suitable buffers that can be used in the aqueous nasal spray suspension include, but are not limited to, citric acid, acetic acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, phosphate salts (eg, dibasic sodium phosphate, such as dibasic sodium phosphate heptahydrate), or combinations thereof. The suspension according to this invention may contain an amount of buffer sufficient to maintain the pH of the composition from about 3 to about 6. Preferably, the amount of buffer is in the range from about 0.005% w/w. up to about 1% wt./wt. relative to the total weight of the composition.

Examples of suitable sweeteners/taste-masking agents that can be used in the aqueous nasal spray suspension include, but are not limited to, sucralose, thaumatin (e.g. Talin ^(R) ), sucrose, saccharin (including salts such as sodium salts and calcium), fructose, glucose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, neotame, mannitol, eucalyptus oil, camphor, and natural or artificial flavors or flavors (eg, menthol, mint , vanilla, orange, etc.), or combinations of two or more of these agents. A particularly preferred taste masking agent is sucralose. The amount of sweetener/taste-masking agent present in the aqueous nasal spray suspension may vary from about 0.01% w/w. up to about 1% wt./wt. relative to the total weight of the composition.

Examples of suitable antioxidants that can be used in the aqueous nasal spray suspension include, but are not limited to, ascorbic acid, alpha-tocopherol (vitamin-E), butylated hydroxyanisole, butylated hydroxytoluene, glutathione, and any combination of any of the above. The amount of antioxidants present in the aqueous nasal spray composition may vary from about 0.0002% w/w. up to about 0.5% wt./wt. relative to the total weight of the composition.

Examples of suitable humectants that can be used in the aqueous nasal spray suspension include, but are not limited to, glycerin, sorbitol, polyethylene glycol, propylene glycol, or mixtures thereof, which are mixed with a suitable humectant such as water. The amount of humectant present in the aqueous nasal spray suspension may vary from about 0.0002% w/w. up to about 0.5% wt./wt. relative to the total weight of the composition.

Suitable pH adjusting agents include, but are not limited to, sodium hydroxide and hydrochloric acid.

In the context of this invention, a pharmaceutical stable nasal fixed dose suspension composition may have a pH of about 3.3 to about 4.1, or about 3.5 to about 3.9. The inventors have found that olopatadine hydrochloride crystallizes from the fixed dose combination aqueous suspension at pH 5 to 5.5. However, olopatadine hydrochloride remains dissolved in the aqueous suspension at a pH of about 3.3 to about 4.1.

The aqueous pharmaceutical composition is preferably substantially free of olopatadine hydrochloride crystals. In one embodiment, the aqueous pharmaceutical composition contains less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% crystalline olopatadine hydrochloride, based on 100% of the total weight of olopatadine hydrochloride in the composition. In another embodiment, the aqueous pharmaceutical composition is substantially free of olopatadine hydrochloride crystals after 3 or 6 months of storage at 25±2°C and 60%±5% RH and or at 40±2°C and 75%±5% RH relative humidity. In yet another embodiment, the aqueous pharmaceutical composition contains less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% of crystalline olopatadine hydrochloride, based on 100% of the total weight of olopatadine hydrochloride in the composition after 3 or 6 months storage at 25±2°C and RH 60%±5% or at 40±2°C and RH 75%±5%.

The osmolality of the composition may range from about 200 mOsm/kg to about 400 mOsm/kg, or from about 250 mOsm/kg to about 350 mOsm/kg. The viscosity of the composition may vary from about 10 centipoise to about 200 centipoise, or preferably from about 20 centipoise to about 150 centipoise.

In yet another aspect, the pharmaceutical composition is in the form of a suspension and contains mometasone furoate in particles having an average particle size in the range of about 1 µm to about 20 µm, or preferably about 1 µm to about 15 µm. In one aspect, the suspension pharmaceutical composition according to this invention has an average particle size of less than 15 microns, as determined by microscopy.

In yet another aspect, the pharmaceutical composition, when administered nasally (e.g., as a nasal spray) at a dose equivalent to 200 μg of mometasone or its salt in humans, results in (a) an area under the pharmacokinetic curve (AUC) _{of 0-∞} for mometasone or its salt from about 50 pg h/mL to about 140 pg h/mL, preferably from about 68 pg h/mL to about 124 pg h/mL, (b) C _max for mometasone or a salt thereof from about 6.5 pg /ml to about 16 pg/ml, preferably from about 8.6 pg/ml to about 12.9 pg/ml, (c) T _max for mometasone or its salt from about 15 minutes to about 120 minutes, or (d) any combination of any of the above.

In yet another aspect, the pharmaceutical composition, when administered nasally (e.g., as a nasal spray) at a dose equivalent to 2400 μg of olopatadine or a salt thereof in humans, results in (a) an AUC _0-∞ for olopatadine or a salt thereof of about 42.5 ng ⋅h/ml to about 116.5 ng⋅h/ml, preferably from about 56.7 ng⋅h/ml to about 99.8 ng*h/ml, (b) C _max for olopatadine or its salt from about 10 3 ng/mL to about 24.1 ng/mL, preferably from about 13.8 ng/mL to about 20.7 ng/mL, (c) T _max from about 15 minutes to about 120 minutes, or (d) any combinations of any of the above.

In yet another aspect, the pharmaceutical composition, when administered nasally (e.g., as a nasal spray) at a dose equivalent to 100 μg of mometasone or a salt thereof (e.g., mometasone furoate), to a human for the first time, results in (a) the area under the pharmacokinetic curve (AUC) _{of tau} mometasone or its salt from about 12 pg h/ml to about 73 pg h/ml, preferably from about 20 pg h/ml to about 36 pg h/ml, (b) C _max for mometasone or its salt from about 3 pg/ml to about 13 pg/ml, preferably from about 5 pg/ml to about 9 pg/ml, (c) T _max for mometasone or a salt thereof from about 15 minutes to about 120 minutes, or (d) any combinations of any of the above. In yet another aspect, the pharmaceutical composition, when administered nasally (e.g., as a nasal spray) at a dose equivalent to 100 μg of mometasone or a salt thereof (e.g., mometasone furoate) to a human at steady state (e.g., 8 days after administration of 100 μg of mometasone or its salt twice a day) results in (a) an area under the pharmacokinetic curve (AUC) _{of tau} for mometasone or its salt from about 26 pg h/mL to about 124 pg h/mL, preferably from about 40 pg h/mL. ml to about 80 pg h/ml, (b) C _max for mometasone or a salt thereof from about 4 to about 16 pg/ml, preferably from about 8 pg/ml to about 12 pg/ml, (c) T _max mometasone or its salt from about 15 minutes to about 120 minutes, or (d) any combination of any of the above.

In another aspect, the pharmaceutical composition, when delivered as a nasal spray, is in the form of a spray having a longest axis of about 15-75 mm, a shortest axis of about 10-65 mm, and an ellipticity of about 1-2.

In the context of the present invention, the viscosity can be determined by various known instruments such as a dynamic rheometer or a Brookfield viscometer. In a preferred embodiment of the invention, the viscosity is determined using a Brookfield viscometer by measuring the transmission of torque through the sample using a rotating spindle.

In another embodiment, this invention relates to a stable aqueous pharmaceutical composition with a fixed dose (for example, contained in a container) for nasal administration to a person, and the composition contains from about 0.001% wt./wt. up to about 0.075% wt./mass mometasone furoate monohydrate and from about 0.5% wt./wt. up to about 0.8% wt./wt. olopatadine hydrochloride.

Another embodiment is a stable fixed dose pharmaceutical composition in the form of a suspension (e.g., contained in a container) for nasal administration to a pediatric human subject, comprising mometasone furoate monohydrate, olopatadine hydrochloride, and a hydrocolloid that includes xanthan gum at a concentration of about 0. 3% w/w compositions, and the composition has a pH of from about 3.5 to about 3.9.

Another embodiment is a stable fixed dose pharmaceutical composition in the form of a suspension (e.g., contained in a container) for nasal administration to a pediatric human subject, comprising mometasone furoate monohydrate, olopatadine hydrochloride, and a hydrocolloid that contains sodium carboxymethylcellulose at a concentration of about 0.5% w/w compositions, and the composition has a pH of from about 3.5 to about 3.9.

Another embodiment is a stable fixed dose aqueous suspension pharmaceutical composition (e.g., contained in a container) for nasal administration to a pediatric human subject, wherein the composition contains (1) about 0.025% w/w. mometasone furoate monohydrate, (2) about 0.665% w/w. olopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3% wt./wt. xanthan gum and about 0.5% wt./wt. sodium carboxymethylcellulose, (4) about 0.02% wt./wt. benzalkonium chloride, (5) about 0.4% wt./wt. sodium chloride, (6) about 0.01% wt./wt. disodium edetate, (7) about 0.94% wt./wt. sodium phosphate heptahydrate and (8) about 0.01% wt./wt. polysorbate 80.

Another embodiment is a stable fixed dose aqueous suspension pharmaceutical composition (e.g., contained in a container) for nasal administration to a pediatric human subject, wherein the composition contains (1) about 0.050% w/w. mometasone furoate monohydrate, (2) about 0.665% w/w. olopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3% wt./wt. xanthan gum and about 0.5% wt./wt. sodium carboxymethylcellulose, (4) about 0.02% wt./wt. benzalkonium chloride, (5) about 0.4% wt./wt. sodium chloride, (6) about 0.01% wt./wt. disodium edetate, (7) about 0.94% wt./wt. sodium phosphate heptahydrate and (8) about 0.01% wt./wt. polysorbate 80.

Another embodiment is a stable fixed dose aqueous suspension pharmaceutical composition (e.g., contained in a container) for nasal administration to a pediatric human subject, wherein the composition contains (1) about 0.025% w/w. mometasone furoate monohydrate, (2) about 0.665% w/w. olopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3% wt./wt. xanthan gum and about 0.5% wt./wt. sodium carboxymethylcellulose, (4) from about 1% wt./mass. up to about 1.2% wt./wt. a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, (5) about 0.02% wt./wt. benzalkonium chloride, (6) about 0.4% wt./wt. sodium chloride, (7) about 0.01% wt./wt. disodium edetate, (8) about 0.94% wt./wt. sodium phosphate heptahydrate and (9) about 0.01% wt./wt. polysorbate 80.

Another embodiment is a stable fixed dose aqueous suspension pharmaceutical composition (e.g., contained in a container) for nasal administration to a pediatric human subject, wherein the composition contains (1) about 0.050% w/w. mometasone furoate monohydrate, (2) about 0.665% w/w. olopatadine hydrochloride, (3) a hydrocolloid selected from about 0.3% wt./wt. xanthan gum and about 0.5% wt./wt. sodium carboxymethylcellulose, (4) from about 1% wt./mass. up to about 1.2% wt./wt. a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, (5) about 0.02% wt./wt. benzalkonium chloride, (6) about 0.4% wt./wt. sodium chloride, (7) about 0.01% wt./wt. disodium edetate, (8) about 0.94% wt./wt. sodium phosphate heptahydrate and (9) about 0.01% wt./wt. polysorbate 80.

Another embodiment is a stable suspension suitable for nasal administration to a pediatric human subject comprising (a) an aqueous solvent, (b) particles of mometasone furoate suspended in a solvent, wherein the particles have an average particle size of from about 1 to about 20. μm, (c) olopatadine hydrochloride dissolved in a solvent, and (d) a hydrocolloid, the suspension having a viscosity ranging from about 20 centipoise to about 150 centipoise. In one preferred embodiment, the suspension has a pH of about 3.5-3.9 and an osmolality in the range of about 250 mOsm/kg to about 350 mOsm/kg. In one embodiment, the suspension further comprises a chelating agent, a preservative, a buffer, a surfactant, an isotonic agent, and optionally a pH adjusting agent.

Preferably, the suspensions according to the present invention have only one phase (that is, they are preferably a single phase suspension).

In another embodiment, this invention relates to a kit containing a stable aqueous fixed dose pharmaceutical composition according to this invention contained in a container for nasal administration and a leaflet containing instructions for use of said pharmaceutical composition. In one preferred embodiment, the container is part of an atomizer that is powered. When the actuator is actuated, the composition is delivered as a spray.

In a further embodiment, the pharmaceutical composition is contained in a nebulizer and has, upon delivery of the nebulized composition to the human nose, a spray pattern having a longest axis of 15-75 mm, a shortest axis of 10-65 mm, an ellipticity of 1-2.

In the context of this invention, a pharmaceutical composition, when delivered as a nasal spray using a nebulizer, produces a specific spray pattern and spray droplet size. Spray pattern can be determined by various known methods such as ADSA with NSPUA (Innova system) and spray droplet size distribution can be determined by various known methods such as Malvern Spraytec with NSPUA (Innova system).

The following describes a typical procedure for characterizing the spray droplet size distribution - The nebulizer is loaded with the composition as described above and primed with an actuator pump until a fine mist emerges from the nebulizer nozzle. A commercially available laser diffraction tool is arranged so that the nozzle is 3 cm or 6 cm below the laser beam of the laser diffraction tool. The pump is driven by a conventional constant force mechanical drive. The resulting spray from the composition crosses the laser beam. Data is collected for D ₁₀ , D ₅₀ , D ₉₀ , SPAN and % volume <10 µm. Average values are calculated for each of these parameters for three sprays.

One embodiment is a fixed dose stable aqueous pharmaceutical composition comprising mometasone furoate monohydrate, olopatadine hydrochloride and optionally a hydrocolloid contained in a nebulizer, with each spray of the aqueous pharmaceutical composition providing (i) mometasone furoate monohydrate equivalent to about 50 μg of mometasone furoate , and (ii) olopatadine hydrochloride equivalent to about 600 micrograms of olopatadine.

Another embodiment is a fixed dose stable aqueous pharmaceutical composition comprising mometasone furoate monohydrate, olopatadine hydrochloride and optionally a hydrocolloid contained in a nebulizer, with each spray of the aqueous pharmaceutical composition providing (i) mometasone furoate monohydrate equivalent to about 25 μg of mometasone furoate, and (ii) olopatadine hydrochloride equivalent to about 600 µg of olopatadine.

The stable aqueous suspension of mometasone and olopatadine nasal spray may contain one or more additional pharmaceutical actives selected from, but not limited to, the therapeutic category, nonsteroidal anti-inflammatory agents, decongestants, and any combination of any of the above.

An aqueous suspension in the form of a nasal spray may be administered as drops or any other form suitable for topical application. The composition can also be administered using a nasal swab or nasal turundum.

In a preferred embodiment, the aqueous suspension is in the form of a nasal spray, the suspension being administered in a single dose container or in a multi-dose container. Suitable single-dose or multi-dose containers include, but are not limited to, glass, aluminum, polypropylene, or high density polyethylene, such as high density polyethylene containers made using blow-fill-seal manufacturing techniques.

In one embodiment, the pharmaceutical composition is contained in a spray bottle (such as a nebulizer). The spray bottle may include a container for storing the pharmaceutical composition and a pump for intranasal spraying of the pharmaceutical composition. In one embodiment, the container is capable of storing 30, 56, 60, 120, or 240 doses. For example, a container containing 120 doses can provide a 1 month supply of pharmaceutical composition (1 spray in each nostril twice a day (4 sprays per day) for 30 days). A 28 dose container can provide a 1 week supply of pharmaceutical composition (1 spray in each nostril twice daily (4 sprays per day) for 7 days). In one embodiment, the container may be designed to hold 4-5 ml (for example, 4.5 ml or 28 doses), 9-10 ml of a pharmaceutical composition (for example, 9 ml or 60 doses), or 18-19 ml (for example, 18 ml or 120 doses) of a pharmaceutical composition.

In some additional embodiments, the invention provides a multi-dose composition of substances containing: (a) a multiple dosage of a pharmaceutical composition according to this invention; and (b) a container containing: (i) a squeezable chamber holding a multiple dosage of the composition and having an opening from which the dose exits when the squeezable chamber is compressed; and (ii) a removable closing mechanism attached to the opening of the squeezable chamber. In some embodiments, the implementation of the multi-dose container is made of molded polymer.

In such embodiments, suitable polymers include, but are not limited to, polyethylene, polypropylene (PP), polystyrene (PS), nylon (Ny), polyvinyl chloride (PVC), polyethylene terephthalate (PET), polycarbonate (PC), polyoxymethylene (POM), polysulfone (PSF), polyethersulfone (PES), polyacrylate (PAR) and polyamide (PA). In some embodiments, the polymers include polyethylene, in particular medium density polyethylene (MDPE) (or branched polyethylene) or high density polyethylene (HDPE) (or linear polyethylene). In one embodiment, the multi-dose container is made from high density polyethylene (HDPE).

Other means of delivering the nasal spray may also be used, such as inhalation via a metered dose inhaler (MDI). Several types of MDI are regularly used for inhalation administration. These types of devices may include breath-activated MDIs, spacer/holding chambers in combination with a metered dose inhaler, and nebulizers. In the context of this document, the term "MDI" refers to an inhalation delivery system, including, for example, a container containing a mixture of active agent and propellant, optionally with one or more excipients, a metering spray nozzle, an actuator and a mouthpiece. The balloon is typically filled with a suspension of the active agent, such as a nasal spray formulation, and a propellant, e.g., one or more hydrofluoroalkanes [e.g., 1, 1, 1, 2-tetrafluoroethane (HFA-134a) and 1, 1, 1 , 2, 3, 3, 3-heptafluoropropane (HFA-227)], chlorofluorocarbons, and alcohols such as ethanol, isopropanol, butanol, propanol, or mixtures thereof. When the actuator is pressed, a metered dose of the suspension is sprayed for inhalation. The particles containing the active agent are advanced to the mouthpiece where they can then be inhaled by the subject.

An additional embodiment is a stable, fixed dose aqueous pharmaceutical composition (eg, contained in a container) for nasal administration, containing from about 0.025% w/w. up to about 0.05% wt./wt. mometasone or its salts and from about 0.5% wt./wt. up to about 0.8% wt./wt. olopatadine or its salt for the treatment of rhinitis in a person in need thereof.

The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention and should not be construed as limiting the scope of the invention.

EXAMPLES

EXAMPLES 1 AND 2

Suspension compositions containing mometasone furoate, olopatadine hydrochloride and sodium carboxymethylcellulose

Serial number Ingredient Example 1 (% w/w) Example 2 (% w/w) 1 Mometasone furoate monohydrate equivalent to mometasone furoate 0.050 0.025 2 Olopatadine hydrochloride 0.665 0.665 3 Avicel RC 591 (microcrystalline cellulose and sodium carboxymethyl cellulose) 1,200 1,200 4 Benzalkonium chloride (50% solution) 0.040 0.040 5 Sodium carboxymethyl cellulose (Cekol 2000 P) 0.500 0.500 6 Sodium chloride 0.410 0.410 7 Disodium edetat 0.010 0.010 8 Sodium phosphate dibasic heptahydrate 0.940 0.940 9 Polysorbate 80 0.010 0.010 10 Sodium hydroxide in sufficient quantity in sufficient quantity eleven Hydrochloric acid in sufficient quantity in sufficient quantity 12 Water for injections in sufficient quantity in sufficient quantity Observations Physical observation while standing for 24 hours Phase separation was not observed Phase separation was not observed Average particle size by microscopy Below 15 µm. Below 15 µm.

Manufacturing procedure:

1. Avicel RC-591 was added to water for injection with homogenization and left to hydrate.

2. Sodium carboxymethyl cellulose was dispersed in water for injection and added to step 1.

3. Sodium phosphate dibasic heptahydrate, sodium chloride, disodium edetate and olopatadine were dissolved in water. The pH was adjusted to 2.8-3.2 with hydrochloric acid.

4. Step 3 was added to step 1 with homogenization.

5. Polysorbate 80 was dissolved in water for injection. Mometasone furoate monohydrate was added and mixed to form a suspension.

6. Step 5 was added to step 4 with homogenization.

7. Benzalkonium chloride was dissolved in water for injection.

8. Step 7 was added to step 6 with homogenization.

9. The pH was checked and adjusted to 3.5-3.9 with HCl and the total weight was adjusted with water for injection. The osmolality of the composition was about 250-350 mOsm/kg.

The composition was subjected to stability studies under various conditions. The results of the above are as follows:

Container Details: Nebulizer containing HDPE vial crimped by a pump and fitted with an actuator and cap.

Stability study data Study Baseline 3 months 6 months Example 1 Exp. 2 Example 1 Exp. 2 Example 1 Exp. 2 Stability condition (25°C±2°C & 60% RH±5% RH) pH 3.61 3.69 3.73 3.78 3.81 Osmolality (mOsm)* 310 308 299 298 302 311 Viscosity (cP)** 32.5 42.5 42.3 40.6 40.9 Weight per ml (g/ml) 1.01 1.021 1.024 1.029 1.019 Analysis of mometasone furoate (% w/w) 101 102.4 99.1 99.3 98.2 97.2 Analysis of olopatadine hydrochloride (% w/w) 98.2 99.9 97.3 99.1 97.8 97.9 Related substances for mometasone furoate Impurity DMCF (%) 0.02 0.03 0.09 0.10 0.14 0.17 Any other impurity (%) 0.04 0.04 0.03 Total impurity content (%) 0.09 0.23 0.29 0.31 0.34 Related substances for olopatadine hydrochloride E-isomer of olopatadine (%) 0.08 0.07 0.09 0.09 Any other impurity (%) 0.03 0.04 0.09 0.12 0.11 0.11 Total impurity content (%) 0.15 0.16 0.20 0.25 0.37 0.38 Spray pattern (per 6 cm) Main axis (mm) 52 60 63 59 61 Minor axis (mm) 43 47 49 53 49 51 Ellipticity 1.2 1.1 1.2 1.2 1.2 1.2 Droplet size distribution (per 6 cm) D ₁₀ (µm) 18.91 19.45 19.26 19.70 19.33 18.88 _D50 (µm) 36.39 37.61 35.96 37.34 39.28 37.85 D ₉₀ (µm) 72.46 76.44 70.29 75.78 85.42 72.07 SPAN 1.47 1.51 1.42 1.5 1.67 1.46 Stability condition (40°C±2°C & 75% RH±5% RH) pH 3.61 3.68 3.72 3.59 3.68 Osmolality (mOsm) 310 308 298 306 305 299 Viscosity (cP) 32.5 45.2 42.6 41.8 41.5 Weight per ml (g/ml) 1.01 1.023 1.019 1.026 1.025 Analysis of mometasone furoate (%) 101 102.4 99.8 100.4 98.3 98.4 Analysis of olopatadine hydrochloride (%) 98.2 99.9 99.3 102.5 98.7 99.7 Related substances for mometasone furoate Impurity DMCF (%) 0.02 0.03 0.14 0.20 0.25 0.25 Any other impurity (%) 0.04 0.04 0.04 0.03 0.03 0.04 Total impurity content (%) 0.09 0.25 0.39 0.40 0.46 Related substances for olopatadine hydrochloride E-isomer of olopatadine (%) 0.08 0.07 0.08 0.08 0.09 Any other impurity (%) 0.03 0.04 0.21 0.18 0.31 0.30 Total impurity content (%) 0.15 0.16 0.32 0.36 0.68 0.64 Spray pattern (per 6 cm) Main axis (mm) 52 52 61 58 58 58 Minor axis (mm) 43 47 50 49 48 49 Ellipticity 1.2 1.1 1.2 1.2 1.2 1.2 Droplet size distribution (per 6 cm) D ₁₀ (µm) 18.91 19.45 19.49 19.27 18.05 18.09 _D50 (µm) 36.39 37.61 35.29 34.68 36.19 36.12 D ₉₀ (µm) 72.46 76.44 64.66 63.49 71.89 70.06 SPAN 1.47 1.51 1.28 1.27 1.50 1.44

* Determined by Advanced Instruments Osmometer (Model 3250).

** Determined using a Brookfield viscometer.

EXAMPLES 3 AND 4

Suspension compositions containing mometasone furoate, olopatadine hydrochloride and xanthan gum.

Serial number Ingredient Example 3 (% w/w) Example 4 (% w/w) 1 Mometasone furoate monohydrate equivalent to mometasone furoate 0.050 0.025 2 Olopatadine hydrochloride 0.665 0.665 3 Avicel RC 591 (microcrystalline cellulose and sodium carboxymethyl cellulose) 1,000 1,000 4 Benzalkonium chloride (50% solution) 0.040 0.040 5 Xantural 75 (xanthan gum) 0.300 0.300 6 Sodium chloride 0.410 0.410 7 Disodium edetat 0.010 0.010 8 Sodium phosphate dibasic heptahydrate 0.940 0.940 9 Polysorbate 80 0.010 0.010 10 Sodium hydroxide in sufficient quantity in sufficient quantity eleven Hydrochloric acid in sufficient quantity in sufficient quantity 12 Water for injections in sufficient quantity in sufficient quantity Observations Physical observation while standing for 24 hours Phase separation was not observed Phase separation was not observed Average particle size by microscopy Below 15 µm. Below 15 µm.

Manufacturing procedure:

1. Avicel RC-591 was added to water for injection with homogenization and left to hydrate.

2. Xanthan gum was dispersed in water for injection and added to step 1.

3. Sodium phosphate dibasic heptahydrate, sodium chloride, disodium edetate and olopatadine were dissolved in water. The pH was adjusted to 2.8--3.2 with hydrochloric acid.

4. Step 3 was added to step 1.

5. Polysorbate 80 was dissolved in water for injection. Mometasone furoate monohydrate was added and mixed to form a suspension.

6. Step 5 was added to step 4 with homogenization.

7. Benzalkonium chloride was dissolved in water for injection.

8. Step 7 was added to step 6 with homogenization.

9. The pH was checked and adjusted to 3.5-3.9 with HCl and the total weight was adjusted with water for injection. The osmolality of the composition was about 250-350 mOsm/kg.

The composition was subjected to stability studies under various conditions. The results of the above are as follows:

Container Details: Nebulizer containing HDPE vial crimped by a pump and fitted with an actuator and cap.

Stability Study Results Study Baseline 3 months 6 months Example 3 Exp. 4 Example 3 Exp. 4 Example 3 Exp. 4 Stability condition (25°C±2°C & 60% RH±5% RH) pH 3.65 3.67 3.78 3.65 3.70 3.62 Osmolality (mOsm) 307 312 302 316 308 308 Viscosity (cP) 124.2 129.1 127.9 129.9 126.2 126.8 Weight per ml (g/ml) 1.015 1.022 1.02 1.023 1.02 1.019 Analysis of mometasone furoate (%) 99.9 102.8 102.2 99.0 98.7 100.4 Analysis of olopatadine hydrochloride (%) 99.2 100.7 99.7 99.7 99.4 99.6 Related substances for mometasone furoate Impurity DMCF (%) 0.02 0.02 0.04 0.05 0.03 0.05 Any other impurity (%) 0.03 0.04 0.03 0.04 Total impurity content (%) 0.11 0.10 0.15 0.16 0.12 0.16 Related substances for olopatadine hydrochloride E-isomer of olopatadine (%) 0.08 0.07 0.09 0.11 0.11 0.10 Any other impurity (%) 0.03 0.04 0.05 0.05 0.08 0.08 Total impurity content (%) 0.18 0.15 0.24 0.20 0.33 0.33 Spray pattern (per 6 cm) Main axis (mm) 46 59 59 56 54 Minor axis (mm) 38 47 44 35 43 Ellipticity 1.2 1.3 1.4 1.6 1.3 Droplet size distribution (per 6 cm) D ₁₀ (µm) 21.58 21.03 20.95 20.27 18.73 18.34 _D50 (µm) 40.44 39.79 37.86 37.93 36.66 36.16 D ₉₀ (µm) 78.25 77.55 74.07 74.93 70.63 70.99 SPAN 1.40 1.42 1.40 1.44 1.41 1.45 Stability condition (40°C±2°C & 75% RH±5% RH) pH 3.65 3.67 3.70 3.77 3.78 3.65 Osmolality (mOsm) 307 312 309 305 302 316 Viscosity (cP) 124.2 129.1 129.6 124.3 127.9 129.9 Weight per ml (g/ml) 1.015 1.022 1.017 1.027 1.022 1.020 Analysis of mometasone furoate (%) 99.9 102.8 101.7 100.6 99.6 98.9 Analysis of olopatadine hydrochloride (%) 99.2 100.7 99.9 99.4 99.7 99.9 Related substances for mometasone furoate Impurity DMCF (%) 0.02 0.02 0.10 0.12 0.10 0.12 Any other impurity (%) 0.03 0.03 0.02 0.03 0.05 0.03 Total impurity content (%) 0.11 0.10 0.20 0.22 0.18 0.21 Related substances for olopatadine hydrochloride E-isomer of olopatadine (%) 0.08 0.07 0.12 0.13 0.11 0.11 Any other impurity (%) 0.03 0.04 0.06 0.06 0.12 0.12 Total impurity content (%) 0.18 0.15 0.26 0.26 0.41 0.40 Spray pattern (per 6 cm) Main axis (mm) 46 46 56 58 54 55 Minor axis (mm) 38 38 45 49 34 43 Ellipticity 1.2 1.2 1.3 1.2 1.6 1.3 Droplet size distribution (per 6 cm) D ₁₀ (µm) 21.58 21.03 20.67 23.16 19.13 19.16 _D50 (µm) 40.44 39.79 38.06 39.08 37.34 37.26 D ₉₀ (µm) 78.25 77.55 75.63 69.37 72.36 72.49 SPAN 1.40 1.42 1.44 1.19 1.42 1.43

COMPARATIVE EXAMPLES A AND B

Suspension composition containing mometasone furoate and olopatadine hydrochloride.

Serial number Ingredient Example (% w/w) A B 1 Mometasone furoate monohydrate equivalent to mometasone furoate 0.050 0.050 2 Olopatadine hydrochloride 0.665 0.665 3 Avicel RC 591 (microcrystalline cellulose and sodium carboxymethyl cellulose) 1.00 1.00 4 Benzalkonium chloride (50% solution) 0.040 0.040 5 Sodium carboxymethyl cellulose (Cekol 2000 P) 0.00 0.150 6 Sodium chloride 0.410 0.410 7 Disodium edetat 0.010 0.010 8 Sodium phosphate dibasic heptahydrate 0.940 0.940 9 Polysorbate 80 0.010 0.010 10 Sodium hydroxide in sufficient quantity in sufficient quantity eleven Hydrochloric acid in sufficient quantity in sufficient quantity 12 Water for injections in sufficient quantity in sufficient quantity Observations pH 3.7 3.7 Physical observation while standing for 24 hours Phase separation is observed Phase separation is observed

Manufacturing procedure:

The fabrication procedure was as described in Example 1.

COMPARATIVE EXAMPLES C AND D

Suspension composition containing mometasone furoate and olopatadine hydrochloride.

Serial number Ingredient Example (% w/w) C D 1 Mometasone furoate monohydrate equivalent to mometasone furoate 0.050 0.050 2 Olopatadine hydrochloride 0.665 0.665 3 Avicel RC 591 (microcrystalline cellulose and sodium carboxymethyl cellulose) 1,000 1,000 4 Benzalkonium chloride (50% solution) 0.040 0.040 5 Xantural 75 (xanthan gum) 0.00 0.20 6 Sodium chloride 0.410 0.410 7 Disodium edetat 0.010 0.010 8 Sodium phosphate dibasic heptahydrate 0.940 0.940 9 Polysorbate 80 0.010 0.010 10 Sodium hydroxide in sufficient quantity in sufficient quantity eleven Hydrochloric acid in sufficient quantity in sufficient quantity 12 Water for injections in sufficient quantity in sufficient quantity Observations pH 3.73 3.70 Physical observation while standing for 24 hours Phase separation is observed Phase separation is observed

Manufacturing procedure:

The fabrication procedure was as described in Example 3.

EXAMPLE 5

Phase III clinical trial of a fixed-dose combination of mometasone and olopatadine nasal spray in pediatric patients

This study is a double-blind, randomized, parallel-group, 12-week study to evaluate the efficacy, safety, and tolerability of a fixed-dose combination of mometasone furoate and olopatadine hydrochloride nasal spray versus placebo nasal spray in pediatric patients ( 2 years to 12 years of age) with perennial allergic rhinitis (PAR).

Research objectives

To compare the efficacy of mometasone furoate and olopatadine hydrochloride nasal spray (given as 1 spray in each nostril twice daily) with placebo nasal spray in the treatment of pediatric patients (ages 2 to 12 years) with PAR.

The secondary objective is to compare the safety and tolerability of a nasal spray containing mometasone furoate and olopatadine hydrochloride with a placebo nasal spray during 12 weeks of study treatment.

Key Patient Selection Criteria

• Male and non-pregnant female patients aged 2 to 12 years at the date of the screening visit (1st visit).

• Documented clinical history of PAR (≥12 months for patients ≥6 to <12 years of age, ≥6 months for patients ≥2 to <6 years of age prior to screening visit [1st visit]) with exacerbations ( clinical manifestation of active symptoms). In the investigator's opinion, PAR must have been severe enough to have required treatment (both continuous and intermittent) in the past and is expected to require treatment throughout the study.

• Documented positive skin prick test (allergic papule diameter 3 mm larger than negative allergic papule) for at least one allergen known to cause PAR. Documentation of a positive result within 12 months prior to the screening visit (Visit 1) is satisfactory. A positive allergen test for the patient, which must match the PAR medical history. In addition, the patient is expected to be exposed to the PAR allergen for which he or she will test positive on a skin prick test throughout the study.

• 12-hour rTNSS score ≥6 (out of a possible 12) for morning (AM) assessment at screening visit (visit 1).

Study design

Approximately 540 patients (≥2 to <12 years) will be randomized in a 2:1 ratio to a fixed dose combination of mometasone furoate and olopatadine hydrochloride nasal spray (360 patients) versus placebo nasal spray (180 patients). .

Patient participation can last from 22 to 27 days, with a 7-10 day screening/lead-in period and a 14-day treatment period with an allowable variance from the schedule for study visits. Treatment groups are presented in the table below.

Investigational drugs and their administration

Investigational drug(s) Introduction Olopatadine hydrochloride + mometasone furoate (665 mcg + 25 mcg) nasal spray* [fixed dose combination] 1 spray in each nostril, twice a day (BID), morning and evening placebo nasal spray Placebo - 1 spray in each nostril twice a day (BID), morning and evening

* - Each injection provides 665 micrograms of olopatadine hydrochloride and 25 micrograms of mometasone furoate.

Primary Endpoint:

• Change from study entry to mean of patient-reported morning (AM) and evening (PM) 12-hour retrospective global rhinitis symptom score (rTNSS) score during the first 4 weeks of treatment for patients ≥6 to <12 years of age .

Secondary Endpoint(s):

• Change from entry into the study in the mean of the 12-hour patient-reported morning and evening patient-reported iTNSS score during the first 4 weeks of treatment for patients ≥6 to <12 years of age.

• Change from entry into the study in the mean morning and evening patient-reported 12-hour rTNSS score during the first 4 weeks of treatment for patients ≥2 to <12 years of age.

• Change from entry into the study in the mean morning and evening patient-reported 12-hour iTNSS score during the first 4 weeks of treatment for patients ≥2 to <12 years of age.

• Change from entry into the study in the overall pediatric rhinoconjunctivitis quality of life questionnaire (PRQLQ) score at week 4 among treatment groups.

Additional endpoint(s):

Nasal symptoms:

TNSS - first 4 weeks, patients aged ≥ 6 to <12 years:

• Change from study entry in patient-reported morning rTNSS scores during the first 4 weeks of treatment.

• Change from entry into the study in patient-reported evening rTNSS scores during the first 4 weeks of treatment.

• Change from entry into the study in patient-reported iTNSS scores in the morning during the first 4 weeks of treatment.

• Change from entry into the study in patient-reported iTNSS scores in the evening during the first 4 weeks of treatment.

• Changes since entry into the study in patient-reported retrospective assessment of individual nasal symptoms during the first 4 weeks of the treatment period (AM, PM and mean AM and PM).

• Changes since entry into the study in patient-reported current scores of individual nasal symptoms during the first 4 weeks of the treatment period (AM, PM and mean AM and PM).

• Changes since study entry in patient-reported rTNSS and iTNSS scores for each day (AM, PM and mean of AM and PM).

TNSS - first 4 weeks, patients aged ≥ 2 to < 6 years:

• Change from entry into the study in the mean morning and evening patient-reported 12-hour rTNSS score during the first 4 weeks of treatment for patients ≥2 to <6 years of age.

• Change from entry into the study in the mean morning and evening patient-reported 12-hour iTNSS score during the first 4 weeks of treatment for patients ≥2 to <6 years of age.

TNSS - first 4 weeks, patients aged ≥ 2 to <12 years:

• Change from entry into the study in the mean morning and evening patient-reported 12-hour rTNSS score during the first 4 weeks of treatment for patients ≥2 to <12 years of age.

• Change from entry into the study in the mean morning and evening patient-reported 12-hour iTNSS score during the first 4 weeks of treatment for patients ≥2 to <12 years of age.

Additional total rhinitis symptom scale (TNSS) scores will be scored for the following (e.g., AM, PM, individual symptoms):

• 12 weeks, patients aged ≥6 to <12 years.

• 12 weeks, patients aged ≥2 to <6 years.

• 12 weeks, patients aged ≥2 to <12 years.

Physician Nasal Symptom Rating Scale (PNSS):

• Change from entry into the study in PNSS and clinician's assessment of individual nasal symptoms at 4 and 12 weeks.

Pediatric quality of life questionnaire for patients with rhinoconjunctivitis (PRQLQ):

• Separate PRQLQ ranges at 4 and 12 weeks.

EXAMPLE 6

Phase III clinical trial of a fixed-dose combination of mometasone and olopatadine nasal spray in pediatric patients

This study was a double-blind, randomized, parallel-group, 14-day study to evaluate the efficacy, safety, and tolerability of a fixed-dose combination of mometasone furoate and olopatadine hydrochloride nasal spray versus placebo nasal spray in pediatric patients ( 6 years to 12 years of age) with seasonal allergic rhinitis (SAR).

Research objectives

To compare the efficacy of mometasone furoate and olopatadine hydrochloride nasal spray (administered as 1 spray per nostril twice daily) with placebo nasal spray in pediatric patients (≥6 to <12 years of age) with SAR.

The secondary objective was to compare the safety and tolerability of the nasal spray containing mometasone furoate and olopatadine hydrochloride with the placebo nasal spray during the study period.

Key Patient Selection Criteria

• Male and non-pregnant female patients aged ≥6 to <12 years at the date of the screening visit (Visit 1).

• A documented clinical history of SAR (within at least 2 years preceding the Screening Visit [Visit 1]) with exacerbations (clinical manifestation of active symptoms) during the study period for the relevant seasonal allergen (tree/grass pollen). The SAR must have been severe enough to have required treatment (both continuous and intermittent) in the past and, in the opinion of the investigator, is expected to require treatment throughout the study period.

• Shown to be susceptible to at least 1 seasonal allergen (tree/grass pollen) known to induce SAR by documented skin prick test (allergic papule diameter at least 5 mm larger than negative control) to the corresponding seasonal allergen allergen. Documentation of a positive result within 12 months prior to the screening visit (Visit 1) is satisfactory. The patient's positive allergen must match the SAR medical history. In addition, the patient is expected to be adequately exposed to the SAR allergen for which he or she will test positive on a skin prick test throughout the study.

• Significance of a 12-hour retrospective General Rhinitis Symptom Scale (rTNSS) score of ≥6 (out of a possible 12) for the Morning (AM) score at the Screening Visit (Visit 1).

Study design

Approximately 446 patients (≥2 to <12 years) were randomized in a 1:1 ratio to the fixed dose combination of mometasone furoate and olopatadine hydrochloride nasal spray (225 patients) versus placebo nasal spray (225 patients). .

Treatment groups are presented in the table below.

Investigational drugs and their administration

Investigational drug(s) Introduction Olopatadine hydrochloride + mometasone furoate (665 mcg + 25 mcg) [fixed-dose combination] nasal spray* 1 spray in each nostril, twice a day (BID), morning and evening placebo nasal spray Placebo - 1 spray in each nostril twice a day (BID), morning and evening

* - Each injection provides 665 micrograms of olopatadine hydrochloride and 25 micrograms of mometasone furoate.

The duration of the study was 12 weeks, including 7 to 10 days of screening/placebo run-in period and 12 weeks of treatment period with an allowable variance from study visit schedule.

Main evaluation criteria (clinical endpoints):

Primary Endpoint

• Change from entry into the study in the mean value of the morning and evening 12-hour retrospective score of the general rhinitis symptoms scale (rTNSS) reported by patients during the 14-day treatment period.

Secondary Endpoint(s):

• Change from entry into the study in the mean of the patient-reported AM and PM 12-hour Relevant Total Rhinitis Symptoms Scale (iTNSS) score to date during the 14-day treatment period.

• Change from entry into the study in the overall assessment of the pediatric quality of life questionnaire for patients with rhinoconjunctivitis (PRQLQ) on the 15th day (4th visit) among treatment groups.

• Change from entry into the study in the mean of the morning and evening 12-hour retrospective rTOSS score reported by patients during the 14-day treatment period.

Additional Efficiency Endpoint(s):

nasal symptoms

• Change from study entry in patient-reported AM rTNSS score during the 14-day treatment period.

• Change from entry into the study in patient-reported AM iTNSS scores during the 14-day treatment period.

• Change since study entry in patient-reported PM rTNSS score during the 14-day treatment period.

• Change from entry into the study in patient-reported PM iTNSS scores during the 14-day treatment period.

• Changes since entry into the study in patient-reported retrospective assessment of individual nasal symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

• Changes since entry into the study in patient-reported current scores of individual nasal symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

• Change since entry into the study in the mean AM and PM of patient-reported rTNSS and iTNSS scores per day.

• Change since study entry in patient-reported AM rTNSS and iTNSS scores per day.

• Change from entry into the study in each day's patient-reported PM rTNSS and iTNSS score.

Eye symptoms:

• Change from entry into the study in the mean of the morning and evening patient-reported Instantaneous Total Ocular Symptom Scale (iTOSS) scores during the 14-day treatment period.

• Change from entry into the study in patient-reported AM rTOSS over the 14-day treatment period.

• Change from entry into the study in patient-reported AM iTOSS over the 14-day treatment period.

• Change from entry into the study in patient-reported PM rTOSS score during the 14-day treatment period.

• Change from entry into the study in patient-reported PM iTOSS over the 14-day treatment period.

• Changes since entry into the study in patient-reported retrospective assessment of individual ocular symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

• Changes since entry into the study in patient-reported pertinent assessment of individual ocular symptoms during the 14-day treatment period (AM, PM and mean AM and PM).

• Change since entry into the study in the mean AM and PM of patient-reported rTOSS and iTOSS per day.

• Change from entry into the study in each day's patient-reported rTOSS and iTOSS scores.

• Change from entry into the study in each day's patient-reported PM rTOSS and iTOSS scores.

Non-nasal symptoms were assessed similarly to the ocular symptoms described above (as described in the Statistical Analysis Plan [SAP]).

Physician Nasal Symptom Rating Scale (PNSS):

• Change from study entry to PNSS and physician assessment of individual nasal symptoms on Day 15 (Visit 4).

Pediatric quality of life questionnaire for patients with rhinoconjunctivitis (PRQLQ):

• Change from the moment of inclusion in the study in certain areas of PRQLQ values on the 15th day.

The table below summarizes primary clinical endpoints (mean AM and PM rTNSS) and secondary clinical endpoints (mean AM and PM iTNSS, mean AM and PM rTOSS, and PRQLQ [assessment of the Pediatric Quality of Life Questionnaire for Patients with Rhinoconjunctivitis] ) observed during the phase 3 study. For comparison between fixed dose combination nasal spray and placebo nasal spray, a p-value less than 0.05 is considered statistically significant.

Summary of Primary and Secondary Clinical Endpoints

Primary Clinical Endpoint Secondary clinical endpoint
The difference between the least-squares averages (95% Group by treatment option rTNSS (difference of least-squares means [p-value]) iTNSS (difference of least-squares means [p-value]) rTOSS (difference of least-squares means [p-value]) PRQLQ (least squares mean difference [p-value]) Fixed dose combination nasal spray and placebo nasal spray - 0.6 (p=0.001)* -0.6 (p<0.001)* -0.2 (p=0.233) -0.3 (p<0.001)*

* indicates statistical significance

iTNSS = instantaneous score on the General Rhinitis Symptom Scale;

rTNSS = Retrospective Rhinitis Symptom Scale;

rTOSS=Retrospective Overall Ocular Symptom Scale;

PRQLQ = Pediatric Quality of Life Questionnaire score for patients with rhinoconjunctivitis

The table above shows that the fixed-dose combination nasal spray (1 spray in each nostril) administered twice daily was statistically superior to placebo nasal spray (p < 0.05) for the primary endpoint in change in mean AM and PM rTNSS from entry into the study, and for secondary endpoints, change in mean AM and PM iTNSS from entry into the study and overall PRQLQ score.

The table below shows the difference between the least-squares averages for individual retrospective assessment and instantaneous assessment of the scale of general symptoms of rhinitis and separate areas of PRQLQ values for the fixed-dose combination group and the placebo nasal spray group.

Summary of Means of Reflective and Instantaneous Individual AM and PM Scores on the Global Rhinitis Symptoms Scale and Selected PRQLQ Ranges during the 14-Day Treatment

Difference in Least Square Means for AM and PM Means of Reflective and Instantaneous Individual Rhinitis Symptom Scale and Individual PRQLQ Scores for Fixed-Dose Combination Nasal Spray and Placebo Nasal Spray Least-square mean difference (95% confidence interval) p-value reflective Rhinorrhea -0.1 (-0.2, 0.0) 0.016* Nasal congestion -0.1 (-0.2, 0.0) 0.048* Itchy nose -0.2 (-0.3, -0.1) 0.002* sneezing -0.2 (-0.3, -0.1) <0.001* Instant Rhinorrhea -0.1 (-0.2, 0.0) 0.003* Nasal congestion -0.1 (-0.2, -0.1) 0.002* Itchy nose -0.1 (-0.2, 0.1) 0.408 sneezing -0.2 (-0.3, -0.1) <0.001* Difference in Least-Squares Means for Separate PRQLQ Ranges between Fixed-Dose Combination Nasal Spray and Placebo Nasal Spray Activity restrictions -0.2 (-0.5, 0.0) 0.043* Practical problems -0.3 (-0.4, -0.1) 0.006* nasal symptoms -0.6 (-0.9, -0.4) <0.001* Eye symptoms -0.1 (-0.3, 0.1) 0.203 Other symptoms -0.2 (-0.4, 0.0) 0.025*

* indicates statistical significance

As can be seen from the table above, fixed dose combination nasal spray treatment showed a significant difference (p<0.05) compared to placebo nasal spray in mean AM and PM rTNSS values from day 3 to day 14. The fixed dose combination nasal spray showed a significant difference (p < 0.05) compared to placebo nasal spray in mean AM and PM iTNSS values from day 1 to day 14.

In addition, AM rTNSS, PM rTNSS, AM iTNSS, and PM iTNSS were analyzed as a whole and every day, from days 1 to 15. The fixed-dose combination nasal spray was statistically better than placebo nasal spray in change in mean AM rTNSS, mean PM rTNSS, mean AM iTNSS, and mean PM iTNSS. The results also demonstrated a statistically significant difference (p<0.05) in favor of the nasal spray from the fixed dose combination from days 4 to 15 for both AM rTNSS and PM rTNSS. The results were also statistically significant (p < 0.05) for AM iTNSS and PM iTNSS in favor of the nasal spray from the fixed dose combination from days 1 to 15, except for a p-value of 0.55 for PM iTNSS on the 2nd day.

The table below shows the difference between the AM and PM least-squares averages of the reflective and instantaneous individual scores on the Global Rhinitis Symptoms Scale for the fixed-dose combination group and the placebo nasal spray group.

Summary of mean AM and PM values of reflective and instantaneous individual scores on the scale of general symptoms of rhinitis during the 14-day treatment

Least-square mean difference between AM and PM reflective and instantaneous individual scores on the scale of general symptoms of rhinitis and individual ranges of PRQLQ values when using a nasal spray from a combination of a fixed dose and a placebo nasal spray Least-square mean difference (95% confidence interval) p-value AM reflective General -0.7 (-1.0, -0.3) <0.001* Rhinorrhea -0.2 (-0.3, 0.0) 0.006* Nasal congestion -0.1 (-0.2, 0.0) 0.038* Itchy nose -0.2 (-0.3, -0.1) 0.003* sneezing -0.3 (-0.4, -0.2) <0.001* PM reflective General -0.5 (-0.9, -0.2) 0.003* Rhinorrhea -0.1 (-0.2, 0.0) 0.015* Nasal congestion -0.1 (-0.2, 0.0) 0.057 Itchy nose -0.2 (-0.3, -0.1) 0.002* sneezing -0.2 (-0.3, -0.1) <0.001* Instant AM instant General -0.7 (-1.0, -0.3) <0.001* Rhinorrhea -0.2 (-0.3, -0.1) 0.002* Nasal congestion -0.2 (-0.3, -0.1) <0.001* Itchy nose -0.1 (-0.2, 0.0) 0.014* sneezing -0.2 (-0.3, -0.1) <0.001* PM instant General -0.7 (-1.1, -0.4) <0.001* Rhinorrhea -0.2 (-0.3, -0.1) 0.002* Nasal congestion -0.2 (-0.3, -0.1) <0.001* Itchy nose -0.1 (-0.2, 0.1) 0.293 sneezing -0.3 (-0.4, -0.2) <0.001*

* indicates statistical significance

The table below shows the results of the Physician's Nasal Symptom Rating Scale (PNSS) and the physician's assessment of selected nasal symptoms (rhinorrhea, nasal congestion, nasal itching, and sneezing).

Summary of mean PNSS and individual PNSS ranges during 14 days of treatment

Difference between Least Square Means for PNSS and Separate PNSS Ranges for Fixed-Dose Combination Nasal Spray and Placebo Nasal Spray Least-square mean difference (95% confidence interval) p-value Total PNSS -0.9 (-1.5, -0.2) 0.01* Rhinorrhea -0.3 (-0.4, -0.1) <0.001* Nasal congestion -0.2 (-0.5, 0.0) 0.022* Itchy nose -0.3 (-0.4, -0.1) <0.001* sneezing -0.2 (-0.4, -0.1) <0.001*

* indicates statistical significance

The safety profile of the fixed dose combination nasal spray was well tolerated and was similar to placebo nasal spray in subjects aged 6 to <12 years. Of a total of 446 randomized subjects, 27 (12.0%) subjects experienced at least 1 NEEP in the fixed dose combination nasal spray group and 23 (10.4%) subjects experienced at least 1 NEEP in the placebo nasal spray group. No deaths were reported and only 1 SAE was reported in the placebo nasal spray group. All AEs, except for one SAE, were mild or moderate in severity. The most common AELVs associated with study treatment (>1% of subjects in any treatment group) were dysgeusia, headache, epistaxis, and abnormal ENT examination. There were no clinically significant differences in vital signs, physical examinations, or targeted ENT examinations.

While the present invention has been described with reference to specific embodiments of the invention, it should be understood that these embodiments are merely illustrative of the principles and practice of the present invention. Therefore, it should be understood that numerous modifications may be made to the exemplary embodiments.

All publications, patents and patent applications mentioned in this application are incorporated herein by reference to the same extent as if each individual publication, patent or patent application were specifically and separately indicated for inclusion by reference.

Claims (8)

1. A method of treating a human subject of a pediatric age group aged 6 to 11 years suffering from allergic rhinitis, comprising the step of administering to the subject a pharmaceutical composition for nasal administration twice a day in the form of a single injection into each nostril, wherein (i) the pharmaceutical composition contains (a) 0.025% wt./wt. mometasone furoate, (b) 0.665% w/w olopatadine hydrochloride and (c) hydrocolloid at a concentration of 0.1% wt./wt. up to 3% w/w, (ii) the pharmaceutical composition provides an onset of action within 15 minutes for the treatment of allergic rhinitis, and (iii) each injection of the pharmaceutical composition contains 25 μg mometasone furoate in particulate form and 665 μg olopatadine hydrochloride. 2. The method of claim 1, wherein the allergic rhinitis is selected from seasonal allergic rhinitis, perennial allergic rhinitis, and persistent allergic rhinitis. 3. The method of claim 1, wherein said method provides relief from one or more symptoms of allergic rhinitis. 4. The method of claim 3, wherein the symptoms of allergic rhinitis are selected from nasal symptoms and non-nasal symptoms. 5. The method of claim 4 wherein the nasal symptoms are selected from nasal congestion, rhinorrhea, itching and sneezing.