RU2799761C2 - Treatment of allergic rhinitis using a combination of mometasone and olopatadin - Google Patents

Abstract

FIELD: medicine; allergology and otorhinolaryngology.

SUBSTANCE: group of inventions is intended for the treatment of allergic rhinitis and/or nasal symptoms associated with it. A method of treating allergic rhinitis and/or associated nasal symptoms in a person requiring the said treatment comprises nasal administering of an effective amount of a pharmaceutical composition containing mometasone furoate and olopatadine or a salt thereof. The composition is administered nasally as 1 or 2 injections into each nostril of the said person at least once a day, each injection contains mometasone furoate and olopatadine or its salt in a mass ratio of 1:12 to 1:53 based on the equivalent weight of the free base of olopatadine. The said mometasone furoate is presented in the form of particles, and olopatadine or its salt are presented in dissolved form. The said administration provides relief of one or more symptoms associated with allergic rhinitis faster than nasal administration of two sprays of 665 μg of olopatadine hydrochloride alone twice daily. The use of the said pharmaceutical composition for the treatment of allergic rhinitis in a patient requiring the said treatment is provided.

EFFECT: acceleration of the relief of symptoms of allergic rhinitis and/or nasal symptoms associated with it in a patient requiring the said treatment, and, accordingly, increasing the effectiveness of treatment.

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Description

This patent application claims priority under Indian Provisional Patent Application No. 3174/MUM/2013 filed October 4, 2013, the entire contents of which are hereby incorporated by reference.

FIELD OF TECHNOLOGY

The present patent application relates to a method for treating allergic rhinitis in a subject (preferably a human) 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 shed skin and hair), is inhaled by a subject with a sensitive immune system. Allergic rhinitis can cause additional symptoms such as runny nose (copious nasal discharge), sneezing, nasal itching, nasal congestion and obstruction, cough, headache, fatigue, and malaise. Symptoms can vary in severity between people.

Many treatments 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.

Olopatadine hydrochloride is 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 Pat.^®, which contains 0.6% wt./about. olopatadine (as base) in non-sterile aqueous solution. Olopatadine hydrochloride is indicated for the relief of symptoms of seasonal allergic rhinitis (SAR) in adults and children 6 years of age and older.

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

International Publication No. WO 2011/141929 describes an aqueous nasal spray solution containing fluticasone and olopatadine.

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

US Pat. Nos. 7,977,376 and 8,399,508 describe a topical dosage form of olopatadine hydrochloride.

International Publication No. WO 2011/008923 describes 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.

There remains a need for user-friendly and effective treatments for allergic rhinitis.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to a fixed dose combination of mometasone or a salt thereof and olopatadine or a fixed dose salt thereof and its use in the treatment of rhinitis in a subject in need of said treatment. The inventors have surprisingly found that mometasone furoate and olopatadine hydrochloride have a synergistic effect in the treatment of allergic rhinitis and are more effective and provide better therapeutic value than treatment with any one active ingredient alone.

In an embodiment, the present invention relates to a method of treating allergic rhinitis in a subject (e.g., human) in need of said treatment, comprising nasally administering to said 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 or 2 sprays into each nostril of said subject at least once a day. 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 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, the fixed dose pharmaceutical composition is a suspension, wherein 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 subject (e.g., human) in need of said treatment, comprising nasally administering to said subject an effective amount of a fixed dose pharmaceutical composition comprising mometasone furoate monohydrate and olopatadine hydrochloride. According to one preferred embodiment of the invention, the composition is administered nasally in the form of 1 or 2 injections into each nostril of the specified subject at least once a day. Each injection of a pharmaceutical composition may contain an olopatadin hydrochloride, equivalent to approximately 300 mcg, approximately 450 mcg, approximately 600 mcg, approximately 750 mcg or approximately 900 μg olopatadin, and about 12.5 mcg, approximately 25 μg, about 37.5 μg, approximately 50 μg, about 62.5 mcg of Momethason Furoat. In one embodiment, each injection contains olopatadine hydrochloride equivalent to about 600 μg of olopatadine and about 25 μg of mometasone furoate. According to another implementation variant, each injection contains olopatadine hydrochloride, equivalent to about 600 μg of olopatadine, and about 50 μg of mometasone furoate.

Allergic rhinitis in the context of the present invention includes, but is not limited to, inflammation and irritation of the nasal mucosa and associated nasal and/or non-nasal symptoms. Allergic rhinitis includes, for example, persistent allergic rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, chronic rhinitis, drug-induced rhinitis, vasomotor rhinitis, infectious rhinitis, autonomic rhinitis, hormonal rhinitis, drug-induced 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 the present 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, ocular pruritis, excessive tearing, headache, fatigue, and malaise.

Another embodiment of the present invention relates to a method of treating allergic rhinitis in a subject (e.g., a human) in need of said treatment, comprising nasally administering to said 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, or from about 1:12 to about 1:53, wherein (i) the composition is administered nasally as 1 or 2 injections in each nostril once or twice a day, and (ii) each spray contains olopatadine hydrochloride equivalent to about 600 micrograms of olopatadine and about 25 micrograms to about 50 micrograms of mometasone furoate. In one embodiment, the composition is administered over about 1 week. According to another aspect of the embodiment, the composition is administered over a period of about 2 weeks.

Another embodiment of the invention relates to a method of treating allergic rhinitis in a subject representing a human in need of said treatment, comprising nasal administration to said human of a fixed dose pharmaceutical composition containing mometasone or its salt and olopatadine or its salt, wherein (i) the composition is administered nasally in the form of 1 or 2 injections in each nostril once or twice a day for at least 1 or 2 weeks, and (ii) each injection contains olop atadine hydrochloride equivalent to about 600 µg of olopatadine and about 25 µg to about 50 µg of mometasone furoate. According to one embodiment of the invention, the Total Nasal Symptom Severity Score (TNSS) in said human subject after 1 or 2 weeks of treatment is reduced by at least 40%, preferably at least 50%, from baseline. According to another embodiment of the invention, the Total Ocular Symptom Severity Score (TOSS) in said human subject after 1 or 2 weeks of treatment is reduced by at least 30%, preferably at least 40%, from baseline.

According to one implementation variant, the subject suffers from persistent allergic rhinitis and receives treatment for 4 or 6 weeks.

In another embodiment, the subject has a positive skin prick test for the allergen. Alternatively, the subject may also have a positive blood test for allergy.

According to another implementation variant, the method includes the absence of the specified subject after 1 or 2 weeks of treatment of significant side effects associated with the treatment.

Another embodiment relates to a method of treating seasonal allergic rhinitis and/or nasal symptoms associated with seasonal allergic rhinitis in a subject (e.g., human) in need of said treatment, comprising nasal administration to said subject of a synergistic combination containing mometasone furoate and olopatadine hydrochloride, the combination being presented as 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 olopatadine free base).

In additional embodiments, methods for treating allergic rhinitis in a subject (e.g., a human) described herein comprise nasally administering to said subject a fixed-dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof, according to one of the following schedules:

a) the composition is administered nasally as 1 spray in each nostril once a day for a period of at least 1 week;

b) the composition is administered nasally as 2 sprays in each nostril once a day for a period of at least 1 week;

c) the composition is administered nasally as 1 spray in each nostril twice a day for a period of at least 1 week;

d) the composition is administered nasally as 2 sprays in each nostril twice a day for a period of at least 1 week;

e) the composition is administered nasally as 1 spray in each nostril once a day for a period of 2 weeks;

f) the composition is administered nasally as 2 sprays in each nostril once a day over a period of 2 weeks;

g) the composition is administered nasally as 1 spray in each nostril twice a day for a period of 2 weeks; or

h) the composition is administered nasally as 2 sprays in each nostril twice a day over a period of 2 weeks.

According to an aspect of the invention, the composition is administered as 1 or 2 sprays into each nostril of the specified subject (eg, human) at least once a day for a period of 1 week or 2 weeks. According to another aspect of the embodiment, each injection of the composition contains olopatadine hydrochloride equivalent to about 600 micrograms of olopatadine and about 25 micrograms to about 50 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 or about 50 micrograms of mometasone furoate. In yet another aspect of the embodiment, the total nasal symptom severity score (TNSS) in said human subject after 1 or 2 weeks of treatment is reduced by at least 40% or at least 50% from baseline. According to another aspect of an embodiment of the invention, a person's Total Ocular Symptom Severity Score (TOSS) after 1 or 2 weeks of treatment is reduced by at least 30% or at least 40% from baseline. In yet another aspect of the embodiment, said individual does not experience significant treatment-related side effects after 1 or 2 weeks of treatment. According to another aspect of the embodiment, the human subject is a patient who has a positive skin prick test for an allergen.

Another embodiment of the invention relates to the use of 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 the manufacture of a fixed dose pharmaceutical composition for the treatment of allergic rhinitis in a subject (for example, a human) in need of said treatment. Preferably, the composition is administered nasally as 1 or 2 sprays into each nostril of said subject once or twice daily. In one aspect, 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. According to another aspect of an embodiment of the invention, the composition is administered over a period of about 1 or 2 weeks. The total nasal symptom severity score (TNSS) in a human subject after 1 or 2 weeks of treatment is preferably reduced by at least 40% or at least 50% from baseline. The Total Ocular Symptom Severity Score (TOSS) in a human subject after 1 or 2 weeks of treatment is preferably reduced by at least 30% or at least 40% from baseline. In yet another aspect of the embodiment, said human subject does not experience significant treatment-related side effects after 1 or 2 weeks of treatment. According to another aspect of an embodiment of the invention, a human subject is a patient who has a positive skin prick test for an allergen.

Another embodiment of the invention relates to a fixed dose pharmaceutical composition containing 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 use in the treatment of allergic rhinitis in a subject (e.g., a human) in need of said treatment, said composition being administered nasally as 1 or 2 injections into each nostril of said subject at least once a day. In one aspect, the fixed dose pharmaceutical composition is a suspension, wherein mometasone or a salt thereof is present in particulate form (e.g., having an average particle size of about 1 to about 20 microns, or about 1 to about 15 microns), and olopatadine or a salt thereof is present in dissolved form.

The composition can be administered over a period of about 1 week, 2 weeks, 4 weeks, 6 weeks, or 8 weeks. The total nasal symptom severity score (TNSS) in said human subject after 1 or 2 weeks of treatment is preferably reduced by at least 40% or at least 50% from baseline. The Total Ocular Symptom Severity Score (TOSS) in said human subject after 1 or 2 weeks of treatment is preferably reduced by at least 30% or at least 40% from baseline. According to another aspect of an embodiment of the invention, said human subject does not experience significant treatment-related side effects after 1 or 2 weeks of treatment. According to another aspect of an embodiment of the invention, a human subject is a patient who has a positive skin prick test for an allergen.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a bar graph showing the effect of saline control, ovalbumin control, olopatadine hydrochloride (equivalent to 50 μg olopatadine base), mometasone furoate (10 μg), and the combination of mometasone furoate (10 μg) and olopatadine hydrochloride (equivalent to 50 μg olopatadine base) on response in guinea pigs sneezing as described in Example 1.

Figure 2 is a bar graph showing the effect of controls using saline, ovalbumin control, olopatadine hydrochloride (equivalent to 50 μg olopatadine base), mometasone furoate (10 μg) and the combination of mometasone furoate (10 μg) and olopatadine hydrochloride (equivalent to 50 μg olopatadine base) on the total number of cells in the nasal cavity. washing guinea pigs as described in Example 1.

Figure 3 is a bar graph showing the effect of saline control, ovalbumin control, olopatadine hydrochloride (equivalent to 50 µg olopatadine base), mometasone furoate (10 µg) and the combination of mometasone furoate (10 µg) and olopatadine hydrochloride (equivalent to 50 µg olopatadine base) on eosinophil count per hall flush of guinea pigs as described in Example 1.

Figure 4 is a bar graph showing the effect of saline control, ovalbumin control, olopatadine hydrochloride (equivalent to 120 μg olopatadine base), mometasone furoate (10 μg) and the combination of mometasone furoate (10 μg) and olopatadine hydrochloride (equivalent to 120 μg olopatadine base) on eosinophil count in guinea pig nasal flush as described in Example 2.

Figure 5 is a bar graph showing the effect of controls using saline, ovalbumin control, olopatadine hydrochloride (equivalent to 120 μg olopatadine base), mometasone furoate (10 μg) and the combination of mometasone furoate (10 μg) and olopatadine hydrochloride (equivalent to 120 μg olopatadine base) on the total number of cells in the nas flushing of guinea pigs as described in Example 2.

Figure 6 is a bar graph showing the effect of saline control, ovalbumin control, olopatadine hydrochloride (equivalent to 120 μg olopatadine base), mometasone furoate (10 μg), and the combination of mometasone furoate (10 μg) and olopatadine hydrochloride (equivalent to 120 μg olopatadine base) on the response to sneeze anemia, in guinea pigs, as described in Example 2.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The following are definitions of terms used in this application. In the event of inconsistency between the definition given in this application and the definition given earlier in the provisional application according to which priority in this application is claimed, the definition given in this application shall prevail.

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, provides the intended therapeutic benefit in the subject. The term "active ingredient" (used interchangeably with the term "active" or "active substance" or "drug") as used herein includes mometasone or a salt thereof and olopatadine or a salt thereof.

The term "salt" or "pharmaceutically acceptable salt" means those salts which, after careful medical examination, are suitable for use in contact with tissues of humans and lower animals and do not cause excessive toxicity, irritation and allergic reactions, in accordance with a favorable benefit/risk ratio, and are effective for their intended use. Examples of acid addition salts include, but are not limited to, the following salts: hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, furoate, succinate, tartrate, ascorbate, glucoseep tonate, lactobionate and lauryl sulfate. Examples of 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.

When used in this application, 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 references to olopatadine or its salt or olopatadine or its salts, are based on the equivalent weight of olopatadine free base, unless otherwise specifically noted.

The term "treat" or "treatment" as used herein also includes the prevention, amelioration, prevention, alleviation or suppression of a disorder.

The term "synergistic" or "synergistic effect" as used in this application refers to a combination that provides an effect that exceeds the effect expected from the sum of the effects of the individual components of the specified combination. The term "synergistic" or "synergistic effect" in relation to the combination of mometasone or its salt with olopatadine or its salt, which is used for the treatment of allergic rhinitis (for example, in the form of a pharmaceutical composition, combination product or kit in accordance with the invention), refers to the effectiveness of the treatment of allergic rhinitis in excess of the effectiveness expected from the sum of the effects of its individual components. Benefits of the synergistic combinations of the present invention include, but are not limited to, increased efficacy over each of the ingredients when used alone, reduced dose requirement of one or more active ingredients of the combination, reduced side effects of one or more active compounds in the combination, and/or improved tolerability of one or more active ingredients in a subject in need of treatment for allergic rhinitis.

The term "pharmaceutically acceptable excipients" means any of the components of a pharmaceutical composition, other than active agents, and which is approved by regulatory authorities or is considered generally safe for use in humans or animals.

The term "subject" includes mammals such as humans and other animals such as pets (eg, pets, including cats and dogs) and non-pets (eg, wild animals). Preferably the subject is a human. The human patient may be of any age. In one embodiment, the human subject is at least 2 years old, at least 12 years old, or at least 18 years old. According to another embodiment of the invention, the age of the subject, representing a person, is from 18 to 65 years.

The term "allergic rhinitis" as used herein refers to 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-induced rhinitis, vasomotor rhinitis, infectious rhinitis, autonomic rhinitis, hormonal rhinitis, drug-induced 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 the present 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, ocular pruritis, excessive tearing, 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 fixed dose salt thereof for the treatment of allergic rhinitis in a subject in need of said treatment. The inventors have unexpectedly found that mometasone furoate and olopatadine hydrochloride have a synergistic effect in the treatment of allergic rhinitis, and their combination is more effective and provides a better therapeutic value compared to treatment with any one active ingredient.

In an embodiment, the present invention relates to a method of treating allergic rhinitis in a subject (e.g., human) in need of said treatment, comprising nasally administering to said 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 or 2 sprays into each nostril of said subject at least once a day. Each injection may contain mometasone or a salt thereof and olopatadine or a salt thereof in a weight ratio of from about 1:5 to about 1:60, from about 1:10 to about 1:55, or from about 1:12 to about 1:53, or from about 1:13.3 to about 1:50. Preferably, the weight ratio of mometasone or a salt thereof to olopatadine or a salt thereof ranges from about 1:18 to about 1:40, or from 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 of the invention relates to a method of treating allergic rhinitis in a subject (e.g. human) in need of said treatment, comprising nasally administering to said 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 or 2 sprays into each nostril of said subject at least once a day. Each injection of a pharmaceutical composition may contain an olopatadin hydrochloride, equivalent to approximately 300 mcg, approximately 450 mcg, approximately 600 mcg, approximately 750 mcg or approximately 900 μg olopatadin, and about 12.5 mcg, approximately 25 μg, about 37.5 μg, approximately 50 μg, about 62.5 mcg of Momethason Furoat. In one embodiment, each injection contains olopatadine hydrochloride equivalent to about 600 μg of olopatadine and about 25 μg of mometasone furoate. According to another embodiment of the invention, each injection contains olopatadine hydrochloride equivalent to about 600 μg of olopatadine and about 50 μg of mometasone furoate. Preferably, each injection contains about 665 µg of olopatadine hydrochloride (equivalent to about 600 µg of olopatadine) and about 25 µg or about 50 µg of mometasone furoate.

Another embodiment relates to a method of treating allergic rhinitis in a subject in need of said treatment, 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 from about 1:5 to about 1:60, or from about 1:12 to about 1:53, or from about 1:13.3 to about 1:50, or from about 1:18 to about 1:40, when this composition is administered nasally in the form of 1 or 2 injections in each nostril once or twice a day. Each injection may contain olopatadine hydrochloride equivalent to about 600 micrograms of olopatadine and about 25 micrograms to about 50 micrograms of mometasone furoate. According to one aspect of the embodiment, the composition is administered over a period of about 1 week. According to another aspect of the embodiment, the composition is administered over a period of about 2 weeks.

Another embodiment of the invention relates to a method of treating allergic rhinitis in a subject (for example, a human) in need of said treatment, comprising nasal administration to said subject of a fixed dose pharmaceutical composition containing mometasone or a salt thereof and olopatadine or a salt thereof, said composition being administered nasally in the form of 1 or 2 injections in each nostril once or twice a day for at least 1 or 2 weeks. Each injection may contain olopatadine hydrochloride equivalent to about 600 micrograms of olopatadine and about 25 micrograms to about 50 micrograms of mometasone furoate. In one embodiment, the total nasal symptom severity score (TNSS) in said subject after 1 or 2 weeks of treatment is reduced by at least 40%, or preferably at least 50%, from baseline. In another aspect of the embodiment, the subject's Total Ocular Symptom Severity Score (TOSS) after 1 or 2 weeks of treatment is reduced by at least 30%, or preferably at least 40%, from baseline.

In the context of the present invention, the Nasal Syndrome Severity Scale (TNSS) score includes the sum of nasal congestion, rhinorrhea, itching, and sneezing at the end of treatment (eg, 1 or 2 weeks) compared to baseline. Additional ocular symptom severity scale (TOSS) scores include itchy eyes, increased lacrimation/watery eyes, and redness of the eyes at the end of treatment compared to baseline.

Another embodiment is a method of treating allergic rhinitis in a subject, wherein said subject has a positive allergen skin prick test. An injection skin test can be performed by piercing the skin with a needle or pin containing a small amount of hay fever. In one embodiment, prior to administration of the combination of olopatadine and mometasone described herein, said subject is subjected to a skin prick test that results in a papule at least 3 mm larger in diameter compared to a negative control such as saline.

The methods of treatment described in this application can be used in subjects, while subjects who, for example, after 1 or 2 weeks of treatment, there are no significant side effects associated with the treatment.

Treatment-related side effects in the context of the present invention may include, but are not limited to, ocular disorders (eg, conjunctivitis), gastrointestinal disorders (eg, bloating, diarrhea, dyspepsia, dysphagia and gastric ulcers, hemorrhoids, hyperchlorhydria, nausea and vomiting, and toothache), general disorders (eg, fatigue, local swelling, peripheral edema, pain, and fever ), infections and infestations (eg, oral herpes and upper respiratory infections), injury, poisoning, and complications from study procedures, skeletal muscle and connective tissue disorders (eg, arthralgia), nervous system disorders (eg, impaired attention, dizziness, dysgeusia, and headache), reproductive and breast disorders (eg, dysmenorrhea), respiratory, thoracic, and mediastinal disorders (eg, dry throat, breathing difficulties, epistaxis, nasal congestion, nasal discomfort, respiratory bleeding, rhinorrhea, throat irritation and upper respiratory tract cough syndrome), skin and subcutaneous tissue disorders (eg, rash and urticaria).

Another embodiment relates to a method of treating seasonal allergic rhinitis and/or nasal symptoms associated with seasonal allergic rhinitis in a subject (e.g., human) in need of said treatment, comprising nasal administration to said subject of a synergistic combination containing mometasone furoate and olopatadine hydrochloride, the combination being presented as 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 olopatadine free base).

The synergistic effects of the combination of mometasone furoate and olopatadine hydrochloride can be assessed in various ways. One way to evaluate the effectiveness of an agent for the treatment of allergic rhinitis is the ovalbumin-induced rhinitis model in guinea pigs. In such models, the effect of treatment is examined in animals sensitized and stimulated with ovalbumin, followed by a detailed analysis of their sneezing response using whole body plethysmography and counting the total number of eosinophils in a nasal wash sample.

A fixed dose pharmaceutical composition comprising mometasone or a salt thereof and olopatadine or a salt thereof may be administered to the subject according to one of the following schedules:

a) the composition is administered nasally as 1 spray in each nostril once a day for a period of at least 1 week;

b) the composition is administered nasally as 2 sprays in each nostril once a day for a period of at least 1 week;

c) the composition is administered nasally as 1 spray in each nostril twice a day for a period of at least 1 week;

d) the composition is administered nasally as 2 sprays in each nostril twice a day for a period of at least 1 week;

e) the composition is administered nasally as 1 spray in each nostril once a day for a period of 2 weeks;

f) the composition is administered nasally as 2 sprays in each nostril once a day over a period of 2 weeks;

g) the composition is administered nasally as 1 spray in each nostril twice a day for a period of 2 weeks; or

h) the composition is administered nasally as 2 sprays in each nostril twice a day over a period of 2 weeks.

According to an aspect of the invention, the composition is administered as 1 or 2 sprays into each nostril of said subject at least once a day over a period of 1 week or 2 weeks. According to another aspect of an embodiment of the invention, each injection of the composition contains olopatadine hydrochloride equivalent to about 600 micrograms of olopatadine and about 25 micrograms to about 50 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 or about 50 micrograms of mometasone furoate.

In yet another aspect of the embodiment, the total nasal symptom severity score (TNSS) in said subject after 1 or 2 weeks of treatment is reduced by at least 40% or at least 50% from baseline. According to another aspect of an embodiment of the invention, the total severity score of ocular symptoms (TOSS) in the specified subject after 1 or 2 weeks of treatment is reduced by at least 30% or at least 40% compared to baseline. According to another aspect of an embodiment of the invention, said subject does not experience significant treatment-related side effects after 1 or 2 weeks of treatment. According to another aspect of an embodiment of the invention, said subject is a patient who has a positive skin prick test for an allergen.

Another embodiment of the invention relates to the use of mometasone or its salt 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 the manufacture of a fixed dose pharmaceutical composition for the treatment of allergic rhinitis in a subject in need of said treatment, said composition being administered nasally in the form of 1 or 2 injections into each nostril of said subject once or twice a day. In one embodiment, the fixed dose pharmaceutical composition is a suspension, wherein mometasone or a salt thereof is present in particulate form and olopatadine or a salt thereof is present in dissolved form.

According to another aspect of the embodiment, the composition is administered over a period of about 1 or 2 weeks. According to yet another aspect of an embodiment of the invention, the total nasal symptom severity score (TNSS) in the specified subject after 1 or 2 weeks of treatment is reduced by at least 40% or at least 50% compared to baseline. According to another aspect of an embodiment of the invention, the total ocular symptom severity score (TOSS) in said subject after 1 or 2 weeks of treatment is reduced by at least 30% or at least 40% compared to baseline. According to another aspect of an embodiment of the invention, said subject does not experience significant treatment-related side effects after 1 or 2 weeks of treatment. According to another aspect of an embodiment of the invention, said subject has a positive skin prick test for an allergen.

Another embodiment relates to 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, or from about 1:12 to about 1:53, for use in the treatment of allergic rhinitis in a subject in need of said treatment, said composition being administered nasally as 1 or 2 sprays into each nostril of said subject at least once a day. In yet another aspect, the fixed dose pharmaceutical composition is a suspension wherein mometasone or a salt thereof is present in particulate form (e.g., having an average particle size of about 1 to about 20 microns, or about 1 to about 15 microns) and olopatadine or a salt thereof is present in dissolved form. According to another aspect of an embodiment of the invention, the composition is administered over a period of about 1 or 2 weeks. According to another embodiment of the invention, the total rhinitis symptom severity score (TNSS) in the specified subject after 1 or 2 weeks of treatment is reduced by at least 40% or at least 50% compared to baseline. According to another aspect of an embodiment of the invention, the total ocular symptom severity score (TOSS) in said subject after 1 or 2 weeks of treatment is reduced by at least 30% or at least 40% compared to baseline. According to another embodiment of the invention, the specified subject after 1 or 2 weeks of treatment does not experience significant side effects associated with the treatment. According to another aspect of an embodiment of the invention, the subject is a patient who has a positive skin prick test for an allergen.

The composition can be administered over a period of about 1 week, 2 weeks, 4 weeks, 6 weeks, or 8 weeks.

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 presented as a nasal spray in a container with one or more pharmaceutically acceptable excipients (e.g. chelating agents, preservatives, buffer, surfactants, isotonic agent, taste correcting agents, suspending agents, humectants, antioxidants and diluents) and a kit providing recommendations for the use and administration of said composition. The pharmaceutical composition may, for example, be presented in any of the dosage forms described in International Patent Application No. PCT/IB2014/064251 filed September 4, 2014 or Patent Application No. 14/483837 filed September 11, 2014, both of which are incorporated herein by reference.

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

The following examples are provided to enable those skilled in the art to practice the invention and are provided by way of illustration only and do not limit the scope of the present invention.

EXAMPLES

EXAMPLE 1

Effect of mometasone and olopatadine and their combination in a male guinea pig model of ovalbumin-induced rhinitis.

Male Dunkin Hartley guinea pigs were vigorously sensitized by subcutaneous injection of 1.5 mg ovalbumin and 20 mg aluminum hydroxide gel on days 0 and 7. Guinea pigs were intranasally sensitized with 2% ovalbumin from days 14 to 17. On day 28, the animals underwent intranasal stimulation with 6% ovalbumin.

Division of animals into groups

Actively sensitized animals during the experiment were randomly assigned to one of the following 5 groups ( see Table 1).

A: Saline control (vehicle treatment / saline stimulation),

B: Ovalbumin control (vehicle treatment/ovalbumin stimulation),

C: 50 mcg of olopatadine hydrochloride (based on the equivalent weight of olopatadine free base) (treatment with 50 mcg of olopatadine hydrochloride/stimulation with ovalbumin),

D: 10 mcg mometasone furoate (treatment with 10 mcg mometasone furoate/ovalbumin stimulation) and

E: Combination (treatment with 10 µg mometasone furoate + 50 µg olopatadine hydrochloride (based on the equivalent weight of free base of olopatadine) / stimulation with ovalbumin).

Compound introduction

10 μg of mometasone furoate was administered intranasally 24 hours and 1 hour before the final ovalbumin stimulation. Olopatadine hydrochloride was administered intranasally 1 hour before the final ovalbumin challenge. The dosing volume was 40 μl per animal. The saline control group and the ovalbumin control group received vehicle (40 µl, 0.1% Tween 80 in distilled water).

Table 1

animal groups

Group Group name Treatment Ovalbumin stimulation Number of animals per group A Saline control Carrier - 6 B Ovalbumin control Carrier + 7 C 50 mcg olopatadine 50 mcg olopatadine hydrochloride + 7 D 10 mcg mometasone 10 mcg mometasone furoate + 6 E Combination 50 mcg olopatadine hydrochloride + 10 mcg mometasone furoate + 7

Grade in vivo

Measuring the sneezing response

The sneezing response was determined using whole body plethysmography (Buxco Research Systems, USA) for 50 minutes after the final stimulation with saline or ovalbumin.

nasal flush

A nasal wash was obtained 4 hours after stimulation of the animals with saline or ovalbumin on day 28. Animals were anesthetized with an overdose of urethane, the trachea was exposed, and nasal lavage was performed using 2 ml of pre-warmed normal saline. Nasal swabs were collected for total cell count using a hemocytometer. The nasal wash was centrifuged and the cell pellet was resuspended in 15 µl of guinea pig serum and used to obtain swabs. Slides were stained with Leishman's stain and a manually differentiated count of 100 cells was performed based on their standard morphology.

Calculations

The total number of eosinophils in each nasal wash sample was calculated using the formula:

Percent eosinophil suppression was calculated using the following formula:

Data analysis

Statistical processing of data was performed using one-way ANOVA followed by Dunnett's multiple comparison test.

results

Monotherapy with mometasone furoate resulted in a significant suppression of the total number of cells and eosinophils in the nasal wash, but was not effective in suppressing the sneezing response. Monotherapy with olopatadine hydrochloride did not result in significant suppression of any of the parameters in the present model. The use of the combination of mometasone furoate and olopatadine hydrochloride resulted in a synergistic effect in terms of suppression of the sneezing response (Figure 1), cellular infiltration in the nasal wash (Figure 2) and nasal eosinophilia (Figure 3) compared with the corresponding groups receiving monotherapy treatment (see Table 2).

table 2

Summary effects of the combination of mometasone furoate and olopatadine hydrochloride in a guinea pig model of ovalbumin-induced rhinitis.

Treatment Physiological control
logical solution Ovalbumin control Olopatadine hydrochloride
(OG) mometasone furoate
(MF) Combination
(OG and MF) Dose
(mcg per animal) - - 50 10 50 (OG) and 10 (MF) Number of episodes of sneezing
(0-50 min) 0.5** 22 12.29 18.83 6* Sneeze suppression in percent - - 45 15 74 Total cells x 10 ⁵ /ml nasal wash 0.48*** 6.79 6.63 3.90* 2.46*** Suppression of the total number of cells in percent - - 3 46 69 Eosinophils x 10 ⁵ /ml nasal wash 0.03*** 3.71 3.64 2.00* 1.26** suppression of eosinophils, % - - 2 46 67

* P<0.05 compared to ovalbumin control, ** P<0.01 compared to ovalbumin control,

*** P<0.001 compared to ovalbumin control

The use of a combination of mometasone furoate and olopatadine hydrochloride resulted in an increased beneficial effect compared to separate monotherapy regimens. The combination of mometasone furoate and olopatadine hydrochloride had a synergistic effect in the treatment of allergic rhinitis in the present model.

EXAMPLE 2

Effect of mometasone and olopatadine and their combination in a male guinea pig model of ovalbumin-induced rhinitis.

The method described in Example 1 was repeated except that 120 μg of olopatadine hydrochloride (based on the equivalent weight of olopatadine free base) was used. The groups of animals listed in Table 3 below were used during the experiment.

Table 3

animal groups

Group Group name Treatment Ovalbumin stimulation Number of animals per group A Saline control Carrier - 9 B Ovalbumin control Carrier + 10 C 120 mcg olopatadine 120 mcg olopatadine hydrochloride + 10 D 10 mcg mometasone 10 mcg mometasone furoate + 9 E Combination 120 mcg olopatadine hydrochloride + 10 mcg mometasone furoate + 10

The compound was administered in the same manner as in Example 1, except that the dose was administered in a volume of 60 μl/animal. The saline control group and the ovalbumin control group received vehicle (60 µl, 0.1% Tween 80 in distilled water). In vivo evaluations were carried out in the same way as in Example 1.

results

Monotherapy with mometasone resulted in a significant suppression of the total number of cells and eosinophils in the nasal wash, but was not effective in suppressing the sneezing response. Monotherapeutic treatment with olopatadine did not cause significant suppression of any parameter in the present model. The combination of mometasone and olopatadine was synergistic in the suppression of nasal eosinophilia, cellular infiltration in the nasal wash and the sneezing response compared to the respective monotherapy regimens (see Figures 4-6 and Table 4).

Table 4

The summed effects of the combination of mometasone and olopatadine in a model of ovalbumin-induced rhinitis in guinea pigs

Treatment Saline control Ovalbumin control Olopatadine hydrochloride (OH) mometasone furoate
(MF) Combination
(OG and MF) Dose
(mcg per animal) - - 120 10 120 (OG) and
10 (MF) Number of episodes of sneezing
(0-50 min) 0.89*** 35.70 17.90 37.33 13.30* suppression
percentage of sneezes - - 51 -5 64 Total cells x 10 ⁵ /ml nasal wash 0.58*** 6.88 5.83 4.96 3.66*** Suppression of the total number of cells in percent - - 17 thirty 51 Eosinophils x 10 ⁵ /ml nasal wash 0.03*** 3.36 3.08 2.69 1.66** Eosinophil suppression, % - - 8 20 51

* P<0.05 compared to ovalbumin control, ** P<0.01 compared to ovalbumin control,

*** P<0.001 compared to ovalbumin control

The use of a combination of mometasone furoate and olopatadine hydrochloride resulted in an increased beneficial effect compared to separate monotherapy regimens. The use of a combination of mometasone and olopatadine resulted in a synergistic effect in the present guinea pig model of rhinitis.

EXAMPLE 3

Clinical study of a nasal spray containing a fixed dose combination of mometasone and olopatadine in human patients

The study was a single-center, double-blind, randomized, parallel-group, double-dummy, parallel-group study in an Environmental Exposure Chamber (EEC) to evaluate the efficacy, safety, and tolerability of (i) two nasal sprays containing fixed-dose combination products containing mometasone furoate and holopatadine hydrochloride, (ii) a nasal spray containing a fixed-dose combination of azelastine hydrochloride and fluticasone propion and (DYMISTA ^® ), (iii) nasal spray containing olopatadine (PATANASE ^® ), and (iv) nasal spray containing placebo in patients suffering from seasonal allergic rhinitis (SAR).

Main goals

• To evaluate the efficacy of two concentrations of a fixed dose combination (FDC) nasal spray containing mometasone furoate and olopatadine hydrochloride compared to a nasal spray containing placebo.

• To assess the comparative efficacy of (i) two regimens containing products containing FFD nasal spray containing mometasone furoate and olopatadine hydrochloride, (ii) a nasal spray containing a fixed-dose combination of azelastine hydrochloride and fluticasone propionate (DYMISTA ^® ), and (iii) a nasal spray containing olopatadine (PATANASE ^® ).

• Compare the efficacy of (i) a fixed dose combination nasal spray containing azelastine hydrochloride and fluticasone propionate and (ii) a nasal spray containing olopatadine versus a nasal spray containing placebo.

• Compare the onset of action of a drug, defined as "the first time point after the start of treatment at which the drug causes a significant decrease in the current TNSS score compared with placebo treatment, observed over a long period of time from the indicated time point", in active substance treatment groups after the first dose.

• Compare the EEC Quality of Life Questionnaire (QoLQ) value and tolerability and acceptability for the fixed-dose combination of mometasone furoate and olopatadine hydrochloride given once daily versus the fixed-dose combination of mometasone furoate and olopatadine hydrochloride given twice daily.

• Assess the relative safety of different treatment groups.

Sample size

For the study as a whole, 36 patients were randomized per treatment group. The total number of randomized subjects in the five groups was 180.

Patient population

The study included subjects suffering from seasonal allergic rhinitis requiring treatment with intranasal antihistamines and/or intranasal steroids within the past two years.

Main criteria for selecting subjects

1. Patients of either sex ≥ 18 and ≤ 65 years of age, inclusive;

2. A patient with a known history of seasonal allergic rhinitis (for at least 2 years) who has a positive skin prick test (papule diameter at least 3 mm larger than saline control) for one of the locally distributed allergens;

3. Patients who are able to understand and sign the written informed consent that must be obtained prior to the commencement of the screening study; And

4. Patients willing to comply with protocol requirements.

Study scheme

Patients were randomly allocated for treatment into the following five treatment groups in a 1:1:1:1:1 ratio at one study site:

1. Fixed dose combination of 665 mcg of olopatadine hydrochloride and 25 mcg of mometasone furoate, twice a day (BID)

2. Fixed-dose combination of 665 mcg olopatadine hydrochloride and 50 mcg mometasone furoate once daily (QD)

3. ^DYMISTA® nasal spray (137 mcg azelastine hydrochloride + 50 mcg fluticasone propionate), twice a day (BID)

4. PATANASE ^® nasal spray (665 mcg of olopatadine hydrochloride), twice a day (BID)

5. Nasal spray containing placebo

For the present study, a dual sham regimen was used, including four masked nasal spray bottles (two evening dosing and two morning dosing) (see Table A).

Table A

Therapeutic administration using four masked nasal spray bottles

Treatment group In the morning In the evening first vial second vial first vial second vial 1 IP-1: Fixed-dose combination of 25 mcg mometasone furoate + 665 mcg olopatadine hydrochloride, twice daily (BID) Active substance Active substance Active substance Active substance 2 IP-2: Fixed dose combination of 50 mcg mometasone furoate + 665 mcg olopatadine hydrochloride, once daily (QD) Active substance Active substance placebo placebo 3 DYMISTA ^® twice a day (BID) placebo Active substance placebo Active substance 4 PATANASE ^® twice a day (BID) Active substance Active substance Active substance Active substance 5 placebo placebo placebo placebo placebo

The present study included five study site visits and a 12 day dosing period at home (and 2 days of dosing at the study site for a total of 14 dosing days). Efficacy endpoints were recorded outside the allergy season at the EEC facility. After the baseline screening visit (Visit 1), patients who met all study criteria (including the primary criteria for inclusion in the study: a positive skin prick test (SPT) and a 2-year history of allergic rhinitis (AR) for ragweed allergen) underwent a further screening/introductory step in the EEC (Visit 2). During a session at the EEC, patients were exposed to ragweed pollen at a concentration of 3500±500 particles/m ³ for 6 hours. Patients used an electronic diary (ePDAT™) to record ocular and nasal symptoms every 30 minutes in the EEC. Patients who met the minimum required TNSS score of 6/12, including a nasal congestion score of at least 2, on two consecutive diary entries continued to participate in the study. At visit 3 the next day (day 1), patients who met the minimum criteria returned to the EEC for a subsequent second session at the EEC. Patients were exposed to the allergen for approximately 10 hours during said visit. During the first 6 hours, patients used an electronic diary to record symptom scores every 30 minutes and were required to meet the minimum required symptom score to continue participation in the study. Patients who met the minimum required symptom score were randomized to receive one of the five study drugs after 6 hours in the EEC. Following dosing (at about noon), patients were asked to record symptom scores at 5 minutes, 10 minutes, 15 minutes, 25 minutes, 30 minutes, 45 minutes, 60 minutes, and then every 30 minutes for the remainder of the visit. Post-treatment EEC symptom scores were used to determine the onset of action of study regimens. Patients were then sent home with study drug to continue dosing BID at home, starting with the evening dose on day 1. Patients continued dosing at home for a period of 12 days. After 12 days (days 2-13) of home dosing, patients returned to the EEC on day 14 (visit 4) for a 6-hour post-treatment EEC induction session. Patients were administered the morning dose of study drug one hour prior to entry into the EEC. Symptoms were assessed every 30 minutes in the EEC. Patients took their last dose of study drug at midnight on the same day and returned the next morning (Day 15, Visit 5) for a 6-hour EEC session. Over a 6-hour period, patients used an electronic diary to record symptom scores every 30 minutes. In addition to recording nasal and ocular symptoms, an electronic diary was used to complete the EEC Quality of Life Questionnaires (EEC-QoLQ) at visits 2, 3, 4, and 5 and acceptability and tolerability at visit 5. Visit 5 was the final study visit.

Introductory stage

Satisfaction of the following criteria in each of two consecutive patient diary entries at the opening visit: a minimum TNSS score of 6 out of 12, including a nasal congestion score of at least 2.

Randomization

• To progress to the treatment visit (visit 3), patients had to meet the same criteria at both introductory visits with a 3-hour chamber study.

• For the treatment visit (Visit 3), the minimum TNSS score was 6 out of 12 (including a nasal congestion score of at least 2).

Forms of the drug

The study used the following dosage forms of the study product:

Study product 1 (IP-1)

Nasal spray containing mometasone furoate monohydrate and olopatadine hydrochloride (25 mcg + 600 mcg)

Each injection resulted in delivery of mometasone furoate monohydrate equivalent to 25 µg of mometasone furoate and olopatadine hydrochloride equivalent to 600 µg of olopatadine.

Research product 2 (IP-2)

Nasal spray containing mometasone furoate monohydrate and olopatadine hydrochloride (50 mcg + 600 mcg)

Each injection resulted in delivery of mometasone furoate monohydrate equivalent to 50 µg of mometasone furoate and olopatadine hydrochloride equivalent to 600 µg of olopatadine.

Dosing schedule

1. Researched Products

• IP-1: Fixed dose combination of olopatadine hydrochloride (665 µg) and mometasone furoate (25 µg) nasal spray: 2 sprays in each nostril twice a day (BID) for two weeks.

• IP-2: Nasal spray containing a fixed dose combination of olopatadine hydrochloride (665 µg) and mometasone furoate (50 µg): 2 sprays in each nostril once a day (QD) for two weeks

2. Comparator drugs

• Nasal spray containing olopatadine hydrochloride ( ^PATANASE® 0.6%): 2 sprays in each nostril twice a day for two weeks.

• ^DYMISTA® nasal spray (azelastine hydrochloride + fluticasone propionate) 137 µg / 50 µg: 1 spray in each nostril twice a day for two weeks.

• Placebo nasal spray (based on study product vehicle): 2 sprays in each nostril twice daily for two weeks.

Key Evaluation Criteria (Clinical Endpoints)

• Change in mean post-treatment summary rhinitis symptom severity score (TNSS) from baseline for the fixed-dose combination of mometasone furoate and olopatadine hydrochloride compared with placebo. Mean TNSS was calculated for 6 hours in the EEC after treatment at visit 5 (from 18 to 24 hours after the first dose on day 14), baseline was taken as the TNSS value in the EEC at visit 3 (within 6 hours before the first dose).

• Change in mean post-treatment TNSS from baseline for two fixed-dose mometasone furoate and olopatadine hydrochloride combination regimens compared to reference products: DYMISTA ^® nasal spray and PATANASE ^® nasal spray. The mean TNSS value was calculated for 6 hours in the EEC after treatment at visit 5 (from 18 to 24 hours after the first dose on day 14), the baseline was taken as the TNSS value in the EEC at visit 3 (within 6 hours before the first dose).

• Change in mean post-treatment TNSS score for the two fixed-dose mometasone furoate and olopatadine hydrochloride combination regimens, DYMISTA ^® nasal spray, and PATANASE ^® nasal spray, from baseline. Mean post-treatment TNSS was calculated for 6 hours in EEC post-treatment at visit 4 (from 1 to 7 hours after the first dose on day 14), baseline was taken as EEC TNSS at visit 2 (over 6 hours).

• Post-treatment mean TNSS change from baseline for two fixed-dose mometasone furoate and olopatadine hydrochloride combination regimens compared to reference products: DYMISTA ^® nasal spray and PATANASE ^® nasal spray. The mean TNSS value was calculated for 12 hours in the EEC after treatment (at visit 4 from 1 to 7 hours after the first dose on day 14 and at visit 5 from 18 to 24 hours after the first dose on day 14), the baseline was taken as the TNSS value in the EEC at visit 2 and 3 (within 12 hours before the first dose).

• The onset of action for each fixed dose combination of mometasone furoate and olopatadine hydrochloride, ^DYMISTA® and ^PATANASE® was assessed by comparing the post-treatment change in TNSS score from baseline between each active agent regimen and placebo at each time point after the first treatment session. The change from baseline in the TNSS score was calculated at each time point after the first treatment dose according to the study in the EEC at visit 3 (i.e., the last four hours in the EEC at visit 3), where the baseline (visit 3) was determined as the average of the last two time points before the dose.

• Change in mean total symptom score (TSS), single nasal symptom scores (NSS, four nasal symptoms including rhinorrhea, pruritis, sneezing, and nasal congestion) and TOSS after treatment from baseline for 6 hours in the EEC at visit 5, with baseline taken as visit 3 (within 6 hours prior to first dose).

• Change in Post-Treatment Mean Total Symptom Score (TSS), Single Nasal Symptom Scores (NSS, four nasal symptoms including rhinorrhea, pruritis, sneezing, and nasal congestion), and TOSS from baseline for 6 hours in the EEC at visit 4, with baseline taken as visit 2 (within 6 hours in the EEC).

• Change in mean total symptom score (TSS), individual nasal symptom scores (NSS, four nasal symptoms including rhinorrhea, pruritis, sneezing, and nasal congestion) and TOSS after treatment from baseline for 12 hours in the EEC at Visit 4 and Visit 5, with baseline taken as the 12 hour pre-dose EEC period at Visit 2 and Visit 3.

• EEC-QoLQ for all treatment groups by comparing 1) pre-EEC-QoLQ at baseline (visit 2 and pre-EEC at visit 4; 2) post-EEC at baseline (visit 2) and post-EEC at visit 4; 3) 6 hours later at EEC at visit 3 (before first dosing) and post-EEC at visit 5.

• Retrospective assessment of tolerability and acceptability for treatment groups versus placebo after EEC at visit 5.

results

Table B shows the post-treatment cumulative change in TNSS score from baseline for 6 hours in the EEC (ITT population).

Table B

Options placebo IP-1 IP-2 DYMISTA®
(Reference product) PATANASE®
(Reference product) N 36 36 36 36 36 Baseline EEC Average 7.64 8.07 8.20 8.67 8.27 EEC at the end of treatment
(2 weeks) Average 6.61 3.31 3.94 4.80 6.38 Change from baseline, % - 13.35 58.98 51.95 45.67 22.85

Table C shows the cumulative results of the measurement of the TNSS value after treatment for 12 hours in the EEC (ITT population) relative to baseline. (Data for NASONEX in Table C are from its FDA-approved label.)

Table C

Options IP-1 IP-2 ^PATANASE®
(Reference product) ^NASONEX® * ^DYMISTA®
(Reference product) N 36 36 36 176 36 Baseline EEC Average 7.58 7.85 7.90 9.60 8.25 EEC value at the end of treatment (2 weeks) Average 2.85 3.36 5.72 - 4.34 Change relative to the initial level, % - 62.4 57.07 27.5 27.92 48.24

* NASONEX ^® (nasal spray containing mometasone furoate), FDA approved label (January 19, 2011)

Table D shows the cumulative results of measuring TOSS after treatment for 12 hours in the EEC (ITT population) relative to baseline.

Table D

Options IP-1 IP-2 ^PATANASE®
(Reference product) ^DYMISTA®
(Reference product) N 36 36 36 36 Baseline EEC Average 3.97 4.17 3.92 4.54 EEC value at the end of treatment (2 weeks) Average 1.97 2.34 2.82 2.82 Change relative to the initial level, % - 50.37 43.6 28.3 37.88

The results of the study show that the combination of mometasone furoate and olopatadine hydrochloride, when administered nasally to a human patient, provides effective treatment of seasonal allergic rhinitis and a clinically significant reduction in both associated nasal and non-nasal symptoms. The TNSS symptom relief score was clinically significant (i.e., the difference between study products and placebo was more than 2 units, which is generally considered to be a clinically significant difference). Study Product 1 provided overall improved symptom relief with a faster onset of action compared to reference products ( ^PATANASE® and ^DYMISTA® ).

EXAMPLE 4

Phase II clinical trial of a nasal spray containing a fixed dose combination of mometasone and olopatadine,
in human patients.

The study was a double-blind, randomized, parallel-group comparison study to evaluate the efficacy, safety, and tolerability of two different concentrations and regimens of nasal spray containing a fixed-dose combination of mometasone furoate and olopatadine hydrochloride versus a nasal spray containing placebo and separate monotherapy dosage forms of nasal spray containing olopatadine hydrochloride and nasal spray containing mometasone furo. at, in subjects (12 years and older) suffering from seasonal allergic rhinitis (SAR).

Main goals

• To compare the efficacy of once daily mometasone furoate and olopatadine hydrochloride nasal spray versus twice daily mometasone furoate and olopatadine hydrochloride nasal spray with placebo nasal spray and single agent monotherapy at the same dosage and same vehicle for 14 days of treatment in the study .

• To compare the onset of action of mometasone furoate and olopatadine hydrochloride nasal spray once daily versus twice daily mometasone furoate and olopatadine hydrochloride nasal spray with placebo and single agent monotherapy at the same dosage and in the same vehicle after the first dose of study drug.

• Assess safety and tolerability in individual treatment groups.

Table E

Investigated products and their introduction

Name Research product(s) Introduction IP-1 Nasal spray containing olopatadine hydrochloride + mometasone furoate
(665 mcg + 25 mcg) Twice daily (BID) morning and evening IP-2 Nasal spray containing olopatadine hydrochloride + mometasone furoate
(665 mcg + 50 mcg) Once a day (QD) in the morning GO-1 Nasal spray containing olopatadine hydrochloride (665 mcg) Once a day (QD) in the morning GO-2 Nasal spray containing olopatadine hydrochloride (665 mcg) Twice daily (BID) morning and evening GM-1 Nasal spray containing mometasone furoate (50 mcg) Once a day (QD) in the morning GM-2 Nasal spray containing mometasone furoate (25 mcg) Twice daily (BID) morning and evening

Sample size:

Overall, approximately 1106 randomized subjects (158 subjects per treatment group) were included in the study.

The main criteria for selecting a subject:

1. Age ≥ 12, inclusive, any gender.

2. A documented history of SAD (within at least 2 years prior to the screening visit) with exacerbations (clinical manifestations of active symptoms) who has a documented positive SPT (papule diameter at least 5 mm larger than a control papule) for Mexican juniper allergen.

3. The 12-hour TNSS retrospective score is ≥ 8 out of 12 possible scores, and the nasal congestion score is ≥ 2 for the morning administration at the screening visit (Visit 1).

Study scheme:

Subjects were randomized to treatment in the following seven treatment groups in a ratio of 1:1:1:1:1:1:1 at multiple study sites.

For the present study, a double sham regimen was used, including two identical nasal spray bottles (one morning [M] dose and one evening [B] dose) (Table F). A double sham design was used to ensure an acceptable blind study given that the compared regimens varied in dose frequency (BID vs. QD).

Table F

Therapeutic administration using two identical nasal spray bottles
(2 sprays per nostril for a total of 4 sprays from each vial per day)

Name Treatment group In the morning (U) In the evening
(IN) first vial second vial IP-1 665 mcg olopatadine hydrochloride +
25 mcg mometasone furoate twice a day (BID) Active substance Active substance IP-2 665 mcg olopatadine hydrochloride +
50 mcg mometasone furoate once daily (QD) Active substance placebo GO-1 Nasal spray containing olopatadine hydrochloride (665 mcg) once daily (QD) Active substance placebo GO-2 Nasal spray containing olopatadine hydrochloride (665 mcg) twice daily (BID) Active substance Active substance GM-1 Nasal spray containing mometasone furoate (50 mcg) once daily (QD) Active substance placebo GM-2 Nasal spray containing mometasone furoate (25 mcg) twice daily (BID) Active substance Active substance Pbo Nasal spray containing placebo placebo placebo

The present study included four visits to the study site. Following the baseline screening visit (Visit 1), subjects who met all study selection criteria underwent a single-blind placebo run-in period of 7-10 days. Following the completion of the lead-in period, eligible subjects who met the randomization criteria were enrolled in the study and randomly allocated to one of seven treatment groups. Subjects were prescribed treatment according to the randomization list. Randomized subjects were required to complete a 2-week (14-day) treatment period according to the protocol to evaluate the efficacy and safety of the prescribed treatment.

Main evaluation criteria (clinical endpoints):

Primary Endpoint

• Change from baseline in the 12 hour mean rTNSS recorded by the subject (TNSS retrospective assessment) for Y and B administration during the 14 day treatment period.

Secondary Endpoints

• Change in the 12 hour mean iTNSS value recorded by the subject (current TNSS score) for U and B administration over the 14 day treatment period from baseline.

• Change in the average 12 hour rTOSS value recorded by the subject (retrospective TOSS) for U and B administration over the 14 day treatment period from baseline.

• Onset of action for each treatment regimen was assessed by comparing the change in post-treatment iTNSS value from baseline between treatment with each active substance and placebo at specific time points (before the first dose (pre-dose), 15 min, 30 min, 45 min, 60 min, 90 min, 120 min, 150 min, 180 min, 210 min, and 240 min) after the first 4 hour study treatment session.

• Change from baseline in Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score at day 15 between treatment groups for subjects with impaired quality of life at baseline, as defined by an RQLQ value of 3.0 or greater at randomized visit (RV) (RQLQ population).

Tertiary Performance Criteria

Nasal symptoms:

• Change from baseline in the rTNSS value recorded by the subject for Y administration during the 14 day treatment period.

• Change from baseline in the iTNSS value recorded by the subject for Y administration during the 14 day treatment period.

• Change from baseline in the rTNSS value recorded by the subject for B administration during the 14 day treatment period.

• Change from baseline in the iTNSS value recorded by the subject for B administration during the 14 day treatment period.

• Change from baseline in the retrospective single nasal symptom score recorded by the subject during the 14-day treatment period (Y, B and mean of Y and B).

• Change from baseline in the subject's current single nasal symptom score during the 14-day treatment period (Y, B and mean of Y and B).

• Change from baseline in the mean rTNSS and iTNSS recorded by the subject for Y and B administration for each day.

• Change from baseline in the rTNSS and iTNSS value recorded by the subject for Y administration for each day.

• Change from baseline in the rTNSS and iTNSS value recorded by the subject for B administration for each day.

Eye symptoms:

• Change from baseline in the mean iTOSS value recorded by the subject (current TOSS value) for U and B administration, during the 14-day treatment period.

• Change from baseline in the rTOSS value recorded by the subject for Y administration during the 14 day treatment period.

• Change from baseline in the iTOSS value recorded by the subject for Y administration during the 14 day treatment period.

• Change from baseline in the rTOSS value recorded by the subject for B administration during the 14 day treatment period.

• Change from baseline in the iTOSS value recorded by the subject for B administration during the 14 day treatment period.

• Change from baseline in the retrospective individual ocular symptom score recorded by the subject during the 14-day treatment period (Y, B and mean of Y and B).

• Change from baseline in the subject's current individual ocular symptom score during the 14-day treatment period (Y, B, and mean of Y and B).

• Change from baseline in the mean rTOSS and iTOSS recorded by the subject for Y and B administration for each day.

• Change from baseline in the rTOSS and iTOSS value recorded by the subject for Y administration for each day.

• Change from baseline in the rTOSS and iTOSS value recorded by the subject for B administration for each day.

Non-nasal symptoms were scored in a similar manner to the above ocular symptom scores.

Physician-assessed Nasal Symptom Scale (PNSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ):

• Physician-rated Nasal Symptom Scale (PNSS) score and physician-rated individual nasal symptoms at Day 15 (Visit 4).

• Separate RQLQ fields at day 15 (visit 4) for the RQLQ population (defined as the population of subjects with impaired quality of life at baseline).

• RQLQ at day 15 (Visit 4) for the full analysis sample (FAS).

While the invention has been described herein with reference to specific embodiments, it should be understood that these embodiments are provided solely to illustrate the principles and methods of application of the present invention. Thus, it is to be understood that many modifications of these illustrative embodiments of the invention are possible.

All publications, patents and patent applications cited 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 incorporated into this application by reference.

Claims (16)

1. A method of treating allergic rhinitis and/or associated nasal symptoms in a person in need of said treatment, comprising nasal administration to said person of an effective amount of a pharmaceutical composition containing mometasone furoate and olopatadine or a salt thereof, wherein (i) the composition is administered nasally in the form of 1 or 2 injections into each nostril of said person at least once a day, (ii) each injection contains mometasone furoate and olopatadine or its salt in a weight ratio of 1:12 to 1:53, based on the equivalent weight of olopatadine free base, (iii) mometasone furoate is in particulate form and olopatadine or its salt is in dissolved form, and (iv) said administration provides relief from one or more symptoms associated with allergic rhinitis faster than nasal administration of two sprays of 665 μg of olopatadine hydrochloride alone but twice a day. 2. The method according to p. 1, characterized in that each injection contains 25 μg or 50 μg of mometasone furoate. 3. The method according to any one of paragraphs. 1, 2, characterized in that said salt of olopatadine is olopatadine hydrochloride. 4. The method according to claim 3, characterized in that each injection contains olopatadine hydrochloride equivalent to 600 μg of olopatadine. 5. The method according to any one of paragraphs. 1-4, characterized in that said composition is administered as a 1st injection into each nostril twice a day. 6. The method according to any one of paragraphs. 1-5, characterized in that said composition is administered as 2 injections into each nostril twice a day. 7. The method according to any one of paragraphs. 1-6, characterized in that allergic rhinitis is perennial allergic rhinitis and/or associated symptoms. 8. The method according to any one of paragraphs. 1-6, characterized in that allergic rhinitis is a seasonal allergic rhinitis and/or associated symptoms. 9. The use of a pharmaceutical composition containing mometasone furoate and olopatadine or its salt in a mass ratio of 1:12 to 1:53, based on the equivalent weight of the free base of olopatadine, for the treatment of allergic rhinitis in a person in need of said treatment, wherein (i) said composition is administered nasally in the form of 1 or 2 injections into each nostril of said person at least once a day, (ii) momet azona furoate is in particulate form and olopatadine or its salt is in dissolved form, and (iii) said administration provides relief of one or more symptoms associated with allergic rhinitis faster than nasal administration of two sprays of 665 μg of olopatadine hydrochloride alone twice daily. 10. Use according to claim 9, characterized in that said salt of olopatadine is olopatadine hydrochloride. 11. Use according to claim 10, characterized in that each injection contains olopatadine hydrochloride equivalent to 600 micrograms of olopatadine. 12. Application according to any one of paragraphs. 9-12, characterized in that each injection contains 25 μg or 50 μg of mometasone furoate and 665 μg of olopatadine hydrochloride. 13. Application according to any one of paragraphs. 9-12, characterized in that said composition is administered as a 1st injection into each nostril twice a day. 14. Application according to any one of paragraphs. 9-12, characterized in that said composition is administered as 2 injections into each nostril twice a day. 15. Application according to any one of paragraphs. 9-14, characterized in that allergic rhinitis is perennial allergic rhinitis and/or associated symptoms. 16. Application according to any one of paragraphs. 9-14, characterized in that the allergic rhinitis is a seasonal allergic rhinitis and/or associated symptoms.