TREATMENT OF ALLERGIC RHINITIS USING A COMBINATION OF
MOMETASONE AND OLOPATADINE
This patent application claims priority to Indian Provisional Patent Application
Number 3174/MUM/2013 filed October 04, 2013, the entire contents of which are
incorporated by reference herein.
TECHNICAL FIELD OF THE INVENTION
The present patent application relates to a method of treating allergic rhinitis in a
subject (preferably a human) by administering a combination of mometasone or its salt
and olopatadine or its salt.
BACKGROUND OF THE INVENTION
Allergic rhinitis is a medical term for inflammation and irritation of the mucous
membrane inside the nose. It generally occurs when an allergen such as pollen, dust, or
animal dander (particles of shed skin and hair) is inhaled by an individual with a
sensitized immune system. Allergic rhinitis may cause additional symptoms such as
rhinorrhea (excess nasal secretion), sneezing, nasal itching, nasal congestion and
obstruction, coughing, headache, fatigue and malaise. Symptoms may vary in severity
between individuals.
Many treatment options are available for treating allergic rhinitis such as, for
example, antihistamines (e.g., cetirizine and loratadine), steroids (e.g., triamcinolone),
decongestants, and leukotriene receptor antagonists (e.g., montelukast). These treatments
are generally administered orally or nasally.
Olopatadine hydrochloride, an antihistamine, is chemically described as (Z)-l l -
[3-(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid
hydrochloride, and is disclosed in U.S. Patent Nos. 4,871,865 and 4,923,892. It is
commercially available in the United States as PATANASE ® Nasal Spray, which
contains 0.6% w/v olopatadine (base) in a non-sterile aqueous solution. It is indicated for
the relief of the 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
inflammation of the skin or in the airways. 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, (iii) the prophylaxis of seasonal allergic rhinitis in patients >12 years of age,
and (iv) the treatment of nasal polyps in patients > 18 years of age. It is available as 50
meg in a metered-dose, manual pump spray unit containing an aqueous suspension of
mometasone furoate monohydrate equivalent to 0.05% w/w mometasone furoate
(calculated on the anhydrous basis).
International Publication No. WO 201 1/141929 discloses an aqueous nasal spray
solution comprising fluticasone and olopatadine.
U.S. Patent No. 6,127,353 discloses a pharmaceutical composition of mometasone
furoate monohydrate.
U.S. Patent Nos. 7,977,376 and 8,399,508 disclose a topical formulation of
olopatadine hydrochloride.
International Publication No. WO 201 1/008923 discloses a nasal spray regimen of
olopatadine for children.
International Publication No. WO 1995/020393 discloses the use of mometasone
furoate for treating airway passage and lung diseases.
International Publication No. WO 2010/025236 discloses a combination of a nasal
steroid and a nasal antihistamine for the treatment of viral upper respiratory tract
infections, upper respiratory infections, and common colds.
There still exists a need for easy to use and effective treatments for allergic
rhinitis.
SUMMARY OF THE INVENTION
The present invention relates to a fixed dose combination of mometasone or its
salt and olopatadine or its salt and its use for the treatment of rhinitis in a subject in need
thereof. The inventors have surprisingly found that mometasone furoate and olopatadine
hydrochloride act synergistically in the treatment of allergic rhinitis and is more effective
and provides better therapeutic value than treatment with either active ingredient alone.
In an embodiment, the present invention relates to a method of treating allergic
rhinitis in a subject (e.g., a human) in need thereof comprising nasally administering to
the subject an effective amount of a fixed-dose pharmaceutical composition comprising
mometasone or its salt and olopatadine or its salt. Preferably, the composition is nasally
administered as 1 or 2 sprays per nostril of the subject at least once daily. Each spray
preferably comprises mometasone or its salt and olopatadine or its salt in a weight ratio
of about 1:5 to about 1:60, such as 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, the fixed-dose
pharmaceutical composition is a suspension wherein the mometasone or its salt is present
in particulate form and the olopatadine or its salt is present in dissolved form.
Another embodiment relates to a method of treating allergic rhinitis in a subject
(e.g., a human) 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 nasally administered as 1 or 2 sprays per nostril of the subject at least once
daily. Each spray of the pharmaceutical composition may comprise olopatadine
hydrochloride equivalent to about 300 meg, about 450 meg, about 600 meg, about 750
meg, or about 900 meg of olopatadine, and about 12.5 meg, about 25 meg, about 37.5
meg, about 50 meg, or about 62.5 meg of mometasone furoate. In one embodiment, each
spray comprises olopatadine hydrochloride equivalent to about 600 meg of olopatadine
and about 25 meg of mometasone furoate. In another embodiment, each spray comprises
olopatadine hydrochloride equivalent to about 600 meg of olopatadine and about 50 meg
of mometasone furoate.
Allergic rhinitis in the context of present invention includes, but is not limited to,
inflammation and irritation of the mucous membrane inside the nose, and nasal and/or
non-nasal symptoms associated therewith. It includes, for example, persistent allergic
rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, chronic rhinitis, rhinitis
medicamentosa, vasomotor rhinitis, infective rhinitis, autonomic rhinitis, hormonal
rhinitis, drug-induced rhinitis, atrophic rhinitis, and gustatory rhinitis. Preferably, the
allergic rhinitis is selected from perennial allergic rhinitis, persistent allergic rhinitis,
seasonal allergic rhinitis, and nasal and/or non-nasal symptoms associated therewith.
In the context of present invention, the nasal and/or non-nasal symptoms
associated with allergic rhinitis include, for example, sneezing, nasal itching, rhinorrhea
(runny nose or excess nasal secretion), nasal congestion, coughing, ocular pruritis, excess
lacrimation, 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 thereof, the method comprising
nasally administering to the subject an effective amount of a fixed-dose pharmaceutical
composition comprising mometasone or its salt and olopatadine or its salt in a weight
ratio of about 1:5 to about 1:60 or from about 1:12 to about 1:53, wherein (i) the
composition is nasally administered as 1 or 2 sprays per nostril, once or twice daily, and
(ii) each spray comprises olopatadine hydrochloride equivalent to about 600 meg of
olopatadine and about 25 meg to about 50 meg of mometasone furoate. In one
embodiment, the composition is administered for about 1 week. In another aspect of the
embodiment, the composition is administered for about 2 weeks.
Yet another embodiment relates to a method of treating allergic rhinitis in a
human subject in need thereof comprising nasally administering to the human, a fixeddose
pharmaceutical composition comprising mometasone or its salt and olopatadine or
its salt, wherein (i) the composition is nasally administered as 1 or 2 sprays per nostril,
once or twice daily for at least 1 or 2 weeks, and (ii) each spray comprises olopatadine
hydrochloride equivalent to about 600 meg of olopatadine and about 25 meg to about 50
meg of mometasone furoate. In one embodiment, the total nasal symptoms score (TNSS)
of the human subject is reduced by at least 40 %, preferably by at least 50 % from
baseline after 1 or 2 weeks treatment. In another embodiment, the total ocular symptom
score (TOSS) of the human subject is reduced by at least 30 %, preferably by at least 40
% from baseline after 1 or 2 weeks treatment.
In one embodiment, the subject suffers from persistent allergic rhinitis and is
treated for 4 or 6 weeks.
In another embodiment, the subject exhibits a positive skin prick test to an
allergen. Alternately, the subject may also exhibit positive blood tests showing an allergy.
In yet another embodiment, the method involves no significant treatment-related
adverse effects in the subject after 1 or 2 weeks 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., a
human) in need thereof comprising nasally administering to the subject a synergistic
combination comprising mometasone furoate and olopatadine hydrochloride, wherein the
combination is in the form of a pharmaceutical composition comprising mometasone
furoate and olopatadine hydrochloride in a weight ratio of 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, the methods of treating allergic rhinitis in a subject
(e.g., a human) described herein comprises nasal administration of the fixed-dose
pharmaceutical composition comprising mometasone or its salt and olopatadine or its salt
to the subject according to one of the following regimens:
a) the composition is nasally administered as 1 spray per nostril once daily
for a period of at least 1 week;
b) the composition is nasally administered as 2 sprays per nostril once daily
for a period of at least 1 week;
c) the composition is nasally administered as 1 spray per nostril twice daily
for a period of at least 1 week;
d) the composition is nasally administered as 2 sprays per nostril twice daily
for a period of at least 1 week;
e) the composition is nasally administered as 1 spray per nostril once daily
for a period of 2 weeks;
f) the composition is nasally administered as 2 sprays per nostril once daily
for a period of 2 weeks;
g) the composition is nasally administered as 1 spray per nostril twice daily
for a period of 2 weeks; or
h) the composition is nasally administered as 2 sprays per nostril twice daily
for a period of 2 weeks.
In an aspect of the invention, the composition is administered as 1 or 2 sprays per
nostril of the subject (e.g., a human), at least once daily for a period of 1 week or 2
weeks. In another aspect of the embodiment, each spray of the composition comprises
olopatadine hydrochloride equivalent to about 600 meg of olopatadine and about 25 meg
to about 50 meg of mometasone furoate. Preferably, each spray of the composition
comprises about 665 meg of olopatadine hydrochloride (equivalent to about 600 meg of
olopatadine) and about 25 meg or about 50 meg of mometasone furoate. In yet another
aspect of the embodiment, the total nasal symptoms score (TNSS) of the human subject is
reduced by at least 40 % or at least 50 % from baseline after 1 or 2 weeks treatment. In
yet another aspect of the embodiment, the total ocular symptom score (TOSS) of the
human is reduced by at least 30 % or at least 40 % from baseline after 1 or 2 weeks
treatment. In yet another aspect of the embodiment, no significant treatment-related
adverse effects are observed in the human after 1 or 2 weeks treatment. In yet another
aspect of the embodiment, the human subject is a patient exhibiting a positive skin prick
test to an allergen.
Another embodiment relates to the use of mometasone or its salt and olopatadine
or its salt in a weight ratio of 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 (e.g., a human) in need thereof. Preferably, the composition is nasally
administered as 1 or 2 sprays per nostril of the subject once or twice daily. In an aspect,
the fixed-dose pharmaceutical composition is a suspension where mometasone or its salt
is present in particulate form and the olopatadine or its salt is present in dissolved form.
In another aspect of the embodiment, the composition is administered for a period of
about 1 or 2 weeks. The total nasal symptoms score (TNSS) of a human subject is
preferably reduced by at least 40 % or at least 50 % from baseline after 1 or 2 weeks
treatment. The total ocular symptom score (TOSS) of a human subject is preferably
reduced by at least 30 % or at least 40 % from baseline after 1 or 2 weeks treatment. In
yet another aspect of the embodiment, no significant treatment-related adverse effects are
observed in the human subject after 1 or 2 weeks treatment. In yet another aspect of the
embodiment, the human subject is a patient exhibiting a positive skin prick test to an
allergen.
Another embodiment relates to a fixed-dose pharmaceutical composition
comprising mometasone or its salt and olopatadine or its salt in a weight ratio of about
1:5 to about 1:60 for use in treating allergic rhinitis in a subject (e.g., a human) in need
thereof, wherein the composition is nasally administered as 1 or 2 sprays per nostril of the
subject at least once daily. In an aspect, the fixed-dose pharmaceutical composition is a
suspension wherein mometasone or its salt is present in particle form (e.g., having a mean
particle size of from about 1 to about 20 , or from about 1 to about 15 ) and
olopatadine or its salt is present in dissolved form.
The composition may be administered for a period of about lweek, 2 weeks, 4
weeks, 6 weeks or 8 weeks. The total nasal symptoms score (TNSS) of the human subject
is preferably reduced by at least 40 % or at least 50 % from baseline after 1 or 2 weeks
treatment. The total ocular symptom score (TOSS) of the human subject is preferably
reduced by at least 30 % or at least 40 % from baseline after 1 or 2 weeks treatment. In
yet another aspect of the embodiment, no significant treatment-related adverse effects are
observed in the human subject after 1 or 2 weeks treatment. In yet another aspect of the
embodiment, the human subject is a patient exhibiting a positive skin prick test to an
allergen.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a bar graph depicting the effect of a saline control, ovalbumin control,
olopatadine hydrochloride (equivalent to 50 g olopatadine base), mometasone furoate
(10 g), and a combination of mometasone furoate (10 g) and olopatadine
hydrochloride (equivalent to 50 g olopatadine base) on the sneezing response in guinea
pigs as described in Example 1.
Figure 2 is a bar graph depicting the effect of a saline control, ovalbumin control,
olopatadine hydrochloride (equivalent to 50 g olopatadine base), mometasone furoate
(10 g), and a combination of mometasone furoate (10 g) and olopatadine
hydrochloride (equivalent to 50 g olopatadine base) on total cell count in the nasal
lavage of guinea pigs as described in Example 1.
Figure 3 is a bar graph depicting the effect of a saline control, ovalbumin control,
olopatadine hydrochloride (equivalent to 50 g olopatadine base), mometasone furoate
(10 g), and a combination of mometasone furoate (10 g) and olopatadine
hydrochloride (equivalent to 50 g olopatadine base) on the number of eosinophils in the
nasal lavage of guinea pigs as described in Example 1.
Figure 4 is a bar graph depicting the effect of a saline control, ovalbumin control,
olopatadine hydrochloride (equivalent to 120 g olopatadine base), mometasone furoate
(10 g), and a combination of mometasone furoate (10 g) and olopatadine
hydrochloride (equivalent to 120 g olopatadine base) on the number of eosinophils in
the nasal lavage of guinea pigs as described in Example 2 .
Figure 5 is a bar graph depicting the effect of a saline control, ovalbumin control,
olopatadine hydrochloride (equivalent to 120 g olopatadine base), mometasone furoate
(10 g), and a combination of mometasone furoate (10 g) and olopatadine
hydrochloride (equivalent to 120 g olopatadine base) on the total cell count in the nasal
lavage of guinea pigs as described in Example 2 .
Figure 6 is a bar graph depicting the effect of a saline control, ovalbumin control,
olopatadine hydrochloride (equivalent to 120 g olopatadine base), mometasone furoate
(10 g), and a combination of mometasone furoate (10 g) and olopatadine
hydrochloride (equivalent to 120 g olopatadine base) on the sneezing response in guinea
pigs as described in Example 2 .
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The terms used herein are defined as follows. If a definition set forth in the
present application and a definition set forth earlier in a provisional application from
which the present applications claims priority are in conflict, the definition in the present
application shall control the meaning of the terms.
The term "effective amount" or "therapeutically effective amount" denotes an
amount of an active ingredient that, when administered to a subject for treating allergic
rhinitis, produces an intended therapeutic benefit in a subject. The term "active
ingredient" (used interchangeably with "active" or "active substance" or "drug") as used
herein includes mometasone or its salt and olopatadine or its salt.
By "salt" or "pharmaceutically acceptable salt", it is meant those salts which are,
within the scope of sound medical judgment, suitable for use in contact with the tissues of
humans and lower animals without undue toxicity, irritation, and allergic response,
commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
Representative acid additions salts include, but are not limited to, hydrochloride,
hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate,
laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate,
fumarate, furoate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl
sulphate salts. Representative 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 (e.g., mometasone furoate monohydrate) and the olopatadine
salt is olopatadine hydrochloride.
As used herein, the term "mometasone and its salt" also includes hydrates of
mometasone and its salts, such as a monohydrate, for example mometasone furoate
monohydrate.
All references to the weight of, or a weight ratio including, "olopatadine or its
salt" or "olopatadine or its salts" are based on the equivalent weight of olopatadine free
base, unless otherwise specified.
The term "treating" or "treatment" as used herein also covers the prophylaxis,
mitigation, prevention, amelioration, or suppression of a disorder.
The term "synergistic" or "synergy" as used herein 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 alone. The term "synergistic" or "synergy"
with regard to the combination of mometasone or its salt with olopatadine or its salt
which is used in the treatment allergic rhinitis (for example, in the form of a
pharmaceutical composition, a combination product or a kit according to the invention)
refers to an efficacy for the treatment of the allergic rhinitis that is greater than would be
expected from the sum of their individuals effects. The advantages for the synergistic
combinations of the present invention include, but are not limited to, exhibiting enhanced
efficacy compared to each of the ingredients when used alone, lowering the required dose
of one or more of the active ingredients of the combination, reducing the side effects of
one or more of the active compounds of the combination and/or rendering one or more of
the active ingredients more tolerable to the subject in need of treatment of the allergic
rhinitis.
By "pharmaceutically acceptable excipients", it is meant any of the components
of a pharmaceutical composition other than the actives and which are approved by
regulatory authorities or are generally regarded as safe for human or animal use.
The term "subject" includes mammals like humans and other animals, such as
domestic animals (e.g., household pets including cats and dogs) and non-domestic
animals (such as wildlife). Preferably, the subject is a human. The human patient can be
of any age. In one embodiment, the human subject is at least 2 years of age, at least 12
years of age, or at least 18 years of age. In another embodiment, the human subject is 18
to 65 years of age.
The term "allergic rhinitis" as used herein refers to an allergic and/or
inflammatory disease of nasal mucosa, and includes, but is not limited to, inflammation
and irritation of the mucous membrane inside the nose, and nasal and/or non-nasal
symptoms associated therewith. Typically the allergic rhinitis includes persistent allergic
rhinitis, perennial allergic rhinitis, seasonal allergic rhinitis, chronic rhinitis, rhinitis
medicamentosa, vasomotor rhinitis, infective rhinitis, autonomic rhinitis, hormonal
rhinitis, drug-induced rhinitis, atrophic rhinitis, and gustatory rhinitis. Preferably, the
allergic rhinitis includes perennial allergic rhinitis, persistent allergic rhinitis, seasonal
allergic rhinitis, and nasal and/or non-nasal symptoms associated therewith. More
preferably, the allergic rhinitis includes seasonal allergic rhinitis, and nasal and/or nonnasal
symptoms associated therewith.
In the context of present invention, the nasal and/or non-nasal symptoms
associated with allergic rhinitis include, for example, sneezing, nasal itching, rhinorrhea
(runny nose or excess nasal secretion), nasal congestion, coughing, ocular pruritis, excess
lacrimation, headache, fatigue, and malaise.
Methods of Treatment
The present invention relates to use of a fixed dose combination of mometasone
or its salt and olopatadine or its salt for the treatment of allergic rhinitis in a 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
either active ingredient alone.
In an embodiment, the present invention relates to a method of treating allergic
rhinitis in a subject (e.g., a human) in need thereof comprising nasally administering to
the subject, an effective amount of a fixed-dose pharmaceutical composition comprising
mometasone or its salt and olopatadine or its salt. Preferably, the composition is nasally
administered as 1 or 2 sprays per nostril of the subject at least once daily. Each spray
may comprise mometasone or its salt and olopatadine or its salt in a weight ratio of 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 its salt to
olopatadine or its salt 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
wherein mometasone or its salt is present in particulate form and the olopatadine or its
salt is present in dissolved form.
Another embodiment relates to a method of treating allergic rhinitis in a subject
(e.g., a human) 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 may be nasally
administered as 1 or 2 sprays per nostril of the subject at least once daily. Each spray of
the pharmaceutical composition may comprise olopatadine hydrochloride equivalent to
about 300 meg, about 450 meg, about 600 meg, about 750 meg, or about 900 meg of
olopatadine, and about 12.5 meg, about 25 meg, about 37.5 meg, about 50 meg, or about
62.5 meg of mometasone furoate. In one embodiment, each spray comprises olopatadine
hydrochloride equivalent to about 600 meg of olopatadine and about 25 meg of
mometasone furoate. In another embodiment, each spray comprises olopatadine
hydrochloride equivalent to about 600 meg of olopatadine and about 50 meg of
mometasone furoate. Preferably, each spray comprises about 665 meg of olopatadine
hydrochloride (equivalent to about 600 meg of olopatadine) and about 25 meg or about
50 meg of mometasone furoate.
Another embodiment relates to a method of treating allergic rhinitis in a subject in
need thereof comprising nasally administering to the human, a fixed-dose pharmaceutical
composition comprising mometasone or its salt and olopatadine or its salt in a weight
ratio of 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, wherein the composition is nasally
administered as 1 or 2 sprays per nostril, once or twice daily. Each spray may comprise
olopatadine hydrochloride equivalent to about 600 meg of olopatadine and about 25 meg
to about 50 meg of mometasone furoate. In an aspect of the embodiment, the composition
is administered for about 1 week. In another aspect of the embodiment, the composition
is administered for about 2 weeks.
Yet another embodiment relates to a method of treating allergic rhinitis in a
subject (e.g., a human) in need thereof comprising nasally administering to the subject a
fixed-dose pharmaceutical composition comprising mometasone or its salt and
olopatadine or its salt, wherein the composition is nasally administered as 1 or 2 sprays
per nostril, once or twice daily for at least 1 or 2 weeks. Each spray may comprise
olopatadine hydrochloride equivalent to about 600 meg of olopatadine and about 25 meg
to about 50 meg of mometasone furoate. In one embodiment, the total nasal symptoms
score (TNSS) of the subject is reduced by at least 40 %, or preferably at least 50 % from
baseline after 1 or 2 weeks treatment. In another aspect of the embodiment, the total
ocular symptom score (TOSS) of the subject is reduced at least 30 %, or preferably by at
least 40 % from baseline after 1 or 2 weeks treatment.
In the context of present invention, evaluation of total nasal symptoms scores
(TNSS) include the sum of scores of nasal congestion, rhinorrhea, itching and sneezing
from baseline to the end of treatment (e.g., 1 or 2 weeks). Further evaluation of the total
ocular symptoms scores (TOSS) includes ocular itching, tearing/watery eyes and ocular
redness from baseline to the end of treatment.
Another embodiment is a method of treating allergic rhinitis in a subject, wherein
the subject exhibits a positive skin prick test to an allergen. The skin prick test can be
performed by pricking the skin with a needle or pin containing a small amount of
ragweed allergen. In one embodiment, prior to administration of a combination of
olopatadine and mometasone as described herein, the skin prick test was performed on
the subject and resulted in a wheal diameter of at least 3 mm greater than a negative
control such as saline.
The methods of treatment described herein can be administered to a subject
without the subject exhibiting any significant treatment-related adverse effects, for
example, after 1 or 2 weeks treatment.
The treatment related adverse effects in the context of the present invention may
include, but are not limited to, eye disorders (e.g., conjunctivitis), gastrointestinal
disorders (e.g., abdominal distension, diarrhoea, dyspepsia, dysphagia and gastric ulcer,
haemorrhoidal haemorrhage, hyperchlorhydria, nausea and vomiting, and toothache),
general disorders (e.g., fatigue, local swelling, peripheral oedema, pain and pyrexia),
infections and infestations (e.g., oral herpes and upper respiratory tract infection), injury,
poisoning and procedural complications, musculoskeletal and connective tissue disorders
(e.g., arthralgia), nervous system disorders (e.g., disturbance in attention, dizziness,
dysgeusia, and headache), reproductive system and breast disorder (e.g., dysmenorrhea)
respiratory, thoracic and mediastinal disorders (e.g., dry throat, dyspnea, epitaxis, nasal
congestion, nasal discomfort, respiratory tract haemorrhage, rhinorrhea, throat irritation,
and upper-airway cough syndrome), skin and subcutaneous tissue disorders (e.g., 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., a
human) in need thereof comprising nasally administering to the subject a synergistic
combination comprising mometasone furoate and olopatadine hydrochloride, wherein the
combination is in the form of a pharmaceutical composition comprising mometasone
furoate and olopatadine hydrochloride in a weight ratio of 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).
Synergistic effects for the combination of mometasone furoate and olopatadine
hydrochloride can be evaluated by various methods. One method for evaluating the
efficacy of an agent for treating allergic rhinitis is the ovalbumin induced rhinitis model
in guinea pigs. In such models, the effect of the treatment is studied in animals sensitized
and challenged with ovalbumin, followed by detailed analysis of their sneezing response
using whole body plethysmography and the total number of eosinophils in a nasal lavage
sample.
The fixed-dose pharmaceutical composition comprising mometasone or its salt
and olopatadine or its salt may be administered to the subject according to one of the
following regimens:
a) the composition is nasally administered as 1 spray per nostril once daily
for a period of at least 1 week;
b) the composition is nasally administered as 2 sprays per nostril once daily
for a period of at least 1 week;
c) the composition is nasally administered as 1 spray per nostril twice daily
for a period of at least 1 week;
d) the composition is nasally administered as 2 sprays per nostril twice daily
for a period of at least 1 week;
e) the composition is nasally administered as 1 spray per nostril once daily
for a period of 2 weeks;
f) the composition is nasally administered as 2 sprays per nostril once daily
for a period of 2 weeks;
g) the composition is nasally administered as 1 spray per nostril twice daily
for a period of 2 weeks; or
h) the composition is nasally administered as 2 sprays per nostril twice daily
for a period of 2 weeks.
In an aspect of the invention, the composition is administered as 1 or 2 sprays per
nostril of the subject, at least once daily for a period of 1 week or 2 weeks. In another
aspect of the embodiment, each spray of the composition comprises olopatadine
hydrochloride equivalent to about 600 meg of olopatadine and about 25 meg to about 50
meg of mometasone furoate. Preferably, each spray of the composition comprises about
665 meg of olopatadine hydrochloride (equivalent to about 600 meg of olopatadine) and
about 25 meg or about 50 meg of mometasone furoate.
In yet another aspect of the embodiment, the total nasal symptoms score (TNSS)
of the subject is reduced by at least 40 % or at least 50 % from baseline after 1 or 2 weeks
treatment. In yet another aspect of the embodiment, the total ocular symptom score
(TOSS) of the subject is reduced by at least 30 % or at least 40 % from baseline after 1 or
2 weeks treatment. In yet another aspect of the embodiment, no significant treatmentrelated
adverse effects are observed in the subject after 1 or 2 weeks treatment. In yet
another aspect of the embodiment, the subject is a patient exhibiting a positive skin prick
test to an allergen.
Another embodiment relates to the use of mometasone or its salt and olopatadine
or its salt in a weight ratio of 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 thereof, wherein the composition is nasally administered as 1
or 2 sprays per nostril of the subject once or twice daily. In one embodiment the fixeddose
pharmaceutical composition is a suspension wherein the mometasone or its salt is
present in particulate form and the olopatadine or its salt is present in dissolved form.
In another aspect of the embodiment, the composition is administered for a period
of about 1 or 2 weeks. In yet another aspect of the embodiment, total nasal symptoms
score (TNSS) of the subject is reduced by at least 40 % or at least 50 % from baseline
after 1 or 2 weeks treatment. In yet another aspect of the embodiment, total ocular
symptom score (TOSS) of the subject is reduced by at least 30 % or at least 40 % from
baseline after 1 or 2 weeks treatment. In yet another aspect of the embodiment, no
significant treatment-related adverse effects are observed in the subject after 1 or 2 weeks
treatment. In yet another aspect of the embodiment, the subject exhibits a positive skin
prick test to an allergen.
Another embodiment relates to a fixed-dose pharmaceutical composition
comprising mometasone or its salt and olopatadine or its salt in a weight ratio of about
1:5 to about 1:60 or from about 1:12 to about 1:53 for use in treating allergic rhinitis in a
subject in need thereof, wherein the composition is nasally administered as 1 or 2 sprays
per nostril of the subject at least once daily. In an aspect, the fixed-dose pharmaceutical
composition is a suspension wherein the mometasone or its salt is present in particulate
form (e.g., having a mean particle size of from about 1 to about 20 , or from about 1 to
about 15 ) and the olopatadine or its salt is present in dissolved form. In another
aspect of the embodiment, the composition is administered for a period of about 1 or 2
weeks. In yet another embodiment, the total nasal symptoms score (TNSS) of the subject
is reduced by at least 40 % or at least 50 % from baseline after 1 or 2 weeks treatment. In
yet another aspect of the embodiment, total ocular symptom score (TOSS) of the subject
is reduced by at least 30 % or at least 40 % from baseline after 1 or 2 weeks treatment. In
yet another embodiment, no significant treatment-related adverse effects are observed in
the subject after 1 or 2 weeks treatment. In yet another aspect of the embodiment, the
subject is a patient exhibiting a positive skin prick test to an allergen.
The composition may be administered for a period of about lweek, 2 weeks, 4
weeks, 6 weeks or 8 weeks.
In the context of the present invention, the fixed dose pharmaceutical composition
comprising mometasone or its salt, olopatadine or its salt are preferably supplied in the
form of nasal spray with one or more pharmaceutical acceptable excipients (e.g.,
chelating agents, preservatives, buffer, surfactants, isotonic agent, taste masking agents,
suspending agents, humectants, antioxidants and diluents) in a container and a kit
providing directions on its usage and administration. The pharmaceutical composition
may, for example, have any one of the formulations described in International Patent
Application No. PCT/IB2014/064251, filed September 4, 2014, or U.S. Patent
Application No. 14/483,837, filed September 11, 2014, both of which are hereby
incorporated by reference.
The pharmaceutical composition can be nasally administered with a nasal spray
device (e.g., one capable of delivery a mist spray in the nostrils of a subject for local
action on nasal mucosa).
The following examples are provided to enable one skilled in the art to practice
the invention and these are merely illustrative of the invention and should not be read as
limiting the scope of the invention.
EXAMPLES
EXAMPLE 1
Effect of mometasone and olopatadine and their combination on ovalbumin induced
rhinitis model in male guinea pigs.
Male Dunkin Hartley guinea pigs were actively sensitized with a subcutaneous
injection of 1.5 mg of ovalbumin and 20 mg of aluminum hydroxide gel on days 0 and 7 .
Guinea pigs were sensitized intranasally with 2% ovalbumin from days 14-17. On day
28, the animals were challenged with 6% ovalbumin intranasally.
Animal Grouping
Actively sensitized animals were randomly assigned to one of the following 5
groups during the experiment {see Table 1).
A: Saline Control (vehicle treated / saline challenged),
B: Ovalbumin Control (vehicle treated / ovalbumin challenged),
C: Olopatadine hydrochloride 50 g (based on the equivalent weight of
olopatadine free base) (olopatadine hydrochloride 50 g treated / ovalbumin challenged),
D: Mometasone furoate 10 g (mometasone furoate 10 g treated / ovalbumin
challenged) and
E : Combination (mometasone furoate 10 g + olopatadine hydrochloride 50 g
(based on the equivalent weight of olopatadine free base) treated / ovalbumin
challenged).
Compound Administration
Mometasone furoate 10g was given intranasally 24 hours and 1 hour prior to the
final ovalbumin challenge. Olopatadine hydrochloride was given intranasally 1 hour
before the final ovalbumin challenge. The dosing volume was 40 ΐ/animal. The saline
control group and ovalbumin control group received vehicle (40 ΐ, 0.1% Tween 80 in
distilled water).
Table 1
Animal Groups
Group Group Code Treatment Ovalbumin Animals/ group
Challenge
A Saline Vehicle - 6
Control
B Ovalbumin Vehicle + 7
Control
C Olopatadine Olopatadine Hydrochloride + 7
5050 
D Mometasone Mometasone Furoate + 6
1010 
E Combination Olopatadine Hydrochloride + 7
50 g + Mometasone
Furoate 10 g
In Vivo Evaluation
Measurement of Sneezing Response
Sneezing response was determined by using whole body plethysmography (Buxco
Research Systems, USA) for 50 minutes after final saline or ovalbumin challenge.
Nasal Lavage
Nasal lavage was performed at 4 hours after challenge of 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 pre-warmed normal
saline. The collected nasal lavage was taken for total cell count using a hemocytometer.
The nasal lavage was centrifuged, and the cell pellet resuspended in 15 guinea pig
serum and used for preparation of smears. Slides were stained with Leishman's stain and
a differential cell count of 100 cells based on standard morphology was performed
manually.
Calculations
The total number of eosinophils in each nasal lavage sample was calculated using
the formula:
Total cell count X 105/mL X Percent eosinophils
Total No. of eosinophils (in nasal lavage) =
100
Percent inhibition of eosinophils was calculated using the following formula:
Avg. eosinophils (Ovalbumin control) eosinophils (compound)
%Inhibition of = X 100
eosinophils Avg. eosinophils (Ovalbumin control) - Avg. eosinophils (Sa line Control)
Data analysis
Data was statistically analyzed using one way ANOVA followed by Dunnett's multiple
comparison tests.
Results
Mometasone furoate monotherapy showed significant inhibition of total cell and
eosinophils in nasal lavage but was not effective in inhibiting sneezing response.
Olopatadine hydrochloride monotherapy did not show significant inhibition of any of the
parameters in this model. The combination of mometasone furoate with olopatadine
hydrochloride showed synergy for inhibition of sneezing response (Figure 1), cellular
infiltration in nasal lavage (Figure 2) and nasal eosinophilia (Figure 3) as compared to
respective monotherapy arms {see Table 2).
Table 2
Summary of the effects of a combination of mometasone furoate and olopatadine
hydrochloride on ovalbumin induced rhinitis model in guinea pigs.
P<0.05 vs. Ovalbumin Control, ** P .01 vs. Ovalbumin Control,
*** PO.001 vs. Ovalbumin control
The combination of mometasone furoate and olopatadine hydrochloride showed a
beneficial effect greater than the individual monotherapies. The combination of
mometasone furoate and olopatadine hydrochloride showed synergy in the treatment of
allergic rhinitis in this model.
EXAMPLE 2
Effect of mometasone and olopatadine and their combination on ovalbumin induced
rhinitis model in male guinea pigs.
The procedure in Example 1 was repeated except 120 g of olopatadine
hydrochloride (based on the equivalent weight of olopatadine free base) was used. The
animal groups in Table 3 below were used during this experiment.
Table 3
Animal Groups
Compound administration was performed as in Example 1, except the dosing
volume was 60 ΐ/animal. The saline control group and ovalbumin control group
received vehicle (60 ΐ , 0.1% Tween 80 in distilled water). In vivo evaluations were
performed as in Example 1.
Results
Mometasone monotherapy showed significant inhibition of total cell and
eosinophils in nasal lavage but was not effective in inhibiting sneezing response.
Olopatadine monotherapy did not show significant inhibition of any of the parameter in
this model. The combination of mometasone with olopatadine showed synergy for the
inhibition of nasal eosinophilia, cellular infiltration in nasal lavage and sneezing response
as compared to the respective monotherapies {see Figures 4-6 and Table 4).
Table 4
Summary of the effects of combination of mometasone and olopatadine on ovalbumin
induced rhinitis model in guinea pigs
* P<0.05 vs. Ovalbumin Control, ** P .01 vs. Ovalbumin Control,
*** PO.001 vs. Ovalbumin Control
The combination of mometasone furoate and olopatadine hydrochloride showed a
beneficial effect greater than the individual monotherapies. The combination of
mometasone and olopatadine showed synergy in this guinea pig rhinitis model.
EXAMPLE 3
Clinical study of fixed dose combination of mometasone and olopatadine nasal spray in
human patients
The study was a single-centre, double blind, double-dummy, randomized,
parallel-group, comparative Environmental Exposure Chamber (EEC) study to evaluate
the efficacy, safety and tolerability of (i) two fixed dose combination products of
mometasone furoate and olopatadine hydrochloride nasal spray, (ii) a fixed dose
combination of azelastine hydrochloride and fluticasone propionate nasal spray
(DYMISTA ®), (in) olopatadine nasal spray (PATANASE ®), and () a placebo nasal
spray in patients with seasonal allergic rhinitis (SAR).
Key Objectives
• To evaluate the efficacy of two strengths of the fixed dose combination
(FDC) of mometasone furoate and olopatadine hydrochloride nasal spray when compared
with a placebo nasal spray.
• To evaluate the comparative efficacy of (i) two regimens of FDC products
containing mometasone furoate and olopatadine hydrochloride nasal spray, (ii) a fixed
dose combination of azelastine hydrochloride and fluticasone propionate nasal spray
(DYMISTA ®), and (hi) Olopatadine nasal spray (PATANASE ®) .
• To compare the efficacy of (i) a fixed dose combination of azelastine
hydrochloride and fluticasone propionate nasal spray and (ii) olopatadine nasal spray,
when compared with a placebo nasal spray.
• To compare the onset of action between active treatments groups after the
first dose defined as "the first time point after initiation of treatment when the drug
demonstrates a significant reduction in instantaneous TNSS compared to the placebo
treatment that proves durable from this point."
• To compare the EEC-Quality of Life Questionnaire (QoLQ) and
tolerability and acceptability between a fixed dose combination of mometasone furoate
and olopatadine hydrochloride once daily and a fixed dose combination of mometasone
furoate and olopatadine hydrochloride twice daily.
• To evaluate the comparative safety between the various treatment arms.
Sample Size
A total of 36 patients per treatment arm were randomized in the study. The total
number of randomized subjects throughout the five treatment arms was 180.
Patient Population
Subjects suffering from seasonal allergic rhinitis for the last two years that require
treatment either with intranasal antihistamines and/or intranasal steroids were included in
the study.
Key Subject Selection Criteria
1. Patients age > 18 and < 65 years inclusive of either sex;
2 . Patient with a known clinical history of seasonal allergic rhinitis (for at
least 2 years) and exhibiting a positive skin prick test (wheal diameter at least 3 mm
greater than saline control) to one of the regional allergens;
3 . Patients with the ability to understand and sign a written informed consent
form, which must have been obtained prior to screening; and
4 . Patients willing to comply with the protocol requirements.
Study Deign
Patients were randomized to treatment in a 1:1:1:1:1 ratio to the following five
treatment arms, at one study site:
1. Fixed dose combination of olopatadine hydrochloride 665 meg and
mometasone furoate 25 meg twice daily (BID)
2 . Fixed dose combination of olopatadine hydrochloride 665 meg and
mometasone furoate 50 meg once daily (QD)
3 . DYMISTA® nasal spray (azelastine hydrochloride 137 meg + fluticasone
propionate 50 meg) Spray twice daily (BID)
4 . PATANASE® nasal spray (olopatadine hydrochloride 665 meg) twice daily
(BID)
5. Placebo nasal spray
The double-dummy design including four masked nasal spray bottles (two for
evening dosing and two for morning dosing) were utilized for this study {see Table A).
Table A
Treatment Administration Using Four Masked Bottles of Nasal Sprays
Treatment Arm Morning Evening
1st bottle 2nd bottle 1st bottle 2nd bottle
1 TP-1: Fixed dose combination of Active Active Active Active
mometasone furoate 25 meg +
olopatadine hydrochloride 665 meg
twice daily (BID)
2 TP-2: Fixed dose combination of Active Active Placebo Placebo
mometasone furoate 50 meg +
olopatadine hydrochloride 665 meg
once daily (QD)
3 DYMISTA® twice daily (BID) Placebo Active Placebo Active
4 PATANASE twice daily (BID) Active Active Active Active
5 Placebo Placebo Placebo Placebo Placebo
This study consisted of five visits to the study site and a 12 day at-home dosing
period (and 2 days of onsite dosing - a total of 14 days of dosing). Assessment of
efficacy endpoints were done out of season, in an EEC facility. After the initial screening
visit (Visit 1), patients who met all study criteria (including the main criteria for
inclusion: a positive skin prick test (SPT) and a 2 year medical history of allergic rhinitis
(AR) to ragweed allergen) underwent further screening/priming in the EEC (Visit 2).
During the EEC session 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 rate
their ocular and nasal symptoms every 30 minutes in the EEC Patients who met a
minimum qualifying TNSS of 6/12, including a score of at least 2 for nasal congestion on
two consecutive diary entries continued in the study. At Visit 3, on the following day
(Day 1), patients who met the minimum criteria returned to the EEC for a second
consecutive EEC session. Patients were exposed to allergen for approximately 10 hours
during this visit. During the first 6 hours, patients used the electronic diary to complete
symptom assessments every 30 minutes and met the minimum qualifying symptom score
in order to continue. Those who met the minimum qualifying symptom score were
randomized to receive one of the five study drugs after the 6 hours time point in the EEC.
After dosing (at approximately noon), patients were asked to complete symptom
assessments at 5 minute, 10 minutes, 15 minutes, 25 minutes, 30 minute, 45 minutes, 60
minutes and then every 30 minutes for the remainder of the visit Post-treatment symptom
assessments in the EEC were used to determine onset of action for study treatments.
Patients were then sent home with their study medication to continue at-home BID
dosing starting from the evening dose for Day 1. Patients continued at-home dosing for a
period of 12 days. Following the 12 days (Days 2-13) of at-home dosing, patients
returned to the EEC on Day 14 (Visit 4) for a post-treatment 6-hour priming EEC session.
Patients were dosed with the morning dose of study drug one hour prior to entering the
EEC. Symptoms were assessed every 30 minutes in the EEC Patients took their last dose
of study treatment at midnight on the same day, and returned on the following morning
(Day 15, Visit 5) for a 6 hour EEC session Over a period of 6 hours, patients used the
electronic diary to complete symptom assessments every 30 minutes. In addition to
collection of nasal and ocular symptoms, the electronic diary was used to collect EECQuality-
of-Life Questionnaires (EEC-QoLQ) at Visits 2, 3, 4 and 5, and acceptability and
tolerability at Visit 5. Visit 5 was the final visit for the study.
Priming
Fulfillment of the following criteria on each of two consecutive diary cards
reading at priming visit: minimum TNSS of 6 out of 12, including a score of at least 2 for
nasal congestion.
Randomization
• Patients meeting these same criteria at both priming visits of 3 hours
chamber duration in order to proceed to the treatment visit (Visit 3).
• At the treatment visit (Visit 3), a minimum TNSS of 6 out of 12 (including
a score of at least 2 for nasal congestion).
Drug Formulations
The test product formulations used in the study were as follows:
Test Product 1 (TP-l)
Mometasone Furoate Monohydrate and Olopatadine Hydrochloride Nasal Spray
(25 meg + 600 meg)
Each spray delivered mometasone furoate monohydrate equivalent to 25 meg
mometasone furoate and olopatadine hydrochloride equivalent to 600 meg olopatadine.
Test Product 2 (TP-2)
Mometasone Furoate Monohydrate and Olopatadine Hydrochloride Nasal Spray
(50 meg + 600 meg)
Each spray delivered mometasone furoate monohydrate equivalent to 50 meg
mometasone furoate and olopatadine hydrochloride equivalent to 600 meg olopatadine.
Dosage Regimen
1. Investigational Products
• TP-1: Fixed dose combination of Olopatadine hydrochloride (665 meg)
and Mometasone furoate (25 meg) Nasal Spray: 2 sprays per nostril were delivered
Twice daily (BID) for two weeks.
• TP-2: Fixed dose combination of Olopatadine hydrochloride (665 meg)
and Mometasone furoate (50 meg) Nasal Spray: 2 sprays per nostril were delivered once
daily (QD) for two weeks
2 . Reference Therapies
• Olopatadine hydrochloride Nasal Spray (PATANASE® 0.6%): 2 sprays
per nostril were delivered twice daily for two weeks.
• DYMISTA® (azelastine hydrochloride + fluticasone propionate) 137 meg
/ 50 meg Nasal Spray: 1 spray per nostril was delivered twice daily for two weeks.
• Placebo Nasal Spray (based on vehicle of Investigational product): 2
sprays per nostril were delivered twice daily for two weeks.
Key Evaluation Criteria (Clinical Endpoints)
• Change from baseline in mean post-treatment Total Nasal Symptoms
Score (TNSS) over placebo for fixed dose combination of mometasone furoate and
olopatadine hydrochloride. Mean TNSS were calculated over 6 hours in the EEC for
post-treatment at Visit 5 (over hours 18 to 24 after the first dosing on Day 14) and
matched baseline TNSS in the EEC at Visit 3 (over 6 hours prior to first dosing).
• Change from baseline in mean post-treatment TNSS for two regimens of
fixed dose combination of mometasone furoate and olopatadine hydrochloride with
reference products: DYMISTA® nasal spray and PATANASE® nasal spray. Mean TNSS
were calculated over 6 hours in the EEC for post-treatment at Visit 5 (over hours 18 to 24
after the first dosing on Day 14) and matched baseline TNSS in the EEC at Visit 3 (over
6 hours prior to first dosing).
• Change from baseline in mean post-treatment TNSS for two regimens of
fixed dose combination of mometasone furoate and olopatadine hydrochloride,
DYMISTA® nasal spray and PATANASE® nasal spray. Mean post-treatment TNSS were
calculated over 6 hours in the EEC for post-treatment at Visit 4 (over hours 1 to 7 after
first dosing on Day 14) and matched baseline TNSS in the EEC at Visit 2 (over 6 hours).
• Change from baseline in mean post-treatment TNSS for two regimens of
fixed dose combination of mometasone furoate and olopatadine hydrochloride compared
with reference products: DYMISTA® nasal spray and PATANASE® nasal spray. Mean
TNSS were calculated over 12 hours in the EEC for post-treatment (at Visit 4 over 1 to 7
hours after first dosing on Day 14, and at Visit 5 over 18 to 24 hours after first dosing on
Day 14) and matched baseline TNSS in the EEC at Visit 2 and Visit 3 (over 12 hours
prior to first dosing).
• Onset of Action for each treatment of fixed dose combination of
mometasone furoate and olopatadine hydrochloride, DYMISTA® and PATANASE®
were assessed by comparing change from baseline in post-treatment TNSS between each
active treatment and placebo at every time point after the first treatment. Change from
baseline in TNSS were calculated at every time point after the first dose of study
treatment in the EEC at Visit 3 (i.e., over the last four hours in the EEC at Visit 3) with
baseline (Visit 3) defined as the average of the last two time points pre-dosing.
• Change from baseline in mean post-treatment Total Symptoms Score
(TSS), Individual Nasal Symptoms Scores (NSS, four nasal symptoms of rhinorrhea,
pruritus, sneezing and nasal congestion) and TOSS over 6 hours in the EEC at Visit 5 and
matched baseline at Visit 3 (over 6 hours prior to first dosing).
• Change from baseline in mean post-treatment Total Symptoms Score
(TSS), Individual Nasal Symptoms Scores (NSS, four nasal symptoms of rhinorrhea,
pruritus, sneezing and nasal congestion) and TOSS over the 6 hours in the EEC at Visit 4
and matched baseline at Visit 2 (over the 6 hours in the EEC).
• Change from baseline in mean post-treatment Total Symptoms Score
(TSS), Individual Nasal Symptoms Scores (NSS, four nasal symptoms of rhinorrhea,
pruritus, sneezing and nasal congestion) and TOSS over 12 hours in the EEC at Visit 4
and Visit 5 and matched baseline over 12 hours in the EEC prior to dosing at Visit 2 and
Visit 3 .
• EEC-QoLQ for all treatment arms by comparing 1) pre-EEC-QoLQ at
baseline (Visit 2) with pre-EEC at Visit 4; 2) post-EEC at baseline Visit 2 with post-EEC
at Visit 4; 3) after 6 hours in the EEC at Visit 3 (prior to first dosing) with post-EEC at
Visit 5 .
• Reflective tolerability and acceptability for treatment arms compared to
placebo post-EEC at Visit 5.
Results
Table B shows a summary of the TNSS change from baseline to post-treatment
over 6 hours in EEC (ITT Population).
Table B
Table C shows a summary of the TNSS change from baseline to post-treatment
over 12 hours in EEC (ITT Population). (The data for NASONEX in Table C is sourced
from its U.S. FDA approved label.)
Table C
* NASONEX (mometasone furoate nasal spray) US FDA Approved label (Jan.
201 1)
Table D shows a summary of the TOSS change from baseline to post-treatment
1 hours in EEC (ITT Population).
Table D
The results of the study show that a combination of mometasone furoate and
olopatadine hydrochloride, when administered nasally to a human patient, provides an
effective treatment of seasonal allergic rhinitis and clinically significant reduction in both
nasal and non-nasal symptoms associated therewith. The magnitude of this relief for
TNSS was clinically relevant (i.e., greater than 2 units in difference - which is generally
considered as clinically relevant - between the Test Products and Placebo). Test Product-
1 showed overall better symptom relief with a faster onset of action as compared to the
Reference Products (PATANASE® and DYMISTA®) .
EXAMPLE 4
Phase II clinical study of fixed dose combination of mometasone and olopatadine
nasal spray in human patients.
The study is a double-blind, randomized, parallel-group, comparative study to evaluate
the efficacy, safety and tolerability of two different strengths and regimens of a fixed
dose combination of mometasone furoate and olopatadine hydrochloride nasal spray
compared with a placebo nasal spray and individual monotherapy formulations of
olopatadine hydrochloride nasal spray and mometasone furoate nasal spray, in subjects
(12 years of age and older) with seasonal allergic rhinitis (SAR).
Key Objectives
• To compare the efficacy of mometasone furoate and olopatadine hydrochloride nasal
spray once daily and mometasone furoate and olopatadine hydrochloride nasal spray
twice daily with the placebo nasal spray and with the individual constituent
monotherapies at the same dose in the same vehicle over 14 days of study treatment.
To compare the onset of action between mometasone furoate and olopatadine
hydrochloride nasal spray once daily and mometasone furoate and olopatadine
hydrochloride nasal spray twice daily with the placebo and the individual constituent
monotherapies at the same dose in the same vehicle, after the first dose of study drug
administration.
To assess the safety and tolerability of individual treatment arms.
Table E
Investigational products and their administration
Sample Size:
A total of approximately 1,106 randomized subjects (158 subjects per treatment arm) will
be enrolled in the study.
Key Subject Selection Criteria:
1. Age >\2 and older inclusive of either sex.
2. Documented clinical history of SAR (for at least 2 years preceding the
screening visit) with exacerbations (clinical evidence of active symptoms)
and exhibiting a documented positive SPT (wheal diameter at least 5 mm
greater than control wheal) to mountain cedar allergen.
3. A 12-hour reflective TNSS >8 out of a possible 12 and a congestion score of
> 2 for the AM assessment at the Screening Visit (Visit 1).
Study Design:
Subjects will be randomized to treatment in a 1:1:1:1:1:1:1 ratio to the following seven
treatment arms, at multiple study sites.
The double-dummy design including two identical nasal spray bottles (one for morning
[AM] dosing and one for evening [PM] dosing) are utilized for this study (Table F). The
double-dummy design is ensured for adequate blinding considering that treatments being
compared vary in dosing frequency (BID compared with QD).
Table F
Treatment Administration Using Two Identical Bottles of Nasal Sprays
(2 sprays per nostril, total 4 sprays each bottle, per day)
This study consists of four visits to the study site. After the initial screening visit (Visit
1), subjects who meet all study selection criteria are required to undergo a single-blind
placebo run-in period for 7-10 days. Following the completion of the run-in period,
eligible subjects meeting the randomization criteria are enrolled and randomized to one of
the seven treatment arms. Subjects are dispensed medication as per the randomization
list. Randomized subjects are required to undergo a 2 week (14 days) treatment period as
per the protocol to assess the efficacy and safety of the assigned treatment.
Key Evaluation Criteria (Clinical Endpoints):
Primary Endpoint
• Change from baseline in average AM and PM subject-reported 12-hour rTNSS
(reflective TNSS) over the 14-day treatment period.
Secondary Endpoints
• Change from baseline in average AM and PM subject-reported 12-hour iTNSS
(instantaneous TNSS) over the 14 day treatment period.
• Change from baseline in average AM and PM subject-reported 12-hour rTOSS
(reflective TOSS) over the 14-day treatment period.
• Onset of action for each treatment are assessed by comparing the change from baseline
in post-treatment iTNSS between each active treatment and placebo at defined time
points (prior to 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 study treatment for
4 hours.
• Change from baseline in the rhinoconjunctivitis quality of life questionnaire (RQLQ)
on day 15 between treatment arms for subjects with impaired quality of life at baseline
as defined by the RQLQ Score at the randomization visit (RV) of 3.0 or greater
(RQLQ population).
Tertiary Efficacy Endpoints
Nasal symptoms:
• Change from baseline in AM subject-reported rTNSS over the 14-day treatment
period.
• Change from baseline in AM subject-reported iTNSS over the 14-day treatment
period.
• Change from baseline in PM subject-reported rTNSS over the 14-day treatment
period.
• Change from baseline in PM subject-reported iTNSS over the 14-day treatment
period.
• Change from baseline in subject-reported reflective individual nasal symptoms over
the 14-day treatment period (AM, PM and average of AM and PM).
• Change from baseline in subject-reported instantaneous individual nasal symptoms
over the 14-day treatment period (AM, PM and average of AM and PM).
• Change from baseline in average AM and PM subject-reported rTNSS and iTNSS for
each day.
• Change from baseline in AM subject-reported rTNSS and iTNSS for each day.
• Change from baseline in PM subject-reported rTNSS and iTNSS for each day.
Ocular symptoms:
• Change from baseline in average AM and PM subject-reported iTOSS (instantaneous
TOSS) over the 14-day treatment period.
• Change from baseline in AM subject-reported rTOSS over the 14-day treatment
period.
• Change from baseline in AM subject-reported iTOSS over the 14-day treatment
period.
• Change from baseline in PM subject-reported rTOSS over the 14-day treatment
period.
• Change from baseline in PM subject-reported iTOSS over the 14-day treatment
period.
• Change from baseline in subject-reported reflective individual ocular symptoms over
the 14-day treatment period (AM, PM and average AM and PM).
• Change from baseline in subject-reported instantaneous individual ocular symptoms
over the 14-day treatment period (AM, PM and average AM and PM).
• Change from baseline in average of the AM and PM subject-reported rTOSS and
iTOSS for each day.
• Change from baseline in AM subject-reported rTOSS and iTOSS for each day.
• Change from baseline in PM subject-reported rTOSS and iTOSS for each day.
The non-nasal symptoms are assessed in a similar manner to the ocular symptoms above.
Physician assessed Nasal Symptom Score (PNSS) and Rhinoconiuntivitis Quality of Life
Questionnaire (RQLQ):
• Physician assessed Nasal Symptom Score (PNSS) and physician assessed individual
nasal symptoms at Day 15 (Visit 4).
• Individual domains of the RQLQ at Day 15 (Visit 4) for the RQLQ population
(defined as subject with impaired Quality of Life at baseline).
• RQLQ at Day 15 (Visit 4) for the full analysis set (FAS).
Although the invention herein has been described with reference to particular
embodiments, it is to be understood that these embodiments are merely illustrative of the
principles and application of the present invention. It is therefore to be understood that
numerous modifications may be made to the illustrative embodiments.
All publications, patents, and patent applications cited in this application are
herein incorporated by reference to the same extent as if each individual publication,
patent, or patent application was specifically and individually indicated to be
incorporated herein by reference.
WE CLAIM:
1. A method of treating allergic rhinitis in a human in need thereof
comprising nasally administering to the human an effective amount of a fixed-dose
pharmaceutical composition comprising mometasone or its salt and olopatadine or its
salt, wherein (i) the composition is nasally administered as 1 or 2 sprays per nostril of the
human at least once daily, and (ii) each spray comprises mometasone or its salt and
olopatadine or its salt in a weight ratio of about 1:5 to about 1:60 (based on the equivalent
weight of olopatadine free base).
2 . The method according to claim 1, wherein the weight ratio of mometasone
or its salt to olopatadine or its salt ranges from about 1:12 to about 1:53 (based on the
equivalent weight of olopatadine free base).
3 . The method according to any one of claims 1-2, wherein the mometasone
salt is mometasone furoate and the olopatadine salt is olopatadine hydrochloride.
4 . The method according to claim 3, wherein each spray comprises about 25
meg or about 50 meg mometasone furoate.
5. The method according to claim 3, wherein each spray comprises
olopatadine hydrochloride equivalent to about 600 meg olopatadine.
6 . The method according to any one of claims 1-5, wherein the
pharmaceutical composition is a suspension comprising mometasone or its salt in
particulate form and olopatadine or its salt in solution.
7 . The method according to any one of claims 1-6, wherein the composition
is administered as 1 spray per nostril once daily.
8. The method according to any one of claims 1-6, wherein the composition
is administered as 2 sprays per nostril once daily.
9 . The method according to any one of claims 1-6, wherein the composition
is administered as 1 spray per nostril twice daily.
10 . The method according to any one of claims 1-6, wherein the composition
is administered as 2 sprays per nostril twice daily.
11. The method according to any one of claims 1-10, wherein the composition
is administered for a period of at least 1 week.
12. The method according to any one of claims 1-10, wherein the composition
is administered for a period of at least 2 weeks.
13. The method according to any one of claims 1-12, wherein the allergic
rhinitis is selected from perennial allergic rhinitis, persistent allergic rhinitis, seasonal
allergic rhinitis, and nasal and/or non-nasal symptoms associated therewith.
14. The method according to any one of claims 1-12, wherein the allergic
rhinitis is seasonal allergic rhinitis and/or nasal symptoms associated therewith.
15. The method according to any one of claims 1-14, wherein the total nasal
symptoms score (TNSS) of the human is reduced by at least 50 % from baseline after 2
weeks treatment.
16. The method according to any one of claims 1-15, wherein the total ocular
symptom score (TOSS) of the human is reduced by at least 40 % from baseline after 2
weeks treatment.
17. The method according to any one of claims 1-16, wherein no significant
treatment- related adverse effects are observed in the human after 2 weeks treatment.
18. The method according to any one of claims 1-17, wherein the human
exhibits a positive skin prick test to an allergen.
19. A method of treating seasonal allergic rhinitis and/or nasal symptoms
associated with seasonal allergic rhinitis in a human in need thereof comprising nasally
administering to the human a synergistic combination comprising mometasone furoate
and olopatadine hydrochloride, wherein the combination is in the form of a
pharmaceutical composition comprising mometasone furoate in particulate form and
olopatadine hydrochloride in solution in a weight ratio of about 1:13.3 to about 1:53.2,
and wherein the composition is administered as 1 or 2 sprays per nostril of the human, at
least once daily for a period of at least 1 week.
20. The method according to claim 19, wherein the composition is
administered once daily or twice daily for a period of 2 weeks.
21. The method according to any one of claims 19-20, wherein each spray
comprises about 25 meg or about 50 meg of mometasone furoate and about 665 meg of
olopatadine hydrochloride.
22. The method according to any one of claims 19-21, wherein the total nasal
symptoms score (TNSS) of the human is reduced by at least 50 % from baseline after 2
weeks treatment.
23. The method according to any one of claims 19-22, wherein the total ocular
symptom score (TOSS) of the human is reduced by at least 40 % from baseline after 2
weeks treatment.
24. The method according to any one of claims 19-23, wherein no significant
treatment-related adverse effects are observed in the human after 2 weeks treatment.
25. The method according to any one of claims 19-24, wherein the human
exhibits a positive skin prick test to an allergen.
26. Use of mometasone or its salt and olopatadine or its salt in a weight ratio
of about 1:5 to about 1:60 (based on the equivalent weight of olopatadine free base) for
the manufacture of a fixed-dose pharmaceutical composition for the treatment of allergic
rhinitis in a human in need thereof, wherein the composition is nasally administered as 1
or 2 sprays per nostril of the human at least once daily.
27. The use according to claim 26, wherein the weight ratio of mometasone or
its salt to olopatadine or its salt ranges from about 1:12 to about 1:53 (based on the
equivalent weight of olopatadine free base).
28. The use according to any one of claims 26-27, wherein the mometasone
salt is mometasone furoate and the olopatadine salt is olopatadine hydrochloride.
29. The use according to any one of claims 26-28, wherein each spray
comprises about 25 meg or about 50 meg of mometasone furoate and about 665 meg of
olopatadine hydrochloride.
30. The use according to any one of claims 26-29, wherein the composition is
administered as 1 or 2 sprays per nostril once daily or twice daily for a period of at least 1
week.
31. The use according to any one of claims 26-29, wherein the composition is
administered as 1 or 2 sprays per nostril once daily or twice daily for a period of at least 2
weeks.
32. The use according to any one of claims 26-31, wherein the allergic rhinitis
is seasonal allergic rhinitis and/or nasal symptoms associated therewith.
33. The use according to any one of claims 26-32, wherein the total nasal
symptoms score (TNSS) of the human is reduced by at least 50 % from baseline after 2
weeks treatment.
34. The use according to any one of claims 26-33, wherein the total ocular
symptom score (TOSS) of the human is reduced by at least 40 % from baseline after 2
weeks treatment.
35. The use according to any one of claims 26-34, wherein the human exhibits
a positive skin prick test to an allergen.
36. A fixed-dose pharmaceutical composition comprising mometasone or its
salt and olopatadine or its salt in a weight ratio of about 1:5 to about 1:60 (based on the
equivalent weight of olopatadine free base) for use in treating allergic rhinitis in a human
in need thereof, wherein the composition is nasally administered as 1 or 2 sprays per
nostril of the human at least once daily.
37. The composition according to claim 36, wherein the weight ratio of
mometasone or its salt to olopatadine or its salt ranges from about 1:12 to about 1:53
(based on the equivalent weight of olopatadine free base).
38. The composition according to any one of claims 36-37, wherein the
mometasone salt is mometasone furoate and the olopatadine salt is olopatadine
hydrochloride.
39. The composition according to any one of claims 36-38, wherein each
spray comprises about 25 meg or about 50 meg of mometasone furoate and about 665
meg of olopatadine hydrochloride.
40. The composition according to any one of claims 36-39, wherein the
composition is administered as 1 or 2 sprays per nostril once daily or twice daily for a
period of at least 1 week.
41. The composition according to any one of claims 36-39, wherein the
composition is administered as 1 or 2 sprays per nostril once daily or twice daily for a
period of at least 2 weeks.
42. The composition according to any one of claims 36-41, wherein the
composition is a suspension wherein mometasone or its salt is present in particulate form
and olopatadine or its salt is present in solution.
43. The composition according to any one of claims 36-42, wherein the
allergic rhinitis is seasonal allergic rhinitis and/or nasal symptoms associated therewith.
44. The composition according to any one of claims 36-43, wherein the total
nasal symptoms score (TNSS) of the human is reduced by at least 50 % from baseline
after 2 weeks treatment.
45. The composition according to any one of claims 36-44, wherein the total
ocular symptom score (TOSS) of the human is reduced by at least 40 % from baseline
after 2 weeks treatment.
46. The composition according to any one of claims 36-45, wherein the
human exhibits a positive skin prick test to an allergen.