STABLE FIXED DOSE PHARMACEUTICAL COMPOSITION
COMPRISING MOMETASONE AND OLOPATADINE
PRIORITY DOCUMENT
This patent application claims priority to Indian Provisional Patent Application
number 2975/MUM/2013 (filed on Sep 13, 2013), the contents of which are
incorporated by reference herein.
FIELD OF THE INVENTION
The present patent application relates to a stable fixed dose, aqueous
pharmaceutical composition for nasal administration to a human comprising
mometasone or its salt and olopatadine or its salt. The application also relates to a
process for preparing the pharmaceutical composition and its use in the treatment of
rhinitis in a subject.
BACKGROUND OF THE INVENTION
Rhinitis is a medical term for irritation and inflammation of the mucous
membrane inside the nose. Rhinitis may cause additional symptoms, such as sneezing,
nasal itching, coughing, headache, fatigue, malaise, and cognitive impairment.
Olopatadine hydrochloride is chemically described as (Z)-l l-[3-
(dimethylamino) propylidene]-6, 11-dihydrodibenz [b, e] oxepin-2-acetic acid
hydrochloride, as disclosed in U.S. Patent Nos. 4,871,865 and 4,923,892. It is
commercially available in the U.S as PATANASE ®Nasal Spray, which contains 0.6%
w/v olopatadine in a non-sterile aqueous solution. It is indicated for the relief of the
symptoms of seasonal allergic rhinitis 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 is commercially
available as NASONEX ® in the U.S. as a nasal spray indicated for upper respiratory
conditions such as nasal sinus inflammation. It is available as 50 meg in a metereddose,
manual pump spray unit containing an aqueous suspension of mometasone
furoate monohydrate equivalent to 0.05% w/w mometasone furoate.
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.
WO 2014/092346 discloses a bitter taste masked pharmaceutical composition
comprising a corticosteroid, an antihistamine and stevia.
WO 2006/057769 discloses a method of delivering a nasal spray containing
olopatadine.
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 of rhinitis.
SUMMARY OF THE INVENTION
The present invention relates to a stable fixed dose, aqueous pharmaceutical
composition for nasal administration to a human. The composition comprises
mometasone or its salt and olopatadine or its salt. The pharmaceutical composition
may be contained within a container suitable for nasal administration.
One embodiment is a stable fixed dose, aqueous pharmaceutical composition
(e.g., contained in a container) for nasal administration to a human, where the
composition comprises about 0.001 % w/w to about 0.075 % w/w mometasone or its
salt and about 0.5 % w/w to about 0.8 % w/w olopatadine or its salt. The
pharmaceutical composition may be in the form of a solution or a suspension, but
preferably the composition is in the form of a suspension, wherein mometasone or its
salt is present in particle form and olopatadine or its salt is present in dissolved form.
In one aspect, the mometasone or its salt and olopatadine or its salt are present in a
weight ratio of about 1:3 to about 1:106, or from about 1:5 to about 1:53, or
preferably from about 1:5 to about 1:36.
The composition preferably also includes a hydrocolloid. In one embodiment,
the composition is a suspension and includes a hydrocolloid in a sufficient amount to
prevent phase separation (i.e., separation of the particles and solution) after 3 or 6
months of storage at 25 ± 2°C and 60% ± 5 % relative humidity (RH) or at 40 ± 2°C
and 75% ± 5 % RH.
Another embodiment is a stable fixed dose, aqueous pharmaceutical
composition (e.g., contained in a container) for nasal administration to a human,
where the composition comprises about 0.001 % w/w to about 0.075 % w/w
mometasone furoate monohydrate and about 0.5 % w/w to about 0.8 % w/w
olopatadine hydrochloride.
Yet another embodiment is a stable fixed dose, aqueous pharmaceutical
suspension composition (e.g., contained in a container) for nasal administration to a
human, where the composition comprises about 0.025 % w/w to about 0.05 % w/w
mometasone or its salt, about 0.6 % w/w to about 0.7 % w/w olopatadine or its salt
and a hydrocolloid.
Yet another embodiment is a stable fixed dose, aqueous pharmaceutical
suspension composition (e.g., contained in a container) for nasal administration to a
human, where the composition comprises about 0.025 % w/w to about 0.05 % w/w
mometasone or its salt, about 0.6 % w/w to about 0.7 % w/w olopatadine or its salt
and a hydrocolloid which includes carboxymethylcellulose sodium and xanthan gum.
The hydrocolloid may be present at a concentration of at least about 0 .1% w/w of the
composition.
One embodiment is a stable fixed dose, aqueous pharmaceutical suspension
composition (e.g., contained in a container) for nasal administration to a human,
comprising about 0.025 % w/w to about 0.05 % w/w mometasone furoate, about 0.6
% w/w to about 0.7 % w/w olopatadine hydrochloride and a hydrocolloid, where the
hydrocolloid is xanthan gum. The xanthan gum may be present at a concentration of
at least about 0 .1% w/w, or preferably between about 0 .1% w/w to about 3 % w/w of
the composition.
Another embodiment is a stable fixed dose, aqueous pharmaceutical
suspension composition (e.g., contained in a container) for nasal administration to a
human, comprising about 0.025 % w/w to about 0.05 % w/w mometasone furoate,
about 0.6 % w/w to about 0.7 % w/w olopatadine hydrochloride and a hydrocolloid,
where the hydrocolloid comprises sodium carboxymethyl cellulose. The sodium
carboxymethyl cellulose may be present at a concentration of at least about 0 .1%
w/w, or preferably between about 0 .1% w/w to about 3 % w/w of the composition.
Yet another embodiment is a stable fixed dose aqueous pharmaceutical
composition in the form of suspension (e.g., contained in a container) for nasal
administration to a human, comprising mometasone or its pharmaceutically
acceptable salt, olopatadine or its pharmaceutically acceptable salt, a hydrocolloid at a
concentration of at least about 0 .1% w/w of the composition and a pharmaceutical
acceptable excipient.
Suitable pharmaceutical acceptable excipients include, but are not limited to,
chelating agents, preservatives, buffers, surfactants, isotonicity agents, taste masking
agents, antioxidants, humectants, pH adjusting agents, and mixtures thereof.
In one embodiment, the pharmaceutical composition has a pH between about
3.3 and about 4 .1, or between about 3.5 and about 3.9.
The osmolality of the pharmaceutical composition may range between about
200 mOsm/kg to about 400 mOsm/kg, or about 250 mOsm/kg to about 350 mOsm/kg.
The viscosity of the pharmaceutical composition may range from about 10 cps
to about 200 cps or preferably from about 20 cps to about 150 cps.
In yet another aspect, the pharmaceutical composition is in the form of
suspension and contains mometasone furoate in particles having a mean particle size
in the range of from about 1 to about 20 , or preferably from about 1 to
about 15 . In an aspect, the suspension pharmaceutical composition of the present
invention has mean particle size of less than 15 when determined by microscopy
technique.
In yet another aspect, the pharmaceutical composition, when delivered as a
nasal spray has spray characteristics comprising a spray pattern having a longest axis
of about 15-75 mm, a shortest axis of about 10-65 mm, and an ellipticity of about 1-2.
Another embodiment is a stable fixed dose pharmaceutical composition in the
form of a suspension (e.g., contained in a container) for nasal administration to a
human, comprising mometasone furoate monohydrate, olopatadine hydrochloride and
a hydrocolloid which comprises xanthan gum at a concentration of about 0.3 % w/w
of the composition, wherein the composition has a pH between about 3.5 to about 3.9.
Yet another embodiment is a stable fixed dose pharmaceutical composition in
the form of suspension (e.g., contained in a container) for nasal administration to a
human, comprising mometasone furoate monohydrate, olopatadine hydrochloride and
a hydrocolloid which comprises sodium carboxymethyl cellulose at a concentration of
about 0.5 % w/w of the composition, wherein the composition has a pH between
about 3.5 to about 3.9.
In a further embodiment, the stable fixed dose, aqueous pharmaceutical
composition is contained in a sprayer, and on delivering a spray of the composition to
a human nose results in a spray pattern having a longest axis of 15-75 mm, a shortest
axis of 10-65 mm, and an ellipticity of 1-2.
In an embodiment, the present invention relates to a stable fixed dose
pharmaceutical aqueous suspension composition (e.g., contained in a container) for
nasal administration to a human, where the composition comprises (1) about 0.025 %
w/w mometasone furoate monohydrate, (2) about 0.665% w/w olopatadine
hydrochloride, (3) a hydrocolloid selected from about 0.3 % >w/w of xanthan gum and
about 0.5 % >w/w carboxymethyl cellulose sodium (4) about 0.02% w/w benzalkonium
chloride, (5) about 0.4 % > w/w sodium chloride, (6) about 0.01 % > w/w di-sodium
edetate, (7) about 0.94% w/w sodium phosphate heptahydrate, and (8) about 0.01 % >
w/w polysorbate 80.
Another embodiment is a stable fixed dose pharmaceutical aqueous suspension
composition (e.g., contained in a container) for nasal administration to a human,
where the composition comprises (1) about 0.050 % > w/w mometasone furoate
monohydrate, (2) about 0.665% w/w olopatadine hydrochloride, (3) a hydrocolloid
selected from about 0.3 % >w/w of xanthan gum and about 0.5 % >w/w carboxymethyl
cellulose sodium, (4) about 0.02%> w/w benzalkonium chloride, (5) about 0.4 % > w/w
sodium chloride, (6) about 0.01 % > w/w di-sodium edetate, (7) about 0.94% w/w
sodium phosphate heptahydrate, and (8) about 0.01 % w/w polysorbate 80.
Yet another embodiment is a stable fixed dose pharmaceutical aqueous
suspension composition (e.g., contained in a container) for nasal administration to a
human, where the composition comprises (1) about 0.025 % w/w mometasone furoate
monohydrate, (2) about 0.665% w/w olopatadine hydrochloride, (3) a hydrocolloid
selected from about 0.3 % >w/w of xanthan gum and about 0.5 % w/w carboxymethyl
cellulose sodium, (4) about 1%> w/w to about 1.2% w/w mixture of microcrystalline
cellulose and carboxymethyl cellulose sodium, (5) about 0.02% w/w benzalkonium
chloride, (6) about 0.4 % w/w sodium chloride, (7) about 0.01 % w/w di-sodium
edetate, (8) about 0.94% w/w sodium phosphate heptahydrate, and (9) about 0.01 %
w/w polysorbate 80.
Yet another embodiment is a stable fixed dose pharmaceutical aqueous
suspension composition (e.g., contained in a container) for nasal administration to a
human, where the composition comprises (1) about 0.050 % w/w mometasone furoate
monohydrate, (2) about 0.665% w/w olopatadine hydrochloride, (3) a hydrocolloid
selected from about 0.3 % w/w of xanthan gum and about 0.5 % w/w carboxymethyl
cellulose sodium, (4) about 1% w/w to about 1.2% w/w mixture of microcrystalline
cellulose and carboxymethyl cellulose sodium, (5) about 0.02% w/w benzalkonium
chloride, (6) about 0.4 % w/w sodium chloride, (7) about 0.01 % w/w di-sodium
edetate, (8) about 0.94% w/w sodium phosphate heptahydrate, and (9) about 0.01 %
w/w polysorbate 80.
Yet another embodiment is a stable suspension suitable for nasal
administration to a human, comprising (a) an aqueous solvent, (b) particles of
mometasone furoate suspended in the solvent, the particles having a mean particle
size of from about 1 to about 20 , (c) olopatadine hydrochloride dissolved in the
solvent, and (d) a hydrocolloid, the suspension having a viscosity in the range of
about 20 cps to about 150 cps. In one preferred embodiment, the suspension has a pH
of about 3.5-3.9, and osmolality in the range of about 250 mOsm/kg to about 350
mOsm/kg. In one embodiment, the suspension further comprises a chelating agent, a
preservative, a buffer, a surfactant, an isotonicity agent, and optionally a pH adjusting
agent.
In another embodiment, the present invention relates to a method of treating
rhinitis in a human in need thereof comprising administering by the nasal route a
stable fixed dose, aqueous pharmaceutical composition of the present invention. In
one embodiment, the pharmaceutical composition comprises about 0.025 % w/w to
about 0.05 % w/w mometasone or its salt and about 0.5 % w/w to about 0.8 % w/w
olopatadine or its salt, as disclosed herein.
In a further embodiment, the present invention relates to use of a
pharmaceutical composition of the present invention for the treatment of rhinitis in a
human in need thereof. For example, one embodiment is the use of about 0.025 %
w/w to about 0.05 % w/w mometasone or its salt and about 0.5 % w/w to about 0.8 %
w/w olopatadine or its salt in the preparation of a stable fixed dose, aqueous
pharmaceutical composition (e.g., contained in a container) for the treatment of
rhinitis in a human in need thereof.
In a further embodiment, the present invention relates to a stable fixed dose,
aqueous pharmaceutical composition (e.g., contained in a container) for nasal
administration comprising about 0.025 % w/w to about 0.05 % w/w mometasone or
its salt and about 0.5 % w/w to about 0.8 % w/w olopatadine or its salt for the
treatment of rhinitis in a human in need thereof.
In a further embodiment, the present invention relates to a kit comprising a
stable fixed dose, aqueous pharmaceutical composition contained in a container, for
nasal administration and a package insert containing instructions about the use of the
pharmaceutical composition.
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 in a provisional application from which
priority is claimed are in conflict, the definition in the present application shall control
the meaning of the terms.
The term "effective amount" when used in connection with an active
ingredient denotes an amount of the active ingredient that, when administered to a
subject for treating 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.
In the context of present invention, the effective amount of mometasone or its
salt can range from about 0.01 mg to about 10 mg or preferably from about 0.02 mg to
about 5 mg. The effective amount of olopatadine or its salt can range from about 0.05
mg to about 20 mg, or preferably from about 0 .1mg to about 15 mg.
In an aspect of this invention, for daily administration by the nasal route, the
effective amount of mometasone or its salt can range from about 10 meg to about 500
meg, or preferably from about 20 meg to about 400 meg, and that for olopatadine or
its salt can ranges from about 50 meg to about 7000 meg, or preferably from about
100 meg to about 5400 meg.
By "salt" or "pharmaceutically acceptable salt", it is meant those salts and
esters 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
hydrochloride, furoate, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate,
oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate,
mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate,
lactobionate, and lauryl sulphate salts. Representative alkali or alkaline earth metal
salts include sodium, calcium, potassium and magnesium salts.
The term "treating" or "treatment" as used herein includes the prophylaxis,
mitigation, prevention, amelioration, or suppression of a disorder modulated by
mometasone or its salt or olopatadine or its salt, or by a combination of the two in a
mammal.
By "pharmaceutically acceptable excipients", it is meant any of the
components of a pharmaceutical composition other than the active ingredients and
which are approved by regulatory authorities or are generally regarded as safe for
human or animal use.
As used herein, the term "average particle size" (or synonymously, "mean
particle size") refers to the distribution of particles, wherein about 50 volume percent
of all the particles measured have a size less than the defined average particle size
value and about 50 volume percent of all particles measured have a particle size
greater than the defined average particle size value. This can be identified by the term
"D50" or "d The average particle size can be measured using various techniques
such as microscopy, laser diffraction, photon correlation spectroscopy (PCS) and
Coulter's principle.
In the context of present invention, the "hydrocolloid" refers to a colloid
system wherein hydrophilic colloid particles (e.g., hydrophilic polymers) are
dispersed in water. The hydrocolloid system can exist in gel state or sol (liquid) state.
In suspension compositions, the hydrocolloids function as thickening, stabilizing and
suspending agents. Non-limiting examples of hydrocolloid include xanthan gum, gum
arabic, guar gum, locust bean gum, alginate, starch, agar-agar, carrageenan, gelatin,
Avicel RC591 ® (mixture of microcrystalline cellulose & sodium carboxymethyl
cellulose) and cellulose derivatives (e.g., carboxymethyl cellulose sodium).
Preferably, the hydrocolloid includes xanthan gum or carboxymethylcellulose sodium.
As used herein, the term "container" refers to single unit-dose container or
multi-dose container. Suitable single unit-dose containers or multi-dose containers
include, but are not limited to, glass, aluminum, polypropylene or high density
polyethylene, for example, high density polyethylene containers produced using a
blow-fill-seal manufacturing technique. In one embodiment, the container is a sprayer
which delivers the pharmaceutical composition in the form of a fine mist. A sprayer
generally includes a container containing a pharmaceutical composition, a pump
sealed (e.g., hermetically engaged) with the container, an actuator removably
receiving a top portion of the pump, and a cap removably engaged with the container
and the actuator.
The present invention relates to a stable fixed dose, aqueous pharmaceutical
composition (e.g., contained in a container) for nasal administration to a human. The
comprises about 0.001 % w/w to about 0.075 % w/w mometasone or its salt and about
0.5 % w/w to about 0.8 % w/w olopatadine or its salt.
The pharmaceutical composition may be in the form of a solution or a
suspension, but preferably the composition is in the form of a suspension, wherein
mometasone or its salt is present in particle form and olopatadine or its salt is present
in dissolved form. The mometasone or its salt and olopatadine or its salt may be
present at a weight ratio of about 1:3 to about 1:106, or from about 1:5 to about 1:53
or preferably from about 1:5 to about 1:36.
The composition preferably also includes a hydrocolloid. In one embodiment,
the composition is a suspension and includes a hydrocolloid in a sufficient amount to
prevent phase separation (i.e., separation of the particles and solution) after 3 or 6
months of storage at 25 ± 2°C and 60% ± 5 % relative humidity (RH) or at 40 ± 2°C
and 75% ± 5 % RH.
The term 'stable' as used in connection with aqueous suspensions refers to a
composition when shaken and then stored for at least 24 hours at ambient condition
does not show phase separation on visual inspection. Preferably, such stable
composition does not show phase separation for a period of at least 3 days, or at least
5 days, or at least 7 days. In one aspect, the 'stable' composition of the present
invention shows, upon shaking (e.g., for 1 minute) and visual inspection , no lump
formation and a total impurity content of no more than 1.0% after storage at ambient
conditions (at about 25 °C and a relative humidity of about 60 %) for a period of at
least 6 months.
In the context of the present invention, the drug content and impurities can be
determined by various analytical techniques such as HPLC, LC-MS, TLC and the
like.
It was observed that when various pharmaceutical compositions for nasal
administration comprising mometasone or its salt and olopatadine or its salt were
prepared, the compositions generally showed physical separation in the suspension
composition. This physical instability further leads to lack of dose uniformity.
Surprisingly, it was found that addition of a hydrocolloid at certain concentrations
(e.g. at a concentration of at least about 0 .1% w/w) in the suspension composition
yielded a physically stable composition (with no separation) suitable for nasal
administration.
Another embodiment is a stable fixed dose, aqueous pharmaceutical
suspension composition (e.g., contained in a container) for nasal administration to a
human, where the composition comprises about 0.025 % w/w to about 0.05 % w/w
mometasone or its salt, about 0.6 % w/w to about 0.7 % w/w olopatadine or its salt
and a hydrocolloid.
Yet another embodiment is a stable fixed dose, aqueous pharmaceutical
suspension composition (e.g., contained in a container) for nasal administration to a
human, where the composition comprises about 0.025 % w/w to about 0.05 % w/w
mometasone or its salt, about 0.6 % w/w to about 0.7 % w/w olopatadine or its salt
and a hydrocolloid which includes carboxymethylcellulose sodium and xanthan gum.
The hydrocolloid may be present at a concentration of at least about 0 .1% w/w of the
composition.
Yet another embodiment is a stable fixed dose, aqueous pharmaceutical
suspension composition (e.g., contained in a container) for nasal administration to a
human, comprising about 0.025 % w/w to about 0.05 % w/w mometasone furoate,
about 0.6 % w/w to about 0.7 % w/w olopatadine hydrochloride and a hydrocolloid
which comprises xanthan gum. The xanthan gum may be present at a concentration of
at least about 0 .1% w/w, or preferably between about 0.3 % w/w to about 3 % w/w of
the composition.
Yet another embodiment is a stable fixed dose, aqueous pharmaceutical
suspension composition (e.g., contained in a container) for nasal administration to a
human, comprising about 0.025 % w/w to about 0.05 % w/w mometasone furoate,
about 0.6 % w/w to about 0.7 % w/w olopatadine hydrochloride and a hydrocolloid
which comprises sodium carboxymethyl cellulose. The sodium carboxymethyl
cellulose may be present at a concentration of at least about 0 .1% w/w, or preferably
between about 0 .1% w/w to about 3 % w/w of the composition.
Yet another embodiment is a stable fixed dose aqueous pharmaceutical
composition in the form of suspension (e.g., contained in a container) for nasal
administration to a human, comprising mometasone or its pharmaceutically
acceptable salt, olopatadine or its pharmaceutically acceptable salt, a hydrocolloid
(e.g., at a concentration of at least about 0 .1% w/w of the composition) and a
pharmaceutical acceptable excipient.
It will also be appreciated to the skilled artisan that in order to improve the
physical properties, appearances, or smells of the composition of the present
invention, one or more further pharmaceutically acceptable excipients may be added
as desired. Suitable pharmaceutical acceptable excipients include, but are not limited
to, chelating agents, preservatives, buffers, surfactants, isotonicity agents, taste
masking agents, antioxidants, humectants, pH adjusting agents, and any combination
of any of the foregoing.
Suitable surfactants which can be used for preparing aqueous nasal spray
composition may include one or more of anionic, cationic, non-ionic or zwitterionic
surfactants.
Examples of suitable surfactants which can be employed in the aqueous nasal
spray suspension may be selected from, but not limited to, polyethoxylated sorbitan
derivatives such as polysorbates, their ether ethoxylates, produced by reaction of
sorbitan esters with ethylene oxide, polyoxyethylene alkyl phenol, polyoxyethylene
cetyl ether, polyoxyethylene alkyl-aryl ether, polyoxyethylene monolaurate,
polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate,
polyoxyethylene esters or mixed fatty and resin acids, polyoxyethylene sorbitol
lanolin derivative, polyoxyethylene tridecyl ether, polyoxyethylene sorbitan esters of
mixed fatty and resin acids, , polyoxyethylene sorbitan monostearate,
polyoxyethylene sorbitan monooleate, polyoxyethylene monostearate,
polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene tridecyl
ether, polyoxyethylene fatty alcohol, polyoxyethylene alkyl amine, polyoxyethylene
glycol monopalmitate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene
cetyl ether, polyoxyethylene oxypropylene stearate, polyoxyethylene lauryl ether,
polyoxyethylene lanolin derivative, sodium oleate, quaternary ammonium derivative,
potassium oleate, N-cetyl N-ethyl morpholinium ethosulfate, sodium lauryl sulfate or
mixtures thereof. Preferred surfactants are polyethoxylated sorbitan derivatives (such
as polysorbate 80). The amount of surfactant may range from about 0.001% to about
1% w/w relative to the total weight of the composition.
In order to improve the ability of the aqueous nasal spray suspension to be
tolerated on administration to the nasal mucous membrane, it is advantageous to
formulate it as isotonic. The osmolality can be set by variation of the amounts of the
substances present in the aqueous nasal spray suspension besides mometasone,
olopatadine and any further substances present, and/or by addition of an isotonicity
agent, preferably a physiologically tolerated salt, such as, for example, sodium
chloride or potassium chloride, or a physiologically tolerated polyol, such as, for
example, a sugar alcohol, in particular sorbitol or glycerol, in the concentration
necessary for rendering isotonic.
Examples of suitable preservatives which can be employed in the aqueous
nasal spray suspension include, but are not limited to, benzyl alcohol, quaternary
ammonium halides, phenylcarbinol, thimerosal, and disodium edetate. Quaternary
ammonium halide preservatives are preferred. Suitable quaternary ammonium halide
preservatives include polyquaternium-1 and benzalkonium halides. Preferred
benzalkonium halides include benzalkonium chloride and benzalkonium bromide. The
amount of the preservative present in the aqueous nasal spray suspension may range
from about 0.005 to about 0.2% w/w relative to the total weight of the composition.
Preferably, the preservative is present at a concentration of about 0.02% w/w relative
to the total weight of the composition.
Examples of suitable chelating agents which can be employed in the aqueous
nasal spray suspension include, but are not limited to, edetate disodium (EDTA),
edetate trisodium, edetate tetrasodium, and diethyleneamine pentaacetate, preferably
EDTA. The amount of the chelating agent present in the aqueous nasal spray
suspension of the present invention may range from about 0.0002 to about 0.5% w/w
relative to the total weight of the composition.
Examples of suitable buffers which can be employed in the aqueous nasal
spray suspension include, but are not limited to, citric acid, acetic acid, fumaric acid,
hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric
acid, tartaric acid, phosphate salts (e.g., dibasic sodium phosphate, such as dibasic
sodium phosphate heptahydrate), or combinations thereof. The suspension of the
present invention may comprise an amount of a buffer sufficient to maintain the pH of
the composition to from about 3 to about 6 . Preferably, the amount of buffer ranges
from about 0.005%> to about 1%> w/w relative to the total weight of the composition.
Examples of suitable sweetener/taste masking agents which can be employed
in the aqueous nasal spray suspension include, but are not limited to, sucralose,
thaumatin (e.g., Talin (R ), sucrose, saccharin (including salt forms such as sodium and
calcium salts), fructose, glucose, dextrose, corn syrup, aspartame, acesulfame-K,
xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, neotame, mannitol, eucalyptus
oil, camphor, and natural or artificial flavors or flavoring agents (for example
menthol, mints, vanilla, orange, etc.), or combinations of two or more of such agents.
A particularly preferred taste masking agent is sucralose. The amount of the
sweetener/taste masking agent present in the aqueous nasal spray suspension may
range from about 0.01 % to about 1% w/w relative to the total weight of the
composition.
Examples of suitable antioxidants which can be employed in the aqueous nasal
spray suspension include, but are not limited to, ascorbic acid, alpha-tocopherol
(vitamin-E), butylated hydroxyanisole, butylated hydroxytoluene, glutathione, and
any combination of any of the foregoing. The amount of the antioxidants present in
the aqueous nasal spray composition may range from about 0.0002 % to about 0.5%
w/w relative to the total weight of the composition.
Examples of suitable humectants which can be employed in the aqueous nasal
spray suspension include, but are not limited to, glycerin, sorbitol, polyethylene
glycol, propylene glycol or mixtures thereof, which are mixed with a suitable
humectant vehicle such as water. The amount of humectant present in the aqueous
nasal spray suspension may range from about 0.0002 % to about 0.5% w/w relative to
the total weight of the composition.
Suitable pH adjusting agents include, but are not limited to, sodium hydroxide
and hydrochloric acid.
In the context of present invention, the pharmaceutical stable fixed dose
suspension composition for nasal administration may have a pH of between about 3.3
and about 4 .1, or between about 3.5 and about 3.9. The osmolality of the composition
may range between about 200 mOsm/kg and about 400 mOsm/kg, or about 250
mOsm/kg and about 350 mOsm/kg. The viscosity of the composition may be about
10 cps to about 200 cps or preferably from about 20 cps to about 150 cps.
In yet another aspect, the pharmaceutical composition in the form of
suspension and contains mometasone furoate in particles having mean particle size in
the range of from about 1 to about 20 , or preferably from about 1 to about
15 . In an aspect, the suspension pharmaceutical composition of the present
invention has mean particle size of less than 15 when determined by microscopy
technique.
In yet another aspect, the pharmaceutical composition, when delivered as a
nasal spray has a spray pattern having a longest axis of about 15-75 mm, a shortest
axis of about 10-65 mm, and an ellipticity of about 1-2.
In the context of present invention, the viscosity can be determined by various
known instruments such as a Dynamic stress rheometer or Brookfield viscometer. In a
preferred embodiment, the viscosity is determined by a Brookfield viscometer by
measuring torque transmission through a sample using a rotating spindle.
In another embodiment, the present invention relates to a stable fixed dose,
aqueous pharmaceutical composition (e.g., contained in a container) for nasal
administration to a human, where the composition comprises about 0.001 % w/w to
about 0.075 % w/w mometasone furoate monohydrate and about 0.5 % w/w to about
0.8 % w/w olopatadine hydrochloride.
Another embodiment is a stable fixed dose pharmaceutical composition in the
form of suspension (e.g., contained in a container) for nasal administration to a
human, comprising mometasone furoate monohydrate, olopatadine hydrochloride and
a hydrocolloid which comprises xanthan gum at a concentration of about 0.3 % w/w
of the composition, wherein the composition has a pH between about 3.5 and about
3.9.
Yet another embodiment is a stable fixed dose pharmaceutical composition in
the form of suspension (e.g., contained in a container) for nasal administration to a
human, comprising mometasone furoate monohydrate, olopatadine hydrochloride and
a hydrocolloid which comprises sodium carboxymethyl cellulose at a concentration of
about 0.5 % w/w of the composition, wherein the composition has a pH between
about 3.5 and about 3.9.
Yet another embodiment is a stable fixed dose pharmaceutical aqueous
suspension composition (e.g., contained in a container) for nasal administration to a
human, where the composition comprises (1) about 0.025 % w/w mometasone furoate
monohydrate, (2) about 0.665% w/w olopatadine hydrochloride, (3) a hydrocolloid
selected from about 0.3 % w/w of xanthan gum and about 0.5 % w/w carboxymethyl
cellulose sodium, (4) about 0.02% w/w benzalkonium chloride, (5) about 0.4 % w/w
sodium chloride, (6) about 0.01 % w/w di-sodium edetate, (7) about 0.94% w/w
sodium phosphate heptahydrate, and (8) about 0.01 % w/w polysorbate 80.
Yet another embodiment is a stable fixed dose pharmaceutical aqueous
suspension composition (e.g., contained in a container) for nasal administration to a
human, where the composition comprises (1) about 0.050 % w/w mometasone furoate
monohydrate, (2) about 0.665% w/w olopatadine hydrochloride, (3) a hydrocolloid
selected from about 0.3 % w/w of xanthan gum and about 0.5 % w/w carboxymethyl
cellulose sodium, (4) about 0.02% w/w benzalkonium chloride, (5) about 0.4 % w/w
sodium chloride, (6) about 0.01 % w/w di-sodium edetate, (7) about 0.94% w/w
sodium phosphate heptahydrate, and (8) about 0.01 % w/w polysorbate 80.
Yet another embodiment is a stable fixed dose pharmaceutical aqueous
suspension composition (e.g., contained in a container) for nasal administration to a
human, where the composition comprises (1) about 0.025 % w/w mometasone furoate
monohydrate, (2) about 0.665% w/w olopatadine hydrochloride, (3) a hydrocolloid
selected from about 0.3 % w/w of xanthan gum and about 0.5 % w/w carboxymethyl
cellulose sodium, (4) about 1%> w/w to about 1.2% w/w mixture of microcrystalline
cellulose and carboxymethyl cellulose sodium, (5) about 0.02% w/w benzalkonium
chloride, (6) about 0.4 % w/w sodium chloride, (7) about 0.01 % w/w di-sodium
edetate, (8) about 0.94% w/w sodium phosphate heptahydrate, and (9) about 0.01 %
w/w polysorbate 80.
Yet another embodiment is a stable fixed dose pharmaceutical aqueous
suspension composition (e.g., contained in a container) for nasal administration to a
human, where the composition comprises (1) about 0.050 % w/w mometasone furoate
monohydrate, (2) about 0.665% w/w olopatadine hydrochloride, (3) a hydrocolloid
selected from about 0.3 % w/w of xanthan gum and about 0.5 % w/w carboxymethyl
cellulose sodium, (4) about 1% w/w to about 1.2% w/w mixture of microcrystalline
cellulose and carboxymethyl cellulose sodium, (5) about 0.02% w/w benzalkonium
chloride, (6) about 0.4 % w/w sodium chloride, (7) about 0.01 % w/w di-sodium
edetate, (8) about 0.94% w/w sodium phosphate heptahydrate, and (9) about 0.01 %
w/w polysorbate 80.
Yet another embodiment is a stable suspension suitable for nasal
administration to a human, comprising (a) an aqueous solvent, (b) particles of
mometasone furoate suspended in the solvent, the particles having a mean particle
size of from about 1 to about 20 , (c) olopatadine hydrochloride dissolved in the
solvent, and (d) a hydrocolloid, the suspension having a viscosity in the range of
about 20 cps to about 150 cps. In one preferred embodiment, the suspension has a pH
of about 3.5-3.9, and osmolality in the range of about 250 mOsm/kg to about 350
mOsm/kg. In one embodiment, the suspension further comprises a chelating agent, a
preservative, a buffer, a surfactant, an isotonicity agent, and optionally a pH adjusting
agent.
In a further embodiment, the present invention relates to kit comprising a
stable fixed dose, aqueous pharmaceutical composition of the present invention
contained in a container for nasal administration and a package insert containing
instructions about the use of said pharmaceutical composition. In one preferred
embodiment, the container is part of a sprayer which has an actuator. When the
actuator is actuated, the composition is delivered in the form of a spray.
In a further embodiment, the pharmaceutical composition is contained in a
sprayer, and has, on deliver a spray of the composition to a human nose, a spray
pattern having a longest axis of 15-75 mm, a shortest axis of 10-65 mm, and an
ellipticity of 1-2.
In the context of present invention, the pharmaceutical composition when
delivered as a nasal spray using a sprayer yields a specific spray pattern and spray
droplet size. The spray pattern can be determined by various known techniques such
as with an ADSA with NSPUA set up (Innova System) and the spray droplet size
distribution can be determined by various known techniques such as with a Malvern
Spraytec with NSPUA set up (Innova System).
The following describes a typical procedure for characterizing droplet size
distribution of the spray - The sprayer is loaded with a composition as described
above and primed by an actuating pump via an actuator until a fine mist appears out
of the nozzle of the sprayer. A commercially available laser diffraction instrument is
arranged so that the nozzle is about 3 cm or 6 cm below the laser beam of the laser
diffraction instrument. The pump is actuated with a conventional mechanical actuator
using a constant force. The resulting spray of the composition crosses the laser beam.
Data are collected for D10, D50, D 0, SPAN, and % Volume <10 . The average
values for each of these parameters for three sprays are calculated.
The stable aqueous nasal spray suspension of mometasone and olopatadine
may comprise one or more additional pharmaceutical active agent/s selected from the
therapeutic category of, but not limited to, non-steroidal anti-inflammatory agents,
decongestants, and any combination of any of the foregoing.
The aqueous nasal spray suspension can be administered as a drop or any other
form suitable for topical administration. The composition may also be administered
using a nasal tampon or a nasal sponge.
In a preferred embodiment, the aqueous suspension is provided in the form of
nasal spray wherein the suspension is administered in a single unit-dose container or
multi-dose container. Suitable single unit-dose containers or multi-dose containers
include, but are not limited to, glass, aluminum, polypropylene or high density
polyethylene, for example, high density polyethylene containers produced using a
blow-fill-seal manufacturing technique.
In certain additional embodiments, the invention provides a multi dosage
composition of matter, comprising: (a) a multi-unit dosage of a pharmaceutical
composition of the present invention; and (b) a container comprising: (i) a squeezable
chamber holding the multi dosage of the composition and having an opening wherein
the dosage exits the opening when the squeezable chamber is squeezed; and (ii) a
closure mechanism removably attached to the opening of the squeezable chamber. In
certain embodiments, the multi dosage container is made of a moldable polymer.
In such embodiments, suitable polymers include, but are not limited to,
polyethylene, polypropylene (PP), polystyrene (PS), nylon (Ny), polyvinyl chloride
(PVC), polyethylene terephthalate (PET), polycarbonate (PC), polyoxymethylene
(POM), polysulfon (PSF), polyethersulfon (PES), polyacrylate (PAR), and polyamid
(PA). In certain embodiments, polymers include polyethylene, particularly mediumdensity
polyethylene (MDPE) (or branched polyethylene) or high density
polyethylene (HDPE) (or linear, polyethylene). In one embodiment, the multi dose
container is made of high density polyethylene (HDPE).
Other means for delivering the nasal spray, such as inhalation via a metered
dose inhaler (MDI), may also be used. Several types of MDIs are regularly used for
administration by inhalation. These types of devices can include breath-actuated
MDIs, spacer/holding chambers in combination with MDIs, and nebulizers. The term
"MDI" as used herein refers to an inhalation delivery system comprising, for example,
a canister containing a mixture of an active agent and a propellant optionally with one
or more excipients, a metered dose valve, an actuator, and a mouthpiece. The canister
is usually filled with a suspension of an active agent, such as the nasal spray
composition, and a propellant, such as one or more hydrofluoroalkanes [e.g. 1, 1, 1, 2-
tetrafluoroethane (HFA-134a) and 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (HFA-227)],
chlorofluorocarbons, and alcohols such as ethanol, isopropanol, butanol, propanol or
mixtures thereof. When the actuator is depressed a metered dose of the suspension is
aerosolized for inhalation. Particles comprising the active agent are propelled towards
the mouthpiece where they may then be inhaled by a subject.
The present invention also relates to a method of treating rhinitis in a human in
need thereof comprising administering by the nasal route a stable fixed dose, aqueous
pharmaceutical composition of the present invention. For example, the
pharmaceutical composition which may be contained in a container comprises about
0.025 % w/w to about 0.05 % w/w mometasone or its salt and about 0.5 % w/w to
about 0.8 % w/w olopatadine or its salt.
In a further embodiment, the present invention relates to use of about 0.025 %
w/w to about 0.05 % w/w mometasone or its salt and about 0.5 % w/w to about 0.8 %
w/w olopatadine or its salt in the preparation of a stable fixed dose, aqueous
pharmaceutical composition (e.g., contained in a container) for the treatment of
rhinitis in a human in need thereof. Any pharmaceutical composition described herein
may be used.
In a further embodiment, the present invention relates to a stable fixed dose,
aqueous pharmaceutical composition (e.g., contained in a container) for nasal
administration comprising about 0.025 % w/w to about 0.05 % w/w mometasone or
its salt and about 0.5 % w/w to about 0.8 % w/w olopatadine or its salt for the
treatment of rhinitis in a human in need thereof.
Rhinitis in the context of present invention includes, but is not limited to,
irritation and inflammation of the mucous membrane inside the nose and nasal and
non-nasal symptoms associated therewith. It includes allergic rhinitis, persistent
rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, rhinitis medicamentosa,
vasomotor rhinitis, infective rhinitis, autonomic rhinitis, hormonal rhinitis, druginduced
rhinitis, atrophic rhinitis, and gustatory rhinitis. Preferably, it includes
allergic rhinitis, perennial rhinitis, persistent rhinitis, seasonal rhinitis and nasal and
non-nasal symptoms associated therewith.
In the context of present invention, the nasal and non-nasal symptoms
associated with allergic rhinitis include sneezing, nasal itching, rhinorrhea (runny
nose), nasal obstruction, coughing, ocular pruritis, excess lacrimation, headache,
fatigue, common cold (also known as nasopharyngitis, rhinopharyngitis, acute coryza,
or cold), malaise and cognitive impairment.
It will be understood that various modifications may be made to the
embodiments disclosed herein. Therefore the above description should not be
construed as limiting, but merely as exemplifications of preferred embodiments.
Other arrangements and methods may be implemented by those skilled in the art
without departing from the scope and spirit of this invention.
The following examples are provided to enable one skilled in the art to
practice the invention and are merely illustrative of the invention. The examples
should not be read as limiting the scope of the invention.
EXAMPLES
EXAMPLES 1-2: Suspension compositions containing Mometasone furoate,
Olopatadine HC1 and Carboxymethylcellulose Sodium
SN Ingredient Example 1 Example 2
(% w/w) (% w/w)
1 Mometasone Furoate monohydrate 0.050 0.025
Eq. to Mometasone furoate
2 Olopatadine Hydrochloride 0.665 0.665
3 Avicel RC 591 (Microcrystalline Cellulose 1.200 1.200
and Carboxymethylcellulose Sodium)
4 Benzalkonium chloride (50 % solution) 0.040 0.040
5 Carboxymethylcellulose Sodium 0.500 0.500
(Cekol 2000 P)
6 Sodium chloride 0.410 0.410
7 Edetate disodium 0.010 0.010
8 Dibasic sodium phosphate heptahydrate 0.940 0.940
9 Polysorbate 80 0.010 0.010
10 Sodium Hydroxide Q.S. Q.S.
11 Hydrochloric acid Q.S. Q.S.
12 Water for injection Q.S. Q.S.
Observations
Physical observation on standing for 24 No phase No phase
hours separation separation
observed observed
Mean Particle size by microscopy Below 15 Below 15 .
Manufacturing procedure:
1. Avicel RC-591 was added in water for injection with homogenization and
allowed to hydrate.
2. Carboxymethyl cellulose Sodium was dispersed in water for injection and
added to step -1.
3. Dibasic sodium phosphate heptahydrate, Sodium chloride, Edetate disodium
and Olopatadine were dissolved in water. The pH was adjusted to 2.8 - 3.2
with Hydrochloric acid.
4. Step-3 was added to Step-1 with homogenization.
5. Polysorbate 80 was dissolved in water for injection. Mometasone Furoate
monohydrate was added and stirred to form slurry.
6. Step-5 was added to Step-4 with homogenization.
7. Benzalkonium chloride was dissolved in water for injection.
8. Step-7 was added to Step-6 with homogenization.
9. The pH was checked and adjusted to 3.5-3.9 with HC1 and the total weight
was adjusted with Water for injection. The osmolality of the composition was
about 250-350 mOsm/kg.
The composition was subjected to stability studies at different conditions. The results
of the same are as follows:
Container details: Sprayer containing HDPE bottle crimped with pump and fitted with
an actuator and cap.
Stability Study Data
Test Initial 3 months 6 months
Ex.1 Ex. 2 Ex.1 Ex. 2 Ex. 1 Ex. 2
Stability condition (25°C ± 2°C & 60% RH ± 5 % RH)
pH 3.61 3.69 3.73 3.78 3.81
Osmolality (mOsm)* 310 308 299 298 302 3 11
Viscosity (cps)** 32.5 42.5 42.3 40.6 40.9
Weight per ml (g/ml) 1.01 1.021 1.024 1.029 1.019
Assay of mometasone furoate 101 102.4 99.1 99.3 98.2 97.2
Stability Study Data
Test Initial 3 months 6 months
Ex.1 Ex. 2 Ex.1 Ex. 2 Ex. 1 Ex. 2
(% w/w)
Assay of olopatadine 98.2 99.9 97.3 99.1 97.8 97.9
hydrochloride (% w/w)
Related substances for mometasone furoate
Impurity DMCF (%) 0.02 0.03 0.09 0.10 0.14 0.17
Any other impurity (%) 0.04 0.04 0.03
Total impurities (%) 0.09 0.23 0.29 0.31 0.34
Related substances for olopatadine hydrochloride
Olopatadine E-isomer (%) 0.08 0.07 0.09 0.09
Any other impurity (%) 0.03 0.04 0.09 0.12 0.1 1 0.1 1
Total impurities (%) 0.15 0.16 0.20 0.25 0.37 0.38
Spray Pattern fat 6cm)
Major Axis (mm) 52 60 63 59 6 1
Minor Axis (mm) 43 47 49 53 49 5 1
Ellipticity 1.2 1.1 1.1 1.2 1.1 1.2
Droplet size distribution fat 6 cm)
Dio () 18.91 19.45 19.26 19.70 19.33 18.88
D50 () 36.39 37.61 35.96 37.34 39.28 37.85
D 0 () 72.46 76.44 70.29 75.78 85.42 72.07
SPAN 1.47 1.51 1.42 1.5 1.67 1.46
Stability condition (40°C ± 2°C & 75% RH ± 5 % RH)
pH 3.61 3.68 3.72 3.59 3.68
Osmolality (mOsm) 310 308 298 306 305 299
Viscosity (cps) 32.5 45.2 42.6 41.8 41.5
Weight per ml (g/ml) 1.01 1.023 1.019 1.026 1.025
Assay of mometasone furoate 101 102.4 99.8 100.4 98.3 98.4
(%)
Assay of oloptadine 98.2 99.9 99.3 102.5 98.7 99.7
hydrochloride (%)
Stability Study Data
Test Initial 3 months 6 months
Ex.1 Ex. 2 Ex.1 Ex. 2 Ex. 1 Ex. 2
Related substances for mometasone furoate
Impurity DMCF (%) 0.02 0.03 0.014 0.20 0.25 0.25
Any other impurity (%) 0.04 0.04 0.04 0.03 0.03 0.04
Total impurities (%) 0.09 0.25 0.39 0.40 0.46
Related substances for olopatadine hydrochloride
Olopatadine E-isomer (%) 0.08 0.07 0.08 0.08 0.09
Any other impurity (%) 0.03 0.04 0.21 0.18 0.31 0.30
Total impurities (%) 0.15 0.16 0.32 0.36 0.68 0.64
Spray Pattern fat 6 cm)
Major Axis (mm) 52 52 6 1 58 58 58
Minor Axis (mm) 43 47 50 49 48 49
Ellipticity 1.2 1.1 1.2 1.2 1.2 1.2
Droplet size distribution (at 6 cm)
Dio () 18.91 19.45 19.49 19.27 18.05 18.09
D50 () 36.39 37.61 35.29 34.68 36.19 36.12
D 0 () 72.46 76.44 64.66 63.49 71.89 70.06
SPAN 1.47 1.51 1.28 1.27 1.50 1.44
* Determined by Advanced Instruments Osmometer (Model 3250).
** Determined by Brookfield viscometer.
EXAMPLES 3-4: Suspension compositions containing Mometasone furoate,
Olopatadine HC1 and Xanthan Gum.
SN Ingredient Example 3 Example 4
( %w/w) ( %w/w)
1 Mometasone Furoate monohydrate 0.050 0.025
Eq. to Mometasone furoate
2 Olopatadine HC1 0.665 0.665
3 Avicel RC 591 (Microcrystalline Cellulose and 1.000 1.000
Carboxymethylcellulose Sodium)
4 Benzalkonium chloride (50 % solution) 0.040 0.040
5 Xantural 75 (Xanthan Gum) 0.300 0.300
6 Sodium chloride 0.410 0.410
7 Edetate disodium 0.010 0.010
8 Dibasic sodium phosphate heptahydrate 0.940 0.940
9 Polysorbate 80 0.010 0.010
10 Sodium Hydroxide Q.S. Q.S.
11 Hydrochloric acid Q.S. Q.S.
12 Water for injection Q.S. Q.S.
Observations
Physical observation on standing for 24 hours No phase No phase
separation separation
observed observed
Mean Particle size by microscopy Below 15 Below 15 .
.
Manufacturing procedure:
1. Avicel RC-591 was added in Water for injection with homogenization and
allowed to hydrate.
2. Xanthan gum was dispersed in Water for injection and added to step - 1.
3. Dibasic sodium phosphate heptahydrate, Sodium chloride, Edetate disodium
and Olopatadine were dissolved in water. The pH was adjusted to 2.8 -3.2
with Hydrochloric acid.
4. Step-3 was added to Step-1.
5. Polysorbate 80 was dissolved in water for injection. Mometasone Furoate
monohydrate was added to it and stirred to form slurry.
6. Step-5 was added to Step-4 with homogenization.
7. Benzalkonium chloride was dissolved in water for injection.
8. Step-7 was added to Step-6 with homogenization.
9. The pH was checked and adjusted to 3.5-3.9 with HCl and the weight was
adjusted with water for injection. The osmolality of the composition was
about 250-350 mOsm/kg.
The composition was subjected to stability studies at different conditions. The
results of the same are as follows:
Container details: Sprayer containing HDPE bottle crimped with pump and fitted with
a actuator and cap
Stability Study Results
Test Initial 3 months 6 months
Ex.3 Ex. 4 Ex.3 Ex. 4 Ex. 3 Ex. 4
Stability condition (25°C ± 2°C & 60% RH ± 5 % RH)
pH 3.65 3.67 3.78 3.65 3.70 3.62
Osmolality (mOsm) 307 312 302 316 308 308
Viscosity (cps) 124.2 129.1 127.9 129.9 126.2 126.8
Weight per ml (g/ml) 1.019 1.022 1.02 1.023 1.02 1.019
Assay of mometasone 99.9 102.8 102.2 99.9 98.7 100.4
furoate (%)
Assay of olopatadine 99.2 100.7 99.7 99.7 99.4 99.6
hydrochloride (%)
Related substances for mometasone furoate
Impurity DMCF (%) 0.02 0.03 0.04 0.05 0.03 0.05
Any other impurity (%) 0.03 0.0^ 0.03 0.04
Total impurities (%) 0.1 1 0.10 0.15 0.16 0.12 0.16
Related substances for olopatadine hvc rochloride
Olopatadine E-isomer 0.08 0.07 0.09 0.1 1 0.1 1 0.10
(%)
Any other impurity (%) 0.03 0.04 0.05 0.05 0.08 0.08
Total impurities (%) 0.18 0.15 0.24 0.20 0.33 0.33
Spray Pattern fat 6cm)
Major Axis (mm) 46 59 59 56 54
Minor Axis (mm) 38 47 44 35 43
Ellipticity 1.2 1.3 1.4 1.6 1.3
Droplet size distribution (at 6 cm)
Dio () 21.58 21.03 20.95 20.27 18.73 18.34
D50 () 40.44 39.79 37.86 37.93 36.66 36.16
D 0 () 78.25 77.55 74.07 74.93 70.63 70.99
Stability Study Results
Test Initial 3 months 6 months
Ex.3 Ex. 4 Ex.3 Ex. 4 Ex. 3 Ex. 4
SPAN 1.40 1.42 1.40 1.44 1.40 1.45
Stability condition (40°C ± 2°C & 75% RH ± 5 % RH)
pH 3.65 3.67 3.70 3.77 3.78 3.65
Osmolality (mOsm) 307 312 309 305 302 316
Viscosity (cps) 124.2 129.1 129.6 124.3 127.9 129.9
Weight per ml (g/ml) 1.05 1.022 1.017 1.027 1.022 1.020
Assay of mometasone 99.9 102.8 101.7 100.6 99.6 98.4
furoate (%)
Assay of oloptadine 99.2 100.7 101.7 99.4 99.7 99.9
hydrochloride (%)
Related substances for mometasone furoate
Impurity DMCF (%) 0.02 0.02 0.010 0.12 0.10 0.12
Any other impurity (%) 0.03 0.03 0.02 0.03 0.05 0.03
Total impurities (%) 0.01 1 0.10 0.20 0.22 0.18 0.21
Related substances for olopatadine hvc rochloride
Olopatadine E-isomer 0.08 0.07 0.12 0.13 0.1 1 0.1 1
(%)
Any other impurity (%) 0.03 0.04 0.06 0.06 0.12 0.12
Total impurities (%) 0.18 0.15 0.26 0.26 0.18 0.21
Spray Pattern fat 6cm)
Major Axis (mm) 46 46 56 58 54 55
Minor Axis (mm) 38 38 45 49 34 43
Ellipticity 1.2 1.2 1.3 1.2 1.3 1.6
Droplet size distribution fat 6 cm)
Dio () 21.58 21.03 20.67 23.16 19.13 19.16
D50 () 40.44 39.79 38.06 39.08 37.34 37.26
D 0 () 78.25 77.55 75.63 69.37 72.36 72.49
SPAN 1.40 1.42 1.44 1.19 1.42 1.43
COMPARATIVE EXAMPLES A and B : Suspension composition containing
Mometasone furoate, and Olopatadine HC1.
Manufacturing procedure:
The manufacturing procedure as mentioned in Example 1 was followed.
COMPARATIVE EXAMPLES C and D: Suspension composition containing
Mometasone furoate and Olopatadine HC1.
SN Ingredient Example (% w/w)
C D
1 Mometasone Furoate monohydrate
Eq. to Mometasone furoate 0.050 0.050
2 Olopatadine HC1 0.665 0.665
3 Avicel RC 591 (Microcrystalline Cellulose and 1.000 1.000
Carboxymethyl cellulose Sodium)
4 Benzalkonium chloride (50 % solution) 0.040 0.040
5 Xantural 75 (Xanthan Gum) 0.00 0.20
6 Sodium chloride 0.410 0.410
7 Edetate disodium 0.010 0.010
8 Dibasic sodium phosphate heptahydrate 0.940 0.940
9 Polysorbate 80 0.010 0.010
10 Sodium Hydroxide Q.S. Q.S.
11 Hydrochloric acid Q.S. Q.S.
12 Water for injection Q.S. Q.S.
Observations
pH 3.73 3.70
Physical observation on standing for 24 hours Phase Phase
separation separation
observed observed
Manufacturing procedure:
The manufacturing procedure as mentioned in Example 3 was followed.
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 and that
other arrangements may be devised without departing from the spirit and scope of the
present invention as described.
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.
CLAIMS
We claim:
1. A stable fixed dose aqueous pharmaceutical composition for nasal administration
to a human, said composition comprising about 0.001 % w/w to about 0.075 %
w/w mometasone or its salt and about 0.5 % w/w to about 0.8 % w/w olopatadine
or its salt.
2. The pharmaceutical composition of claim 1, wherein mometasone or its salt and
olopatadine or its salt are present in a weight ratio of about 1:3 to about 1:106.
3. The pharmaceutical composition of claim 1 or 2, wherein the mometasone salt is
mometasone furoate and the olopatadine salt is olopatadine hydrochloride.
4. The pharmaceutical composition of any one of claims 1-3, wherein the
composition is in the form of a suspension.
5. The pharmaceutical composition of any one of claims 1-4, wherein the
composition further comprises a hydrocolloid at a concentration of at least about
0 .1% w/w of the composition.
6. The pharmaceutical composition of any one of claims 1-5, wherein the
composition has a pH of about 3.3-4.1, and an osmolality in the range of about
200 mOsm/kg to about 400 mOsm/kg.
7. The pharmaceutical composition of claim 4, wherein the particles in the
suspension composition have a mean particle size in the range of about 1 to
about 20 .
8. The pharmaceutical composition of any one of claims 1-7, wherein the
composition has a viscosity in the range of about 20 cps to about 150 cps.
9. The pharmaceutical composition of any one of claims 1-8, wherein the
composition is contained in a container, and when delivered as a nasal spray has a
spray pattern having a longest axis of about 15-75 mm, a shortest axis of about 10-
65 mm, and an ellipticity of about 1-2.
10. A stable fixed dose pharmaceutical aqueous suspension composition for nasal
administration to a human, said composition comprising about 0.025 % w/w to
about 0.05 % w/w mometasone or its salt, about 0.6 % w/w to about 0.7 % w/w
olopatadine or its salt and a hydrocolloid selected from carboxymethylcellulose
sodium and xanthan gum.
11. The pharmaceutical composition of claim 10, wherein the composition comprises
about 0.025 % w/w mometasone furoate.
12. The pharmaceutical composition of claim 10, wherein the composition comprises
about 0.05 % w/w mometasone furoate.
13. The pharmaceutical composition of any one of claims 10-12, wherein the
composition comprises about 0.665 % w/w olopatadine hydrochloride.
14. The pharmaceutical composition of any one of claims 10-13, wherein the
hydrocolloid is present at a concentration in the range of about 0.3 % w/w to about
0.5 % w/w, said hydrocolloid includes xanthan gum, carboxymethylcellulose
sodium, or both.
15. The pharmaceutical composition of any one of claims 10-14, wherein the
composition further comprises a pharmaceutically acceptable excipient selected
from the group consisting of chelating agents, preservatives, buffers, surfactants
isotonicity agents, taste masking agents, antioxidants, humectants, pH adjusting
agents, and mixtures thereof.
16. The pharmaceutical composition of claim 15, wherein the chelating agent is
selected from the group consisting of edetate disodium (EDTA), edetate
trisodium, edetate tetrasodium, diethyleneamine pentaacetate, and any
combination of any of the foregoing, and said chelating agent is present in the
range of about 0.002% w/w to about 0.5% w/w.
17. The pharmaceutical composition of claim 15 or 16, wherein the preservative is
selected from the group consisting of benzyl alcohol, quaternary ammonium
halides, phenylcarbinol, thimerosal, and any combination of any of the foregoing,
and said preservative is present in the range of about 0.005 to about 0.2% w/w.
18. The pharmaceutical composition of any one of claims 15-17, wherein the buffer is
selected from the group consisting of citric acid, acetic acid, fumaric acid,
hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric
acid, tartaric acid, phosphate salts, and any combination of any of the foregoing.
19. The pharmaceutical composition of any one of claims 15-18, wherein the
surfactant is selected from the group consisting of polyethoxylated sorbitan
derivatives, polyoxy ethylene vegetable oil, polyoxyethylene sorbitan monolaurate,
sodium oleate, and any combination of any of the foregoing.
20. The pharmaceutical composition of any one of claims 10-19, wherein the
composition has a pH of about 3.5-3.9, and an osmolality in the range of about
250 mOsm/kg to about 350 mOsm/kg.
21. The pharmaceutical composition of any one of claims 10-20, wherein the
composition is in a suspension form and has a mean particle size in the range of
from of about 1 to about 20 .
22. The pharmaceutical composition of any one of claims 10-21, wherein the
composition has a viscosity in the range of about 20 cps to about 150 cps.
23. The pharmaceutical composition of claim any one of claims 10-22, wherein the
composition is contained in a container, and when delivered as a nasal spray has a
spray pattern having a longest axis of about 15-75 mm, a shortest axis of about 10-
65 mm, and an ellipticity of about 1-2.
24. A stable fixed dose pharmaceutical aqueous suspension composition for nasal
administration to a human, where the composition comprises (1) about 0.025 %
w/w mometasone furoate monohydrate, (2) about 0.665% w/w olopatadine
hydrochloride, (3) a hydrocolloid selected from about 0.3 % w/w of xanthan gum
and about 0.5 % w/w carboxymethyl cellulose sodium (4) about 0.02% w/w
benzalkonium chloride, (5) about 0.4 % > w/w sodium chloride, (6) about 0.01 % >
w/w di-sodium edetate, (7) about 0.94% w/w sodium phosphate heptahydrate, and
(8) about 0.01 % w/w polysorbate 80.
25. A stable fixed dose pharmaceutical aqueous suspension composition for nasal
administration to a human, where the composition comprises (1) about 0.050 % >
w/w mometasone furoate monohydrate, (2) about 0.665% w/w olopatadine
hydrochloride, (3) a hydrocolloid selected from about 0.3 % >w/w of xanthan gum
and about 0.5 % > w/w carboxymethyl cellulose sodium, (4) about 0.02%> w/w
benzalkonium chloride, (5) about 0.4 % > w/w sodium chloride, (6) about 0.01 % >
w/w di-sodium edetate, (7) about 0.94% w/w sodium phosphate heptahydrate, and
(8) about 0.01 % w/w polysorbate 80.
26. The pharmaceutical composition of claim 24 or 25, wherein the composition has a
pH of about 3.5-3.9, and osmolality in the range of about 250 mOsm/kg to about
350 mOsm/kg.
27. The pharmaceutical composition of claim 24 or 25, wherein the composition has a
mean particle size in the range of from of about 1 to about 20 .
28. The pharmaceutical composition of claim 24 or 25, wherein the composition has a
viscosity in the range of about 20 cps to about 150 cps.
29. The pharmaceutical composition of claim 24 or 25, wherein the composition is
contained in a container, and when delivered as a nasal spray has a spray pattern
having a longest axis of about 15-75 mm, a shortest axis of about 10-65 mm, and
an ellipticity of about 1-2.
30. A stable suspension suitable for nasal administration to a human, comprising (a)
an aqueous solvent, (b) particles of mometasone furoate suspended in the solvent,
the particles having a mean particle size of from about 1 to about 20 , (c)
olopatadine hydrochloride dissolved in the solvent, and (d) a hydrocolloid, the
suspension having a viscosity in the range of about 20 cps to about 150 cps.
31. The suspension of claim 30, wherein the suspension has a pH of about 3.5-3.9,
and osmolality in the range of about 250 mOsm/kg to about 350 mOsm/kg.
32. The suspension of claim 30 or 31, further comprising a chelating agent, a
preservative, a buffer, a surfactant, an isotonicity agent, and optionally a pH
adjusting agent.
33. A method of treating rhinitis in a human in need thereof comprising administering
by the nasal route, to the human a pharmaceutical composition according to any
one of claims 1-29 or a suspension according to any one of claims 30-32.
34. The method according to claim 33, wherein the composition or suspension is
administered in the form of a nasal spray or nasal drops to the human.
35. Use of the pharmaceutical composition for nasal administration according to any
one of claims 1-29 or the suspension or a suspension according to any one of
claims 30-32, for the treatment of rhinitis in a human in need thereof.
36. The use according to claim 35, wherein the composition or suspension is
administered in the form of nasal spray or nasal drops to the human.
37. The pharmaceutical composition according to any one of claims 1-29 or the
suspension according to any one of claims 30-32, for the treatment of rhinitis in a
human.
38. A method of delivering a pharmaceutical composition according to any one of the
claims 1-29 or a suspension according to any one of claims 30-32, said method
comprising containing said composition or suspension in a sprayer, and delivering
a spray of said composition to a human nose having a spray pattern having a
longest axis of 15-75 mm, a shortest axis of 10-65 mm, and an ellipticity of 1-2.
39. A kit comprising the pharmaceutical composition of any one of claims 1-29 or a
suspension according to any one of claims 30-32 and a package insert containing
instructions about the use of said pharmaceutical composition or suspension.