DESC:BACKGROUND OF THE INVENTION
Allergic rhinitis is symptomatic disorder of nasal mucosa caused by exposure of allergens which induce IgE - dependent inflammation. Running nose, sneezing, nasal blockage and itchy nose are characteristic symptoms of allergic rhinitis. The IgE - mediated inflammation is often associated with asthma and is also considered as risk factor for asthma. Classical pharmacotherapy of allergic rhinitis includes use of oral or topical antihistamines, oral antileukotrienes, topical corticosteroids, mast cell stabilizers, decongestants, and an anticholinergic agent. Of which, antihistamines are common first-line treatment for the symptoms of allergic rhinitis by blocking the action of histamine H1 receptors, a chemical released by the immune system in allergic reactions.

Bepotastine, (+)-(S)-4-[4-[(4-Chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid is an antiallergic, highly selective and non-sedating H1 receptor antagonist. US Patent No. 4,929,618 discloses bepotastine. Apart from its antihistaminic action, bepotastine regulates eosinophil migration into inflamed tissues and also acts as mast cell stabilizer. Because of this, bepotastine is often seen as molecule with multiple actions. Hence beptastine and pharmacological salts have both an antiallergic and antihistaminic actions.

Bepotastine (TALION®) has been approved in Japan for systemic use for the treatment of allergic rhinitis since 2000 and urticaria/pruritus since 2002. ISTA Pharmaceuticals' eye drop formulation of bepotastine besilate, BEPREVE® (bepotastine besilate ophthalmic solution) 1.5% w/v, was approved by the U.S. Food and Drug Administration (FDA) in September 2009 for the treatment of ocular itching associated with allergic conjunctivitis.

The US Patent Application No. 20130046240 A1 discloses sorbitol-free bepotastine nasal sprays which comprises of 0.5% w/v to 8% w/v of bepotastine or pharmaceutical salt. Further, US Patent Application No. 20120323178 A1 discloses pharmaceutical composition comprising combination of bepotastine (0.5% w/v to 8% w/v) and corticosteroids (0.01% w/v to 1% w/v) in the form of nasal spray. Chinese Patent Application No. 103816121 A discloses 1% w/v to 10% w/v of bepotastine nasal spray comprising polyethylene glycol 400 and caprylocaproyl macrogolglycerides. All the applications disclose relatively high concentration of bepotastine to be administered as nasal spray. A reduction in dose in comparison to the above disclosed inventions will be of added advantage for local targeted delivery and provide minimal exposure of the drug avoiding any potential side effects.

Therefore, there is need to develop the compositions of bepotastine, decongestant and/or corticosteroid. The inventors found a pharmaceutical composition for nasal administration of bepotastine, decongestant and/or corticosteroid and the composition is efficient for treatment of allergic rhinitis and other nasal inflammatory conditions.

SUMMARY OF THE INVENTION
In one general aspect of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop. In one embodiment, bepotastine or pharmaceutically acceptable salt thereof is present in a concentration of about 0.01 % w/v to about 4% w/v or about 1% w/v. In one embodiment, the decongestant or pharmaceutically acceptable salt thereof is present in the concentration of about 0.05% w/v to about 5% w/v or about 2% w/v.

In one general aspect of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop, and wherein the pharmaceutically acceptable excipient comprises a viscosity enhancer, a humectant, a preservative, a wetting agent, a buffer, a solvent or mixtures thereof.

In one embodiment, the viscosity enhancer comprises a blend of microcrystalline cellulose and carmellose sodium present in concentration from about 0.5% w/v to about 3% w/v. In one embodiment, the preservative comprises benzalkonium chloride present in the concentration from about 0.01% w/v to about 0.05% w/v. In one embodiment, the wetting agent comprises polysorbate 80 present in the concentration from about 0.01% w/v to about 0.05% w/v and the humectant comprises glycerol present in the concentration from about 1% w/v to about 3% w/v.

In one aspect of the invention, there is provided a pharmaceutical composition for a nasal administration having a pH of about 5 to about 8 or about 6.4 to about 6.8 or about 6.4.

In one aspect of the invention, there is provided a pharmaceutical composition comprising:
a) about 1% w/v of bepotastine besilate,
b) about 2% w/v of levocloperastine fendizoate,
c) about 2% w/v of blend of microcrystalline cellulose and carmellose sodium,
d) about 2.1% w/v of glycerol,
e) about 0.02% w/v benzalkonium chloride,
f) about 0.01% w/v polysorbate 80, and
g) about 0.2% w/v of citrate buffer;
wherein a pH of the composition is about 5 to about 8 and the composition is formulated as a nasal spray or nasal drop.

In one general aspect of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprising: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, c) a corticosteroid or pharmaceutically acceptable salt thereof, and d) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop. In one embodiment, bepotastine or pharmaceutically acceptable salt thereof is present in a concentration of about 0.01 % w/v to about 4% w/v. or about 1% w/v.

In one embodiment, the decongestant or pharmaceutically acceptable salt thereof is present in the concentration of about 0.05% w/v to about 5% w/v or about 2% w/v. In one embodiment, the corticosteroids or pharmaceutically acceptable salt is present in about 0.01% w/v to about 1% w/v or 0.05% w/v.
In one general aspect of the invention, there is provided a pressurized container adapted for dispensing a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

In one general aspect of the invention, there is provided a pressurized container adapted for dispensing a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, c) a corticosteroid or pharmaceutically acceptable salt thereof and d) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

In one general aspect of the invention, there is provided a pressurized container adapted for dispensing a pharmaceutical composition comprising:
a) about 1% w/v of bepotastine besilate,
b) about 2% w/v of levocloperastine fendizoate,
c) about 2% w/v of blend of microcrystalline cellulose and carmellose sodium,
d) about 2.1% w/v of glycerol,
e) about 0.02% w/v benzalkonium chloride,
f) about 0.01% w/v polysorbate 80, and
g) about 0.2% w/v of citrate buffer;
wherein a pH of the composition is about 5 to about 8 and the composition is formulated as a nasal spray or nasal drop.

In one general aspect of the invention, there is provided a use of a pharmaceutical composition for a nasal administration, for the treatment of allergic rhinitis of patient in a need thereof, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

In one general aspect of the invention, there is provided a use of a pharmaceutical composition for a nasal administration, for the treatment of allergic rhinitis of patient in a need thereof, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, c) a corticosteroid or pharmaceutically acceptable salt thereof and d) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

In one general aspect of the invention, there is provided a process for preparing a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop, said process comprises:
i. preparing a main bulk containing suspension of a blend of microcrystalline cellulose and carmellose sodium and glycerol in water with stirring,
ii. preparing separately a solution of citric acid and sodium citrate and adding it separately to the main bulk,
iii. preparing a solution of polysorbate 80 in water and adding to this, bepotastine besilate and the decongestant to get a uniform slurry,
iv. adding benzalkonium chloride (as 10% w/v) solution to the above slurry, and
v. adding the slurry of step (iv) to the main bulk under continuous stirring and finally adjusting a pH and making up the volume.

In one general aspect of the invention, there is provided a process for preparing a pharmaceutical composition comprising:
a) about 1% w/v of bepotastine besilate,
b) about 2% w/v of levocloperastine fendizoate,
c) about 2% w/v of blend of microcrystalline cellulose and carmellose sodium,
d) about 2.1% w/v of glycerol,
e) about 0.02% w/v benzalkonium chloride,
f) about 0.01% w/v polysorbate 80, and
g) about 0.2% w/v of citrate buffer,
wherein a pH of the composition is about 5 to about 8 and the composition is formulated as a nasal spray or nasal drop, said process comprises:
i. preparing a main bulk containing suspension of a blend of microcrystalline cellulose and carmellose sodium and glycerol in water with stirring,
ii. preparing separately a solution of citric acid and sodium citrate and adding it separately to the main bulk,
iii. preparing a solution of polysorbate 80 in water and adding to this, bepotastine besilate and levocloperastine fendizoate to get a uniform slurry,
iv. adding benzalkonium chloride (as 10% w/v) solution to the above slurry, and
v. adding the slurry of step (iv) to the main bulk under continuous stirring and finally adjusting a pH and making up the volume.

DETAILED DESCRIPTION OF THE INVENTION
There is provided is a pharmaceutical composition comprising bepotastine or pharmaceutically acceptable salt thereof, decongestants and/or cortiocosteroids and at least one pharmaceutically acceptable excipient, wherein the composition is formulated as nasal spray or nasal drop.

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Definitions:
Unless otherwise indicated, this disclosure uses the following definitions.

“Pharmaceutical composition” refers to the composition of one or more drug substances and one or more excipients.
The term “bepotastine” refers to (+)-(S)-4-[4-[(4-Chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or pharmaceutically acceptable salt thereof.

“Pharmaceutically acceptable” substances refers to those substances which are within the scope of sound medical judgment suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit-to-risk ratio, and effective for their intended use.

“Pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art and includes any pharmaceutically acceptable salt soluble in water to form an aqueous solution.

“Pharmaceutically acceptable excipient” refers to non-active pharmaceutical ingredient substances which are within the scope of sound medical judgment suitable for use in formulating pharmaceutical products.

“Spray” relates to a spray device or a pressurized container for receiving the pharmaceutical composition.

The term “buffer” refers to a pharmaceutically acceptable excipient, which stabilizes the pH of a pharmaceutical preparation.

The term “rhinitis” may generally include any inflammation of the nasal mucous membrane. Symptoms of rhinitis can generally include one or more cold-like symptoms including, for example, rhinorrhea, increased nasal secretion, nasal congestion, sneezing and catarrh. Rhinitis can also include both allergic rhinitis and non-allergic rhinitis. “Allergic rhinitis” refers to any allergic reaction of the nasal mucosa and may include hay fever (seasonal allergic rhinitis) and perennial rhinitis (non-seasonal allergic rhinitis). “Non-allergic rhinitis” refers to eosinophilic non-allergic rhinitis which is found in subjects with negative skin tests and those who have numerous eosinophils in their nasal secretions. In one embodiment, the compositions provided herein are useful in treating allergic rhinitis and inflammatory conditions.

In one general embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) about 0.01 % w/v to about 4% w/v of bepotastine or pharmaceutically acceptable salt thereof, b) about 0.05% w/v to about 5% w/v of a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) about 1 % w/v of bepotastine or pharmaceutically acceptable salt thereof, b) about 2% w/v of a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop, and wherein the pharmaceutically acceptable excipient comprises a viscosity enhancer, a humectant, a preservative, a wetting agent, a buffer, a solvent or mixtures thereof, and wherein i) the viscosity enhancer comprises a blend of microcrystalline cellulose and carmellose sodium present in concentration from about 0.5% w/v to about 3% w/v, ii) the preservative comprises benzalkonium chloride present in the concentration from about 0.01% w/v to about 0.05% w/v, iii) the wetting agent comprises polysorbate 80 present in the concentration from about 0.01% w/v to about 0.05% w/v and iv) the humectant comprises glycerol present in the concentration from about 1% w/v to about 3% w/v.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) about 0.01 % w/v to about 4% w/v of bepotastine or pharmaceutically acceptable salt thereof, b) about 0.05% w/v to about 5% w/v of a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop, and wherein the pharmaceutically acceptable excipient comprises a viscosity enhancer, a humectant, a preservative, a wetting agent, a buffer, a solvent or mixtures thereof, and wherein i) the viscosity enhancer comprises a blend of microcrystalline cellulose and carmellose sodium present in concentration from about 0.5% w/v to about 3% w/v, ii) the preservative comprises benzalkonium chloride present in the concentration from about 0.01% w/v to about 0.05% w/v, iii) the wetting agent comprises polysorbate 80 present in the concentration from about 0.01% w/v to about 0.05% w/v and iv) the humectant comprises glycerol present in the concentration from about 1% w/v to about 3% w/v.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) about 1 % w/v of bepotastine or pharmaceutically acceptable salt thereof, b) about 2% w/v of a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop, and wherein the pharmaceutically acceptable excipient comprises a viscosity enhancer, a humectant, a preservative, a wetting agent, a buffer, a solvent or mixtures thereof, and wherein i) the viscosity enhancer comprises a blend of microcrystalline cellulose and carmellose sodium present in concentration from about 0.5% w/v to about 3% w/v, ii) the preservative comprises benzalkonium chloride present in the concentration from about 0.01% w/v to about 0.05% w/v, iii) the wetting agent comprises polysorbate 80 present in the concentration from about 0.01% w/v to about 0.05% w/v and iv) the humectant comprises glycerol present in the concentration from about 1% w/v to about 3% w/v.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration having a pH of about 5 to about 8 or about 6.4 to about 6.8 or about 6.4.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop, and wherein the pharmaceutically acceptable excipient comprises a viscosity enhancer, a humectant, a preservative, a wetting agent, a buffer, a solvent or mixtures thereof, and wherein i) the viscosity enhancer comprises a blend of microcrystalline cellulose and carmellose sodium present in concentration from about 0.5% w/v to about 3% w/v, ii) the preservative comprises benzalkonium chloride present in the concentration from about 0.01% w/v to about 0.05% w/v, iii) the wetting agent comprises polysorbate 80 present in the concentration from about 0.01% w/v to about 0.05% w/v and iv) the humectant comprises glycerol present in the concentration from about 1% w/v to about 3% w/v, and wherein a pH of the composition is about 5 to about 8 or about 6.4 to about 6.8 or about 6.4.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) about 0.01 % w/v to about 4% w/v of bepotastine or pharmaceutically acceptable salt thereof, b) about 0.05% w/v to about 5% w/v of a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop, and wherein the pharmaceutically acceptable excipient comprises a viscosity enhancer, a humectant, a preservative, a wetting agent, a buffer, a solvent or mixtures thereof, and wherein i) the viscosity enhancer comprises a blend of microcrystalline cellulose and carmellose sodium present in concentration from about 0.5% w/v to about 3% w/v, ii) the preservative comprises benzalkonium chloride present in the concentration from about 0.01% w/v to about 0.05% w/v, iii) the wetting agent comprises polysorbate 80 present in the concentration from about 0.01% w/v to about 0.05% w/v and iv) the humectant comprises glycerol present in the concentration from about 1% w/v to about 3% w/v, and wherein a pH of the composition is about 5 to about 8 or about 6.4 to about 6.8 or about 6.4.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) about 1 % w/v of bepotastine or pharmaceutically acceptable salt thereof, b) about 2% w/v of a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop, and wherein the pharmaceutically acceptable excipient comprises a viscosity enhancer, a humectant, a preservative, a wetting agent, a buffer, a solvent or mixtures thereof, and wherein i) the viscosity enhancer comprises a blend of microcrystalline cellulose and carmellose sodium present in concentration from about 0.5% w/v to about 3% w/v, ii) the preservative comprises benzalkonium chloride present in the concentration from about 0.01% w/v to about 0.05% w/v, iii) the wetting agent comprises polysorbate 80 present in the concentration from about 0.01% w/v to about 0.05% w/v and iv) the humectant comprises glycerol present in the concentration from about 1% w/v to about 3% w/v, and wherein a pH of the composition is about 6.4.

In one embodiment of the invention, there is provided a pharmaceutical composition comprising:
a) about 1% w/v of bepotastine besilate,
b) about 2% w/v of levocloperastine fendizoate,
c) about 2% w/v of blend of microcrystalline cellulose and carmellose sodium,
d) about 2.1% w/v of glycerol,
e) about 0.02% w/v benzalkonium chloride,
f) about 0.01% w/v polysorbate 80, and
g) about 0.2% w/v of citrate buffer;
wherein a pH of the composition is about 5 to about 8 and the composition is formulated as a nasal spray or nasal drop.

In one embodiment of the invention, there is provided a pharmaceutical composition comprising:
a) about 1% w/v of bepotastine besilate,
b) about 2% w/v of levocloperastine fendizoate,
c) about 2% w/v of blend of microcrystalline cellulose and carmellose sodium,
d) about 2.1% w/v of glycerol,
e) about 0.02% w/v benzalkonium chloride,
f) about 0.01% w/v polysorbate 80, and
g) about 0.2% w/v of citrate buffer;
wherein a pH of the composition is about 6.4 and the composition is formulated as a nasal spray or nasal drop.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprising: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, c) a corticosteroid or pharmaceutically acceptable salt thereof, and d) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprising: a) about 0.01 % w/v to about 4% w/v of bepotastine or pharmaceutically acceptable salt thereof, b) about 0.05% w/v to about 5% w/v of a decongestant or pharmaceutically acceptable salt thereof, c) about 0.01% w/v to about 1% w/v of a corticosteroid or pharmaceutically acceptable salt thereof, and d) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprising: a) about 1% w/v of bepotastine or pharmaceutically acceptable salt thereof, b) about 2% w/v of a decongestant or pharmaceutically acceptable salt thereof, c) about 0.05% w/v of a corticosteroid or pharmaceutically acceptable salt thereof, and d) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprising: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, c) a corticosteroid or pharmaceutically acceptable salt thereof, and d) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop, and wherein the pharmaceutically acceptable excipient comprises a viscosity enhancer, a humectant, a preservative, a wetting agent, a buffer, a solvent or mixtures thereof, and wherein i) the viscosity enhancer comprises a blend of microcrystalline cellulose and carmellose sodium present in concentration from about 0.5% w/v to about 3% w/v, ii) the preservative comprises benzalkonium chloride present in the concentration from about 0.01% w/v to about 0.05% w/v, iii) the wetting agent comprises polysorbate 80 present in the concentration from about 0.01% w/v to about 0.05% w/v and iv) the humectant comprises glycerol present in the concentration from about 1% w/v to about 3% w/v, and wherein a pH of the composition is about 5 to about 8 or about 6.4 to about 6.8 or about 6.4.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprising: a) about 0.01 % w/v to about 4% w/v of bepotastine or pharmaceutically acceptable salt thereof, b) about 0.05% w/v to about 5% w/v of a decongestant or pharmaceutically acceptable salt thereof, c) about 0.01% w/v to about 1% w/v of a corticosteroid or pharmaceutically acceptable salt thereof, and d) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop, and wherein the pharmaceutically acceptable excipient comprises a viscosity enhancer, a humectant, a preservative, a wetting agent, a buffer, a solvent or mixtures thereof, and wherein i) the viscosity enhancer comprises a blend of microcrystalline cellulose and carmellose sodium present in concentration from about 0.5% w/v to about 3% w/v, ii) the preservative comprises benzalkonium chloride present in the concentration from about 0.01% w/v to about 0.05% w/v, iii) the wetting agent comprises polysorbate 80 present in the concentration from about 0.01% w/v to about 0.05% w/v and iv) the humectant comprises glycerol present in the concentration from about 1% w/v to about 3% w/v, and wherein a pH of the composition is about 5 to about 8 or about 6.4 to about 6.8 or about 6.4.

In one embodiment of the invention, there is provided a pharmaceutical composition for a nasal administration, wherein said composition comprising: a) about 1% w/v of bepotastine or pharmaceutically acceptable salt thereof, b) about 2% w/v of a decongestant or pharmaceutically acceptable salt thereof, c) about 0.05% w/v of a corticosteroid or pharmaceutically acceptable salt thereof, and d) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop, and wherein the pharmaceutically acceptable excipient comprises a viscosity enhancer, a humectant, a preservative, a wetting agent, a buffer, a solvent or mixtures thereof, and wherein i) the viscosity enhancer comprises a blend of microcrystalline cellulose and carmellose sodium present in concentration from about 0.5% w/v to about 3% w/v, ii) the preservative comprises benzalkonium chloride present in the concentration from about 0.01% w/v to about 0.05% w/v, iii) the wetting agent comprises polysorbate 80 present in the concentration from about 0.01% w/v to about 0.05% w/v and iv) the humectant comprises glycerol present in the concentration from about 1% w/v to about 3% w/v, and wherein a pH of the composition is about 6.4.

In one aspect of the invention, there is provided a pharmaceutical composition comprising:
a) about 1% w/v of bepotastine besilate,
b) about 2% w/v of levocloperastine fendizoate,
c) about 0.05% w/v of fluticasone propionate,
d) about 2% w/v of blend of microcrystalline cellulose and carmellose sodium,
e) about 2.1% w/v of glycerol,
f) about 0.02% w/v benzalkonium chloride,
g) about 0.01% w/v polysorbate 80, and
h) about 0.2% w/v of citrate buffer;
wherein a pH of the composition is about 5 to about 8 and the composition is formulated as a nasal spray or nasal drop.

In one aspect of the invention, there is provided a pharmaceutical composition comprising:
a) about 1% w/v of bepotastine besilate,
b) about 2% w/v of levocloperastine fendizoate,
c) about 0.05% w/v of fluticasone propionate,
d) about 2% w/v of blend of microcrystalline cellulose and carmellose sodium,
e) about 2.1% w/v of glycerol,
f) about 0.02% w/v benzalkonium chloride,
g) about 0.01% w/v polysorbate 80, and
h) about 0.2% w/v of citrate buffer;
wherein a pH of the composition is about 6.4 and the composition is formulated as a nasal spray or nasal drop.

In one embodiment, the composition comprises a) about 1% w/v of bepotastine besilate, b) about 0.05% w/v of fluticasone propionate, c) about 2% w/v of levocloperastine fendizoate, d) about 0.5% w/v of hydroxylpropyl methyl cellulose, e) about 0.02% w/v benzalkonium chloride, f) about 0.01% w/v polysorbate 80, g) about 0.3% w/v of sodium citrate, and h) about 0.4% w/v of sodium chloride, wherein pH of composition is about 5 to about 8, wherein composition is formulated as nasal spray or nasal drop.

The active ingredient of the invention compositions provided here in is bepotastine, (+)-(S)-4-[4-[(4-Chlorophenyl)(2-pyridyl)methoxy]piperidino]butyric acid or pharmaceutically acceptable salt thereof.

According to the invention, pharmaceutically acceptable salt of bepotastine comprises, but not limited to, salts with hydrohalic acid such as hydrochloride, hydrobromide and the like; salts with inorganic acid such as sulfate, nitrate, phosphate and the like; salts with organic acid such as acetate, propionate, hydroxyacetate, 2-hydroxypropionate, pyruvate, malonate, succinate, maleate, fumarate, dihydroxyfumarate, oxalate, benzoate, cinnamate, salicylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, 4-aminosalicylate and the like; and the like can be mentioned. The above-mentioned compound to be used in the compositions provided herein is generally preferably an acid addition salt, and of these acid addition salts, benzenesulfonate and benzoate are more preferable, and monobenzenesulfonate is particularly preferable (besilate). In one embodiment, the active ingredient of the compositions provided herein is bepotastine besilate.

In an another embodiment, the concentration of bepotastine or pharmaceutically acceptable salt thereof is about 0.01% w/v to about 4% w/v. In one embodiment, the preferred concentration of bepotastine or pharmaceutically acceptable salt thereof is about 0.05 % w/v to about 2 % w/v. In one embodiment, the preferred concentration of bepotastine or pharmaceutically acceptable salt is about 0.05 % w/v to about 1.5 % w/v; more preferably about 0.05 % w/v or about 1% w/v.

Alternatively in another embodiment, the concentration of bepotastine or pharmaceutically acceptable salt thereof is about 0.02% w/v, or about 0.03% w/v, or about 0.04% w/v, or about 0.05% w/v, or about 0.06% w/v, or about 0.07% w/v, or about 0.08% w/v, or about 0.09% w/v, or about 0.1% w/v, or about 0.15% w/v, or about 0.2% w/v, or about 0.25% w/v, or about 0.3% w/v, or about 0.4% w/v, or about 0.5% w/v, or about 0.6% w/v, or about 0.8% w/v, or about 1% w/v, or about 2% w/v. Each of these concentration constitutes and alternate embodiment of the invention.

Examples of corticosteroids comprise, but are not limited to, formoterol, salmeterol, fluticasone propionate, fluticasone furoate, budesonide, ciclesonide, tiotropium, beclomethasone, flunisolide, mometasone, triamcinolone, vilanterol and umeclidinium. In another preferred embodiment, said corticosteroid is fluticasone propionate or tiotropium bromide.

Alternatively, the concentration of corticosteroids or pharmaceutically acceptable salt thereof is about 0.02% w/v, or about 0.03% w/v, or about 0.04% w/v, or about 0.05% w/v, or about 0.06% w/v, or about 0.07% w/v, or about 0.08% w/v, or about 0.09% w/v. Each of this concentration constitutes and alternate embodiment of the invention.

Examples of decongestant comprise, but not limited to, epinastine, montelukast, cetrizine, levocetirizine, levocloperastine, cromolyn sodium, ketotifen, alcaftadine, azelastine, emadastine, ketorolac, ladoxamine, loteprednol, naphazoline, nedocromil, olopatadine, pemirolast. In another embodiment, said decongestant is levocloperastine or pharmaceutically acceptable salt thereof. Alternatively, the decongestant is levocloperastine fendizoate.

In another embodiment, the concentration of decongestant or pharmaceutically acceptable salt thereof is from about 0.05% w/v to about 5% w/v. In one embodiment, the preferred concentration of corticosteroids or pharmaceutically acceptable salt thereof is from about 1 % w/v to about 5% w/v; most preferred is 2% w/v.

Alternatively, the concentration of decongestant or pharmaceutically acceptable salt thereof is about 0.06% w/v, or about 0.08% w/v, or about 0.1% w/v, or about 0.2% w/v, or about 0.3% w/v, or about 0.4% w/v, or about 0.5% w/v, or about 0.6% w/v, or about 0.7% w/v, or about 0.8% w/v, or about 0.9% w/v, or about 1% w/v, or about 2% w/v, or about 3% w/v, or about 4% w/v.

In another embodiment, the composition comprises antimicrobial preservative. Preservative can be used in effective amount that is sufficient to inhibit the growth of microorganisms (e.g., bacterial or yeast) in the composition. Examples of pharmaceutically acceptable preservative include, but not limited to, benzethonium chloride, butylparaben, methyl paraben, ethyl paraben, propyl paraben, benzalkonium chloride, cetyl pyridinium chloride, thimerosal, chlorobutanol, phenylethyl alcohol, benzyl alcohol, potassium sorbate, sodium benzoate, sorbic acid, oxychloro complexes (otherwise known as Purite®), phenylmercuric acetate, chlorobutanol, benzyl alcohol, parabens, and thimerosal or combinations thereof. In one embodiment, the preservative is benzalkonium chloride. In one embodiment, the antimicrobial preservative (e.g. benzalkonium chloride) can be present in the composition in an amount of from about 0.01% w/v to about 0.05% w/v. In another embodiment, the antimicrobial preservative (e.g. benzalkonium chloride) can be present in the composition in an amount of about 0.01% w/v to about 0.03% w/v. In yet another preferred embodiment, the antimicrobial preservative (e.g. benzalkonium chloride) can be present in the composition in an amount of about 0.02% w/v; more preferred is 0.02% w/v. Alternatively, the antimicrobial preservative (e.g. benzalkonium chloride) can be present in the composition in an amount of about 0.02% w/v, or about 0.03% w/v, or about 0.04% w/v.
In one embodiment, composition comprises viscosity enhancer which provides for optimized residence time of the active ingredient in nasal tissue and minimized agent ingredient outside nasal tissue (e.g., in the throat), while beneficially providing thixotropic properties that still permit expression of the composition from a spray or other administration orifice. Examples of viscosity enhancers include, but not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxy methyl cellulose, ethyl cellulose, microcrystalline cellulose, blend of microcrystalline cellulose and carboxymethyl cellulose, blend of microcrystalline cellulose and carmellose sodium. In one embodiment, the most preferred viscosity enhancer is blend of microcrystalline cellulose and carmellose sodium. In another embodiment, the concentration of viscosity enhancer (e.g., blend of microcrystalline cellulose and carmellose sodium) is about 0.5% w/v to about 3% w/v. Preferred concentration of viscosity enhancers (e.g., blend of microcrystalline cellulose and carmellose sodium in the weight ratio of 1:1) is about 2% w/v. Alternatively, the concentration of viscosity enhancer is about 0.5% w/v, or about 1% w/v, or about 1.5% w/v or about 2% w/v.
In another embodiment, composition comprises a humectant, which avoids nasal irritation. Examples of humectants comprise, but not limited to, polyethylene glycols, polyglycerols, alginates, carrageenan, pectins, tragacanth gum, gum arabic, polyvinyl alcohols, polyvinyl pyrrolidones and derivatives. Most preferred humectant is glycerol. In another embodiment, the concentration of humectant (e.g., glycerol) is about 1% w/v to about 3% w/v. Preferred concentration of humectant (e.g. glycerol) is about 2.5% w/v. Most preferred concentration of humectants is 2.1% w/v. Alternatively, the concentration of humectants is about 1.5%, or about 2%, or about 2.5%.
In another embodiment, composition comprises a wetting agent. Examples of wetting agent comprise, but not limited to, glyceryl monooleate, glyceryl dioleate, lecithin, polysorbate 20 and 80. It is preferred to use a hydrophilic, non-ionic surfactant, like polysorbate 80. In an embodiment, the composition comprises about 0.01% w/v to about 0.05% w/v of wetting agent. Preferably, the composition comprises about 0.01% w/v of wetting agent. Alternatively, the composition comprises about 0.02% w/v, or about 0.03% w/v, or about 0.04% w/v of wetting agent.
In yet another embodiment, composition comprises a buffer, which stabilizes the pH of a pharmaceutical preparation. Examples of pharmaceutically acceptable buffers comprise but are not limited to acetic acid, citric acid, sodium acetate, citrate and phosphate, potassium phosphate, dibasic sodium phosphate heptahydrate or combination thereof. Preferably, the composition comprises citrate buffer. The composition of citrate buffer is citric acid (e.g., citric acid monohydrate) and/or sodium citrate dehydrate.
In one embodiment, the citric acid and/or sodium citrate buffer may be present in the composition in an amount of about 0.1% w/v to about 1 % w/v. In one embodiment, the compositions provided herein have a concentration of citric acid or sodium citrate from about 0.1% w/v to about 0.2% w/v, or from about 0.2% w/v to about 0.5% w/v, or from about 0.5% w/v to about 0.75% w/v, or from about 0.75% w/v to about 1% w/v. In one embodiment, the compositions provided herein have about 0.2% w/v, or about 0.3% w/v, or about 0.4% w/v, or about 0.5% w/v, or about 0.7% w/v of citric acid. In one embodiment, the compositions provided herein have about 0.28% w/v, or about 0.38% w/v, or about 0.48% w/v, or about 0.58% w/v, or about 0.78% w/v sodium citrate. Preferably, the composition comprises about 0.2% w/v of citrate buffer. Alternatively, the concentration of citric acid is about 2% w/v and concentration of sodium citrate is about 0.28% w/v.
In another embodiment, the composition comprises of sodium chloride as a tonicity adjuster. In one embodiment, the compositions provided herein have a concentration of sodium chloride in about 0.1% w/v to about 1% w/v. The preferred concentration is about 0.4% w/v.
In another embodiment pH of composition can be adjusted at a value of from about 4.0 to about 9.0 and preferably about 5.0 to about 8.0 and still preferably about 6.0 to about 7.0 and most preferably about 6.4 to about 6.8 with an acid or a base as known in the art, e.g., hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, sodium hydroxide and potassium hydroxide. The pH of the compositions provided herein is adjusted to not less than about 4.0, 5.0, or 6.0, and not more than about 8.5, 8.0, or 9.0. Alternatively, the pH of the invention composition is 6.4 or 6.8.
In another embodiment, the composition contains suitable solvent known to person skilled in the art. The solvent used in invention composition is water for injection or saline or dextrose.
In one general embodiment of the invention, there is provided a pressurized container adapted for dispensing a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

In one general embodiment of the invention, there is provided a pressurized container adapted for dispensing a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, c) a corticosteroid or pharmaceutically acceptable salt thereof and d) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

In one general aspect of the invention, there is provided a pressurized container adapted for dispensing a pharmaceutical composition comprising:
a) about 1% w/v of bepotastine besilate,
b) about 2% w/v of levocloperastine fendizoate,
c) about 2% w/v of blend of microcrystalline cellulose and carmellose sodium,
d) about 2.1% w/v of glycerol,
e) about 0.02% w/v benzalkonium chloride,
f) about 0.01% w/v polysorbate 80, and
g) about 0.2% w/v of citrate buffer;
wherein a pH of the composition is about 5 to about 8 and the composition is formulated as a nasal spray or nasal drop.

In one general aspect of the invention, there is provided a pressurized container adapted for dispensing a pharmaceutical composition comprising:
a) about 1% w/v of bepotastine besilate,
b) about 2% w/v of levocloperastine fendizoate,
c) about 0.05% w/v of fluticasone propionate,
d) about 2% w/v of blend of microcrystalline cellulose and carmellose sodium,
e) about 2.1% w/v of glycerol,
f) about 0.02% w/v benzalkonium chloride,
g) about 0.01% w/v polysorbate 80, and
h) about 0.2% w/v of citrate buffer;
wherein a pH of the composition is about 5 to about 8 and the composition is formulated as a nasal spray or nasal drop.
In one general embodiment of the invention, there is provided a process for preparing a pharmaceutical composition for a nasal administration, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop, said process comprises:
i. preparing a main bulk containing suspension of a blend of microcrystalline cellulose and carmellose sodium and glycerol in water with stirring,
ii. preparing separately a solution of citric acid and sodium citrate and adding it separately to the main bulk,
iii. preparing a solution of polysorbate 80 in water and adding to this, bepotastine besilate and the decongestant to get a uniform slurry,
iv. adding benzalkonium chloride (as 10% w/v) solution to the above slurry, and
v. adding the slurry of step (iv) to the main bulk under continuous stirring and finally adjusting a pH and making up the volume.

In one general embodiment of the invention, there is provided a process for preparing a pharmaceutical composition comprising:
a) about 1% w/v of bepotastine besilate,
b) about 2% w/v of levocloperastine fendizoate,
c) about 2% w/v of blend of microcrystalline cellulose and carmellose sodium,
d) about 2.1% w/v of glycerol,
e) about 0.02% w/v benzalkonium chloride,
f) about 0.01% w/v polysorbate 80, and
g) about 0.2% w/v of citrate buffer,
wherein a pH of the composition is about 5 to about 8 and the composition is formulated as a nasal spray or nasal drop, said process comprises:
i. preparing a main bulk containing suspension of a blend of microcrystalline cellulose and carmellose sodium and glycerol in water with stirring,
ii. preparing separately a solution of citric acid and sodium citrate and adding it separately to the main bulk,
iii. preparing a solution of polysorbate 80 in water and adding to this, bepotastine besilate and levocloperastine fendizoate to get a uniform slurry,
iv. adding benzalkonium chloride (as 10% w/v) solution to the above slurry, and
v. adding the slurry of step (iv) to the main bulk under continuous stirring and finally adjusting a pH and making up the volume.

In one general aspect of the invention, there is provided a process for preparing a pharmaceutical composition comprising:
a) about 1% w/v of bepotastine besilate,
b) about 2% w/v of levocloperastine fendizoate,
c) about 0.05% w/v of fluticasone propionate,
d) about 2% w/v of blend of microcrystalline cellulose and carmellose sodium,
e) about 2.1% w/v of glycerol,
f) about 0.02% w/v benzalkonium chloride,
g) about 0.01% w/v polysorbate 80, and
h) about 0.2% w/v of citrate buffer,
wherein a pH of the composition is about 5 to about 8 and the composition is formulated as a nasal spray or nasal drop, said process comprises:
i. preparing a main bulk containing suspension of a blend of microcrystalline cellulose and carmellose sodium and glycerol in water with stirring,
ii. preparing separately a solution of citric acid and sodium citrate and adding it separately to the main bulk,
iii. preparing a solution of polysorbate 80 in water and adding to this, bepotastine besilate, levocloperastine fendizoate and fluticasone propinonate to get a uniform slurry,
iv. adding benzalkonium chloride (as 10% w/v) solution to the above slurry, and
v. adding the slurry of step (iv) to the main bulk under continuous stirring and finally adjusting a pH and making up the volume.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLE 1: Pharmaceutical spray composition containing Bepotastine and Levocloperastine

Table 1

S No Name Composition (%w/v)
1. Bepotastine besilate 1.0
2. Levocloperastine fendizoate 2.0
3. Microcrystalline cellulose and Carmellose sodium NF (1:1) 2.0
4. Glycerol USP 2.1
5. Benzalkonium chloride NF (10% w/v) 0.02
6. Polysorbate 80 0.01
7. Citric acid monohydrate USP 0.2
8. Sodium citrate dehydrate USP 0.28
9. Water for injection q.s to 100 g
pH 6.4

Manufacturing process:
1. A blend of microcrystalline cellulose and carmellose sodium was dissolved in water to obtain a lump free suspension.
2. Glycerol was added to suspension of step 1 under stirring.
3. A separate solution of citric acid was prepared and added to a mixture of step 2.
4. This was followed by the addition of separate solution of sodium citrate to the mixture of step 2.
5. Polysorbate 80 was dissolved in water, to this bepotastine besilate and levocloperastine fendizoate was added to get uniform slurry.
6. Benzalkonium chloride (as 10% w/v) solution was added to the slurry of step 5.
7. The slurry of step 6 was added to the mixture of step 4 under continuous stirring.
8. The pH was adjusted and the volume was made up and filled aseptically in a pressurized container with a valve assembly including an actuator and tubing for releasing the composition as spray.

EXAMPLE 2-5: Pharmaceutical compositions for nasal administration
Table 2
S No Ingredient Compositions
2 3 4 5
Concentration (%w/v)
1. Bepotastine besilate 0.5 1.0 1.5 2.0
2. Levocloperastine fendizoate 1.0 2.0 3.0 4.0
3. Fluticasone propionate 0.02 0.03 0.04 0.05
4. Microcrystalline cellulose and Carmellose sodium NF (1:1) 0.5 1.0 1.5 2.0
5. Glycerol USP 1 1.5 2 2.5
6. Benzalkonium chloride NF (10% w/v) 0.01 0.02 0.03 0.05
7. Polysorbate 80 0.02 0.03 0.04 0.05
8. Citric acid monohydrate USP 0.1 0.2 0.3 0.4
9. Sodium citrate dehydrate USP 0.1 0.28 0.38 0.48
10. Water for injection q.s to 100 ml q.s to 100 ml q.s to 100 ml q.s to 100 ml
pH 6.4

Manufacturing process:
1. A blend of microcrystalline cellulose and carmellose sodium was dissolved in water to obtain a lump free suspension.
2. Glycerol was added to suspension of step 1 under stirring.
3. A separate solution of citric acid was prepared and added to a mixture of step 2.
4. This was followed by the addition of separate solution of sodium citrate to the mixture of step 2.
5. Polysorbate 80 was dissolved in water, to this bepotastine besilate, levocloperastine fendizoate and fluticasone propionate was added to get uniform slurry.
6. Benzalkonium chloride (as 10% w/v) solution was added to the slurry of step 5.
7. The slurry of step 6 was added to the mixture of step 4 under continuous stirring.
8. The pH was adjusted and the volume was made up and filled aseptically in a container for dispensing the composition as spray or drop.
,CLAIMS:1. A pharmaceutical composition for a nasal administration, wherein said composition comprises: a) bepotastine or pharmaceutically acceptable salt thereof, b) a decongestant or pharmaceutically acceptable salt thereof, and c) at least one pharmaceutically acceptable excipient, and wherein the composition is formulated as a nasal spray or nasal drop.

2. The pharmaceutical composition of claim 1, wherein bepotastine or pharmaceutically acceptable salt thereof is present in a concentration of about 1% w/v.

3. The pharmaceutical composition of claim 1, wherein the decongestant or pharmaceutically acceptable salt thereof is present in the concentration of about 2% w/v.

4. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipient comprises a viscosity enhancer, a humectant, a preservative, a wetting agent, a buffer, a solvent or mixtures thereof.

5. The pharmaceutical composition of claim 4, wherein the viscosity enhancer comprises a blend of microcrystalline cellulose and carmellose sodium present in the concentration from about 0.5% w/v to about 3% w/v.

6. The pharmaceutical composition of claim 4, wherein the preservative comprises benzalkonium chloride present in the concentration from about 0.01% w/v to about 0.05% w/v.

7. The pharmaceutical composition of claim 4, wherein the wetting agent comprises polysorbate 80 present in the concentration from about 0.01% w/v to about 0.05% w/v and the humectant comprises glycerol present in the concentration from about 1% w/v to about 3% w/v.

8. The pharmaceutical composition of claim 1, wherein a pH of the composition is about 5 to about 8.

9. A pharmaceutical composition comprising:
a) about 1% w/v of bepotastine besilate,
b) about 2% w/v of levocloperastine fendizoate,
c) about 2% w/v of blend of microcrystalline cellulose and carmellose sodium,
d) about 2.1% w/v of glycerol,
e) about 0.02% w/v benzalkonium chloride,
f) about 0.01% w/v polysorbate 80, and
g) about 0.2% w/v of citrate buffer;
wherein a pH of the composition is about 5 to about 8 and the composition is formulated as a nasal spray or nasal drop.

10. The pharmaceutical composition of any preceding claim, wherein the composition further comprises about 0.01% w/v to about 1% w/v of a corticosteroid or pharmaceutical acceptable salt thereof.