PRIORITY DOCUMENT

This patent application claims priority to Indian Provisional Patent Application number 202221058339 (filed on 12 October 2022), the contents of which is incorporated by reference herein.

FIELD OF THE INVENTION

The invention relates to a novel process of assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of a container, a cap, a pump, a dip tube, an actuator and a dispensing orifice. The invention also relates to a process for preparing said pharmaceutical composition and its use in the treatment of various disorders like allergy and symptoms associated with allergic rhinitis.

BACKGROUND OF THE INVENTION

Nasal spray devices for the delivery of active ingredient to the nasal cavity, mostly the nasal mucosa, can be useful for the prophylaxis and/or treatment of certain diseases and disorders of the nasal cavity. Such devices are also capable of delivering medicament to the systemic circulation via the turbinates and lymphoid tissues located at the back of the nasal cavity and to the central nervous system via the olfactory region at the top of the nasal cavity.

A known metered dose nasal spray device comprises a container containing an aqueous suspension or solution of a suitable medicament. The container is provided with a manually operated pump adapted to atomise metered doses of the medicament formulation for delivery to the nasal cavity. Examples of this type of nasal spray device include FLONASE ALLERGY RELIEF® (Fluticasone propionate, Glaxo), NASACORT ALLERGY 24 HOUR® (triamcinolone acetonide, Sanofi), RYALTRIS® (mometasone furoate and olopatadine hydrochloride, Glenmark), DYMISTA (fluticasone propionate and azelastine hydrochloride, Mylan) and NASONEX® (mometasone furoate, Schering-Plough).

The nasal spray devices pumps have achieved some success in the marketplace however, they have a number of drawbacks. The clogging of nasal spray device is observed in many metered nasal spray products. To address the clogging problems associated with metered dose nasal spray devices, several nasal spray device manufacturing companies have developed advanced next generation devices, for example Nemera has developed ADVANCIA®, whose closing tip prevents clogging, which can be a particular problem with formulations prone to crystallisation. Another device company, Aptar has developed CPS technology platform, which uses spring loaded tip seal technology to prevent clogging of nasal spray device.

Still, there is an unmet need to develop cost effective and simple method to prevent or minimize the above mentioned problems associated with the nasal spray devices.

SUMMARY OF THE INVENTION

The invention in one embodiment relates to a process of assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein assembling of actuator on filled and sealed container is done in an inverted orientation.

Another embodiment relates to a process of assembling nasal spray device wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container.

Another embodiment relates to a process of assembling nasal spray device wherein assembling of actuator on filled and sealed container is done in an inverted orientation wherein open end of dip tube is not in direct contact with majority portion of pharmaceutical composition.

Another embodiment relates to a process of assembling nasal spray device wherein said container is having a conically shaped internal bottom.

Another embodiment relates to a process of assembling nasal spray device wherein said container is having flat internal bottom.

Another embodiment relates to a process of assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container to minimize or prevent clogging inside dip tube or actuator.

Another embodiment relates to a process of assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container to minimize or prevent clogging inside dip tube or actuator within 6 or 12 or 24 months of storage at 25° C ± 2° C and 60% ± 5% RH or at 40° C ± 2° C and 75% ± 5% RH.

Another embodiment relates to a process of assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein, the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein assembling of actuator on filled and sealed container is done in an inverted orientation to minimize or prevent clogging inside dip tube or actuator within 6 or 12 or 24 months of storage at 25° C ± 2° C and 60% ± 5% RH or at 40° C ± 2° C and 75% ± 5% RH.

Another embodiment relates to a process of assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container to minimize or prevent clogging inside dip tube or actuator within 2 months or 3 months of storage at 25° C ± 2° C and 60% ± 5% RH or at 40° C ± 2° C and 75% ± 5% RH.

Another embodiment relates to a process of assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein, the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein assembling of actuator on filled and sealed container is done in an inverted orientation to minimize or prevent clogging inside dip tube or actuator within 2 months or 3 months of storage at 25° C ± 2° C and 60% ± 5% RH or at 40° C ± 2° C and 75% ± 5% RH.

The invention in one embodiment relates to a process of filling and assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein filling of pharmaceutical composition in container and assembling of actuator on filled and sealed container are done in opposite orientation from each other.

The invention in one embodiment relates to a process of filling and assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein filling of pharmaceutical composition in container and sealing is done in upright orientation. Another embodiment relates to a process of filling and assembling nasal spray device wherein assembling of actuator on filled and sealed container is done in an inverted orientation.

Another embodiment relates to a process of filling and assembling nasal spray device wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container.

Another embodiment relates to a process of filling and assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container to prevent clogging inside dip tube or actuator.

Another embodiment relates to a process of filling and assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container to minimize clogging inside dip tube or actuator.

Another embodiment relates to a process of filling and assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container to minimize or prevent clogging inside dip tube or actuator within 6 or 12 or 24 months of storage at 25° C ± 2° C and 60% ± 5% RH or at 40° C ± 2° C and 75% ± 5% RH.

Another embodiment relates to a process of filling and assembling nasal spray device wherein assembling of actuator on filled and sealed container is done in an inverted orientation wherein open end of dip tube is not in direct contact with majority portion of pharmaceutical composition.

In another embodiment, the cap is releasably attachable to the nasal spray device for covering at least the dispensing orifice.

Another embodiment relates to a process of assembling nasal spray device comprising a pharmaceutical composition in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein pharmaceutical composition comprises from about 0.01 % to about 2 % by weight of steroid and from about 0.05 % to about 2 % by weight of antiallergic and a pharmaceutically acceptable excipient wherein assembling of actuator on filled and sealed container is done in an inverted orientation.

Another embodiment relates to a process of assembling nasal spray device comprising a pharmaceutical composition in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein pharmaceutical composition comprises from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and a pharmaceutically acceptable excipient wherein assembling of actuator on filled and sealed container is done in an inverted orientation.

Another embodiment relates to a nasal spray device comprising a container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein the container contains fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and a pharmaceutically acceptable excipient, wherein assembling of actuator on filled and sealed container is done in an inverted orientation.

Another embodiment relates to a process of assembling nasal spray device comprising a pharmaceutical composition in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein pharmaceutical composition comprises from about 0.01 % to about 2 % by weight of corticosteroid and from about 0.05 % to about 2 % by weight of antiallergic and a pharmaceutically acceptable excipient wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container.

In another embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt in a weight ratio ranging from about 1 : 1 to about 1 :5 and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.

In one aspect of this embodiment, each spray of the composition delivers about 50 mcg of mometasone furoate and about 140 mcg of azelastine hydrochloride.

In a specific embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.

In a specific embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride and neotame wherein, the composition is administered as one spray per nostril twice daily to the subject in need thereof.

In another embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and an excipient selected from the group consisting of carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid or mixtures thereof.

In a specific embodiment, the present invention relates to a stable fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid and water wherein, the composition is administered as one spray per nostril twice daily to a subject in need thereof.

In an embodiment, the stable fixed dose pharmaceutical composition of the present invention has pH in the range of about 4.0 to about 5.0, Osmolality in the range of about 270 mOsm to about 370 mOsm, viscosity in the range of about 50 cPs to about 100 cPs and weight per ml in the range of about 0.90 g/ml to about 1.20 g/ml.

In another embodiment, the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and water.

In another embodiment, the present invention relates to a method of treating rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily of a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and water.

In another embodiment, the present invention relates to a method for relief of nasal and non-nasal symptoms associated with rhinitis in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and water.

In another embodiment, the present invention relates to a method of treating rhinitis in a subject by reducing the nasal and non-nasal symptoms associated with rhinitis (such as sneezing, nasal itching, rhinorrhea, nasal obstruction, ocular pruritis, excess lacrimation and the like) in a subject in need thereof, said method comprising administering nasally to the subject as one spray per nostril twice daily of a stable fixed dose pharmaceutical composition in the form of nasal spray comprising about 0.07 % by weight of mometasone furoate, about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, citric acid, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and water.

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, drug-induced 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 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.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the invention can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the various embodiments of the invention. Figure 1 shows process of filling and assembling nasal spray device resulting in clogging of nasal spray device.

Figure 2 shows process of filling and assembling nasal spray device according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

It is also to be understood that the terminology used herein is for describing particular embodiments only, and is not intended to be limiting. The term singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

The term “active ingredient” (used interchangeably with “active” or “active agent” or “drug” or “medicament”) as used herein include corticosteroids, antihistaminic, antiinflammatory, steroids or anti-allergic drugs but not limited to fluticasone, mometasone, budesonide, triamcinolone, olopatadine, azelastine or its pharmaceutically acceptable salt or ester thereof or combination thereof.

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.

The pharmaceutical composition according to present invention is solution or suspension of one or more active ingredients.

The term "effective amount" or "therapeutically effective amount" denotes an amount of an 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, azelastine or a pharmaceutically acceptable salt thereof.

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 the 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 the sodium, calcium, potassium and magnesium salts. The term “treating” or “treatment” as used herein also covers the prophylaxis, mitigation, prevention, amelioration or suppression of a disorder modulated by the mometasone or azelastine or by a combination of the two in a mammal.

The term "subject" includes mammals like human and other animals such as domestic animals (e.g. household pets including cats and dogs) and non-domestic animals (such as wildlife). Preferably, the subject is a human.

By “pharmaceutically acceptable excipients”, it is meant any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.

The therapeutically effective amount of mometasone (or its pharmaceutically acceptable salt) to be administered per day may range from about 100 mcg to about 500 mcg, preferably from about 200 mcg to about 400 mcg. Preferably, the discrete dosage strengths of mometasone (or its pharmaceutically acceptable salt) may be about 25 mcg, about 50 mcg, about 75 mcg and about 100 mcg.

The therapeutically effective amount of azelastine (or its pharmaceutically acceptable salt) to be administered per day may range from about 300 mcg to about 2000 mcg, preferably from about 500 mcg to about 1800 mcg. Preferably, the discrete dosage strengths of azelastine (or its pharmaceutically acceptable salt) to be administered per day may be about 100 mcg, about 125 mcg, about 140 mcg, about 150 mcg, about 200 mcg, about 275 mcg, about 300 mcg and about 500 mcg.

Combinations

The present invention relates to a fixed dose pharmaceutical composition in the form of nasal spray that includes steroids (like but not limited to fluticasone, mometasone, triamcinolone) and antiallergic drug (like but not limited to azelastine, olopatadine, cetirizine, loratadine).

According to the invention, the term “orientation” means position of container during filling and sealing process and during assembling of actuator to the filled and sealed container. The term “orientation” and “position” can be used interchangeably. The term “opposite orientation” means upright position of container during filling and sealing process and inverted position of container during assembling of actuator on filled and sealed container.

According to the invention, the term “sealed” include attachment of nasal spray pump on filled container using “crimp-on” or “screw-on” or “snap-on” arrangement.

According to the invention, the term “majority portion of pharmaceutical composition” means not less than 95 % w/w of total quantity of pharmaceutical composition. Nasal Spray Device

Generally, nasal spray device includes (a) a container for the pharmaceutical composition; (b) a cap; (c) a pump; (d) a dip tube extending along the longitudinal axis of the container, the dip tube having a proximal end communicating with the pump and an open distal end extending into the container; (e) an actuator; (f) a dispensing channel; (g) and dispensing orifice. The pharmaceutical composition is released in the form of a uniform spray. Actuators include but are not limited to spray actuators, foam actuators, solid-stream actuators, and special actuators.

The container of the dispensing device can be a round or oval; preferably, the container is round. The container can further have a flat bottom or a conically shaped bottom. The conically shaped bottom is angled downwardly from a side of the container to a center of the bottom, the center being a low point of the bottom of the container. The center of the bottom is preferably located along a longitudinal axis of the container.

A dip tube is located within the container. In the flat bottom embodiment of the container, the distal (open) end of the dip tube is located near the flat bottom. In the conically shaped embodiment of the container, the distal end of the dip tube is located in the conically shaped portion (down in the low point) of the container. Locating the distal end of the dip tube as close as possible to the low point of the bottom of the container assists in avoidance of dead volume residue in the container during multiple actuations (especially when the container nears exhaustion).

It is observed in suspension based nasal spray products that the actuator or the dip tube is clogged and medicament is not getting delivered after pressing the actuator. Not wishing to be bound by any particular theory, it seems that evaporation of the water or solvent from the composition which is remaining on the tip of actuator or inside the dip tube is responsible for dry mass clogging the actuator or the dip tube. In another theory, the clogging of actuator may occur as a result of presence of small amount of pharmaceutical composition, during the assembling process of the device, more specifically during the assembling of actuator on the filled container. This small amount of pharmaceutical composition in the actuator gets dried, if the nasal spray device is not used for long time and results in clogging.

The clogging of the dip tube or the actuator can be overcome by the process of filling and assembling nasal spray device. Further, nasal spray device of the present invention further comprises a cap equipped to cover the actuator. The cap is made of polymeric substances. Preferably, the cap is an Antilop cap also known as Anti-Loss On Priming cap. The cap has a sealing element extending from an inside of a top wall thereof, the sealing element providing a sealing between the cap and dispensing orifice of the nasal spray device. The sealing element prevents the distal tip of the actuator tip from drying and prevents misfiring of the pharmaceutical composition from the actuator upon accidental actuation.

Figure 1 illustrates process of filling and assembling nasal spray device resulting in clogging of nasal spray device. The pharmaceutical composition B is filled in container in upright orientation and container is sealed in upright orientation on the conveyer belt at station 1. The open end of the Dip Tube A is in contact with bottom of container. The Actuator D is assembled on the filled and sealed container, by pressing down the Actuator D in upright position in Station 2. During assembling of actuator in this condition, small amount of pharmaceutical composition enters in the Dip Tube A. If this small amount of pharmaceutical composition remains in Dip Tube A for long time and gets dried, C, will result in clogging of Dip Tube A.

Figure 2 illustrates novel process of filling and assembling nasal spray device according to the present invention. The pharmaceutical composition B is filled in container in upright orientation and container is sealed in upright orientation at station 1. The filled and sealed container is vertically flipped from upright position to an inverted position on the conveyer belt. The open end of the Dip Tube A is in contact with bottom of container, but open end of Dip Tube A is not in direct contact with majority portion of pharmaceutical composition. The Actuator D is assembled on the filled and sealed container, by pressing up the Actuator D in an inverted orientation in Station 2. During assembling of actuator in this condition, there will be no pharmaceutical composition in the Dip Tube A.

The container can be made of any polymeric substance. In such embodiments, suitable polymers include, but are not limited to, polyethylene, polypropylene (PP), polystyrene (PS), nylon (Ny), polyvinyl chloride (PVC), polyethylene terephthalate (PET), polycarbonate (PC), polyoxymethylene (POM), polysulfone (PSF), polyethersulfone (PES), polyacrylate (PAR), and polyamide (PA). In certain embodiments, the polymer is polyethylene, particularly medium-density polyethylene (MDPE) (or branched polyethylene) or high density polyethylene (HDPE) (or linear polyethylene). In one embodiment, the bottle is made of high density polyethylene (HDPE). The container may have an inert coating on an inner surface thereof to avoid any interaction of the container component with the pharmaceutical compositions of the present invention.

One embodiment of the invention relates to a process of filling and assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein filling of pharmaceutical composition in container and assembling of actuator on filled and sealed container are done in opposite orientation from each other.

The invention in one embodiment relates to a process of filling and assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein filling of pharmaceutical composition in container and sealing is done in upright orientation.

Another embodiment relates to a process of filling and assembling nasal spray device wherein assembling of actuator on filled and sealed container is done in an inverted orientation.

Another embodiment relates to a process of filling and assembling nasal spray device wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container.

Another embodiment relates to a process of filling and assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container to prevent clogging inside dip tube or actuator.

Another embodiment relates to a process of filling and assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container to minimize clogging inside dip tube or actuator.

Another embodiment relates to a process of filling and assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container to minimize or prevent clogging inside dip tube or actuator within 6 or 12 or 24 months of storage at 25° C ± 2° C and 60% ± 5% RH or at 40° C ± 2° C and 75% ± 5% RH.

Another embodiment relates to a process of filling and assembling nasal spray device wherein assembling of actuator on filled and sealed container is done in an inverted orientation wherein open end of dip tube is not in direct contact with majority portion of pharmaceutical composition.

Another embodiment relates to a process of filling and assembling nasal spray device wherein said container is having a conically shaped internal bottom.

Another embodiment relates to a process of filling and assembling nasal spray device wherein said container is having flat internal bottom.

In another embodiment, the cap is releasably attachable to the nasal spray device for covering at least the dispensing orifice.

Another embodiment relates to a process of assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator and a dispensing orifice wherein assembling of actuator on the filled and sealed container is done in an inverted orientation.

Another embodiment relates to a process of assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator, and a dispensing orifice wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container to minimize or prevent clogging inside dip tube or actuator.

Another embodiment relates to a process of assembling nasal spray device wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling of the actuator on the sealed container.

Another embodiment relates to a process of assembling nasal spray device wherein open end of dip tube is not in direct contact with majority portion of pharmaceutical composition.

Another embodiment relates to a process of assembling nasal spray device containing pharmaceutical composition wherein the pharmaceutical composition comprises one or more active ingredient selected from mometasone, fluticasone, triamcinolone, azelastine, olopatadine and combination thereof.

Another embodiment relates to a process of assembling nasal spray device containing pharmaceutical composition wherein pharmaceutical composition is fixed dose composition comprising steroid and antiallergic drug.

Another embodiment relates to a process of assembling nasal spray device wherein pharmaceutical composition comprises from about 0.01 % to about 2 % by weight of steroid and from about 0.05 % to about 2 % by weight of antiallergic drug and a pharmaceutically acceptable excipient.

Another embodiment relates to a process of assembling nasal spray device wherein pharmaceutical composition comprises from about 0.01 % to about 2 % by weight of steroid selected from fluticasone, mometasone or triamcinolone and from about 0.05 % to about 2 % by weight of antiallergic drug selected from azelastine, olopatadine or loratadine and a pharmaceutically acceptable excipient.

Another embodiment relates to a process of assembling nasal spray device containing pharmaceutical composition wherein pharmaceutical composition is fixed dose composition comprising mometasone furoate and azelastine hydrochloride.

Another embodiment relates to a process of assembling nasal spray device containing pharmaceutical composition herein pharmaceutical composition is fixed dose composition comprising mometasone furoate and olopatadine hydrochloride.

Another embodiment relates to a process of assembling nasal spray device comprising a pharmaceutical composition of one or more active ingredient in a nasal spray device wherein the nasal spray device comprises of container, a cap, a pump, a dip tube, an actuator, and a dispensing orifice wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container to minimize or prevent clogging inside dip tube or actuator within 6 or 12 or 24 months of storage at 25° C ± 2° C and 60% ± 5% RH or at 40° C ± 2° C and 75% ± 5% RH.

Another embodiment relates to a process of assembling nasal spray device wherein filling of pharmaceutical composition in container and sealing is done in upright orientation.

Another embodiment relates to a process of assembling nasal spray device wherein assembling of actuator on filled and sealed container is done in an inverted orientation.

Another embodiment relates to a process of assembling nasal spray device wherein filled and sealed container is vertically flipped from upright position to an inverted position before assembling the actuator on the sealed container to minimize or prevent clogging inside dip tube or actuator within 6 or 12 or 24 months of storage at 25° C ± 2° C and 60% ± 5% RH or at 40° C ± 2° C and 75% ± 5% RH.

In another embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof. In an aspect of the embodiment, the pharmaceutical composition comprises mometasone or its salt is present in an amount from about 0.05 % to about 1 % by weight. In an aspect of the embodiment, the pharmaceutical composition comprises azelastine or its salt is present in an amount from about 0.1 % to about 1 % by weight.

In another embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt in a weight ratio ranging from about 1 : 1 to about 1 :5 and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof. In an aspect of this embodiment, each spray of the composition delivers about 50 mcg of mometasone furoate and about 140 mcg of azelastine hydrochloride.

In a specific embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride and a pharmaceutically acceptable excipient, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.

In a specific embodiment, the present invention relates to a fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride and neotame, wherein the composition is administered as one spray per nostril twice daily to the subject in need thereof.

In another embodiment, the present invention relates to a the fixed dose pharmaceutical composition comprising from about 0.01 % to about 2 % by weight of mometasone or its salt and from about 0.05 % to about 2 % by weight of azelastine or its salt and an excipient selected from the group consisting of carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame and citric acid or mixtures thereof.

In a specific embodiment, the present invention relates to a stable fixed dose pharmaceutical composition comprising about 0.07 % by weight of mometasone furoate and about 0.2 % by weight of azelastine hydrochloride, carmellose sodium, microcrystalline cellulose, carboxymethyl cellulose sodium, dextrose, sodium citrate, polysorbate 80, benzalkonium chloride, di-sodium edetate, neotame, citric acid and water wherein, the composition is administered as one spray per nostril twice daily to a subject in need thereof.

In an embodiment, the stable fixed dose pharmaceutical composition of the present invention has pH in the range of about 4.0 to about 5.0, Osmolality in the range of about 270 mOsm to about 370 mOsm, viscosity in the range of about 50 cPs to about 100 cPs and weight per ml in the range of about 0.90 g/ml to about 1.20 g/ml. As set forth above, the pharmaceutical composition includes at least one pharmaceutically acceptable excipient, which includes but is not limited to one or more of the following; preservatives, buffering agents, hydrocolloid, chelating agents, polymers, surfactants, sweeteners, solvents and the like.

Examples of suitable buffering agents may be selected from but not limited to phosphate, borate, sodium citrate and other organic acids like citric acid, suitable carbohydrates may be selected from dextrose, mannose or dextrins and the like.

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, carmellose sodium, 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. The hydrocolloid may be present in the range of about 0.3% w/w to about 3% w/w of the composition.

Suitable surfactants which can be used may include one or more of anionic, cationic, non-ionic or zwitterionic surfactants.

Examples of suitable surfactants 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 tri decyl ether, polyoxyethylene sorbitan esters of mixed fatty and resin acids, polyethoxylated sorbitan derivatives or esters of fatty acids (e.g. Polysorbates), 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. Particularly preferred surfactants are polyethoxylated sorbitan derivatives.

Examples suitable of the preservatives which can be employed may be selected from but not limited to benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, disodium edetate. Quaternary ammonium halide preservatives are preferred. Suitable quaternary ammonium halide preservatives include polyquatemium-1 and benzalkonium halides. Preferred benzalkonium halides are benzalkonium chloride and benzalkonium bromide.

Examples of suitable chelating agents which can be employed may be selected from but not limited to edetate di sodium (EDTA), edetate trisodium, edetate tetrasodium, and diethyleneamine pentaacetate, preferably EDTA.

Examples of suitable sweeteners which can be employed may be selected from, but not limited to sucralose, sucrose, saccharin, fructose, dextrose, corn syrup, aspartame, acesulfame- K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor.

Examples suitable solvents are all solvents which are suitable for nasal administration, in particular water and alcohols, such as for example, ethanol, propanol, propanediol or glycerol.

The optimal dose of the active ingredient or the combination of the active ingredients can vary as a function of the severity of disease, route of administration, composition type, the patient body weight, the age and the general state of mind of the patient, and the response to behavior to the active ingredient or the combination of the active ingredients.

EXAMPLES

EXAMPLE 1 : Compositions of mometasone and azelastine for nasal administration.

Table 1 : Composition of mometasone and azelastine

Manufacturing procedure:

1. Dextrose was dissolved in purified water. Sifted microcrystalline cellulose- carboxymethyl cellulose sodium and carmellose sodium were dispersed in the above solution under homogenization.

2. Polysorbate 80 was dissolved in purified water under stirring and mometasone furoate was added and stirred. This suspension was added to step 1 under homogenization.

3. Azelastine hydrochloride was dissolved in purified water under stirring and neotame was added under homogenization. This solution was added to step 2 under homogenization.

4. Sodium ci trate/Di sodium hydrogen phosphate dihydrate was dissolved in purified water under stirring and citric acid was added to this. This solution was added to step 3 under homogenization.

5. Disodium edetate was dissolved in purified water under stirring and added to step 4 under homogenization.

6. Benzalkonium Chloride was dissolved in purified water under stirring and added to step 5 under homogenization.

7. The pH was adjusted with 10 % citric acid solution and the volume was made up with purified water.

8. The composition was homogenized and filled in container and sealed.

9. The actuator was placed on filled and sealed container in upright position (as shown in Figure

1) and inverted position (as shown in Figure 2).

EXAMPLE 2: a. 80 sealed bottles from Example 1 were selected. b. The sealed bottles were divide into two groups (Group A and Group B). In Group A, the actuator was placed on sealed bottle in upright position (as shown in Figure 1) and for Group B, the actuator was placed on sealed bottle in inverted position (as shown in Figure 2). c. Both group samples were kept in controlled room condition (25° C ± 2° C and 60% ± 5% RH) for two months with proper labelling. d. After two months, each bottle was primed to check the blockage of actuator.

EXAMPLE S:

Table 2: Blockage study results for Example 2

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 above.