Nasal spray composition

Abstract

This invention relates to pharmaceutical compositions in the form of an aqueous suspension suitable for nasal administration. The compositions comprise mometasone furoate or its hydrate, olopatadine or a pharmaceutically acceptable salt thereof (e.g., olopatadine hydrochloride), and components for controlling clogging of the actuator and / or draw tube in a nasal spray device for administering the compositions. The compositions are suitable for providing consistent delivery, for example, for at least 5 days, without clogging the actuator or draw tube of the nasal spray device. The invention also relates to a method for preparing the compositions in the form of an aqueous suspension.

Description

[0001] Related applications

[0002] This application claims the benefit of Indian Provisional Patent Application No. 202321078834, filed on November 21, 2023, the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] This invention relates to pharmaceutical compositions in the form of an aqueous suspension suitable for nasal administration. The composition comprises mometasone furoate or its hydrate, olopatadine or a pharmaceutically acceptable salt thereof (e.g., olopatadine hydrochloride), and components for controlling clogging of the actuator and / or draw tube in a nasal spray device for administering the composition. The composition is suitable for providing consistent delivery, for example, for at least 30 days, without clogging the actuator or draw tube of the nasal spray device. The invention also relates to a method for preparing the composition in the form of an aqueous suspension. Background Technology

[0004] Nasal spray devices used to deliver active ingredients to the nasal cavity (primarily the nasal mucosa) can be used to prevent and / or treat certain diseases and conditions of the nasal cavity. These devices can also deliver medication into the systemic circulation via the nasal turbinates and lymphatic tissue located at the back of the nasal cavity, and into the central nervous system via the olfactory region at the top of the nasal cavity.

[0005] Nasal spray pharmaceutical products contain a therapeutic active ingredient dissolved or suspended in a mixture of solutions or excipients, such as preservatives, viscosity modifiers, emulsifiers, and buffers, in a non-pressurized dispenser that delivers a metered dose of the active ingredient in the spray. The dose can be metered by a spray pump or pre-metered during manufacturing. Nasal spray units can be designed for unit delivery or can dispense metered sprays of up to hundreds of formulations containing the pharmaceutical substance.

[0006] The dosage can be delivered into the nasal cavity via the integral pump component of the container-closed system to achieve local and / or systemic effects.

[0007] The container closure system for these pharmaceutical products includes a container, closure, actuator, and pump. It may also include protective packaging, such as a dust cap. Regardless of the design, the most critical attributes of this nasal spray are the repeatability of dosage, spray plume, spray content uniformity, and droplet size distribution. These parameters are important and can affect drug delivery to the application site and the intended biological target.

[0008] Metered-dose nasal spray compositions comprising mometasone furoate and olopatadine hydrochloride are disclosed in International Publication No. WO2015 / 036902. Although those compositions are stable, they may cause blockage of the actuator and / or the suction tube, which could affect the consistent delivery of the suspension from the metered-dose nasal spray.

[0009] To address this clogging issue associated with metered-dose nasal spray devices, patient information leaflets typically instruct patients to wipe the spray pump tip with a clean, dry tissue or cloth after use, hold the spray pump unit, and push the dust cap back onto the spray pump tip on the bottle. However, if patients do not follow these instructions correctly, they may experience inconsistent delivery due to clogging of the actuator and / or the suction tube. Therefore, these patient instructions are generally not an effective solution for controlling clogging issues associated with metered-dose nasal spray devices.

[0010] There is a need for novel methods to control clogging problems associated with compositions containing mometasone furoate or its hydrate and olopatadine hydrochloride delivered via a metered-dose nasal spray device. This invention addresses these needs. Summary of the Invention

[0011] In one aspect, the present invention relates to a pharmaceutical composition comprising mometasone, an ester thereof (e.g., mometasone furoate) or a salt thereof, and olopatadine or a salt thereof (e.g., olopatadine hydrochloride), and means for controlling blockage associated with a nasal spray device (e.g., a metered-dose nasal spray device). The means for controlling blockage may be a deblocking agent. The pharmaceutical composition is adapted to a nasal spray device comprising an actuator and a suction tube through which the composition is delivered. The means for controlling blockage (such as by comprising a deblocking agent) avoids or minimizes blockage in the actuator and / or suction tube of the nasal spray device.

[0012] In one embodiment, the pharmaceutical composition can be used to treat allergic rhinitis in a human subject.

[0013] Adding a device for controlling blockage (e.g., a blockage remover) to the pharmaceutical composition enables consistent administration of the mometasone and olopatadine components and avoids blockage of the nasal spray actuator and / or suction tube.

[0014] In one embodiment, the composition comprises mometasone furoate, olopatadine hydrochloride, and a deblocking agent.

[0015] In one embodiment, the pharmaceutical composition is an aqueous suspension comprising a hydrocolloid, wherein mometasone (or its ester, such as mometasone furoate, or its salt) is present in particulate form, and olopatadine or its salt (e.g., olopatadine hydrochloride) is present in dissolved form. In one embodiment, the pharmaceutical composition comprises a amount of hydrocolloid such that the viscosity of the pharmaceutical composition is from about 10 cps to about 200 cps, such as from about 20 cps to about 150 cps or from about 20 cps to about 120 cps. The pharmaceutical composition may comprise from about 0.001 wt% to about 0.075 wt% of mometasone, its ester (e.g., mometasone furoate), or its salt in particulate form, and from about 0.5 wt% to about 0.8 wt% of olopatadine or its salt (e.g., olopatadine hydrochloride) in dissolved form.

[0016] In one embodiment, the pharmaceutical composition comprises about 0.001% to about 0.075% by weight of mometasone, its ester (e.g., mometasone furoate) or its salt in particulate form and about 0.5% to about 0.8% by weight of olopatadine or its salt (e.g., olopatadine hydrochloride) in soluble form, and means for controlling blockage of the nasal spray actuator and / or suction tube, such as a deblocking agent.

[0017] In another embodiment, the pharmaceutical composition comprises about 0.025% to about 0.05% by weight of mometasone, its ester (e.g., mometasone furoate) or its salt in particulate form, about 0.5% to about 0.8% by weight of olopatadine or its salt (e.g., olopatadine hydrochloride), and about 0.05% to about 5% by weight of a deblocking agent.

[0018] In yet another embodiment, the pharmaceutical composition comprises about 0.025% to about 0.05% by weight of mometasone, its ester (e.g., mometasone furoate) or its salt in particulate form, about 0.6% to about 0.7% by weight of olopatadine or its salt (e.g., olopatadine hydrochloride), and about 0.05% to about 5% by weight of a deblocking agent.

[0019] In yet another embodiment, the pharmaceutical composition comprises about 0.025% to about 0.05% by weight of mometasone, its ester (e.g., mometasone furoate) or its salt in particulate form, about 0.6% to about 0.7% by weight of olopatadine or its salt (e.g., olopatadine hydrochloride), and about 0.1% to about 5% by weight of a deblocking agent.

[0020] In yet another embodiment, the pharmaceutical composition comprises about 0.025% to about 0.05% of mometasone furoate in particulate form, about 0.6% to about 0.7% of olopatadine hydrochloride, and about 0.1% to about 3% of an unblocking agent.

[0021] In another embodiment, the pharmaceutical composition comprises about 0.025% by weight of mometasone furoate in particulate form, about 0.665% by weight of olopatadine hydrochloride in soluble form, and means for controlling blockage at the actuator for delivering the composition, thereby promoting consistent delivery of the composition.

[0022] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.05% by weight to about 5% by weight glycerin.

[0023] In yet another embodiment, the pharmaceutical composition described herein comprises an amount of glycerol of about 0.05% to about 3% by weight, about 0.05% to about 2% by weight, or about 0.05% to about 1% by weight.

[0024] In yet another embodiment, the pharmaceutical composition described herein comprises an amount of glycerol of about 0.075% to about 3% by weight, about 0.075% to about 2% by weight, or about 0.075% to about 1% by weight.

[0025] In yet another embodiment, the pharmaceutical composition described herein comprises about 0.05% by weight, about 0.06% by weight, about 0.07% by weight, about 0.075% by weight, about 0.08% by weight, about 0.085% by weight, about 0.09% by weight, about 0.095% by weight, about 0.1% by weight, about 0.125% by weight, about 0.15% by weight, about 0.17% by weight, about 0.18% by weight, about 0.19% by weight, about 0.2% by weight, about 0.225% by weight, about 0.25% by weight, about 0.27% by weight, about 0.28% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 1% by weight, about 2% by weight, or about 3% by weight.

[0026] In another embodiment, the dispensing device (such as a nasal spray actuator and a pump) dispenses about 100 μl of the drug composition with each actuation, wherein a single actuation dispenses about 665 μg of olopatadine hydrochloride and about 25 μg or about 50 μg of mometasone furoate (preferably 25 μg of mometasone furoate).

[0027] In another embodiment, the dispensing device may include a container, a cap, and a dispensing head, which may include a pump, a suction tube, an actuator, a dispensing channel, and a dispensing orifice. The pump is designed to dispense the drug composition through the suction tube into the pump via an actuator fitted with a dispensing orifice. The drug composition is released in the form of a uniform spray. The pump may operate in series with the actuator, which allows for easy on / off operation of the pump and provides the desired spray characteristics. Actuators include, but are not limited to, spray actuators, foam actuators, solid flow actuators, and special actuators. The dispensing device delivers a nasal spray in the form of a uniform dose, such as mometasone (e.g., mometasone furoate) and olopatadine (e.g., olopatadine hydrochloride), wherein the dose is dispensed whenever the user actuates the dispensing device.

[0028] The dispensing device may require activation, for example, approximately 2-6 times, to consistently dispense the composition. Activation can be achieved by releasing 6 sprays or until a fine mist appears. The droplet size of the nasal spray can be controlled by the size of the dispensing orifice on the container. The size of the dispensing orifice can also affect the characteristics of the spray pattern. Brief description of the attached diagram

[0030] The invention can be better understood by referring to the following description taken in conjunction with the accompanying drawings. For illustrative purposes, certain embodiments of the invention are shown in the drawings. However, it should be understood that the invention is not limited to the precise arrangements, dimensions, and apparatus shown:

[0031] Figure 1 A nasal spray device is shown, comprising a container, a suction tube, a nasal spray pump, an actuator, an actuator tip, and a dust cap, as well as the pharmaceutical composition of the present invention. Detailed Implementation

[0032] In nasal spray products containing suspension formulations, patient information leaflets typically instruct patients to wipe the spray pump tip with a clean, dry tissue or cloth after use, hold the spray pump unit, and push the dust cap back onto the spray pump tip on the bottle. However, patients often forget to wipe the tip actuator or improperly install the dust cap, which can lead to actuator and / or draw tube blockage. This blockage further results in a lack of repeatability in dose uniformity, spray plume, spray content uniformity, and droplet size distribution. These problems then lead to inaccurate drug delivery into the nasal cavity.

[0033] The inventors were surprised and unexpected to discover that adding a deblocking agent can substantially control blockages in the actuator and / or the suction tube.

[0034] In one aspect, the present invention relates to a pharmaceutical composition for nasal administration to a human subject to treat rhinitis, the pharmaceutical composition comprising mometasone, an ester thereof (e.g., mometasone furoate) or a salt thereof, olopatadine or a salt thereof (e.g., olopatadine hydrochloride), and means for controlling blockage associated with a nasal spray device (e.g., a metered-dose nasal spray device).

[0035] In another aspect, the present invention relates to a dispensing device containing a pharmaceutical composition comprising mometasone, an ester thereof (e.g., mometasone furoate) or a salt thereof, and olopatadine or a salt thereof (e.g., olopatadine hydrochloride), and means for controlling clogging problems associated with a metered-dose nasal spray device.

[0036] In one embodiment, the device for controlling blockage is a deblocking agent. Suitable deblocking agents include, but are not limited to, sugar alcohols (polyols), polyethers, or any combination thereof.

[0037] In one embodiment, the unblocking agent is glycerol (or glycerol), sorbitol, mannitol, propylene glycol, polyethylene glycol, or any combination of the aforementioned unblocking agents.

[0038] In one embodiment, the unblocking agent is present in the pharmaceutical composition in an amount sufficient to control actuator blockage, such as during storage for 1, 2, 3, 4, 5, or 6 months, for example, at 25°C and 60% relative humidity (RH), or 30°C and 65% RH, or 30°C and 75% RH, or 40°C and 75% RH. In another embodiment, the unblocking agent is present in the pharmaceutical composition in an amount from about 0.01% by weight to about 5% by weight, based on the total weight of the pharmaceutical composition. In yet another embodiment, the unblocking agent is present in the pharmaceutical composition in an amount from about 0.05% by weight to about 5% by weight (such as from about 0.05% to about 2% by weight), based on the total weight of the pharmaceutical composition.

[0039] The advantage offered by this nasal spray composition is that patients do not need to wipe the tip of the actuator after each use, and no blockage is observed even if the cap is not properly installed on the dispensing device, for example, for up to 30 days.

[0040] Another embodiment is a pharmaceutical composition comprising about 0.025% by weight of mometasone furoate in particulate form, about 0.665% by weight of olopatadine hydrochloride in soluble form, and means for controlling blockage at the actuator for delivering the composition, thereby promoting consistent delivery of the composition.

[0041] In another embodiment, when the dispensing device remains open without a dust cover, adding an unblocking agent to the pharmaceutical composition (e.g., an aqueous suspension composition) containing mometasone furoate and olopatadine hydrochloride can control (or avoid, reduce, or inhibit) blockage of the nasal spray actuator and / or draw tube (through which the pharmaceutical composition is delivered) for at least 5 days (e.g., when stored at 25 ± 2 °C and 60% ± 5% relative humidity).

[0042] In one embodiment of any of the pharmaceutical compositions described herein, the pharmaceutical composition is stored under standard conditions (25 ± 2 °C and 60% ± 5% relative humidity).

[0043] In another embodiment, when the dispensing device remains open without a dust cover, adding an unblocking agent to the pharmaceutical composition (e.g., an aqueous suspension composition) containing mometasone furoate and olopatadine hydrochloride can control (or avoid, reduce, or inhibit) clogging of the nasal spray actuator and / or extraction tube for at least about 10 days.

[0044] In one embodiment, when the dispensing device remains open without a dust cover, adding an unblocking agent to a pharmaceutical composition (e.g., an aqueous suspension composition) containing mometasone furoate and olopatadine hydrochloride can control (or avoid, reduce, or inhibit) clogging of the nasal spray actuator and / or suction tube for at least about 15 days.

[0045] One embodiment is a pharmaceutical composition (e.g., an aqueous suspension composition) comprising mometasone furoate, olopatadine hydrochloride, and a sufficient amount of unblocking agent to control (or reduce or inhibit) clogging of the nasal spray actuator and / or extraction tube (e.g., for at least about 30 days) while the dispensing device remains open without a dust cap placed on it.

[0046] In another respect, when the dispensing device remains open without a dust cover, the addition of an unblocking agent to a pharmaceutical composition (e.g., an aqueous suspension composition) containing mometasone furoate and olopatadine hydrochloride can control (or avoid, reduce, or inhibit) clogging of the nasal spray actuator and / or suction tube for at least about 5 days, such as about 10 days, about 15 days, or about 30 days.

[0047] In one embodiment, when the dispensing device remains open without a dust cover, the addition of a declogging agent to the aqueous suspension composition can control (or avoid, reduce, or inhibit) clogging of the nasal spray actuator and / or suction tube for approximately 15 days, approximately 20 days, approximately 25 days, or approximately 30 days.

[0048] In another embodiment, when the dispensing device remains open without a dust cover, the addition of an unblocking agent to the aqueous suspension composition can control clogging of the nasal spray actuator and / or suction tube for approximately 5 to approximately 30 days, approximately 5 to approximately 25 days, approximately 5 to approximately 20 days, approximately 5 to approximately 15 days, and approximately 5 to approximately 10 days.

[0049] In another embodiment, when the dispensing device remains open without a dust cover, the addition of an unblocking agent to the aqueous suspension composition can control clogging of the nasal spray actuator and / or suction tube for approximately 8 days, approximately 12 days, approximately 16 days, approximately 22 days, and approximately 28 days.

[0050] In another embodiment, when the dispensing device remains open without a dust cover, the addition of an unblocking agent to the aqueous suspension composition can control clogging of the nasal spray actuator and / or suction tube for approximately 7 to approximately 17 days, approximately 10 to approximately 20 days, approximately 15 to approximately 20 days, approximately 15 to approximately 25 days, and approximately 15 to approximately 30 days.

[0051] In another embodiment, when the dispensing device remains open without a dust cover, the addition of an unblocking agent to the aqueous suspension composition can control clogging of the nasal spray actuator and / or suction tube for approximately 10 to approximately 30 days, or approximately 10 to approximately 25 days.

[0052] In one embodiment of any pharmaceutical composition described herein, the composition is an aqueous suspension comprising a hydrocolloid, mometasone in particulate form, its ester (e.g., mometasone furoate) or a salt thereof, and olopatadine or a salt thereof (e.g., olopatadine hydrochloride) in dissolved form, and an unblocking agent.

[0053] In one embodiment of any pharmaceutical composition described herein, the composition comprises about 0.001% to about 0.075% by weight of mometasone, its ester (e.g., mometasone furoate) or its salt in particulate form, about 0.5% to about 0.8% by weight of olopatadine or its salt (e.g., olopatadine hydrochloride) in soluble form, and about 0.05% to about 5% by weight of an unblocking agent.

[0054] In one embodiment of any of the pharmaceutical compositions described herein, the composition comprises about 0.025% to about 0.05% by weight of mometasone, its ester (e.g., mometasone furoate), or a salt thereof in particulate form; and about 0.5% to about 0.8% by weight of olopatadine or a salt thereof (e.g., olopatadine hydrochloride). In this embodiment, the pharmaceutical composition may also comprise a hydrocolloid and about 0.05% to about 5% by weight of a deblocking agent.

[0055] In one embodiment of any of the pharmaceutical compositions described herein, the composition comprises about 0.025% to about 0.05% by weight of mometasone, its ester (e.g., mometasone furoate), or a salt thereof in particulate form; and about 0.5% to about 0.8% by weight of olopatadine or a salt thereof (e.g., olopatadine hydrochloride). In this embodiment, the pharmaceutical composition may also comprise a hydrocolloid and about 0.1% to about 5% by weight of a deblocking agent.

[0056] In one embodiment of any of the pharmaceutical compositions described herein, the composition comprises (a) about 0.025% to about 0.05% by weight of mometasone furoate in particulate form, (b) about 0.5% to about 0.8% by weight of olopatadine hydrochloride, and (c) about 0.1% to about 5% by weight of a deblocking agent. The pharmaceutical composition may also comprise a hydrocolloid.

[0057] Another embodiment is a pharmaceutical composition suitable for a nasal spray device comprising an actuator and a suction tube through which the composition is delivered, wherein (a) the composition is in the form of an aqueous suspension suitable for nasal administration, and (b) the composition comprises mometasone furoate (e.g., in particulate form at about 0.025% by weight), olopatadine or a pharmaceutically acceptable salt thereof (e.g., olopatadine hydrochloride in dissolved form at about 0.665% by weight), and an amount of unblocking agent sufficient to control blockage at the actuator and suction tube for delivery of the composition, thereby facilitating consistent delivery of the composition. The unblocking agent can be any such agent described herein. In one embodiment, the unblocking agent is selected from glycerin, sorbitol, mannitol, propylene glycol, polyethylene glycol, and any combination of the foregoing unblocking agents. In a preferred embodiment, the unblocking agent is glycerin. In one embodiment, glycerin is present at about 0.05% by weight to about 5% by weight. In another embodiment, glycerin is present at about 0.05% by weight to about 1% by weight.

[0058] Another embodiment is a method for delivering a pharmaceutical composition comprising mometasone furoate and olopatadine hydrochloride to a patient in need via an actuator and suction tube of a nasal spray device, while reducing blockage of the actuator or suction tube. The method includes administering the pharmaceutical composition into the patient's nose via the actuator and suction tube of the nasal spray device, wherein the pharmaceutical composition is in the form of an aqueous suspension suitable for nasal administration, and (b) the composition comprises mometasone furoate (e.g., in particulate form at about 0.025% by weight), olopatadine or a pharmaceutically acceptable salt thereof (e.g., olopatadine hydrochloride, in dissolved form at about 0.665% by weight), and means for controlling blockage at the actuator and suction tube for delivering the composition, thereby facilitating consistent delivery of the composition. In one embodiment, the patient suffers from allergic rhinitis, such as seasonal allergic rhinitis or perennial allergic rhinitis. In one embodiment, the unblocking agent is selected from glycerin, sorbitol, mannitol, propylene glycol, polyethylene glycol, and any combination of the foregoing unblocking agents. In a preferred embodiment, the unblocking agent is glycerin. In one embodiment, glycerol is present in an amount of about 0.05% by weight to about 5% by weight. In another embodiment, glycerol is present in an amount of about 0.05% by weight to about 1% by weight.

[0059] In yet another embodiment, the nasal spray device or dispensing device may include a container, a cap, and a dispenser head, which may include a pump, a suction tube, an actuator, a dispensing channel, and a dispensing orifice, such as Figure 1 As shown. The pump is designed to dispense a drug composition through a draw tube into the pump via an actuator fitted with a dispensing orifice. The drug composition is released in the form of a uniform spray. The pump can operate in series with the actuator, which allows for easy on / off operation of the pump and provides the desired spray characteristics. Actuators include, but are not limited to, spray actuators, foam actuators, solid flow actuators, and special actuators. The container of the nasal spray device can be round or oval; preferably, the container is round. The container may have a conical inner bottom or a flat bottom. A cap may or may not be included. The dispensing device delivers a uniform dose of nasal spray, for example, mometasone (e.g., mometasone furoate) and olopatadine (e.g., olopatadine hydrochloride), wherein the dose is dispensed whenever the user actuates the dispensing device.

[0060] As further detailed below, in some embodiments, the dispensing device is sufficient to dispense about 100 μl of the pharmaceutical composition per actuation, wherein a single actuation dispenses about 665 μg of olopatadine hydrochloride and about 25 μg or about 50 μg of mometasone furoate, preferably 25 μg of mometasone furoate.

[0061] definition

[0062] Unless the context clearly indicates otherwise, the singular forms “a / an” and “the” contain plural indicators. Thus, for example, reference to a compound refers to one or more compounds or at least one compound. Therefore, the terms “a / an,” “a or more / a,” and “at least one / a” are used interchangeably herein.

[0063] As used herein, when referring to a number or range of values, the term “about” means that the number or range of values ​​mentioned is an approximation within experimental variability (or within statistical experimental error), and that the number or range of values ​​may vary between, for example, 1% and 15% of the number or range of values.

[0064] When used in conjunction with an active ingredient, the term "effective amount" refers to the amount of active ingredient that produces the expected therapeutic benefit in a subject when administered to a subject for the treatment of rhinitis.

[0065] As used herein, the term "active ingredient" (which may be used interchangeably with "active substance" or "drug") includes mometasone (or its esters, such as mometasone furoate) or a salt thereof, and olopatadine or a salt thereof (e.g., olopatadine hydrochloride). An effective amount of mometasone (or its esters, such as mometasone furoate) or a salt thereof may be from about 0.01 mg to about 10 mg, preferably from about 0.02 mg to about 5 mg, or more preferably from about 0.02 mg to about 3 mg. An effective amount of olopatadine or a salt thereof (e.g., olopatadine hydrochloride) may be in the range of from about 0.05 mg to about 20 mg, preferably from about 0.1 mg to about 15 mg, or more preferably from about 0.1 mg to about 10 mg.

[0066] As used herein, the term “α-hydroxyollotatidine” for olopatadine refers to “(Z)-2-{11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenzo[b,e]oxazo-2-yl}-2-hydroxyacetic acid”.

[0067] As used herein, the term “ollotatine E-isomer” refers to “11-[(E)-3-(dimethylamino)propylidene]-6,11-dihydrodibenzo[b,e]oxazo-2-acetic acid”.

[0068] As used herein, the term “ollotatine formaldehyde (Z) isomer” refers to “(Z)-11-(3-(dimethylamino)propylidene)-6,11-dihydrodibenzo[b,e]oxazo-2-carboxaldehyde hydrochloride”.

[0069] As used herein, the term “ollotatine-related compound B” refers to “(Z)-3-{2-(carboxymethyl)dibenzo[b,e]oxazo-11(6H)-ylidene}-N,N-dimethylpropyl-1-amine oxide”.

[0070] As used in this article, the term "8-DM" for mometasone refers to "(9β,11β-epoxy-17α,21-dihydroxy-16α-methylpregn-1,4-diene-3,20-dione)".

[0071] As used in this article, the term "DMC" for mometasone refers to "(21-chloro-9β,11β-epoxy,17α,-hydroxy-16α-methylpregn-1,4-diene-3,20-dione)".

[0072] As used in this article, the term "DMCF" for mometasone refers to "(21-chloro-9β,11β-epoxy-16α-methyl-3,20-dioxopregn-1,4-diene-17-furan-2-carboxylate)".

[0073] In one aspect of the invention, for daily administration via the nasal route, the effective amount of mometasone (or its esters, such as mometasone furoate) or its salts may be in the range of about 10 μg to about 500 μg, preferably about 20 μg to about 400 μg, and the effective amount of olopatadine or its salts (such as olopatadine hydrochloride) may be in the range of about 50 μg to about 7000 μg, preferably about 100 μg to about 5400 μg.

[0074] "Salt" or "pharmaceutically acceptable salt" means that salts, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, or anaphylactic response, are commensurate with a reasonable benefit-risk ratio, and are effective for their intended use. Representative acid addition salts include, for example, hydrochlorides, hydrobroms, sulfates, hydrogen sulfates, acetates, oxalates, valerates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, phosphates, toluenesulfonates, methanesulfonates, citrates, maleates, fumarates, succinates, tartrates, ascorbic acid salts, glucoheponicates, lactobionates, and lauryl sulfates. Representative alkali metal or alkaline earth metal salts include, for example, sodium, calcium, potassium, and magnesium salts.

[0075] As used herein, the terms "treatment" and "treating" refer to methods used to obtain beneficial or desired outcomes, including but not limited to therapeutic and / or preventative benefits. A therapeutic benefit means the eradication or improvement of the underlying condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with the underlying condition, such that improvement is observed in a patient, even though the patient may still have the underlying condition. For preventative benefits, the composition may be administered to patients at risk of developing a specific disease, or to patients who report one or more physical symptoms of a disease, even if the disease may not yet have been diagnosed.

[0076] "Pharmaceutical acceptable excipients" refers to any component of a pharmaceutical composition other than the active ingredient that is approved by a regulatory agency or is generally considered safe for use in humans or animals.

[0077] As used herein, the term "average particle size" (or synonymously, "average particle diameter") refers to the distribution of particles in which approximately 50% by volume of all measured particles have a size smaller than the defined average particle size value, and approximately 50% by volume of all measured particles have a particle size larger than the defined average particle size value. This can be understood through the term "D 50 "or "d (0.5) "To identify. Average particle size can be measured using various techniques, such as microscopy, laser diffraction, photon correlation spectroscopy (PCS), and the Coulter principle."

[0078] As used in this article, the term "D" 10 "" refers to the distribution of particles in which approximately 10% by volume of all measured particles have a size smaller than the defined particle size value. This can also be identified by the term "d(0.1)". Similarly, as used herein, the term "D" 80 "" refers to the distribution of particles in which approximately 80% by volume of all measured particles have a size smaller than the defined particle size value. This can also be identified by the term "d(0.8)". Similarly, as used herein, the term "D" 90 "" refers to the distribution of particles in which approximately 90% by volume of all measured particles have a size smaller than the defined particle size value. This can also be identified by the term "d(0.9)".

[0079] As used herein, the term "hydrocolloid" refers to a colloidal system in which hydrophilic colloidal particles (e.g., hydrophilic polymers) are dispersed in water. Hydrocolloid systems may exist in a gel or sol (liquid) state. In suspension compositions, hydrocolloids act as thickeners, stabilizers, and suspending agents. Non-limiting examples of hydrocolloids include cellulose derivatives (such as sodium carboxymethyl cellulose), xanthan gum, gum arabic, guar gum, locust bean gum, alginate, starch, agar, carrageenan, gelatin, microcrystalline cellulose, and sodium carboxymethyl cellulose, or any combination of the foregoing hydrocolloids. Preferably, the hydrocolloid comprises xanthan gum or sodium carboxymethyl cellulose.

[0080] A hydrocolloid containing a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose can be a colloid, a water-dispersible, spray-dried blend of microcrystalline cellulose and sodium carboxymethyl cellulose, or a co-processed mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, or a simple physical mixture of microcrystalline cellulose and sodium carboxymethyl cellulose. (Available from FMC Biopolymer, Philadelphia, Pennsylvania), containing 8.3% to 13.8% sodium carboxymethyl cellulose.

[0081] Some embodiments of the present invention provide compositions comprising sodium carboxymethyl cellulose. In some embodiments, the composition comprises at least about 0.1 wt% sodium carboxymethyl cellulose. In some embodiments, the composition comprises about 0.1 wt% to about 3 wt% sodium carboxymethyl cellulose. In some embodiments, the composition comprises about 0.6 wt% to about 2 wt% sodium carboxymethyl cellulose. In some embodiments, the composition comprises about 0.5 wt% to about 1.5 wt% sodium carboxymethyl cellulose. In some embodiments, the composition comprises about 0.5 wt% to about 1 wt% sodium carboxymethyl cellulose. In some embodiments, the composition comprises about 0.5 wt% to about 0.75 wt% sodium carboxymethyl cellulose. In some embodiments, the composition comprises about 0.67 wt% sodium carboxymethyl cellulose. In some embodiments, the composition comprises about 0.68 wt% sodium carboxymethyl cellulose. In some embodiments, the composition comprises about 0.9 wt% sodium carboxymethyl cellulose. In some embodiments, the composition comprises 1 wt% sodium carboxymethyl cellulose. In some embodiments, the composition comprises about 0.7 wt% sodium carboxymethyl cellulose. In some embodiments, the composition comprises 0.6656% by weight of sodium carboxymethyl cellulose.

[0082] The term "unblocking agent" refers to a pharmaceutical agent that controls, prevents, reduces, or minimizes blockage of the nasal spray actuator and / or suction tube. Non-limiting examples of unblocking agents include glycerin (or glycerol), sorbitol, mannitol, propylene glycol, polyethylene glycol, and mixtures thereof.

[0083] The term "controlling blockage" refers to preventing, avoiding, reducing, or minimizing blockage of the nasal spray actuator and / or suction tube.

[0084] The term “consistent delivery” refers to a spray having desired in vitro parameters such as spray pattern, spray content uniformity, and droplet size distribution, wherein each spray contains, for example, about 25 μg of mometasone furoate and about 665 μg of olopatadine hydrochloride.

[0085] The terms “formulation” and “composition” are used interchangeably and refer to a mixture of at least one compound, element, or molecule. In some aspects, the terms “formulation” and “composition” can be used to refer to a mixture of one or more active agents with one or more pharmaceutically acceptable excipients.

[0086] The pharmaceutical compositions described herein for nasal administration to humans may comprise about 0.001% to about 0.075% by weight of mometasone, its ester (e.g., mometasone furoate) or a salt thereof, about 0.5% to about 0.8% by weight of olopatadine or a salt thereof (e.g., olopatadine hydrochloride) and a deblocking agent.

[0087] The pharmaceutical compositions described herein may be in the form of a solution or a suspension. In a preferred embodiment, the composition is in the form of a suspension (such as a single-phase suspension) wherein mometasone, its ester (e.g., mometasone furoate) or its salt are present in particulate form, and olopatadine or its salt (e.g., olopatadine hydrochloride) is present in a dissolved form.

[0088] The compositions described herein preferably further comprise hydrocolloids. In one embodiment, the composition is a suspension and comprises about 0.3% to about 5% by weight of hydrocolloids to prevent phase separation (i.e., separation of particles and solution) after storage at 25±2°C and 60%±5% relative humidity (RH) or at 40±2°C and 75%±5% RH for 3 or 6 months. In one embodiment, the aqueous pharmaceutical composition is a single-phase suspension that remains a single-phase suspension after storage at 25±2°C and 60%±5% RH or at 40±2°C and 75%±5% RH for 3 or 6 months.

[0089] In another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, wherein the composition comprises about 0.025% to about 0.05% by weight of mometasone, its ester (e.g., mometasone furoate) or a salt thereof, about 0.6% to about 0.7% by weight of olopatadine or a salt thereof (e.g., olopatadine hydrochloride), about 0.3% to about 3% by weight of a hydrocolloid, and about 0.05% to about 5% by weight of a deblocking agent.

[0090] In another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, wherein the composition comprises about 0.025% to about 0.05% by weight of mometasone, its ester (e.g., mometasone furoate) or a salt thereof, about 0.6% to about 0.7% by weight of olopatadine or a salt thereof (e.g., olopatadine hydrochloride), about 0.3% to about 3% by weight of a hydrocolloid, and about 0.1% to about 5% by weight of a deblocking agent.

[0091] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, wherein the composition comprises about 0.025% to about 0.05% mometasone furoate, about 0.6% to about 0.7% olopatadine hydrochloride, about 0.3% to about 2% a hydrocolloid selected from sodium carboxymethyl cellulose and xanthan gum, and about 0.05% to about 5% a deblocking agent, such as, for example, glycerin (or glycerol), sorbitol, mannitol, propylene glycol, polyethylene glycol, and any combination thereof.

[0092] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, wherein the composition comprises about 0.025% to about 0.05% by weight of mometasone furoate, about 0.6% to about 0.7% by weight of olopatadine hydrochloride, about 0.3% to about 2% by weight of a hydrocolloid selected from sodium carboxymethyl cellulose and xanthan gum, and about 0.1% to about 5% by weight of a deblocking agent, such as, for example, glycerin (or glycerol), sorbitol, mannitol, propylene glycol, polyethylene glycol, and any combination thereof.

[0093] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, wherein the composition comprises about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, at least about 0.3 wt% a hydrocolloid selected from sodium carboxymethyl cellulose and xanthan gum, and about 0.1 wt% to about 3 wt% a deblocking agent, such as, for example, glycerin (or glycerol), sorbitol, mannitol, propylene glycol, polyethylene glycol, and any combination thereof.

[0094] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% to about 0.05% by weight of mometasone furoate, about 0.6% to about 0.7% by weight of olopatadine hydrochloride, and an unblocking agent, such as, for example, glycerin (or glycerol), sorbitol, mannitol, propylene glycol, polyethylene glycol, and any combination thereof. The unblocking agent may be present at a concentration of at least about 0.05% by weight of the composition, such as between about 0.1% by weight and about 3% by weight.

[0095] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% to about 0.05% by weight of mometasone furoate, about 0.6% to about 0.7% by weight of olopatadine hydrochloride, and a deblocking agent, such as, for example, glycerin (or glycerol), sorbitol, mannitol, propylene glycol, polyethylene glycol, and any combination thereof. The deblocking agent may be present at a concentration of at least about 0.05% by weight or at least about 0.1% by weight of the composition.

[0096] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% to about 0.05% by weight of mometasone furoate, about 0.6% to about 0.7% by weight of olopatadine hydrochloride, and an unblocking agent, such as, for example, glycerin (or glycerol), sorbitol, mannitol, propylene glycol, polyethylene glycol, and any combination thereof. The unblocking agent may be present at concentrations of about 0.05% by weight, about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.8% by weight, about 1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.5% by weight, about 2% by weight, about 2.5% by weight, about 3% by weight, about 3.5% by weight, about 4% by weight, about 4.5% by weight, or about 5% by weight of the composition.

[0097] In another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% to about 0.05% by weight of mometasone furoate, about 0.6% to about 0.7% by weight of olopatadine hydrochloride, and an unblocking agent, such as, for example, glycerin (or glycerol), sorbitol, mannitol, propylene glycol, polyethylene glycol, and any combination thereof. The unblocking agent may be present at concentrations of about 0.05% to about 1% by weight, about 0.1% to about 1% by weight, about 1% to about 1.5% by weight, about 1.5% to about 2.5% by weight, about 2.5% to about 3% by weight, about 3% to about 3.5% by weight, about 3.5% to about 4% by weight, or about 4% to about 5% by weight of the composition.

[0098] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.05% to about 5% by weight an unblocking agent.

[0099] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.1% to about 5% by weight an unblocking agent.

[0100] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.1% to about 3% by weight an unblocking agent.

[0101] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.1% to about 1% by weight unblocking agent.

[0102] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and an amount of unblocking agent at a concentration of about 0.05% by weight or about 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.8% by weight, about 1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.5% by weight, about 2% by weight, about 2.5% by weight, about 3% by weight, about 3.5% by weight, about 4% by weight, 4.5% by weight, or about 5% by weight of the composition.

[0103] In another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and an amount of unblocking agent at a concentration of about 0.05% by weight to about 1% by weight, about 0.1% by weight to about 1% by weight, about 1% by weight to about 1.5% by weight, about 1.5% by weight to about 2.5% by weight, about 2.5% by weight to about 3% by weight, about 3% by weight to about 3.5% by weight, about 3.5% by weight to about 4% by weight, or about 4% by weight to about 5% by weight.

[0104] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.05% by weight to about 5% by weight glycerin.

[0105] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.1% to about 5% by weight glycerin.

[0106] In yet another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.1% to about 3% by weight glycerin.

[0107] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.1% to about 2% by weight glycerin.

[0108] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.01% to about 1% by weight (such as about 0.1% to about 1% by weight) glycerin.

[0109] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.1% by weight glycerin.

[0110] In another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.05 wt% to about 5 wt% of a deblocking agent that controls blockage of the nasal spray actuator and / or suction tube (e.g., for at least about 5 days), through which the pharmaceutical composition is delivered.

[0111] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.05 wt% to about 5 wt% of a deblocking agent that controls blockage of the nasal spray actuator and / or suction tube (through which the pharmaceutical composition is delivered) for at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, or at least about 30 days.

[0112] In one implementation, control of nasal spray actuator and / or suction tube blockage for up to 30 days was observed even when the dispensing device remained open without a dust cover, or when the dust cover was improperly installed on the dispensing device.

[0113] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.05 wt% to about 5 wt% of a deblocking agent that controls blockage of the nasal spray actuator and / or suction tube for about 5 to about 30 days, about 5 to about 25 days, about 5 to about 20 days, about 5 to about 15 days, and about 5 to about 10 days.

[0114] In another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.1 wt% to about 5 wt% of a deblocking agent that controls blockage of the nasal spray actuator and / or suction tube for at least about 5 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, or at least about 30 days.

[0115] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.1 wt% to about 5 wt% of a deblocking agent that controls blockage of the nasal spray actuator and / or suction tube for about 5 to about 30 days, about 5 to about 25 days, about 5 to about 20 days, about 5 to about 15 days, and about 5 to about 10 days.

[0116] In another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.1 wt% to about 3 wt% of a deblocking agent that controls blockage of the nasal spray actuator and / or suction tube for at least about 5 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, and at least about 30 days.

[0117] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.1 wt% to about 3 wt% of a deblocking agent that controls blockage of the nasal spray actuator and / or suction tube for about 5 to about 30 days, about 5 to about 25 days, about 5 to about 20 days, about 5 to about 15 days, and about 5 to about 10 days.

[0118] In another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.1 wt% to about 1 wt% of a deblocking agent that controls blockage of the nasal spray actuator and / or suction tube for at least about 5 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, or at least about 30 days.

[0119] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.1 wt% to about 1 wt% of a deblocking agent that controls blockage of the nasal spray actuator and / or suction tube for about 5 to about 30 days, about 5 to about 25 days, about 5 to about 20 days, about 5 to about 15 days, and about 5 to about 10 days.

[0120] In another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.05 wt% to about 5 wt% glycerin, wherein the unblocking agent controls blockage of the nasal spray actuator and / or suction tube for at least about 5 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, or at least about 30 days.

[0121] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.05 wt% to about 5 wt% glycerin, wherein the unblocking agent controls blockage of the nasal spray actuator and / or suction tube for about 5 to about 30 days, about 5 to about 25 days, about 5 to about 20 days, about 5 to about 15 days, and about 5 to about 10 days.

[0122] In another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.1 wt% to about 5 wt% glycerin, wherein the unblocking agent controls blockage of the nasal spray actuator and / or suction tube for at least about 5 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, or at least about 30 days.

[0123] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.1 wt% to about 5 wt% glycerin, wherein the unblocking agent controls blockage of the nasal spray actuator and / or suction tube for about 5 to about 30 days, about 5 to about 25 days, about 5 to about 20 days, about 5 to about 15 days, and about 5 to about 10 days.

[0124] In another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.1 wt% to about 3 wt% glycerin, wherein the unblocking agent controls blockage of the nasal spray actuator and / or suction tube for at least about 5 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, or at least about 30 days.

[0125] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.1 wt% to about 3 wt% glycerin, which controls blockage of the nasal spray actuator and / or suction tube for about 5 to about 30 days, about 5 to about 25 days, about 5 to about 20 days, about 5 to about 15 days, and about 5 to about 10 days.

[0126] In another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.1 wt% to about 1 wt% glycerin, wherein the unblocking agent controls blockage of the nasal spray actuator and / or suction tube for at least about 5 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, or at least about 30 days.

[0127] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025 wt% mometasone furoate, about 0.665 wt% olopatadine hydrochloride, and about 0.1 wt% to about 1 wt% glycerin, which controls blockage of the nasal spray actuator and / or suction tube for about 5 to about 30 days, about 5 to about 25 days, about 5 to about 20 days, about 5 to about 15 days, and about 5 to about 10 days.

[0128] In another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.1% by weight glycerin, wherein the unblocking agent controls blockage of the nasal spray actuator and / or suction tube for at least about 5 days, at least about 10 days, at least about 15 days, at least about 20 days, at least about 25 days, or at least about 30 days.

[0129] In yet another embodiment, the pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, and about 0.1% by weight glycerin, which controls blockage of the nasal spray actuator and / or suction tube for about 5 days to about 30 days, about 5 days to about 25 days, about 5 days to about 20 days, about 5 days to about 15 days, and about 5 days to about 10 days.

[0130] In another embodiment, the unblocking agent may be present at a concentration of about 0.05% by weight to about 1% by weight, about 0.1% by weight to about 2% by weight, about 1% by weight to about 3% by weight, about 1.5% by weight to about 4% by weight, about 2.5% by weight to about 4% by weight, about 3% by weight to about 3.5% by weight, about 3.5% by weight to about 4% by weight, or about 4% by weight to about 5% by weight.

[0131] In another embodiment, the unblocking agent is glycerol (or glycerol) present in concentrations of about 0.05% by weight to about 1% by weight, about 0.1% by weight to about 2% by weight, about 0.1% by weight to about 3% by weight, about 1% by weight to about 3% by weight, about 1.5% by weight to about 4% by weight, about 2.5% by weight to about 4% by weight, about 3% by weight to about 3.5% by weight, about 3.5% by weight to about 4% by weight, or about 4% by weight to about 5% by weight.

[0132] In another embodiment, the unblocking agent is glycerol (or glycerol), which is present at a concentration of about 0.1% by weight to about 5% by weight.

[0133] In another embodiment, the unblocking agent is glycerol (or glycerol) present at concentrations of about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.125 wt%, about 0.15 wt%, about 0.17 wt%, about 0.18 wt%, about 0.19 wt%, about 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.8 wt%, 2 wt%, 2.5 wt%, or 3 wt%.

[0134] In another embodiment, the unblocking agent is sorbitol, which is present at a concentration of about 0.05 wt%, about 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.8 wt%, 2 wt%, 2.5 wt%, or 3 wt% of the composition.

[0135] In another embodiment, the unblocking agent is sorbitol, which is present in concentrations of about 0.05% by weight to about 1% by weight, about 0.1% by weight to about 2% by weight, about 0.1% by weight to about 3% by weight, about 1% by weight to about 3% by weight, about 1.5% by weight to about 4% by weight, about 2.5% by weight to about 4% by weight, about 3% by weight to about 3.5% by weight, about 3.5% by weight to about 4% by weight, or about 4% by weight to about 5% by weight.

[0136] In another embodiment, the unblocking agent is mannitol, which is present in concentrations of about 0.05% by weight to about 1% by weight, about 0.1% by weight to about 2% by weight, about 1% by weight to about 3% by weight, about 1.5% by weight to about 4% by weight, about 2.5% by weight to about 4% by weight, about 3% by weight to about 3.5% by weight, about 3.5% by weight to about 4% by weight, or about 4% by weight to about 5% by weight.

[0137] In another embodiment, the unblocking agent is mannitol, which is present at a concentration of about 0.05 wt%, about 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.8 wt%, 2 wt%, 2.5 wt%, or 3 wt% of the composition.

[0138] In another embodiment, the unblocking agent is propylene glycol, which is present in concentrations of about 0.05 wt% to about 1 wt%, about 0.1 wt% to about 2 wt%, about 1 wt% to about 3 wt%, about 1.5 wt% to about 4 wt%, about 2.5 wt% to about 4 wt%, about 3 wt% to about 3.5 wt%, about 3.5 wt% to about 4 wt%, or about 4 wt% to about 5 wt% of the composition.

[0139] In another embodiment, the unblocking agent is propylene glycol, which is present at a concentration of about 0.05 wt%, about 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.8 wt%, 2 wt%, 2.5 wt%, or 3 wt% of the composition.

[0140] In another embodiment, the unblocking agent is polyethylene glycol, which is present in concentrations of about 0.05% by weight to about 1% by weight, about 0.1% by weight to about 2% by weight, about 1% by weight to about 3% by weight, about 1.5% by weight to about 4% by weight, about 2.5% by weight to about 4% by weight, about 3% by weight to about 3.5% by weight, about 3.5% by weight to about 4% by weight, or about 4% by weight to about 5% by weight.

[0141] In another embodiment, the unblocking agent is polyethylene glycol, which is present at a concentration of about 0.05 wt%, about 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.8 wt%, 2 wt%, 2.5 wt%, or 3 wt% of the composition.

[0142] In another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% to about 0.05% mometasone furoate, about 0.6% to about 0.7% olopatadine hydrochloride, about 0.5% to about 0.7% sodium carboxymethyl cellulose, and about 0.1% glycerin.

[0143] In another embodiment, any pharmaceutical composition described herein is an aqueous suspension for nasal administration to humans, comprising about 0.025% by weight mometasone furoate, about 0.665% by weight olopatadine hydrochloride, about 0.67% by weight sodium carboxymethyl cellulose and about 0.1% by weight glycerin.

[0144] Those skilled in the art will also understand that, in order to improve the physical properties, appearance, and / or odor of the compositions of the present invention, one or more additional pharmaceutically acceptable excipients may be added as needed. Suitable pharmaceutically acceptable excipients include, but are not limited to, chelating agents, preservatives, buffers, surfactants, isotonic agents, flavor masking agents, antioxidants, humectants, pH adjusters, and any combination of the foregoing excipients.

[0145] Suitable surfactants for preparing aqueous nasal spray compositions may include, for example, one or more of anionic, cationic, nonionic, or zwitterionic surfactants. Examples of suitable surfactants for use in aqueous nasal spray suspensions may be selected from, but are not limited to, polyethoxylated dehydrated sorbitol derivatives such as polysorbate esters, their ether ethoxylated derivatives (produced by the reaction of dehydrated sorbitol esters with ethylene oxide), polyoxyethylene alkylphenols, polyoxyethylene cetyl ethers, polyoxyethylene alkyl-aryl ethers, polyoxyethylene monolaurates, polyoxyethylene vegetable oils, polyoxyethylene dehydrated sorbitol monolaurates, polyoxyethylene esters or mixed fatty acids and resin acids, polyoxyethylene sorbitol lanolin derivatives, polyoxyethylene tridecyl ethers, polyoxyethylene dehydrated sorbitol esters of mixed fatty acids and resin acids. Sorbitol esters, polyoxyethylene dehydrated sorbitol monostearate, polyoxyethylene dehydrated sorbitol monooleate, polyoxyethylene monostearate, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene tridecyl ether, polyoxyethylene fatty alcohol, polyoxyethylene alkylamine, polyoxyethylene glycol monopalmitate, polyoxyethylene dehydrated sorbitol monopalmitate, polyoxyethylene cetyl ether, polyoxyethylene oxypropylene stearate, polyoxyethylene lauryl ether, polyoxyethylene lanolin derivatives, sodium oleate, quaternary ammonium derivatives, potassium oleate, N-cetyl N-ethylmorpholinon ethyl sulfate, sodium lauryl sulfate, or mixtures thereof. A preferred surfactant is a polyethoxylated dehydrated sorbitol derivative (e.g., polysorbate 80). The amount of surfactant relative to the total weight of the composition can range from about 0.001% to about 1% by weight.

[0146] To improve the tolerability of aqueous nasal spray suspensions when applied to the nasal mucosa, it is advantageous to formulate them as isotonic. The osmotic pressure can be set by varying the amount of substances present in the aqueous nasal spray suspension other than the active agent and / or by adding an isotonic agent (preferably a physiologically tolerable salt, such as, for example, sodium chloride or potassium chloride). The amount of the isotonic agent can range from about 0.001% to about 1% by weight relative to the total weight of the composition.

[0147] Examples of suitable preservatives that can be used in the aqueous nasal spray suspension described herein include, but are not limited to, benzyl alcohol, quaternary ammonium halides, benzyl alcohol, thimerosal, and disodium edetate. Quaternary ammonium halides are preferred. Suitable quaternary ammonium halides include, for example, polyquaternary ammonium salt-1 and benzalkonium halide. Preferred benzalkonium halide includes benzalkonium chloride and benzalkonium bromide. The amount of preservative relative to the total weight of the composition can range from about 0.005 to about 0.2% by weight. Preferably, the preservative is present at a concentration of about 0.02% by weight relative to the total weight of the composition.

[0148] Examples of suitable chelating agents that can be used in the aqueous nasal spray suspension described herein include, but are not limited to, disodium ethylenediaminetetraacetate (EDTA), trisodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate, and diethyleneethyleneaminepentaacetate, with EDTA being preferred. The amount of chelating agent present in the aqueous nasal spray suspension described herein may range from about 0.0002% by weight to about 0.5% by weight relative to the total weight of the composition.

[0149] Examples of suitable buffers that can be used in the aqueous nasal spray suspension described herein include, but are not limited to, citric acid, acetic acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, phosphates (e.g., disodium hydrogen phosphate, such as disodium hydrogen phosphate heptahydrate), or combinations thereof. The suspension of the present invention may contain an amount of buffer sufficient to maintain the pH of the composition at about 3 to about 6. Preferably, the amount of buffer is in the range of about 0.005% to about 2% by weight relative to the total weight of the composition.

[0150] Examples of suitable sweeteners / maskers that may be used in the aqueous nasal spray suspension described herein include, but are not limited to, sucralose, sematrandextrose, sucrose, saccharin (including salt forms such as sodium and calcium salts), fructose, glucose, dextrose, corn syrup, aspartame, acesulfame potassium, xylitol, sorbitol, erythritol, ammonium glycyrrhizate, neotame, mannitol, eucalyptus oil, camphor, and natural or artificial flavorings or tastes (e.g., menthol, peppermint, vanilla, orange, etc.), or combinations of two or more of such agents. A preferred masking agent is sucralose. The amount of sweetener / masker present in the aqueous nasal spray suspension relative to the total weight of the composition may range from about 0.01% to about 1% by weight.

[0151] Examples of suitable antioxidants that may be used in the aqueous nasal spray suspension described herein include, but are not limited to, ascorbic acid, α-tocopherol (vitamin E), butylated hydroxyanisole, butylated hydroxytoluene, glutathione, and any combination of the foregoing antioxidants. The amount of antioxidant present in the aqueous nasal spray suspension relative to the total weight of the composition may range from about 0.0002% by weight to about 0.5% by weight.

[0152] Suitable pH adjusters include, but are not limited to, sodium hydroxide and hydrochloric acid.

[0153] The pH of the aqueous suspension for nasal administration as described herein may be between about 3.3 and about 4.1 or between about 3.5 and about 3.9.

[0154] The osmotic pressure of any composition described herein can be in the range of about 200 mOsm / kg and about 400 mOsm / kg, or about 250 mOsm / kg and about 350 mOsm / kg. The viscosity of any composition described herein can be from about 10 cps to about 200 cps, such as from about 20 cps to about 150 cps or from about 20 cps to about 120 cps. Viscosity can be determined using various known instruments, such as a dynamic stress rheometer or a Brookfield viscometer. In a preferred embodiment, viscosity is determined by a Brookfield viscometer by measuring the torque transmitted through the sample using a rotating spindle.

[0155] In another aspect, any composition described herein may be in the form of a suspension comprising particles of mometasone, its esters (such as mometasone furoate), or salts thereof, wherein the average particle size of these particles is in the range of about 1 μm to about 20 μm, such as about 1 μm to about 15 μm. In one embodiment, the average particle size of the suspension containing the particles is less than 15 μm when determined by microscopic techniques.

[0156] In another aspect, when delivered in a dispensing device, any of the compositions described herein exhibits a spray pattern with a longest axis of about 15-75 mm, a shortest axis of about 10-65 mm, and an ellipticity of about 1-2.

[0157] In yet another embodiment, any composition described herein is an aqueous suspension for nasal administration to humans, comprising mometasone furoate monohydrate, olopatadine hydrochloride, and a deblocking agent comprising glycerol (or glycerol) at a concentration of at least about 0.1% by weight of the composition, wherein the pH of the composition is between about 3.5 and about 4.1.

[0158] In yet another embodiment, any composition described herein is an aqueous suspension for nasal administration to humans, comprising mometasone furoate monohydrate, olopatadine hydrochloride, and a deblocking agent comprising glycerol (or glycerol) at a concentration of at least about 0.1% by weight of the composition.

[0159] In yet another embodiment, any composition described herein is an aqueous suspension for nasal administration to humans, comprising mometasone furoate monohydrate, olopatadine hydrochloride, and a deblocking agent comprising glycerol (or glycerol) at a concentration between about 0.1% by weight and about 5% by weight of the composition.

[0160] In yet another embodiment, any of the compositions described herein is an aqueous suspension for nasal administration to humans, comprising mometasone furoate monohydrate, olopatadine hydrochloride, and a sorbitol-containing unblocking agent at a concentration of at least about 0.1% by weight of the composition.

[0161] In yet another embodiment, any composition described herein is an aqueous suspension for nasal administration to humans, comprising mometasone furoate monohydrate, olopatadine hydrochloride, and a deblocking agent comprising polyethylene glycol at a concentration of at least about 0.1% by weight of the composition.

[0162] In yet another embodiment, any composition described herein further comprises:

[0163] - About 0.0002% by weight to about 0.5% by weight of chelating agent;

[0164] - Approximately 0.001% to approximately 1% by weight of isotonic agent;

[0165] - A surfactant in amounts of about 0.001% to about 1% by weight;

[0166] - A preservative in an amount of about 0.005 to about 0.2% by weight; and

[0167] - A buffer amount of about 0.005% to about 1% by weight.

[0168] In yet another embodiment, any composition described herein, in addition to olopatadine (e.g., olopatadine hydrochloride) and mometasone furoate, comprises (i) about 0.1% glycerol; (ii) 0.5% sodium carboxymethyl cellulose; (iii) about 1.2% by weight of a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose; (iv) about 0.02% by weight benzalkonium chloride; (v) about 0.41% by weight sodium chloride; (vi) about 0.01% by weight disodium edetate; (vii) about 0.94% by weight disodium hydrogen phosphate; and (viii) about 0.01% polysorbate 80.

[0169] In yet another embodiment, any composition described herein is an aqueous suspension composition for nasal administration to humans, wherein the composition comprises (1) about 0.025 wt% mometasone furoate monohydrate; (2) about 0.665 wt% olopatadine hydrochloride; (3) a deblocking agent selected from about 0.1 wt% glycerol (or glycerol), about 0.1 wt% sorbitol, about 0.1 wt% polyethylene glycol and about 0.1 wt% mannitol; (4) a hydrocolloid selected from about 0.3 wt% xanthan gum and about 0.67 wt% sodium carboxymethyl cellulose; (5) about 0.02 wt% benzalkonium chloride; (6) about 0.4 wt% sodium chloride; (7) about 0.01 wt% disodium edetate; (8) about 0.94 wt% sodium phosphate heptahydrate; and (9) about 0.01 wt% polysorbate 80.

[0170] In yet another embodiment, any composition described herein is an aqueous suspension composition for nasal administration to humans, wherein the composition comprises (1) about 0.025 wt% mometasone furoate monohydrate; (2) about 0.665 wt% olopatadine hydrochloride; (3) a deblocking agent selected from about 0.1 wt% glycerol (or glycerol), about 0.1 wt% sorbitol, about 0.1 wt% polyethylene glycol, and about 0.1 wt% mannitol; (4) The hydrocolloid is selected from about 0.3% xanthan gum and about 0.5% sodium carboxymethyl cellulose; (5) a mixture of about 1% to about 1.2% microcrystalline cellulose and sodium carboxymethyl cellulose; (6) about 0.02% benzalkonium chloride; (7) about 0.41% sodium chloride; (8) about 0.01% disodium edetate; (9) about 0.94% sodium phosphate heptahydrate; and (10) about 0.01% polysorbate 80.

[0171] In another embodiment, the dispensing device described herein contains any of the pharmaceutical compositions described herein in the form of a kit having a packaging insert containing instructions on using the pharmaceutical composition.

[0172] In one embodiment, when stored in a dispensing device at 25±2°C and 60%±5% relative humidity for up to 12 months, the composition has one or more of the following properties:

[0173] (i) The composition contains no more than 1% total impurities (after storage);

[0174] (ii) The composition contains not more than 0.5% DMC (after storage);

[0175] (iii) The composition contains not more than 0.5% DMCF (after storage);

[0176] (iv) The composition contains not more than 0.5% α-hydroxyolopatadine (after storage);

[0177] (v) The composition contains not more than 0.5% of the olopatadine E-isomer (after storage);

[0178] (vi) The composition contains not more than 0.5% of olopatadine-related compound B (after storage); and / or

[0179] (vii) The composition contains no more than 0.2% of other impurities of olopatadine (after storage).

[0180] (viii) The composition contains not more than 8 DM (after storage).

[0181] In another embodiment, when dispensed from the dispensing device described herein, the pharmaceutical composition described herein can provide a spray pattern with a longest axis of about 15-75 mm, a shortest axis of about 10-65 mm, and an ellipticity of about 1-2. The spray pattern can be determined by various known techniques, such as using an ADSA (Innova System) with an NSPUA setting, and the spray droplet size distribution can be determined by various known techniques, such as using a MalvernSpraytec (Innova System) with an NSPUA setting.

[0182] The following describes a typical procedure for characterizing the droplet size distribution of a spray. A sprayer is loaded with the composition as described herein and actuated via an actuator using an actuated pump until a fine mist appears outside the nozzle of the sprayer. A commercially available laser diffractometer is positioned such that the nozzle is approximately 3 cm or 6 cm below the laser beam of the laser diffractometer. The pump is actuated by the actuator using a constant force. The resulting aerosol composition passes through the laser beam. D is collected. 10 D 50 D 90 and SPAN(D 90 –D 10 / D 50 The data is used to calculate the average of these parameters for each of the three sprays.

[0183] In another embodiment, when dispensed from a dispensing device, the pharmaceutical composition described herein can provide the following droplet size distribution:

[0184] D 10 At a distance of 3cm, the micrometer is approximately 5μm-35μm, more preferably approximately 10μm-30μm, and most preferably approximately 10μm-25μm; and at a distance of 6cm, the micrometer is approximately 5μm-40μm, more preferably approximately 10μm-35μm, and most preferably approximately 10-30μm.

[0185] D 50 At a distance of 3cm or 6cm, the micrometer is approximately 10μm-90μm, more preferably approximately 20μm-80μm, and most preferably approximately 25μm-75μm.

[0186] D 90 At a distance of 3cm or 6cm, the micrometer is approximately 30μm-180μm, more preferably approximately 40μm-170μm, and most preferably approximately 50μm-160μm.

[0187] SPAN: not more than about 4, more preferably about 3, such as about 2-3;

[0188] Where D 10 This is the droplet size distribution of 10% of the droplets, D 50 This is the droplet size distribution of 50% of the droplets, D 90 It is the droplet size distribution of 90% of the droplets; SPAN is (D 90 -D 10 ) / D 50 The ratio. In another embodiment, when dispensed from the dispensing device, the pharmaceutical composition described herein can provide uniformity of delivery dose or spray content collected from each of 10 individual containers at the start of a unit lifetime and at the label-claimed number of metered sprays, thereby meeting the following acceptance criteria: no more than 2 of the 20 doses are outside the range of approximately 80% to approximately 120% of the label-claimed range, and no dose is outside the range of approximately 75% to approximately 125% of the label-claimed range, while the average of each dose in the start and end doses falls within the range of approximately 85% to approximately 115% of the label-claimed range. If 3-6 of the 20 collected doses are outside the range of approximately 80% to approximately 120% of the label-claimed range, but no dose is outside the range of approximately 75% to approximately 125% of the label-claimed range, and the average of each dose in the start and end doses falls within the range of approximately 85% to approximately 115% of the label-claimed range, then an additional 20 containers are selected for secondary testing. For secondary testing, the requirement is met if no more than 6 of the 60 doses collected are outside the range of approximately 80% to approximately 120% of the label statement, no dose is outside the range of approximately 75% to approximately 125% of the label statement, and the average of each dose in the start and end doses falls within the range of approximately 85% to approximately 115% of the label statement.

[0189] To ensure repeatable in vitro dose collection, a mechanical device using an actuated pump assembly can be employed to deliver the dose for collection. The mechanical actuation procedure should have adequate control over key mechanical actuation parameters, such as actuation force, actuation speed, stroke length, rest period, etc. Testing is performed on a unit that has been induced according to the patient instructions. The test unit should be actuated in an upright or near-upright position with the valve facing upwards. The two doses collected at the beginning and end of the container's lifespan should be the dose immediately following induced actuation and the dose corresponding to the quantity declared on the last label from the container.

[0190] The uniformity of delivered dose or spray content can be determined by delivering the dose to a suitable container (e.g., a scintillation vial) in which quantitative transfer from the test container can be completed. Validated analytical methods are used to determine the amount of drug in each delivered dose, and the data are reported.

[0191] Example

[0192] Examples 1 and 2

[0193]

[0194] Manufacturing process :

[0195] For Example 1 :

[0196] 1. Under homogenization, a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose is added to water for injection and hydrated.

[0197] 2. Disperse sodium carboxymethyl cellulose in water for injection and add it to the product of step-1.

[0198] 3. Dissolve disodium hydrogen phosphate heptahydrate, sodium chloride, disodium edetate, and olopatadine HCl in water. Adjust the pH to 2.8-3.2 with hydrochloric acid.

[0199] 4. Add the product from step-3 to the product from step-1 under homogenization.

[0200] 5. Dissolve polysorbate 80 in water for injection. Add mometasone furoate monohydrate and stir to form a slurry.

[0201] 6. Add the product from step-5 to the product from step-4 under homogenization.

[0202] 7. Dissolve benzalkonium chloride in water for injection.

[0203] 8. Add the product from step-7 to the product from step-6 under homogenization.

[0204] 9. Check the pH and adjust it to 3.5-3.9 with HCl / NaOH, then adjust the total weight with water for injection. The osmotic pressure of the composition is approximately 250-350 mOsm / kg. Conduct stability studies on the composition under different conditions.

[0205] For Example 2 :

[0206] 1. Under homogenization, a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose is added to water for injection and hydrated.

[0207] 2. Disperse sodium carboxymethyl cellulose in water for injection and add it to the product of step-1.

[0208] 3. Dissolve disodium hydrogen phosphate heptahydrate, sodium chloride, disodium edetate, and olopatadine HCl in water. Adjust the pH to 2.8-3.2 with hydrochloric acid.

[0209] 4. Add the product from step-3 to the product from step-1 under homogenization.

[0210] 5. Dissolve polysorbate 80 in water for injection. Add mometasone furoate monohydrate and stir to form a slurry.

[0211] 6. Add the product from step-5 to the product from step-4 under homogenization.

[0212] 7. Dissolve benzalkonium chloride in water for injection.

[0213] 8. Add the product from step-7 to the product from step-6 under homogenization.

[0214] 9. Dissolve glycerin in water

[0215] 10. Add the product from step-9 to the product from step-3 under homogenization.

[0216] 11. Check the pH and adjust it to 3.5-3.9 with HCl / NaOH, then adjust the total weight with water for injection. The osmotic pressure of the composition is approximately 250-350 mOsm / kg. Conduct stability studies on the composition under different conditions.

[0217] The test investigated the clogging issues of the preparations in the dispensing device for Examples 1 and 2.

[0218] Packaging size: 240 doses

[0219] Study duration: 30 days

[0220]

[0221] Batch #3 was manufactured using the formulation from Example 2.

[0222] Research Procedures

[0223] A) Uncapped sample

[0224] 1. At the start of the study, the bottles were open (i.e., the caps were not closed after spraying), and as a control, the caps were closed (the caps were placed on the actuators after spraying). The study continued for 30 days at ambient temperature.

[0225] 2. Before starting the study, all actuators were triggered 6 times.

[0226] 3. Spray each bottle 8 times a day for 30 days.

[0227] 4. Visually observe the spray pattern during spraying.

[0228] 5. Observe the blockage of each actuator during spraying.

[0229] 6. If a blockage is observed, set the bottle aside and repeat the same procedure the next day to check if the actuator is still blocked.

[0230] 7. If any blockage (partial or complete) is observed, set the bottles aside and record the observations.

[0231] B) Samples with lids:

[0232] 1. For samples studied with caps, follow the procedures described above.

[0233] 2. Place the cover on the actuator and follow the instructions below.

[0234] a) Wipe the tip of the spray pump with a clean, dry paper towel or cloth.

[0235] b) Hold the spray pump unit and push the dust cap back onto the spray pump tip on the bottle.

[0236] Actuator and / or suction tube blockage study - visual observation and conclusions

[0237]

[0238] It can be seen that the formulation containing 0.1% by weight of glycerol (or glycerol) controlled the actuator without clogging during 30 days of use.

[0239] 2. Stability data for Example 2:

[0240] A)25℃±2℃ and 60%RH±5%RH

[0241]

[0242] B) 40℃±2℃ and 75% RH±5% RH

[0243]

[0244]

Claims

1. A pharmaceutical composition suitable for a nasal spray device, the nasal spray device comprising an actuator and a suction tube through which the composition is delivered, wherein (a) the composition is in the form of an aqueous suspension suitable for nasal administration, and (b) the composition comprises about 0.025% by weight of mometasone furoate in particulate form, about 0.665% by weight of olopatadine hydrochloride in dissolved form, and a decongestant.

2. The pharmaceutical composition according to claim 1, wherein the unblocking agent is a sugar alcohol, a polyether, or any combination thereof.

3. The pharmaceutical composition according to claim 1, wherein the unblocking agent is selected from glycerol, sorbitol, mannitol, propylene glycol, polyethylene glycol, and any combination thereof.

4. The pharmaceutical composition of claim 1, wherein the unblocking agent is present in an amount sufficient to prevent blockage of the actuator and the extraction tube for at least 5 days.

5. The pharmaceutical composition of claim 1, wherein the unblocking agent is present in an amount sufficient to prevent blockage of the actuator and the extraction tube for at least 10 days.

6. The pharmaceutical composition of claim 1, wherein the unblocking agent is present in an amount sufficient to prevent blockage of the actuator and the extraction tube for about 20 days.

7. The pharmaceutical composition of claim 1, wherein the unblocking agent is present in an amount sufficient to prevent blockage of the actuator and the extraction tube for about 30 days.

8. The pharmaceutical composition of claim 1, wherein when the dispensing device remains open without a dust cover, the unblocking agent is present in an amount sufficient to prevent blockage of the actuator and the extraction tube for about 5 days to about 30 days.

9. The pharmaceutical composition of claim 1, wherein the unblocking agent is present in an amount of about 0.05% by weight to about 5% by weight.

10. The pharmaceutical composition of claim 9, wherein the unblocking agent is present in an amount of about 0.05% by weight to 3% by weight.

11. The pharmaceutical composition of claim 10, wherein the unblocking agent is present in an amount of about 0.1% to 1% by weight.

12. The pharmaceutical composition according to claim 3, wherein the unblocking agent is glycerin.

13. The pharmaceutical composition of claim 12, wherein the glycerol is present in an amount of about 0.05% by weight to about 5% by weight.

14. The pharmaceutical composition of claim 13, wherein the glycerol is present in an amount of about 0.05% by weight to about 1% by weight.

15. The pharmaceutical composition of claim 14, wherein the glycerol is present in an amount of about 0.1% by weight.

16. The pharmaceutical composition according to claim 1, wherein the mometasone furoate is present as mometasone furoate monohydrate.

17. A method of treating a patient suffering from allergic rhinitis, the method comprising administering to the patient an effective amount of the pharmaceutical composition as claimed in claim 1.

18. The pharmaceutical composition of claim 1, wherein the composition further comprises about 0.3% by weight to about 3% by weight of a hydrocolloid.

19. The pharmaceutical composition according to claim 18, wherein the hydrocolloid is selected from sodium carboxymethyl cellulose and xanthan gum.

20. The pharmaceutical composition of claim 18, wherein the composition further comprises - About 0.0002% by weight to about 0.5% by weight of chelating agent; - Approximately 0.001% to approximately 1% by weight of isotonic agent; - A surfactant in amounts of about 0.001% to about 1% by weight; - A preservative in an amount of about 0.005 to about 0.2% by weight; and - A buffer amount of about 0.005% to about 1% by weight.

21. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition comprises about 0.1% glycerol, 0.5% sodium carboxymethyl cellulose, about 1.2% by weight of a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose, about 0.02% by weight benzalkonium chloride, about 0.41% by weight sodium chloride, about 0.01% by weight disodium edetate, about 0.94% by weight disodium hydrogen phosphate, and about 0.01% polysorbate 80.

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