Stable fixed dose pharmaceutical composition comprising mometasone and olopatadine.

STABLE FIXED PHARMACEUTICAL COMPOSITION THAT INCLUDES

MOMETASONE AND OLOPATADINE

FIELD OF THE INVENTION

The present patent application refers to a stable fixed dose aqueous pharmaceutical composition for nasal administration to a human being comprising mometasone or its salt and olopatadine or its salt. The application also refers to a process for preparing the pharmaceutical composition and its use in the treatment of rhinitis in a subject.

BACKGROUND OF THE INVENTION

Rhinitis is a medical term for irritation and inflammation of the mucous membrane inside the nose. Rhinitis can cause additional symptoms such as sneezing, nasal itching, cough, headache, fatigue, malaise and cognitive impairment.

Olopatadine hydrochloride is chemically described as (Z) -11- [3- (dimethylamino) propylidene] -6,11-dihydrodibenz [b, e] oxepin-2-acetic acid hydrochloride, as described in US Patent Nos. 4,871,865 and 4,923,892. It is commercially available in the US as PATANASE® Nasal Spray, which contains 0.6% w / v olopatadine in a non-sterile aqueous solution. It is indicated for the relief of the symptoms of seasonal allergic rhinitis in adults and in children from 6 years.

Mometasone furoate is a glucocorticosteroid that is used topically to reduce inflammation of the skin or respiratory tract. Mometasone furoate is commercially available as NASONEX® in the US as a nasal inhaler indicated for upper respiratory conditions such as inflammation of the sinuses. It is available as 50 mcg in a fixed dose manual pump inhaler unit containing an aqueous suspension of mometasone furoate monohydrate equivalent to 0.05% w / w mometasone furoate.

WO 2011/141929 describes an aqueous nasal inhaler solution comprising fluticasone and olopatadine.

US Patent No. 6,127,353 describes a pharmaceutical composition of mometasone furoate monohydrate.

U.S. Patent Nos. 7,977,376 and 8,399,508 describe a topical formulation of olopatadine.

WO 2014/092346 describes a masked pharmaceutical composition of bitter taste comprising a corticosteroid, an antihistamine and stevia.

WO 2006/057769 describes a method for administering a nasal inhaler containing olopatadine.

WO 2010/025236 describes a combination of a nasal spheroid and a nasal antihistamine for the treatment of viral upper respiratory tract infections, upper respiratory tract infections and the common cold.

There is still a need for easy-to-use and effective rhinitis treatments.

BRIEF DESCITION OF ΙΛ INVENTION

The present invention relates to a stable fixed dose aqueous pharmaceutical composition for nasal administration to a human being. The composition comprises mometasone or its salt and olopatadine or its salt. The pharmaceutical composition may be contained within a container suitable for nasal administration.

One embodiment is a stable fixed dose aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration to a human being, wherein the composition comprises between about 0.001% w / w and about 0.075% w / w of mometasone or its salt and between approximately 0.5% w / w and approximately 0.8% w / w of olopatadine or its salt. The pharmaceutical composition may be in the form of a solution or a suspension, but preferably the composition is in the form of a suspension, wherein the mometasone or its salt is present in the form of particles and the olopatadine or its salt is present in dissolved form. In one aspect, mometasone or its salt and olopatadine or its salt are present in a weight ratio of between about 1: 3 and about 1: 106, or between about 1: 5 and about 1:53, or preferably between about 1: 5 and about 1:36.

The composition preferably also includes a hydrocolloid. In one embodiment, the composition is a suspension and includes a hydrocolloid in an amount sufficient to prevent phase separation (i.e., separation of particles and solution) after 3 or 6 months of storage at 25 ± 2 ° C and 60% ± 5% relative humidity (RH) or 40 ± 2 ° C and 75% ± 5% RH.

Another embodiment is a stable fixed dose aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration to a human being, wherein the composition comprises between about 0.001% w / w and about 0.075% w / w of mometasone furoate monohydrate and between about 0.5% w / w and about 0.8% w / w of olopatadine hydrochloride.

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human being, wherein the composition comprises between about 0.025% w / w and about 0.05 % w / w of mometasone or its salt, between about 0.6% w / w and about 0.7% w / w of olopatadine or its salt and a hydrocolloid.

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human being, wherein the composition comprises between about 0.025% w / w and about 0.05 % w / w of mometasone or its salt, between about 0.6% w / w and about 0.7% w / w of olopatadine or its salt and a hydrocolloid that includes sodium carboxymethylcellulose and xanthan gum. The hydrocolloid may be present in a concentration of at least about 0.1% w / w of the composition.

One embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human comprising between about 0.025% w / w and about 0.05% w / w of mometasone furoate, between about 0.6% w / w and about 0.7% w / w of olopatadine hydrochloride and a hydrocolloid, where the hydrocolloid is xanthan gum. The xanthan gum may be present in a concentration of at least about 0.1% w / w, or preferably between about 0.1% w / w and about 3% w / w of the composition.

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human comprising between about 0.025% w / w and about 0.05% w / w of mometasone furoate, between about 0.6% w / w and about 0.7% w / w of olopatadine hydrochloride and a hydrocolloid, wherein the hydrocolloid comprises sodium carboxymethylcellulose. The sodium carboxymethyl cellulose may be present in a concentration of at least about 0.1% w / w, or preferably between about 0.1% w / w and about 3% w / w of the composition.

Another embodiment is a stable fixed dose aqueous pharmaceutical composition in suspension form (eg, contained in a container) for nasal administration to a

<td>human being</td><td>understands</td><td>mometasone</td><td>or</td><td>his</td><td>Salt</td>

<td>pharmaceutically</td><td>acceptable,</td><td>olopatadine</td><td>or</td><td>his</td><td>Salt</td>

<td>pharmaceutically</td><td>acceptable,</td><td colspan="2">a hydrocolloid</td><td>to</td><td>a</td>

concentration of at least about 0.1% w / w of the composition and an acceptable pharmaceutical excipient.

Suitable acceptable pharmaceutical excipients include, but are not limited to, chelating agents, preservatives, Lampones, surfactants, isotonicity agents, taste masking agents, antioxidants, humectants, pH adjusting agents and mixtures thereof.

In one embodiment, the pharmaceutical composition has a pH of between about 3.3 and about 4.1, or between about 3.5 and about 3.9.

The osmolality of the pharmaceutical composition may range between about 200 mOsm / kg and about 400 mOsm / kg, or between about 250 mOsm / kg and about 350 mOsm / kg.

The viscosity of the pharmaceutical composition may range between about 10 cps and about 200 cps or, preferably, between about 20 cps and about 150 cps.

In another aspect, the pharmaceutical composition is in the form of a suspension and contains mometasone furoate in particles having an average particle size in the range between about 1 pm and about 20 pm, or preferably between about 1 pm and about 15 pm . In one aspect, the pharmaceutical suspension composition of the present invention has an average particle size of less than 15 pm when determined by a microscopy technique.

In another aspect, the pharmaceutical composition, when administered as a nasal inhaler, has inhaler characteristics comprising a spray pattern having a longer axis of approximately 15-75 mm, a shorter axis of approximately 10-65 mm and an ellipticity of about 1-2.

Another embodiment is a stable fixed dose pharmaceutical composition in the form of a suspension (e.g., contained in a container) for nasal administration to a human being, comprising mometasone furoate monohydrate, olopatadine hydrochloride and a hydrocolloid comprising gum. Xanthan in a concentration of about 0.3% w / w of the composition, wherein the composition has a pH between about 3.5 and about 3.9.

Another embodiment is a stable fixed dose pharmaceutical composition in suspension form (e.g., contained in a container) for nasal administration to a human being, comprising mometasone furoate monohydrate, olopatadine hydrochloride and a hydrocolloid comprising carboxymethylcellulose carboxymethylcellulose. sodium in a concentration of about 0.5% w / w of the composition, wherein the composition has a pH between about 3.5 and about 3.9.

In another embodiment, the stable fixed dose aqueous pharmaceutical composition is contained in an inhaler and upon spraying the composition to a human nose a spray pattern having a longer axis of 15-75 mm, one more axis, is produced. short of 10-65 mm and an ellipticity of 1-2.

In one embodiment, the present invention relates to a stable fixed dose aqueous pharmaceutical suspension composition (e.g. eg, contained in a container) for nasal administration to a human being, wherein the composition comprises (1) approximately 0.025% w / w mometasone furoate monohydrate, (2) approximately 0.665% w / w hydrochloride olopatadine, (3) a hydrocolloid selected from 0.3% w / w xanthan gum and approximately 0.5% w / w sodium carboxymethylcellulose (4) approximately 0.02% w / w benzalkonium chloride, (5) approximately 0.4% w / w sodium chloride, (6) approximately 0.01% w / w disodium edetate, (7) approximately 0.94% w / w sodium phosphate heptahydrate and (8) approximately 0.01% w / w polysorbate 80 .

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g. eg, contained in a container) for nasal administration to a human being, wherein the composition comprises (1) approximately 0.050% w / w mometasone furoate monohydrate, (2) approximately 0.665% w / w hydrochloride olopatadine, (3) a hydrocolloid selected from 0.3% w / w xanthan gum and approximately 0.5% w / w sodium carboxymethylcellulose (4) approximately 0.02% w / w benzalkonium chloride, (5) approximately 0.4% w / w sodium chloride, (6) approximately 0.01% w / w disodium edetate, (7) approximately 0.94% w / w sodium phosphate heptahydrate and (8) approximately 0.01% w / w polysorbate 80 .

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g. eg, contained in a container) for nasal administration to a human being, wherein the composition comprises (1) approximately 0.025% w / w mometasone furoate monohydrate, (2) approximately 0.665% w / w hydrochloride olopatadine, (3) a hydrocolloid selected from 0.3% w / w xanthan gum and approximately 0.5% w / w sodium carboxymethylcellulose, (4) between approximately 1% w / w and approximately 1.2% w / w mixture of microcrystalline cellulose and sodium carboxymethylcellulose, (5) approximately 0.02% w / w benzalkonium chloride, (6) approximately 0.4% w / w sodium chloride, (7) approximately 0.01% w / w disodium edetate, (8) approximately 0.94% w / w sodium phosphate heptahydrate and ( 9) approximately 0.01% w / w polysorbate 80.

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g. eg, contained in a container) for nasal administration to a human being, wherein the composition comprises (1) approximately 0.050% w / w mometasone furoate monohydrate, (2) approximately 0.665% w / w hydrochloride olopatadine, (3) a hydrocolloid selected from 0.3% w / w xanthan gum and approximately 0.5% w / w sodium carboxymethylcellulose, (4) between approximately 1% w / w and approximately 1.2% w / w mixture of microcrystalline cellulose and sodium carboxymethylcellulose, (5) approximately 0.02% w / w benzalkonium chloride, (6) approximately 0.4% w / w sodium chloride, (7) approximately 0.01% w / w disodium edetate, (8) approximately 0.94% w / w sodium phosphate heptahydrate and ( 9) approximately 0.01% w / w polysorbate 80.

Another embodiment is a stable suspension suitable for nasal administration to a human being, comprising (a) an aqueous solvent, (b) mometasone furoate particles suspended in the solvent, which particles have an average particle size of between about 1 and about 20 μιη, (c) olopatadine hydrochloride dissolved in the solvent and (d) a hydrocolloid, which suspension has a viscosity in the range of between about 20 cps and about 150 cps. In a preferred embodiment, the suspension has a pH of about 3.5-3.9 and an osmolality in the range of between about 250 mOsm / kg and about 350 mOsm / kg. In one embodiment, the suspension further comprises a chelating agent, a preservative, a buffer, a surfactant, an isotonicity agent and, optionally, a pH adjusting agent.

In another embodiment, the present invention relates to a method for treating rhinitis in a human being who needs it comprising administering a stable fixed dose aqueous pharmaceutical composition of the present invention nasally. In one embodiment, the pharmaceutical composition comprises between about 0.025% w / w and about 0.05% w / w of mometasone or its salt and between about 0.5% w / w and about 0.8% w / w of olopatadine or its salt, as described herein.

In another embodiment, the present invention relates to the use of a pharmaceutical composition of the present invention for the treatment of rhinitis in a human being in need thereof. For example, one mode is the use of between about 0.025% w / w and about 0.05% w / w of mometasone or its salt and between about 0.5% w / w and about 0.8% w / olopatadine p or its salt in the preparation of a stable fixed dose aqueous pharmaceutical composition (e.g. , contained in a container) for the treatment of rhinitis in a human being who needs it.

In another embodiment, the present invention relates to a stable fixed dose aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration, comprising between about 0.025% w / w and about 0.05% w / p of mometasone or its salt and between approximately 0.5% w / w and approximately 0.8% w / w of olopatadine or its salt for the treatment of rhinitis in a human being in need.

In another embodiment, the present invention relates to a kit comprising a stable fixed dose aqueous pharmaceutical composition, contained in a container, for nasal administration and a leaflet containing instructions on the use of the pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The terms used herein are defined as follows. If a definition presented in this application and a definition presented in a request

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<td>request will govern</td><td colspan="2">The meaning of the terms.</td><td></td><td></td>

<td>The term</td><td>quantity</td><td>effective when</td><td>use</td><td>with</td>

<td colspan="2">relation to an ingredient</td><td>active, denotes a</td><td>quantity</td><td>of the</td>

active ingredient that, when administered to a subject to treat rhinitis, produces an intentional therapeutic benefit in a subject. The term active ingredient (used interchangeably with active or active substance or drug), as used herein, includes mometasone or its salt and olopatadine or its salt.

In the context of the present invention, the effective amount of mometasone or its salt may range between about 0.01 mg and about 10 mg, or preferably, between about 0.02 mg and about 5 mg. The effective amount of olopatadine or its salt may range between about 0.05 mg and about 20 mg, or preferably, between about 0.1 mg and about 15 mg.

In one aspect of the present invention, for daily nasal administration, the effective amount of mometasone or its salt may range between about 10 mcg and about 500 mcg, or preferably, between about 20 mcg and about 400 mcg, and for olopatadine or its salt can range between about 50 mcg and about 7000 mcg, or preferably, between about 100 mcg and about 5400 mcg.

Pharmaceutically acceptable salt or salt refers to those salts and esters that are, within the scope of the well-founded medical criteria, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation and allergic response, according to a reasonable and effective risk benefit ratio for its intended use. Representative acid addition salts include hydrochloride, furoate, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate salts. , succinate, tartrate, ascorbate, glucoheptonate, lactobionate and lauryl sulfate. Representative alkali or alkaline earth metal salts include sodium, calcium, potassium and magnesium salts.

The term "treat" or "treatment", as used herein, includes the prophylaxis, mitigation, prevention, improvement or suppression of a disorder modulated by mometasone or its salt or olopatadine or its salt, or by a combination of the two in a mammal.

Pharmaceutically acceptable excipients refers to any of the components of a pharmaceutical composition other than the active ingredients and which are approved by the regulatory authorities or to which reference is generally made as safe for human or animal use.

As used herein, the term "average particle size" refers to the distribution of the particles, wherein approximately 50 percent by volume of all the measured particles is smaller than the value of the defined average particle size and approximately 50 percent by volume of all measured particles have a particle size greater than the value of the defined average particle size. This can be identified with the term D50 od (0.5). The average particle size can be measured using various techniques such as microscopy, laser diffraction, photon correlation spectroscopy (PCS) and Coulter principle.

In the context of the present invention, the hydrocolloid refers to a colloid system where hydrophilic colloid particles (eg, hydrophilic polymers) are dispersed in water. The hydrocolloid system may exist in a gel or solution (liquid) state. In suspension compositions, hydrocolloids function as thickening, stabilizing and suspending agents. Some non-exhaustive examples of hydrocolloid include xanthan gum, arabic gum, guar gum, locust bean gum, alginate, starch, agar-agar, carrageenan, gelatin, Avicel RC591® (mixture of microcrystalline cellulose and sodium carboxymethylcellulose) and cellulose derivatives ( e.g. sodium carboxymethyl cellulose). Preferably, the hydrocolloid includes xanthan gum or sodium carboxymethyl cellulose.

As used herein, the term "container" refers to a single unit dose container or a multiple dose container. Single unit dose containers or suitable multiple dose containers include, but are not limited to, glass, aluminum, polypropylene or high density polyethylene, for example, high density polyethylene containers produced using a blow, fill and seal manufacturing technique. In one embodiment, the container is an inhaler that administers the pharmaceutical composition in the form of a fine vapor. An inhaler generally includes a container containing a pharmaceutical composition, a sealed pump (e.g., hermetically connected) with the container, an actuator that removably receives a top of the pump and a removably connected cap with the container and the actuator.

The present invention relates to a stable fixed dose aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration to a human being. This comprises between about 0.001% w / w and about 0.075% w / w of mometasone or its salt and between about 0.5% w / w and about 0.8% w / w of olopatadine or its salt.

The pharmaceutical composition may be in the form of a solution or a suspension, but preferably the composition is in the form of a suspension, wherein the mometasone or its salt is present in the form of particles and the olopatadine or its salt is present in dissolved form. Mometasone or its salt and olopatadine or its salt may be present in a weight ratio of between about 1: 3 and about 1: 106, or between about 1: 5 and about 1:53, or preferably between about 1: 5 and about 1:36.

The composition preferably also includes a hydrocolloid. In one embodiment, the composition is a suspension and includes a hydrocolloid in an amount sufficient to prevent phase separation (i.e., separation of particles and solution) after 3 or 6 months of storage at 25 ± 2 ° C and 60% ± 5% relative humidity (RH) or 40 ± 2 ° C and 75% ± 5% RH.

The term stable, as used in relation to aqueous suspensions, refers to a composition that when stirred and stored for at least 24 hours in ambient conditions does not show phase separation in a visual inspection. Preferably, said stable composition does not show phase separation for a period of at least 3 days, or at least 5 days or at least 7 days. In one aspect, the stable composition of the present invention, after stirring (e.g. e.g., for 1 minute) and visual inspection, it does not show lump formation and a total impurity content that does not exceed 1.0% after storage under ambient conditions (at approximately 25 ° C and a relative humidity of approximately 60%) for a period of at least 6 months.

In the context of the present invention, the drug content and impurities can be determined through various analytical techniques such as HPLC, LC-MS, TLC and the like.

It was observed that when various pharmaceutical compositions were prepared for nasal administration comprising mometasone or its salt and olopatadine or its salt, the compositions generally showed physical separation in the suspension composition. This physical instability also leads to a lack of dose uniformity. Surprisingly, it was discovered that the addition of a hydrocolloid in certain concentrations (e.g. eg, at a concentration of at least about 0.1% w / w) in the suspension composition provided a physically stable composition (without separation) suitable for nasal administration.

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human being, wherein the composition comprises between about 0.025% w / w and about 0.05 % w / w of mometasone or its salt, between about 0.6% w / w and about 0.7% w / w of olopatadine or its salt and a hydrocolloid.

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human being, wherein the composition comprises between about 0.025% w / w and about 0.05 % w / w of mometasone or its salt, between about 0.6% w / w and about 0.7% w / w of olopatadine or its salt and a hydrocolloid that includes sodium carboxymethylcellulose and xanthan gum. The hydrocolloid may be present in a concentration of at least about 0.1% w / w of the composition.

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human comprising between about 0.025% w / w and about 0.05% w / w of mometasone furoate, between about 0.6% w / w and about 0.7% w / w of olopatadine hydrochloride and a hydrocolloid comprising xanthan gum. The xanthan gum may be present in a concentration of at least about 0.1% w / w, or preferably between about 0.3% w / w and about 3% w / w of the composition.

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g., contained in a container) for nasal administration to a human comprising between about 0.025% w / w and about 0.05% w / w of mometasone furoate, between about 0.6% w / w and about 0.7% w / w of olopatadine hydrochloride and a hydrocolloid comprising sodium carboxymethylcellulose. The sodium carboxymethyl cellulose may be present in a concentration of at least about 0.1% w / w, or preferably between about 0.1% w / w and about 3% w / w of the composition.

Another embodiment is a stable fixed dose aqueous pharmaceutical composition in the form of a suspension (e.g., contained in a container) for nasal administration to a human being, comprising mometasone or its pharmaceutically acceptable salt, olopatadine or its pharmaceutically acceptable salt, a hydrocolloid (e.g., at a concentration of at least about 0.1% w / w of the composition) and an acceptable pharmaceutical excipient.

Those skilled in the art will also appreciate that to improve the physical properties, aspects or odors of the composition of the present invention, one or more additional pharmaceutically acceptable excipients may be added, as desired. Suitable acceptable pharmaceutical excipients include, but are not limited to, chelating agents, preservative, Lampons, surfactants, isotonicity agents, taste masking agents, antioxidants, humectants, pH adjusting agents and any combination of the foregoing.

Suitable surfactants that can be used to prepare the aqueous nasal inhaler composition may include one or more of anionic, cationic, non-ionic or zwitterionic surfactants.

Examples of suitable surfactants that can be used in the aqueous nasal inhaler suspension can be selected, among others, from polyethoxylated sorbitan derivatives such as polysorbates, their ethoxylated ether, produced by the reaction of sorbitan ethers with ethylene oxide, alkyl phenol · polyoxyethylene, polyoxyethylene cetyl ether, polyoxyethylene alkyl aryl ether, polyoxyethylene monolaurate, polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene esters or mixed fatty acids and resin acids, derived from polyoxyethylene sorbitol lanolin, polyoxyethylene tridecyl ether, polyoxyethylene sorbitan esters of mixed fatty acids and resin, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyethylene stearate monostearate, polyethylene stearate monostearate polyoxyethylene, 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, sodium oleate, quaternary ammonium derivative, potassium nitrate etheate -ethyl morpholinium, sodium lauryl sulfate or mixtures thereof. Preferred surfactants are polyethoxylated sorbitan derivatives (such as polysorbate 80). The amount of surfactant can range from about 0.001% to about 1% w / w with respect to the total weight of the composition.

To improve the ability of the aqueous nasal inhaler suspension to be tolerated after administration to the nasal mucous membrane, it would be convenient to formulate it as isotonic. The osmolality can be established according to the variation of the amounts of the substances present in the aqueous nasal inhaler suspension in addition to the mometasone, olopatadine and any other substance present and / or by the addition of an isotonicity agent, preferably a physiologically tolerated salt. , such as, for example, sodium chloride or potassium chloride, or a physiologically tolerated polyol, such as, for example, a sugar alcohol, in particular sorbitol or glycerol, in a concentration necessary to make it isotonic.

Some examples of suitable preservatives that can be used in the aqueous nasal inhaler suspension include, among others, benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal and disodium edetate. Quaternary ammonium halide preservatives are preferred. Suitable quaternary ammonium halide preservatives include benzalkonium halides and polyquaternium-1. Preferred benzalkonium findings include benzalkonium chloride and benzalkonium bromide. The amount of preservative present in the aqueous nasal inhaler suspension may range from about 0.005 to about 0.2% w / w with respect to the total weight of the composition. Preferably, the preservative is present in a concentration of between about 0.02% w / w with respect to the total weight of the composition.

Some examples of suitable chelating agents that can be used in the aqueous nasal inhaler suspension include, among others, disodium edetate (EDTA), trisodium edetate, tetrasodium edetate and diethylenamine pentaacetate, preferably EDTA. The amount of chelating agent present in the aqueous nasal inhaler suspension of the present invention may range from about 0.0002 to about 0.5% w / w with respect to the total weight of the composition.

Examples of suitable buffers that can be used in the aqueous nasal inhaler suspension include, among others, citric acid, acetic acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, phosphate salts (e.g., dibasic sodium phosphate, such as dibasic sodium phosphate heptahydrate) or combinations thereof. The suspension of the present invention may comprise an amount of buffer sufficient to maintain the pH of the composition at between about 3 and about 6. Preferably, the amount of buffer ranges from about 0.005% to about 1% w / w with respect to to the total weight of the composition.

Examples of suitable sweeteners / taste masking agents that can be used in the aqueous nasal inhaler suspension include, among others, sucralose, thaumatine (eg, Talin^(R)) sucrose z, saccharin (including salt forms such as sodium and calcium salts), fructose, glucose, dextrose, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, neotame, mannitol, oil of eucalyptus, camphor and natural or artificial flavors or flavoring agents (for example, menthol, mints, vanilla, orange, etc.), or combinations of two or more of said agents. A particularly preferred flavor masking agent is sucralose. The amount of flavor sweetener / masking agent present in the aqueous nasal inhaler suspension may range from about 0.01% to about 1% w / w with respect to the total weight of the composition.

Examples of suitable antioxidants that can be employed in the aqueous nasal inhaler suspension include, among others, ascorbic acid, alpha-tocopherol (vitamin-E), butylated hydroxyanisole, butylated hydroxytoluene, glutathione, and any combination of the foregoing. The amount of antioxidant present in the aqueous inhaler composition

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<td>Examples</td><td colspan="2">of humectants</td><td>adequate</td><td>what</td><td>can be</td>

used in the aqueous suspension of nasal inhaler include, among others, glycerin, sorbitol, polyethylene glycol, propylene glycol or mixtures thereof, which are mixed with a suitable moisturizing vehicle such as water. The amount of humectant present in the aqueous nasal inhaler suspension may range from about 0.0002% to about 0.5% w / w with respect to the total weight of the composition.

Suitable pH adjusting agents include, among others, sodium hydroxide and hydrochloric acid.

In the context of the present invention, the pharmaceutical stable fixed dose suspension composition for nasal administration may have a pH of between about 3.3 and about 4.1 or between about 3.5 and about 3.9. The osmolality of the composition may range between about 200 mOsm / kg and about 400 mOsm / kg, or between about 250 mOsm / kg and about 350 mOsm / kg. The viscosity of the composition may range between about 10 cps and about 200 cps or, preferably, between about 20 cps and about 150 cps.

In another aspect, the pharmaceutical composition is in the form of a suspension and contains mometasone furoate in particles having an average particle size in the range between about 1 pm and about 20 pm, or preferably between about 1 pm and about 15 pm . In one aspect, the pharmaceutical suspension composition of the present invention has an average particle size of less than 15 pm when determined by a microscopy technique.

In another aspect, the pharmaceutical composition, when administered as a nasal inhaler, has a spray pattern having a longer axis of approximately 15-75 mm, a shorter axis of approximately 10-65 mm and an ellipticity of approximately 1 -two.

In the context of the present invention, viscosity can be determined through various instruments known as a dynamic stress rheometer or a

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<td>Brookfield</td><td>measuring torque transmission to</td><td>through</td><td>a</td>

Sample using a rotating spindle.

In another embodiment, the present invention relates to a stable fixed dose aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration to a human being, wherein the composition comprises between about 0.001% w / w approximately 0.075% w / w mometasone furoate monohydrate and between approximately 0.5% w / w and approximately 0.8% w / w olopatadine hydrochloride.

Another embodiment is a stable fixed dose pharmaceutical composition in the form of a suspension (e.g., contained in a container) for nasal administration to a human being, comprising mometasone furoate monohydrate, olopatadine hydrochloride and a hydrocolloid comprising gum. Xanthan in a concentration of about 0.3% w / w of the composition, wherein the composition has a pH between about 3.5 and about 3.9.

Another embodiment is a stable fixed dose pharmaceutical composition in suspension form (e.g., contained in a container) for nasal administration to a human being, comprising mometasone furoate monohydrate, olopatadine hydrochloride and a hydrocolloid comprising carboxymethylcellulose carboxymethylcellulose. sodium in a concentration of about 0.5% w / w of the composition, wherein the composition has a pH between about 3.5 and about 3.9.

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g. eg, contained in a container) for nasal administration to a human being, wherein the composition comprises (1) approximately 0.025% w / w mometasone furoate monohydrate, (2) approximately 0.665% w / w hydrochloride olopatadine, (3) a hydrocolloid selected from 0.3% w / w xanthan gum and approximately 0.5% w / w sodium carboxymethylcellulose (4) approximately 0.02% w / w benzalkonium chloride, (5) approximately 0.4% w / w sodium chloride, (6) approximately 0.01% w / w disodium edetate, (7) approximately 0.94% w / w sodium phosphate heptahydrate and (8) approximately 0.01% w / w polysorbate 80 .

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g. eg, contained in a container) for nasal administration to a human being, wherein the composition comprises (1) approximately 0.050% w / w mometasone furoate monohydrate, (2) approximately 0.665% w / w hydrochloride olopatadine, (3) a hydrocolloid selected from 0.3% w / w xanthan gum and approximately 0.5% w / w sodium carboxymethylcellulose (4) approximately 0.02% w / w benzalkonium chloride, (5) approximately 0.4% w / w sodium chloride, (6) approximately 0.01% w / w disodium edetate, (7) approximately 0.94% w / w sodium phosphate heptahydrate and (8) approximately 0.01% w / w polysorbate 80 .

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g. eg, contained in a container) for nasal administration to a human being, wherein the composition comprises (1) approximately 0.025% w / w mometasone furoate monohydrate, (2) approximately 0.665% w / w hydrochloride olopatadine, (3) a hydrocolloid selected from 0.3% w / w xanthan gum and approximately 0.5% w / w sodium carboxymethylcellulose, (4) between about 1% w / w and about 1.2% w / w mixture of microcrystalline cellulose and sodium carboxymethylcellulose, (5) about 0.02% w / w benzalkonium chloride, (6 ) approximately 0.4% w / w sodium chloride, (7) approximately 0.01% w / w disodium edetate, (8) approximately 0.94% w / w sodium phosphate heptahydrate and (9) approximately 0.01% w / w polysorbate 80.

Another embodiment is a stable fixed dose aqueous pharmaceutical suspension composition (e.g. eg, contained in a container) for nasal administration to a human being, wherein the composition comprises (1) approximately 0.050% w / w mometasone furoate monohydrate, (2) approximately 0.665% w / w hydrochloride olopatadine, (3) a hydrocolloid selected from 0.3% w / w xanthan gum and approximately 0.5% w / w sodium carboxymethylcellulose, (4) between approximately 1% w / w and approximately 1.2% w / w mixture of microcrystalline cellulose and sodium carboxymethylcellulose, (5) approximately 0.02% w / w benzalkonium chloride, (6) approximately 0.4% w / w sodium chloride, (7) approximately 0.01% w / w disodium edetate, (8) approximately 0.94% w / w sodium phosphate heptahydrate and ( 9) approximately 0.01% w / w polysorbate 80.

Another embodiment is a stable suspension suitable for nasal administration to a human being, comprising (a) an aqueous solvent, (b) mometasone furoate particles suspended in the solvent, which particles have an average particle size of between about 1 and about 20 μιη, (c) olopatadine hydrochloride dissolved in the solvent and (d) a hydrocolloid, which suspension has a viscosity in the range of between about 20 cps and about 150 cps. In a preferred embodiment, the suspension has a pH of about 3.5-3.9 and an osmolality in the range of between about 250 mOsm / kg and about 350 mOsm / kg. In one embodiment, the suspension further comprises a chelating agent, a preservative, a buffer, a surfactant, an isotonicity agent and, optionally, a pH adjusting agent.

In another embodiment, the present invention relates to a kit comprising a stable fixed dose aqueous pharmaceutical composition of the present invention, contained in a container, for nasal administration and a package leaflet containing instructions on the use of said pharmaceutical composition. In a preferred embodiment, the container is part of an inhaler that has an actuator. When the actuator is activated, the composition is administered in the form of a spray.

In another embodiment, the pharmaceutical composition is contained in an inhaler and, by administering a spray of the composition to a human nose, has a spray pattern having a longer axis of 15-75 mm, a shorter axis of 10- 65 mm and an ellipticity of 1-2.

In the context of the present invention, the pharmaceutical composition, when administered as a nasal inhaler using an inhaler, provides a specific spray pattern and spray droplet size. The spray pattern can be determined through various techniques known as with an ADSA with NSPUA configured (Innova System) and the spray drop size distribution can be determined through various techniques known as with a Malvern Spraytec with NSPUA configured (Innova System).

A typical procedure for characterizing the drop size distribution of the inhaler is described below. The inhaler is charged with a composition as described above and primed by an actuator pump by an actuator until a fine vapor comes out of the inhaler nozzle. A commercially available laser diffraction instrument is arranged so that the nozzle is approximately 3 cm or 6 cm below the laser beam of the laser diffraction instrument. The pump is operated with a conventional mechanical actuator using a constant force. The resulting spray of the composition crosses the laser beam. Data are collected for Dio, D50, D90, SPAN and% volume &lt;10 pm. The average values ​​for each of these parameters are calculated for three sprays.

The aqueous suspension of mometasone and olopatadine stable nasal inhaler may comprise one or more additional active pharmaceutical agents selected from the therapeutic category, among others, of non-steroidal anti-inflammatory agents, decongestants and any combination thereof.

The aqueous nasal inhaler suspension may be administered as a drop or in any other form suitable for topical administration. The composition can also be administered using a nasal buffer or a nasal sponge.

In a preferred embodiment, the aqueous suspension is provided in the form of a nasal inhaler where the suspension is administered in a single unit dose container or a multiple dose container. Single unit dose containers or suitable multiple dose containers include, but are not limited to, glass, aluminum, polypropylene or high density polyethylene, for example, high density polyethylene containers produced using a blow, fill and seal manufacturing technique.

In certain additional embodiments, the invention provides a multiple dosage composition of matter comprising: (a) a multiple unit dosage of a pharmaceutical composition of the present invention; and (b) a container comprising: (i) a flexible chamber that contains the multiple dosage of the composition and which has an opening, wherein the dosage comes out of the opening when the flexible chamber is squeezed; and (ii) a closing mechanism removably connected to the opening of the flexible chamber. In certain embodiments, the multiple dosage container is made of a moldable polymer.

In such embodiments, suitable polymers include, among others, polyethylene, polypropylene (PP), polystyrene (PS), nylon (Ny), polyvinyl chloride (PVC), polyethylene terephthalate (PET), polycarbonate (PC), polyoxymethylene (POM), polysulfon (PSF), polyethersulfon (PES), polyacrylate (PAR) and polyamide (PA). In certain embodiments, the polymers include polyethylene, particularly medium density polyethylene (MDPE) (or branched polyethylene) or high density polyethylene (HDPE) (or linear polyethylene). In one embodiment, the multiple dose container is made of high density polyethylene (HDPE).

Other means can also be used to administer the nasal inhaler, such as inhalation through a metered dose inhaler (MDI). Various types of MDI are used regularly for administration by inhalation. These types of devices may include breath-actuated MDI, spacers / containers in combination with MDI and nebulizers. The term MDI, as used herein, refers to an inhalation delivery system comprising, for example, a container containing a mixture of an active agent and a propellant, optionally, with one or more excipients, a valve of measured dose, an actuator and a mouthpiece. The container is generally filled with a suspension of an active agent, such as the composition of the nasal inhaler, and a propellant, such as one or more hydrofluoroalkanes [p. ex. , 1, 1, 1, 2-tetraf luoroethane (HFA-134a) and 1, 1, 1, 2, 3, 3, 3heptafluoropropane (HFA-227)], chlorofluorocarbons and alcohols such as ethanol, isopropanol, butanol, propanol or mixtures of these. When the actuator is pressed, a measured dose of the suspension for inhalation is sprayed. The particles comprising the active agent are propelled towards the mouthpiece where they can then be inhaled by a subject.

The present invention also relates to a method of treating rhinitis in a human being who needs it comprising administering a stable fixed dose aqueous pharmaceutical composition of the present invention nasally. For example, the pharmaceutical composition that may be contained in a container comprises between about 0.025% w / w and about 0.05% w / w of mometasone or its salt and between about 0.5% w / w and about 0 , 8% w / w of olopatadine or its salt.

In another embodiment, the present invention relates to the use of between about 0.025% w / w and about 0.05% w / w of mometasone or its salt and between about 0.5% w / w and about 0.8 % w / w of olopatadine or its salt in the preparation of a stable fixed dose aqueous pharmaceutical composition (e.g., contained in a container) for the treatment of rhinitis in a human being in need. Any pharmaceutical composition described herein can be used.

In another embodiment, the present invention relates to a stable fixed dose aqueous pharmaceutical composition (e.g., contained in a container) for nasal administration, comprising between about 0.025% w / w and about 0.05% w / p of mometasone or its salt and between approximately 0.5% w / w and approximately 0.8% w / w of olopatadine or its salt for the treatment of rhinitis in a human being in need.

Rhinitis, in the context of the present invention, includes, among others, irritation and inflammation of the mucous membrane inside the nose and the nasal and non-nasal symptoms associated with them. It includes allergic rhinitis, persistent rhinitis, perennial rhinitis, seasonal rhinitis, chronic rhinitis, drug rhinitis, vasomotor rhinitis, infectious 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 the nasal and non-nasal symptoms associated with them.

In the context of the present invention, nasal and non-nasal symptoms associated with allergic rhinitis include sneezing, nasal itching, rhinorrhea (runny nose), nasal obstruction, cough, pruritus of the eye, excessive tearing, headache, fatigue, common cold ( also known as nasopharyngitis, rhinopharyngitis, acute coryza or cold), malaise and cognitive impairment.

It will be understood that various modifications may be made to the modalities described herein. Therefore, the above description should not be considered as limiting, but as merely exemplifying the preferred modalities. Those skilled in the art can implement other arrangements and methods without departing from the scope and spirit of the present invention.

The following examples are provided to enable the person skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be construed as limitations on the scope of the invention.

EXAMPLES

EXAMPLES 1-2: suspension compositions containing mometasone furoate, olopatadine HC1 and sodium carboxymethylcellulose

<td>SN</td><td>Ingredient</td><td>Example 1 (% w / w)</td><td>Example 2 (% w / w)</td>

<td> 1</td><td>Mometasone Furoate Monohydrate Eq. to mometasone furoate</td><td> 0,050</td><td> 0,025</td>

<td> 2</td><td>Olopatadine hydrochloride</td><td> 0,665</td><td> 0,665</td>

<td> 3</td><td>Avicel RC 591 (microcrystalline cellulose and sodium carboxymethyl cellulose)</td><td> 1,200</td><td> 1,200</td>

<td> 4</td><td>Benzalkonium Chloride (solution fifty %)</td><td> 0,040</td><td> 0,040</td>

<td> 5</td><td>Sodium carboxymethylcellulose (Cekol 2000 P)</td><td> 0,500</td><td> 0,500</td>

<td> 6</td><td>Sodium chloride</td><td> 0,410</td><td> 0,410</td>

<td> 7</td><td>Disodium edetate</td><td> 0,010</td><td> 0,010</td>

<td> 8</td><td>Dibasic sodium phosphate heptahydrate</td><td> 0,940</td><td> 0,940</td>

<td> 9</td><td>Polysorbate 80</td><td> 0,010</td><td> 0,010</td>

<td> 10</td><td>Sodium hydroxide</td><td>QS</td><td>QS</td>

<td> 11</td><td>Hydrochloric acid</td><td>QS</td><td>QS</td>

<td> 12</td><td>Water for injection</td><td>QS</td><td>QS</td>

<td colspan="4">Observations</td>

<td></td><td>Physical observation at rest for 24 hours</td><td>I dont know observed phase separation</td><td>I dont know observed phase separation</td>

<td></td><td>Average particle size per microscopy</td><td>Less than 15 pm</td><td>Less than 15 pm</td>

Manufacturing Procedure:

one. Avicel RC-591 in water for injection with homogenization was added and allowed to hydrate.

two. Sodium carboxymethylcellulose was dispersed in water

<td colspan="4">for injection and added to step -1.</td><td colspan="2" rowspan="2">dibasic sodium</td>

<td>3. Be</td><td>dissolved</td><td>phosphate</td><td>from</td>

<td>heptahydrate,</td><td>chloride</td><td>sodium,</td><td colspan="2">edetate</td><td>disodium and</td>

<td>olopatadine in</td><td colspan="2">Water. PH adjusted</td><td> 3 2 ¿</td><td> 8 -</td><td>3.2 with acid</td>

<td>hydrochloric.</td><td></td><td></td><td></td><td></td><td></td>

<td>4. Be</td><td>added the</td><td>stage-3</td><td>to</td><td>the</td><td>stage-1 with</td>

homogenization

5. Polysorbate 80 was dissolved in water for injection. Mometasone furoate monohydrate was added and stirred to form a suspension.

6. Stage-5 was added to stage-4 with homogenization.

7. Benzalkonium chloride was dissolved in water for injection.

8. Stage-7 was added to stage-6 with homogenization.

9. The pH was checked and adjusted to 3.5-3.9 with HC1 and the total weight was adjusted with water for injection. The osmolality of the composition was approximately 250350 mOsm / kg.

The composition was subjected to stability studies under different conditions. The results of these are as follows:

Container details: inhaler containing a corrugated HDPE bottle with pump and equipped with an actuator and a lid.

<td colspan="7">Stability study data</td>

<td>Test</td><td colspan="2">Initial</td><td colspan="2">3 months</td><td colspan="2">6 months</td>

<td></td><td>Ex. L</td><td>Ex 2</td><td>Ex. L</td><td>1 Ex. 2</td><td>Ex 1</td><td>Ex 2</td>

<td colspan="7">Stability condition (25 ° C ± 2 ° C and 60% RH ± 5% RH)</td>

<td>pH</td><td colspan="2"> 3,61</td><td> 3,69</td><td> 3,73</td><td> 3,78</td><td> 3,81</td>

<td>Osmolality (mOsm) *</td><td> 310</td><td> 308</td><td> 299</td><td> 298</td><td> 302</td><td> 311</td>

<td>Viscosity (cps) **</td><td colspan="2"> 32,5</td><td> 42,5</td><td> 42,3</td><td> 40,6</td><td> 40,9</td>

<td>Weight per mi (g / ml)</td><td colspan="2"> 1,01</td><td> 1,021</td><td> 1,024</td><td> 1,029</td><td> 1,019</td>

<td>Mometasone furoate assay (% w / w)</td><td> 101</td><td> 102,4</td><td> 99,1</td><td> 99,3</td><td> 98,2</td><td> 97,2</td>

<td>Olopatadine hydrochloride test (% w / w)</td><td> 98,2</td><td> 99,9</td><td> 97,3</td><td> 99,1</td><td> 97,8</td><td> 97,9</td>

<td colspan="7">Related substances for mometasone furoate</td>

<td>DMCF impurity (%)</td><td> 0,02</td><td> 0,03</td><td> 0,09</td><td> 0,10</td><td> 0,14 |</td><td> 0,17</td>

<td>Any other impurity (%)</td><td colspan="2"> 0,04</td><td colspan="2"> 0,04</td><td colspan="2"> 0,03</td>

<td>Total impurities (%)</td><td colspan="2"> 0,09</td><td> 0,23 |</td><td> 0,29</td><td> 0,31 |</td><td> 0,34</td>

<td colspan="7">Related substances for olopatadine hydrochloride</td>

<td>Isomer E of olopatadine (%)</td><td colspan="2"> 0,08</td><td> 0,07</td><td> 0,09</td><td colspan="2"> 0,09</td>

<td>Any other impurity (%)</td><td> 0,03</td><td> 0,04</td><td> 0,09</td><td> 0,12</td><td> 0,11</td><td> 0,11</td>

<td>Total impurities (%)</td><td> 0,15</td><td> 0,16</td><td> 0,20</td><td> 0,25</td><td> 0,37</td><td> 0,38</td>

<td colspan="7">Spray pattern (at 6 cm)</td>

<td>Main shaft (mm)</td><td colspan="2"> 52</td><td> 60</td><td> 63</td><td> 59</td><td> 61</td>

<td>Minor axis (mm)</td><td> 43</td><td> 47</td><td> 49</td><td> 53</td><td> 49</td><td> 51</td>

<td>Ellipticity</td><td> 1,2</td><td> 1,1</td><td> 1,2</td><td> 1,2</td><td> 1,2</td><td> 1,2</td>

<td colspan="7">Drop size distribution (at 6 cm)</td>

<td>Dio (μπι)</td><td> 18,91</td><td> 19,45</td><td> 19,26</td><td> 19,70</td><td> 19,33</td><td> 18,88</td>

<td>D₅or (μη)</td><td> 36,39</td><td> 37,61</td><td> 35,96</td><td> 37,34</td><td> 39,28</td><td> 37,85</td>

<td>Dgo (μπι)</td><td> 72,46</td><td> 76,44</td><td> 70,29</td><td> 75,78</td><td> 85,42</td><td> 72,07</td>

<td>SPAN</td><td> 1,47</td><td> 1,51</td><td> 1,42</td><td> 1,5</td><td> 1, 67</td><td> 1,46</td>

<td colspan="7">Stability condition (40 ° C ± 2 ° C and 75% RH ± 5% RH)</td>

<td>PH</td><td colspan="2"> 3,61</td><td> 3,68</td><td> 3,72</td><td> 3,59</td><td> 3,68</td>

<td>Osmolality (mOsm)</td><td> 310</td><td> 308</td><td> 298</td><td> 306</td><td> 305</td><td> 299</td>

<td>Viscosity (cps)</td><td colspan="2"> 32,5</td><td> 45,2</td><td> 42, 6</td><td> 41,8</td><td> 41,5</td>

<td>Weight per mi (g / ml)</td><td colspan="2"> 1, 01</td><td> 1,023</td><td> 1,019</td><td> 1,026</td><td> 1,025</td>

<td>Mometasone furoate assay (%)</td><td> 101</td><td> 102,4</td><td> 99,8</td><td> 100,4</td><td> 98,3</td><td> 98,4</td>

<td>Olopatadine hydrochloride test (%)</td><td> 98,2</td><td> 99,9</td><td> 99,3</td><td> 102,5</td><td> 98,7</td><td> 99,7</td>

<td colspan="7">Related substances for mometasone furoate</td>

<td>DMCF impurity (%)</td><td> 0,02</td><td> 0,03</td><td> 0,14</td><td> 0,20</td><td> 0,25</td><td> 0,25</td>

<td>Any other impurity (%)</td><td> 0,04</td><td> 0,04</td><td> 0,04</td><td> 0,03</td><td> 0,03</td><td> 0,04</td>

<td>Total impurities (%)</td><td colspan="2"> 0,09</td><td> 0,25</td><td> 0,39</td><td> 0,40</td><td> 0,46</td>

<td colspan="7">Related substances for olopatadine hydrochloride</td>

<td>E isomer olopatadine (%)</td><td>from</td><td colspan="2"> 0,08</td><td> 0,07</td><td> 0,08</td><td> 0,08</td><td> 0,09</td>

<td>Any impurity (%)</td><td>other</td><td> 0,03</td><td> 0,04</td><td> 0,21</td><td> 0,18</td><td> 0,31</td><td> 0,30</td>

<td>Total impurities</td><td> (%)</td><td> 0,15</td><td> 0,16</td><td> 0,32</td><td> 0,36</td><td> 0, 68</td><td> 0,64</td>

<td colspan="2">Spray pattern</td><td colspan="2">(at 6 cm)</td><td></td><td></td><td></td><td></td>

<td colspan="2">Main shaft (mm)</td><td> 52</td><td> 52</td><td> 61</td><td> 58</td><td> 58</td><td> 58</td>

<td colspan="2">Minor axis (mm)</td><td> 43</td><td> 47</td><td> 50</td><td> 49</td><td> 48</td><td> 49</td>

<td colspan="2">Ellipticity</td><td> 1,2</td><td> 1,1</td><td> 1,2</td><td> 1,2</td><td> 1,2</td><td> 1,2</td>

<td colspan="3">Drop size distribution</td><td colspan="2">(at 6 cm)</td><td></td><td></td><td></td>

<td colspan="2">Dio (pm)</td><td> 18,91</td><td> 19,45</td><td> 19,49</td><td> 19,27</td><td> 18,05</td><td> 18,09</td>

<td colspan="2">D₅or (pm)</td><td> 36,39</td><td> 37,61</td><td> 35,29</td><td> 34,68</td><td> 36,19</td><td> 36,12</td>

<td colspan="2">Dgo (pm)</td><td> 72,46</td><td> 76,44</td><td> 64,66</td><td> 63,49</td><td> 71,89</td><td> 70,06</td>

<td colspan="2">SPAN</td><td> 1,47</td><td> 1,51</td><td> 1,28</td><td> 1,27</td><td> 1,50</td><td> 1,44</td>

* Determined by Advanced Instruments osmometer (model 3250).

★★ Determined by Brookfield viscometer.

EXAMPLES 3-4; suspension compositions containing mometasone furoate, olopatadine HC1 and xanthan gum.

<td>SN</td><td>Ingredient</td><td>Example 3 (% w / w)</td><td>Example 4 (% w / w)</td>

<td> 1</td><td>Mometasone Furoate Monohydrate Eq. to mometasone furoate</td><td> 0,050</td><td> 0,025</td>

<td> 2</td><td>Olopatadine HC1</td><td> 0,665</td><td> 0,665</td>

<td> 3</td><td>Avicel RC 591 (microcrystalline cellulose and sodium carboxymethyl cellulose)</td><td> 1,000</td><td> 1,000</td>

<td> 4</td><td>Benzalkonium Chloride (solution fifty %)</td><td> 0,040</td><td> 0,040</td>

<td> 5</td><td>Xantural 75 (xanthan gum)</td><td> 0,300</td><td> 0,300</td>

<td> 6</td><td>Sodium chloride</td><td> 0,410</td><td> 0,410</td>

<td> 7</td><td>Disodium edetate</td><td> 0,010</td><td> 0,010</td>

<td> 8</td><td>Dibasic sodium phosphate heptahydrate</td><td> 0,940</td><td> 0,940</td>

<td> 9</td><td>Polysorbate 80</td><td> 0,010</td><td> 0,010</td>

<td> 10</td><td>Sodium hydroxide</td><td>QS</td><td>QS</td>

<td> 11</td><td>Hydrochloric acid</td><td>QS</td><td>QS</td>

<td> 12</td><td>Water for injection</td><td>QS</td><td>QS</td>

<td colspan="4">Observations</td>

<td></td><td>Physical observation at rest for 24 hours</td><td>I dont know observed phase separation</td><td>I dont know observed phase separation</td>

<td></td><td>Average particle size per microscopy</td><td>Less than 15 pm.</td><td>Less than 15 pm</td>

Manufacturing Procedure:

one. Avicel RC-591 in water for injection with homogenization was added and allowed to hydrate.

two. Xanthan gum was dispersed in water for injection and added to step -1.

3. Dibasic sodium phosphate heptahydrate, sodium chloride, disodium edetate and olopatadine were dissolved in water. The pH was adjusted to 2.8-3.2 with hydrochloric acid.

Four. Stage-3 was added to stage-1.

5. Polysorbate 80 was dissolved in water for injection. Mometasone furoate monohydrate was added and stirred to form a suspension.

6. Stage-5 was added to stage-4 with homogenization.

7. Benzalkonium chloride was dissolved in water for injection.

8. Stage-7 was added to stage-6 with homogenization.

9. The pH was checked and adjusted to 3.5-3.9 with HC1 and the weight was adjusted with water for injection. The osmolality of the composition was approximately 250-350 mOsm / kg.

The composition was subjected to stability studies under different conditions. The results of these are as follows:

Container details: inhaler containing a corrugated HDPE bottle with pump and equipped with an actuator and a lid.

<td colspan="7">Results of the stability study</td>

<td>Test</td><td colspan="2">Initial</td><td colspan="2">3 months</td><td colspan="2">6 months</td>

<td></td><td>Ex. 3</td><td>I j. 4</td><td>Ex.3</td><td>Ex. 4</td><td>Ex 3</td><td>Ex 4</td>

<td colspan="7">Stability condition (25 ° C ± 2 ° C and 60% RH ± 5% RH)</td>

<td>PH</td><td> 3, 65</td><td> 3,67</td><td> 3,78</td><td> 3,65</td><td> 3,70</td><td> 3,62</td>

<td>Osmolality (mOsm)</td><td> 307</td><td> 312</td><td> 302</td><td> 316</td><td> 308</td><td> 308</td>

<td>Viscosity (cps)</td><td> 124,2</td><td> 129,1</td><td> 127,9</td><td> 129, 9</td><td> 126,2</td><td> 126, 8</td>

<td>Weight per mi (g / ml)</td><td> 1, 015</td><td> 1,022</td><td> 1, 02</td><td> 1,023</td><td> 1,02</td><td> 1,019</td>

<td>Mometasone furoate assay (%)</td><td> 99, 9</td><td> 102,8</td><td> 102,2</td><td> 99,0</td><td> 98,7</td><td> 100,4</td>

<td>Olopatadine hydrochloride test (%)</td><td> 99,2</td><td> 100,7</td><td> 99,7</td><td> 99,7</td><td> 99,4</td><td> 99, 6</td>

<td colspan="6">Related substances for mometasone furoate</td><td rowspan="2"></td>

<td colspan="6"></td>

<td>DMCF impurity (%)</td><td> 0,02</td><td> | 0,02</td><td> 0,04</td><td> | 0,05</td><td> 0,03</td><td> 0,05</td>

<td>Any other impurity (%)</td><td colspan="2"> 0,03</td><td colspan="2"> 0,04</td><td> 0,03</td><td> 0,04</td>

<td>Total impurities (%)</td><td> 0,11</td><td> 0,10</td><td> 0,15</td><td> 0,16</td><td> 0,12</td><td> 0,16</td>

<td colspan="6">Related substances for olopatadine hydrochloride</td><td rowspan="2"></td>

<td colspan="6"></td>

<td>E isomer of olopatadine (%)</td><td> 0,08</td><td> 0,07</td><td> 0,09</td><td> 0,11</td><td> 0,11</td><td> 0,10</td>

<td>Any other impurity (%)</td><td> 0,03</td><td> 0,04</td><td> 0,05</td><td> 0,05</td><td> 0,08</td><td> 0,08</td>

<td>Total impurities (%)</td><td> 0,18</td><td> 0,15</td><td> 0,24</td><td> 0,20</td><td> 0,33</td><td> 0,33</td>

<td colspan="3">Spray pattern (at 6 cm)</td><td colspan="4" rowspan="2"></td>

<td colspan="3"></td>

<td>Principal axis (mm)</td><td colspan="2"> 46</td><td> 59</td><td> 59</td><td> 56</td><td> 54</td>

<td>Minor axis (mm)</td><td colspan="2"> 38</td><td> 47</td><td> 44</td><td> 35</td><td> 43</td>

<td>Ellipticity</td><td colspan="2"> 1,2</td><td> 1,3</td><td> 1,4</td><td> 1, 6</td><td> 1,3</td>

<td colspan="7">Drop size distribution (at 6 cm)</td>

<td>Dio (pin)</td><td> 21,58</td><td> 21,03</td><td> 20,95</td><td> 20,27</td><td> 18,73</td><td> 18,34</td>

<td>D50 (pm)</td><td> 40,44</td><td> 39,79</td><td> 37,86</td><td> 37,93</td><td> 36, 66</td><td> 36,16</td>

<td>Dgo (pin)</td><td> 78,25</td><td> 77,55</td><td> 74,07</td><td> 74,93</td><td> 70,63</td><td> 70,99</td>

<td colspan="7">Results of the stability study</td>

<td>Test</td><td colspan="2">Initial</td><td colspan="2">3 months</td><td colspan="2">6 months</td>

<td></td><td>Ex. 3</td><td>Ex. 4</td><td>Ex. 3</td><td>Ex. 4</td><td>Ex 3</td><td>Ex 4</td>

<td>SPAN</td><td> 1, 40</td><td> 1,42</td><td> 1,40</td><td> 1,44</td><td> 1,41</td><td> 1,45</td>

<td colspan="7">Stability condition (40 ° C ± 2 ° C and 75% RH ± 5% RH)</td>

<td>pH</td><td> 3, 65</td><td> 3,67</td><td> 3,70</td><td> 3,77</td><td> 3,78</td><td> 3, 65</td>

<td>Osmolality (mOsm)</td><td> 307</td><td> 312</td><td> 309</td><td> 305</td><td> 302</td><td> 316</td>

<td>Viscosity (cps)</td><td> 124,2</td><td> 129,1</td><td> 129,6</td><td> 124,3</td><td> 127,9</td><td> 129,9</td>

<td>Weight for me (g / ml)</td><td> 1,015</td><td> 1,022</td><td> 1,017</td><td> 1,027</td><td> 1, 022</td><td> 1,020</td>

<td>Mometasone furoate assay (%)</td><td> 99,9</td><td> 102,8</td><td> 101,7</td><td> 100,6</td><td> 99, 6</td><td> 98,9</td>

<td>Olopatadine hydrochloride test (%)</td><td> 99,2</td><td> 100,7</td><td> 99, 9</td><td> 99,4</td><td> 99,7</td><td> 99,9</td>

<td colspan="6">Related substances for mometasone furoate</td><td rowspan="2"></td>

<td colspan="6"></td>

<td>DMCF impurity (%)</td><td> 0,02</td><td> 0,02</td><td> 0,10</td><td> 0,12</td><td> 0,10</td><td> 0,12</td>

<td>Any other impurity (%)</td><td> 0,03</td><td> 0,03</td><td> 0,02</td><td> 0,03</td><td> 0,05</td><td> 0,03</td>

<td>Total impurities (%)</td><td> 0, 11</td><td> 0,10</td><td> 0,20</td><td> 0,22</td><td> 0,18</td><td> 0,21</td>

<td colspan="6">Related substances for olopatadine hydrochloride</td><td rowspan="2"></td>

<td colspan="6"></td>

<td>E isomer of olopatadine (%)</td><td> 0,08</td><td> 0,07</td><td> 0,12</td><td> 0,13</td><td> 0,11</td><td> 0,11</td>

<td>Any other impurity (%)</td><td> 0,03</td><td> 0,04</td><td> 0,06</td><td> 0,06</td><td> 0,12</td><td> 0,12</td>

<td>Total impurities (%)</td><td> 0,18</td><td> 0,15</td><td> 0,26</td><td> 0,26</td><td> 0,41</td><td> 0,40</td>

<td colspan="3">Spray pattern (at 6 cm)</td><td colspan="4" rowspan="2"></td>

<td colspan="3"></td>

<td>Principal axis (mm)</td><td> 46</td><td> 46</td><td> 56</td><td> 58</td><td> 54</td><td> 55</td>

<td>Minor axis (mm)</td><td> 38</td><td> 38</td><td> 45</td><td> 49</td><td> 34</td><td> 43</td>

<td>Ellipticity</td><td> 1,2</td><td> 1,2</td><td> 1,3</td><td> 1,2</td><td> 1, 6</td><td> 1,3</td>

<td colspan="4">Drop size distribution (at 6 cm)</td><td colspan="3" rowspan="2"></td>

<td colspan="4"></td>

<td>Dio (pm)</td><td> 21,58</td><td> 21,03</td><td> 20,67</td><td> 23,16</td><td> 19,13</td><td> 19,16</td>

<td>D₅or (pm)</td><td> 40,44</td><td> 39,79</td><td> 38,06</td><td> 39,08</td><td> 37,34</td><td> 37,26</td>

<td>Dgo (pm)</td><td> 78,25</td><td> 77,55</td><td> 75, 63</td><td> 69,37</td><td> 72,36</td><td> 72,49</td>

<td>SPAN</td><td> 1,40</td><td> 1,42</td><td> 1,44</td><td> 1,19</td><td> 1,42</td><td> 1,43</td>

COMPARATIVE EXAMPLES A and B: suspension composition containing mometasone furoate and olopatadine HC1.

<td rowspan="2">SN</td><td rowspan="2">Ingredient</td><td colspan="2">Example (% w / w)</td>

<td>TO</td><td>B</td>

<td> 1</td><td>Mometasone Furoate Monohydrate Eq. to mometasone furoate</td><td> 0,050</td><td> 0,050</td>

<td> 2</td><td>Olopatadine HC1</td><td> 0, 665</td><td> 0, 665</td>

<td> 3</td><td>Avicel RC 591 (microcrystalline cellulose and sodium carboxymethyl cellulose)</td><td> 1,00</td><td> 1,00</td>

<td> 4</td><td>Benzalkonium Chloride (solution fifty %)</td><td> 0,040</td><td> 0, 040</td>

<td> 5</td><td>Sodium carboxymethylcellulose (Cekol 2000 P)</td><td> 0,00</td><td> 0,150</td>

<td> 6</td><td>Sodium chloride</td><td> 0,410</td><td> 0,410</td>

<td> 7</td><td>Disodium edetate</td><td> 0,010</td><td> 0,010</td>

<td> 8</td><td>Dibasic sodium phosphate heptahydrate</td><td> 0,940</td><td> 0, 940</td>

<td> 9</td><td>Polysorbate 80</td><td> 0,010</td><td> 0,010</td>

<td> 10</td><td>Sodium hydroxide</td><td>QS</td><td>QS</td>

<td> 11</td><td>Hydrochloric acid</td><td>QS</td><td>QS</td>

<td> 12</td><td>Water for injection</td><td>QS</td><td>QS</td>

<td colspan="4">Observations</td>

<td></td><td>pH</td><td> 3,7</td><td> 3,7</td>

<td></td><td>Physical observation at rest for 24 hours</td><td>Phase separation was observed</td><td>Phase separation was observed</td>

Manufacturing Procedure:

The manufacturing procedure mentioned in example 1 was followed.

COMPARATIVE EXAMPLES C and D: suspension composition containing mometasone furoate and olopatadine HC1.

<td rowspan="2">SN</td><td rowspan="2">Ingredient</td><td colspan="2">Example (% w / w)</td>

<td>C</td><td>D</td>

<td> 1</td><td>Mometasone Furoate Monohydrate Eq. to mometasone furoate</td><td> 0,050</td><td> 0,050</td>

<td> 2</td><td>Olopatadine HC1</td><td> 0,665</td><td> 0,665</td>

<td> 3</td><td>Avicel RC 591 (microcrystalline cellulose and sodium carboxymethyl cellulose)</td><td> 1,000</td><td> 1,000</td>

<td> 4</td><td>Benzalkonium Chloride (solution fifty %)</td><td> 0,040</td><td> 0,040</td>

<td> 5</td><td>Xantural 75 (xanthan gum)</td><td> 0,00</td><td> 0,20</td>

<td> 6</td><td>Sodium chloride</td><td> 0,410</td><td> 0,410</td>

<td> 7</td><td>Disodium edetate</td><td> 0,010</td><td> 0,010</td>

<td> 8</td><td>Dibasic sodium phosphate heptahydrate</td><td> 0,940</td><td> 0,940</td>

<td> 9</td><td>Polysorbate 80</td><td> 0,010</td><td> 0,010</td>

<td> 10</td><td>Sodium hydroxide</td><td>QS</td><td>QS</td>

<td> 11</td><td>Hydrochloric acid</td><td>QS</td><td>QS</td>

<td> 12</td><td>Water for injection</td><td>QS</td><td>QS</td>

<td colspan="4">Observations</td>

<td></td><td>pH</td><td> 3,73</td><td> 3,70</td>

<td></td><td>Physical observation at rest during 24 hours</td><td>Separation of phases</td><td>Phase separation was observed</td>

Manufacturing Procedure:

The manufacturing procedure mentioned in example 3 was followed.

Although the invention herein is described with reference to particular modalities, it should be understood that these modalities are merely illustrative of the principles and applications of the present invention. Therefore, it will be understood that numerous modifications to the illustrative embodiments can be made and that other arrangements can be designed without departing from the spirit and scope of the present invention as described.

All publications, patents and patent applications cited in this application are incorporated by reference to the same extent that they would be incorporated if it were indicated that each publication, patent or patent application is specifically incorporated herein by reference.